SHP2 inhibitors and their use

Abstract

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

Description

Detailed description of the invention

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

[0002] This invention 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.

[0003] [Background technology] Src homologous region 2-domain phosphatase-2 (SHP2) is a protein tyrosine phosphatase (PTP), also known as PTPN11 (protein tyrosine phosphatase nonreceptor type 11), PTP-1D (protein tyrosine phosphatase 1D), or PTP-2C (protein tyrosine phosphatase 2C). SHP2 is known as a signaling molecule that regulates various cellular functions, including cell growth, differentiation, the cell cycle, and oncogenic transformation. SHP2, along with SHP1, consists of two tandem SH2 domains at its N-terminus. In the inactive state, the N-terminal SH2 domain binds to the PTP domain, preventing substrate binding to the active site and thereby inhibiting SHP2. When a phosphotyrosyl residue binds, 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 associated with cancers such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colorectal cancer, head cancer, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma, glioblastoma, pancreatic cancer, biliary tract cancer, uterine cancer, endometrial cancer, liver cancer, and neurofibromatosis type 1.

[0005] Therefore, there is a need to develop novel compounds that can inhibit the activity of SHP2, methods for preparing them, pharmaceutical compositions containing them, and methods for preventing or treating diseases related to abnormal SHP2 activity using them.

[0006] [Detailed description of the invention] [Technical issues] The present invention provides novel compounds capable of inhibiting the activity of SHP2, their stereoisomers or solvates, or pharmaceutically acceptable salts thereof.

[0007] This invention provides a pharmaceutical composition for preventing or treating diseases associated with abnormal activity of SHP2, using a novel compound capable of inhibiting SHP2 activity, its stereoisomer or solvate, or pharmaceutically acceptable salt thereof.

[0008] This invention provides a method for preventing or treating diseases associated with abnormal activity of SHP2, using novel compounds capable of inhibiting SHP2 activity, their stereoisomers or solvates, or pharmaceutically acceptable salts thereof.

[0009] The present invention provides novel compounds capable of inhibiting SHP2 activity, their stereoisomers or solvates, or pharmaceutically acceptable salts thereof.

[0010] Solving the problem Each description and embodiment disclosed herein may also apply 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 any specific description below.

[0011] In one aspect, provided is a compound represented by Formula 1A, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.

[0012] [Formula 1A] [Chemical Structure] The compound represented by Formula 1A may have a structure in which a pyrazine ring, a ring A, and a condensed ring of a benzene ring are connected via a sulfide group (-S-), and the pyrazine ring and a piperidine ring are connected.

[0013] In Formula 1A, R 1 is H, halogen, hydroxy, cyano or C1-C6 haloalkyl. In some embodiments, R 1 can be H, halogen or C1-C6 haloalkyl. In some embodiments, R 1 can be halogen or C1-C3 haloalkyl. In some embodiments, R 1 can be halogen. For example, R 1 can be F or Cl.

[0014] In Formula 1A, R 2 is H, halogen, hydroxy, oxo, C1-C 20 alkyl, C1-C 20 alkoxy, C1-C 20 haloalkyl, hydroxy-(C1-C 20 alkyl)-, C2-C 20 alkoxyalkyl (e.g., (C1-C 10 alkoxy)-(C1-C 10 alkyl)-), C1-C 20 alkyl substituted with an amine group (e.g., H2N-(C1-C 20 alkyl)-), an amine group (e.g., -NH2, -NH(C1-C 20 alkyl), -N(C1-C 20Alkyl)2), imine group (e.g., =NH), nitro, cyano, amidino, -C(O)NH2, -C(O)(C1~C 20 Alkyl), -C(O)O(C1~C 20 Selected from the group consisting of alkyl, carboxy, or salts thereof.

[0015] In some embodiments, R 2 The group can be selected from H, halogen, hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy-(C1-C6 alkyl)-, (C1-C6 alkoxy)-(C1-C6 alkyl)-, H2N-(C1-C6 alkyl)-, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, nitro, cyano, amidino, -C(O)NH2, -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), and carboxy or salts thereof. In some embodiments, R 2 The group can be selected from H, halogen, hydroxy, oxo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxy-(C1-C3 alkyl)-, (C1-C3 alkoxy)-(C1-C3 alkyl)-, H2N-(C1-C3 alkyl)-, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, nitro, cyano, -C(O)NH2, -C(O)(C1-C3 alkyl), -C(O)O(C1-C3 alkyl), and carboxy or salts thereof. In some embodiments, R 2 R can be selected from the group consisting of H, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-(C1-C6 alkyl)-, -NH2, -C(O)NH2 and -C(O)(C1-C6 alkyl). In some embodiments, R 2 The group can be selected from H, C1-C3 alkyl, hydroxy-(C1-C3 alkyl)-, -NH2, -C(O)NH2, and -C(O)(C1-C3 alkyl).

[0016] In some embodiments, R 2This may include H, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, amino, methylcarbonyl(acetyl), ethylcarbonyl(propanoyl), carbamoyl, etc. For example, R 2 This can be H, -CH3, -CH2OH, -NH2, -C(O)NH2, or -C(O)CH3.

[0017] In equation 1A, p is an integer between 0 and 2. In some embodiments, when p is 2, two R 2 They may be the same or different from one another.

[0018] In formula 1A, the positional numbers of the atoms constituting the pyrazine ring are [ka] It is also acceptable. In this case, [ka] The symbol indicates the bond position with the sulfur atom, and the asterisk (*) indicates the bond position with the nitrogen atom of the piperidine ring.

[0019] In some embodiments, R 2 The pyrazine ring may be bonded at the 3rd and / or 6th positions. For example, R 2 R is a halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NH2, or cyano, and may be bonded to the 3-position of the pyrazine ring. In some embodiments, R 2 is hydroxy-(C1-C6 alkyl)-, -C(O)NH2 or -C(O)(C1-C6 alkyl)-, and may be bonded at the 6-position of the pyrazine ring. In some embodiments, when p is 2, R 2 These can be attached to positions 3 and 6 of the pyrazine ring, respectively.

[0020] In equation 1A, R 3 and R 4Each of these may independently be H, a C1-C6 alkyl group, an amine group (e.g., -NH2, -NH(C1-C6 alkyl)), -N(C1-C6 alkyl)2), or a C1-C6 alkyl group substituted with an amine group (e.g., H2N-(C1-C6 alkyl)-), and R 3 and R 4 They may bond to each other to form ring B. For example, R 3 and R 4 When the elements bond to each other to form ring B, a spiropolycyclic ring containing ring B and a piperidine ring may be formed.

[0021] Ring B may contain one oxygen atom and is a 3- to 8-membered cyclic ring group that is optionally substituted. Ring B may optionally be fused with a cycloalkyl, aryl, or heteroaryl ring. The cycloalkyl, aryl, or heteroaryl ring fused with ring B is optionally substituted.

[0022] In some embodiments, R 3 and R 4 Each of these can independently be H, C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, or H2N-(C1-C3 alkyl)-. In some embodiments, R 3 and R 4 One of them may be a C1-C3 alkyl group, and the other may be -NH2 or H2N-(C1-C3 alkyl)-. In one embodiment, R 3 R can be methyl or ethyl, 4 R can be amino, aminomethyl, or aminoethyl. For example, R 3 It can be methyl, R 4 It may be amino or aminomethyl.

[0023] In some embodiments, ring B may be a C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl ring containing one oxygen atom. Ring B has at least one R B It may be substituted in some cases. In some embodiments, ring B may contain one oxygen atom and may contain at least one RB It may be a C4-C6 cycloalkyl or 4-6 membered heterocycloalkyl ring substituted with a cyclopentane ring. For example, ring B may be a cyclopentane ring or a tetrahydrofuran ring.

[0024] R B This can be selected from the group consisting of deuterium, (C1-C6 alkyl), amine groups (e.g., -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2) and C1-C6 alkyl substituted with amine groups (e.g., H2N-(C1-C6 alkyl)-). In some embodiments, R B The group can be selected from deuterium, (C1-C3 alkyl), -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, and H2N-(C1-C3 alkyl)-. In some embodiments, ring B is at least one R selected from deuterium, C1-C3 alkyl and -NH2. B It is replaced depending on the case. For example, R B This can be one or more selected from deuterium, methyl, and -NH2.

[0025] In some embodiments, ring B may be a C3-C8 cycloalkyl, C6-C 10 It may be condensed with a ring BB selected from a 5- to 10-membered heteroaryl group containing an aryl group and one or two heteroatoms selected from N, O, and S. In this case, the ring BB may optionally contain at least one R BB It may be substituted in some cases. In some embodiments, the ring BB is a C3-C6 cycloalkyl, C6-C 10 The ring BB can be selected from an aryl group and a 5- to 7-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S. For example, the ring BB may be a C3- to C6 cycloalkyl ring, a benzene ring, a pyridine ring, or a thiazole ring.

[0026] In some embodiments, ring B is a cyclopentane ring and may be fused with ring BB selected from a cyclopropane ring, a benzene ring, a pyridine ring, and a thiazole ring. In some embodiments, ring B is a tetrahydrofuran ring and may be fused with ring BB selected from a benzene ring and a pyridine ring.

[0027] R BB The group can be selected from halogens, hydroxyl, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy-(C1-C6 alkyl)-, (C1-C6 alkoxy)-(C1-C6 alkyl)-, H2N-(C1-C6 alkyl)-, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, nitro, cyano, and amidino. In some embodiments, R BB The group can be selected from halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxy-(C1-C3 alkyl)-, (C1-C3 alkoxy)-(C1-C3 alkyl)-, H2N-(C1-C3 alkyl)-, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, nitro, and cyano. In some embodiments, R BB R can be at least one selected from the group consisting of halogens, cyano, hydroxy, C1-C3 alkyl and C1-C3 alkoxy. For example, R BB This can be one or more selected from the group consisting of halogen, cyano, hydroxy, methyl, and methoxy.

[0028] In some embodiments, Formula 1A [ka] The structure is as follows: [ka] , and [ka] It can be selected from the following.

[0029] In the above structure, R 41 q may be a C1-C3 alkyl group, and q may be an integer from 0 to 3. For example, R 41 may be methyl, and q may be 0 or 1.

[0030] In the above structure, ring B is at least one R selected from deuterium, methyl and -NH2. B It may be substituted in some cases. Furthermore, ring BB is at least one R selected from the group consisting of halogen, cyano, hydroxy, methyl and methoxy BB It may be replaced depending on the circumstances.

[0031] For example, equation 1A [ka] The structure is as follows: [ka] , and [ka] It can be selected from the following.

[0032] (In the above structure, R 41 (where is methyl and q is 0 or 1) In this case, ring B is at least one R selected from methyl and -NH2. B The ring BB is optionally substituted, and the ring BB is at least one R selected from the group consisting of halogen, cyano, hydroxy, methyl and methoxy BB It may be replaced depending on the circumstances.

[0033] In some embodiments, Formula 1A [ka] The structure is as follows: [ka] [ka] JPEG0007843785000013.jpg25149 , and [ka] It can be selected from the following.

[0034] For example, equation 1A [ka] The structure is as follows: [ka] , and [ka] It can be selected from the following.

[0035] Furthermore, Equation 1A [ka] This may include corresponding structures disclosed in International Publication No. 2019 / 183367, International Publication No. 2020 / 063760, International Publication No. 2020 / 201991, International Publication No. 2020 / 081848, International Publication No. 2020 / 073949, International Publication No. 2021 / 197452, International Publication No. 2021 / 147879, International Publication No. 2020 / 049079, International Publication No. 2021 / 218752, International Publication No. 2021 / 218755, International Publication No. 2022 / 017444, International Publication No. 2021 / 115286, International Publication No. 2021 / 088944, etc., or structures readily derivable by a person skilled in the art.

[0036] In Equation 1A, [ka] The following fused ring structure: [ka] and [ka] Selected from.

[0037] In the above condensed ring structure, [ka] A single or double bond is formed depending on the valence allowed by the ring element. (For example, a nitrogen atom allows for three bonds, and a carbon atom allows for four bonds.)

[0038] For example, if X is N, Y is N, and Z is C(O), then between X and Z [ka] It is a single bond, CR 6 Between Y [ka] This is a double bond. For example, W is C, U is N, and V is NR 6 If so, between V and W [ka] It is a single bond between W and U. [ka] Since it is a double bond, it is shared by the 5-membered ring and the 6-membered ring. [ka] It is a double bond. For example, if W and U are N and V is CH, then between each of V and U and each carbon atom shared by the 6-membered ring [ka] It is a double bond between W and V [ka] and between W and U [ka] Since it is a single bond, it is shared by the 5-membered ring and the 6-membered ring. [ka] It is a single bond.

[0039] In the above condensed ring structure, X can be N or C, Y can be N, CH or CH2, and Z can be C(O), S(O)2, or N. In this case, when Z is N, X is C and Y is CH, and when Z is S(O)2, both X and Y are N.

[0040] In some embodiments, in the above condensed ring structure, X can be N or C, Y can be N, CH or CH2, and Z can be C(O) or S(O)2. In this case, when Z is S(O)2, both X and Y can be N.

[0041] In the above condensed ring structure, U is N, NR 6 or CHR 6 It may also be CH, C(O), S, O, N, or NR 6 It may be that W is N or C. In this case, if W is C, then one of U and V is N and the other is S, O or NR. 6 Furthermore, if W is N, then U is CHR 6 And V is C(O), or U is N and V is CH. One or two of U, V, and W are N.

[0042] In some embodiments, in the above condensed ring structure, U is N or NR 6 It could be CH, N, or NR 6 It is possible that W is N or C. In this case, when W is C, one of U and V is N and the other is NR 6 Therefore, if W is N, then U is N and V is CH.

[0043] In some embodiments, the formula 1A [ka] The structure is as follows: [ka] [ka] , and [ka] It can be selected from the following.

[0044] In some embodiments, [ka] The structure is as follows: [ka] [ka] , and [ka] It can be selected from the following.

[0045] R 5 These are, independently, H, halogen atom, hydroxyl group, ketone group, and C1-C1. 20 Alkyl, C1-C 20 Alkoxy, C2~C 20 Alkoxyalkyl groups, amine groups, C1-C substituted with amine groups 20 Alkyl, imine group, nitro, cyano, amidino, carboxyl group or salt thereof, C1-C 20 Heteroalkyl, C3~C 20 Heterocycloalkyl, C6~C 20 Aryl, C6~C 20 Arylalkyl, C1-C 20 Heteroaryl, C1~C 20 Heteroarylalkyl, C1-C 20 Heteroaryloxy, C1~C 20 Heteroaryloxyalkyl and C3-C 20Heterocycloalkyl, and polycyclic C5-C 12 It may be selected from the group consisting of heteroarylalkyl.

[0046] R 5 may be H, a C1-C6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted thiazolylalkyl group, a substituted or unsubstituted imidazolylalkyl group, a substituted or unsubstituted pyrrolidinylalkyl group, a substituted or unsubstituted pyridinylalkyl group, a substituted or unsubstituted pyrimidinylalkyl group, a substituted or unsubstituted pyrazinylalkyl group, a substituted or unsubstituted benzimidazolylalkyl group, or a substituted or unsubstituted pyrrolopyridinylalkyl group. The phenyl group, benzyl group, thiazolylalkyl group, imidazolylalkyl group, pyrrolidinylalkyl group, pyridinylalkyl group, pyrimidinylalkyl group, pyrazinylalkyl group, benzimidazolylalkyl group, or pyrrolopyridinylalkyl group may be unsubstituted, halogen, C1-C6 alkyl substituted with a halogen atom, -CN, -NH2, -NO2, -OR a , and -SO2R a is optionally substituted with at least one substituent selected from the group consisting of. C1-C6 alkyl substituted with a halogen atom may be -CF3. R a may be H, a halogen atom, or C1-C6 alkyl substituted with a halogen atom. -OR a may be -OCH3. -SO2R a may be -SO2F.

[0047] In one embodiment, in the above condensed ring structure, R 5 are each independently the following (i)-(vi): (i) H, halogen, hydroxy, an amine group (-NH2 etc.), an imine group (=NH etc.), -C(O)NH2, nitro, cyano, amidino or carboxy or salts thereof; (ii) halogen, hydroxy, C1-C 20 alkyl, C1-C 20 haloalkyl, C1-C 20Alkoxy, C1-C 20 C1-C12 20 Alkyl or C1-C 20 Alkoxy; (iii) C6~C 20 Ariel, (C6~C 12 Aryl)-(C1~C8 alkyl)-, C6~C 20 Aryloxy, (C6~C 12 Aryloxy)-(C1~C8 alkyl)-, C6~C 20 Arylcarbonyl, (C6~C 12 Arylcarbonyl)-(C1~C8 alkyl)-,-CONH-(C6~C 12 aryl), -CONH-(C1~C8 alkyl)-(C6~C 12 Aaryl), -NHCO-(C6~C 12 aryl) or -NHCO-(C1~C8 alkyl)-(C6~C 12 Aryl; (iv) heteroaryl, heteroaryl-(C1~C8 alkyl)-, heteroaryloxy, heteroaryloxy-(C1~C8 alkyl)-, heteroarylcarbonyl, heteroarylcarbonyl-(C1~C8 alkyl)-, -CONH-heteroaryl, -CONH-(C1~C8 alkyl)-heteroaryl, -NHCO-heteroaryl or -NHCO-(C1~C8 alkyl)-heteroaryl (where the heteroaryl ring may be a 4-10 membered heteroaryl containing at least one heteroatom selected from N, O and S, or the heteroaryl ring may be C1~C 20 It may be a heteroaryl ring; (v) Heterocycloalkyl, heterocycloalkyl-(C1~C8alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C1~C8alkyl)-, heterocycloalkylcarbonyl, heterocycloalkylcarbonyl-(C1~C8alkyl)-, -CONH-heterocycloalkyl, -CONH-(C1~C8alkyl)-heterocycloalkyl, -NHCO-heterocycloalkyl or -NHCO-(C1~C8alkyl)-heterocycloalkyl (where the heterocycloalkyl ring may be a 3-10 member fully saturated or partially unsaturated heterocycloalkyl containing at least one heteroatom selected from N, O and S, or the heterocycloalkyl ring may be C3-C 20 It may be heterocycloalkyl; and (vi) C3~C 10 Cycloalkyl, (C3~C 10 Cycloalkyl)-(C1~C8 alkyl)-, C3~C 10 Cycloalkyloxy, (C3~C 10 Cycloalkyloxy)-(C1~C8 alkyl)-, C3~C 10 Cycloalkylcarbonyl, (C3~C 10 Cycloalkylcarbonyl)-(C1~C8 alkyl)-,-CONH-(C3~C 10 Cycloalkyl), -CONH-(C1~C8 alkyl)-(C3~C 10 Cycloalkyl), -NHCO-(C3~C 10 Cycloalkyl) or -NHCO-(C1~C8 alkyl)-(C3~C 10 Cycloalkyl) It can be selected from the following.

[0048] R' and R'' are independently H or C1~C 10 It is alkyl. In some embodiments, R' and R'' may each be independently H or a C1-C6 alkyl group. For example, R' and R'' may each be independently H or a C1-C3 alkyl group. Also, R' and R'' may each be independently H, methyl, or ethyl.

[0049] The aryl rings, heteroaryl rings, heterocycloalkyl rings, and cycloalkyl rings described in (iii) to (vi) above may be substituted as appropriate. In (iii) to (vi) above, "aryl ring," "heteroaryl ring," "heterocycloalkyl ring," and "cycloalkyl ring" are used to refer collectively to the ring portion of substituents to which the ring is bonded together with other chemical structures. For example, "aryl ring" is used to refer collectively to the aryl and aryl rings included in arylalkyl, aryloxy, aryloxyalkyl, arylcarbonyl, arylcarbonylalkyl, -CONH-aryl, -CONH-alkyl-aryl, -NHCO-aryl, and -NHCO-alkyl-aryl.

[0050] In some embodiments, R 5 Each of them operates independently. (i) H, halogen, hydroxyl, -NH2, =NH, -C(O)NH2, nitro, cyano, amidino or carboxyl or their salts (e.g., H, halogen, hydroxyl, -NH2, -C(O)NH2, nitro, cyano or carboxyl or their salts); (ii) C1-C6 alkyl or C1-C6 alkoxy, optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -NR'R'', R'C(O)-, R'S(O)2-, R'S(O)2NR''-, R''R'NC(O)- and R'C(O)NR''- (e.g., H, halogen, hydroxyl, -NH2, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkoxy)-(C1-C6 alkyl)- or (C1-C6 alkoxy)-(C1-C6 alkoxy)-); (iii) C6~C 10 Ariel, (C6~C 10 Aryl)-(C1~C5 alkyl)-, C6~C 10 Aryloxy, (C6~C 10 Aryloxy)-(C1~C5 alkyl)-, C6~C 10 Arylcarbonyl, (C6~C10 Arylcarbonyl)-(C1~C5 alkyl)-,-CONH-(C6~C 10 aryl), -CONH-(C1~C5 alkyl)-(C6~C 10 Aaryl), -NHCO-(C6~C 10 aryl) or -NHCO-(C1~C5 alkyl)-(C6~C 10 (Aryl) (For example, C6~C 10 Ariel, (C6~C 10 Aryl)-(C1~C3 alkyl)-, C6~C 10 Aryloxy, (C6~C 10 Aryloxy)-(C1~C3 alkyl)-, C6~C 10 Arylcarbonyl, or (C6~C 10 It is an arylcarbonyl)-(C1~C3 alkyl)-, and the aryl ring has at least one R 5a This may be replaced depending on the circumstances. (iv) heteroaryl, heteroaryl-(C1~C5 alkyl)-, heteroaryloxy, heteroaryloxy-(C1~C5 alkyl)-, heteroarylcarbonyl, heteroarylcarbonyl-(C1~C5 alkyl)-, -CONH-heteroaryl, -CONH-(C1~C5 alkyl)-heteroaryl, -NHCO-heteroaryl or -NHCO-(C1~C5 alkyl)-heteroaryl (for example, heteroaryl, heteroaryl-(C1~C3 alkyl)-, heteroaryloxy, heteroaryloxy-(C1~C3 alkyl)-, heteroarylcarbonyl, or heteroarylcarbonyl-(C1~C3 alkyl)- (wherein the formula, the heteroaryl ring is a 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S; containing 1 or 2 heteroatoms selected from N, O and S, and at least 1 R 5a (In some cases, these are substituted, or 5 or 6-membered monocyclic heteroaryls or 9 or 10-membered bicyclic heteroaryls); (v) Heterocycloalkyl, heterocycloalkyl-(C1~C5alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C1~C5alkyl)-, heterocycloalkylcarbonyl, heterocycloalkylcarbonyl-(C1~C5alkyl)-, -CONH-heterocycloalkyl, -CONH-(C1~C5alkyl)-heterocycloalkyl, -NHCO-heterocycloalkyl or -NHCO-(C1~C5alkyl)-heterocycloalkyl (for example, heterocycloalkyl, heterocycloalkyl-(C1~C3alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C1~C3alkyl)-, heterocycloalkylcarbonyl, or heterocycloalkylcarbonyl-(C1~C3alkyl)-, where the heterocycloalkyl ring is a 3-10 member fully saturated or partially unsaturated heterocycloalkyl containing one or three heteroatoms selected from N, O, and S, or containing one or two heteroatoms selected from N, O, and S, and at least one R 5a (where 4-7 member fully saturated or partially unsaturated heterocycloalkyl groups are substituted in some cases); or (vi) C3~C8 cycloalkyl, (C3~C8 cycloalkyl)-(C1~C5 alkyl)-, C3~C8 cycloalkyloxy, (C3~C8 cycloalkyloxy)-(C1~C5 alkyl)-, C3~C8 cycloalkylcarbonyl, (C3~C8 cycloalkylcarbonyl)-(C1~C5 alkyl)-, -CONH-(C3~C8 cycloalkyl), -CONH-(C1~C5 alkyl)-(C3~C8 cycloalkyl), -NHCO-(C3~C8 cycloalkyl (C1~C5 alkyl) or -NHCO-(C3~C8 cycloalkyl) (for example, C4~C8 cycloalkyl, (C4~C8 cycloalkyl)-(C1~C3 alkyl)-, C4~C8 cycloalkyloxy, (C4~C8 cycloalkyloxy)-(C1~C3 alkyl)-, C4~C8 cycloalkylcarbonyl, or (C4~C8 cycloalkylcarbonyl)-(C1~C3 alkyl)-, where the cycloalkyl ring has at least one R 5a (This may be replaced depending on the circumstances.) Selected from.

[0051] R' and R'' are independently H or C1~C 10 It is alkyl. In some embodiments, R' and R'' may each be independently H or a C1-C6 alkyl group. For example, R' and R'' may each be independently H or a C1-C3 alkyl group. Also, R' and R'' may each be independently H, methyl, or ethyl.

[0052] R 5a The group can be selected from halogens, hydroxyl, -NH2, -NH(C1~C6 alkyl), -N(C1~C6 alkyl)2, cyano, oxo, nitro, C1~C6 alkyl, C1~C6 alkoxy; halogens, hydroxyl, C1~C6 alkoxy, C1~C6 alkyl substituted with -NH2 or cyano; halogens, hydroxyl, C1~C6 alkyl, C1~C6 alkoxy substituted with -NH2 or cyano; and halogens -SO2-, (C1~C6 alkyl)-SO2-, -SO2NH2, -SO2NH(C1~C6 alkyl), and -SO2N(C1~C6 alkyl)2. In some embodiments, R 5a The group can be selected from halogen, hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy-(C1-C6 alkyl)-, (C1-C6 alkoxy)-(C1-C6 alkyl)-, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, nitro, cyano, halogen-SO2-, (C1-C6 alkyl)-SO2-, and -SO2NH2.

[0053] In one embodiment, R 5 Each of these is independent of the following (i)~(vi) (i) H, halogen, hydroxyl, -NH2, -C(O)NH2, nitro, cyano or carboxyl, or salts thereof; (ii) C1-C6 alkyl; C1-C6 alkoxy; or (C1-C6 alkoxy)-(C1-C6 alkoxy)- (wherein R' and R'' are independently H or C1-C3 alkyl); optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -NR'R'', R'C(O)-, R'S(O)2-, R'S(O)2NR''-, R''R'NC(O)-, and R'C(O)NR''-); (iii) Phenyl, phenyl-(C1-C3 alkyl)-, phenyloxy, phenyloxy-(C1-C3 alkyl)-, phenylcarbonyl, or phenylcarbonyl-(C1-C3 alkyl)-, (the phenyl ring has at least one R 5a It may be replaced depending on the circumstances); (iv) Selected from the group consisting of heteroaryl, heteroaryl-(C1~C3 alkyl)-, heteroaryloxy, heteroaryloxy-(C1~C3 alkyl)-, heteroarylcarbonyl, or heteroarylcarbonyl-(C1~C3 alkyl)- (the heteroaryl ring is selected from the group consisting of pyrrolyl, furanil, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, indolyl, benzofuranil, benzothiophenyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, and 1H-pyrrolo[2,3-b]pyridinyl, with at least one R 5a It may be replaced depending on the circumstances); (v) Selected from the group consisting of heterocycloalkyl, heterocycloalkyl-(C1~C3 alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C1~C3 alkyl)-, heterocycloalkylcarbonyl, or heterocycloalkylcarbonyl-(C1~C3 alkyl)- (where the heterocycloalkyl ring is azilidinyl, oxylanil, oxetanil, azetidinil, pyrrolidinyl, tetrahydrofuranil, tetrahydrothiophenyl, piperidinyl, tetrahydropyranil, 4H-pyranil, 3,6-dihydro-2H-pyranil, 3,4-dihydro-2H-pyranil, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridinyl, piperazinyl, morpholinil, thiomorpholinil, oxazolidinyl, and 2-oxo-oxazolidinyl, and at least one R 5a This may be replaced depending on the circumstances); and (vi) C5-C7 cycloalkyl, (C5-C7 cycloalkyl)-(C1-C3 alkyl)-, C5-C7 cycloalkyloxy, (C5-C7 cycloalkyloxy)-(C1-C3 alkyl)-, C5-C7 cycloalkylcarbonyl, or (C5-C7 cycloalkylcarbonyl)-(C1-C3 alkyl)-(where the cycloalkyl ring has at least one R 5a (May be replaced depending on the circumstances) It can be selected from the following.

[0054] In this case, R 5a The group is selected from halogen, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxy-(C1-C3 alkyl)-, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, nitro, cyano, -SO2F, and -SO2Cl.

[0055] In one embodiment, the heteroaryl ring of (iii) may be selected from the group consisting of pyridinyl, pyrazolyl, isoxazolyl, furanyl, pyrimidinyl, thiazolyl, pyrazinyl, benzimidazolyl, benzoxazolyl, and 1H-pyrrolo[2,3-b]pyridinyl. Furthermore, the heterocycloalkyl ring of (iv) may be selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 3,6-dihydro-2H-pyranyl, morpholinyl, oxetanyl, piperidinyl, and 2-oxo-oxazolidinyl.

[0056] For example, R 5 R is selected from the group consisting of phenyl, benzyl, 1-phenylethyl, phenoxy, pyridinylmethyl, pyridinyloxy, pyridinylcarbonylmethyl, pyrazolylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, isoxazolylmethyl, tetrahydrofuranylmethyl, tetrahydrofuranyloxy, tetrahydropyranylmethyl, 3,6-dihydro-2H-pyranylmethyl, morpholinylmethyl, oxetanylmethyl, piperidinylcarbonylmethyl, 2-oxo-oxazolidinylethyl, 2-oxo-oxazolidinylmethyl, furanylmethyl, pyrimidinylmethyl, thiazolylmethyl, pyrazinylmethyl, benzimidazolylmethyl, benzoxazolylmethyl, 1H-pyrrolo[2,3-b]pyridinylmethyl, and cyclohexyl, where R 5 This includes at least one R selected from the group consisting of at least one F, Cl, OH, -CH3, -OCH3, cyano, oxo, -NH2, NO2, SO2F, and CF3. 5a It may be replaced depending on the circumstances.

[0057] In some embodiments, R 5 The structure is as follows: H, CH3-, HOCH2CH2-, HOCH2CH2CH2-, CF3CH2-, CF3CH2CH2-, [ka] , FCH2CH2CH2-, [ka] [ka] , and [ka] It can be selected from the following.

[0058] (In the above structure, [ka] (This indicates the binding position with the remaining residues of the compound.) In the above condensed ring structure, R 6 is H or C1-C6 alkyl. In some embodiments, R 6 This can be H or C1-C3 alkyl. In some embodiments, R 6 This can be H or methyl.

[0059] In some embodiments, the compound represented by formula 1A may be the compound represented by the following formula 1A-1.

[0060] [C1A-1] [ka] In formula 1A-1, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 The definitions of ring B and p are as described above for equation 1A.

[0061] In some embodiments, the compound represented by formula 1A may be selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] , and [ka] In some embodiments, the compound represented by formula 1A may be a compound represented by any one of the following formulas 1A-2 to 1A-9.

[0062] [Formula 1A-2] [ka] [Formula 1A-3] [ka] [Formula 1A-4] [ka] [Formula 1A-5] [ka] [Formula 1A-6] [ka] [Formula 1A-7] [ka] [Formula 1A-8] [ka] [Formula 1A-9] [ka] In equations 1A-2 to 1A-9, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 The definitions of ring B and p are as described above for equation 1A.

[0063] In one embodiment, the compound may be a compound of formula 1A-4, 1A-5, 1A-8, or 1A-9.

[0064] In compounds of formula 1A-4, 1A-5, 1A-8, or 1A-9, the formula 1A [ka] teeth [ka] Therefore, U, V, and W are defined as follows:

[0065] W is N, U is N, V ​​is CH, or U is CHR 6 And V is C(O); or W is C, and either U or V is N, and the other is NR 6 That is the case.

[0066] In one embodiment, R of formulas 1A-4, 1A-5, 1A-8, or 1A-9 5 (i)~(vi) (i) H, halogen, hydroxyl, -NH2, =NH, -C(O)NH2, nitro, cyano, amidino or carboxyl or their salts; (ii) C1-C6 alkyl; C1-C6 alkoxy; or (C1-C6 alkoxy)-(C1-C6 alkoxy)- (for example, C1-C6 alkyl, C1-C6 alkoxy, or (C1-C6 alkoxy)-(C1-C6 alkoxy)-, and may be methyl, ethyl, methoxy, ethoxy, methoxyethoxy, ethoxyethoxy, etc.); (iii) C6~C 10 Ariel, (C6~C 10 Aryl)-(C1~C3 alkyl)- or C6~C 10 Aryloxy (for example, the aryl ring may be phenyl); (iv) heteroaryl, heteroaryl-(C1-C3 alkyl)-, or heteroaryloxy (for example, the heteroaryl ring may be a 5-membered or 6-membered monocyclic heteroaryl containing one or two N atoms, for example, the heteroaryl ring may be a pyrimidinyl or pyridinyl); (v) heterocycloalkyl, heterocycloalkyl-(C1~C3 alkyl)- or heterocycloalkyloxy (for example, a heterocycloalkyl may be a 4-7 member fully saturated or partially unsaturated heterocycloalkyl containing one or two heteroatoms selected from N and O, for example the heterocycloalkyl ring may be tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl or morpholinyl); and (vi) C3-C8 cycloalkyl, C3-C8 cycloalkyl-(C1-C3 alkyl)-, or C3-C8 cycloalkyloxy It can be selected from the following.

[0067] The aryl rings, heteroaryl rings, heterocycloalkyl rings, and cycloalkyl rings described in (iii) to (vi) above are optionally substituted. For example, these rings are optionally substituted with at least one substituent selected from halogens, hydroxyl, oxo, -NH2, cyano, nitro, C1-C6 alkyl, and C1-C6 alkoxy.

[0068] In one embodiment, R of formulas 1A-4, 1A-5, 1A-8, or 1A-9 5 This can be C1-C6 alkyl (e.g., methyl, ethyl), benzyl, phenyl, phenoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, methoxy, ethoxy, methoxyethoxy, ethoxyethoxy, pyridinyl, pyridinyloxy, pyridinylmethyl, pyrimidinyl, pyrimidinylmethyl, pyrimidinyloxy, methoxyphenyl, or methoxybenzyl.

[0069] In some embodiments, the compounds represented by formulas 1A-2 to 1A-9 may be selected from the following: [ka] [ka] , and [ka]

[0070] In some embodiments, the pyrazine core of the compound represented by formula 1A may be replaced with another heteroaryl ring, such as a 5- to 10-membered heteroaryl ring containing a nitrogen atom. The 5- to 10-membered heteroaryl ring containing a nitrogen atom may include pyridine, pyridazine, pyrimidine, triazine, imidazopyrimidine, pyrazolopyrazine, or pyrazolopyrimidine.

[0071] In this case, the compound represented by formula 1A may also be represented by the following formula 1.

[0072] [Formula 1] [ka] In Equation 1, ring D is selected from the following structures. [ka] , and [ka] (* indicates the bond position with the sulfur atom) R 1 , R 2 , R 3 , R 4 The definitions of ring A, ring B, and p are as described above for equation 1A.

[0073] Among the compounds represented by formula 1, those having a structure other than a pyrazine core as ring D include, for example, the following: [ka] [ka] and [ka] It is a compound represented by [formula].

[0074] In one embodiment, a compound represented by the following formula 2, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof is provided.

[0075] [Formula 2] [ka] In equation 2, T may be C or N.

[0076] In formula 2, R 7 This may be H, a halogen atom, or a C1-C6 haloalkyl group.

[0077] In formula 2, R 8 -COOR c , -SO2R c -SO2NR c R d , -COR c , -NHCOR c or -CONHR c It is also acceptable. c and R d These are, independently, H, halogen, C1-C6 alkyl, and -(CH2) m -(C6~C 10 Aryl), -(CH2) m -It can be a (5- to 10-membered heteroaryl). m may be an integer of 0, 1, or 2.

[0078] C6~C 10 The aryl group can be phenyl. A 5- to 10-membered heteroaryl group may contain one or two heteroatoms selected from N, O, and S. For example, a 5- to 10-membered heteroaryl group may be a 5- or 6-membered heteroaryl group containing one or two N atoms (e.g., pyrrolyl, pyridinyl, pyrimidinyl, etc.).

[0079] In one embodiment, R 8 This can be -CONH-CH2-phenyl, -CONH-CH2-pyridinyl, -COOCH3, -SO2F, -SO2-NH2, -SO2-NH-CH3, or -SO2-NH-CH2-phenyl.

[0080] In Equation 2, R 9 H, halogen, hydroxyl, oxo, C1-C 20 Alkyl, C1-C 20 Alkoxy, C2~C 20 Alkoxyalkyl groups, amine groups, C1-C substituted with amine groups 20 The group may be selected from alkyl, imine, nitro, cyano, amidino, and carboxyl groups or salts thereof.

[0081] In formula 2, R 10 and R 11 Each of these may independently be H, C1-C6 alkyl, amine group, or C1-C6 alkyl substituted with an amine group, and R 10 and R 11 These elements may be linked to each other to form a ring C.

[0082] R 10 This may be an amine group or an aminomethyl group.

[0083] R 11 It may be a methyl group.

[0084] Ring C is a cyclic group of 3, 4, 5, 6, 7, or 8 members, which may contain one oxygen atom, and is optionally substituted with a C1-C6 alkyl group, an amine group, or a C1-C6 alkyl group substituted with an amine group. Ring C may be substituted or unsubstituted tetrahydrofuran. Tetrahydrofuran is optionally substituted with one or more selected from the group consisting of C1-C6 alkyl groups, amine groups, and C1-C6 alkyl groups substituted with an amine group.

[0085] Ring C may be fused with an aryl ring or a heteroaryl ring, depending on the circumstances.

[0086] In one embodiment, R 10 and R 11 These elements may be linked to each other to form a C ring, which may be cyclopentane or tetrahydrofuran, and may be optionally substituted with a C1-C6 alkyl group or -NH2 group. Furthermore, the C ring may be condensed with phenyl or pyridine.

[0087] In one embodiment, Equation 2 [ka] You can choose from the following options. [ka] and [ka] That is the case.

[0088] In Equation 2, q may be an integer of 0, 1, or 2.

[0089] The compound of formula 2 may be selected from the group consisting of the following formulas. [ka] [ka] and [ka]

[0090] In one embodiment, a compound represented by formula 3A, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof is provided.

[0091] [Formula 3A] [ka] In equation 3A, J may be omitted or may be S.

[0092] In formula 3A, G may be C or N.

[0093] In equation 3A, o may be an integer of 0, 1, 2, 3, 4, or 5. o may be an integer of 0 or 1.

[0094] In equation 3A, R 31 This may be H, a halogen atom, or a C1-C6 alkyl group substituted with a halogen atom. 31 This may be H or a halogen atom.

[0095] In equation 3A, R 32 H, halogen atom, hydroxyl group, ketone group, C1-C 20 Alkyl, C1-C 20 Alkoxy, C2~C 20 Alkoxyalkyl groups, amine groups, C1-C substituted with amine groups 20 Alkyl, imine group, nitro, cyano, amidino, carboxyl group or salt thereof, C1-C 20 Heteroalkyl, C6~C 20 Aryl, C6~C 20 Arylalkyl, C6~C 20 Heteroaryl, C6~C 20 Heteroarylalkyl, C6~C 20 Heteroaryloxy, C6~C 20 Heteroaryloxyalkyl and C6~C 20 It can be selected from the group consisting of heterocycloalkyls. 32 This includes H, halogen atoms, amine groups, -COOH or -COOR e You may choose from the group consisting of R. e This may be H, a halogen atom, or a C1-C6 alkyl group optionally substituted with a halogen atom.

[0096] In equation 3A, R 31 and R 32 These may each be halogens.

[0097] In equation 3A, R 33 and R 34 Each of these may independently be H, a C1-C6 alkyl group, an amine group, or a C1-C6 alkyl group substituted with an amine group. 33 and R 34 Each of these may independently be H, methyl, an amine group, or a C1-C6 alkyl group substituted with an amine group.

[0098] In formula 3A, R 35 R may have two or more substituents. 35 They may be the same or different from one another.

[0099] R 35 H, halogen, hydroxyl, C1-C 20 Alkyl, C1-C 20 Alkoxy, C2~C 20 C1-C substituted with alkoxyalkyl, amine, imine, nitro, cyano, amidino, or carboxyl groups 20 Alkyl or its salt, C1-C 20 Heteroalkyl, substituted or unsubstituted C6-C 20 Aryl, substituted, or unsubstituted C6-C 20 Arylalkyl, substituted or unsubstituted C6-C 20 Heteroaryl, substituted or unsubstituted C6-C 20 Heteroarylalkyl, substituted or unsubstituted C6-C 20 Heteroaryloxy, substituted or unsubstituted C6-C 20 Heteroaryloxyalkyl and substituted or unsubstituted C6-C 20 It may be at least one selected from the group consisting of heterocycloalkyls. 35 - represents H, halogen atoms, C1~C 20 C1-C atoms substituted with alkyl, amine, or amine groups. 20 Alkyl, substituted, or unsubstituted C6-C 20Aryl, substituted, or unsubstituted C6-C 20 Arylalkyl, substituted or unsubstituted C6-C 20 Heteroaryls, and substituted or unsubstituted C6-C 20 It may be at least one selected from the group consisting of heteroarylalkyls. For example, R 35 This can be a C1-C6 alkyl group or an NH2 group.

[0100] In one embodiment, a compound represented by the following formula 3B, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof is provided.

