Nitrogen-containing heterocyclic compounds, processes for their preparation and uses thereof

Abstract

The application discloses a nitrogen-containing heterocyclic compound and a preparation method and application thereof. Specifically, the application discloses a compound shown in formula I or a pharmaceutically acceptable salt thereof. The compound of the application has good SHP2 inhibitory activity and / or tumor cell inhibitory activity.

Description

Technical Field

[0001] This invention relates to a nitrogen-containing heterocyclic compound, its preparation method, and its application. Background Technology

[0002] SHP2 is a cytoplasmic protein tyrosine phosphatase encoded by the PTPN11 gene. SHP2 is widely expressed in most tissues and participates in the signaling pathways of various growth factors and cytokines, playing a crucial regulatory role in cell proliferation, migration, differentiation, and death. Currently, SHP2 is known to be associated with a variety of human diseases, such as Noonan syndrome, panther skin syndrome, diabetes, neuroblastoma, melanoma, juvenile leukemia, juvenile myelomonocytic leukemia, chronic myelomonocytic leukemia, acute myeloleukemia, HER2-positive breast cancer, triple-negative breast cancer, ductal carcinoma of the breast, invasive ductal carcinoma of the breast, non-small cell lung cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma, neutropenia, and systemic lupus erythematosus, etc. SHP2 inhibitors hold promise for the treatment of these diseases.

[0003] Several patent applications have disclosed SHP2 inhibitors, including CN111825700A, WO2019158019A1, WO2020094104A1, WO2021148010A1, WO2021115286A1, CN112166110A, and WO2021143680A1. Some SHP2 inhibitors have entered clinical trials, including RMC-4630, JAB-3068, JAB-3312, and TNO-155.

[0004] Although some progress has been made in the research of SHP2, there are still no effective drugs on the market, and it is still necessary to continue to research and develop new SHP2 inhibitors. Summary of the Invention

[0005] The technical problem to be solved by this invention is the limited variety of known SHP2 inhibitor structures. Therefore, this invention provides a novel SHP2 inhibitor. Specifically, this invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, which exhibits good SHP2 inhibitory activity and / or tumor cell inhibitory activity.

[0006] This invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0007]

[0008] Where X is CH or N;

[0009] B is In the above structure, the a-end is connected to L, and the b-end is connected to the N atom in the structure of formula I.

[0010] B1 is O, S, NH, or NR. b1 ;R b1 It is a C1-C4 alkyl group;

[0011] B3 is H, NH2, or a C1-C4 alkyl group;

[0012] B4, B7, B8, B 11 B 12 B 14 B 16 B 18 B 20 and B 22 Each can be independently CH or N;

[0013] B5 is N or CR b5 ;R b5 It is H or C1-C4 alkyl;

[0014] B6 is H, NH2, or a C1-C4 alkyl group;

[0015] B9 is H, OH, or a C1-C4 alkyl group;

[0016] B 10 It can be H, NH2, halogen, or C1-C4 alkyl;

[0017] B 13 It is H or halogen;

[0018] B 15 It is H or C1-C4 alkyl;

[0019] B 17 It can be H, halogen, CN, C1-C4 alkyl or -C1-C4 alkylene-OH;

[0020] B 19 It is H or NH2;

[0021] B 21 For O, NH or NR b21 ;R b21 It is a C1-C4 alkyl group;

[0022] L is a single bond, -O-, -S-, -NH-, -N(R1)-, -CH2-, -CH(R1)-, -C(R1)(R2)-, or

[0023] Each R1 and R2 is independently a C1-C4 alkyl group;

[0024] A is a saturated or partially unsaturated 3-10 membered cyclic hydrocarbon group, a saturated or partially unsaturated 3-10 membered heterocyclic group, a phenyl group, a 5-6 membered heteroaryl group, a naphthyl group, or an 8-10 membered fused heteroaryl group; the hydrogen atoms on the 3-10 membered cyclic hydrocarbon group, 3-10 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group, naphthyl group, and 8-10 membered fused heteroaryl group are unsubstituted or substituted by n R3 groups;

[0025] n is 1, 2, 3, 4 or 5;

[0026] Each R3 is independently F, Cl, Br, I, NH2, OH, cyano, C1-C4 alkyl, C1-C4 alkoxy, or m R groups. 3a Substituted C1-C4 alkyl groups or m R groups 3b Substituted C1-C4 alkoxy groups;

[0027] Each m is independently 1, 2, 3, 4 or 5;

[0028] Each R 3a and R 3b Each can be independently represented by F, Cl, Br, I, NH2, OH, or cyano groups;

[0029] The number of heteroatoms in the 3-10 membered heterocyclic group, 5-6 membered heteroaryl group and 8-10 membered fused heteroaryl group is 1, 2, 3 or 4, and each heteroatom is independently N, O or S.

[0030] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, B is...

[0031] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, B is...

[0032] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when B is hour, It can be

[0033] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when B is hour, It can be

[0034] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when B is hour, for

[0035] In some embodiments, the compound represented by Formula I has a structure represented by any one of Formulas I-1 to I-11:

[0036]

[0037]

[0038] In some embodiments, in the compounds of formula I or I-3 as described in any of the preceding embodiments, R b5 It is H or C1-C4 alkyl, such as H or methyl.

[0039] In some embodiments, in the compounds of formula I or I-4 as described in any of the preceding embodiments, B3 is H or a C1-C4 alkyl group, such as H or methyl.

[0040] In some embodiments, B3 is NH2 in the compound of formula I or I-9 as described in any of the preceding embodiments.

[0041] In some embodiments, in the compounds of formula I or I-10 as described in any of the preceding embodiments, R b1 It is a C1-C4 alkyl group, such as methyl, ethyl or isopropyl.

[0042] In some embodiments, the compound represented by Formula I or I-1 is a compound with the following characteristics:

[0043]

[0044] In some embodiments, the compound represented by Formula I or I-2 is any of the following compounds:

[0045]

[0046] In some embodiments, the compound represented by Formula I or I-3 is a compound with the following characteristics:

[0047]

[0048] In some embodiments, the compound represented by Formula I or I-4 is any of the following compounds:

[0049]

[0050]

[0051] In some embodiments, the compound represented by Formula I or I-5 is a compound with the following characteristics:

[0052]

[0053] In some embodiments, the compound represented by Formula I or I-6 is any of the following compounds:

[0054]

[0055] In some embodiments, the compound represented by Formula I or I-7 is any of the following compounds:

[0056]

[0057] In some embodiments, the compound represented by Formula I or I-8 is any of the following compounds:

[0058]

[0059] In some embodiments, the compound represented by Formula I or I-9 is any of the following compounds:

[0060]

[0061] In some embodiments, the compound represented by Formula I or I-10 is any of the following compounds:

[0062]

[0063] In some embodiments, the compound represented by Formula I or I-11 is a compound with the following characteristics:

[0064]

[0065] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, B is...

[0066] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when B is hour, It can be

[0067] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when B is hour, It can be

[0068] In some embodiments, the compound represented by Formula I has the structure shown in Formula I-12 or I-13:

[0069]

[0070] In some embodiments, in the compounds represented by Formula I or I-12 as described in any of the preceding embodiments, B6 is NH2.

[0071] In some embodiments, in the compounds of formula I or I-13 as described in any of the preceding embodiments, B6 is H or NH2.

[0072] In some embodiments, the compound represented by Formula I or I-12 is any of the following compounds:

[0073]

[0074] In some embodiments, the compound represented by Formula I or I-13 is any of the following compounds:

[0075]

[0076] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, B is...

[0077] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when B is hour, It can be

[0078] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when B is hour, It can be

[0079] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when B is hour, It can be

[0080] In some embodiments, the compound represented by Formula I has a structure represented by any one of Formulas I-14 to I-17:

[0081]

[0082] In some embodiments, the compound represented by Formula I has the structure shown in Formulas I-18:

[0083]

[0084] In some embodiments, in the compounds of formula I, I-15 or I-16 as described in any of the preceding embodiments, B 10 It can be H, NH2, Cl or CH3, preferably H.

[0085] In some embodiments, in the compounds of formula I or I-15 as described in any of the preceding embodiments, B 10It is H, NH2 or C1-C4 alkyl (e.g. methyl), preferably H.

[0086] In some embodiments, in the compounds of formula I or I-16 as described in any of the preceding embodiments, B 10 It is H or a halogen (e.g., Cl), preferably H.

[0087] In some embodiments, in the compound of formula I or I-17 as described in any of the preceding embodiments, B9 is H or OH, preferably H.

[0088] In some embodiments, the compound represented by Formula I or I-14 is any of the following compounds:

[0089]

[0090]

[0091] In some embodiments, the compound represented by formula I, I-15, or I-18 is any of the following compounds:

[0092]

[0093]

[0094] In some embodiments, the compound represented by Formula I or I-16 is any of the following compounds:

[0095]

[0096] In some embodiments, the compound represented by Formula I or I-17 is any of the following compounds:

[0097]

[0098] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, B is...

[0099] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when B is hour, It can be

[0100] In some embodiments, the compound represented by Formula I has the structure shown in Formula I-19:

[0101]

[0102] In some embodiments, in the compound represented by Formula I or I-19, B 13 It can be H or F, preferably F.

[0103] In some embodiments, the compound represented by Formula I or I-19 is any of the following compounds:

[0104]

[0105] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, B is...

[0106] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when B is hour, It can be

[0107] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when B is hour, It can be

[0108] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when B is hour, It can be

[0109] In some embodiments, the compound represented by Formula I has a structure represented by any one of Formulas I-20 to I-23:

[0110]

[0111] In some embodiments, the compound represented by formula I, I-20, or I-21 as described in any of the preceding embodiments, B 15 It is H or C1-C4 alkyl (e.g., methyl), preferably H.

[0112] In some embodiments, the compound represented by formula I or I-22 as described in any of the preceding embodiments, B 17 It can be H, halogen (e.g., F), CN, C1-C4 alkyl (e.g., methyl) or -C1-C4 alkylene-OH (e.g., -CH2OH), preferably H.

[0113] In some embodiments, the compound represented by Formula I or I-20 is any of the following compounds:

[0114]

[0115] In some embodiments, the compound represented by Formula I or I-21 is any of the following compounds:

[0116]

[0117] In some embodiments, the compound represented by Formula I or I-22 is any of the following compounds:

[0118]

[0119] In some embodiments, the compound represented by Formula I or I-23 is the following compound:

[0120]

[0121] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, B is...

[0122] In some embodiments, the compound represented by Formula I has the structure shown in Formula I-24 or I-25:

[0123]

[0124] In some embodiments, the compound represented by Formula I or I-24 is the following compound:

[0125]

[0126] In some embodiments, the compound represented by Formula I or I-25 is a compound with the following characteristics:

[0127]

[0128] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, B is...

[0129] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when B is hour, It can be

[0130] In some embodiments, the compound represented by Formula I has the structure shown in Formula I-26 or I-27:

[0131]

[0132] In some embodiments, in the compounds of formula I, I-26 or I-27 as described in any of the preceding embodiments, B 19 For example, NH2. In some embodiments, the compound represented by formula I or I-26 is a compound with the following properties:

[0133]

[0134] In some embodiments, the compound represented by Formula I or I-27 is any of the following structural compounds:

[0135]

[0136] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, B is... In some embodiments, the compound represented by Formula I has the structure shown in Formulas I-28:

[0137]

[0138] In some embodiments, the compound represented by Formula I or I-28 is a compound with the following characteristics:

[0139]

[0140] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, B is... In some embodiments, the compound represented by Formula I has the structure shown in Formulas I-29:

[0141]

[0142] In some embodiments, the compound represented by Formula I or I-29 is the following compound:

[0143]

[0144]

[0145] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, B is... In some embodiments, the compound represented by Formula I has the structure shown in Formulas I-30:

[0146]

[0147] In some embodiments, the compound represented by Formula I or I-30 is any of the following compounds:

[0148]

[0149] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, B is... In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when B is hour, It can be

[0150] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when B is hour, It can be

[0151] In some embodiments, the compound represented by Formula I has the structure shown in Formulas I-31 to I-34 as follows:

[0152]

[0153] In some embodiments, the compound represented by Formula I has the structure shown in Formulas I-31:

[0154]

[0155] In some embodiments, in the compounds of formula I or I-33 as described in any of the preceding embodiments, R b21 It can be methyl, ethyl, or isopropyl.

[0156] In some embodiments, the compound represented by Formula I or I-31 is any of the following compounds:

[0157]

[0158]

[0159] In some embodiments, the compound represented by Formula I or I-32 is a compound with the following characteristics:

[0160]

[0161] In some embodiments, the compound represented by Formula I or I-34 is any of the following compounds:

[0162]

[0163] In some embodiments, in compounds of formula I as described in any of the preceding embodiments and of any of formulas I-1 to I-34, L is a single bond.

[0164] In some embodiments, L is -O- in compounds of formula I as described in any of the preceding embodiments and of any of formulas I-1 to I-34.

[0165] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, L is -S-.

[0166] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, L is -NH-.

[0167] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, L is -N(R1)-.

[0168] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, L is -CH2-.

[0169] In some embodiments, in compounds of formula I as described in any of the preceding embodiments and of any of formulas I-1 to I-34, L is -CH(R1)-.

[0170] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, L is -C(R1)(R2)-.

[0171] In some embodiments, in compounds of formula I as described in any of the preceding embodiments and of any of formulas I-1 to I-34, L is

[0172] In some embodiments, R1 is a methyl group in the compound of formula I as described in any of the preceding embodiments and in any of formulas I-1 to I-34.

[0173] In some embodiments, R2 is a methyl group in the compound of formula I as described in any of the preceding embodiments and in any of formulas I-1 to I-34.

[0174] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, A is a saturated or partially unsaturated 3-10 membered ring hydrocarbon group, wherein the hydrogen atoms on the 3-10 membered ring hydrocarbon group are unsubstituted or substituted by n R3 atoms.

[0175] In some embodiments, in the compounds of formula I as described in any of the preceding embodiments and of any of formulas I-1 to I-34, in the definition of A, the saturated or partially unsaturated 3-10 membered ring hydrocarbon group can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. (For example )or (For example ).

[0176] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, A is a saturated or partially unsaturated 3-10 membered heterocyclic group, wherein the hydrogen atoms on the 3-10 membered heterocyclic group are unsubstituted or substituted by n R3 atoms.

[0177] In some embodiments, in compounds of formula I as described in any of the preceding embodiments and of any of formulas I-1 to I-34, the saturated or partially unsaturated 3-10 membered heterocyclic group, as defined in A, can be (For example ), (For example ), (For example )or (For example ).

[0178] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, A is a phenyl group, and the hydrogen atoms on the phenyl group are either unsubstituted or substituted by n R3 atoms.

[0179] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, A is a 5-6 membered heteroaryl group, wherein the hydrogen atoms on the 5-6 membered heteroaryl group are unsubstituted or substituted by n R3 atoms.

[0180] In some embodiments, in compounds of formula I as described in any of the preceding embodiments and of formulas I-1 to I-34, the 5-6 heteroaryl group, as defined in A, can be pyrrole, furan, thiophene, oxazole, or isoxazole. Thiazoles (e.g.) ), isothiazole, pyrazole (e.g.) ), imidazole, pyridine (e.g.) ), pyrimidine or pyrazine.

[0181] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, A is a naphthyl group, and the hydrogen atoms on the naphthyl group are either unsubstituted or substituted by n R3 atoms.

[0182] In some embodiments, in compounds of formula I as described in any of the preceding embodiments and of any of formulas I-1 to I-34, the naphthyl group, in the definition of A, can be...

[0183] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, A is an 8-10 fused heteroaryl group, wherein the hydrogen atoms on the 8-10 fused heteroaryl group are unsubstituted or substituted by n R3 atoms.

[0184] In some embodiments, in compounds of formula I as described in any of the preceding embodiments and of any of formulas I-1 to I-34, the 8-10 member fused aryl group can be, in the definition of A, […]. (For example ), (For example )or (For example ).

[0185] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, n is 1, 2 or 3.

[0186] In some embodiments, in compounds of formula I as described in any of the preceding embodiments and of any of formulas I-1 to I-34, each R 3a and R 3b Each can be either F or OH.

[0187] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, each R3 is independently F, Cl, Br, NH2, OH, cyano, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, or hydroxymethyl.

[0188] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, when A is a saturated or partially unsaturated 3-10 membered ring hydrocarbon group, and the hydrogen atoms on the 3-10 membered ring hydrocarbon group are unsubstituted or substituted by n R3 atoms, A can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0189] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, when A is a saturated or partially unsaturated 3-10 membered heterocyclic group, and the hydrogen atoms on the 3-10 membered ring hydrocarbon group are unsubstituted or substituted by n R3 atoms, A can be

[0190] In some embodiments, in compounds of formula I as described in any of the preceding embodiments and of formulas I-1 to I-34, when A is a phenyl group and the hydrogen atoms on the phenyl group are unsubstituted or substituted by n R3 atoms, A can be...

[0191]

[0192] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, when A is a 5-6 membered heteroaryl group, and the hydrogen atoms on the 5-6 membered heteroaryl group are unsubstituted or substituted by n R3 atoms, A can be

[0193] In some embodiments, in compounds of formula I as described in any of the preceding embodiments and of formulas I-1 to I-34, when A is a naphthyl group and the hydrogen atoms on the naphthyl group are unsubstituted or substituted by n R3 groups, A can be

[0194] In some embodiments, in the compounds represented by Formula I as described in any of the preceding embodiments and any of Formulas I-1 to I-34, when A is an 8-10 fused heteroaryl group, and the hydrogen atoms on the 8-10 fused heteroaryl group are unsubstituted or substituted by n R3 atoms, A can be

[0195] In some embodiments, in compounds of formula I as described in any of the preceding embodiments and of any of formulas I-1 to I-34, AL- is

[0196] In some embodiments, X is CH in the compound represented by Formula I as described in any of the preceding embodiments and in any of the compounds represented by Formulas I-1 to I-34.

[0197] In some embodiments, X is N in the compound represented by Formula I as described in any of the preceding embodiments and in any of Formulas I-1 to I-34.

[0198] The present invention also discloses a method for preparing the compound shown in Formula I as described above, which includes the following steps: removing the tert-butyl sulfinyl group from the compound shown in Formula II in the presence of an acid (e.g., HCl) in a solvent (e.g., dioxane) to obtain the compound shown in Formula I;

[0199]

[0200] The definitions of A, L, B, and X are as described above.

[0201] The present invention also provides a compound of formula II:

[0202]

[0203] The definitions of A, L, B, and X are as described above.

[0204] The present invention also provides a method for preparing the compound represented by Formula II, which may be scheme 1, 2, 3 or 4:

[0205] Scheme 1 includes the following steps: the compound shown in Formula III-1 and the compound of Formula IV are coupled in a solvent in the presence of a palladium catalyst, a ligand and a base as shown below to obtain the compound shown in Formula II;

[0206]

[0207] Wherein, Hal is a halogen (e.g., Cl or Br), and the definitions of A, L, B and X are as described above;

[0208] Scheme 2 includes the following steps: the compound shown in Formula III-2 and the compound of Formula IV are coupled in a solvent in the presence of a base as shown below to obtain the compound shown in Formula II;

[0209]

[0210] The definitions of A, L, B, and X are as described above;

[0211] Scheme 3 includes the following steps: the compound shown in Formula III-3 and the compound of Formula V are coupled in a solvent in the presence of a palladium catalyst and a base as shown below to obtain the compound shown in Formula II;

[0212]

[0213] Where Hal is a halogen (e.g., Br), and the definitions of A, L, B, and X are as described above;

[0214] Scheme 4 includes the following steps: the compound shown in Formula III-4 and the compound of Formula V are coupled in a solvent in the presence of a palladium catalyst and a base as shown below to obtain the compound shown in Formula II;

[0215]

[0216] Hal is a halogen (e.g., Br), and the definitions of A, L, B, and X are as described above.

[0217] The present invention also provides a compound of formula III-1, III-2 or V:

[0218]

[0219] The definitions of Hal, A, L, B, and X are as described above.

[0220] The present invention also discloses a pharmaceutical composition comprising a compound as described in any of the preceding embodiments or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

[0221] The present invention also discloses the use of a compound as described in any of the preceding embodiments or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above in the preparation of an SHP2 inhibitor.

[0222] The present invention also discloses the use of a compound as described in any of the preceding embodiments or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above in the preparation of a medicament for treating SHP2-related diseases.

[0223] The present invention also discloses a method for inhibiting SHP2 in a subject, comprising administering the subject a therapeutically effective amount of a compound as described in any of the preceding protocols or a pharmaceutically acceptable salt thereof.

[0224] The present invention also discloses a method for treating SHP2-related diseases in a subject, comprising administering the subject a therapeutically effective amount of a compound as described in any of the preceding protocols or a pharmaceutically acceptable salt thereof.

[0225] In some implementations, the SHP2-related diseases are Noonan syndrome, panther syndrome, diabetes, neuroblastoma, melanoma, juvenile leukemia, juvenile myelomonocytic leukemia, chronic myelomonocytic leukemia, acute myelomonocytic leukemia, HER2-positive breast cancer, triple-negative breast cancer, ductal carcinoma of the breast, invasive ductal carcinoma of the breast, non-small cell lung cancer, colorectal cancer, esophageal cancer, gastric cancer, squamous cell carcinoma of the head and neck, neutropenia, or systemic lupus erythematosus.

[0226] Definitions and Explanations

[0227] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0228] In this document, the term "substitution" or "substituent" refers to the replacement of a hydrogen atom in a group by a specified group. Substitution can occur at any position unless the substitution site is specified, but it is only permitted if a stable or chemically viable chemical is formed. Examples are given below: The structure indicates that the hydrogen atoms on ring A are replaced by m R1 atoms.

[0229] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0230] When a linking group is a single bond, the groups connected to both sides of the linking group are directly linked by single bonds. For example, when L in ALZ is a single bond, the resulting structure is AZ.

[0231] In this document, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. C1-C4 alkyl refers to an alkyl group having 1-4 carbon atoms, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0232] In this article, the term "hydrocarbon group" refers to a group consisting of carbon and hydrogen atoms.

[0233] In this article, the term "halogen" refers to F, Cl, Br, or I.

[0234] In this document, the term "alkoxy" refers to -O-alkyl, where alkyl is defined as previously stated. C1-C4 alkoxy refers to -O-(C1-C4 alkyl), where C1-C4 alkyl is defined as previously stated, that is, C1-C4 alkoxy can specifically be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0235] In this document, the term "cyclic hydrocarbon group" refers to a cyclic hydrocarbon group that is monocyclic or polycyclic (e.g., fused, spiro, or bridged), and can be saturated, partially unsaturated, or aromatic. In a saturated cyclic hydrocarbon group, each carbon atom on the ring is saturated; examples of saturated cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In aromatic cyclic hydrocarbon groups, each ring is aromatic; examples of aromatic cyclic hydrocarbon groups include, but are not limited to, phenyl and naphthyl. In partially unsaturated cyclic hydrocarbon groups, at least one carbon atom on the ring is saturated and at least one carbon atom is unsaturated; examples of partially unsaturated cyclic hydrocarbon groups include, but are not limited to, […]. In some embodiments, the partially unsaturated cyclic hydrocarbon group is a polycyclic cyclic hydrocarbon group, wherein at least one ring is an aromatic ring and at least one ring is a non-aromatic ring, which can be connected to other structures through atoms on the aromatic ring or through atoms on the non-aromatic ring. Specifically, the 3-10 membered cyclic hydrocarbon group can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered cyclic hydrocarbon group. In some embodiments, the cyclic hydrocarbon group is monocyclic. In some embodiments, the cyclic hydrocarbon group is polycyclic (e.g., fused ring, spiro ring, or bridged ring).

[0236] In this document, the term "heterocyclic group" refers to a monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged) cyclic group formed by a carbon atom and at least one heteroatom, wherein the heteroatom is independently selected from N, O, and S. Heterocyclic groups can be saturated, partially unsaturated, or aromatic. Heterocyclic groups can be connected to other structures via carbon atoms and heteroatoms on the ring. In saturated heterocyclic groups, all atoms on the ring are saturated; examples of saturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrroleyl, piperidinyl, piperazinyl, and morpholinyl. In aromatic heterocyclic groups, each ring is aromatic, i.e., heteroaryl in this document. In partially unsaturated heterocyclic groups, at least one atom on the ring is saturated and at least one atom is unsaturated; examples of partially unsaturated heterocyclic groups include, but are not limited to, […]. In some embodiments, the partially unsaturated heterocyclic group is a polycyclic heterocyclic group, wherein at least one ring is an aromatic ring and at least one ring is a non-aromatic ring, and it can be linked to other structures through atoms on the aromatic ring or through atoms on the non-aromatic ring. Specifically, the 3-10 membered heterocyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic group. In some embodiments, the heterocyclic group is monocyclic. In some embodiments, the heterocyclic group is polycyclic (e.g., fused ring, spiro ring, or bridged ring).

[0237] In this document, the term "heteroaryl" refers to an aromatic monocyclic or fused-ring group formed by a carbon atom and at least one heteroatom, wherein the heteroatom is independently selected from N, O, and S. Each ring in a heteroaryl group is aromatic. 5-6 membered heteroaryls are monocyclic, and specific examples include, but are not limited to, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine, and pyrazine. Examples of 8-10 membered fused heteroaryls include, but are not limited to, benzopyrrole, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzopyrazole, benzimazole, benzopyridine, benzopyrimidine, benzopyrazine, thiazothiazolyl, pyridopyridine, pyridopyrazine, and pyridopyrimidine.

[0238] In this article, the chemical structural formula Indicates the connection position. When Contained in cyclic groups and not specified When the ring atoms are connected, It can attach to any ring atom, but it is only permitted to form a stable or chemically viable chemical compound. For example, include Structures such as...

[0239] In this document, the term "pharmaceutically acceptable salt" refers to a salt formed from a suitable nontoxic organic acid, inorganic acid, organic base, or inorganic base with a compound, which retains the biological activity of the compound. The organic acid may be one or more of the conventional salt-forming organic acids in the art, preferably methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, hydroxyethylsulfonic acid, naphthalenesulfonic acid, and salicylic acid. The inorganic acid may be one or more of the conventional salt-forming inorganic acids in the art, preferably hydrochloric acid, sulfuric acid, and phosphoric acid. The organic base may be one or more of the conventional salt-forming organic bases in the art, preferably pyridines, imidazoles, pyrazines, indoles, purines, tertiary amines, and anilines. The tertiary amine organic bases are preferably triethylamine and / or N,N-diisopropylethylamine. The aniline organic bases are preferably N,N-dimethylaniline. The pyridine organic base is preferably one or more of pyridine, methylpyridine, 4-dimethylaminopyridine, and 2-methyl-5-ethylpyridine. The inorganic base can be any conventional salt-forming inorganic base in the art, preferably one or more of alkali metal hydrides, alkali metal hydroxides, alkali metal alkoxides, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate, and sodium bicarbonate. The alkali metal hydrides are preferably sodium hydride and / or potassium hydride. The alkali metal hydroxides are preferably one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide. The alkali metal alkoxides are preferably one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium tert-butoxide.

[0240] In this document, the term "subject" includes any animal, preferably a mammal, and more preferably a human.

[0241] In this document, the term "therapeutic effective dose" refers to a sufficient amount of a non-toxic drug or agent that achieves the desired effect. The determination of the effective dose varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective dose in a given case can be determined by a person skilled in the art based on routine testing.

[0242] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0243] All reagents and raw materials used in this paper are commercially available.

[0244] The positive and progressive effects of this invention are as follows: This invention provides a compound with a novel structure, which has good SHP2 inhibitory activity and / or tumor cell inhibitory activity. Detailed Implementation

[0245] The present disclosure is further illustrated below by way of embodiments, but these embodiments are not intended to limit the scope of the present disclosure. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected in accordance with the product instructions.

[0246] Example 1

[0247] (S)-1'-(2,3-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0248]

[0249] Step 1: 4-Azide-6-bromonicoraldehyde

[0250]

[0251] Under N2, trimethylsilane azido (115 mg, 1.0 mmol, 1.0 eq) and TBAF (262 mg, 1.0 mmol, 1.0 eq) were added to a suspension of 4-azido-6-bromonicoraldehyde (221 mg, 1.0 mmol, 1.0 eq) in tetrahydrofuran (10 mL), and the reaction mixture was stirred overnight at 25 °C. After the reaction was complete, water and ethyl acetate were added to the reaction mixture. The organic layer was separated and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography, eluting with hexane and ethyl acetate (ethyl acetate range 0-50%) to give a product as a white solid (146 mg, 64.2%).

[0252] Step 2: (E)-1-(4-azido-6-bromopyridin-3-yl)-N-(2,3-dichlorophenyl)methylimine

[0253]

[0254] At 25 °C, 2,3-dichloroaniline (104 mg, 0.643 mmol, 1.0 eq) was added to a solution of 4-azido-6-bromonicoraldehyde (146 mg, 0.643 mmol, 1.0 eq) in CH₂Cl₂ (20 mL). Then, triethylamine (195 mg, 1929 mmol, 3 eq) and titanium(IV) chloride (73.2 mg, 0.386 mmol, 0.6 eq) were added sequentially at 0 °C. The mixture was stirred at 0 °C for 3 h, then at room temperature for 3 h. The solvent was evaporated under vacuum. The product was suspended in toluene, filtered, and the solution was concentrated to give a crude product as a yellow solid, which was used for the next step without further purification. MS (ESI) m / z 341.9 [m-28+H] +.

[0255] Step 3: 6-Bromo-2-(2,3-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine

[0256]

[0257] A solution of (E)-1-(4-azido-6-bromopyridin-3-yl)-N-(2,3-dichlorophenyl)toluidine (239 mg, 0.644 mmol, 1.0 eq) in toluene (20 mL) was stirred overnight at 110 °C under N2. After cooling to room temperature, the solvent was evaporated under vacuum, and the residue was purified by silica gel rapid column chromatography, eluting with (DCM / CH3OH = 30 / 1) to give a white solid 6-bromo-2-(2,3-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (127 mg, 57.5%). MS (ESI) m / z 342.1 [m+H] + .

[0258] Step 4: N-((S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-thioamide

[0259]

[0260] At 25 °C, N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (40.2 mg, 0.131 mmol, 1.5 eq), BINAP (10.89 mg, 0.017 mmol, 0.2 eq), sodium 2-methylpropane-2-ol (8.41 mg, 0.087 mmol, 1.0 equivalent), and Pd2(dba)3 (8.01 mg, 8.75 μmol, 0.1 equivalent) were added to a solution of 6-bromo-2-(2,3-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (30 mg, 0.087 mmol, 1.0 eq) in dioxane (8 mL). The mixture was stirred in a microwave at 90 °C for 1 h. After cooling to room temperature, the solution was concentrated, and the residue was purified by rapid silica gel column chromatography. Elution with (DCM / CH3OH = 30 / 1) yielded N-((S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolyl[4,3-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (37 mg, 74.4%), a yellow solid. MS (ESI) m / z 568.3 [m+H] + .

