SHP2 inhibitors and their uses

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, stereoisomers or solvates thereof, or pharmaceutically acceptable salts thereof as SHP2 inhibitors, and their use for the prevention or treatment of diseases associated with abnormal activity of SHP2.

[0002] This invention was supported by the National New Drug Development Project Support (HN22C0066) of the KOREA DRUG DEVELOPMENT FUND, 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 homology region 2 domain-containing phosphatase-2 (SHP2), also known as PTPN11 (protein tyrosine phosphatase non-receptor type 11), PTP-1D (protein-tyrosine phosphatase 1D), or PTP-2C (protein-tyrosine phosphatase 2C), is a protein tyrosine phosphatase (PTP). SHP2 is known as a signaling molecule that regulates various cellular functions, including cell growth, differentiation, cell cycle, and oncogenic transformation. Along with SHP1, SHP2 consists of two tandem SH2 domains at its N-terminus. In its inactive state, the N-terminal SH2 domain binds to the PTP domain, preventing substrate binding to the active site, thereby inhibiting SHP2. Upon binding of a phosphotyrosyl residue, the N-terminal SH2 domain is released from the PTP domain, activating the enzyme.

[0004] Mutations in SHP2 are known to cause Noonan syndrome and Leopard syndrome, and are known to be associated with cancers such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colorectal cancer, head cancer, 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 the same, pharmaceutical compositions containing the same, and methods for preventing or treating diseases associated with abnormal activity of SHP2 using the same.

[0006] [Detailed Description of the Invention] [Technical issues] Provided are novel compounds, stereoisomers or solvates thereof, or pharmaceutically acceptable salts thereof, which are capable of inhibiting the activity of SHP2.

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

[0008] The present invention provides a method for preventing or treating diseases associated with abnormal SHP2 activity, using a novel compound capable of inhibiting SHP2 activity, a stereoisomer or solvate thereof, or a pharmaceutically acceptable salt thereof.

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

[0010] Resolving the issue Each description and embodiment disclosed herein may be applied to other descriptions and embodiments. That is, all combinations of the various elements disclosed herein fall within the scope of this application. Furthermore, the scope of this application should not be construed as being limited by the specific descriptions set forth below.

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

[0012] [Formula 1A] [ka] The compound represented by formula 1A may have a structure in which the pyrazine ring is bonded to the fused ring of ring A and benzene ring via a sulfide group (-S-), and the pyrazine ring is bonded to the piperidine ring.

[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 C1-C substituted with alkyl, amine groups 20 Alkyl (e.g., H2N-(C1-C 20 alkyl)-), amine groups (e.g., -NH, -NH(C 20 alkyl), -N(C1-C 20alkyl), imine group (e.g., =NH), nitro, cyano, amidino, -C(O)NH, -C(O)(C1-C 20 alkyl), -C(O)O(C1-C 20 alkyl), and carboxy or a salt thereof.

[0015] In some embodiments, R 2 may be selected from the group consisting of 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 a salt thereof. In some embodiments, R 2 may be selected from the group consisting of 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 a salt thereof. In some embodiments, R 2 may be selected from the group consisting of H, halogen, hydroxy, 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 may be selected from the group consisting of H, C1-C3 alkyl, hydroxy-(C1-C3 alkyl)-, —NH2, —C(O)NH2, and —C(O)(C1-C3 alkyl).

[0016] In some embodiments, R 2can include H, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, amino, methylcarbonyl (acetyl), ethylcarbonyl (propanoyl), carbamoyl, etc. For example, R 2 can be H, —CH 3 , —CH 2 OH, —NH 2 , —C(O)NH 2 or —C(O)CH 3 .

[0017] In Formula 1A, p is an integer from 0 to 2. In some embodiments, when p is 2, two R 2 may be the same or different from each other.

[0018] In formula 1A, the position numbers of the atoms constituting the pyrazine ring are [ka] In this case, [ka] indicates the bonding position to the sulfur atom, and * indicates the bonding position to the nitrogen atom of the piperidine ring.

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

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

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

[0022] In some embodiments, R 3 and R 4 may each 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 R can be C1-C3 alkyl and the other can be -NH2 or H2N-(C1-C3 alkyl)-. 3 may be methyl or ethyl, R 4 can be amino, aminomethyl, or aminoethyl. For example, R 3 can be methyl, R 4 can be amino or aminomethyl.

[0023] In some embodiments, Ring B can be a C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl ring, optionally containing one oxygen atom. Ring B contains at least one R B In some embodiments, ring B optionally contains one oxygen atom and optionally at least one RB For example, ring B can be a cyclopentane ring or a tetrahydrofuran ring.

[0024] R B may be selected from the group consisting of deuterium, (C1-C6 alkyl), an amine group (e.g., —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2), and a C1-C6 alkyl substituted with an amine group (e.g., H2N—(C1-C6 alkyl)—). In some embodiments, R B may be selected from the group consisting of deuterium, (C1-C3 alkyl), -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, and H2N-(C1-C3 alkyl)-. In some embodiments, ring B contains at least one R selected from deuterium, C1-C3 alkyl, and -NH2. B For example, R B can be one or more selected from deuterium, methyl, and -NH2.

[0025] In some embodiments, Ring B is optionally C3-C8 cycloalkyl, C6-C 10 It may be fused with a ring BB selected from aryl and 5-10 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S. In this case, the ring BB may optionally be fused with at least one R BB In some embodiments, ring BB is optionally substituted with C-C cycloalkyl, C-C 10 It may be selected from aryl and 5- to 7-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S. For example, ring BB may be a C3-C6 cycloalkyl ring, a benzene ring, a pyridine ring or a thiazole ring.

[0026] In some embodiments, ring B is a cyclopentane ring and is optionally fused to ring B selected from a cyclopropane ring, a benzene ring, a pyridine ring, and a thiazole ring, hi some embodiments, ring B is a tetrahydrofuran ring and is optionally fused to ring B selected from a benzene ring and a pyridine ring.

[0027] R BB may be selected from the group consisting of 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, and amidino. BB may be selected from the group consisting of 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, and cyano. BB can be at least one selected from the group consisting of halogen, cyano, hydroxy, C1-C3 alkyl, and C1-C3 alkoxy. For example, R BB can be one or more selected from the group consisting of halogen, cyano, hydroxy, methyl and methoxy.

[0028] In some embodiments, the compound of formula 1A [ka] has the following structure: [ka] , and [ka] may be selected from:

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

[0030] Ring B in the above structure is at least one R selected from deuterium, methyl, and -NH B Additionally, ring BB may optionally be substituted with at least one R selected from the group consisting of halogen, cyano, hydroxy, methyl, and methoxy. BB is optionally replaced by

[0031] For example, in Equation 1A [ka] has the following structure: [ka] , and [ka] may be selected from:

[0032] (In the above structure, R 41 is methyl and q is 0 or 1) In this case, ring B contains at least one R selected from methyl and -NH B and ring BB is optionally substituted with at least one R selected from the group consisting of halogen, cyano, hydroxy, methyl, and methoxy. BB is optionally replaced by

[0033] In some embodiments, the compound of formula 1A [ka] has the following structure: [ka] [ka] , and [ka] may be selected from:

[0034] For example, in Equation 1A [ka] has the following structure: [ka] , and [ka] may be selected from:

[0035] Furthermore, in Equation 1A [ka] may include corresponding structures disclosed in WO 2019 / 183367, WO 2020 / 063760, WO 2020 / 201991, WO 2020 / 081848, WO 2020 / 073949, WO 2021 / 197452, WO 2021 / 147879, WO 2020 / 049079, WO 2021 / 218752, WO 2021 / 218755, WO 2022 / 017444, WO 2021 / 115286, WO 2021 / 088944, etc., or structures readily derived by those skilled in the art.

[0036] In Formula 1A, [ka] is the following fused ring structure: [ka] and [ka] is selected from.

[0037] In the above fused ring structure, [ka] is a single or double bond depending on the valences allowed by the ring elements (e.g., a nitrogen atom allows three bonds, a carbon atom allows four bonds).

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

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

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

[0041] In the above fused ring structure, U is N, NR 6 or CHR 6 and V may be CH, C(O), S, O, N, or NR 6and W may be N or C. In this case, when W is C, 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 fused ring structure, U is N or NR 6 and V can be CH, N, or NR 6 and W can be N or C. In this case, when W is C, one of U and V is N and the other is NR 6 Also, if W is N, then U is N and V is CH.

[0043] In some embodiments, in Formula 1A [ka] has the following structure: [ka] [ka] , and [ka] may be selected from:

[0044] In some embodiments, [ka] has the following structure: [ka] [ka] , and [ka] may be selected from:

[0045] R 5 are each independently H, a halogen atom, a hydroxy group, a ketone group, or a C1-C 20 Alkyl, C1-C 20 Alkoxy, C2-C 20 Alkoxyalkyl, amine group, C1-C substituted with amine group 20 Alkyl, imine group, nitro, cyano, amidino, carboxyl group or salts thereof, C1-C 20 Heteroalkyl, C3-C 20 Heterocycloalkyl, C6-C 20 Aryl, C6-C 20 Aryl alkyl, C1-C 20 Heteroaryl, C1-C 20 Heteroarylalkyl, C1-C 20 Heteroaryloxy, C1-C 20 Heteroaryloxyalkyl and C3-C 20 Heterocycloalkyl and polycyclic C5-C 12 Heteroarylalkyl may be selected from the group consisting of:

[0046] R 5may be H, a C1-C6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted thiazolyl alkyl group, a substituted or unsubstituted imidazolyl alkyl group, a substituted or unsubstituted pyrrolidinyl alkyl group, a substituted or unsubstituted pyridinyl alkyl group, a substituted or unsubstituted pyrimidinyl alkyl group, a substituted or unsubstituted pyrazinyl alkyl group, a substituted or unsubstituted benzimidazolyl alkyl group, or a substituted or unsubstituted pyrrolopyridinyl alkyl group. The phenyl group, benzyl group, thiazolyl alkyl group, imidazolyl alkyl group, pyrrolidinyl alkyl group, pyridinyl alkyl group, pyrimidinyl alkyl group, pyrazinyl alkyl group, benzimidazolyl alkyl group, or pyrrolopyridinyl alkyl group may be unsubstituted, and may be a halogen, a C1-C6 alkyl substituted with a halogen atom, -CN, -NH2, -NO2, -OR a , and -SO2R a The C1-C6 alkyl substituted with a halogen atom may be -CF3. a may be H, a halogen atom, or a C1-C6 alkyl substituted with a halogen atom. a may be -OCH3. -SO2R a may be -SO2F.

[0047] In one embodiment, in the above fused ring structure, R 5 are each independently selected from the following (i) to (vi): (i) H, halogen, hydroxy, an amine group (such as -NH2), an imine group (such as =NH), -C(O)NH2, nitro, cyano, amidino, or carboxy, or a salt thereof; (ii) Halogen, hydroxy, C1-C 20 Alkyl, C1-C 20 Haloalkyl, C1-C 20 Alkoxy, C1-C 20C1-C1 alkyl, optionally substituted with at least one substituent selected from the group consisting of haloalkoxy, amine (e.g., -NR'R"), carbonyl (e.g., R'C(O)-), sulfonyl (e.g., R'S(O)-), alkylsulfonylamine (e.g., R'S(O)NR"-), aminocarbonyl, or alkylaminocarbonyl (e.g., R"R'NC(O)-) and R'C(O)NR" 20 Alkyl or C1-C 20 Alkoxy; (iii) C6 to C 20 Aryl, (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 aryl), -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, wherein the heteroaryl ring can be a 4-10 membered heteroaryl containing at least one heteroatom selected from N, O, and S, or the heteroaryl ring is a C1-C8 alkyl. 20 may be a heteroaryl ring); (v) heterocycloalkyl, heterocycloalkyl-(C1-C8 alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C1-C8 alkyl)-, heterocycloalkylcarbonyl, heterocycloalkylcarbonyl-(C1-C8 alkyl)-, -CONH-heterocycloalkyl, -CONH-(C1-C8 alkyl)-heterocycloalkyl, -NHCO-heterocycloalkyl, or -NHCO-(C1-C8 alkyl)-heterocycloalkyl, wherein the heterocycloalkyl ring can be a 3- to 10-membered fully saturated or partially unsaturated heterocycloalkyl containing at least one heteroatom selected from N, O, and S, or the heterocycloalkyl ring can be a C3-C 20 may be heterocycloalkyl); and (vi) C3 to 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) may be selected from:

[0048] R' and R" are each independently H or C1-C 10 In some embodiments, R' and R" can each independently be H or C1-C6 alkyl. For example, R' and R" can each independently be H or C1-C3 alkyl. Also, R' and R" can each independently be H, methyl, or ethyl.

[0049] The aryl ring, heteroaryl ring, heterocycloalkyl ring, and cycloalkyl ring described in (iii) to (vi) above are each optionally substituted. In the above (iii) to (vi), the terms "aryl ring," "heteroaryl ring," "heterocycloalkyl ring," and "cycloalkyl ring" are used to collectively refer to the ring moiety in a substituent to which the ring is attached along with other chemical structures. For example, the term "aryl ring" is used to collectively refer to the aryl and aryl rings contained in arylalkyl, aryloxy, aryloxyalkyl, arylcarbonyl, arylcarbonylalkyl, -CONH-aryl, -CONH-alkyl-aryl, -NHCO-aryl, and -NHCO-alkyl-aryl.

[0050] In some embodiments, R 5 are each independently (i) H, halogen, hydroxy, -NH2, =NH, -C(O)NH2, nitro, cyano, amidino, or carboxy, or a salt thereof (e.g., H, halogen, hydroxy, -NH2, -C(O)NH2, nitro, cyano, or carboxy, or a salt thereof); (ii) C-C alkyl or C-C alkoxy optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, -NR'R", R'C(O)-, R'S(O)-, R'S(O)NR"-, R"R'NC(O)-, and R'C(O)NR"- (e.g., H, halogen, hydroxy, -NH, cyano, nitro, C-C alkyl, C-C alkoxy, (C-C alkoxy)-(C-C alkyl)-, or (C-C alkoxy)-(C-C alkoxy)-); (iii) C6 to C 10 Aryl, (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 aryl), -NHCO-(C6-C 10 aryl) or -NHCO-(C1-C5 alkyl)-(C6-C 10 aryl) (e.g., C6-C 10 Aryl, (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 arylcarbonyl)-(C1-C3 alkyl)-, and the aryl ring is 5a optionally replaced by ); (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 (e.g., heteroaryl, heteroaryl-(C1-C3 alkyl)-, heteroaryloxy, heteroaryloxy-(C1-C3 alkyl)-, heteroarylcarbonyl, or heteroarylcarbonyl-(C1-C3 alkyl)-, wherein the heteroaryl ring is a 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S; containing 1 or 2 heteroatoms selected from N, O, and S and at least one R 5a optionally substituted by, or a 5- or 6-membered monocyclic heteroaryl or a 9- or 10-membered bicyclic heteroaryl; (v) heterocycloalkyl, heterocycloalkyl-(C1-C5 alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C1-C5 alkyl)-, heterocycloalkylcarbonyl, heterocycloalkylcarbonyl-(C1-C5 alkyl)-, -CONH-heterocycloalkyl, -CONH-(C1-C5 alkyl)-heterocycloalkyl, -NHCO-heterocycloalkyl, or -NHCO-(C1-C5 alkyl)-heterocycloalkyl (e.g., heterocycloalkyl, heterocycloalkyl-(C1-C3 alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C1-C3 alkyl)-, heterocycloalkylcarbonyl, or heterocycloalkylcarbonyl-(C1-C3 alkyl)-, where 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, or containing one or two heteroatoms selected from N, O, and S, and at least one R 5a 4-7 membered fully saturated or partially unsaturated heterocycloalkyl optionally substituted with; 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 cyclo or —NHCO—(C1-C5 alkyl)-(C3-C8 cycloalkyl) (e.g., 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)-, wherein the cycloalkyl ring is substituted with at least one R 5a (possibly replaced by is selected from.

[0051] R' and R" are each independently H or C1-C 10 In some embodiments, R' and R" can each independently be H or C1-C6 alkyl. For example, R' and R" can each independently be H or C1-C3 alkyl. Also, R' and R" can each independently be H, methyl, or ethyl.

[0052] R 5a may be selected from the group consisting of halogen, hydroxy, -NH, -NH(C-C alkyl), -N(C-C alkyl), cyano, oxo, nitro, C-C alkyl, C-C alkoxy; C-C alkyl substituted with halogen, hydroxy, C-C alkoxy, -NH, or cyano; C-C alkoxy substituted with halogen, hydroxy, C-C alkyl, -NH, or cyano; and halogen -SO-, (C-C alkyl)-SO-, -SONH, -SONH(C-C alkyl), and -SON(C-C alkyl). In some embodiments, R 5a may be selected from the group consisting of 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 —SONH2.

[0053] In one embodiment, R 5 are each independently selected from the following (i) to (vi): (i) H, halogen, hydroxy, -NH2, -C(O)NH2, nitro, cyano, or carboxy, or a salt thereof; (ii) C1-C6 alkyl optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, 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"-; C1-C6 alkoxy; or (C1-C6 alkoxy)-(C1-C6 alkoxy)-, where R' and R" are each independently H or C1-C3 alkyl; (iii) phenyl, phenyl-(C1-C3 alkyl)-, phenyloxy, phenyloxy-(C1-C3 alkyl)-, phenylcarbonyl, or phenylcarbonyl-(C1-C3 alkyl)-, wherein the phenyl ring is 5a may be optionally substituted with ); (iv) selected from the group consisting of heteroaryl, heteroaryl-(C1-C3 alkyl)-, heteroaryloxy, heteroaryloxy-(C1-C3 alkyl)-, heteroarylcarbonyl, or heteroarylcarbonyl-(C1-C3 alkyl)-, wherein the heteroaryl ring is selected from the group consisting of pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, and 1H-pyrrolo[2,3-b]pyridinyl, and at least one R 5a may be optionally substituted with ); (v) heterocycloalkyl, heterocycloalkyl-(C1-C3 alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C1-C3 alkyl)-, heterocycloalkylcarbonyl, or heterocycloalkylcarbonyl-(C1-C3 alkyl)-, wherein the heterocycloalkyl ring is aziridinyl, oxiranyl, 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 5a Optionally substituted with ); 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)-, wherein the cycloalkyl ring is selected from the group consisting of at least one R 5a (which may be optionally replaced by may be selected from:

[0054] In this case, R 5a is selected from the group consisting of halogen, hydroxy, 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 in (iii) can be selected from the group consisting of pyridinyl, pyrazolyl, isoxazolyl, furanyl, pyrimidinyl, thiazolyl, pyrazinyl, benzimidazolyl, benzoxazolyl, and 1H-pyrrolo[2,3-b]pyridinyl.Further, the heterocycloalkyl ring in (iv) can 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 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; 5 is at least one R selected from the group consisting of at least one F, Cl, OH, —CH, —OCH, cyano, oxo, —NH, NO, SO, F, and CF; 5a is optionally replaced by

[0057] In some embodiments, R 5 has the following structure: H, CH3-, HOCH2CH2-, HOCH2CH2CH2-, CF3CH2-, CF3CH2CH2-, [ka] , FCH2CH2CH2-, [ka] [ka] , and [ka] may be selected from:

[0058] (In the above structure, [ka] represents the bond position to the remaining residue of the compound) In the above fused ring structure, R 6 is H or C1-C6 alkyl. In some embodiments, R 6 can be H or C1-C3 alkyl. In some embodiments, R 6 can be H or methyl.

[0059] In some embodiments, the compound represented by formula 1A can be a compound represented by formula 1A-1 below.

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

[0061] In some embodiments, the compound represented by formula 1A can be selected from the following: [ka] [ka] JPEG2024527535000047.jpg49149 [ka] JPEG2024527535000049.jpg53149 [ka] JPEG2024527535000051.jpg49149 [ka] [ka] [ka] [ka] JPEG2024527535000056.jpg61149 [ka] JPEG2024527535000058.jpg34149 [ka] [ka] , and [ka] In some embodiments, the compound represented by formula 1A can be a compound represented by any one of formulas 1A-2 to 1A-9 below.

[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 Formula 1A-2 to Formula 1A-9, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , ring B and p are defined as described above for formula 1A.

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

[0064] In the compound of formula 1A-4, 1A-5, 1A-8 or 1A-9, [ka] teeth [ka] and 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, one of U and V is N, and the other is NR 6 is.