[0101] [Formula 3B] [ka] In equation 3B, J may or may not exist, or it may be S.

[0102] In equation 3B, o may be an integer of 0, 1, 2, 3, 4, or 5. o may be an integer of 0 or 1.

[0103] In equation 3B, R 31 This may be H, a halogen atom, or a C1-C6 alkyl group substituted with a halogen atom. 31 This may be H or a halogen atom.

[0104] In equation 3B, R 33 and R 34 Each of these may independently be H, a C1-C6 alkyl group, an amine group, or a C1-C6 alkyl group substituted with an amine group. 33 and R 34 Each of these may independently be H, methyl, an amine group, or a C1-C6 alkyl group substituted with an amine group.

[0105] In formula 3B, R 35 R may have two or more substituents. 35 They may be the same or different from one another.

[0106] R 35 H, halogen atom, hydroxyl group, C1-C 20 Alkyl, C1-C 20 Alkoxy, C2~C 20 C1-C substituted with alkoxyalkyl, amine, imine, nitro, cyano, amidino, or carboxyl groups 20 Alkyl or its salt, C1-C 20 Heteroalkyl, substituted or unsubstituted C6-C 20 Aryl, substituted, or unsubstituted C6-C 20 Arylalkyl, substituted or unsubstituted C6-C 20 Heteroaryl, substituted or unsubstituted C6-C 20 Heteroarylalkyl, substituted or unsubstituted C6-C 20 Heteroaryloxy, substituted or unsubstituted C6-C 20 Heteroaryloxyalkyl and substituted or unsubstituted C6-C 20 It may be at least one selected from the group consisting of heterocycloalkyls. 35 - represents H, halogen atoms, C1~C 20 C1-C atoms substituted with alkyl, amine, or amine groups. 20 Alkyl, substituted, or unsubstituted C6-C 20 Aryl, substituted, or unsubstituted C6-C 20 Arylalkyl, substituted or unsubstituted C6-C 20 Heteroaryls, and substituted or unsubstituted C6-C 20 It may be at least one selected from the group consisting of heteroarylalkyls. For example, R 35 This can be a C1-C6 alkyl group or an NH2 group.

[0107] In equation 3B, [ka] teeth [ka] That's fine.

[0108] R 21 and R 22 These are, independently, H, halogen atom, hydroxyl group, ketone group, and C1-C1. 20 Alkyl, C1-C 20 Alkoxy, C2~C 20 Alkoxyalkyl groups, amine groups, C1-C substituted with amine groups 20 Alkyl, imine, nitro, cyano, amidino, carboxyl groups or their salts, C1-C 20 Heteroalkyl, C6~C 20 Aryl, C6~C 20 Arylalkyl, C6~C 20 Heteroaryl, C6~C 20 Heteroarylalkyl, C6~C 20 Heteroaryloxy, C6~C 20 Heteroaryloxyalkyl and C6~C 20 The group consisting of heterocycloalkyls may be selected.

[0109] R 21 and R 22 These are H, C1~C, and are independent of each other. 20 C1-C atoms substituted with alkyl, amine, or amine groups. 20 Alkyl, C6~C 20 Aryl, C6~C 20 Arylalkyl, C6~C 20 Heteroaryls, and C6~C 20 The group consisting of heteroarylalkyls may be selected.

[0110] R 21 and R 22 Each of these may independently be an H group or a phenyl group.

[0111] In one embodiment, a compound represented by the following formula 3C, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof is provided.

[0112] [Formula 3C] [ka] In equation 3C, J may or may not exist, or it may be S.

[0113] In equation 3C, G may be C or N.

[0114] In formula 3C, L may be C, N, or O. When L is CH2 or NH, R 35 This is optionally substituted with a carbon or nitrogen atom of L.

[0115] In equation 3C, o may be an integer of 0, 1, 2, 3, 4, or 5. o may be an integer of 0 or 1.

[0116] In equation 3C, R 31 This may be H, a halogen atom, or a C1-C6 alkyl group substituted with a halogen atom. 1 This may be H or a halogen atom.

[0117] In equation 3C, R 32 H, halogen atom, hydroxyl group, ketone group, C1-C 20 Alkyl, C1-C 20 Alkoxy, C2~C 20 Alkoxyalkyl groups, amine groups, C1-C substituted with amine groups 20 Alkyl, imine, nitro, cyano, amidino, carboxyl groups or their salts, C1-C 20 Heteroalkyl, C6~C 20 Aryl, C6~C 20 Arylalkyl, C6~C 20 Heteroaryl, C6~C 20 Heteroarylalkyl, C6~C 20 Heteroaryloxy, C6~C 20 Heteroaryloxyalkyl and C6~C 20 The group consisting of heterocycloalkyls may be selected. 32 This includes H, halogen atoms, amine groups, -COOH or -COOR fYou may choose from the group consisting of R. f This may be H, a halogen atom, or a C1-C6 alkyl group optionally substituted with a halogen atom.

[0118] In equation 3C, R 31 and R 32 These may each be halogens.

[0119] In equation 3C, R 33 and R 34 Each of these may independently be H, a C1-C6 alkyl group, an amine group, or a C1-C6 alkyl group substituted with an amine group. 33 and R 34 Each of these may independently be H, methyl, an amine group, or a C1-C6 alkyl group substituted with an amine group. For example, R 33 and R 34 These are, independently, H, C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or H2N-(C1-C6 alkyl)-. In some embodiments, R 33 and R 34 Each of these can independently be a C1-C3 alkyl group or an -NH2 group. In some embodiments, R 33 It can be -NH2, and R 34 It can be methyl.

[0120] In formula 3C, R 35 R may have two or more substituents. 35 They may be the same or different from one another.

[0121] R 35 H, halogen atom, hydroxyl, C1-C 20 Alkyl, C1-C 20 Alkoxy, C2~C 20 C1-C substituted with alkoxyalkyl, amine, imine, nitro, cyano, amidino, or carboxyl groups 20 Alkyl or its salt, C1-C 20 Heteroalkyl, substituted or unsubstituted C6-C20 Aryl, substituted, or unsubstituted C6-C 20 Arylalkyl, substituted or unsubstituted C6-C 20 Heteroaryl, substituted or unsubstituted C6-C 20 Heteroarylalkyl, substituted or unsubstituted C6-C 20 Heteroaryloxy, substituted or unsubstituted C6-C 20 Heteroaryloxyalkyl and substituted or unsubstituted C6-C 20 It may be at least one selected from the group consisting of heterocycloalkyls. 35 - represents H, halogen atoms, C1~C 20 C1-C atoms substituted with alkyl, amine, or amine groups. 20 Alkyl, substituted, or unsubstituted C6-C 20 Aryl, substituted, or unsubstituted C6-C 20 Arylalkyl, substituted or unsubstituted C6-C 20 Heteroaryls, and substituted or unsubstituted C6-C 20 It may be at least one selected from the group consisting of heteroarylalkyls. 35 R may represent two or more substituents. For example, R 35 These are -NH2, 5-10 member heteroaryl (e.g., pyridinyl) and C6-C 10 It may be a C1-C6 alkyl group substituted with at least one substituent selected from the group consisting of aryls (e.g., phenyls).

[0122] According to some embodiments, the formula 3C [ka] The following structures can be selected. [ka] and [ka]

[0123] In some embodiments, in formulas 3A to 3C, R 35 H, halogen, hydroxyl, oxo, C1-C 20 Alkyl, C1-C 20 Alkoxy, (C1~C 10 Alkoxy)-(C1~C 10 Alkyl)-,H2N-(C1~C 20 Alkyl)-, -NH2, -NH(C1~C 20 Alkyl), -N(C1~C 20 Alkyl)2, =NH, nitro, cyano, amidino, carboxyl or their salts, heterocycloalkyl, C6~C 20 Ariel, (C6~C 12 The group is selected from aryl)-(C1~C8 alkyl)-, heteroaryl, heteroaryl-(C1~C8 alkyl)-, heteroaryloxy and heteroaryloxy-(C1~C8 alkyl)-. In this case, (C6~C 12 The -(C1~C8 alkyl)-, heteroaryl-(C1~C8 alkyl)-, and heteroaryloxy-(C1~C8 alkyl)- are optionally substituted with halogens, hydroxy, -NH2, nitro, or cyano.

[0124] In some embodiments, the compound represented by formula 3A, 3B, or 3C is the following: [ka] [ka] [ka] , and [ka] A compound can be selected from those represented by [the formula shown].

[0125] As used herein, the terms "halogen" or "halogen atom" refer to atoms belonging to Group 17 of the periodic table. Examples of halogen atoms include F, Cl, Br, and I.

[0126] The term "alkyl" refers to fully saturated branched or unbranched (or straight-chain or straight-chain) hydrocarbons. Alkyls may be substituted or unsubstituted alkyls. C1-C 20 Alkyls are, for example, C1-C 15 , C1~C 10 Alternatively, it may be a C1-C6 alkyl group. The C1-C6 alkyl group may be a C1-C5, C1-C4, C1-C3, or C1-C2 alkyl group. The alkyl group may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, isoamyl, or n-hexyl.

[0127] The term "haloalkyl" refers to an alkyl group that is substituted with at least one halogen.

[0128] The term "hydroxy" refers to the -OH functional group (hydroxyl group).

[0129] The term "oxo" refers to =O, and "oxo substitution" means that the carbon atom has an =O substituent in the form of -C(=O)-.

[0130] The term "carbonyl" refers to -C(=O)-.

[0131] The term "alkoxy" refers to alkyl groups bonded to an oxygen atom. C1~C 20 Alkoxy compounds are, for example, C1-C 15 , C1~C 10 Alternatively, it may be a C1-C6 alkoxy. The C1-C6 alkoxy may be a C1-C5, C1-C4, C1-C3, or C1-C2 alkoxy. The alkoxy may be methoxy, ethoxy, propoxy, butoxy, etc.

[0132] The term "alkoxyalkyl" refers to an alkoxy bonded to an alkyl group. C2~C 20 Alkoxyalkyls are, for example, C2-C 15 , C2~C 10 Alternatively, it may be a C2-C6 alkoxyalkyl group. For example, C2-C 20 Alkoxyalkyls are (C1~C 10 Alkoxy)-(C1~C 10 The group may be an alkyl group, a (C1-C6 alkoxy)-(C1-C6 alkyl) group, etc., and the number of carbon atoms in the alkoxy group and the alkyl group may be the same or different. Examples of alkoxy groups include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, etc.

[0133] The term "alkoxyalkoxy" refers to an alkoxy compound bonded to an alkoxy molecule. Examples of alkoxyalkoxy compounds include methoxymethoxy, methoxyethoxy, ethoxymethoxy, and ethoxyethoxy.

[0134] The term "amino" refers to -NH2.

[0135] The term "amine group" refers to a substituent in which one, two, or all three hydrogen atoms of ammonia are replaced by an organic functional group, and includes all primary, secondary, and tertiary amines, as well as amino groups.

[0136] The term "imine" refers to a functional group that contains a double bond between a carbon atom and a nitrogen atom.

[0137] The term "nitro" refers to -NO2.

[0138] The term "cyano" refers to the -CN functional group, which consists of a triple bond between a carbon atom and a nitrogen atom.

[0139] The term "amidino" refers to -C(-NH2)=NH.

[0140] The term "carboxyl" refers to the -COOH group. Carboxylate salts refer to the conjugate base of a carboxylic acid.

[0141] The term "sulfonyl" refers to the -SO2- group.

[0142] The terms "cycloalkyl," "cyclic ring," or "carbocyclic" refer to saturated or partially unsaturated non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon groups. Cyclic groups may contain 3 to 20 carbon atoms, for example, 5 to 10, 3 to 8, or 3 to 6 carbon atoms. Monocyclic groups may include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl. Bicyclic ring groups may include, for example, bornyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, or bicyclo[2.2.2]octyl. Tricyclic ring groups may include, for example, adamantyl.

[0143] The term "aryl" also includes groups in which an aromatic ring is fused to one or more carbon rings. C6~C 30 Aryl is, for example, C6~C 15 Or C6~C 10 It may be an aryl compound. The aryl compound may be phenyl, naphthyl, or tetrahydronaphthyl.

[0144] The term "arylalkyl" refers to alkyl groups that have been substituted with an aryl group.

[0145] The term "aryloxy" refers to an aryl group bonded to an oxygen atom.

[0146] 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 may contain, for example, 1 to 5, 1 to 3, 1 or 2 heteroatoms, or 5 to 10 ring members. Examples of heteroaryls include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, indolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, or benzoisothiazolyl.

[0147] The term "heteroarylalkyl" refers to alkyl groups that have been substituted with heteroaryl groups.

[0148] The term "heteroaryloxy" refers to a heteroaryl compound bonded to an oxygen atom.

[0149] The terms "heterocycloalkyl" or "heterocyclyl" refer to saturated or partially unsaturated cyclic hydrocarbons containing at least one heteroatom. The heterocyclyl ring group may be monocyclic, dicyclic, or tricyclic. The two ring groups may be spirocyclic, bridging, 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 selected from the group consisting of N, O, and S, for example, 1, 2, or 3 heteroatoms. For example, heterocycloalkyls may include azilidinyl, oxylanil, oxetanil, azetidinil, pyrrolidinyl, tetrahydrofuranil, tetrahydrothiophenyl, piperidinyl, tetrahydropyranil, dihydropyranil, morpholinil, thiomorpholinil, or oxazolidinil.

[0150] The term "heterocycloalkylalkyl" refers to alkyl groups that have been substituted with heterocycloalkyl groups.

[0151] The term "heterocycloalkyloxy" refers to a heterocycloalkyl group bonded to an oxygen atom.

[0152] A heteroatom can be one or more selected from the group consisting of N, O, P, and S. A heteroatom can be one, two, or three heteroatoms selected from the group consisting of N, O, and S.

[0153] The term "substitution" in "substituted or unsubstituted" refers to the substitution of one or more hydrogen atoms in an organic compound with another group of atoms to form a derivative, where the hydrogen atom is replaced and another group of atoms is introduced. "Substitution" refers to the introduced group of atoms. As used herein, "substitution" is not limited to substituents, and may include, for example, halogen atoms, C1-C atoms substituted with halogen atoms. 20 Alkyl (e.g., CCF3, CHCF2, CH2F, CCl3, etc.), C1-C 20 Alkoxy, C2~C 20 Alkoxyalkyl groups, hydroxyl groups, -NH2, =NH, nitro, cyano, amidino, hydrazine, hydrazone, carboxy or their salts, sulfonyl, sulfamoyl, sulfonic acid groups or their salts, phosphoric acid or its salts, C1-C 20 Alkyl, C2~C 20 Alkenyl, C2~C 20 Alkinyl, C6~C 20 Aryl, C6~C 20 Arylalkyl, C6~C 20 Heteroaryl, C7~C 20 Heteroarylalkyl, C6~C 20 Heteroaryloxy, C6~C 20 Heteroaryloxyalkyl or C6~C 20 This could mean substitution with heteroarylalkyl groups, etc.

[0154] The term "isomer" in "stereoisomers" refers to compounds that have the same molecular formula but differ in the atomic bonding and spatial arrangement of their constituent atoms. Examples of isomers include structural isomers and stereoisomers. Stereoiomers can be diastereomers or enantiomers. Enantiomers are a pair of isomers that are mirror images of each other, such as the relationship between a left hand and a right hand, and are not superimposed; they are also called optical isomers. Enantiomers are divided into R (Rectus: clockwise) and S (Sinister: counterclockwise) when four or more substituents on the chiral central carbon are different from each other. Diastereomers are non-mirror image stereoisomers, which are isomers produced by different spatial arrangements of atoms. Diastereomers can be divided into cis-trans isomers and conformational isomers or conformational isomers.

[0155] The term "solvate" refers to a compound that has been solvated in an organic or inorganic solvent. A solvate is, for example, a hydrate.

[0156] The term "salt" refers to inorganic and organic acid addition salts of a compound. A pharmaceutically acceptable salt may be one that does not cause serious irritation to an organism administered with the compound and does not impair the biological activity and properties of the compound. Inorganic salts may be hydrochlorides, bromates, phosphates, sulfates, or disulfates. Organic salts may be formates, acetates, propions, lactates, oxalates, tartrates, malates, maleates, citrates, fumarates, besilates, cansilates, disylates, trichloroacetates, trifluoroacetates, benzoates, glucons, methanesulfons, glycolates, succinates, 4-toluenesulfons, galacturonic acid, embonates, glutamates, ethanesulfons, benzenesulfons, p-toluenesulfons, or aspartates. Metal salts may be calcium salts, sodium salts, magnesium salts, strontium salts, or potassium salts.

[0157] One or more compounds from formulas 1, 1A, 1A-1 to 1A-9, 2, 3A, 3B, and 3C may be inhibitors of Src homologous region 2-domain phosphatase-2 (SHP2). Src homologous region 2-domain phosphatase-2 (SHP2) may be a protein belonging to the protein tyrosine phosphatase (PTP) group. 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 its N-terminus together with SPP1. SHP2 may be a protein containing the amino acid sequence of Uniprot No. Q06124 in humans or Uniprot No. P35235 in mice. SHP2 may be wild-type SHP2 or an SHP2 mutant. SHP2 inhibitors may be inhibitors that inhibit the expression or activity of SHP2.

[0158] In another embodiment, a pharmaceutical composition is provided comprising a compound according to one embodiment, a stereoisomer or solvate thereof, or a pharmaceutically acceptable salt thereof.

[0159] In another embodiment, a pharmaceutical composition is provided for preventing or treating a disease associated with abnormal activity of Src homologous region 2-domain phosphatase-2 (SHP2), comprising a compound described in one embodiment, a stereoisomer or solvate thereof, or a pharmaceutically acceptable salt thereof.

[0160] The above compounds, stereoisomers, solvates, pharmaceutically acceptable salts, and SHP2 are as described above.

[0161] Diseases associated with abnormal SHP2 activity may be selected from a group consisting of cancer, cancer metastasis, cardiovascular disease, immunodeficiency, fibrosis, and ocular disorders.

[0162] 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, colorectal cancer, gastric cancer, prostate cancer, bladder cancer, urethral cancer, liver cancer, kidney cancer, skin cancer, brain and spinal cord tumors, brain cancer, 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 cancers, and sarcomas.

[0163] Cancer metastasis refers to the spread of a tumor from its primary site to another part of the body, where it establishes itself and proliferates. Cancer metastasis can involve the spread of cancer cells through blood vessels, lymphatic vessels, or tissues.

[0164] Cardiovascular disease refers to diseases affecting the heart or major arteries (e.g., the aorta, pulmonary artery, carotid artery, cerebrovascular artery, renal artery, and lower extremity arteries). 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.

[0165] An immune disorder refers to a condition in which a normal immune response does not occur. Immune disorders may be selected from the group consisting of acquired immunodeficiency, autoimmune diseases, systemic lupus erythematosus, scleroderma, Sjögren's syndrome, polymyositis, dermatomyositis, polymyalgia rheumatica, temporal arteritis, polyarteritis nodosa, and Behçet's syndrome.

[0166] Fibrosis is a condition characterized by an excessive increase in fibrous tissue in a part of a tissue or organ. Fibrosis can be selected from a group consisting of hepatic fibrosis, cystic fibrosis, myelofibrosis, endocardial cardiomyopathy, and retroperitoneal fibrosis.

[0167] Ocular disorders refer to disorders that affect various structures of the eye. Ocular disorders may be selected from a group consisting of endophthalmitis, degenerative myopia, degenerative disorders of the eye, hypotonia, foreign bodies in the eye, hematoma, and ocular dislocation.

[0168] Diseases associated with abnormal SHP2 activity 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, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma, glioblastoma, pancreatic cancer, biliary tract cancer, uterine cancer, endometrial cancer, liver cancer, and neurofibromatosis type 1.

[0169] The term "prevention" refers to any effect of the pharmaceutical composition that inhibits the onset of or delays the onset of SHP2-related diseases. The term "treatment" refers to any effect of the pharmaceutical composition that improves or beneficially alters the symptoms of SHP2-related diseases.

[0170] Pharmaceutical compositions may contain pharmaceutically acceptable carriers. The term "carrier" is used in the sense of including excipients, diluents, or adjuvants. For example, carriers 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, physiological saline, buffers such as PBS, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. Compositions may also contain fillers, anti-flocculation agents, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, or combinations thereof.

[0171] Pharmaceutical compositions can be prepared in any formulation according to conventional methods. Compositions can be formulated, for example, as oral dosage forms (e.g., powders, tablets, capsules, syrups, pills, or granules) or parenteral dosage forms (e.g., injections). Furthermore, compositions can be prepared as systemic or topical formulations.

[0172] In a pharmaceutical composition, an orally administered solid preparation may be a tablet, pill, powder, granule, or capsule. The solid preparation may further contain excipients. Excipients may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. The solid preparation may also further contain lubricants such as magnesium stearate or talc. In a pharmaceutical composition, an orally administered liquid preparation may be a suspension, oral solution, emulsion, or syrup. The liquid preparation may contain water or liquid paraffin. The liquid preparation may contain excipients, such as humectants, sweeteners, fragrances, or preservatives. In a pharmaceutical composition, a parenterally administered preparation may be a sterile aqueous solution, a non-aqueous solution, a suspension, an emulsion, a lyophilized preparation, or a suppository. A non-aqueous solution or suspension may contain 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 base of the suppository may be whitepzol, macrogol, tween 61, cocoa butter, laurin butter, or glycerol gelatin.

[0173] The pharmaceutical composition comprises, as an active ingredient of the pharmaceutical composition, a compound described in one embodiment, its stereoisomer, solvate, or a pharmaceutically acceptable salt thereof. "Active ingredient" refers to a physiologically active substance used to achieve pharmacological activity (e.g., treatment of a disease associated with abnormal activity of SHP2).

[0174] A pharmaceutical composition may contain an effective amount of a compound in one embodiment, its stereoisomer, solvate, or pharmaceutically acceptable salt. The term "effective amount" refers to an amount sufficient to produce a preventive or therapeutic effect on a target requiring it. The effective amount can be appropriately selected by those skilled in the art depending on the cells or target selected. The preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the target, 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. 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, compounds, stereoisomers, solvates, or pharmaceutically acceptable salts thereof may be administered in amounts, 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 per day, 1 to 7 times every 2 days to 1 week, or 1 to 24 times every 1 to 12 months. In a pharmaceutical composition, compounds, stereoisomers, solvates, or pharmaceutically acceptable salts thereof may be present in amounts 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.

[0175] The method of administration may be oral or parenteral. The method of administration may be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intra-arterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal route. The composition may be administered systemically or topically, alone, or in combination with other pharmaceutically active compounds.

[0176] In another embodiment, a method is provided for preventing or treating a disease associated with abnormal activity of SHP2, comprising the step of administering a compound according to one embodiment, a stereoisomer or solvate thereof, or a pharmaceutically acceptable salt thereof to a target.

[0177] The above-mentioned compounds, stereoisomers, solvates, pharmaceutically acceptable salts, SHP2, diseases associated with the abnormal activity of SHP2, prevention, and treatment are as described above.

[0178] The subjects may be mammals such as humans, mice, rats, cattle, horses, pigs, dogs, monkeys, sheep, goats, or cats. The subjects may be those suffering from or highly likely to suffer from symptoms associated with diseases related to abnormal activity of SHP2.

[0179] The method may further include administering an active ingredient known to have an effect in preventing or treating diseases associated with SHP2 to the target. The known active ingredient may be administered to the target simultaneously, separately, or sequentially to the target, in one embodiment, as a compound, its stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

[0180] The administration method may be oral or parenteral. The administration method may be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intra-arterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal route. The pharmaceutical composition may be administered systemically or topically, alone, or in combination with other pharmaceutically active compounds.

[0181] 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. The dosage may be in the range of, for example, 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 for adults. Administration can be once daily, two to twenty-four times daily, once to twice every three days, once to six times per week, once to ten times every two weeks, once to fifteen times every three weeks, once to three times every four weeks, or once to twelve times per year.

[0182] In another embodiment, a compound according to one embodiment, a stereoisomer or solvate thereof, or a pharmaceutically acceptable salt thereof is provided for use in the prevention or treatment of diseases associated with abnormal activity of SHP2.

[0183] The above-mentioned compounds, stereoisomers, solvates, pharmaceutically acceptable salts, SHP2, diseases associated with the abnormal activity of SHP2, prevention, and treatment are as described above.

[0184] In another embodiment, the use of a compound, a stereoisomer or solvate thereof, or a pharmaceutically acceptable salt thereof, described in one embodiment, is provided for use in the manufacture of a pharmaceutical product for the prevention or treatment of a disease associated with abnormal activity of SHP2.

[0185] The above-mentioned compounds, stereoisomers, solvates, pharmaceutically acceptable salts, SHP2, diseases associated with the abnormal activity of SHP2, prevention, and treatment are as described above.

[0186] [Effects of the invention]

[0187] Diseases associated with SHP2 can be effectively prevented or treated by SHP2 inhibitors, pharmaceutical compositions containing them for the prevention or treatment of SHP2-related diseases, methods for treating and preventing diseases using them, and by the use of these.

[0188] [Detailed description of how to implement the invention] The present invention will be described in more detail below with reference to examples. However, the following examples are for illustrative purposes only and do not limit the scope of the present invention.

[0189] Preparation Example 1: Synthesis of tert-butyl(1-(5-bromopyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate (intermediate I-1) [ka]

[0190] In a round-bottom flask, Et3N (5.6 mL, 42 mmol) was added dropwise to a reaction mixture of 2,5-dibromopyrazine (2 g, 8.4 mmol) and tert-butyl(4-methylpiperidine-4-yl)carbamate (1.98 g, 9.25 mmol) dissolved in DMF (dimethylformamide, 34 mL, 0.25 M). The reaction mixture was stirred at 80°C for 2 hours. The reaction was stopped with H2O and extracted with ethyl acetate (EA). The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC (medium-pressure liquid chromatography) (EA:hexane (Hx) = 1:9) and concentrated to obtain intermediate I-1 (2.43 g, 78%). 1 H NMR(400 MHz,DMSO)δ8.20(d,J=1.2 Hz,1H),8.14(d,J=1.6 Hz,1H),6.63(b,1H),3.84-3.79(m,2H),3.25-3.20(m,2H),2.09(d,J=13.2 Hz,2H),1.47-1.41(m,2H),1.39(s,9H),1.25(s,3H);MS m / z:371 [M+H] + .

[0191] Preparation Example 2: Synthesis of tert-butyl((1-(5-bromopyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate (intermediate I-2) [ka]

[0192] In a round-bottom flask, Et3N (5.6 mL, 39.8 mmol) was added dropwise to a reaction mixture of 2,5-dibromopyrazine (1.89 g, 7.96 mmol) and tert-butyl((4-methylpiperidine-4-yl)methyl)carbamate (2 g, 8.76 mmol) dissolved in DMF (N,N-dimethylformamide, 32 mL, 0.25 M). The reaction mixture was stirred at 90°C for 2 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, concentrated, and separated by MPLC (EA:Hx=1:1). The resulting compound was concentrated to obtain intermediate I-2 (2 g, 65%). 1H NMR(400 MHz,DMSO)δ8.19(d,J=1.6 Hz,1H),8.13(d,J=1.2 Hz,1H),6.91(t,J=6.4 Hz,1H),3.78-3.72(m,2H),3.39-3.33(m,2H),2.88(b,J=6.8 Hz,2H),1.45-1.40(m,2H),1.38(s,9H),1.29-1.23(m,2H),0.90(s,3H);MS m / z:385 [M+H] + .

[0193] Preparation Example 3: Synthesis of N-((3S,4S)-8-(5-bromopyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)-2-methylpropane-2-sulfanilamide (intermediate I-3) [ka]

[0194] Step 1: 2-Methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl)propan-2-sulfanilamide tert-butyl(3S,4S)-4-((tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (3 g, 8.0 mmol) was dissolved in dichloromethane (DCM) (200 mL, 0.04 M). Trifluoroacetic acid (TFA) (6.1 mL, 80.1 mmol) was slowly added dropwise to the reaction mixture, and the mixture was then stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated to obtain [2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)propan-2-sulfanilamide].

[0195] Step 2: N-((3S,4S)-8-(5-bromopyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl)-2-methylpropane-2-sulfanilamide (intermediate I-3) 2-Methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl)propan-2-sulfanilamide and 2,5-dibromopyrazine (4.4 g, 16.0 mmol) were dissolved in dimethylformamide (DMF) (16 mL, 0.5 M). N,N-diisopropylethylamine (DIPEA) (14 mL, 80.1 mmol) was added to the reaction mixture, and the mixture was stirred at 100 °C for 3 hours. The reaction was stopped with H2O, and the mixture was extracted with ethyl acetate (EA). The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC (EA:Hx=1:1) and concentrated to obtain intermediate I-3 (2.4 g, 70%). 1 H NMR(400 MHz,DMSO)δ8.21(d,J=1.6 Hz,1H),8.16(d,J=1.2 Hz,1H),7.96(s,1H),5.12(d,J=11.2 Hz,1H),4.14-3.99(m,2H),3.86(d,J=8.8 Hz,1H),3.51(d,J=8.8 Hz,1H),3.41(dd,J=11.2,6.0 Hz,1H),3.13-3.02(m,2H),1.80-1.70(m,2H),1.61-1.54(m,2H),1.16(s,9H),1.10(d,J=6.4 Hz,3H);MS m / z:431 [M+H] + .

[0196] Preparation Example 4: Synthesis of tert-butyl((3S,4S)-8-(5-bromopyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl)carbamate (intermediate I-4) [ka]

[0197] tert-butyl((3S,4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl)carbamate (200 mg, 0.74 mmol) and 2,5-dibromopyrazine (260 mg, 1.1 mmol) were dissolved in DMF (1.5 mL, 0.5 M). DIPEA (0.64 mL, 3.7 mmol) was added to the reaction mixture and the mixture was stirred at 100 °C for 1 hour. The reaction was stopped with H2O and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC (EA:Hx=1:1) and concentrated to obtain intermediate I-4 (265 mg, 84%). 1 H NMR(400 MHz,DMSO)δ8.21(d,J=1.6 Hz,1H),8.15(d,J=1.6 Hz,1H),7.02(d,J=10.4 Hz,1H),4.20-1.12(m,1H),3.88(dd,J=10.4,5.2 MS m / z:427 [M+H] + .

[0198] Preparation Example 5: Synthesis of methyl 2-chloro-3-mercaptobenzoate (intermediate I-5) [ka]

[0199] Step 1: Methyl 2-chloro-3-((3-ethoxy-3-oxopropyl)thio)benzoate In a round-bottom flask, DIPEA (1.4 mL, 8.0 mmol) was added to a reaction mixture of methyl 3-bromo-2-chlorobenzoate (1 g, 4.0 mmol), ethyl 3-mercaptopropionate (0.7 mL, 5.2 mmol), Pd2(dba)3 (180 mg, 0.2 mmol), and xanthophos (230 mg, 0.4 mmol) dissolved in 1,4-dioxane (7 mL, 0.6 M). The reaction mixture was purged with nitrogen and then stirred at 100°C for 3 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (EA:Hx=1:20) and concentrated to obtain methyl 2-chloro-3-((3-ethoxy-3-oxopropyl)thio)benzoate (940 mg, 73%).

[0200] Step 2: Methyl 2-chloro-3-mercaptobenzoate (intermediate I-5) In a round-bottom flask, methyl 2-chloro-3-((3-ethoxy-3-oxopropyl)thio)benzoate (300 mg, 1.0 mmol) was dissolved in THF (tetrahydrofuran, 2 mL, 0.5 M), and the temperature was then lowered to 0°C. 1 M potassium tert-butoxide solution (1.5 mL, 1 M in THF) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated using a concentrator. The resulting product was separated by MPLC (EA:Hx = 1:100) and concentrated to obtain intermediate I-5 (110 mg, 54%). 1 H NMR(400 MHz,DMSO)δ7.75(dd,J=7.6,1.6 Hz,1H),7.50(dd,J=7.6,1.2 Hz,1H),7.32(t,J=8.0 Hz,1H),6.02(bs,1H),3.86(s,3H);MS m / z:202 [M+H] + .

[0201] Preparation Example 6: Synthesis of ethyl 2-chloro-3-mercaptobenzoate (intermediate I-6) [ka]

[0202] Step 1: Methyl 2-chloro-3-((3-ethoxy-3-oxopropyl)thio)benzoate In a round-bottom flask, DIPEA (1.4 mL, 8.0 mmol) was added to a reaction mixture of methyl 3-bromo-2-chlorobenzoate (1 g, 4.0 mmol), ethyl 3-mercaptopropionate (0.66 mL, 5.21 mmol), Pd2(dba)3 (183 mg, 0.2 mmol), and xanthophos (231 mg, 0.4 mmol) dissolved in 1,4-dioxane (7 mL, 0.6 M). The reaction mixture was purged with nitrogen and then stirred at 100°C for 3 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLCEA:Hx (EA 2%) and concentrated to obtain methyl 2-chloro-3-((3-ethoxy-3-oxopropyl)thio)benzoate (2.06 g, 52%).

[0203] Step 2: Ethyl 2-chloro-3-mercaptobenzoate (intermediate I-6) In a round-bottom flask, methyl 2-chloro-3-((3-ethoxy-3-oxopropyl)thio)benzoate (200 mg, 0.66 mmol) was dissolved in THF (2.64 mL, 0.25 M), and the temperature was then lowered to 0°C. Sodium ethoxide solution (21% by weight in ethanol) (517 μL, 1.32 mmol) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated and separated by MPLC (MC:MeOH = 20:1). The resulting compound was concentrated to obtain intermediate I-6 (89 mg, 61%). 1 H NMR(400 MHz,DMSO)δ7.75(d,J=1.6 Hz,1H),7.73(d,J=1.6 Hz,1H),7.48(d,J=7.6 Hz,1H),7.32(t,J=7.6 Hz,1H),6.00(b,1H),4.32(q,J=7.2 Hz,2H),1.31(t,J=7.2 Hz,3H);MS m / z:217 [M+H] + .

[0204] Preparation Example 7: Synthesis of 3-amino-2-chlorothiophenol (intermediate I-7) [ka]

[0205] Step 1: Ethyl 3-((3-amino-2-chlorophenyl)thio)propionate In a round-bottom flask, DIPEA (5.1 mL, 29.06 mmol) was added to a reaction mixture of 3-bromo-2-chloroaniline (3 g, 14.53 mmol) dissolved in 1,4-dioxane (30 mL, 0.5 M), ethyl-3-mercaptopropionate (2.4 mL, 18.89 mmol), Pd2(dba)3 (665 mg, 0.73 mmol), and xanthophos (840 mg, 1.45 mmol). The reaction mixture was purged with nitrogen and then stirred at 100°C for 12 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (EA:Hx=1:5) and concentrated to obtain ethyl 3-((3-amino-2-chlorophenyl)thio)propionate (4.0 g, 99%).

[0206] Step 2: 3-amino-2-chlorothiophenol (intermediate I-7) In a round-bottom flask, ethyl 3-((3-amino-2-chlorophenyl)thio)propionate (4.0 g, 14.53 mmol) was dissolved in THF (73 mL, 0.2 M), and the temperature was then lowered to 0°C. 1 M potassium tert-butoxide solution (19 mL, 1 M in THF) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. The reaction was terminated with H2O. The inorganic layer was adjusted to pH 4-5 using 1N HCl, and then extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC (EA:Hx=1:10) and concentrated to obtain intermediate I-7 (2.1 g, 91%). 1H NMR(400 MHz,DMSO)δ6.86(t,J=8.0 Hz,1H),6.68(dd,J=7.6,1.2 Hz,1H),6.55(dd,J=8.0,1.6 Hz,1H),5.39(s,2H),5.33(s,1H);MS m / z:159 [M+H] + .

[0207] Preparation Example 8: Synthesis of 5-chloro-6-mercaptoquinazoline-4(3H)-one (intermediate I-8) [ka]

[0208] Step 1: Ethyl 3-((5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)propionate DIPEA (9.2 mL, 52.9 mmol) was added dropwise to a reaction mixture of 6-bromo-5-chloroquinazoline-4(3H)-one (6.87 g, 26.47 mmol) dissolved in 1,4-dioxane (66 mL, 0.4 M), ethyl-3-mercaptopropionate (4 mL, 34.41 mmol), Pd2(dba)3 (1.21 g, 1.32 mmol), and xanthophos (1.53 g, 2.65 mmol). The reaction mixture was purged with nitrogen and then stirred at 140°C for 16 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried with MgSO4, filtered, and then concentrated to obtain ethyl 3-((5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)propionate (7.03 g, 91%).

[0209] Step 2: 5-Chloro-6-mercaptoquinazoline-4(3H)-one (intermediate I-8) Ethyl 3-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propionate (7.03 g, 22.5 mmol) was dissolved in THF (113 mL, 0.2 M), and the temperature was then lowered to -78°C. Potassium tert-butoxide solution (45 mL, 1 M in THF) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated, water was added, and the pH was adjusted to 1-2 with 1N HCl, followed by extraction with EA and THF. The extracted compound was concentrated to obtain intermediate I-8 (5.17 g, 91%). 1 H NMR(400 MHz,DMSO)δ12.31(brs,1H),8.03(d,J=3.2 Hz,1H),7.95(d,J=8.4 Hz,1H),7.51(d,J=8.8 Hz,1H),6.00(brs,1H);MS m / z:212 [M+H] + .

[0210] Preparation Example 9: Synthesis of 5-chloro-6-mercapto-2-methylquinazoline-4(3H)-one (intermediate I-9) [ka]

[0211] Step 1: 6-amino-3-bromo-2-chlorobenzoic acid In a round-bottom flask, 2-amino-6-chlorobenzoic acid (4 g, 23.3 mmol) was dissolved in DMF (47 mL, 0.5 M), and the mixture was cooled to 0°C. NBS (N-bromosuccinimide, 4.6 g, 25.6 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. After the reaction was complete, water was added, and the precipitated solid was filtered off. The resulting compound was dried to obtain 6-amino-3-bromo-2-chlorobenzoic acid (4.6 g, 79%).

[0212] Step 2: 6-Bromo-5-chloro-2-methylquinazoline-4(3H)-one 6-amino-3-bromo-2-chlorobenzoic acid (250 mg, 1.0 mmol) and acetic anhydride (4 mL, 0.25 M) were placed in a round-bottom flask and stirred at 140°C for 3 hours. After the reaction was complete, the reaction mixture was concentrated, and then NH3 solution (28% in H2O) (4 mL, 0.25 M) was added and stirred at 100°C for 12 hours. The solid precipitated during the reaction was collected by filtration, washed with H2O and MeOH, and dried to obtain 6-bromo-5-chloro-2-methylquinazoline-4(3H)-one (203 mg, 74%).

[0213] Step 3: Ethyl 3-((5-chloro-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)thio)propionate In a round-bottom flask, DIPEA (240 μL, 1.38 mmol) was added dropwise to a reaction mixture of 6-bromo-5-chloro-2-methylquinazoline-4(3H)-one (190 mg, 0.69 mmol), ethyl-3-mercaptopropionate (97 μL, 0.76 mmol), Pd2(dba)3 (32 mg, 0.034 mmol), and xanthophos (40 mg, 0.07 mmol) dissolved in 1,4-dioxane (2.8 mL, 0.25 M). The reaction mixture was purged with nitrogen and then stirred at 100°C for 4 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (EA:Hx=9:1) and concentrated to obtain ethyl 3-((5-chloro-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)thio)propionate (128 mg, 57%).

[0214] Step 4: 5-Chloro-6-mercapto-2-methylquinazoline-4(3H)-one (intermediate I-9) In a round-bottom flask, ethyl 3-((5-chloro-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)thio)propionate (123 mg, 0.38 mmol) was dissolved in THF (1.9 mL, 0.2 M), and the temperature was then lowered to 0°C. Potassium tert-butoxide solution (0.49 mL, 1 M in THF) was slowly added dropwise to the reaction mixture, and the mixture was stirred for 1 hour. After the reaction was complete, the concentrated compound was filtered through EA to obtain intermediate I-9. The obtained compound was used in the next reaction without further purification. MS m / z: 227 [M+H] + .

[0215] Preparation Example 10: Synthesis of tert-butyl(1-(5-mercaptopyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate (intermediate I-10) [ka]

[0216] Step 1: Methyl 3-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)propane In a round-bottom flask, DIPEA (2.3 mL, 13.47 mmol) was added dropwise to a reaction mixture of tert-butyl(1-(5-bromopyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate (2.5 g, 6.73 mmol), methyl-3-mercaptopropionate (0.82 mL, 7.41 mmol), Pd2(dba)3 (308 mg, 0.337 mmol), and xanthophos (195 mg, 0.337 mmol) dissolved in 1,4-dioxane (15 mL, 0.45 M). The reaction mixture was purged with nitrogen and then stirred at 100°C for 4 hours. The reaction was stopped with H2O and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (EA:Hx=9:1) and concentrated to obtain methyl 3-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)propanate (2.7g, 98%).

[0217] Step 2: tert-butyl(1-(5-mercaptopyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate (intermediate I-10) In a round-bottom flask, methyl 3-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)propanate (2.7 g, 6.58 mmol) was dissolved in THF (10 mL, 0.67 M), and the temperature was then lowered to 0°C. 1 M potassium tert-butoxide solution (5 mL, 1 M in THF) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated using a concentrator. The resulting product was separated by MPLC and concentrated to obtain intermediate I-10 (1.2 g, 56%). MS m / z: 325 [M+H] + .

