Heterocyclic compounds that inhibit SHP2 activity

Abstract

The compound of formula (I), wherein ring A, Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , X, a, b, c and d are as defined in the specification. #imgabs0#

Description

Technical Field

[0001] This invention relates to novel heterobicyclic compounds that inhibit SHP2 activity, pharmaceutical compositions comprising said compounds, and uses of said compounds. Background Technology

[0002] Protein tyrosine phosphatase 2 (SHP2), which includes the Src homology region 2 (SH2), is a widely expressed protein tyrosine phosphatase encoded by the PTPN11 gene. SHP2 consists of two N-terminal longitudinally arranged SH2 domains (N-SH2, C-SH2), a catalytic phosphatase (PTP) domain, and a C-terminal tail with two tyrosine phosphorylation sites.

[0003] Due to the self-inhibitory interaction between the N-SH2 and PTP domains, SHP2 switches between an "open" active form and a "closed" inactive form. When the bistyrosine phosphorylated peptide binds to the N-SH2 domain and SHP2 adopts an "open" conformation, the naturally occurring self-inhibitory interaction is released, resulting in enzyme activation and exposure of the PTP domain for substrate recognition and catalysis.

[0004] PTPN11 mutations are associated with several human diseases, including cancer. Germline PTPN11 mutations are associated with developmental disorders such as Noonan syndrome and panther syndrome, while somatic mutations occur in several hematologic malignancies such as JMML and are less common in solid tumors.

[0005] SHP2 is essential downstream of receptor tyrosine kinase (EGFR, ALK, PDGFR) signaling and plays an active role in regulating many cellular processes, such as proliferation in response to growth factor and cytokine stimulation. Previous studies have shown that SHP2 acts upstream of Ras and is essential for the complete and sustained activation of the MAPK pathway. RTK dysregulation commonly triggers various cancers, making SHP2 an important target for RTK-activated cancers. It has also been reported that SHP2 plays a role in regulating immune responses by mediating immune checkpoint pathways (such as PD-1) because the inhibitory motif (ITIM) based on immune receptor tyrosine binds to the SH2 domain of SHP2 to mediate negative signaling.

[0006] It has been reported that certain SHP2 inhibitor compounds have inhibitory effects on the proliferation of cancer cells and the increase in tumor volume in mouse xenograft models (Nature (2016) 535: 148-152).

[0007] Citation List

[0008] Non-patent literature

[0009] NPL 1: Nature(2016)535:148-152 Invention Overview

[0011] Technical issues

[0012] The purpose of this invention is to provide a series of new compounds that selectively inhibit SHP2 and can be used to treat SHP2-mediated diseases or conditions.

[0013] Solution

[0014] The inventors conducted extensive research to achieve the above-mentioned objectives and thereby discovered that the compound group represented by formula (I) exhibits excellent SHP2 inhibitory activity and can be used as a pharmaceutical preparation for treating SHP2-mediated diseases such as cancer. Thus, the present invention is completed.

[0015] This invention includes the following items.

[0016] Item 1. Compound of formula (I):

[0017] [Chemical Formula 1]

[0018]

[0019] Or its tautomers or solvates or pharmaceutically acceptable salts, wherein:

[0020] X is CH or N;

[0021] R 1 It is -CH3;

[0022] R 2 and R 3 Independently selected from H and C 1-4 alkyl;

[0023] Q is either C or N;

[0024] When Q is C, then:

[0025] (i)R 4 It is amino, amino C 1-4 Alkyl or single C 1-4 Alkylamino;

[0026] R 5 It is hydrogen, C 1-4 Alkyl, halogen, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or C 1-4 Alkoxy C 1-4 alkyl;

[0027] or

[0028] (ii)R 4 and R 5 Together with Q, they form a 4-6 membered ring, which may optionally contain elements independently selected from N, O, S, NH, C(O), and S(O). m 1-3 heteroatoms or groups, and R 4 and R 5 The formed ring may be unsubstituted or substituted with 1-4 groups, wherein the groups are independently selected from: amino, halogen, halogenated C. 1-4 Alkyl, hydroxyl, methoxy, methylamino and C 1-4 Alkyl group, and m is selected from 1 and 2;

[0029] When Q is N, then:

[0030] R 4 It does not exist; and

[0031] R 5 It is hydrogen;

[0032] R 6 and R 7 Independently selected from halogens, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and hydroxyl groups, provided that when Q is N, then R 6 or R 7 It is neither halogen nor hydroxyl;

[0033] Or, selected from R 2 R 3 R 6 and R 7 Any two groups together form a 1-3 bridging group, which is selected from C 1-3 Alkylene, C 2-3 Idenoyl, methylene-NR q -methylene and methylene-O-methylene, wherein the bridging group is optionally selected from C 1-4 Alkyl, hydroxyl, and halogen groups are substituted, and R q Selected from hydrogen and C 1-4 alkyl;

[0034] Or, R 4 and R 7 Forming 4-6 membered rings containing nitrogen atoms;

[0035] Or, R 5 and R 7 Forming 3-6 member rings;

[0036] Or, R 6 and R 7 Forming direct bonds;

[0037] a is selected from 0, 1, and 2;

[0038] b is selected from 0, 1, and 2;

[0039] c is selected from 0, 1, and 2;

[0040] Alternatively, Q is C, c is 2, and R is... 4 It is hydrogen, and has two Rs. 7 The links form 4-6 nitrogen-containing rings;

[0041] Ring A is:

[0042] (i) a five-membered nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O and S, or