[0066] In one embodiment, R of formula 1A-4, 1A-5, 1A-8, or 1A-9 5 are the following (i) to (vi) (i) H, halogen, hydroxy, -NH2, =NH, -C(O)NH2, nitro, cyano, amidino, or carboxy, or a salt thereof; (ii) C1-C6 alkyl optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6; 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)-, which may be methyl, ethyl, methoxy, ethoxy, methoxyethoxy, ethoxyethoxy, etc.); (iii) C6 to C 10 Aryl, (C6-C 10 aryl)-(C1-C3 alkyl)- or C6-C 10aryloxy (e.g., the aryl ring may be phenyl); (iv) heteroaryl, heteroaryl-(C1-C3 alkyl)-, or heteroaryloxy (e.g., the heteroaryl ring can be a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 N atoms, e.g., the heteroaryl ring can be pyrimidinyl or pyridinyl); (v) heterocycloalkyl, heterocycloalkyl-(C1-C3 alkyl)-, or heterocycloalkyloxy (e.g., heterocycloalkyl can be a 4-7 membered fully saturated or partially unsaturated heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O, e.g., the heterocycloalkyl ring can be tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, or morpholinyl); and (vi) C3-C8 cycloalkyl, C3-C8 cycloalkyl-(C1-C3 alkyl)- or C3-C8 cycloalkyloxy may be selected from:

[0067] The aryl ring, heteroaryl ring, heterocycloalkyl ring, and cycloalkyl ring described in (iii) to (vi) above are each optionally substituted, for example, with at least one substituent selected from halogen, hydroxy, oxo, —NH, cyano, nitro, C1-C6 alkyl, and C1-C6 alkoxy.

[0068] In one embodiment, R of formula 1A-4, 1A-5, 1A-8, or 1A-9 5 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 through 1A-9 can be selected from the following: [ka] [ka] , and [ka]

[0070] In some embodiments, the pyrazine core of the compound of 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 be represented by formula 1 below:

[0072] [Formula 1] [ka] In Formula 1, ring D is selected from the following structures: [ka] , and [ka] (* indicates the bond position to the sulfur atom) R 1 , R 2 , R 3 , R 4 , ring A, ring B, and p are as defined for formula 1A above.

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

[0074] In one aspect, there is provided a compound represented by Formula 2 below, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof:

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

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

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

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

[0079] In one embodiment, R 8 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 is H, halogen, hydroxy, oxo, C1-C 20 Alkyl, C1-C 20 Alkoxy, C2-C 20 Alkoxyalkyl, amine group, C1-C substituted with amine group 20 It may be selected from the group consisting of alkyl, imine group, nitro, cyano, amidino, and carboxyl group or salts thereof.

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

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

[0083] R 11 may be a methyl group.

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

[0085] Ring C may optionally be fused to an aryl or heteroaryl ring.

[0086] In one embodiment, R 10 and R 11 may be linked together to form ring C, which may be cyclopentane or tetrahydrofuran, and which is optionally substituted with C1-C6 alkyl or -NH2. Ring C may also be optionally fused with phenyl or pyridine.

[0087] In one embodiment, the compound of formula 2 [ka] can be selected from the following: [ka] and [ka] is.

[0088] In formula 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 formulae: [ka] [ka] and [ka]

[0090] In one aspect, there is provided a compound represented by Formula 3A, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof:

[0091] [Formula 3A] [ka] In formula 3A, J can be absent or can be S.

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

[0093] In Formula 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 Formula 3A, R 31 may be H, a halogen atom, or a C1-C6 alkyl substituted with a halogen atom. 31 may be H or a halogen atom.

[0095] In Formula 3A, R 32 is H, halogen atom, hydroxy group, ketone group, C1-C 20 Alkyl, C1-C 20 Alkoxy, C2-C 20 Alkoxyalkyl, amine group, C1-C substituted with amine group 20 Alkyl, imine group, nitro, cyano, amidino, carboxyl group or salts thereof, C1-C 20 Heteroalkyl, C6-C 20 Aryl, C6-C 20 Aryl alkyl, C6-C 20 Heteroaryl, C6-C 20Heteroarylalkyl, C6-C 20 Heteroaryloxy, C6-C 20 Heteroaryloxyalkyl and C6-C 20 R may be selected from the group consisting of heterocycloalkyl. 32 is H, a halogen atom, an amine group, -COOH or -COOR e R e may be H, a halogen atom, or a C1-C6 alkyl optionally substituted with a halogen atom.

[0096] In Formula 3A, R 31 and R 32 may each be a halogen.

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

[0098] In formula 3A, R 35 may represent two or more substituents. 35 may be the same or different from each other.

[0099] R 35 is H, halogen, hydroxy, 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 C-C 20 Aryl, substituted or unsubstituted C6-C 20 Aryl alkyl, substituted or unsubstituted C6-C 20Heteroaryl, substituted or unsubstituted C-C 20 Heteroarylalkyl, substituted or unsubstituted C6-C 20 Heteroaryloxy, substituted or unsubstituted C6-C 20 Heteroaryloxyalkyl and substituted or unsubstituted C6-C 20 R can be at least one selected from the group consisting of heterocycloalkyl. 35 - is H, halogen atom, C1-C 20 Alkyl, amine group, C1-C substituted with amine group 20 Alkyl, substituted or unsubstituted C6-C 20 Aryl, substituted or unsubstituted C6-C 20 Aryl alkyl, substituted or unsubstituted C6-C 20 Heteroaryl and substituted or unsubstituted C-C 20 For example, R 35 can be C1-C6 alkyl or NH2.

[0100] In one aspect, there is provided a compound represented by Formula 3B below, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof:

[0101] [Formula 3B] [ka] In formula 3B, J can be absent or can be S.

[0102] In Formula 3B, o can be an integer of 0, 1, 2, 3, 4, or 5. o can also be an integer of 0 or 1.

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

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

[0105] In formula 3B, R 35 may represent two or more substituents. 35 may be the same or different from each other.

[0106] R 35 is H, halogen atoms, hydroxyl groups, 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 C-C 20 Aryl, substituted or unsubstituted C6-C 20 Aryl alkyl, substituted or unsubstituted C6-C 20 Heteroaryl, substituted or unsubstituted C-C 20 Heteroarylalkyl, substituted or unsubstituted C6-C 20 Heteroaryloxy, substituted or unsubstituted C6-C 20 Heteroaryloxyalkyl and substituted or unsubstituted C6-C 20 R can be at least one selected from the group consisting of heterocycloalkyl. 35 - is H, halogen atom, C1-C 20 Alkyl, amine group, C1-C substituted with amine group 20 Alkyl, substituted or unsubstituted C6-C 20 Aryl, substituted or unsubstituted C6-C 20 Aryl alkyl, substituted or unsubstituted C6-C 20 Heteroaryl and substituted or unsubstituted C-C 20For example, R 35 can be C1-C6 alkyl or NH2.

[0107] In Equation 3B, [ka] teeth [ka] may be.

[0108] R 21 and R 22 are each independently H, a halogen atom, a hydroxyl group, a ketone group, or a C1-C 20 Alkyl, C1-C 20 Alkoxy, C2-C 20 Alkoxyalkyl, amine group, C1-C substituted with amine group 20 Alkyl, imine group, nitro group, cyano group, amidino group, carboxyl group or salts thereof, C1-C 20 Heteroalkyl, C6-C 20 Aryl, C6-C 20 Aryl alkyl, C6-C 20 Heteroaryl, C6-C 20 Heteroarylalkyl, C6-C 20 Heteroaryloxy, C6-C 20 Heteroaryloxyalkyl and C6-C 20 It may be selected from the group consisting of heterocycloalkyl.

[0109] R 21 and R 22 are each independently H, C1 to C 20 Alkyl, amine group, C1-C substituted with amine group 20 Alkyl, C6-C 20 Aryl, C6-C 20 Aryl alkyl, C6-C 20 Heteroaryl and C6-C 20Heteroarylalkyl may be selected from the group consisting of:

[0110] R 21 and R 22 may each independently be H or a phenyl group.

[0111] In one aspect, there is provided a compound represented by Formula 3C below, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof:

[0112] [Formula 3C] [ka] In formula 3C, J may be absent or may be S.

[0113] In formula 3C, G can be C or N.

[0114] In Formula 3C, L can be C, N, or O. When L is CH or NH, R 35 is optionally substituted at a carbon or nitrogen atom of L.

[0115] In Formula 3C, o can be an integer of 0, 1, 2, 3, 4, or 5. o can also be an integer of 0 or 1.

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

[0117] In Formula 3C, R 32 is H, halogen atom, hydroxy, ketone group, C1-C 20 Alkyl, C1-C 20 Alkoxy, C2-C 20 Alkoxyalkyl, amine group, C1-C substituted with amine group 20Alkyl, imine group, nitro group, cyano group, amidino group, carboxyl group or salts thereof, C1-C 20 Heteroalkyl, C6-C 20 Aryl, C6-C 20 Aryl alkyl, C6-C 20 Heteroaryl, C6-C 20 Heteroarylalkyl, C6-C 20 Heteroaryloxy, C6-C 20 Heteroaryloxyalkyl and C6-C 20 R may be selected from the group consisting of heterocycloalkyl. 32 is H, a halogen atom, an amine group, -COOH or -COOR f R f may be H, a halogen atom, or a C1-C6 alkyl optionally substituted with a halogen atom.

[0118] In Formula 3C, R 31 and R 32 may each be a halogen.

[0119] In Formula 3C, R 33 and R 34 may each independently be H, a C1-C6 alkyl, an amine group, or a C1-C6 alkyl substituted with an amine group. 33 and R 34 may each independently be H, methyl, an amine group, or a C1-C6 alkyl substituted with an amine group. For example, R 33 and R 34 are each 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 may each independently be C1-C3 alkyl or -NH2. In some embodiments, R 33 can be -NH2, and R 34 can be methyl.

[0120] In formula 3C, R 35 may represent two or more substituents. 35 may be the same or different from each other.

[0121] R 35 is H, halogen atom, hydroxy, 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 C-C 20 Aryl, substituted or unsubstituted C6-C 20 Aryl alkyl, substituted or unsubstituted C6-C 20 Heteroaryl, substituted or unsubstituted C-C 20 Heteroarylalkyl, substituted or unsubstituted C6-C 20 Heteroaryloxy, substituted or unsubstituted C6-C 20 Heteroaryloxyalkyl and substituted or unsubstituted C6-C 20 R can be at least one selected from the group consisting of heterocycloalkyl. 35 - is H, halogen atom, C1-C 20 Alkyl, amine group, C1-C substituted with amine group 20 Alkyl, substituted or unsubstituted C6-C 20 Aryl, substituted or unsubstituted C6-C 20 Aryl alkyl, substituted or unsubstituted C6-C 20 Heteroaryl and substituted or unsubstituted C-C 20 R may be at least one selected from the group consisting of heteroarylalkyl. 35 may represent two or more substituents. For example, R 35 is —NH, 5-10 membered heteroaryl (e.g., pyridinyl), and C-C 10 It may be a C1-C6 alkyl substituted with at least one substituent selected from the group consisting of aryl (eg, phenyl).

[0122] According to some embodiments, the compound of formula 3C [ka] may be selected from the following structures: [ka] and [ka]

[0123] In some embodiments, in Formulas 3A-3C, R 35 is H, halogen, hydroxy, 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), ═NH, nitro, cyano, amidino, carboxyl or its salts, heterocycloalkyl, C6-C 20 Aryl, (C6-C 12 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 halogen, hydroxy, -NH2, nitro or cyano.

[0124] In some embodiments, the compound represented by Formula 3A, 3B, or 3C has the following formula: [ka] [ka] [ka] , and [ka] The compound may be selected from compounds represented by:

[0125] As used herein, the term "halogen" or "halogen atom" refers to an atom belonging to Group 17 of the periodic table. Halogen atoms include F, Cl, Br, I, and the like.

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

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

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

[0129] The term "oxo" refers to =0, and "oxo-substituted" means that a carbon atom has an =0 substituent of the form -C(=O)-.

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

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

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

[0133] The term "alkoxyalkoxy" refers to an alkoxy bonded to an alkoxy. Alkoxyalkoxy can include, for example, methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, and the like.

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

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

[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 functional group --CN, 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 "carboxy" refers to -COOH. A salt of carboxy refers to the conjugate base of a carboxylic acid.

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

[0142] The terms "cycloalkyl," "cyclic ring," or "carbocycle" refer to a saturated or partially unsaturated non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon group. The cyclic group can contain 3 to 20 carbon atoms, e.g., 5 to 10, 3 to 8, or 3 to 6 carbon atoms. Monocyclic groups can be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl. Bicyclic groups can be, 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 groups can be, for example, adamantyl.

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

[0144] The term "arylalkyl" refers to an alkyl substituted with an aryl.

[0145] The term "aryloxy" refers to an aryl 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 can contain, for example, 1 to 5, 1 to 3, 1, or 2 heteroatoms, and can contain 5 to 10 ring members. A "heteroaryl" can be, for example, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, or benzisothiazolyl, and the like.

[0147] The term "heteroarylalkyl" refers to an alkyl substituted with a heteroaryl.

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

[0149] The term "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon containing at least one heteroatom. The heterocyclyl ring group may be a monocyclic group, a bicyclic group, or a tricyclic group. The two ring groups may be spirocyclic groups, bridged ring groups, and fused ring groups. The heterocyclyl ring group may contain 3 to 20, 3 to 10, 3 to 8, 3 to 7, 5 to 7, 4 to 6, or 5 to 6 ring atoms. The heteroatom may be any one or more, for example, 1, 2, or 3, selected from the group consisting of N, O, and S. For example, the heterocycloalkyl may be aziridinyl, oxiranyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, dihydropyranyl, morpholinyl, thiomorpholinyl, oxazolidinyl, or the like.

[0150] The term "heterocycloalkylalkyl" refers to an alkyl substituted with a heterocycloalkyl.

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

[0152] The heteroatoms may be any one or more selected from the group consisting of N, O, P, and S. The heteroatoms may be 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S.

[0153] The term "substituted" included in "substituted or unsubstituted" refers to the introduction of another atomic group by replacing one or more hydrogen atoms in an organic compound to form a derivative, and the term "substituent" refers to the introduced atomic group. The term "substituted" as used herein is not limited to a substituent, and includes, for example, a halogen atom, a C1-C substituted with a halogen atom, and the like. 20 Alkyl (e.g., CCF3, CHCF2, CH2F, CCl3, etc.), C1-C 20 Alkoxy, C2-C 20Alkoxyalkyl, hydroxy group, -NH2, =NH, nitro, cyano, amidino, hydrazine, hydrazone, carboxy or its salt, sulfonyl, sulfamoyl, sulfonic acid group or its salt, phosphoric acid or its salt, C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C6-C 20 Aryl, C6-C 20 Aryl alkyl, C6-C 20 Heteroaryl, C7-C 20 Heteroarylalkyl, C6-C 20 Heteroaryloxy, C6-C 20 Heteroaryloxyalkyl or C6-C 20 It may refer to substitution by heteroarylalkyl and the like.

[0154] The term "isomer" in the context of "stereoisomers" refers to compounds that have the same molecular formula but differ in the atomic connectivity or spatial arrangement of the constituent atoms within the molecule. Examples of isomers include structural isomers and stereoisomers. Stereoisomers can be diastereomers or enantiomers. Enantiomers refer to a pair of isomers that are non-superimposable mirror images, such as the relationship between left and right hands, and are also called optical isomers. Enantiomers are divided into R (rectus: clockwise) and S (sinister: counterclockwise) when four or more substituents at the chiral central carbon are different from each other. Diastereomers refer to non-mirror image stereoisomers and are isomers resulting from 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 solvated in an organic or inorganic solvent. An example of a solvate is a hydrate.

[0156] The term "salt" refers to inorganic and organic acid addition salts of a compound. Pharmaceutically acceptable salts may be salts that do not cause significant irritation to the organism to which the compound is administered and do not impair the biological activity and properties of the compound. Inorganic acid salts may be hydrochloride, bromate, phosphate, sulfate, or disulfate salts. Organic acid salts may be formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, disylate, trichloroacetate, trifluoroacetate, benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, embonate, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspartate. Metal salts may be calcium, sodium, magnesium, strontium, or potassium salts.

[0157] Any one or more compounds of Formulae 1, 1A, 1A-1 to 1A-9, 2, 3A, 3B, and 3C may be inhibitors of Src homology 2 domain-containing phosphatase-2 (SHP2). Src homology 2 domain-containing phosphatase-2 (SHP2) may be a protein belonging to the protein tyrosine phosphatase (PTP) family. SHP2 may also be called tyrosine-protein phosphatase non-receptor type 11 (PTPN11), protein-tyrosine phosphatase 1D (PTP-1D), or protein-tyrosine phosphatase 2C (PTP-2C). SHP2 may contain two tandem SH2 domains at the N-terminus, along with SPP1. SHP2 may be a protein comprising the amino acid sequence of Uniprot No. Q06124 in humans or the amino acid sequence of Uniprot No. P35235 in mice. SHP2 may be wild-type SHP2 or an SHP2 mutant. The inhibitor of SHP2 can be an inhibitor that inhibits the expression or activity of SHP2.

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

[0159] In another aspect, there is provided a pharmaceutical composition for preventing or treating a disease associated with abnormal activity of Src homology 2 domain-containing phosphatase-2 (SHP2), the pharmaceutical composition comprising a compound according to one aspect, a stereoisomer or solvate thereof, or a pharmaceutically acceptable salt thereof.

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

[0161] The disease associated with abnormal activity of SHP2 may be selected from the group consisting of cancer, cancer metastasis, cardiovascular disease, immune disorders, fibrosis, and eye disorders.

[0162] The cancer may be selected from the group consisting of ovarian cancer, cervical cancer, endometrial cancer, uterine sarcoma, vulvar cancer, breast cancer, skin cancer, head and neck cancer, pancreatic cancer, lung cancer, colon cancer, colorectal cancer, gastric cancer, prostate cancer, bladder cancer, urethral cancer, liver cancer, kidney cancer, skin cancer, brain and spinal cord tumors, 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 cancer, and sarcoma.

[0163] Cancer metastasis refers to the spread of a tumor from its primary site to another part of the body where the tumor takes hold and grows. Cancer metastasis can involve the spread of cancer cells into blood vessels, lymphatic vessels, or tissues.

[0164] Cardiovascular disease refers to a disease that occurs in the heart or major arteries (e.g., aorta, pulmonary artery, carotid artery, cerebrovascular, renal artery, arteries of the lower limbs). Cardiovascular disease may be selected from the group consisting of hypertension, ischemic heart disease, coronary artery disease, angina pectoris, myocardial infarction, atherosclerosis (arteriosclerosis), cerebrovascular disease, stroke, arrhythmia, acute heart failure, chronic heart failure, and hypotension.

[0165] The immune disorder refers to a state in which a normal immune response is not achieved, and may be selected from the group consisting of acquired immune deficiency, autoimmune disease, systemic lupus erythematosus, scleroderma, Sjogren's syndrome, polymyositis, dermatomyositis, polymyalgia rheumatica, temporal arteritis, polyarteritis nodosa, and Behcet's syndrome.

[0166] Fibrosis refers to a condition in which there is an excessive increase in fibrous tissue in a part of a tissue or organ, and the fibrosis may be selected from the group consisting of hepatic fibrosis, cystic fibrosis, myelofibrosis, endomyocardial fibrosis, and retroperitoneal fibrosis.

[0167] Ocular disorders refer to disorders that affect various structures of the eye. The ocular disorder may be selected from the group consisting of endophthalmitis, degenerative myopia, degenerative disorders of the eye, hypotony of the eye, intraocular foreign body, blood in the eye, and dislocation of the eye.

[0168] The disease associated with abnormal activity of SHP2 may be selected from the group consisting of Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia (JMML), neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colorectal cancer, head cancer, 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 action that inhibits or delays the occurrence of an SHP2-related disease upon administration of a pharmaceutical composition. The term "treatment" refers to any action that improves or beneficially alters the symptoms of an SHP2-related disease upon administration of a pharmaceutical composition.

[0170] The pharmaceutical composition may include a pharmaceutically acceptable carrier. The term "carrier" is used to include excipients, diluents, or adjuvants. For example, the carrier may be selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, saline, buffers such as PBS, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. The composition may include a filler, an anti-agglomerating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, or a combination thereof.

[0171] The pharmaceutical composition can be prepared in any formulation according to conventional methods. The composition can be formulated, for example, as an oral dosage form (e.g., powder, tablet, capsule, syrup, pill or granule) or a parenteral dosage form (e.g., injection). Furthermore, the composition can be prepared as a systemic or local formulation.

[0172] In the pharmaceutical composition, the solid formulation for oral administration may be a tablet, pill, powder, granule, or capsule. The solid formulation may further contain an excipient. The excipient may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. The solid formulation may also contain a lubricant such as magnesium stearate or talc. In the pharmaceutical composition, the liquid formulation for oral administration may be a suspension, oral solution, emulsion, or syrup. The liquid formulation may contain water or liquid paraffin. The liquid formulation may contain an excipient such as a wetting agent, a sweetener, a flavoring agent, or a preservative. In the pharmaceutical composition, the formulation for parenteral administration may be a sterile aqueous solution, a non-aqueous solution, a suspension, an emulsion, a lyophilized preparation, or a suppository. The non-aqueous solution or suspension may contain a vegetable oil or an ester. The vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil. The ester may be, for example, ethyl oleate. The suppository base can be witepsol, macrogol, tween 61, cocoa butter, laurin butter, or glycerogelatin.