[0261] Step 5: (S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0262]

[0263] N-((S)-1'-(2-(2-(2,3-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (37 mg, 0.065 mmol, 1.0 eq) was dissolved in hydrochloric acid / dioxane (3 ml) and stirred at 25 °C for 30 min. The mixture was concentrated and the residue was purified by pre-HPLC to give (S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (3.6 mg, 11.91%), a white solid. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.98 (s, 1H), 8.82 (s, 1H), 7.84 (dd, J = 8.1, 1.2Hz, 1H), 7 .68(dd,J=7.9,1.2Hz,1H),7.60–7.51(m,1H),7.32–7.24(m,1H),7.20–7.06(m,3H),6. 56(s,1H),4.17–4.01(m,2H),3.83(s,1H),3.08–2.92(m,3H),2.60(d,J=15.6Hz,1H),1 .89–1.74(m,1H),1.75–1.63(m,1H),1.51–1.39(m,1H),1.16–1.04(m,1H).MS(ESI)m / z 464.4[M+H] + .

[0264] Compounds of Examples 2-7 were prepared according to Example 1.

[0265] Example 2

[0266] (S)-1'-(2,3-dichlorobenzyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0267]

[0268] 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.86 (s, 1H), 8.54 (s, 1H), 7.60 (d, J = 8.0Hz, 1H), 7.3 9–7.22(m,2H),7.20–7.07(m,3H),7.03(d,J=7.6Hz,1H),6.50(s,1H),5.69(s,2H) ,4.09–3.87(m,2H),3.80(s,1H),3.04–2.81(m,3H),2.57(d,J=15.6Hz,1H),1.86– 1.73(m,1H),1.76–1.60(m,1H),1.51–1.39(m,1H),1.13–0.99(m,1H).MS(ESI)m / z 478.3[M+H] + .

[0269] Example 3

[0270] (1S)-1'-(2-(2,3-dihydro-1H-inden-1-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0271]

[0272] 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.82(s,1H),8.43(s,1H),7.40–7.32(m,1H),7.33–7.22(m ,2H),7.19–6.99(m,5H),6.48(s,1H),6.18–6.04(m,1H),4.10–3.89(m,2H),3.79(s,1H) ,3.29–3.13(m,1H),3.06–2.81(m,5H),2.75–2.62(m,1H),2.62–2.43(m,1H),1.90–1.74 (m,1H),1.74–1.58(m,1H),1.53–1.37(m,1H),1.16–0.98(m,1H).MS(ESI)m / z436.4[M+H] + .

[0273] Example 4

[0274] (S)-1'-(2-(3-chloro-2-fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0275]

[0276] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.00(s,1H),8.92(s,1H),7.95–7.85(m,1H),7.76– 7.66(m,1H),7.46–7.38(m,1H),7.34–7.25(m,1H),7.21–7.07(m,3H),6.58(s,1H) ,4.17–4.01(m,2H),3.82(s,1H),3.11–2.90(m,3H),2.60(d,J=15.6Hz,1H),1.89– 1.76(m,1H),1.76–1.62(m,1H),1.56–1.40(m,1H),1.15–1.04(m,1H); MS(ESI)m / z 449.4[M+H] + .

[0277] Example 5

[0278] (S)-1'-(2-(3-chloro-2-methylphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0279]

[0280] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.00 (s, 1H), 8.74 (s, 1H), 7.68 (d, J = 7.7Hz, 1H), 7.55– 7.39(m,2H),7.37–7.28(m,1H),7.27–7.08(m,3H),6.63(s,1H),4.24–4.02(m,2H),3 .85(s,1H),3.13–2.91(m,3H),2.62(d,J=15.6Hz,1H),2.51(s,2H),2.17(s,3H),1.9 4–1.80(m,1H),1.80–1.68(m,1H),1.60–1.43(m,1H),1.21–1.05(m,1H).MS(ESI)m / z 445.4[M+H] + .

[0281] Example 6

[0282] (1S)-1'-(2-(1,2,3,4-tetrahydronaphthyl-1-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0283]

[0284] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.83 (s, 1H), 8.29 (s, 1H), 7.29 (d, J = 6.2Hz, 1H), 7.24–7.10 (m, 5H), 7.10 –7.02(m,1H),6.75(d,J=7.7Hz,1H),6.52(s,1H),5.88–5.76(m,1H),4.10–3.94(m,2H),3.82(s,1H),3 .08–2.85(m,4H),2.85–2.75(m,1H),2.59(d,J=15.6Hz,1H),2.43–2.29(m,1H),2.29–2.14(m,1H),1.9 9–1.88(m,1H),1.88–1.75(m,2H),1.76–1.63(m,1H),1.53–1.42(m,1H),1.16–1.04(m,1H).MS(ESI)m / z 450.5[M+H] + .

[0285] Example 7

[0286] (S)-1'-(2-(naphth-1-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0287]

[0288] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.03(s,1H),8.86(s,1H),8.16–8.03(m,2H),7 .79–7.50(m,5H),7.37–7.23(m,1H),7.22–7.06(m,3H),6.66(s,1H),4.22–4. 02(m,2H),3.84(s,1H),3.10–2.94(m,3H),2.61(d,J=15.6Hz,1H),1.94–1.80 (m,1H),1.80–1.66(m,1H),1.57–1.42(m,1H),1.19–1.06(m,1H).MS(ESI)m / z 446.4[M+H] +

[0289] Example 8

[0290] (S)-1'-(4-amino-2-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0291]

[0292] Step 1: 4-Azide-6-chloro-2-(methylthio)pyrimidine-5-carboxaldehyde

[0293]

[0294] To a solution of 4,6-dichloro-2-(methylthio)pyrimidin-5-carboxaldehyde (779 mg, 3.53 mmol, 1.0 eq) in tetrahydrofuran (10 mL), trimethyl azidosilane (407 mg, 3.53 mmol, 1.0 eq) and TBAF (924 mg, 3.53 mmol, 1.0 eq) were added sequentially, and the mixture was stirred overnight at 25 °C. Water was added to the mixture, the solution was extracted with ethyl acetate, the organic layer was washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid silica gel column chromatography, eluting with PE / EA = 4 / 1, to give a white solid 4-azido-6-bromonaphthal (536 mg, 66.8%).

[0295] Step 2: (E)-1-(4-azido-6-chloro-2-(methylthio)pyrimidin-5-yl)-N-(2,3-dichlorophenyl)methylimine

[0296]

[0297] 2,3-Dichloroaniline (437 mg, 2.70 mmol, 1.0 eq), triethylamine (820 mg, 8.10 mmol, 3.0 eq), and titanium tetrachloride (307 mg, 1.620 mmol, 0.6 eq) were sequentially added to a solution of 4-azido-6-chloro-2-(methylthio)pyrimidin-5-carboxaldehyde (620 mg, 2.70 mmol, 1.0 eq) in CH2Cl2 (20 mL) at 0 °C. The mixture was stirred at 0 °C for 3 h, then stirred at room temperature for 3 h. After concentration, the residue was suspended in toluene. The solution was filtered and concentrated to give a yellow solid (E)-1-(4-azido-6-chloro-2-(methylthio)pyrimidin-5-yl)-N-(2,3-dichlorophenyl)methylimine (1009 mg, 100%). MS (ESI) m / z 345.0 [M-28+H] + .

[0298] Step 3: 4-Chloro-2-(2,3-dichlorophenyl)-6-(methylthio)-2H-pyrazolo[3,4-d]pyrimidine

[0299]

[0300] Under N2, a solution of (E)-1-(4-azido-6-chloro-2-(methylthio)pyrimidin-5-yl)-N-(2,3-dichlorophenyl)methylimine (1.0 g, 2.68 mmol, 1.0 eq) in toluene (20 mL) was stirred overnight at 110 °C. The solution was concentrated, and the residue was purified by silica gel rapid column chromatography, eluting with DCM / CH3OH = 30 / 1, to give a white solid 4-chloro-2-(2,3-dichlorophenyl)-6-(methylthio)-2H-pyrazolo[3,4-d]pyrimidine (580 mg, 62.7%).

[0301] MS(ESI) m / z 345.1 [M+H] + .

[0302] Step 4: 2-(2,3-dichlorophenyl)-N-(2,4-dimethoxybenzyl)-6-(methylthio)-2H-pyrazolo[3,4-d]pyrimidine-4-amine

[0303]

[0304] Add (2,4-dimethoxyphenyl)methylamine (116 mg, 0.694 mmol, 1.2 eq) and N-ethyl-N-isopropylpropane-2-amine (112 mg, 0.868 mmol, 1.5 eq) to a solution of 4-chloro-2-(2,3-dichlorophenyl)-6-(methylthio)-2H-pyrazolo[3,4-d]pyrimidine (200 mg, 0.579 mmol, 1.0 eq) in dimethyl sulfoxide (10 mL) and stir at 25 °C for 2 h. Then add water and ethyl acetate to the mixture. Wash the combined organic layers with brine (100 mL), dry with Na₂SO₄, filter, and concentrate. The residue was purified by rapid silica gel column chromatography, eluting with PE / EA = 1 / 1, to give a white solid 2-(2,3-dichlorophenyl)-N-(2,4-dimethoxybenzyl)-6-(methylthio)-2H-pyrazolo[3,4-d]pyrimidine-4-amine (262 mg, 95%). MS (ESI) m / z 477.6 [M+H] + .

[0305] Step 5: 2-(2,3-dichlorophenyl)-N-(2,4-dimethoxybenzyl)-6-(methyl sulfoxide)-2H-pyrazolo[3,4-d]pyrimidine-4-amine

[0306]

[0307] Add 1-chloro-3-hydroperoxybenzyl (80 mg, 0.550 mmol, 1.0 eq) to a solution of 2-(2,3-dichlorophenyl)-N-(2,4-dimethoxybenzyl)-6-(methylthio)-2H-pyrazolo[3,4-d]pyrimidin-4-amine (262 mg, 0.550 mmol, 1.0 eq) in CH2Cl2 (10 mL). Stir the mixture at 0 °C for 30 min. Add saturated NaHCO3 (aq) to the mixture. Extract the solution with ethyl acetate, wash the organic layer with brine (100 mL), dry with Na2SO4, filter and concentrate to give a white solid 2-(2,3-dichlorophenyl)-N-(2,4-dimethoxybenzyl)-6-(methylsulfinyl)-2H-pyrazolo[3,4-d]pyrimidin-4-amine (270 mg, 100%).

[0308] Step 6: N-((S)-1'-(2-(2,3-dichlorophenyl)-4-((2,4-dimethoxybenzyl)amino)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0309]

[0310] At room temperature, N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (84 mg, 0.274 mmol, 1.5 eq) and N-ethyl-N-isopropylpropylamine-2 (70.9 mg, 0.548 mmol, 3.0 eq) were added to a solution of 2-(2,3-dichlorophenyl)-N-(2,4-dimethoxybenzyl)-6-(methylsulfonylurea)-2H-pyrazolo[3,4-d]pyrimidin-4-amine (90 mg, 0.183 mmol, 1.0 eq) in butanol (5 mL). The mixture was stirred at 140 °C under N2 for 1.5 h. Water and ethyl acetate were added to the mixture. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography, eluting with DCM / CH3OH = 50 / 1, to give N-((S)-1-(2,3-dichlorophenyl)-4-((2,4-dimethoxybenzyl)amino)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (75 mg, 55.8%) as a white solid.

[0311] MS(ESI) m / z 736.4 [M+H] +

[0312] Step 7: (S)-1'-(4-amino-2-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0313]

[0314] Under N2, N-((S)-1'-(2-(2,3-dichlorophenyl)-4-((2,4-dimethoxybenzyl)amino)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (90 mg, 0.122 mmol, 1.0 eq) was stirred at 60 °C for 2 hours. After concentration, it was dissolved in HCl / dioxane (8 mL). The mixture was stirred at room temperature for 2 hours, and the solution was concentrated. Ammonia-methanol solution was added to the residue. The solution was concentrated and the residue was purified by pre-HPLC to give a white solid (S)-1'-(4-amino-2-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (5.5 mg, 9.35%). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.50 (s, 1H), 7.80 (d, J = 8.0Hz, 1H), 7.69 (d, J = 7.0Hz ,1H),7.57(t,J=8.1Hz,1H),7.52–7.38(m,1H),7.36–7.28(m,1H),7.26–7.11(m,3H ),4.73–4.56(m,2H),3.86(s,1H),3.20–3.01(m,3H),2.66(d,J=15.6Hz,1H),1.81 –1.66(m,1H),1.67–1.53(m,1H),1.49–1.39(m,1H),1.14–1.01(m,1H).MS(ESI)m / z 480.3[M+H] + .

[0315] Example 9

[0316] (S)-1'-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0317]

[0318] Step 1: 4-Azide-2-(methylthio)pyrimidine-5-carboxaldehyde

[0319]

[0320] Add trimethyl azidosilane (305 mg, 2.65 mmol, 1.0 eq) and TBAF (693 mg, 2.65 mmol, 1.0 eq) to a tetrahydrofuran (10 mL) solution of 4-chloro-2-(methylthio)pyrimidine-5-carboxaldehyde (500 mg, 2.65 mmol, 1.0 eq). Stir the mixture at 0 °C for 3 h. Add water and ethyl acetate to the reaction mixture. Separate the organic layer, wash with brine (100 mL), dry to anhydrous Na₂SO₄, filter, and concentrate. Purify the residue by rapid silica gel column chromatography, eluting with PE / EA = 4 / 1, to give a white solid 4-azido-2-(methylthio)pyrimidine-5-carboxaldehyde (460 mg, 89%). MS (ESI) m / z 168.1 [M-28+H] +

[0321] Step 2: (E)-1-(4-azido-2-(methylthio)pyrimidin-5-yl)-N-(2,3-dichlorophenyl)methylimine

[0322]

[0323] To a solution of 4-azido-2-(methylthio)pyrimidine-5-carboxaldehyde (516 mg, 2.64 mmol, 1.0 eq) in CH₂Cl₂ (20 mL), 2,3-dichloroaniline (428 mg, 2.64 mmol, 1.0 eq), triethylamine (802 mg, 7.93 mmol, 3.0 eq), and titanium tetrachloride (301 mg, 1.586 mmol, 0.6 eq) were added sequentially. The mixture was stirred at 0 °C for 3 h, followed by stirring at rt for 3 h. After concentration, the product was suspended in toluene. The solution was filtered and concentrated to give a crude product (897 mg, 100%) as a yellow solid, which was used for the next step without further purification. MS (ESI) m / z 311.1 [M-28+H] +

[0324] Step 3: 2-(2,3-dichlorophenyl)-6-(methylthio)-2H-pyrazolo[3,4-d]pyrimidine

[0325]

[0326] Under N2, a solution of (E)-1-(4-azido-2-(methylthio)pyrimidin-5-yl)-N-(2,3-dichlorophenyl)methylimine (897 mg, 2.64 mmol, 1.0 eq) in toluene (20 mL) was stirred overnight at 110 °C. After concentration, the crude product was purified by rapid silica gel column chromatography, eluting with DCM / CH3OH = 30 / 1, to give a yellow solid 2-(2,3-dichlorophenyl)-6-(methylthio)-2H-pyrazolo[3,4-d]pyrimidine (442 mg, 53.7%). MS (ESI) m / z 311.2 [M+H] +

[0327] Step 4: 2-(2,3-dichlorophenyl)-6-(methyl sulfoxide)-2H-pyrazolo[3,4-d]pyrimidine

[0328]

[0329] To a solution of 2-(2,3-dichlorophenyl)-6-(methylthio)-2H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.321 mmol, 1.0 eq) in CH₂Cl₂ (10 mL), 1-chloro-3-hydroperoxybenzene (46.5 mg, 0.321 mmol, 1.0 eq) was added, and the mixture was stirred at 0 °C for 30 min. Saturated NaHCO₃ (aq) was slowly added. The solution was extracted with ethyl acetate, the organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give a yellow solid of 2-(2,3-dichlorophenyl)-6-(methylsulfoxide)-2H-pyrazolo[3,4-d]pyrimidine (105 mg, 100%). MS (ESI) m / z 327.2 [M+H] + .

[0330] Step 5: N-((S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0331]

[0332] Under N2, N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (148 mg, 0.481 mmol, 1.5 eq) and N-ethyl-N-isopropylpropane-2-amine (124 mg, 0.963 mmol, 3 eq) were added to a butanol (5 mL) solution of 2-(2,3-dichlorophenyl)-6-(methylsulfonylurea)-2H-pyrazolo[3,4-d]pyrimidine (105 mg, 0.321 mmol, 1.0 eq) and stirred at 140 °C for 1.5 h. Water and ethyl acetate were added. The organic layer was separated, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel column chromatography, eluting with DCM / CH3OH = 50 / 1, to give N-((S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (83 mg, 45.4%) as a white solid. MS (ESI) m / z 571.3 [M+H] +

[0333] Step 6: (S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0334]

[0335] HCl / dioxane (8 mL) was added to a solution of N-((S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (90 mg, 0.158 mmol, 1.0 eq) in dioxane. The mixture was stirred at room temperature for 2 hours. After concentration, ammonia-methanol solution was added. The solution was concentrated again. The crude product was purified by pre-HPLC to give a white solid (S)-1'-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (13.6 mg, 18.49%). 1H NMR (400MHz, DMSO-d6) δ (ppm) 9.19 (s, 1H), 8.74 (s, 1H), 7.83 (d, J = 8.1Hz, 1H), 7.70–7.63(m,1H),7.61–7.49(m,1H),7.31–7.23(m,1H),7.20–7.04(m,3H),4.6 8–4.47(m,2H),3.80(s,1H),3.19–3.00(m,3H),2.62(d,J=15.6Hz,1H),1.79–1. 67(m,1H),1.65–1.53(m,1H),1.51–1.40(m,1H),1.14–0.99(m,1H); MS(ESI)m / z 465.4 [M+H] +

[0336] Compounds of Examples 10-40 were prepared according to Example 9.

[0337] Example 10

[0338] (S)-1'-(2-chloro-3-methylphenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0339]

[0340] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.22(s,1H),8.70(s,1H),7.60–7.41(m,3H),7. 37–7.26(m,1H),7.25–7.10(m,3H),4.72–4.52(m,2H),3.84(s,1H),3.26–3.17 (m,2H),3.13(d,J=11.3Hz,1H),2.65(d,J=15.6Hz,1H),2.46(s,3H),1.82–1.7 1(m,1H),1.70–1.57(m,1H),1.57–1.45(m,1H),1.16–1.05(m,1H); MS(ESI)m / z 445.8 [M+H] + .

[0341] Example 11

[0342] (S)-1'-(2-chloro-6-methylphenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0343]

[0344] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.26(s,1H),8.65(s,1H),7.65–7.44(m,3H),7. 40–7.29(m,1H),7.30–7.11(m,3H),4.79–4.54(m,2H),3.88(s,1H),3.30–3.21 (m,2H),3.15(d,J=15.5Hz,1H),2.68(d,J=15.5Hz,1H),2.07(s,3H),1.90–1.7 6(m,1H),1.76–1.63(m,1H),1.62–1.47(m,1H),1.23–1.08(m,1H); MS(ESI)m / z 445.4[M+H] +

[0345] Example 12

[0346] (S)-1'-(2,6-dichlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0347]

[0348] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.24(s,1H),8.72(s,1H),7.81–7.70(m,2H),7.70 –7.58(m,1H),7.36–7.26(m,1H),7.23–7.06(m,3H),4.80–4.42(m,2H),3.84(s, 1H),3.33–3.16(m,2H),3.11(d,J=15.6Hz,1H),2.65(d,J=15.6Hz,1H),1.87–1. 70(m,1H),1.70–1.57(m,1H),1.58–1.44(m,1H),1.16–1.02(m,1H); MS(ESI)m / z 465.4 [M+H] +

[0349] Example 13

[0350] (S)-1'-(2-(3-bromo-2-chlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0351]

[0352] 1H NMR(400MHz,DMSO-d6)δ(ppm)9.19(s,1H),8.73(s,1H),7.95(dd,1H),7.68(dd,J=7.9,1 .1Hz,1H),7.54–7.42(m,1H),7.34–7.22(m,1H),7.22–7.07(m,3H),4.68–4.48(m,2H),3. 82(s,1H),3.27–3.14(m,2H),3.07(d,J=15.7Hz,1H),2.63(d,J=15.6Hz,1H),1.78–1.66 (m,1H),1.66–1.52(m,1H),1.52–1.40(m,1H),1.14–1.02(m,1H); MS(ESI)m / z511.4[M+H] +

[0353] Example 14

[0354] (S)-1'-(2-chloro-4,5-difluorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0355]

[0356] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.25(s,1H),8.78(s,1H),8.18–7.96(m,2H), 7.40–7.26(m,1H),7.27–7.05(m,3H),4.76–4.51(m,2H),3.84(s,1H),3.32 –3.18(m,2H),3.13(d,J=15.6Hz,1H),2.66(d,J=15.5Hz,1H),1.86–1.71(m ,1H),1.71–1.57(m,1H),1.57–1.40(m,1H),1.17–1.04(m,1H); MS(ESI)m / z 467.4[M+H] + .

[0357] Example 15

[0358] (S)-1'-(2-chloro-3-fluorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0359]

[0360] 1H NMR(400MHz,DMSO-d6)δ(ppm)9.25(s,1H),8.82(s,1H),7.74–7.54(m,3H), 7.42–7.26(m,1H),7.25–7.04(m,3H),4.75–4.51(m,2H),3.84(s,1H),3.34 –3.16(m,2H),3.12(d,J=15.6Hz,1H),2.66(d,J=15.7Hz,1H),1.83–1.71(m ,1H),1.72–1.58(m,1H),1.58–1.40(m,1H),1.18–1.01(m,1H); MS(ESI)m / z 449.4[M+H] +

[0361] Example 16

[0362] (S)-1'-(2-chloro-3-methoxyphenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0363]

[0364] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.22 (s, 1H), 8.73 (s, 1H), 7.53 (t, J = 8.2Hz, 1H), 7.43 –7.33(m,1H),7.32–7.25(m,2H),7.26–7.09(m,3H),4.76–4.50(m,2H),3.97(s,3H), 3.84(s,1H),3.32–3.17(m,1H),3.13(d,J=15.6Hz,1H),2.66(d,J=15.7Hz,1H),1.8 4–1.72(m,1H),1.71–1.60(m,1H),1.59–1.45(m,1H),1.19–1.04(m,1H); MS(ESI)m / z 461.4[M+H] +

[0365] Example 17

[0366] (S)-1'-(2-(pyridin-4-yl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0367]

[0368] 1H NMR (400MHz, DMSO-d6) δ (ppm) 9.27 (s, 1H), 9.24 (s, 1H), 8.73 (dd, J = 4.8, 1.5Hz, 2H), 8. 03(dd,J=4.8,1.6Hz,2H),7.37–7.23(m,1H),7.23–7.04(m,3H),4.74–4.50(m,2H),3.83 (s,1H),3.27–3.17(m,2H),3.10(d,J=15.6Hz,1H),2.64(d,J=15.7Hz,1H),1.81–1.70( m,1H),1.71–1.56(m,1H),1.60–1.46(m,1H),1.20–1.01(m,1H); MS(ESI)m / z398.3[M+H] +

[0369] Example 18

[0370] (S)-1'-(2-chloro-6-methoxyphenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0371]

[0372] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.16(s,1H),8.52(s,1H),7.64–7.50(m,1H),7. 33–7.21(m,3H),7.21–7.07(m,3H),4.71–4.47(m,2H),3.82(s,1H),3.75(s,3H ),3.27–3.13(m,2H),3.09(d,J=15.7Hz,1H),2.63(d,J=15.6Hz,1H),1.80–1.6 8(m,1H),1.69–1.55(m,1H),1.54–1.41(m,1H),1.15–1.01(m,1H); MS(ESI)m / z 461.3[M+H] +

[0373] Example 19

[0374] (S)-3-(6-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-2-chlorophenol

[0375]

[0376] 1H NMR(400MHz, DMSO-d6)δ(ppm)9.19(s,1H),8.67(s,1H),7.38–7.24(m,2H),7.25–6.95(m,5H),4.72–4.46(m,2H),3.84(s,1H),3.32–3. 15(m,2H),3.10(d,J=15.7Hz,1H),2.65(d,J=15.6Hz,1H),1.84–1.69(m,1H),1.69–1.56(m,1H),1.56–1.40(m,1H),1.16–0.99(m,1H).

[0377] Example 20

[0378] (S)-2-(6-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-3-chlorophenol

[0379]

[0380] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.18(s,1H),8.52(s,1H),7.40–7.28(m,2H), 7.27–7.12(m,3H),7.12–6.93(m,2H),4.73–4.46(m,2H),3.87(s,1H),3.33 –3.19(m,2H),3.13(d,J=15.7Hz,1H),2.68(d,J=15.7Hz,1H),1.85–1.72(m ,1H),1.73–1.58(m,1H),1.59–1.44(m,1H),1.18–1.07(m,1H); MS(ESI)m / z 447.4[M+H] +

[0381] Example 21

[0382] (S)-1'-(2-(3-amino-2-chlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0383]

[0384] MS(ESI) m / z 446.4 [M+H] +

[0385] Example 22

[0386] (S)-1'-(2-(2-chloro-6-isopropylphenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0387]

[0388] MS(ESI) m / z 473.3 [M+H] +

[0389] Example 23

[0390] (S)-1'-(2-(2-chloro-6-ethylphenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0391]

[0392] MS(ESI) m / z 459.4 [M+H] +

[0393] Example 24

[0394] (S)-1'-(2-(2,6-dichloro-4-fluorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0395]

[0396] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.23 (s, 1H), 8.68 (s, 1H), 7.85 (d, J = 8.4Hz, 2 H),7.36–7.25(m,1H),7.24–7.04(m,3H),4.70–4.50(m,2H),3.87(s,1H),3. 27–3.16(m,2H),3.10(d,J=15.7Hz,1H),2.67(d,J=15.7Hz,1H),1.87–1.70( m,1H),1.67–1.56(m,1H),1.54–1.42(m,1H),1.20–1.06(m,1H); MS(ESI)m / z 483.5[M+H] +

[0397] Example 25

[0398] (S)-1'-(2-(2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0399]

[0400] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.18(s,1H),8.53(s,1H),7.43–7.32(m,1H),7. 32–7.23(m,3H),7.23–7.11(m,3H),4.72–4.51(m,2H),3.83(s,1H),3.31–3.15 (m,2H),3.10(d,J=15.6Hz,1H),2.64(d,J=15.6Hz,1H),1.96(s,6H),1.82–1.7 0(m,1H),1.71–1.58(m,1H),1.58–1.43(m,1H),1.16–1.04(m,1H); MS(ESI)m / z 425.5 [M+H] +

[0401] Example 26

[0402] (S)-2-(6-(1-amino-1,3-dihydrospiro[inden-2,4'-piperidin]-1'-yl)-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-3-chlorobenzonitrile

[0403]

[0404] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.30 (s, 1H), 8.86 (s, 1H), 8.13 (d, J = 8.0Hz, 2H), 7.83 (t ,J=8.0Hz,1H),7.34–7.26(m,1H),7.26–7.07(m,3H),4.73–4.44(m,2H),3.85(s,1H),3 .31–3.17(m,2H),3.12(d,J=15.6Hz,1H),2.66(d,J=15.6Hz,1H),2.05–1.92(m,1H),1 .83–1.73(m,1H),1.72–1.59(m,1H),1.57–1.48(m,1H),1.17–1.04(m,1H); MS(ESI)m / z 456.4[M+H] +

[0405] Example 27

[0406] (S)-1'-(2-(2-chloro-6-(trifluoromethyl)phenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0407]

[0408] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.28 (s, 1H), 8.76 (s, 1H), 8.13 (d, J = 8.0Hz, 1H), 8.03 (d, J=7.6Hz,1H),7.90(t,J=8.1Hz,1H),7.38–7.29(m,1H),7.28–7.11(m,3H),4.77–4.51( m,2H),3.87(s,1H),3.33–3.20(m,2H),3.14(d,J=15.6Hz,1H),2.68(d,J=15.6Hz,1H), 1.84–1.75(m,1H),1.75–1.61(m,1H),1.58–1.49(m,1H),1.20–1.07(m,1H); MS(ESI)m / z 499.7[M+H] +

[0409] Example 28

[0410] (S)-4-(6-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-3,5-dichlorobenzonitrile

[0411]

[0412] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.30(s,1H),8.77(s,1H),8.46(s,2H),7.3 7–7.27(m,1H),7.27–7.11(m,4H),4.75–4.51(m,2H),3.86(s,1H),3.32–3 .20(m,2H),3.14(d,J=15.6Hz,1H),2.68(d,J=15.4Hz,1H),1.86–1.73(m, 1H),1.72–1.61(m,1H),1.61–1.44(m,1H),1.21–1.06(m,1H); MS(ESI)m / z 490.3[M+H] +

[0413] Example 29

[0414] (S)-1'-(2-(2,6-dichloro-3-methylphenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0415]

[0416] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.26(s,1H),8.71(s,1H),7.67(s,2H),7.32(d, J=6.1Hz,1H),7.25–7.09(m,3H),4.78–4.52(m,2H),3.86(s,1H),3.32–3.18( m,2H),3.14(d,J=15.7Hz,1H),2.67(d,J=15.5Hz,1H),2.45(s,3H),1.85–1.7 2(m,1H),1.72–1.61(m,1H),1.61–1.46(m,1H),1.17–1.07(m,1H); MS(ESI)m / z 479.3 [M+H] +

[0417] Example 30

[0418] (S)-1'-(2-(1H-indazol-4-yl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0419]

[0420] 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.47(s,1H),9.22(s,1H),9.16(s,1H),8.56(s,1H),7.68(d,J =7.4Hz,1H),7.62(d,J=8.3Hz,1H),7.57–7.44(m,1H),7.38–7.27(m,1H),7.27–7.09(m,4H), 4.83–4.49(m,2H),3.89(s,1H),3.34–3.19(m,2H),3.12(d,J=15.7Hz,1H),2.69(d,J=15.7Hz ,1H),1.83–1.71(m,1H),1.73–1.58(m,1H),1.55–1.43(m,1H),1.18–1.05(m,1H); MS(ESI)m / z 437.7[M+H] +

[0421] Example 31

[0422] (S)-1'-(2-(6-chloroquinolin-5-yl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0423]

[0424] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.31 (s, 1H), 9.04 (dd, J = 3.5, 2.3Hz, 1H), 8.86 (s, 1H), 8.31 (d, J=9.1Hz,1H),8.09(d,J=9.1Hz,1H),7.75–7.52(m,2H),7.38–7.27(m,1H),7.26–7.09(m,3H), 4.77–4.55(m,2H),3.86(s,1H),3.33–3.18(m,2H),3.14(d,J=15.6Hz,1H),2.67(d,J=15.7Hz ,1H),1.87–1.73(m,1H),1.72–1.61(m,1H),1.59–1.47(m,1H),1.18–1.07(m,1H); MS(ESI)m / z 482.4[M+H] +

[0425] Example 32

[0426] (S)-1'-(2-(7-chloroquinolin-8-yl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0427]

[0428] 1H NMR(400MHz, DMSO-d6)δ(ppm)9.24(s,1H),8.88(dd,J=4.2,1.6Hz,1H),8.68(s,1H),8.58(dd,J=8.4 ,1.6Hz,1H),8.29(d,J=8.9Hz,1H),7.93(d,J=8.9Hz,1H),7.80–7.55(m,1H),7.34–7.23(m,1H),7.23 –7.04(m,3H),4.76–4.48(m,2H),3.83(s,1H),3.29–3.16(m,1H),3.11(d,J=15.7Hz,1H),2.65(d,J= 15.6Hz,1H),1.88–1.71(m,1H),1.70–1.57(m,1H),1.56–1.43(m,1H),1.16–1.00(m,1H); MS(ESI)m / z 482.5[M+H] +

[0429] Example 33

[0430] (S)-1'-(2-(2,4-dichloronaphthyl-1-yl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indenyl-2,4'-piperidine]-1-amine