[0043] (ii) a six-membered nitrogen-containing aromatic heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O and S, or

[0044] (iii) A six-membered nitrogen-containing non-aromatic heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N and S;

[0045] R 8 Selected from hydrogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl and halogen;

[0046] R 9 Selected from hydrogen and halogens;

[0047] R 10 Selected from halogenated C 1-4 Alkyl, C 1-4 Alkyl, halogen, hydrogen or C 1-4 Alkoxy;

[0048] R 11 Independently selected from halogen, cyano, cyano C 1-4 Alkyl, hydroxyl, oxo (=O), C substituted with a 5- or 6-membered heterocyclic group containing one or two heteroatoms selected from O, N or S 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Alkyl sulfone, amino, single C 1-4 Alkylamino, diC 1-4 Alkylamino, amino C 1-4 Alkyl, -C 1-4 Alkylene-C(=O)NH (2-q) (C1-6 alkyl) q ), -C 1-4 Alkylene-NHC(=O)C 1-6 Alkyl, sulfonamide, sulfonamide C 1-4 Alkyl, 3-6 membered cycloalkyl, C substituted with 3-6 membered cycloalkyl 1-4 Alkyl groups, comprising 5- or 6-membered unsaturated heterocyclic groups containing 1, 2, 3, or 4 heteroatoms selected from O, N, or S, and optionally substituted 4- to 6-membered saturated heterocyclic groups containing 1 or 2 heteroatoms selected from O, N, or S, wherein the optional substituents are selected from C. 1-4 alkyl;

[0049] q is selected from 0, 1, or 2; and

[0050] d is selected from 0, 1, and 2.

[0051] Item 2. The compound or its tautomer or solvate or pharmaceutically acceptable salt according to Item 1, wherein:

[0052] Ring A is a five- or six-membered nitrogen-containing heteroaromatic ring, wherein the ring optionally contains one or two other heteroatoms selected from N, O and S.

[0053] Item 3. A compound or its tautomer or solvate or pharmaceutically acceptable salt according to Item 1 or Item 2, wherein the compound is selected from R 2 R 3 R 6 and R 7 Any two groups together form a 1-3 bridging group, which is selected from C 1-3 Alkylene, C 2-3 Idenoyl, methylene-NR q -methylene and methylene-O-methylene, wherein the bridging group is optionally selected from C 1-4 Alkyl, hydroxyl, and halogen groups are substituted, and R q Selected from hydrogen and C 1-4 alkyl.

[0054] Item 4. The compound or its tautomer or solvate or pharmaceutically acceptable salt according to any one of items 1-3, wherein

[0055] Q is C.

[0056] Item 5. The compound or its tautomer or solvate or pharmaceutically acceptable salt according to any one of items 1-4, wherein

[0057] R 4 It is amino, amino C 1-4 Alkyl or mono-C 1-4 Alkylamino;

[0058] R 5 It is hydrogen, C 1-4 Alkyl, halogen, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or C 1-4 Alkoxy C 1-4 alkyl.

[0059] Item 6. A compound or its tautomer or solvate or pharmaceutically acceptable salt according to any one of items 1-4, wherein...

[0060] R 4 and R 5 Together with Q, they form a 4-6 membered ring, which may optionally contain elements independently selected from N, O, S, NH, C(O), and S(O). m 1-3 heteroatoms or groups, and R 4 and R 5 The formed ring may be unsubstituted or substituted with 1-4 groups, wherein the groups are independently selected from: amino, halogen, halogenated C. 1-4 Alkyl, hydroxyl, methoxy, methylamino and C 1-4 Alkyl group, and m is selected from 1 and 2.

[0061] Item 7. A compound or its tautomer or solvate or pharmaceutically acceptable salt according to any one of items 1-5, wherein Q is N.

[0062] Item 8. A compound or its tautomer or solvate or pharmaceutically acceptable salt according to any one of items 1-7, wherein X is CH.

[0063] Item 9. A compound or its tautomer or solvate or pharmaceutically acceptable salt according to any one of items 1-7, wherein X is N.

[0064] Item 10. The compound or its tautomer or solvate or pharmaceutically acceptable salt according to Item 1, wherein the compound is selected from:

[0065] 2-(3,8-diazabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0066] 2-(4-(aminomethyl)-4-methylpiperidin-1-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0067] 2-(4-amino-4-methylpiperidin-1-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0068] 2-(exo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0069] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0070] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(7-chloro-2-ethylbenzo[d]thiazo-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0071] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(7-chloro-2-methylbenzo[d]thiazo-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0072] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0073] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(2-(tert-butyl)-4-chloro-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0074] 2-(exo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0075] (R)-2-(1-amino-8-azaspiro[4.5]decane-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0076] (S)-2-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0077] 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-2-(endo-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0078] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(endo-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0079] 2-(endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0080] 2-(endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0081] 2-(3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0082] (R)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(3-methylpiperazin-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0083] (S)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-2-(3-(hydroxymethyl)piperazin-1-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0084] (R)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-2-(3-(2-hydroxyethyl)piperazin-1-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0085] 2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0086] 2-(7-amino-3-oxa-9-azabicyclo[3.3.1]nonane-9-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0087] 2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0088] 2-(exo-8-amino-3-azabicyclo[3.2.1]octane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0089] 2-(endo-8-amino-3-azabicyclo[3.2.1]octane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0090] rac-2-((1S,2R,3R,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0091] 2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0092] 2-(3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0093] 2-(3,6-diazabicyclo[3.1.1]heptane-6-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0094] 2-(3,9-diazabicyclo[3.3.1]nonane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0095] 2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0096] 2-(2,5-diazabicyclo[2.2.2]octane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0097] 2-(exo-6-amino-3-azabicyclo[3.1.1]heptane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0098] 2-(endo-6-amino-3-azabicyclo[3.1.1]heptane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0099] 2-(5-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0100] 2-(exo-3-amino-9-azabicyclo[3.3.1]nonane-9-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0101] 2-(endo-3-amino-9-azabicyclo[3.3.1]nonane-9-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0102] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(1,8-diazaspiro[4.5]decane-8-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0103] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(piperazin-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0104] 2-(3,7-diazabicyclo[4.2.0]octane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0105] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(1,9-diazaspiro[5.5]undecane-9-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0106] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(1,7-diazaspiro[3.5]nonane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0107] (S)-2-(3-aminopyrrolidone-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0108] (R)-2-(3-aminopyrrolidone-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0109] (S)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(3-methylpiperazin-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0110] 2-((1S,2S,4R)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0111] (R)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(2-methylpiperazin-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0112] (S)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(2-methylpiperazin-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0113] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0114] 2-((3R,4S)-3-amino-4-fluoropyrrolidine-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0115] rac-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0116] 2-((3S,4S)-3-amino-4-fluoropyrrolidine-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0117] 2-(4-amino-3,3-difluoropyrrolidone-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0118] (S)-2-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0119] (R)-2-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0120] 2-((3R,4R)-3-amino-4-methylpyrrolidone-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0121] 2-((3R,4S)-3-amino-4-methylpyrrolidone-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0122] 2-(3-amino-3-(hydroxymethyl)pyrrolidone-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0123] 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0124] (R)-2-(3-(aminomethyl)pyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0125] 2-(1-Amino-3-azabicyclo[3.1.0]hexane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0126] 2-(6-amino-3-azabicyclo[3.1.0]hexane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0127] (S)-2-(3-(aminomethyl)pyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0128] 2-(4-(aminomethyl)-4-methoxypiperidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0129] 2-(4-(aminomethyl)-4-fluoropiperidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0130] 2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0131] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-3-methyl-5-(2-methyl-2H-indazol-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0132] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(7-chloro-2-methylbenzo[d]oxazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0133] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(7-chloro-2-ethylbenzo[d]oxazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0134] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0135] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(6,7-difluoro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0136] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(6-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0137] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-methoxy-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0138] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(7-chloro-1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0139] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0140] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2,7-dimethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0141] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(1H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0142] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0143] 2-(endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octane-8-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0144] 2-(3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0145] 2-(3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-yl)-5-(7-chloro-2-methylbenzo[d]thiazo-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0146] 2-(5-(2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,4-dichloro-2H-indazol-2-yl)-N,N-dimethylacetamide,

[0147] 3-(5-(2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,4-dichloro-2H-indazol-2-yl)-N,N-dimethylpropionamide,

[0148] 2-(6-(2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-7-chlorobenzo[d]thiazolyl)-N,N-dimethylacetamide,

[0149] 2-(3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0150] 2-(5-(2-(3,8-diazabicyclo[3.2.1]octane-8-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-chloro-2H-indazol-2-yl)-N,N-dimethylacetamide,

[0151] 2-(3,8-diazabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0152] 3-(5-(2-(3,8-diazabicyclo[3.2.1]octane-8-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-chloro-2H-indazol-2-yl)-N,N-dimethylpropionamide,

[0153] 3-(5-(2-(3,8-diazabicyclo[3.2.1]octane-8-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,4-dichloro-2H-indazol-2-yl)-N,N-dimethylpropionamide,

[0154] 2-(3,8-diazabicyclo[3.2.1]octane-8-yl)-5-(7-chloro-2-methylbenzo[d]thiazolyl-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0155] 2-(3,8-diazabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0156] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0157] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0158] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2,3-dimethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0159] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(7-chloro-2-methylbenzo[d]thiazolyl-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0160] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3-chloro-4-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0161] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0162] 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0163] 2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0164] 2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-5-(3-chloro-4-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0165] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(7-chlorobenzo[d]thiazolyl-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0166] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-ethyl-3-methoxy-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0167] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3,4-dichloro-2-(fluoromethyl)-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0168] 5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0169] 5-(7-chlorobenzo[d]thiazolyl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0170] 5-(3-chloro-4-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0171] 5-(7-chloro-2-methylbenzo[d]thiazolyl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0172] 2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-5-(7-chlorobenzo[d]thiazolyl-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0173] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-3-(difluoromethyl)-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0174] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-ethyl-3-(hydroxymethyl)-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0175] 6-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0176] 6-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0177] 6-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-(7-chloro-2-methylbenzo[d]thiazolyl-6-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0178] 6-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0179] 6-(endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octane-8-yl)-3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0180] 6-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0181] 6-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0182] 3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0183] 3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0184] 3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0185] 3-(3-chloro-4-fluoro-2-methyl-2H-indazol-5-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0186] 6-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-3-(7-chlorobenzo[d]thiazolyl-6-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0187] 3-(7-chlorobenzo[d]thiazolyl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0188] 3-(7-chloro-2-methylbenzo[d]thiazolyl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0189] rac-6-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0190] rac-6-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0191] 6-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-(3,4-dichloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0192] 3-(3,4-dichloro-2-ethyl-2H-indazol-5-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0193] 2-((1R,2S,3R,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0194] 2-((1S,2R,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0195] 2-((1R,2R,3R,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0196] 2-((1S,2S,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0197] rac-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0198] rac-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-3-(7-chlorobenzo[d]thiazolyl-6-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0199] rac-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-((1S,4S,7S)-7-(methylamino)-2-azabicyclo[2.2.1]heptane-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0200] endo-6-[3-amino-8-azabicyclo[3.2.1]octane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0201] 3-(4-chloro-2-methyl-2H-indazol-5-yl)-6-{3,8-diazabicyclo[3.2.1]octane-8-yl}-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0202] 6-[(1R,3S)-1-amino-3-hydroxy-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0203] 6-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0204] exo-6-[3-amino-8-azabicyclo[3.2.1]octane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0205] 3-(4-chloro-2-methyl-2H-indazol-5-yl)-6-{2,7-diazaspiro[3.5]nonane-7-yl}-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0206] 6-[(1R)-1-amino-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0207] 6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0208] 6-[(1R,3R)-1-amino-3-fluoro-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0209] 3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-6-{3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-yl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0210] 3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-6-{3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-yl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0211] 6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0212] 6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0213] 6-[(1S,2R,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0214] 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0215] 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-(1,4-diazacycloheptane-1-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0216] rac-2-[(1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-yl]-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0217] rac-5-(4-chloro-2-methyl-2H-indazol-5-yl)-2-[(1R,6S)-3,9-diazabicyclo[4.2.1]nonane-9-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0218] rac-2-(4-aminoazacycloheptan-1-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0219] rel-2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0220] rel-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0221] rel-2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0222] rel-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0223] 5-(2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-chloro-2-ethyl-2H-indazole-3-carboxynitrile,

