SHP2 inhibitors and their uses

Abstract

The present invention relates to an SHP2 inhibitor, a pharmaceutical composition containing an SHP2 inhibitor for preventing or treating SHP2-related diseases, a method for treating and preventing diseases using the pharmaceutical composition, and use of the pharmaceutical composition. Thus, the present invention can effectively prevent or treat SHP2-related diseases.

Description

[Technical Field]

[0001] The present invention relates to compounds, stereoisomers, isotopically labeled compounds or solvates thereof, or pharmaceutically acceptable salts thereof as SHP2 inhibitors, and their use for the prevention or treatment of diseases associated with abnormal activity of SHP2.

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

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

[0004] Mutations in SHP2 are known to cause Noonan syndrome and Leopard syndrome, and are known to be associated with cancers such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colorectal cancer, head cancer, squamous cell carcinoma of the head and neck, 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 thought to be substances that can effectively penetrate the blood-brain barrier (BBB). Therefore, based on their excellent brain penetration ability, SHP2 inhibitors are expected to be therapeutic agents for primary and metastatic malignant brain tumors.

[0006] Therefore, there is a need to develop novel compounds that can inhibit the activity of SHP2, methods for preparing the same, pharmaceutical compositions containing the same, and methods for preventing or treating diseases associated with abnormal activity of SHP2 using the same.

[0007] technical challenges Provided are novel compounds capable of inhibiting the activity of SHP2, their stereoisomers, isotopically labeled compounds or solvates, or pharmaceutically acceptable salts thereof.

[0008] Provided is a pharmaceutical composition for preventing or treating diseases associated with abnormal SHP2 activity, using a novel compound capable of inhibiting SHP2 activity, its stereoisomer, isotopically labeled compound or solvate, or a pharmaceutically acceptable salt thereof.

[0009] The present invention provides a method for preventing or treating diseases associated with abnormal activity of SHP2 using a novel compound capable of inhibiting the activity of SHP2, a stereoisomer thereof, an isotopically labeled compound or solvate thereof, or a pharmaceutically acceptable salt thereof.

[0010] The present invention provides the use of novel compounds, their stereoisomers, isotopically labeled compounds or solvates, or pharmaceutically acceptable salts thereof, which can inhibit the activity of SHP2.

[0011] Resolving the issue Each description and embodiment disclosed herein may be applied to other descriptions and embodiments. That is, all combinations of the various elements disclosed herein fall within the scope of this application. Furthermore, the scope of this application should not be construed as being limited by the specific descriptions set forth below.

[0012] In one aspect, there is provided a compound represented by Formula 1, or a stereoisomer, solvate, or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof: [Formula 1] [ka] In Formula 1, Z is N or CH, X is H or halogen, and W 1 and W 2 One of them is S and the other is N. 1 is H, C 6~10 Aryl, or C 1~6 C optionally substituted with alkoxy 1~6 alkyl, and R x and R y are each independently H or C 1~6 is alkyl, [ka] is a single bond or a double bond.

[0013] In some embodiments, the compound represented by Formula 1 can be represented by Formula 1A below: [Formula 1A] [ka]

[0014] In Formula 1A, X is H or a halogen, and W 1 and W 2 One of them is S and the other is N. 1A is H, C6~10 Aryl, or C 1~6 C optionally substituted with alkoxy 1~6 alkyl, and R x and R y are each independently H or C 1~6 It is an alkyl group. For example, W 1 can be S, and W 2 can be N. Alternatively, W 1 can be N, and W 2 can be S. In this case, the N-bonded [ka] can be a double bond and is bonded to S [ka] can be a single bond.

[0015] In Formula 1A, X is H or a halogen. In Formula 1A, X can be H, F, Cl, Br, or I. For example, X can be H or Cl.

[0016] In Equation 1A, R 1A is H, C 6~10 Aryl, or C 1~6 C optionally substituted with alkoxy 1~6 It is an alkyl. C 1~6 C optionally substituted with alkoxy 1~6 Alkyl is 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 It may contain alkyl.

[0017] In Equation 1A, R1A is H, C 6~10 Aryl, or C 1~6 C optionally substituted with alkoxy 1~6 In some embodiments, R 1A may 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, H, phenyl, CH3, CH2CH3, [ka] In some embodiments, R 1A teeth, [ka] It could be something other than that.

[0018] In Equation 1A, R x and R y are each independently H or C 1~6 In some embodiments, R x and R y may be the same or different. In some embodiments, R x and R y are each independently H or C 1~4 In some embodiments, R x and R y are each independently H or C 1~3 For example, R x and R y may each be H.

[0019] In some embodiments, in Formula 1A, X is H or Cl and R 1A is H, phenyl, CH3, CH2CH3, [ka] and R x and R y can each be H.

[0020] In some embodiments, the compound represented by formula 1A can be represented by the following formula 1A-1: [Case 1A-1] [ka]

[0021] In Formula 1A-1, X is H or halogen and R 1a is H or C 1~6 alkyl, and R x and R y are each independently H or C 1~6 It may also be alkyl.

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

[0023] In Formula 1A-1, R 1a is H or C 1~6 In some embodiments, R 1a can be H, methyl, ethyl, propyl, butyl, pentyl, or hexyl. For example, R 1a are H, CH3, CH2CH3, [ka] may be selected from the group consisting of:

[0024] In Formula 1A-1, R x and R y are each independently H or C 1~6 In some embodiments, R x and R y may be the same or different. In some embodiments, R x and Ry are each independently H or C 1~4 In some embodiments, R x and R y are each independently H or C 1~3 For example, R x and R y may each be H.

[0025] In some embodiments, in Formula 1A-1, X is H or Cl and R 1A are H, CH3, CH2CH3, [ka] and R x and R y can each be H.

[0026] In some embodiments, the compound represented by Formula 1A or Formula 1A-1 can be selected from compounds represented by the following formulas: [ka]

[0027] In some embodiments, the compound represented by Formula 1 can be represented by Formula 1B below: [Formula 1B] [ka]

[0028] In Formula 1B, X is H or halogen, and R 1B is H or C 1~6 alkyl, and R x and R y are each independently H or C 1~6 It is alkyl.

[0029] In Formula 1B, X is H or a halogen. In some embodiments, X can be a halogen. For example, X can be Cl.

[0030] In Equation 1B, R 1B is H or C 1~6 It is an alkyl. C 1~6 Alkyl is C 1~4 Alkyl or C 1~3 In some embodiments, R 1B is C 1~6 In some embodiments, R 1B can be methyl or propyl. In some embodiments, propyl can be isopropyl.

[0031] In Equation 1B, R x and R y are each independently H or C 1~6 In some embodiments, R x and R y may be the same or different. In some embodiments, R x and R y are each independently H or C 1~4 In some embodiments, R x and R y are each independently H or C 1~3 For example, R x and R y may each be H.

[0032] In some embodiments, in Formula 1B, X is halogen and R 1B is C 1~6 alkyl, and R x and R y can each be H.

[0033] In some embodiments, the compound represented by Formula 1B can be a compound represented by the following chemical formula: [ka]

[0034] In one aspect, there is provided a compound represented by the following Formula 2, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof: [Formula 2] [ka]

[0035] In Formula 2, Z is N or CH and V is N or CR a2 and X is H or halogen. a1 , H, NR i R ii or C 1~6 alkyl, and R a2 is H, or OH or C 1~6 Alkoxy-substituted C 1~6 It is alkyl. Y 1 is O or CH2, and Y 2 is N or CH. 2 is H, C 6~10 aryl, 5- to 7-membered heteroaryl containing a heteroatom selected from N and O, and OH or C 1~6 C optionally substituted with alkoxy 1~6 alkyl, and R i and R ii are each independently H or C 1~6 alkyl, and R x and R y are each independently H or C 1~6 It is alkyl.

[0036] In some embodiments, the compound represented by Formula 2 can be represented by Formula 2A below: [Formula 2A] [ka]

[0037] In Formula 2A, Z is N or CH, Q is N or CH, X is H or halogen, and Y 2 is N or CH. 2A is H, C 6~10 aryl, 5- to 7-membered heteroaryl containing a heteroatom selected from N and O, or OH or C 1~6 C optionally substituted with alkoxy 1~6 alkyl, and R x and R y are each independently H or C 1~6 It is alkyl.

[0038] 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 can be CH.

[0039] In Formula 2A, X is H or a halogen. In some embodiments, X can be a halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0040] In Equation 2A, R 2A is H, C 6~10 aryl, 5- to 7-membered heteroaryl containing a heteroatom selected from N and O, or OH or C 1~6 C optionally substituted with alkoxy 1~6 In some embodiments, OH or C 1~6 Alkoxy-substituted C 1~6 Alkyl is C 1~6 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, C substituted with OH 1~6 Alkyl, branched C substituted with OH 3~6 Alkyl, branched C substituted with OH 4~6 Alkyl, C 1~6 Alkoxy-substituted C 1~6 Alkyl, C 1~6 Alkoxy-substituted C 3~6 Alkyl, C 1~6Alkoxy-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 It may contain alkyl.

[0041] In some embodiments, R 2A is H, phenyl, naphthyl, 5- to 7-membered heteroaryl containing N as a heteroatom, or OH or C 1~6 C optionally substituted with alkoxy 1~6 For example, R 2A is methyl, phenyl, pyridinyl, [ka] In some embodiments, R 2A teeth, [ka] In some embodiments, when Z is N, R 2A teeth, [ka] It could be something other than that.

[0042] In Equation 2A, R x and R y are each independently H or C 1~6 In some embodiments, R x and R y may be the same or different. In some embodiments, R x and R y are each independently H or C 1~4 In some embodiments, R x and R y are each independently H or C 1~3 For example, Rx and R y may each be H.

[0043] In some embodiments, in Formula 2A, X is halogen and R 2A is methyl, phenyl, pyridinyl, [ka] and R x and R y may each independently be H.

[0044] In some embodiments, the compound represented by formula 2A can be represented by formula 2A-1 below: [Formula 2A-1] [ka]

[0045] In formula 2A-1, X is H or a halogen, and Y 2 is N or CH, and R 2a is H or C 1~6 alkyl, and R x and R y are each independently H or C 1~6 It can be alkyl.

[0046] In Formula 2A-1, X is H or a halogen. In some embodiments, X can be a halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0047] In Equation 2A-1, Y 2 is N or CH.

[0048] In Equation 2A-1, R 2a is H or C 1~6 In some embodiments, R 2a is C 1~6 In some embodiments, R 2acan be methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R 2a is C 1~4 Alkyl or C 1~3 For example, R 2a may be CH3.

[0049] In Equation 2A-1, R x and R y are each independently H or C 1~6 In some embodiments, R x and R y may be the same or different. In some embodiments, R x and R y are each independently H or C 1~4 In some embodiments, R x and R y are each independently H or C 1~3 For example, R x and R y may each be H.

[0050] In some embodiments, in Formula 2A-1, X is halogen and R 2a is C 1~6 alkyl, and R x and R y may each independently be H.

[0051] In some embodiments, the compound represented by Formula 2A or Formula 2A-1 can be selected from compounds represented by the following formulas: [ka]

[0052] In some embodiments, the compound represented by Formula 2 can be represented by Formula 2B below: [Formula 2B] [ka]

[0053] In Formula 2B, Z is N or CH and X is H or halogen. a3 is NR i R ii or C 1~6 R is alkyl. a4 is H, or OH or C 1~6 Alkoxy-substituted C 1~6 R is alkyl. 2B is C optionally substituted with H and OH 1~6 Alkyl or C 1~6 R is selected from alkoxy. i and R ii are each independently H or C 1~6 R is alkyl. x and R y are each independently H or C 1~6 It is alkyl.

[0054] In Formula 2B, X is H or a halogen. In some embodiments, X can be a halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0055] In Equation 2B, R 2B H, and OH or C 1~6 C optionally substituted with alkoxy 1~6 C is selected from alkyl. 1~6 Alkoxy can be methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy. In some embodiments, C 1~6 Alkoxy is C 1~4 Alkoxy or C 1~3 It can be alkoxy, for example, C 1~6 The alkoxy can be methoxy. 1~6 Alkyl can be methyl, ethyl, propyl, butyl, pentyl or hexyl. For example, C 1~6 Alkyl can be methyl, ethyl, propyl, or isobutyl. In some embodiments, R 2Bis C optionally substituted with OH 1~6 Alkyl or C 1~6 For example, R 2B is CH3, [ka] may be selected from the group consisting of:

[0056] In Equation 2B, R a3 is NR i R ii or C 1~6 R is alkyl. a4 is H, or OH or C 1~6 Alkoxy-substituted C 1~6 In some embodiments, R a3 is NR i R ii R a4 can be H. Alternatively, R a3 is C 1~6 R may be alkyl; a4 is OH or C 1~6 Alkoxy-substituted C 1~6 In some embodiments, R a3 can be NH2, and R a4 can be H. Furthermore, R a3 is C 1~4 R may be alkyl; a4 is OH or C 1~6 Alkoxy-substituted C 1~4 For example, R a3 may be NH2, and R a4 may be H. Furthermore, R a3 may be methyl, R a4 may be hydroxymethyl.

[0057] In Equation 2B, R i and R ii are each independently H or C 1~6 In some embodiments, R i and R iimay be the same or different. In some embodiments, R i and R ii are each independently H or C 1~4 In some embodiments, R i and R ii are each independently H or C 1~3 For example, R i and R ii may each be H.

[0058] In Equation 2B, R x and R y are each independently H or C 1~6 In some embodiments, R x and R y may be the same or different. In some embodiments, R x and R y are each independently H or C 1~4 In some embodiments, R x and R y are each independently H or C 1~3 For example, R x and R y may each be H.

[0059] In some embodiments, in Formula 2B, X is halogen and R 2B is CH3, [ka] and R i , R ii , R x and R y may each independently be H.

[0060] In some embodiments, the compound represented by formula 2B can be represented by formula 2B-1 below: [Formula 2B-1] [ka]

[0061] In formula 2B-1, X is H or halogen and R 2B H, and OH or C 1~6 C optionally substituted with alkoxy 1~6 alkyl, and R i and R ii are each independently H or C 1~6 alkyl, and R x and R y are each independently H or C 1~6 It is alkyl.

[0062] In Formula 2B-1, X is H or a halogen. In some embodiments, X can be a halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0063] In Equation 2B-1, R 2B H, and OH or C 1~6 C optionally substituted with alkoxy 1~6 C is selected from alkyl. 1~6 Alkoxy can be methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy. In some embodiments, C 1~6 Alkoxy is C 1~4 Alkoxy or C 1~3 It can be alkoxy, for example, C 1~6 The alkoxy can be methoxy. 1~6 Alkyl can be methyl, ethyl, propyl, butyl, pentyl or hexyl. For example, C 1~6 Alkyl can be methyl, ethyl, propyl, or isobutyl. In some embodiments, R 2B is C optionally substituted with OH 1~6 Alkyl or C 1~6 For example, R 2B is CH3, [ka] may be selected from the group consisting of:

[0064] In Equation 2B-1, R i and R ii are each independently H or C 1~6 In some embodiments, R i and R ii may be the same or different. In some embodiments, R i and R ii are each independently H or C 1~4 In some embodiments, R i and R ii are each independently H or C 1~3 For example, R i and R ii may each be H. In Equation 2B-1, R x and R y are each independently H or C 1~6 In some embodiments, R x and R y may be the same or different. In some embodiments, R x and R y are each independently H or C 1~4 In some embodiments, R x and R y are each independently H or C 1~3 For example, R x and R y may each be H.

[0065] In some embodiments, in formula 2B-1, X can be a halogen and R 2B is CH3, [ka] and R i , R ii, R x and R y may each independently be H.

[0066] In some embodiments, the compound represented by formula 2B or formula 2B-1 can be selected from compounds represented by the following formulas: [ka]

[0067] In some embodiments, the compound represented by formula 2 can be represented by formula 2C below: [Formula 2C] [ka]

[0068] In Formula 2C, X is H or halogen and R 2C is H, C 6~10 Aryl and OH or C 1~6 C optionally substituted with alkoxy 1~6 R is selected from alkyl. x and R y are each independently H or C 1~6 It is alkyl.

[0069] In Formula 2C, X is H or a halogen. In some embodiments, X can be a halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0070] In Equation 2C, R 2C is H, C 6~10 Aryl and OH or C 1~6 C optionally substituted with alkoxy 1~6 C is selected from alkyl. 1~6 Alkoxy can be methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy. In some embodiments, C 1~6 Alkoxy is C 1~4 Alkoxy or C 1~3It can be alkoxy, for example, C 1~6 The alkoxy can be methoxy. 1~6 Alkyl can be methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, C 1~6 Alkyl is C 1~4 It can be alkyl, for example, C 1~6 Alkyl can be methyl, ethyl, or butyl (e.g., n-butyl, isobutyl, or tert-butyl). In some embodiments, R 2C is C 6~10 Aryl, or OH or C 1~6 C optionally substituted with alkoxy 1~6 For example, R 2C teeth, [ka] It can be methyl, CD3 or phenyl.

[0071] In Equation 2C, R x and R y are each independently H or C 1~6 In some embodiments, R x and R y may be the same or different. In some embodiments, R x and R y are each independently H or C 1~4 In some embodiments, R x and R y are each independently H or C 1~3 For example, R x and R y may each be H.

[0072] In some embodiments, in Formula 2C, X can be a halogen and R 2C is OH or C 1~6 Alkoxy-substituted C 1~6 R may be alkyl; x and R ymay each independently be H.

[0073] In some embodiments, the compound represented by formula 2C can be a compound represented by the following formula: [ka]

[0074] In one aspect, there is provided a compound represented by the following Formula 3, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof: [Formula 3] [ka]

[0075] In Formula 3, Z is N or CH and R z is H or C 1~6 R is alkyl and X is H or halogen. 3 is H, C 1~6 Alkyl-substituted -(C 1~6 alkylene)-oxanyl, or C 1~6 Alkyl, -(C 1~6 alkylene)-(C 3~6 cycloalkyl) or -(C 1~6 alkylene)-piperidinyl, each of which is R 31 optionally substituted with 1 to 3 occurrences of R 31 are halogens, cyano, OH, C 1~6 Alkoxy or C 6~12 Aryl. R a1 are H, NH2, C 1~6 Alkylamino or di(C 1~6 alkyl)amino. b and R c are each independently H or C 1~6 alkyl, or they are joined together with the carbon atoms to which they are attached to form Ring A, a 5-membered ring that optionally contains O. Ring A is R A Optionally substituted with R Ais H or C 1~6 R is alkyl. x and R y are each independently H or C 1~6 It is alkyl.

[0076] In some embodiments, the compound represented by formula 3 can be represented by formula 3A below: [Formula 3A] [ka]

[0077] In Formula 3A, Z is N or CH, X is H or halogen, and R z is H or C 1~6 R is alkyl. 3A is H, C 1~6 Alkyl-substituted -(C 1~6 alkylene)-oxanyl, or C 1~6 Alkyl, -(C 1~6 alkylene)-(C 3~6 cycloalkyl) or -(C 1~6 alkylene)-piperidinyl, and each R 31A Optionally substituted with 1 to 3 occurrences of R 31A is halogen, cyano or C 1~6 Alkoxy. R A is H or C 1~6 R is alkyl. x and R y are each independently H or C 1~6 It is alkyl.

[0078] In Formula 3A, X is H or a halogen. In some embodiments, X can be a halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0079] In Equation 3A, R z is H or C 1~6 In some embodiments, R z is H or C 1~4In some embodiments, R z is H or C 1~3 For example, R z can be H or methyl. In some embodiments, R z C 1~6 When alkyl, Z can be N.

[0080] In Equation 3A, R 3A is H, C 1~6 Alkyl-substituted -(C 1~6 alkylene)-oxanyl, or C 1~6 Alkyl, -(C 1~6 alkylene)-(C 3~6 cycloalkyl) or -(C 1~6 alkylene)-piperidinyl, each of which is R 31A Optionally substituted with 1 to 3 occurrences of R 31A is halogen, cyano, OH or C 1~6 Alkoxy. Two or more R 31A may be the same or different. C 1~6 Alkyl can be methyl, ethyl, propyl, butyl, pentyl or hexyl. For example, C 1~6 Alkyl can be methyl, ethyl, n-propyl, isopropyl or isobutyl. 3~6 Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. For example, C 3~6 The cycloalkyl can be cyclopropyl. In some embodiments, -(C 1~6 alkyl)-(C 3~6 Cycloalkyl) is -(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 Cycloalkyl) can be methyl substituted with cyclopropyl (cyclopropylmethyl-). 1~6 Alkyl-substituted -(C 1~6Alkylene)-oxanyl is C 1~6 Alkyl-substituted -(C 1~4 alkylene)-oxanyl or C 1~6 Alkyl-substituted -(C 1~3 alkylene)-oxanyl. For example, C 1~6 Alkyl-substituted -(C 1~6 The -(C alkylene)-oxanyl may be oxanylmethyl. 1~6 Alkylene)-piperidinyl is -(C 1~4 alkylene)-piperidinyl or -(C 1~3 For example, -(C 1~6 Alkylene)-piperidinyl can be piperidinylmethyl.

[0081] In some embodiments, R 31A is halogen, cyano or C 1~6 In some embodiments, R 31A is halogen, cyano or C 1~4 In some embodiments, R 31A is halogen, cyano or C 1~3 For example, R 31A can be cyano, F or methoxy. For example, R 3A is CH3, [ka] In some embodiments, R 3A H, [ka] In some embodiments, when Z is N, R 3A teeth, [ka] It could be something other than that.

[0082] In Equation 3A, R A is H or C 1~6 It is an alkyl. C 1~6 Alkyl can be methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R A is C 1~6 In some embodiments, C 1~6 Alkyl is C 1~4 Alkyl or C 1~3 For example, R A can be methyl.

[0083] In Equation 3A, R x and R y are each independently H or C 1~6 In some embodiments, R x and R y may be the same or different. In some embodiments, R x and R y are each independently H or C 1~4 In some embodiments, R x and R y are each independently H or C 1~3 For example, R x and R y may each be H.

[0084] In some embodiments, in Formula 3A, X can be a halogen and R 3A is CH3, [ka] and R A is C 1~6 R may be alkyl; x and R y may each independently be H.

[0085] In some embodiments, the compound represented by formula 3A can be represented by formula 3A-1 below: [Formula 3A-1] [ka]

[0086] In Formula 3A-1, Z is N or CH, X is H or halogen, and R 3a is H or C 1~6 Alkyl or -(C 1~6 alkyl)-(C 3~6 cycloalkyl), each of which is R 31a optionally substituted with 1 to 3 occurrences of R 31a is a halogen, OH or C 1~6 is alkoxy, and R A is H or C 1~6 alkyl, and R x and R y are each independently H or C 1~6 It is alkyl.

[0087] In Formula 3A-1, X is H or a halogen. In some embodiments, X can be a halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0088] In Equation 3A-1, R 3a is H or C 1~6 Alkyl or -(C 1~6 alkyl)-(C 3~6 cycloalkyl), each of which is R 31a optionally substituted with 1 to 3 occurrences of R 31a is a halogen, OH or C 1~6 Alkoxy. Two or more R 31a may be the same or different. C 1~6 Alkyl can be methyl, ethyl, propyl, butyl, pentyl or hexyl. For example, C 1~6 Alkyl can be methyl, ethyl, propyl or isobutyl. 3~6Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. For example, C 3~6 The cycloalkyl can be cyclopropyl. In some embodiments, -(C 1~6 alkyl)-(C 3~6 Cycloalkyl) is -(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 Cycloalkyl) can be methyl substituted with cyclopropyl (cyclopropylmethyl-). In some embodiments, R 31a is a halogen or C 1~6 In some embodiments, R 31a is a halogen or C 1~4 In some embodiments, R 31a is a halogen or C 1~3 For example, R 3a is CH3, [ka] may be selected from the group consisting of:

[0089] In some embodiments, Z can be N and R 3a is C 1~6 Alkyl or -(C 1~6 alkyl)-(C 3~6 cycloalkyl), each of which can be R 3a is substituted with 1 to 3 occurrences of R 3a is halogen, OH or C 1~6 It may be alkoxy.

[0090] In some embodiments, Z can be CH and R 3a can be H or R 3a optionally substituted with C 1~6 It can be alkyl, in which case R3a is OH or C 1~6 It may be alkoxy.

[0091] In Equation 3A-1, R A is H or C 1~6 It is an alkyl. C 1~6 Alkyl can be methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R A is C 1~6 In some embodiments, C 1~6 Alkyl is C 1~4 Alkyl or C 1~3 For example, R A can be methyl. In Equation 3A-1, R x and R y are each independently H or C 1~6 In some embodiments, R x and R y may be the same or different. In some embodiments, R x and R y are each independently H or C 1~4 In some embodiments, R x and R y are each independently H or C 1~3 For example, R x and R y may each be H.