[0431]

[0432] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.30 (s, 1H), 8.83 (s, 1H), 8.33 (d, J = 8.5Hz, 1H), 8.19 (s, 1 H),7.91–7.81(m,1H),7.78–7.67(m,1H),7.37–7.27(m,1H),7.24–7.09(m,4H),4.80–4.5 4(m,2H),3.85(s,1H),3.32–3.19(m,2H),3.13(d,J=15.6Hz,1H),2.67(d,1H),1.88–1.74 (m,1H),1.71–1.59(m,1H),1.59–1.42(m,1H),1.18–1.02(m,1H); MS(ESI)m / z515.4[M+H] +

[0433] Example 36

[0434] (S)-1'-(2-(2-methylquinolin-8-yl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0435]

[0436] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.53 (s, 1H), 9.25 (s, 1H), 8.42 (d, J = 8.3Hz, 1H), 8.31 (d, J = 7.5Hz, 1H) ,8.02(d,J=7.8Hz,1H),7.78–7.64(m,1H),7.57(d,J=8.4Hz,1H),7.39–7.25(m,1H),7.23–7.05(m,3H ),4.77–4.51(m,2H),3.83(s,1H),3.30–3.18(m,2H),3.10(d,J=15.5Hz,1H),2.71(s,3H),2.64(d,J= 15.6Hz,1H),1.83–1.68(m,1H),1.72–1.56(m,1H),1.55–1.38(m,1H),1.15–1.03(m,1H); MS(ESI)m / z 462.4[M+H] +

[0437] Example 35

[0438] (S)-(2-(6-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-3-chlorophenyl)methanol

[0439]

[0440] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.22(s,1H),8.62(s,1H),7.70–7.58(m,3H),7.41 –7.25(m,1H),7.23–7.06(m,3H),5.47–5.25(m,1H),4.80–4.49(m,2H),4.20(s,2 H),3.83(s,1H),3.31–3.17(m,2H),3.14(d,1H),2.65(d,J=15.6Hz,1H),1.88–1 .71(m,1H),1.69–1.56(m,1H),1.57–1.41(m,1H),1.15–0.98(m,1H); MS(ESI)m / z 461.7 [M+H]+

[0441] Example 36

[0442] (S)-1'-(2-(5-chlorobenzo[d][1,3]dioxolane-4-yl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0443]

[0444] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.22(s,1H),8.68(s,1H),7.37–7.24(m,1H ),7.23–7.07(m,5H),6.18(s,2H),4.72–4.47(m,2H),3.83(s,1H),3.30–3 .15(m,2H),3.11(d,J=15.6Hz,1H),2.65(d,J=15.7Hz,1H),1.82–1.70(m, 1H),1.70–1.56(m,1H),1.56–1.43(m,1H),1.19–1.01(m,1H); MS(ESI)m / z 475.5[M+H] +

[0445] Example 37

[0446] (S)-1'-(2,6-dichlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-5-amine

[0447]

[0448] MS(ESI) m / z 466.2 [M+H] +

[0449] Example 38

[0450] (S)-1'-(2-(5-chloro-1H-indazol-4-yl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0451]

[0452] MS(ESI) m / z 471.7 [M+H] +

[0453] Example 39

[0454] (S)-1'-(2-(5,7-dichloroquinoline-6-yl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0455]

[0456] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.33 (s, 1H), 9.24 (d, J = 3.7Hz, 2H), 8.85 (s, 1H), 8.60(s,1H),7.43–7.28(m,1H),7.28–7.10(m,3H),4.79–4.58(m,2H),3.88(s,1 H),3.34–3.19(m,2H),3.15(d,J=15.7Hz,1H),2.69(d,J=15.7Hz,1H),1.90–1. 76(m,1H),1.75–1.60(m,1H),1.61–1.50(m,1H),1.20–1.07(m,1H); MS(ESI)m / z 517.2[M+H] +

[0457] Example 40

[0458] (S)-1'-(2-(5,7,8-trichloroquinoxalin-6-yl)-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0459]

[0460] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.38–9.29(m,1H),8.84(s,1H),7.41–7.30(m,1H),7.30–7.14(m,1H),4.81–4.56(m,2H),3.90(s,1H),3.35–3.23 (m,2H),3.16(d,J=15.7Hz,1H),2.71(d,J=15.4Hz,1H),1.89–1.76(m,1 H),1.76–1.62(m,1H),1.64–1.48(m,1H),1.24–1.08(m,1H); MS(ESI)m / z 551.4[M+H] +

[0461] Example 41:

[0462] (S)-1'-(2,3-dichlorophenyl)-4-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0463]

[0464] Step 1: 2-(2,3-dichlorophenyl)-4-methyl-6-(methylthio)-2H-pyrazolo[3,4-d]pyrimidine

[0465]

[0466] To a solution of 4-chloro-2-(2,3-dichlorophenyl)-6-(methylthio)-2H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.289 mmol, 1.0 eq) in dioxane (12 mL) / water (3 mL), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboranecyclohexane (363 mg, 1.447 mmol, 5.0 eq), Na₂CO₃ (153 mg, 1.447 mmol, 5.0 eq), and PdCl₂ (dppf) (42.3 mg, 0.058 mmol, 0.2 eq) were added. The mixture was stirred at 110 °C for 3 hours. Water and ethyl acetate were added to the solution. The organic layer was separated, washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid silica gel column chromatography, eluting with PE / EA = 1 / 1, to give a white solid 2-(2,3-dichlorophenyl)-4-methyl-6-(methylthio)-2H-pyrazolo[3,4-d]pyrimidine (36 mg, 38.3%). MS (ESI) m / z 325.2 [M+H] +

[0467] Step 2: 2-(2,3-dichlorophenyl)-4-methyl-6-(methyl sulfoxide)-2H-pyrazolo[3,4-d]pyrimidine

[0468]

[0469] 1-Chloro-3-hydroperoxybenzene (16.00 mg, 0.111 mmol, 1.0 eq) was added to a solution of 2-(2,3-dichlorophenyl)-4-methyl-6-(methylthio)-2H-pyrazolo[3,4-d]pyrimidine (36 mg, 0.111 mmol, 1.0 eq) in CH2Cl2 (10 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min. Saturated NaHCO3 (aq) was added to the reaction mixture. The solution was extracted with ethyl acetate. The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to give a yellow solid of 2-(2,3-dichlorophenyl)-4-methyl-6-(methylsulfoxide)-2H-pyrazolo[3,4-d]pyrimidine (37.8 mg, 100%).

[0470] Step 3: N-((S)-1'-(2-(2,3-dichlorophenyl)-4-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0471]

[0472] To a solution of 2-(2,3-dichlorophenyl)-4-methyl-6-(methylsulfoxide)-2H-pyrazolo[3,4-d]pyrimidine (37.8 mg, 0.111 mmol, 1.0 eq) in butane-1-ol (5 mL), N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (40.7 mg, 0.133 mmol, 1.2 eq) and N-ethyl-N-isopropylpropane-2-amine (43.0 mg, 0.332 mmol, 3 eq) were added. The mixture was stirred in a microwave at 130 °C for 1.0 h. Water and ethyl acetate were added, the organic layer was separated, washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a column and eluted with DCM / CH3OH = 50 / 1 to give N-((S)-1'-(2-(2,3-dichlorophenyl)-4-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (40 mg, 61.9%) as a white solid. MS (ESI) m / z 584.7 [M+H] +

[0473] Step 4: (S)-1'-(2-(2,3-dichlorophenyl)-4-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0474]

[0475] HCl / dioxane (5 ml) was added to N-((S)-1'-(2-(2,3-dichlorophenyl)-4-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (40 mg, 0.069 mmol, 1.0 eq) in dioxane (5 ml), and the mixture was stirred at rt for 2 h. After concentration, ammonia-methanol solution was added, and the solution was concentrated again. The crude product was purified by pre-HPLC to give a white solid (S)-1'-(2,3-dichlorophenyl)-4-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (5.9 mg, 17.95%).

[0476] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.90 (s, 1H), 7.88 (d, J = 8.0Hz, 1H), 7.75–7.68 (m, 1 H),7.65–7.56(m,1H),7.38–7.27(m,1H),7.26–7.10(m,3H),4.80–4.55(m,2H),3 .84(s,1H),3.29–3.17(m,2H),3.12(d,J=15.6Hz,1H),2.74–2.59(m,4H),1.84–1 .68(m,1H),1.71–1.57(m,1H),1.57–1.47(m,1H),1.19–1.04(m,1H); MS(ESI)m / z 479.4[M+H] +

[0477] Example 42

[0478] (S)-1'-(2,3-dichlorophenyl)-2H-indazol-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0479]

[0480] Step 1: 2-Azide-4-bromobenzaldehyde

[0481]

[0482] Trimethyl azidosilane (1.152 g, 10.00 mmol, 1.0 eq) and TBAF (2.61 g, 10.00 mmol, 1.0 eq) were continuously added to a tetrahydrofuran (15 mL) solution of 4-bromo-2-fluorobenzaldehyde (2.03 g, 10.00 mmol, 1.0 eq) at room temperature. The mixture was stirred overnight at 25 °C. Water and ethyl acetate were added to the mixture. The organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid silica gel column chromatography, eluting with PE / EA = 99 / 1, to give a white solid 2-azido-4-bromobenzaldehyde (1.53 g, 67.7%).

[0483] Step 2: (E)-1-(2-azido-4-bromophenyl)-N-(2,3-dichlorophenyl)methylimine

[0484]

[0485] At 0 °C, 2,3-dichloroaniline (163 mg, 1.004 mmol, 1.0 eq), triethylamine (305 mg, 3.01 mmol, 3.0 eq), and titanium(IV) chloride (114 mg, 0.603 mmol, 0.6 eq) were added sequentially to a CH₂Cl₂ (20 mL) solution of 2-azido-4-bromobenzaldehyde (227 mg, 1.004 mmol, 1.0 eq). The mixture was stirred at 0 °C for 3 hours, followed by stirring at room temperature for 3 hours. After concentration, the residue was suspended in toluene. The concentrated residue (372 mg, 100%) was filtered and used for the next step without further purification.

[0486] Step 3: 6-Bromo-2-(2,3-dichlorophenyl)-2H-indazole

[0487]

[0488] A solution of (E)-1-(2-azido-4-bromophenyl)-N-(2,3-dichlorophenyl)methylimine (372 mg, 1.0 mmol, 1.0 eq) in toluene (20 mL) was stirred overnight at 110 °C under N2 conditions. After concentration, the residue was purified by silica gel chromatography using a 30 / 1 eluent with DCM / CH3OH to give a white solid, 6-bromo-2-(2,3-dichlorophenyl)-2H-indazole (254 mg, 73.9%). MS (ESI) m / z 341.0 [M+H] + .

[0489] Step 4: N-((S)-1'-(2-(2,3-dichlorophenyl)-2H-indazol-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide

[0490]

[0491] At 25 °C, N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (94 mg, 0.307 mmol, 1.5 eq), xantphos (11.84 mg, 0.020 mmol, 0.1 eq), Cs₂CO₃ (133 mg, 0.409 mmol, 2.0 eq) and Pd₂(dba)₃ (9.37 mg, 10.23 μmol, 0.05 eq) were added to a solution of 6-bromo-2-(2,3-dichlorophenyl)-2H-indazole (70 mg, 0.205 mmol, 1.0 eq) in dioxane (8 mL). The mixture was heated to 120 °C overnight under N₂. After concentration, the residue was purified by rapid silica gel column chromatography, eluting with DCM / CH3OH = 30 / 1, to give a yellow solid N-((S)-1'-(2-(2,3-dichlorophenyl)-2H-indazol-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (40 mg, 34.4%). MS (ESI) m / z 567.5 [M+H] + .

[0492] Step 5

[0493] (S)-1'-(2-(2,3-dichlorophenyl)-2H-indazol-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0494]

[0495] N-((S)-1'-(2-(2,3-dichlorophenyl)-2H-indazole-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-thionamide (40 mg, 0.070 mmol, 1.0 eq) was stirred in HCl / dioxane (3 ml) for 30 min at 25 °C. After concentration, the residue was purified by pre-HPLC to give (S)-1'-(2,3-dichlorophenyl)-2H-indazole-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (1.25 mg, 3.83%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ(ppm)8.51(s,1H),7.87–7.74(m,1H),7.70–7.61(m,1 H),7.60–7.48(m,2H),7.36–7.26(m,2H),7.23–7.08(m,4H),7.06–6.97(m,1H ),6.81(s,1H),3.90(s,1H),3.68–3.52(m,2H),3.06–2.80(m,3H),2.70–2.57 (m,1H),2.02–1.71(m,2H),1.59–1.47(m,1H),1.48–1.35(m,1H).MS(ESI)m / z 463.3[M+H] + .

[0496] Example 43

[0497] (S)-1'-(4-chloro-2-(2,3-dichlorophenyl)-2H-indazol-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0498]

[0499] It was prepared according to Example 42. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.67 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 6. 9Hz,1H),7.58(t,J=8.1Hz,1H),7.37–7.27(m,1H),7.23–7.10(m,4H),6.82(s,1 H),3.87(s,1H),3.70–3.53(m,2H),3.07–2.86(m,3H),2.61(d,J=15.7Hz,1H),1 .97–1.85(m,1H),1.79(d,J=11.9Hz,1H),1.59–1.48(m,1H),1.21–1.10(m,1H).

[0500] Example 44

[0501] (S)-1'-(2-(2,3-dichlorophenyl)-3-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0502]

[0503] Step 1

[0504] 1-(4-azido-2-(methylthio)pyrimidin-5-yl)ethane-1-one

[0505]

[0506] TBAF (1.5 mmol, 0.74 mmol, 194.0 mg) was added to a solution of 1-(4-chloro-2-(methylthio)pyrimidin-5-yl)ethane-1-one (0.49 mmol, 100.0 mg) and TMSN3 (1.5 equivalence, 0.74 mmol, 85.0 mg) in DCM (5 mL). The reaction mixture was then stirred at rt for 12 h. After solvent removal, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 80%) to give 102.0 mg of product as a yellow solid in 99% yield. MS (ESI) m / z 210.22 [M+H] + .

[0507] Step 2

[0508] (E)-4-azido-5-(1-(2,3-dichlorophenyl)prop-1-en-2-yl)-2-(methylthio)pyrimidine

[0509]

[0510] TiCl4 (0.5 equivalent, 0.24 mmol, 46.2 mg) was added to a solution of 1-(4-azido-2-(methylthio)pyrimidin-5-yl)ethane-1-one (0.49 mmol, 102.0 mg), 2,3-dichloroaniline (1.2 equivalent, 0.59 mmol, 95.0 mg), and Et3N (3.0 equivalent, 1.46 mmol, 148.0 mg) in DCM (5 mL). The reaction mixture was then stirred at 25 °C for 12 hours. After solvent removal, the residue was diluted with toluene and concentrated under vacuum to give a crude product of 172.0 mg brown solid, which was used directly for the next step. MS (ESI) m / z 352.10 and 354.05 [M+H] + .

[0511] Step 3: 2-(2,3-dichlorophenyl)-3-methyl-6-(methylthio)-2H-pyrazolo[3,4-d]pyrimidine

[0512]

[0513] Add (E)-4-azido-5-(1-(2,3-dichlorophenyl)prop-1-en-2-yl)-2-(methylthio)pyrimidine (0.49 mmol, 172.0 mg) and toluene (5 mL) to a vial. The reaction mixture was then stirred at 120 °C for 20 hours. After solvent removal, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 80%) to give 26.0 mg of a yellow solid product in 16% (two-step yield), MS (ESI) m / z 325.10 and 327.05 [M+H]. + .

[0514] Step 4: 2-(2,3-dichlorophenyl)-3-methyl-6-(methyl sulfoxide)-2H-pyrazolo[3,4-d]pyrimidine

[0515]

[0516] To a solution of 2-(2,3-dichlorophenyl)-3-methyl-6-(methylthio)-2H-pyrazolo[3,4-d]pyrimidine (0.08 mmol, 26.0 mg) in DCM (2 mL) under ice-water bath conditions, m-CPBA (1.05 equivalent, 0.08 mmol, 14.49 mg) was added. The reaction mixture was then stirred at 0 °C for 1 hour. After solvent removal, the residue was diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give 27.3 mg of crude product as a pale yellow solid, which was used directly for the next step. MS (ESI) m / z 341.10 and 343.05 [M+H] + .

[0517] Step 5N-((S)-1'-(2-(2,3-dichlorophenyl)-3-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-thioamide

[0518]

[0519] N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.5 equivalents, 0.12 mmol, 36.8 mg) was added to a solution of 2-(2,3-dichlorophenyl)-3-methyl-6-(methylsulfonyl)-2H-pyrazolo[3,4-d]pyrimidine (0.08 mmol, 27.3 mg) and DIEA (5.0 equivalents, 0.4 mmol, 51.7 mg) in n-BuOH (2 mL). The reaction mixture was then stirred in a microwave at 140 °C for 1 hour. After solvent removal, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product of 46.7 mg light brown solid, which was used directly for the next step. MS (ESI) m / z 583.10 and 585.15 [M+H] + .

[0520] Step 6 (S)-1'-(2-(2,3-dichlorophenyl)-3-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0521]

[0522] To a solution of N-((S)-1'-(2-(2,3-dichlorophenyl)-3-methyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.08 mmol, 46.7 mg) in THF (2 mL), HCl / dioxane (1 N, 1 mL) was slowly added, and the reaction mixture was stirred at rt for 1 hour. After solvent removal, the residue was diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography to give 5.3 mg of a white solid product (14% yield in three steps).

[0523] 1H NMR (400MHz, DMSO-d6) δ (ppm) 9.22 (s, 1H), 7.92 (dd, J = 7.9, 1.7Hz, 1H), 7.68–7.60 (m, 2H), 7 .30(d,J=6.0Hz,1H),7.21–7.15(m,3H),4.61(t,J=14.3Hz,2H),3.82(s,1H),3.28–3.16(m, 2H),3.11(d,J=15.6Hz,1H),2.64(d,J=15.7Hz,1H),2.41(s,3H),1.75(td,J=12.6,4.0Hz,1 H),1.62(td,J=12.6,3.8Hz,1H),1.50(d,J=12.7Hz,1H),1.08(d,J=12.7Hz,1H).MS(ESI)m / z 479.46 and 481.21[M+H] + .

[0524] Example 45

[0525] (S)-6-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-2-(2,6-dichlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-3-ol

[0526]

[0527] Step 1: Methyl 2-chloro-4-(2,6-dichlorophenyl)hydrazyl)pyrimidine-5-carboxylic acid

[0528]

[0529] To a solution of methyl 2,4-dichloropyrimidin-5-carboxylate (7.73 mmol, 1.6 g) and Et3N (3.0 equivalent, 23.19 mmol, 2.35 g) in DMF (70 mL), hydrazine (1.2 equivalent, 9.27 mmol, 1.64 g) was added. The reaction mixture was then stirred at rt for 2 h. After solvent removal, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 60%) to give 2.32 g of a pale yellow solid in 86% yield. 1H NMR (400MHz, DMSO-d6) δ (ppm) 9.98 (d, J = 2.9 Hz, 1H), 8.69 (s, 1H), 7.74 (d, J = 3. 0Hz,1H),7.37(d,J=8.1Hz,2H),6.98(t,J=8.1Hz,1H),3.89(s,3H).MS(ESI)m / z 347.04 and 349.06[M+H] + .

[0530] Step 2: 6-Chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-3-ol

[0531]

[0532] Under ice-water bath conditions, KHMDS (1N in THF, 1.15 mL) was added to a THF (5 mL) solution of methyl 2-chloro-4-(2,6-dichlorophenyl)hydrazinopyrimidine-5-carboxylate (0.58 mmol, 200.0 mg). The reaction mixture was then stirred at 0 °C for 1 hour. After solvent removal, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (DCM and MeOH, MeOH ranging from 0 to 10%) to give 112.0 mg of a brown solid in a yield of 62%. MS (ESI) m / z 315.07 and 317.06 [M+H] + .

[0533] Step 3N-((S)-1'-(2-(2,6-dichlorophenyl)-3-hydroxy-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0534]

[0535] N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.5 equivalents, 0.13 mmol, 39.3 mg) was added to a solution of 6-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-3-ol (0.09 mmol, 27.0 mg) and DIEA (5.0 equivalents, 0.43 mmol, 55.3 mg) in n-BuOH (2 mL). The reaction mixture was then stirred in a microwave at 140 °C for 1 hour. After solvent removal, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product of 50.1 mg of light brown solid, which was used directly for the next step. MS (ESI) m / z 585.31 and 587.57 [M+H] + .

[0536] Step 4(S)-6-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-2-(2,6-dichlorophenyl)-2H-pyrazolo[3,4-d]pyrimidin-3-ol

[0537]

[0538] To a solution of N-((S)-1'-(2-(2,6-dichlorophenyl)-3-hydroxy-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.09 mmol, 50.1 mg) in tetrahydrofuran (2 mL), HCl / dioxane (1 N, 1 mL) was slowly added, and the reaction mixture was stirred at rt for 1 hour. After solvent removal, the residue was diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography to give 6.6 mg of a yellow solid product in 16% (two-step yield).

[0539] 1H NMR(400MHz, DMSO-d6)δ(ppm)8.34(s,1H),7.56(d,J=8.1Hz,2H),7.44(d,J=7.5Hz,2H),7.31(d,J=4.0Hz,2H),7.28–7.24(m,1H),4.57( t,J=14.2Hz,2H),4.22(s,1H),3.16–3.08(m,3H),2.92(d,J=16.1Hz,1H),1.73–1.61(m,2H),1.39(dd,J=34.4,13.0Hz,2H).MS(ESI)m / z 481.41and 483.40[M+H] + .

[0540] Example 46

[0541] (S)-1'-(2,3-dichlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0542]

[0543] Step 1: 2-Bromo-6-(2,3-dichlorophenyl)imidazo[2,1-b][1,3,4]thiadiazole

[0544]

[0545] Under Ar conditions, 5-bromo-1,3,4-thiadiazol-2-amine (0.2 g, 1.111 mmol, 1.0 eq) and 2-bromo-1-(2,3-dichlorophenyl)ethane-1-one (0.446 g, 1.666 mmol, 1.5 eq) were dissolved in ethanol (10 mL) to give a yellow solution. The reaction mixture was stirred at 85 °C for 12 hours. The reaction mixture was diluted with ethyl acetate. The reaction mixture was filtered through a Buchner funnel, and the filter cake was washed with ethyl acetate to give a brown solid product (0.31 g, 80%). MS (ESI) m / z 347.97 [M+H] + .

[0546] Step 2 (R)-N-((S)-1'-(6-(2,3-dichlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide

[0547]

[0548] Under Ar conditions, 2-bromo-6-(2,3-dichlorophenyl)imidazo[2,1-b][1,3,4]thiadiazole (0.1 g, 0.287 mmol, 1.0 eq), (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.105 g, 0.344 mmol, 1.2 eq), and DIEA (0.111 g, 0.860 mmol, 3) were dissolved in DMF (3 mL) to give a yellow solution. The reaction mixture was stirred at 90 °C for 12 hours. H₂O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0% to 3% methanol / dichloromethane to give a yellow oily product (0.12 g, 72.9%). MS (ESI) m / z 547.32 [M+H] + .

[0549] Step 3 (S)-1'-(6-(2,3-dichlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0550]

[0551] Under argon atmosphere, (R)-N-((S)-1'-(6-(2,3-dichlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (0.12 g, 0.209 mmol, 1.000) and HCl (0.076 g, 2.085 mmol, 9.98) were dissolved in 1,4-dioxane (3 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 hour. Saturated NaHCO3 (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give a white solid (25.4 mg, 25.9%).

[0552] 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.42 (s, 1H), 8.03 (dd, J = 7.9, 1.5Hz, 1H), 7.54 (dd, J = 7.9 ,1.5Hz,1H),7.40(t,J=8.0Hz,1H),7.31(d,J=6.0Hz,1H),7.21–7.13(m,3H),3.89(s,1H ),3.74(t,J=14.4Hz,2H),3.41(d,J=12.3Hz,2H),3.07(d,J=15.6Hz,1H),2.65(d,J=15. 9Hz,1H),1.93–1.72(m,2H),1.58(d,J=13.9Hz,1H),1.19(d,J=13.1Hz,1H).MS(ESI)m / z 470.29[M+H] + .

[0553] Example 47

[0554] (R)-N-((S)-1'-(6-Cyclopropylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0555]

[0556] Step 1 (R)-N-((S)-1'-(5-amino-1,3,4-thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-thioamide

[0557]

[0558] Under Ar conditions, 5-bromo-1,3,4-thiadiazol-2-amine (0.070 g, 0.392 mmol, 1 eq), (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.12 g, 0.392 mmol, 1.0 eq), and TEA (0.119 g, 1.175 mmol, 3 eq) were dissolved in ethanol (20 mL) to give a brown solution. The reaction mixture was stirred at 85 °C for 2 hours. The crude product was added to a silica gel column and eluted with 0% to 4% methanol / dichloromethane to give a product as a brown solid (0.14 g, 88%). MS (ESI) m / z 406.38 [M+H] + .

[0559] Step 2

[0560] (R)-N-((S)-1'-(6-Cyclopropylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0561]

[0562] Under Ar conditions, (R)-N-((S)-1'-(5-amino-1,3,4-thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.14 g, 0.345 mmol, 1.0 eq) and 2-bromo-1-cyclopropyl-1-one (0.113 g, 0.690 mmol, 2 eq) were dissolved in ethanol (10 mL) to give a yellow solution. The reaction mixture was stirred at 85 °C for 12 hours. H₂O (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography to give a white solid (16.0 mg, 9.9%). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.53 (s, 1H), 7.31 (d, J = 5.3Hz, 1H), 7.21–7.14 (m, 3H), 3 .89(s,1H),3.74–3.59(m,2H),3.30–3.22(m,2H),3.05(d,J=15.8Hz,1H),2.64(d,J=1 5.8Hz,1H),1.89–1.79(m,2H),1.74(td,J=12.7,4.4Hz,1H),1.53(d,J=14.9Hz,1H),1 .16(d,J=13.8Hz,1H),0.80–0.75(m,2H),0.68–0.62(m,2H).MS(ESI)m / z366.26[M+H] + .

[0563] Example 48

[0564] (S)-1'-(6-(2,3-dichlorophenyl)-5-fluoroimidozolo[2,1-b][1,3,4]thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0565]

[0566] Under Ar conditions, (S)-1'-(6-(2,3-dichlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (0.025 g, 0.053 mmol, 1.0 eq) and 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo[2.2.2]octanebis(tetrafluoroborate) (0.028 g, 0.080 mmol, 1.5 eq) were dissolved in acetonitrile (10 mL) to give a yellow solution. The reaction mixture was stirred at 50 °C for 12 hours. H₂O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography to give a white solid (3.2 mg, 12.3%).

[0567] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.65 (dd, J=8.0, 1.5Hz, 1H), 7.59 (dd, J=7.8, 1.5Hz, 1H), 7.4 4(t,J=7.9Hz,1H),7.31(d,J=6.2Hz,1H),7.22–7.12(m,3H),3.88(s,1H),3.75(dd,J=19.2 ,8.8Hz,2H),3.44(s,2H),3.06(d,J=15.7Hz,1H),2.64(d,J=15.7Hz,1H),1.88(td,J=13.0 ,4.4Hz,1H),1.82–1.71(m,1H),1.57(d,J=13.5Hz,1H),1.18(d,J=13.9Hz,1H).MS(ESI)m / z 488.28[M+H] + .

[0568] Example 49

[0569] (S)-1'-(5-(2,3-dichlorophenyl)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0570]

[0571] Step 1: N-((S)-1'-(5-bromothiazo[5,4-d]thiazolyl-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide

[0572]

[0573] Under N2, N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (153 mg, 0.500 mmol, 1.5 eq) and triethylamine (67.5 mg, 0.667 mmol, 2.0 eq) were added to a solution of 2,5-dibromothiazo[5,4-d]thiazole (100 mg, 0.333 mmol, 1.0 eq) in acetonitrile (15 mL). The mixture was stirred at 110 °C for 3 hours. The product was dissolved in water and ethyl acetate. The organic layer was separated, washed with brine (100 ml), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid silica gel column chromatography, eluting with PE / EA = 1 / 1, to give N-((S)-1'-(5-bromothiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (129 mg, 73.6%) as a white solid. MS (ESI) m / z 525.3 [M+H] +

[0574] Step 2: N-((S)-1'-(5-(2,3-dichlorophenyl)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0575]

[0576] At room temperature and under N2, (2,3-dichlorobenzene)boronic acid (56.2 mg, 0.295 mmol, 1.2 eq), PdCl2 (17.96 mg, 0.025 mmol, 0.1 eq), and K2CO3 (102 mg, 0.736 mmol, 3.0 eq) were added to a solution of N-((S)-1'-(5-bromothiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (129 mg, 0.245 mmol, 1.0 eq) in dioxane (10 mL) / water (2 mL). The mixture was stirred at 110 °C under N2 for 16 hours. Water and ethyl acetate were added. The organic layer was separated, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel column chromatography, eluting with PE / EA = 1 / 1, to give N-((S)-1'-(5-(2,3-dichlorophenyl)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (88 mg, 60.6%) as a white solid. MS (ESI) m / z 591.4 [M+H] +

[0577] Step 3: (S)-1'-(5-(2,3-dichlorophenyl)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0578]

[0579] HCl / dioxane (8 mL) was added to a solution of N-((S)-1'-(5-(2,3-dichlorophenyl)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (87 mg, 0.147 mmol, 1.0 eq) in dioxane, and the mixture was stirred at rt for 2 h. After concentration, ammonia-methanol solution was added, and the solution was concentrated again. The crude product was purified by pre-HPLC to give (S)-1'-(5-(2,3-dichlorophenyl)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (5.8 mg, 8.09%) as a white solid.

[0580] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.10 (dd, J=8.0, 1.5Hz, 1H), 7.72 (dd, J=8.0, 1.5H z,1H),7.49(t,J=8.0Hz,1H),7.38–7.27(m,1H),7.24–7.10(m,3H),4.04–3.83(m ,3H),3.56–3.37(m,2H),3.08(d,J=15.7Hz,1H),2.65(d,J=15.8Hz,1H),1.92–1 .82(m,1H),1.81–1.71(m,1H),1.64–1.53(m,1H),1.23–1.14(m,2H); MS(ESI)m / z 487.3 [M+H] +

[0581] Example 50:

[0582] (S)-1'-(5-((2,3-dichlorophenyl)thio)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0583]

[0584] Step 1: N-((S)-1'-(5-((2,3-dichlorophenyl)thio)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide

[0585]

[0586] At room temperature and under N2, 2,3-dichlorobenzylthiol (51.1 mg, 0.285 mmol, 1.5 eq), Pd2(dba)3 (8.71 mg, 9.51 μmol, 0.05), xantphos (11.01 mg, 0.019 mmol, 0.1 eq), and N-ethyl-N-isopropylpropane-2-amine (49.2 mg, 0.381 mmol, 2.0 eq) were added to a solution of N-((S)-1'-(5-bromothiazo[5,4-d]thiazolyl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (100 mg, 0.190 mmol, 1.0 eq) in dioxane (3 mL). The mixture was stirred in a microwave at 90 °C for 1.5 h. Water and ethyl acetate were added to the solution. The organic layer was washed with brine (100 ml), dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid silica gel column chromatography, eluting with PE / EA = 1 / 1, to give N-((S)-1'-(5-((2,3-dichlorophenyl)thio)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (100 mg, 84%) as a white solid. MS (ESI) m / z 623.3 [M+H] +

[0587] Step 2: (S)-1'-(5-((2,3-dichlorophenyl)thio)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0588]

[0589] A solution of 4N HCl / dioxane (8 mL) was added to a solution of dioxane in N-((S)-1'-(5-((2,3-dichlorophenyl)thio)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (100 mg, 0.160 mmol, 1.0 eq). The mixture was stirred at room temperature for 2 hours. After concentration, the solution was concentrated again by adding ammonia-methanol solution. The crude product was purified by pre-HPLC to give (S)-1'-(5-((2,3-dichlorophenyl)thio)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (14.1 mg, 16.93%) as a white solid.