[0224] 6-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0225] 6-(endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octane-8-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0226] 6-((3R,4S)-4-amino-3-fluoropiperidin-1-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0227] 2-((1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0228] 2-(rac-(1R,2S,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0229] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-((1S,2S,4R)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0230] 2-((1R,2S,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0231] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0232] 2-((1R,2S,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-methyl-5-(3,4,7-trichloro-2-methyl-2H-indazol-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0233] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(5-chloro-3-methoxyquinoxalin-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0234] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(5-chloro-3-(dimethylamino)quinoxalin-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0235] 6-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0236] 2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0237] rac-2-((1R,2R,4S)-2-amino-2-methyl-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0238] 2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(3-chloro-4-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0239] rac-6-((1R,2R,4S)-2-amino-2-methyl-7-azabicyclo[2.2.1]heptane-7-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0240] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(5-chloroquinoxalin-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0241] 3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-6-((1R,2R,4S)-2-(ethylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0242] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-(2-methoxyethyl)-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0243] 3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-6-((1R,2R,4S)-2-(isopropylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0244] 2-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(2-ethyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0245] 2-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(2-ethyl-4-fluoro-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0246] 2-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(7-chloro-2-ethyl-2H-indazol-6-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0247] 2-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(2-ethyl-2H-indazol-6-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0248] 2-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(2-ethyl-7-fluoro-2H-indazol-6-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0249] 2-[(endo)-3-amino-3-(difluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl]-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0250] 2-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(2-ethyl-7-fluoro-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0251] 2-[(3R,4S)-4-amino-3-fluoropiperidin-1-yl]-5-(7-chloro-1,3-benzothiazo-6-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0252] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-2-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-9-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0253] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-2-[(1R,6S)-3,9-diazabicyclo[4.2.1]nonane-9-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0254] 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-{(1R,5R)-3,6-diazabicyclo[3.2.1]octane-3-yl}-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0255] 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-{(1S,5S)-3,6-diazabicyclo[3.2.1]octane-3-yl}-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0256] 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-[(1S,5R)-3,6-diazabicyclo[3.2.1]octane-6-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0257] 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-[(1R,5S)-3,6-diazabicyclo[3.2.1]octane-6-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0258] 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(4-chloro-7-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0259] 2-[(endo)-2-amino-2-methyl-7-azabicyclo[2.2.1]heptane-7-yl]-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0260] Rac-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-{2,6-diazaspiro[3,4]octane-6-yl}-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0261] 2-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl]-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0262] 2-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl]-5-[8-chloro-2-(dimethylamino)quinolin-7-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, and

[0263] 2-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl]-5-[8-chloro-2-(methylamino)quinolin-7-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one.

[0264] Item 11. A pharmaceutical composition comprising any one of the compounds described in items 1-10 and a pharmaceutically acceptable carrier.

[0265] Item 12. The pharmaceutical composition according to Item 11, used for the prevention or treatment of SHP2-mediated diseases or conditions.

[0266] Item 13. The compound described in any of items 1-10, which is used for treatment.

[0267] Item 14. A compound described in any of items 1-10, used for the prevention or treatment of SHP2-mediated diseases or conditions.

[0268] Item 15. Use of the compound described in any one of items 1-10 in the preparation of a medicament for the prevention or treatment of SHP2-mediated diseases or conditions.

[0269] Item 16. A method for preventing or treating SHP2-mediated diseases or conditions, comprising administering to a patient any of the compounds described in Items 1-10.

[0270] Item 17. The pharmaceutical composition described in items 11 and 12, the compound described in items 13 and 14, the use described in item 15, or the method described in item 16, wherein the subject of treatment or the SHP2-mediated disease or condition is cancer.