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

[0174] The pharmaceutical composition may contain an effective amount of a compound according to one embodiment, its stereoisomer, solvate, or pharmaceutically acceptable salt. The term "effective amount" refers to an amount sufficient to prevent or treat a disease when administered to a subject in need thereof. The effective amount can be appropriately selected by one skilled in the art depending on the cell or subject selected. The preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the subject, the severity of the disease, the drug form, the route of administration, and the duration of administration, but can be appropriately selected by one skilled in the art. The effective amount may be about 0.5 μg to about 2 g, about 1 μg to about 1 g, about 10 μg to about 500 mg, about 100 μg to about 100 mg, or about 1 mg to about 50 mg per pharmaceutical composition. However, the compound, stereoisomer, solvate, or pharmaceutically acceptable salt thereof may be administered in an amount of, for example, about 0.0001 mg / kg to about 100 mg / kg, or about 0.001 mg / kg to about 100 mg / kg, which may be administered in divided doses of 1 to 24 times daily, 1 to 7 times every 2 days to a week, or 1 to 24 times every 1 to 12 months. In the pharmaceutical composition, the compound, stereoisomer, solvate, or pharmaceutically acceptable salt thereof may be contained in an amount of about 0.0001% to about 10% by weight, or about 0.001% to about 1% by weight, based on the total weight of the entire composition.

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

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

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

[0178] The subject can be a mammal, such as a human, mouse, rat, cow, horse, pig, dog, monkey, sheep, goat, ape, or cat. The subject can be one suffering from or likely to suffer from a condition associated with a disease associated with abnormal activity of SHP2.

[0179] The method may further include administering to the subject an active ingredient known to be effective in preventing or treating a disease associated with SHP2. The known active ingredient may be administered to the subject simultaneously, separately, or sequentially with the compound according to one embodiment, its stereoisomer, solvate, or pharmaceutically acceptable salt.

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

[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. For example, the dosage for an adult may be in the range of about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. Administration may be once daily, twice to 24 times daily, once to twice every three days, once to six times a week, once to 10 times every two weeks, once to 15 times every three weeks, once to three times every four weeks, or once to 12 times a year.

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

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

[0184] In another aspect, there is provided use of a compound according to one aspect, a stereoisomer or solvate thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the prevention or treatment of a disease associated with abnormal activity of SHP2.

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

[0186] [Effects of the invention]

[0187] SHP2-associated diseases can be effectively prevented or treated by an SHP2 inhibitor, a pharmaceutical composition containing the same for preventing or treating SHP2-associated diseases, a method for treating and preventing diseases using the same, and uses thereof.

[0188] [Detailed Description for Carrying Out the Invention] The present invention will be described in more detail below with reference to examples. However, the following examples are for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention.

[0189] Preparation Example 1: Synthesis of tert-butyl (1-(5-bromopyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate I-1) [ka]

[0190] In a round-bottom flask, EtN (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-methylpiperidin-4-yl)carbamate (1.98 g, 9.25 mmol) dissolved in DMF (dimethylformamide, 34 mL, 0.25 M), and the reaction mixture was stirred at 80 °C for 2 h. The reaction was quenched with HO and extracted with ethyl acetate (EA). The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (medium pressure liquid chromatography) (EA:hexane (Hx) = 1:9) and concentrated to give 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-bromopyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate I-2) [ka]

[0192] In a round-bottom flask, EtN (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-methylpiperidin-4-yl)methyl)carbamate (2 g, 8.76 mmol) dissolved in DMF (N,N-dimethylformamide, 32 mL, 0.25 M), and the reaction mixture was stirred at 90 °C for 2 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, concentrated, and separated by MPLC (EA:Hx = 1:1). The resulting compound was concentrated to give intermediate I-2 (2 g, 65%). 1 H 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-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-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]decan-4-yl)propane-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, which was then stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated to give 2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfanilamide.

[0195] Step 2: N-((3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfanilamide (Intermediate I-3) 2-Methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-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, which was then stirred at 100 °C for 3 h. The reaction was quenched with H2O, and the mixture was extracted with ethyl acetate (EA). The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was isolated by MPLC (EA:Hx = 1:1) and concentrated to give intermediate I-3 (2.4 g, 70%). 1H 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-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (Intermediate I-4) [ka]

[0197] tert-Butyl ((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-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, which was then stirred at 100 °C for 1 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was isolated by MPLC (EA:Hx = 1:1) and concentrated to give intermediate I-4 (265 mg, 84%). 1H 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), Pd(dba) (180 mg, 0.2 mmol), and Xantphos (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 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=1:20) and concentrated to give 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. A 1 M potassium tert-butoxide solution (1.5 mL, 1 M in THF) was slowly added dropwise to the reaction mixture, which was then stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was concentrated using a condenser. The resulting product was separated by MPLC (EA:Hx = 1:100) and concentrated to give 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), Pd(dba) (183 mg, 0.2 mmol), and Xantphos (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 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLCEA:Hx (EA 2%) and concentrated to give 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 then the temperature was lowered to 0 °C. Sodium ethoxide solution (21 wt % in ethanol) (517 μL, 1.32 mmol) was slowly added dropwise to the reaction mixture, which was then stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated and separated by MPLC (MC:MeOH=20:1). The resulting compound was concentrated to give 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), ethyl 3-mercaptopropionate (2.4 mL, 18.89 mmol), Pd(dba) (665 mg, 0.73 mmol), and Xantphos (840 mg, 1.45 mmol) dissolved in 1,4-dioxane (30 mL, 0.5 M). The reaction mixture was purged with nitrogen and then stirred at 100 °C for 12 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=1:5) and concentrated to give 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. A 1 M potassium tert-butoxide solution (19 mL, 1 M in THF) was slowly added dropwise to the reaction mixture, which was then stirred at room temperature for 4 h. The reaction was quenched with HO. The inorganic layer was adjusted to pH 4-5 with 1N HCl and then extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx = 1:10) and concentrated to give intermediate I-7 (2.1 g, 91%). 1 H 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-mercaptoquinazolin-4(3H)-one (Intermediate I-8) [ka]

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

[0209] Step 2: 5-Chloro-6-mercaptoquinazolin-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, which was then stirred at room temperature for 3 hours. After the reaction was completed, 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 give 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-methylquinazolin-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 then cooled to 0°C. NBS (N-bromosuccinimide, 4.6 g, 25.6 mmol) was added to the reaction mixture, which was then stirred at room temperature for 24 hours. After the reaction was completed, water was added, and the precipitated solid was collected by filtration. The resulting compound was dried to give 6-amino-3-bromo-2-chlorobenzoic acid (4.6 g, 79%).

[0212] Step 2: 6-Bromo-5-chloro-2-methylquinazolin-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 completion of the reaction, the reaction mixture was concentrated, and then NH solution (28% in HO) (4 mL, 0.25 M) was added and stirred at 100° C. for 12 hours. The solid that precipitated during the reaction was collected by filtration, washed with HO and MeOH, and dried to give 6-bromo-5-chloro-2-methylquinazolin-4(3H)-one (203 mg, 74%).

[0213] Step 3: Ethyl 3-((5-chloro-2-methyl-4-oxo-3,4-dihydroquinazolin-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-methylquinazolin-4(3H)-one (190 mg, 0.69 mmol), ethyl-3-mercaptopropionate (97 μL, 0.76 mmol), Pd(dba) (32 mg, 0.034 mmol), and Xantphos (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 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=9:1) and concentrated to give ethyl 3-((5-chloro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propionate (128 mg, 57%).

[0214] Step 4: 5-Chloro-6-mercapto-2-methylquinazolin-4(3H)-one (Intermediate I-9) In a round-bottom flask, ethyl 3-((5-chloro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propionate (123 mg, 0.38 mmol) was dissolved in THF (1.9 mL, 0.2 M), and then the temperature was lowered to 0° C. Potassium tert-butoxide solution (0.49 mL, 1 M in THF) was slowly added dropwise to the reaction mixture, followed by stirring for 1 hour. After the reaction was completed, the concentrated compound was filtered with 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-mercaptopyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate I-10) [ka]

[0216] Step 1: Methyl 3-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)propanate In a round-bottom flask, DIPEA (2.3 mL, 13.47 mmol) was added dropwise to a reaction mixture of tert-butyl (1-(5-bromopyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (2.5 g, 6.73 mmol), methyl-3-mercaptopropionate (0.82 mL, 7.41 mmol), Pd(dba) (308 mg, 0.337 mmol), and Xantphos (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 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=9:1) and concentrated to give methyl 3-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)propanate (2.7 g, 98%).

[0217] Step 2: tert-Butyl (1-(5-mercaptopyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate I-10) In a round-bottom flask, methyl 3-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)propanate (2.7 g, 6.58 mmol) was dissolved in THF (10 mL, 0.67 M), and then the temperature was lowered to 0° C. 1 M potassium tert-butoxide solution (5 mL, 1 M in THF) was slowly added dropwise to the reaction mixture, which was then stirred at room temperature for 30 minutes. After the reaction was completed, the reaction mixture was concentrated using a concentrator. The resulting product was separated by MPLC and concentrated to give 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, followed by extraction. The organic layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC and concentrated to give 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 Lawesson'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 further stirred at 110° C. for 18 hours. The organic layer was dried over MgSO4, filtered, and concentrated. After the reaction was completed, the reaction mixture was cooled to room temperature and extracted with water and EA. The organic layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC and concentrated to give 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 solid trimethyloxonium tetrafluoroborate (250 mg, 1.70 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 4 hours. Aqueous NaHCO3 solution was added to the mixture, followed by extraction. The organic layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC and concentrated to give 5-bromo-4-chloro-2-methyl-2H-indazole (300 mg, 79%).

[0223] Step 2: Methyl 3-((4-chloro-2-methyl-2H-indazol-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), Pd(dba) (112 mg, 0.122 mmol), and Xantphos (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 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=9:1) and concentrated to give methyl 3-((4-chloro-2-methyl-2H-indazol-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-indazol-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, which was then stirred at room temperature for 30 minutes. After the reaction was completed, the reaction mixture was concentrated using a concentrator. The resulting product was separated by MPLC and concentrated to give intermediate I-12 (100 mg, 47.8%). MS m / z: 199 [M+H] + .

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

[0226] Step 1: 6-Bromo-5-chloro-3-phenylquinazolin-4(3H)-one Aniline (0.18 mL, 1.92 mmol) and NH₄Cl (43 mg, 0.80 mmol) were added dropwise to 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) in a round-bottom flask, followed by stirring at 100°C for 16 hours. The reaction was quenched with H₂O, and the mixture was extracted with EA. The EA layer was dried over MgSO₄, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hex=1:3) and concentrated to give 6-bromo-5-chloro-3-phenylquinazolin-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-dihydroquinazolin-6-yl)thio)propanoate In a round-bottom flask, a reaction mixture of 6-bromo-5-chloro-3-phenylquinazolin-4(3H)-one (390 mg, 1.16 mmol) dissolved in dioxane was added with methyl 3-mercaptopropanoate (0.17 mL, 1.51 mmol), Pd2 (dba )3 (106 mg, 0.12 mmol), Xantphos (69 mg, 0.12 mmol), and DIPEA (0.40 mL, 2.32 mmol) were added dropwise, followed by stirring at 100° C. for 3 hours. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and then concentrated. The resulting product was separated by MPLC (EA:Hex=1:3) and concentrated to give methyl 3-((5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)thio)propanoate (116 mg, 27%). MS m / z: 375.10 [M+H] + .

[0228] Step 3: 5-Chloro-6-mercapto-3-phenylquinazolin-4(3H)-one (Intermediate I-13) To a reaction mixture of methyl 3-((5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)thio)propanoate (116 mg, 0.31 mmol) dissolved in THF in a round-bottom flask, KOT-bu (69 mg, 0.62 mmol) was added dropwise, and the reaction mixture was then stirred at -78 °C for 1 hour. The reaction was quenched with 1 M aqueous HCl, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hex=1:3) and concentrated to give 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-oxo-pyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate (Intermediate I-14) [ka]

[0230] Step 1: tert-butyl (1-(4-amino-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-4-methylpiperidin-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-methylpiperidin-4-yl)carbamate (758 mg, 3.54 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After LCMS confirmed that the reactants had completely disappeared, the reaction mixture was extracted with brine (20 mL) and EtOAc (20 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting product was separated by preparative HPLC (neutral) and concentrated to give tert-butyl (1-(4-amino-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-4-methylpiperidin-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-dihydropyridin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate I-14) tert-Butyl (1-(4-amino-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-4-methylpiperidin-4-yl)carbamate (260 mg, 950 μmol) was dissolved in ACN (3 mL, 0.25 M), and then NIS (N-iodosuccinimide, 214 mg, 950 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After a white precipitate was formed and LCMS confirmed that the reactant had completely disappeared, the reaction was quenched with aqueous 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 give 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, which was then stirred at room temperature for 2 hours. The reaction was quenched with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hex=1:3) and concentrated to give 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 stirred at 100° C. for 1 hour. After completion of the reaction, water was added to the mixture and extracted with DCM. The DCM layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by MPLC and concentrated to give intermediate I-15 (100 mg, 77%). MS m / z: 321 [M+H] + .

[0235] Preparation Example 16: Synthesis of tert-butyl ((3S,4S)-8-(5-mercaptopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (Intermediate I-16) [ka]

[0236] Intermediate I-16 was synthesized according to Preparation Example 10 using Intermediate I-4 as the starting material. 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), followed by the addition of NaH (34 mg, 0.86 mmol). Benzyl bromide (74 mg, 0.43 mmol) was added to the reaction mixture, which was then stirred at room temperature for 2 hours. The reaction was quenched with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The two isomers were then separated by MPLC (EA:Hex=1:3) and concentrated to give 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 1N NaOH solution (7.29 mL, 7.29 mmol) was added dropwise to methyl 3,4-dichloropicolinate (500 mg, 2.43 mmol) and stirred at 40°C for 1 hour. After the reaction was completed, 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-dichloropicolinamide 3,4-Dichloropicolinic acid (100 mg, 0.5 mmol) and phenylmethanamine (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). The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx = 1:2) and concentrated to give N-benzyl-3,4-dichloropicolinamide (92 mg, 66%). MS m / z: 281 [M+H] + .

[0241] Step 3: Ethyl 3-((2-(benzylcarbamoyl)-3-chloropyridin-4-yl)thio)propanoate N-Benzyl-3,4-dichloropicolinamide (92 mg, 0.33 mmol), ethyl-3-mercaptopropionate (63 μL, 0.495 mmol), Pd(dba) (18 mg, 0.02 mmol), and Xantphos (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 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=1:2) and concentrated to give ethyl 3-((2-(benzylcarbamoyl)-3-chloropyridin-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-chloropyridin-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, followed by stirring at room temperature for 1 hour. After completion of the reaction, 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 19: 3-chloro-4-mercapto-N-(pyridin-3-ylmethyl)picolinamide (Intermediate I-19) [ka]

[0244] Intermediate I-19 was obtained in the same manner as in Preparation Example 18, except that in Step 2 of Preparation Example 18, pyridin-3-ylmethanamine was used instead of phenylmethanamine. MS m / z: 280 [M+H] + .

[0245] Preparation 20: 2-Benzyl-8-chloro-7-mercapto-3,4-dihydroisoquinolin-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 min. 4-Nitrophenyl chloroformate (2015 mg, 10.0 mmol) was added to the reaction mixture, which was then stirred at 0 °C for 1 h. The reaction was quenched with HO, and the mixture was extracted with EA and subsequently washed with brine. The EA layer was dried over MgSO, filtered, and concentrated to give 4-nitrophenyl (4-bromophenethyl)carbamate (3630 mg, 99%).

[0247] Step 2: 7-Bromo-3,4-dihydroisoquinolin-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, which was then stirred at 0°C for 10 minutes. The reaction temperature was raised to 80°C and stirred for 3 hours. The reaction was then quenched with H2O and extracted with EA. The EA layer was washed with 1N aqueous sodium hydroxide solution and brine. The EA layer was dried over MgSO4, filtered, and concentrated. Crystallization from EA and Hx gave 7-bromo-3,4-dihydroisoquinolin-1(2H)-one (1150 mg, 51%).

[0248] Step 3: 2-benzyl-7-bromo-3,4-dihydroisoquinolin-1(2H)-one 7-Bromo-3,4-dihydroisoquinolin-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 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx = 1:10) and concentrated to give 2-benzyl-7-bromo-3,4-dihydroisoquinolin-1(2H)-one (110 mg, 80%).

[0249] Step 4: 2-benzyl-7-bromo-8-chloro-3,4-dihydroisoquinolin-1(2H)-one 2-Benzyl-7-bromo-3,4-dihydroisoquinolin-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 quenched with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx = 1:10) and concentrated to give 2-benzyl-7-bromo-8-chloro-3,4-dihydroisoquinolin-1(2H)-one (96 mg, 26%).

[0250] Step 5: Ethyl 3-((2-benzyl-8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)thio)propanoate 2-Benzyl-7-bromo-8-chloro-3,4-dihydroisoquinolin-1(2H)-one (96 mg, 0.27 mmol), ethyl 3-mercaptopropionate (0.05 mL, 0.41 mmol), Pd(dba) (25 mg, 0.03 mmol), Xantphos (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 h. The reaction was quenched with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=1:10) and concentrated to give ethyl 3-((2-benzyl-8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)thio)propanoate (100 mg, 91%).

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

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

[0253] Step 1: N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-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, which was then stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated to give N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide.

[0254] Step 2: N-((S)-1'-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide N-((S)-1,3-Dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-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, which was then stirred at 80 °C for 3 h. The reaction was quenched with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx = 1:3) and concentrated to give intermediate I-21 (150 mg, 26%).

[0255] Preparation 22: 6-Bromo-5-chloro-3H-quinazolin-4-one (Intermediate I-22) [ka]

[0256] Step 1: 6-Amino-3-bromo-2-chloro-benzoic acid To a solution of 2-amino-6-chloro-benzoic acid (10.0 g, 58.2 mmol) in DMF (100 mL) was added NBS (12.4 g, 69.9 mmol) in four portions at 0-10°C. The reaction mixture was stirred at 0-25°C for 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The organic layer was washed with brine (2 x 50 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 6-amino-3-bromo-2-chloro-benzoic 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 6-amino-3-bromo-2-chlorobenzoic acid (10.0 g, 27.9 mmol) in formamide (18.2 g, 405 mmol) was stirred at 140 °C for 5 h. The reaction mixture was diluted with NH Cl (20 mL) and filtered. The filter cake was dried under vacuum to give intermediate I-22 (4.00 g, 55% yield) 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 23: 3-Benzyl-6-((5-bromopyrazin-2-yl)thio)-5-chloroquinazolin-4(3H)-one (Intermediate I-23) [ka]

[0259] Step 1: 3-benzyl-6-bromo-5-chloro-quinazolin-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 EtOAc (10 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na2SO4, then filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 2:1) to give 3-benzyl-6-bromo-5-chloro-quinazolin-4-one (2.00 g, 46% yield) 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-dihydroquinazolin-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), Pd(dba) (41 mg, 457 μmol), Xantphos (529 mg, 915 μmol), and DIEA (1.77 g, 13.7 mmol) in dioxane (10 mL) was stirred at 110 °C for 16 h under N. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 3:1) to give 2-ethylhexyl 3-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate (2.00 g, 89% yield) as a yellow oil.