[0092] In some embodiments, in formula 3A-1, X can be halogen and R 3A is CH3, [ka] and R A is C 1~6 R may be alkyl; x and R y may each independently be H.

[0093] In some embodiments, the compound represented by formula 3A or formula 3A-1 can be selected from compounds represented by the following formulas: [ka]

[0094] In some embodiments, the compound represented by formula 3 can be represented by formula 3B below: [Formula 3B] [ka]

[0095] In Formula 3B, X is H or halogen. 3B OH, C 1~6 Alkoxy or C 6~10 C optionally substituted with aryl 1~6 R is alkyl. A is H or C 1~6 alkyl, and R i and R ii are each independently H or C 1~6 alkyl, and R x and R y are each independently H or C 1~6 It is alkyl.

[0096] In Formula 3B, X is H or a halogen. In some embodiments, X can be a halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0097] In Equation 3B, R 3B OH, C 1~6 Alkoxy or C 6~10 C optionally substituted with aryl 1~6 It is an alkyl. C 1~6 Alkoxy is C 1~4 Alkoxy or C 1~3 It can be alkoxy, for example, C 1~6 The alkoxy can be methoxy. 6~10Aryl can be phenyl or naphthyl. For example, C 6~10 The aryl may be phenyl. 1~6 Alkyl can be methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, C 1~6 Alkyl is C 1~4 Alkyl or C 1~3 It can be alkyl, for example, C 1~6 The alkyl can be methyl or isobutyl. In some embodiments, R 3B is C 1~6 Alkoxy or C 6~10 Aryl-substituted C 1~6 For example, R 3B is 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 is C 1~4 Alkoxy or C 6~10 Aryl-substituted C 1~4 For example, R 3B is phenylmethyl (benzyl) or [ka] In some embodiments, R 3B teeth, [ka] It could be something other than that.

[0098] In Equation 3B, R A is H or C 1~6 It is an alkyl. C1~6 Alkyl can be methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R A is C 1~6 In some embodiments, C 1~6 Alkyl is C 1~4 Alkyl or C 1~3 For example, R A can be methyl.

[0099] In Equation 3B, R i and R ii are each independently H or C 1~6 In some embodiments, R i and R ii may be the same or different. In some embodiments, R i and R ii are each independently H or C 1~4 In some embodiments, R i and R ii are each independently H or C 1~3 For example, R i and R ii may each be H.

[0100] In Equation 3B, R x and R y are each independently H or C 1~6 In some embodiments, R x and R y may be the same or different. In some embodiments, R x and R y are each independently H or C 1~4 In some embodiments, R x and R y are each independently H or C 1~3 For example, R x and R y may each be H.

[0101] In some embodiments, X can be a halogen and R 3B is C 6~10 Aryl-substituted C 1~6 R may be alkyl; A is C 1~6 R may be alkyl; i , R ii , R x and R y may each independently be H.

[0102] In some embodiments, the compound represented by formula 3B can be a compound represented by the following formula: [ka]

[0103] In some embodiments, the compound represented by formula 3 can be represented by formula 3C below: [Formula 3C] [ka] In Formula 3C, X is H or halogen and R 3C is C 6~10 C optionally substituted with aryl 1~6 alkyl, and R c is H or C 1~6 alkyl, and R i and R ii are each independently H or C 1~6 alkyl, and R x and R y are each independently H or C 1~6 It is alkyl.

[0104] In Formula 3C, X is H or a halogen. In some embodiments, X can be a halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0105] In Equation 3C, R 3C is C6~10 C optionally substituted with aryl 1~6 It is an alkyl. C 6~10 Aryl can be phenyl or naphthyl. For example, C 6~10 The aryl may be phenyl. 1~6 Alkyl can be methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, C 1~6 Alkyl is C 1~4 Alkyl or C 1~3 It can be alkyl, for example, C 1~6 The alkyl can be methyl. For example, R 3C can be phenylmethyl (benzyl).

[0106] In Equation 3C, R c is H or C 1~6 It is an alkyl. C 1~6 Alkyl can be methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R A is C 1~6 In some embodiments, C 1~6 Alkyl is C 1~4 Alkyl or C 1~3 For example, R c can be methyl.

[0107] In Equation 3C, R i and R ii are each independently H or C 1~6 In some embodiments, R i and R ii may be the same or different. In some embodiments, R i and R ii are each independently H or C 1~4 In some embodiments, R i and R ii are each independently H or C 1~3 For example, R i and R ii may each be H.

[0108] In Equation 3C, R x and R y are each independently H or C 1~6 In some embodiments, R x and R y may be the same or different. In some embodiments, R x and R y are each independently H or C 1~4 In some embodiments, R x and R y are each independently H or C 1~3 For example, R x and R y may each be H.

[0109] In some embodiments, the compound represented by formula 3C can be a compound represented by the following formula: [ka]

[0110] 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.

[0111] The term "alkyl" refers to a fully saturated branched or unbranched (or straight or linear) hydrocarbon. Alkyl may be substituted or unsubstituted alkyl. C1-C 20 Alkyl is, for example, C1-C 15 , C1~C 10 Or it can be C1-C6 alkyl. The C1-C6 alkyl can be C1-C5, C1-C4, C1-C3 or C1-C2 alkyl. The alkyl can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, isoamyl or n-hexyl.

[0112] The term "haloalkyl" refers to an alkyl substituted with at least one halogen.

[0113] The term "hydroxy" refers to an -OH functional group (a hydroxyl group).

[0114] The term "carbonyl" refers to -C(=O)-.

[0115] The term "alkoxy" refers to an alkyl bonded to an oxygen atom. 20 Alkoxy is, for example, C1-C 15 , C1~C 10 Or it can be C1-C6 alkoxy. The C1-C6 alkoxy can be C1-C5, C1-C4, C1-C3 or C1-C2 alkoxy. The alkoxy can be methoxy, ethoxy, propoxy, butoxy, etc.

[0116] The term "alkoxyalkyl" refers to an alkoxy bonded to an alkyl. C-C 20 The alkoxyalkyl is, for example, C2 to C 15 , C2~C 10 Or it can be C2 to C6 alkoxyalkyl. For example, C2 to C 20 Alkoxyalkyl is (C1-C 10 Alkoxy)-(C1-C 10 The number of carbon atoms in the alkoxy group and the alkyl group may be the same or different. The alkoxy may be, for example, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, etc.

[0117] The term "amino" refers to -NH2.

[0118] The term "amine group" refers to a substituent in which one, two, or all three hydrogens of ammonia are replaced with an organic functional group, and includes all primary amines, secondary amines, and tertiary amines, as well as amino groups.

[0119] The term "alkylamine" refers to an amine in which one H of the amino (-NH2) is replaced with an alkyl.

[0120] The term "di(alkyl)amine" refers to an amine in which both H of the amino (-NH2) are replaced with alkyl. The two alkyls in a di(alkyl)amine can be the same or different.

[0121] The term "nitro" refers to -NO2.

[0122] The term "cyano" refers to the functional group --CN, which consists of a triple bond between a carbon atom and a nitrogen atom.

[0123] The term "carboxy" refers to -COOH. A salt of carboxy refers to the conjugate base of a carboxylic acid.

[0124] The term "sulfonyl" refers to the group -SO2-.

[0125] The term "cycloalkyl" refers to a saturated non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon group. A cycloalkyl can contain 3 to 20 carbon atoms, for example, 5 to 10, 3 to 8, or 3 to 6 carbon atoms. A monocyclic cycloalkyl can be, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. A bicyclic cycloalkyl can be, for example, bornyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, or bicyclo[2.2.2]octyl. A tricyclic cycloalkyl can be, for example, adamantyl.

[0126] The term "cycloalkane ring" refers to a saturated non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring. The cycloalkane ring may be a complete (non-radical) functional group of the above-mentioned cycloalkyl. The cycloalkane ring may contain 3 to 20 carbon atoms, for example, 5 to 10, 3 to 8, or 3 to 6 carbon atoms. The monocyclic cycloalkane ring may be, for example, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring.

[0127] The term "aryl" also includes groups in which an aromatic ring is fused to one or more carbocyclic rings. 30 Aryl is, for example, C to C 15 or C6~C 10 It can be aryl. The aryl can be phenyl, naphthyl or tetrahydronaphthyl.

[0128] The term "arylalkyl" refers to an alkyl substituted with an aryl.

[0129] The term "aryloxy" refers to an aryl bonded to an oxygen atom.

[0130] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic compound containing one or more heteroatoms, with the remaining ring atoms being carbon. A heteroaryl can contain, for example, 1 to 5, 1 to 3, 1, or 2 heteroatoms, and can contain 5 to 10 ring members. A "heteroaryl" can be, for example, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, or benzisothiazolyl, and the like.

[0131] The term "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon containing at least one heteroatom. The heterocyclyl ring group may be a monocyclic group, a bicyclic group, or a tricyclic group. The two ring groups may be spirocyclic groups, bridged ring groups, and fused ring groups. The heterocyclyl ring group may 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 may be any one or more, for example, 1, 2, or 3, selected from the group consisting of N, O, and S. For example, the heterocycloalkyl may be aziridinyl, oxiranyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, dihydropyranyl, morpholinyl, thiomorpholinyl, oxazolidinyl, or the like.

[0132] The heteroatoms may be any one or more selected from the group consisting of N, O, P, and S. The heteroatoms may be 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S.

[0133] The term "substituted" included in "substituted or unsubstituted" refers to the introduction of another atomic group by replacing one or more hydrogen atoms in an organic compound to form a derivative, and the term "substituent" refers to the introduced atomic group. The term "substituted" as used herein is not limited to a substituent, and includes, for example, a halogen atom, a C1-C substituted with a halogen atom, and the like. 20 Alkyl (e.g., CCF3, CHCF2, CH2F, CCl3, etc.), C1-C 20 Alkoxy, C2-C 20 Alkoxyalkyl, hydroxy group, -NH2, =NH, nitro, cyano, amidino, hydrazine, hydrazone, carboxy or its salt, sulfonyl, sulfamoyl, sulfonic acid group or its salt, phosphoric acid or its salt, C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C6-C 20Aryl, C6-C 20 Aryl alkyl, C6-C 20 Heteroaryl, C7-C 20 Heteroarylalkyl, C6-C 20 Heteroaryloxy, C6-C 20 Heteroaryloxyalkyl or C6-C 20 It may refer to substitution by heteroarylalkyl and the like.

[0134] The term "isomer" includes "stereoisomers" and refers to compounds that have the same molecular formula but differ in atomic connectivity or spatial arrangement of the constituent atoms within the molecule. Examples of isomers include 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 left and right hands, and are also called optical isomers. Enantiomers are divided into R (rectus: clockwise) and S (sinister: counterclockwise) when four or more substituents at the chiral central carbon are different from each other. Diastereomers refer to non-mirror stereoisomers and are isomers created by different spatial arrangements of atoms. Diastereomers can be divided into cis-trans isomers and conformational isomers.

[0135] The term "solvate" refers to a compound solvated in an organic or inorganic solvent. An example of a solvate is a hydrate.

[0136] The term "isotope" refers to the same element but with different mass numbers, i.e., the same number of protons but different numbers of neutrons. For example, isotopes are: 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, 125Isotopically labeled compounds may include, but are not limited to, I, etc. Isotopically labeled compounds may be advantageous in that they may have improved stability and longer half-lives in the body.

[0137] The term "salt" refers to inorganic and organic acid addition salts of a compound. Pharmaceutically acceptable salts may be salts that do not cause significant irritation to the organism to which the compound is administered and do not impair the biological activity and properties of the compound. Inorganic acid salts may be hydrochloride, bromate, phosphate, sulfate, or disulfate salts. Organic acid salts may be formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, disylate, trichloroacetate, trifluoroacetate, benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, embonate, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspartate. Metal salts may be calcium, sodium, magnesium, strontium, or potassium salts.

[0138] Any one or more compounds of Formulas 1 to 3 may be inhibitors of Src homology 2 domain-containing phosphatase-2 (SHP2). Src homology 2 domain-containing phosphatase-2 (SHP2) may be a protein belonging to the protein tyrosine phosphatase (PTP) family. SHP2 may also be called tyrosine-protein phosphatase non-receptor type 11 (PTPN11), protein-tyrosine phosphatase 1D (PTP-1D), or protein-tyrosine phosphatase 2C (PTP-2C). SHP2 may contain two tandem SH2 domains at the N-terminus, along with SPP1. SHP2 may be a protein comprising the amino acid sequence of Uniprot No. Q06124 in humans or the amino acid sequence of Uniprot No. P35235 in mice. SHP2 may be wild-type SHP2 or an SHP2 mutant. The SHP2 inhibitor may inhibit the expression or activity of SHP2.

[0139] In another aspect, there is provided a pharmaceutical composition comprising a compound according to an aspect, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

[0140] In another aspect, there is provided 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 isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

[0141] The compounds, stereoisomers, solvates, isotopically labeled compounds, pharmaceutically acceptable salts and SHP2 are as described above.

[0142] The disease associated with abnormal activity of SHP2 may be selected from the group consisting of cancer, cancer metastasis, cardiovascular disease, immune disorders, fibrosis, and eye disorders.

[0143] The cancer may 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, bronchial cancer, nasopharyngeal cancer, pharyngeal cancer, esophageal cancer, biliary tract 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.

[0144] Cancer metastasis refers to the spread of a tumor from its primary site to another part of the body where the tumor takes hold and grows. Cancer metastasis can involve the spread of cancer cells into blood vessels, lymphatic vessels, or tissues.

[0145] In particular, the compounds of the present disclosure may exhibit improved blood-brain barrier (BBB) ​​permeability. Specifically, the compounds of the present disclosure may 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 may exhibit excellent therapeutic effects against brain tumors such as glioblastoma, anaplastic astrocytoma, and low-grade glioma, as well as cancers that originate in sites other than the brain and metastasize to the brain, such as lung cancer, breast cancer, and melanoma that metastasize to the brain.

[0146] In some embodiments, the disease associated with aberrant SHP2 activity can be EGFR / RAS pathway-dependent brain metastasis or glioblastoma. For example, brain metastasis can occur in non-small cell lung cancer (NSCLC) patients treated with EGFR inhibitors.

[0147] Cardiovascular disease refers to a disease that occurs in the heart or major arteries (e.g., aorta, pulmonary artery, carotid artery, cerebrovascular, renal artery, arteries of the lower limbs). Cardiovascular disease may be selected from the group consisting of hypertension, ischemic heart disease, coronary artery disease, angina pectoris, myocardial infarction, atherosclerosis (arteriosclerosis), cerebrovascular disease, stroke, arrhythmia, acute heart failure, chronic heart failure, and hypotension.

[0148] The immune disorder refers to a state in which a normal immune response is not achieved, and may be selected from the group consisting of acquired immune deficiency, autoimmune disease, systemic lupus erythematosus, scleroderma, Sjogren's syndrome, polymyositis, dermatomyositis, polymyalgia rheumatica, temporal arteritis, polyarteritis nodosa, and Behcet's syndrome.

[0149] Fibrosis refers to a condition in which fibrous tissue increases excessively in a part of a tissue or organ. The fibrosis may be selected from the group consisting of hepatic fibrosis, cystic fibrosis, myelofibrosis, endomyocardial fibrosis, and retroperitoneal fibrosis.

[0150] 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, hypotony of the eye, intraocular foreign body, blood in the eye, and dislocation of the eye.

[0151] The disease associated with abnormal activity of SHP2 may 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.

[0152] The term "prevention" refers to any action that inhibits or delays the occurrence of an SHP2-related disease upon administration of a pharmaceutical composition. The term "treatment" refers to any action that improves or beneficially alters the symptoms of an SHP2-related disease upon administration of a pharmaceutical composition.

[0153] The pharmaceutical composition may include a pharmaceutically acceptable carrier. The term "carrier" is used to include excipients, diluents, or adjuvants. For example, the carrier may be selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, saline, buffers such as PBS, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. The composition may include a filler, an anti-agglomerating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, or a combination thereof.

[0154] The pharmaceutical composition can be prepared in any formulation according to conventional methods. The composition can be formulated, for example, as an oral dosage form (e.g., powder, tablet, capsule, syrup, pill or granule) or a parenteral dosage form (e.g., injection). Furthermore, the composition can be prepared as a systemic or local formulation.

[0155] In the pharmaceutical composition, the solid formulation for oral administration may be a tablet, pill, powder, granule, or capsule. The solid formulation may further contain an excipient. The excipient may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. The solid formulation may also contain a lubricant such as magnesium stearate or talc. In the pharmaceutical composition, the liquid formulation for oral administration may be a suspension, oral solution, emulsion, or syrup. The liquid formulation may contain water or liquid paraffin. The liquid formulation may contain an excipient such as a wetting agent, a sweetener, a flavoring agent, or a preservative. In the pharmaceutical composition, the formulation for parenteral administration may be a sterile aqueous solution, a non-aqueous solution, a suspension, an emulsion, a lyophilized preparation, or a suppository. The non-aqueous solution or suspension may contain a vegetable oil or an ester. The vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil. The ester may be, for example, ethyl oleate. The suppository base can be witepsol, macrogol, tween 61, cocoa butter, laurin butter, or glycerogelatin.

[0156] The pharmaceutical composition comprises a compound according to one embodiment, a stereoisomer, solvate, or isotopically 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 a pharmacological activity (e.g., treatment of a disease associated with abnormal activity of SHP2).

[0157] The pharmaceutical composition may contain an effective amount of a compound according to one embodiment, its stereoisomer, solvate, or isotope-labeled compound, or a pharmaceutically acceptable salt thereof. The term "effective amount" refers to an amount sufficient to prevent or treat a disease when administered to a subject in need thereof. The effective amount can be appropriately selected by one skilled in the art depending on the cell or subject selected. The preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the subject, the severity of the disease, the drug form, the route of administration, and the duration of administration, but can be appropriately selected by one skilled in the art. The effective amount may be about 0.5 μg to about 2 g, about 1 μg to about 1 g, about 10 μg to about 500 mg, about 100 μg to about 100 mg, or about 1 mg to about 50 mg per pharmaceutical composition. However, the compound, stereoisomer, solvate, isotope-labeled compound, or pharmaceutically acceptable salt thereof may 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 may be administered in divided doses of 1 to 24 times daily, 1 to 7 times every 2 days to a week, or 1 to 24 times every 1 to 12 months. In the pharmaceutical composition, the compound, stereoisomer, solvate, isotope-labeled compound, or pharmaceutically acceptable salt thereof may be contained in an amount of about 0.0001% to about 10% by weight, or about 0.001% to about 1% by weight, based on the total weight of the entire composition.

[0158] The administration method may be oral or parenteral. The administration method may be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal. The composition may be administered systemically or locally, alone or in combination with other pharmaceutically active compounds.

[0159] In another aspect, there is provided a method for preventing or treating a disease associated with abnormal activity of SHP2, the method comprising administering to a subject a compound according to an aspect, a stereoisomer, solvate, or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

[0160] The compounds, stereoisomers, solvates, isotopically labeled compounds, pharmaceutically acceptable salts, SHP2, diseases associated with abnormal activity of SHP2, prevention and treatment are as described above.

[0161] 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 one suffering from or likely to suffer from a condition associated with a disease associated with abnormal activity of SHP2.

[0162] The method may further include administering to the subject an active ingredient known to be effective in preventing or treating a disease associated with SHP2. The known active ingredient may be administered to the subject simultaneously, separately, or sequentially with a compound according to one embodiment, its stereoisomer, solvate, or isotopically labeled compound, or a pharmaceutically acceptable salt thereof.

[0163] The administration method may be oral or parenteral. The administration method may be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal. The pharmaceutical composition may be administered systemically or locally, alone or in combination with other pharmaceutically active compounds.

[0164] The preferred dosage of the pharmaceutical composition varies depending on the patient's condition and weight, the severity of the disease, the drug form, the route of administration, and the duration of administration, but can be appropriately selected by those skilled in the art. For example, the dosage for an adult may be in 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 may be once daily, twice to 24 times daily, once to twice every three days, once to six times a week, once to 10 times every two weeks, once to 15 times every three weeks, once to three times every four weeks, or once to 12 times a year.

[0165] In another aspect, there is provided a compound according to one aspect, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease associated with abnormal activity of SHP2.

[0166] The compounds, stereoisomers, solvates, isotopically labeled compounds, pharmaceutically acceptable salts, SHP2, diseases associated with abnormal activity of SHP2, prevention and treatment are as described above.

[0167] In another aspect, there is provided use of a compound according to one aspect, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the prevention or treatment of a disease associated with abnormal activity of SHP2.

[0168] The compounds, stereoisomers, solvates, isotopically labeled compounds, pharmaceutically acceptable salts, SHP2, diseases associated with abnormal activity of SHP2, prevention and treatment are as described above.

[0169] Effect of the invention SHP2-associated diseases can be effectively prevented or treated by an SHP2 inhibitor, a pharmaceutical composition containing the same for preventing or treating SHP2-associated diseases, a method for treating and preventing diseases using the same, and the use of these.

[0170] The present invention will be described in more detail below with reference to examples. However, the following examples are for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention.

[0171] Preparation Example 1: tert-butyl 2-chloro-6-oxo-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (Intermediate I-1) [ka]

[0172] Step 1: (2-chlorothiazol-4-yl)methanol To a solution of ethyl 2-chlorothiazol-4-carboxylate (30 g, 157 mmol) in EtOH (300 mL) was added NaBH (41.5 g, 1.10 mol), and the mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched with aqueous ammonium chloride (100 mL) at 0 °C, diluted with water (100 ml), and then extracted with EA (200 mL × 3). The combined organic layer was washed with brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give (2-chlorothiazol-4-yl)methanol (22 g, 94% yield) as a colorless oil. 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] + .

[0173] Step 2: (2-chlorothiazol-4-yl)methyl methanesulfonate To a solution of ethyl 2-chlorothiazol-4-carboxylate (30 g, 157 mmol) in DCM (300 mL) was added TEA (27.1 g, 267 mmol) and MsCl (21.4 g, 187 mmol) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with aqueous NaHCO (100 mL) at 25 °C, diluted with water (100 ml), and then extracted with DCM (200 mL × 3). The combined organic layer was washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2-chlorothiazol-4-yl)methyl methanesulfonate (28 g, crude product) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ=7.29(s,1H),5.19(s,2H),3.01(s,3H)

[0174] Step 3: O1-tert-butyl O4-ethyl 4-[(2-chlorothiazol-4-yl)methyl]piperidine-1,4-dicarboxylate A solution of ethyl 2-chlorothiazole-4-carboxylate (30 g, 157 mmol) in THF (30 mL) was stirred at −60° C. under nitrogen, and LDA (2 M, 81.6 mL) was added dropwise. The reaction mixture was stirred at −60° C. for 0.5 h, and (2-chlorothiazol-4-yl)methyl methanesulfonate (26.5 g, 117 mmol) in THF (15 mL) was added dropwise. The reaction mixture was stirred at −60° C. for 0.5 h, then slowly warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with aqueous ammonium chloride solution (100 mL), diluted with water (200 mL), and then extracted with EA (300 mL×3). The combined organic layer was washed with brine (150 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0.1% FA) to give O1-tert-butyl O4-ethyl 4-[(2-chlorothiazol-4-yl)methyl]piperidine-1,4-dicarboxylate (14 g, 31% yield) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ=6.80(s,1H),4.15(q,J=7.2 Hz,2H),3.89(s,2H),2.94-2.84(m,4H),2.11(d,J=13.2 Hz,2H),1.52-1.47(m,2H),1.45(s,9H),1.24(t,J=7.2 Hz,3H).

[0175] Step 4: tert-Butyl 2-chloro-6-oxo-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate 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), LDA (2 M, 44.4 mL) was added dropwise, and the reaction mixture was stirred at 70 °C for 0.5 h. The reaction mixture was quenched with aqueous ammonium chloride solution (100 mL) at 0 °C, diluted with water (100 ml), and then extracted with EA (200 mL × 3). The combined organic layer was washed with brine (200 mL × 3), dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate I-1 (6.1 g, 50% yield) as a yellow oil. 1 H NMR(400 MHz,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).