[0271] It should be understood that the term "compound" in the pharmaceutical compositions, compounds, uses or methods described in items 11-17 includes tautomers or solvates of the corresponding compound or pharmaceutically acceptable salts.

[0272] The rac-2-[(1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-yl]-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one referred to herein as compound 152 may be independently claimed as a compound or its tautomer, solvate, or pharmaceutically acceptable salt, outside the scope of paragraph 1. Pharmaceutical compositions, compounds, uses, or methods of administration containing, using, or administering compound 152 may be claimed in a manner similar to that described in paragraphs 11-17.

[0273] Beneficial effects of the invention

[0274] Compounds of formula (I) or their tautomers, solvates, or pharmaceutically acceptable salts have been shown to possess excellent SHP2 inhibitory activity. Therefore, the compounds of the present invention or their derivatives can be used as substances for the prevention and / or treatment of SHP2-mediated diseases such as cancer.

[0275] Compounds of formula (I) or their tautomers or solvates or pharmaceutically acceptable salts have superior properties in certain respects, such as efficacy, selectivity, pharmacokinetic properties such as ADME properties, oral bioavailability, ability to cross the blood-brain barrier, duration of action, physicochemical properties, hERG activity, QT prolongation, etc.

[0276] Detailed implementation plan

[0277] The compound represented by formula (I) of the present invention is a novel pyrrolopyrimidinone or pyrazolopyrimidinone compound comprising (i) a nitrogen-containing 5-7 membered saturated heterocyclic group of a monocyclic, bicyclic, bridged, or spirocyclic form and (ii) an aromatic or non-aromatic fused ring containing a benzo-ring, and a 5- or 6-membered nitrogen-containing heterocycle.

[0278] In this specification, unless otherwise stated, * indicates a bonding location.

[0279] In this specification, examples of "halogen" include fluorine, chlorine, bromine, iodine, etc., preferably fluorine, chlorine, bromine or iodine, and more preferably fluorine or chlorine.

[0280] In this specification, "alkyl" can be straight-chain or branched. 1-6 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, and n-hexyl. 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0281] In this specification, "alkylene" is a divalent group, wherein one hydrogen atom is removed from the aforementioned alkyl group. C 1-4 Examples of alkylene groups include straight-chain C 1-4 Alkyl groups, such as methylene, ethylene, propylene, butylene, and branched C4 groups. 1-4 Alkylene, for example

[0282] [Chemical Formula 2]

[0283]

[0284] In this specification, "heterocycle" includes any monocyclic or polycyclic, saturated or unsaturated ring system comprising a carbon atom and at least one heteroatom. "Heterocycle" encompasses aromatic and non-aromatic groups.

[0285] In this specification, "C" 2-3 Examples of "alkenyl" include vinylene and allylene.

[0286] In this specification, "3-6 membered cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0287] In this specification, "amino C" 1-4 "alkyl" refers to the above straight-chain or branched C-chain containing one amino group. 1-4 Alkyl, denoted by -C 1-4 The group represented by alkylene (-NH2). Examples include -methylene-amino, -ethylene-amino, -propylene-amino, -butylene-amino, etc.

[0288] "Single C" 1-4 Examples of "alkylamino" include those with straight or branched C-chains. 1-4 Alkyl monosubstituted amino groups, such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, etc.

[0289] "2C" 1-4 Examples of "alkylamino" include those with the same or different straight-chain or branched C24 groups. 1-4 Alkyl disubstituted amino groups, such as dimethylamino, diethylamino, di(n-propyl)amino, diisopropylamino, di(n-butyl)amino, diisobutylamino, di(tert-butyl)amino, etc.

[0290] In this specification, "hydroxyl C" 1-4 Examples of "alkyl" include the above-described straight-chain or branched alkyl groups containing at least one hydroxyl group (e.g., one or two hydroxyl groups). Specific examples include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-methyl-2-hydroxyethyl, 4-hydroxybutyl, 2,2-dimethyl-2-hydroxyethyl, etc., preferably hydroxyalkyl groups containing one hydroxyl group.

[0291] In this specification, "C" 1-4 "Alkoxy" refers to the above straight-chain or branched C 1-4 Alkyl groups are bonded to their oxygen groups (-O-). Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0292] In this specification, "cyano C" 1-4 Examples of "alkyl" include the above-described straight-chain or branched C-type structures containing at least one cyano group (e.g., one or two cyano groups). 1-4 Alkyl groups. Specific examples include cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 2-cyanopropyl, 1-methyl-2-cyanoethyl, 4-cyanobutyl, 2,2-dimethyl-2-cyanoethyl, etc., preferably cyanoalkyl groups containing one cyano group.

[0293] In this specification, "halogenated C" 1-4 "alkyl" refers to the above-mentioned straight-chain or branched C atoms containing 1-7 halogen atoms. 1-4 Alkyl groups (halogen-substituted C) 1-4 Alkyl groups. Examples include fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, fluoroethyl, 1,1,1-trifluoroethyl, monofluoro-n-propyl, perfluoro-n-propyl, and perfluoroisopropyl.

[0294] In this specification, "C" 1-4 Alkoxy C 1-4 "alkyl" is a compound containing one of the above C atoms. 1-4 The above straight-chain or branched C of alkoxy groups 1-4 Alkyl groups, excluding -C 1-4 Alkylene-C 1-4 Alkoxy (-C) 1-4 Alkylene-OC 1-4The group indicated by alkyl). The above lists C... 1-4 Alkylene, C 1-4 Alkoxy and C 1-4 Examples of alkyl groups.