[0261] Step 3: Sodium 3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazoline-6-thiolate To a solution of 2-ethylhexyl 3-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate (500 mg, 1.03 mmol) in THF (5 mL) was added t-BuONa (147 mg, 1.54 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 hour. After completion of the reaction, PE was added to the reaction mixture, which was then filtered. The filter cake was dried under vacuum to give sodium 3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazolin-6-thiolate (230 mg, 68% yield) 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-bromopyrazin-2-yl)thio)-5-chloroquinazolin-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) was added sodium 3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazoline-6-thiolate (230 mg, 708 μmol) in DMF (10 mL) at 0 °C. The reaction mixture was stirred at 0–25 °C for 16 h. The reaction mixture was diluted with water (30 mL), and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, then filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE:EtOAc = 2:1) to give intermediate I-23 (110 mg, 33% yield) 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 24: (R)-2-methyl-N-[(1R)-spiro[indan-2,4'-piperidin]-1-yl]propane-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) (2.27 g, 9.95 mmol) in THF (5 mL) was stirred at 70 °C for 36 h. 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 EtOAc (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 3:1) to give tert-butyl 1-[(R)-tert-butylsulfinyl]iminospiro[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 tert-butyl 1-[(R)-tert-butylsulfinyl]iminospiro[indene-2,4'-piperidine]-1'-carboxylate (800 mg, 1.98 mmol) in THF (10 mL) was added LiBH (129 mg, 5.93 mmol) under N at −78°C. The reaction mixture was stirred at −78 to 25°C for 16 h. The reaction mixture was quenched at 0°C by the addition of NH Cl (10 mL) and then diluted with water (10 mL), and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na SO , filtered, and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: WelchUltimateXB-CN250*70*10 μm; mobile phase: [hexane-EtOH (0.1% NH₃·H₂O)]; B%: 1%-35%, 15 min) to give tert-butyl (1S)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indane-2,4′-piperidine]-1′-carboxylate (540 mg, 67%) and tert-butyl (1R)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indene-2,4′-piperidine]-1′-carboxylate (130 mg, 16%) as white solids, respectively. 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[indene-2,4'-piperidin]-1-yl]propane-2-sulfinamide A mixture of tert-butyl (1R)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indane-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 h. The reaction mixture was diluted with saturated aqueous NaHCO (10 mL), and the mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over NaSO, then filtered and concentrated in vacuo to give intermediate I-24 (90 mg, 91% yield) 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 25: (R)-2-methyl-N-[(5S)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4′-piperidin]-5-yl]propane-2-sulfinamide (Intermediate I-25) and (R)-2-methyl-N-[(5R)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4′-piperidin]-5-yl]propane-2-sulfinamide (Intermediate I-26) [ka]

[0268] Step 1: 3-Bromo-2-(bromomethyl)pyridine To a solution of 3-bromo-2-methyl-pyridine (20.0 g, 116 mmol) in CCl (200 mL), N-bromosuccinimide (NBS) (22.8 g, 128 mmol) and azobisisobutyronitrile (AIBN) (1.91 g, 11.6 mmol) were added and the mixture was stirred at 80 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by MPLC (PE / EA = 30:1) to give 3-bromo-2-(bromomethyl)pyridine (12.5 g, 42% yield) as a brown solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.60-8.53(m,1H),8.16-8.08(m,1H),7.38-7.26(m,1H),4.80-4.70(m,2H);MS(EI)m / z:251.8 [M+H] + .

[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) was added lithium diisopropylamide (LDA) (2 M, 23.9 mL), followed by stirring at −78° C. for 0.5 h. 3-Bromo-2-(bromomethyl)pyridine (10.0 g, 39.9 mmol) in THF (100 mL) was then slowly added to the reaction mixture, which was then stirred at −78° C. for 2.5 h. The reaction mixture was quenched at 0° C. by the addition of aqueous ammonium chloride solution (100 mL), diluted with water (100 mL), and extracted with EA (3×200 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash column chromatography (0.1% FA) to afford tert-butyl 4-[(3-bromo-2-pyridyl)methyl]-4-cyano-piperidine-1-carboxylate (13.5 g, 89% yield) as a brown solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.60-8.53(m,1H),8.14-8.07(m,1H),7.32-7.24(m,1H),4.01-3.90(m,2H),3.25(s ,2H),3.01-2.78(m,2H),2.12-2.03(m,2H),1.73-1.56(m,2H),1.44-1.35(m,9H);MS(EI)m / z:402.0 [M+23] + .

[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), 4-di-tert-butylphosphanyl-N,N-dimethyl-aniline; dichloropalladium (Pd(AmPhos)Cl) (1.10 g, 1.55 mmol), TEA (6.28 g, 62.1 mmol) in dimethylacetamide (DMA) (120 mL) and HO (12 mL) was degassed and then purged with N three times. The mixture was stirred at 130 °C under a N atmosphere for 12 h. The reaction mixture was quenched at 25 °C by the addition of aqueous ammonium chloride (50 mL), then diluted with water (50 mL), and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (PE / EA = 3:1) to give tert-butyl 5-oxospiro[7H-cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate (3.2 g, 68% yield) as a brown solid. 1 H NMR(400 MHz, CDCl3)δ=8.89-8.79(m,1H),8.09-8.00(m,1H),7.40-7.32(m,1H),4.22-4.05(m,2H) ,3.10(s,2H),3.12-3.02(m,2H),2.01-1.90(m,2H),1.51-1.44(m,11H);MS(EI)m / z:303.4 [M+H] + .

[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) was added Ti(OEt) (34.0 g, 149 mmol) and (R)-2-methylpropane-2-sulfinamide (4.81 g, 39.7 mmol). The mixture was stirred at 70 °C for 12 h. The reaction mixture was diluted with EA (300 mL), quenched with water (50 mL), filtered, and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash column chromatography (0.1% ammonium hydroxide) to afford tert-butyl (5Z)-5-[(R)-tert-butylsulfinyl]iminospiro[7H-cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate (3.35 g, 83% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)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) was added LiBH (537 mg, 24.7 mmol) and stirred at -70 °C for 2 h. The reaction mixture was quenched at 0 °C by the addition of aqueous ammonium chloride (20 mL), then diluted with water (30 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC column: Welch UltimateXB-CN250*50*10um, mobile phase: [hexane-EtOH (0.1%NH3·H2O)], B%: 10%-50%, 15 min to give 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, 31% yield): 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, 7% yield): 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'-piperidin]-5-yl]propane-2-sulfinamide and (R)-2-methyl-N-[(5R)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidin]-5-yl]propane-2-sulfinamide To a solution of tert-butyl (5S)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (200 mg, 491 μmol) in DCM (5 mL) was added TFA (1.68 g, 14.7 mmol) and stirred at 0 °C for 1 h. The reaction mixture was poured into aqueous KCO (20 mL) at 25 °C, then diluted with water (30 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate I-25 (140 mg, 92% yield) as a yellow solid. 1 H NMR(400 MHz, CDCl3)=8.49-8.42(m,1H),8.12-8.04(m,1H),7.25-7.19(m,1H),4.55-4.50(m,1H),3.38-3.32(m,2H),3. 26-3.06(m,1H),2.85-2.81(m,2H),2.30-2.14(m,2H),1.99-1.82(m,2H),1.37-1.31(m,11H);MS(EI)m / z:308.4 [M+H] + .

[0274] On the other hand, intermediate I-26 (100 mg, 90% yield) was obtained as a yellow solid in the same manner as in the preparation of intermediate I-25 using tert-butyl (5R)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate. 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 26: 6-((5-bromopyrazin-2-yl)thio)-5-chloro-3-((tetrahydrofuran-3-yl)methyl)quinazolin-4(3H)-one (Intermediate I-27) [ka]

[0276] Intermediate I-27 was obtained as a yellow solid in the same manner as in Preparation Example 23, except that 3-(bromomethyl)tetrahydrofuran was used instead of bromomethylbenzene in Step 1 of Preparation Example 23. 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 27: 5-chloro-6-((5-iodopyrazin-2-yl)thio)-3-(pyridin-3-ylmethyl)quinazolin-4(3H)-one (Intermediate I-28) [ka]

[0278] Step 1: 6-Amino-3-bromo-2-chloro-benzoic acid To a solution of 2-amino-6-chloro-benzoic acid (5 g, 29.1 mmol) in DMF (50 mL) was added NBS (5.71 g, 32.1 mmol) and stirred at 0° C. for 2 h. The reaction mixture was quenched with water (100 mL) and extracted with EA (100 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 6-amino-3-bromo-2-chloro-benzoic acid (7 g, 96% yield) 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-(pyridin-3-ylmethyl)quinazolin-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 stirred at 80 °C for 12 h. 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 × 3). The combined organic layer was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with MeOH (30 mL) to give 6-bromo-5-chloro-3-(pyridin-3-ylmethyl)quinazolin-4(3H)-one (1.5 g, 36% yield) 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] Step 3 to Step 5: 5-chloro-6-((5-iodopyrazin-2-yl)thio)-3-(pyridin-3-ylmethyl)quinazolin-4(3H)-one Using 5-chloro-6-((5-iodopyrazin-2-yl)thio)-3-(pyridin-3-ylmethyl)quinazolin-4(3H)-one as a starting material, and in a similar manner to steps 2-4 of Preparation 23, intermediate I-28 was obtained as a yellow solid. 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 28: 6-((5-bromopyrazin-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazolin-4(3H)-one (Intermediate I-29) [ka]

[0282] Step 1: 2-Ethylhexyl 3-((5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate To a solution of ethyl 3-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propionate (10 g, 25.2 mmol) in DMF (100 mL), 1-bromo-2-methoxyethane (4.2 g, 30.2 mmol), K2CO3 (6.96 g, 50.4 mmol), and TBAI (931 mg, 2.52 mmol) were added and stirred at 55 °C for 3 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). The combined organic layer was washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0.1% formic acid) to give 2-ethylhexyl 3-(5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate (6.8 g, 59% yield) as a yellow solid. 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] Step 2 and Step 3: 6-((5-bromopyrazin-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazolin-4(3H)-one Using 2-ethylhexyl 3-(5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate as a starting material, intermediate I-29 (1.4 g, 22%) was obtained as a yellow solid in a similar manner to steps 3 and 4 of Preparation 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 29: 3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-5-chloro-6-(5-iodopyrazin-2-yl)thio-quinazolin-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 in Step 1 of Preparation Example 28, (3-bromopropoxy)(tert-butyl)dimethylsilane was used instead of 1-bromo-2-methoxyethane. 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 30: 6-(5-bromopyrazin-2-yl)thio-5-chloro-3-(3-fluoropropyl)quinazolin-4(3H)-one (Intermediate I-31) [ka]

[0287] Intermediate I-31 (320 mg, 20%) was prepared in a similar manner to that of Preparation 28, except that in Step 1 of Preparation 28, 1-bromo-3-fluoropropane was used instead of 1-bromo-2-methoxyethane. 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 31: 6-(5-bromopyrazin-2-yl)thio-3-[3-[tert-butyl(dimethyl)silyloxybutyl]-5-chloro-quinazolin-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 stirred at 0 °C for 12 h. The reaction mixture was quenched with aqueous ammonium chloride (50 mL), diluted with water (50 mL), and then extracted with DCM (100 mL × 3). The combined organic layer was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 6-amino-3-bromo-2-chlorobenzoic acid (7 g, 96% yield) as a yellow solid. The residue was purified by column chromatography (PE / EA = 3 / 1) to give 3-hydroxybutyl-4-methylbenzenesulfonate (4.2 g, 77% yield). 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 solution of 3-hydroxybutyl-4-methylbenzenesulfonate (4.0 g, 16.4 mmol) in DCM (40 mL) were added imidazole (2.79 g, 40.9 mmol) and DMAP (200 mg, 1.64 mmol), and TBSCl (2.96 g, 19.7 mmol) was slowly added dropwise. The mixture was stirred at 0 °C for 12 h. The reaction mixture was quenched with aqueous ammonium chloride (50 mL), diluted with water (100 mL), and then extracted with DCM (100 mL × 3). The combined organic layer was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 give 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 to 5: 6-(5-bromopyrazin-2-yl)thio-3-[3-[tert-butyl(dimethyl)silyl]oxybutyl]-5-chloro-quinazolin-4(3H)-one Intermediate I-32 (320 mg, 19%) was prepared in the same manner as in Preparation Example 28 using 3-[tert-butyl(dimethyl)silyl]oxybutyl 4-methylbenzenesulfonate obtained in Step 2 above as a starting material. 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 32: Sodium 5-((3S,4S)-4-(tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazine-2-thiolate (Intermediate I-33) [ka]

[0293] Step 1: (3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine To a solution of (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (5.00 g, 20.6 mmol, 2HCl) in DMF (50 mL) were added TEA (6.24 g, 61.7 mmol) and 2,5-dibromopyrazine (4.89 g, 20.6 mmol) and stirred for 12 h at 25° C. The reaction mixture was quenched by the addition of aqueous ammonium chloride (100 mL) at 25° C., then diluted with water (100 mL) and extracted with EA (3×200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give (3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (6.7 g, crude) as a yellow oil, which was used directly in the next step. MS (EI) m / z: 329.1 [M+H] + .

[0294] Step 2: tert-butyl N-[(3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate To a solution of (3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (6.7 g, 20.5 mmol) in DMF (50 mL) were added BocO (6.70 g, 30.7 mmol) and TEA (3.11 g, 30.7 mmol) and stirred at 25 °C for 2 h. The reaction mixture was quenched by the addition of aqueous ammonium chloride solution (100 mL) at 25 °C, then diluted with water (100 mL) and extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA=5:1) to give tert-butyl N-[(3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (5.5 g, 63% yield) as a yellow solid. MS(EI) m / z: 429.1 [M+H] + .

[0295] Step 3: 2-Ethylhexyl 3-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)propanoate A mixture of tert-butyl N-[(3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (5.50 g, 12.9 mmol), 2-ethylhexyl 3-sulfanylpropanoate (4.22 g, 19.3 mmol), Pd(dba) (1.18 g, 1.29 mmol), Xantphos (1.49 g, 2.57 mmol), and DIEA (4.96 g, 38.6 mmol) in dioxane (80 mL) was degassed and purged with N three times, and then the mixture was stirred under N at 110 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA=3:1) to give 2-ethylhexyl 3-[5-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazin-2-yl]sulfanylpropanoate (5.00 g, 69% yield) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ=8.08(s,1H),8.06(s,1H),4.63(d,J=10.8 Hz,1H),4.23-4.13(m,1H),4.01(dd,J=5.8,2.6 Hz,2H),3.82-3.59(m,4H),3.57-3.46(m,1H),3.44-3.33(m,1H),3.28(t,J=7.2 Hz,2H),2.69(t,J=7.2 Hz,2H),1.92-1.71(m,4H),1.62-1.52(m,2H),1.45(s,9H),1.41-1.32(m,3H),1.30-1.27(m,6H),1.21(d,J=6.4 Hz,2H),0.93-0.86(m,6H);MS(EI)m / z:565.4 [M+H] + .

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

[0297] Preparation 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 To a solution of phenylmethanethiol (BnSH) (3.23 g, 26.0 mmol) in EtOH (50 mL) was added EtONa (1.95 g, 28.7 mmol). 1,2-Dichloro-3-nitro-benzene (5.0 g, 26.0 mmol) was then added and stirred at 80 °C for 1 h. The reaction mixture was quenched by adding aqueous ammonium chloride solution (20 mL) at 25 °C, then diluted with water (30 mL) and extracted with EA (3 × 50 mL). The combined organic layer was washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA = 10:1) to give benzyl (2-chloro-6-nitrophenyl) sulfane (5.7 g, 78% yield) 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 To a solution of 2-benzylsulfanyl-1-chloro-3-nitrobenzene (3.70 g, 13.2 mmol) in AcOH (40 mL) and HO (13 mL) was added NCS (7.06 g, 52.9 mmol). The mixture was stirred at 0 °C for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA = 5:1) to give 2-chloro-6-nitrobenzenesulfonyl chloride (2.70 g, 79% yield) 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 phenylmethanamine (BnNH) (1.76 g, 16.40 mmol) were added and stirred at 0 °C for 12 h. 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 layer was washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA = 5:1) to give N-benzyl-2-chloro-6-nitrobenzenesulfonamide (2.5 g, 70% yield) 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) was added Pt-V / C (239 mg, 1.22 mmol), and the mixture was stirred under H atmosphere (15 psi) at 25° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 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-chloro-benzenesulfonamide (2.00 g, 6.74 mmol) in DMF (20 mL) was added N-iodosuccinimide (NIS) (1.67 g, 7.41 mmol) and stirred at 80° C. for 2 hours. The reaction mixture was quenched by adding aqueous ammonium chloride solution (20 mL) at 25° C., then diluted with water (50 mL) and extracted with EA (3×50 mL). The combined organic layer was washed with brine (3×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA=3:1) to give 6-amino-N-benzyl-2-chloro-3-iodobenzenesulfonamide (2.4 g, 84% yield) 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 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), triethyl orthoformate was added and stirred at 150 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was triturated with MeOH (30 mL) to give intermediate I-34 (2.1 g, 89% yield) as an off-white solid.

[0304] Preparation 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) was added NBS (5.16 g, 29.0 mmol), 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 layers were washed with brine (3×100 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA=10 / 1) to give 4-bromo-3-chloro-2-nitroaniline (5.35 g, 73% yield) 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) was added Pt-V / C (983 mg, 151 μmol, purity 3%) and stirred under H atmosphere (15 psi) at 25° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give 4-bromo-3-chloro-benzene-1,2-diamine (3.1 g, 90% yield) 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-dihydrobenzimidazol-2-one To a solution of 4-bromo-3-chloro-benzene-1,2-diamine (470 mg, 2.12 mmol) in DMF (25 mL) was added 1,1'-carbodiimide (CDI) (413 mg, 2.55 mmol) and stirred at 25 °C for 2 hours. The reaction mixture was poured into water (40 mL), resulting in an off-white precipitate. The solid was collected, washed with EA (40 mL), and then dried under vacuum to give 5-bromo-4-chloro-1,3-dihydrobenzimidazol-2-one (370 mg, 71% yield) 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-dihydrobenzimidazol-2-one (350 mg, 1.41 mmol) in POCl (2 mL) was stirred at 100° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was quenched by adding aqueous NaHCO (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, then filtered and concentrated under reduced pressure to give 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 To a solution of 6-bromo-2,7-dichloro-1H-benzimidazole (290 mg, 1.09 mmol) in DMF (5 mL) was added NaH (48.0 mg, 1.20 mmol) and stirred at 0° C. for 0.5 h. Then, 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (273 mg, 1.64 mmol) in THF (5 mL) was slowly added to the mixture, which was then stirred at 0° C. for 1.5 h. 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 brine (3×20 mL), dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA=30 / 1) to give 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 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-benzimidazol-1-yl)methoxy]ethyl-trimethyl-silane To a mixture of tetrahydrofuran-3-ol (166 mg, 1.89 mmol) in THF (5 mL) was added NaH (75.5 mg, 1.89 mmol, 60% purity) at 0° C. The mixture was stirred under a nitrogen atmosphere at 0° C. for 0.5 h. 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 h. 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 in vacuo. The crude product was purified by reverse-phase flash column chromatography (0.1% FA condition) to give 2-[(6-bromo-7-chloro-2-tetrahydrofuran-3-yloxy-benzimidazol-1-yl)methoxy]ethyl-trimethyl-silane (230 mg, 41% yield) as a yellow oil. 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-benzimidazol-1-yl)methoxy]ethyl-trimethyl-silane (230 mg, 513 μmol) in DCM (2 mL) was added TFA (3.08 g, 27.0 mmol, 2 mL). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted with water (10 mL) and basified with saturated aqueous K2CO3 until 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 in vacuo to give 6-bromo-7-chloro-2-tetrahydrofuran-3-yloxy-1H-benzimidazole (160 mg, 98% yield) 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 To a mixture of 6-bromo-7-chloro-2-tetrahydrofuran-3-yloxy-1H-benzimidazole (160 mg, 503 μmol) and CsCO (492 mg, 1.51 mmol) in DMF (5 mL) was added MeI (107 mg, 755 μmol). The reaction mixture was stirred at 20 °C for 2 h, 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 in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18150 * 25 mm * 10 μm; mobile phase: [water (FA)-I]; B%: 44%-64%, 2 min) to give intermediates I-36 and I-37, respectively, as yellow solids. 6-Bromo-7-chloro-1-methyl-2-tetrahydrofuran-3-yloxy-benzimidazole (53 mg, 31% yield): 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, 24% yield): 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 36: tert-Butyl ((3S,4S)-8-(5-bromo-3-(hydroxymethyl)-6-methylpyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (Intermediate I-38) [ka]

[0315] Step 1: Ethyl 3-hydroxy-5-methyl-pyrazine-2-carboxylate To a stirred mixture of propane-1,2-diamine (25.5 g, 344 mmol) in EtOH (300 mL) was added diethyl 2-oxopropanedioate (59.9 g, 344 mmol) dropwise at 0° C., and the mixture was warmed to 25° C. After stirring the reaction mixture at 25° C. for 2 h, the reaction mixture was stirred at 95° C. for 18 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with EA (100 mL) to give ethyl 3-hydroxy-5-methyl-pyrazine-2-carboxylate (10 g, 16% yield) 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-methyl-pyrazine-2-carboxylate To a solution of ethyl 3-hydroxy-5-methyl-pyrazine-2-carboxylate (2.85 g, 15.6 mmol) in DMF (60 mL) was added NBS (2.92 g, 16.4 mmol) and stirred at 0 °C for 1 h. 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 × 3). The combined organic layer was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA = 10 / 1 to 5:1) to give ethyl 6-bromo-3-hydroxy-5-methyl-pyrazine-2-carboxylate (2.65 g, 65% yield) 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-methyl-pyrazine-2-carboxylate To PPh3 (3.01 g, 11.5 mmol) in dioxane (30 mL) was added NCS (1.56 g, 11.68 mmol), warmed to 25 °C, and stirred for 30 min. After that, ethyl 6-bromo-3-hydroxy-5-methyl-pyrazine-2-carboxylate (1 g, 3.83 mmol) was added in one portion, warmed to 100 °C, and stirred for 1 h. The reaction mixture was then cooled to room temperature, and triethyl acetonitrile (TEA) (3.88 g, 38.3 mmol) was added. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA = 15 / 1 to 10:1) to give ethyl 6-bromo-3-chloro-5-methyl-pyrazine-2-carboxylate (0.3 g, 28% yield) 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]decan-8-yl]-6-bromo-5-methyl-pyrazine-2-carboxylate To a solution of ethyl 6-bromo-3-chloro-5-methyl-pyrazine-2-carboxylate (0.3 g, 1.07 mmol) in DMA (4 mL), DIEA (694 mg, 5.37 mmol), (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (287 mg, 1.18 mmol, 2HCl) were added and stirred at 60° 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 (50 mL×3). The combined organic layer was washed with brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash column chromatography (0.1% FA) to give ethyl 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-bromo-5-methyl-pyrazine-2-carboxylate (350 mg, crude) as a yellow oil. 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]decan-8-yl]-5-methyl-pyrazine-2-carboxylate To a solution of ethyl 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-bromo-5-methyl-pyrazine-2-carboxylate (250 mg, 605 μmol) in DCM (10 mL) was added BocO (198 mg, 907 μmol) and TEA (184 mg, 1.81 mmol). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash column chromatography (0.1% FA) to give ethyl 6-bromo-3-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methyl-pyrazine-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-methyl-pyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate To a solution of ethyl 6-bromo-3-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methyl-pyrazine-2-carboxylate (150 mg, 292 μmol) in DCM (5 mL) was added diisobutylaluminum hydride (DIBAL-H) ​​(1 M in toluene, 1.17 mL) and stirred at −70° C. for 2 hours. The reaction mixture was quenched at −70° C. by the addition of 2 mL of MeOH and then diluted with DCM (50 mL). The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by pre-TLC (PE / EA=1:1) to give intermediate I-38 (120 mg, 87% yield) as a yellow solid. MS (EI) m / z: 471.3 [M+H] + .