[0590] 1 H NMR(400MHz,DMSO-d6)δ(ppm)7.57(dd,J=8.0,1.2Hz,1H),7.38–7.27(m,2H),7.21–7.11(m,3H),7.03(dd,J=8.0,1.2Hz,1H),4.01–3.80(m,3H),3.51 –3.38(m,2H),3.07(d,J=15.7Hz,1H),2.64(d,J=15.7Hz,1H),1.91–1.80(m ,1H),1.80–1.67(m,1H),1.64–1.51(m,1H),1.28–1.10(m,1H); MS(ESI)m / z 519.1[M+H] +

[0591] Compounds of Examples 51 and 52 were prepared with reference to Example 50.

[0592] Example 51

[0593] (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0594]

[0595] MS(ESI) m / z 501.2 [M+H] +

[0596] Example 52

[0597] (S)-1'-(5-((2-amino-3-chloropyridin-4-yl)thio)thiazo[5,4-d]thiazo-2-yl)-5,7-dihydrospiro[b]pyridin-6,4'-piperidine]-5-amine

[0598]

[0599] 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.32(d,J=4.3Hz,1H),7.73(d,J=5.4Hz,1H),7 .66(d,J=7.4Hz,1H),7.27–7.09(m,1H),6.49(s,2H),5.93(d,J=5.4Hz,1H),4 .03–3.75(m,3H),3.60–3.39(m,2H),3.13(d,J=16.3Hz,1H),2.77(d,J=16.3 Hz,1H),1.96–1.71(m,2H),1.68–1.55(m,1H),1.30–1.16(m,1H); MS(ESI)m / z 501.0[M+H] +

[0600] Example 53 (S)-1'-(5-(2,3-dichlorophenoxy)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0601]

[0602] Step 1: 2-Bromo-5-(2,3-dichlorophenoxy)thiazo[5,4-d]thiazolyl

[0603]

[0604] Under Ar conditions, 2,5-dibromothiazo[5,4-d]thiazole (0.2 g, 0.667 mmol, 1.0 eq), 2,3-dichlorophenol (0.109 g, 0.667 mmol, 1 eq), and K₂CO₃ (0.184 g, 1.333 mmol, 2 eq) were dissolved in DMF (3 mL) to give a yellow suspension. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with H₂O (20 mL). The reaction mixture was filtered through a Buchner funnel, and the filter cake was washed with water to give a brown solid product (0.23 g, 90%), MS (ESI) m / z 382.17 [M+H]. + .

[0605] Step 2N-((S)-1'-(5-(2,3-dichlorophenoxy)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide

[0606]

[0607] Under Ar conditions, 2-bromo-5-(2,3-dichlorophenoxy)thiazo[5,4-d]thiazole (0.05 g, 0.131 mmol, 1.0 eq), (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.060 g, 0.196 mmol, 1.5 eq), and K₂CO₃ (0.054 g, 0.393 mmol, 3 eq) were dissolved in NMP (2 mL) to give a yellow suspension. The reaction mixture was stirred at 115 °C for 3 hours. H₂O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0% to 3% methanol / dichloromethane to give a yellow oily product (0.05 g, 62.9%), MS (ESI) m / z 607.28 [M+H]. + .

[0608] Step 3 (S)-1'-(5-(2,3-dichlorophenoxy)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0609]

[0610] Under Ar conditions, N-((S)-1'-(5-(2,3-dichlorophenoxy)thiazo[5,4-d]thiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.05 g, 0.082 mmol, 1.0 eq) and HCl (0.030 g, 0.823 mmol, 10 eq) were dissolved in 1,4-dioxane (2 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 hour. Saturated NaHCO3 (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give a white solid (3.3 mg, 7.9%).

[0611] 1H NMR (400MHz, DMSO-d6) δ (ppm) 7.64 (dd, J=8.0, 1.5Hz, 1H), 7.57 (dd, J=8.3, 1.5Hz, 1H), 7.49 (t ,J=8.2Hz,1H),7.31(d,J=5.3Hz,1H),7.20–7.14(m,3H),3.88(s,1H),3.80(ddd,J=13.2,9.6,3 .9Hz,2H),3.24(d,J=3.0Hz,2H),3.05(d,J=15.7Hz,1H),2.63(d,J=15.7Hz,1H),1.88–1.79(m ,1H),1.73(dd,J=12.4,8.4Hz,1H),1.54(d,J=13.5Hz,1H),1.17(d,J=13.8Hz,1H).MS(ESI)m / z 503.23[M+H] + .

[0612] The compounds of Examples 54-55 were prepared with reference to Example 53.

[0613] Example 54 (S)-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-N-(2,3-dichlorophenyl)thiazo[5,4-d]thiazo-2-amine

[0614]

[0615] 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.19(d,J=8.3Hz,1H),7.36–7.29(m,2H),7.26(d,J=7.9H z,1H),7.18(d,J=4.3Hz,3H),3.91(s,1H),3.78(t,J=11.4Hz,2H),3.24(d,J=12.4Hz,3H ),3.06(d,J=15.8Hz,1H),2.66(d,J=15.5Hz,1H),1.85(td,J=12.5,4.0Hz,1H),1.74(t, J=10.5Hz,1H),1.54(d,J=13.1Hz,1H),1.19(d,J=13.9Hz,1H).MS(ESI)m / z502.26[M+H] + .

[0616] Example 55

[0617] (S)-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-N-(2,3-dichlorophenyl)-N-methylthiazo[5,4-d]thiazo-2-amine

[0618]

[0619] 1 H NMR(400MHz, DMSO-d6)δ(ppm)7.73(dd,J=8.1,1.5Hz,1H),7.65–7.61(m,1H),7.52(t,J=8.0H z,1H),7.30(d,J=5.9Hz,1H),7.20–7.12(m,3H),3.85(s,1H),3.78–3.67(m,2H),3.37(s,3H) ,3.26–3.14(m,2H),3.03(d,J=15.7Hz,1H),2.61(d,J=15.7Hz,1H),1.83(td,J=12.9,4.5Hz, 1H),1.71(td,J=12.7,4.3Hz,1H),1.51(d,J=13.4Hz,1H),1.13(d,J=13.6Hz,1H).MS(ESI)m / z 516.17[M+H] + .

[0620] Example 56

[0621] (S)-1'-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0622] Step 1: 3,5-Dichloropyrazine-2-formyl

[0623]

[0624] Step 1: 3,5-Dichloropyrazine-2-formaldehyde

[0625]

[0626] Under N2 at -30°C, 2.5N n-butyllithium (0.774 g, 12.08 mmol, 1.2 eq) was added to a solution of 2,2,6,6-tetramethylpiperidine (2.133 g, 15.10 mmol, 1.5 eq) in 15 mL of 2-methyltetrahydrofuran. The mixture was stirred at 0°C for 1 hour. Then, 2,6-dichloropyrazine (1.5 g, 10.07 mmol, 1.0 eq) was added at -78°C, and the mixture was stirred at -78°C under N2 for 2 hours. Methyl formate (0.907 g, 15.10 mmol, 1.5 eq) was added under nitrogen at -78°C, and the mixture was stirred at -78°C for 2 hours. Acetic acid and water were slowly added to neutralize the solution. The solution was extracted with ethyl acetate. The organic layer was separated, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel column chromatography, eluting with PE / EA = 5 / 1, to give a white solid 3,5-dichloropyrazine-2-carboxaldehyde (980 mg, 55.0%). MS (ESI) m / z 177.0 [M+H] +

[0627] Step 2: N-((S)-1'-(6-chloro-5-formylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide

[0628]

[0629] At room temperature, N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (100 mg, 0.326 mmol, 1.0 eq) and CsF (248 mg, 1.63 mmol, 5.0 eq) were added to a solution of 3,5-dichloropyrazine-2-carboxaldehyde (87 mg, 0.489 mmol, 1.5 eq) in DMF (5 mL). The mixture was stirred at 140 °C under N2 for 1.5 h. Water and ethyl acetate were added. The organic layer was separated, washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel column chromatography, eluting with DCM / CH3OH = 50 / 1, to give a yellow solid N-((S)-1'-(6-chloro-5-formylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (81 mg, 55.5%). MS (ESI) m / z 448.4 [M+H] +

[0630] Step 3: N-((S)-1'-(6-azido-5-formylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide

[0631]

[0632] Add trimethyl azidosilane (20.88 mg, 0.181 mmol, 1.0 eq) and tetrabutylammonium fluoride (47.4 mg, 0.181 mmol, 1.0 eq) to a solution of N-((S)-1'-(6-chloro-5-formylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (81 mg, 0.181 mmol, 1.0 eq) in tetrahydrofuran (10 mL). Stir the mixture at 0 °C for 3 hours. Add ethyl acetate and water. Separate the organic layer, wash with saturated brine (100 mL), dry to anhydrous Na₂SO₄, filter, and concentrate. The crude product was purified by rapid silica gel column chromatography, eluting with DCM / CH3OH = 50 / 1, to give a white solid N-((S)-1'-(6-azido-5-formylpyrazin-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (60 mg, 73.0%). MS (ESI) m / z 454.6 [M+H] +

[0633] Step 4: N-((S)-1'-(6-azido-5-((E)-(2,3-dichlorophenyl)imino)methyl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide

[0634]

[0635] At 0 °C, 2,3-dichloroaniline (21.75 mg, 0.134 mmol, 1.0 eq), triethylamine (40.7 mg, 0.403 mmol, 3.0 eq), and titanium(IV) chloride (15.28 mg, 0.081 mmol, 0.6 eq) were added sequentially to a solution of N-((S)-1'-(6-chloro-5-formylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (60 mg, 0.134 mmol, 1.0 eq) in DCM (15 mL). The mixture was stirred at 0 °C for 3 h, followed by stirring at rt for 3 h. After concentration, the product was suspended in toluene. The solution was filtered and concentrated into a yellow solid form of ((S)-1'-(6-azido-5-((E)-(2,3-dichlorophenyl)imino)methyl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (80 mg, 100%).

[0636] Step 5: N-((S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide

[0637]

[0638] Under N2, a toluene (15 ml) solution of (N-((S)-1'-(6-azido-5-((E)-(2,3-dichlorophenyl)imino)methyl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (80 mg, 0.134 mmol, 1.0 eq) was stirred overnight at 110 °C. After concentration, the crude product was purified by rapid silica gel column chromatography, eluted with DCM / CH3OH = 50 / 1, to give N-((S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (30 mg, 39.3%) as a yellow solid.

[0639] Step 6: (S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0640]

[0641] HCl / dioxane (5 ml) was added to a solution of N-((S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (30 mg, 0.053 mmol, 1.0 eq) dioxane (5 ml). The mixture was stirred at room temperature for 2 hours. After concentration, ammonia-methanol solution was added, and the solution was concentrated again. The crude product was purified by pre-HPLC to give a white solid (S)-1'-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (1 mg, 4.08%).

[0642] MS(ESI) m / z 465.3 [M+H] +

[0643] Example 57:

[0644] (S)-1'-(2,3-dichlorophenyl)oxazolo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0645]

[0646] Step 1: 2,3-Dichloro-N-(4,6-dibromopyridin-3-yl)benzamide

[0647]

[0648] Pyridine (94 mg, 1.191 mmol, 3.0 eq) and 2,3-dichlorobenzoyl chloride (125 mg, 0.595 mmol, 1.5 eq) were added to a CH₂Cl₂ (10 mL) solution of 4,6-dibromopyridin-3-amine (100 mg, 0.397 mmol, 1.0 eq) at 0 °C. The mixture was stirred at 25 °C under N₂ for 16 h. Water and dichloromethane were added. The organic layer was separated, washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid silica gel column chromatography, eluting with DCM / CH₃OH = 50 / 1, to give 2,3-dichloro-N-(4,6-dibromopyridin-3-yl)benzamide (150 mg, 89%) as a white solid. MS (ESI) m / z 423.0 [M+H] +

[0649] Step 2: 6-Bromo-2-(2,3-dichlorophenyl)oxazolo[4,5-c]pyridine

[0650]

[0651] Na₂CO₃ (698 mg, 6.59 mmol, 10 eq) was added to a DMF (10 mL) solution of 2,3-dichloro-N-(4,6-dibromopyridin-3-yl)benzamide (280 mg, 0.659 mmol, 1.0 eq) at 25 °C. The mixture was stirred at 110 °C for 16 h. Water and ethyl acetate were added. The organic layer was separated, washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid silica gel column chromatography, eluting with DCM / CH₃OH = 50 / 1, to give a white solid 6-bromo-2-(2,3-dichlorophenyl)oxazolo[4,5-c]pyridine (140 mg, 61.8%). MS (ESI) m / z 343.0 [M+H] +

[0652] Step 3: N-((S)-1'-(2-(2,3-dichlorophenyl)oxazolo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0653]

[0654] At 25 °C under nitrogen atmosphere, N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfonamide (134 mg, 0.436 mmol, 1.5 eq), sodium 2-methylpropane-2-ol (84 mg, 0.872 mmol, 3.0 eq), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (36.2 mg, 0.058 mmol, 0.2 eq) and Pd2(dba)3 (26.6 mg, 0.029 mmol, 0.1 eq) were added to 6-bromo-2 In a solution of 5 ml of dioxane (2-(2,3-dichlorophenyl)oxazolo[4,5-c]pyridine, the mixture was stirred at 90 °C for 1 hour under microwave. The solution was cooled to room temperature and concentrated. The residue was purified by rapid silica gel column chromatography, eluting with DCM / CH3OH = 30 / 1, to give N-((S)-1'-(2,3-dichlorophenyl)oxazolo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (23 mg, 13.89%) as a yellow solid. MS (ESI) m / z 570.9 [M+H] +

[0655] Step 4: (S)-1'-(2-(2,3-dichlorophenyl)oxazolo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0656] HCl / dioxane (5 mL) was added to a solution of N-((S)-1'-(2-(2,3-dichlorophenyl)oxazolo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (22 mg, 0.039 mmol, 1.0 eq) dioxane (5 mL). The mixture was stirred at room temperature for 2 hours. After concentration, the solution was concentrated again by adding ammonia-methanol solution. The residue was purified by pre-HPLC to give (S)-1'-(2,3-dichlorophenyl)oxazolo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine (3.9 mg, 21.70%) as a white solid. MS (ESI) m / z 465.4 [M+H] +

[0657] Example 58

[0658] (S)-4-amino-6-(1-amino-1,3-dihydrospiro[inden-2,4'-piperidin]-1'-yl)-2-(2,3-dichlorobenzyl)isoindolin-1-one

[0659]

[0660] Step 1: Methyl 5-bromo-3-(tert-butoxycarbonyl)amino)-2-methylbenzoate

[0661]

[0662] Boc₂O (1.05 mmol, 10.5 mmol, 2.29 g) was added to a suspension of methyl 3-amino-5-bromo-2-methylbenzoate (10.0 mmol, 2.44 g), DMAP (5 mol%, 0.5 mmol, 61.0 mg), and Et₃N (3.0 equivalence, 30.0 mmol, 3.04 g) in MeCN (100 mL). The reaction mixture was then stirred at rt for 12 hours. After the reaction was complete, the resulting mixture was diluted with ethyl acetate and washed with brine. The separated organic layer was dried over MgSO₄, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 60%) to give 1.94 g of a pale yellow solid product in 56% yield. MS (ESI) m / z 344.20 and 346.14 [M+H] + .

[0663] Step 2: Methyl 5-bromo-2-(bromomethyl)-3-(tert-butoxycarbonyl)amino)benzoate

[0664]

[0665] NBS (1.1 equivalent, 6.2 mmol, 1.1 g) was added to a suspension of methyl 5-bromo-3-(tert-butoxycarbonyl)amino)-2-methylbenzoate (5.64 mmol, 1.94 g) and AIBN (20 mol%, 1.13 mmol, 185.0 mg) in CCl4 (50 mL). The reaction mixture was then stirred at 80 °C for 3 hours. After the reaction was complete, the resulting mixture was diluted with DCM and washed with brine. The separated organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 40%) to give 1.14 g of a pale yellow oily product in 48% yield. MS (ESI) m / z 421.95 and 423.87 [M+H] + .

[0666] Step 3: (6-Bromo-2-(2,3-dichlorobenzyl)-1-oxoisoindoline-4-yl)tert-butyl carbamate

[0667]

[0668] (2,3-Dichlorophenyl)methylamine (1.2 equivalents, 1.01 mmol, 178.0 mg) was added to a suspension of methyl 5-bromo-2-(bromomethyl)-3-((tert-butoxycarbonyl)amino)benzoate (0.84 mmol, 356.0 mg) and Cs₂CO₃ (4.0 equivalences, 3.37 mmol, 1.09 g) in THF (8 mL). The reaction mixture was then stirred at rt for 12 h. After the reaction was complete, the resulting mixture was diluted with EA and washed with brine. The separated organic layer was dried on MgSO₄, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 70%) to give 338.0 mg of a light brown solid in 83% yield. MS (ESI) m / z 485.16 and 487.11 [M+H] + .

[0669] Step 4: tert-butyl(6-((1S)-1-((tert-butylsulfonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-2-(2,3-dichlorobenzyl)-1-oxoisoindoline-4-yl)carbamate

[0670]

[0671] Under Ar conditions, N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.2 equivalents, 0.37 mmol, 113.0 mg) was added to a solution of tert-butyl(6-bromo-2-(2,3-dichlorobenzyl)-1-oxoisoindoline-4-yl)carbamate (0.31 mmol, 150.0 mg), Pd2(dba)3 (10 mol%, 0.03 mmol, 28.3 mg), xantphos (20 mol%, 0.06 mmol, 35.7 mg), and Cs2CO3 (3.0 equivalents, 0.93 mmol, 302.0 mg) in dioxane (3 mL). The reaction mixture was then stirred at 120 °C for 12 hours. After solvent removal, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain a crude product, which was then purified by column chromatography (DCM and MeOH, MeOH ranging from 0 to 10%) to give 111.0 mg of product, a yield of 51%, as a light brown solid. MS (ESI) m / z 710.85 and 712.89 [M+H] + .

[0672] Step 5: (S)-4-amino-6-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-2-(2,3-dichlorobenzyl)isoindoline-1-one

[0673]

[0674] HCl / dioxane (1.0 ml, 2.0 ml) was added to a solution of tert-butyl(6-((1S)-1-((tert-butylsulfonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-2-(2,3-dichlorobenzyl)-1-oxoisoindoline-4-yl)carbamate (0.16 mmol, 111.0 mg) in dioxane (2 ml). The reaction mixture was then stirred at room temperature for 2 hours. After solvent removal, the residue was diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography to give 1.5 mg of a white solid product in a yield of 2%.

[0675] 1H NMR (400MHz, DMSO-d6) δ (ppm) 7.61 (d, J = 8.6Hz, 1H), 7.39–7.31 (m, 1H), 7.19–7.13 (m, 5H), 6.47(d,J=25.5Hz,2H),5.20(s,2H),4.82(s,2H),4.07(s,2H),3.86(s,1H),3.51(t,J=11. 2Hz,1H),3.00(d,J=15.7Hz,1H),2.93–2.84(m,1H),2.67–2.58(m,1H),2.03–1.96(m,2H), 1.89–1.72(m,1H),1.51–1.42(m,1H),1.33–1.14(m,3H),0.85(t,J=6.5Hz,1H).MS(ESI)m / z 507.36 and 509.23[M+H] + .

[0676] The compound of Example 59 was prepared according to Example 58.

[0677] Example 59

[0678] (S)-4-amino-6-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-2-(2,3-dichlorophenyl)isoindolin-1-one

[0679]

[0680] 1 H NMR(400MHz, DMSO-d6)δ(ppm)7.71(dd,J=8.1,1.4Hz,1H),7.59(dd,J=7.9,1.4Hz,1H),7.52–7.45(m,1H),7 .35(d,J=4.5Hz,1H),7.20(dd,J=7.5,3.6Hz,4H),6.53(dd,J=11.5,1.7Hz,1H),5.32(d,J=7.7Hz,1H),4.52 (s,1H),3.96(s,1H),3.55(d,J=13.0Hz,1H),3.03(d,J=15.6Hz,1H),2.96–2.90(m,2H),2.71–2.66(m,2H), 2.03–1.94(m,2H),1.89–1.75(m,1H),1.52–1.41(m,1H),1.32–1.23(m,3H),0.87–0.83(m,1H).MS(ESI)m / z 493.35 and 495.26[M+H] + .

[0681] Example 60

[0682] (S)-4-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-(2,3-dichlorobenzyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0683]

[0684] Step 1: 5-((2,3-dichlorobenzyl)amino)methyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid

[0685]

[0686] (2,3-Dichlorophenyl)formamide (2.0 equivalents, 19.22 mmol, 3.38 g) was added to a suspension of 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (9.61 mmol, 1.5 g) and formaldehyde (5.0 equivalents, 48.0 mmol, 1.443 g) in ethanol (100 mL). The reaction mixture was then stirred at 100 °C for 16 hours. After the reaction was complete, the resulting mixture was filtered to give 2.12 g of crude product as a white solid in 64% yield, which was used directly for the next step. MS (ESI) m / z 344.14 and 346.10 [M+H] + .

[0687] Step 2 6-(2,3-dichlorobenzyl)-2,4-dihydroxy-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0688]

[0689] HCl (20.0 equivalents, 123.0 mmol, 4.49 g) was added to a suspension of 5-((2,3-dichlorobenzyl)amino)methyl)-2,6-dioxy-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (6.16 mmol, 2.12 g) in 50 mL of 2-methoxyethanol. The reaction mixture was then stirred at 130 °C for 16 h. After solvent removal, the residue was diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 70%) to give 835.0 mg of the product in 42% yield as a pale yellow solid.

[0690] MS(ESI)m / z 326.15 and 328.06[M+H] + .

[0691] Step 3: 2,4-Dichloro-6-(2,3-dichlorobenzyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0692]

[0693] DIEA (3.0 equivalent, 7.68 mmol, 993.0 mg) was added to a suspension of 6-(2,3-dichlorobenzyl)-5,6-dihydro-1H-pyrrolo[3,4-d]pyrimidine-2,4,7(3H)-trione (2.56 mmol, 835.0 mg) in POCl3 (25 mL). The reaction mixture was then stirred at 90 °C for 3 hours. After solvent removal, the residue was diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 70%) to give 44.0 mg of a pale yellow solid in a yield of 5%. (ESI) m / z 364.04 and 366.09 [M+H] + .

[0694] Step 4: 2-Chloro-6-(2,3-dichlorobenzyl)-4-((3,4-dimethylbenzyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0695]

[0696] (2,4-Dimethoxyphenyl)methylamine (1.2 equivalents, 0.15 mmol, 24.32 mg) was added to a DMSO (2 mL) suspension of 2,4-dichloro-6-(2,3-dichlorobenzyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (0.12 mmol, 44.0 mg) and DIEA (5.0 equivalence, 0.61 mmol, 78.0 mg). The reaction mixture was then stirred at 120 °C for 12 h. After the reaction was complete, the resulting mixture was diluted with EA and washed with brine. The separated organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 70%) to give 60.0 mg of a pale yellow solid in 100% yield. MS (ESI) m / z 493.23 and 495.18 [M+H] + .

[0697] Step 5N-((S)-1'-(6-(2,3-dichlorobenzyl)-4-((3,4-dimethylbenzyl)amino)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0698]

[0699] N-((S)-1,3-dichlorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (0.12 mmol, 60.0 mg) and DIEA (5.0 equivalent, 0.61 mmol, 79.0 mg) in n-BuOH (2 mL) was added to a solution of N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.5, 9 mg equivalent). The reaction mixture was then stirred in a microwave at 140 °C for 2 hours. After solvent removal, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain a crude product. This crude product was purified by column chromatography (DCM and MeOH, with MeOH ranging from 0% to 10%) to give 80.0 mg of a light brown solid in 86% yield. MS (ESI) m / z 763.57 and 765.63 [M+H] + .

[0700] Step 6 (S)-4-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-(2,3-dichlorobenzyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0701]

[0702] TFA (2.0 mL) was added to a solution of N-((S)-1'-(6-(2,3-dichlorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.11 mmol, 80.0 mg). The reaction mixture was then stirred at 40 °C for 2 hours. After solvent removal, the residue was diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography to give 5.7 mg of a white solid product in 11% yield.

[0703] 1H NMR(400MHz, DMSO-d6)δ(ppm)7.61(dd,J=8.0,1.2Hz,1H),7.37(t,J=7.9Hz,1H),7.31–7.29(m,1H), 7.22(dd,J=7.7,1.0Hz,1H),7.20–7.18(m,1H),7.17–7.14(m,2H),6.86(s,2H),4.82(s,2H),4.51(t, J=13.2Hz,1H),4.04(s,2H),3.82(s,1H),3.15–3.05(m,4H),2.62(d,J=15.7Hz,1H),2.03–1.96(m,1 H),1.71–1.52(m,1H),1.43(d,J=13.4Hz,1H),1.30–1.23(m,2H),1.04(d,J=13.4Hz,1H).MS(ESI)m / z 509.38 and 511.49[M+H] + .

[0704] Example 61

[0705] (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-(2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one

[0706]

[0707] Reagents and conditions: (a) 1-ethoxy vinyl tributyl stannan, Pd(PPh3)2Cl2, DMF, 100℃, 12h; (b) ozone, 10min, then Me2S, DCM, -78℃, 2h; (c) NBS, BPO, CCl4, 80℃, 18h; (d) 2,3-dichloroaniline, Et3N, MeCN, 60℃, 18h; (e) acetic acid, 110℃, 20h; (f) DIEA, DMF, 90℃, 3h. Step 1: 2-Chloro-4-(1-ethoxyvinyl)-5-methylpyrimidine

[0708]

[0709] Under Ar conditions, Pd(PPh3)2Cl2 (1.06 g, 0.05 eq) was added to a DMF (50 mL) solution of 2,4-dichloro-5-methylpyrimidine (4.5 g, 1.0 eq) and 1-ethoxyvinyltributyltin (10.9 g, 1.0 eq), and the reaction was heated at 100 °C for 12 h. After cooling to room temperature, a saturated KF aqueous solution was added, and the mixture was stirred for another 30 min at room temperature. After the reaction was complete, the slurry was filtered through diatomaceous earth, and the filtrate was collected and concentrated under reduced pressure. The residue was then purified by rapid chromatography to obtain the intermediate 2-chloro-4-(1-ethoxyvinyl)-5-methylpyrimidine in high yield. [M+H] + =199 / 201.

[0710] Step 2: Ethyl 2-chloro-5-methylpyrimidine-4-carboxylate

[0711]

[0712] Ozone was pumped into a DCM solution of 2-chloro-4-(1-ethoxyvinyl)-5-methylpyrimidine at -78°C for 30 minutes continuously. After the reaction was complete, excess dimethyl sulfide was added, and the reaction was stirred again at the same temperature for 2 hours. The volatiles were then removed under reduced pressure, and the residue was purified by rapid chromatography to give the intermediate ethyl 2-chloro-5-methylpyrimidine-4-carboxylate. [M+H] + =201 / 203. 1 H NMR (400MHz, Chloroform-d) δ8.60 (s, 1H), 4.46 (q, J = 6.9Hz, 2H), 2.49 (s, 3H), 1.42 (t, J = 6.9Hz, 3H).

[0713] Step 3: Ethyl 5-(bromomethyl)-2-chloropyrimidine-4-carboxylic acid

[0714]

[0715] BPO (122 mg, 0.05 eq) was added to a CCl4 solution of ethyl 2-chloro-5-methylpyrimidine-4-carboxylate (2 g, 1.0 eq) and NBS (1.97 g, 1.1 eq), and the reaction mixture was heated at 80 °C under an argon atmosphere for 18 h. After cooling to room temperature, the mixture was poured into a separating funnel containing a saturated aqueous NaCl solution and extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The volatiles were then removed under reduced pressure, and the residue was purified by rapid chromatography to give the intermediate ethyl 5-(bromomethyl)-2-chloropyrimidine-4-carboxylate. [M+H] + =279 / 281.

[0716] Step 4: Ethyl 2-chloro-5-((2,3-dichlorophenyl)amino)methyl)pyrimidine-4-carboxylic acid

[0717]

[0718] Et3N (0.45 mL, 3.0 eq) was added to a MeCN solution of ethyl 5-(bromomethyl)-2-chloropyrimidine-4-carboxylate (300 mg, 1.0 eq) and 2,3-dichloroaniline (209 mg, 1.2 eq), and the reaction was heated at 60 °C for 18 h. Volatile substances were removed under reduced pressure, and the residue was purified by rapid chromatography to give the intermediate ethyl 2-chloro-5-((2,3-dichlorophenyl)amino)methyl)pyrimidine-4-carboxylate. [M+H] + =360 / 362. 1 H NMR(600MHz,Chloroform-d)δ8.75(s,1H),7.01(t,J=8.1Hz,1H),6.86(dd,J=8.1,1.3Hz,1H),6.40(dd,J= 8.1,1.3Hz,1H),5.19(t,J=6.2Hz,1H),4.73(d,J=6.2Hz,2H),4.50(q,J=7.1Hz,2H),1.44(t,J=7.1Hz,3H).

[0719] Step 5: 2-Chloro-6-(2,3-dichlorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0720]

[0721] Ethyl 2-chloro-5-((2,3-dichlorophenyl)amino)methyl)pyrimidin-4-carboxylic acid was dissolved in acetic acid, and the mixture was heated at 110 °C for 20 hours. After the reaction was complete, the acetic acid was removed under reduced pressure, and the resulting residue was suspended in water. Then, an aqueous solution of NaHCO3 was added to adjust the pH to 7-8. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The volatiles were then removed under reduced pressure, and the residue was purified by rapid chromatography to give the intermediate 2-chloro-6-(2,3-dichlorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [M+H]. + =314 / 316. 1 H NMR(400MHz,Chloroform-d)δ9.00(s,1H),7.62–7.55(m,1H),7.38–7.34(m,2H),4.91(s,2H).

[0722] Step 6(S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-(2,3-dichlorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0723]

[0724] DIEA (132 μL, 5.0 eq) was added to a DMF solution of 2-chloro-6-(2,3-dichlorophenyl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (50 mg, 1.0 eq) and (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (52 mg, 1.2 eq), and the reaction was heated at 90 °C for 3 h. After cooling to room temperature, the mixture was poured into a separating funnel containing saturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The volatiles were then removed under reduced pressure, and the residue was purified by prep HPLC with MeCN / H2O as eluent and TFA as a modifier, providing the target compound as a white solid.