[0176] Preparation Example 2: (R)-2-methyl-N-[(6S)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidin]-6-yl]propane-2-sulfinamide (Intermediate I-2) [ka]

[0177] Step 1: tert-Butyl (6Z)-6-[(R)-tert-butylsulfinyl]imino-2-chloro-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of tert-butyl 2-chloro-6-oxo-spiro[4H-cyclo[d]thiazole-5,4'-piperidine]-1'-carboxylate (3.0 g, 8.75 mmol) and (R)-2-methylpropane-2-sulfinamide (4.24 g, 35.0 mmol) in THF (30 mL), Ti(OEt) (29.9 g, 131 mmol) was added dropwise, and the reaction mixture was stirred at 90 °C for 12 h. EA (300 mL) was added to the reaction mixture, diluted with water (50 mL), and then extracted with EA (100 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl (6Z)-6-[(R)-tert-butylsulfinyl]imino-2-chloro-spiro[4H-cyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylate (3.5 g, 90% yield) as a yellow solid. 1 H NMR(400 MHz,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] + .

[0178] Step 2: tert-Butyl (6S)-6-[[(R)-tert-butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of tert-butyl (6Z)-6-[(R)-tert-butylsulfinyl]imino-2-chloro-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (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 h. The reaction mixture was quenched with MeOH (10 mL) at 0 °C, diluted with water (100 ml), and then extracted with EA (100 mL x 3). The combined organic layer was washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl (6S)-6-[[(R)-tert-butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylate (660 mg, 20% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=8.78(s,1H),4.57(d,J=8.6 Hz,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=14.0 Hz,2H),1.47(s,9H),1.24-1.21(s,9H).

[0179] Step 3: (R)-2-methyl-N-[(6S)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidin]-6-yl]propane-2-sulfinamide To a solution of tert-butyl (6S)-6-[[(R)-tert-butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (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 h. The reaction mixture was quenched with saturated aqueous KCO solution (20 mL) at 25 °C, diluted with water (30 ml), and then extracted with DCM (50 mL × 3). The combined organic layer was washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate I-2 (140 mg, crude product) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=8.77(s,1H),4.58(d,J=8.8 Hz,1H),3.67(d,J=8.8 Hz,1H),3.16-3.05(m,2H),2.90-2.84(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).

[0180] Preparation 3: 6-(5-bromopyrazin-2-yl)sulfanyl-5-chloro-3H-quinazolin-4-one (Intermediate I-3) [ka]

[0181] To a solution of 5-chloro-6-mercaptoquinazolin-4(3H)-one (880 mg, 3.75 mmol) in DMF (20 mL) were added KCO (1.56 g, 11.3 mmol) and 2,5-dibromopyrazine (3.57 g, 15.00 mmol), and the mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by adding aqueous ammonium chloride solution (50 mL) at 25 °C, diluted with water (50 mL), and extracted with EA (100 mL × 3). The combined organic layer was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA = 1 / 1 to 0:1) to give intermediate I-3 (500 mg, 36% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=12.50(br s,1H),8.71(d,J=1.0 Hz,1H),8.46-8.43(m,1H),8.15(s,1H),7.98(d,J=8.8 Hz,1H),7.61(d,J=8.8 Hz,1H);MS(EI)m / z:371.1 [M+H] + .

[0182] Preparation Example 4: (R)—N-[(6S)-1′-[5-[(5-chloro-4-oxo-3H-quinazolin-6-yl)sulfanyl]pyrazin-2-yl]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4′-piperidin]-6-yl]-2-methyl-propane-2-sulfinamide (Intermediate I-4) [ka]

[0183] 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-G (76.8 mg, 98.9 μmol), and KCO (410 mg, 2.97 mmol), and the mixture was stirred at 100° C. for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give intermediate I-4 (300 mg, 53% yield) as a yellow solid. 1 H NMR(400 MHz,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=8.8 Hz,1H),7.29(s,1H),4.68(d,J=8.8 Hz,1H),4.41(d,J=13.2 Hz,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).

[0184] Preparation 5: 6-((5-bromopyrazin-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazolin-4(3H)-one (Intermediate I-5) [ka]

[0185] Step 1: 2-Ethylhexyl 3-((5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate To a solution of ethyl 3-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propionate (10 g, 25.2 mmol) in DMF (100 mL), 1-bromo-2-methoxyethane (4.2 g, 30.2 mmol), K2CO3 (6.96 g, 50.4 mmol), and TBAI (931 mg, 2.52 mmol) were added and stirred at 55 °C for 3 h. The reaction mixture was quenched with aqueous ammonium chloride solution (50 mL), diluted with water (50 mL), and then extracted with EA (100 mL x 3). The combined organic layer was washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, 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. 1 H NMR(400 MHz,CDCl3)δ=8.04(s,1H),7.67-7.59(m,2H),4.15(t,J=4.8 Hz,2H),4.05(dd,J=2.0,5.8 Hz,2H),3.71-3.65(m,2H),3.33(s,3H),3.30-3.25(m,2H),2.71(t,J=7.6 Hz,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] + .

[0186] Step 2 and Step 3: 6-((5-bromopyrazin-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazolin-4(3H)-one Using 2-ethylhexyl 3-(5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate as the starting material, intermediate I-5 (1.4 g, 22%) was obtained as a yellow solid in the same manner as in Steps 3 and 4 of Preparation 9. 1H NMR(400 MHz,CDCl3)δ=8.44(s,1H),8.19(s,1H),8.13(s,1H),7.92(d,J=8.4 Hz,1H),7.65(d,J=8.4 Hz,1H),4.17(t,J=4.8 Hz,2H),3.73-3.66(m,2H),3.35(s,3H);MS(EI)m / z:429.1 [M+H] + .

[0187] Preparation 6: 6-(3-amino-5-chloro-pyrazin-2-yl)sulfanyl-5-chloro-3-(2-methoxyethyl)quinazolin-4-one (Intermediate I-6) [ka]

[0188] A mixture of [5-chloro-3-(2-methoxyethyl)-4-oxo-quinazolin-6-yl]sulfanyl chloride (630 mg, 2.15 mmol), 3-bromo-6-chloro-pyrazin-2-amine (538 mg, 2.58 mmol), Pd(dba) (197 mg, 215 μmol), Xantphos (249 mg, 431 μmol), and DIEA (835 mg, 6.46 mmol) in dioxane (20 mL) was degassed and purged with N three times, then stirred at 100 °C under N for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash column chromatography (0.1% FA) to give intermediate I-6 (120 mg, 14% yield) as a yellow solid. 1 H NMR(400 MHz,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=4.8 Hz,2H),3.68(t,J=4.8 Hz,2H),3.33(s,3H);MS(EI)m / z:398.0 [M+H] + .

[0189] Preparation 7: 6-(3-amino-5-chloro-pyrazin-2-yl)sulfanyl-5-chloro-3-(2-methoxypropyl)quinazolin-4-one (Intermediate I-7) [ka]

[0190] Step 1: 2-Methoxypropyl 4-methylbenzenesulfonate To a solution of 2-methoxypropan-1-ol (3.80 g, 42.1 mmol) in DCM (40 mL) were added TosCl (12.0 g, 63.2 mmol) and Py (10.0 g, 126 mmol, 10.2 mL). The mixture was stirred at 0 °C for 12 h. Upon completion of the reaction, the reaction mixture was quenched by adding aqueous ammonium chloride (20 mL) at 25 °C, diluted with water (30 mL), and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. Purification by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1 to 5 / 1) afforded 2-methoxypropyl 4-methylbenzenesulfonate (9.80 g, 95% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=7.77(d,J=8.0 Hz,2H),7.33(d,J=8.0 Hz,2H),3.93(dd,J=1.6,4.8 Hz,2H),3.55-3.47(m,1H),3.26(s,3H),2.42(s,3H),1.08(d,J=6.4 Hz,3H).

[0191] Step 2: 2-Ethylhexyl 3-[5-chloro-3-(2-methoxypropyl)-4-oxo-quinazolin-6-yl]sulfanylpropanoate 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 mixture was stirred at 50 °C for 12 h. Upon completion of the reaction, the reaction mixture was quenched by the addition of aqueous ammonium chloride solution (20 mL) at 25 °C, diluted with water (30 mL), and extracted with EA (3 × 50 mL). The combined organic layer was washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1 to 3 / 1) to give 2-ethylhexyl 3-[5-chloro-3-(2-methoxypropyl)-4-oxo-quinazolin-6-yl]sulfanylpropanoate (1.00 g, 28% yield) as a red solid. MS(EI)m / z:469.2 [M+H] + .

[0192] Step 3: [5-chloro-3-(2-methoxypropyl)-4-oxo-quinazolin-6-yl]sulfanyl sodium 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 for 1 hour at 25° C. Upon completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to afford [5-chloro-3-(2-methoxypropyl)-4-oxo-quinazolin-6-yl]sulfanyl sodium (300 mg, 92% yield) as a yellow solid. MS(EI)m / z:285.1 [M+H] + .

[0193] Step 4: 6-(3-amino-5-chloro-pyrazin-2-yl)sulfanyl-5-chloro-3-(2-methoxypropyl)quinazolin-4-one A mixture of [5-chloro-3-(2-methoxypropyl)-4-oxo-quinazolin-6-yl]sulfanyl sodium (327 mg, 1.07 mmol), 3-bromo-6-chloro-pyrazin-2-amine (222 mg, 1.07 mmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (123 mg, 213 μmol), Pd(dba) (97.6 mg, 106 μmol) and DIEA (413 mg, 3.20 mmol, 557 μL) in dioxane (10 mL) was degassed and purged with N three times, then the mixture was stirred at 100 °C under N atmosphere for 12 h. Upon completion of the reaction, the reaction mixture was quenched by adding aqueous ammonium chloride solution (10 mL) at 25 °C, then diluted with water (10 mL) and extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 3 / 1 to 1 / 2) to give intermediate I-7 (100 mg, 23% yield) as a black solid. MS(EI)m / z:411.9 [M+H] + .

[0194] Preparation 8: Sodium 5-((3S,4S)-4-(tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazine-2-thiolate (Intermediate I-8) [ka]

[0195] Step 1: (3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine To a solution of (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (5.00 g, 20.6 mmol, 2HCl) in DMF (50 mL) were added TEA (6.24 g, 61.7 mmol) and 2,5-dibromopyrazine (4.89 g, 20.6 mmol), and the mixture was stirred for 12 h at 25° C. The reaction mixture was quenched by the addition of aqueous ammonium chloride (100 mL) at 25° C., then diluted with water (100 mL) and extracted with EA (3×200 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give (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. MS(EI)m / z:329.1 [M+H] + .

[0196] Step 2: tert-butyl N-[(3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate To a solution of (3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (6.7 g, 20.5 mmol) in DMF (50 mL) were added BocO (6.70 g, 30.7 mmol) and TEA (3.11 g, 30.7 mmol) and stirred at 25 °C for 2 h. The reaction mixture was quenched by the addition of aqueous ammonium chloride solution (100 mL) at 25 °C, then diluted with water (100 mL) and extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA=5:1) to give tert-butyl N-[(3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (5.5 g, 63% yield) as a yellow solid. MS(EI) m / z: 429.1 [M+H] + .

[0197] Step 3: 2-Ethylhexyl 3-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)propanoate A mixture of tert-butyl N-[(3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-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 three times, and then the mixture was stirred under N at 110 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give 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]decan-8-yl]pyrazin-2-yl]sulfanylpropanoate (5.00 g, 69% yield) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ=8.08(s,1H),8.06(s,1H),4.63(d,J=10.8 Hz,1H),4.23-4.13(m,1H),4.01(dd,J=5.8,2.6 Hz,2H),3.82-3.59(m,4H),3.57-3.46(m,1H),3.44-3.33(m,1H),3.28(t,J=7.2 Hz,2H),2.69(t,J=7.2 Hz,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=6.4 Hz,2H),0.93-0.86(m,6H);MS(EI)m / z:565.4 [M+H] + .

[0198] Step 4: Sodium 5-((3S,4S)-4-(tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazine-2-thiolate To a solution of 2-ethylhexyl 3-[5-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-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. MS(EI)m / z:381.1 [M+H] + .

[0199] Preparation Example 9: 7-Bromo-8-chloroisoquinolin-1(2H)-one (Intermediate I-9) [ka]

[0200] Step 1: (E)-1-(3-bromo-2-chloro-phenyl)-N-(2,2-dimethoxyethyl)methanimine To a mixture of 3-bromo-2-chloro-benzaldehyde (14 g, 63.7 mmol) in toluene (200 mL), 2,2-dimethoxyethanamine (6.71 g, 63.7 mmol) was added and stirred for 64 hours at 125° C. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give (E)-1-(3-bromo-2-chloro-phenyl)-N-(2,2-dimethoxyethyl)methanimine (19 g, 97% yield) as a yellow oil. 1 H NMR(400 MHz,DMSO-d6)δ=8.68(s,1H),7.94-7.86(m,2H),7.34(t,J=7.6 Hz,1H),4.64(t,J=5.4 Hz,1H),3.78(d,J=5.4 Hz,2H),3.30(s,6H).

[0201] Step 2: 7-Bromo-8-chloro-isoquinoline To a mixture of (E)-1-(3-bromo-2-chloro-phenyl)-N-(2,2-dimethoxyethyl)methanimine (2 g, 6.52 mmol) in DCM (20 mL) was added trifluoromethanesulfonic acid (20 mL) and stirred at 120 °C for 0.5 h. The reaction mixture was then cooled to 25 °C and stirred at 25 °C for 0.5 h. Upon completion of the reaction, MeOH (200 mL) was added to the reaction mixture. The mixture was poured into NH 3 HO (200 mL) and extracted with EA (3 × 300 mL). The organic phase was concentrated under reduced pressure. The residue was triturated with water at 25 °C for 30 min to give 7-bromo-8-chloro-isoquinoline (820 mg, 51% yield) as a brown solid. 1 H NMR(400 MHz,DMSO-d6)δ=9.56(s,1H),8.68(d,J=5.6 Hz,1H),8.06(d,J=8.8 Hz,1H),7.96-7.94(m,2H).

[0202] Step 3: 7-Bromo-8-chloro-2-oxideisoquinolin-2-ium To a mixture of 7-bromo-8-chloroisoquinoline (820 mg, 3.38 mmol) in DCM (20 mL), m-CPBA (1.37 g, 6.76 mmol, 85% purity) was added and stirred at 25 °C for 16 h. Upon completion of the reaction, Na2O3S2 (50 mL) was added to the mixture. The mixture was concentrated under reduced pressure. The residue was extracted with EA (3 × 40 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EA / MeOH = 1 / 0 / 0 to 0 / 10 / 1) to give 7-bromo-8-chloro-2-oxide-isoquinolin-2-ium (690 mg, 78% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.88(s,1H),8.32(d,J=7.2 Hz,1H),8.06(d,J=7.2 Hz,1H),7.90(s,2H).

[0203] Step 4: 7-Bromo-8-chloroisoquinolin-1(2H)-one A mixture of 7-bromo-8-chloro-2-oxide-isoquinolin-2-ium (640 mg, 2.48 mmol) in AcO (6 mL) was stirred at 120 °C for 3 h. After completion of the reaction, the mixture was concentrated under reduced pressure to give (7-bromo-8-chloro-1-isoquinolyl)acetate (640 mg, crude product). A mixture of (7-bromo-8-chloro-1-isoquinolyl)acetate (640 mg, 2.13 mmol) in a mixture of NaOH (2 M, 32.00 mL) and HO (8 mL) was stirred at 100 °C for 1 h. Upon completion of the reaction, the mixture was acidified to pH 6 with citric acid (5% aqueous solution) and extracted with DCM (3 × 100 mL). The combined organic phase was concentrated under reduced pressure to give intermediate I-9 (320 mg, 58% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=10.76-10.32(m,1H),7.86(d,J=8.4 Hz,1H),7.32(d,J=8.4 Hz,1H),7.19(d,J=6.8 Hz,1H),6.48(d,J=7.2 Hz,1H).

[0204] Preparation 10: Sodium 5-((S)-6-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrazine-2-thiolate (Intermediate I-10) [ka]

[0205] Step 1: (R)—N-((S)-1′-(5-bromopyrazin-2-yl)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-6-yl)-2-methylpropane-2-sulfinamide To a solution of intermediate I-2 (500 mg, 1.59 mmol) in DMF (8 mL) were added DIEA (2.06 g, 16.0 mmol) and 2,5-dibromopyrazine (1.14 g, 4.78 mmol). The mixture was stirred at 100° C. for 2 hours. Upon completion of the reaction, the reaction mixture was quenched by adding aqueous ammonium chloride solution (20 mL) at 25° C., then diluted with water (30 mL) and extracted with EA (3×50 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give (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, 31% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=8.80(s,1H),8.12(d,J=1.2 Hz,1H),7.90(d,J=1.2 Hz,1H),4.63(d,J=9.2 Hz,1H),4.27-4.12(m,2H),3.66(d,J=9.2 Hz,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=2.4,13.2 Hz,1H),1.72(dd,J=2.4,13.2 Hz,1H),1.23(s,9H);MS(EI)m / z:472.2 [M+H] + .

[0206] Step 2: 2-Ethylhexyl 3-((5-((S)-6-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)propanoate A mixture of (R)-N-((S)-1'-(5-bromopyrazin-2-yl)-4,6-dihydrospiro[cyclopenta[d]thiazol-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 three times, and then the mixture was stirred under N at 100 °C for 3 h. Upon completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, PE / EA = 3 / 1 to 1 / 5) to give 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 (240 mg, 81% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=8.80(s,1H),8.09(d,J=1.2 Hz,1H),8.06(d,J=1.2 Hz,1H),4.63(d,J=8.8 Hz,1H),4.26-4.14(m,2H),4.13-4.08(m,2H),4.01(dd,J=2.8,5.6 Hz,2H),3.67(d,J=8.8 Hz,1H),3.28(t,J=7.2 Hz,2H),3.22-3.07(m,2H),3.04-2.89(m,2H),2.04-1.95(m,2H),1.83-1.71(m,2H),1.37-1.27(m,9H),1.22(s,9H),0.91-0.86(m,6H).

[0207] Step 3: Sodium 5-((S)-6-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrazine-2-thiolate 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. Upon 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) as a yellow solid. MS(EI)m / z:424.2 [M-Na] + .

[0208] Preparation Example 11: 7-Bromo-8-chloro-2-methylisoquinolin-1(2H)-one (Intermediate I-11) [ka]

[0209] To a mixture 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 h. Upon completion of the reaction, water (20 mL) was added to the mixture and extracted with EA (3 × 30 mL). The combined organic phase was washed with brine (3 × 30 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give intermediate I-11 (60 mg, 57% yield) as a white solid. 1 H NMR(400 MHz,CDCl3)δ=7.83(d,J=8.4 Hz,1H),7.28(s,1H),7.17(d,J=7.2 Hz,1H),6.41(d,J=7.2 Hz,1H),3.60(s,3H).

[0210] Preparation 12: (R)-2-methyl-N-[(5S)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidin]-5-yl]propane-2-sulfinamide (Intermediate I-12) [ka]

[0211] Step 1: 3-Bromo-2-(bromomethyl)pyridine To a solution of 3-bromo-2-methyl-pyridine (20.0 g, 116 mmol) in CCl (200 mL), N-bromosuccinimide (NBS) (22.8 g, 128 mmol) and azobisisobutyronitrile (AIBN) (1.91 g, 11.6 mmol) were added and the mixture was stirred at 80 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by MPLC (PE / EA = 30:1) to give 3-bromo-2-(bromomethyl)pyridine (12.5 g, 42% yield) as a brown solid. 1 H NMR(400 MHz,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] + .

[0212] Step 2: tert-butyl 4-[(3-bromo-2-pyridyl)methyl]-4-cyano-piperidine-1-carboxylate To a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (10.1 g, 47.8 mmol) in THF (100 mL) was added lithium diisopropylamide (LDA) (2 M, 23.9 mL) and stirred at −78° C. for 0.5 h. Then, 3-bromo-2-(bromomethyl)pyridine (10.0 g, 39.9 mmol) in THF (100 mL) was slowly added to the reaction mixture, which was then stirred at −78° C. for 2.5 h. The reaction mixture was quenched at 0° C. by the addition of aqueous ammonium chloride solution (100 mL), diluted with water (100 mL), and extracted with EA (3×200 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash column chromatography (0.1% FA) to afford tert-butyl 4-[(3-bromo-2-pyridyl)methyl]-4-cyano-piperidine-1-carboxylate (13.5 g, 89% yield) as a brown solid. 1 H NMR(400 MHz,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] + .

[0213] Step 3: tert-Butyl 5-oxospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate A mixture of tert-butyl 4-[(3-bromo-2-pyridyl)methyl]-4-cyano-piperidine-1-carboxylate (5.90 g, 15.5 mmol), 4-di-tert-butylphosphanyl-N,N-dimethyl-aniline; dichloropalladium (Pd(AmPhos)Cl) (1.10 g, 1.55 mmol), TEA (6.28 g, 62.1 mmol) in dimethylacetamide (DMA) (120 mL) and HO (12 mL) was degassed and then purged with N three times. The mixture was stirred at 130 °C under a N atmosphere for 12 h. The reaction mixture was quenched at 25 °C by the addition of aqueous ammonium chloride (50 mL), then diluted with water (50 mL), and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (PE / EA = 3:1) to give tert-butyl 5-oxospiro[7H-cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate (3.2 g, 68% yield) as a brown solid. 1 H NMR(400 MHz, 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] + .

[0214] Step 4: tert-butyl (5Z)-5-[(R)-tert-butylsulfinyl]iminospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate To a solution of tert-butyl 5-oxospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (3.00 g, 9.92 mmol) in THF (30 mL) was added Ti(OEt) (34.0 g, 149 mmol) and (R)-2-methylpropane-2-sulfinamide (4.81 g, 39.7 mmol). The mixture was stirred at 70 °C for 12 h. The reaction mixture was diluted with EA (300 mL), quenched with water (50 mL), filtered, and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a 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. 1 H NMR(400 MHz,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),3.0 2-2.89(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] + .

[0215] Step 5: tert-butyl (5S)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate To a solution of tert-butyl (5Z)-5-[(R)-tert-butylsulfinyl]iminospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (2.00 g, 4.93 mmol) in THF (20 mL) was added LiBH (537 mg, 24.7 mmol), and the mixture was stirred at -70 °C for 2 h. The reaction mixture was quenched at 0 °C by the addition of aqueous ammonium chloride (20 mL), then diluted with water (30 mL), and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to give 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%, 15 min) to give tert-butyl (5S)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (630 mg, 31% yield) as a yellow solid. 1 H NMR(400 MHz, 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),3.60-3.5 1(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] + .

[0216] Step 6: (R)-2-methyl-N-[(5S)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidin]-5-yl]propane-2-sulfinamide To a solution of tert-butyl (5S)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (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 h. The reaction mixture was poured into aqueous KCO solution (20 mL) at 25 °C, then diluted with water (30 mL), and extracted with DCM (3 × 50 mL). The combined organic layer was washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to give intermediate I-12 (140 mg, 92% yield) as a yellow solid. 1 H NMR(400 MHz, 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] + .

[0217] Preparation Example 13: N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (Intermediate I-13) [ka]

[0218] tert-Butyl (1S)-1-((tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (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, which was then stirred at room temperature for 3 hours. Upon completion of the reaction, the resulting product was concentrated to give intermediate I-13. MS(EI)m / z:307.4[M+H]+ .

[0219] Preparation 14: 6-((5-bromopyrazin-2-yl)thio)-5-chloro-3-methylquinazolin-4(3H)-one (Intermediate I-14) [ka]

[0220] Step 1: 2-Ethylhexyl 3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate 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. Upon completion of the reaction, the reaction mixture was quenched by adding aqueous ammonium chloride solution (30 mL) at 25° C., then diluted with water (50 mL) and extracted with EA (3×80 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give 2-ethylhexyl 3-(5-chloro-3-methyl-4-oxo-quinazolin-6-yl)sulfanylpropanoate (850 mg, yield 82%) as a yellow solid. 1H NMR(400 MHz,DMSO-d6)δ=8.36(s,1H),7.79(d,J=8.8 Hz,1H),7.60(d,J=8.8 Hz,1H),3.96(d,J=5.6 Hz,2H),3.44(s,3H),3.30(d,J=6.8 Hz,2H),2.73(d,J=5.2 Hz,2H),1.55-1.49(m,1H),1.31-1.26(m,2H),1.24-1.23(m,1H),1.22(d,J=2.0 Hz,4H),1.21-1.15(m,2H),0.83(d,J=7.2 Hz,6H).

[0221] Step 2: Sodium 5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-thiolate To a solution of 2-ethylhexyl 3-(5-chloro-3-methyl-4-oxo-quinazolin-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. Upon completion of the reaction, the reaction mixture was dissolved in PE (50 mL) and filtered. The filter cake was dried to give sodium 5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-thiolate (400 mg, crude product) as a yellow solid, which was used in the next step without further purification.