[0295] In this specification, "C" 1-4 "alkyl sulfone" refers to -SO2-C 1-4 Alkyl groups. Examples include methyl sulfone, ethyl sulfone, propyl sulfone, butyl sulfone, etc.

[0296] In this specification, "-C 1-4 Alkylene-C(=O)NH (2-q) (C 1-6 alkyl) q Examples of -C (where q is an integer 0, 1, or 2) include q. 1-4 Alkylene -C(=O)NH2, -C 1-4 Alkylene-C(=O)NH(C) 1-6 alkyl) and -C 1-4 Alkylene-C(=O)N(C) 1-6 Alkyl)2. C 1-4 Alkylene and C 1-6 Examples of alkyl groups are listed above.

[0297] In this specification, "-C 1-4 Alkylene-NHC(=O)C 1-6 "alkyl" refers to the C mentioned above. 1-4 Alkylene and C 1-6 Alkyl groups are groups linked by amide bonds (-NHC(=O)-). C 1-4 Alkylene and C 1-6 Examples of alkyl groups are listed above.

[0298] In this specification, "sulfonamide C" 1-4 "alkyl" refers to -C 1-4 The group represented by alkylene-SO2-NH2. Examples include -SO2-NH2, -methylene-SO2-NH2, -ethylene-SO2-NH2, -propylene-SO2-NH2, -butylene-SO2-NH2, etc.

[0299] In the compounds represented by formula (I) of this invention, X represents CH or N. When X represents CH, the compound represented by formula (I) is a pyrrolopyrimidinone compound, while when X represents N, the compound represented by formula (I) is a pyrazolopyrimidinone compound.

[0300] In the compound represented by formula (I) of this invention, R 1 It represents methyl (-CH3).

[0301] In the compound represented by formula (I) of this invention, the following portion (hereinafter referred to as the Z portion):

[0302] [Chemical Formula 3]

[0303]

[0304] Among them, Q and R 2 R 3 R 4 R 5 R 6 and R 7 a, b, and c are as defined above;

[0305] It is a nitrogen-containing saturated heterocyclic group that is monocyclic, bicyclic, bridged, or spirocyclic.

[0306] In the compound represented by formula (I) of this invention, R 2 and R 3 Independently selected from hydrogen and C 1-4 Any of the alkyl groups.

[0307] In the compound represented by formula (I) of this invention, R 6 and R 7 Independently indicated by selection from halogen, C 1-4 Alkyl, hydroxyl C 1-4 Either alkyl or hydroxyl. When Q is N, then R 6 or R 7 It does not represent halogen or hydroxyl, therefore it represents C. 1-4 alkyl.

[0308] In the compound represented by formula (I) of this invention, Q represents C or N.

[0309] In one implementation, when Q represents C, R 4 It is amino, amino C 1-4 Alkyl or mono-C 1-4 Alkylamino;

[0310] R 5 It is hydrogen, C 1-4 Alkyl, halogen, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or C 1-4 Alkoxy C 1-4 Alkyl group. In one embodiment, when R... 4 When it is an amino group, then R 5 Selected from hydrogen, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4Alkyl and C 1-4 Alkoxy C 1-4 alkyl.

[0311] In the described embodiment, the Z portion is a monocyclic, nitrogen-containing saturated 5-7 membered heterocyclic group containing one nitrogen atom, represented by the following formula:

[0312] [Chemical Formula 4]

[0313]

[0314] Where R 2 R 3 R 4 R 5 R 6 and R 7 a, b, and c are as defined above;

[0315] In another implementation, when Q represents C, R 4 and R 5 Together with Q, it forms a 4-6 membered ring, which may optionally contain elements independently selected from N, O, S, NH, C(O), and S(O). m 1-3 heteroatoms or groups, and R 4 and R 5 The formed ring may be unsubstituted or substituted with 1 to 4 independently selected groups chosen from amino, halogen, and halogenated C groups. 1-4 Alkyl, hydroxyl, methoxy, methylamino, C 1-4 Alkyl group, and m is selected from 1 and 2.

[0316] In the embodiment, the Z portion is a spirocyclic nitrogen-containing saturated heterocyclic group comprising 8-12 members (including Q), wherein 1-4 of the members are nitrogen, and 1-4 of the members are optionally the same or different heteroatoms selected from oxygen and sulfur. In the embodiment, the Z portion is represented by the following formula:

[0317] [Chemical Formula 5]

[0318]

[0319] Where R 2 R 3 R 6 R 7 a, b, and c are as defined above;

[0320] The B ring is a saturated 4-6 membered ring, which may optionally contain 1-3 independent members selected from N, O, S, NH, C(O) and S(O). m heteroatoms or groups,

[0321] R12 Independently selected from amino, halogen, and halogenated C 1-4 Alkyl, hydroxyl, methoxy, methylamino, C 1-4 alkyl,

[0322] l is an integer selected from 0, 1, 2, 3, and 4.

[0323] m is an integer selected from 1 and 2.

[0324] It may optionally include elements independently selected from N, O, C(O), and S(O). m Examples of 4-6 membered rings with 1-3 heteroatoms or groups include

[0325] [Chemical Formula 6]

[0326]

[0327] Where R 12 The same as the definition above.

[0328] In one implementation, when Q represents N, then R 4 It does not exist, and R 5 It is hydrogen.