[0725] Example 62:

[0726] (S)-1'-(2-(2,6-dichlorophenyl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0727]

[0728] Step 1: 2,6-Dichloro-N-(2,4-dichloropyrimidin-5-yl)benzamide

[0729]

[0730] To a suspension of 2,4-dichloropyrimidin-5-amine (2.46 mmol, 404.0 mg), 2,6-dichlorobenzoic acid (1.5 equivalences, 3.7 mmol, 706.0 mg), and Et3N (5.0 equivalences, 12.32 mmol, 1.25 g) in THF (30 mL), 2,4,6-tripropyl-1,3,5,2,4,6-trioxotriphosphate-2,4,6-trioxide (3.0 equivalences, 7.39 mmol, 2.35 g) was added. The reaction mixture was then stirred at 90 °C for 36 hours. After the reaction was complete, the resulting mixture was diluted with EA and washed with brine. The separated organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 60%) to give 487.0 mg of the product as a pale yellow solid, in a yield of 59%. MS(ESI)m / z 336.06 and 338.05[M+H] + .

[0731] Step 2: 5-Chloro-2-(2,6-dichlorophenyl)oxazolo[5,4-d]pyrimidine

[0732]

[0733] Na₂CO₃ (2.0 equivalent, 0.75 mmol, 79.0 mg) was added to a DMF (5 mL) suspension of 2,6-dichloro-N-(2,4-dichloropyrimidin-5-yl)benzamide (0.38 mmol, 126.2 mg). The reaction mixture was then stirred at 80 °C for 2 hours. After the reaction was complete, the resulting mixture was diluted with EA and washed with brine. The separated organic layer was dried over MgSO₄, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 60%) to give 71.0 mg of a pale yellow solid in 63% yield. MS (ESI) m / z 300.08 and 302.07 [M+H] + .

[0734] Step 3N-((S)-1'-(2-(2,6-dichlorophenyl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0735]

[0736] N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.5 equivalents, 0.35 mmol, 109.0 mg) was added to a solution of 5-chloro-2-(2,6-dichlorophenyl)oxazolo[5,4-d]pyrimidine (0.24 mmol, 71.0 mg) and DIEA (5.0 equivalence, 1.18 mmol, 153.0 mg) in n-BuOH (2 mL). The reaction mixture was then stirred in a microwave at 140 °C for 1 hour. After solvent removal, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product of 135.0 mg light brown solid, which was used directly for the next step. MS (ESI) m / z 570.56 and 572.67 [M+H] + .

[0737] Step 4: (S)-1'-(2-(2,6-dichlorophenyl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0738]

[0739] HCl / dioxane (1N, 1 mL) was slowly added to a THF (2 mL) solution of N-((S)-1'-(2-(2,6-dichlorophenyl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.24 mmol, 135.0 mg). The reaction mixture was then stirred at rt for 1 hour. After solvent removal, the residue was diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography to give 9.4 mg of a white solid product (9% yield in two steps).

[0740] 1H NMR(400MHz,DMSO-d6)δ(ppm)8.96(s,1H),7.76–7.68(m,3H),7.31–7.29(m,1H) ,7.21–7.15(m,3H),4.53(t,J=13.4Hz,2H),3.85(s,1H),3.26–3.23(m,2H),3.10 (d,J=15.7Hz,1H),2.65(d,J=15.6Hz,1H),1.77(td,J=12.7,4.2Hz,1H),1.65(td ,J=12.7,4.1Hz,1H),1.53(d,J=13.0Hz,1H),1.13(d,J=13.3Hz,1H).MS(ESI)m / z 466.35 and 468.14 [M+H] + .

[0741] The compounds of Examples 63-80 were prepared with reference to Example 62.

[0742] Example 63

[0743] (S)-1'-(2-(2,3-dichlorophenyl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0744]

[0745] MS(ESI)m / z 465.11

[0746] Example 64

[0747] (S)-1'-(2-(2-(trifluoromethyl)pyridin-3-yl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0748]

[0749] 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.96 (s, 1H), 8.95 (d, J = 1.0Hz, 1H), 8.59 (d, J = 7.3Hz, 1H), 7.96 (dd,J=8.0,4.7Hz,1H),7.31–7.29(m,1H),7.20–7.14(m,3H),4.53(t,J=14.0Hz,2H),3.84(s ,1H),3.29–3.23(m,2H),3.10(d,J=15.7Hz,1H),2.64(d,J=15.6Hz,1H),1.77(td,J=12.7,4. 3Hz,1H),1.65(td,J=12.6,4.2Hz,1H),1.55–1.52(m,1H),1.13(d,J=13.2Hz,1H).MS(ESI)m / z 467.44[M+H] + .

[0750] Example 65

[0751] (S)-1'-(2-(5-methylthiazo-4-yl)oxazolo[5,4-d]pyrimidin-5-yl)-5,7-dihydrospiro[b]pyridine-6,4'-piperidine]-5-amine

[0752]

[0753] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.07 (s, 1H), 8.85 (s, 1H), 8.31 (d, J = 4.4Hz, 1H), 7.65 (d, J = 7 .5Hz,1H),7.17(dd,J=7.4,5.0Hz,1H),4.53(t,J=12.5Hz,2H),3.89(s,1H),3.28–3.22(m,2 H),3.13(d,J=16.3Hz,1H),2.86(s,3H),2.76(d,J=16.3Hz,1H),1.77(td,J=12.7,4.3Hz,1H ),1.68(td,J=12.9,4.2Hz,1H),1.55(d,J=12.5Hz,1H),1.14(d,J=13.4Hz,1H).MS(ESI)m / z 420.31[M+H] + .

[0754] Example 66

[0755] (S)-1'-(2-(2,6-dimethylphenyl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0756]

[0757] 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.87(s,1H),7.40–7.37(m,1H),7.31–7.29(m,1H),7.23(d,J=7.7H z,2H),7.20(dd,J=6.5,1.6Hz,1H),7.17–7.15(m,2H),4.53(t,J=15.0Hz,2H),3.84(s,1H),3.28 –3.20(m,2H),3.10(d,J=15.7Hz,1H),2.64(d,J=15.7Hz,1H),2.27(s,6H),1.76(td,J=12.7,4.3 Hz,1H),1.64(td,J=12.7,4.2Hz,1H),1.52(d,J=13.2Hz,1H),1.12(d,J=13.1Hz,1H).MS(ESI)m / z 425.35 and 427.37[M+H] + .

[0758] Example 67

[0759] (S)-1'-(2-(naphth-1-yl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0760]

[0761] 1H NMR(400MHz,DMSO-d6)δ(ppm)9.38(d,J=8.6Hz,1H),8.90(s,1H),8.35(d,J=6.8Hz,1H),8.19(d,J=8.2Hz,1 H),8.08(d,J=8.1Hz,1H),7.77–7.73(m,1H),7.71–7.64(m,2H),7.32–7.30(m,1H),7.20–7.15(m,3H),4.54( t,J=14.3Hz,2H),3.85(s,1H),3.23–3.20(m,2H),3.09(d,J=15.7Hz,1H),2.64(d,J=15.7Hz,1H),1.77(td,J =12.7,4.3Hz,1H),1.65(td,J=12.8,4.2Hz,1H),1.53(d,J=12.9Hz,1H),1.13(d,J=13.2Hz,1H).MS(ESI)m / z 447.44 and 449.53[M+H] + .

[0762] Example 68

[0763] (S)-1'-(2-(2-methylnaphthyl-1-yl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0764]

[0765] 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.97(s,1H),8.12(d,J=8.4Hz,1H),8.03(dd,J=5.8,3.0Hz,1H),7.85– 7.82(m,1H),7.58(t,J=7.7Hz,3H),7.34(d,J=5.2Hz,1H),7.21–7.19(m,3H),4.58(t,J=13.0Hz,2H) ,3.89(s,1H),3.26–3.19(m,2H),3.13(d,J=15.6Hz,1H),2.69(d,J=15.7Hz,1H),2.52(s,3H),1.80( t,J=10.5Hz,1H),1.68(t,J=10.7Hz,1H),1.55(d,J=12.7Hz,1H),1.17(d,J=13.1Hz,1H).MS(ESI)m / z 461.45 and 463.54[M+H] + .

[0766] Example 69

[0767] (S)-1'-(2-(2-chloro-6-(trifluoromethyl)phenyl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0768]

[0769] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.98 (s, 1H), 8.09 (d, J = 8.1Hz, 1H), 8.02 (d, J = 7.8Hz, 1H), 7. 93(t,J=8.1Hz,1H),7.30(d,J=6.1Hz,1H),7.20–7.15(m,3H),4.53(s,2H),3.84(s,1H),3.2 8–3.23(m,2H),3.10(d,J=15.6Hz,1H),2.64(d,J=15.6Hz,1H),1.77(td,J=12.7,4.2Hz,1H ),1.65(td,J=12.8,4.2Hz,1H),1.53(d,J=13.0Hz,1H),1.12(d,J=13.4Hz,1H).MS(ESI)m / z 500.57 and 502.32[M+H] + .

[0770] Example 70

[0771] (S)-1'-(2-(2,4-dimethylpyridin-3-yl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0772]

[0773] 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.90 (s, 1H), 8.49 (d, J = 5.0Hz, 1H), 7.31 (d, J = 5.0Hz, 2H), 7 .19–7.16(m,3H),4.54(t,J=14.4Hz,2H),3.84(s,1H),3.24(d,J=12.1Hz,2H),3.11(d,J=1 5.6Hz,1H),2.65(d,J=15.6Hz,1H),2.50(s,3H),2.34(s,3H),1.76(td,J=12.8,4.0Hz,1H) ,1.64(td,J=13.0,3.9Hz,1H),1.53(d,J=13.2Hz,1H),1.12(d,J=13.7Hz,1H).MS(ESI)m / z 426.45 and 428.46[M+H] + .

[0774] Example 71

[0775] (S)-1'-(2-(3,5-dichloropyridin-4-yl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[indenyl-2,4'-piperidine]-1-amine

[0776]

[0777] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.02 (s, 1H), 8.93 (s, 2H), 7.30 (d, J = 6.1Hz, 1H), 7.20–7.15(m,3H),4.53(s,2H),3.84(s,1H),3.26(d,J=12.2Hz,2H),3.10(d,J =15.6Hz,1H),2.64(d,J=15.6Hz,1H),1.77(td,J=12.7,4.2Hz,1H),1.65(td,J =12.7,3.8Hz,1H),1.54(d,J=12.9Hz,1H),1.12(d,J=13.6Hz,1H).MS(ESI)m / z 467.29 and 469.08 [M+H] + .

[0778] Example 72

[0779] (S)-1'-(2-(2,4-dichloropyridin-3-yl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0780]

[0781] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.00 (s, 1H), 8.67 (d, J = 5.4Hz, 1H), 7.93 (d, J = 5.4Hz, 1H), 7 .33–7.31(m,1H),7.23–7.15(m,3H),4.54(s,2H),3.90(s,1H),3.25–3.17(m,2H),3.12(d, J=15.7Hz,1H),2.69(d,J=15.6Hz,1H),1.75(td,J=12.7,4.2Hz,1H),1.65(td,J=12.7,3. 8Hz, 1H), 1.54 (d, J = 12.3Hz, 1H), 1.17 (d, J = 14.1Hz, 1H). MS (ESI) m / z 467.17 and 469.35 [M+H] + .

[0782] Example 73

[0783] (S)-1'-(2-(1,4-dimethyl-1H-pyrazol-3-yl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0784]

[0785] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.77 (s, 1H), 7.71 (s, 1H), 7.30 (d, J = 6.1Hz, 1H), 7.20–7.15 (m,3H),4.50(t,J=14.6Hz,2H),3.90(s,3H),3.83(s,1H),3.22(dd,J=21.3,11.0Hz,2H), 3.08(d,J=15.6Hz,1H),2.63(d,J=15.6Hz,1H),2.32(s,3H),1.75(td,J=12.7,4.1Hz,1H) ,1.63(td,J=12.6,4.0Hz,1H),1.51(d,J=13.2Hz,1H),1.11(d,J=13.2Hz,1H).MS(ESI)m / z 415.21 and 417.30[M+H] + .

[0786] Example 74

[0787] (S)-1'-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0788]

[0789] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.70 (s, 1H), 7.29 (d, J = 6.1Hz, 1H), 7.20–7.13 (m, 3H), 4 .49(t,J=15.2Hz,2H),3.82(s,1H),3.74(s,3H),3.28–3.16(m,2H),3.09(d,J=15.6Hz, 1H),2.63(d,J=15.7Hz,1H),2.58(s,3H),2.42(s,3H),1.75(td,J=12.7,4.2Hz,1H),1. 62(td,J=12.7,4.1Hz,1H),1.50(d,J=13.0Hz,1H),1.09(d,J=13.3Hz,1H).MS(ESI)m / z 428.34 and 430.45[M+H] + .

[0790] Example 75

[0791] (S)-1'-(2-(3,5-dimethylisoxazol-4-yl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0792]

[0793] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.82 (s, 1H), 7.29 (d, J = 6.1Hz, 1H), 7.20–7.15 (m, 3H) ,4.51(t,J=15.4Hz,2H),3.83(s,1H),3.28–3.19(m,2H),3.09(d,J=15.6Hz,1H),2. 77(s,3H),2.63(d,J=15.7Hz,1H),2.52(s,3H),1.75(td,J=12.7,4.2Hz,1H),1.63( td,J=12.6,4.1Hz,1H),1.52(d,J=13.0Hz,1H),1.11(d,J=13.1Hz,1H).MS(ESI)m / z 415.35 and 417.58[M+H] + .

[0794] Example 76

[0795] (S)-1'-(2-(2,5-dimethylthiazolyl-4-yl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0796]

[0797] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.81 (s, 1H), 7.31 (d, J = 5.4Hz, 1H), 7.18 (dt, J = 6.6, 5.8 Hz,3H),4.52(t,J=13.0Hz,2H),3.87(s,1H),3.25–3.20(m,2H),3.10(d,J=15.7Hz,1H ),2.78(s,3H),2.66(s,3H),2.66(d,J=15.4Hz,1H),1.76(td,J=12.7,4.0Hz,1H),1.6 4(dt,J=17.6,5.3Hz,1H),1.52(d,J=13.2Hz,1H),1.14(d,J=13.8Hz,1H).MS(ESI)m / z 432.38 and 434.35[M+H] + .

[0798] Example 77

[0799] (S)-1'-(2-(2,6-dichlorophenyl)oxazolo[5,4-d]pyrimidin-5-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-5-amine

[0800]

[0801] 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.98 (s, 1H), 8.34 (d, J = 4.5Hz, 1H), 7.77–7.70 (m, 2H), 7. 68(d,J=7.4Hz,1H),7.19(dd,J=7.2,5.1Hz,2H),4.56(s,2H),3.97(s,1H),3.27–3.24( m,2H),3.16(d,J=16.3Hz,1H),2.81(d,J=16.2Hz,1H),1.77(td,J=12.7,4.0Hz,1H),1. 68(td,J=12.9,4.1Hz,1H),1.56(d,J=13.4Hz,1H),1.21(d,J=13.3Hz,1H).MS(ESI)m / z 467.29 and 469.04[M+H] + .

[0802] Example 78

[0803] (S)-1'-(2-(2,4-dimethylpyridin-3-yl)oxazolo[5,4-d]pyrimidin-5-yl)-5,7-dihydrospiro[cyclopenta[b]pyridin-6,4'-piperidine]-5-amine

[0804]

[0805] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.91 (s, 1H), 8.49 (d, J = 5.1Hz, 1H), 8.31 (d, J = 4.6Hz, 1H), 7.65 (d, J = 7.4H z,1H),7.31(d,J=5.0Hz,1H),7.17(dd,J=7.3,5.1Hz,1H),4.55(t,J=12.0Hz,2H),3.89(s,1H),3.26(d, J=13.5Hz,2H),3.14(d,J=16.3Hz,1H),2.77(d,J=16.3Hz,1H),2.50(s,3H),2.34(s,3H),1.76(td,J=12 .7,4.2Hz,1H),1.68(td,J=12.9,4.1Hz,1H),1.55(d,J=12.9Hz,1H),1.14(d,J=13.3Hz,1H).MS(ESI)m / z 428.38[M+H] + .

[0806] Example 79

[0807] (S)-1'-(2-(2-chloro-6-methylphenyl)oxazolo[5,4-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0808]

[0809] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.92 (s, 1H), 7.56–7.51 (m, 2H), 7.42 (dd, J = 6.9, 1.4Hz, 1H), 7.31–7.29(m,1H),7.21–7.15(m,3H),4.53(t,J=14.2Hz,2H),3.84(s,1H),3.27–3.22(m,2H ),3.10(d,J=15.6Hz,1H),2.65(d,J=15.6Hz,1H),2.28(s,3H),1.76(td,J=12.7,4.3Hz,1H ),1.64(td,J=12.7,4.1Hz,1H),1.53(d,J=12.8Hz,1H),1.12(d,J=13.2Hz,1H).MS(ESI)m / z 446.41 and 448.63[M+H] + .

[0810] Example 80

[0811] (S)-1'-(2-(5-methylthiazo-4-yl)oxazolo[5,4-d]pyrimidin-5-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-5-amine

[0812]

[0813] 1H NMR (400MHz, DMSO-d6) δ (ppm) 9.07 (s, 1H), 8.85 (s, 1H), 8.31 (d, J = 4.4Hz, 1H), 7.65 (d, J = 7 .5Hz,1H),7.17(dd,J=7.4,5.0Hz,1H),4.53(t,J=12.5Hz,2H),3.89(s,1H),3.28–3.22(m,2 H),3.13(d,J=16.3Hz,1H),2.86(s,3H),2.76(d,J=16.3Hz,1H),1.77(td,J=12.7,4.3Hz,1H ),1.68(td,J=12.9,4.2Hz,1H),1.55(d,J=12.5Hz,1H),1.14(d,J=13.4Hz,1H).MS(ESI)m / z 420.31[M+H] + .

[0814] Example 81

[0815] (S)-1'-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0816]

[0817] Reagents and conditions: (a) hydrazine hydrate, EtOH, 60℃, 12h, 90%; (b) 2,3-dichlorobenzaldehyde, EtOH, rt, 5h; (c) IBD, DCM, rt, 18h; (d) 1N HCl, 1h; (e) Et3N / MeCN, 90℃, 1h.

[0818] Step 1 4-Chloro-6-hydrazinopyrimidine

[0819]

[0820] Hydrazine hydrate (3.25 mL, 2.0 eq) was added to an ethanolic solution of 4,6-dichloropyrimidine (5 g, 1.0 eq) at 0 °C, and the mixture was then heated at 60 °C for 12 h. After the reaction was complete, 50% of the volatiles were removed under reduced pressure, and the solid was added. The slurry was filtered, the filter cake was washed with cold ethanol, and dried under vacuum to give the intermediate 4-chloro-6-hydrazinopyrimidine, [M+H], in high yield. + =144.90 / 146.66. 1H NMR(400MHz,Chloroform-d)δ8.35(s,1H),6.84(s,1H),6.43(s,1H),3.83(s,2H).

[0821] Step 2(E)-4-chloro-6-(2-(2,3-dichlorobenzyl)hydrazino)pyrimidine

[0822]

[0823] 2,3-Dichlorobenzaldehyde (2.66 g, 1.1 eq) dissolved in EtOH was added dropwise to a solution of 4-chloro-6-hydrazinopyrimidine (2 g, 1.0 eq) in EtOH, and the reaction was stirred at room temperature for 5 h. After the reaction was complete, 50% of the volatiles were removed under reduced pressure. The resulting slurry was filtered, the filter cake was washed with cold ethanol, and dried under vacuum to give the intermediate (E)-4-chloro-6-(2-(2,3-dichlorobenzyl)hydrazinopyrimidine) in high yield. [M+H] + =301.04 / 302.84 / 304.94 / 306.96. 1 H NMR (400MHz, DMSO-d6) δ12.09 (s, 1H), 8.57 (s, 1H), 8.49 (d, J = 0.9Hz, 1H), 8.15 (dd, J=7.9,1.6Hz,1H),7.69(dd,J=7.9,1.6Hz,1H),7.43(t,J=7.9Hz,1H),7.33(s,1H).

[0824] Step 3: 7-Chloro-2-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidine

[0825]

[0826] IBD (1.39 g, 1.3 eq) was added in portions to a DCM suspension of (E)-4-chloro-6-(2-(2,3-dichlorobenzyl)hydrazino)pyrimidine (1 g, 1.0 eq), and the reaction was stirred at room temperature for 18 hours. After rapid completion of the reaction, volatiles were removed under reduced pressure, and the resulting residue was redissolved in a mixture of EtOH / 1N hydrochloric acid (30 mL / 10 mL). The reaction was stirred at room temperature for another 2 hours. Volatiles were removed, and the resulting slurry was poured into a separating funnel containing saturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. Volatiles were then removed under reduced pressure, and the residue was purified by rapid chromatography to give the intermediate 7-chloro-2-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidine. [M+H] +=298.97 / 300.96 / 302.91. 1 H NMR (400MHz, Chloroform-d) δ9.33(d,J=1.2Hz,1H),7.89(dd,J=7.9,1.6Hz,1H),7.76(d,J=1.2Hz,1H),7.63(dd,J=7.9,1.6Hz,1H),7.36(t,J=7.9Hz,1H).

[0827] Step 4 (S)-1'-(2,3-dichlorophenyl)-[1,2,4]triazolyl[1,5-c]pyrimidin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0828]

[0829] Et3N (2 mL) was added to a MeCN suspension of 7-chloro-2-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidine (100 mg, 1.0 eq) and (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (110 mg, 1.0 eq), and the mixture was heated at 90 °C for 1 h. Afterwards, volatiles were removed, and the residue was purified by prep HPLC using MeCN / H2O as eluent and TFA as a modifier to provide the target compound, thus providing the target compound in the form of a white solid, [M+H]. + =465.18 / 467.09 / 469.15;[M-NH2] + = 448.15 / 450.03 / 451.90. 1 H NMR(400MHz, Methanol-d4)δ9.22(s,1H),7.76(dd,J=7.9,1.6Hz,1H),7.72(dd,J=7.9,1.6Hz,1H),7.51–7.41(m,2H),7.40–7.28(m, 3H),6.69(s,1H),4.46–4.36(m,1H),4.36–4.24(m,2H),3.45–3.26(m,2H),3.25–3.06(m,2H),1.94–1.77(m,2H),1.75–1.56(m,2H).

[0830] Example 82

[0831] (S)-1'-(2-((2,3-dichlorophenyl)thio)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0832]

[0833] Step 1: 5-Chlorothiazolo[4,5-d]pyrimidine-2-thiol

[0834]

[0835] O-ethyl dithiocarbonate (3.0 equivalents, 14.39 mmol, 2.31 g) was added to a DMF (50 mL) suspension of 5-bromo-2-chloropyrimidin-4-amine (4.8 mmol, 1.0 g). The reaction mixture was then stirred at 130 °C for 10 h. After the reaction was complete, the resulting mixture was diluted with EA and washed with 1 N HCl solution. The separated organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 60%) to give 909.0 mg of a yellow solid in 93% yield. MS (ESI) m / z 204.05 and 206.04 [M+H] + .

[0836] Step 2:

[0837] 5-Chloro-2-((2,3-dichlorophenyl)thio)thiazo[4,5-d]pyrimidine

[0838]

[0839] Under Ar conditions, 1,2-dichloro-3-iodobenzene (1.5 equivalents, 1.46 mmol, 398.0 mg) was added to a suspension of 5-chlorothiazo[4,5-d]pyrimidine-2-thiol (0.97 mmol, 198.0 mg), Pd2(dba)3 (10 mol%, 0.01 mmol, 89.0 mg), xantphos (20 mol%, 0.19 mmol, 113.0 mg), and DIEA (3.0 equivalents, 2.92 mmol, 377.0 mg) in dioxane (10 mL). The reaction mixture was then stirred at 100 °C for 10 hours. After the reaction was complete, the resulting mixture was diluted with EA and washed with brine. The separated organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 60%) to give a pale yellow solid product in a yield of 259.0 mg. MS(ESI)m / z 348.00 and 350.03[M+H] + .

[0840] Step 3

[0841] N-((S)-1'-(2-((2,3-dichlorophenyl)thio)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0842]

[0843] N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.5 equivalents, 0.26 mmol, 79.0 mg) was added to a solution of 5-chloro-2-((2,3-dichlorophenyl)thio)thiazo[4,5-d]pyrimidine (0.17 mmol, 60.0 mg) and DIEA (3.0 equivalents, 0.52 mmol, 66.7 mg) in n-BuOH (2 mL). The reaction mixture was then stirred in a microwave at 140 °C for 1 hour. After solvent removal, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (DCM and MeOH, MeOH ranging from 0 to 10%) to give 72.4 mg of a light brown solid in 68% yield. MS(ESI)m / z 618.43 and 620.42[M+H] + .

[0844] Step 4

[0845] (S)-1'-(2-((2,3-dichlorophenyl)thio)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0846]

[0847] A solution of HCl / dioxane (1N, 1 mL) was slowly added to THF (2 mL) of N-((S)-1'-(2-((2,3-dichlorophenyl)thio)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.12 mmol, 72.4 mg). The reaction mixture was then stirred at rt for 1 hour. After solvent removal, the residue was diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography to give 3.0 mg of a white solid in 5% yield.

[0848] 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.75 (s, 1H), 7.79–7.77 (m, 2H), 7.45 (t, J = 7.9Hz, 1H), 7. 31(d,J=5.2Hz,1H),7.21–7.14(m,4H),3.90(s,1H),3.08(d,J=15.7Hz,1H),2.66(d,J=1 5.7 Hz, 1H), 2.03–1.96 (m, 1H), 1.77 (dt, J = 27.4, 12.1 Hz, 1H), 1.60 (d, J = 12.8 Hz, 1H), 1.48–1.38 (m, 1H), 1.30–1.17 (m, 5H), 0.93–0.77 (m, 1H). MS (ESI) m / z 514.30 and 516.10 [M+H] + .

[0849] Example 83

[0850] (S)-1'-(2-(2,3-dichlorophenyl)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0851]

[0852] Step 1: 2,5-Dichlorothiazo[4,5-d]pyrimidine

[0853]

[0854] Sulfonyl chloride (10.0 equivalent, 34.9 mmol, 4.71 g) was slowly added dropwise to a DCM (30 mL) suspension of 5-chlorothiazo[4,5-d]pyrimidine-2-thiol (3.49 mmol, 710.0 mg). The reaction mixture was then stirred at rt for 2 hours. After the reaction was complete, the resulting mixture was diluted with DCM and washed with brine. The separated organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 50%) to give 538.0 mg of a yellow solid in 75% yield. MS (ESI) m / z 206.00 and 207.95 [M+H] + .

[0855] Step 2: 5-Chloro-2-(2,3-dichlorophenyl)thiazo[4,5-d]pyrimidine

[0856]

[0857] Under Ar conditions, (2,3-dichlorophenyl)boronic acid (1.5 equivalents, 1.6 mmol, 306.0 mg) was added to a suspension of 2,5-dichlorothiazo[4,5-d]pyrimidine (1.07 mmol, 220.0 mg), PdCl2 (dppf) (10 mol%, 0.11 mmol, 78.0 mg), and K2CO3 (3.0 equivalents, 3.2 mmol, 443.0 mg) in dioxane (10 mL) and water (1 mL). The reaction mixture was then stirred at 100 °C for 10 hours. After the reaction was complete, the resulting mixture was diluted with EA and washed with brine. The separated organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 60%) to give a pale yellow solid product in a yield of 224.0 mg. MS(ESI)m / z 316.01 and 318.23[M+H] + .

[0858] Step 3

[0859] N-((S)-1'-(2-(2,3-dichlorophenyl)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0860]

[0861] N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.5 equivalents, 0.28 mmol, 87.0 mg) was added to a solution of 5-chloro-2-(2,3-dichlorophenyl)thiazo[4,5-d]pyrimidine (0.19 mmol, 60.0 mg) and DIEA (3.0 equivalents, 0.57 mmol, 73.5 mg) in n-BuOH (2 mL). The reaction mixture was then stirred in a microwave at 140 °C for 1 hour. After solvent removal, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (DCM and MeOH, MeOH ranging from 0 to 10%) to give 79.0 mg of product in 71% yield as a light brown solid. MS(ESI) m / z 586.48 and 588.70 [M+H] + .

[0862] Step 4

[0863] (S)-1'-(2,3-dichlorophenyl)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0864]

[0865] A solution of HCl / dioxane (1N, 1 mL) was slowly added to a THF (2 mL) solution of N-((S)-1'-(2-(2,3-dichlorophenyl)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.14 mmol, 79.0 mg). The reaction mixture was then stirred at rt for 1 hour. After solvent removal, the residue was diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography to give 3.0 mg of a yellow solid product in a yield of 5%.

[0866] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.25 (s, 1H), 8.17 (d, J = 7.0Hz, 1H), 7.92 (d, J = 7.1Hz, 1H), 7.60 (t ,J=8.0Hz,1H),7.31(d,J=5.3Hz,1H),7.19(dt,J=6.9,4.4Hz,3H),4.59(t,J=13.7Hz,2H),3.88 (s,1H),3.12(d,J=15.7Hz,1H),2.68(d,J=15.5Hz,1H),2.00(q,J=7.7Hz,1H),1.81–1.61(m,1H ),1.55–1.42(m,1H),1.32–1.23(m,3H),1.15(d,J=13.2Hz,1H),0.86–0.83(m,1H).MS(ESI)m / z 482.31 and 484.30[M+H] + .

[0867] The compounds of Examples 84-89 were prepared by referring to Example 83.

[0868] Example 84

[0869] (S)-1'-(2-(2,3-dichlorophenyl)-7-methylthiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0870] 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.20 (dd, J=8.0, 1.4Hz, 1H), 7.92 (dd, J=8.0, 1.4Hz, 1H), 7.60 (t, J=8.0Hz,1H),7.32–7.30(m,1H),7.22–7.16(m,3H),4.60(t,J=14.0Hz,2H),3.85(s,1H),3.28– 3.20(m,2H),3.12(d,J=15.6Hz,1H),2.68(d,J=4.1Hz,1H),2.65(s,3H),1.76(td,J=12.7,4.3H z,1H),1.64(td,J=12.7,4.0Hz,1H),1.52(d,J=13.8Hz,1H),1.13(d,J=13.1Hz,1H).MS(ESI)m / z 496.35 and 496.34[M+H] + .

[0871] Example 85

[0872] (S)-1'-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0873]

[0874] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.04 (s, 1H), 7.36–7.34 (m, 1H), 7.22 (td, J = 8.8 ,5.1Hz,3H),4.58(td,J=8.1,3.7Hz,2H),3.94(s,1H),3.77(s,3H),3.21(dd, J=20.2,8.2Hz,2H),3.13(d,J=15.8Hz,1H),2.73(d,J=15.8Hz,1H),2.66(s,3 H),2.47(s,3H),1.79–1.61(m,1H),1.47(dt,J=13.8,10.5Hz,3H).MS(ESI)m / z 446.57[M+H] + .

[0875] Example 86

[0876] (S)-1'-(2-(3,5-dimethylisoxazol-4-yl)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[indenyl-2,4'-piperidine]-1-amine

[0877]

[0878] 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.88(s,1H),7.32–7.31(m,1H),7.22–7.16(m,3H),4 .55(t,J=12.8Hz,2H),3.87(s,1H),3.19(dd,J=27.7,12.7Hz,2H),3.10(d,J=15.7 Hz,1H),2.67(d,J=15.7Hz,1H),2.39(s,6H),1.74(td,J=12.7,4.3Hz,1H),1.62(t d,J=12.8,3.8Hz,1H),1.49(d,J=13.1Hz,1H),1.12(d,J=11.8Hz,1H).MS(ESI)m / z 433.38 [M+H] + .