[0222] Step 3: 6-((5-bromopyrazin-2-yl)thio)-5-chloro-3-methylquinazolin-4(3H)-one To a solution of sodium 5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-thiolate (400 mg, 1.61 mmol) and 2,5-dibromopyrazine (1.15 g, 4.83 mmol) in DMF (30 mL) was added K2CO3 (666 mg, 4.83 mmol). The mixture was stirred at 0 °C for 4 h. Upon completion of the reaction, the reaction mixture was quenched by adding aqueous ammonium chloride solution (20 mL) at 25 °C, then diluted with water (50 mL), and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give intermediate I-14 (180 mg, 29% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.72(d,J=1.2 Hz,1H),8.48-8.47(m,2H),7.98(d,J=8.4 Hz,1H),7.64(d,J=8.4 Hz,1H),3.47(s,3H).

[0223] Preparation 15: 6-((3-amino-5-chloropyrazin-2-yl)thio)-5-chloro-3-methylquinazolin-4(3H)-one (Intermediate I-15) [ka]

[0224] Intermediate I-15 (260 mg, 18% yield) was synthesized using sodium 5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-thiolate in place of [5-chloro-3-(2-methoxyethyl)-4-oxo-quinazolin-6-yl]sulfanyl sodium in Preparation Example 6. MS(EI)m / z:354.0 [M+H] + .

[0225] Preparation 16: 6-((3-amino-5-chloropyrazin-2-yl)thio)-3-benzyl-5-chloroquinazolin-4(3H)-one (Intermediate I-16) [ka]

[0226] Intermediate I-16 (300 mg, 23% yield) was synthesized using 6-((3-amino-5-chloropyrazin-2-yl)thio)-3-benzyl-5-chloroquinazolin-4(3H)-one in place of 5-chloro-3-(2-methoxyethyl)-4-oxo-quinazolin-6-yl]sulfanyl sodium in Preparation 6. MS(EI)m / z:430.0 [M+H] + .

[0227] Preparation 17: 6-((3-amino-5-chloropyrazin-2-yl)thio)-5-chloroquinazolin-4(3H)-one (Intermediate I-17) [ka]

[0228] Intermediate I-17 (700 mg, 28% yield) was synthesized using sodium 5-chloro-4-oxo-3,4-dihydroquinazoline-6-thiolate in place of [5-chloro-3-(2-methoxyethyl)-4-oxo-quinazolin-6-yl]sulfanyl sodium in Preparation Example 6. 1 H NMR(400 MHz,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).

[0229] Preparation 18: 6-((5-bromopyrazin-2-yl)thio)-3-methylquinazolin-4(3H)-one (Intermediate I-18) [ka]

[0230] Intermediate I-18 (500 mg, 31% yield) was synthesized by substituting sodium 3-methyl-4-oxo-3,4-dihydroquinazoline-6-thiolate for [5-chloro-3-(2-methoxyethyl)-4-oxo-quinazolin-6-yl]sulfanyl sodium and 2,5-dibromopyrazine for 3-bromo-6-chloro-pyrazin-2-amine in Preparation Example 6. MS(EI)m / z:349.2 [M+H] + .

[0231] Preparation Example 19: tert-Butyl ((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]decan-4-yl)carbamate (Intermediate I-19) [ka]

[0232] Intermediate I-19 (200 mg, 34% yield) was synthesized using sodium 5-chloro-4-oxo-3,4-dihydroquinazoline-6-thiolate instead of [5-chloro-3-(2-methoxyethyl)-4-oxo-quinazolin-6-yl]sulfanyl sodium and the product from Step 2 of Preparation 8 instead of 3-bromo-6-chloro-pyrazin-2-amine in Preparation 6. 1H NMR(400 MHz,CDCl3)δ=11.11(br s,1H),8.24(d,J=1.2 Hz,1H),8.18(d,J=1.2 Hz,1H),7.98(s,1H),7.47(d,J=8.8 Hz,1H),7.22(d,J=8.8 Hz,1H),4.30-4.22(m,2H),4.20-4.12(m,1H),3.93(d,J=9.2 Hz,1H),3.69(d,J=9.2 Hz,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=6.4 Hz,3H);MS(EI)m / z:559.1 [M+H] + .

[0233] Preparation 20: tert-Butyl ((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]decan-4-yl)carbamate (Intermediate I-20) [ka]

[0234] Step 1: tert-butyl (R)-(1'-(5-bromopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate In a round-bottom flask, (R)-3H-spiro[benzofuran-2,4'-piperidine]-3-amine (200 mg, 0.72 mmol), 2,5-dibromopyrazine (296 mg, 1.08 mmol), and TEA (0.8 mL, 3.6 mmol) were dissolved in DMF (3.6 mL, 0.2 M) and stirred at 90 °C for 5 h. Di-tert-butyl dicarbonate (0.25 mL, 1.08 mmol) was added to the reaction mixture, and the mixture was stirred at 90 °C for 5 h. The reaction was quenched with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=1:10) and concentrated to give tert-butyl (R)-(1′-(5-bromopyrazin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-yl)carbamate (200 mg, 60%).

[0235] Step 2: tert-butyl (R)-(1'-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate 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 h. The reaction was quenched with HO, 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%).

[0236] Preparation 21: 6-Bromo-5-chloroquinazolin-4(3H)-one (Intermediate I-21) [ka]

[0237] Step 1: 6-Amino-3-bromo-2-chlorobenzoic acid To a solution of 2-amino-6-chloro-benzoic acid (100 g, 583 mmol) in DMF (1000 mL) was added NBS (114 g, 641 mmol), and the mixture was stirred at 0° C. for 2 hours. Upon completion of stirring, the reaction mixture was quenched with water (3 L) and extracted with ethyl acetate (1.5 L×3). The combined organic layers were washed with brine (1 L×3), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to give a residue. The residue was triturated with EA (500 mL) to give 6-amino-3-bromo-2-chloro-benzoic acid (113 g, 77% yield) as a brown solid. MS(EI)m / z:[M+H] + 251.9, 1 H NMR(400 MHz,DMSO-d6)δ=7.40(d,J=8.8 Hz,1H),6.64(d,J=8.8 Hz,1H),3.42(br s,2H).

[0238] Step 2: 6-Bromo-5-chloroquinazolin-4(3H)-one A solution of 6-amino-3-bromo-2-chlorobenzoic acid (80 g, 319 mmol) in formamide (216 g, 4.79 mol) was stirred at 140 °C for 12 hours. Upon completion of stirring, the reaction mixture was poured into aqueous ammonium chloride (500 mL) at 25 °C, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with MeOH (500 mL) to give intermediate I-21 (68 g, 82% yield) as a yellow solid. MS(EI)m / z:[M+H] + 261.2, 1 H NMR(400 MHz,DMSO-d6)δ=12.45(br s,1H),8.16-8.06(m,2H),7.54(d,J=8.8 Hz,1H).

[0239] Preparation 22: Sodium 5-chloro-4-oxo-3,4-dihydroquinazoline-6-thiolate (Intermediate I-22) [ka]

[0240] Step 1: 2-Ethylhexyl 3-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate A mixture of intermediate I-21 (64 g, 247 mmol), 2-ethylhexyl 3-sulfanylpropanoate (80.8 g, 370 mmol), Pd(dba) (11.3 g, 12.3 mmol), Xantphos (14.3 g, 24.7 mmol), and DIEA (95.6 g, 740 mmol) in dioxane (1000 mL) was degassed and purged with N three times, and then the mixture was stirred under a N atmosphere at 100 °C for 12 h. Upon completion of stirring, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by MPLC (petroleum ether / ethyl acetate = 1:1 to 1:2) to give 2-ethylhexyl 3-[(5-chloro-4-oxo-3H-quinazolin-6-yl)sulfanyl]propanoate (81 g, 83% yield) as a brown solid. MS(EI)m / z:[M+H]+397.2 1 H NMR(400 MHz,CDCl3)δ=11.42-10.88(m,1H),8.10-8.04(m,1H),7.71-7.65(m,2H),4.09-4.03(m,2H),3.30(t,J=7.4 Hz,2H),2.73(t,J=7.4 Hz,2H),1.42-1.25(m,9H),0.94-0.85(m,6H).

[0241] Step 2: Sodium 5-chloro-4-oxo-3,4-dihydroquinazoline-6-thiolate 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 stirred at 25 °C for 0.5 h. After stirring was complete, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with PE (2 L) to give intermediate I-22 (24.5 g, crude) as a yellow solid. MS(EI)m / z:[M+H] + 213.3, 1 H NMR(400 MHz,MeOD)δ=7.91(s,1H),7.89(d,J=8.6 Hz,1H),7.12-7.08(d,J=8.6 Hz,1H).

[0242] Preparation Example 23: 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]decan-4-yl)-2-methylpropane-2-sulfinamide (Intermediate I-23) [ka]

[0243] Step 1: 2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide To a solution of tert-butyl (3S,4S)-4-(tert-butylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (40 g, 107 mmol) in DCM (400 mL) was added TFA (244 g, 2.14 mol), and the mixture was stirred for 2 hours at 25° C. After stirring was complete, the reaction mixture was concentrated under reduced pressure to give 2-methyl-N-[(3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]propane-2-sulfinamide (29.3 g, crude product) as a colorless oil. MS(EI)m / z:[M+H] + 275.4

[0244] Step 2: N-((3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide To a solution of 2-methyl-N-[(3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]propane-2-sulfinamide (29.3 g, 107 mmol) and 2,5-dibromopyrazine (50.8 g, 214 mmol) in DMF (200 mL) was added DIEA (138 g, 1.07 mol), and the mixture was stirred at 100 °C for 3 h. After stirring was complete, the reaction mixture was quenched by adding aqueous ammonium chloride solution (200 mL) at 25 °C, then diluted with water (300 mL), and extracted with EA (500 mL x 3). The combined organic layer was washed with brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by MPLC (petroleum ether / ethyl acetate = 2 / 1 to 1:1) to give N-[(3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methyl-propane-2-sulfinamide (43 g, 93% yield) as a yellow solid. MS(EI)m / z:[M+H] + 431.2, 1 H NMR(400 MHz,CDCl3)δ=8.10(d,J=1.2 Hz,1H),7.85(d,J=1.2 Hz,1H),4.26-4.20(m,1H),4.10(td,J=4.4,13.2 Hz,1H),4.01(td,J=4.4,13.2 Hz,1H),3.87(d,J=9.2 Hz,1H),3.67(d,J=9.2 Hz,1H),3.51(dd,J=5.6,10.4 Hz,1H),3.35(d,J=10.4 Hz,1H),3.18-3.04(m,2H),2.07-1.93(m,2H),1.74-1.69(m,1H),1.50(d,J=7.6 Hz,1H),1.26(s,9H),1.23(d,J=6.4 Hz,3H).

[0245] 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]decan-4-yl)-2-methylpropane-2-sulfinamide A mixture of intermediate I-22 (24 g, 102 mmol), N-[(3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methyl-propane-2-sulfinamide (35.3 g, 81.8 mmol), Pd(dba) (9.37 g, 10.2 mmol), Xantphos (11.8 g, 20.5 mmol), and DIEA (39.7 g, 307 mmol) in dioxane (400 mL) was degassed and purged with N three times, then the mixture was stirred under N at 110 °C for 12 h. Upon completion of stirring, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0 / 1 to EA / MeOH = 9 / 1) to give the crude product. The residue was triturated with EA:MeOH = 3:1 (400 mL) to give intermediate I-23 (20 g, 34% yield) as a yellow solid. MS(EI)m / z:[M+H] + 563.2, 1 H NMR(400 MHz,CDCl3)δ=11.11(br s,1H),8.24(d,J=1.2 Hz,1H),8.18(d,J=1.2 Hz,1H),7.98(s,1H),7.47(d,J=8.8 Hz,1H),7.22(d,J=8.8 Hz,1H),4.30-4.22(m,2H),4.20-4.12(m,1H),3.93(d,J=9.2 Hz,1H),3.69(d,J=9.2 Hz,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=6.4 Hz,3H).

[0246] Preparation 24: Sodium 5-((3S,4S)-4-((tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazine-2-thiolate (Intermediate I-24) [ka]

[0247] Step 1: 2-Ethylhexyl 3-((5-((3S,4S)-4-((tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)propanoate A mixture of the product of Step 2 of Preparation 23 (6.0 g, 13.9 mmol), 2-ethylhexyl 3-sulfanylpropanoate (3.64 g, 16.7 mmol), Pd(dba) (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 N three times, then the mixture was stirred under a N atmosphere at 100° C. for 3 hours. Upon completion of stirring, the reaction mixture was concentrated under reduced pressure to provide 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]decan-8-yl]pyrazin-2-yl]sulfanylpropanoate (7.4 g, 91% yield) as a yellow oil. MS(EI)m / z:[M+H] + 569.3. 1 H NMR(400 MHz,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=9.2 Hz,1H),3.68(d,J=9.2 Hz,1H),3.54-3.48(m,1H),3.34(d,J=10.4 Hz,1H),3.27(t,J=7.2 Hz,2H),3.17-3.02(m,2H),2.68(t,J=7.2 Hz,2H),2.04-1.93(m,2H),1.72(d,J=13.2 Hz,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).

[0248] Step 2: Sodium 5-((3S,4S)-4-((tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazine-2-thiolate To a solution of 2-ethylhexyl 3-[5-[(3S,4S)-4-(tert-butylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-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. Upon completion of stirring, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with PE (15 mL) at 20 °C to give intermediate I-24 (1.5 g, crude) as a pale yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=7.73(d,J=1.6 Hz,1H),7.54(s,1H),4.13-4.05(m,1H),3.77(d,J=8.8 Hz,1H),3.69-3.63(m,1H),3.63-3.57(m,2H),3.48-3.42(m,1H),3.36(d,J=6.4 Hz,1H),2.65(d,J=15.6 Hz,1H),1.78-1.74(m,2H),1.56-1.52(m,1H),1.24(d,J=2.0 Hz,1H),1.18-1.11(m,9H),1.08(d,J=6.4 Hz,3H).

[0249] Preparation 25: (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (Intermediate I-25) [ka]

[0250] Step 1: tert-Butyl (R)-1-((tert-butylsulfinyl)imino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate A mixture of tert-butyl 1-oxospiro[indan-2,4'-piperidine]-1'-carboxylate (1.00 g, 3.32 mmol), (R)-2-methylpropane-2-sulfinamide (402 mg, 3.32 mmol), and Ti(OEt) (2.27 g, 9.95 mmol) in THF (5 mL) was stirred at 70 °C for 36 h. Upon completion of stirring, the reaction mixture was poured into water (10 mL) at 0 °C and filtered. The filtrate was diluted with water (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 3:1) to give tert-butyl 1-[(R)-tert-butylsulfinyl]iminospiro[indan-2,4'-piperidine]-1'-carboxylate (900 mg, yield 67%) as a yellow solid. 1 H NMR(400 MHz, CDCl3)δ=8.41(d,J=6.4 Hz,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=14.4 Hz,1H),1.32(s,9H),1.28-1.24(m,1H).

[0251] Step 2: tert-Butyl (S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate To a solution of tert-butyl 1-[(R)-tert-butylsulfinyl]iminospiro[indan-2,4'-piperidine]-1'-carboxylate (800 mg, 1.98 mmol) in THF (10 mL) was added LiBH (129 mg, 5.93 mmol) at −78° C. under N. The reaction mixture was stirred at −78 to 25° C. for 16 h. Upon completion of stirring, the reaction mixture was quenched at 0° C. by the addition of NH Cl (10 mL), then diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na SO , then filtered and concentrated under reduced pressure to give 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 min) to give tert-butyl (1S)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indan-2,4′-piperidine]-1′-carboxylate (540 mg, 67% yield) as a white solid and tert-butyl (1R)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indan-2,4′-piperidine]-1′-carboxylate (130 mg, 16% yield) as a white solid. tert-Butyl (1S)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indane-2,4'-piperidine]-1'-carboxylate was used in the next reaction. 1 H NMR(400 MHz,CDCl3)δ=7.23(d,J=6.4 Hz,1H),7.18-7.12(m,3H),4.43(d,J=9.2 Hz,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).

[0252] Step 3: (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide A mixture of tert-butyl (1S)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indan-2,4'-piperidine]-1'-carboxylate (100 mg, 245 μmol) and TFA (1 mL) in DCM (5 mL) was stirred at 0 °C for 1 h. Upon completion of stirring, the reaction mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over NaSO, then filtered and concentrated under reduced pressure to give intermediate I-25 (70 mg, 92% yield) as a colorless oil. 1 H NMR(400 MHz,CDCl3)δ=7.29(s,1H),7.26-7.19(m,3H),4.49(d,J=10.4 Hz,1H),4.01(br s,1H),3.63(d,J=10.4 Hz,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=1.6 Hz,1H).

[0253] Preparation 26: Sodium 5-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-thiolate (Intermediate I-26) [ka]

[0254] Step 1: (R)—N-((S)-1′-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropane-2-sulfinamide To a solution of intermediate I-25 (2.3 g, 7.50 mmol) in DMF (20 mL) were 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 h. Upon completion of stirring, the reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO® 40 g SepaFlash® silica 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-methyl-propane-2-sulfinamide (2 g, 55% yield) as a pale yellow solid. MS(EI) m / z: [M+H]+ 465.3; 1 H NMR(400 MHz,DMSO-d6)δ=8.20(d,J=1.2 Hz,1H),8.16(d,J=1.2 Hz,1H),7.28-7.24(m,1H),7.24-7.19(m,3H),5.65(d,J=10.4 Hz,1H),4.42(d,J=10.4 Hz,1H),4.27-4.15(m,2H),3.14(d,J=16.0 Hz,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=12.8 Hz,1H),1.30-1.24(m,1H),1.19(s,9H).

[0255] Step 2: 2-Ethylhexyl 3-((5-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)propanoate A mixture of (R)-N-[(1S)-1'-(5-bromopyrazin-2-yl)spiro[indan-2,4'-piperidin]-1-yl]-2-methyl-propane-2-sulfinamide (1 g, 2.16 mmol), 2-ethylhexyl 3-sulfanylpropanoate (565 mg, 2.59 mmol), Pd(dba) (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 N three times, then the mixture was stirred under N at 100° C. for 16 h. Upon completion of stirring, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO® 40 g SepaFlash® silica 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′-piperidin]-1′-yl]pyrazin-2-yl]sulfanylpropanoate (1.2 g, 90% yield) as a pale yellow oil. 1 H NMR(400 MHz,CDCl3)δ=8.10-8.03(m,2H),7.35-7.31(m,1H),7.27-7.22(m,3H),4.57(d,J=12.0 Hz,1H),4.23-4.16(m,2H),4.04-3.99(m,2H),3.58(d,J=12.0 Hz,1H),3.27(t,J=7.2 Hz,2H),3.18-3.03(m,3H),2.78(d,J=15.6 Hz,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).

[0256] Step 3: Sodium 5-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazine-2-thiolate To a mixture of 2-ethylhexyl 3-[5-[(1S)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indan-2,4'-piperidin]-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 stirred at 25 °C for 0.5 h. After stirring was complete, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with PE (15 mL) at 20 °C to give intermediate I-26 (110 mg, crude) as a yellow solid. MS(EI) m / z:[M+H]+438.5

[0257] Preparation 27: (4-methyltetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (Intermediate I-27) [ka]

[0258] To a solution of (4-methyltetrahydropyran-4-yl)methanol (400 mg, 3.07 mmol) in DCM (5 mL) was added TEA (932 mg, 9.22 mmol) and 4-methylbenzenesulfonyl chloride (878 mg, 4.61 mmol). The mixture was stirred at 30 °C for 12 h. Upon completion of stirring, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give intermediate I-27 (800 mg, 91% yield) as a white solid. 1H NMR(400 MHz,CDCl3)δ=7.79(d,J=8.4 Hz,2H),7.36(d,J=8.0 Hz,2H),3.77(s,2H),3.68-3.52(m,4H),2.46(s,3H),1.50(dd,J=4.4,13.6 Hz,2H),1.34-1.23(m,2H),1.03(s,3H).

[0259] Preparation 28: 6-Bromo-5-chloro-3-(2-hydroxy-2-methylpropyl)quinazolin-4(3H)-one (Intermediate I-28) [ka]

[0260] To a solution of intermediate I-21 (1 g, 3.85 mmol) in DMF (20 mL) were added CsCO (3.77 g, 11.6 mmol) and 2,2-dimethyloxirane (2.78 g, 38.5 mmol). The mixture was stirred at 60 °C for 12 h. Upon completion of stirring, the reaction mixture was quenched by adding aqueous ammonium chloride (20 mL) at 25 °C, then diluted with water (30 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash column chromatography (0.1% FA) to give intermediate I-28 (540 mg, 42% yield) as a white solid. 1 H NMR(400 MHz,CDCl3)δ=8.20(s,1H),7.97(d,J=8.8 Hz,1H),7.51(d,J=8.8 Hz,1H),4.08(s,2H),2.16-2.12(m,1H),1.33(s,6H).

[0261] Preparation 29: 6-Bromo-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one (Intermediate I-29) [ka]

[0262] To a solution of intermediate I-28 (350 mg, 1.06 mmol) in ACN (8 mL) was added AgO (1.22 g, 5.28 mmol) and MeI (749 mg, 5.28 mmol). The mixture was stirred at 25 °C for 12 h. Upon completion of stirring, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash column chromatography (0.1% FA) to give intermediate I-29 (70 mg, 19% yield) as a white solid. 1 H NMR(400 MHz, CDCl3)δ=8.22(s,1H),7.94(d,J=8.8 Hz,1H),7.49(d,J=8.8 Hz,1H),4.07(s,2H),3.21(s,3H),1.21(s,6H).

[0263] Preparation 30: 6-Bromo-5-chloro-3-(1-fluoro-2-methoxy-2-methylpropyl)quinazolin-4(3H)-one (Intermediate I-30) [ka]

[0264] Step 1: Ethyl 2-(6-bromo-5-chloro-4-oxoquinazolin-3(4H)-yl)-2-fluoroacetate To a solution of intermediate I-21 (16 g, 61.6 mmol) and K2CO3 (25.5 g, 184 mmol) in DMF (200 mL) was added ethyl 2-bromo-2-fluoroacetate (12.5 g, 67.8 mmol). The reaction mixture was stirred at 30 °C for 2 h. Upon completion of stirring, the reaction mixture was added to water (1 L) and extracted with EA (3 × 200 ml). The combined organic layers were washed with brine (2 × 200 ml), dried over Na2SO4, and concentrated under reduced pressure to give ethyl 2-(6-bromo-5-chloro-4-oxo-quinazolin-3-yl)-2-fluoroacetate (16 g, 71% yield) as a yellow solid. 1H NMR(400 MHz,DMSO-d6)δ=8.61(s,1H),8.24(d,J=8.8 Hz,1H),7.63(d,J=8.8 Hz,1H),6.96-6.74(m,1H),4.35-4.20(m,2H),1.20(t,J=7.2 Hz,3H).

[0265] Step 2: 6-Bromo-5-chloro-3-(1-fluoro-2-hydroxy-2-methylpropyl)quinazolin-4(3H)-one To a solution of ethyl 2-(6-bromo-5-chloro-4-oxo-quinazolin-3-yl)-2-fluoro-acetate (10 g, 27.5 mmol) in THF (100 mL) was added MeMgBr (3 M, 18.3 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Upon completion of stirring, the reaction mixture was added to saturated NH Cl solution (500 mL) and extracted with EA (3 × 100 mL). The combined organic layers were dried over Na SO and concentrated under reduced pressure. The crude product was purified by reverse-phase flash column chromatography (0.1% FA) to give 6-bromo-5-chloro-3-(1-fluoro-2-hydroxy-2-methyl-propyl)quinazolin-4-one (1.4 g, 14% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.48(s,1H),8.19(d,J=8.8 Hz,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=1.6 Hz,3H).

[0266] Step 3: 6-Bromo-5-chloro-3-(1-fluoro-2-methoxy-2-methylpropyl)quinazolin-4(3H)-one A solution of 6-bromo-5-chloro-3-(1-fluoro-2-hydroxy-2-methyl-propyl)quinazolin-4-one (0.3 g, 858 μmol), AgO (994 mg, 4.29 mmol), and MeI (609 mg, 4.29 mmol) in ACN (6 mL) was stirred at 60 °C for 16 h in the dark. After stirring was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1). The residue was then purified by prep-TLC (SiO, PE:EA = 6:1) to give intermediate I-30 (0.1 g, 32% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.40(s,1H),8.19(d,J=8.8 Hz,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=1.6 Hz,3H).