[0218] Preparation Example 11: Synthesis of 6-bromo-7-chloro-2-methylbenzo[d]thiazole (intermediate I-11) [ka]

[0219] Step 1: N-(4-bromo-3-chloro-2-fluorophenyl)acetamide 4-Bromo-3-chloro-2-fluoroaniline (250 mg, 1.11 mmol) and diisopropylethylamine (DIPEA, 0.485 mL, 2.78 mmol) were dissolved in dichloromethane (DCM, 2 mL, 0.56 M) at 0°C, and acetic anhydride (0.1 mL, 1.17 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. 1 M HCl and aqueous NaHCO3 were added to the mixture, and then extracted. The organic layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC and concentrated to obtain N-(4-bromo-3-chloro-2-fluorophenyl)acetamide (200 mg, 83%).

[0220] Step 2: 6-bromo-7-chloro-2-methylbenzo[d]thiazole (intermediate I-11) N-(4-bromo-3-chloro-2-fluorophenyl)acetamide (200 mg, 0.75 mmol) was dissolved in xylene (3 mL, 0.25 M), and Lawson's reagent (300 mg, 0.45 mmol) was added. The reaction mixture was stirred at 110°C for 18 hours. Cesium carbonate (800 mg, 1.5 mmol) was added to the reaction mixture, and the mixture was stirred again at 110°C for another 18 hours. The organic layer was dried over MgSO4, filtered, and then concentrated. After the reaction was complete, the reaction mixture was cooled to room temperature, and then water and EA were added for extraction. The organic layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC and concentrated to obtain intermediate I-11 (150 mg, 76%). MS m / z: 262 [M+H] + .

[0221] Preparation Example 12: Synthesis of 4-chloro-2-methyl-2H-indazole-5-thiol (intermediate I-12) [ka]

[0222] Step 1: 5-bromo-4-chloro-2-methyl-2H-indazole 5-bromo-4-chloro-1H-indazole (360 mg, 1.56 mmol) was dissolved in ethyl acetate (3 mL, 0.52 M), and then solid trimethyloxonium tetrafluoroborate (250 mg, 1.70 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 4 hours. An aqueous solution of NaHCO3 was added to the mixture, and then extracted. The organic layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC and concentrated to obtain 5-bromo-4-chloro-2-methyl-2H-indazole (300 mg, 79%).

[0223] Step 2: Methyl 3-((4-chloro-2-methyl-2H-indazole-5-yl)thio)propanoate In a round-bottom flask, DIPEA (0.43 mL, 2.44 mmol) was added dropwise to a reaction mixture of 5-bromo-4-chloro-2-methyl-2H-indazole (250 mg, 1.56 mmol), methyl-3-mercaptopropionate (0.2 mL, 1.83 mmol), Pd2(dba)3 (112 mg, 0.122 mmol), and xanthophos (71 mg, 0.122 mmol) dissolved in 1,4-dioxane (5 mL, 0.31 M). The reaction mixture was purged with nitrogen and then stirred at 100°C for 4 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (EA:Hx=9:1) and concentrated to obtain methyl 3-((4-chloro-2-methyl-2H-indazole-5-yl)thio)propanoate (300 mg, 86%).

[0224] Step 3: 4-Chloro-2-methyl-2H-indazole-5-thiol (Intermediate I-12) In a round-bottom flask, methyl 3-((4-chloro-2-methyl-2H-indazole-5-yl)thio)propanoate (300 mg, 1.22 mmol) was dissolved in THF (2 mL, 0.61 M), and the temperature was then lowered to 0°C. 1 M potassium tert-butoxide solution (1 mL, 1 M in THF) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated using a concentrator. The resulting product was separated by MPLC and concentrated to obtain intermediate I-12 (100 mg, 47.8%). MS m / z: 199 [M+H] + .

[0225] Preparation Example 13: Synthesis of 5-chloro-6-mercapto-3-phenylquinazoline-4(3H)-one (intermediate I-13) [ka]

[0226] Step 1: 6-Bromo-5-chloro-3-phenylquinazoline-4(3H)-one In a round-bottom flask, a reaction mixture of methyl 6-amino-3-bromo-2-chlorobenzoate (600 mg, 1.60 mmol) dissolved in triethyl orthoformate (0.4 mL, 2.40 mmol) was met with the dropwise addition of aniline (0.18 mL, 1.92 mmol) and NH4Cl (43 mg, 0.80 mmol). The mixture was then stirred at 100°C for 16 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC (EA:Hex=1:3), concentrated, and yielded 6-bromo-5-chloro-3-phenylquinazoline-4(3H)-one (503 mg, 94%). MS m / z: 535.00 [M+H] + .

[0227] Step 2: Methyl 3-((5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazoline-6-yl)thio)propanoate In a round-bottom flask, a reaction mixture of 6-bromo-5-chloro-3-phenylquinazoline-4(3H)-one (390 mg, 1.16 mmol) dissolved in dioxane was mixed with methyl 3-mercaptopropanoate (0.17 mL, 1.51 mmol) and Pd2 (dba )3 (106 mg, 0.12 mmol), xanthophos (69 mg, 0.12 mmol), and DIPEA (0.40 mL, 2.32 mmol) were added dropwise, and the mixture was stirred at 100°C for 3 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC (EA:Hex=1:3) and concentrated to obtain methyl 3-((5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazoline-6-yl)thio)propanoate (116 mg, 27%). MS m / z: 375.10 [M+H] + .

[0228] Step 3: 5-Chloro-6-mercapto-3-phenylquinazoline-4(3H)-one (intermediate I-13) In a round-bottom flask, KOt-bu (69 mg, 0.62 mmol) was added dropwise to a reaction mixture of methyl 3-((5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazoline-6-yl)thio)propanoate (116 mg, 0.31 mmol) dissolved in THF. The reaction mixture was then stirred at -78°C for 1 hour. The reaction was stopped with 1 M aqueous HCl solution, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC (EA:Hex=1:3) and concentrated to obtain intermediate I-13 (62 mg, 69%). MS m / z: 289.00 [M+H] + .

[0229] Preparation Example 14: Synthesis of t-butyl N-[1-(4-amino-5-iodo-1-methyl-6-oxopyrimidine-2-yl)-4-methylpiperidine-4-yl]carbamate (intermediate I-14) [ka]

[0230] Step 1: tert-butyl(1-(4-amino-1-methyl-6-oxo-1,6-dihydropyridine-2-yl)-4-methylpiperidine-4-yl)carbamate 6-amino-3-methyl-1H-pyrimidine-2,4-dione (500 mg, 3.54 mmol), BOP (1.57 g, 3.54 mmol), and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 539 mg, 3.54 mmol, 534.02 μL) were dissolved in DMF (10 mL, 0.35 M), and tert-butyl(4-methylpiperidine-4-yl)carbamate (758 mg, 3.54 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After confirming that the reactants had completely disappeared by LC-MS, brine (20 mL) and ethyl acetate (20 mL x 3) were added to the reaction mixture and extracted. The organic layer was dried over Na2SO4, filtered, and then concentrated. The obtained product was separated by preparative HPLC (neutral) and concentrated to obtain tert-butyl(1-(4-amino-1-methyl-6-oxo-1,6-dihydropyridine-2-yl)-4-methylpiperidine-4-yl)carbamate (320 mg, 26.8%). MS m / z: 338 [M+H] + .

[0231] Step 2: tert-butyl(1-(4-amino-5-iodo-1-methyl-6-oxo-1,6-dihydropyridine-2-yl)-4-methylpiperidine-4-yl)carbamate (intermediate I-14) 260 mg, 950 μmol of tert-butyl(1-(4-amino-1-methyl-6-oxo-1,6-dihydropyridine-2-yl)-4-methylpiperidine-4-yl)carbamate was dissolved in 3 mL, 0.25 M ACN, and then 214 mg, 950 μmol of NIS (N-iodosuccinimide) was added. The reaction mixture was stirred at room temperature for 1 hour. After a white precipitate formed and LC-MS confirmed that the reactants had completely disappeared, the reaction was stopped with an aqueous solution of NaHCO3, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC and concentrated to obtain intermediate I-14 (360 mg, 82%). MS m / z: 464 [M+H] + .

[0232] Preparation Example 15: Synthesis of 2-benzyl-6-bromo-7-chloro-1H-benzo[d]imidazole (intermediate I-15) [ka]

[0233] Step 1: N-(6-amino-3-bromo-2-chlorophenyl)-2-phenylacetate In a round-bottom flask, 4-bromo-3-chlorobenzene-1,2-diamine (100 mg, 0.45 mmol) was dissolved in DMF (2 mL), and triethylamine (0.13 mL, 0.9 mmol) was added. 2-phenylacetyl chloride (70 mg, 0.45 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC (EA:Hex=1:3) and concentrated to obtain N-(6-amino-3-bromo-2-chlorophenyl)-2-phenylacetate (135 mg, 89%). MS m / z:339 [M+H] + .

[0234] Step 2: 2-benzyl-6-bromo-7-chloro-1H-benzo[d]imidazole Acetic acid (5 mL) was added to N-(6-amino-3-bromo-2-chlorophenyl)-2-phenylacetate (135 mg, 0.4 mmol), and the mixture was stirred at 100°C for 1 hour. After the reaction was complete, water was added to the mixture, and it was extracted by DCM. The DCM layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC and concentrated to obtain intermediate I-15 (100 mg, 77%). MS m / z: 321 [M+H] + .

[0235] Preparation Example 16: Synthesis of tert-butyl((3S,4S)-8-(5-mercaptopyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl)carbamate (intermediate I-16) [ka]

[0236] Intermediate I-16 was synthesized using intermediate I-4 as the starting material, according to Preparation Example 10. MS m / z: 381 [M+H] + .

[0237] Preparation Example 17: Synthesis of 2-benzyl-5-bromo-4-chloro-2H-indazole (intermediate I-17) [ka] In a round-bottom flask, 5-bromo-4-chloro-2H-indazole (100 mg, 0.43 mmol) was dissolved in DMF (3 mL), and then NaH (34 mg, 0.86 mmol) was added. Benzyl bromide (74 mg, 0.43 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The two isomers were then separated by MPLC (EA:Hex=1:3) and concentrated to obtain intermediate I-17 (50 mg, 36%). MS m / z:321 [M+H] + .

[0238] Preparation Example 18: N-benzyl-3-chloro-4-mercaptopicolinamide (intermediate I-18) [ka]

[0239] Step 1: 3,4-Dichloropicolinic acid A 1N NaOH solution (7.29 mL, 7.29 mmol) was added dropwise to methyl 3,4-dichloropicolinate (500 mg, 2.43 mmol), and the mixture was stirred at 40°C for 1 hour. After the reaction was complete, a 5M HCl solution was added dropwise to adjust the pH to 4. The precipitated solid was filtered to obtain 3,4-dichloropicolinic acid (354.6 mg, 76%). The obtained compound was used in the next reaction without further purification. MS m / z: 191 [M+H] + .

[0240] Step 2: N-benzyl-3,4-dichloropicoramide 3,4-Dichloropicolinic acid (100 mg, 0.5 mmol) and phenylmethaneamine (65 μL, 0.6 mmol) were dissolved in DMF, and DIPEA (260 μL, 1.5 mmol) was added dropwise, followed by HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (380 mg, 1.0 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC (EA:Hx=1:2) and concentrated to obtain N-benzyl-3,4-dichloropicolinamide (92 mg, 66%). MS m / z:281 [M+H] + .

[0241] Step 3: Ethyl 3-((2-(benzylcarbamoyl)-3-chloropyridine-4-yl)thio)propanoate N-benzyl-3,4-dichloropicolinamide (92 mg, 0.33 mmol), ethyl-3-mercaptopropionate (63 μL, 0.495 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), and xanthophos (19 mg, 0.033 mmol) were dissolved in 1,4-dioxane (1 mL, 0.4 M), and DIPEA (115 μL, 0.66 mmol) was added. The reaction mixture was purged with nitrogen and then stirred at 100°C for 18 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (EA:Hx=1:2) and concentrated to obtain ethyl 3-((2-(benzylcarbamoyl)-3-chloropyridine-4-yl)thio)propanoate (61 mg, 49%). MS m / z:379 [M+H] + .

[0242] Step 4: N-benzyl-3-chloro-4-mercaptopicolinamide Ethyl 3-((2-(benzylcarbamoyl)-3-chloropyridine-4-yl)thio)propanoate (120 mg, 0.32 mmol) was dissolved in THF (1.6 mL, 0.2 M) and then cooled to 0°C. Sodium ethoxide solution (21% by weight in ethanol) (128 μL, 0.35 mmol) was slowly added dropwise to the reaction mixture, and then the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated, methylene chloride (MC) was added, and the precipitated solid was filtered to obtain intermediate I-18. The obtained compound was used in the next reaction without further purification. MS m / z: 279 [M+H] + .

[0243] Preparation Example 19: 3-Chloro-4-mercapto-N-(pyridine-3-ylmethyl)picolinamide (Intermediate I-19) [ka]

[0244] Intermediate I-19 was obtained using the same method as in Preparation Example 18, except that pyridine-3-ylmethaneamine was used instead of phenylmethaneamine in step 2. MS m / z: 280 [M+H] + .

[0245] Preparation Example 20: 2-benzyl-8-chloro-7-mercapto-3,4-dihydroisoquinoline-1(2H)-one (intermediate I-20) [ka]

[0246] Step 1: 4-Nitrophenyl (4-bromophenethyl)carbamate 4-bromophenethylamine (2000 mg, 10.0 mmol) and sodium carbonate (1170 mg, 11.0 mmol) were dissolved in 1,2-dichloroethane (1,2-DCE) (100 mL, 0.1 M) and stirred at 0°C for 30 minutes. 4-nitrophenyl chloroformate (2015 mg, 10.0 mmol) was added to the reaction mixture, and the mixture was stirred at 0°C for 1 hour. The reaction was terminated with H2O, the mixture was extracted with EA, and then washed with brine. The EA layer was dried over MgSO4, filtered, and concentrated to obtain 4-nitrophenyl (4-bromophenethyl)carbamate (3630 mg, 99%).

[0247] Step 2: 7-Bromo-3,4-dihydroisoquinoline-1(2H)-one 4-nitrophenyl (4-bromophenethyl)carbamate (3630 mg, 9.95 mmol) was dissolved in 1,2-DCE (100 mL, 0.1 M), purged with nitrogen, and stirred at 0°C. Trifluoromethanesulfonic acid (TfOH) (8.8 mL, 99.5 mmol) was slowly added to the reaction mixture, and the mixture was stirred at 0°C for 10 minutes. The reaction temperature was raised to 80°C and stirred for 3 hours, after which the reaction was stopped with H2O and extracted with EA. The EA layer was washed with 1N sodium hydroxide aqueous solution and brine. The EA layer was dried over MgSO4, filtered, and then concentrated. Crystallization with EA and Hx yielded 7-bromo-3,4-dihydroisoquinoline-1(2H)-one (1150 mg, 51%).

[0248] Step 3: 2-benzyl-7-bromo-3,4-dihydroisoquinoline-1(2H)-one 7-Bromo-3,4-dihydroisoquinoline-1(2H)-one (100 mg, 0.44 mmol), benzyl chloride (0.1 mL, 0.93 mmol), cesium carbonate (400 mg, 1.24 mmol), and potassium iodide (50 mg, 0.22 mmol) were dissolved in DMF (6.2 mL, 0.1 M) and stirred at room temperature for 24 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC (EA:Hx=1:10), concentrated, and obtained 2-benzyl-7-bromo-3,4-dihydroisoquinoline-1(2H)-one (110 mg, 80%).

[0249] Step 4: 2-benzyl-7-bromo-8-chloro-3,4-dihydroisoquinoline-1(2H)-one 2-benzyl-7-bromo-3,4-dihydroisoquinoline-1(2H)-one (340 mg, 1.07 mmol) was dissolved in H2SO4 (2.1 mL, 0.5 M) and stirred at 0°C. N-chlorosuccinimide (NCS) (160 mg, 1.18 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction was stopped with H2O and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC (EA:Hx=1:10), concentrated, and obtained 2-benzyl-7-bromo-8-chloro-3,4-dihydroisoquinoline-1(2H)-one (96 mg, 26%).

[0250] Step 5: Ethyl 3-((2-benzyl-8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)thio)propanoate 2-Benzyl-7-bromo-8-chloro-3,4-dihydroisoquinoline-1(2H)-one (96 mg, 0.27 mmol), ethyl-3-mercaptopropionate (0.05 mL, 0.41 mmol), Pd2(dba)3 (25 mg, 0.03 mmol), xanthophos (16 mg, 0.03 mmol), and DIPEA (0.1 mL, 0.55 mmol) were dissolved in 1,4-dioxane (0.7 mL, 0.4 M). The reaction mixture was purged with nitrogen and then stirred at 100°C for 1 hour. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (EA:Hx=1:10) and concentrated to obtain ethyl 3-((2-benzyl-8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)thio)propanoate (100 mg, 91%).

[0251] Step 6: 2-benzyl-8-chloro-7-mercapto-3,4-dihydroisoquinoline-1(2H)-one Ethyl 3-((2-benzyl-8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)thio)propanoate (100 mg, 0.25 mmol) was dissolved in DMF (1.3 mL, 0.2 M) and then stirred at 0°C. 1 Mtert-butoxide (0.37 mL, 0.37 mmol) was added to the reaction mixture and then stirred at room temperature for 1 hour. After stopping the reaction, the mixture was concentrated using a concentrator to obtain intermediate I-20 (crude product). MS m / z: 304 [M+H] + .

[0252] Preparation Example 21: N-((S)-1'-(5-bromopyrazine-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (intermediate I-21) [ka]

[0253] Step 1: N-((S)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide 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, and the mixture was then stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated to obtain N-((S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide.

[0254] Step 2: N-((S)-1'-(5-bromopyrazine-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide N-((S)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-yl)-2-methylpropan-2-sulfinamide and 2,5-dibromopyrazine (0.51 g, 1.84 mmol) were dissolved in DMF (8.2 ml, 0.15 M). Triethylamine (TEA) (0.83 mL, 5.90 mmol) was added to the reaction mixture, and the mixture was stirred at 80°C for 3 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC (EA:Hx=1:3) and concentrated to obtain intermediate I-21 (150 mg, 26%).

[0255] Preparation Example 22: 6-bromo-5-chloro-3H-quinazolin-4-one (intermediate I-22) [ka]

[0256] Step 1: 6-amino-3-bromo-2-chlorobenzoic acid To a solution of DMF (100 mL) containing 2-amino-6-chlorobenzoic acid (10.0 g, 58.2 mmol), NBS (12.4 g, 69.9 mmol) was added in four portions at 0-10°C. The reaction mixture was stirred at 0-25°C for 16 hours. The mixture was diluted with water (20 mL) and extracted with dimethyl ammonium compound (3 × 20 mL). The organic layer was washed with saline solution (2 × 50 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain 6-amino-3-bromo-2-chlorobenzoic acid (14.0 g, 95% yield) as a brown oil. 1 H NMR(400 MHz,DMSO-d6)δ=7.40(d,J=8.8 Hz,1H),6.65(d,J=8.8 Hz,1H).

[0257] Step 2: 6-Bromo-5-chloro-3H-quinazolin-4-one A mixture of formamide (18.2 g, 405 mmol) containing 6-amino-3-bromo-2-chlorobenzoic acid (10.0 g, 27.9 mmol) was stirred at 140°C for 5 hours. The reaction mixture was diluted with NH4Cl (20 mL) and filtered. The filtered cake was dried under vacuum to obtain intermediate I-22 (4.00 g, yield 55%) as a brown solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.13(s,1H),8.11(d,J=8.8 Hz,1H),7.54(d,J=8.8 Hz,1H).

[0258] Preparation Example 23: 3-benzyl-6-((5-bromopyrazine-2-yl)thio)-5-chloroquinazoline-4(3H)-one (intermediate I-23) [ka]

[0259] Step 1: 3-benzyl-6-bromo-5-chloroquinazoline-4-one A mixture of intermediate I-22 (4.00 g, 12.3 mmol), bromomethylbenzene (2.53 g, 14.8 mmol), and K2CO3 (3.41 g, 24.6 mmol) in DMF (40 mL) was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with siRNA (10 mL). The combined organic layers were washed with saline solution (2 × 20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography (PE:siRNA = 2:1) to obtain 3-benzyl-6-bromo-5-chloroquinazolin-4-one (2.00 g, yield 46%) as a brown solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.68(s,1H),8.14(d,J=8.8 Hz,1H),7.58(d,J=8.8 Hz,1H),7.41-7.29(m,5H),5.17(s,2H).

[0260] Step 2: 2-Ethylhexyl 3-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)propanoate A mixture of 3-benzyl-6-bromo-5-chloroquinazolin-4-one (1.60 g, 4.58 mmol), 2-ethylhexyl 3-sulfanylpropanoate (999 mg, 4.58 mmol), Pd2(dba)3 (41 mg, 457 μmol), xanthophos (529 mg, 915 μmol), and DIEA (1.77 g, 13.7 mmol) in dioxane (10 mL) was stirred at 110 °C for 16 hours under N2. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography (PE:HCl = 3:1) to obtain 2-ethylhexyl 3-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate (2.00 g, yield 89%) as a yellow oil.

[0261] Step 3: Sodium 3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazoline-6-thiolate t-BuONa (147 mg, 1.54 mmol) was added at 25°C to a solution of 2-ethylhexyl 3-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)propanoate (500 mg, 1.03 mmol) in THF (5 mL). The reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, PE was added to the reaction mixture and then filtered. The filtered cake was dried under vacuum to obtain sodium 3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazoline-6-thiolate (230 mg, yield 68%) as a red solid. 1 H NMR(400 MHz,D2O)δ=8.28(s,1H),7.98(d,J=8.8 Hz,1H),7.38-7.32(m,5H),7.28(d,J=8.8 Hz,1H),5.17(s,2H).

[0262] Step 4: 3-benzyl-6-((5-bromopyrazine-2-yl)thio)-5-chloroquinazoline-4(3H)-one To a solution of 2,5-dibromopyrazine (1.00 g, 4.20 mmol) and K2CO3 (195 mg, 1.42 mmol) in DMF (10 mL), DMF (10 mL) containing sodium 3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazoline-6-thiolate (230 mg, 708 μmol) was added at 0°C. The reaction mixture was stirred at 0-25°C for 16 hours. The reaction mixture was diluted with water (30 mL), and the mixture was extracted with ELISA (2 × 20 mL). The combined organic layers were washed with saline (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography (PE:ELISA = 2:1) to obtain intermediate I-23 (110 mg, yield 33%) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ=8.36(d,J=1.6 Hz,1H),8.12(d,J=1.6 Hz,1H),8.09(s,1H),7.83(d,J=8.8 Hz,1H),7.56(d,J=8.8 Hz,1H),7.33-7.25(m,5H),5.10(s,2H).

[0263] Preparation Example 24: (R)-2-methyl-N-[(1R)-spiro[indan-2,4'-piperidine]-1-yl]propan-2-sulfinamide (Intermediate I-24) [ka]

[0264] Step 1: tert-butyl 1-[(R)-tert-butylsulfinyl]iminospiro[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)4 (2.27 g, 9.95 mmol) in THF (5 mL) was stirred at 70°C for 36 hours. The reaction mixture was poured into water (10 mL) at 0°C and then filtered. The filtrate was diluted with water (10 mL), and the mixture was extracted with ELISA (2 × 20 mL). The combined organic layers were washed with saline solution (20 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography (PE:siRNA=3:1) to obtain tert-butyl 1-[(R)-tert-butylsulfinyl]iminospiro[indene-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).

[0265] Step 2: tert-butyl(1R)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indene-2,4'-piperidine]-1'-carboxylate To a solution of THF (10 mL) containing tert-butyl 1-[(R)-tert-butylsulfinyl]iminospiro[indene-2,4'-piperidine]-1'-carboxylate (800 mg, 1.98 mmol), LiBH4 (129 mg, 5.93 mmol) was added under N2 at -78°C. The reaction mixture was stirred at -78 to 25°C for 16 hours. The reaction mixture was quenched at 0°C by adding NH4Cl (10 mL), then diluted with water (10 mL), and the mixture was extracted with ELISA (2 × 20 mL). The combined organic layers were washed with saline (2 × 20 mL), dried over Na2SO4, then filtered, and concentrated under vacuum to obtain the residue. The residue was purified by Prep-HPLC (column: Welch Ultimate XB-CN 250*70*10um; mobile phase: [hexane-EtOH (0.1%NH3·H2O)]; B%: 1%-35%, 15 min) to obtain tert-butyl(1S)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indane-2,4'-piperidine]-1'-carboxylate (540 mg, yield 67%) and tert-butyl(1R)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indene-2,4'-piperidine]-1'-carboxylate (130 mg, yield 16%) as white solids. tert-butyl(1S)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indene-2,4'-piperidine]-1'-carboxylate: 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). tert-butyl(1R)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indene-2,4'-piperidine]-1'-carboxylate: 1H NMR(400 MHz,CDCl3)δ=7.63-7.60(m,1H),7.24-7.18(m,3H),4.47(d,J=8.0 Hz,1H),4.02-3.92(m,2H),3.31-3.28(m,1H),3.08-3.04(m,1H),2.98-2.92(m,2H) ,2.70-2.66(m,1H),1.74-1.70(m,2H),1.58-1.54(m,2H),1.47(s,9H),1.29(s,9H).

[0266] Step 3: (R)-2-methyl-N-[(1R)-spiro[inden-2,4'-piperidine]-1-yl]propan-2-sulfinamide A mixture of tert-butyl(1R)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indan-2,4'-piperidine]-1'-carboxylate (130 mg, 319 μmol) and TFA (1.30 mL) in DCM (5 mL) was stirred at 0°C for 1 hour. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (10 mL), and the mixture was extracted with SiO2 (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain intermediate I-24 (90 mg, yield 91%) as a colorless oil. 1 H NMR(400 MHz,CDCl3)δ=7.66-7.64(m,1H),7.26-7.18(m,3H),4.48(d,J=9.2 Hz,1H),4.11-3.98(m,2H),3.32(d,J=9.2 Hz,1H),3.18-3.02(m,3H),2.97-2.81(m,2H),2.70(d,J=15.2 Hz,1H),1.65(d,J=15.2 Hz,2H),1.31(s,9H).

[0267] Preparation Example 25: (R)-2-methyl-N-[(5S)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-yl]propan-2-sulfinamide (intermediate I-25) and (R)-2-methyl-N-[(5R)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-yl]propan-2-sulfinamide (intermediate I-26) [ka]

[0268] Step 1: 3-Bromo-2-(bromomethyl)pyridine To a solution of 3-bromo-2-methylpyridine (20.0 g, 116 mmol) in CCl4 (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 obtain the residue. The residue was purified by MPLC (PE / EA = 30:1) to obtain 3-bromo-2-(bromomethyl)pyridine (12.5 g, yield 42%) 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] + .

[0269] 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), lithium diisopropylamide (LDA) (2 M, 23.9 mL) was added and the mixture was stirred at -78°C for 0.5 hours. Then, 3-bromo-2-(bromomethyl)pyridine (10.0 g, 39.9 mmol) was slowly added to THF (100 mL) of the reaction mixture and the mixture was stirred at -78°C for 2.5 hours. The reaction mixture was quenched at 0°C by adding 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 saline solution (3 × 100 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reverse-phase flash column chromatography (0.1% FA) to obtain tert-butyl 4-[(3-bromo-2-pyridyl)methyl]-4-cyano-piperidine-1-carboxylate (13.5 g, yield 89%) 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] + .

[0270] 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) and 4-di-tert-butylphosphanyl-N,N-dimethylaniline; dichloropalladium (Pd(AmPhos)Cl2) (1.10 g, 1.55 mmol) and TEA (6.28 g, 62.1 mmol) in dimethylacetamide (DMA) (120 mL) and H2O (12 mL) was degassed and then purged three times with N2. The mixture was stirred under an N2 atmosphere at 130°C for 12 hours. The reaction mixture was quenched at 25°C by adding 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 saline solution (3 × 50 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (PE / EA = 3:1) to obtain tert-butyl 5-oxospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (3.2 g, yield 68%) 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] + .

[0271] 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), Ti(OEt)4 (34.0 g, 149 mmol) and (R)-2-methylpropane-2-sulfinamide (4.81 g, 39.7 mmol) were added. The mixture was stirred at 70°C for 12 hours. 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 saline (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reverse-phase flash column chromatography (0.1% ammonium hydroxide) to obtain tert-butyl(5Z)-5-[(R)-tert-butylsulfinyl]iminospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (3.35 g, yield 83%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.79-8.74(m,1H),8.69-8.61(m,1H),7.50-7.44(m,1H),4.00-3.93(m,2H),3.00(s,2H),3.02-2.89( m,2H),1.81-1.68(m,2H),1.58-1.50(m,2H),1.44-1.42(m,9H),1.27-1.22(m,9H);MS(EI)m / z:406.2 [M+H] + .

[0272] Step 5: tert-butyl(5S)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate and tert-butyl(5R)-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), LiBH4 (537 mg, 24.7 mmol) was added and the mixture was stirred at -70°C for 2 hours. The reaction mixture was quenched at 0°C by adding aqueous ammonium chloride solution (20 mL), then diluted with water (30 mL), and extracted with EA (3 × 50 mL). The combined organic layers were washed with saline solution (3 × 20 mL), dried on anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC using a Welch Ultimate XB-CN 250*50*10um column, mobile phase [hexane-EtOH (0.1%NH3·H2O)], B%: 10%-50%, for 15 minutes, yielding the following compounds as yellow solids. tert-butyl(5S)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (630 mg, yield 31%): 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] + . tert-butyl(5R)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (150 mg, yield 7%): 1H NMR(400 MHz, CDCl3)δ=8.59-8.52(m,1H),7.94-7.86(m,1H),7.39-7.31(m,1H),4.60-4.55(m,1H),4.09-3.97(m,2H),3.7 4-3.64(m,1H),3.54-3.39(m,1H),3.05-2.94(m,2H),1.55-1.49(m,2H),1.47-1.46(m,10H),1.30-1.25(m,11H).

[0273] Step 6: (R)-2-methyl-N-[(5S)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-yl]propan-2-sulfinamide and (R)-2-methyl-N-[(5R)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-yl]propan-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), TFA (1.68 g, 14.7 mmol) was added and the mixture was stirred at 0°C for 1 hour. The reaction mixture was poured into an aqueous solution of K2CO3 at 25°C (20 mL), then diluted with water (30 mL), and extracted with DCM (3 × 50 mL). The combined organic layers were washed with saline solution (3 × 20 mL), dried on anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain intermediate I-25 (140 mg, yield 92%) 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] + .

[0274] On the other hand, using tert-butyl(5R)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate, intermediate I-26 (100 mg, 90% yield) was obtained as a yellow solid by the same method as the preparation of intermediate I-25. 1 H NMR(400 MHz, CDCl3)=8.46-8.41(m,1H),7.61-7.59(m,1H),7.16-7.12(m,1H),4.55-4.52(m,1H),4.08-4.01(m,1H),3.23-3.11( m,2H),2.91-2.81(m,3H),2.26-2.20(m,1H),1.81-1.75(m,1H),1.67-1.63(m,1H),1.33-1.31(m,11H),MS(EI)m / z:308.4 [M+H] + .

[0275] Preparation Example 26: 6-((5-bromopyrazine-2-yl)thio)-5-chloro-3-((tetrahydrofuran-3-yl)methyl)quinazoline-4(3H)-one (intermediate I-27) [ka]

[0276] Intermediate I-27 was obtained as a yellow solid by the same method as in Preparation Example 23, except that 3-(bromomethyl)tetrahydrofuran was used instead of bromomethylbenzene in step 1. 1 H NMR(400 MHz,CDCl3)δ=8.37(s,1H),8.16(s,1H),8.13(s,1H),8.00(s,1H),7.85(d,J=8.8 Hz,1H),7.58(d,J=8.8 Hz,1H),3.97-3.90(m,2H),3.73-3.70(m,2H),3.58-3.54(m,1H),2.89-2.77(m,1H),2.10-2.00(m,1H),1.67-1.59(m,1H).

[0277] Preparation Example 27: 5-Chloro-6-((5-iodopyrazine-2-yl)thio)-3-(pyridine-3-ylmethyl)quinazoline-4(3H)-one (intermediate I-28) [ka]

[0278] Step 1: 6-amino-3-bromo-2-chlorobenzoic acid 2-amino-6-chlorobenzoic acid (5 g, 29.1 mmol) was dissolved in DMF (50 mL) and NBS (5.71 g, 32.1 mmol) was added, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with water (100 mL) and extracted with EA (100 mL x 3 times). The combined organic layers were washed with saline solution (50 mL x 3 times), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-amino-3-bromo-2-chlorobenzoic acid (7 g, yield 96%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=7.40(d,J=8.8 Hz,1H),6.65(d,J=8.8 Hz,1H),3.47(br s,2H);MS(EI)m / z:249.8 [M+H] + .

[0279] Step 2: 6-Bromo-5-chloro-3-(pyridine-3-ylmethyl)quinazoline-4(3H)-one To a solution of 6-amino-3-bromo-2-chlorobenzoic acid (3 g, 12.0 mmol) in EtOH (60 mL), I2 (304 mg, 1.20 mmol), diethoxymethoxyethane (2.66 g, 18.0 mmol), and 3-pyridylmethanamine (1.94 g, 18.0 mmol) were added and the mixture was stirred at 80°C for 12 hours. 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 (100 mL x 3 times). The combined organic layers were washed with saline solution (50 mL x 3 times), dried on anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain the residue. The residue was triturated with MeOH (30 mL) to obtain 6-bromo-5-chloro-3-(pyridine-3-ylmethyl)quinazoline-4(3H)-one (1.5 g, yield 36%) as a brown solid. 1 H NMR(400 MHz,CDCl3)δ=8.69(d,J=1.6 Hz,1H),8.60(dd,J=1.2,4.6 Hz,1H),8.17(s,1H),7.96(d,J=8.8 Hz,1H),7.77(d,J=8.0 Hz,1H),7.50(d,J=8.8 Hz,1H),7.31(dd,J=4.8,8.0 Hz,1H),5.17(s,2H);MS(EI)m / z:351.9 [M+H] + .

[0280] Steps 3-5: 5-Chloro-6-((5-iodopyrazine-2-yl)thio)-3-(pyridine-3-ylmethyl)quinazoline-4(3H)-one Using 5-chloro-6-((5-iodopyrazine-2-yl)thio)-3-(pyridine-3-ylmethyl)quinazoline-4(3H)-one as a starting material, intermediate I-28 was obtained as a yellow solid by the same method as steps 2-4 of Preparation Example 23. 1H NMR(400 MHz,CDCl3)δ=8.72(s,1H),8.61(s,1H),8.44(s,1H),8.22(s,2H),7.92(d,J=8.4 Hz,1H),7.81(d,J=7.6 Hz,1H),7.65(d,J=8.6 Hz,1H),7.35(dd,J=5.2,7.6 Hz,1H),5.19(s,2H);MS(EI)m / z:508.0 [M+H] + .

[0281] Preparation Example 28: 6-((5-bromopyrazine-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazoline-4(3H)-one (intermediate I-29) [ka]

[0282] Step 1: 2-Ethylhexyl 3-((5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazoline-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 the mixture was stirred at 55°C for 3 hours. 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 times). The combined organic layers were washed with saline solution (50 mL x 3 times), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0.1% formic acid) to obtain 2-ethylhexyl 3-(5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazoline-6-yl)thio)propanoate (6.8 g, yield 59%) as a yellow solid. 1H 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] +

[0283] Steps 2 and 3: 6-((5-bromopyrazine-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazoline-4(3H)-one Using 2-ethylhexyl 3-(5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazoline-6-yl)thio)propanoate as a starting material, intermediate I-29 (1.4 g, 22%) was obtained as a yellow solid by the same method as in steps 3 and 4 of Preparation Example 23. 1 H 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] + .

[0284] Preparation Example 29: 3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-5-chloro-6-(5-iodopyrazine-2-yl)thioquinazoline-4(3H)-one (intermediate I-30) [ka]

[0285] Intermediate I-30 (470 mg, 32%) was prepared in the same manner as in Preparation Example 28, except that (3-bromopropoxy)(tert-butyl)dimethylsilane was used instead of 1-bromo-2-methoxyethane in step 1 of Preparation Example 28. 1 H NMR(400 MHz,CDCl3)δ=8.60-8.42(m,1H),8.23-8.17(m,1H),8.13(s,1H),7.91(d,J=8.4 Hz,1H),7.68-7.61(m,1H),4.13(t,J=6.4 Hz,2H),3.67(t,J=5.6 Hz,2H),2.06-1.97(m,2H),0.92(s,9H),0.08(s,6H).

[0286] Preparation Example 30: 6-(5-bromopyrazine-2-yl)thio-5-chloro-3-(3-fluoropropyl)quinazoline-4(3H)-one (intermediate I-31) [ka]

[0287] Intermediate I-31 (320 mg, 20%) was prepared in the same manner as in Preparation Example 28, except that 1-bromo-3-fluoropropane was used instead of 1-bromo-2-methoxyethane in step 1 of Preparation Example 28. 1 H NMR(400 MHz,CDCl3)δ=8.45(d,J=1.2 Hz,1H),8.20(d,J=1.2 Hz,1H),8.11(s,1H),7.93(d,J=8.8 Hz,1H),7.66(d,J=8.8 Hz,1H),4.62(t,J=5.6 Hz,1H),4.50(t,J=5.6 Hz,1H),4.16(t,J=6.8 Hz,2H),2.32-2.26(m,1H),2.23-2.18(m,1H);MS(EI)m / z:431.1 [M+H] + .

[0288] Preparation Example 31: 6-(5-bromopyrazine-2-yl)thio-3-[3-[tert-butyl(dimethyl)silyloxybutyl]-5-chloroquinazoline-4(3H)-one (intermediate I-32) [ka]

[0289] Step 1: 3-Hydroxybutyl-4-methylbenzenesulfonate To a solution of butane-1,3-diol (2.0 g, 22.2 mmol) and TEA (6.74 g, 66.6 mmol) in DMF (30 mL), TosCl (5.08 g, 26.6 mmol) and DMAP (271 mg, 2.22 mmol) were added, and the mixture was stirred at 0°C for 12 hours. The reaction mixture was quenched with aqueous ammonium chloride (50 mL), diluted with water (50 mL), and then extracted with DCM (100 mL x 3). The combined organic layers were washed with saline solution (50 mL x 3 times), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-amino-3-bromo-2-chlorobenzoic acid (7 g, yield 96%) as a yellow solid. The residue was purified by column chromatography (PE / EA = 3 / 1) to obtain 3-hydroxybutyl-4-methylbenzenesulfonate (4.2 g, yield 77%). 1 H NMR(400 MHz,CDCl3)δ=7.80(d,J=8.0 Hz,2H),7.35(d,J=8.0 Hz,2H),4.28-4.21(m,1H),4.16-4.08(m,1H),3.97-3.91(m,1H),2.45(s,3 H),1.88-1.78(m,1H),1.74-1.72(m,1H),1.72-1.65(m,1H),1.19(d,J=6.0 Hz,3H).

[0290] Step 2: 3-[tert-butyl(dimethyl)silyl]oxybutyl 4-methylbenzenesulfonate To a 40 mL solution of 3-hydroxybutyl-4-methylbenzenesulfonate (4.0 g, 16.4 mmol) in DCM, imidazole (2.79 g, 40.9 mmol) and DMAP (200 mg, 1.64 mmol) were added, and TBSCl (2.96 g, 19.7 mmol) was slowly added dropwise. The mixture was stirred at 0°C for 12 hours. The reaction mixture was quenched with 50 mL of aqueous ammonium chloride solution, diluted with 100 mL of water, and then extracted with DCM (100 mL x 3). The combined organic layers were washed with saline solution (50 mL x 3 times), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-amino-3-bromo-2-chlorobenzoic acid (7 g, 96% yield) as a yellow solid. The residue was purified by column chromatography (PE / EA = 15 / 1) to obtain 3-[tert-butyl(dimethyl)silyl]oxybutyl 4-methylbenzenesulfonate (5.3 g, yield 90%). 1 H NMR(400 MHz,CDCl3)δ=7.80(d,J=8.0 Hz,2H),7.35(d,J=8.0 Hz,2H),4.14-4.08(m,2H),3.95-3.87(m,1H),2.46(s,3H),1.82-1.65(m,2H),1.11(d,J=6.0 Hz,3H),0.82(s,9H),0.00(d,J=17.6 Hz,6H).

[0291] Steps 3-5: 6-(5-bromopyrazine-2-yl)thio-3-[3-[tert-butyl(dimethyl)silyl]oxybutyl]-5-chloroquinazoline-4(3H)-one Using 3-[tert-butyl(dimethyl)silyl]oxybutyl 4-methylbenzenesulfonate obtained in step 2 above as a starting material, intermediate I-32 (320 mg, 19%) was prepared by the same method as in preparation example 28. 1H NMR(400 MHz,CDCl3)δ=8.44(d,J=1.2 Hz,1H),8.19(d,J=1.2 Hz,1H),8.09(s,1H),7.91(d,J=8.8 Hz,1H),7.64(d,J=8.8 Hz,1H),4.10-4.06(m,2H),4.02-3.96(m,1H),2.03-1.95(m,1H),1.90-1.81(m,1H),1.22(d,J=6.4 Hz,3H),0.93(s,9H),0.10(s,6H);MS(EI)m / z:557.1 [M+H] + .