[0879] Example 87

[0880] (S)-1'-(2-(3,4-dihydroquinolin-1(2H)-yl)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[indenyl-2,4'-piperidine]-1-amine

[0881]

[0882] 1 H NMR(400MHz, DMSO-d6)δ(ppm)8.60(s,1H),7.93(d,J=8.0Hz,1H),7.33–7.31(m,1H),7.28(d,J=8.0H z,2H),7.21–7.16(m,4H),4.54–4.45(m,2H),4.00(t,J=6.1Hz,1H),3.88(s,1H),3.21–3.14(m,3H), 3.10(d,J=15.6Hz,1H),2.80(t,J=6.4Hz,1H),2.68(d,J=15.3Hz,1H),2.03–1.95(m,4H),1.75–1.68 (m,1H),1.66–1.54(m,1H),1.48–1.45(m,1H),1.40–1.29(m,1H),1.12(d,J=13.5Hz,1H).MS(ESI)m / z 469.43 and 471.62[M+H] + .

[0883] Example 88

[0884] (S)-1'-(2-(indololin-1-yl)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[indenyl-2,4'-piperidine]-1-amine

[0885]

[0886] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.71 (s, 1H), 7.34–7.30 (m, 3H), 7.19 (dt, J = 6.9, 4.5Hz, 4H), 7.08 (t, J =7.4Hz,1H),4.54(t,J=13.1Hz,2H),4.17(t,J=8.3Hz,2H),3.86(s,1H),3.23–3.16(m,3H),3.10(d, J=15.8Hz,1H),2.66(d,J=15.6Hz,1H),2.00(q,J=7.6Hz,1H),1.74(td,J=12.6,4.1Hz,1H),1.62(td ,J=12.6,4.0Hz,1H),1.49(d,J=13.4Hz,1H),1.32–1.23(m,2H),1.12(d,J=13.1Hz,1H).MS(ESI)m / z 455.46 and 457.61[M+H] + .

[0887] Example 89

[0888] (S)-1'-(2-(3,4-dihydro-1,5-naphthidin-1(2H)-yl)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[indenyl-2,4'-piperidine]-1-amine

[0889]

[0890] MS(ESI) m / z 470.48 [M+H] + .

[0891] The compounds of Examples 90-93 were prepared by referring to Example 82.

[0892] Example 90

[0893] (S)-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-N-(2,3-dichlorophenyl)thiazo[4,5-d]pyrimidine-2-amine

[0894]

[0895] MS(ESI)m / z 498.27 and 500.33[M+H] + .

[0896] Example 91

[0897] (S)-1'-(2-(2,3-dichlorophenoxy)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0898]

[0899] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.73 (s, 1H), 7.58 (dd, J = 8.0, 1.3Hz, 1H), 7.45 (t, J = 8.1Hz ,1H),7.38(dd,J=8.1,1.3Hz,1H),7.31(d,J=5.5Hz,1H),7.20–7.15(m,3H),3.89(s,1H) ,3.08(d,J=15.7Hz,1H),2.66(d,J=15.7Hz,1H),1.78(dt,J=22.7,10.0Hz,1H),1.60(d, J=13.6Hz,1H),1.56(d,J=11.7Hz,1H),1.49–1.37(m,1H),1.30–1.15(m,4H).MS(ESI)m / z 498.38 and 500.57[M+H] + .

[0900] Example 92

[0901] (S)-1'-(2-(cyclohexylynyl)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0902]

[0903] MS(ESI) m / z 444.50 [M+H] + .

[0904] Example 93

[0905] (S)-1'-(2-((2,3-dichlorophenyl)ethynyl)thiazo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0906]

[0907] MS(ESI)m / z 506.30 and 508.18[M+H] + .

[0908] Example 94

[0909] (S)-1'-(2-(2,3-dichlorophenyl)benzo[d]thiazolyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0910]

[0911] Step 15-bromo-2-iodobenzo[d]thiazole

[0912]

[0913] Add 1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane (1.1 equivalent, 3.59 mmol, 1.24 g) to a DMF (30 mL) suspension of 5-bromobenzothiazole (3.26 mmol, 698.0 mg) and sodium tert-butoxide (1.0 equivalent, 3.26 mmol, 313.0 mg). The reaction mixture was then stirred at rt for 1 hour. After the reaction was complete, the resulting mixture was diluted with EA and washed with brine. The separated organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 50%) to give 1.0 g of a pale yellow solid in 90% yield.

[0914] MS(ESI)m / z 339.93 and 341.92[M+H] + .

[0915] Step 25 - Bromo-2-(2,3-dichlorophenyl)benzo[d]thiazole

[0916]

[0917] Under Ar conditions, (2,3-dichlorophenyl)boronic acid (1.5 equivalents, 0.61 mmol, 116.0 mg) was added to a suspension of 5-bromo-2-iodobenzothiazole (0.41 mmol, 138.0 mg), PdCl2 (dppf) (10 mol%, 0.04 mmol, 29.7 mg), and K2CO3 (3.0 equivalents, 1.22 mmol, 168.0 mg) in dioxane (5 mL) and water (0.5 mL). The reaction mixture was then stirred in a microwave at 80 °C for 1 hour. After the reaction was complete, the resulting mixture was diluted with EA and washed with brine. The separated organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0% to 60%) to give 103.0 mg of a pale yellow solid product in 71% yield. MS(ESI)m / z 358.07 and 360.06[M+H] + .

[0918] Step 3N-((S)-1'-(2-(2,3-dichlorophenyl)benzo[d]thiazolyl-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0919]

[0920] Under Ar conditions, N-((S)-1,3-dihydrospiro[d]thiazole (0.29 mmol, 103.0 mg), Pd2(dba)3 (10 mol%, 0.03 mmol, 26.3 mg), xantphos (20 mol%, 0.06 mmol, 33.2 mg), and Cs2CO3 (3.0 equivalent, 0.86 mmol, 280.0 mg) of dioxane (5 mL) were added to a solution of N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.5 equivalent, 0.43 mmol, 132.0 mg), and the reaction mixture was stirred at 100 °C for 12 h. After solvent removal, the residue was diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography (DCM and MeOH, with MeOH ranging from 0% to 10%) to give 138.0 mg of a light brown solid in 82% yield. MS (ESI) m / z 584.49 and 586.40 [M+H] + .

[0921] Step 4

[0922] (S)-1'-(2,3-dichlorophenyl)benzo[d]thiazolyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0923]

[0924] A solution of HCl / dioxane (1N, 1 mL) was slowly added to a THF (2 mL) solution of N-((S)-1'-(2-(2,3-dichlorophenyl)benzo[d]thiazolyl-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.18 mmol, 103.0 mg). The reaction mixture was then stirred at rt for 1 hour. After solvent removal, the residue was diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography to give 14.5 mg of a yellow solid product in 17% yield.

[0925] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.09 (dd, J=7.9, 1.2Hz, 1H), 7.97 (d, J=9.0Hz, 1H), 7.85 ( dd,J=8.0,1.3Hz,1H),7.58–7.54(m,2H),7.31(dd,J=8.8,2.4Hz,2H),7.21–7.14(m,3H ), 3.89(s, 1H), 3.69(t, J = 13.3Hz, 2H), 3.01(ddd, J = 27.4, 10.9, 3.5Hz, 3H), 2.62(d, J = 15.7Hz, 1H), 2.03–1.79(m, 2H), 1.55(d, J = 12.3Hz, 1H), 1.29–1.18(m, 3H). MS(ESI) m / z 480.36 and 482.31 [M+H] + .

[0926] Compounds of Examples 95-98 were prepared with reference to Example 94.

[0927] Example 95

[0928] (S)-1'-(2-((2,3-dichlorophenyl)thio)thiazo[5,4-c]pyridin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0929]

[0930] 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.75 (s, 1H), 7.68 (dd, J=8.0, 1.0Hz, 1H), 7.47–7.45 (m, 1H), 7.39 (t, J= 7.9Hz,1H),7.32(d,J=5.0Hz,1H),7.19(t,J=6.8Hz,3H),7.10(s,1H),3.92(s,1H),3.46(dd,J=25.6,1 1.8Hz,2H),3.08(d,J=15.7Hz,1H),2.67(d,J=15.8Hz,1H),2.03–1.96(m,2H),1.87–1.69(m,1H),1.58 (d,J=13.2Hz,1H),1.47(dd,J=13.8,6.7Hz,1H),1.34–1.24(m,2H),0.85(t,J=6.6Hz,1H).MS(ESI)m / z 513.33 and 515.16[M+H] + .

[0931] Example 96

[0932] (S)-1'-(2-(2,3-dichlorophenyl)thiazo[5,4-c]pyridin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0933]

[0934] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.98 (s, 1H), 8.08 (dd, J = 7.8, 1.2Hz, 1H), 7.91 (dd, J = 8.0, 1.3Hz,1H),7.59(t,J=8.0Hz,1H),7.44(s,1H),7.35(t,J=4.0Hz,1H),7.24–7.18(m,2H) ,6.63(s,1H),4.24(d,J=13.1Hz,1H),3.97(s,1H),3.17–3.09(m,1H),2.75–2.67(m,1H) ,2.34–2.31(m,1H),1.84–1.69(m,1H),1.49–1.42(m,2H),1.31–1.24(m,5H).MS(ESI)m / z 481.29 and 483.40[M+H] + .

[0935] Example 97

[0936] (S)-1'-(2-((2,3-dichlorophenyl)thio)thiazo[4,5-b]pyridin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0937]

[0938] 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.11(d,J=8.0Hz,1H),7.68(dd,J=8.0,1.3Hz,1H),7.50(dd,J=7.8,1 .3Hz,1H),7.39(t,J=7.9Hz,1H),7.33–7.32(m,1H),7.22–7.16(m,3H),6.95(d,J=8.0Hz,1H),3.93 (s,2H),3.47–3.41(m,1H),3.09(d,J=15.8Hz,1H),2.68(d,J=15.7Hz,1H),1.99(dt,J=13.3,6.8Hz ,1H),1.87–1.65(m,2H),1.58(d,J=13.3Hz,1H),1.49–1.43(m,1H),1.30–1.19(m,3H).MS(ESI)m / z 513.33 and 515.28[M+H] + .

[0939] Example 98

[0940] (S)-1'-(2-(2,3-dichlorophenyl)thiazo[4,5-b]pyridin-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0941]

[0942] 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.32 (d, J = 9.0 Hz, 1H), 8.16 (dd, J = 7.9, 1.2 Hz, 1H), 7.86 (dd ,J=8.0,1.1Hz,1H),7.57(t,J=8.0Hz,1H),7.45–7.34(m,1H),7.25–7.15(m,4H),4.32–4.2 8(m,1H),3.97(s,1H),3.12(d,J=15.8Hz,1H),2.75(d,J=15.7Hz,1H),2.03–1.95(m,2H),1 .82–1.66(m,2H),1.54–1.44(m,1H),1.35(d,J=4.5Hz,1H),1.29–1.23(m,3H).MS(ESI)m / z 481.33 and 483.36[M+H] + .

[0943] Example 99

[0944] (S)-1'-(2-(2,3-dichlorophenyl)oxazolo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0945]

[0946] Step 1 4-Amino-2-chloropyrimidine-5-ol

[0947]

[0948] BBr3·Et2O (5.0 equivalents, 37.5 mmol) was slowly added to a suspension of 2-chloro-5-methoxypyrimidine-4-amine (7.5 mmol, 1.2 g) in DCM (40 mL). The reaction mixture was then stirred at room temperature for 20 hours. After the reaction was complete, the resulting mixture was diluted with methanol and washed with brine. The separated organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to give a crude product as a pale yellow solid. MS (ESI) m / z 146.05 and 148.08 [M+H] + .

[0949] Step 25 - Chloro-2-(2,3-dichlorophenyl)oxazolo[4,5-d]pyrimidine

[0950]

[0951] 2,3-Dichlorobenzoic acid (1.5 equivalents, 10.31 mmol, 1.97 g) was added to a suspension of 4-amino-2-chloropyrimidin-5-ol (6.87 mmol, 1.0 g) in POCl3 (50 mL). The reaction mixture was then stirred at 110 °C for 48 hours. After the reaction was complete, the resulting mixture was diluted with EA and washed with saturated NaHCO3 solution. The separated organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 70%) to give 242.0 mg of a pale yellow solid, in 12% yield. MS (ESI) m / z 300.12 and 302.17 [M+H] + .

[0952] Step 3N-((S)-1'-(2-(2,3-dichlorophenyl)oxazolo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0953]

[0954] N-((S)-1,3-dichlorophenyl)oxazolo[4,5-d]pyrimidine (0.27 mmol, 80.0 mg) and DIEA (5.0 equivalence, 1.33 mmol, 172.0 mg) in n-BuOH (3 mL) was added to a solution of N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.5 equivalence, 0.4 mmol, 122.0 mg). The reaction mixture was then stirred in a microwave at 140 °C for 1 hour. After solvent removal, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product of 152.0 mg light brown solid, which was used directly for the next step. MS (ESI) m / z 570.56 and 572.67 [M+H] + .

[0955] Step 4 (S)-1'-(2-(2,3-dichlorophenyl)oxazolo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0956]

[0957] A solution of HCl / dioxane (1N, 1 mL) was slowly added to a THF (3 mL) solution of N-((S)-1'-(2-(2,3-dichlorophenyl)oxazolo[4,5-d]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.27 mmol, 152.0 mg). The reaction mixture was then stirred at rt for 1 hour. After solvent removal, the residue was diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography to give 13.2 mg of a yellow solid (11% yield in two steps).

[0958] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.99 (s, 1H), 8.27 (s, 2H), 8.16 (dd, J = 7.9, 1.5Hz, 1H), 7. 99(dd,J=8.1,1.5Hz,1H),7.64(t,J=8.0Hz,1H),7.51(d,J=7.3Hz,1H),7.37–7.29(m,3 H),4.57(dd,J=24.6,13.7Hz,2H),4.37(d,J=4.8Hz,1H),3.33–3.26(m,2H),3.20(d,J= 16.2Hz,1H),3.04(d,J=16.2Hz,1H),1.77–1.68(m,2H),1.55–1.49(m,2H).MS(ESI)m / z 466.35 and 468.07[M+H] + .

[0959] Example 100

[0960] (S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-d]thiazolyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0961]

[0962] Step 1: N-((S)-1'-(4-chloro-5-formylthiazolyl-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide

[0963]

[0964] N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.5 equivalents, 2.06 mmol, 631.0 mg) was added to a solution of 2,4-dichlorothiazol-5-carboxaldehyde (1.37 mmol, 250.0 mg) and DIEA (5.0 equivalents, 6.87 mmol, 888.0 mg) in MeCN (15 mL). The reaction mixture was then stirred at rt for 2 h. After solvent removal, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 100%) to give 615.0 mg of product as a pale yellow solid in 99% yield. MS (ESI) m / z 452.46 and 454.21 [M+H] + .

[0965] Step 2

[0966] N-((S)-1'-(4-azido-5-formylthiazo-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0967]

[0968] TBAF (5 equivalents, 1.66 mmol, 434.0 mg) was added to a solution of N-((S)-1'-(4-chloro-5-formylthiazolyl-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.33 mmol, 150.0 mg) and TMSN3 (5.0 equivalents, 1.66 mmol, 191.0 mg) in DCM (5 mL). The reaction mixture was then stirred at 35 °C for 48 hours. After solvent removal, the residue was diluted with DCM and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 80%) to give 142.0 mg of product in 93% yield as a yellow solid. MS (ESI) m / z 459.56 [M+H] + .

[0969] Step 3:

[0970] N-((S)-1'-(4-azido-5-((E)-(2,3-dichlorophenyl)imino)methyl)thiazo-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0971]

[0972] TiCl4 (0.5 mmol, 0.16 mmol, 29.8 mg) was added to a solution of N-((S)-1'-(4-chloro-5-formylthiazolyl-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.31 mmol, 142.0 mg), 2,3-dichloroaniline (1.5 equivalence, 0.47 mmol, 76.0 mg), and Et3N (3.0 equivalence, 0.94 mmol, 95.0 mg) in DCM (5 mL). The reaction mixture was then stirred at 25 °C for 12 hours. After solvent removal, the residue was diluted with toluene and concentrated under vacuum to give a crude product of 189.0 mg brown solid, which was used directly for the next step. MS (ESI) m / z 602.44 and 604.35 [M+H] + .

[0973] Step 4

[0974] N-((S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-d]thiazolyl-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0975]

[0976] N-((S)-1'-(4-azido-5-((E)-2,3-dichlorostyryl)thiazolyl-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.31 mmol, 189.0 mg) and toluene (5 mL) were added to a vial. The reaction mixture was then stirred at 120 °C for 5 hours. After solvent removal, the residue was diluted with EA and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 80%) to give 47.3 mg of a yellow solid product in 26% yield. MS (ESI) m / z 574.34 and 576.46 [M+H] + .

[0977] Step 5

[0978] (S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-d]thiazolyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0979]

[0980] HCl / dioxane (1N, 1 mL) was slowly added to a THF (2 mL) solution of N-((S)-1'-(2-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-d]thiazolyl-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.08 mmol, 47.2 mg). The reaction mixture was then stirred at rt for 1 hour. After solvent removal, the residue was diluted with EA and washed with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by column chromatography to give 2.6 mg of a pale yellow solid in 7% yield.

[0981] 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.14(s,1H),7.73(dd,J=8.0,1.5Hz,1H),7.59(dd,J=8.0,1.5Hz ,1H),7.52(t,J=8.0Hz,1H),7.32–7.30(m,1H),7.20–7.15(m,3H),3.96–3.92(m,2H),3.87(s,1 H),3.46–3.42(m,2H),3.08(d,J=15.7Hz,1H),2.65(d,J=15.7Hz,1H),1.85(td,J=12.8,4.4Hz ,1H),1.74(td,J=12.8,4.4Hz,1H),1.57(d,J=13.4Hz,1H),1.17(d,J=13.3Hz,1H).MS(ESI)m / z 470.29 and 472.28[M+H] + .

[0982] The compound of Example 101 was prepared according to Example 100.

[0983] Example 101

[0984] (S)-1'-(2-(2,3-dichlorobenzyl)-2H-pyrazolo[3,4-d]thiazolyl-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0985]

[0986] 1H NMR (400MHz, DMSO-d6) δ (ppm) 7.86 (s, 1H), 7.60 (dd, J = 8.0, 1.0 Hz, 1H), 7.32 (dd, J = 15.6, 7 .6Hz,2H),7.20–7.15(m,3H),6.87(d,J=7.5Hz,1H),5.46(s,2H),3.89–3.81(m,3H),3.27(d ,J=2.7Hz,2H),3.06(d,J=15.7Hz,1H),2.63(d,J=15.7Hz,1H),1.82(td,J=12.7,4.4Hz,1H ),1.71(td,J=12.7,4.3Hz,1H),1.54(d,J=12.9Hz,1H),1.15(d,J=13.5Hz,1H).MS(ESI)m / z 484.34 and 486.36[M+H] + .

[0987] Example 102

[0988] (S)-1'-(2-(2,3-dichlorophenyl)imidazo[1,2-a]pyridin-7-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0989]

[0990] Step 1: 7-Bromo-2-(2,3-dichlorophenyl)imidazo[1,2-a]pyridine

[0991]

[0992] Under Ar conditions, 4-bromopyridin-2-amine (0.5 g, 2.89 mmol, 1.0 eq), 2-bromo-1-(2,3-dichlorophenyl)ethane-1-one (1.549 g, 5.78 mmol, 2 eq), and NaHCO3 (0.486 g, 5.78 mmol, 2 eq) were dissolved in ethanol (20 mL) to give a yellow suspension. The reaction mixture was stirred at 85 °C for 12 h. H2O (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0% to 15% ethyl acetate / hexane to give a yellow solid (0.36 g, 36.4%). MS (ESI) m / z 341.14 [M+H] + .

[0993] Step 2 (R)-N-((S)-1'-(2-(2,3-dichlorophenyl)imidazo[1,2-a]pyridin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[0994]

[0995] Under Ar conditions, 7-bromo-2-(2,3-dichlorophenyl)imidazo[1,2-a]pyridine (0.1 g, 0.292 mmol, 1.000 eq), (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.108 g, 0.351 mmol, 1.2 eq), Pd2(dba)3 (0.027 g, 0.029 mmol, 0.1 eq), Cs2CO3 (0.286 g, 0.877 mmol, 3 eq), and Xantphos (0.034 g, 0.058 mmol, 0.2 eq) were dissolved in 1,4-dioxane (8 mL) to give a brown suspension. The reaction mixture was stirred at 100 °C for 12 hours. H₂O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0% to 3% methanol / dichloromethane to give a yellow solid (0.086 g, 51.8%). MS (ESI) m / z 567.38 [M+H] + .

[0996] Step 3 (S)-1'-(2,3-dichlorophenyl)imidazo[1,2-a]pyridin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[0997]

[0998] Under argon atmosphere, (R)-N-((S)-1'-(2-(2,3-dichlorophenyl)imidazo[1,2-a]pyridin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.086 g, 0.152 mmol, 1.0 eq) and HCl (0.0554 g, 1.520 mmol, 10.03 eq) were dissolved in 1,4-dioxane (3 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 hour. Saturated NaHCO3 (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give a white solid (17.4 mg, 24.8%).

[0999] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.35 (d, J = 9.3 Hz, 2H), 8.21 (dd, J = 7.9, 1.6 Hz, 1H), 7.57 (dd, J = 7.9, 1.6Hz,1H),7.43(t,J=7.9Hz,1H),7.31(d,J=6.0Hz,1H),7.23–7.12(m,3H),6.90(dd,J=7.7,2.3H z,1H),6.70(d,J=1.8Hz,1H),3.86(s,1H),3.70(dd,J=16.8,13.0Hz,2H),3.08–2.91(m,3H),2.61 (d,J=15.6Hz,1H),1.91–1.71(m,2H),1.53(d,J=12.0Hz,1H),1.15(d,J=13.2Hz,1H).MS(ESI)m / z 463.38[M+H] + .

[1000] The compound of Example 103 was prepared according to Example 102.

[1001] Example 103

[1002] (S)-1'-(2-(2,3-dichlorophenyl)-5-methylimidazo[1,2-a]pyridin-7-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[1003]

[1004] 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.18 (dd, J = 7.9, 1.4 Hz, 1H), 8.09 (s, 1H), 7.59 (dd, J =7.9,1.4Hz,1H),7.44(t,J=7.9Hz,1H),7.38–7.30(m,1H),7.23–7.15(m,3H),6.83 (s,1H),6.65(s,1H),3.92(s,1H),3.72(td,J=10.7,4.6Hz,2H),3.08–2.92(m,3H) ,2.70–2.62(m,1H),2.58(s,3H),1.92–1.72(m,2H),1.59–1.39(m,2H).MS(ESI)m / z 477.26[M+H] + .

[1005] Example 104

[1006] (S)-1'-(2-(2,3-dichlorophenyl)imidazo[1,2-a]pyrazin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[1007]

[1008] Step 1: 6-Bromo-2-(2,3-dichlorophenyl)imidazo[1,2-a]pyrazine

[1009]

[1010] Under Ar conditions, 5-bromopyrazin-2-amine (0.2 g, 1.149 mmol, 1.0 eq) and 2-bromo-1-(2,3-dichlorophenyl)ethane-1-one (0.616 g, 2.299 mmol, 2 eq) were dissolved in ethanol (15 mL) to give a yellow solution. The reaction mixture was stirred at 85 °C for 24 h. H₂O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0% to 20% ethyl acetate / hexane to give a yellow solid (0.073 g, 18.52%). MS (ESI) m / z 341.92 [M+H] + .

[1011] Step 2 (R)-N-((S)-1'-(2-(2,3-dichlorophenyl)imidazo[1,2-a]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide

[1012]

[1013] Under Ar conditions, 6-bromo-2-(2,3-dichlorophenyl)imidazo[1,2-a]pyrazine (0.05 g, 0.146 mmol, 1.000), (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.067 g, 0.219 mmol, 1.5), BINAP (0.018 g, 0.029 mmol, 0.2), sodium tert-butoxide (0.042 g, 0.437 mmol, 3), and Pd2(dba)3 (0.013 g, 0.015 mmol, 0.1) were dissolved in 1,4-dioxane (4 ml) to give a brown suspension. The reaction mixture was stirred in a microwave at 90 °C for 1 hour. H₂O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0% to 3% methanol / dichloromethane to give a yellow oily product (0.02 g, 24.13%). MS (ESI) m / z 568.26 [M+H] + .

[1014] Step 3 (S)-1'-(2-(2,3-dichlorophenyl)imidazo[1,2-a]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1015]

[1016] Under Ar conditions, (R)-N-((S)-1'-(2-(2,3-dichlorophenyl)imidazo[1,2-a]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.02 g, 0.035 mmol, 1.0 eq) and HCl (1.282 mg, 0.035 mmol, 1.0 eq) were dissolved in 1,4-dioxane (4 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 hour. Saturated NaHCO3 (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give a white solid (2.3 mg, 14.1%).

[1017] 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.90 (s, 1H), 8.58 (s, 1H), 8.14 (dd, J = 7.9, 1.4Hz, 1H), 8.02 (s, 1H), 7 .67(dd,J=8.0,1.5Hz,1H),7.49(t,J=7.9Hz,1H),7.34(d,J=5.3Hz,1H),7.19(dd,J=7.3,4.1Hz,3H) ,3.93(s,1H),3.86(d,J=12.8Hz,2H),3.06(d,J=15.7Hz,1H),2.98(dd,J=21.8,10.4Hz,2H),2.72– 2.62(m,1H),1.93–1.84(m,1H),1.84–1.73(m,1H),1.54(d,J=13.7Hz,1H),1.34(s,1H).MS(ESI)m / z 464.33[M+H] + .

[1018] Example 105

[1019] (S)-1'-(2-(2,3-dichlorophenyl)imidazo[1,2-c]pyrimidin-7-yl)-1,3-dihydrospiro[indenyl-2,4'-piperidine]-1-amine

[1020]

[1021] Step 1 (R)-N-((S)-1'-(6-aminopyrimidin-4-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1022]

[1023] Under Ar conditions, 6-bromopyrimidine-4-amine (0.114 g, 0.653 mmol, 2 eq), (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.1 g, 0.326 mmol, 1.0 eq), and DIEA (0.127 g, 0.979 mmol, 3 eq) were dissolved in n-butanol (4 mL) to give a yellow solution. The reaction mixture was stirred in a microwave oven at 140 °C for 1.5 h. The crude product was added to a silica gel column and eluted with 0% to 6% methanol / dichloromethane to give a colorless oily product (0.09 g, 69.0%). MS (ESI) m / z 400.34 [M+H] + .

[1024] Step 2 (R)-N-((S)-1'-(2-(2,3-dichlorophenyl)imidazo[1,2-c]pyrimidin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1025]

[1026] Under Ar conditions, (R)-N-((S)-1'-(6-aminopyrimidin-4-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.063 g, 0.158 mmol, 1.0 eq), 2-bromo-1-(2,3-dichlorophenyl)ethane-1-one (0.127 g, 0.473 mmol, 3 eq), and NaHCO3 (0.040 g, 0.473 mmol, 3 eq) were dissolved in ethanol (15 mL) to give a yellow solution. The reaction mixture was stirred at 85 °C for 12 hours. H2O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0% to 3% methanol / dichloromethane to give a yellow oily product (0.038 g, 42.4%). MS (ESI) m / z 568.26 [M+H] + .

[1027] Step 3 (S)-1'-(2-(2,3-dichlorophenyl)imidazo[1,2-c]pyrimidin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1028]

[1029] Under Ar conditions, (R)-N-((S)-1'-(2,3-dichlorophenyl)imidazo[1,2-c]pyrimidin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.038 g, 0.067 mmol, 1.0 eq) and HCl (0.024 g, 0.668 mmol, 10 eq) were dissolved in 1,4-dioxane (3 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 hour. Saturated NaHCO3 (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give a white solid (10.0 mg, 32.2%).

[1030] 1H NMR(400MHz,DMSO-d6)δ(ppm)9.16(d,J=1.0Hz,1H),8.41(s,1H),8.20(dd,J=7.9,1.6Hz,1H),7 .63(dd,J=7.9,1.6Hz,1H),7.46(t,J=7.9Hz,1H),7.36–7.30(m,1H),7.23–7.16(m,3H),6.57(s, 1H),4.16–4.06(m,2H),3.91(s,1H),3.11(dd,J=24.1,14.0Hz,3H),2.68(d,J=15.7Hz,1H),1.86 –1.75(m,1H),1.70(d,J=3.7Hz,1H),1.51(d,J=12.7Hz,1H),1.17(d,J=12.4Hz,1H).MS(ESI)m / z 464.38[M+H] + .

[1031] Compounds of Examples 106-107 were prepared according to Example 105.

[1032] Example 106

[1033] (S)-1'-(2-(2,3-dichlorophenyl)-5-methylimidazo[1,2-c]pyrimidin-7-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[1034]

[1035] 1 H NMR(400MHz, DMSO-d6)δ(ppm)8.18(s,1H),8.15(dd,J=7.9,1.6Hz,1H),7.63(dd,J=7.9,1.6Hz ,1H),7.46(t,J=7.9Hz,1H),7.34–7.30(m,1H),7.21–7.16(m,3H),6.48(s,1H),4.19–4.06(m, 2H),3.88(s,1H),3.13–3.00(m,3H),2.76(s,3H),2.65(d,J=15.6Hz,1H),1.80(td,J=12.8,4. 3Hz,1H),1.75–1.63(m,1H),1.51(d,J=13.0Hz,1H),1.14(dd,J=12.4,5.1Hz,1H).MS(ESI)m / z 478.28[M+H] + .

[1036] Example 107

[1037] (S)-1'-(2-(2,3-dichlorophenyl)-8-fluoroimidozolo[1,2-c]pyrimidin-7-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[1038]

[1039] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.08 (s, 1H), 8.55 (d, J = 3.0Hz, 1H), 8.22 (dd, J = 8.0, 1.6Hz, 1H), 7 .67(dd,J=8.0,1.6Hz,1H),7.49(t,J=8.0Hz,1H),7.36–7.31(m,1H),7.20(dt,J=8.4,4.1Hz,3H) ,4.04–3.96(m,2H),3.94(s,1H),3.23(d,J=6.6Hz,2H),3.10(d,J=15.8Hz,1H),2.74–2.67(m,1H ),1.87(d,J=3.3Hz,1H),1.78(d,J=3.6Hz,1H),1.53(d,J=12.3Hz,1H),1.18(s,1H).MS(ESI)m / z 482.32[M+H] + .

[1040] Example 108

[1041] (S)-7-(1-amino-1,3-dihydrospiro[inden-2,4'-piperidin]-1'-yl)-2-(2,3-dichlorophenyl)imidazo[1,2-c]pyrimidin-8-carboxynitrile

[1042]

[1043] MS(ESI) m / z 489.33 [M+H] + .

[1044] Example 109

[1045] (S)-(7-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-2-(2,3-dichlorophenyl)imidazo[1,2-c]pyrimidin-8-yl)methanol

[1046]

[1047] Step 14-((S)-1-((R)-tert-butylsulfonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-chloropyrimidine-5-carboxylic acid methyl ester

[1048]

[1049] Methyl 4,6-dichloropyrimidin-5-carboxylate (0.2 g, 0.966 mmol, 1.0 eq), (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.296 g, 0.966 mmol, 1.0 eq), and CsF (0.440 g, 2.90 mmol, 3 eq) were dissolved in DMF (2 mL) under Ar conditions to give a yellow suspension. The reaction mixture was stirred at 60 °C for 2 h. H₂O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with 0% to 3% methanol / dichloromethane to give a yellow oily product (0.46 g, 100%). MS(ESI) m / z 477.19 [M+H] + .