[0267] Preparation 31: 6-Bromo-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one (Intermediate I-31) [ka]

[0268] Step 1: 6-Bromo-3-(2-hydroxy-2-methylpropyl)quinazolin-4(3H)-one To a solution of 6-bromo-3H-quinazolin-4-one (1.00 g, 4.44 mmol) and 2,2-dimethyloxirane (3.20 g, 44.4 mmol) in DMF (10 mL) was added CsCO (4.34 g, 13.3 mmol). The mixture was stirred at 60 °C for 12 h. Upon completion of stirring, the reaction mixture was diluted with 30 mL of water and extracted with EA (3 × 50 mL). The combined organic layers were washed with aqueous NaCl (3 × 30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. Purification by column chromatography (SiO, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) afforded 6-bromo-3-(2-hydroxy-2-methyl-propyl)quinazolin-4-one (1.10 g, 83% yield) as a yellow solid. MS(EI)m / z:[M+H] + 299.0 1 H NMR(400 MHz, CDCl3)δ=8.37(d,J=2.0 Hz,1H),8.12(s,1H),7.77(dd,J=2.4,8.4 Hz,1H),7.53(d,J=8.4 Hz,1H),4.01(s,2H),1.24(s,6H).

[0269] Step 2: 6-Bromo-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one 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 μL) in ACN (5 mL) was added AgO (1.17 g, 5.05 mmol). The mixture was stirred at 60° C. for 16 h. Upon completion of stirring, the reaction mixture was dissolved in EA (50 mL) and filtered. The filtrate was concentrated under reduced pressure to give 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)]; gradient: 1%-30% B over 15 min) and prep-TLC (SiO₂, PE / EA=1 / 1) to give intermediate I-31 (85.0 mg, 27% yield) as a white solid. MS(EI)m / z:[M+H] + 311.0. 1 H NMR(400 MHz,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).

[0270] Preparation 32: 6-Bromo-5-chloro-3-phenylquinazolin-4(3H)-one (Intermediate I-32) [ka]

[0271] Step 1: Methyl 6-amino-3-bromo-2-chlorobenzoate To a solution of 6-amino-3-bromo-2-chlorobenzoic acid (5 g, 20.0 mmol) in DMF (50 mL) was added KCO (3.31 g, 24.0 mmol) and MeI (3.40 g, 24.0 mmol). The mixture was stirred at 25 °C for 12 h. Upon completion of stirring, the reaction mixture was quenched at 25 °C by the addition of 20 mL of aqueous ammonium chloride solution, diluted with water (30 mL), and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give methyl 6-amino-3-bromo-2-chlorobenzoate (5 g, 95% yield) as a yellow oil. 1 H NMR(400 MHz, CDCl3)δ=7.39(d,J=8.8 Hz,1H),6.50(d,J=8.8 Hz,1H),4.69(s,2H),3.94(s,3H).

[0272] Step 2: 6-Bromo-5-chloro-3-phenylquinazolin-4(3H)-one To a solution of methyl 6-amino-3-bromo-2-chlorobenzoate (2.0 g, 7.56 mmol) in diethoxymethoxyethane (1.68 g, 11.3 mmol) was added aniline (845 mg, 9.07 mmol) and NHCl (324 mg, 6.05 mmol). The mixture was stirred at 100 °C for 12 hours. Upon completion of stirring, the reaction mixture was diluted with ethyl acetate (30 mL) and carefully poured into 50 mL of water. The suspension was filtered, and the filter cake was washed with 50 mL of MeOH and then dried under reduced pressure to give a yellow solid. The solid was triturated with EA (30 mL) to give intermediate I-32 (900 mg, 35% yield) as a yellow solid. m / z ES+[M+H] + 336.9. 1 H NMR(400 MHz,DMSO-d6)δ=8.40(s,1H),8.18(d,J=8.8 Hz,1H),7.61(d,J=8.8 Hz,1H),7.60-7.50(m,5H).

[0273] Preparation 33: 6-Bromo-5-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one (Intermediate I-33) [ka]

[0274] To a solution of the product from Step 1 of Preparation 32 (1 g, 3.78 mmol) in diethoxymethoxyethane (840 mg, 5.67 mmol), pyridin-3-amine (427 mg, 4.54 mmol) and NH4Cl (162 mg, 3.02 mmol) were added. The mixture was stirred at 100 °C for 12 hours. Upon completion of stirring, the reaction mixture was diluted with ethyl acetate (50 mL) and carefully poured into 100 mL of water. The suspension was filtered, and the filter cake was collected to give a yellow solid. The residue was purified by preparative HPLC (column: Welch Ultimate XB-NH2 250*50*10 μm; mobile phase: [hexane-EtOH (0.1% NH3·HO)]; gradient: 1%-35% B over 25 min) to give intermediate I-33 (230 mg, 18% yield) as a yellow solid. m / z ES+[M+H] + 337.9. 1 H NMR(400 MHz,CDCl3)δ=8.75(d,J=4.8 Hz,1H),8.71-8.66(m,1H),8.11(s,1H),8.02(d,J=8.8 Hz,1H),7.85(dd,J=1.6,8.0 Hz,1H),7.57(d,J=8.8 Hz,1H),7.27(s,1H).

[0275] Preparation 34: 6-Bromo-5-chloro-3-((1-methylpiperidin-4-yl)methyl)quinazolin-4(3H)-one (Intermediate I-34) [ka]

[0276] Step 1: tert-butyl 4-((6-bromo-5-chloro-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate To a solution of intermediate I-21 (2.0 g, 7.71 mmol) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (3.22 g, 11.6 mmol) in DMF (20 mL) was added KCO (3.20 g, 23.1 mmol) and TBAI (569 mg, 1.54 mmol). The mixture was stirred at 60 °C for 12 h. Upon completion of stirring, the reaction mixture was quenched by adding aqueous ammonium chloride solution (50 mL) at 25 °C, then diluted with water (50 mL) and extracted with EA (3 × 100 mL). The collected organic layer was washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 1 to 1 / 5) to give 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. 1H NMR(400 MHz,CDCl3)δ=7.98-7.94(m,2H),7.49(d,J=8.8 Hz,1H),4.21-4.06(m,2H),3.90-3.77(m,2H),2.67(t,J=12.0 Hz,2H),2.17-2.06(m,1H),1.71-1.64(m,2H),1.45(s,9H),1.27-1.17(m,2H).

[0277] Step 2: 6-Bromo-5-chloro-3-(piperidin-4-ylmethyl)quinazolin-4(3H)-one To a solution of tert-butyl 4-[(6-bromo-5-chloro-4-oxo-quinazolin-3-yl)methyl]piperidine-1-carboxylate (2.8 g, 6.13 mmol) in DCM (30 mL) was added TFA (14.0 g, 123 mmol), and the mixture was stirred at 25 °C for 0.5 h. After stirring was complete, the reaction mixture was concentrated. The residue was basified to pH = 10 with saturated aqueous KCO solution. The suspension was filtered, and the filter cake was washed with 30 mL of water and dried under reduced pressure to give 6-bromo-5-chloro-3-(4-piperidylmethyl)quinazolin-4-one (2 g, 83% yield) as a white solid. MS(EI)m / z:[M+H] + 358.0, 1 H NMR(400 MHz,DMSO-d6)δ=8.45(s,1H),8.13(d,J=8.8 Hz,1H),7.55(d,J=8.8 Hz,1H),3.84(d,J=7.2 Hz,2H),3.07(d,J=12.0 Hz,2H),2.57(t,J=12.0 Hz,2H),2.00-1.91(m,1H),1.59(d,J=13.2 Hz,2H),1.30-1.17(m,2H).

[0278] Step 3: 6-Bromo-5-chloro-3-((1-methylpiperidin-4-yl)methyl)quinazolin-4(3H)-one To a solution of 6-bromo-5-chloro-3-(4-piperidylmethyl)quinazolin-4-one (550 mg, 1.54 mmol) and HCHO (6.26 g, 77.1 mmol, 37% purity) in MeOH (5 mL) was added HOAc (278 mg, 4.63 mmol) and NaBH(OAc) (980 mg, 4.63 mmol). The mixture was stirred at 25 °C for 2 h. Upon completion of stirring, the reaction mixture was quenched at 25 °C by the addition of aqueous NaHCO (20 mL), then diluted with water (30 mL), and extracted with DCM / MeOH (3 / 1) (3 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Al2O3, petroleum ether / ethyl acetate=0 / 1 to EA / MeOH=10 / 1) to give intermediate I-34 (450 mg, 79% yield) as a white solid. MS(EI)m / z:[M+H] + 371.8, 1 H NMR(400 MHz,DMSO-d6)δ=8.43(s,1H),8.14-8.07(m,1H),7.54(d,J=8.8 Hz,1H),3.83(d,J=7.2 Hz,2H),2.73(d,J=10.8 Hz,2H),2.11(s,3H),1.79-1.67(m,3H),1.51(d,J=11.6 Hz,2H),1.31-1.17(m,2H).

[0279] Preparation 35: (R)—N-((S)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-6-yl)-2-methylpropane-2-sulfinamide (Intermediate I-35) [ka]

[0280] Step 1: (2-chlorothiazol-4-yl)methanol To a solution of ethyl 2-chlorothiazol-4-carboxylate (90 g, 467 mmol) in EtOH (800 mL) was added NaBH (88.8 g, 2.35 mol), and the mixture was stirred at 50 °C for 2 h. Upon completion of stirring, the reaction mixture was quenched at 0 °C by the addition of aqueous ammonium chloride (300 mL), then diluted with water (500 mL), and extracted with ethyl acetate (3 × 800 mL). The collected organic layers were washed with brine (3 × 300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by MPLC (SiO, petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to give (2-chlorothiazol-4-yl)methanol (67 g, 95% yield) as a yellow oil. 1 H NMR(400 MHz, CDCl3)δ=7.12(s,1H),4.71(s,2H),2.59-2.48(m,1H).

[0281] Step 2: (2-chlorothiazol-4-yl)methyl methanesulfonate To a solution of (2-chlorothiazol-4-yl)methanol (33 g, 221 mmol) in DCM (350 mL) was added TEA (44.6 g, 441 mmol) and MsCl (35.5 g, 310 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Upon completion of stirring, the reaction mixture was quenched at 25 °C by the addition of aqueous NaHCO (100 mL), then diluted with water (100 mL) and extracted with DCM (3 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to afford (2-chlorothiazol-4-yl)methyl methanesulfonate (42 g, crude product) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ 7.36(s,1H),5.25(s,2H),3.07(s,3H).

[0282] Step 3: 1-(tert-butyl) 4-ethyl 4-((2-chlorothiazol-4-yl)methyl)piperidine-1,4-dicarboxylate O1-tert-Butyl O4-ethylpiperidine-1,4-dicarboxylate (47 g, 183 mmol) was dissolved in THF (500 mL). The solution was cooled to -60°C under a nitrogen atmosphere, and then LDA (2 M, 128 mL) was added dropwise. Upon completion of the addition, the reaction solution was stirred at -60°C for 30 minutes. A solution of (2-chlorothiazol-4-yl)methyl methanesulfonate (41.6 g, 183 mmol) in THF (150 mL) was added dropwise. Upon completion of the addition, the reaction solution was stirred at -60°C for 30 minutes, then slowly warmed to 25°C and stirred for 2 hours. Upon completion of the stirring, the reaction mixture was quenched by the addition of aqueous ammonium chloride (100 mL) at 25°C, then diluted with water (200 mL), and extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by MPLC (SiO, petroleum ether / ethyl acetate = 15 / 1 to 10 / 1) to give O1-tert-butyl O4-ethyl 4-[(2-chlorothiazol-4-yl)methyl]piperidine-1,4-dicarboxylate (31 g, 44% yield) as a yellow oil. MS(EI) m / z:[M-Boc+H] + 289.3, 1 H NMR(400 MHz,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=13.2 Hz,2H),1.51(d,J=4.0 Hz,2H),1.45(s,9H),1.26-1.22(m,3H).

[0283] Step 4: tert-Butyl 2-chloro-6-oxo-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of O1-tert-butyl O4-ethyl 4-[(2-chlorothiazol-4-yl)methyl]piperidine-1,4-dicarboxylate (62 g, 159 mmol) in THF (1100 mL) was added LDA (2 M, 199 mL), and the mixture was stirred at −70° C. for 0.5 h. Upon completion of stirring, the reaction mixture was quenched at 0° C. by the addition of aqueous ammonium chloride (100 mL), then diluted with water (200 mL), and extracted with EA (3×300 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to give a residue. The residue was purified by MPLC (SiO2, petroleum ether / ethyl acetate = 15 / 1 to 10 / 1) to give 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. 1 H NMR(400 MHz, 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).

[0284] Step 5: tert-Butyl (R,Z)-6-((tert-butylsulfinyl)imino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of tert-butyl 2-chloro-6-oxo-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (33 g, 96.3 mmol) in THF (100 mL) was added Ti(OEt) (329 g, 1.44 mol) and (R)-2-methylpropane-2-sulfinamide (58.3 g, 481 mmol). The mixture was stirred at 90 °C for 12 h. Upon completion of stirring, the reaction mixture was diluted with EA (1000 mL) and quenched by the addition of water (500 mL). The combined organic layers were washed with brine (3 × 500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by MPLC (SiO, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give 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. 1 H NMR(400 MHz, 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).

[0285] Step 6: tert-butyl (S)-6-(((R)-tert-butylsulfinyl)amino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of tert-butyl (6Z)-6-[(R)-tert-butylsulfinyl]imino-2-chloro-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (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. Upon completion of stirring, the reaction mixture was quenched at -70°C by the addition of MeOH (10 mL) and then diluted with DCM (1000 mL). The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 3 / 1 to 2 / 1) to give tert-butyl (6S)-6-[[(R)-tert-butylsulfinyl]amino]-2-chloro-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylate (28 g, 82% yield) as a yellow solid. MS(EI)m / z:[M+H] + 448.2, 1 H NMR(400 MHz,CDCl3)δ=4.52(d,J=8.8 Hz,1H),4.13-3.93(m,2H),3.59(d,J=7.6 Hz,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)

[0286] Step 7: tert-butyl (S)-6-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of tert-butyl (6S)-6-[[(R)-tert-butylsulfinyl]amino]-2-chloro-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (12 g, 26.9 mmol) in MeOH (120 mL) was added Pd / C (6.00 g, 5.65 mmol, 10% purity) and TEA (8.13 g, 80.4 mmol). The mixture was stirred at 40 °C under H (50 psi) for 12 h. Upon completion of stirring, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl (6S)-6-[[(R)-tert-butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylate (12 g, crude) as a yellow solid. MS(EI)m / z:[M+H] + 414.2, 1 H NMR(400 MHz,CDCl3)δ=8.78(s,1H),4.56(d,J=8.8 Hz,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=13.6 Hz,2H),1.47-1.45(s,9H),1.22(s,9H).

[0287] Step 8: (R)—N-((S)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidine]-6-yl)-2-methylpropane-2-sulfinamide To a solution of tert-butyl (6S)-6-[[(R)-tert-butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (8 g, 19.3 mmol) in DCM (100 mL) was added TFA (17.6 g, 155 mmol), and the mixture was stirred at 25 °C for 1 h. Upon completion of stirring, the reaction mixture was quenched at 25 °C by the addition of aqueous KCO (50 mL), then diluted with water (100 mL), and extracted with DCM (3 × 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to give intermediate I-35 (3.5 g, crude product) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=8.80-8.75(m,1H),4.60(d,J=8.8 Hz,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=2.0,12.4 Hz,1H),1.67-1.60(m,1H),1.25-1.22(s,9H).

[0288] Preparation 36: Sodium 5-((S)-4-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrazine-2-thiolate (Intermediate I-36) [ka]

[0289] 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. MS(EI) m / z:[M-Na] + 424.2

[0290] Preparation 37: (R)-2-methyl-N-[(4S)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidin]-4-yl]propane-2-sulfinamide (Intermediate I-37) [ka]

[0291] Step 1: 1-(tert-butyl) 4-ethyl 4-((2-chlorothiazol-5-yl)methyl)piperidine-1,4-dicarboxylate To a mixture of O1-tert-butyl O4-ethylpiperidine-1,4-dicarboxylate (30.3 g, 118 mmol) in THF (200 mL) was added LDA (2 M, 64.3 mL) at −70° C. 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 completed, the reaction mixture was poured into saturated NH4Cl (300 mL) solution and then extracted with EA (3 × 200 mL). The organic layer was washed with brine (2 × 200 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 give O1-tert-butyl O4-ethyl 4-[(2-chlorothiazol-5-yl)methyl]piperidine-1,4-dicarboxylate (25 g, 60% yield) as a yellow oil. 1 HNMR(400 MHz,CDCl3)δ=7.22(s,1H),4.18(q,J=7.2 Hz,2H),3.97-3.77(m,2H),3.00(s,2H),2.95(s,2H),2.11(d,J=13.2 Hz,2H),1.46(s,9H),1.41(d,J=4.4 Hz,2H),1.26(t,J=7.2 Hz,3H).

[0292] Step 2: tert-Butyl 2-chloro-4-oxo-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a mixture of O1-tert-butyl O4-ethyl 4-[(2-chlorothiazol-5-yl)methyl]piperidine-1,4-dicarboxylate (15 g, 38.6 mmol) in THF (350 mL) was added LDA (2 M, 30.9 mL) at −70° C. The mixture was stirred at −70° C. for 1 h. Upon completion of stirring, the reaction mixture was poured into saturated NH4Cl (500 mL) solution at 0° C. and then extracted with EA (3×100 mL). The organic layer was washed with brine (2×200 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 give tert-butyl 2-chloro-4-oxo-spiro[6H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (4.0 g, 30% yield) as a yellow solid. 1 HNMR(400 MHz,CDCl3)δ=4.26-4.03(m,2H),3.11(s,2H),2.99(t,J=12.0 Hz,2H),2.03-1.92(m,2H),1.55-1.51(m,1H),1.48(s,9H),1.47-1.44(m,1H).

[0293] Step 3: tert-Butyl (R,Z)-4-((tert-butylsulfinyl)imino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of tert-butyl 2-chloro-4-oxo-spiro[6H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (4 g, 11.7 mmol) in THF (40 mL) was added (R)-2-methylpropane-2-sulfinamide (5.66 g, 46.7 mmol), Ti(OEt) (39.9 g, 175 mmol), and the mixture was stirred at 95 °C for 16 h. Upon completion of stirring, the reaction mixture was diluted with EtOAc (150 mL) and quenched by the addition of 200 mL of water. The mixture was filtered and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 4 / 1) to give tert-butyl (4Z)-4-[(R)-sulfinyl]imino-2-chloro-spiro[6H-cyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylate (4.3 g, 76% yield) as a pale yellow solid. MS(EI)m / z:[M+H] + 446.2, 1 H NMR(400 MHz,CDCl3)δ=4.17(d,J=12.0 Hz,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).

[0294] Step 4: tert-butyl (S)-4-(((R)-tert-butylsulfinyl)amino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of tert-butyl (4Z)-4-[(R)-tert-butylsulfinyl]imino-2-chloro-spiro[6H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (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. Upon completion of stirring, the reaction mixture was quenched at 0 °C by the addition of MeOH (2 mL) and then diluted with DCM (100 mL). The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 1 to 1 / 3) to give tert-butyl (4S)-4-[[(R)-tert-butylsulfinyl]amino]-2-chloro-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (1.25 g, 62% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=4.40(d,J=9.2 Hz,1H),4.05-3.87(m,2H),3.09-3.01(m,2H),2.89-2.73(m,2H),1.97(t,J=9.6 Hz,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).

[0295] Step 5: tert-butyl (S)-4-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of tert-butyl (4S)-4-[[(R)-tert-butylsulfinyl]amino]-2-chloro-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (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 an atmosphere of H (50 psi) at 40° C. for 12 h. Upon completion of stirring, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash chromatography (0.1% FA) to give tert-butyl (4S)-4-[[(R)-tert-butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylate (0.88 g, 79% yield) as a yellow solid. 1 H NMR(400 MHz, CDCl3)δ=8.72(s,1H),4.47(d,J=9.0 Hz,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).

[0296] Step 6: (R)—N-((S)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidine]-4-yl)-2-methylpropane-2-sulfinamide To a solution of tert-butyl (4S)-4-[[(R)-tert-butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (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. Upon completion of stirring, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was then quenched by the addition of aqueous KCO solution (2 mL) at 25 °C, diluted with water (5 mL), and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to give intermediate I-37 (260 mg, crude product) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=8.74(s,1H),4.49(d,J=9.2 Hz,1H),3.84(d,J=8.8 Hz,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=13.2 Hz,1H),1.57(d,J=14.0 Hz,1H),1.28(s,9H).

[0297] Preparation 38: Sodium 5-((S)-4-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrazine-2-thiolate (Intermediate I-38) [ka]

[0298] 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. MS(EI) m / z:[M-Na] + 424.5

[0299] Preparation 39: Sodium 3-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-1,2,4-triazine-6-thiolate (Intermediate I-39) [ka]

[0300] Step 1: 3,6-Dibromo-1,2,4-triazine To a solution of 6-bromo-1,2,4-triazin-3-amine (2 g, 11.4 mmol) in MeCN (20 mL) was added tert-butyl nitrite (1.89 g, 18.3 mmol) and CuBr (3.32 g, 14.9 mmol). The mixture was stirred at 70 °C for 2 h. After stirring was complete, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give 3,6-dibromo-1,2,4-triazine (1.25 g, 46% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ=8.55(s,1H)

[0301] 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-sulfinamide To a solution of intermediate I-25 (500 mg, 1.19 mmol) in dioxane (8 mL), DIEA (1.54 g, 11.9 mmol) and 3,6-dibromo-1,2,4-triazine (284 mg, 1.19 mmol) were added. The mixture was stirred at 60 °C for 1 h. Upon completion of stirring, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 3 / 1 to 2 / 1) to give (R)-N-[(1S)-1'-(6-bromo-1,2,4-triazin-3-yl)spiro[indan-2,4'-piperidin]-1-yl]-2-methyl-propane-2-sulfinamide (510 mg, 92% yield) as a yellow solid. m / z ES+[M+H] + 466.0 1 H NMR(400 MHz,CDCl3)δ=8.12(s,1H),7.34-7.29(m,1H),7.27-7.21(m,3H),4.78-4.65(m,2H),4.57(d,J=10.4 Hz,1H),3.58(d,J=10.4 Hz,1H),3.27-3.18(m,2H),3.16-2.95(m,1H),2.81(d,J=15.6 Hz,1H),2.31(dt,J=4.4,12.4 Hz,1H),1.84(dt,J=4.4,12.4 Hz,1H),1.70(dd,J=2.0,13.6 Hz,1H),1.38(dd,J=2.0,13.6 Hz,1H),1.30(s,9H)

[0302] Step 3 and Step 4: Sodium 3-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-1,2,4-triazine-6-thiolate Using (R)-N-((S)-1'-(6-bromo-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide as a starting material, intermediate I-39 (170 mg, 80%) was obtained as a yellow solid in a manner similar to that of Steps 2 and 3 of Preparation Example 26. MS(EI)m / z:[M+H] + 418.1

[0303] Preparation 40: N-((S)-1'-(3-(hydroxymethyl)-5-mercapto-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (Intermediate I-40) [ka]

[0304] Step 1: Ethyl 6-bromo-3-((1S)-1-((tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-methylpyrazine-2-carboxylate To a solution of ethyl 6-bromo-3-chloro-5-methyl-pyrazine-2-carboxylate (0.3 g, 1.07 mmol) in DMA (6 mL) were added DIEA (694 mg, 5.37 mmol) and intermediate I-25 (361 mg, 859 μmol). The mixture was stirred at 60° C. for 4 hours. Upon completion of stirring, the reaction mixture was quenched at 25° C. by the addition of aqueous ammonium chloride solution, then diluted with water (30 mL) and extracted with EA (3×50 mL). The combined organic layer was washed with brine (3×20 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 3 / 1 to 2 / 1) to give ethyl 6-bromo-3-[(1S)-1-(tert-butylsulfinylamino)spiro[indan-2,4'-piperidin]-1'-yl]-5-methyl-pyrazine-2-carboxylate (450 mg, 76% yield) as a yellow solid. MS(EI)m / z:[M+H] + 551.1. 1H NMR(400 MHz,CDCl3)δ=7.32(d,J=7.2 Hz,1H),7.29-7.26(m,1H),7.25-7.21(m,2H),4.53(d,J=9.6 Hz,1H),4.40(q,J=7.2 Hz,2H),3.94(d,J=13.2 Hz,1H),3.85(d,J=13.2 Hz,1H),3.54(d,J=9.6 Hz,1H),3.31-3.20(m,2H),3.15(d,J=16.0 Hz,1H),2.80(d,J=16.0 Hz,1H),2.53(s,3H),2.20(dt,J=4.4,12.4 Hz,1H),1.86(dt,J=4.4,12.4 Hz,1H),1.65-1.59(m,1H),1.43-1.35(m,4H),1.28(s,9H).