[0292] Preparation Example 32: Sodium 5-((3S,4S)-4-(tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4,5]decane-8-yl]pyrazine-2-thiolate (intermediate I-33) [ka]

[0293] Step 1: (3S,4S)-8-(5-bromopyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine To a solution of (3S,4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine (5.00 g, 20.6 mmol, 2HCl) in DMF (50 mL), TEA (6.24 g, 61.7 mmol) and 2,5-dibromopyrazine (4.89 g, 20.6 mmol) were added and the mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched by adding 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 saline solution (3 × 100 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (3S,4S)-8-(5-bromopyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (6.7 g, crude product) as a yellow oil, which was used directly in the next step. MS(EI)m / z:329.1 [M+H] + .

[0294] Step 2: tert-butyl N-[(3S,4S)-8-(5-bromopyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl]carbamate (3S,4S)-8-(5-bromopyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (6.7 g, 20.5 mmol) in DMF (50 mL) was mixed with Boc2O (6.70 g, 30.7 mmol) and TEA (3.11 g, 30.7 mmol) and stirred at 25°C for 2 hours. The reaction mixture was quenched by adding 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 saline solution (3 × 100 mL), dried on anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to obtain the residue. Purification of the residue by column chromatography (PE / EA=5:1) yielded tert-butyl N-[(3S,4S)-8-(5-bromopyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate (5.5 g, yield 63%) as a yellow solid. MS(EI)m / z:429.1 [M+H] + .

[0295] Step 3: 2-Ethylhexyl 3-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)propanoate A mixture of dioxane (80 mL) containing tert-butyl N-[(3S,4S)-8-(5-bromopyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl]carbamate (5.50 g, 12.9 mmol), 2-ethylhexyl 3-sulfanylpropanoate (4.22 g, 19.3 mmol), Pd2(dba)3 (1.18 g, 1.29 mmol), xanthophos (1.49 g, 2.57 mmol), and DIEA (4.96 g, 38.6 mmol) was degassed, purged three times with N2, and then stirred at 110°C for 12 hours under an N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (PE / EA = 3:1) to obtain 2-ethylhexyl 3-[5-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]pyrazine-2-yl]sulfanylpropanoate (5.00 g, yield 69%) 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] + .

[0296] Step 4: Sodium 5-((3S,4S)-4-(tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4,5]decane-8-yl]pyrazine-2-thiolate 2-ethylhexyl 3-[5-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]pyrazine-2-yl]sulfanylpropanoate (270 mg, 478 μmol) was dissolved in THF (5 mL), to which t-BuONa (68.9 mg, 717 μmol) was added and the mixture was stirred at 25 °C for 0.5 hours. The residue was polished with PE (10 mL) to obtain intermediate I-33 (150 mg, crude product) as a yellow solid, which was used directly in the next step. MS(EI)m / z:381.1 [M+H] + .

[0297] Preparation Example 33: 2-benzyl-8-chloro-7-iodo-2H-benzo[e][1,2,4]thiazine 1,1-dioxide (intermediate I-34) [ka]

[0298] Step 1: Benzyl(2-chloro-6-nitrophenyl)sulfane EtONa (1.95 g, 28.7 mmol) was added to a solution of phenylmethanethiol (BnSH) (3.23 g, 26.0 mmol) in EtOH (50 mL). Then, 1,2-dichloro-3-nitrobenzene (5.0 g, 26.0 mmol) was added, and the mixture was stirred at 80°C for 1 hour. 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 saline solution (3 × 20 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (PE / EA = 10:1) to obtain benzyl(2-chloro-6-nitrophenyl)sulfan (5.7 g, yield 78%) as a yellow solid. 1H NMR(400 MHz,DMSO-d6)δ=7.86(dd,J=8.0,1.2 Hz,1H),7.76(dd,J=8.0,1.2 Hz,1H),7.60-7.56(m,1H),7.25-7.19(m,3H),7.12-7.07(m,2H),4.15(s,2H).

[0299] Step 2: 2-Chloro-6-nitrobenzenesulfonyl chloride 2-benzylsulfanyl-1-chloro-3-nitrobenzene (3.70 g, 13.2 mmol) was added to a solution of AcOH (40 mL) and H2O (13 mL) containing NCS (7.06 g, 52.9 mmol). The mixture was stirred at 0°C for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (3 × 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (PE / EA = 5:1) to obtain 2-chloro-6-nitrobenzenesulfonyl chloride (2.70 g, yield 79%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=7.65-7.60(m,1H),7.50-7.46(m,2H).

[0300] Step 3: N-benzyl-2-chloro-6-nitrobenzenesulfonamide To a solution of 2-chloro-6-nitrobenzenesulfonyl chloride (2.80 g, 10.9 mmol) in dioxane (30 mL), TEA (1.66 g, 16.4 mmol) and phenylmethaneamine (BnNH2) (1.76 g, 16.40 mmol) were added, and the mixture was stirred at 0°C for 12 hours. 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 combined organic layers were washed with saline solution (3 × 50 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (PE / EA = 5:1) to obtain N-benzyl-2-chloro-6-nitrobenzenesulfonamide (2.5 g, yield 70%) as a yellow solid. 1H NMR(400 MHz,DMSO-d6)δ=9.09(br s,1H),7.81-7.76(m,1H),7.75-7.69(m,2H),7.24-7.11(m,5H),4.14(s,2H).

[0301] Step 4: 2-amino-N-benzyl-6-chlorobenzenesulfonamide To a solution of N-benzyl-2-chloro-6-nitrobenzenesulfonamide (2.00 g, 6.12 mmol) in THF (30 mL), Pt-V / C (239 mg, 1.22 mmol) was added and the mixture was stirred at 25°C for 2 hours under an H2 atmosphere (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to obtain 2-amino-N-benzyl-6-chlorobenzenesulfonamide (1.8 g, 99% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.20(t,J=6.4 Hz,1H),7.30-7.16(m,5H),7.10(t,J=8.0 Hz,1H),6.73(dd,J=8.4,0.8 Hz,1H),6.59(dd,J=7.6,0.8 Hz,1H),6.55(s,2H),4.03(d,J=6.4 Hz,2H);MS(EI)m / z:297.0 [M+H] + .

[0302] Step 5: 6-amino-N-benzyl-2-chloro-3-iodobenzenesulfonamide To a solution of 2-amino-N-benzyl-6-chlorobenzenesulfonamide (2.00 g, 6.74 mmol) in DMF (20 mL), N-iodosuccinimide (NIS) (1.67 g, 7.41 mmol) was added and the mixture was stirred at 80°C for 2 hours. The reaction mixture was quenched by adding aqueous ammonium chloride (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 saline solution (3 × 20 mL), dried on anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (PE / EA = 3:1) to obtain 6-amino-N-benzyl-2-chloro-3-iodobenzenesulfonamide (2.4 g, yield 84%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.34(t,J=6.4 Hz,1H),7.56(d,J=9.0 Hz,1H),7.26-7.14(m,5H),6.70(br s,2H),6.55(d,J=9.0 Hz,1H),4.02(d,J=6.4 Hz,2H);MS(EI)m / z:422.9 [M+H] + .

[0303] Step 6: 2-benzyl-8-chloro-7-iodo-2H-benzo[e][1,2,4]thiazine 1,1-dioxide Triethyl orthoformate was added to a solution of 6-amino-N-benzyl-2-chloro-3-iodobenzenesulfonamide (2.3 g, 5.44 mmol) in diethoxymethoxyethane (24.1 g, 163 mmol), and the mixture was stirred at 150°C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was triturated with MeOH (30 mL) to obtain intermediate I-34 (2.1 g, yield 89%) as an off-white solid.

[0304] Preparation Example 34: 6-bromo-2,7-dichloro-1-((2-trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (intermediate I-35) [ka]

[0305] Step 1: 4-Bromo-3-chloro-2-nitroaniline To a solution of 3-chloro-2-nitroaniline (5.0 g, 29.0 mmol) in HOAc (250 mL), NBS (5.16 g, 29.0 mmol) was added, and the mixture was stirred at 120 °C for 1 hour. The reaction mixture was quenched with water (100 mL) and extracted with EA (3 × 100 mL). The combined organic layer was washed with saline solution (3 × 100 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (PE / EA = 10 / 1) to obtain 4-bromo-3-chloro-2-nitroaniline (5.35 g, yield 73%) as a brown solid. 1 H NMR(400 MHz,DMSO-d6)δ=7.56(d,J=9.2 Hz,1H),6.83(d,J=9.2 Hz,1H),6.42(s,2H).

[0306] Step 2: 4-Bromo-3-chlorobenzene-1,2-diamine To a solution of 4-bromo-3-chloro-2-nitroaniline (3.8 g, 15.1 mmol) in THF (40 mL), Pt-V / C (983 mg, 151 μmol, purity 3%) was added and the mixture was stirred at 25°C for 1 hour under an H2 atmosphere (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to obtain 4-bromo-3-chlorobenzene-1,2-diamine (3.1 g, yield 90%) as a brown solid. 1 H NMR(400 MHz,DMSO-d6)δ=6.70(d,J=8.4 Hz,1H),6.42(d,J=8.4 Hz,1H),4.97(br s,4H).

[0307] Step 3: 5-bromo-4-chloro-1,3-dihydrobenzimidazole-2-one 4-bromo-3-chlorobenzene-1,2-diamine (470 mg, 2.12 mmol) was dissolved in DMF (25 mL) and 1,1'-carbodiimide (CDI) (413 mg, 2.55 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (40 mL) to obtain an off-white precipitate. The solid was collected, washed with EA (40 mL), and dried under vacuum to obtain 5-bromo-4-chloro-1,3-dihydrobenzimidazole-2-one (370 mg, yield 71%) as an off-white solid. 1 H NMR(400 MHz,DMSO-d6)δ=11.36(s,1H),11.05(s,1H),7.28(d,J=8.0 Hz,1H),6.85(d,J=8.0 Hz,1H).

[0308] Step 4: 6-bromo-2,7-dichloro-1H-benzimidazole A solution of 5-bromo-4-chloro-1,3-dihydrobenzimidazole-2-one (350 mg, 1.41 mmol) in POCl3 (2 mL) was stirred at 100°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was quenched by adding aqueous NaHCO3 (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 obtain 6-bromo-2,7-dichloro-1H-benzimidazole (340 mg, 90% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=7.55(d,J=8.4 Hz,1H),7.43(d,J=8.4 Hz,1H);MS(EI)m / z:267.0 [M+H] + .

[0309] Step 5: 6-bromo-2,7-dichloro-1-((2-trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole 6-bromo-2,7-dichloro-1H-benzimidazole (290 mg, 1.09 mmol) was dissolved in DMF (5 mL) and NaH (48.0 mg, 1.20 mmol) was added, and the mixture was stirred at 0°C for 0.5 hours. Then, 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (273 mg, 1.64 mmol) was slowly added to the mixture in THF (5 mL), and the mixture was then stirred at 0°C for 1.5 hours. 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 saline solution (3 × 20 mL), dried on anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (PE / EA=30 / 1) to obtain intermediate I-35 (400 mg, 93% yield) as a yellow solid. 1 H NMR(400 MHz, CDCl3)δ=7.61(d,J=8.4 Hz,1H),7.28(d,J=8.4 Hz,1H),3.66-3.63(m,2H),3.60-3.53(m,2H),0.94-0.88(m,2H),0.04(s,9H);MS(EI)m / z:397.1 [M+H] + .

[0310] Preparation Example 35: 6-bromo-7-chloro-1-methyl-2-tetrahydrofuran-3-yloxy-benzimidazole (intermediate I-36) and 5-bromo-4-chloro-1-methyl-2-tetrahydrofuran-3-yloxy-benzimidazole (intermediate I-37) [ka]

[0311] Step 1: 2-[(6-bromo-7-chloro-2-tetrahydrofuran-3-yloxy-benzimidazole-1-yl)methoxy]ethyl-trimethyl-silane To a mixture of THF (5 mL) containing tetrahydrofuran-3-ol (166 mg, 1.89 mmol), NaH (75.5 mg, 1.89 mmol, 60% purity) was added at 0°C. The mixture was stirred under a nitrogen atmosphere at 0°C for 0.5 hours. Then, a solution of intermediate I-35 (500 mg, 1.26 mmol) in THF (2 mL) was added at 0°C. The mixture was stirred under a nitrogen atmosphere at 20°C for 1 hour. The reaction mixture was quenched with water (10 mL) at 0°C, then diluted with water (20 mL), and extracted with EA (3 × 20 mL). The organic layer was washed with brine (2 × 30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. Purification of the crude product by reverse-phase flash column chromatography (0.1% FA conditions) yielded 2-[(6-bromo-7-chloro-2-tetrahydrofuran-3-yloxy-benzimidazole-1-yl)methoxy]ethyl-trimethyl-silane (230 mg, yield 41%) as a yellow oily substance. 1 H NMR(400 MHz,CDCl3)δ=7.41(d,J=8.4 Hz,1H),7.11(d,J=8.4 Hz,1H),5.91-5.83(m,1H),5.35(s,2H),4.14-4.06(m,2H),4.05-3.99(m,1H),3.98- 3.91(m,1H),3.54-3.49(m,2H),2.44-2.33(m,1H),2.31-2.22(m,1H),0.90(d,J=8.4 Hz,2H),-0.03(d,J=1.2 Hz,9H).

[0312] Step 2: 6-Bromo-7-chloro-2-tetrahydrofuran-3-yloxy-1H-benzimidazole To a mixture of 2-[(6-bromo-7-chloro-2-tetrahydrofuran-3-yloxy-benzimidazole-1-yl)methoxy]ethyl-trimethyl-silane (230 mg, 513 μmol) in DCM (2 mL), TFA (3.08 g, 27.0 mmol, 2 mL) was added. The reaction mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with water (10 mL) and basicized with saturated K2CO3 aqueous solution until the pH was 7. The mixture was extracted with EA (3 × 10 mL). The organic layer was washed with brine (2 × 50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain 6-bromo-7-chloro-2-tetrahydrofuran-3-yloxy-1H-benzimidazole (160 mg, yield 98%) as a yellow oil. MS(EI)m / z:318.9 [M+H] + .

[0313] Step 3: 6-Bromo-7-chloro-1-methyl-2-tetrahydrofuran-3-yloxy-benzimidazole and 5-bromo-4-chloro-1-methyl-2-tetrahydrofuran-3-yloxy-benzimidazole MeI (107 mg, 755 μmol) was added to a mixture of 6-bromo-7-chloro-2-tetrahydrofuran-3-yloxy-1H-benzimidazole (160 mg, 503 μmol) and Cs2CO3 (492 mg, 1.51 mmol) in DMF (5 mL). The reaction mixture was stirred at 20°C for 2 hours, diluted with water (20 mL), and extracted with EA (3 × 20 mL). The organic layer was washed with brine (2 × 50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenexluna C18 150 * 25 mm * 10 μm; mobile phase: [water (FA)-I]; B%: 44%-64%, 2 min) to obtain intermediates I-36 and I-37 as yellow solids, respectively. 6-Bromo-7-chloro-1-methyl-2-tetrahydrofuran-3-yloxy-benzimidazole (53 mg, yield 31%): 1H NMR(400 MHz,CDCl3)δ=7.40(d,J=8.4 Hz,1H),7.28(d,J=8.4 Hz,1H),5.71-5.63(m,1H),4.15-4.09(m,1H),4.09-4.02(m,2H),3.98-3.91(m,1H),3.87(s,3H),2.43-2.34(m,1H),2.33-2.24(m,1H). 5-Bromo-4-chloro-1-methyl-2-tetrahydrofuran-3-yloxy-benzimidazole (40 mg, yield 24%): 1 H NMR(400 MHz,CDCl3)δ=7.39(d,J=8.4 Hz,1H),6.95(d,J=8.4 Hz,1H),5.87-5.82(m,1H),4.15-4.10(m,1H),4.09-4.02(m,2H),3.97-3.91(m,1H),3.55(s,3H),2.46-2.34(m,1H),2.33-2.22(m,1H).

[0314] Preparation Example 36: tert-butyl((3S,4S)-8-(5-bromo-3-(hydroxymethyl)-6-methylpyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (intermediate I-38) [ka]

[0315] Step 1: Ethyl 3-hydroxy-5-methylpyrazine-2-carboxylate To a stirred mixture of propane-1,2-diamine (25.5 g, 344 mmol) in EtOH (300 mL), diethyl 2-oxopropanediol (59.9 g, 344 mmol) was added dropwise at 0°C, and the mixture was heated to 25°C. The reaction mixture was stirred at 25°C for 2 hours, and then stirred at 95°C for 18 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was polished with EA (100 mL) to obtain ethyl 3-hydroxy-5-methylpyrazine-2-carboxylate (10 g, yield 16%) as a red solid. 1H NMR(400 MHz, CDCl3)δ=11.46(br s,1H),8.16(s,1H),4.55(q,J=7.2 Hz,2H),2.58(s,3H),1.49(t,J=7.2 Hz,3H).

[0316] Step 2: Ethyl 6-bromo-3-hydroxy-5-methylpyrazine-2-carboxylate To a solution of ethyl 3-hydroxy-5-methylpyrazine-2-carboxylate (2.85 g, 15.6 mmol) in DMF (60 mL), NBS (2.92 g, 16.4 mmol) was added and the mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched by adding aqueous ammonium chloride (50 mL) at 25°C, then diluted with water (50 mL), and extracted with EA (100 mL x 3 times). The combined organic layers were washed with saline solution (50 mL x 3 times), dried on anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (PE / EA = 10 / 1~5:1) to obtain ethyl 6-bromo-3-hydroxy-5-methylpyrazine-2-carboxylate (2.65 g, yield 65%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=12.56(br s,1H),4.35(q,J=7.2 Hz,2H),3.37(s,3H),1.34(t,J=7.2 Hz,3H);MS(EI)m / z:261.3 [M+H] + .

[0317] Step 3: Ethyl 6-bromo-3-chloro-5-methylpyrazine-2-carboxylate To PPh3 (3.01 g, 11.5 mmol) in dioxane (30 mL), NCS (1.56 g, 11.68 mmol) was added, and the mixture was heated to 25°C and stirred for 30 minutes. Then, 6-bromo-3-hydroxy-5-methylpyrazine-2-carboxylate ethyl (1 g, 3.83 mmol) was added all at once, and the mixture was heated to 100°C and stirred for 1 hour. Next, the reaction mixture was cooled to room temperature, and TEA (3.88 g, 38.3 mmol) was added. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (PE / EA = 15 / 1~10:1) to obtain 6-bromo-3-chloro-5-methylpyrazine-2-carboxylate ethyl (0.3 g, yield 28%) as a yellow oil. 1 H NMR(400 MHz, CDCl3)δ=4.53-4.44(m,2H),2.71(s,3H),1.44(t,J=7.2 Hz,3H).

[0318] Step 4: Ethyl 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4,5]decano-8-yl]-6-bromo-5-methylpyrazine-2-carboxylate To a DMA (4 mL) solution of ethyl 6-bromo-3-chloro-5-methylpyrazine-2-carboxylate (0.3 g, 1.07 mmol), DIEA (694 mg, 5.37 mmol) and (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (287 mg, 1.18 mmol, 2HCl) were added and the mixture was stirred at 60°C for 12 hours. 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 (50 mL x 3 times). The combined organic layers were washed with saline solution (20 mL x 3 times), dried on anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reverse-phase flash column chromatography (0.1% FA) to obtain ethyl 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-6-bromo-5-methylpyrazine-2-carboxylate (350 mg, crude product) as a yellow oily substance. MS(EI)m / z:415.3 [M+H]+ .

[0319] Step 5: Ethyl 6-bromo-3-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-methylpyrazine-2-carboxylate To a 10 mL solution of ethyl 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-6-bromo-5-methylpyrazine-2-carboxylate (250 mg, 605 μmol) in DCM (10 mL), Boc2O (198 mg, 907 μmol) and TEA (184 mg, 1.81 mmol) were added. The mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by reverse-phase flash column chromatography (0.1% FA) to obtain ethyl 6-bromo-3-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-methylpyrazine-2-carboxylate (250 mg, 80% yield) as a yellow solid. MS(EI)m / z:513.2 [M+H] + .

[0320] Step 6: tert-butyl N-[(3S,4S)-8-[5-bromo-3-(hydroxymethyl)-6-methylpyrazine-2-yl]-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl]carbamate To a solution of ethyl 6-bromo-3-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-methylpyrazine-2-carboxylate (150 mg, 292 μmol) in DCM (5 mL), diisobutylaluminum hydride (DIBAL-H) ​​(1 M in toluene, 1.17 mL) was added, and the mixture was stirred at -70°C for 2 hours. The reaction mixture was quenched at -70°C by adding 2 mL of MeOH, and then diluted with DCM (50 mL). The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by Pre-TLC (PE / EA = 1:1) to obtain intermediate I-38 (120 mg, yield 87%) as a yellow solid. MS(EI) m / z: 471.3 [M+H] + .

[0321] Preparation Example 37: (R)-N-((S)-1'-(5-((5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-5-yl)-2-methylpropane-2-sulfinamide (intermediate I-39) [ka]

[0322] Step 1: 6-(5-bromopyrazine-2-yl)sulfanyl-5-chloro-3H-quinazoline-4-one To a solution of 5-chloro-6-mercaptoquinazolin-4(3H)-one (880 mg, 3.75 mmol) in DMF (20 mL), K2CO3 (1.56 g, 11.3 mmol) and 2,5-dibromopyrazine (3.57 g, 15.00 mmol) were added, and the mixture was stirred at 0°C for 2 hours. 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 (100 mL x 3 times). The combined organic layers were washed with saline solution (50 mL x 3 times), dried on anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (PE / EA = 1 / 1 to 0:1) to obtain 6-(5-bromopyrazine-2-yl)sulfanyl-5-chloro-3H-quinazolin-4-one (500 mg, yield 36%) 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] + .

[0323] Step 2: (R)-N-((S)-1'-(5-((5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-5-yl)-2-methylpropane-2-sulfinamide A mixture of 6-(5-bromopyrazine-2-yl)sulfanyl-5-chloro-3H-quinazolin-4-one (150 mg, 406 μmol), intermediate I-25 (150 mg, 487 μmol), and [2-(2-aminophenyl)phenyl]-chloropalladium; dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (RuPhos-Pd-G2) (31.5 mg, 40.6 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (37.8 mg, 81.2 μmol) and K2CO3 (168 mg, 1.22 mmol) in dioxane (5 mL) was degassed, purged three times with N2, and the mixture was then stirred at 100°C for 12 hours under an N2 atmosphere. The reaction mixture was quenched at -70°C by adding MeOH (2 mL), diluted with DCM (50 mL), filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reverse-phase flash column chromatography (0.1% FA) to obtain intermediate I-39 (80 mg, yield 33%) as a yellow solid. MS(EI) m / z: 596.1 [M+H] + .

[0324] Preparation Example 38: 3-benzyl-7-bromo-8-chloroquinazolin-4-one (intermediate I-40) [ka]

[0325] Step 1: Methyl 2-amino-4-bromo-3-chlorobenzoate NCS (12.7 g, 95.6 mmol) was added to a solution of methyl 2-amino-4-bromo-benzoate (20.0 g, 86.9 mmol) in DMF (200 mL). The mixture was stirred at 100°C for 4 hours. The reaction mixture was diluted with water (300 mL) and extracted with siRNA (3 × 200 mL). The combined organic layers were washed with brine (3 × 150 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (PE:EA = 1:0), and the crude product was purified by reverse-phase flash column chromatography (0.1% FA conditions) to obtain methyl 2-amino-4-bromo-3-chlorobenzoate (4 g, yield 17%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=7.67(d,J=8.8 Hz,1H),6.92(d,J=8.8 Hz,1H),6.49(br s,2H),3.89(s,3H).

[0326] Step 2: 2-amino-4-bromo-3-chlorobenzoic acid NaOH (1.51 g, 37.8 mmol) was added to a solution of THF (18 mL) and water (6 mL) containing methyl 2-amino-4-bromo-3-chlorobenzoate (2.00 g, 7.56 mmol). The mixture was stirred at 40°C for 12 hours. The residue was adjusted to pH 6 with 1 M HCl to obtain a white solid precipitate. After collecting the solid, it was dried under vacuum to obtain 2-amino-4-bromo-3-chlorobenzoic acid (1.80 g, yield 95%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ=13.16(br s,1H),7.64(d,J=8.8 Hz,1H),7.09(br s,2H),6.94(d,J=8.8 Hz,1H).

[0327] Step 3: 7-Bromo-8-chloro-3H-quinazolin-4-one A solution of 2-amino-4-bromo-3-chlorobenzoic acid (1.00 g, 3.99 mmol) in formamide (6.78 g, 150 mmol, 6 mL) was stirred at 140°C for 16 hours. The reaction mixture was filtered, and the filtrate was washed with EA (20 mL). The filtration cake was dried under vacuum to obtain 7-bromo-8-chloro-3H-quinazolin-4-one (900 mg, crude product) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.24(s,1H),7.97(d,J=8.8 Hz,1H),7.84(d,J=8.8 Hz,1H).

[0328] Step 4: 3-benzyl-7-bromo-8-chloroquinazoline-4-one A mixture of acetonitrile (MeCN) (2 mL) containing 7-bromo-8-chloro-3H-quinazolin-4-one (300 mg, 1.16 mmol), benzyl bromide (395 mg, 2.31 mmol), and K2CO3 (479 mg, 3.47 mmol) was stirred at 80°C for 24 hours. The reaction mixture was filtered, and the filtrate was purified by reverse-phase flash column chromatography (0.1% FA) to obtain intermediate I-40 (60 mg, yield 14%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.74(s,1H),7.90(d,J=8.8 Hz,1H),7.88(d,J=8.8 Hz,1H),7.28~7.38(m,5H),5.19(s,2H).

[0329] Preparation Example 39: 2-benzyl-7-chloro-6-iodoisoindorin-1-one (intermediate I-41) [ka]

[0330] Step 1: Methyl 2-chloro-6-methylbenzoate To a solution of 2-chloro-6-methylbenzoic acid (10.0 g, 58.6 mmol) in DMF (100 mL), MeI (24.9 g, 175 mmol) and K2CO3 (12.1 g, 87.9 mmol) were added and the mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched by adding 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 obtain methyl 2-chloro-6-methylbenzoate (10.5 g, 97% yield) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ=7.25-7.21(m,2H),7.13-7.10(m,1H),3.99(s,3H),2.36(s,3H);MS(EI)m / z:185.0 [M+H] + .

[0331] Step 2: Methyl 2-(bromomethyl)-6-chlorobenzoate To a solution of methyl 2-chloro-6-methyl benzoate (7.90 g, 42.8 mmol) in CCl4 (70 mL), NBS (8.38 g, 47.1 mmol) and benzoyl peroxide (BPO) (207 mg, 856 μmol) were added, and the mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain methyl 2-(bromomethyl)-6-chloro-benzoate (10 g, crude product) as a yellow oily substance. MS(EI)m / z:263.0 [M+H] + .

[0332] Step 3: 7-Chloroisoindoline-1-one To a solution of methyl 2-(bromomethyl)-6-chlorobenzoate (10.0 g, 38.0 mmol) in THF (50 mL), NH3·H2O (53.2 g, 379 mmol, purity 30%) was added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched by adding aqueous ammonium chloride (50 mL) at 25°C, then diluted with water (100 mL), and extracted with EA (3 × 150 mL). The combined organic layers were washed with saline solution (3 × 100 mL), dried on anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (PE / EA = 0 / 1) to obtain 7-chloroisoindorin-1-one (2.8 g, yield 44%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.69(br s,1H),7.60-7.52(m,2H),7.46(d,J=7.2 Hz,1H),4.35(s,2H).

[0333] Step 4: 7-Chloro-6-iodoisoindoline-1-one To a solution of 7-chloroisoindorin-1-one (12 g, 71.6 mmol) in H2SO4 (120 mL), NIS (20.9 g, 93.0 mmol) was added and the mixture was stirred at 0°C for 2.5 hours. The reaction mixture was poured into ice water, then diluted with water (200 mL), and extracted with EA (3 × 300 mL). The combined organic layers were washed with saline solution (3 × 150 mL), dried on anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (PE / EA = 1:1) to obtain 7-chloro-6-iodoisoindorin-1-one (3 g, yield 14%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.75(br s,1H),8.15(d,J=8.4 Hz,1H),7.32(d,J=8.4 Hz,1H),4.27(s,2H);MS(EI)m / z:293.8 [M+H] + .

[0334] Step 5: 2-benzyl-7-chloro-6-iodoisoindoline-1-one 7-Chloro-6-iodoisoindorin-1-one (500 mg, 1.70 mmol) and bromomethylbenzene (437 mg, 2.56 mmol) were dissolved in DMF (10 mL), to which Cs2CO3 (1.11 g, 3.41 mmol) was added and the mixture was stirred at 25°C for 12 hours. 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 layers were washed with saline solution (3 × 20 mL), dried on anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex lunaC18 150*40mm*15um; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 10 min) to obtain intermediate I-41 (80 mg, yield 20%) as a white solid. 1 H NMR(400 MHz, CDCl3)δ=8.00(d,J=8.0 Hz,1H),7.37-7.27(m,5H),7.02(d,J=8.0 Hz,1H),4.79(s,2H),4.17(s,2H).

[0335] Preparation Example 40: 6-(3-amino-5-chloropyrazine-2-yl)sulfanyl-5-chloro-3-(2-methoxyethyl)quinazolin-4-one (intermediate I-42) [ka]

[0336] The mixture obtained in step 2 of Preparation Example 28, consisting of [5-chloro-3-(2-methoxyethyl)-4-oxo-quinazolin-6-yl]sulfanyl chloride (630 mg, 2.15 mmol), 3-bromo-6-chloropyrazine-2-amine (538 mg, 2.58 mmol), Pd2(dba)3 (197 mg, 215 μmol), xanthophos (249 mg, 431 μmol), and DIEA (835 mg, 6.46 mmol), was degassed in dioxane (20 mL), purged three times with N2, and stirred at 100°C for 12 hours under an N2 atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by reverse-phase flash column chromatography (0.1% FA) to obtain intermediate I-42 (120 mg, yield 14%) 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] + .

[0337] Preparation Example 41: 6-bromo-7-chloro-2-(3-methoxybenzyl)-1H-benzo[d]imidazole (intermediate I-43) [ka]

[0338] 4-Bromo-3-chlorobenzene-1,2-diamine (150 mg, 0.677 mmol) was dissolved in DMF (8.2 mL, 0.15 M), and 2-(3-methoxyphenyl)acetic acid (113 mg, 0.677 mmol), HATU (515 mg, 1.354 mmol), and TEA (0.19 mL, 1.354 mmol) were added. The mixture was stirred at room temperature for 8 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC (EA:Hx=1:3) and concentrated to obtain intermediate I-43 (150 mg, 60% yield). MS(EI)m / z:351.6 [M+H] + .

[0339] Preparation Example 42: (S)-2-methyl-N-[(1R)-spiro[indan-2,4'-piperidine]-1-yl]propan-2-sulfinamide (intermediate I-44) [ka]

[0340] Step 1: tert-butyl(S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate To a solution of THF (10 mL) containing tert-butyl 1-[(R)-tert-butylsulfinyl]iminospiro[indene-2,4'-piperidine]-1'-carboxylate (800 mg, 1.98 mmol), LiBH4 (129 mg, 5.93 mmol) was added under N2 at -78°C. The reaction mixture was stirred at -78 to 25°C for 16 hours. The reaction mixture was quenched at 0°C by adding NH4Cl (10 mL), then diluted with water (10 mL), and extracted with ELISA (2 × 20 mL). The combined organic layers were washed with saline (2 × 20 mL), dried over Na2SO4, then filtered, and concentrated under vacuum to obtain the residue. The residue was purified by Prep-HPLC (column: Welch Ultimate XB-CN 250*70*10 μm; mobile phase: [hexane-EtOH (0.1% NH3·H2O)]; B%: 1%-35%, 15 min) to obtain tert-butyl(1S)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indane-2,4'-piperidine]-1'-carboxylate (540 mg, yield 67%) and tert-butyl(1R)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indene-2,4'-piperidine]-1'-carboxylate (130 mg, yield 16%) as white solids. tert-butyl(1S)-1-[indene-2,4'-piperidine]spiro-1'-carboxylate: 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).

[0341] Step 3: (R)-N-((S)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-yl]-2-methylpropane-2-sulfinamide A mixture of tert-butyl(1S)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indene-2,4'-piperidine]-1'-carboxylate (100 mg, 245 μmol) and TFA (1.30 mL) in DCM (5 mL) was stirred at 0°C for 1 hour. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (10 mL) and extracted with SiO2 (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain intermediate I-44 (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).

[0342] Preparation Example 43: 6-bromo-7-chloro-2-(pyrazine-2-ylmethyl)-1H-benzo[d]imidazole (intermediate I-45) [ka]

[0343] Intermediate I-45 (100 mg, 20%) was prepared in the same manner as in Preparation Example 41, except that 2-(pyrazine-2-yl)acetic acid was used instead of 2-(3-methoxyphenyl)acetic acid. MS(EI)m / z:323.5 [M+H] + .

[0344] Preparation Example 44: 6-bromo-7-chloro-2-(pyridine-3-ylmethyl)-1H-benzo[d]imidazole (intermediate I-46) [ka]

[0345] Intermediate I-46 (100 mg, 20%) was prepared in the same manner as in Preparation Example 41, except that 2-(pyridine-3-yl)acetic acid was used instead of 2-(3-methoxyphenyl)acetic acid. MS(EI)m / z:322.5 [M+H] + .

[0346] Preparation Example 45: tert-butyl 2-chloro-6-oxo-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (intermediate I-47) [ka]

[0347] Step 1: (2-Chlorothiazol-4-yl)methanol To a solution of ethyl 2-chlorothiazole-4-carboxylate (30 g, 157 mmol) in EtOH (300 mL), NaBH4 (41.5 g, 1.10 mol) was added and the mixture was stirred at 50°C for 2 hours. The reaction mixture was quenched at 0°C with aqueous ammonium chloride (100 mL), diluted with water (100 mL), and then extracted with EA (200 mL x 3 times). The combined organic layers were washed with saline solution (200 mL x 3 times), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain (2-chlorothiazole-4-yl)methanol (22 g, yield 94%) as a colorless oil. 1 H NMR(400 MHz,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] + .

[0348] Step 2: (2-chlorothiazole-4-yl)methylmethanesulfonate To a solution of ethyl 2-chlorothiazole-4-carboxylate (30 g, 157 mmol) in DCM (300 mL), TEA (27.1 g, 267 mmol) and MsCl (21.4 g, 187 mmol) were added at 0°C and the mixture was stirred at 0°C for 0.5 hours. The reaction mixture was quenched with aqueous NaHCO3 solution (100 mL) at 25°C, diluted with water (100 mL), and then extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (2-chlorothiazole-4-yl)methylmethanesulfonate (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)

[0349] 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 under nitrogen at -60°C, and LDA (2 M, 81.6 mL) was added dropwise. The reaction mixture was stirred at -60°C for 0.5 hours, and (2-chlorothiazole-4-yl)methylmethanesulfonate (26.5 g, 117 mmol) in THF (15 mL) was added dropwise. The reaction mixture was stirred at -60°C for 0.5 hours, then slowly raised to room temperature and stirred for 2 hours. The reaction mixture was quenched with aqueous ammonium chloride (100 mL), diluted with water (200 mL), and then extracted with EA (300 mL x 3 times). The combined organic layers were washed with saline solution (150 mL x 3 times), dried on anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0.1% FA) to obtain O1-tert-butyl O4-ethyl 4-[(2-chlorothiazol-4-yl)methyl]piperidine-1,4-dicarboxylate (14 g, yield 31%) as a yellow oil. 1H 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).

[0350] 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 hours. The reaction mixture was quenched at 0°C with aqueous ammonium chloride (100 mL), diluted with water (100 mL), and then extracted with EA (200 mL x 3 times). The combined organic layers were washed with saline solution (200 mL x 3 times), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain intermediate I-47 (6.1 g, yield 50%) 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).

[0351] Preparation Example 46: (R)-2-methyl-N-[(6S)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-6-yl]propan-2-sulfinamide (intermediate I-48) [ka]

[0352] Step 1: tert-butyl(6Z)-6-[(R)-tert-butylsulfinyl]imino-2-chlorospiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of intermediate I-47 (3.0 g, 8.75 mmol) and (R)-2-methylpropane-2-sulfinamide (4.24 g, 35.0 mmol) in THF (30 mL), Ti(OEt)4 (29.9 g, 131 mmol) was added dropwise, and the reaction mixture was stirred at 90 °C for 12 hours. EA (300 mL) was added to the reaction mixture, diluted with water (50 mL), and then extracted with EA (100 mL x 3 times). The combined organic layers were washed with saline solution (100 mL x 3 times), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain tert-butyl(6Z)-6-[(R)-tert-butylsulfinyl]imino-2-chlorospiro[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] + .

[0353] 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-chlorospiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (3.5 g, 7.85 mmol) in THF (30 mL), BH3.THF (1 M, 31.4 mL) was added, and the reaction mixture was stirred at -70°C for 2 hours. The reaction mixture was quenched with MeOH (10 mL) at 0°C, diluted with water (100 mL), and then extracted with EA (100 mL x 3 times). The combined organic layers were washed with saline solution (50 mL x 3 times), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by column chromatography yielded tert-butyl(6S)-6-[[(R)-tert-butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (660 mg, 20%) as a yellow solid. 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).

[0354] Step 3: (R)-2-methyl-N-[(6S)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-6-yl]propan-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), TFA (2.76 g, 24.2 mmol) was added, and the reaction mixture was stirred at 25°C for 0.5 hours. The reaction mixture was quenched at 25°C with saturated K2CO3 aqueous solution (20 mL), diluted with water (30 mL), and then extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate I-48 (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).

[0355] Preparation Example 47: (S)-2-methyl-N-[(6R)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-6-yl]propan-2-sulfinamide (intermediate I-49) [ka]

[0356] Step 1: tert-butyl(6Z)-6-[(S)-tert-butylsulfinyl]imino-2-chlorospiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of intermediate I-47 (3.0 g, 8.75 mmol) in THF (30 mL), Ti(OEt)4 (29.9 g, 131 mmol) and (S)-2-methylpropane-2-sulfinamide (4.24 g, 35.0 mmol) were added, and the reaction mixture was stirred at 90°C for 12 hours. The reaction mixture was quenched with water (30 mL) and extracted with EA (300 mL). After filtration, the filtrate was concentrated under reduced pressure, EA (100 mL) was added, and the mixture was washed with saline solution (20 mL x 3 times), dried on anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography to obtain tert-butyl(6Z)-6-[(S)-tert-butylsulfinyl]imino-2-chlorospiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (3.7 g, 94% yield) as a yellow solid. 1 H NMR(400 MHz, CDCl3)δ=4.28-4.15(m,2H),2.97-2.86(m,4H),2.06-1.98(m,1H),1.97-1.91(m,1H),1.58-1.52(m,2H),1.49(s,9H),1.28(s,9H).

[0357] Step 2: tert-butyl(6R)-6-[[(S)-tert-butylsulfinyl]amino]-2-chlorospiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of tert-butyl(6Z)-6-[(S)-tert-butylsulfinyl]imino-2-chlorospiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (2.0 g, 4.48 mmol) in DCM (20 mL), DIBAL-H (1 M, 13.4 mL) was added, and the reaction mixture was stirred at -60°C for 1 hour. The reaction mixture was quenched with methanol (0.5 mL) at -60°C and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain tert-butyl(6R)-6-[[(S)-tert-butylsulfinyl]amino]-2-chlorospiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (1.6 g, yield 78%) as a pale yellow solid. 1 H NMR(400 MHz,CDCl3)δ=4.53(d,J=8.4 Hz,1H),4.10-3.94(m,2H),3.55(d,J=8.4 Hz,1H),3.07-2.77(m,4H),1.90-1.75(m,2H),1.63(d,J=8.0 Hz,1H),1.57(br s,1H),1.47(s,9H),1.23(s,9H);MS(EI)m / z:448.2 [M+H] + .

[0358] Step 3: tert-butyl(6R)-6-[[(S)-tert-butylsulfanyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of methanol (10 mL) containing tert-butyl(6R)-6-[[(S)-tert-butylsulfinyl]amino]-2-chlorospiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (1.0 g, 2.23 mmol), TEA (677 mg, 6.70 mmol) was added, and the mixture was subsequently purged three times with N2. Pd / C (100 mg, 10% purity) was added to the reaction mixture, and H2 gas was injected. The reaction mixture was stirred at 40°C for 16 hours. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl(6R)-6-[[(S)-tert-butylsulfanyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (880 mg, yield 93%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ=8.79(s,1H),4.58(d,J=8.8 Hz,1H),4.09-3.90(m,2H),3.68-3.53(m,1H),3.08-2.81(m,4H),1.93-1. 76(m,2H),1.68-1.57(m,2H),1.47(s,9H),1.23(s,9H);MS(EI)m / z:414.2 [M+H] + .