[1050] Step 2: Methyl 4-amino-6-((S)-1-((R)-tert-butylsulfonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrimidine-5-carboxylic acid

[1051]

[1052] Methyl 4-((S)-1-((R)-tert-butylsulfonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-chloropyrimidin-5-carboxylic acid (0.46 g, 0.964 mmol, 1.0 eq) and 25% ammonia (3.28 g, 48.2 mmol, 50 eq) were dissolved in 1,4-dioxane (3 mL) under Ar conditions. The reaction mixture was stirred in a microwave oven at 90 °C for 1.5 h. The crude product was added to a silica gel column and eluted with 0% to 6% methanol / dichloromethane to give a white solid product (0.223 g, 50.5%). MS (ESI) m / z 458.26 [M+H] + .

[1053] Step 3

[1054] (R)-N-((S)-1'-(6-amino-5-(hydroxymethyl)pyrimidin-4-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-1-yl)-2-methylpropane-2-thioamide

[1055]

[1056] Methyl 4-amino-6-((S)-1-((R)-tert-butylsulfonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrimidine-5-carboxylic acid (0.223 g, 0.487 mmol, 1.0 eq) was dissolved in THF (10 mL) under Ar conditions to obtain a solution. The reaction mixture was cooled to 0 °C using an ice / water bath. LiAlH4 (0.092 g, 2.437 mmol, 5 eq) was added to the reaction mixture in a single addition. The reaction mixture was stirred at room temperature for 16 hours. H2O (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL x 2). The combined organic layers were dried over Na2SO4 g, filtered, and concentrated to give a yellow oily product (0.2 g, 96%), MS (ESI) m / z 430.38 [M+H]. + .

[1057] Step 4 (R)-N-((S)-1'-(2-(2,3-dichlorophenyl)-8-(hydroxymethyl)imidazo[1,2-c]pyrimidin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1058]

[1059] Under Ar conditions, (R)-N-((S)-1'-(6-amino-5-(hydroxymethyl)pyrimidin-4-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.2 g, 0.466 mmol, 1.0 eq), 2-bromo-1-(2,3-dichlorophenyl)ethane-1-one (0.374 g, 1.397 mmol, 3 eq), and NaHCO3 (0.196 g, 2.328 mmol, 5 eq) were dissolved in ethanol (10 mL), and the reaction mixture was stirred at 85 °C for 16 hours. The crude product was added to a silica gel column and eluted with 0% to 6% methanol / dichloromethane to give a yellow oily product (0.063 g, 22.61%).

[1060] MS(ESI) m / z 598.34 [M+H] + .

[1061] Step 5

[1062] (S)-(7-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-2-(2,3-dichlorophenyl)imidazo[1,2-c]pyrimidin-8-yl)methanol

[1063]

[1064] Under Ar conditions, (R)-N-((S)-1'-(2,3-dichlorophenyl)-8-(hydroxymethyl)imidazo[1,2-c]pyrimidin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (0.063 g, 0.105 mmol, 1.0 eq) and HCl (0.038 g, 1.052 mmol, 10 eq) were dissolved in 1,4-dioxane (3 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 hour. Saturated NaHCO3 (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give a white solid (0.6 mg, 1.1%). MS (ESI) m / z 494.35 [M+H] + .

[1065] Example 110

[1066] (S)-1'-(2-(2,3-dichlorophenyl)oxazolo[5,4-c]pyridin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[1067]

[1068] Step 1: 2,6-Dibromo-3-fluoropyridine-4-amine

[1069]

[1070] 1-Chloromethyl-4-fluoro-1,4-diazotized bicyclo[2.2.2]octanebis(tetrafluoroborate) (5.06 g, 14.29 mmol, 1.2 eq) was added to a mixture of 2,6-dibromopyridin-4-amine (3 g, 11.91 mmol, 1.0 eq) in anhydrous DMF (20 mL) and anhydrous acetonitrile (20 mL). The reaction was stirred at 80 °C for 0.5 h. Volatiles were removed under reduced pressure, and the residue was purified by silica gel chromatography, first by elution with DCM to give a crude product, which was further purified by 0% to 30% hexane / ethyl acetate to give the compound 2,6-dibromo-3-fluoropyridin-4-amine (850 mg, 26.4%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ6.93(br,2H),6.84–6.80(m,1H).MS:268.9(M+H + ).

[1071] Step 2: 2,3-Dichloro-N-(2,6-dibromo-3-fluoropyridin-4-yl)benzamide

[1072]

[1073] Under Ar conditions, an anhydrous DCM solution (20 mL) of 2,6-dibromo-3-fluoropyridin-4-amine (600 mg, 2.22 mmol, 1.0 eq), 2,3-dichlorobenzoic acid (425 mg, 2.22 mmol, 1.0 eq), EDC (852 mg, 4.45 mmol, 2.0 eq), and DMAP (407 mg, 3.33 mmol, 1.5 eq) was stirred at 35 °C for 18 hours. Volatile substances were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with 0 to 35% hexane / ethyl acetate, to give a white solid compound, 2,3-dichloro-N-(2,6-dibromo-3-fluoropyridin-4-yl)benzamide (550 mg, 55.9%).

[1074] MS: 440.9 (M+H) + ).

[1075] Step 3: 6-Bromo-2-(2,3-dichlorophenyl)oxazolo[5,4-c]pyridine

[1076]

[1077] A mixture of 2,3-dichloro-N-(2,6-dibromo-3-fluoropyridin-4-yl)benzamide (22 mg, 0.05 mmol, 1.0 eq) and NaH (2 mg, 0.05 mmol, 1.0 eq) in NMP (3 mL) was microwaved at 200 °C for 2 hours. The solution was poured into H2O. The precipitate was filtered and collected, purified by silica gel chromatography, and eluted with 0–15% hexane / ethyl acetate to give a white solid compound 6-bromo-2-(2,3-dichlorophenyl)oxazolo[5,4-c]pyridine (5 mg, 29.3%). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.06 (d, J = 0.5Hz, 1H), 8.29 (d, J = 0.5Hz, 1H), 8.19 (dd, J=7.9,1.5Hz,1H),8.01(dd,J=8.1,1.5Hz,1H),7.65(t,J=8.0Hz,1H).MS:343.1(M+H + ).

[1078] Step 4: N-((S)-1'-(2-(2,3-dichlorophenyl)oxazolo[5,4-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1079]

[1080] A mixture of 6-bromo-2-(2,3-dichlorophenyl)oxazolo[5,4-c]pyridine (5 mg, 0.015 mmol, 1.0 eq), N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (11.14 mg, 0.036 mmol, 2.5 eq), Pd2dba3 (2.66 mg, 2.91 μmol, 0.2 eq), BINAP (3.62 mg, 5.81 μmol, 0.4 eq), potassium tert-butoxide (6.52 mg, 0.058 mmol, 4.0 eq), and anhydrous dioxane (3 mL) was microwaved at 120 °C for 2 hours. The volatiles were removed under reduced pressure to obtain a crude product, which was purified by silica gel chromatography by elution with 0% to 9% DCM / MeOH to give compound N-((S)-1'-(2-(2,3-dichlorophenyl)oxazolo[5,4-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (10 mg, crude). MS: 570.9 (M+H) + ).

[1081] Step 5(S)-1'-(2-(2,3-dichlorophenyl)oxazolo[5,4-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1082]

[1083] A solution of HCl / dioxane was added to a solution of N-((S)-1'-(2-(2,3-dichlorophenyl)oxazolo[5,4-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (40 mg, 0.07 mmol, 1.0 eq) in 4 mL of dioxane, and stirred at room temperature for 1 hour. The pH of the solution was adjusted to 7 using a saturated sodium carbonate solution, and then partitioned between ethyl acetate / H₂O. Organic matter was collected, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product, which was purified by preparative HPLC to give compound -1'-(2,3-dichlorophenyl)oxazolo[5,4-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (2 mg, 6.12%) as a yellow solid, MS: 465.3 (M+H). + Purity: 98.8%.

[1084] Example 111

[1085] (S)-1'-(2-(2,3-dichlorophenyl)-4-methylbenzo[d]oxazol-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[1086]

[1087] Step 1 2-Amino-4-bromo-3-methylphenol

[1088]

[1089] A mixture of 4-bromo-3-methyl-2-nitrophenol (500 mg, 2.155 mmol, 1.0 eq) and stannous chloride(II) dihydrate (1.23 g, 6.46 mmol, 3.0 eq) in ethanol (10 mL) was refluxed for 3 hours. Additional SnCl2 (4.5 equivalents) was added. The reaction was refluxed for another 2 hours. Volatiles were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with 0 to 15% hexane / ethyl acetate, to give compound 2-amino-4-bromo-3-methylphenol (418 mg, 96%). MS: 202.2 (M+H) + ).

[1090] Step 2 5-Bromo-2-(2,3-dichlorophenyl)-4-toluidine[d]oxazole

[1091]

[1092] A solution of 2-amino-4-bromo-3-methylphenol (418 mg, 2.07 mmol, 1.0 eq), 2,3-dichlorobenzoyl chloride (433 mg, 2.07 mmol, 1.0 eq), and methanesulfonic acid (596 mg, 6.21 mmol, 3.0 eq) in anhydrous dioxane (20 mL) was stirred at 100 °C for 6 hours. Volatiles were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with 0–10% hexane / ethyl acetate, to give compound 5-bromo-2-(2,3-dichlorophenyl)-4-methylbenzo[d]oxazole (400 mg, 54.2%). MS: 357.1 (M+H) + ).

[1093] Step 3N-((S)-1'-(2-(2,3-dichlorophenyl)-4-methylbenzo[d]oxazol-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide

[1094]

[1095] The following medications were administered: N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (129 mg, 0.42 mmol, 1.5 eq), 5-bromo-2-(2,3-dichlorophenyl)-4-methylbenzo[d]oxazole (100 mg, 0.28 mmol, 1.0 eq), Pd2(dba)3 (51.3 mg, 0.056 mmol, 0.2 eq), and xantphos (48.6 mg, 0.084 mmol, 0.3 eq). A solution of anhydrous dioxane (5 mL) and sodium tert-butoxide (81 mg, 0.84 mmol, 3.0 eq) was stirred at 90 °C for 2 hours. Volatile substances were removed under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0% to 5% DCM / MeOH to give the product N-((S)-1'-(2-(2,3-dichlorophenyl)-4-methylbenzo[d]oxazol-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (12 mg, 7.35%).

[1096] MS: 582.5 (M+H) + ).

[1097] Step 4 (S)-1'-(2-(2,3-dichlorophenyl)-4-methylbenzo[d]oxazol-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1098]

[1099] At room temperature, a solution of HCl / dioxane (6N) was added to a solution of N-((S)-1'-(2-(2,3-dichlorophenyl)-4-methylbenzo[d]oxazol-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (12 mg, 0.021 mmol, 1.0 eq) dioxane (3 mL). The reaction mixture was stirred for 0.5 h. The solution was diluted with ethyl acetate, and the pH was adjusted to 7 with saturated NaHCO3 solution. The solution was partitioned between ethyl acetate and H2O. Organic matter was collected, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product. This crude product was purified by preparative HPLC and given as a white solid: (S)-1'-(2-(2,3-dichlorophenyl)-4-methylbenzo[d]oxazol-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (2.6 mg, 26.4%). MS: 478.4 (M+H) + Purity: 89.6%.

[1100] Example 112

[1101] (S)-1'-(2-(2,3-dichlorophenyl)oxazolo[4,5-b]pyridin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1102]

[1103] Step 1: 5-Bromooxazolo[4,5-b]pyridine-2-thiol

[1104]

[1105] A mixture of 2-amino-6-bromopyridin-3-ol (1 g, 5.29 mmol, 1.0 eq) and O-ethyl dithiocarbonate (1.02 g, 6.35 mmol, 1.2 eq) in anhydrous ethanol (15 mL) was stirred at 100 °C for 16 hours. Volatile substances were removed under reduced pressure, the residue was diluted with H₂O, and the pH was adjusted to 7 with aqueous hydrochloric acid. The precipitate was collected and dried to give the crude compound 5-bromooxazolo[4,5-b]pyridin-2-thiol (750 mg, 61.3%). MS: 231.1 (M+H) + ).

[1106] Step 2: 5-Bromo-2-chlorooxazolo[4,5-b]pyridine

[1107]

[1108] Oxaloyl chloride (618 mg, 4.87 mmol, 1.5 eq) was added dropwise to a solution of 5-bromooxazolo[4,5-b]pyridine-2-thiol (750 mg, 3.25 mmol, 1.0 eq) in anhydrous DMF (5 mL) at 0 °C. The reaction mixture was slowly heated to room temperature and stirred for 2 hours. The solution was separated in an aqueous solution of ethyl acetate / NaHCO3, the organic matter was collected, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel chromatography by elution with 0% to 5% hexane / ethyl acetate to give the product 5-bromo-2-chlorooxazolo[4,5-b]pyridine (450 mg, 59.4%). MS: 233.4 (M+H) + ).

[1109] Step 3: 5-Bromo-2-(2,3-dichlorophenyl)oxazolo[4,5-b]pyridine

[1110]

[1111] Under Ar conditions, a mixture of 5-bromo-2-chlorooxazolo[4,5-b]pyridine (210 mg, 0.90 mmol, 1.0 eq), (2,3-dichlorophenyl)boronic acid (206 mg, 1.08 mmol, 1.2 eq), PdCl2(dppf)-CH2Cl2 adduct (147 mg, 0.18 mmol, 0.2 eq), and K2CO3 (373 mg, 2.70 mmol, 3 eq) in dioxane (5 mL) and H2O (0.5 mL) was stirred at 70 °C for 70 min. Volatiles were removed under reduced pressure, and the mixture was purified by silica gel chromatography, eluting with 0% to 10% hexane / ethyl acetate, to give the product 5-bromo-2-(2,3-dichlorophenyl)oxazolo[4,5-b]pyridine (130 mg, 42%), MS: 343.4 (M+H). + ).

[1112] Step 4N-((S)-1'-(2-(2,3-dichlorophenyl)oxazolo[4,5-b]pyridin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1113]

[1114] A mixture of anhydrous toluene (7 ml) of 5-bromo-2-(2,3-dichlorophenyl)oxazolo[4,5-b]pyridine (110 mg, 0.32 mmol, 1.0 eq), N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (147 mg, 0.48 mmol, 1.5 eq), Pd2(dba)3 (58.6 mg, 0.064 mmol, 0.2 eq), BINAP (59.7 mg, 0.096 mmol, 0.3 eq), and sodium tert-butoxide (92 mg, 0.96 mmol, 3.0 eq) was microwaved at 90 °C for 50 minutes under Ar conditions. Volatile substances were removed under reduced pressure, and the product was purified by silica gel chromatography, eluting with 0% to 5% DCM / MeOH to give N-((S)-1'-(2,3-dichlorophenyl)oxazolo[4,5-b]pyridin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (50 mg, 27.5%). MS: 569.5 (M+H) + ).

[1115] Step 5(S)-1'-(2-(2,3-dichlorophenyl)oxazolo[4,5-b]pyridin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1116]

[1117] At room temperature, a solution of HCl / dioxane (6N) was added to a solution of N-((S)-1'-(2-(2,3-dichlorophenyl)oxazolo[4,5-b]pyridin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (50 mg, 0.088 mmol, 1.0 eq) dioxane (2 mL). The reaction was stirred for 0.5 h. The solution was diluted with ethyl acetate, and the pH was adjusted to 7 with saturated NaHCO3 solution. The solution was partitioned between ethyl acetate and H2O. Organic matter was collected, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product. This crude product was purified by preparative HPLC and presented as a yellow solid: (S)-1'-(2-(2,3-dichlorophenyl)oxazolo[4,5-b]pyridin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (2.4 mg, 5.87%). MS: 465.2 (M+H) + Purity: 85.8%.

[1118] Example 113

[1119] (S)-1'-(5-amino-3-(2,3-dichlorophenyl)-1,6-naphthidin-7-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[1120]

[1121] Step 1: 5,7-Dichloro-3-iodo-1,6-naphthylidine

[1122]

[1123] A solution of 5,7-dichloro-1,6-naphthidine (2 g, 10.05 mmol, 1.0 eq) and 1-iodopyrrolidine-2,5-dione (4.52 g, 20.10 mmol, 2.0 eq) in acetic acid (25 mL) was stirred at 110 °C for 17 h under Ar conditions. Volatiles were removed under reduced pressure, the residue was diluted with DCM, and purified by silica gel chromatography, eluting with hexane / ethyl acetate from 0% to 10%, to give the compound 5,7-dichloro-3-iodo-1,6-naphthidine (1.0 g, 30.6%) as a gray solid.

[1124] 1 H NMR(400MHz, DMSO-d6)δ(ppm)9.39(d,J=2.0Hz,1H),9.01(dd,J=1.9,0.9Hz,1H),8.14(d,J=0.7Hz,1H).MS:324.9(M+H + ).

[1125] Step 2: 5,7-Dichloro-3-(2,3-dichlorophenyl)-1,6-naphthidine

[1126]

[1127] 5,7-Dichloro-3-iodo-1,6-naphthidine (600 mg, 1.85 mmol, 1.0 eq), (2,3-dichlorophenyl)boronic acid (423 mg, 2.22 mmol, 1.2 eq), PdCl2 (dppf) (270 mg, 0.37 mmol, 0.2 eq), and sodium carbonate (391 mg, 3.69 mmol, 2.0 eq) were microwaved at 80 °C for 45 min. The precipitate, the crude compound 5,7-dichloro-3-(2,3-dichlorophenyl)-1,6-naphthidine (1.6 g, crude product), was collected as a gray solid and used directly for the next step. MS: 345.2 (M+H) + ).

[1128] Step 3: 7-Chloro-3-(2,3-dichlorophenyl)-N-(2,4-dimethoxybenzyl)-1,6-naphthidine-5-amine

[1129]

[1130] At room temperature, (2,4-dimethoxyphenyl)methylamine (1.4 g, 8.37 mmol, 1.8 eq) was added to a solution of 5,7-dichloro-3-(2,3-dichlorophenyl)-1,6-naphthidine (1.6 g, 4.65 mmol, 1.0 eq) in dioxane (10 mL). The reaction was stirred at 100 °C for 3 h. Volatiles were removed under reduced pressure, and the residue was diluted with DCM. The solid was filtered, the filtrate was concentrated, and purified by silica gel chromatography, eluting with DCM, to give a yellow solid compound 7-chloro-3-(2,3-dichlorophenyl)-N-(2,4-dimethoxybenzyl)-1,6-naphthidine-5-amine (815 mg, 36.9%). MS: 474.5 (M+H) + ).

[1131] Step 4N-((S)-1'-(3-(2,3-dichlorophenyl)-5-((2,4-dimethoxybenzyl)amino)-1,6-naphthidin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1132]

[1133] Under Ar conditions, an anhydrous dioxane (10 mL) of 7-chloro-3-(2,3-dichlorophenyl)-N-(2,4-dimethoxybenzyl)-1,6-naphthidine-5-amine (700 mg, 1.47 mmol, 1.0 eq), N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (678 mg, 2.21 mmol, 1.5 eq), sodium tert-butoxide (425 mg, 4.42 mmol, 3.0 eq), xantphos (256 mg, 0.44 mmol, 0.3 eq), and Pd2(dba)3 (270 mg, 0.30 mmol, 0.2 eq) was reacted in a microwave at 110 °C for 1 hour. Volatile substances were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with DCM / MeOH from 0% to 9%, to give compound N-((S)-1'-(3-(2,3-dichlorophenyl)-5-((2,4-dimethoxybenzyl)amino)-1,6-naphthidin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (100 mg, 9.11%). MS: 744.5 (M+H) + ).

[1134] Step 5N-((S)-1'-(5-amino-3-(2,3-dichlorophenyl)-1,6-naphthidin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1135]

[1136] Under Ar and at room temperature, TFA (2 mL) was added dropwise to a solution of N-((S)-1'-(3-(2,3-dichlorophenyl)-5-((2,4-dimethoxybenzyl)amino)-1,6-naphthidin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (100 mg, 0.13 mmol, 1.0 eq) in DCM (6 mL). The solution was stirred for 0.5 hours. To remove volatiles under reduced pressure, the next step involved directly using compound N-((S)-1'-(5-amino-3-(2,3-dichlorophenyl)-1,6-naphthidin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (80 mg, crude). MS: 594.3 (M+H) + ).

[1137] Step 6 (S)-1'-(5-amino-3-(2,3-dichlorophenyl)-1,6-naphthidin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1138]

[1139] Under Ar and at room temperature, an HCl / dioxane solution was added dropwise to a solution of N-((S)-1'-(5-amino-3-(2,3-dichlorophenyl)-1,6-naphthidin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (80 mg, 0.14 mmol, 1.0 eq) in anhydrous dioxane (5 mL). The solution was stirred for 0.5 h, and the pH was adjusted to 7 using saturated NaHCO3 solution. The solution was partitioned between ethyl acetate and H2O. Organic matter was collected and concentrated to obtain a crude product. The crude product was purified by HPLC to provide compound (S)-1'-(5-amino-3-(2,3-dichlorophenyl)-1,6-naphthidin-7-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (6 mg, 9.09%) as a white solid.

[1140] MS: 490.3 (M+H) + Purity: 86.8%.

[1141] Example 114

[1142] (S)-1'-(4-amino-6-(2,3-dichlorophenyl)pyridin[2,3-d]pyrimidin-2-yl)-1,3-dihydrospiro[indenyl-2,4'-piperidine]-1-amine

[1143]

[1144] Step 1: 6-Bromopyridine[2,3-d]pyrimidine-2,4-diol

[1145]

[1146] A mixture of 2-amino-5-bromonicotinic acid (1 g, 4.61 mmol, 1.0 eq) and urea (2.77 g, 46.1 mmol, 10 eq) was heated at 180 °C (oil bath) for 5 hours. The reaction was cooled and diluted with 2N NaOH solution. The pH of the solution was adjusted to 8 using 6N HCl solution. The precipitate was filtered and dried to give 0.6 g, 53.8%, of the compound 6-bromopyridine[2,3-d]pyrimidine-2,4-diol as a gray solid. MS: 242.3 (M+H) + ).

[1147] Step 2: 6-Bromo-2,4-dichloropyridine[2,3-d]pyrimidine

[1148]

[1149] A mixture of 6-bromopyridine[2,3-d]pyrimidine-2,4-diol (600 mg, 2.48 mmol, 1.0 eq), DIPEA (740 mg, 5.73 mmol, 2.31 eq), and POCl3 (8 mL) was reacted at 120 °C for 48 h. Volatiles were removed under reduced pressure, and the pH of the residue was adjusted to 7. The solution was partitioned between DCM and H2O. The organic matter was collected, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give crude 6-bromo-2,4-dichloropyridine[2,3-d]pyrimidine (500 mg, 72.3%), which was used directly for the next step. MS: 278.8 (M+H) + ).

[1150] Step 3: 6-Bromo-2-chloro-N-(2,4-dimethoxybenzyl)pyridine[2,3-d]pyrimidine-4-amine

[1151]

[1152] A solution of 6-bromo-2,4-dichloropyridine[2,3-d]pyrimidine (500 mg, 1.79 mmol, 1.0 eq), DIPEA (695 mg, 5.38 mmol, 3.0 eq), and (2,4-dimethoxyphenyl)methylamine (291 mg, 2.15 mmol, 1.2 eq) in butanol (5 mL) and tetrahydrofuran (5 mL) was stirred at 40 °C for 1 h. Volatiles were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with 0–10% hexane / ethyl acetate, to give compound 6-bromo-2-chloro-N-(2,4-dimethoxybenzyl)pyridine[2,3-d]pyrimidine-4-amine (200 mg, 29.5%).

[1153] MS: 377.6 (M+H) + ).

[1154] Step 4N-((S)-1'-(6-bromo-4-((2,4-dimethoxybenzyl)amino)pyridin[2,3-d]pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1155]

[1156] 6-Bromo-2-chloro-N-(2,4-dimethoxybenzyl)pyridine[2,3-d]pyrimidin-4-amine (200 mg, 0.49 mmol, 1.0 eq) solution, DIPEA (126 mg, 0.98 mmol, 2.0 eq) and N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (180 mg, 0.59 mmol, 1.2 eq) in butanol (5 The reaction mixture (ml) was stirred at 140℃ for 1 h, and the volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography and eluted with hexane / ethyl acetate to give compound N-((S)-4-(6-bromo-4-((2,4-dimethoxybenzyl)amino)pyridin[2,3-d]pyrimidin-2-yl)-1',3'-dihydrospiro[cyclohexane-1,2'-indene]-1'-yl)-2-methylpropane-2-sulfinamide (245 mg, 73.9%).

[1157] MS: 679.7 (M+H) + ).

[1158] Step 5N-((S)-1'-(6-(2,3-dichlorophenyl)-4-((2,4-dimethoxybenzyl)amino)pyridin[2,3-d]pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1159]

[1160] PdCl2 (dppf) (6.47 mg, 8.84 μmol, 0.1 eq), potassium carbonate (36.7 mg, 0.27 mmol, 3.0 eq), (2,3-dichlorophenyl)boronic acid (33.7 mg, 0.18 mmol, 2.0 eq), and N-((S)-4-(6-bromo-4-((2,4-dimethoxybenzyl)amino)pyridin[2,3-d]pyrimidin-2-yl)-1',3'-dihydrospiro[cyclohexane-1,2'-indene]-1'-yl)-2-methylpropane-2-sulfinamide (60 mg, 0.09 mmol, 1.0 eq) were microwaved at 115 °C for 0.5 h in dioxane (2 mL) and H2O (0.5 mL). Volatile substances were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with DCM / MeOH from 0% to 8% to give compound N-((S)-4-(6-(2,3-dichlorophenyl)-4-((2,4-dimethoxybenzyl)amino)pyridin[2,3-d]pyrimidin-2-yl)-1',3'-dihydrospiro[cyclohexane-1,2'-indene]-1'-yl)-2-methylpropane-2-sulfinamide (50 mg, 76%). MS: 744.6 (M+H) + ).

[1161] Step 6N-((S)-1'-(4-amino-6-(2,3-dichlorophenyl)pyridin[2,3-d]pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1162]

[1163] At room temperature, 2 mL of TFA was added to a 2 mL solution of N-((S)-4-(6-(2,3-dichlorophenyl)-4-((2,4-dimethoxybenzyl)amino)pyridin[2,3-d]pyrimidin-2-yl)-1',3'-dihydrospiro[1,2'-indene]-1'-yl)-2-methylpropane-2-sulfinamide (50 mg, 0.067 mmol, 1.0 eq) in DCM. The reaction mixture was stirred for 18 hours. After removing volatiles under reduced pressure, the crude product N-((S)-4-(4-amino-6-(2,3-dichlorophenyl)pyridin[2,3-d]pyrimidin-2-yl)-1',3'-dihydrospiro[cyclohexane-1,2'-indene]-1'-yl)-2-methylpropane-2-sulfinamide (40 mg, 100%) was directly used in the next step. MS: 595.2 (M+H) + ).

[1164] Step 7 (S)-1'-(4-amino-6-(2,3-dichlorophenyl)pyridin[2,3-d]pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1165]

[1166] At room temperature, HCl / dioxane solution was added dropwise to a solution of N-((S)-4-(4-amino-6-(2,3-dichlorophenyl)pyridin[2,3-d]pyrimidin-2-yl)-1',3'-dihydrospiro[cyclohexane-1,2'-indene]-1'-yl)-2-methylpropane-2-thioamide (40 mg, 0.067 mmol, 1.0 eq) in dioxane (4 mL). The reaction mixture was stirred for 20 minutes. The pH of the solution was adjusted to 7 using an aqueous solution of NaHCO3. Organic matter was collected, dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product, which was further purified by preparative HPLC to provide compound 2-(1'-amino-1',3'-dihydrospiro[cyclohexane-1,2'-indene]-4-yl)-6-(2,3-dichlorophenyl)pyridine[2,3-d]pyrimidine-4-amine (6.8 mg, 20.61%).

[1167] 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.69 (d, J = 2.3Hz, 1H), 8.49 (d, J = 2.4Hz, 1H), 7. 80–7.60(m,3H),7.52–7.46(m,2H),7.37–7.27(m,1H),7.24–7.14(m,3H),4.75 –4.60(m,2H),3.86(s,1H),3.26–3.07(m,3H),2.72–2.62(m,1H),1.78–1.68( m,1H),1.68–1.57(m,1H),1.54–1.44(m,1H),1.14–1.06(m,1H).MS:490.2(M+H + Purity: 93.3%.

[1168] The compound of Example 115 was prepared according to Example 114.

[1169] Example 115

[1170] (S)-1'-(4-amino-6-((2,3-dichlorophenyl)thio)pyridin[2,3-d]pyrimidin-2-yl)-1,3-dihydrospiro[indenyl-2,4'-piperidine]-1-amine

[1171]

[1172] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.69–8.64 (m, 2H), 7.83–7.72 (m, 1H), 7.45 (dd, J = 8 .0,1.2Hz,1H),7.36–7.31(m,1H),7.27–7.14(m,4H),6.67(dd,J=8.1,1.2Hz,1H) ,4.74–4.60(m,2H),3.89(s,1H),3.25–3.05(m,3H),2.73–2.65(m,1H),1.79–1.6 6(m,1H),1.66–1.56(m,1H),1.53–1.43(m,1H),1.18–1.08(m,1H).MS:523.2(M+H + Purity: 91.9%.

[1173] Example 116

[1174] (S)-1'-(8-(2,3-dichlorophenyl)-7H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1175]

[1176] Step 1: 2-Chloro-8-(2,3-dichlorophenyl)-9H-purine

[1177]

[1178] Under Ar conditions, a mixture of 2-chloropyrimidine-4,5-diamine (378 mg, 2.62 mmol, 1.0 eq) and 2,3-dichlorobenzoic acid (500 mg, 2.62 mmol, 1.0 eq) in POCl3 (10 mL) was stirred at 100 °C for 5 hours. Volatiles were removed under reduced pressure, and the residue was partitioned in ethyl acetate / saturated NaHCO3 solution. The organic matter was collected, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product. This crude product was eluted with hexane / ethyl acetate from 0% to 20% by silica gel chromatography to give the product 2-chloro-8-(2,3-dichlorophenyl)-9H-purine (130 mg, 16.58%). MS: 299.2 (M+H). + ).