[0305] 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-sulfinamide To a solution of ethyl 6-bromo-3-[(1S)-1-(tert-butylsulfinylamino)spiro[indan-2,4'-piperidin]-1'-yl]-5-methyl-pyrazine-2-carboxylate (600 mg, 1.09 mmol) in DCM (15 mL) was added DIBAL-H (1 M, 4.37 mL), and the mixture was stirred at -65 °C for 3 h. Upon completion of stirring, the reaction mixture was quenched by the addition of MeOH (1 mL) below -60 °C and then extracted with EA (50 mL). The suspension was allowed to warm to room temperature. The suspension was then filtered through a Celite pad, and the filter cake was washed with EA (3 x 30 mL). The combined filtrates were concentrated and dried to give a residue. Purification by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) gave N-[(1S)-1'-[5-bromo-3-(hydroxymethyl)-6-methyl-pyrazin-2-yl]spiro[indan-2,4'-piperidin]-1-yl]-2-methyl-propane-2-sulfinamide (410 mg, 74% yield) as a yellow solid. MS(EI)m / z:[M+H] +507.1 1 H NMR(400 MHz,CDCl3)δ=7.33(d,J=7.6 Hz,1H),7.27-7.20(m,3H),4.67(s,2H),4.57(d,J=10.0 Hz,1H),3.59(d,J=10.0 Hz,1H),3.57-3.51(m,1H),3.50-3.43(m,2H),3.16-2.99(m,3H),2.75(d,J=15.8 Hz,1H),2.55(s,3H),2.36(dt,J=4.0,12.4 Hz,1H),1.99(dt,J=4.0,12.4 Hz,1H),1.66(dd,J=2.4,13.2 Hz,1H),1.40(dd,J=2.4,13.2 Hz,1H),1.30(s,9H).

[0306] Step 3 and Step 4: N-((S)-1'-(3-(hydroxymethyl)-5-mercapto-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide Starting from N-((S)-1'-(5-bromo-3-(hydroxymethyl)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide, intermediate I-40 (200 mg, 70%) was obtained as a yellow solid in a similar manner to steps 2 and 3 of Preparation Example 26. MS(EI)m / z:[M+H] + 461.1

[0307] Preparation 41: 6-((3-amino-5-chloropyrazin-2-yl)thio)-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one (Intermediate I-41) [ka]

[0308] Step 1 and Step 2: Sodium 5-chloro-3-(2-methoxy-2-methylpropyl)-4-oxo-3,4-dihydroquinazoline-6-thiolate 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 in a similar manner to Steps 2 and 3 of Preparation 26. MS(EI)m / z:[M+H] + 299.1

[0309] Step 3: 6-((3-amino-5-chloropyrazin-2-yl)thio)-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one A mixture of [3-(2-methoxy-2-methyl-propyl)4-oxo-quinazolin-6-yl]sulfanyl sodium (330 mg, 1.15 mmol), 3-bromo-6-chloro-pyrazin-2-amine (216 mg, 1.04 mmol), Pd(dba) (106 mg, 115 μmol), Xantphos (133 mg, 231 μmol), and DIEA (447 mg, 3.46 mmol) in dioxane (10 mL) was degassed and purged with N three times, then the mixture was stirred under N atmosphere at 100° C. for 1 h. Upon completion of stirring, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-CN 250*50*10 μm; mobile phase: [hexane-EtOH (0.1% NH3·H2O)]; gradient: 1%-40% B over 15 min) to give intermediate I-41 (150 mg, 31% yield) as a yellow solid. MS(EI)m / z:[M+H] + 426.0 1 H NMR(400 MHz, 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).

[0310] Preparation 42: 7-Bromo-8-chloroisoquinolin-1(2H)-one (Intermediate I-42) [ka]

[0311] Step 1: (E)-1-(3-bromo-2-chlorophenyl)-N-(2,2-dimethoxyethyl)methanimine To a mixture of 3-bromo-2-chloro-benzaldehyde (14 g, 63.7 mmol) in toluene (200 mL), 2,2-dimethoxyethanamine (6.71 g, 63.7 mmol) was added and stirred for 64 hours at 125° C. After stirring was complete, the reaction mixture was concentrated under reduced pressure to give (E)-1-(3-bromo-2-chloro-phenyl)-N-(2,2-dimethoxyethyl)methanimine (19 g, 97% yield) as a yellow oil. 1 H NMR(400 MHz,DMSO-d6)δ=8.68(s,1H),7.94-7.86(m,2H),7.34(t,J=7.6 Hz,1H),4.64(t,J=5.4 Hz,1H),3.78(d,J=5.4 Hz,2H),3.30(s,6H).

[0312] Step 2: 7-Bromo-8-chloroisoquinoline To a mixture of (E)-1-(3-bromo-2-chloro-phenyl)-N-(2,2-dimethoxyethyl)methanimine (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 h. The reaction mixture was then cooled to 25 °C and stirred at 25 °C for 0.5 h. Upon completion of stirring, MeOH (200 mL) was added to the reaction mixture. The mixture was poured into NH 3 HO (200 mL) and extracted with EA (3 × 300 mL). The organic layer was concentrated under reduced pressure. The residue was triturated with water at 25 °C for 30 min to give 7-bromo-8-chloro-isoquinoline (820 mg, 51% yield) as a brown solid. 1H NMR(400 MHz,DMSO-d6)δ=9.56(s,1H),8.68(d,J=5.6 Hz,1H),8.06(d,J=8.8 Hz,1H),7.96-7.94(m,2H).

[0313] Step 3: 7-Bromo-8-chloroisoquinoline 2-oxide To a mixture of 7-bromo-8-chloroisoquinoline (820 mg, 3.38 mmol) in DCM (20 mL), m-CPBA (1.37 g, 6.76 mmol, 85% purity) was added and stirred at 25 °C for 16 h. After stirring was complete, Na2O3S2 (50 mL) was added to the mixture. The mixture was concentrated under reduced pressure. The residue was extracted with EA (3 × 40 mL). The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EA / MeOH = 1 / 0 / 0 to 0 / 10 / 1) to give 7-bromo-8-chloro-2-oxide-isoquinolin-2-ium (690 mg, 78% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.88(s,1H),8.32(d,J=7.2 Hz,1H),8.06(d,J=7.2 Hz,1H),7.90(s,2H)

[0314] Step 4: 7-Bromo-8-chloroisoquinolin-1(2H)-one A mixture of 7-bromo-8-chloro-2-oxide-isoquinolin-2-ium (640 mg, 2.48 mmol) in AcO (6 mL) was stirred at 120 °C for 3 h. After stirring was complete, the mixture was concentrated under reduced pressure to give (7-bromo-8-chloro-1-isoquinolyl)acetate (640 mg, crude product). A mixture of (7-bromo-8-chloro-1-isoquinolyl)acetate (640 mg, 2.13 mmol) in a mixture of NaOH (2 M, 32.00 mL) and HO (8 mL) was stirred at 100 °C for 1 h. After stirring was complete, the mixture was acidified to pH 6 with citric acid (5% in water) and extracted with DCM (3 × 100 mL). The combined organic layers were concentrated under reduced pressure to give intermediate I-42 (320 mg, 58% yield) as a yellow solid. 1H NMR(400 MHz,CDCl3)δ=10.76-10.32(m,1H),7.86(d,J=8.4 Hz,1H),7.32(d,J=8.4 Hz,1H),7.19(d,J=6.8 Hz,1H),6.48(d,J=7.2 Hz,1H).

[0315] Preparation 43: 7-Bromo-8-chloro-2-methylisoquinolin-1(2H)-one (Intermediate I-43) [ka]

[0316] To a solution of intermediate I-42 (1.0 g, 3.87 mmol) and CHI (1.10 g, 7.74 mmol) in DMF (10 mL) was added KCO (1.60 g, 11.6 mmol) and TBAI (143 mg, 387 μmol). The mixture was stirred at 40 °C for 2 h. Upon completion of stirring, the reaction mixture was quenched by adding aqueous ammonium chloride (20 mL) at 25 °C, then diluted with water (30 mL), and extracted with EA (3 × 50 mL). The combined organic layer was washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to give intermediate I-43 (1.0 g, 95% yield) as a yellow solid. MS(EI)m / z:[M+H] + 274.0. 1 H NMR(400 MHz, 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).

[0317] Preparation Examples 44-46 Intermediates I-44 to I-46 were prepared in the same manner as in Preparation 43 using Intermediate I-42 as the starting material, except that the appropriate alkyl halide was used.

[0318] [Table 1]

[0319] Preparation 47: 7-Bromo-2-(2-methoxy-2-methylpropyl)isoquinolin-1(2H)-one (Intermediate I-47) [ka]

[0320] 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. m / z ES+[M+H] + 310.0. 1 H NMR(400 MHz,CDCl3)δ=8.57(d,J=2.0 Hz,1H),7.71(dd,J=2.0,8.4 Hz,1H),7.38(d,J=8.4 Hz,1H),7.30(d,J=7.6 Hz,1H),6.40(d,J=7.6 Hz,1H),4.10(s,2H),3.23(s,3H),1.21(s,6H).

[0321] Preparation 48: 7-Bromo-2-methylisoquinolin-1(2H)-one (Intermediate I-48) [ka] To a solution of 7-bromoisoquinolin-1-ol (600 mg, 2.68 mmol) in DMA (8 mL) were added CsCO (2.62 g, 8.03 mmol) and MeI (760 mg, 5.36 mmol). The mixture was stirred at 50 °C for 3 h. Upon completion of stirring, the reaction mixture was quenched by adding aqueous ammonium chloride (20 mL) at 25 °C, then diluted with water (30 mL), and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to give intermediate I-48 (600 mg, 94% yield) as a white solid. MS(EI)m / z:[M+H] + 238.0 1 H NMR(400 MHz,CDCl3)δ=8.57(d,J=1.6 Hz,1H),7.71(dd,J=1.6,8.4 Hz,1H),7.39(d,J=8.4 Hz,1H),7.09(d,J=7.2 Hz,1H),6.45(d,J=7.2 Hz,1H),3.61(s,3H).

[0322] Preparation 49: 7-((3-amino-5-chloropyrazin-2-yl)thio)-8-chloro-2-methylisoquinolin-1(2H)-one (Intermediate I-49) [ka]

[0323] 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. MS(EI)m / z:[M+H] + 352.9 1H NMR(400 MHz,CDCl3)δ=7.91(s,1H),7.32(s,2H),7.14(d,J=7.2 Hz,1H),6.40(d,J=7.2 Hz,1H),5.24-5.15(m,2H),3.58(s,3H)

[0324] Preparation Examples 50 and 51 Intermediates I-50 and I-51 were prepared in the same manner as in Preparation 49, using the appropriate intermediates as starting materials.

[0325] [Table 2]

[0326] Preparation 52: (R)-2-methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfinamide (Intermediate I-52) [ka]

[0327] Step 1: tert-Butyl (R,E)-3-((tert-butylsulfinyl)imino)-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate In Step 1 of Preparation 25, tert-butyl 3-oxospiro[benzofuran-2,4'-piperidine]-1'-carboxylate was used instead of tert-butyl 1-oxospiro[indan-2,4'-piperidine]-1'-carboxylate to give (R,E)-3-((tert-butylsulfinyl)imino)-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate (5.4 g, 80% yield). m / z ES+[M+Na] + 429.2. 1H NMR(400 MHz,DMSO-d6)δ=8.28-8.20(m,1H),7.71-7.64(m,1H),7.23(d,J=8.4 Hz,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).

[0328] Step 2: tert-butyl (R)-3-(((R)-tert-butylsulfinyl)amino)-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate To a solution of tert-butyl rac-(3E)-3-[(R)-tert-butylsulfinyl]iminospiro[benzofuran-2,4'-piperidine]-1'-carboxylate (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. Upon completion of stirring, the reaction mixture was quenched at -78°C by the addition of MeOH (10 mL), 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 provide a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 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. m / z ES+[M+Na] + 431.1. 1 H NMR(400 MHz,CDCl3)δ=7.29(s,1H),7.26-7.20(m,1H),6.94-6.90(m,1H),6.82(d,J=8.0 Hz,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).

[0329] Step 3: (R)-2-methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfinamide Intermediate I-52 (2.2 g, 65% yield) was obtained in a similar manner to Step 3 of Preparation Example 25. m / z ES+[M+H] + 309.1

[0330] Preparation 53: Sodium 5-((R)-3-(((R)-tert-butylsulfinyl)amino)-3H-spiro[benzofuran-2,4'-piperidine]-1'-yl)pyrazine-2-thiolate (Intermediate I-53) [ka]

[0331] Intermediate I-52 was used in place of Intermediate I-25 in Step 1 of Preparative Example 26 to give Intermediate I-53 (3.15 g, 85% yield). m / z ES+[M+Na] + 441.1

[0332] Preparation 54: 6-Bromo-5-chloro-3-methylquinazolin-4(3H)-one (Intermediate I-54) [ka]

[0333] Intermediate I-21 was used in place of Intermediate I-42 in Preparation 43 to give Intermediate I-54 (2.5 g, 79% yield). 1 H NMR(400 MHz,DMSO-d6)δ=8.45(s,1H),8.10(d,J=8.8 Hz,1H),7.54(d,J=8.8 Hz,1H),3.45(s,3H).

[0334] Preparation 55: 6-Bromo-5-chloro-3-(methyl-d3)quinazolin-4(3H)-one [ka]

[0335] In Preparation 54, CD3I was used instead of CH3I to give intermediate I-55 (100 mg, 75% yield). 1 H NMR(400 MHz,DMSO-d6)δ=10.01(s,1H),7.73(d,J=8.8 Hz,1H),7.52(d,J=8.8 Hz,1H) m / z ES+[M+H] + 275.9

[0336] Example 1: (S)-6-((5-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloroquinazolin-4(3H)-one [ka]

[0337] To a solution of intermediate I-4 (50 mg, 83.0 μmol) in methanol (5 mL), HCl / dioxane (4 M, 1.04 mL) was added, and the mixture was stirred at 25° C. for 0.5 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. The filtrate was purified by column chromatography to give Example 1 (30 mg, 73% yield) as a yellow solid. 1 H NMR(400 MHz,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=8.8 Hz,1H),7.21(d,J=8.8 Hz,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=13.2 Hz,2H),1.89-1.80(m,1H),1.71-1.60(m,3H);MS(EI)m / z:481.1 [M-NH2] + .

[0338] Example 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 [ka]

[0339] Step 1: (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 To a solution of intermediate I-4 (45 mg, 74.7 μmol) in DMF (1 mL) were added methyl iodide (15.9 mg, 112 μmol), KCO (31.0 mg, 224 μmol), and TBAI (2.76 mg, 7.47 mmol), and the mixture was stirred at 25 °C for 2 h. The reaction was quenched with aqueous NaHCO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The residue was purified by column chromatography to give 15 mg (33% yield) of (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 as a yellow solid. 1H NMR(400 MHz,DMSO-d6)δ=9.06(s,1H),8.50(s,1H),8.35(s,1H),8.31(s,1H),7.50(d,J=8.8 Hz,1H),7.18(d,J=8.8 Hz,1H),5.97(d,J=10.0 Hz,1H),4.51(d,J=10.0 Hz,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).

[0340] 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 The compound of Example 2 (5 mg, yield 40%) was synthesized in the same manner as in Example 1. 1 H NMR(400 MHz,DMSO-d6)δ=8.99(s,1H),8.49(d,J=1.2 Hz,1H),8.36(s,1H),8.30(d,J=1.2 Hz,1H),8.23(s,1H),7.51(d,J=8.8 Hz,1H),7.20(d,J=8.8 Hz,1H),4.28-4.15(m,2H),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] + .

[0341] Examples 3 to 5 The compounds of Examples 3 to 5 were prepared in the same manner as in Example 2, except that an appropriate alkyl halide compound was used instead of (1R)-1-(3-bromophenyl)ethanamine.

[0342] [Table 3]

[0343] Example 6: (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 [ka]

[0344] 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′-piperidine]-5-yl)-2-methylpropane-2-sulfinamide 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), KCO (86.4 mg, 625 μmol), [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (16.2 mg, 20.8 μmol), and RuPhos (19.4 mg, 41.7 μmol) were added. The mixture was stirred at 100° C. for 12 hours. Upon completion of the reaction, the reaction mixture was quenched by adding aqueous ammonium chloride solution (20 mL) at 25° C., then diluted with water (20 mL), and extracted with EA (3×30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 1 to 1 / 4) to give (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-sulfinamide (70.0 mg, 55% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=8.47(d,J=4.4 Hz,1H),8.29(d,J=1.2 Hz,1H),8.24(d,J=1.2 Hz,1H),8.03-8.00(m,2H),7.46(d,J=8.8 Hz,1H),7.30(s,1H),7.20(dd,J=5.2,7.6 Hz,1H),4.33-4.24(m,2H),3.57(s,4H),3.34-3.24(m,4H),2.94(d,J=16.4 Hz,1H),1.80-1.75(m,2H),1.46(d,J=12.0 Hz,2H),1.27(s,9H).

[0345] Step 2: (S)-6-((5-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-methylquinazolin-4(3H)-one The compound of Example 6 (25.6 mg, yield 62%) was synthesized in the same manner as in Example 1. 1 H NMR(400 MHz,DMSO-d6)δ=8.49(s,1H),8.38-8.29(m,3H),7.68(d,J=7.6 Hz,1H),7.52(d,J=8.8 Hz,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=16.4 Hz,1H),2.80(d,J=16.0 Hz,1H),1.85-1.70(m,2H),1.62-1.53(m,1H),1.20(d,J=13.2 Hz,1H);MS(EI)m / z:506.2 [M+H] + .

[0346] Example 7: (S)-6-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-methylquinazolin-4(3H)-one [ka]

[0347] The compound of Example 7 (32 mg, yield 77%) was synthesized in the same manner as in Example 6, except that in Step 1 of Example 6, intermediate I-13 was used as a starting material instead of intermediate I-12. 1H NMR(400 MHz,DMSO-d6)δ=8.49(s,1H),8.38-8.36(m,1H),8.31(d,J=0.8 Hz,1H),8.27(s,1H),7.52(d,J=8.8 Hz,1H),7.39-7.36(m,1H),7.24-7.20(m,4H),4.30(d,J=13.6 Hz,2H),4.01(s,1H),3.45(s,3H),3.24(d,J=12.0 Hz,2H),3.13(d,J=15.6 Hz,1H),2.76(d,J=15.6 Hz,1H),1.82-1.68(m,2H),1.55(d,J=12.8 Hz,1H),1.29-1.24(m,1H);MS(EI)m / z:506.1 [M+H] + .

[0348] Example 8: (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 [ka]

[0349] 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-sulfinamide To a solution of intermediate I-6 (50 mg, 126 μmol) in DMSO (1 mL), DIEA (811 mg, 6.28 mmol) and intermediate I-13 (38.5 mg, 126 μmol) were added, and the mixture was stirred at 100° C. for 12 hours. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The residue was purified by column chromatography to give (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-sulfinamide (15 mg, 33% yield) as a yellow solid. 1 H NMR(400 MHz,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=8.8 Hz,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=15.6 Hz,1H),1.89-1.86(m,1H),1.75-1.69(m,1H),1.42-1.36(m,2H),1.31(s,9H).

[0350] Step 2: (S)-6-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazolin-4(3H)-one The compound of Example 8 (25 mg, yield 59%) was synthesized in the same manner as in Example 1. 1H NMR(400 MHz,CDCl3)δ=8.02(s,1H),7.69(s,1H),7.46(d,J=8.8 Hz,1H),7.34(d,J=5.2 Hz,1H),7.26-7.22(m,3H),7.17(d,J=8.8 Hz,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=4.8 Hz,2H),3.33(s,3H),3.27-3.17(m,2H),3.11(d,J=15.6 Hz,1H),2.75(d,J=15.6 Hz,1H),1.87(d,J=4.4 Hz,1H),1.86-1.73(m,2H),1.39(d,J=12.0 Hz,1H);MS(EI)m / z:564.3 [M+H] + .

[0351] Example 9: 6-((3-amino-5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxypropyl)quinazolin-4(3H)-one [ka]

[0352] The compound of Example 9 (5.10 mg, yield 20%) was synthesized in the same manner as in Example 6, except that in Step 1 of Example 6, Intermediate I-7 was used as a starting material instead of Intermediate I-6. 1H NMR(400 MHz,CDCl3)δ=8.03(s,1H),7.68(s,1H),7.42(d,J=7.2 Hz,2H),7.31-7.28(m,1H),7.26(s,2H),7.15(d,J=8.8 Hz,1H),4.96(d,J=11.6 Hz,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=3.2 Hz,3H),3.22-3.16(m,2H),3.12(s,1H),2.87-2.80(m,1H),1.62-1.58(m,2H),1.52-1.46(m,2H),1.26(d,J=2.0 Hz,3H);MS(EI)m / z:578.3 [M+H] + .

[0353] Example 10: (S)-6-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-methylquinazolin-4(3H)-one [ka]

[0354] The compound of Example 10 (5.85 mg, yield 13%) was synthesized in the same manner as in Example 6, except that in Step 1 of Example 6, intermediate I-15 was used as a starting material instead of intermediate I-6. 1 H NMR(400 MHz,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=8.8 Hz,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] + .

[0355] Example 11: (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 [ka]

[0356] 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-sulfinamide In Step 1 of Example 8, using intermediate I-17 instead of intermediate I-6 as the starting material, (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 (90 mg, yield 50%) was synthesized in the same manner as in Example 8. 1 H NMR(400 MHz,CDCl3)δ=7.86(s,1H),7.54(s,1H),7.39(d,J=8.8 Hz,1H),7.27-7.23(m,2H),7.17(s,2H),7.02(d,J=8.4 Hz,1H),4.52(d,J=10.0 Hz,1H),4.18(dd,J=4.0,8.4 Hz,2H),3.80(d,J=10.0 Hz,1H),3.11-2.95(m,4H),2.72-2.63(m,2H),2.26-2.19(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] + .

[0357] 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-sulfinamide 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 h. Upon completion of the reaction, the reaction mixture was quenched by adding aqueous ammonium chloride solution (20 mL) at 25° C., then diluted with water (30 mL) and extracted with EA (3×20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give (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-sulfinamide (15.0 mg, 38% yield) as a yellow solid. 1H NMR(400 MHz,DMSO-d6)δ=8.20(s,1H),7.68(s,1H),7.51(d,J=8.8 Hz,1H),7.26(s,2H),7.24-7.22(m,1H),7.20-7.17(m,2H),6.98(d,J=8.8 Hz,1H),6.17(s,2H),4.82(s,1H),4.06(s,2H),3.96(s,2H),3.25(d,J=11.2 Hz,2H),3.17(d,J=5.2 Hz,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).

[0358] Step 3: (S)-6-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-hydroxy-2-methylpropyl)quinazolin-4(3H)-one In the same manner as in Example 1, the compound of Example 11 (4.63 mg, yield 36%) was synthesized. 1 H NMR(400 MHz,DMSO-d6)δ=8.20-8.17(m,1H),7.69(s,1H),7.52(d,J=8.8 Hz,1H),7.44-7.39(m,1H),7.29-7.23(m,3H),6.98(d,J=8.8 Hz,1H),6.16(s,2H),4.82(s,1H),4.25(d J=12.0 Hz,2H),4.12(s,1H),3.95(s,2H),3.15(d,J=2.4 Hz,4H),2.85-2.81(m,2H),1.77-1.66(m,2H),1.54-1.49(m,1H),1.32(d,J=14.8 Hz,1H),1.11(s,6H);MS(EI)m / z:578.3 [M+H] + .

[0359] Example 12: 6-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-benzyl-5-chloroquinazolin-4(3H)-one [ka]

[0360] The compound of Example 12 (12.1 mg, yield 23%) was synthesized in the same manner as in Step 1 of Example 6, except that in Step 1 of Example 6, intermediate I-16 was used instead of intermediate I-6 and (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine was used as the starting material instead of intermediate I-13. 1 H NMR(400 MHz,DMSO-d6)δ=8.55(s,1H),7.66(s,1H),7.55-7.52(m,1H),7.35(d,J=4.4 Hz,4H),7.30(d,J=4.4 Hz,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=8.4 Hz,2H),3.51(d,J=8.4 Hz,2H),2.96(d,J=5.2 Hz,1H),1.76-1.69(m,1H),1.67-1.60(m,1H),1.56-1.45(m,2H),1.09(d,J=6.4 Hz,3H);MS(EI)m / z:564.2 [M+H] + .