[0321] Preparation 37: (R)—N-((S)-1′-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-5-yl)-2-methylpropane-2-sulfinamide (Intermediate I-39) [ka]

[0322] Step 1: 6-(5-bromopyrazin-2-yl)sulfanyl-5-chloro-3H-quinazolin-4-one To a solution of 5-chloro-6-mercaptoquinazolin-4(3H)-one (880 mg, 3.75 mmol) in DMF (20 mL) were added KCO (1.56 g, 11.3 mmol) and 2,5-dibromopyrazine (3.57 g, 15.00 mmol), and the mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by adding aqueous ammonium chloride solution (50 mL) at 25 °C, then diluted with water (50 mL), and extracted with EA (100 mL × 3). The combined organic layer was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA = 1 / 1 to 0:1) to obtain 6-(5-bromopyrazin-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-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-5-yl)-2-methylpropane-2-sulfinamide A mixture of 6-(5-bromopyrazin-2-yl)sulfanyl-5-chloro-3H-quinazolin-4-one (150 mg, 406 μmol), intermediate I-25 (150 mg, 487 μmol), [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 and purged with N2 three times, then the mixture was stirred at 100 °C under N2 atmosphere for 12 h. The reaction mixture was quenched at -70°C by the addition of MeOH (2 mL), diluted with DCM (50 mL), and then filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash column chromatography (0.1% FA) to give intermediate I-39 (80 mg, 33% yield) as a yellow solid. MS (EI) m / z: 596.1 [M+H] + .

[0324] Preparation 38: 3-Benzyl-7-bromo-8-chloro-quinazolin-4-one (Intermediate I-40) [ka]

[0325] Step 1: 2-amino-4-bromo-3-chloro-benzoate methyl To a solution of methyl 2-amino-4-bromobenzoate (20.0 g, 86.9 mmol) in DMF (200 mL) was added NCS (12.7 g, 95.6 mmol). The mixture was stirred at 100 °C for 4 hours. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 150 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give a 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 condition) to give methyl 2-amino-4-bromo-3-chlorobenzoate (4 g, 17% yield) 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-chloro-benzoic acid To a solution of methyl 2-amino-4-bromo-3-chlorobenzoate (2.00 g, 7.56 mmol) in THF (18 mL) and water (6 mL) was added NaOH (1.51 g, 37.8 mmol). The mixture was stirred at 40° C. for 12 hours. The residue was adjusted to pH 6 with 1 M HCl to give a white solid precipitate. The solid was collected and dried under vacuum to give 2-amino-4-bromo-3-chlorobenzoic acid (1.80 g, 95% yield) 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 h. The reaction mixture was filtered, and the filtrate was washed with EA (20 mL). The filter cake was dried under vacuum to give 7-bromo-8-chloro-3H-quinazolin-4-one (900 mg, crude) 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-chloro-quinazolin-4-one A mixture of 7-bromo-8-chloro-3H-quinazolin-4-one (300 mg, 1.16 mmol), benzyl bromide (395 mg, 2.31 mmol), and KCO (479 mg, 3.47 mmol) in acetonitrile (MeCN) (2 mL) was stirred at 80° C. for 24 h. The reaction mixture was filtered, and the filtrate was purified by reverse-phase flash column chromatography (0.1% FA) to give intermediate I-40 (60 mg, 14% yield) 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 39: 2-Benzyl-7-chloro-6-iodoisoindolin-1-one (Intermediate I-41) [ka]

[0330] Step 1: Methyl 2-chloro-6-methylbenzoate To a solution of 2-chloro-6-methyl-benzoic acid (10.0 g, 58.6 mmol) in DMF (100 mL) were added MeI (24.9 g, 175 mmol) and KCO (12.1 g, 87.9 mmol) and stirred at 25 °C for 12 h. 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, then filtered and concentrated under reduced pressure to give methyl 2-chloro-6-methyl-benzoate (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-chloro-benzoate To a solution of methyl 2-chloro-6-methylbenzoate (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 stirred at 80 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give methyl 2-(bromomethyl)-6-chlorobenzoate (10 g, crude product) as a yellow oil. MS (EI) m / z: 263.0 [M+H] + .

[0332] Step 3: 7-Chloroisoindolin-1-one To a solution of methyl 2-(bromomethyl)-6-chlorobenzoate (10.0 g, 38.0 mmol) in THF (50 mL) was added NH3·HO (53.2 g, 379 mmol, 30% purity), and the mixture was stirred at 25 °C for 2 h. 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 brine (3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA = 0 / 1) to give 7-chloroisoindolin-1-one (2.8 g, 44% yield) 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-iodo-isoindolin-1-one To a solution of 7-chloroisoindolin-1-one (12 g, 71.6 mmol) in HSO (120 mL) was added NIS (20.9 g, 93.0 mmol) and stirred at 0 °C for 2.5 h. The reaction mixture was poured into ice water, then diluted with water (200 mL), and extracted with EA (3 × 300 mL). The combined organic layer was washed with brine (3 × 150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA = 1:1) to give 7-chloro-6-iodo-isoindolin-1-one (3 g, 14% yield) 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-iodoisoindolin-1-one To a solution of 7-chloro-6-iodo-isoindolin-1-one (500 mg, 1.70 mmol), bromomethylbenzene (437 mg, 2.56 mmol) in DMF (10 mL) was added CsCO (1.11 g, 3.41 mmol) and stirred at 25 °C for 12 h. 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 brine (3 × 20 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18150*40mm*15um; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 10 min) to give intermediate I-41 (80 mg, 20% yield) 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 40: 6-(3-amino-5-chloro-pyrazin-2-yl)sulfanyl-5-chloro-3-(2-methoxyethyl)quinazolin-4-one (Intermediate I-42) [ka]

[0336] A mixture of [5-chloro-3-(2-methoxyethyl)-4-oxo-quinazolin-6-yl]sulfanyl chloride (630 mg, 2.15 mmol), 3-bromo-6-chloro-pyrazin-2-amine (538 mg, 2.58 mmol), Pd(dba) (197 mg, 215 μmol), Xantphos (249 mg, 431 μmol), and DIEA (835 mg, 6.46 mmol) in dioxane (20 mL) was degassed and purged with N three times, then stirred at 100 °C under N for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash column chromatography (0.1% FA) to give intermediate I-42 (120 mg, 14% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=8.08(s,1H),7.92(s,1H),7.57-7.53(m,1H),7.49-7.45(m,1H),5.16(br s,2H),4.16(t,J=4.8 Hz,2H),3.68(t,J=4.8 Hz,2H),3.33(s,3H);MS(EI)m / z:398.0 [M+H] + .

[0337] Preparation 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 quenched with H2O and extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx = 1:3) and concentrated to give intermediate I-43 (150 mg, 60% yield). MS (EI) m / z: 351.6 [M+H] + .

[0339] Preparation 42: (S)-2-methyl-N-[(1R)-spiro[indan-2,4'-piperidin]-1-yl]propane-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 tert-butyl 1-[(R)-tert-butylsulfinyl]iminospiro[indene-2,4'-piperidine]-1'-carboxylate (800 mg, 1.98 mmol) in THF (10 mL) was added LiBH (129 mg, 5.93 mmol) under N at −78°C. The reaction mixture was stirred at −78 to 25°C for 16 h. The reaction mixture was quenched at 0°C by the addition of NH Cl (10 mL), then diluted with water (10 mL), and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na SO , filtered, and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: WelchUltimateXB-CN250*70*10 μm; mobile phase: [hexane-EtOH (0.1% NH₃·H₂O)]; B%: 1%-35%, 15 min) to give tert-butyl (1S)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indane-2,4′-piperidine]-1′-carboxylate (540 mg, 67%) and tert-butyl (1R)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indene-2,4′-piperidine]-1′-carboxylate (130 mg, 16%) as white solids, respectively. 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[indene-2,4'-piperidin]-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 h. The reaction mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over NaSO, then filtered and concentrated in vacuo to give 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 43: 6-Bromo-7-chloro-2-(pyrazin-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-(pyrazin-2-yl)acetic acid was used instead of 2-(3-methoxyphenyl)acetic acid. MS (EI) m / z: 323.5 [M+H] + .

[0344] Preparation 44: 6-Bromo-7-chloro-2-(pyridin-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-(pyridin-3-yl)acetic acid was used instead of 2-(3-methoxyphenyl)acetic acid. MS (EI) m / z: 322.5 [M+H] + .

[0346] Preparation 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-chlorothiazol-4-carboxylate (30 g, 157 mmol) in EtOH (300 mL) was added NaBH (41.5 g, 1.10 mol) and stirred at 50 °C for 2 h. The reaction mixture was quenched with aqueous ammonium chloride (100 mL) at 0 °C, diluted with water (100 mL), and then extracted with EA (200 mL x 3). The combined organic layer was washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give (2-chlorothiazol-4-yl)methanol (22 g, 94% yield) as a colorless oil. 1 H NMR(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-chlorothiazol-4-yl)methyl methanesulfonate To a solution of ethyl 2-chlorothiazol-4-carboxylate (30 g, 157 mmol) in DCM (300 mL) was added TEA (27.1 g, 267 mmol) and MsCl (21.4 g, 187 mmol) at 0 °C and stirred at 0 °C for 0.5 h. The reaction mixture was quenched with aqueous NaHCO (100 mL) at 25 °C, diluted with water (100 ml), and then extracted with DCM (200 mL × 3). The combined organic layer was washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2-chlorothiazol-4-yl)methyl methanesulfonate (28 g, crude product) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ=7.29(s,1H),5.19(s,2H),3.01(s,3H)

[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 at −60° C. under nitrogen, and LDA (2 M, 81.6 mL) was added dropwise. The reaction mixture was stirred at −60° C. for 0.5 h, and (2-chlorothiazol-4-yl)methyl methanesulfonate (26.5 g, 117 mmol) in THF (15 mL) was added dropwise. The reaction mixture was stirred at −60° C. for 0.5 h, then slowly warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with aqueous ammonium chloride (100 mL), diluted with water (200 mL), and then extracted with EA (300 mL×3). The combined organic layer was washed with brine (150 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0.1% FA) to give O1-tert-butyl O4-ethyl 4-[(2-chlorothiazol-4-yl)methyl]piperidine-1,4-dicarboxylate (14 g, 31% yield) as a yellow oil. 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 h. The reaction mixture was quenched with aqueous ammonium chloride solution (100 mL) at 0 °C, diluted with water (100 ml), and then extracted with EA (200 mL × 3). The combined organic layer was washed with brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate I-47 (6.1 g, 50% yield) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ=4.16(br s,2H),3.09-3.02(s,2H),3.01-2.90(m,2H),2.02-1.92(m,2H),1.52-1.48(m,11H).

[0351] Preparation 46: (R)-2-Methyl-N-[(6S)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidin]-6-yl]propane-2-sulfinamide (Intermediate I-48) [ka]

[0352] Step 1: tert-Butyl (6Z)-6-[(R)-tert-butylsulfinyl]imino-2-chloro-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of 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) (29.9 g, 131 mmol) was added dropwise, and the reaction mixture was stirred at 90 °C for 12 h. EA (300 mL) was added to the reaction mixture, diluted with water (50 mL), and then extracted with EA (100 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl (6Z)-6-[(R)-tert-butylsulfinyl]imino-2-chloro-spiro[4H-cyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylate (3.5 g, 90% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ=4.28-4.14(m,2H),2.96-2.84(m,4H),2.05-1.91(m,2H),1.61-1.55(m,2H),1.49(s,9H),1.28(s,9H);MS(EI)m / z:446.0 [M+H] + .

[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-chloro-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (3.5 g, 7.85 mmol) in THF (30 mL) was added BH3.THF (1 M, 31.4 mL), and the reaction mixture was stirred at -70 °C for 2 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). The combined organic layer was washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl (6S)-6-[[(R)-tert-butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylate (660 mg, 20%) 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'-piperidin]-6-yl]propane-2-sulfinamide To a solution of tert-butyl (6S)-6-[[(R)-tert-butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (200 mg, 484 μmol) in DCM (6 mL) was added TFA (2.76 g, 24.2 mmol), and the reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched with saturated aqueous KCO solution (20 mL) at 25 °C, diluted with water (30 ml), and then extracted with DCM (50 mL × 3). The combined organic layer was washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate I-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 47: (S)-2-Methyl-N-[(6R)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidin]-6-yl]propane-2-sulfinamide (Intermediate I-49) [ka]

[0356] Step 1: tert-butyl (6Z)-6-[(S)-tert-butylsulfinyl]imino-2-chloro-spiro[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) were added Ti(OEt) (29.9 g, 131 mmol) and (S)-2-methylpropane-2-sulfinamide (4.24 g, 35.0 mmol), and the reaction mixture was stirred at 90 °C for 12 h. 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, washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl (6Z)-6-[(S)-tert-butylsulfinyl]imino-2-chloro-spiro[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-chloro-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate To a solution of tert-butyl (6Z)-6-[(S)-tert-butylsulfinyl]imino-2-chloro-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (2.0 g, 4.48 mmol) in DCM (20 mL) was added DIBAL-H (1 M, 13.4 mL), and the reaction mixture was stirred at −60° C. for 1 h. 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 give tert-butyl (6R)-6-[[(S)-tert-butylsulfinyl]amino]-2-chloro-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (1.6 g, 78% yield) 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 tert-butyl (6R)-6-[[(S)-tert-butylsulfinyl]amino]-2-chloro-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (1.0 g, 2.23 mmol) in methanol (10 mL) was added TEA (677 mg, 6.70 mmol), followed by purging with N three times. Pd / C (100 mg, 10% purity) was added to the reaction mixture, and H gas was injected. The reaction mixture was stirred at 40 °C for 16 h. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give tert-butyl (6R)-6-[[(S)-tert-butylsulfanyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylate (880 mg, 93% yield) 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'-piperidin]-6-yl]propane-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) was added TFA (3 mL) and stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure and adjusted to pH 9 with saturated K2CO3 solution. It was then extracted 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 give intermediate I-49 (310 mg, crude product) as a pale yellow oil. MS (EI) m / z: 314.2 [M+H] + .

[0360] Preparation 48: 6-(5-bromopyrazin-2-yl)sulfanyl-5-chloro-3H-quinazolin-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) were added KCO (1.56 g, 11.3 mmol) and 2,5-dibromopyrazine (3.57 g, 15.00 mmol), and the mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by adding aqueous ammonium chloride solution (50 mL) at 25 °C, diluted with water (50 mL), and extracted with EA (100 mL × 3). The combined organic layer was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE / EA = 1 / 1 to 0:1) to give intermediate I-50 (500 mg, 36% yield) 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 49: (S)—N—[(6R)-1′-[5-[(5-chloro-4-oxo-3H-quinazolin-6-yl)sulfanyl]pyrazin-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-G (76.8 mg, 98.9 μmol), and KCO (410 mg, 2.97 mmol) were added, and the mixture was stirred at 100° C. for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give intermediate I-51 (180 mg, 28% yield) 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 50: (R)—N-[(6S)-1′-[5-[(5-chloro-4-oxo-3H-quinazolin-6-yl)sulfanyl]pyrazin-2-yl]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4′-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 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) was added LDA (2 M, 64.3 mL) at −70° C., and the mixture was stirred at −70° C. for 1 h. 2-Chloro-5-(chloromethyl)thiazole (18 g, 107 mmol) in THF (40 mL) was added dropwise to the reaction mixture, and the mixture was stirred at −70° C. for 1 h. The reaction mixture was quenched with aqueous ammonium chloride and extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give O4-ethyl 4-[(2-chlorothiazol-5-yl)methyl]piperidine-1,4-dicarboxylate (25 g, 60% yield) 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-chlorothiazol-5-yl)methyl]piperidine-1,4-dicarboxylate (15 g, 38.6 mmol) in THF (350 mL) was added LDA (2 M, 30.9 mL) at −70° C., and the mixture was stirred at −70° C. for 1 h. The reaction mixture was quenched with aqueous ammonium chloride solution (500 mL) at 0° C. and extracted with EA (3×100 mL). The combined organic layer was washed with brine (200 mL×2), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate I-53 (4.0 g, 30% yield) 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 52: (S)-2-Methyl-N-[(4R)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidin]-4-yl]propane-2-sulfinamide (Intermediate I-54) [ka]

[0370] Intermediate I-54 (50 mg, crude product) was prepared in the same manner as in Preparation 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 53: (R)-2-methyl-N-[(4S)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidin]-4-yl]propane-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 54: (S)—N—[(4R)-1′-[5-[(5-chloro-4-oxo-3H-quinazolin-6-yl)sulfanyl]pyrazin-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 55: tert-Butyl N-[(3S,4S)-8-[5-bromo-3-(hydroxymethyl)pyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (Intermediate I-57) [ka]

[0376] Step 1: Methyl 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-bromo-pyrazine-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]decan-4-amine (384 mg, 1.86 mmol, HCl) were added and stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give methyl 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-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]decan-8-yl]pyrazine-2-carboxylate To a solution of methyl 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-bromo-pyrazine-2-carboxylate (650 mg, 1.69 mmol) in CM (10 mL) was added DIPEA (436 mg, 3.37 mmol) and (Boc)2O (552 mg, 2.53 mmol) and stirred at 20 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (3 × 10 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain methyl 6-bromo-3-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazine-2-carboxylate (710 mg, 83% yield) 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)pyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate To a solution of methyl 6-bromo-3-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazine-2-carboxylate (300 mg, 618 μmol) in DCM (10 mL) was added DIBAL-H (1 M, 1.85 mL) at −60° C. and stirred at 20° C. for 16 hours. The reaction mixture was quenched with methanol (0.5 mL) at −60° C. and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give 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 56: tert-Butyl N-[(3S,4S)-8-(6-amino-5-bromo-3-carbamoyl-pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (Intermediate I-58) [ka]

[0380] Step 1: 5-amino-3-chloro-pyrazine-2-carbonitrile To a solution of 5-bromo-6-chloro-pyrazine-2-amine (10 g, 48.0 mmol) in NMP (100 mL) was added Pd(PPh3)4 (2.77 g, 2.40 mmol) and stirred at 100 °C for 12 h. The reaction mixture was quenched with aqueous ammonium chloride solution (100 mL) at room temperature, 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, then filtered and concentrated under high vacuum. The residue was purified by column chromatography to give 5-amino-3-chloro-pyrazine-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]decan-8-yl]pyrazine-2-carbonitrile To a solution of 5-amino-3-chloro-pyrazine-2-carbonitrile (1.0 g, 6.47 mmol) in DMF (10 mL) were added (3S,4S)-3-methyl-oxa-8-azaspiro[4.5]decan-4-amine (1.21 g, 7.12 mmol, 2HCl) and DIEA (4.18 g, 32.4 mmol) and stirred for 12 h at 80° C. 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 NaSO, then filtered and concentrated in vacuo to give 5-amino-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazine-2-carbonitrile (1.8 g, crude) as a yellow solid. MS (EI) m / z: 289.4 [M+H] + .