[0359] Step 4: (S)-2-methyl-N-[(6R)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-6-yl]propan-2-sulfinamide To a solution of tert-butyl(6R)-6-[[(S)-tert-butylsulfanyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (400 mg, 967 μmol) in DCM (9 mL), TFA (3 mL) was added and the mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure and adjusted to pH 9 with saturated K2CO3 solution. Extraction was then performed with DCM / i-PrOH = 3 / 1 (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain intermediate I-49 (310 mg, crude product) as a pale yellow oil. MS(EI) m / z: 314.2 [M+H] + .

[0360] Preparation Example 48: 6-(5-bromopyrazine-2-yl)sulfanyl-5-chloro-3H-quinazoline-4-one (intermediate I-50) [ka]

[0361] To a solution of 5-chloro-6-mercaptoquinazolin-4(3H)-one (880 mg, 3.75 mmol) in DMF (20 mL), K2CO3 (1.56 g, 11.3 mmol) and 2,5-dibromopyrazine (3.57 g, 15.00 mmol) were added, and the mixture was stirred at 0°C for 2 hours. 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 x 3 times). The combined organic layers were washed with saline solution (50 mL x 3 times), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (PE / EA = 1 / 1 ~ 0:1) to obtain intermediate I-50 (500 mg, yield 36%) as a yellow solid. 1H 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] + .

[0362] Preparation Example 49: (S)-N-[(6R)-1'-[5-[(5-chloro-4-oxo-3H-quinazoline-6-yl)sulfanyl]pyrazine-2-yl]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]spiro-6-yl]-2-methyl-propane-2-sulfinamide (intermediate I-51) [ka]

[0363] To a solution of intermediate I-50 (402 mg, 1.09 mmol) in dioxane (5 mL), intermediate I-49 (310 mg, 989 μmol), RuPhos (92.3 mg, 198 μmol), RuPhos-Pd-G2 (76.8 mg, 98.9 μmol), and K2CO3 (410 mg, 2.97 mmol) were added, and the mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain intermediate I-51 (180 mg, yield 28%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=8.83(s,1H),8.28(s,1H),8.24(s,1H),7.96(s,1H),7.50(d,J=8.8 Hz,1H),7.30(s,1H),4.67(d,J=8.4 Hz,1H),4.49-4.22(m,2H),3.89(d,J=9.6 Hz,1H),3.31-3.25(m,1H),3.23-3.13(m,2H),3.11-2.93(m,2H),1.84(s,2H),1.78(d,J=4.4 Hz,1H),1.75(d,J=4.0 Hz,1H),1.26(s,9H);MS(EI)m / z:602.3 [M+H] + .

[0364] Preparation Example 50: (R)-N-[(6S)-1'-[5-[(5-chloro-4-oxo-3H-quinazoline-6-yl)sulfanyl]pyrazine-2-yl]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]spiro-6-yl]-2-methyl-propane-2-sulfinamide (intermediate I-52) [ka]

[0365] Intermediate I-52 (300 mg, 53%) was prepared in the same manner as in Preparation Example 49, except that intermediate I-48 was used instead of intermediate I-49. 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).

[0366] Preparation Example 51: tert-butyl 2-chloro-4-oxo-spiro[6H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (intermediate I-53) [ka]

[0367] Step 1: O4-ethyl 4-[(2-chlorothiazol-5-yl)methyl]piperidine-1,4-dicarboxylate To a solution of O1-tert-butyl O4-ethylpiperidine-1,4-dicarboxylate (30.3 g, 118 mmol) in THF (200 mL), LDA (2 M, 64.3 mL) was added at -70°C, and the mixture was stirred at -70°C for 1 hour. THF (40 mL) containing 2-chloro-5-(chloromethyl)thiazole (18 g, 107 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at -70°C for 1 hour. The reaction mixture was quenched with aqueous ammonium chloride solution and extracted with EA (3 × 200 mL). The combined organic layers were washed with saline solution (200 mL × 2 times), dried on anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain O4-ethyl 4-[(2-chlorothiazole-5-yl)methyl]piperidine-1,4-dicarboxylate (25 g, yield 60%) as a yellow oil. 1 H NMR(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).

[0368] Step 2: tert-butyl 2-chloro-4-oxo-spiro[6H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of O4-ethyl 4-[(2-chlorothiazole-5-yl)methyl]piperidine-1,4-dicarboxylate (15 g, 38.6 mmol) in THF (350 mL), LDA (2 M, 30.9 mL) was added at -70°C, and the mixture was stirred at -70°C for 1 hour. The reaction mixture was quenched at 0°C with aqueous ammonium chloride (500 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with saline solution (200 mL × 2 times), dried on anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain intermediate I-53 (4.0 g, yield 30%) as a yellow solid. 1H NMR(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).

[0369] Preparation Example 52: (S)-2-methyl-N-[(4R)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-4-yl]propan-2-sulfinamide (intermediate I-54) [ka]

[0370] Intermediate I-54 (50 mg, crude product) was prepared in the same manner as in Preparation Example 46, except that intermediate I-53 was used instead of intermediate I-47, and (S)-2-methylpropane-2-sulfinamide was used instead of (R)-2-methylpropane-2-sulfinamide. 1 H NMR(400 MHz, CDCl3)δ=9.91-9.65(m,1H),8.76-8.52(m,1H),4.59(s,1H),3.53-3.37(m,2H),3.33-3.16( m,2H),3.10-3.01(m,1H),2.93-2.85(m,1H),2.37-2.14(m,2H),2.00-1.81(m,2H),1.28(s,9H).

[0371] Preparation Example 53: (R)-2-methyl-N-[(4S)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-4-yl]propan-2-sulfinamide (intermediate I-55) [ka]

[0372] Intermediate I-55 (260 mg) was prepared in the same manner as in Preparation Example 52, except that (R)-2-methylpropane-2-sulfinamide was used instead of (S)-2-methylpropane-2-sulfinamide. 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).

[0373] Preparation Example 54: (S)-N-[(4R)-1'-[5-[(5-chloro-4-oxo-3H-quinazoline-6-yl)sulfanyl]pyrazine-2-yl]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]spiro-4-yl]-2-methyl-propane-2-sulfinamide (intermediate I-56) [ka]

[0374] Intermediate I-56 (240 mg, 34%) was prepared in the same manner as in Preparation Example 49, except that intermediate I-54 was used instead of intermediate I-49. 1 H NMR(400 MHz,DMSO-d6)δ=12.48-12.11(m,1H),8.98(s,1H),8.51(d,J=1.2 Hz,1H),8.31(d,J=1.2 Hz,1H),8.04(s,1H),7.50(d,J=8.8 Hz,1H),7.19(d,J=8.8 Hz,1H),5.78(d,J=10.4 Hz,1H),4.35-4.20(m,3H),3.29-3.15(m,2H),3.04-2.94(m,1H),2.92-2.85( m,1H),1.97-1.90(m,1H),1.85-1.76(m,1H),1.74-1.66(m,2H),1.16(s,9H).

[0375] Preparation Example 55: tert-butyl N-[(3S,4S)-8-[5-bromo-3-(hydroxymethyl)pyrazine-2-yl]-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl]carbamate (intermediate I-57) [ka]

[0376] Step 1: Methyl 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4,5]decano-8-yl]-6-bromopyrazine-2-carboxylate To a solution of methyl 3,6-dibromopyrazine-2-carboxylate (500 mg, 1.69 mmol) in ACN (10 mL), DIPEA (1.09 g, 8.45 mmol) and (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (384 mg, 1.86 mmol, HCl) were added and the mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain methyl 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-6-bromopyrazine-2-carboxylate (650 mg, crude product) as a brown oil. MS(EI)m / z:387.0 [M+H] + .

[0377] Step 2: Methyl 6-bromo-3-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4,5]decane-8-yl]pyrazine-2-carboxylate To a 10 mL solution of methyl 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-6-bromopyrazine-2-carboxylate (650 mg, 1.69 mmol) in CM (10 mL), DIPEA (436 mg, 3.37 mmol) and (Boc)2O (552 mg, 2.53 mmol) were added, and the mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 6-bromo-3-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]pyrazine-2-carboxylate methyl (710 mg, yield 83%) as a yellow solid. 1 H NMR(400 MHz, CDCl3)δ=8.12(s,1H),4.55-4.47(m,1H),4.14-4.04(m,1H),3.96-3.81(m,4H),3.64-3.57(m,2H),3.57-3.44(m,2H), 3.38-3.29(m,1H),3.27-3.13(m,1H),1.78-1.73(m,1H),1.72-1.63(m,2H),1.57-1.52(m,1H),1.38(s,9H),1.12(d,J=6.4 Hz,3H);MS(EI)m / z:487.0 [M+H] + .

[0378] Step 3: tert-butyl N-[(3S,4S)-8-[5-bromo-3-(hydroxymethyl)pyrazine-2-yl]-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl]carbamate To a solution of 6-bromo-3-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]pyrazine-2-carboxylate methyl (300 mg, 618 μmol) in DCM (10 mL), DIBAL-H (1 M, 1.85 mL) was added at -60 °C, and the mixture was stirred at 20 °C for 16 hours. The reaction mixture was quenched with methanol (0.5 mL) at -60 °C and filtered. After concentrating the filtrate under reduced pressure, the residue was purified by column chromatography to obtain intermediate I-57 (90 mg, 31%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ=8.20(s,1H),4.65(s,2H),4.60(d,J=10.4 Hz,1H),4.22-4.15(m,1H),3.98(dd,J=4.4,10.8 Hz,1H),3.70-3.65(m,2H),3.40-3.27(m,2H),3.15-3.09(m,1H),3.03-2.97(m,1H),1.96-1.83(m,2H),1.81(d,J=3.2 Hz,1H),1.68-1.62(m,1H),1.46(s,9H),1.20(d,J=6.4 Hz,3H);MS(EI)m / z:459.0 [M+H] + .

[0379] Preparation Example 56: tert-butyl N-[(3S,4S)-8-(6-amino-5-bromo-3-carbamoylpyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl]carbamate (intermediate I-58) [ka]

[0380] Step 1: 5-amino-3-chloropyrazine-2-carbonitrile 5-bromo-6-chloropyrazine-2-amine (10 g, 48.0 mmol) was dissolved in NMP (100 mL) and Pd(PPh3)4 (2.77 g, 2.40 mmol) was added, and the mixture was stirred at 100 °C for 12 hours. The reaction mixture was quenched at room temperature with aqueous ammonium chloride (100 mL), diluted with water (100 mL), and then extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over Na₂SO₄, filtered, and concentrated under high pressure. The residue was purified by column chromatography to obtain 5-amino-3-chloropyrazine-2-carbonitrile (2.6 g, 35%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.11(s,2H),7.87(s,1H).

[0381] Step 2: 5-Amino-3-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4,5]decane-8-yl]pyrazine-2-carbonitrile To a solution of 5-amino-3-chloropyrazine-2-carbonitrile (1.0 g, 6.47 mmol) in DMF (10 mL), (3S,4S)-3-methyl-oxa-8-azaspiro[4.5]decane-4-amine (1.21 g, 7.12 mmol, 2HCl) and DIEA (4.18 g, 32.4 mmol) were added, and the mixture was stirred at 80°C for 12 hours. The reaction mixture was quenched with aqueous ammonium chloride (20 mL) at room temperature, diluted with water (30 mL), and then extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain 5-amino-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]pyrazine-2-carbonitrile (1.8 g, crude product) as a yellow solid. MS(EI)m / z:289.4 [M+H] + .

[0382] Step 3: tert-butyl N-[(3S,4S)-8-(6-amino-3-cyanopyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl]carbamate To a solution of 5-amino-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4,5]decane-8-yl]pyrazine-2-carbonitrile (1.8 g, 6.24 mmol) in DMF (15 mL), Boc2O (2.04 g, 9.36 mmol) and TEA (1.90 g, 18.7 mmol) were added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with aqueous ammonium chloride (20 mL) at room temperature, diluted with water (30 mL), and then extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over Na2SO4, filtered, and concentrated under high pressure. The residue was purified by column chromatography to obtain tert-butyl N-[(3S,4S)-8-(6-amino-3-cyanopyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate (1.3 g, 54%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=7.39(s,1H),4.86-4.81(m,2H),4.62(d,J=10.8 Hz,1H),4.20-4.15(m,1H),3.98(dd,J=4.4,10.8 Hz,1H),3.93-3.82(m,2H),3.71-3.63(m,3H),3.62-3.54(m,1H),1.90-1.72(m,3H),1.65-1.60(m,1H),1.46(s,9H),1.20(d,J=6.4 Hz,3H).

[0383] Step 4: tert-butyl N-[(3S,4S)-8-(6-amino-3-carbamoylpyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl]carbamate To a solution of 6 mL of DMSO containing tert-butyl N-[(3S,4S)-8-(6-amino-3-cyanopyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl]carbamate (300 mg, 772 μmol), NaOH (92.7 mg, 2.32 mmol) and H2O2 (4.38 g, 38.6 mmol) were added, and the mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched with aqueous sodium thiosulfate solution (5 mL) at room temperature, diluted with water (30 mL), and then extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over Na2SO4, filtered, and concentrated under high pressure. The residue was purified by column chromatography to obtain tert-butyl N-[(3S,4S)-8-(6-amino-3-carbamoylpyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate (160 mg, yield 51%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=7.39(s,1H),7.32(s,1H),5.42-5.33(m,1H),4.71-4.65(m,2H),4.61(d,J=10.4 Hz,1H),4.18-4.13(m,1H),3.95(dd,J=4.4,10.8 Hz,1H),3.71-3.66(m,1H),3.65-3.59(m,1H),3.58-3.49(m,1H),3.37-3.30(m,1H),3.29-3.2 1(m,1H),1.89-1.83(m,1H),1.81-1.72(m,2H),1.68-1.62(m,1H),1.44(s,9H),1.18(d,J=6.4 Hz,3H);MS(EI)m / z:407.4 [M+H] + .

[0384] Step 5: tert-butyl N-[(3S,4S)-8-(6-amino-5-bromo-3-carbamoylpyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl]carbamate To a solution of tert-butyl N-[(3S,4S)-8-(6-amino-3-carbamoylpyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate (160 mg, 394 μmol) in DCM (2 mL), NBS (77.1 mg, 433 μmol) was added, and the mixture was stirred at 0°C for 0.25 hours. The reaction mixture was quenched with aqueous ammonium chloride (10 mL) at room temperature, diluted with water (20 mL), and then extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over Na₂SO₄, filtered, and concentrated under high pressure. The residue was purified by column chromatography to obtain intermediate I-58 (160 mg, yield 84%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=7.17(s,1H),5.29-5.23(m,1H),5.10(s,2H),4.61(d,J=10.4 Hz,1H),4.19-4.12(m,1H),3.95(dd,J=4.4,10.4 Hz,1H),3.68(d,J=7.6 Hz,1H),3.63-3.58(m,1H),3.59-3.51(m,1H),3.37-3.32(m,1H),3.30-3.23(m,1H),1.89-1.83(m,1H),1.77(d,J=5.4 Hz,1H),1.67-1.58(m,2H),1.44(s,9H),1.21-1.16(m,3H);MS(EI)m / z:487.3 [M+H] + .

[0385] Preparation Example 57: 6-Bromo-5-fluoro-3-(2-methoxyethyl)quinazolin-4-one (Intermediate I-59) [ka]

[0386] Step 1: 6-amino-3-bromo-2-fluorobenzoic acid 2-amino-6-fluorobenzoic acid (20.0 g, 129 mmol) was dissolved in DMF (200 mL) and NBS (24.1 g, 135 mmol) was added, and the mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with water (200 mL) and then extracted with EA (3 × 100 mL). The combined organic layer was washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain 6-amino-3-bromo-2-fluorobenzoic acid (24.3 g, yield 73.3%) as a pale solid. 1 H NMR(400 MHz,DMSO-d6)δ=7.39(dd,J=7.6,8.8 Hz,1H),6.56(dd,J=1.2,8.8 Hz,1H);MS(EI)m / z:234.0 [M+H] + .

[0387] Step 2: 6-Bromo-5-fluoro-3-(2-methoxyethyl)quinazolin-4-one To a solution of 6-amino-3-bromo-2-fluorobenzoic acid (2.0 g, 8.55 mmol) in ethanol (20 mL), I2 (217 mg, 855 μmol), diethoxymethoxyethane (1.90 g, 12.8 mmol), and 2-methoxyethaneamine (963 mg, 12.8 mmol) were added and the mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with water (20 mL) and then extracted with EA (3 × 15 mL). The combined organic layer was dried over Na2SO4, then filtered and concentrated under vacuum. Depositphotos (10 mL) was added to the residue to obtain intermediate I-59 (970 mg, yield 37%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ=8.08(s,1H),7.87(dd,J=6.8,8.8 Hz,1H),7.42(dd,J=1.2,8.8 Hz,1H),4.19-4.14(m,2H),3.70-3.66(m,2H),3.33(s,3H).

[0388] Preparation Example 58: (S)-N-((R)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-6-yl)-2-methylpropane-2-sulfinamide (intermediate I-60) [ka]

[0389] Intermediate I-60 (300 mg, 53%) was prepared according to the same procedure as in Preparation Example 47, excluding step 3. MS(EI)m / z:348.1 [M+H] + .

[0390] Preparation Example 59: (R)-N-((S)-5-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-3-yl]-2-methylpropane-2-sulfinamide (intermediate I-61) [ka]

[0391] Step 1: tert-butyl 6-methoxy-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate To a solution of 6-methoxy-2,3-dihydro-1H-inden-1-one (5.0 g, 30.8 mmol) in DMF (30 mL), NaH (3.70 g, 92.5 mmol, 60% purity) was added, and the mixture was stirred at 60°C for 0.5 hours. Tert-butyl N,N-bis(2-chloroethyl)carbamate (8.21 g, 33.9 mmol) was slowly added dropwise to the reaction mixture, and the mixture was then stirred at 60°C for 1.5 hours. The reaction mixture was quenched by adding aqueous ammonium chloride (100 mL) at 25°C, diluted with water (100 mL), and extracted with EA (3 × 200 mL). The combined organic layers were washed with saline solution (3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. When the residue was separated by column chromatography, tert-butyl 6-methoxy-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (640 mg, yield 6%) was obtained as a yellow solid. 1H NMR(400 MHz, CDCl3)δ=7.37-7.34(m,1H),7.21(s,2H),4.21-4.07(m,2H),3.84(s ,3H),3.09-2.95(m,4H),1.95-1.87(m,2H),1.49(s,9H),1.39(d,J=13.2 Hz,2H).

[0392] Step 2: tert-butyl(R,Z)-1-((tert-butylsulfinyl)imino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate To a solution of tert-butyl 6-methoxy-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (630 mg, 1.90 mmol) in THF (6 mL), Ti(OEt)4 (6.50 g, 28.5 mmol) and (R)-2-methylpropane-2-sulfinamide (922 mg, 7.60 mmol) were added, and the mixture was stirred at 90°C for 12 hours. The reaction mixture was diluted with EA (100 mL), quenched with water (20 mL), filtered, and concentrated under reduced pressure. The mixture was 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. The residue was separated by column chromatography to obtain tert-butyl(R,Z)-1-((tert-butylsulfinyl)imino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (800 mg, 97%) as a yellow solid. 1 H NMR(400 MHz, CDCl3)δ=8.08-7.97(m,1H),7.30-7.24(m,1H),7.14-7.10(m,1H),4.20-4.08(m,2H),3.87(s,3H) ,3.01-2.98(m,2H),2.97-2.88(m,2H),1.54-1.50(m,2H),1.49(s,9H),1.46-1.40(m,2H),1.34(s,9H).

[0393] Step 3: tert-butyl(S)-1-(((R)-tert-butylsulfinyl)amino)-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate To a solution of tert-butyl(R,Z)-1-((tert-butylsulfinyl)imino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (800 mg, 1.84 mmol) in DCM (10 mL), DIBAL-H (1 M, 5.52 mL) was added, and the mixture was stirred at -70°C for 1 hour. The reaction mixture was quenched with methanol (2 mL), diluted with DCM (100 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography to obtain tert-butyl(S)-1-(((R)-tert-butylsulfinyl)amino)-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (520 mg, 65%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=7.11(d,J=8.0 Hz,1H),6.85(s,1H),6.79(dd,J=2.0,8.0 Hz,1H),4.46(d,J=9.6 Hz,1H),4.02(d,J=13.2 Hz,1H),3.79(s,3H),3.62-3.46(m,1H),3.05-2.96(m,1H),2.90(dt,J=2.8,12.8 Hz,2H),2.68-2.57(m,1H),1.81-1.54(m,2H),1.54-1.49(m,1H),1.49-1.47(m,1H),1.46(s,9H),1.30(s,9H).

[0394] Step 4: (R)-N-((S)-5-methoxy-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl]-2-methylpropane-2-sulfinamide To a solution of tert-butyl(S)-1-(((R)-tert-butylsulfinyl)amino)-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (520 mg, 1.19 mmol) in DCM (6 mL), TFA (2.72 g, 23.8 mmol) was added, and the mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was quenched with aqueous calcium carbonate solution (20 mL), diluted with water (30 mL), and then extracted with DCM (3 × 50 mL). The mixture was washed with saline solution (3 × 20 mL), dried on anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain intermediate I-61 (390 mg, crude product) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=7.11(d,J=8.0 Hz,1H),6.82(d,J=2.0 Hz,1H),6.78(dd,J=2.4,8.0 Hz,1H),4.43(d,J=10.4 Hz,1H),3.79(s,3H),3.63(d,J=10.4 Hz,1H),3.11-3.02(m,3H),2.87(dd,J=2.0,12.4 Hz,1H),2.79-2.74(m,1H),2.63(d,J=15.2 Hz,1H),2.15(dt,J=4.4,12.8 Hz,1H),1.69-1.61(m,1H),1.56(dd,J=2.4,13.2 Hz,1H),1.31(s,9H).

[0395] Preparation Example 60: (S)-N-[(4R)-1'[5-[(5-chloro-4-oxo-3H-quinazoline-6-yl)sulfanyl]pyrazine-2-yl]spiro-[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]spiro-4-yl]-2-methyl-propane-2-sulfinamide (intermediate I-62) [ka]

[0396] Intermediate I-62 (300 mg, yield 41%) was prepared in the same manner as in Preparation Example 49, except that intermediate I-55 was used instead of intermediate I-49. 1 H NMR(400 MHz,CDCl3)δ=8.76(s,1H),8.26(d,J=1.2 Hz,1H),8.23(s,1H),7.97-7.94(m,1H),7.48(d,J=8.8 Hz,1H),7.27-7.23(m,1H),4.58(d,J=9.2 Hz,1H),4.35-4.28(m,1H),4.23(d,J=13.6 Hz,1H),4.01-3.96(m,1H),3.50(s,2H),3.31(dd,J=2.0,13.6 Hz,2H),1.87-1.81(m,2H),1.77-1.73(m,2H),1.30(s,9H);MS(EI)m / z:602.1 [M+H] + .

[0397] Preparation Example 61: (R)-N-[(6S)-2-chlorospiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-6-yl]-2-methyl-propane-2-sulfinamide (intermediate I-63) [ka]

[0398] Intermediate I-63 (100 mg, crude product) was prepared using the same procedure as in Preparation Example 58, except that (R)-2-methylpropane-2-sulfinamide was used instead of (S)-2-methylpropane-2-sulfinamide. MS(EI)m / z:348.3 [M+H] + .

[0399] Preparation Example 62: (R)-N-((S)-5-hydroxy-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide (intermediate I-64) [ka]

[0400] Step 1: 6-Hydroxyspiro[indene-2,4'-piperidine]-1(3H)-one To a solution of tert-butyl 6-methoxy-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (1.5 g, 4.53 mmol) in DCM (15 mL), BBr3 (11.3 g, 45.3 mmol) was added, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched at 0°C by adding water (50 mL), and then extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-hydroxyspiro[indene-2,4'-piperidine]-1(3H)-one (980 mg, crude product) as a yellow solid. MS(EI)m / z:217.3 [M+H] + .

[0401] Step 2: tert-butyl 6-hydroxy-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate To a solution of 6-hydroxyspiro[indene-2,4'-piperidine]-1(3H)-one (980 mg, 4.51 mmol) in THF (10 mL) and water (10 mL), Boc2O (1.97 g, 9.02 mmol) and NaOH (902 mg, 22.6 mmol) were added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched by adding aqueous ammonium chloride solution (20 mL) at 25°C, diluted with water (30 mL), and extracted with EA (50 mL x 3 times). The combined organic layers were washed with saline solution (20 mL x 3 times), dried on anhydrous sodium sulfate, then filtered and concentrated under reduced pressure. The residue was separated by column chromatography to obtain tert-butyl6-hydroxy-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (1.3 g, yield 91%) as a yellow solid. MS(EI)m / z:340.3 [M+Na] + .

[0402] Steps 3-5: (R)-N-((S)-5-hydroxy-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide

[0403] In step 1 of Preparation Example 47, (R)-2-methylpropane-2-sulfinamide was used instead of (S)-2-methylpropane-2-sulfinamide, and the resulting intermediate was used in steps 2 and 4 to prepare intermediate I-64 (90 mg, yield 66%). MS(EI)m / z:323.4 [M+H] + .

[0404] Preparation Example 63: 6-((3-amino-5-chloropyrazine-2-yl)thio)-5-chloroquinazoline-4(3H)-one (intermediate I-65) [ka]

[0405] To a solution of intermediate I-8 (1.7 g, 7.25 mmol) in dioxane (50 mL), 3-bromo-6-chloropyrazine-2-amine (1.66 g, 7.97 mmol), Pd2(dba)3 (664 mg, 725 μmol), xanthophos (838 mg, 1.45 mmol), and DIEA (2.81 g, 21.7 mmol) were added, and the mixture was stirred at 100 °C for 12 hours. The reaction mixture was quenched by adding aqueous ammonium chloride solution (50 mL) at 25 °C, and the resulting solid was filtered. After washing the solid with EA (50 mL) and methanol (30 mL), it was concentrated under reduced pressure to obtain intermediate I-65 (0.7 g, yield 28%) as a black solid. 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).

[0406] Preparation Example 64: 6-bromo-3-((S)-6-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-yl)pyrazine-2-carboxamide (intermediate I-66) [ka]

[0407] Step 1: 3,6-Dibromopyrazine-2-carboxamide To a solution of 3,6-dibromopyrazine-2-carboxylic acid (1.0 g, 3.55 mmol) in DMF (10 mL), NH4Cl (570 mg, 10.6 mmol), HATU (1.62 g, 4.26 mmol), and DIEA (2.29 g, 17.7 mmol) were added and the mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched by adding aqueous ammonium chloride (20 mL) at 25°C, then water (30 mL) was added, and the mixture was extracted with EA (50 mL x 3 times). The combined organic layer was washed with saline solution (20 mL x 3 times), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 3,6-dibromopyrazine-2-carboxamide (310 mg, yield 31%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.51(s,1H),8.44(s,1H),8.19(s,1H)

[0408] Step 2: 6-bromo-3-((S)-6-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-yl)pyrazine-2-carboxamide To a solution of 3,6-dibromopyrazine-2-carboxamide (100 mg, 0.36 mmol) in ACN (3 mL), DIEA (230 mg, 1.78 mmol) and intermediate I-48 (112 mg, 0.36 mmol) were added, and the mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography to obtain intermediate I-66 (130 mg, yield 71%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=8.80(s,1H),8.20(s,1H),7.30(s,1H),5.95-5.88(m,1H),4.60(d,J=8.8 Hz,1H),3.97(t,J=13.2 Hz,2H),3.87(d,J=8.8 Hz,1H),3.36-3.24(m,2H),3.03-2.93(m,2H),2.02(dd,J=3.6,13.2 Hz,2H),1.77-1.68(m,2H),1.22(s,9H).

[0409] Preparation Example 65: 6-bromo-3-((S)-4-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-yl)pyrazine-2-carboxamide (intermediate I-67) [ka]

[0410] Intermediate I-67 (80 mg, 55% yield) was synthesized in the same manner as in Preparation Example 64, except that intermediate I-55 was used instead of intermediate I-48 in step 2 of Preparation Example 64. 1H NMR(400 MHz,CDCl3)δ=8.73(s,1H),8.20(s,1H),7.28(s,1H),5.73(s,1H),4.50(d,J=9.2 Hz,1H),3.98-3.85(m,2H),3.72(d,J=9.2 Hz,1H),3.42-3.32(m,2H),3.06-3.00(m,1H),2.95-2.89(m,1H),2.17-2.07(m,1H),2.05-2.00(m,1H),1.72(d,J=2.4 Hz,2H),1.25(s,9H).

[0411] Preparation Example 66: 6-bromo-3-((S)-4-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-yl)pyrazine-2-carboxamide (intermediate I-68) [ka]

[0412] Intermediate I-68 (70 mg, yield 78%) was synthesized in the same manner as in Preparation Example 64, except that intermediate I-25 was used instead of intermediate I-48 in step 2 of Preparation Example 64. 1 H NMR(400 MHz,CDCl3)δ=8.44(d,J=4.4 Hz,1H),8.21(s,1H),7.98(d,J=7.6 Hz,1H),7.31-7.27(m,2H),7.16(dd,J=4.4,7.6 Hz,1H),5.57-5.49(m,1H),4.54(d,J=10.0 Hz,1H),3.95-3.87(m,2H),3.36-3.27(m,2H),3.26-3.20(m,2H),1.97(d,J=4.0 Hz,1H),1.84(d,J=4.0 Hz,2H),1.70-1.64(m,1H),1.65-1.64(m,1H),1.28(s,9H).

[0413] Preparation Example 67: Sodium 5-chloro-4-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroquinazoline-6-thiolate (intermediate I-69) [ka]

[0414] Intermediate I-69 (85 mg, crude product) was synthesized in the same manner as in steps 1 and 2 of Preparation Example 28, except that 4-(bromomethyl)tetrahydro-2H-pyran was used instead of 1-bromo-2-methoxyethane in step 1 of Preparation Example 28. MS(EI)m / z:310.9 [M+H] + .

[0415] Preparation Example 68: 6-((5-bromopyrazine-2-yl)thio)-5-chloro-3-(2-fluoro-2-methylpropyl)quinazoline-4(3H)-one (intermediate I-70) [ka]

[0416] Intermediate I-70 (150 mg, 65% yield) was synthesized in the same manner as in Preparation Example 28, except that 1-bromo-2-fluoro-2-methylpropane was used instead of 1-bromo-2-methoxyethane in step 1 of Preparation Example 28. 1 H NMR(400 MHz,CDCl3)δ=9.08(d,J=0.8 Hz,1H),8.69(d,J=0.8 Hz,1H),8.49(s,1H),7.80(d,J=8.8 Hz,1H),7.65(d,J=8.8 Hz,1H),3.27(d,J=17.2 Hz,2H),1.58(s,3H),1.53(s,3H).

[0417] Preparation Example 69: 6-((3-amino-5-chloropyrazine-2-yl)thio)-5-chloro-3-(2-methoxypropyl)quinazoline-4(3H)-one (intermediate I-71) [ka]

[0418] Intermediate I-71 (150 mg, 65% yield) was synthesized in the same manner as in Preparation Example 28, except that 2-methoxypropyl 4-methylbenzenesulfonic acid was used instead of 1-bromo-2-methoxyethane in step 1 of Preparation Example 28. MS(EI)m / z:411.9 [M+H] + .

[0419] Preparation Example 70: Synthesis of N-((R)-8-(5-bromopyrazine-2-yl)-8-azaspiro[4.5]decane-1-yl)-2-methylpropane-2-sulfinamide (intermediate I-72) [ka]

[0420] Step 1: tert-butyl(1R)-1-((tert-butylsulfinyl)amino)-8-azaspiro[4.5]decane-8-carboxylate tert-butyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate (2 g, 7.89 mmol), titanium(IV) ethoxide (6.63 mL, 31.6 mmol), and (R)-2-methylpropane-2-sulfinamide (1.91 g, 15.78 mmol) were dissolved in THF (36 mL, 0.22 M) and stirred at 90°C for 1 hour. The mixture was cooled to 0°C, LiBH4 (21 mg, 9.7 mmol) was added, and the mixture was stirred for 30 minutes. The reaction was stopped with MeOH, and the mixture was concentrated. The resulting product was diluted with brine and then extracted with EA. The precipitated white solid was filtered to obtain tert-butyl(1R)-1-((tert-butylsulfinyl)amino)-8-azaspiro[4.5]decane-8-carboxylate (912.7 mg, 32%) in a flask. MS m / z:373.5 [M+H] + .

[0421] Step 2: 2-Methyl-N-((R)-8-azaspiro[4.5]decane-1-yl)propan-2-sulfinamide 913 mg, 2.55 mmol of tert-butyl(1R)-1-((tert-butylsulfinyl)amino)-8-azaspiro[4.5]decane-8-carboxylate was dissolved in 51 mL, 0.05 M of DCM. Trifluoroacetic acid (2.9 mL, 38.3 mmol) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated to obtain 2-methyl-N-((R)-8-azaspiro[4.5]decane-1-yl)propan-2-sulfinamide. MS m / z: 273.5 [M+H] + .

[0422] Step 3: N-((R)-8-(5-bromopyrazine-2-yl)-8-azaspiro[4.5]decane-1-yl)-2-methylpropane-2-sulfinamide 2-Methyl-N-((R)-8-azaspiro[4.5]decane-1-yl)propan-2-sulfinamide (crude product, 2.55 mmol) and 2,5-dibromopyrazine (1.4 g, 5.1 mmol) were dissolved in DMF (5.1 mL, 0.5 M). DIPEA (6.6 mL, 38.25 mmol) was added to the mixture, and the mixture was stirred at 100°C for 3 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC (EA:Hx=1:1) and concentrated to obtain intermediate I-72 (382 mg, 36%). MS m / z: 430.5 [M+H] + .

[0423] Preparation Example 71: Potassium 5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazoline-6-thiolate (intermediate I-73) [ka]

[0424] Step 1: 6-Bromo-5-chloro-3-(2-methoxyethyl)quinazoline-4(3H)-one In a round-bottom flask, 6-bromo-5-chloroquinazolin-4(3H)-one (58.7 g, 226.1 mmol), 1-bromo-2-methoxyethane (32 mL, 339.2 mmol), and cesium carbonate (147 g, 452.3 mmol) were dissolved in DMF (565 mL, 0.4 M) and then stirred at 50°C for 2 hours. The reaction was stopped with aqueous NaHCO3 solution, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. After adding EA and Hx to precipitate the solid, the solid was filtered to obtain 6-bromo-5-chloro-3-(2-methoxyethyl)quinazolin-4(3H)-one (53.5 g, 74.5%). MS m / z: 318.5 [M+H] + .

[0425] Step 2: Ethyl 3-((5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazoline-6-yl)thio)propanoate In a round-bottom flask, 6-bromo-5-chloro-3-(2-methoxyethyl)quinazolin-4(3H)-one (26.7 g, 84.2 mmol), ethyl-3-mercaptopropionate (20.4 mL, 160 mmol), Pd2(dba)3 (3.7 g, 4.0 mmol), and xanthophos (4.6 g, 8.0 mmol) were dissolved in 1,4-dioxane (267 mL, 0.3 M), and then DIPEA (28 mL, 160.4 mmol) was added dropwise. The reaction mixture was purged with nitrogen and then stirred at 120°C for 5 hours. After filtration through celite, H2O was added to the mixture and extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. After adding EA and Hx, the precipitated solid was filtered to obtain ethyl 3-((5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazoline-6-yl)thio)propanoate (58.7 g, 99%). MS m / z: 371.5 [M+H] + .

[0426] Step 3: Potassium 5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazoline-6-thiolate In a round-bottom flask, ethyl 3-((5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate (29.4 g, 79.2 mmol) was dissolved in THF (400 mL, 0.2 M), and the temperature was then lowered to 0°C. Potassium tert-butoxide (9.7 g, 87.1 mmol) was slowly added dropwise to the reaction mixture, and the mixture was stirred at 0°C for 30 hours. After the reaction was complete, the reaction mixture was concentrated to obtain intermediate I-73 (45.7 g, 93%). MS m / z: 270.5 [M+H] + .

[0427] Preparation Example 72: Synthesis of N-((S)-1'-(6-chloro-1,2,4-triazine-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (intermediate I-74) and N-((S)-1'-(3-chloro-1,2,4-triazine-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (intermediate I-75) [ka]

[0428] Step 1: N-((S)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide 201 mg, 0.49 mmol of tert-butyl(1S)-1-((tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate was dissolved in DCM (1.63 mL, 0.3 M). Trifluoroacetic acid (TFA) (0.38 mL, 4.94 mmol) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated to obtain N-((S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide. MS m / z: 307.5 [M+H] + .

[0429] Step 2: N-((S)-1'-(6-chloro-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (intermediate I-74) and N-((S)-1'-(3-chloro-1,2,4-triazin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (intermediate I-75) N-((S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (crude product, 0.49 mmol) was concentrated, and 3,6-dichloro-1,2,4-triazine (73 mg, 0.49 mmol) was dissolved in 1,4-dioxane (2.45 mL, 0.2 M). DIPEA (0.85 mL, 4.9 mmol) was added to the mixture, and the mixture was stirred at 50°C for 4 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was purified by MPLC (EA:Hx=1:1), and then concentrated to obtain intermediate I-74 (65.6 mg, 32%) and intermediate I-75 (55.7 mg, 27%). MS m / z:420.5 [M+H] + .

[0430] Preparation Example 73: Synthesis of 6-amino-5-((2,3-dichlorophenyl)thio)-3-methyl-2-(piperazin-1-yl)pyrimidine-4(3H)-one (intermediate I-76) [ka]

[0431] Step 1: t-butyl 4-(4-amino-1-methyl-6-oxopyrimidine-2-yl)piperazine-1-carboxylate 6-amino-3-methyl-1H-pyrimidine-2,4-dione (2 g, 14.17 mmol), BOP (benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 6.27 g, 14.17 mmol), and DBU (1,8-diazabicyclo[5.4.0]undeca-7-ene, 2.16 g, 14.17 mmol, 2.14 mL) were dissolved in DMF (30.0 mL, 0.47 M), and tert-butylpiperazine-1-carboxylate (2.90 g, 15.59 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After confirming that the reactants had completely disappeared by LC-MS, brine (20.0 mL) and siRNA (20.0 mL × 3) were added to the reaction mixture and extracted. The organic layer was dried over Na2SO4, filtered, and then concentrated. The obtained product was separated by preparative HPLC (neutral) and concentrated to obtain t-butyl 4-(4-amino-1-methyl-6-oxopyrimidine-2-yl)piperazine-1-carboxylate (1.8 g, 40.7%). 1 H NMR(400 MHz,CHLOROFORM-d)δ=5.23(s,1H),4.50(s,2H),3.62-3.52(m,4H),3.42(s,3H),3.18-3.09(m,4H),1.49(s,9H);MS m / z:310.3 [M+H] + .

[0432] Step 2: t-butyl 4-(4-amino-5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)piperazine-1-carboxylate 1.6 g, 5.17 mmol of tert-butyl 4-(4-amino-1-methyl-6-oxopyrimidine-2-yl)piperazine-1-carboxylate was dissolved in 10 mL, 0.52 M of DMF, and 1.16 g, 5.17 mmol of NIS (N-iodosuccinimide) was added. The reaction mixture was stirred at room temperature for 1 hour. After a white precipitate formed and LC-MS confirmed that the reactants had completely disappeared, the reaction was terminated by adding 5 mL of aqueous Na2SO3 solution. After filtration, the filtered cake was washed with MBTE (methyl tertiary-butyl ether, 200 mL). The filtered cake was dried to obtain 1.8 g, 75.6% t-butyl 4-(4-amino-5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)piperazine-1-carboxylate as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ=3.44(br s,4H),3.32(s,3H),3.13-3.02(m,4H),1.42(s,9H);MS m / z:435.9 [M+H] + .

[0433] Step 3: tert-butyl 4-(4-amino-5-((2,3-dichlorophenyl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)piperazine-1-carboxylate 2,3-Dichlorobenzenethiol (395 mg, 2.21 mmol), t-butyl 4-(4-amino-5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)piperazine-1-carboxylate (800 mg, 1.84 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (26.14 mg, 183.80 μmol), and K3PO4 (780.28 mg, 3.68 mmol) were dissolved in dioxane (15 mL), and CuI (35.00 mg, 183.80 μmol) was added. The reaction mixture was stirred at 90°C for 16 hours. Aqueous NaHCO3 solution and ELISA were added to the reaction mixture and extracted. The organic layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC and concentrated to obtain tert-butyl 4-(4-amino-5-((2,3-dichlorophenyl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)piperazine-1-carboxylate (640.0 mg, 71%). MS m / z: 486 [M+H] + .

[0434] Step 4: 6-amino-5-((2,3-dichlorophenyl)thio)-3-methyl-2-(piperazin-1-yl)pyrimidine-4(3H)-one 640 mg, 1.32 mmol of tert-butyl 4-(4-amino-5-((2,3-dichlorophenyl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)piperazine-1-carboxylate was dissolved in 3 mL, 0.4 M dichloromethane (DCM). Then, 1 mL of TFA was added to the reaction mixture, and the mixture was stirred at 25°C for 30 minutes. After concentrating the reaction solution, it was separated by MPLC to obtain intermediate I-76 (400 mg, 79%). MS m / z: 386 [M+H] + .