[0361] Example 13: 6-((3-amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-benzyl-5-chloroquinazolin-4(3H)-one [ka]

[0362] The compound of Example 13 (15.1 mg, yield 60%) was synthesized in the same manner as in Example 6, except that in Step 1 of Example 6, intermediate I-16 was used instead of intermediate I-6, and tert-butyl N-[(4-methyl-4-piperidyl)methyl]carbamate was used as the starting material instead of intermediate I-13. 1 H NMR(400 MHz,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=8.8 Hz,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] + .

[0363] Example 14: 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-8-chloro-2-(2-methoxypropyl)isoquinolin-1(2H)-one [ka]

[0364] 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]decan-4-yl)carbamate Intermediate I-9 (150 mg, 0.58 mmol), Intermediate I-8 (235 mg, 0.58 mmol), Pd(dba) (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 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by preparative HPLC and concentrated to give 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]decan-4-yl)carbamate (100 mg, 30% yield). 1 H NMR(400 MHz,CDCl3)δ=10.28-10.14(m,1H),8.25(s,1H),8.18(s,1H),7.24(s,1H),7.14(d,J=8.4 Hz,1H),7.06(d,J=4.0 Hz,1H),6.38(d,J=7.2 Hz,1H),4.28-4.22(m,2H),4.16(d,J=13.6 Hz,1H),3.92(d,J=9.2 Hz,1H),3.68(d,J=9.2 Hz,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=6.4 Hz,3H).

[0365] 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]decan-4-yl)carbamate 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]decan-4-yl)carbamate (50 mg, 88.9 μmol) in DMF (2 mL) were added 2-methoxypropyl 4-methylbenzenesulfonate (65.1 mg, 266 μmol), KCO (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, which was then extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The residue was purified by column chromatography to give 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]decan-4-yl)carbamate (40 mg, 70% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=8.22(d,J=14.8 Hz,1H),7.82(d,J=8.0 Hz,2H),7.36(d,J=8.0 Hz,2H),7.18-7.14(m,1H),6.32(d,J=7.2 Hz,1H),4.32(dd,J=2.4,13.2 Hz,1H),4.26-4.22(m,1H),4.20-4.12(m,1H),3.96(d,J=5.2 Hz,2H),3.92(d,J=9.2 Hz,1H),3.82-3.74(m,1H),3.58-3.52(m,1H),3.38(d,J=10.4 Hz,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=6.8 Hz,3H),1.12(d,J=6.4 Hz,3H).

[0366] Step 3: 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-8-chloro-2-(2-methoxypropyl)isoquinolin-1(2H)-one The compound of Example 14 (15.3 mg, yield 50%) was synthesized in the same manner as in Example 1. 1 H NMR(400 MHz,METHANOL-d4)δ=8.30(d,J=1.2 Hz,1H),8.26(s,1H),7.40(d,J=8.8Hz,1H),7.34(d,J=7.4 Hz,1H),7.16(d,J=8.8 Hz,1H),6.54(d,J=7.2 Hz,1H),4.29-4.26(m,1H),4.24-4.20(m,1H),4.18-4.13(m,2H),3.92(d,J=9.2 Hz,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=4.8 Hz,1H),1.88-1.78(m,3H),1.74-1.66(m,1H),1.26(d,J=6.4 Hz,3H),1.20(d,J=5.6 Hz,3H);MS(EI)m / z:530.3 [M+H] + .

[0367] Example 15: 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-8-chloro-2-methylisoquinolin-1(2H)-one [ka]

[0368] 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]decan-4-yl)carbamate 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]decan-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. Upon completion of the reaction, the reaction mixture was partitioned between EA (30 mL) and HO (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 give 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]decan-4-yl)carbamate (6.00 mg, 23% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=8.26(d,J=1.2 Hz,1H),8.21-8.17(m,1H),7.25-7.23(m,1H),7.12(d,J=8.4 Hz,1H),7.07(d,J=7.2 Hz,1H),6.35(d,J=7.2 Hz,1H),4.26(s,2H),4.19-4.13(m,1H),3.94-3.89(m,1H),3.70(d,J=9.2 Hz,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).

[0369] Step 2: 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-8-chloro-2-methylisoquinolin-1(2H)-one The compound of Example 15 (3.12 mg, yield 37%) was synthesized in the same manner as in Example 1. 1H NMR(400 MHz,MeOD)δ=8.57-8.47(m,1H),8.33-8.28(m,2H),7.44-7.36(m,2H),7.18(d,J=8.4 Hz,1H),6.58(d,J=7.2 Hz,1H),4.36-4.28(m,2H),4.27-4.20(m,1H),4.02-3.95(m,1H),3.87(d,J=9.2 Hz,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=6.4 Hz, 3H); MS(EI) m / z: 472.2 [M+H] + .

[0370] Example 16: (S)-7-((5-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-chloro-2-methylisoquinolin-1(2H)-one [ka]

[0371] The compound of Example 16 (20.7 mg, yield 80%) was synthesized in the same manner as in Example 14, except that in Step 1 of Example 14, intermediate I-11 was used instead of intermediate I-9, and intermediate I-10 was used instead of intermediate I-8 as the starting material. 1H NMR(400 MHz,MeOD)δ=9.14(s,1H),8.35(d,J=1.2 Hz,1H),8.29(d,J=1.2 Hz,1H),7.40(dd,J=8.0,11.6 Hz,2H),7.17(d,J=8.0 Hz,1H),6.57(d,J=7.2 Hz,1H),4.54-4.48(m,1H),4.48-4.45(m,1H),4.37(d,J=14.2 Hz,1H),3.57(s,3H),3.40-3.38(m,1H),3.30-3.24(m,1H),3.22-3.16(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] + .

[0372] Example 17: (S)-6-((5-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-3-methylquinazolin-4(3H)-one [ka]

[0373] The compound of Example 17 (16 mg, yield 85%) was synthesized in the same manner as in Example 6, except that in Step 1 of Example 6, intermediate I-18 was used instead of intermediate I-14, and intermediate I-2 was used instead of intermediate I-12 as the starting material. 1 H NMR(400 MHz,CDCl3)δ=8.78(s,1H),8.23(d,J=1.4 Hz,1H),8.19-8.16(m,1H),8.15(d,J=1.9 Hz,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] + .

[0374] Example 18: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one [Synthesis method 1] [ka]

[0375] 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]decan-4-yl)carbamate 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. Upon completion of the reaction, the mixture was filtered, and the filtrate was concentrated. The residue was purified by reverse-phase HPLC (0.1% FA condition) to give 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]decan-4-yl)carbamate (300 mg, 87% yield) as a yellow solid. 1H NMR(400 MHz,CDCl3)δ=8.27(d,J=1.2 Hz,1H),8.19(d,J=1.2 Hz,1H),8.15(s,1H),7.47(d,J=8.8 Hz,1H),7.25(s,1H),4.64(d,J=10.8 Hz,1H),4.24-4.16(m,1H),4.07(s,2H),4.02(dd,J=4.4,10.8 Hz,1H),3.86(dd,J=3.6,9.6 Hz,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).

[0376] Step 2: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one The compound of Example 18 (27.1 mg, yield 93%) was synthesized in the same manner as in Example 1. 1 H NMR(400 MHz,CDCl3)δ=8.26(s,1H),8.21-8.18(m,1H),8.15(s,1H),7.42(d,J=8.8 Hz,1H),7.21(d,J=8.8 Hz,1H),4.28-4.20(m,2H),4.20-4.17(m,1H),4.06(s,2H),3.98(d,J=9.2 Hz,1H),3.79(d,J=9.2 Hz,1H),3.27(d,J=4.4 Hz,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=6.4 Hz,3H),1.21(s,6H). MS(EI)m / z:545.3 [M+H] + .

[0377] [Synthesis method 2] The compound of Example 18 (88.5 mg, yield 57%) was synthesized in the same manner as in Example 25, except that in Step 1 of Example 25, intermediate I-24 was used instead of intermediate I-26, and intermediate I-29 was used instead of intermediate I-28 as the starting material. 1 H NMR(400 MHz,CDCl3)δ=8.27(d,J=1.2 Hz,1H),8.21(d,J=1.2 Hz,1H),8.15(s,1H),7.45(d,J=8.8 Hz,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=8.8 Hz,1H),3.71(d,J=8.8 Hz,1H),3.55-3.45(m,1H),3.44-3.35(m,1H),3.21(s,3H),3.02(d,J=4.4 Hz,1H),1.97-1.87(m,1H),1.85-1.67(m,3H),1.26(d,J=6.4 Hz,3H),1.21(s,6H). MS(EI)m / z:545.3 [M+H] + .

[0378] Examples 19 to 21 The compounds of Examples 19 to 21 were prepared in the same manner as in Example 18, except that in Synthesis Method 1 of Example 18, an appropriate compound having a trifluoromethanesulfonic acid functional group was used instead of 2-methoxy-2-methylpropyl trifluoromethanesulfonate.

[0379] [Table 4]

[0380] Example 22: (R)-6-((5-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazolin-4(3H)-one [ka]

[0381] The compound of Example 22 (27 mg, yield 58%) was synthesized in the same manner as in Example 18, except that in Step 1 of Example 18, Intermediate I-20 was used instead of Intermediate I-19 and 2-bromoethyl methyl ether was used as the starting material instead of 2-methoxy-2-methylpropyl trifluoromethanesulfonate. 1 H NMR(500 MHz,DMSO)δ 8.67(bs,2H),8.57(s,1H),8.36(s,1H),8.29(s,1H),7.63(d,J=7.4 Hz,1H),7.53(d,J=8.8 Hz,1H),7.37(t,J=8.0 Hz,1H),7.27(d,J=8.8 Hz,2H),7.04-6.98(m,2H),4.68(d,J=4.7 Hz,1H),4.56-4.53(m,1H),4.41-4.39(m,1H),4.13(t,J=5.0 Hz,2H),3.61(t,J=5.0 Hz,2H),3.26(s,3H),2.13-2.00(m,2H),1.91-1.80(m,2H);MS m / z:552.0 [M+H] + .

[0382] Example 23: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-((4-methyltetrahydro-2H-pyran-4-yl)methyl)quinazolin-4(3H)-one [ka]

[0383] 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]decan-4-yl)-2-methylpropane-2-sulfinamide 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 h. Upon completion of stirring, the reaction mixture was partitioned between EA (40 mL) and HO (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 (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient: 41%-71% B over 10 min) to give 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]decan-4-yl]-2-methyl-propane-2-sulfinamide (40.0 mg, 33% yield) as a white solid. 1 H NMR(400 MHz,CDCl3)δ=8.19(d,J=1.2 Hz,1H),8.12(d,J=1.2 Hz,1H),7.85(s,1H),7.38(d,J=8.8 Hz,1H),7.19-7.16(m,1H),4.22-4.14(m,2H),4.10(dd,J=4.0,13.6 Hz,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=5.6,10.4 Hz,1H),3.30(d,J=10.4 Hz,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=13.6 Hz,2H),1.20-1.19(m,9H),1.16(d,J=6.4 Hz,3H),1.03(s,3H).

[0384] Step 2: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-((4-methyltetrahydro-2H-pyran-4-yl)methyl)quinazolin-4(3H)-one 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]decan-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. Upon completion of stirring, the reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient: 18%-48% B over 7 min) to give the compound of Example 23 (24.6 mg, yield 69%) as a white solid. MS(EI)m / z:[M+H] + 571.2. 1 H NMR(400 MHz,MeOD)δ=8.35(d,J=1.2 Hz,1H),8.31(d,J=1.2 Hz,1H),8.24(s,1H),7.49(d,J=8.8 Hz,1H),7.30(d,J=8.8 Hz,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=9.2 Hz,1H),3.83(d,J=4.4,11.6 Hz,2H),3.72-3.65(m,2H),3.40(d,J=4.4 Hz,1H),3.31-3.19(m,2H),1.91-1.87(m,2H),1.86-1.81(m,1H),1.75(s,1H),1.71-1.63(m,2H),1.42(d,J=2.8 Hz,1H),1.38(s,1H),1.33(d,J=6.4 Hz,3H),1.11(s,3H).

[0385] Example 24: 3-(6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-4-oxoquinazolin-3(4H)-yl)propanenitrile [ka]

[0386] 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]decan-4-yl)-2-methylpropane-2-sulfinamide 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 prop-2-enenitrile (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, which was then extracted with EA (3×30 ml). The combined organic layers were dried under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient: 28%-68% B over 10 min) to give 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]decan-4-yl]-2-methyl-propane-2-sulfinamide (45 mg, 85% yield) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ=8.48(d,J=1.2 Hz,1H),8.40(s,1H),8.30(d,J=1.2 Hz,1H),7.53(d,J=8.8 Hz,1H),7.21(d,J=8.8 Hz,1H),5.13(d,J=12.0 Hz,1H),4.24-4.20(m,3H),4.19-4.07(m,2H),3.89(d,J=8.8 Hz,1H),3.52(d,J=8.8 Hz,1H),3.46-3.40(m,1H),3.23-3.12(m,2H),3.03(t,J=6.4 Hz,2H),1.85-1.71(m,2H),1.68-1.53(m,2H),1.16(s,9H),1.10(d,J=6.4 Hz,3H).

[0387] Step 2: 3-(6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-4-oxoquinazolin-3(4H)-yl)propanenitrile 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]decan-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. Upon completion of stirring, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (0.1% FA) to give Example 24 (42.92 mg, 78% yield) as a white solid. MS(EI)m / z:[M+H] + 512.3. 1H NMR(400 MHz,DMSO-d6)δ=8.47(s,1H),8.41(s,1H),8.30(d,J=1.2 Hz,1H),8.24(s,1H),7.53(d,J=8.8 Hz,1H),7.23(d,J=8.8 Hz,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=6.4 Hz,3H).

[0388] Example 25: (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 [ka]

[0389] 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-sulfinamide 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 Pd(dba) (31.0 mg, 33.9 μmol) in dioxane (5 mL) was degassed and purged with N three times, then the mixture was stirred under N atmosphere at 100° C. for 2 h. Upon completion of stirring, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-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-sulfinamide (90.0 mg, 60% yield) as a white solid. MS(EI)m / z:[M+H] + 667.2. 1 H NMR(400 MHz,DMSO-d6)δ=8.51(s,1H),8.32(s,1H),8.22(s,1H),7.51(d,J=8.8 Hz,1H),7.28-7.18(m,5H),5.69(d,J=10.8 Hz,1H),4.82(s,1H),4.47(s,1H),4.49-4.43(m,1H),4.39(d,J=12.8 Hz,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).

[0390] Step 2: (S)-6-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-hydroxy-2-methylpropyl)quinazolin-4(3H)-one 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[indan-2,4'-piperidine]spiro-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. Upon completion of stirring, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: C18 150 x 30 mm; mobile phase: [water (FA)-ACN]; gradient: 10%-40% B over 7 min) to give Example 25 (84.7 mg, 80% yield) as a white solid. MS(EI)m / z:[M+H] + 563.3. 1 H NMR(400 MHz,DMSO-d6)δ=8.48(d,J=1.2 Hz,1H),8.30(d,J=1.2 Hz,1H),8.21(d,J=4.4 Hz,2H),7.52(d,J=8.8 Hz,1H),7.37-7.34(m,1H),7.23(s,1H),7.21(d,J=3.6 Hz,3H),4.81(s,1H),4.31(s,1H),4.28(d,J=1.6 Hz,1H),3.97(s,1H),3.95(s,2H),3.13-3.09(m,2H),2.73(d,J=15.6 Hz,1H),1.83-1.77(m,1H),1.72-1.66(m,1H),1.55(d,J=13.6 Hz,1H),1.25-1.21(m,1H),1.11(s,6H).

[0391] Example 26: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-((1-methylpiperidin-4-yl)methyl)quinazolin-4(3H)-one [ka]

[0392] The compound of Example 26 (33.3 mg, yield 78%) was synthesized in the same manner as in Example 25, except that in Step 1 of Example 25, intermediate I-24 was used instead of intermediate I-26 and intermediate I-34 was used instead of intermediate I-28 as the starting material. MS(EI)m / z:[M+H] + 570.1, 1 H NMR(400 MHz,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=8.8 Hz,1H),7.23(d,J=8.8 Hz,1H),4.37-4.21(m,3H),4.02-3.94(m,3H),3.86(d,J=9.2 Hz,1H),3.50-3.43(m,2H),3.41(d,J=4.2 Hz,1H),3.30-3.16(m,2H),2.91(t,J=11.6 Hz,2H),2.80(s,3H),2.24-2.12(m,1H),1.94(d,J=13.6 Hz,2H),1.90-1.80(m,3H),1.78-1.56(m,3H),1.31(d,J=6.4 Hz,3H).

[0393] Example 27: (S)-6-((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 [ka]

[0394] The compound of Example 27 (45 mg, yield 65%) was synthesized in the same manner as in Example 25, except that in Step 1 of Example 25, Intermediate I-29 was used as a starting material instead of Intermediate I-28. MS(EI)m / z:[M+H] + 577.3 1H NMR(400 MHz,CDCl3)δ=8.28(d,J=1.2 Hz,1H),8.23(d,J=1.2 Hz,1H),8.15(s,1H),7.46(d,J=8.8 Hz,1H),7.34(d,J=5.6 Hz,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=15.6 Hz,1H),2.76(d,J=15.6 Hz,1H),1.96-1.78(m,2H),1.67-1.63(m,1H),1.45-1.40(m,1H),1.22(s,6H).

[0395] Example 28: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(1-fluoro-2-methoxy-2-methylpropyl)quinazolin-4(3H)-one [ka]

[0396] The compound of Example 28 (11.38 mg, yield 44%) was synthesized in the same manner as in Example 25, except that in Step 1 of Example 25, intermediate I-30 was used instead of intermediate I-28 and intermediate I-24 was used instead of intermediate I-26 as starting materials. MS(EI)m / z:[M+H] + 563.3. 1H NMR(400 MHz,MeOD)δ=8.37(s,1H),8.32(s,1H),8.29(s,1H),7.48(d,J=8.8 Hz,1H),7.28(d,J=8.8 Hz,1H),6.79-6.61(m,1H),4.30-4.23(m,1H),4.22-4.08(m,2H),3.92(d,J=8.8 Hz,1H),3.77(d,J=8.8 Hz,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=6.4 Hz,3H), 1.14(d,J=1.6 Hz,3H)

[0397] Example 29: (S)-6-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one [ka]

[0398] The compound of Example 29 (60.3 mg, yield 58%) was synthesized in the same manner as in Example 25, except that in Step 1 of Example 25, Intermediate I-31 was used as a starting material instead of Intermediate I-28. MS(EI)m / z:[M+H] + 543.5. 1 H NMR(400 MHz, 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),2.8 1-2.73(m,1H),1.90-1.80(m,2H),1.80-1.77(m,1H),1.46-1.40(m,1H),1.20(s,6H).

[0399] Example 30: (S)-6-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-phenylquinazolin-4(3H)-one [ka]

[0400] The compound of Example 30 (101 mg, yield 79%) was synthesized in the same manner as in Example 25, except that in Step 1 of Example 25, Intermediate I-32 was used as a starting material instead of Intermediate I-28. m / z ES+[M+H] + 567.1 1 H NMR(400 MHz, CDCl3)δ=8.31(d,J=1.2 Hz,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,3 H),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=16.0 Hz,1H),1.93-1.75(m,2H),1.65-1.57(m,2H).

[0401] Example 31: (S)-6-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one [ka]

[0402] The compound of Example 31 (45 mg, yield 52%) was synthesized in the same manner as in Example 25, except that in Step 1 of Example 25, Intermediate I-32 was used as a starting material instead of Intermediate I-28. m / z ES+[M+H] + 568.3. 1 H NMR(400 MHz, CDCl3)δ=8.31(d,J=1.2 Hz,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).

[0403] Example 32: (S)-6-((5-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one [ka]

[0404] The compound of Example 32 (55 mg, yield 58%) was synthesized in the same manner as in Example 29, except that in Step 1 of Example 29, Intermediate I-36 was used as a starting material instead of Intermediate I-26. m / z ES+[M+H] + 584.2; 1 H NMR(400 MHz,CDCl3)δ=8.78(s,1H),8.28(s,1H),8.24(s,1H),8.15(s,1H),7.46(d,J=8.8 Hz,1H),7.29(d,J=8.8 Hz,1H),4.29(d,J=13.2 Hz,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).

[0405] Examples 33 to 35 The compounds of Examples 33-35 were prepared in the same manner as Example 32, except that the appropriate intermediate was used instead of Intermediate I-36 of Example 32.

[0406] [Table 5]

[0407] Example 36: (S)-6-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one [ka]

[0408] 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-sulfinamide 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. Upon completion of stirring, the reaction mixture was quenched by adding aqueous ammonium chloride solution (20 mL) at 25° C., then diluted with water (30 mL), and extracted with EA (3×50 mL). The combined organic layer was washed with brine (3×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient: 55%-85% B over 10 min) to give 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'-piperidin]-1-yl]-2-methyl-propane-2-sulfinamide (60 mg, 46% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=8.14(s,1H),7.67(s,1H),7.47(d,J=8.8 Hz,1H),7.34-7.31(m,1H),7.29-7.27(m,1H),7.27-7.22(m,2H),7.14(d,J=8.8 Hz,1H),4.84(br.s,2H),4.58(d,J=10.0 Hz,1H),4.37-4.28(m,2H),4.07(s,2H),3.60(d,J=10.0 Hz,1H),3.21(s,3H),3.20-3.16(m,1H),3.15-3.06(m,2H),2.79(d,J=15.6 Hz,1H),2.33(dt,J=4.4,12.8 Hz,1H),1.92-1.84(m,1H),1.49-1.36(m,2H),1.31(s,9H),1.22(s,6H).

[0409] Step 2: (S)-6-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one 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[indan-2,4'-piperidin]-1-yl]-2-methyl-propane-2-sulfinamide (60 mg, 86.2 μmol) in MeOH (3 mL), HCl / dioxane (4 M) was added, and the mixture was stirred at 25 ° C. for 0.5 hours. After stirring was completed, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium hydroxide v / v) -ACN]; gradient: 35%-65% B / min) to obtain the compound of Example 36 (34 mg, 66% yield) as an off-white solid. MS(EI)m / z:[M+H] + 592.3. 1 H NMR(400 MHz,CDCl3)δ=8.14(s,1H),7.69(s,1H),7.44(d,J=8.8 Hz,1H),7.40-7.33(m,1H),7.26-7.19(m,3H),7.16(d,J=8.8 Hz,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=15.6 Hz,1H),2.77(d,J=15.6 Hz,1H),1.90-1.77(m,2H),1.55-1.50(m,1H),1.45-1.39(m,1H),1.22(s,6H).

[0410] Example 37: 6-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one [ka]

[0411] The compound of Example 37 (41 mg, yield 69%) was synthesized in the same manner as in Example 25, except that in Step 1 of Example 36, the product obtained in Step 1 of Preparation 23 was used as the starting material instead of Intermediate I-25. m / z ES+[M+H] + 560.2. 1 H NMR(400 MHz,CDCl3)δ=8.14(s,1H),7.67(s,1H),7.43(d,J=8.8 Hz,1H),7.14(d,J=8.8 Hz,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=8.8 Hz,1H),3.71(d,J=8.8 Hz,1H),3.43-3.40(m,1H),3.36-3.29(m,1H),3.21(s,3H),3.02(d,J=4.4 Hz,1H),1.93-1.86(m,1H),1.80-1.70(m,3H),1.26(d,J=6.4 Hz,3H),1.22(s,6H).

[0412] Example 38: (S)-6-((5-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-phenylquinazolin-4(3H)-one [ka]

[0413] The compound of Example 38 (115 mg, yield 75%) was synthesized in the same manner as in Example 25, except that in Step 1 of Example 25, intermediate I-36 was used instead of intermediate I-26, and intermediate I-32 was used instead of intermediate I-28 as the starting material. m / z ES+[M+H] + 573.1 1 H NMR(400 MHz,CDCl3)δ=8.81(s,1H),8.27(d,J=9.6 Hz,2H),8.05(s,1H),7.58-7.45(m,4H),7.41(d,J=7.2 Hz,2H),7.30(d,J=8.8 Hz,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).