[0382] Step 3: tert-butyl N-[(3S,4S)-8-(6-amino-3-cyano-pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate To a solution of 5-amino-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazine-2-carbonitrile (1.8 g, 6.24 mmol) in DMF (15 mL) were added BocO (2.04 g, 9.36 mmol) and TEA (1.90 g, 18.7 mmol) and stirred at 25 °C for 2 h. The reaction mixture was quenched with aqueous ammonium chloride solution (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 NaSO, filtered, and concentrated under high vacuum. The residue was purified by column chromatography to give tert-butyl N-[(3S,4S)-8-(6-amino-3-cyano-pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-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-carbamoyl-pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate To a solution of tert-butyl N-[(3S,4S)-8-(6-amino-3-cyano-pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (300 mg, 772 μmol) in DMSO (6 mL) was added NaOH (92.7 mg, 2.32 mmol) and HO (4.38 g, 38.6 mmol), and the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with aqueous sodium thiosulfate (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 NaSO, filtered, and concentrated under high vacuum. The residue was purified by column chromatography to give tert-butyl N-[(3S,4S)-8-(6-amino-3-carbamoyl-pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (160 mg, 51% yield) 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-carbamoyl-pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate To a solution of tert-butyl N-[(3S,4S)-8-(6-amino-3-carbamoyl-pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (160 mg, 394 μmol) in DCM (2 mL) was added NBS (77.1 mg, 433 μmol), and the mixture was stirred at 0 °C for 0.25 h. 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 NaSO, filtered, and concentrated under high vacuum. The residue was purified by column chromatography to give intermediate I-58 (160 mg, 84% yield) 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 57: 6-Bromo-5-fluoro-3-(2-methoxyethyl)quinazolin-4-one (Intermediate I-59) [ka]

[0386] Step 1: 6-Amino-3-bromo-2-fluoro-benzoic acid To a solution of 2-amino-6-fluorobenzoic acid (20.0 g, 129 mmol) in DMF (200 mL) was added NBS (24.1 g, 135 mmol) and 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 layers were washed with brine (100 mL), dried over NaSO, then filtered and concentrated in vacuo to give 6-amino-3-bromo-2-fluorobenzoic acid (24.3 g, 73.3% yield) 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), I (217 mg, 855 μmol), diethoxymethoxyethane (1.90 g, 12.8 mmol), and 2-methoxyethanamine (963 mg, 12.8 mmol) were added and 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 layers were dried over Na SO , then filtered and concentrated in vacuo. EtOAc (10 mL) was added to the residue to give intermediate I-59 (970 mg, 37% yield) 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 58: (S)—N-((R)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-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 47, excluding step 3. MS (EI) m / z: 348.1 [M+H] + .

[0390] Preparation 59: (R)-N-((S)-5-Methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-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) was added NaH (3.70 g, 92.5 mmol, purity 60%), and the mixture was stirred at 60° C. for 0.5 h. tert-Butyl N,N-bis(2-chloroethyl)carbamate (8.21 g, 33.9 mmol) was slowly added dropwise to the reaction mixture, which was then stirred at 60° C. for 1.5 h. The reaction mixture was quenched by adding aqueous ammonium chloride solution (100 mL) at 25° C., diluted with water (100 mL), and extracted with EA (3×200 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure. The residue was separated by column chromatography to give tert-butyl 6-methoxy-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (640 mg, 6% yield) 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) were added Ti(OEt) (6.50 g, 28.5 mmol) and (R)-2-methylpropane-2-sulfinamide (922 mg, 7.60 mmol), and the mixture was stirred at 90 °C for 12 h. The reaction mixture was diluted with EA (100 mL) and quenched with water (20 mL), then filtered and concentrated under reduced pressure. The mixture was extracted with EA (3 × 50 mL), and the combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure. The residue was separated by column chromatography to give 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) was added DIBAL-H (1 M, 5.52 mL), and the mixture was stirred at -70 °C for 1 h. The reaction mixture was quenched with methanol (2 mL), diluted with DCM (100 mL), and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 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[indene-2,4'-piperidin]-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) was added TFA (2.72 g, 23.8 mmol), and the mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was quenched with aqueous calcium carbonate (20 mL), diluted with water (30 mL), and then extracted with DCM (3 × 50 mL). The mixture was washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure. The residue was separated by column chromatography to give 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 60: (S)—N—[(4R)-1′[5-[(5-chloro-4-oxo-3H-quinazolin-6-yl)sulfanyl]pyrazin-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, 41% yield) 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 61: (R)-N-[(6S)-2-chlorospiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidin]-6-yl]-2-methyl-propane-2-sulfinamide (Intermediate I-63) [ka]

[0398] Intermediate I-63 (100 mg, crude) was prepared using the same procedure as in Preparation 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 62: (R)-N-((S)-5-hydroxy-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfinamide (Intermediate I-64) [ka]

[0400] Step 1: 6-Hydroxyspiro[indene-2,4'-piperidin]-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) was added BBr3 (11.3 g, 45.3 mmol), and the mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched at 0 °C by the addition of water (50 mL) and then extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 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) were added BocO (1.97 g, 9.02 mmol) and NaOH (902 mg, 22.6 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by adding aqueous ammonium chloride (20 mL) at 25 °C, diluted with water (30 mL), and extracted with EA (50 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl 6-hydroxy-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (1.3 g, 91% yield) as a yellow solid. MS(EI)m / z:340.3 [M+Na] + .

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

[0403] Intermediate I-64 (90 mg, 66% yield) was prepared by using (R)-2-methylpropane-2-sulfinamide instead of (S)-2-methylpropane-2-sulfinamide in Step 1 of Preparation Example 47 and carrying out Steps 2 and 4 using the resulting intermediate. MS (EI) m / z: 323.4 [M+H] + .

[0404] Preparation 63: 6-((3-amino-5-chloropyrazin-2-yl)thio)-5-chloroquinazolin-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-chloro-pyrazin-2-amine (1.66 g, 7.97 mmol), Pd(dba) (664 mg, 725 μmol), Xantphos (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 h. The reaction mixture was quenched by adding aqueous ammonium chloride solution (50 mL) at 25 °C, and the resulting solid was then filtered. The solid was washed with EA (50 mL) and methanol (30 mL), and then concentrated under reduced pressure to give intermediate I-65 (0.7 g, 28% yield) 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 64: 6-Bromo-3-((S)-6-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazol-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 stirred at 25 °C for 1 h. The reaction mixture was quenched by adding aqueous ammonium chloride (20 mL) at 25 °C, followed by the addition of water (30 mL) and extraction with EA (50 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 3,6-dibromopyrazine-2-carboxamide (310 mg, 31% yield) 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]thiazol-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) were added DIEA (230 mg, 1.78 mmol) and intermediate I-48 (112 mg, 0.36 mmol), and the mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate I-66 (130 mg, 71% yield) 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 65: 6-Bromo-3-((S)-4-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazol-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 66: 6-Bromo-3-((S)-4-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidine]-1'-yl)pyrazine-2-carboxamide (Intermediate I-68) [ka]

[0412] Intermediate I-68 (70 mg, 78% yield) 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 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 a manner similar to Steps 1 and 2 of Preparation 28, except that 4-(bromomethyl)tetrahydro-2H-pyran was used instead of 1-bromo-2-methoxyethane in Step 1 of Preparation 28. MS (EI) m / z: 310.9 [M+H] + .

[0415] Preparation 68: 6-((5-bromopyrazin-2-yl)thio)-5-chloro-3-(2-fluoro-2-methylpropyl)quinazolin-4(3H)-one (Intermediate I-70) [ka]

[0416] Intermediate I-70 (150 mg, 65% yield) was synthesized in a manner similar to that of Preparation 28, except that 1-bromo-2-fluoro-2-methylpropane was used instead of 1-bromo-2-methoxyethane in Step 1 of Preparation 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 69: 6-((3-amino-5-chloropyrazin-2-yl)thio)-5-chloro-3-(2-methoxypropyl)quinazolin-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-methylbenzenesulfonate 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-bromopyrazin-2-yl)-8-azaspiro[4.5]decan-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 h. The temperature was lowered to 0 °C, and LiBH (21 mg, 9.7 mmol) was added and stirred for 30 min. The reaction was quenched 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 give tert-butyl (1R)-1-((tert-butylsulfinyl)amino)-8-azaspiro[4.5]decane-8-carboxylate (912.7 mg, 32%) in the flask. MS m / z: 373.5 [M+H] + .

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

[0422] Step 3: N-((R)-8-(5-bromopyrazin-2-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide 2-Methyl-N-((R)-8-azaspiro[4.5]decan-1-yl)propane-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, which was then stirred at 100 °C for 3 h. The reaction was quenched with H O, and the mixture was extracted with EA. The EA layer was dried over MgSO , filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=1:1) and then concentrated to give intermediate I-72 (382 mg, 36%). MS m / z: 430.5 [M+H] + .

[0423] Preparation 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)quinazolin-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 stirred at 50° C. for 2 hours. The reaction was quenched with aqueous NaHCO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. EA and Hx were added to precipitate a solid, which was then filtered to give 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-dihydroquinazolin-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), Pd(dba) (3.7 g, 4.0 mmol), and Xantphos (4.6 g, 8.0 mmol) were dissolved in 1,4-dioxane (267 mL, 0.3 M), followed by dropwise addition of DIPEA (28 mL, 160.4 mmol). The reaction mixture was purged with nitrogen and then stirred at 120 °C for 5 h. After filtration through celite, the mixture was added with HO and extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. After adding EA and Hx, the precipitated solid was filtered to give ethyl 3-((5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-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 then the temperature was lowered to 0° C. Potassium tert-butoxide (9.7 g, 87.1 mmol) was slowly added dropwise to the reaction mixture, which was then stirred at 0° C. for 30 hours. After completion of the reaction, the reaction mixture was concentrated to give 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-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) [ka]

[0428] Step 1: N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide tert-Butyl (1S)-1-((tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (201 mg, 0.49 mmol) 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, which was then stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated to give N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-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'-piperidin]-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, which was then stirred at 50 °C for 4 h. The reaction was quenched with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was purified by MPLC (EA:Hx = 1:1) and then concentrated to give intermediate I-74 (65.6 mg, 32%) and intermediate I-75 (55.7 mg, 27%). MS m / z: 420.5 [M+H] + .

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

[0431] Step 1: t-butyl 4-(4-amino-1-methyl-6-oxo-pyrimidin-2-yl)piperazine-1-carboxylate 6-Amino-3-methyl-1H-pyrimidine-2,4-dione (2 g, 14.17 mmol), BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 6.27 g, 14.17 mmol), and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 2.16 g, 14.17 mmol, 2.14 mL) were dissolved in DMF (30 mL, 0.47 M), and tert-butyl piperazine-1-carboxylate (2.90 g, 15.59 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After LCMS confirmed the complete disappearance of the reactants, the reaction mixture was extracted with brine (20 mL) and EtOAc (20 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting product was separated by preparative HPLC (neutral) and concentrated to give t-butyl 4-(4-amino-1-methyl-6-oxo-pyrimidin-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-dihydropyrimidin-2-yl)piperazine-1-carboxylate tert-Butyl 4-(4-amino-1-methyl-6-oxo-pyrimidin-2-yl)piperazine-1-carboxylate (1.6 g, 5.17 mmol) was dissolved in DMF (10 mL, 0.52 M) and NIS (N-iodosuccinimide, 1.16 g, 5.17 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After a white precipitate formed and complete disappearance of the reactant was confirmed by LCMS, the reaction was terminated by the addition of aqueous NaSO (5 mL). After filtration, the filter cake was washed with MBTE (methyl tertiary-butyl ether, 200 mL). The filter cake was dried to give tert-butyl 4-(4-amino-5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperazine-1-carboxylate (1.8 g, 75.6%) 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-dihydropyrimidin-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-dihydropyrimidin-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 h. Aqueous NaHCO3 and EtOAc were added to the reaction mixture, followed by extraction. The organic layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC and concentrated to give tert-butyl 4-(4-amino-5-((2,3-dichlorophenyl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-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)pyrimidin-4(3H)-one tert-Butyl 4-(4-amino-5-((2,3-dichlorophenyl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperazine-1-carboxylate (640 mg, 1.32 mmol) was dissolved in DCM (dichloromethane, 3 mL, 0.4 M). Then, TFA (1 mL) was added to the reaction mixture and stirred at 25° C. for 30 minutes. The reaction solution was concentrated and then separated by MPLC to give intermediate I-76 (400 mg, 79%). MS m / z: 386 [M+H] + .

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

[0436] Preparation 75: Synthesis of t-butyl N-[2-[4-(4-amino-5-iodo-1-methyl-6-oxo-pyrimidin-2-yl)piperazin-1-yl]ethyl]carbamate (Intermediate I-78) [ka]

[0437] Step 1: t-butyl N-[2-[4-(4-amino-1-methyl-6-oxo-pyrimidin-2-yl)-piperazin-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-butyl piperazine-1-carboxylate (812 mg, 3.54 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After LCMS confirmed that the reaction material had completely disappeared, the reaction mixture was extracted with brine (20 mL) and EtOAc (20 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting product was separated by preparative HPLC (neutral) and concentrated to give t-butyl N-[2-[4-(4-amino-1-methyl-6-oxo-pyrimidin-2-yl)-piperazin-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-oxo-pyrimidin-2-yl)-piperazin-1-yl]ethyl]carbamate tert-Butyl N-[2-[4-(4-amino-1-methyl-6-oxo-pyrimidin-2-yl)-piperazin-1-yl]ethyl]carbamate (260 mg, 737 μmol) was dissolved in DMF (3 mL, 0.25 M), and NIS (166 mg, 737 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After a white precipitate formed and LCMS confirmed the complete disappearance of the reactant, the reaction was quenched with aqueous NaHCO3 and extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC and concentrated to give 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 76: Synthesis of tert-butyl (1-(4-amino-5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate I-79) [ka]

[0440] Step 1: tert-butyl (1-(4-amino-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate In a round-bottom flask, 6-amino-3-methylpyrimidine-2,4(1H,3H)-dione (300 mg, 2.13 mmol), BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 942 mg, 2.13 mmol), and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 324 mg, 2.13 mmol, 0.32 mL) were dissolved in DMF, followed by the dropwise addition of 1-(tert-butyl) 2-methyl(S)-piperazine-1,2-dicarboxylate (502.1 mg, 2.34 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (MeOH:DCM=1:10) and concentrated to give tert-butyl (1-(4-amino-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-methylpiperidin-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-dihydropyrimidin-2-yl)-4-methylpiperidin-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-dihydropyrimidin-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 quenched with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC (MeOH:DCM = 1:10) and concentrated to give intermediate I-79 (981 mg, 94%). MS m / z: 494.10 [M+H] + . Example 1: Synthesis of methyl 3-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorobenzoate [ka]

[0442] Step 1: Methyl 3-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorobenzoate In a round-bottom flask, intermediate I-1 (220 mg, 0.59 mmol), intermediate I-5 (110 mg, 0.53 mmol), Pd(dba) (50 mg, 0.053 mmol), and Xantphos (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 h. The resulting product was washed with EA, filtered through celite, and the filtrate was concentrated. The resulting product was separated by MPLC (EA:Hx=1:5) and then concentrated to give methyl 3-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorobenzoate (230 mg, 87%). MS m / z: 494.1 [M+H] + .

[0443] Step 2: Methyl 3-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorobenzoate In a round-bottom flask, methyl 3-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorobenzoate (22 mg, 0.045 mmol) was dissolved in DCM (0.15 mL, 0.3 M). 4 M HCl in dioxane (0.15 mL) was slowly added dropwise to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction was quenched with aqueous 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 (MeOH:MC=1:10) and concentrated to give 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-methylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)thio)-2-chlorobenzoate [ka]

[0445] Step 1: Ethyl 3-((6-amino-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)thio)-2-chlorobenzoate 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 K(PO) (217 mg, 1.02 mmol) were dissolved in 1,4-dioxane (0.8 mL, 0.5 M) in a round-bottom flask and subsequently stirred at 100 °C for 1 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (MC:MeOH=20:1) and concentrated to give ethyl 3-((6-amino-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-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-methylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)thio)-2-chlorobenzoate In a round-bottom flask, ethyl 3-((6-amino-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)thio)-2-chlorobenzoate (38 mg, 0.11 mmol), tert-butyl (4-methylpiperidin-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), followed by stirring at room temperature for 1 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=4:1) and concentrated to give ethyl 3-((4-amino-2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-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-methylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)thio)-2-chlorobenzoate In a round-bottom flask, ethyl 3-((4-amino-2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)thio)-2-chlorobenzoate (31 mg, 0.06 mmol) was dissolved in methanol (1.2 mL, 0.05 M). 4 M HCl in dioxane (1.5 mL) was added to the reaction mixture, which was then stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was concentrated using a concentrator. The resulting product was separated by MPLC (MC:MeOH=20:1) and concentrated to give 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-methylpiperidin-1-yl)pyrazin-2-yl)thio)-5-chloroquinazolin-4(3H)-one [ka]

[0449] Step 1: tert-butyl ((1-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate In a round-bottom flask, intermediate I-8 (150 mg, 0.6 mmol), intermediate I-2 (154 mg, 0.4 mmol), Pd(dba) (36 mg, 0.04 mmol), and Xantphos (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 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (MC:MeOH=9:1) and concentrated to give tert-butyl ((1-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (5 mg, 3%). MS m / z: 518.1 [M+H] + .

[0450] Step 2: 6-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-5-chloroquinazolin-4(3H)-one tert-Butyl ((1-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-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 in dioxane (0.25 mL) was slowly added dropwise to the reaction mixture, followed by stirring at room temperature for 30 minutes. After completion of the reaction, the resulting product was concentrated, and EA was added dropwise. The precipitated solid was filtered off with EA to obtain the compound of 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-methylpiperidin-1-yl)pyrazin-2-yl)thio)-5-chloroquinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloroquinazolin-4(3H)-one [ka]

[0454] Step 1: N-((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfanilamide In a round-bottom flask, intermediate I-8 (108 mg, 0.43 mmol), intermediate I-3 (170 mg, 0.39 mmol), Pd(dba) (36 mg, 0.04 mmol), and Xantphos (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 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (MC:MeOH=9:1) and concentrated to give N-((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloroquinazolin-4(3H)-one N-((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfanilamide (10.3 mg, 0.017 mmol) was placed in a round-bottom flask and dissolved in DCM (0.25 mL). 4 M HCl in dioxane (63 μL) was slowly added dropwise to the reaction mixture, which was then stirred at room temperature for 30 minutes. After the reaction was completed, the resulting product was concentrated, and EA was added dropwise. The precipitated solid was filtered off with EA to give 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-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorobenzenesulfonyl fluoride [ka]

[0457] Step 1: tert-butyl ((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate In a round-bottom flask, intermediate I-2 (200 mg, 0.52 mmol), intermediate I-7 (100 mg, 0.62 mmol), Pd(dba) (48 mg, 0.052 mmol), and Xantphos (30 mg, 0.052 mmol) were dissolved in 1,4-dioxane (2.1 mL, 0.25 M), followed by the addition of DIPEA (0.18 mL, 1.04 mmol). The reaction mixture was purged with nitrogen and then stirred at 100 °C for 1 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=1:5) and concentrated to give tert-butyl ((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-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)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate In a round-bottom flask, tert-butyl ((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-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% by weight 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 stirred at room temperature for 30 minutes. The resulting product was concentrated using a condenser. The reaction mixture was placed in a round-bottom flask and mixed with 1,4-diazabicyclo[2,2,2]octane (1,4-diazabicyclo[2.2.2]octane bis(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%), dissolved in acetonitrile (2.3 mL, 0.2 M). The reaction mixture was purged with nitrogen and stirred at room temperature for 3 h. The reaction was quenched with aqueous NaHCO3, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=1:5) and concentrated to give tert-butyl ((1-(5-((2-chloro-3-(fluorosulfonyl)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (13 mg, 7%). MS m / z: 532.1 [M+H] + .