[1179] Step 2N-((S)-1'-(8-(2,3-dichlorophenyl)-7H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1180]

[1181] A mixture of 2-chloro-8-(2,3-dichlorophenyl)-9H-purine solution (110 mg, 0.367 mmol, 1.0 eq), N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (113 mg, 0.367 mmol, 1.0 eq), and DIPEA (47.5 mg, 0.367 mmol, 1.0 eq) in n-butanol (5 mL) was microwaved at 150 °C for 1 hour. Volatile substances were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with DCM / ethyl acetate to give the product N-((S)-1'-(8-(2,3-dichlorophenyl)-7H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (50 mg, 23.91%). MS: 569.6 (M+H) + )

[1182] Step 3 (S)-1'-(8-(2,3-dichlorophenyl)-7H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1183]

[1184] A solution of HCl / dioxane (6N) at room temperature was added to a solution of N-((S)-1'-(8-(2,3-dichlorophenyl)-7H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (50 mg, 0.088 mmol, 1.0 eq) in dioxane (4 mL). The reaction was stirred for 0.5 h. The solution was diluted with ethyl acetate, and the pH was adjusted to 7 with saturated NaHCO3 solution. The solution was partitioned between ethyl acetate and H2O. Organic matter was collected, washed with brine, dried with anhydrous Na2SO4, filtered and concentrated to obtain a crude product, which was purified by preparative HPLC to obtain a white solid product ((S)-1'-(8-(2,3-dichlorophenyl)-7H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (10 mg, 24.48%). 1 H NMR(400MHz, DMSO-d6)δ(ppm)8.77(s,1H),7.83(dd,J=8.1,0.7Hz,1H),7.75(d,J=7.4Hz,1H),7.58–7.51(m,1H),7.47–7.31(m,1H),7.30–7.20(m,3H ),4.61–4.50(m,2H),4.11–3.90(m,1H),3.31–3.11(m,3H),2.84–2.76(m,1 H),1.82–1.61(m,2H),1.55–1.45(m,1H),1.34–1.27(m,1H).MS:465.2(M+H + Purity: 95.6%.

[1185] Example 117

[1186] (S)-1'-(4-amino-2-((2,3-dichlorophenyl)thio)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[1187]

[1188] Step 1 6-Chloro-N 2 N 2 -bis(4-methoxybenzyl)-3-nitropyridine-2,4-diamine

[1189]

[1190] A solution of 2,6-dichloro-3-nitropyridine-4-amine (2 g, 9.62 mmol, 1.0 eq), bis(4-methoxybenzyl)amine (2.55 g, 9.90 mmol, 1.03 eq), and triethylamine (1.46 g, 14.42 mmol, 1.5 eq) in anhydrous DCM (40 mL) was stirred at room temperature for 18 hours. Volatile substances were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with DCM to give the compound 6-chloro-N. 2 N 2 -Bis(4-methoxybenzyl)-3-nitropyridine-2,4-diamine (4g, 97%) as foam

[1191] MS: 429.2 (M+H) + ).

[1192] Step 2N-((S)-1'-(4-amino-6-(bis(4-methoxybenzyl)amino)-5-nitropyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1193]

[1194] 6-Chloro-N 2 N 2 A mixture of bis(4-methoxybenzyl)-3-nitropyridine-2,4-diamine (1.4 g, 3.26 mmol, 1.0 eq), N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.0 g, 3.26 mmol, 1.0 eq), and N-ethyl-N-isopropylpropane-2-amine (844 mg, 6.53 mmol, 2.0 eq) was microwaved at 133 °C for 135 min. The solution was poured into H₂O to form a precipitate, which was filtered and dissolved in DCM. The precipitate was first purified by silica gel chromatography using DCM to recover unreacted starting materials. The compound N-((S)-1'-(4-amino-6-(bis(4-methoxybenzyl)amino)-5-nitropyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.5 g, 65.7%) was then eluted with DCM / MeOH from 0% to 9%, yielding a brown foam. MS: 699.3 (M+H) + ).

[1195] Step 3N-((S)-1'-(4,5-diamino-6-(bis(4-methoxybenzyl)amino)pyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1196]

[1197] A mixture of N-((S)-1'-(4-amino-6-(bis(4-methoxybenzyl)amino)-5-nitropyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (700 mg, 1.002 mmol, 1.0 eq) and Raney nickel in ethanol (50 mL) was substituted three times with H2. The reaction was stirred at room temperature for 16 hours. The solution was filtered. The filtrate was concentrated to provide compound N-((S)-1'-(4,5-diamino-6-(bis(4-methoxybenzyl)amino)pyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (670 mg, crude) directly for the next step, MS: 669.3 (M+H). + ).

[1198] Step 4N-((S)-1'-(4-(bis(4-methoxybenzyl)amino)-2-mercapto-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1199]

[1200] The mixture of N-((S)-1'-(4,5-diamino-6-(bis(4-methoxybenzyl)amino)pyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (670 mg, 1.002 mmol, 1.0 eq) and O-ethyl dithiocarbonate (193 mg, 1.202 mmol, 1.2 eq) in ethanol (5 mL) and pyridine (3 mL) was stirred at 100 °C for 16 hours. Volatile substances were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with DCM / ethyl acetate from 0% to 30% to give compound N-((S)-1'-(4-(bis(4-methoxybenzyl)amino)-2-mercapto-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (110 mg, 15.45%). MS: 711.2 (M+H) + ).

[1201] Step 5N-((S)-1'-(4-(bis(4-methoxybenzyl)amino)-2-((2,3-dichlorophenyl)thio)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1202]

[1203] A mixture of N-((S)-1'-(4-(bis(4-methoxybenzyl)amino)-2-mercapto-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (83 mg, 0.117 mmol, 1.0 eq), 1,2-dichloro-3-iodobenzene (38.2 mg, 0.14 mmol, 1.2 eq), Pd2(dba)3 (21.38 mg, 0.023 mmol, eq), BINAP (21.81 mg, 0.035 mmol, 0.3 eq), and dioxane (45.3 mg, 0.350 mmol, 3.0 eq) in 5 mL was microwaved at 90 °C for 50 minutes. Volatile substances were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with DCM / ethyl acetate from 0% to 30%, to give compound N-((S)-1'-(4-(bis(4-methoxybenzyl)amino)-2-((2,3-dichlorophenyl)thio)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (80 mg, 80%). MS: 855.9 (M+H) + ).

[1204] Step 6N-((S)-1'-(4-amino-2-((2,3-dichlorophenyl)thio)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1205]

[1206] A solution of N-((S)-1'-(4-(bis(4-methoxybenzyl)amino)-2-((2,3-dichlorophenyl)thio)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (80 mg, 0.093 mmol, 1.0 eq) in TFA (3 mL) and DCM (3 mL) was stirred at 35 °C for 1 hour. Using saturated...

[1207] The pH of the solution was adjusted to 7 using NaHCO3. The organic matter was collected, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give compound N-((S)-1'-(4-amino-2-((2,3-dichlorophenyl)thio)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (57 mg, 99%), which was used directly for the next step. MS: 615.6 (M+H) + ).

[1208] Step 7 (S)-1'-(4-amino-2-((2,3-dichlorophenyl)thio)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1209]

[1210] At room temperature, HCl / dioxane (6N, 1.5 mL) was added to a solution of N-((S)-1'-(4-amino-2-((2,3-dichlorophenyl)thio)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (57 mg, 0.093 mmol, 1.0 eq) in dioxane (4 mL). The reaction was stirred for 0.5 h. The pH of the solution was adjusted to 7 using saturated NaHCO3. Organic matter was collected, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product, which was purified by preparative HPLC to provide compound (S)-1'-(4-amino-2-((2,3-dichlorophenyl)thio)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (3 mg, 6.34%) as a white solid.

[1211] 1 H NMR(400MHz,DMSO-d6)δ(ppm)7.55–7.50(m,1H),7.37–7.26(m,2H),7.24–7.15 (m,3H),6.84–6.76(m,1H),6.18–6.06(m,2H),5.87(s,1H),4.05–3.96(m,2H),3 .90(s,1H),3.09–3.00(m,1H),2.99–2.87(m,2H),2.69–2.61(m,1H),1.85–1.73 (m,1H),1.72–1.62(m,1H),1.50–1.42(m,1H),1.20–1.11(m,1H).MS:511.4(M+H+ ).

[1212] Example 118

[1213] (S)-1'-(2-((2,3-dichlorophenyl)thio)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[1214]

[1215] Step 1: N-((S)-1'-(4-amino-5-nitropyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1216]

[1217] Under Ar conditions, a solution of 2-chloro-5-nitropyridine-4-amine (850 mg, 4.90 mmol, 1.0 eq), N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.65 g, 5.39 mmol, 1.1 eq) and DIPEA (1.9 g, 14.69 mmol, 3.0 eq) in butanol (10 mL) was stirred at 135 °C for 18 hours. Volatile substances were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with 0 to 30% hexane / ethyl acetate to give compound N-((S)-1'-(4-amino-5-nitropyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.7 g, 78%). MS: 444.6 (M+H) + ).

[1218] Step 2N-((S)-1'-(4,5-diaminopyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1219]

[1220] N-((S)-1'-(4-amino-5-nitropyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (200 mg, 0.451 mmol, 1.0 eq) and Raney nickel in ethanol (10 mL) were substituted with H2 three times. The reaction was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated to provide compound N-((S)-1'-(4,5-diaminopyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (186 mg, 100%), which was used directly in the next step. MS: 414.5 (M+H) + ).

[1221] Step 3N-((S)-1'-(2-mercapto-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1222]

[1223] A solution of N-((S)-1'-(4,5-diaminopyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (60 mg, 0.145 mmol, 1.0 eq) and O-ethyl dithiocarbonate (27.9 mg, 0.174 mmol, 1.2 eq) in ethanol (5 mL) and pyridine (3 mL) was stirred at 100 °C for 10 hours. Volatile substances were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with DCM / ethyl acetate from 0% to 30% to give compound N-((S)-1'-(2-mercapto-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (50 mg, 76%). MS: 456.2 (M+H) + ).

[1224] Step 4N-((S)-1'-(2-((2,3-dichlorophenyl)thio)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-thioamide

[1225]

[1226] A solution of N-((S)-1'-(2-mercapto-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (50 mg, 0.11 mmol, 1.0 eq), 1,2-dichloro-3-iodobenzene (35.9 mg, 0.132 mmol, 1.2 eq), Pd2(dba)3 (20.10 mg, 0.022 mmol, 0.2 eq), BINAP (20.50 mg, 0.033 mmol, 0.3 eq), and DIPEA (42.5 mg, 0.329 mmol, 3.0 eq) in dioxane (5 mL) was microwaved at 90 °C for 70 minutes. Volatile substances were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with DCM / ethyl acetate from 0% to 30% to give compound N-((S)-1'-(2-((2,3-dichlorophenyl)thio)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (20 mg, 30.3%), MS: 600.2 (M+H). + ).

[1227] Step 5(S)-1'-(2-((2,3-dichlorophenyl)thio)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1228]

[1229] At room temperature, a solution of 6N HCl / dioxane was added to a solution of N-((S)-1'-(2-((2,3-dichlorophenyl)thio)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (20 mg, 0.033 mmol, 1.0 eq) in 3 ml of dioxane. The reaction was stirred for 1 hour. The pH of the solution was adjusted to 7 using saturated NaHCO3 solution. Organic matter was collected, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to provide compound (S)-1'-(2-((2,3-dichlorophenyl)thio)-3H-imidazo[4,5-c]pyridin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (1.0 mg, 6.05%) as a white solid, MS: 496.4 (M+H). + ).

[1230] Examples 119 and 120

[1231] (S)-1'-(8-(2,3-dichlorophenyl)-9-methyl-9H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1232] (S)-1'-(8-(2,3-dichlorophenyl)-7-methyl-7H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1233]

[1234] Step 1: 2-Chloro-8-(2,3-dichlorophenyl)-9-methyl-9H-purine and 2-chloro-8-(2,3-dichlorophenyl)-7-methyl-7H-purine

[1235]

[1236] Under Ar conditions, a mixture of 2-chloro-8-(2,3-dichlorophenyl)-9H-purine (200 mg, 0.668 mmol, 1.0 eq) and NaH (16.02 mg, 0.668 mmol, 1.0 eq) in anhydrous DMF (3 mL) was stirred at 0 °C for 15 min. Then, MeI (95 mg, 0.668 mmol, 1.0 eq) was added dropwise. The solution was gently heated to room temperature and stirred for 1 h. The reaction was stopped with saturated NH4Cl solution. The solution was partitioned between ethyl acetate and H2O. The organic matter was collected, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography by elution of hexane / ethyl acetate from 0% to 40% to give products 119-A (relatively low polarity, 38 mg, 18.15%) and 120-A (relatively high polarity, 13 mg, 6.21%). MS: 313.5 (M+H) + ).

[1237] Step 2: N-((S)-1'-(8-(2,3-dichlorophenyl)-9-methyl-9H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide and N-((S)-1'-(8-(2,3-dichlorophenyl)-7-methyl-7H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide

[1238]

[1239] A solution of 119-A (38 mg, 0.121 mmol, 1.0 eq), N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (37.1 mg, 0.121 mmol, 1.0 eq), and DIPEA (31.3 mg, 0.242 mmol, 2.0 eq) in BuOH (5 mL) was microwaved at 150 °C for 1 h. Volatiles were removed under reduced pressure, and the residue was purified by silica gel chromatography after elution with DCM / ethyl acetate to give compound 119-B (50 mg, 70.7%). MS: 583.5 (M+H) + ).

[1240] A solution of 120-A (13 mg, 0.041 mmol, 1.0 eq), N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (12.71 mg, 0.041 mmol, 1.0 eq), and DIPEA (10.72 mg, 0.083 mmol, 2.0 eq) in BuOH (5 mL) was microwaved at 150 °C for 1 hour. Volatiles were removed under reduced pressure, and the residue was purified by silica gel chromatography after elution with DCM / ethyl acetate to give compound 120-B (15 mg, 62.0%). MS: 583.5 (M+H) + ).

[1241] Step 3: (S)-1'-(8-(2,3-dichlorophenyl)-9-methyl-9H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine and (S)-1'-(8-(2,3-dichlorophenyl)-7-methyl-7H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1242]

[1243] At room temperature, 6NHCl / dioxane was added to a solution of 119-B (50 mg, 0.086 mmol, 1.0 eq) in dioxane (2 ml). The reaction was stirred for 1 hour. The pH of the solution was adjusted to 7 using saturated NaHCO3 solution. The organic matter was collected, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product, which was purified by preparative HPLC to provide compound 119 as a white solid. 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.80 (s, 1H), 8.26–8.16 (m, 2H), 7.91 (d, J = 7.6Hz, 1H), 7 .66–7.62(m,1H),7.61–7.56(m,1H),7.51(d,J=7.2Hz,1H),7.39–7.35(m,2H),7.34–7 .28(m,1H),4.72–4.56(m,2H),4.42–4.34(m,1H),3.47(s,3H),3.25–4.16(m,3H),3.0 8–3.01(m,1H),2.07–1.91(m,1H),1.82–1.63(m,2H),1.49–1.40(m,1H).MS:479.2(M+H + Purity: 90.5%.

[1244] At room temperature, 6NHCl / dioxane was added to a solution of 120-B (15 mg, 0.026 mmol, 1.0 eq) in dioxane (2 ml). The reaction was stirred for 1 hour. The pH of the solution was adjusted to 7 using saturated NaHCO3 solution. The organic matter was collected, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product, which was purified by preparative HPLC to provide compound 120 (1.0 mg, 8.12%) as a white solid, MS: 479.2 (M+H). + Purity: 88.1%.

[1245] The compounds of Examples 121-124 were prepared according to Examples 119 and 120.

[1246] Examples 121 and 122

[1247] (S)-1'-(8-(2,3-dichlorophenyl)-7-ethyl-7H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine and (S)-1'-(8-(2,3-dichlorophenyl)-9-ethyl-9H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1248]

[1249] Example 121: 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.76 (s, 1H), 7.90 (dd, J = 8.0, 1.3Hz, 1H), 7.65 (dd, J = 7.6, 1.3Hz, 1H),7.58(t,J=7.8Hz,1H),7.33–7.31(m,1H),7.22–7.14(m,3H),4.58(t,J=12.6Hz,2H),3.92(q ,J=7.1Hz,2H),3.87(s,1H),3.25–3.17(m,2H),3.11(d,J=15.7Hz,1H),2.67(d,J=15.7Hz,1H), 1.81–1.61(m,1H),1.51(d,J=13.2Hz,1H),1.28–1.23(m,2H),1.18(t,J=7.2Hz,3H).MS(ESI)m / z 493.39 and 495.34[M+H] +

[1250] Example 122: MS(ESI) m / z 493.42 and 495.73 [M+H] + .

[1251] Examples 123 and 124

[1252] (S)-1'-(8-(2,3-dichlorophenyl)-7-isopropyl-7H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine and (S)-1'-(8-(2,3-dichlorophenyl)-9-isopropyl-9H-purin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1253]

[1254] Example 123: 1H NMR(400MHz, DMSO-d6)δ(ppm)8.74(s,1H),7.89(dd,J=7.9,1.6Hz,1H),7.63(dd,J=7.6,1.7Hz,1H),7.56(t ,J=7.8Hz,1H),7.31–7.29(m,1H),7.17(dtd,J=8.2,5.5,2.5Hz,3H),4.53(t,J=12.6Hz,2H),4.11–4.04(m,1 H),3.84(s,1H),3.26–3.18(m,2H),3.10(d,J=15.7Hz,1H),2.65(d,J=15.6Hz,1H),1.99(dt,J=12.3,6.9Hz, 1H),1.78(td,J=12.6,4.2Hz,1H),1.69–1.46(m,5H),1.33–1.23(m,2H),1.12(d,J=13.0Hz,1H).MS(ESI)m / z 507.36 and 509.78[M+H] + .

[1255]

[1256] Example 124: 1 H NMR(400MHz, DMSO-d6)δ(ppm)9.05(s,1H),7.90(dd,J=7.7,1.8Hz,1H),7.62(dd,J=7.7,1.8Hz,1H),7.59 (d,J=7.7Hz,1H),7.34–7.32(m,1H),7.21(dt,J=8.5,4.8Hz,3H),4.54(td,J=9.5,4.8Hz,2H),4.20–4.14( m,1H),3.90(s,1H),3.20(dd,J=27.3,13.7Hz,2H),3.12(d,J=15.8Hz,1H),2.71(d,J=15.8Hz,1H),1.79– 1.71(m,1H),1.67–1.56(m,3H),1.49–1.40(m,3H),1.31–1.24(m,2H),1.14(d,J=13.5Hz,1H).MS(ESI)m / z 507.40 and 509.38[M+H] + .

[1257] Example 125

[1258] (S)-1'-(2-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1259]

[1260] Step 1:

[1261]

[1262] 5-Chloropyrazin-2-amine (3.0 g, 1.0 eq) was added in portions to a dioxane solution of ethoxycarbonyl isothiocyanate (4.56 g, 1.5 eq). The reaction mixture was stirred at room temperature for 24 h. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The volatiles were then removed under reduced pressure, and the residue was purified by rapid chromatography to give the title compound.

[1263] Step 2: 6-Chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-amine

[1264]

[1265] DIEA (2.86 mL, 1.5 eq) was added dropwise to an EtOH solution of hydroxylamine hydrochloride (1.20 g, 1.5 eq) at 0 °C, and the mixture was stirred at 0 °C for 10 min. Then, the intermediate obtained in step 1 (3 g, 1.0 eq) was added, and the reaction mixture was heated at 90 °C for 12 h. Volatile substances were removed under reduced pressure, and the residue was purified by rapid chromatography to give the title compound. [M+H] + =232.95 / 234.94 / 236.89.

[1266] Step 3: 2-Bromo-6-chloro-[1,2,4]triazolo[1,5-a]pyrazine

[1267]

[1268] CuBr (3.38 g, 2.0 eq) was added to a MeCN solution of 6-chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-amine (2.0 g, 1.0 eq) and isoamyl nitrite (2.76 g, 2.0 eq), and the mixture was then heated at 60 °C for 1 hour under an argon atmosphere. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography to give the title compound. [M+H] + =232.95 / 234.94 / 236.89.

[1269] Step 4: 6-Chloro-2-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-a]pyrazine

[1270]

[1271] Pd(PPh3)4 (124 mg, 0.05 eq) was added to a MeCN / H2O (30 mL / 3 mL) solution of 2-bromo-6-chloro-[1,2,4]triazolo[1,5-a]pyrazine (500 mg, 1.0 eq), 2,3-dichlorophenylboronic acid (450 mg, 1.1 eq), and K2CO3 (887 mg, 3.0 eq). The reaction mixture was heated at 110 °C for 3 hours under an argon atmosphere. After cooling to room temperature, the mixture was poured into a separatory funnel containing a saturated aqueous solution of NaCl and extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The volatiles were then removed under reduced pressure, and the residue was purified by rapid chromatography to give the title compound. [M+H] + =299.01 / 301.00 / 302.95.

[1272] Step 5: (S)-N-((S)-1'-(2-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide

[1273]

[1274] RuPhos Pd G2 (CAS: 2361069-97-6) (146 mg, 0.2 eq) was added to an anhydrous toluene solution of 6-chloro-2-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-a]pyrazine (300 mg, 1.0 eq), (S)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (486 mg, 1.2 eq), and sodium tert-butoxide (961 mg, 10.0 eq). The reaction mixture was then heated at 115 °C for 3 hours under an argon atmosphere. The reaction mixture was cooled to room temperature and poured into a separatory funnel containing a saturated aqueous solution of NaCl. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The volatiles were then removed under reduced pressure. The residue was purified by rapid chromatography to give the title compound. [M+H] + =569.27 / 571.18 / 573.13.

[1275] Step 6: (S)-1'-(2-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine

[1276]

[1277] Add 5 mL of 4 M HCl / dioxane to a methanol solution (5 mL) of (S)-N-((S)-1'-(2-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide, and stir the reaction mixture at room temperature for 3 hours. Remove volatiles and purify the residue by prep-HPLC (MeCN / H2O as eluent, TFA as modifier) ​​to obtain a white solid of the target compound. [M-NH2] + =448.15 / 450.07 / 451.98. 1 H NMR(400MHz, Methanol-d4)δ(ppm)9.03(s,1H),8.30(s,1H),7.83(dd,J=7.9,1.5Hz,1H),7.71(dd,J=7.9,1.5Hz,1H),7.52(d,J=7.5Hz,1H),7.45 (t,J=7.9Hz,1H),7.42–7.31(m,3H),4.43(s,1H),4.26–4.13(m,1H),4.1 0–3.94(m,1H),3.28–3.10(m,4H),2.07–1.74(m,3H),1.74–1.63(m,1H).

[1278] Test Example 1: Determination of the inhibitory effect of the compound of the present invention on SHP-2 kinase activity

[1279] Experimental objective:

[1280] The purpose of this test is to measure the ability of the compound to inhibit the allosteric activity of the full-length SHP-2 protein.

[1281] Experimental instruments: Centrifuge (5810R) purchased from Eppendorf, pipettes purchased from Eppendorf or Rainin, and microplate reader purchased from BioTek, USA, model SynergyH1 full-function microplate reader.

[1282] Experimental Method: First, 50 μl of MasterMix was added to a 96-well black low-adsorption microplate (Corning, #3915). This MasterMix consisted of 25 nM SHP-2 Enzyme (RD, #1894-SH-100UG), 0.5 μM MIR 1 Peptide (GenScript, #Sequence:LN{pTYR}IDLDLV{PEG8}LST{pTYR}ASINFQK-NH2) and 5 mM DTT in a reaction buffer solution with a final concentration of 1X. Then, 1 μl of the test compound was added to each well (the test compound was dissolved in DMSO to prepare a 10 mM stock solution, and then serially diluted three times, with 9 concentrations and 1 DMSO control well, so that the final reaction concentration ranged from 10 μM to 0.5 nM). After gentle shaking, the reaction was carried out at room temperature for 30 minutes. After the reaction was complete, 50 μL of Substrate Solution was added to each well. The reaction system contained 200 μM DiFMUP and 5 mM DTT. After gentle shaking, the reaction was allowed to proceed at room temperature for 30 minutes. After the reaction was complete, the excitation wavelength was set to 340 nm, the emission wavelength to 450 nm, and the gain value to 100 on a full-function microplate reader (Biotek, Synergy H1) for reading.

[1283] Experimental data processing methods:

[1284] Using the full-activity control and full-inhibition control as Max and Min values, the percentage inhibition rate (% inhibition rate) of the wells treated with the compound was calculated from the positive control wells (DMSO control wells) and negative control wells (wells without kinase) on the reaction plate: {% inhibition rate = 100 - [(test compound - Min average) / (Max average - Min average)] x 100}. The IC50 of the test compound was calculated using a GraphPad Prism fit of the percentage inhibition rate and 9-point concentration data to a 4-parameter nonlinear logic formula. 50 value.

[1285] Test Example 2: Determination of the inhibitory activity of the compounds of the present invention on the proliferation of MV-4-11 and HCC827 cells.

[1286] Experimental objective:

[1287] The purpose of this test case is to determine the inhibitory effect of the compounds in this invention on the proliferative activity of tumor cells.

[1288] Experimental instruments: Centrifuge (5810R) purchased from Eppendorf, pipettes purchased from Eppendorf or Rainin, and microplate reader purchased from BioTek, USA, model SynergyH1 full-function microplate reader.

[1289] Experimental Methods: 1000 cells were seeded per well in a 96-well cell culture plate (Corning, #3917) with 95 μl of cell suspension. The plate was incubated overnight at 37°C in a 5% CO2 incubator. The next day, serially diluted test compound solutions were added to the cells (the test compound was dissolved in DMSO to prepare a 10 mM stock solution, then serially diluted 3-fold, with one DMSO control well for every nine concentrations, resulting in a final concentration range from 10 μM to 0.5 nM). A full-activity control (compound with only DMSO) and a full-inhibition control (no cells) were also set up on the plate. The plate was incubated for 5 days. After incubation, 50 μl of Cell Titer-Glo reagent (Promega, #G7573) was added to each well of the cell culture plate, shaken at room temperature for 2 minutes, and then incubated for 10 minutes. Chemiluminescence signal values ​​were read using a Synergy H1 microplate reader (Biotek).

[1290] Experimental data processing: Based on the full-activity control and full-inhibition control as Max and Min values, the percentage inhibition ratio of the wells treated with the compound was calculated as {% inhibition rate = 100 - [(test compound - Min average) / (Max average - Min average)] x 100}. The IC50 of the test compound was calculated using a GraphPad Prism fit of the percentage inhibition ratio and 9-point concentration data to a 4-parameter nonlinear logic formula. 50 value.

[1291] The activity test data of some compounds of this invention are shown in Table 1 below:

[1292]

[1293]

[1294]

[1295]

[1296]

[1297]

[1298]

[1299]

[1300]

[1301] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof: in, X is CH or N; B is In the above structure, the a-end is connected to L, and the b-end is connected to the N atom in the structure of formula I. B 11 and B 12 Each can be independently CH or N; B9 is H, OH, or a C1-C4 alkyl group; B 10 It is H, NH2 or C1-C4 alkyl; L is a single bond, -O-, -S-, -NH-, -N(R1)-, -CH2-, -CH(R1)-, -C(R1)(R2)-, or Each R1 and R2 is independently a C1-C4 alkyl group; A is a saturated or partially unsaturated 3-10 membered cyclic hydrocarbon group, a saturated or partially unsaturated 3-10 membered heterocyclic group, a phenyl group, a 5-6 membered heteroaryl group, a naphthyl group, or an 8-10 membered fused heteroaryl group; the hydrogen atoms on the 3-10 membered cyclic hydrocarbon group, 3-10 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group, naphthyl group, and 8-10 membered fused heteroaryl group are unsubstituted or substituted by n R3 groups; n is 1, 2, 3, 4 or 5; Each R3 is independently F, Cl, Br, I, NH2, OH, cyano, C1-C4 alkyl, C1-C4 alkoxy, or m R groups. 3a Substituted C1-C4 alkyl groups or m R groups 3b Substituted C1-C4 alkoxy groups; Each m is independently 1, 2, 3, 4 or 5; Each R 3a and R 3b Each can be independently represented by F, Cl, Br, I, NH2, OH, or cyano groups; The number of heteroatoms in the 3-10 membered heterocyclic group, 5-6 membered heteroaryl group and 8-10 membered fused heteroaryl group is 1, 2, 3 or 4, and each heteroatom is independently N, O or S.

2. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I satisfies one or more of the following conditions: (1) L is a single bond or -CH2-; (2) A is a saturated or partially unsaturated 3-10 membered cyclic hydrocarbon group, a saturated or partially unsaturated 3-10 membered heterocyclic group, a phenyl group, a naphthyl group, or an 8-10 membered fused heteroaryl group, wherein the hydrogen atoms on the saturated or partially unsaturated 3-10 membered cyclic hydrocarbon group, a saturated or partially unsaturated 3-10 membered heterocyclic group, a phenyl group, a naphthyl group, or an 8-10 membered fused heteroaryl group are unsubstituted or substituted by n R3 groups; (3) n is 1, 2 or 3; (4) Each R3 is independently F, Cl, Br, NH2, OH, cyano, methyl, ethyl, isopropyl, methoxy, trifluoromethyl or hydroxymethyl.

3. The compound of formula I as claimed in claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I satisfies the following conditions: for 4. The compound of formula I as claimed in claim 3, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I has the structure shown in any of the following formulas:

5. The compound of formula I as claimed in claim 4, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I satisfies one of the following conditions: (1) In equation I-15, B 10 It can be H, NH2, or methyl; (2) In equation I-16, B 10 It is H or Cl; (3) In formula I-17, B9 is H.

6. The compound of formula I as claimed in claim 5, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I satisfies one of the following conditions: (1) In equation I-15, B 10 For H; (2) In equation I-16, B 10 For H.

7. The compound of formula I as claimed in claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I satisfies one of the following conditions: (1) In the definition of A, the saturated or partially unsaturated 3-10 membered cyclic hydrocarbon group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, (2) In the definition of A, the saturated or partially unsaturated 3-10 member heterocyclic group is... (3) In the definition of A, the 5-6 heteroaryl group is pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine or pyrazine; (4) In the definition of A, the 8-10 fused heteroaryl group is 8. The compound of formula I as claimed in claim 7, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I satisfies one of the following conditions: (1) In the definition of A, the saturated or partially unsaturated 3-10 membered cyclic hydrocarbon group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, (2) In the definition of A, the saturated or partially unsaturated 3-10 member heterocyclic group is... (3) In the definition of A, the 5-6 member heteroaryl group is pyrrole, furan, thiophene, oxazole, Isothiazole, pyrazole, imidazole Pyrimidine or pyrazine; (4) In the definition of A, the naphthyl group is (5) In the definition of A, the 8-10 fused heteroaryl group is 9. The compound of formula I as claimed in any one of claims 1-8, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I satisfies one of the following conditions: (1) A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, (2) AL- is 10. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I is any of the following compounds:

11. A method for preparing a compound of Formula I, comprising the following steps: removing the tert-butylsulfinyl group from a compound of Formula II in a solvent in the presence of an acid to obtain the compound of Formula I; in, The definitions of A, L, B, and X are as described in any one of claims 1-9.

12. A compound represented by Formula II: in, The definitions of A, L, B, and X are as described in any one of claims 1-9.

13. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-10 or a pharmaceutically acceptable salt thereof and at least one pharmaceutical excipient.

14. Use of a compound as described in any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 13, in the preparation of an SHP2 inhibitor or a medicament for treating SHP2-related diseases.

15. The application as described in claim 14, characterized in that, The SHP2-related diseases mentioned are Noonan syndrome, panther syndrome, diabetes, neuroblastoma, melanoma, juvenile leukemia, juvenile myelomonocytic leukemia, chronic myelomonocytic leukemia, acute myelomonocytic leukemia, HER2-positive breast cancer, triple-negative breast cancer, ductal carcinoma of the breast, invasive ductal carcinoma of the breast, non-small cell lung cancer, colorectal cancer, esophageal cancer, gastric cancer, squamous cell carcinoma of the head and neck, neutropenia, or systemic lupus erythematosus.

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