[0414] Example 39: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxypropyl)-2-methylquinazolin-4(3H)-one [ka]

[0415] 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]decan-4-yl)-2-methylpropane-2-sulfinamide In Step 1 of Example 25, 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]decan-4-yl)-2-methylpropane-2-sulfinamide (90 mg, yield 38%) was synthesized in the same manner as in Example 25, except that in Step 1 of Example 25, intermediate I-24 was used instead of intermediate I-26 and 6-bromo-5-chloro-2-methylquinazolin-4(3H)-one was used as the starting material instead of intermediate I-28. 1 H NMR(400 MHz,DMSO-d6)δ=12.81-11.83(m,1H),8.46(d,J=1.2 Hz,1H),8.28(d,J=1.2 Hz,1H),7.40(d,J=8.8 Hz,1H),7.14(d,J=8.8 Hz,1H),5.13(d,J=10.8 Hz,1H),4.26-4.19(m,1H),4.18-4.11(m,2H),3.88(d,J=8.8 Hz,1H),3.52(d,J=8.8 Hz,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=6.4 Hz,3H).

[0416] 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]decan-4-yl)-2-methylpropane-2-sulfinamide 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]decan-4-yl]-2-methyl-propane-2-sulfinamide (70 mg, 121 μmol), 2-methoxypropyl 4-methylbenzenesulfonate (88.8 mg, 363 μmol), KCO (50.2 mg, 363 μmol), and TBAI (4.48 mg, 12.1 μmol) in DMF (2 mL) was stirred at 60 °C for 2 h. After stirring was complete, water (40 mL) was added to the reaction mixture, which was then extracted with EA (3 × 80 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by prep-TLC (SiO, EA:MeOH=10:1) to give 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]decan-4-yl]-2-methyl-propane-2-sulfinamide (30 mg, 38% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=8.27-8.23(m,1H),8.19(d,J=1.2 Hz,1H),8.03(s,1H),7.40(d,J=8.8 Hz,1H),4.40-4.20(m,1H),4.28-4.19(m,2H),4.19-4.12(m,1H),3.91(d,J=9.2 Hz,1H),3.86-3.77(m,1H),3.69(d,J=9.2 Hz,1H),3.56-3.50(m,1H),3.38(d,J=10.4 Hz,1H),3.22(s,2H),2.96(s,3H),2.89(s,3H),2.66(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=6.4 Hz,3H).

[0417] Step 3: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxypropyl)-2-methylquinazolin-4(3H)-one The compound of Example 39 (7.41 mg, yield 26%) was synthesized in the same manner as in Step 2 of Example 25. MS(EI)m / z:[M+H] + 545.3, 1 H NMR(400 MHz,MeOD)δ=8.56-8.50(m,1H),8.30(s,1H),8.27(s,1H),7.37(d,J=8.8 Hz,1H),7.25(d,J=8.8 Hz,1H),4.33-4.28(m,2H),4.27-4.18(m,2H),3.99-3.89(m,2H),3.85(d,J=9.2 Hz,1H),3.82-3.70(m,1H),3.36(d,J=4.4 Hz,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=6.4 Hz,3H),1.26(d,J=6.4 Hz,3H).

[0418] Example 40: (S)-7-((5-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-chloro-2-isopropylisoquinolin-1(2H)-one [ka]

[0419] The compound of Example 40 (2.34 mg, yield 25%) was synthesized in the same manner as in Example 25, except that in Step 1 of Example 25, intermediate I-36 was used instead of intermediate I-26 and intermediate I-44 was used instead of intermediate I-28 as starting materials. MS(EI)m / z:[M+H] + 539.0, 1 H NMR(400 MHz,MeOD)δ=9.01(s,1H),8.58-8.45(m,1H),8.33(s,1H),8.28(s,1H),7.45(d,J=7.6 Hz,1H),7.40(d,J=8.8 Hz,1H),7.15(d,J=8.8 Hz,1H),6.63(d,J=7.6 Hz,1H),5.33-5.18(m,1H),4.46-4.36(m,1H),4.35-4.27(m,1H),4.23(s,1H),3. 47-3.34(m,2H),3.02(s,2H),2.05-1.87(m,2H),1.84-1.76(m,2H),1.40(d,J=6.8 Hz,6H).

[0420] Example 41: (S)-7-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-8-chloro-2-methylisoquinolin-1(2H)-one [ka]

[0421] The compound of Example 41 (19 mg, yield 73%) was synthesized in the same manner as in Example 25, except that in Step 1 of Example 25, Intermediate I-43 was used as a starting material instead of Intermediate I-28. MS(EI)m / z:[M+H] + 504.3 1 H NMR(400 MHz,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=8.8 Hz,1H),6.56(d,J=7.2 Hz,1H),4.50-4.30(m,1H),4.34-4.27(m,2H),3.56(s,3H),3.40-3.30(m,2H) ,3.25-3.15(m,1H),3.13-3.05(m,1H),1.88-1.80(m,2H),1.71-1.62(m,2H).

[0422] Examples 42 to 45 The compounds of Examples 42 to 45 were prepared in the same manner as in Example 41, except that intermediate I-43 in Example 41 was replaced with the appropriate intermediate.

[0423] [Table 6] TIFF2026503032000137.tif76149

[0424] Example 46: 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-8-chloro-2-isopropylisoquinolin-1(2H)-one [ka]

[0425] The compound of Example 46 (10 mg, yield 66%) was synthesized in the same manner as in Example 40, except that Intermediate I-24 was used as the starting material instead of Intermediate I-36. MS(EI)m / z:[M+H] + 500.2 1 H NMR(400 MHz,MeOD)δ=8.30(s,1H),8.26(d,J=1.2 Hz,1H),7.45(d,J=7.6 Hz,1H),7.39(d,J=8.4 Hz,1H),7.15(d,J=8.4 Hz,1H),6.62(d,J=7.6 Hz,1H),5.25-5.20(m,1H),4.37-4.20(m,3H),3.98(d,J=9.2 Hz,1H),3.86(d,J=9.2 Hz,1H),3.740(d,J=4.0 Hz,1H),3.29-3.14(m,2H),1.90-1.80(m,3H),1.76-1.68(m,1H),1.40(d,J=6.8 Hz,6H),1.31(d,J=6.4 Hz,3H).

[0426] Example 47: (S)-7-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-8-chloro-2-methylisoquinolin-1(2H)-one [ka]

[0427] The compound of Example 47 (20 mg, yield 59%) was synthesized in the same manner as in Example 36, except that Intermediate I-49 was used as the starting material instead of Intermediate I-41. MS(EI)m / z:[M+H] + 519.2 1 H NMR(400 MHz,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=7.2 Hz,1H),4.87(s,2H),4.24-4.15(m,2H),4.04(s,1H),3.57(s,3H),3.26-3.17(m,2H),3.13(d,J=15.2 Hz,1H),2.78(d,J=15.2 Hz,1H),1.89-1.80(m,2H),1.66-1.63(m,1H),1.47-1.45(m,1H)

[0428] Example 48: (S)-7-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-8-chloro-2-isopropylisoquinolin-1(2H)-one [ka]

[0429] The compound of Example 48 (20 mg, yield 59%) was synthesized in the same manner as in Example 36, except that Intermediate I-50 was used as the starting material instead of Intermediate I-41. MS(ESI) m / z:[M+H] + 547.2; 1 H NMR(400 MHz,CDCl3)δ=7.67(s,1H),7.39-7.35(m,1H),7.24(d,J=2.8 Hz,3H),7.21(d,J=8.4 Hz,1H),7.12(d,J=7.2 Hz,1H),7.05(d,J=8.4 Hz,1H),6.41(d,J=7.2 Hz,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=15.6 Hz,1H),2.78(d,J=15.6 Hz,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=6.8 Hz,6H)

[0430] Example 49: 7-((3-amino-5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-8-chloro-2-(2-methoxypropyl)isoquinolin-1(2H)-one [ka]

[0431] The compound of Example 49 (32 mg, yield 62%) was synthesized in the same manner as in Example 36, except that Intermediate I-51 was used as a starting material instead of Intermediate I-41. MS(EI)m / z:[M+H] + 577.3. 1H NMR(400 MHz,CDCl3)δ=7.72(s,1H),7.39(d,J=4.4 Hz,1H),7.33-7.29(m,2H),7.27-7.21(m,2H),7.18(d,J=7.2 Hz,1H),7.10(d,J=8.4 Hz,1H),6.36(d,J=7.2 Hz,1H),4.89(s,2H),4.35(dd,J=2.8,13.6 Hz,1H),4.29-4.20(m,2H),4.05(s,1H),3.87-3.78(m,1H),3.59(dd,J=8.4,13.6 Hz,1H),3.31(s,3H),3.29-3.19(m,2H),3.15(d,J=15.6 Hz,1H),2.79(d,J=15.6 Hz,1H),1.95-1.83(m,2H),1.82-1.77(m,1H),1.46-1.41(m,1H),1.26(d,J=6.4 Hz,3H).

[0432] Example 50: (R)-6-((5-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one [ka]

[0433] The compound of Example 50 (49 mg, yield 48%) was synthesized in the same manner as in Example 25, except that in Step 1 of Example 25, Intermediate I-53 was used as a starting material instead of Intermediate I-26. m / z ES+[M-NH2] + 562.3. 1H NMR(400 MHz,CDCl3)δ=8.29(d,J=1.2 Hz,1H),8.26(d,J=1.2 Hz,1H),8.15(s,1H),7.47(d,J=8.8 Hz,1H),7.34(d,J=7.2 Hz,1H),7.29(d,J=8.8 Hz,1H),7.25-7.21(m,1H),6.95(t,J=7.2 Hz,1H),6.84(d,J=8.0 Hz,1H),4.36(d,J=13.6 Hz,1H),4.26(d,J=13.6 Hz,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).

[0434] Example 51: (R)-6-((5-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-methylquinazolin-4(3H)-one [ka]

[0435] The compound of Example 51 (44 mg, yield 47%) was synthesized in the same manner as in Example 50, except that Intermediate I-54 was used as the starting material instead of Intermediate I-28. m / z ES+[M+Na] + 529.1. 1H NMR(CDCl3,400 MHz)δ=8.30(d,J=1.2 Hz,1H),8.27(d,J=1.2 Hz,1H),7.99(s,1H),7.47(d,J=8.8 Hz,1H),7.38(d,J=7.6 Hz,1H),7.29(s,1H),7.25-7.21(m,1H),7.05-6.90(m,1H),6.85(d,J=8.0 Hz,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).

[0436] Example 52: (R)-6-((5-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-phenylquinazolin-4(3H)-one [ka]

[0437] The compound of Example 52 (54 mg, yield 63%) was synthesized in the same manner as in Example 50, except that Intermediate I-32 was used as the starting material instead of Intermediate I-28. m / z ES+[M+Na] + 591.2. 1 H NMR(400 MHz,CDCl3)δ=8.32(d,J=1.2 Hz,1H),8.29(d,J=1.2 Hz,1H),8.07(s,1H),7.62-7.48(m,5H),7.43(d,J=1.6 Hz,1H),7.41(s,1H),7.37-7.32(m,2H),7.25-7.20(m,1H),7.00-6.92(m,1H),6.85(d,J=8.0 Hz,1H),4.39(m,1H),4.32-4.25(m,1H),4.19(s,1H),3.61-3.52(m,2H),2.00-1.90(m,2H),1.89-1.76(m,2H).

[0438] 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 [ka]

[0439] The compound of Example 53 (25 mg, yield 40%) was synthesized in the same manner as in Example 50, except that Intermediate I-55 was used as the starting material instead of Intermediate I-28. m / z ES+[M+H] + 510.2. 1 H NMR(DMSO,400 MHz)δ=8.77(s,1H),8.64(s,1H),8.36(s,1H),8.09(s,1H),7.40(d,J=8.8 Hz,1H),7.31(d,J=7.6 Hz,1H),7.25(s,1H),7.23-7.19(m,1H),7.05-6.87(m,1H),6.82(d,J=8.0 Hz,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).

[0440] Experimental Example Experimental Example 1: Phosphatase assay (IC 50 ) I C 50 Values ​​were measured using 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) as substrate. Reactions were performed in 384-well plates and fluorescence measurements were obtained using a PerkinElmer EnVision plate reader.

[0441] SHP2 (full-length, diluted to a final concentration of 100 pM in reaction buffer, BPS Bioscience, US) was incubated with the 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 min to activate SHP2. After activation, DMSO (1% (v / v) or compounds described in the Examples (concentrations ranging from 0.6 nM to 10 μM)) was added. As positive controls, we used the selective SHP2 inhibitors SHP099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine, FOCUSbioscience, Australia; concentrations ranging 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 ranging from 0.6 nM to 10 μM). [ka]

[0442] DiFMUP (80 μM) was added to the reaction mixture and allowed to incubate for a total of 2 hours. Fluorescence (340 nm excitation, 450 nm emission) values ​​were then measured. IC values ​​were calculated using a Grafford prism from the measured values ​​depending on the concentration. 50 The IC values ​​of the compounds according to the examples obtained were 50 The values ​​are summarized in Table 7 below.

[0443] In the phosphatase assay (PTPase assay), IC 50 Values ​​above 100 nM are marked as +, IC 50 Values ​​greater than or equal to 3 nM and less than 100 nM are considered ++, and IC 50 Values ​​below 3 nM were rated +++.

[0444] [Table 7]

[0445] Referring to Table 7, it was confirmed that the compounds according to the present disclosure have excellent SHP2 inhibitory effects.

[0446] Experimental Example 2: Phospho-ERK assay H358 cells (20,000 cells / well) were placed in 40 μL of cell culture medium (RPMI, 10% FBS, penicillin, streptomycin) and placed in a 384-well plate. After 24 hours, serially diluted compounds (minimum 0.13 nM, maximum 10 μM) were added to the wells containing the cells in 10 μL of cell culture medium and incubated for 1.5 hours in a cell incubator. As a positive control, TNO155 (Chemietek, US; concentrations ranging from 0.13 nM to 10 μM), a selective SHP2 inhibitor, was used.

[0447] Phospho-ERK was then labeled using a PerkinElmer AlphaLisa system according to the manufacturer's instructions, and fluorescence (excitation wavelength 680 nm, emission wavelength 615 nm) values ​​were measured using a Thermo Varioskan instrument. IC values ​​were calculated using a Grafford prism from the measured values ​​according to the concentration. 50 The IC values ​​of the compounds according to the examples obtained were 50 The values ​​are summarized in Table 8 below.

[0448] In the phospho-ERK assay, IC 50 Values ​​above 1.5 μM are considered positive, IC 50 Values ​​≥ 45 nM and < 1.5 μM were defined as ++, and IC 50 Values ​​below 45 nM were rated +++.

[0449] [Table 8]

[0450] Intracellular SHP2 activity can be confirmed by measuring the level of phosphorylation of ERK (extracellular signal-regulated kinase), which represents the Ras / Raf / ERK downstream signaling pathway of SHP2. Inhibition of ERK phosphorylation by SHP2 inhibitors was confirmed by phospho-ERK analysis, confirming that the SHP2 inhibitors of the present disclosure have excellent inhibitory activity against SHP2-mediated ERK phosphorylation.

[0451] Experimental Example 3: Cell viability Human non-small cell lung cancer cell line H358 cells were purchased from the Korean Cell Line Bank. The cancer cell line was cultured in the recommended RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin. The monolayer cultured cancer cell line was detached by treatment with trypsin / EDTA, and 4 × 10 cells were cultured. 3 100 μL of cell suspension containing cells was dispensed into SPL3D™ Cell Floater 96-well round plates according to cell line counting. After 72 hours of culture to allow spheroid formation, the cells were individually treated with serially diluted example compounds (minimum 1.5 nM, maximum 10 μM) and cultured in a cell incubator for 5 days. To analyze cell viability, the cells were treated with 50 μL of 3D CellTiter-Glo, agitated at 500 rpm for 5 minutes in a Thermo Fisher Scientific plate shaker, and incubated at room temperature for 25 minutes. Luminescence values ​​were then measured using a Thermo Fisher Scientific Varioskan instrument. IC values ​​were calculated from the measured values ​​as a function of concentration using GraphPad Prism. 50 The IC values ​​of the compounds according to the examples were obtained. 50 The values ​​are summarized in Table 9 below.

[0452] In cell viability assays, IC 50 Values ​​above 50 nM are considered positive, IC 50 Values ​​greater than or equal to 10 nM but less than 50 nM are considered ++, and IC 50 Values ​​below 10 nM were rated +++.

[0453] [Table 9]

[0454] Experimental Example 4: Brain-plasma pharmacokinetics Nine male CD-1 mice (ICR mice) aged 6 to 9 weeks were treated with a compound from the Examples at a concentration of 20 mg / kg. 0.025 mL of blood and brain tissue were collected 1, 8, and 24 hours after treatment. The collected blood was placed in an EDTA-K2 tube and centrifuged at 3,200 × g for 10 minutes at 4 °C to collect the supernatant plasma. After blood collection, the CD-1 mice were euthanized, and brain tissue samples were collected immediately after cardiac perfusion with cold saline. After collection, the brain tissue was washed with cold saline, wiped dry, weighed, and homogenized in homogenization buffer (15 mM PBS (pH 7.4):MeOH = 2:1) at a ratio of 1:3 (1 g tissue to 3 mL buffer, dilution ratio 4). The plasma and homogenized brain tissue samples were transferred to polypropylene microcentrifuge tubes and stored at -60 °C or below. The concentrations of 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: Brain-to-plasma ratio = AUC(0-t) brain tissue / AUC(0-t) plasma

[0455] In the brain-plasma pharmacokinetics assay, a brain-plasma ratio value of 0.05 or greater but less than 0.1 was rated as +, a brain-plasma ratio value of 0.1 or greater but less than 0.25 was rated as ++, and a brain-plasma ratio value of greater than 0.25 was rated as +++.

[0456] [Table 10]

[0457] Referring to Table 10, it was confirmed that the compounds of the present disclosure have excellent blood-brain barrier permeability, specifically, that the compounds of the present disclosure have a blood-brain concentration ratio of at least 0.05, at least 0.1, at least 0.2, or at least 0.25.

Claims

1. A compound represented by formula 1A, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, [Formula 1A] 【Chemistry 1】 During the ceremony, X is H or halogen; W １ and W ２ one is S and the other is N, R １Ａ is H, C ６～１０ Aryl, or C １～６ C optionally substituted with alkoxyl １～６ is alkyl, R ｘ and R ｙ are each independently H or C １～６ is alkyl, A compound represented by formula 1A, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

2. X is H or Cl; R １Ａ H, phenyl, CH ３ , C.H. ２ CH ３ , 【Chemistry 2】 is selected from the group consisting of R ｘ and R ｙ are H, respectively.

10. The compound of claim 1, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

3. The compound is 【Transformation 3】 2. The compound of claim 1, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, selected from:

4. A compound represented by formula 1B, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, [Formula 1B] 【Chemistry 4】 During the ceremony, X is H or halogen; R １Ｂ is H or C １～６ is alkyl, R ｘ and R ｙ are each independently H or C １～６ is alkyl, A compound represented by formula 1B, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

5. X is a halogen; R １Ｂ But C １～６ is alkyl, R ｘ and R ｙ are H, respectively.

5. The compound of claim 4, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

6. The compound is 【Transformation 5】 5. The compound of claim 4, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, selected from:

7. A compound represented by formula 2A, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, [Formula 2A] 【Transformation 6】 During the ceremony, Z is N or CH; Q is N or CH; X is H or halogen; Y ２ is N or CH, R ２Ａ is H, C ６～１０ aryl, 5-7 membered heteroaryl containing a heteroatom selected from N and O, or OH or C １～６ C optionally substituted with alkoxy １～６ is alkyl, R ｘ and R ｙ are each independently H or C １～６ is alkyl, A compound represented by formula 2A, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

8. X is a halogen; R ２Ａ However, methyl, phenyl, pyridinyl, 【Transformation 7】 and R ｘ and R ｙ are each independently H; 8. The compound of claim 7, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

9. The compound is 【Transformation 8】 8. The compound of claim 7, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, selected from:

10. A compound represented by formula 2B, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, [Formula 2B] 【Chemistry 9】 During the ceremony, Z is N or CH; X is H or halogen; R ａ３ is NR ｉ R ｉｉ or C １～６ is alkyl, R ａ４ is H, or OH or C １～６ Alkoxy-substituted C １～６ is alkyl, R ２Ｂ is C optionally substituted with H and OH １～６ Alkyl or C １～６ alkoxy; R ｉ and R ｉｉ are each independently H or C １～６ is alkyl, R ｘ and R ｙ are each independently H or C １～６ is alkyl, A compound represented by formula 2B, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

11. X is a halogen; R ２Ｂ But CH ３ , 【Chemistry 10】 is selected from the group consisting of R ｉ , R ｉｉ , R ｘ and R ｙ are each independently H; 11. The compound of claim 10, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

12. The compound is 【Chemistry 11】 11. The compound of claim 10, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, selected from:

13. A compound represented by formula 2C, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, [Formula 2C] 【Chemistry 12】 During the ceremony, X is H or halogen; R ２Ｃ is H, C ６～１０ aryl, and OH or C １～６ C optionally substituted with alkoxy １～６ alkyl, R ｘ and R ｙ are each independently H or C １～６ is alkyl, A compound represented by formula 2C, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

14. X is a halogen; R ２Ｃ But C ６～１０ aryl, and OH or C １～６ C optionally substituted with alkoxy １～６ alkyl, R ｘ and R ｙ are each independently H; 14. The compound of claim 13, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

15. The compound is 【Chemistry 13】 14. The compound of claim 13, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, selected from:

16. A compound represented by formula 3A, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, [Formula 3A] 【Chemistry 14】 During the ceremony, Z is N or CH; X is H or halogen; R ｚ is H or C １～６ is alkyl, R ３Ａ is H, C １～６ Alkyl-substituted -(C １～６ alkylene)-oxanyl, or C １～６ Alkyl, -(C １～６ alkylene)-(C ３～６ cycloalkyl) or -(C １～６ alkylene)-piperidinyl, each of which is R ３１Ａ optionally substituted with 1 to 3 occurrences of R ３１Ａ is halogen, cyano or C １～６ is an alkoxy, R Ａ is H or C １～６ is alkyl, R ｘ and R ｙ are each independently H or C １～６ is alkyl, A compound represented by formula 3A, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

17. X is a halogen; R ３Ａ But CH ３ , 【Chemistry 15】 is selected from the group consisting of R Ａ But C １～６ is alkyl, R ｘ and R ｙ are each independently H; 17. The compound of claim 16, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

18. The compound is 【Chemistry 16】 17. The compound of claim 16, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, selected from:

19. A compound represented by formula 3B, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, [Formula 3B] 【Chemistry 17】 During the ceremony, X is H or halogen; R ３Ｂ OH, C １～６ Alkoxy or C ６～１０ C optionally substituted with aryl １～６ is alkyl, R Ａ is H or C １～６ is alkyl, R ｉ and R ｉｉ are each independently H or C １～６ is alkyl, R ｘ and R ｙ are each independently H or C １～６ is alkyl, A compound represented by formula 3B, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

20. X is a halogen; R ３Ｂ But C １～６ Alkoxy or C ６～１０ Aryl-substituted C １～６ is alkyl, R Ａ But C １～６ is alkyl, R ｉ , R ｉｉ , R ｘ and R ｙ are each independently H; 20. The compound of claim 19, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

21. The compound is [Chemistry 18] 20. The compound of claim 19, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, selected from:

22. A compound represented by formula 3C, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, [Formula 3C] 【Chemistry 19】 During the ceremony, X is H or halogen; R ３Ｃ is C ６～１０ C optionally substituted with aryl １～６ is alkyl, R ｃ is H or C １～６ is alkyl, R ｉ and R ｉｉ are each independently H or C １～６ is alkyl, R ｘ and R ｙ are each independently H or C １～６ is alkyl, A compound represented by formula 3C, a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

23. X is a halogen; R ３Ｃ But C ６～１０ Aryl-substituted C １～６ is alkyl, R ｃ But C １～６ is alkyl, R ｉ , R ｉｉ , R ｘ and R ｙ are each independently H; 23. The compound of claim 22, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

24. The compound is 【Chemistry 20】 23. The compound of claim 22, represented by: or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition for preventing or treating a disease associated with abnormal activity of Src homology region 2 domain-containing phosphatase-2 (SHP2), comprising the compound according to any one of claims 1 to 24, or a stereoisomer, solvate, isotope-labeled compound, or a pharmaceutically acceptable salt thereof.

26. 26. The pharmaceutical composition of claim 25, wherein the disease associated with the abnormal activity of SHP2 is selected from the group consisting of cancer, cancer metastasis, cardiovascular disease, immune disorders, fibrosis, and eye disorders.

27. 26. 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 SHP2 activity, comprising the step of administering to a subject the compound according to any one of claims 1 to 24, or a stereoisomer, solvate, or isotope-labeled compound, 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 isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

30. 25. The compound according to any one of claims 1 to 24, or a stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of 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 isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for preventing or treating a disease associated with abnormal activity of SHP2.

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