[0435] Preparation Example 74: Synthesis of 6-amino-5-((2,3-dichlorophenyl)thio)-3-methyl-2-(1,4-diazepan-1-yl)pyrimidine-4(3H)-one (intermediate I-77) [ka] Intermediate I-77 was synthesized in the same manner as in Preparation Example 73, except that tert-butyl 1,4-diazepane-1-carboxylate was used instead of tert-butylpiperazine-1-carboxylate. MS m / z: 400 [M+H] + .

[0436] Preparation Example 75: Synthesis of t-butyl N-[2-[4-(4-amino-5-iodo-1-methyl-6-oxopyrimidine-2-yl)piperazine-1-yl]ethyl]carbamate (intermediate I-78) [ka]

[0437] Step 1: t-butyl N-[2-[4-(4-amino-1-methyl-6-oxopyrimidine-2-yl)-piperazine-1-yl]ethyl]carbamate 6-amino-3-methyl-1H-pyrimidine-2,4-dione (500 mg, 3.54 mmol), BOP (1.57 g, 3.54 mmol), and DBU (539 mg, 3.54 mmol, 534.02 μL) were dissolved in DMF (10 mL, 0.35 M), and tert-butylpiperazine-1-carboxylate (812 mg, 3.54 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After confirming that the reaction materials had completely disappeared by LC-MS, brine (20 mL) and ethyl acetate (20 mL x 3) were added to the reaction mixture and extracted. The organic layer was dried over Na2SO4, filtered, and then concentrated. The obtained product was separated by preparative HPLC (neutral) and concentrated to obtain t-butyl N-[2-[4-(4-amino-1-methyl-6-oxopyrimidine-2-yl)-piperazine-1-yl]ethyl]carbamate (320 mg, 23.6%). 1H NMR(400 MHz,CHLOROFORM-d)δ=5.22(s,1H),5.04-4.92(m,1H),4.45(br d,J=6.3 Hz,1H),3.41(s,3H),3.28(br d,J=4.8 Hz,2H),3.23-3.17(m,4H),2.63-2.56(m,4H),2.54(t,J=6.0 Hz,2H),1.48(s,9H);MS m / z:353.4 [M+H] + .

[0438] Step 2: t-butyl N-[2-[4-(4-amino-5-iodo-1-methyl-6-oxopyrimidine-2-yl)-piperazine-1-yl]ethyl]carbamate 260 mg, 737 μmol of tert-butyl N-[2-[4-(4-amino-1-methyl-6-oxopyrimidine-2-yl)-piperazine-1-yl]ethyl]carbamate was dissolved in 3 mL, 0.25 M of DMF, and 166 mg, 737 μmol of NIS was added. The reaction mixture was stirred at room temperature for 1 hour. After a white precipitate formed and LC-MS confirmed that the reactants had completely disappeared, the reaction was stopped with an aqueous solution of NaHCO3, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC and concentrated to obtain intermediate I-78 (360 mg, 97%). 1 H NMR(400 MHz,CHLOROFORM-d)δ=5.03(s,2H),4.98(br s,1H),3.47(s,3H),3.29(br d,J=5.1 Hz,2H),3.25-3.18(m,4H),2.61(br s,4H),2.55(br t,J=5.9 Hz,2H),1.48(s,9H);MS m / z:479.3 [M+H] + .

[0439] Preparation Example 76: Synthesis of tert-butyl(1-(4-amino-5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)-4-methylpiperidine-4-yl)carbamate (intermediate I-79) [ka]

[0440] Step 1: tert-butyl(1-(4-amino-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)-4-methylpiperidine-4-yl)carbamate In a round-bottom flask, 6-amino-3-methylpyrimidine-2,4(1H,3H)-dione (300 mg, 2.13 mmol), BOP (benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 942 mg, 2.13 mmol), and DBU (1,8-diazabicyclo[5.4.0]undeca-7-ene, 324 mg, 2.13 mmol, 0.32 mL) were dissolved in DMF, and then 1-(tert-butyl)2-methyl(S)-piperazine-1,2-dicarboxylate (502.1 mg, 2.34 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The obtained product was separated by MPLC (MeOH:DCM=1:10) and concentrated to obtain tert-butyl(1-(4-amino-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)-4-methylpiperidine-4-yl)carbamate (760 mg, 97%). MS m / z: 368.20 [M+H] + .

[0441] Step 2: tert-butyl(1-(4-amino-5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)-4-methylpiperidine-4-yl)carbamate In a round-bottom flask, NIS (567 mg, 2.52 mmol) was added dropwise to a reaction mixture of 1-(tert-butyl)2-methyl(S)-4-(4-amino-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)piperazine-1,2-dicarboxylate (772 mg, 2.52 mmol) dissolved in ACN. The reaction mixture was stirred at room temperature for 2 hours. The reaction was stopped 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 (MeOH:DCM = 1:10) and concentrated to obtain intermediate I-79 (981 mg, 94%). MS m / z: 494.10 [M+H] + . Example 1: Synthesis of methyl 3-((5-(4-amino-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-2-chlorobenzoate [ka]

[0442] Step 1: Methyl 3-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-2-chlorobenzoate In a round-bottom flask, intermediates I-1 (220 mg, 0.59 mmol), I-5 (110 mg, 0.53 mmol), Pd2(dba)3 (50 mg, 0.053 mmol), and xanthophos (30 mg, 0.053 mmol) were dissolved in 1,4-dioxane (2.2 mL, 0.25 M), and then DIPEA (0.19 mL, 1.07 mmol) was added. The reaction mixture was purged with nitrogen and stirred at 100°C for 1 hour. The resulting product was washed with EA, filtered through celite, and the filtrate was concentrated. The obtained product was separated by MPLC (EA:Hx=1:5) and then concentrated to obtain methyl 3-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-2-chlorobenzoate (230 mg, 87%). MS m / z: 494.1 [M+H] + .

[0443] Step 2: Methyl 3-((5-(4-amino-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-2-chlorobenzoate In a round-bottom flask, methyl 3-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-2-chlorobenzoate (22 mg, 0.045 mmol) was dissolved in DCM (0.15 mL, 0.3 M). 4 M HCl (0.15 mL) in dioxane was slowly added dropwise to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction was stopped with aqueous NaHCO3 solution, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC (MeOH:MC=1:10) and concentrated to obtain the compound of Example 1 (8 mg, 43%). 1 H NMR(400 MHz,CDCl3)δ8.23(d,J=1.6 Hz,1H),8.19(d,J=1.2 Hz,1H),7.55(dd,J=6.4,2.0 Hz,1H),7.15(t,J=8.0 Hz,1H),7.08(dd,J=8.0,2.0 Hz,1H),3.93(s,3H),3.83-3.75(m,2H),3.67-3.61(m,2H),1.77-1.66(m,4H),1.32(s,3H);MS m / z:393 [M+H] + .

[0444] Example 2: Synthesis of ethyl 3-((4-amino-2-(4-amino-4-methylpiperidine-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-yl)thio)-2-chlorobenzoate [ka]

[0445] Step 1: Ethyl 3-((6-amino-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)thio)-2-chlorobenzoate In a round-bottom flask, intermediate I-6 (89 mg, 0.4 mmol), 6-amino-5-bromo-3-methylpyrimidine-2,4(1H,3H)-dione (75 mg, 0.34 mmol), CuI (13 mg, 0.068 mmol), TMEDA (tetramethylethylenediamine, 20 μL, 0.136 mmol), and K3(PO)4 (217 mg, 1.02 mmol) were dissolved in 1,4-dioxane (0.8 mL, 0.5 M), and the mixture was subsequently stirred at 100°C for 1 hour. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The obtained product was separated by MPLC (MC:MeOH = 20:1) and concentrated to obtain ethyl 3-((6-amino-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)thio)-2-chlorobenzoate (38 mg, 32%). MS m / z: 356.5 [M+H] + .

[0446] Step 2: Ethyl 3-((4-amino-2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-yl)thio)-2-chlorobenzoate In a round-bottom flask, ethyl 3-((6-amino-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)thio)-2-chlorobenzoate (38 mg, 0.11 mmol), tert-butyl(4-methylpiperidine-4-yl)carbamate (34 mg, 0.16 mmol), BOP (232 mg, 0.33 mmol), and DBU (84 mg, 0.55 mmol) were dissolved in DMF (0.1 mL, 0.1 M) and subsequently stirred at room temperature for 1 hour. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The obtained product was separated by MPLC (EA:Hx=4:1) and concentrated to obtain ethyl 3-((4-amino-2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-yl)thio)-2-chlorobenzoate (31 mg, 54%). MS m / z: 553.1 [M+H]+ .

[0447] Step 3: Ethyl 3-((4-amino-2-(4-amino-4-methylpiperidine-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-yl)thio)-2-chlorobenzoate In a round-bottom flask, ethyl 3-((4-amino-2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-yl)thio)-2-chlorobenzoate (31 mg, 0.06 mmol) was dissolved in methanol (1.2 mL, 0.05 M). 4 M HCl (1.5 mL) in dioxane was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated using a concentrator. The resulting product was separated by MPLC (MC:MeOH = 20:1) and concentrated to obtain the compound of Example 2 (10.4 mg, 38%). 1 H NMR(400 MHz,DMSO)δ7.41(dd,J=6.4,1.2 Hz,1H),7.28(t,J=8 Hz,1H),6.89(dd,J=6.4,1.6 Hz,1H),6.77-6.57(m,2H),4.34(q,J=7.2 MS m / z:452 [M+H] + .

[0448] Example 3: Synthesis of 6-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-5-chloroquinazoline-4(3H)-one [ka]

[0449] Step 1: tert-butyl((1-(5-((5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate In a round-bottom flask, intermediates I-8 (150 mg, 0.6 mmol), I-2 (154 mg, 0.4 mmol), Pd2(dba)3 (36 mg, 0.04 mmol), and xanthophos (46 mg, 0.08 mmol) were dissolved in 1,4-dioxane (1 mL, 0.4 M), and DIPEA (139 μL, 0.8 mmol) was added. The reaction mixture was purged with nitrogen and then stirred at 100 °C for 4 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (MC:MeOH = 9:1) and concentrated to obtain tert-butyl((1-(5-((5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate (5 mg, 3%). MS m / z: 518.1 [M+H] + .

[0450] Step 2: 6-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-5-chloroquinazoline-4(3H)-one tert-butyl((1-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate (5 mg, 0.01 mmol) was placed in a round-bottom flask and dissolved in DCM (0.25 mL). 4 M HCl (0.25 mL) in dioxane was slowly added dropwise to the reaction mixture, and the mixture was then stirred at room temperature for 30 minutes. After the reaction was complete, the resulting product was concentrated, and EA was added dropwise. The precipitated solid was filtered with EA to obtain the compound from Example 3 (3 mg, 66%) as a salt. 1H NMR(400 MHz,DMSO)δ12.51-12.39(m,1H),8.48(d,J=1.6 Hz,1H),8.31(d,J=1.2 Hz,1H),8.07(s,1H),7.90-7.83(m,3H),7.52(d,J=8.8 MS m / z:417 [M+H] + .

[0451] Example 4: Synthesis of 6-((5-(4-amino-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-5-chloroquinazoline-4(3H)-one [ka]

[0452] The compound of Example 4 was synthesized in the same manner as in Example 3, except that intermediate I-1 was used instead of intermediate I-2. 1 H NMR(400 MHz,DMSO)δ8.50(d,J=1.2 Hz,1H),8.34(d,J=1.2 Hz,1H),8.09(s,1H),7.52(d,J=8.8 Hz,1H),7.24(d,J=8.8 MS m / z:403 [M+H] + .

[0453] Example 5: Synthesis of 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloroquinazoline-4(3H)-one [ka]

[0454] Step 1: N-((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)-2-methylpropane-2-sulfanilamide In a round-bottom flask, intermediates I-8 (108 mg, 0.43 mmol), I-3 (170 mg, 0.39 mmol), Pd2(dba)3 (36 mg, 0.04 mmol), and xanthophos (46 mg, 0.08 mmol) were dissolved in 1,4-dioxane (1 mL, 0.4 M), and DIPEA (136 μL, 0.8 mmol) was added. The reaction mixture was purged with nitrogen and then stirred at 100 °C for 4 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (MC:MeOH = 9:1) and concentrated to obtain N-((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)-2-methylpropane-2-sulfanilamide (10.3 mg, 5%). MS m / z: 560.1 [M+H] + .

[0455] Step 2: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4,5]decane-8-yl)pyrazine-2-yl)thio)-5-chloroquinazoline-4(3H)-one N-((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)-2-methylpropane-2-sulfanilamide (10.3 mg, 0.017 mmol) was placed in a round-bottom flask and dissolved in DCM (0.25 mL). 4M HCl (63 μL) in dioxane was slowly added dropwise to the reaction mixture, and the mixture was then stirred at room temperature for 30 minutes. After the reaction was complete, the resulting product was concentrated, and EA was added dropwise. The precipitated solid was filtered with EA to obtain the compound of Example 5 (4 mg, 47%). 1H NMR(400 MHz,DMSO)δ12.61-12.54(m,1H),8.52(d,J=1.6 Hz,1H),8.33(d,J=1.6 Hz,1H),8.10(s,2H),8.09(b,2H),7.52(d,J=8.8 Hz,1H),7.24(d,J=8.8 Hz,1H),4.30-4.19(m,3H),3.93(d,J=9.2 Hz,1H),3.70(d,J=9.2 Hz,1H),3.40(t,J=5.6 MS m / z:459 [M+H] + .

[0456] Example 6: Synthesis of 3-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-2-chlorobenzenesulfonyl fluoride [ka]

[0457] Step 1: tert-butyl((1-(5-((3-amino-2-chlorophenyl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate In a round-bottom flask, intermediates I-2 (200 mg, 0.52 mmol), I-7 (100 mg, 0.62 mmol), Pd2(dba)3 (48 mg, 0.052 mmol), and xanthophos (30 mg, 0.052 mmol) were dissolved in 1,4-dioxane (2.1 mL, 0.25 M), and then DIPEA (0.18 mL, 1.04 mmol) was added. The reaction mixture was purged with nitrogen and then stirred at 100°C for 1 hour. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (EA:Hx=1:5) and concentrated to obtain tert-butyl((1-(5-((3-amino-2-chlorophenyl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate (187 mg, 78%). MS m / z: 465.1 [M+H] + .

[0458] Step 2: tert-butyl((1-(5-((2-chloro-3-(fluorosulfonyl)phenyl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate In a round-bottom flask, tert-butyl((1-(5-((3-amino-2-chlorophenyl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate (210 mg, 0.45 mmol) was dissolved in ethanol (0.5 mL, 1.0 M) and then purged with nitrogen. 48 wt% tetrafluoroboric acid (HBF3, 0.11 mL, 0.91 mmol) was added to the reaction mixture, and the temperature was then lowered to 0°C. tert-butylnitrile (0.15 mL, 1.14 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The resulting product was concentrated using a concentrator. In a round-bottom flask containing the reaction mixture, 1,4-diazabicyclo[2,2,2]octane (1,4-diazabicyclo[2.2.2]octanbis(sulfur dioxide) adduct: DABSO, 110 mg, 0.045 mmol), potassium difluoride (177 mg, 2.27 mmol), copper chloride (12 mg, 20 mol%), and 6,6'-dimethyl-2,2'-pyridyl (17 mg, 20 mol%) were added and dissolved in acetonitrile (2.3 mL, 0.2 M). The reaction mixture was purged with nitrogen and stirred at room temperature for 3 hours. The reaction was stopped with aqueous NaHCO3 solution, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (EA:Hx=1:5) and concentrated to obtain tert-butyl((1-(5-((2-chloro-3-(fluorosulfonyl)phenyl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate (13 mg, 7%). MS m / z: 532.1 [M+H] + .

[0459] Step 3: 3-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-2-chlorobenzenesulfonylfluoride In a round-bottom flask, tert-butyl((1-(5-((2-chloro-3-(fluorosulfonyl)phenyl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate (13 mg, 0.024 mmol) was dissolved in methanol (0.5 mL, 0.05 M). A 4 M HCl solution (0.7 mL, 4 M in dioxane) was added to the reaction mixture, and the mixture was then stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated using a concentrator. After washing with EA, the mixture was filtered to obtain the compound of Example 6 (12 mg, 99%). 1 H NMR(400 MHz,DMSO)δ8.45(d,J=1.6 Hz,1H),8.24(d,J=1.2 Hz,1H),7.74-7.71(m,4H),7.17(t,J=8.0 Hz,1H),6.87(dd,J=7.6,1.6 Hz,1H),3.95-3.92(m,2H),3.46-3.41(m,2H),2.80-2.79(m,2H),1.58-1.52(m,2H),1.49-1.43(m,2H),1.09(s,3H);MS m / z:431 [M+H] + .

[0460] Example 7: Synthesis of 3-((5-(4-amino-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-2-chlorobenzenesulfonyl fluoride [ka]

[0461] The compound of Example 7 was synthesized in the same manner as in Example 6, except that intermediate I-1 was used instead of intermediate I-2. 1 H NMR(400 MHz,DMSO)δ8.49(d,J=1.2 Hz,1H),8.36(d,J=1.2 Hz,1H),8.06(dd,J=8.0Hz,1.2 Hz,1H),7.58((t,J=8.0 Hz,1H),7.40(dd,J=8.0 Hz,1.2 Hz,1H),3.92-3.88(m,2H),3.63-3.60(m,2H),1.65-1.62(m,4H),1.27(s,3H);MS m / z:417 [M+H] +.

[0462] Example 8: Synthesis of 3-((5-(4-amino-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-2-chloro-N-methylbenzenesulfonamide [ka]

[0463] The compound of Example 8 was synthesized in the same manner as in Example 6, except that intermediate I-1 was used instead of intermediate I-2, KCl was used instead of KHF2, and then methylamine (10 equivalents) and DIPEA (3 equivalents) were added. 1 H NMR(400 MHz,DMSO)δ8.45(d,J=1.6 Hz,1H),8.29(d,J=1.6 Hz,1H),7.75(dd,J=8.0 Hz,1.6 Hz,1H),7.41(t,J=8.0 Hz,1H),7.08(dt,J=8.0 Hz,1.2 Hz,1H),3.91-3.80(m,2H),3.63-3.55(m,2H),2.49(s,3H),1.47-1.42(m,4H),1.10(s,3H);MS m / z:428 [M+H] + .

[0464] Example 9: Synthesis of 3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-2-chlorobenzenesulfonamide [ka]

[0465] Step 1: 2-Chloro-3-((5-chloropyrazine-2-yl)thio)aniline 2-Chloro-5-iodopyrazine (116 mg, 0.48 mmol), 3-amino-2-chlorobenzenethiol (100 mg, 0.62 mmol), K3PO4 (266 mg, 1.25 mmol), CuI (18 mg, 0.09 mmol), 1,10-phenanthroline (38 mg, 0.19 mmol), and 1,4-dioxane (1.6 mL, 0.3 M) were placed in a round-bottom flask, purged with nitrogen, and stirred at 80°C for 1.5 hours. The reaction mixture was filtered, the filtrate was concentrated, and then separated by MPLC (EA:Hx=1:2). The resulting product was concentrated to obtain 2-chloro-3-((5-chloropyrazine-2-yl)thio)aniline (75 mg, 57%). MS m / z: 273.1 [M+H] + .

[0466] Step 2: 2-Chloro-3-((5-chloropyrazine-2-yl)thio)benzenesulfonamide In a round-bottom flask, 2-chloro-3-((5-chloropyrazine-2-yl)thio)aniline (75 mg, 0.27 mmol) was dissolved in ethanol (0.2 mL, 1.5 M) and then purged with nitrogen. 48 wt% tetrafluoroboric acid (0.07 mL) was added to the reaction mixture, and then the temperature was lowered to 0°C. tert-butylnitrile (0.08 mL, 0.6 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The resulting product was concentrated using a concentrator. In a round-bottom flask containing the reaction mixture, 1,4-diazabicyclo[2,2,2]octane (73 mg, 0.304 mmol), potassium chloride (144 mg, 1.93 mmol), copper chloride (7.4 mg, 20 mol%), and 6,6'-dimethyl-2,2'-pyridyl (10 mg, 20 mol%) were added and dissolved in acetonitrile (1.3 mL, 0.2 M). The reaction mixture was purged with nitrogen and then stirred at room temperature for 30 minutes. Ammonia solution (0.8 mL, 7 M in MeOH) was added to the reaction mixture and then stirred at room temperature for 30 minutes. The reaction was stopped with aqueous NaHCO3 solution, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC (EA:Hx=1:2), concentrated, and yielded 2-chloro-3-((5-chloropyrazine-2-yl)thio)benzenesulfonamide (10 mg, 11%). MS m / z: 337.1 [M+H] + .

[0467] Step 3: tert-butyl((3S,4S)-8-(5-((2-chloro-3-sulfamoylphenyl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl)carbamate 2-Chloro-3-((5-chloropyrazine-2-yl)thio)benzenesulfonamide (10 mg, 0.03 mmol), tert-butyl((3S,4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl)carbamate (9 mg, 0.03 mmol), and DIPEA (30 μL, 0.18 mmol) were mixed with NMP (N-methyl-2-pyrrolidone, 0.1 mL, 0.3 M) and stirred at 100 °C for 3 hours. The reaction was stopped with aqueous solution, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (EA:Hx=1:1) and concentrated to obtain tert-butyl((3S,4S)-8-(5-((2-chloro-3-sulfamoylphenyl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (10 mg, 59%). MS m / z: 571.1 [M+H] + .

[0468] Step 4: 3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4,5]decane-8-yl)pyrazine-2-yl)thio)-2-chlorobenzenesulfonamide tert-butyl((3S,4S)-8-(5-((2-chloro-3-sulfamoylphenyl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (10 mg, 0.018 mmol) was dissolved in methanol (0.3 mL, 0.05 M). A 4 M HCl solution (0.3 mL, 4 M in dioxane) was added to the reaction mixture, and the mixture was then stirred at room temperature for 30 minutes. EA was slowly added to precipitate the solid, which was then filtered to obtain the compound of Example 9 (5 mg, 55%). 1H NMR(400 MHz,DMSO)δ8.51(d,J=1.2 Hz,1H),8.32(d,J=1.2 Hz,1H),7.81(dd,J=8.0 Hz,1.6 Hz,1H),7.71(s,2H),7.40(t,J=8.0 Hz,1H),7.10(dd,J=8.0Hz,1.2 Hz,1H),4.31-4.18(m,3H),3.70-3.68(m,1H),3.45-3.39(m,1H),3.20-3.12(m,2H),1.84-1.70(m,3H),1.62-1.58(m,1H),1.23(d,J=6.4 Hz,3H);MS m / z:470 [M+H] + .

[0469] Example 10: Synthesis of 3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4,5]decane-8-yl)pyrazine-2-yl)thio)-N-benzyl-2-chlorobenzenesulfonamide [ka]

[0470] The compound of Example 10 was synthesized in the same manner as in Example 9, except that benzylamine was used instead of ammonia. 1 H NMR(400 MHz,DMSO)δ8.55(t,J=6.0 Hz,1H),8.51(d,J=1.2 Hz,1H),8.30(d,J=1.2 Hz,1H),7.74(dd,J=7.6 Hz,1.6 Hz,1H),7.34(t,J=8.0 Hz,1H),7.26-7.18(m,5H),7.07(dd,J=8.0 Hz,1.6 Hz,1H),4.30-4.18(m,3H),4.11(d,J=6.0 Hz,2H),3.91(d,J=9.2 MS m / z:460 [M+H] + .

[0471] Example 11: Synthesis of 3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-2-chlorobenzenesulfonylfluoride [ka]

[0472] The compound of Example 11 was synthesized in the same manner as in Example 9, except that KHF2 was used instead of ammonia. 1 H NMR(400 MHz, CDCl3)δ8.3-8.2(m,2H),7.92(s,1H),7.40-7.35(m,2H),4.38(m,3H),4.05-3.97(m,1H ),3.85-3.80(m,1H),3.30-3.10(m,2H),2.12-1.94(m,2H),1.85-1.78(m,2H),1.40(d,J=4.4 Hz,3H);MS m / z:473 [M+H] + .

[0473] Example 12: Synthesis of 3-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-2-chlorobenzenesulfonamide [ka]

[0474] Step 1: 3-((3-amino-2-chlorophenyl)thio)-6-chloropyrazine-2-amine 3-Bromo-6-chloropyrazine-2-amine (501 mg, 2.409 mmol), 3-amino-2-chlorobenzenethiol (500 mg, 3.132 mmol), K3PO4 (1.3 g, 6.24 mmol), CuI (92 mg, 0.482 mmol), 1,10-phenanthroline (190 mg, 0.96 mmol), and 1,4-dioxane (8.0 mL, 0.3 M) were placed in a round-bottom flask, purged with nitrogen, and stirred at 80°C for 6 hours. The reaction mixture was filtered, the filtrate was concentrated, and then separated by MPLC (EA:Hx=1:2). The resulting product was concentrated to obtain 3-((3-amino-2-chlorophenyl)thio)-6-chloropyrazine-2-amine (155 mg, 22%). MS m / z: 288.1 [M+H] + .

[0475] Step 2: 3-((3-amino-5-chloropyrazine-2-yl)thio)-2-chlorobenzenesulfonamide In a round-bottom flask, 3-((3-amino-2-chlorophenyl)thio)-6-chloropyrazine-2-amine (90 mg, 0.31 mmol) was dissolved in ethanol (0.2 mL, 1.5 M), and then purged with nitrogen. 48 wt% tetrafluoroboric acid (0.06 mL) was added to the reaction mixture, and then the temperature was lowered to 0°C. tert-butylnitrile (0.07 mL, 0.6 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The resulting product was concentrated using a concentrator. In a round-bottom flask containing the reaction mixture, 1,4-diazabicyclo[2,2,2]octane (75 mg, 0.344 mmol), potassium chloride (163 mg, 2.19 mmol), copper chloride (8.4 mg, 20 mol%), and 6,6'-dimethyl-2,2'-pyridyl (11 mg, 20 mol%) were added and dissolved in acetonitrile (1.5 mL, 0.2 M). The reaction mixture was purged with nitrogen and stirred at room temperature for 30 minutes. Ammonia solution (0.8 mL, 7 M in MeOH) was added to the reaction mixture, and the mixture was then stirred at room temperature for 30 minutes. The reaction was stopped with aqueous NaHCO3 solution, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (EA:Hx=1:2), concentrated, and yielded 3-((3-amino-5-chloropyrazine-2-yl)thio)-2-chlorobenzenesulfonamide (16 mg, 15%). MS m / z: 352.1 [M+H] + .

[0476] Step 3: tert-butyl((3S,4S)-8-(6-amino-5-((2-chloro-3-sulfamoylphenyl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate 3-((3-amino-5-chloropyrazine-2-yl)thio)-2-chlorobenzenesulfonamide (15 mg, 0.043 mmol), tert-butyl((3S,4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-yl)carbamate (12 mg, 0.043 mmol), and DIPEA (15 mg, 0.086 mmol) were mixed with NMP (0.1 mL, 0.3 M) and stirred at 100°C for 3 hours. The reaction was stopped with aqueous solution, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (EA:Hx=1:1) and concentrated to obtain tert-butyl((3S,4S)-8-(6-amino-5-((2-chloro-3-sulfamoylphenyl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (10 mg, 40%). MS m / z: 586.1 [M+H] + .

[0477] Step 4: 3-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4,5]decane-8-yl)pyrazine-2-yl)thio)-2-chlorobenzenesulfonamide tert-butyl((3S,4S)-8-(6-amino-5-((2-chloro-3-sulfamoylphenyl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (10 mg, 0.017 mmol) was dissolved in methanol (0.1 mL, 0.1 M). A 4 M HCl solution (0.7 mL, 4 M in dioxane) was added to the reaction mixture, and the mixture was then stirred at room temperature for 30 minutes. EA was slowly added to precipitate the solid, which was then filtered to obtain the compound of Example 12 (5 mg, 56%). 1H NMR(400 MHz,DMSO)δ7.74(dd,J=8.0Hz,1.2Hz,1H),7.69(s,1H),7.68(s,1H),7.36(t,J=8.0Hz,1H),6.81(dd,J=8.0 Hz,1.2 MS m / z:485 [M+H] + .

[0478] Example 13: Synthesis of 6-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-3-benzyl-5-chloroquinazoline-4(3H)-one [ka]

[0479] Step 1: tert-butyl((1-(5-((5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate In a round-bottom flask, intermediates I-2 (275 mg, 0.71 mmol), I-8 (215 mg, 0.86 mmol), Pd2(dba)3 (64 mg, 0.07 mmol), and xanthophos (40 mg, 0.07 mmol) were dissolved in 1,4-dioxane (3.0 mL, 0.25 M), and then DIPEA (0.25 mL, 1.4 mmol) was added. The reaction mixture was purged with nitrogen and stirred at 100°C for 1 hour. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (EA:Hx=1:1) and concentrated to obtain tert-butyl((1-(5-((5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate (144 mg, 40%). MS m / z: 518.1 [M+H] + .

[0480] Step 2: tert-butyl((1-(5-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate In a round-bottom flask, tert-butyl((1-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate (30 mg, 0.05 mmol), benzyl chloride (6 μL, 0.05 mmol), sodium iodide (7 mg, 0.05 mmol), and potassium carbonate (34 mg, 0.25 mmol) were dissolved in acetone (0.5 mL, 0.1 M). The reaction mixture was stirred at 100 °C for 1 hour. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (EA:Hx=1:1) and concentrated to obtain tert-butyl((1-(5-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate (21 mg, 60%). MS m / z: 608.1 [M+H] + .

[0481] Step 3: 6-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-3-benzyl-5-chloroquinazoline-4(3H)-one In a round-bottom flask, tert-butyl((1-(5-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate (21 mg, 0.03 mmol) was dissolved in methanol (0.6 mL, 0.05 M). 4 M hydrochloric acid (0.8 mL, 4 M in dioxane) was added to the reaction mixture and stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated using a concentrator. The reaction mixture was washed with EA, and the solid was collected by filtration to obtain the compound of Example 13 (16 mg, 99%). 1H NMR(400 MHz,DMSO)δ8.61(s,1H),8.47(d,J=1.6 Hz,1H),8.30(d,J=1.2 Hz,1H),7.93(bs,3H),7.55(d,J=8.8 Hz,1H),7.39-7.29(m,5H),7.24(d,J=8.8 MS m / z:507 [M+H] + .

[0482] Example 14: Synthesis of 6-((5-(4-amino-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-5-chloro-3-(3-nitrobenzyl)quinazoline-4(3H)-one [ka]

[0483] The compound of Example 14 was synthesized in the same manner as in Example 13, except that intermediate I-1 was used instead of intermediate I-2, and 3-nitrobenzyl bromide was used instead of benzyl chloride. 1 H NMR(400 MHz,CDCl3)δ8.26(d,J=1.2 Hz,1H),8.21-8.18(m,2H),8.11(s,1H),7.75(d,J=8.0 Hz,1H),7.56(t,J=8.0 Hz,1H),7.47(d,J=8.8 Hz,1H),7.30(d,J=8.8 Hz,1H),7.21(s,1H),5.23(s,2H),3.81-3.65(m,4H),1.67-1.62(m,4H),1.25(s,3H);MS m / z:538 [M+H] + .

[0484] Example 15: Synthesis of 6-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-5-chloro-3-methylquinazoline-4(3H)-one [ka]

[0485] The compound of Example 15 was synthesized in the same manner as in Example 13, except that MeI was used instead of benzyl chloride. 1 H NMR(400 MHz,DMSO)δ8.49(s,1H),8.29(s,1H),8.32(d,J=1.2 Hz,1H),7.86(bs,3H),7.52(d,J=8.8 Hz,1H),7.20(d,J=8.8 MS m / z:531 [M+H] + .

[0486] Example 16: Synthesis of 3-((6-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-5-chloro-4-oxoquinazoline-3(4H)-yl)methyl)benzenesulfonyl fluoride [ka]

[0487] The compound of Example 16 was synthesized in the same manner as in Example 13, except that 3-(bromomethyl)benzenesulfonyl fluoride was used instead of benzyl chloride. 1H NMR(400 MHz,DMSO)δ8.68(s,1H),8.48(d,J=1.2 Hz,1H),8.31(d,J=1.2 Hz,1H),8.23(s,1H),8.11-8.08(m,1H),7.96(d,J=8.0 Hz,1H),7.84(bs,3H),7.79(t,J=8.0 Hz,1H),7.56(d,J=8.4 Hz,1H),7.24(d,J=8.8 MS m / z:589 [M+H] + .

[0488] Example 17: Synthesis of 4-((6-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-5-chloro-4-oxoquinazoline-3(4H)-yl)methyl)benzenesulfonyl fluoride [ka]

[0489] The compound of Example 17 was synthesized in the same manner as in Example 13, except that 4-(bromomethyl)benzenesulfonyl fluoride was used instead of benzyl chloride. 1 H NMR(400 MHz,DMSO)δ8.64(s,1H),8.48(d,J=1.2 Hz,1H),8.31(d,J=1.2 Hz,1H),8.13(d,J=8.4 Hz,2H),7.90(bs,3H),7.75(d,J=8.4 Hz,2H),7.58(d,J=8.8 Hz,1H),7.26(d,J=8.8 MS m / z:589 [M+H] + .

[0490] Example 18: Synthesis of 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-3-benzyl-5-chloroquinazoline-4(3H)-one [ka]

[0491] Step 1: N-((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)-2-methylpropane-2-sulfanilamide In a round-bottom flask, intermediates I-3 (345 mg, 0.8 mmol), I-8 (300 mg, 1.2 mmol), Pd2(dba)3 (73 mg, 0.08 mmol), and xanthophos (46 mg, 0.08 mmol) were dissolved in 1,4-dioxane (3.2 mL, 0.25 M), and DIPEA (0.28 mL, 1.6 mmol) was added. The reaction mixture was purged with nitrogen and then stirred at 100°C for 1 hour. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (MeOH:MC=1:50) and concentrated to obtain N-((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)-2-methylpropane-2-sulfanilamide (190 mg, 42%). MS m / z: 564.1 [M+H] + .

[0492] Step 2: N-((3S,4S)-8-(5-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)-2-methylpropane-2-sulfanilamide In a round-bottom flask, N-((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)-2-methylpropane-2-sulfanilamide (50 mg, 0.09 mmol), benzyl chloride (13 μL, 0.12 mmol), and cesium carbonate (44 mg, 0.13 mmol) were dissolved in DMF (0.9 mL, 0.1 M). The reaction mixture was stirred at 50°C for 2 hours. The reaction was stopped with an aqueous solution of NaHCO3, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (MeOH:MC=1:50) and concentrated to obtain N-((3S,4S)-8-(5-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)-2-methylpropane-2-sulfanilamide (37 mg, 62%). MS m / z: 654.1 [M+H] + .

[0493] Step 3: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4,5]decane-8-yl)pyrazine-2-yl)thio)-3-benzyl-5-chloroquinazoline-4(3H)-one In a round-bottom flask, N-((3S,4S)-8-(5-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)-2-methylpropane-2-sulfanilamide (37 mg, 0.056 mmol) was dissolved in DCM (0.6 mL, 0.1 M). 4 M hydrochloric acid (0.14 mL, 4 M in dioxane) was added to the reaction mixture, and the mixture was then stirred at 40°C for 30 minutes. After the reaction was complete, the reaction mixture was concentrated using a concentrator. After washing the reaction mixture with EA, the solid was collected by filtration to obtain the compound of Example 18 (35 mg, 99%). 1H NMR(400 MHz,DMSO)δ8.61(s,1H),8.51(s,1H),8.33(s,1H),8.07(bs,3H),7.55(d,J=8.8 Hz,1H),7.38-7.31(m,5H),7.52(d,J=8.8 Hz,1H),5.17(s,2H),4.30-4.19(m,3H),3.92(d,J=9.2 Hz,1H),3.70(d,J=9.2 MS m / z:549 [M+H] + .

[0494] Example 19: Synthesis of 3-((6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azospiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-4-oxoquinazoline-3(4H)-yl)methyl)benzenesulfonylfluoride [ka]

[0495] The compound of Example 19 was synthesized in the same manner as in Example 18, except that 3-(bromomethyl)benzenesulfonyl fluoride was used instead of benzyl chloride. 1H NMR(400 MHz,DMSO)δ8.68(s,1H),8.511(d,J=1.2 Hz,1H),8.32(d,J=1.2 Hz,1H),8.23(s,1H),8.11-8.09(m,4H),7.96(d,J=8.0 Hz,1H),7.79(t,J=8.0 Hz,1H),7.56(d,J=8.8 Hz,1H),7.26(d,J=8.8 Hz,1H),5.30(s,2H),4.30-4.19(m,2H),3.93(d,J=8.8 Hz,1H),3.70(d,J=9.2 MS m / z:631 [M+H] + .

[0496] Example 20: Synthesis of 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azospiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(pyridine-3-ylmethyl)quinazolin-4(3H)-one [ka]

[0497] The compound of Example 20 was synthesized in the same manner as in Example 18, except that 3-(bromomethyl)pyridine was used instead of benzyl chloride. 1H NMR(400 MHz,DMSO)δ8.93(s,1H),8.77-8.75(m,1H),8.66(s,1H),8.51(d,J=1.2 Hz,1H),8.38-8.36(m,1H),8.32(d,J=1.2 Hz,1H),8.11(s,3H),7.86-7.83(m,1H),7.56(d,J=8.4 Hz,1H),7.26(d,J=8.4 Hz,1H),5.29(s,2H),4.30-4.19(m,3H),3.93(d,J=8.8 Hz,1H),3.70(d,J=8.8 MS m / z:550 [M+H] + .

[0498] Example 21: Synthesis of 3-((6-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-5-chloro-2methyl-4-oxoquinazoline-3(4H)-yl)methyl)benzenesulfonyl fluoride [ka]

[0499] Step 1: tert-butyl((1-(5-((5-chloro-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate In a round-bottom flask, intermediates I-2 (132 mg, 0.34 mmol), I-9 (131 mg, 0.58 mmol), Pd2(dba)3 (16 mg, 0.017 mmol), and xanthophos (20 mg, 0.034 mmol) were dissolved in 1,4-dioxane (1 mL, 0.3 M), and then DIPEA (120 μL, 0.68 mmol) was added. The reaction mixture was purged with nitrogen and stirred at 100 °C for 4 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (MC:MeOH = 9:1) and concentrated to obtain tert-butyl((1-(5-((5-chloro-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate (67 mg, 37%). MS m / z: 532.1 [M+H] + .

[0500] Step 2: tert-butyl((1-(5-((5-chloro-3-(3-(fluorosulfonyl)benzyl)-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate In a round-bottom flask, tert-butyl((1-(5-((5-chloro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate (15 mg, 0.03 mmol) was dissolved in DMF (0.5 mL), and then NaH (1.4 mg, 0.06 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and 3-(bromomethyl)benzenesulfonyl fluoride (7.9 mg, 0.031 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours, the reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (EA:Hx=4:1) and concentrated to obtain tert-butyl((1-(5-((5-chloro-3-(3-(fluorosulfonyl)benzyl)-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate (8.2 mg, 39%). MS m / z: 704.1 [M+H] + .

[0501] Step 3: 3-((6-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-5-chloro-2-methyl-4-oxoquinazoline-3(4H)-yl)methyl)benzenesulfonylfluoride tert-butyl((1-(5-((5-chloro-3-(3-(fluorosulfonyl)benzyl)-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate (8.2 mg, 0.012 mmol) was placed in a round-bottom flask and dissolved in DCM (0.25 mL). 4M HCl (0.25 mL) in dioxane was slowly added dropwise to the reaction mixture, and the mixture was then stirred at room temperature for 30 minutes. After the reaction was complete, the mixture was concentrated, and EA was added dropwise. The precipitated solid was filtered with EA to obtain the compound of Example 21 (3.5 mg, 48%). 1H NMR(400 MHz,DMSO)δ8.55(s,1H),8.37(d,J=1.2 Hz,1H),8.1(s,1H),8.15-8.14(m,1H),7.90(b,3H),7.82(d,J=4.4 Hz,2H),7.56(d,J=8.8 Hz,1H),7.30(d,J=8.8 MS m / z:603 [M+H] + .

[0502] Example 22: Synthesis of 6-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-5-chloro-2-methylquinazoline-4(3H)-one [ka]

[0503] The tert-butyl((1-(5-((5-chloro-3-(3-(fluorosulfonyl)benzyl)-2-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)methyl)carbamate obtained in step 2 was deprotected by Boc, and the compound of Example 22 was synthesized in the same manner as in Example 21. 1 H NMR(400 MHz,MeOD)δ8.28(dd,J=10.6,1.4 Hz,2H),7.39(d,J=8.8 Hz,1H),7.27(d,J=8.8 Hz,1H),4.07(dt,J=13.9,4.8 Hz,2H),3.54-3.43(m,2H),2.91(s,2H),2.41(s,3H),1.60(dt,J=8.4,4.3 Hz,4H),1.20(s,3H);MS m / z:431 [M+H] + .

[0504] Example 23: Synthesis of 6-((5-(4-(aminomethyl)-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-3-benzyl-5-chloro-2-methylquinazoline-4(3H)-one [ka]

[0505] The compound of Example 23 was synthesized in the same manner as in Example 21, except that benzyl bromide was used instead of 3-(bromomethyl)benzenesulfonyl fluoride. 1 H NMR(400 MHz,MeOD)δ 8.29(dd,J=9.0,1.4 Hz,2H),7.54-7.45(m,1H),7.45-7.17(m,5H),7.11-7.01(m,1H),5.41(s,2H),4.07(d,J=13.9 MS m / z:521 [M+H] + .