[0459] Step 3: 3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorobenzenesulfonyl fluoride In a round-bottom flask, tert-butyl ((1-(5-((2-chloro-3-(fluorosulfonyl)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (13 mg, 0.024 mmol) was dissolved in methanol (0.5 mL, 0.05 M). 4 M HCl solution (0.7 mL, 4 M in dioxane) was added to the reaction mixture, which was then stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was concentrated using a concentrator. After washing with EA, filtration gave 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-methylpiperidin-1-yl)pyrazin-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-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chloro-N-methylbenzenesulfonamide [ka]

[0463] The compound of Example 8 was synthesized in a similar manner to Example 6 above, except that intermediate I-1 was used instead of intermediate I-2, KCl was used instead of KHF, 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]decan-8-yl)pyrazin-2-yl)thio)-2-chlorobenzenesulfonamide [ka]

[0465] Step 1: 2-chloro-3-((5-chloropyrazin-2-yl)thio)aniline 2-Chloro-5-iodopyrazine (116 mg, 0.48 mmol), 3-amino-2-chlorobenzenethiol (100 mg, 0.62 mmol), KPO (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 and purged with nitrogen. The mixture was stirred at 80 °C for 1.5 h. The reaction mixture was filtered, and the filtrate was concentrated and then separated by MPLC (EA:Hx = 1:2). The resulting product was concentrated to give 2-chloro-3-((5-chloropyrazin-2-yl)thio)aniline (75 mg, 57%). MS m / z: 273.1 [M+H] + .

[0466] Step 2: 2-chloro-3-((5-chloropyrazin-2-yl)thio)benzenesulfonamide In a round-bottom flask, 2-chloro-3-((5-chloropyrazin-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 the temperature was then lowered to 0 °C. tert-Butylnitrile (0.08 mL, 0.6 mmol) was added and stirred at room temperature for 30 minutes. The resulting product was concentrated using a condenser. 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 to the round-bottom flask containing the reaction mixture 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 quenched with aqueous 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 (EA:Hx=1:2) and concentrated to give 2-chloro-3-((5-chloropyrazin-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)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate 2-Chloro-3-((5-chloropyrazin-2-yl)thio)benzenesulfonamide (10 mg, 0.03 mmol), tert-butyl ((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (9 mg, 0.03 mmol), and DIPEA (30 μL, 0.18 mmol) were added to NMP (N-methyl-2-pyrrolidone, 0.1 mL, 0.3 M), and the mixture was stirred at 100° C. for 3 hours. The reaction was quenched with aqueous solution, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=1:1) and concentrated to give tert-butyl ((3S,4S)-8-(5-((2-chloro-3-sulfamoylphenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-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]decan-8-yl)pyrazin-2-yl)thio)-2-chlorobenzenesulfonamide tert-Butyl ((3S,4S)-8-(5-((2-chloro-3-sulfamoylphenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (10 mg, 0.018 mmol) was dissolved in methanol (0.3 mL, 0.05 M). 4 M HCl solution (0.3 mL, 4 M in dioxane) was added to the reaction mixture, which was then stirred at room temperature for 30 minutes. EA was slowly added to precipitate a solid, which was filtered to give 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]decan-8-yl)pyrazin-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]decan-8-yl)pyrazin-2-yl)thio)-2-chlorobenzenesulfonyl fluoride [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]decan-8-yl)pyrazin-2-yl)thio)-2-chlorobenzenesulfonamide [ka]

[0474] Step 1: 3-((3-amino-2-chlorophenyl)thio)-6-chloropyrazin-2-amine 3-Bromo-6-chloropyrazin-2-amine (501 mg, 2.409 mmol), 3-amino-2-chlorobenzenethiol (500 mg, 3.132 mmol), KPO (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 and purged with nitrogen. The mixture was stirred at 80 °C for 6 h. The reaction mixture was filtered, and the filtrate was concentrated and then separated by MPLC (EA:Hx = 1:2). The resulting product was concentrated to give 3-((3-amino-2-chlorophenyl)thio)-6-chloropyrazin-2-amine (155 mg, 22%). MS m / z: 288.1 [M+H] + .

[0475] Step 2: 3-((3-amino-5-chloropyrazin-2-yl)thio)-2-chlorobenzenesulfonamide In a round-bottom flask, 3-((3-amino-2-chlorophenyl)thio)-6-chloropyrazin-2-amine (90 mg, 0.31 mmol) was dissolved in ethanol (0.2 mL, 1.5 M) and then purged with nitrogen. 48% by weight tetrafluoroboric acid (0.06 mL) was added to the reaction mixture, and the temperature was then lowered to 0° C. tert-Butylnitrile (0.07 mL, 0.6 mmol) was added and stirred at room temperature for 30 minutes. The resulting product was concentrated using a condenser. The reaction mixture was placed in a round-bottom flask and charged with 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%), 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, which was then stirred at room temperature for 30 minutes. The reaction was quenched with aqueous NaHCO3, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=1:2) and concentrated to give 3-((3-amino-5-chloropyrazin-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)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate 3-((3-amino-5-chloropyrazin-2-yl)thio)-2-chlorobenzenesulfonamide (15 mg, 0.043 mmol), tert-butyl ((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (12 mg, 0.043 mmol), and DIPEA (15 mg, 0.086 mmol) were added to NMP (0.1 mL, 0.3 M) and stirred at 100° C. for 3 hours. The reaction was quenched with aqueous solution, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=1:1) and concentrated to give tert-butyl ((3S,4S)-8-(6-amino-5-((2-chloro-3-sulfamoylphenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-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]decan-8-yl)pyrazin-2-yl)thio)-2-chlorobenzenesulfonamide tert-Butyl ((3S,4S)-8-(6-amino-5-((2-chloro-3-sulfamoylphenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (10 mg, 0.017 mmol) was dissolved in methanol (0.1 mL, 0.1 M). 4 M HCl solution (0.7 mL, 4 M in dioxane) was added to the reaction mixture, which was then stirred at room temperature for 30 minutes. EA was slowly added to precipitate a solid, which was filtered to give 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-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-benzyl-5-chloroquinazolin-4(3H)-one [ka]

[0479] Step 1: tert-butyl ((1-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate In a round-bottom flask, intermediate I-2 (275 mg, 0.71 mmol), intermediate I-8 (215 mg, 0.86 mmol), Pd(dba) (64 mg, 0.07 mmol), and Xantphos (40 mg, 0.07 mmol) were dissolved in 1,4-dioxane (3.0 mL, 0.25 M), followed by the addition of DIPEA (0.25 mL, 1.4 mmol). The reaction mixture was purged with nitrogen and stirred at 100 °C for 1 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=1:1) and concentrated to give tert-butyl ((1-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-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-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate In a round-bottom flask, tert-butyl ((1-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-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 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=1:1) and concentrated to give tert-butyl ((1-(5-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (21 mg, 60%). MS m / z: 608.1 [M+H] + .

[0481] Step 3: 6-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-benzyl-5-chloroquinazolin-4(3H)-one In a round-bottom flask, tert-butyl ((1-(5-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-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 the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was concentrated using a concentrator. The reaction mixture was washed with EA, and the solid was collected by filtration to give 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-methylpiperidin-1-yl)pyrazin-2-yl)thio)-5-chloro-3-(3-nitrobenzyl)quinazolin-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-methylpiperidin-1-yl)pyrazin-2-yl)thio)-5-chloro-3-methylquinazolin-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-methylpiperidin-1-yl)pyrazin-2-yl)thio)-5-chloro-4-oxoquinazolin-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-methylpiperidin-1-yl)pyrazin-2-yl)thio)-5-chloro-4-oxoquinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-3-benzyl-5-chloroquinazolin-4(3H)-one [ka]

[0491] Step 1: N-((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfanilamide In a round-bottom flask, intermediate I-3 (345 mg, 0.8 mmol), intermediate I-8 (300 mg, 1.2 mmol), Pd(dba) (73 mg, 0.08 mmol), and Xantphos (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 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (MeOH:MC=1:50) and concentrated to give N-((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-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-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-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)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-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 h. The reaction was quenched with aqueous NaHCO3, 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:MC=1:50) and concentrated to give N-((3S,4S)-8-(5-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-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]decan-8-yl)pyrazin-2-yl)thio)-3-benzyl-5-chloroquinazolin-4(3H)-one In a round-bottom flask, N-((3S,4S)-8-(5-((3-benzyl-5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-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, which was then stirred at 40° C. for 30 minutes. After completion of the reaction, the reaction mixture was concentrated using a concentrator. The reaction mixture was washed with EA, and the solid was collected by filtration to give 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-4-oxoquinazolin-3(4H)-yl)methyl)benzenesulfonyl fluoride [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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(pyridin-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-methylpiperidin-1-yl)pyrazin-2-yl)thio)-5-chloro-2methyl-4-oxoquinazolin-3(4H)-yl)methyl)benzenesulfonyl fluoride [ka]

[0499] Step 1: tert-butyl ((1-(5-((5-chloro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate In a round-bottom flask, intermediate I-2 (132 mg, 0.34 mmol), intermediate I-9 (131 mg, 0.58 mmol), Pd(dba) (16 mg, 0.017 mmol), and Xantphos (20 mg, 0.034 mmol) were dissolved in 1,4-dioxane (1 mL, 0.3 M), followed by the addition of DIPEA (120 μL, 0.68 mmol). The reaction mixture was purged with nitrogen and stirred at 100 °C for 4 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (MC:MeOH=9:1) and concentrated to give tert-butyl ((1-(5-((5-chloro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-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-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-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)pyrazin-2-yl)-4-methylpiperidin-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 h, and 3-(bromomethyl)benzenesulfonyl fluoride (7.9 mg, 0.031 mmol) was added. The reaction mixture was stirred at room temperature for 12 h, quenched with HO, and extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (EA:Hx=4:1) and concentrated to give tert-butyl ((1-(5-((5-chloro-3-(3-(fluorosulfonyl)benzyl)-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (8.2 mg, 39%). MS m / z: 704.1 [M+H] + .

[0501] Step 3: 3-((6-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-5-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)methyl)benzenesulfonyl fluoride tert-Butyl ((1-(5-((5-chloro-3-(3-(fluorosulfonyl)benzyl)-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (8.2 mg, 0.012 mmol) was placed in a round-bottom flask and dissolved in DCM (0.25 mL). 4 M HCl in dioxane (0.25 mL) was slowly added dropwise to the reaction mixture, followed by stirring at room temperature for 30 minutes. After completion of the reaction, the mixture was concentrated and then EA was added dropwise. The precipitated solid was filtered off 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-methylpiperidin-1-yl)pyrazin-2-yl)thio)-5-chloro-2-methylquinazolin-4(3H)-one [ka]

[0503] The compound of Example 22 was synthesized in the same manner as in Example 21 by deprotecting the tert-butyl ((1-(5-((5-chloro-3-(3-(fluorosulfonyl)benzyl)-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate obtained in Step 2. 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-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-benzyl-5-chloro-2-methylquinazolin-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]thiazol-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-amine [ka]

[0507] Step 1: tert-butyl (1-(5-((7-chloro-2-methylbenzo[d]thiazol-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate In a round-bottom flask, intermediate I-10 (100 mg, 0.31 mmol), intermediate I-11 (89 mg, 0.34 mmol), Pd(dba) (28 mg, 0.031 mmol), and Xantphos (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 min using a microwave. The reaction mixture was washed with EA and filtered through celite, and the filtrate was concentrated. The resulting product was separated by MPLC (EA:Hx=1:3) and concentrated to give tert-butyl (1-(5-((7-chloro-2-methylbenzo[d]thiazol-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (20 mg, 13%). MS m / z: 506 [M+H] + .

[0508] Step 2: 1-(5-((7-chloro-2-methylbenzo[d]thiazol-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-amine In a round-bottom flask, tert-butyl (1-(5-((7-chloro-2-methylbenzo[d]thiazol-6-yl)thio)pyrazin-2-yl)-4-methylpiperidin-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, which was then stirred at room temperature for 1 hour. The reaction was quenched with aqueous NaHCO3, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated by preparative HPLC and concentrated to give 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-indazol-5-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-amine [ka]

[0510] Step 1: tert-butyl (1-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate In a round-bottom flask, intermediate I-1 (50 mg, 0.135 mmol), intermediate I-12 (32 mg, 0.162 mmol), Pd(dba) (12 mg, 0.0135 mmol), and Xantphos (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 min using a microwave. The reaction mixture was washed with EA and filtered through celite, and the filtrate was concentrated. The resulting product was separated by MPLC (EA:Hx=1:3) and concentrated to give tert-butyl (1-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (15 mg, 23%). MS m / z: 489 [M+H] + .

[0511] Step 2: 1-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-amine In a round-bottom flask, tert-butyl (1-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-4-methylpiperidin-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, which was then stirred at room temperature for 1 hour. The reaction was quenched with aqueous NaHCO3, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. The resulting product was separated and concentrated by preparative HPLC to give the compound of Example 25 (4.1 mg, 35%) as a 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-indazol-5-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-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 MS m / z:445 [M+H] + .

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

[0515] Step 1: Methyl 3-((4-amino-2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-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), KPO (904 mg, 4.26 mmol), CuI (82 mg, 0.43 mmol), and (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (61 mg, 0.43 mmol) were added dropwise. The reaction mixture was stirred at 90 °C for 16 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (MeOH:DCM=1:10) and concentrated to give methyl 3-((4-amino-2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-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-methylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)thio)-2-chlorobenzoic acid In a round-bottom flask, 1 M aqueous NaOH solution (0.5 mL, 0.50 mmol) was added dropwise to a reaction mixture of methyl 3-((4-amino-2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-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 quenched with 1 M aqueous HCl solution, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated to give 3-((4-amino-2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-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-methylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)thio)-2-chlorobenzoic acid tert-Butyl N-[2-[4-[4-amino-5-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-1-methyl-6-oxo-pyrimidin-2-yl]piperazin-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 completion of the reaction, the reaction mixture was concentrated and NH 3· Neutralization was achieved by the addition of H 2 O. The resulting product was separated by preparative HPLC to give 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-methylpiperidin-1-yl)pyrazin-2-yl)thio)-5-chloro-3-phenylquinazolin-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-methylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)thio)-5-chloroquinazolin-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-methylpiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)thio)-5-chloro-3-phenylquinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-4-oxoquinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(1-phenylethyl)quinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(3-fluorobenzyl)quinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(3-trifluoromethyl)benzyl)quinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(thiazol-2-ylmethyl)quinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(3-methoxybenzyl)quinazolin-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]imidazol-2-yl)methyl)-6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-5-chloroquinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-4-oxoquinazolin-3(4H)-yl)methyl)benzenesulfonyl fluoride [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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(pyridin-4-ylmethyl)quinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(4-fluorobenzyl)quinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(4-methoxybenzyl)quinazolin-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]pyridin-6-yl)methyl)-6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-5-chloroquinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-fluorobenzyl)quinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(pyrazin-2-ylmethyl)quinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(pyrimidin-4-ylmethyl)quinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(pyrimidin-5-ylmethyl)quinazolin-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 Hz,1H),3.66-3.57(m,1H),3.34-3.31(m,1H),3.17-3.11(m,2H),1.84-1.70(m,3H),1.62-1.59(m,1H),1.24(d,J=6.5 Hz,3H);MS m / z:550.17 [M+H] + .

[0555] Example 47: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-(benzo[d]oxazol-2-ylmethyl)-5-chloroquinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-3-((6-aminopyridin-3-yl)methyl)-5-chloroquinazolin-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)pyridin-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-indazol-5-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-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]imidazol-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-phenylquinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-3-((2-aminopyridin-3-yl)methyl)-5-chloroquinazolin-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 in Step 2 of Example 18, 3-(chloromethyl)pyridin-2-amine hydrochloride (1:1) was used instead of benzyl chloride. 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-((1-methyl-1H-pyrazol-3-yl)methyl)quinazolin-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 in Step 2 of Example 18, 3-(chloromethyl)-1-methyl-1H-pyrazole was used instead of benzyl chloride 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(pyrrolidin-2-ylmethyl)quinazolin-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 in Step 2 of Example 18, tert-butyl 2-(bromomethyl)pyrrolidine-1-carboxylate was used instead of benzyl chloride 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(pyrrolidin-3-ylmethyl)quinazolin-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 in Step 2 of Example 18, tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate was used instead of benzyl chloride 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(isoxazol-3-ylmethyl)quinazolin-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 in Step 2 of Example 18, 3-(chloromethyl)isoxazole was used instead of benzyl chloride 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(isoxazol-5-ylmethyl)quinazolin-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 in Step 2 of Example 18, 5-(bromomethyl)isoxazole was used instead of benzyl chloride and 1.5 equivalents of potassium iodide was 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-hydroxyethyl)quinazolin-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 in Step 2 of Example 18, 2-chloroethanol was used instead of benzyl chloride 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]decan-8-yl)pyrazin-2-yl)thio)-3-((6-aminopyridin-3-yl)methyl)-5-chloroquinazolin-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 in Step 2 of Example 18, 5-(chloromethyl)pyridin-2-amine hydrochloride (1:1) was used instead of benzyl chloride. 1H 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-((2-chloropyridin-4-yl)methyl)quinazolin-4(3H)-one [ka]

[0582] The compound of Example 60 was synthesized in the same manner as in Example 18, except that in Step 2 of Example 18, 2-chloro-4-(chloromethyl)pyridine was used instead of benzyl chloride. 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-((tetrahydrofuran-3-yl)methyl)quinazolin-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 in Step 2 of Example 18, 3-(bromomethyl)tetrahydrofuran was used instead of benzyl chloride and 1.5 equivalents of potassium iodide was 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-((tetrahydrofuran-2-yl)methyl)quinazolin-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 in Step 2 of Example 18, tetrahydrofurfuryl bromide was used instead of benzyl chloride and 1.5 equivalents of potassium iodide was 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(3-hydroxypropyl)quinazolin-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 in Step 2 of Example 18, 3-bromo-1-propanol was used instead of benzyl chloride 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazolin-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 in Step 2 of Example 18, 2-bromoethyl methyl ether was used instead of benzyl chloride. 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-((tetrahydro-2H-pyran-4-yl)methyl)quinazolin-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 in Step 2 of Example 18, 4-(bromomethyl)tetrahydro-2H-pyran was used instead of benzyl chloride and 1.5 equivalents of potassium iodide was 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(3-hydroxybenzyl)quinazolin-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 in Step 2 of Example 18, 3-(bromomethyl)phenol was used instead of benzyl chloride and 1.5 equivalents of potassium iodide was 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-(dimethylamino)ethyl)quinazolin-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 in Step 2 of Example 18, 2-bromo-N,N-dimethylethylamine was used instead of benzyl chloride 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(3-(dimethylamino)propyl)quinazolin-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 in Step 2 of Example 18, 3-chloro-1-(N,N-dimethyl)propylamine was used instead of benzyl chloride 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-fluoro-4-methylbenzyl)quinazolin-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 in Step 2 of Example 18, 2-fluoro-4-methylbenzyl bromide was used instead of benzyl chloride and 1.5 equivalents of potassium iodide was 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-fluoro-3-methoxybenzyl)quinazolin-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 in Step 2 of Example 18, 2-fluoro-3-methoxybenzyl bromide was used instead of benzyl chloride and 1.5 equivalents of potassium iodide was 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-4-oxoquinazolin-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 in Step 2 of Example 18, 4-(bromomethyl)picolinonitrile was used instead of benzyl chloride 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-fluoro-4-methoxybenzyl)quinazolin-4(3H)-one [ka]

[0606] The compound of Example 72 was synthesized in the same manner as in Example 18, except that in Step 2 of Example 18, 1-(bromomethyl)-2-fluoro-4-methoxybenzene was used instead of benzyl chloride. 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(3-fluoro-4-methoxybenzyl)quinazolin-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 in Step 2 of Example 18, 4-(bromomethyl)-2-fluoro-1-methoxybenzene was used instead of benzyl chloride and 1.5 equivalents of potassium iodide was 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-((1-methylpyrrolidin-2-yl)methyl)quinazolin-4(3H)-one [ka]

[0610] The compound of Example 74 was synthesized in the same manner as in Example 18, except that in Step 2 of Example 18, 2-(bromomethyl)-1-methylpyrrolidine hydrochloride was used instead of benzyl chloride. 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2,2,2 trifluoroethyl)quinazolin-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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(3-fluoro-2-hydroxypropyl)quinazolin-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 in Step 2 of Example 18, 1-chloro-3-fluoroisopropanol was used instead of benzyl chloride 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(3-fluoropropyl)quinazolin-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 in Step 2 of Example 18, 1-iodo-3-fluoropropane was used instead of benzyl chloride 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(morpholinomethyl)quinazolin-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 in Step 2 of Example 18, 4-(2-chloroethyl)morpholine was used instead of benzyl chloride and 1.5 equivalents of potassium iodide was 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)quinazolin-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 in Step 2 of Example 18, 4-(bromomethyl)-4-fluorooxane was used instead of benzyl chloride 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-((3-fluorooxetan-3-yl)methyl)quinazolin-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 in Step 2 of Example 18, 3-(bromomethyl)-3-fluorooxetane was used instead of benzyl chloride 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]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-hydroxy-2-methylpropyl)quinazolin-4(3H)-one [ka]

[0623] The compound of Example 81 (33 mg, 89%) was synthesized in the same manner as in Example 18, except that in Step 2 of Example 18, 1-chloro-2-methyl-2-propanol was used instead of benzyl chloride and 1 equivalent of potassium iodide was added. 1 H NMR(400 MHz,DMSO)δ 8.51(s,1H),8.33(d,J=1.2 Hz,1H),8.24(s,1H),8.08(br s,2H),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),3.96(s,2H),3.92(d,J=9.1 Hz,1H),3.69(d,J=9.2 Hz,1H),3.41-3.40(m,1H),3.20-3.12(m,2H),1.83-1.70(m,3H),1.61-1.58(m,1H),1.23(d,J=6.6 Hz,3H),1.11(s,6H).