[0329] In the described embodiment, the Z portion can be expressed as follows:

[0330] [Chemical Formula 7]

[0331]

[0332] Where R 2 R 3 a, b, and c are as defined above; R 6 and R 7 Independently selected from hydroxyl C 1-4 Alkyl and C 1-4 Alkyl group, provided that a is not 0;

[0333] It is a monocyclic nitrogen-containing saturated 5-7 membered heterocyclic group, containing two nitrogen atoms.

[0334] In the compound represented by formula (I) of this invention, R 2 R 3 R 6 and R 7 Alternatively, it may have the following structure, wherein the material is selected from R 2 R 3 R 6 and R 7 Any two groups together form a 1-3 bridging group, which is selected from C 1-3 Alkylene, C 2-3 Idenoyl, methylene-NRq -methylene and methylene-O-methylene, wherein the bridging group is optionally selected from C 1-4 Alkyl, hydroxyl, and halogen groups are substituted, and R q Selected from hydrogen and C 1-4 alkyl.

[0335] Examples of the implementation schemes include any of the Z portions shown in the following formulas:

[0336] [Chemical Formula 8]

[0337]

[0338] Among them, Q and R 2 R 3 R 4 R 5 R 6 and R 7 a, b, and c are as defined above, provided that in the formula containing “b-1” and / or “c-1”, “b-1” (which may be called b′) and “c-1” (which may be called c′) are independently selected from 0 and 1.

[0339] R B Indicates that it is selected from the straight chain C 1-3 Alkylene, C 2-3 Idenoyl, methylene-NR q -methylene and methylene-O-methylene 1-3 bridging groups, wherein the bridging groups are optionally selected from C 1-4 Alkyl, hydroxyl, and halogen groups are substituted, and R q Selected from hydrogen and C 1-4 alkyl.

[0340] In another embodiment of the compound shown in formula (I) of the present invention, Q is C, c is 2, and R is 2. 4 It is hydrogen, and has two Rs. 7 The links are connected to form nitrogen-containing 4-6 membered rings. Examples of the embodiments include the Z portion shown in any of the following formulas:

[0341] [Chemical Formula 9]

[0342]

[0343] In the compound represented by formula (I) of this invention, R 4 and R 7 Alternatively, a 4-6 membered ring containing one N atom can be formed. Examples of the embodiments include the Z portion shown in any of the following formulas:

[0344] [Chemical Formula 10]

[0345]

[0346] Among them, Q and R 2 R 3 R 5 R 6 and R 7 a, b, and c are as defined above, provided that “c-1” (which can be called c′) is selected from 0 and 1.

[0347] In the compound represented by formula (I) of this invention, R 5 and R 7 Alternatively, 3-6 elemental rings can be formed. Examples of the illustrated implementations include the Z portion shown in any of the following formulas:

[0348] [Chemical Formula 11]

[0349]

[0350] Among them, Q and R 2 R 3 R 4 R 6 and R 7 a, b, and c are as defined above, provided that “c-1” (which can be called c′) is selected from 0 and 1.

[0351] In an alternative implementation, R 6 and R 7 Alternatively, direct bonds are formed. An example of the illustrated implementation includes the Z-part shown in the following formula:

[0352] [Chemical Formula 12]

[0353]

[0354] Among them, Q and R 2 R 3 R 4 R 5 R 6 R 7 b and c are defined as above, provided that “b-1” (which can be called b′) and “c-1” (which can be called c′) are independently selected from 0 and 1.

[0355] In the compound shown in formula (I), a is an integer selected from 0, 1 and 2.

[0356] In the compound shown in formula (I), b is an integer selected from 0, 1 and 2.

[0357] In the compound shown in formula (I), c is an integer selected from 0, 1 and 2.

[0358] Preferred embodiments include any of the Z portions shown in the following formulas:

[0359] [Chemical Formula 13]

[0360]

[0361] Another preferred embodiment includes the Z portion shown in any of the following formulas:

[0362] [Chemical Formula 14]

[0363]

[0364] In the compound represented by formula (I) of this invention, the following portion (hereinafter referred to as the Y portion):

[0365] [Chemical Formula 15]

[0366]

[0367] Among them, rings A and R 8 R 9 R 10 R 11 The same as d as defined above;

[0368] It is an aromatic or non-aromatic fused ring containing a benzo-ring, and a 5-6 member nitrogen-containing heterocycle.

[0369] In the compound shown in formula (I), the ring A shown below

[0370] [Chemical Formula 16]

[0371]

[0372] Together with the benzo[a] ring bonded to this group, they form a 5- or 6-membered nitrogen-containing heterocycle.

[0373] Specifically, ring A is:

[0374] (i) a five-membered nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O and S, or

[0375] (ii) a six-membered nitrogen-containing aromatic heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O and S, or

[0376] (iii) A six-membered nitrogen-containing non-aromatic heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N and S;

[0377] The five-membered nitrogen-containing heterocycle (which optionally contains one or two additional heteroatoms selected from N, O, and S) can be a five-membered nitrogen-containing aromatic heterocycle or a five-membered nitrogen-containing non-aromatic heterocycle. The heterocycle contains 2-4 carbon atoms (including two carbon atoms shared by a benzo[a] ring bonded to the group), 1-3 nitrogen atoms, and one or two carbon atoms not shared with the benzo[a] ring, replaced by oxygen or sulfur atoms.

[0378] Examples of five-membered nitrogen-containing aromatic heterocycles include pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, and isothiazole.

[0379] Examples of five-membered nitrogen-containing non-aromatic heterocycles include pyrrolidine, pyrazolidine, triazolidine, oxazolidine, isoxazolidine, thiazolidinidine, and isothiazolidine.