[0506] Example 24: Synthesis of 1-(5-((7-chloro-2-methylbenzo[d]thiazole-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-amine [ka]

[0507] Step 1: tert-butyl(1-(5-((7-chloro-2-methylbenzo[d]thiazole-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate In a round-bottom flask, intermediates I-10 (100 mg, 0.31 mmol), I-11 (89 mg, 0.34 mmol), Pd2(dba)3 (28 mg, 0.031 mmol), and xanthophos (18 mg, 0.031 mmol) were dissolved in 1,4-dioxane (2 mL, 0.15 M), and then DIPEA (0.11 mL, 0.62 mmol) was added. The reaction was carried out at 150°C for 30 minutes using a microwave apparatus. The reaction mixture was washed with EA, filtered through celite, and then the filtrate was concentrated. The obtained product was separated by MPLC (EA:Hx=1:3) and concentrated to obtain tert-butyl(1-(5-((7-chloro-2-methylbenzo[d]thiazole-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate (20 mg, 13%). MS m / z: 506 [M+H] + .

[0508] Step 2: 1-(5-((7-chloro-2-methylbenzo[d]thiazole-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-amine In a round-bottom flask, tert-butyl(1-(5-((7-chloro-2-methylbenzo[d]thiazole-6-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate (20 mg, 0.31 mmol) was dissolved in DCM (1 mL, 0.3 M). Trifluoroacetic acid (0.5 mL, 0.62 M) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped with aqueous NaHCO3 solution, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by preparative HPLC and concentrated to obtain the compound of Example 24 (4.5 mg, 28%). 1H NMR(400 MHz,MeOD)δ8.26(d,J=1.5 Hz,1H),8.19(d,J=1.4 Hz,1H),7.73(d,J=8.6 Hz,1H),7.33(d,J=8.6 Hz,1H),4.17(dt,J=14.2,4.6 MS m / z:406 [M+H] + .

[0509] Example 25: Synthesis of 1-(5-((4-chloro-2-methyl-2H-indazole-5-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-amine [ka]

[0510] Step 1: tert-butyl(1-(5-((4-chloro-2-methyl-2H-indazole-5-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate In a round-bottom flask, intermediate I-1 (50 mg, 0.135 mmol), intermediate I-12 (32 mg, 0.162 mmol), Pd2(dba)3 (12 mg, 0.0135 mmol), and xanthophos (8 mg, 0.0135 mmol) were dissolved in 1,4-dioxane (1 mL, 0.14 M), and then DIPEA (47 μL, 0.27 mmol) was added. The reaction was carried out at 150°C for 30 minutes using a microwave apparatus. The reaction mixture was washed with EA, filtered through celite, and then the filtrate was concentrated. The obtained product was separated by MPLC (EA:Hx=1:3) and concentrated to obtain tert-butyl(1-(5-((4-chloro-2-methyl-2H-indazole-5-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate (15 mg, 23%). MS m / z: 489 [M+H] + .

[0511] Step 2: 1-(5-((4-chloro-2-methyl-2H-indazole-5-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-amine In a round-bottom flask, tert-butyl(1-(5-((4-chloro-2-methyl-2H-indazole-5-yl)thio)pyrazine-2-yl)-4-methylpiperidine-4-yl)carbamate (15 mg, 0.03 mmol) was dissolved in DCM (1 mL, 0.03 M). Trifluoroacetic acid (0.5 mL, 0.06 M) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped with aqueous NaHCO3 solution, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated and concentrated by preparative HPLC to obtain the compound of Example 25 (4.1 mg, 35%) as the TFA salt. 1 H NMR(400 MHz,MeOD)δ8.31(s,1H),8.20(d,J=1.5 Hz,1H),8.06(d,J=1.5 Hz,1H),7.48(dd,J=8.9,1.0 Hz,1H),7.21(d,J=9.0 Hz,1H),4.22(s,3H),4.13(dt,J=14.2,4.4 Hz,2H),3.43-3.32(m,2H),1.84(m,4H),1.48(s,3H);MS m / z:389 [M+H] + .

[0512] Example 26: Synthesis of (3S,4S)-8-(5-((4-chloro-2-methyl-2H-indazole-5-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine [ka]

[0513] The compound of Example 26 was synthesized in the same manner as in Example 25, except that intermediate I-4 was used instead of intermediate I-1. 1H NMR(400 MHz,MeOD)δ8.17(d,J=1.5 Hz,1H),8.06(d,J=1.4 Hz,1H),7.55(d,J=9.0 Hz,1H),7.53-7.44(m,1H),7.20(d,J=9.0 Hz,1H),3.97(s,3H),3.86-3.75(m,2H),3.41-3.38(m,3H),3.16-3.10(m,2H),1.85-1.68(m,4H),1.30(d,J=6.5 Hz,3H);MS m / z:445 [M+H] + .

[0514] Example 27: Synthesis of 3-((4-amino-2-(4-amino-4-methylpiperidine-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-yl)thio)-2-chlorobenzoic acid [ka]

[0515] Step 1: Methyl 3-((4-amino-2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-yl)thio)-2-chlorobenzoate In a round-bottom flask, intermediate I-79 (1.04 g, 2.13 mmol) was dissolved in 1,4-dioxane, and then intermediate I-5 (763 mg, 4.26 mmol), K3PO4 (904 mg, 4.26 mmol), CuI (82 mg, 0.43 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (61 mg, 0.43 mmol) were added dropwise. The reaction mixture was stirred at 90°C for 16 hours. The reaction was stopped with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The obtained product was separated by MPLC (MeOH:DCM = 1:10) and concentrated to obtain methyl 3-((4-amino-2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-yl)thio)-2-chlorobenzoate (280 mg, 24%). MS m / z: 538.20 [M+H] + .

[0516] Step 2: 3-((4-amino-2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-yl)thio)-2-chlorobenzoic acid In a round-bottom flask, 0.5 mL (0.50 mmol) of 1 M NaOH aqueous solution was added dropwise to a reaction mixture of methyl 3-((4-amino-2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-yl)thio)-2-chlorobenzoate (134 mg, 0.25 mmol) dissolved in EtOH. The reaction mixture was stirred at room temperature for 4 hours. The reaction was stopped with 1 M HCl aqueous solution, and the mixture was extracted with EA. The EA layer was dried with MgSO4, filtered, and concentrated to obtain 3-((4-amino-2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-yl)thio)-2-chlorobenzoic acid (121 mg, 92%). MS m / z: 524.20 [M+H] + .

[0517] Step 3: 3-((4-amino-2-(4-amino-4-methylpiperidine-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-yl)thio)-2-chlorobenzoic acid tert-butyl N-[2-[4-[4-amino-5-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-1-methyl-6-oxopyrimidine-2-yl]piperazine-1-yl]ethyl]carbamate (70.0 mg, 136 μmol) was dissolved in DCM (0.5 mL), and TFA (2.69 g, 23.6 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes. After the reaction was complete, the reaction mixture was concentrated and NH45 was added. 3· The mixture was neutralized by adding H2O. The resulting product was separated by preparative HPLC to obtain the compound of Example 27 (7 mg, 18%). 1 H NMR(400 MHz,MeOD)δ7.48(dd,J=7.7,1.6 Hz,1H),7.18(t,J=7.8 Hz,1H),6.95(dd,J=8.0,1.6 Hz,1H),3.63(d,J=14.2 Hz,2H),3.42(d,J=1.5 Hz,3H),3.30-3.22(m,2H),2.00(td,J=11.8,3.9 Hz,2H),1.89(d,J=13.2 Hz,2H);MS m / z:424.10 [M+H] + .

[0518] Example 28: Synthesis of 6-((5-(4-amino-4-methylpiperidine-1-yl)pyrazine-2-yl)thio)-5-chloro-3-phenylquinazoline-4(3H)-one [ka]

[0519] The compound of Example 28 (33 mg, 82%) was synthesized in the same manner as in Example 26, except that intermediate I-13 was used instead of intermediate I-12. 1H NMR(400 MHz,MeOD)δ8.41-8.31(m,2H),8.26(s,1H),7.63-7.45(m,6H),7.34(d,J=8.8 Hz,1H),4.29-4.20(m,2H),3.52-3.41(m,2H),2.03-1.77(m,4H),1.52(s,3H);MS m / z:479.10 [M+H] + .

[0520] Example 29: Synthesis of 6-((4-amino-2-(4-amino-4-methylpiperidine-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-yl)thio)-5-chloroquinazoline-4(3H)-one [ka]

[0521] The compound of Example 29 (8 mg, 20%) was synthesized in the same manner as in Example 27, except that intermediate I-8 was used instead of intermediate I-6. 1 H NMR(400 MHz,MeOD)δ8.18(s,1H),7.98(s,1H),7.45(d,J=8.8 Hz,1H),7.26(d,J=8.8 Hz,1H),3.65(d,J=14.1 Hz,2H),3.43(s,3H),3.30-3.16(m,2H),2.07-1.98(m,2H),1.94-1.85(m,2H);MS m / z:448.10 [M+H] + .

[0522] Example 30: Synthesis of 6-((4-amino-2-(4-amino-4-methylpiperidine-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-yl)thio)-5-chloro-3-phenylquinazoline-4(3H)-one [ka]

[0523] The compound of Example 30 (9 mg, 13%) was synthesized in the same manner as in Example 27, except that intermediate I-13 was used instead of intermediate I-6. 1 H NMR(400 MHz,MeOD)δ8.22(s,1H),7.63-7.45(m,6H),7.28(d,J=8.7 Hz,1H),3.65(d,J=14.1 Hz,2H),3.44(s,3H),3.34(s,3H),3.32-3.17(m,2H),2.07-1.96(m,2H),1.95-1.87(m,2H);MS m / z:524.20 [M+H] + .

[0524] Example 31: 3-((6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-4-oxoquinazoline-3(4H)-yl)methyl)benzonitrile [ka]

[0525] The compound of Example 31 (18 mg, 97%) was synthesized in the same manner as in Example 18, except that 3-(bromomethyl)benzonitrile was used instead of benzyl chloride. 1 H NMR(400 MHz,DMSO)δ 8.63(s,1H),8.51(d,J=1.5 Hz,1H),8.32(d,J=1.3 Hz,1H),8.17(bs,3H),7.90(d,J=1.9 Hz,1H),7.79(dt,J=7.7,1.5 Hz,1H),7.74(dt,J=8.0,1.5 Hz,1H),7.80-7.73(m,2H),7.26(d,J=8.8 Hz,1H),5.20(s,2H),4.33-4.17(m,3H),3.94(d,J=9.0 Hz,1H),3.69(d,J=9.0 Hz,1H),3.43-3.36(m,1H),3.19-3.12(m,2H),1.85-1.70(m,3H),1.63-1.59(m,1H),1.24(d,J=6.8 Hz,3H);MS m / z:573.17 [M+H] + .

[0526] Example 32: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(1-phenylethyl)quinazoline-4(3H)-one [ka]

[0527] The compound of Example 32 (8.5 mg, 83%) was synthesized in the same manner as in Example 18, except that 1-(bromoethyl)benzene was used instead of benzyl chloride. 1 H NMR(400 MHz,DMSO)δ 8.51(d,J=1.5 Hz,1H),8.43(s,1H),8.32(d,J=1.3 Hz,1H),8.05(bs,3H),7.53(d,J=8.8 Hz,1H),7.46-7.30(m,4H),7.33-7.22(m,1H),7.25(d,J=8.8 Hz,1H),6.05(t,J=7.2 Hz,1H),4.32-4.17(m,3H),3.92(d,J=9.0 Hz,1H),3.70(d,J=9.0 Hz,1H),3.42-3.40(m,1H),1.84(d,J=7.2 Hz,3H),1.79-1.71(m,3H),1.61-1.58(m,1H),1.61-1.58(m,1H),1.23(d,J=6.8 Hz,3H);MS m / z:562.19 [M+H] + .

[0528] Example 33: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(3-fluorobenzyl)quinazoline-4(3H)-one [ka]

[0529] The compound of Example 33 (17 mg, 85%) was synthesized in the same manner as in Example 18, except that 1-(bromomethyl)-3-fluorobenzene was used instead of benzyl chloride. 1 H NMR(400 MHz,DMSO)δ 8.61(s,1H),8.51(d,J=0.8 Hz,1H),8.32(d,J=1.2 Hz,1H),8.12(b,3H),7.56(d,J=8.8 Hz,1H),7.44-7.39(m,1H),7.29-7.20(m,3H),7.15(td,J=8.7,2.7 Hz,1H),5.17(s,2H),4.30-4.20(m,3H),3.41-3.39(m,1H),3.20-3.12(m,2H),1.84-1.71(m,3H),1.61(d,J=13.2 Hz,1H),1.24(d,J=6.8 Hz,4H),1.05(s,1H);MS m / z:566.17 [M+H] + .

[0530] Example 34: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(3-trifluoromethyl)benzyl)quinazoline-4(3H)-one [ka] The compound of Example 34 (15.4 mg, 71%) was synthesized in the same manner as in Example 18, except that 1-(bromomethyl)-3-(fluoromethyl)benzene was used instead of benzyl chloride. 1H NMR(400 MHz,DMSO)δ 8.67(s,1H),8.51(d,J=1.2Hz,1H),8.32(d,J=1.2Hz,1H),8.05(b,3H),7.81(s,1H),7 .69-7.68(m,2H),7.62(d,J=7.6Hz,1H),7.56(d,J=8.8Hz,1H),7.26(d,J=8.8Hz,1H),5 .24(s,2H),4.30-4.19(m,3H),3.92(d,J=8.8Hz,1H),3.41-3.40(m,1H),3.20-3.13(m, 2H),1.82-1.71(m,3H),1.62-1.58(m,1H),1.24-1.23(m,4H),0.87(t,J=6.8Hz,1H);MS m / z:616.16 [M+H] + .

[0531] Example 35: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(thiazole-2-ylmethyl)quinazoline-4(3H)-one [ka]

[0532] The compound of Example 35 (27 mg, 91%) was synthesized in the same manner as in Example 18, except that 2-(chloromethyl)thiazole was used instead of benzyl chloride. 1H NMR(400 MHz,DMSO)δ 8.59(d,J=1.6Hz,1H),8.52(s,1H),8.33(s,1H),8.23(b,3H),7.76-7.74(m,2H),7.5 8(dd,J=8.8Hz,1.6Hz,1H),7.28(dd,J=8.8Hz,2Hz,1H),5.51(s,2H),3.95(d,J=8Hz, 1H),3.68(d,J=8Hz,1H),3.40(b,1H),3.15(b,2H),1.81(b,2H),1.72(d,J=13.2Hz,1 H),1.62(d,J=13.2Hz,1H),1.25(m,4H),1.05(d,J=1.6Hz,1H),0.87-0.86(m,1H);MS m / z:555.13 [M+H] + .

[0533] Example 36: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(3-methoxybenzyl)quinazoline-4(3H)-one [ka]

[0534] The compound of Example 36 (18.7 mg, 87%) was synthesized in the same manner as in Example 18, except that 3-methoxybenzyl bromide was used instead of benzyl chloride. 1 H NMR(400 MHz,DMSO)δ 8.59(s,1H),8.52(s,1H),8.33(s,1H),8.03(bs,3H),7.55(d,J=8.8 Hz,1H),7.32-7.22(m,2H),6.96-6.88(m,3H),5.13(s,2H),4.30(s,1H),4.30-4.21(m,3H),3.92(d,J=8.6 Hz,1H),3.75(s,3H),3.70(d,J=9.0 Hz,1H),3.18-3.13(m,3H),1.79-1.76(m,3H),1.61-1.58(m,1H),1.23(d,J=7.0 Hz, 3H); MS m / z: 578.19 [M+H] + .

[0535] Example 37: 3-((1H-benzo[d]imidazole-2-yl)methyl)-6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloroquinazoline-4(3H)-one [ka]

[0536] The compound of Example 37 (5.1 mg, 74%) was synthesized in the same manner as in Example 18, except that 2-(chloromethyl)benzimidazole was used instead of benzyl chloride. 1 H NMR(400 MHz,DMSO)δ 8.65(s,1H),8.59(s,1H),8.52(d,J=1.4 Hz,1H),8.33(d,J=1.3 Hz,1H),8.12(bs,3H),7.81-7.74(m,2H),7.62(d,J=8.8 Hz,1H),7.52-7.50(m,2H),7.30(d,J=8.8 Hz,1H),5.64(s,2H),4.32-4.18(m,3H),3.93(d,J=8.8 Hz,1H),3.70(d,J=9.0 Hz,1H),3.20-3.12(m,2H),1.83-1.72(m,3H),1.62-1.59(m,1H),1.24(d,J=6.6 Hz,3H);MS m / z:588.18 [M+H] + .

[0537] Example 38: 2-((6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-4-oxoquinazoline-3(4H)-yl)methyl)benzenesulfonylfluoride [ka]

[0538] The compound of Example 38 (8 mg, 67%) was synthesized in the same manner as in Example 18, except that 2-(bromomethyl)benzenesulfonyl fluoride was used instead of benzyl chloride. 1 H NMR(400 MHz,DMSO)δ 8.64(s,1H),8.52(s,1H),8.33(s,1H),8.14-8.11(m,5H),7.75(d,J=7.6Hz,2H),7.59-7.57(m,1H),7.29-7.26(m,1H),5.33(s,2H), MS m / z:630.13 [M+H] + .

[0539] Example 39: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(pyridine-4-ylmethyl)quinazoline-4(3H)-one [ka]

[0540] The compound of Example 39 (1.5 mg, 34%) was synthesized in the same manner as in Example 18, except that 4-(bromomethyl)pyridine was used instead of benzyl chloride. 1H NMR(400 MHz,DMSO)δ 8.78(d,J=6.5 Hz,2H),8.59(s,1H),8.52(d,J=1.5 Hz,1H),8.32(d,J=1.3 Hz,1H),8.14(bs,3H),7.82(d,J=6.0 Hz,2H),7.59(d,J=8.8 Hz,1H),7.28(d,J=8.8 Hz,1H),5.37(s,2H),4.33-4.20(m,3H),3.93(d,J=9.1 Hz,1H),3.69(d,J=9.1 Hz,1H),3.20-3.13(m,3H),1.91-1.71(m,3H),1.63-1.59(m.1H),1.24(d,J=6.5 Hz,3H);MS m / z:549.17 [M+H] + .

[0541] Example 40: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(4-fluorobenzyl)quinazoline-4(3H)-one [ka]

[0542] The compound of Example 40 (22 mg, 81%) was synthesized in the same manner as in Example 18, except that 1-(bromomethyl)-4-fluorobenzene was used instead of benzyl chloride. 1H NMR(400 MHz,DMSO)δ 8.62(s,1H),8.51(d,J=1.1 Hz,1H),8.32(d,J=1.2 Hz,1H),8.08(s,3H),7.54(d,J=8.8 Hz,1H),7.48-7.44(m,2H),7.25(d,J=8.8Hz,1H),7.19(t,J=8.9Hz,2H),5.14(s,2H),4.30-4.18(m,3H),4.25-4.16(m,2H),3.92(d,J=9.1 Hz,1H),3.69(d,J=9.1 Hz,1H),3.42-3.39(m,2H),3.16(q,J=10.1 Hz,2H),1.82-1.70(m,3H),1.60(d,J=13.3 Hz,1H),1.23(d,J=6.6 Hz,3H);MS m / z:566.17 [M+H] + .

[0543] Example 41: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(4-methoxybenzyl)quinazoline-4(3H)-one [ka]

[0544] The compound of Example 41 (32 mg, 97%) was synthesized in the same manner as in Example 18, except that 4-methoxybenzyl chloride was used instead of benzyl chloride. 1H NMR(400 MHz,DMSO)δ 8.60(s,1H),8.51(s,1H),8.32(s,1H),8.09(bs,3H),7.53(d,J=8.7 Hz,1H),7.36(d,J=8.5 Hz,2H),7.24(d,J=8.8 Hz,1H),6.92(d,J=8.3 Hz,2H),5.08(s,2H),4.32-4.16(m,3H),3.92(d,J=9.1 Hz,1H),3.73(s,3H),3.69(d,J=9.2 Hz,1H),3.41-3.39(m,1H),3.19-3.12(m,2H),1.82-1.70(m,3H),1.61-1.58(m,1H),1.23(d,J=6.6 Hz,3H);MS m / z:578.19 [M+H] + .

[0545] Example 42: 3-((1H-pyrrolo[2,3-b]pyridine-6-yl)methyl)-6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloroquinazoline-4(3H)-one [ka]

[0546] The compound of Example 42 (24 mg, 87%) was synthesized in the same manner as in Example 18, except that 6-(chloromethyl)-1H-pyrrolo[2,3-b]pyridine was used instead of benzyl chloride. 1H NMR(400 MHz,DMSO)δ 11.63(s,1H),8.59(s,1H),8.50(s,1H),8.32(s,1H),8.12(bs,3H),7.97(d,J=7.9 Hz,1H),7.58(d,J=8.8 Hz,1H),7.41(t,J=2.8 Hz,1H),7.27(d,J=8.8 Hz,1H),7.15(d,J=8.0 Hz,1H),6.44(s,1H),5.34(s,2H),4.30-4.19(m,3H),3.93(d,J=9.1 Hz,1H),3.68-3.60(m,1H),3.41-3.40(m,1H),3.19-3.12(m,2H),1.84-1.70(m,3H),1.62-1.58(m,1H),1.24(d,J=6.4 Hz,3H);MS m / z:588.18 [M+H] + .

[0547] Example 43: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(2-fluorobenzyl)quinazoline-4(3H)-one [ka]

[0548] The compound of Example 43 (18 mg, 90%) was synthesized in the same manner as in Example 18, except that 1-(bromomethyl)-2-fluorobenzene was used instead of benzyl chloride. 1H NMR(400 MHz,DMSO)δ 8.55(s,1H),8.51(d,J=1.2 Hz,1H),8.32(d,J=1.2 Hz,1H),8.06(b,3H),7.56(d,J=8.8 Hz,1H),7.40-7.31(m,2H),7.27-7.17(m,3H),5.20(s,2H),4.29-4.19(m,3H),3.92(d,J=9 Hz,1H),3.70(d,J=9.2 Hz,1H),3.42-3.40(m,2H),3.20-3.12(m,2H),1.83-1.70(m,3H),1.60(d,J=13 Hz,1H),1.23(d,J=6.6 Hz,3H);MS m / z:566.17 [M+H] + .

[0549] Example 44: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(pyrazine-2-ylmethyl)quinazoline-4(3H)-one [ka]

[0550] The compound of Example 44 (24.4 mg, 72%) was synthesized in the same manner as in Example 18, except that 2-(chloromethyl)pyrazine and sodium hydride were used instead of benzyl chloride and cesium carbonate, and the reaction was carried out at 0°C. 1H NMR(400 MHz,DMSO)δ 9.08(d,J=1.2 Hz,1H),8.79(d,J=5.3 Hz,1H),8.52-8.51(m,2H),8.33(d,J=1.2 Hz,1H),8.14(bs,3H),7.61-7.58(m,1H),7.28(d,J=8.8 Hz,1H),5.30(s,2H),4.31-4.19(m,3H),3.93(d,J=9.1 Hz,1H),3.69(d,J=9.3 Hz,1H),3.41-3.39(m,1H),3.20-3.12(m,2H),1.91-1.70(m,3H),1.62-1.59(m,1H),1.24(d,J=6.6 Hz,3H);MS m / z:550.17 [M+H] + .

[0551] Example 45: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(pyrimidine-4-ylmethyl)quinazoline-4(3H)-one [ka]

[0552] The compound of Example 45 (33 mg, 99%) was synthesized in the same manner as in Example 18, except that 4-(bromomethyl)pyrimidine and sodium hydride were used instead of benzyl chloride and cesium carbonate, and the reaction was carried out at 0°C. 1H NMR(400 MHz,DMSO)δ 8.82(d,J=1.5 Hz,1H),8.61-8.53(m,3H),8.51(d,J=1.5 Hz,1H),8.32(d,J=1.3 Hz,1H),8.25(bs,3H),7.57(d,J=8.8 Hz,1H),7.27(d,J=8.8 Hz,1H),5.35(s,2H),4.22-4.20(m,3H),3.94(d,J=9.1 Hz,1H),3.68(d,J=9.1 MS m / z:550.17 [M+H] + .

[0553] Example 46: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(pyrimidine-5-ylmethyl)quinazoline-4(3H)-one [ka]

[0554] The compound of Example 46 (27 mg, 99%) was synthesized in the same manner as in Example 18, except that 5-(chloromethyl)pyrimidine was used instead of benzyl chloride and 1 equivalent of potassium iodide was added. 1H NMR(400 MHz,DMSO)δ 9.13(s,1H),8.91(s,2H),8.68(s,1H),8.50(d,J=1.5 Hz,1H),8.31(d,J=1.3 Hz,1H),8.16(bs,3H),7.55(d,J=8.8 Hz,1H),7.25(d,J=8.8 Hz,1H),5.19(s,2H),4.32-4.16(m,3H),3.93(d,J=9.0 MS m / z:550.17 [M+H] + .

[0555] Example 47: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-3-(benzo[d]oxazole-2-ylmethyl)-5-chloroquinazoline-4(3H)-one [ka]

[0556] The compound of Example 47 (13.2 mg, 35%) was synthesized in the same manner as in Example 18, except that 2-(chloromethyl)benzo[d]oxazole was used instead of benzyl chloride and 1 equivalent of potassium iodide was added. 1H NMR(400 MHz,DMSO)δ 8.61(s,1H),8.52(s,1H),8.38-8.33(m,1H),8.16(bs,3H),7.76-7.67(m,2H),7.61(d,J=8.8 Hz,1H),7.44-7.36(m,2H),7.31(d,J=8.8 Hz,1H),5.54(s,2H),4.33-4.18(m,3H),3.93(d,J=9.1 Hz,1H),3.69(d,J=9.1 Hz,1H),3.43-3.39(m,1H),3.20-3.12(m,2H),1.85-1.67(m,3H),1.63-1.55(m,1H),1.24(d,J=6.4 Hz,3H);MS m / z:589.17 [M+H] + .

[0557] Example 48: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-3-((6-aminopyridine-3-yl)methyl)-5-chloroquinazoline-4(3H)-one [ka]

[0558] The compound of Example 48 (16 mg, 71%) was synthesized in the same manner as in Example 18, except that 5-(bromomethyl)pyridine-2-amine was used instead of benzyl chloride. 1H NMR(400 MHz,DMSO)δ 13.78-13.77(b,1H),8.54(s,1H),8.51(s,1H),8.33(s,1H),8.24(b,2H),8.03(b,2H),7.94(d,J= 6.3Hz,1H),7.59(d,J=8.8Hz,1H),7.28(d,J=8.8Hz,1H),6.86(d,J=6.6Hz,1H),6.70(s,1H),5.19 (s,2H),4.31-4.28(m,1H),4.23-4.20(m,2H),3.68(d,J=9.1Hz,1H),3.39(m,1H),3.17(m,2H),1. 82-1.79(m,2H),1.71(d,J=13Hz,1H),1.62(d,J=13Hz,1H),1.24(d,J=6.3Hz,3H),1.05(s,1H);MS m / z:565.09 [M+H] + .

[0559] Example 49: (3S,4S)-8-(5-((2-benzyl-4-chloro-2H-indazole-5-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine [ka]

[0560] The compound of Example 49 (3 mg, 20%) was synthesized in the same manner as in Example 25, except that intermediate I-16 was used instead of intermediate I-1, and intermediate I-17 was used instead of intermediate I-2. 1 H NMR(400 MHz,CDCl3)δ 8.07(s,1H),7.92(d,J=12.8 Hz,1H),7.61-7.51(m,2H),7.36-7.30(m,5H),7.22(d,J=8.9 Hz,1H),5.58(s,2H),4.22-4.13(m,3H),3.99(d,J=9.7 Hz,1H),3.76(d,J=9.5 MS m / z:521 [M+H]+ .

[0561] Example 50: (3S,4S)-8-(5-((2-benzyl-7-chloro-1H-benzo[d]imidazole-6-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine [ka]

[0562] The compound of Example 50 (3 mg, 20%) was synthesized in the same manner as in Example 25, except that intermediate I-16 was used instead of intermediate I-1, and intermediate I-15 was used instead of intermediate I-2. 1 H NMR(400 MHz,MeOD)δ 8.22(s,1H),8.14(s,1H),8.00-7.93(m,2H),7.57(d,J=8.4,1H),7.50(d,J=8.6 Hz,1H),7.43-7.29(m,5H),4.20(d,J=14.2 Hz,2H),3.97(d,J=9.2 Hz,1H),3.86(dd,J=9.3Hz,1H),3.40-3.38(m MS m / z:521 [M+H] + .

[0563] Example 51: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-phenylquinazoline-4(3H)-one [ka]

[0564] The compound of Example 51 (5 mg, 22%) was synthesized in the same manner as in Example 26, except that intermediate I-13 was used instead of intermediate I-12. 1H NMR(400 MHz,MeOD)δ 8.34(d,J=1.4 Hz,1H),8.30(d,J=1.4 Hz,1H),8.26(s,1H),7.62-7.43(m,6H),7.31(d,J=8.8 Hz,1H),4.43-4.20(m,3H),4.00(d,J=9.3 Hz,1H),3.89(d,J=9.2 Hz,1H),3.49-3.38(m,1H),3.29-3.11(m,2H),1.91-1.80(m,3H),1.78-1.69(m,1H),1.32(d,J=6.5 Hz,3H);MS m / z:535 [M+H] + .

[0565] Example 52: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-3-((2-aminopyridine-3-yl)methyl)-5-chloroquinazoline-4(3H)-one [ka]

[0566] The compound of Example 52 (2.7 mg, 61%) was synthesized in the same manner as in Example 18, except that 3-(chloromethyl)pyridine-2-amine hydrochloride (1:1) was used instead of benzyl chloride in step 2 of Example 18. 1 H NMR(400 MHz,DMSO)δ 8.54(s,1H),8.52(s,1H),8.32(d,J=1.3Hz,1H),8.17-8.13(m,2H),8.07(br s,2H),7.98(d,J=5.4Hz,1H),7.76(d,J=7.8Hz,1H),7.58(d,J=8.8Hz,1H),7.26(d,J=8.8Hz,1H),6.86 (t,J=6.7Hz,1H),5.07(s,2H),4.30-4.19(m,3H),3.92(d,J=8.6Hz,1H),3.70(d,J=9.1Hz,1H),3.17(br MS m / z:565 [M+H] + .

[0567] Example 53: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-((1-methyl-1H-pyrazole-3-yl)methyl)quinazoline-4(3H)-one [ka]

[0568] The compound of Example 53 (13 mg, 81%) was synthesized in the same manner as in Example 18, except that 3-(chloromethyl)-1-methyl-1H-pyrazole was used instead of benzyl chloride in step 2 of Example 18, and 1 equivalent of potassium iodide was added. 1 H NMR(400 MHz,DMSO)δ 8.51(s,1H),8.46(s,1H),8.32(d,J=1.2 Hz,1H),8.02(br s,3H),7.63(d,J=2.2 Hz,1H),7.53(d,J=8.8 Hz,1H),7.24(d,J=8.8 Hz,1H),6.21(d,J=2.2 Hz,1H),5.10(s 2H),4.29-4.18(m,3H),3.91(d,J=9.1 Hz,1H),3.76(s,3H),3.69(d,J=9.2 Hz,1H),3.50-3.41(m,1H),3.20-3.12(m,2H),1.81-1.66(m,3H),1.61-1.58(m,1H),1.22(d,J=6.6 Hz,3H).

[0569] Example 54: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(pyrrolidine-2-ylmethyl)quinazoline-4(3H)-one [ka]

[0570] The compound of Example 54 (25 mg, 80%) was synthesized in the same manner as in Example 18, except that tert-butyl 2-(bromomethyl)pyrrolidine-1-carboxylate was used instead of benzyl chloride in step 2 of Example 18, and 1 equivalent of potassium iodide was added. 1 H NMR(400 MHz,DMSO)δ 9.30-9.22(m,2H),8.51(s,2H),8.32(d,J=1.2 Hz,1H),8.20(br s,3H),7.55(d,J=8.8 Hz,1H),7.26(d,J=8.8 Hz,1H),4.32-4.19(m,5H),3.94-3.91(m,1H),3.68(d,J=9.1 Hz,1H),3.40-3.37(m,1H),3.34-3.28(m,1H),3.19-3.11(m,4H),2.17-2.11(m,1H),2. 02-1.89(m,2H),1.84-1.78(m,2H),1.75-1.67(m,2H),1.63-1.59(m,1H),1.24(d,J=6.6 Hz,3H).

[0571] Example 55: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(pyrrolidine-3-ylmethyl)quinazoline-4(3H)-one [ka]

[0572] The compound of Example 55 (31 mg, 95%) was synthesized in the same manner as in Example 18, except that tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate was used instead of benzyl chloride in step 2 of Example 18, and 1 equivalent of potassium iodide was added. 1H NMR(400 MHz,DMSO)δ 9.26-9.09(m,2H),8.51-8.48(m,2H),8.32(d,J=1.2 Hz,1H),8.20-8.16(m,3H),7.53(d,J=8.8 Hz,1H),7.24(d,J=8.8 Hz,1H),4.30-4.27(m,1H),4.23-4.19(m,2H),4.03(d,J=7.2 Hz,2H),3.93(d,J=9.1 Hz,1H),3.68(d,J=9.1 Hz,1H),3.40-3.37(m,1H),3.28-3.24(m,2H),3.19-3.12(m,3H),2.99-2.91(m,1H),2. 78-2.72(m,1H),2.06-1.98(m,1H),1.81-1.65(m,4H),1.60-1.59(m,1H),1.24(d,J=6.5 Hz,3H).

[0573] Example 56: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(isoxazole-3-ylmethyl)quinazoline-4(3H)-one [ka]

[0574] The compound of Example 56 (23 mg, 83%) was synthesized in the same manner as in Example 18, except that 3-(chloromethyl)isoxazole was used instead of benzyl chloride in step 2 of Example 18, and 1 equivalent of potassium iodide was added. 1H NMR(400 MHz,DMSO)δ 8.91(d,J=1.6 Hz,1H),8.53(s,1H),8.51(d,J=1.2 Hz,1H),8.33(d,J=1.2 Hz,1H),8.05(br s,3H),7.56(d,J=8.8 Hz,1H),7.27(d,J=8.8 Hz,1H),6.65(d,J=1.7 Hz,1H),5.29(s 2H),4.30-4.18(m,3H),3.91(d,J=9.0 Hz,1H),3.69(d,J=9.0 Hz,1H),3.42-3.41(m,1H),3.20-3.12(m,2H),1.83-1.70(m,3H),1.61-1.58(m,1H),1.23(d,J=6.5 Hz,3H).

[0575] Example 57: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(isoxazole-5-ylmethyl)quinazoline-4(3H)-one [ka]

[0576] The compound of Example 57 (44 mg, 94%) was synthesized in the same manner as in Example 18, except that 5-(bromomethyl)isoxazole was used instead of benzyl chloride in step 2 of Example 18, and 1.5 equivalents of potassium iodide were added. 1 H NMR(400 MHz,DMSO)δ 8.55(d,J=2.5Hz,2H),8.51(s,1H),8.33(s,1H),8.05(br s,2H),7.56(d,J=8.8Hz,1H),7.27(d,J=8.8Hz,1H),6.53(s,1H),5.37(s,2H),4.29-4.19(m,3H),3.91(d,J=9.0 MS m / z:540 [M+H] + .

[0577] Example 58: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(2-hydroxyethyl)quinazoline-4(3H)-one [ka]

[0578] The compound of Example 58 (5 mg, 85%) was synthesized in the same manner as in Example 18, except that 2-chloroethanol was used instead of benzyl chloride in step 2 of Example 18, and 1 equivalent of potassium iodide was added. 1 H NMR(400 MHz,DMSO)δ 8.51(s,1H),8.32(d,J=1.5 Hz,1H),8.26(s,1H),8.00(br s,3H),7.52(d,J=8.8 Hz,1H),7.24(d,J=8.8 Hz,1H),4.29-4.18(m,3H),4.01-3.99(m,2H),3.91(d,J=9.1 Hz,1H),3.71-3.61(m,4H),3.21-3.12(m,3H),1.78-1.71(m,3H),1.61-1.58(m,1H),1.22(d,J=6.8 Hz,3H).

[0579] Example 59: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-3-((6-aminopyridine-3-yl)methyl)-5-chloroquinazoline-4(3H)-one [ka]

[0580] The compound of Example 59 (3.8 mg, 80%) was synthesized in the same manner as in Example 18, except that 5-(chloromethyl)pyridine-2-amine hydrochloride (1:1) was used instead of benzyl chloride in step 2 of Example 18. 11H NMR (400 MHz, DMSO) δ 13.81-13.64(m,1H),8.60(s,1H),8.50(s,1H),8.31(s,1H),8.11-8.08(m,5H ),8.02(d,J=9.2Hz,1H),7.54(d,J=8.8Hz,1H),7.23(d,J=9.0Hz,1H),6.98(d, J=8.8Hz,1H),5.03(s,2H),4.30-4.18(m,3H),3.92(d,J=9.6Hz,1H),3.69(d,J =9.2Hz,1H),3.19-3.11(m,3H),1.80-1.70(m,3H),1.62-1.58(m,1H),1.24(br s,3H);MS m / z:565 [M+H] + .

[0581] Example 60: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-((2-chloropyridine-4-yl)methyl)quinazoline-4(3H)-one [ka]

[0582] The compound of Example 60 was synthesized in the same manner as in Example 18, except that 2-chloro-4-(chloromethyl)pyridine was used instead of benzyl chloride in step 2 of Example 18. 1 H NMR(400 MHz,DMSO)δ 8.56(s,1H),8.51(s,1H),8.37(d,J=5.1 Hz,1H),8.31(s,1H),8.10(br s,3H),7.56(d,J=8.8 Hz,1H),7.52(s,1H),7.35(d,J=5.1 Hz,1H),7.26(d,J=8.8 Hz,1H),5.18(s 2H),4.29-4.18(m,3H),3.91(d,J=9.1 Hz,1H),3.76(s,3H),3.69(d,J=9.2 Hz,1H),3.50-3.41(m,1H),3.20-3.12(m,2H),1.81-1.66(m,3H),1.61-1.58(m,1H),1.22(d,J=6.6 Hz,3H).

[0583] Example 61: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-((tetrahydrofuran-3-yl)methyl)quinazoline-4(3H)-one [ka]

[0584] The compound of Example 61 (57.7 mg, 88%) was synthesized in the same manner as in Example 18, except that 3-(bromomethyl)tetrahydrofuran was used instead of benzyl chloride in step 2 of Example 18, and 1.5 equivalents of potassium iodide were added. 1 H NMR(400 MHz,DMSO)δ 8.51(s,1H),8.45(s,1H),8.32(d,J=1.2Hz,1H),8.19(br s,2H),7.53(d,J=8.8Hz,1H),7.24(d,J=8.8Hz,1H),4.31-4.27(m,1H),4.23-4.20(m,2H),3 .99-3.94(m,3H),3.83-3.78(m,1H),3.71-3.60(m,3H),3.47(dd,J=2.9,5.7Hz,1H),3.39(br s,1H),3.18-3.11(m,2H),2.74-2.67(m,1H),1.95-1.88(m,1H),1.82-1. 79(m,2H),1.73-1.69(m,1H),1.67-1.59(m,2H),1.24(d,J=6.5Hz,3H);MS m / z:543 [M+H] + .

[0585] Example 62: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-((tetrahydrofuran-2-yl)methyl)quinazoline-4(3H)-one [ka]

[0586] The compound of Example 62 (24.5 mg, 70%) was synthesized in the same manner as in Example 18, except that tetrahydrofurfuryl bromide was used instead of benzyl chloride in step 2 of Example 18, and 1.5 equivalents of potassium iodide were added. 1 H NMR(400 MHz,DMSO)δ 8.51(s,1H),8.33(d,J=1.2Hz,1H),8.29(s,1H),7.96(br s,2H),7.52(d,J=8.8Hz,1H),7.24(d,J=8.8Hz,1H),4.29-4.10(m,5H),3.91-3.88(m,1H),3.86-3.76(m,2H),3.71-3.69(m,1H),3.67 -3.61(m,2H),3.18-3.17(m,2H),1.99-1.95(m,1H),1.88-1.81(m,2H),1.77-1.71(m,3H),1.61-1.55(m,2H),1.22(d,J=6.6Hz,3H);MS m / z:543 [M+H] + .

[0587] Example 63: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(3-hydroxypropyl)quinazoline-4(3H)-one [ka]

[0588] The compound of Example 63 (29 mg, 81%) was synthesized in the same manner as in Example 18, except that 3-bromo-1-propanol was used instead of benzyl chloride in step 2 of Example 18, and 1 equivalent of potassium iodide was added. 1H NMR(400 MHz,DMSO)δ 8.51(s,1H),8.56(s,1H),8.32(d,J=1.2 Hz,1H),8.09(br s,3H),7.52(d,J=8.8 Hz,1H),7.23(d,J=8.8 Hz,1H),4.30-4.25(m,1H),4.23-4.19(m,2H),4.04-3.98(m,2H),3.92(d,J=9.2 Hz,1H),3.72-3.60(m,2H),3.45(t,J=6.0 Hz,2H),3.40-3.39(m,1H),3.19-3.12(m,2H),1.86-1.70(m,4H),1.61-1.59(m,1H),1.23(d,J=6.5 Hz,3H).