[0624] Example 82: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-(methylsulfonyl)ethyl)quinazolin-4(3H)-one [ka]

[0625] The compound of Example 82 (77 mg, 99%) was synthesized in the same manner as in Example 18, except that in Step 2 of Example 18, 2-bromomethyl-methylsulfone was used instead of benzyl chloride and 1 equivalent of potassium iodide was added.1 H NMR(400 MHz,DMSO)δ 8.51(d,J=1.1 Hz,1H),8.40(s,1H),8.33(d,J=1.2 Hz,1H),8.11(br s,2H),7.53(d,J=8.8 Hz,1H),7.25(d,J=8.8 Hz,1H),4.37(t,J=6.8 Hz,2H),4.30-4.26(m,2H),4.23-4.19(m,2H),3.92(d,J=9.2 Hz,1H),3.69(d,J=9.0 Hz,1H),3.63(t,J=6.8 Hz,2H),3.45-3.40(m,1H),3.19-3.15(m,2H),3.10(s,3H),1.83-1.70(m,3H),1.62-1.58(m,1H),1.23(d,J=6.6 Hz,3H).

[0626] Example 83: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-5-chloro-3-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)quinazolin-4(3H)-one [ka]

[0627] The compound of Example 83 (6.5 mg, 59%) was synthesized in the same manner as in Example 18, except that in Step 2 of Example 18, 1,6-dioxaspiro[2,5]octane was used instead of benzyl chloride. 1H NMR(400 MHz,DMSO)δ 8.51(s,1H),8.32(d,J=1.2Hz,1H),8.25(s,1H),8.06(br s,2H),7.52(d,J=8.7Hz,1H),7.23(d,J=8.8Hz,1H),4.30-4.23(m,1H),4.22-4.19(m,3H ),4.00(s,2H),3.91(d,J=9.0Hz,1H),3.69(d,J=9.1Hz,1H),3.65-3.55(m,4H),3.41(br MS m / z:573 [M+H] + .

[0628] Example 84: (S)-6-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazolin-4(3H)-one [ka]

[0629] Step 1: N-((S)-1'-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide Intermediate I-21 (150 mg, 0.32 mmol), Intermediate I-8 (106 mg, 0.42 mmol), Pd(dba) (30 mg, 0.032 mmol), and Xantphos (18.5 mg, 0.032 mmol) were dissolved in 1,4-dioxane (3.2 mL, 0.2 M), and DIPEA (0.11 mL, 0.64 mmol) was added. The reaction mixture was purged with nitrogen and stirred at 100 °C for 5 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (MeOH:MC=1:50) and concentrated to give N-((S)-1'-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (140 mg, 73%). MS m / z: 596.1 [M+H] + .

[0630] Step 2: N-((S)-1'-(5-((5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide N-((S)-1'-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (50 mg, 0.084 mmol), 1-bromo-2-methoxyethane (17.5 mg, 0.126 mmol), and cesium carbonate (54.7 mg, 0.168 mmol) were dissolved in DMF (0.84 mL, 0.1 M). The reaction mixture was stirred at 50 °C for 2 h. The reaction was quenched with aqueous NaHCO3, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and concentrated. Separation by MPLC (MeOH:MC=1:50) gave N-((S)-1'-(5-((5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (9.6 mg, 17%). MS m / z: 654.1 [M+H] + .

[0631] Step 3: (S)-6-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazolin-4(3H)-one N-((S)-1'-(5-((5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (9.6 mg, 0.0146 mol) was dissolved in DCM (0.1 mL, 0.1 M). 4 M HCl (0.0036 mL, 4 M in dioxane) was added to the reaction mixture, and the mixture was stirred at 40°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated using a concentrator. The reaction mixture was washed with EA, and the solid was collected by filtration to give the compound of Example 84 (6.3 mg, 74%). 1H NMR(400 MHz,DMSO)δ 8.52(s,1H),8.32-8.28(m,5H),7.53(d,J=8.5 Hz,2H),7.37-7.31(m,3H),7.26-7.24(d,J=8.8 Hz,1H),4.42-4.34(m,2H),4.30-4.24(m,1H),4.14-4.11(m,2H),3.74-3.70( m,2H),3.62-3.59(m,2H),1.78-1.74(m,2H),1.60-1.56(m,2H),1.23(s,3H).

[0632] Example 85: 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-benzyl-8-chloro-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0633] Step 1: N-((3S,4S)-8-(5-((2-benzyl-8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfonamide Intermediate I-20 (0.25 mmol), Intermediate I-3 (160 mg, 0.37 mmol), Pd(dba) (23 mg, 0.02 mmol), Xantphos (14 mg, 0.02 mmol), and DIPEA (0.09 mL, 0.5 mmol) were dissolved in 1,4-dioxane (1.0 mL, 0.25 M). The reaction mixture was purged with nitrogen and stirred at 100 °C for 3 h. The reaction was quenched with HO, and the mixture was extracted with EA. The EA layer was dried over MgSO, filtered, and concentrated. The resulting product was separated by MPLC (MeOH:MC=1:50) and concentrated to give N-((3S,4S)-8-(5-((2-benzyl-8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfonamide (74 mg, 47%). MS m / z: 655.1 [M+H] + .

[0634] Step 2: 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-benzyl-8-chloro-3,4-dihydroisoquinolin-1(2H)-one N-((3S,4S)-8-(5-((2-benzyl-8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-az...

Claims

1. A compound of formula 1A-1, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, wherein [Formula 1A-1] 【Chemical 1】 In the formula,[[]]END]] R １ is H, halogen, hydroxy, cyano or C １ ~C ６ 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 are each independently H, C 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 are linked to each other to form ring B, Ring B may contain one oxygen atom and is a 3- to 8-membered cyclic ring group which may be substituted. Ring B may be condensed with a cycloalkyl, aryl or heteroaryl ring, and the cycloalkyl, aryl and heteroaryl rings condensed with Ring B may be substituted. R ５ are each independently (i) H, halogen, hydroxy, -NH ２ , =NH, -C(O)NH ２ , nitro, cyano, amidino or carboxy or a salt thereof; (ii) halogen, hydroxy, 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 NR"-,, R"R'NC(O)- and R'C(O)NR"-; and is optionally substituted with at least one substituent selected from the group consisting of C １ ~C ２０ alkyl or C １ ~C ２０ alkoxy; (iii) C ６ ~ C ２０ aryl, (C ６ ~ C １２ aryl)-(C １ ~ C ８ alkyl)-, C ６ ~ C ２０ aryloxy, (C ６ ~ C １２ aryloxy)-(C １ ~ C ８ alkyl)-, C ６ ~ C ２０ arylcarbonyl, (C ６ ~ C １２ arylcarbonyl)-(C １ ~ C ８ alkyl)-, -CONH-(C ６ ~ C １２ aryl), -CONH-(C １ ~ C ８ alkyl)-(C ６ ~ C １２ aryl), -NHCO-(C ６ ~ C １２ aryl) or -NHCO-(C １ ~ C ８ alkyl)-(C ６ ~ 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, wherein 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 ring, heteroaryl ring, heterocycloalkyl ring and cycloalkyl ring described in (iii) to (vi) may each be substituted. R' and R" are each independently H or C １ ~C １０ alkyl, R ６ is H or C １ -C ６ alkyl, and p is an integer from 0 to 2. A compound of formula 1A-1, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.

2. R １ is halogen or C １ ~C ３ haloalkyl, and R ２ is selected from the group consisting of H, halogen, hydroxy, oxo, C １ to C ６ alkyl, C １ to C ６ alkoxy, C １ to C ６ haloalkyl, hydroxy-(C １ to C ６ alkyl)-, (C １ to C ６ alkoxy)-(C １ to C ６ alkyl)-, H ２ N-(C １ to C ６ alkyl)-, -NH ２ -, -NH(C １ to C ６ alkyl)-, -N(C １ to C ６ alkyl) ２ nitro, cyano, amidino, -C(O)NH ２ -, -C(O)(C １ to C ６ alkyl)-, -C(O)O(C １ to C ６ alkyl) and carboxy or a salt thereof, R ３ and R ４ are each independently H, C 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 are linked to each other to form ring B, Ring B may contain one oxygen atom and is optionally substituted with at least one R Ｂ and is optionally a C ３ to C ８ cycloalkyl or 3- to 8-membered heterocycloalkyl ring Ring B is C ３ ~C ８ cycloalkyl, C ６ ~C １０ aryl, and may optionally be fused with ring BB selected from 5- to 10-membered heteroaryl containing one or two heteroatoms selected from N, O, and S, where ring BB may be substituted with at least one R ＢＢ and may be substituted with R Ｂ is selected from the group consisting of 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 alkyl)- R ＢＢ is selected from the group consisting of halogen, hydroxy, oxo, C １ to C ６ alkyl, C １ to C ６ alkoxy, C １ to C ６ haloalkyl, hydroxy-(C １ to C ６ alkyl)-, (C １ to C ６ alkoxy)-(C １ to C ６ alkyl)-, H ２ N-(C １ to C ６ alkyl)-, -NH ２ -, -NH(C １ to C ６ alkyl)-, -N(C １ to C ６ alkyl) ２ and is selected from the group consisting of nitro, cyano and amidino, R ５ are each independently (i) H, halogen, hydroxy, -NH ２ , =NH, -C(O)NH ２ , nitro, cyano, amidino or carboxy or a salt thereof; (ii) halogen, hydroxy, 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 NR"-,, R"R'NC(O)- and R'C(O)NR"-; and is optionally substituted with at least one substituent selected from the group consisting of C １ ~C ６ alkyl or C １ ~C ６ alkoxy; (iii) C ６ ~ C １０ aryl, (C ６ ~ C １０ aryl)-(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 aryl), and the aryl ring may be substituted with at least one R ５ａ ; (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 alkyl)-heteroaryl, wherein the heteroaryl ring is a 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, and may be substituted with at least one R ５ａ ; (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 alkyl)-heterocycloalkyl, wherein the heterocycloalkyl ring is a 3- to 10-membered fully saturated or partially unsaturated heterocycloalkyl containing 1 or 3 heteroatoms selected from N, O, and S, and may be substituted with at least one R ５ａ ; 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 cycloalkyl), provided that the cycloalkyl ring may be substituted with at least one R ５ａ ; Selected from R' and R" are each independently H or C １ ~C ６ alkyl, R ５ａ is 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, hydroxy, C １ ~C ６ alkoxy, -NH ２ or cyano-substituted C １ ~C ６ alkyl; halogen, hydroxy, C １ ~C ６ alkyl, -NH ２ or cyano-substituted C 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 alkyl, p is an integer from 0 to 2. The compound according to Claim 1, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.

3. R １ is a halogen, R ２ is selected from the group consisting of H, halogen, hydroxy, oxo, C １ to C ３ alkyl, C １ to C ３ alkoxy, C １ to C ３ haloalkyl, hydroxy-(C １ to C ３ alkyl)-, (C １ to C ３ alkoxy)-(C １ to C ３ alkyl)-, H ２ N-(C １ to C ３ alkyl)-, -NH ２ -, -NH(C １ to C ３ alkyl)-, -N(C １ to C ３ alkyl) ２ nitro, cyano, -C(O)NH ２ -, -C(O)(C １ to C ３ alkyl)-, -C(O)O(C １ to C ３ alkyl) and carboxy or a salt thereof, R ３ and R ４ are each independently H, C 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 are linked to each other to form ring B, Ring B is C ４ to C ６ a cycloalkyl or a 4- to 6-membered heterocycloalkyl ring which may contain one oxygen atom and may be substituted with at least one R Ｂ wherein R Ｂ is deuterium, (C １ to C ３ alkyl), -NH ２ , -NH(C １ to C ３ alkyl), -N(C １ to C ３ alkyl) ２ and H ２ N-(C １ to C ３ alkyl)- and is selected from the group consisting of Ring B may be fused with ring BB, and ring BB is C ３ -C ６ cycloalkyl, C ６ -C １０ aryl, and 5- to 7-membered heteroaryl containing one or two heteroatoms selected from N, O, and S, and ring BB may be substituted with at least one R ＢＢ , and R ＢＢ is 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 , and is selected from the group consisting of nitro and cyano. R ５ is, independently, each of the following (i) to (vi) (i) H, halogen, hydroxy, -NH ２ , -C(O)NH ２ , nitro, cyano or carboxy or salts thereof; (ii) halogen, hydroxy, C １ -C ６ -C alkyl, C １ -C ６ -C haloalkyl, C １ -C ６ -C alkoxy, C １ -C ６ -C haloalkoxy, -NR'R", R'C(O)-, R'S(O) ２ -, R'S(O) ２ -NR", R"R'NC(O)- and R'C(O)NR"-; and optionally substituted with at least one substituent selected from the group consisting of C １ -C ６ -C alkyl or C １ -C ６ -C alkoxy; (iii) C ６ ~ C １０ aryl, (C ６ ~ C １０ aryl)-(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 may be substituted with at least one R ５ａ ; (iv) heteroaryl, heteroaryl-(C １ -C ３ alkyl)-, heteroaryloxy, heteroaryloxy-(C １ -C ３ alkyl)-, heteroarylcarbonyl or heteroarylcarbonyl-(C １ -C ３ alkyl)-, wherein the heteroaryl ring is a 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl ring containing one or two heteroatoms selected from N, O and S, and at least one R ５ａ may be substituted; (v) heterocycloalkyl, heterocycloalkyl-(C １ ~C ３ alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C １ ~C ３ alkyl)-, heterocycloalkylcarbonyl, or heterocycloalkylcarbonyl-(C １ ~C ３ alkyl)-, wherein the heterocycloalkyl ring is a 4- to 7-membered fully saturated or partially unsaturated heterocycloalkyl containing one or two heteroatoms selected from N, O, and S, and may be substituted with at least one R ５ａ or (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)-, wherein the cycloalkyl ring may be substituted with at least one R ５ａ ; Selected from R' and R" are each independently H or C １ ~C ６ alkyl, R ５ａ is selected from the group consisting of halogen, hydroxy, oxo, C １ to C ６ alkyl, C １ to C ６ alkoxy, C １ to C ６ haloalkyl, hydroxy-(C １ to C ６ alkyl)-, (C １ to C ６ alkoxy)-(C １ to C ６ alkyl)-, -NH ２ , -NH(C １ to C ６ alkyl), -N(C １ to C ６ alkyl) ２ , nitro, cyano, halogen-SO ２ -, (C １ to C ６ alkyl)-SO ２ - and -SO ２ NH ２ and is selected from the group consisting of R ６ is H or C １ ~C ６ alkyl, p is an integer from 0 to 2. The compound according to Claim 2, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.

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

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

6. R ２ is 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 alkyl) selected from the group consisting of, the compound according to claim 3, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.

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

8. R ３ and R ４ one of which is C １ -C ３ -alkyl and the other is -NH ２ or H ２ N-(C １ -C ３ -alkyl)-, or R ３ and R ４ are linked to each other to form ring B, where ring B is a cyclopentane ring or a tetrahydrofuran ring, and ring B is substituted with at least one R １ -C ３ -alkyl and -NH ２ selected from Ｂ and may be substituted Ring B is C ３ ~C ６ Ring B 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 optionally substituted with at least one R selected from the group consisting of halogen, cyano, hydroxy, C １ ~C ３ alkyl and C １ ~C ３ alkoxy ＢＢ ​ The compound according to Claim 1, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.

9. Of formula 1A-1 【Chemical 2】 Is the following structure:[[]]END]] 【Chemical Formula 3】 And 【Chemical Formula 4】 Selected from (wherein R ４１ is C １ to C ３ alkyl and q is an integer of 0 to 3) In the formula, ring B in the above structure may be substituted with at least one R selected from deuterium, methyl, and -NH ２ and ring BB may be substituted with at least one R selected from the group consisting of halogen, cyano, hydroxy, methyl, and methoxy. Ｂ and ring BB may be substituted with at least one R selected from the group consisting of halogen, cyano, hydroxy, methyl, and methoxy. ＢＢ ​ The compound according to Claim 8, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.

10. Of formula 1A-1 [Chemical Formula 5] Is the following structure:[[]]END]] ​ And 【Chemical Formula 7】 Selected from (wherein, R ４１ is methyl and q is 0 or 1) In the formula, ring B in the above structure is methyl and -NH ２ and may be substituted with at least one R selected from Ｂ ring BB may be substituted with at least one R selected from the group consisting of halogen, cyano, hydroxy, methyl and methoxy, ＢＢ and The compound according to Claim 9, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.

11. Of formula 1A-1 【Chemical Formula 8】 Is the following structure:[[]]END]] 【Chemical Formula 9】 【Chem.】 【Chemical Formula 10】 , and 【Chemical Formula 11】 Selected from, the compound according to Claim 9, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.

12. Of formula 1A-1 【Chemical Formula 12】 Is the following structure:[[]]END]] 【Chemical 13】 【Chemical 14】 , and 【Chemical Formula 15】 Selected from, the compound according to Claim 11, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.

13. R ５ is, independently of each other, the following (i) to (vi) (i) H, halogen, hydroxy, -NH ２ , -C(O)NH ２ , nitro, cyano or carboxy or salts thereof; (ii) halogen, hydroxy, 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 NR"-, R"R'NC(O)- and R'C(O)NR"-; and is optionally substituted with at least one substituent selected from the group consisting of C 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 each independently H or C １ ~C ３ alkyl); (iii) phenyl, phenyl-(C １ ~C ３ alkyl)-, phenyloxy, phenyloxy-(C １ ~C ３ alkyl)-, phenylcarbonyl, or phenylcarbonyl-(C １ ~C ３ alkyl)-, wherein the phenyl ring may be substituted with at least one R ５ａ ; (iv) heteroaryl, heteroaryl-(C １ ~C ３ alkyl)-, heteroaryloxy, heteroaryloxy-(C １ ~C ３ alkyl)-, heteroarylcarbonyl or heteroarylcarbonyl-(C １ ~C ３ alkyl)-, wherein the heteroaryl ring is selected from the group consisting of pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, and 1H-pyrrolo[2,3-b]pyridinyl, and may be substituted with at least one R ５ａ ; (v) heterocycloalkyl, heterocycloalkyl-(C １ -C ３ alkyl)-, heterocycloalkyloxy, heterocycloalkyloxy-(C １ -C ３ alkyl)-, heterocycloalkylcarbonyl, or heterocycloalkylcarbonyl-(C １ -C ３ alkyl)-, wherein 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 may be substituted with at least one R ５ａ ; 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)-, wherein the cycloalkyl ring may be substituted with at least one R ５ａ and may be Selected from R ５ａ is halogen, hydroxy, oxo, C １ to C ３ alkyl, C １ to C ３ alkoxy, C １ to C ３ haloalkyl, hydroxy-(C １ to C ３ alkyl)-, -NH ２ -, -NH(C １ to C ３ alkyl)-, -N(C １ to C ３ alkyl) ２ , nitro, cyano, -SO ２ F and -SO ２ Cl, selected from the group consisting of: The compound according to Claim 1, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.

14. 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, the compound according to claim 13, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.

15. R ５ is selected from the group consisting of phenyl, benzyl, 1-phenylethyl, phenoxy, pyridinylmethyl, pyridyloxy, 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, wherein R ５ is at least one R ３ substituted with at least one selected from the group consisting of F, Cl, OH, -CH ３ , -OCH ２ , cyano, oxo, -NH ２ , NO ２ F and CF ３ , or a compound according to claim 13, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof. ５ａ ​

16. R ５ is H, CH ３ -, HOCH ２ CH ２ -, HOCH ２ CH ２ CH ２ -, CF ３ CH ２ -, CF ３ CH ２ CH ２ - 【Chemical 16】 , FCH ２ CH ２ CH ２ -, 【Chemical 17】 【Chemical 18】 and 【Chemical Formula 19】 selected from In the above structure, 【Chemical 20】 represents the bonding position with the remaining residues of the compound, the compound according to claim 13, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.

17. The compound is 【Chemical Formula 21】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 and 【Chemical 22】 selected from, the compound according to claim 1, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition for preventing or treating a disease associated with abnormal activity of Src homology 2 domain-containing phosphatase-2 (SHP2), comprising the 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, immune disorder, fibrosis and eye disorder.

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, 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.

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

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