[0589] Example 64: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazoline-4(3H)-one [ka]

[0590] The compound of Example 64 (101 mg, 98%) was synthesized in the same manner as in Example 18, except that 2-bromoethyl methyl ether was used instead of benzyl chloride in step 2 of Example 18. 1 H NMR(400 MHz,DMSO)δ 8.51(s,1H),8.32(d,J=1.2 Hz,1H),8.29(s,1H),8.11(br s,3H),7.52(d,J=8.8 Hz,1H),7.24(d,J=8.8 Hz,1H),4.30-4.27(m,1H),4.23-4.19(m,2H),4.13(t,J=5.0 Hz,2H),3.92(d,J=9.0 Hz,1H),3.69(d,J=8.9 Hz,1H),3.60(t,J=5.1 Hz,2H),3.41-3.37(m,1H),3.25(s,3H),3.19-3.12(m,2H),1.83-1.70(m,3H),1.62-1.58(m,1H),1.23(d,J=6.5 Hz,3H).

[0591] Example 65: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-((tetrahydro-2H-pyran-4-yl)methyl)quinazoline-4(3H)-one [ka]

[0592] The compound of Example 65 (76 mg, 98%) was synthesized in the same manner as in Example 18, except that 4-(bromomethyl)tetrahydro-2H-pyran was used instead of benzyl chloride in step 2 of Example 18, and 1.5 equivalents of potassium iodide were added. 1 H NMR(400 MHz,DMSO)δ 8.51(s,1H),8.36(s,1H),8.32(s,1H),7.99(br s,2H),7.52(d,J=8.7Hz,1H),7.24(d,J=7.7Hz,1H),4.29-4.19(m,3H),3.92-3.90(m,1H),3.85-3.83(m,4H),3.71-3.69(m MS m / z:557 [M+H] + .

[0593] Example 66: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(3-hydroxybenzyl)quinazoline-4(3H)-one [ka]

[0594] The compound of Example 66 (48.8 mg, 81%) was synthesized in the same manner as in Example 18, except that 3-(bromomethyl)phenol was used instead of benzyl chloride in step 2 of Example 18, and 1.5 equivalents of potassium iodide were added. 1 H NMR(400 MHz,DMSO)δ 8.56(s,1H),8.51(s,1H),8.32(s,1H),8.11(br s,2H),7.55(d,J=8.1Hz,1H),7.25(dJ=7.6Hz,1H),7.16-7.13(m,1H),6.7 8-6.67(m,3H),5.08(s,2H),4.30-4.22(m,3H),3.93-3.91(m,2H),3.40(br MS m / z:565 [M+H] + .

[0595] Example 67: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(2-(dimethylamino)ethyl)quinazoline-4(3H)-one [ka]

[0596] The compound of Example 67 (6 mg, 85%) was synthesized in the same manner as in Example 18, except that 2-bromo-N,N-dimethylethylamine was used instead of benzyl chloride in step 2 of Example 18, and 1 equivalent of potassium iodide was added. 1H NMR(400 MHz,DMSO)δ 9.69(br s,1H),8.51(s,1H),8.40(s,1H),8.33(s,1H),8.07(br s,3H),7.54(d,J=9.2 Hz,1H),7.25(d,J=8.7 Hz,1H),4.32-4.19(m,5H),3.93-3.89(m,1H),3.71-3.68(m,1H),3.55-3.47(m,3H), 3.22-3.12(m,2H),2.88(s,6H),1.77-1.64(m,3H),1.62-1.59(m,1H),1.23(d,J=4.4 Hz,3H).

[0597] Example 68: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(3-(dimethylamino)propyl)quinazoline-4(3H)-one [ka]

[0598] The compound of Example 68 (28 mg, 88%) was synthesized in the same manner as in Example 18, except that 3-chloro-1-(N,N-dimethyl)propylamine was used instead of benzyl chloride in step 2 of Example 18, and 1 equivalent of potassium iodide was added. 1 H NMR(400 MHz,DMSO)δ 10.39(br s,1H),8.51(s,1H),8.45(s,1H),8.32(s,1H),8.24(br s,3H),7.54(d,J=8.8 Hz,1H),7.24(d,J=8.8 Hz,1H),4.31-4.28(m,1H),4.22-4.20(m,2H),4.03(t,J=5.9 Hz,2H),3.94(d,J=8.8 Hz,1H),3.69-3.67(m,2H),3.45-3.39(m,2H),3.14-3.12(m,2H),2.74(s,6H),2.13- 2.10(m,2H),1.85-1.80(m,2H),1.73-1.70(m,1H),1.63-1.60(m,1H),1.24(d,J=6.0 Hz,3H).

[0599] Example 69: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(2-fluoro-4-methylbenzyl)quinazoline-4(3H)-one [ka]

[0600] The compound of Example 69 (86 mg, 80%) was synthesized in the same manner as in Example 18, except that 2-fluoro-4-methylbenzyl bromide was used instead of benzyl chloride in step 2 of Example 18, and 1.5 equivalents of potassium iodide were added. 1 H NMR(400 MHz,DMSO)δ 8.50(d,J=9.5Hz,2H),8.31(s,1H),8.09(br s,2H),7.54(d,J=8.8Hz,1H),7.26-7.20(m,2H),7.05(d,J=11.6Hz,1H),6.84( d,J=7.8Hz,1H),5.14(s,2H),4.29-4.18(m,3H),3.92(d,J=9.1Hz,1H),3.70(br s,1H),3.39(br MS m / z:581 [M+H] + .

[0601] Example 70: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(2-fluoro-3-methoxybenzyl)quinazoline-4(3H)-one [ka]

[0602] The compound of Example 70 (31 mg, 67%) was synthesized in the same manner as in Example 18, except that 2-fluoro-3-methoxybenzyl bromide was used instead of benzyl chloride in step 2 of Example 18, and 1.5 equivalents of potassium iodide were added. 1 H NMR(400 MHz,DMSO)δ 8.51(d,J=11.2Hz,2H),8.31(s,1H),8.09(br s,2H),7.55(d,J=8.8Hz,1H),7.26(d,J=8.8Hz,1H),7.14-7.07(m,2H),6.83-6.80(m,1H),5. 19(s,2H),4.29-4.18(m,3H),3.92(d,J=9.1Hz,1H),3.83(s,3H),3.72-3.67(m,1H),3.40(br MS m / z:597 [M+H] + .

[0603] Example 71: 4-((6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-4-oxoquinazoline-3(4H)-yl)methyl)picolinonitrile [ka]

[0604] The compound of Example 71 (82 mg, 99%) was synthesized in the same manner as in Example 18, except that 4-(bromomethyl)picolinonitrile was used instead of benzyl chloride in step 2 of Example 18, and 1 equivalent of potassium iodide was added. 1H NMR(400 MHz,DMSO)δ 8.71(d,J=5.0 Hz,1H),8.54(s,1H),8.50(s,1H),8.31(s,1H),8.13-8.07(m,4H),7.70-7.68(m,1H),7.57(d,J=8.8 Hz,1H),7.28(d,J=8.8 Hz,1H),5.24(s,2H),4.29-4.18(m,3H),3.92(d,J=9.4 Hz,1H),3.69(d,J=8.9 Hz,1H),3.41-3.40(m,1H),3.20-3.12(m,2H),1.82-1.66(m,3H),1.62-1.58(m,1H),1.23(d,J=6.4 Hz,3H).

[0605] Example 72: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(2-fluoro-4-methoxybenzyl)quinazoline-4(3H)-one [ka]

[0606] The compound of Example 72 was synthesized in the same manner as in Example 18, except that 1-(bromomethyl)-2-fluoro-4-methoxybenzene was used instead of benzyl chloride in step 2 of Example 18. 1 H NMR(400 MHz,DMSO)δ 8.51(d,J=4.3 Hz,2H),8.31(s,1H),8.02(br s,3H),7.53(d,J=8.8 Hz,1H),7.13(t,J=8.8 Hz,1H),7.24(d,J=8.8 Hz,1H),6.85(d,J=12.4 Hz,2H),6.76(d,J=8.3 Hz,1H),5.10(s 2H),4.28-4.17(m,3H),3.91-3.89(m,1H),3.41-3.39(m,1H),3.19-3.11(m,2H),1.81-1.73(m,3H),1.60-1.55(m,1H),1.22(d,J=6.5 Hz,3H),1.04(s,3H).

[0607] Example 73: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(3-fluoro-4-methoxybenzyl)quinazoline-4(3H)-one [ka]

[0608] The compound of Example 73 (62 mg, 93%) was synthesized in the same manner as in Example 18, except that 4-(bromomethyl)-2-fluoro-1-methoxybenzene was used instead of benzyl chloride in step 2 of Example 18, and 1.5 equivalents of potassium iodide were added. 1 H NMR(400 MHz,DMSO)δ 8.60(s,1H),8.50(s,1H),8.31(d,J=1.1Hz,1H),8.14(br s,2H),7.53(d,J=8.8Hz,1H),7.32-7.29(m,1H),7.24(d,J=8.8Hz,1H),7.21-7.12(m,2H),5.0 7(s,2H),4.29-4.18(m,3H),3.93(d,J=9.0Hz,1H),3.81(s,3H),3.68(d,J=9.3Hz,1H),3.39(br MS m / z:597 [M+H] + .

[0609] Example 74: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-((1-methylpyrrolidine-2-yl)methyl)quinazoline-4(3H)-one [ka]

[0610] The compound of Example 74 was synthesized in the same manner as in Example 18, except that 2-(bromomethyl)-1-methylpyrrolidine hydrochloride was used instead of benzyl chloride in step 2 of Example 18. 1 H NMR(400 MHz,DMSO)δ 8.50(d,J=7.2 Hz 2H),8.32(s,1H),8.07(br s,3H),7.56(d,J=8.8 Hz,1H),7.25(d,J=8.8 Hz,1H),4.46-4.41(m,1H),4.30-4.19(m,4H),3.92-3.90(m,1H),3.70-3.68(m,3H),3.56(s,2H),3.21-3.08(m,5H),2.90(d,J=4.4 Hz,3H),2.22-2.18(m,1H),2.02-1.98(m,2H),1.84-1.70(m,3H),1.62-1.55(m,1H),1.22(d,J=6.2 Hz,3H).

[0611] Example 75: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(2,2,2trifluoroethyl)quinazoline-4(3H)-one [ka]

[0612] The compound of Example 75 was synthesized in the same manner as in Example 18, except that 2-bromo-1,1,1-trifluoroethane was used instead of benzyl chloride in step 2 of Example 18. MS m / z: 542 [M+H] + .

[0613] Example 76: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(3-fluoro-2-hydroxypropyl)quinazoline-4(3H)-one [ka]

[0614] The compound of Example 76 (60 mg, 87%) was synthesized in the same manner as in Example 18, except that 1-chloro-3-fluoroisopropanol was used instead of benzyl chloride in step 2 of Example 18, and 1 equivalent of potassium iodide was added. 1 H NMR(400 MHz,DMSO)δ 8.51(s,1H),8.32(s,1H),8.26(s,1H),8.15(br s,2H),7.53(d,J=8.8 Hz,1H),7.25(d,J=8.9 Hz,1H),4.53-4.45(m,1H),4.42-4.32(m,1H),4.30-4.27(m,1H),4.22-4.16(m,3H),4.08-4.02(m,2H),3.93(d,J=9.3 Hz,1H),3.80-3.75(m,1H),3.68(d,J=9.2 Hz,1H),3.40(br s,1H),3.16-3.14(m,2H),1.81-1.69(m,3H),1.62-1.59(m,1H),1.23(d,J=6.3 Hz,3H).

[0615] Example 77: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(3-fluoropropyl)quinazoline-4(3H)-one [ka]

[0616] The compound of Example 77 (77 mg, 99%) was synthesized in the same manner as in Example 18, except that 1-iodo-3-fluoropropane was used instead of benzyl chloride in step 2 of Example 18, and 1 equivalent of potassium iodide was added. 1H NMR(400 MHz,DMSO)δ 8.51(s,1H),8.41(s,1H),8.32(s,1H),8.15(br s,2H),7.53(d,J=9.2 Hz,1H),7.24(d,J=8.6 Hz,1H),4.60(t,J=5.2 Hz,1H),4.48(t,J=5.2 Hz,1H),4.30-4.27(m,1H),4.22-4.19(m,2H),4.08-4.05(m,2H),3.93(d,J=9.4 Hz,1H),3.68(d,J=9.5 Hz,1H),3.40(br s,1H),3.16-3.14(m,2H),2.14-2.03(m,2H),1.81-1.70(m,3H),1.62-1.59(m,1H),1.23(d,J=6.1 Hz,3H).

[0617] Example 78: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(morpholinomethyl)quinazoline-4(3H)-one [ka]

[0618] The compound of Example 78 (101.7 mg, 100%) was synthesized in the same manner as in Example 18, except that 4-(2-chloroethyl)morpholine was used instead of benzyl chloride in step 2 of Example 18, and 1.5 equivalents of potassium iodide were added. 1H NMR(400 MHz,DMSO)δ 10.69-10.65(m,1H),8.51(s,1H),8.43(s,1H),8.32(s,1H),8.14(br s,2H),7.55(d,J=9.5Hz,1H),7.25(d,J=8.7Hz,1H),4.36(br s,2H),4.04-3.99(m,2H),3.93(d,J=8.4Hz,1H),3.77-3.68(m,4H),3.59-3.55(m,4H),3.40(br MS m / z:558 [M+H] + .

[0619] Example 79: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)quinazoline-4(3H)-one [ka]

[0620] The compound of Example 79 (31 mg, 99%) was synthesized in the same manner as in Example 18, except that 4-(bromomethyl)-4-fluorooxane was used instead of benzyl chloride in step 2 of Example 18, and 1 equivalent of potassium iodide was added. 1H NMR(400 MHz,DMSO)δ 8.52(s,1H),8.32(d,J=1.2 Hz,1H),8.24(d,J=1.8 Hz,1H),8.12(br s,2H),7.53(d,J=8.8 Hz,1H),7.24(d,J=8.8 Hz,1H),4.27(s,2H),4.23-4.19(m,3H),3.92(d,J=9.0 Hz,1H),3.76-3.74(m,2H),3.69(d,J=9.1 Hz,1H),3.53-3.45(m,2H),3.40-3.37(m,1H),3.19-3.12(m,2H),1.91-1.55(m,8H),1.23(d,J=6.5 Hz,3H). Example 80: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-((3-fluorooxetan-3-yl)methyl)quinazoline-4(3H)-one [ka]

[0621] The compound of Example 80 (34 mg, 99%) was synthesized in the same manner as in Example 18, except that 3-(bromomethyl)-3-fluorooxetane was used instead of benzyl chloride in step 2 of Example 18, and 1 equivalent of potassium iodide was added. 1 H NMR(400 MHz,DMSO)δ 8.51(s,1H),8.32(d,J=1.2 Hz,1H),8.20(d,J=1.5 Hz,1H),8.07(br s,2H),7.53(d,J=8.8 Hz,1H),7.24(d,J=8.8 Hz,1H),4.30-4.27(m,1H),4.23-4.19(m,2H),3.94-3.93(m,2H),3.91-3.89(m,2H),3.70-3.63( m,4H),3.43-3.40(m,1H),3.20-3.12(m,2H),1.82-1.70(m,3H),1.61-1.58(m,1H),1.23(d,J=6.5 Hz,3H).

[0622] Example 81: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-yl)thio)-5-chloro-3-(2-hydroxy-2-methylpropyl)quinazoline-4(3H)-one [ka...

Claims

1. A compound of formula 1A-1, or its stereoisomer, solvate, or pharmaceutically acceptable salt, [Formula 1A-1] 【Chemistry 1】 During the ceremony, R １ However, H, halogen, hydroxy, cyano or C １ ~C ６ It is a haloalkyl, R ２ is selected from the group consisting of H, halogen, hydroxy, oxo, C １ to C ２０ alkyl, C １ to C ２０ alkoxy, C １ to C ２０ haloalkyl, hydroxy-(C １ to C ２０ alkyl)-, (C １ to C １０ alkoxy)-(C １ to C １０ alkyl)-, H ２ N-(C １ to C ２０ alkyl)-, -NH ２ -, -NH(C １ to C ２０ alkyl)-, -N(C １ to C ２０ alkyl) ２ , nitro, cyano, amidino, -C(O)NH ２ , -C(O)(C １ to C ２０ alkyl), -C(O)O(C １ to C ２０ alkyl) and carboxy or a salt thereof, R ３ and R ４ However, H and C are independent of each other. １ ~C ６ Alkyl, -NH ２ ,-NH(C １ ~C ６ Alkyl), -N(C １ ~C ６ Alkyl) ２ , or H ２ N-(C) １ ~C ６ Alkyl)- or R ３ and R ４ These are connected to each other to form ring B, Ring B may contain one oxygen atom and may be substituted; Ring B may be fused with a cycloalkyl, aryl, or heteroaryl ring; and the cycloalkyl, aryl, and heteroaryl rings fused with Ring B may be substituted. R ５ Each of them operates independently. (i) H, halogen, hydroxyl, -NH ２ , =NH, -C(O)NH ２ nitro, cyano, amidino, or carboxy, or their salts; (ii) Halogen, Hydroxyl, C １ ~C ２０ Alkyl, C １ ~C ２０ Haloalkyl, C １ ~C ２０ Alkoxy, C １ ~C ２０ Haloalkoxy, -NR'R'', R'C(O)-, R'S(O) ２ -, R'S(O) ２ C may be substituted with at least one substituent selected from the group consisting of NR''-, R''R'NC(O)-, and R'C(O)NR''-. １ ~C ２０ Alkyl or C １ ~C ２０ Alkoxy; (iii) C ６ to C ２０ aryl, (C ６ to C １２ aryl)-(C １ to C ８ alkyl)-, C ６ to C ２０ aryloxy, (C ６ to C １２ aryloxy)-(C １ to C ８ alkyl)-, C ６ to C ２０ arylcarbonyl, (C ６ to C １２ arylcarbonyl)-(C １ to C ８ alkyl)-, -CONH-(C ６ to C １２ aryl), -CONH-(C １ to C ８ alkyl)-(C ６ to C １２ aryl), -NHCO-(C ６ to C １２ aryl) or -NHCO-(C １ to C ８ alkyl)-(C ６ to C １２ aryl); (iv) heteroaryl, heteroaryl-(C １ ~C ８ alkyl)-, heteroaryloxy, heteroaryloxy-(C １ ~C ８ alkyl)-, heteroarylcarbonyl, heteroarylcarbonyl-(C １ ~C ８ alkyl)-, -CONH-heteroaryl, -CONH-(C １ ~C ８ alkyl)-heteroaryl, -NHCO-heteroaryl, or -NHCO-(C １ ~C ８ alkyl)-heteroaryl, wherein the heteroaryl ring is a 4- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S; (v) Heterocycloalkyl, Heterocycloalkyl-(C １ ~C ８ Alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C １ ~C ８ Alkyl)-, heterocycloalkylcarbonyl, heterocycloalkylcarbonyl-(C １ ~C ８ Alkyl)-, -CONH-heterocycloalkyl, -CONH-(C １ ~C ８ Alkyl)-heterocycloalkyl, -NHCO-heterocycloalkyl, or -NHCO-(C １ ~C ８ Alkyl)-heterocycloalkyl, where the heterocycloalkyl ring is a 3- to 10-membered fully saturated or partially unsaturated heterocycloalkyl containing at least one heteroatom selected from N, O, and S; or (vi) C ３ ~C １０ Cycloalkyl, (C ３ ~C １０ (Cycloalkyl)-(C １ ~C ８ Alkyl)-, C ３ ~C １０ Cycloalkyloxy, (C ３ ~C １０ (Cycloalkyloxy)-(C １ ~C ８ Alkyl)-, C ３ ~C １０ Cycloalkylcarbonyl, (C ３ ~C １０ (Cycloalkylcarbonyl)-(C １ ~C ８ Alkyl)-,-CONH-(C ３ ~C １０ Cycloalkyl), -CONH-(C １ ~C ８ (Alkyl)-(C ３ ~C １０ Cycloalkyl), -NHCO-(C ３ ~C １０ Cycloalkyl) or -NHCO-(C １ ~C ８ (Alkyl)-(C ３ ~C １０ Cycloalkyl) Selected from, The aryl rings, heteroaryl rings, heterocycloalkyl rings, and cycloalkyl rings described in (iii) to (vi) may each be substituted, R' and R'' are independently H or C １ ~C １０ It is alkyl, R ６ However, H or C １ ~C ６ It is alkyl, and p is an integer between 0 and 2. The compound of formula 1A-1, or its stereoisomer, solvate, or pharmaceutically acceptable salt.

2. R １ However, halogen or C １ ~C ３ It is a haloalkyl, R ２ However, H, halogen, hydroxy, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, hydroxy-(C) １ ~C ６ (Alkyl)-, (C １ ~C ６ Alkoxy)-(C １ ~C ６ Alkyl)-, H ２ N-(C) １ ~C ６ Alkyl)-,-NH ２ ,-NH(C １ ~C ６ Alkyl), -N(C １ ~C ６ Alkyl) ２ nitro, cyano, amidino, -C(O)NH ２ , -C(O)(C １ ~C ６ Alkyl), -C(O)O(C １ ~C ６ Selected from the group consisting of alkyl and carboxy or salts thereof, R ３ and R ４ However, H and C are independent of each other. １ ~C ６ Alkyl, -NH ２ ,-NH(C １ ~C ６ Alkyl), -N(C １ ~C ６ Alkyl) ２ , or H ２ N-(C) １ ~C ６ Alkyl)- or R ３ and R ４ However, they are connected to each other to form ring B, Ring B may contain one oxygen atom and at least one R Ｂ C may be replaced with ３ ~C ８ It is a cycloalkyl or a 3- to 8-membered heterocycloalkyl ring. Ring B is C ３ ~C ８ Cycloalkyl, C ６ ~C １０ It may optionally condense with a ring BB selected from 5- to 10-membered heteroaryls containing an aryl and one or two heteroatoms selected from N, O, and S, wherein the ring BB has at least one R ＢＢ It may also be replaced with R Ｂ However, deuterium, (C １ ~C ６ Alkyl), -NH ２ ,-NH(C １ ~C ６ Alkyl), -N(C １ ~C ６ Alkyl) ２ and H ２ N-(C) １ ~C ６ Selected from the group consisting of alkyl)-, R ＢＢ However, halogens, hydroxyl, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, hydroxy-(C) １ ~C ６ (Alkyl)-, (C １ ~C ６ Alkoxy)-(C １ ~C ６ Alkyl)-, H ２ N-(C) １ ~C ６ Alkyl)-,-NH ２ ,-NH(C １ ~C ６ Alkyl), -N(C １ ~C ６ Alkyl) ２ Selected from the group consisting of nitro, cyano, and amidino, R ５ However, each is independent of the others. (i) H, halogen, hydroxyl, -NH ２ , =NH, -C(O)NH ２ nitro, cyano, amidino, or carboxy, or their salts; (ii) Halogen, Hydroxyl, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, -NR'R'', R'C(O)-, R'S(O) ２ -, R'S(O) ２ C may be substituted with at least one substituent selected from the group consisting of NR''-, R''R'NC(O)-, and R'C(O)NR''-. １ ~C ６ Alkyl or C １ ~C ６ Alkoxy; (iii) C ６ ~C １０ Ariel, (C ６ ~C １０ Ariel) - (C １ ~C ５ Alkyl)-, C ６ ~C １０ Aryloxy, (C ６ ~C １０ (aryloxy)-(C) １ ~C ５ Alkyl)-, C ６ ~C １０ Arylcarbonyl, (C ６ ~C １０ (Arylcarbonyl)-(C １ ~C ５ Alkyl)-,-CONH-(C ６ ~C １０ Aryl), -CONH-(C １ ~C ５ (Alkyl)-(C ６ ~C １０ Aryl), -NHCO-(C ６ ~C １０ Aryl) or -NHCO- (C １ ~C ５ (Alkyl)-(C ６ ~C １０ The aryl ring is an aryl ring, and the aryl ring has at least one R ５ａ It may be replaced with; (iv) heteroaryl, heteroaryl-(C １ ~C ５ Alkyl)-, heteroaryloxy, heteroaryloxy-(C １ ~C ５ Alkyl)-, heteroarylcarbonyl, heteroarylcarbonyl-(C １ ~C ５ Alkyl)-, -CONH-heteroaryl, -CONH-(C １ ~C ５ Alkyl)-heteroaryl, -NHCO-heteroaryl, or -NHCO-(C １ ~C ５ It is an alkyl)-heteroaryl, wherein the heteroaryl ring is a 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, and at least 1 R ５ａ It may be replaced with; (v) Heterocycloalkyl, Heterocycloalkyl-(C １ ~C ５ Alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C １ ~C ５ Alkyl)-, heterocycloalkylcarbonyl, heterocycloalkylcarbonyl-(C １ ~C ５ Alkyl)-, -CONH-heterocycloalkyl, -CONH-(C １ ~C ５ Alkyl)-heterocycloalkyl, -NHCO-heterocycloalkyl, or -NHCO-(C １ ~C ５ It is an alkyl)-heterocycloalkyl, wherein the heterocycloalkyl ring is a 3- to 10-membered fully saturated or partially unsaturated heterocycloalkyl containing one or three heteroatoms selected from N, O, and S, and has at least one R ５ａ It may be replaced with; or (vi) C ３ ~C ８ Cycloalkyl, (C ３ ~C ８ (Cycloalkyl)-(C １ ~C ５ Alkyl)-, C ３ ~C ８ Cycloalkyloxy, (C ３ ~C ８ (Cycloalkyloxy)-(C １ ~C ５ Alkyl)-, C ３ ~C ８ Cycloalkylcarbonyl, (C ３ ~C ８ (Cycloalkylcarbonyl)-(C １ ~C ５ Alkyl)-,-CONH-(C ３ ~C ８ Cycloalkyl), -CONH-(C １ ~C ５ (Alkyl)-(C ３ ~C ８ Cycloalkyl), -NHCO-(C ３ ~C ８ Cycloalkyl) or -NHCO-(C １ ~C ５ (Alkyl)-(C ３ ~C ８ The cycloalkyl ring is a cycloalkyl ring, and the cycloalkyl ring has at least one R ５ａ It may be replaced with; Selected from, R' and R'' are independently H or C １ ~C ６ It is alkyl, R ５ａ However, halogen, hydroxy, -NH ２ ,-NH(C １ ~C ６ Alkyl), -N(C １ ~C ６ Alkyl) ２ cyano, oxo, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy; halogen, hydroxyl, C １ ~C ６ Alkoxy, -NH ２ or C substituted with cyano １ ~C ６ Alkyl; halogen, hydroxy, C １ ~C ６ Alkyl, -NH ２ or C substituted with cyano １ ~C ６ Alkoxy; and halogen-SO ２ -, (C １ ~C ６ Alkyl)-SO ２ -, -SO ２ NH ２ , -SO ２ NH(C) １ ~C ６ alkyl), and -SO ２ N(C) １ ~C ６ Alkyl) ２ Selected from the group consisting of, R ６ is H or C １ ~C ６ It is alkyl, p is an integer between 0 and 2. The compound described in claim 1, or its stereoisomer, solvate, or pharmaceutically acceptable salt.

3. R １ It is a halogen, R ２ However, H, halogen, hydroxy, oxo, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl, hydroxy-(C) １ ~C ３ (Alkyl)-, (C １ ~C ３ Alkoxy)-(C １ ~C ３ Alkyl)-, H ２ N-(C) １ ~C ３ Alkyl)-,-NH ２ ,-NH(C １ ~C ３ Alkyl), -N(C １ ~C ３ Alkyl) ２ nitro, cyano, -C(O)NH ２ , -C(O)(C １ ~C ３ Alkyl), -C(O)O(C １ ~C ３ Selected from the group consisting of alkyl and carboxy or salts thereof, R ３ and R ４ However, H and C are independent of each other. １ ~C ３ Alkyl, -NH ２ ,-NH(C １ ~C ３ Alkyl), -N(C １ ~C ３ Alkyl) ２ , or H ２ N-(C) １ ~C ３ Alkyl)- or R ３ and R ４ However, they are connected to each other to form ring B, Ring B is C ４ ~C ６ It may contain a cycloalkyl group or one oxygen atom, and at least one R group. Ｂ A 4-6 member heterocycloalkyl ring which may be substituted with, where R Ｂ is deuterium, (C １ ~C ３ Alkyl), -NH ２ ,-NH(C １ ~C ３ Alkyl), -N(C １ ~C ３ Alkyl) ２ and H ２ N-(C) １ ~C ３ Selected from the group consisting of alkyl)-, Ring B may be condensed with ring BB, and ring BB may be C ３ ~C ６ Cycloalkyl, C ６ ~C １０ Selected from aryls and 5- to 7-membered heteroaryls containing one or two heteroatoms selected from N, O, and S, the ring BB has at least one R ＢＢ It may also be replaced with R ＢＢ However, halogens, hydroxyl, oxo, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl, hydroxy-(C) １ ~C ３ (Alkyl)-, (C １ ~C ３ Alkoxy)-(C １ ~C ３ Alkyl)-, H ２ N-(C) １ ~C ３ Alkyl)-,-NH ２ ,-NH(C １ ~C ３ Alkyl), -N(C １ ~C ３ Alkyl) ２ Selected from the group consisting of nitro and cyano, R ５ However, each is independent of the following (i) to (vi) (i) H, halogen, hydroxyl, -NH ２ , -C(O)NH ２ nitro, cyano, or carboxy, or salts thereof; (ii) Halogen, Hydroxyl, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, -NR'R'', R'C(O)-, R'S(O) ２ -, R'S(O) ２ C may be substituted with at least one substituent selected from the group consisting of NR''-, R''R'NC(O)-, and R'C(O)NR''-. １ ~C ６ Alkyl or C １ ~C ６ Alkoxy; (iii) C ６ ~C １０ Ariel, (C ６ ~C １０ Ariel) - (C １ ~C ３ Alkyl)-, C ６ ~C １０ Aryloxy, (C ６ ~C １０ (aryloxy)-(C) １ ~C ３ Alkyl)-, C ６ ~C １０ Arylcarbonyl or (C ６ ~C １０ (Arylcarbonyl)-(C １ ~C ３ Alkyl)-, and the aryl ring is at least one R ５ａ It may be replaced with; (iv) heteroaryl, heteroaryl-(C １ ~C ３ Alkyl)-, heteroaryloxy, heteroaryloxy-(C １ ~C ３ Alkyl)-, heteroarylcarbonyl or heteroarylcarbonyl-(C １ ~C ３ The alkyl)-, and the heteroaryl ring is a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered bicyclic heteroaryl ring containing one or two heteroatoms selected from N, O, and S, and at least one R ５ａ It may be replaced with; (v) Heterocycloalkyl, Heterocycloalkyl-(C １ ~C ３ Alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C １ ~C ３ Alkyl)-, heterocycloalkylcarbonyl, or heterocycloalkylcarbonyl-(C １ ~C ３ The heterocycloalkyl ring is a 4- to 7-membered fully saturated or partially unsaturated heterocycloalkyl ring containing one or two heteroatoms selected from N, O, and S, and has at least one R ５ａ It may be replaced with, (vi) C ４ ~C ８ Cycloalkyl, (C ４ ~C ８ (Cycloalkyl)-(C １ ~C ３ Alkyl)-, C ４ ~C ８ Cycloalkyloxy, (C ４ ~C ８ (Cycloalkyloxy)-(C １ ~C ３ Alkyl)-, C ４ ~C ８ Cycloalkylcarbonyl, or (C ４ ~C ８ (Cycloalkylcarbonyl)-(C １ ~C ３ Alkyl)-, and the cycloalkyl ring has at least one R ５ａ It may be replaced with; Selected from, R' and R'' are independently H or C １ ~C ６ It is alkyl, R ５ａ However, halogens, hydroxyl, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, hydroxy-(C) １ ~C ６ (Alkyl)-, (C １ ~C ６ Alkoxy)-(C １ ~C ６ Alkyl)-,-NH ２ ,-NH(C １ ~C ６ Alkyl), -N(C １ ~C ６ Alkyl) ２ nitro, cyano, halogen-SO ２ -, (C １ ~C ６ Alkyl)-SO ２ - and -SO ２ NH ２ Selected from the group consisting of, R ６ However, H or C １ ~C ６ It is alkyl, p is an integer between 0 and 2. The compound described in claim 2, or its stereoisomer, solvate, or pharmaceutically acceptable salt.

4. R １ The compound according to claim 1, wherein is F or Cl, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

5. R ２ However, H, halogen, hydroxy, cyano, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, hydroxy-(C) １ ~C ６ Alkyl)-,-NH ２ , -C(O)NH ２ and -C(O)(C １ ~C ６ A compound according to claim 1, selected from the group consisting of alkyls, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

6. R ２ However, H, C １ ~C ３ Alkyl, hydroxy-(C) １ ~C ３ Alkyl)-,-NH ２ , -C(O)NH ２ and -C(O)(C １ ~C ３ A compound according to claim 3, selected from the group consisting of alkyl, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

7. R １ is F or Cl, and R ２ However, H, -CH ３ ien-CH ２ OH, -NH ２ , -C(O)NH ２ or -C(O)CH ３ The compound according to claim 1, or its stereoisomer, solvate, or pharmaceutically acceptable salt.

8. R ３ and R ４ One of them is C １ ~C ３ It is alkyl, and the other is -NH ２ or H ２ N-(C) １ ~C ３ Alkyl)- or R ３ and R ４ These elements are linked to each other to form ring B, where ring B is a cyclopentane ring or a tetrahydrofuran ring, and ring B is composed of deuterium, C １ ~C ３ Alkyl and -NH ２ At least one R selected from Ｂ It may also be replaced with Ring B is C ３ ~C ６ It may be condensed with a ring BB selected from a cycloalkyl ring, a benzene ring, a pyridine ring, or a thiazole ring. Ring BB is halogen, cyano, hydroxy, C １ ~C ３ Alkyl and C １ ~C ３ At least one R selected from the group consisting of alkoxys ＢＢ It may be replaced with The compound described in claim 1, or its stereoisomer, solvate, or pharmaceutically acceptable salt.

9. Equation 1A-1 【Chemistry 2】 However, the structure is as follows: 【Transformation 3】 and 【Chemistry 4】 Selected from, (In the formula, R ４１ C １ ~C ３ (It is an alkyl group, and q is an integer between 0 and 3.) In the formula, ring B in the above structure is deuterium, methyl and -NH ２ At least one R selected from Ｂ The ring BB may be substituted with at least one R selected from the group consisting of halogen, cyano, hydroxy, methyl and methoxy. ＢＢ It may be replaced with The compound described in claim 8, or its stereoisomer, solvate, or pharmaceutically acceptable salt.

10. Equation 1A-1 【Transformation 5】 However, the structure is as follows: 【Transformation 6】 and 【Transformation 7】 Selected from, (In the formula, R ４１ (where is methyl and q is 0 or 1) In the formula, ring B in the above structure is methyl and -NH ２ At least one R selected from Ｂ The ring BB may be substituted with at least one R selected from the group consisting of halogen, cyano, hydroxy, methyl and methoxy. ＢＢ It may be replaced with The compound described in claim 9, or its stereoisomer, solvate, or pharmaceutically acceptable salt.

11. Equation 1A-1 【Transformation 8】 However, the structure is as follows: 【Chemistry 9】 【change】 【Chemistry 10】 , and 【Chemistry 11】 A compound according to claim 9, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, selected from the above.

12. Equation 1A-1 【Chemistry 12】 However, the structure is as follows: 【Chemistry 13】 【Chemistry 14】 , and 【Chemistry 15】 A compound according to claim 11, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, selected from the above.

13. R ５ However, each is independent of the following (i) to (vi) (i) H, halogen, hydroxyl, -NH ２ , -C(O)NH ２ nitro, cyano, or carboxy, or salts thereof; (ii) Halogen, Hydroxyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, -NR'R'', R'C(O)-, R'S(O) ２ -, R'S(O) ２ C may be substituted with at least one substituent selected from the group consisting of NR''-, R''R'NC(O)-, and R'C(O)NR''-. １ ~C ６ Alkyl; C １ ~C ６ Alkoxy; or (C １ ~C ６ Alkoxy)-(C １ ~C ６ Alkoxy)-(wherein R' and R'' are independently H or C) １ ~C ３ (It is alkyl); (iii) Phenyl, Phenyl-(C １ ~C ３ Alkyl)-, phenyloxy, phenyloxy-(C １ ~C ３ Alkyl)-, phenylcarbonyl, or phenylcarbonyl-(C １ ~C ３ Alkyl)-, where the phenyl ring is at least one R ５ａ It may be replaced with; (iv) heteroaryl, heteroaryl-(C １ ~C ３ Alkyl)-, heteroaryloxy, heteroaryloxy-(C １ ~C ３ Alkyl)-, heteroarylcarbonyl or heteroarylcarbonyl-(C １ ~C ３ Alkyl)-, where the heteroaryl ring is selected from the group consisting of pyrrolyl, furanil, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, indolyl, benzofuranil, benzothiophenyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, and 1H-pyrrolo[2,3-b]pyridinyl, and at least one R ５ａ It may be replaced with; (v) Heterocycloalkyl, Heterocycloalkyl-(C １ ~C ３ Alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C １ ~C ３ Alkyl)-, heterocycloalkylcarbonyl, or heterocycloalkylcarbonyl-(C １ ~C ３ Alkyl)-, where the heterocycloalkyl ring is selected from the group consisting of oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, 4H-pyranyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl and 2-oxo-oxazolidinyl, and at least one R ５ａ It may be replaced with; or (vi) C ５ ~C ７ Cycloalkyl, (C ５ ~C ７ (Cycloalkyl)-(C １ ~C ３ Alkyl)-, C ５ ~C ７ Cycloalkyloxy, (C ５ ~C ７ (Cycloalkyloxy)-(C １ ~C ３ Alkyl)-, C ５ ~C ７ Cycloalkylcarbonyl, or (C ５ ~C ７ (Cycloalkylcarbonyl)-(C １ ~C ３ Alkyl)-, where the cycloalkyl ring has at least one R ５ａ It may be replaced with Selected from, R ５ａ However, halogens, hydroxyl, oxo, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl, hydroxy-(C) １ ~C ３ Alkyl)-,-NH ２ ,-NH(C １ ~C ３ Alkyl), -N(C １ ~C ３ Alkyl) ２ nitro, cyano, -SO ２ F and -SO ２ Selected from the group consisting of Cl, The compound described in claim 1, or its stereoisomer, solvate, or pharmaceutically acceptable salt.

14. The compound according to claim 13, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein the heteroaryl ring is selected from the group consisting of pyridinyl, pyrazolyl, isoxazolyl, furanyl, pyrimidinyl, thiazolyl, pyrazinyl, benzimidazolyl, benzoxazolyl, and 1H-pyrrolo[2,3-b]pyridinyl, and the heterocycloalkyl ring is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 3,6-dihydro-2H-pyranyl, morpholinyl, oxetanyl, piperidinyl, and 2-oxo-oxazolidinyl.

15. R ５ The group is selected from phenyl, benzyl, 1-phenylethyl, phenoxy, pyridinylmethyl, pyridinyloxy, pyridinylcarbonylmethyl, pyrazolylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, isoxazolylmethyl, tetrahydrofuranylmethyl, tetrahydrofuranyloxy, tetrahydropyranylmethyl, 3,6-dihydro-2H-pyranylmethyl, morpholinylmethyl, oxetanylmethyl, piperidinylcarbonylmethyl, 2-oxo-oxazolidinylethyl, 2-oxo-oxazolidinylmethyl, furanylmethyl, pyrimidinylmethyl, thiazolylmethyl, pyrazinylmethyl, benzimidazolylmethyl, benzoxazolylmethyl, 1H-pyrrolo[2,3-b]pyridinylmethyl, and cyclohexyl, where R ５ However, at least one F, Cl, OH, -CH ３ , -OCH ３ , cyano, oxo, -NH ２ NO ２ SO ２ F and CF ３ At least one R selected from the group consisting of ５ａ The compound according to claim 13, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, which may be substituted with.

16. R ５ but, H、CH ３ -、HOCH ２ CH ２ -、HOCH ２ CH ２ CH ２ -、CF ３ CH ２ -、CF ３ CH ２ CH ２ -、 【Chemistry 16】 FCH ２ CH ２ CH ２ - 【Chemistry 17】 [Chemistry 18] , and 【Chemistry 19】 Selected from, In the above structure, 【Chemistry 20】 This indicates the binding position with the remaining residues of the compound. The compound according to claim 13, or its stereoisomer, solvate, or pharmaceutically acceptable salt.

17. The aforementioned compound, 【Chemistry 21】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 , and 【Chemistry 22】 A compound according to claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, selected from the above.

18. A pharmaceutical composition for preventing or treating diseases associated with abnormal activity of Src homologous region 2-domain phosphatase-2 (SHP2), comprising a compound according to any one of claims 1 to 17, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition according to claim 18, wherein the disease associated with abnormal activity of SHP2 is selected from the group consisting of cancer, cancer metastasis, cardiovascular disease, immunodeficiency, fibrosis, and ocular disorders.

20. The pharmaceutical composition according to claim 18, 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, 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.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

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