[0380] A six-membered nitrogen-containing aromatic heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O, and S. The heterocycle comprises 2-5 carbon atoms (including two carbon atoms shared by a benzo[a] ring bonded to the group), 1-3 nitrogen atoms, and one, two, or three carbon atoms not shared with the benzo[a] ring, replaced by oxygen or sulfur atoms.

[0381] Examples of six-membered nitrogen-containing aromatic heterocycles include pyridine, pyrazine, pyrimidine, pyridazine, triazine, oxazine, and thiazine.

[0382] A six-membered nitrogen-containing non-aromatic heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N and S. The heterocycle contains 2-5 carbon atoms (including two carbon atoms shared by a benzo[a] ring bonded to the group), 1-3 nitrogen atoms, and carbon atoms (1, 2, or 3 carbon atoms) not shared with the benzo[a] ring but replaced by sulfur atoms.

[0383] Examples of six-membered nitrogen-containing non-aromatic heterocycles include piperidine, piperazine, and morpholine.

[0384] In the compound shown in formula (I), R 8 Indicates that it is selected from hydrogen, C 1-4 Alkyl, Halogenated C 1-4 One of alkyl and halogen.

[0385] In the compound shown in formula (I), R 9 It indicates that it is selected from one of hydrogen and halogens.

[0386] In the compound shown in formula (I), R 10 Indicates selection from halogenated C 1-4 Alkyl, C 1-4 Alkyl, halogen, hydrogen and C 1-4 One of the alkoxy groups.

[0387] In the compound shown in formula (I), R11 Each of these groups independently represents a group selected from one of the following: halogen, cyano, cyano C. 1-4 Alkyl, hydroxyl, oxo (=O), C 1-4 Alkyl group (optionally substituted with a 5- or 6-membered heterocyclic group containing one or two heteroatoms selected from O, N, or S), halogenated C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Alkyl sulfone, amino, single C 1-4 Alkylamino, diC 1-4 Alkylamino, amino C 1-4 Alkyl, -C 1-4 Alkylene-C(=O)NH (2-q) (C 1-6 alkyl) q ), -C 1-4 Alkylene-NHC(=O)C 1-6 Alkyl, sulfonamide, sulfonamide C 1-4 Alkyl, 3-6 membered cycloalkyl, C substituted with 3-6 membered cycloalkyl 1-4 Alkyl groups, comprising 5- or 6-membered unsaturated heterocyclic groups containing 1, 2, 3, or 4 heteroatoms selected from O, N, or S, and optionally substituted 4- to 6-membered saturated heterocyclic groups containing 1 or 2 heteroatoms selected from O, N, or S, wherein the optional substituents are selected from C. 1-4 alkyl;

[0388] When R 11 When it is oxidized (=O), R 11 The atomic bond between ring A and ring R is a double bond. 11 In other cases where it is a monovalent group, R 11 The atomic bond between ring A and ring A is a single bond.

[0389] In the compound shown in formula (I), q is an integer selected from 0, 1 and 2.

[0390] In the compound shown in formula (I), d is an integer selected from 0, 1 and 2.

[0391] The preferred embodiment includes any of the Y portions shown in the following formulas:

[0392] [Chemical Formula 17]

[0393]

[0394] [Chemical Formula 18]

[0395]

[0396] [Chemical Formula 19]

[0397]

[0398] Where R 8 R 10 R 11 The same as d as defined above;

[0399] R 13 Independently selected from hydrogen, halogen, cyano group, cyano C 1-4 Alkyl, C 1-4 Alkyl group (optionally substituted with a 5- or 6-membered heterocyclic group containing one or two heteroatoms selected from O, N, or S), halogenated C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Alkyl sulfone, amino C 2-4 Alkyl, -C 1-4 Alkylene-C(=O)NH (2-q) (C 1-6 alkyl) q ), -C 1-4 Alkylene-NHC(=O)C 1-6 Alkyl, sulfonamide C 1-4 Alkyl, 3-6 membered cycloalkyl, C substituted with 3-6 membered cycloalkyl 1-4 Alkyl groups, comprising 5- or 6-membered unsaturated heterocyclic groups containing 1, 2, 3, or 4 heteroatoms selected from O, N, or S, and optionally substituted 4- to 6-membered saturated heterocyclic groups containing 1 or 2 heteroatoms selected from O, N, or S, wherein the optional substituents are selected from C. 1-4 alkyl.

[0400] Other preferred embodiments include any of the Y portions shown in the following formulas:

[0401] [Chemical Formula 20]

[0402]

[0403] [Chemical Formula 21]

[0404]

[0405] Where R 8 R 10 R 11 The same as d as defined above;

[0406] R 13 Independently selected from hydrogen, cyano, cyano C 1-4 Alkyl, C1-4 Alkyl group (optionally substituted with a 5- or 6-membered heterocyclic group containing one or two heteroatoms selected from O, N, or S), halogenated C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Alkyl sulfone, amino C 2-4 Alkyl, -C 1-4 Alkylene-C(=O)NH (2-q) (C 1-6 alkyl) q ), -C 1-4 Alkylene-NHC(=O)C 1-6 Alkyl, sulfonamide C 1-4 Alkyl, 3-6 membered cycloalkyl, C substituted with 3-6 membered cycloalkyl 1-4 Alkyl groups, comprising 5- or 6-membered unsaturated heterocyclic groups containing 1, 2, 3, or 4 heteroatoms selected from O, N, or S, and optionally substituted 4- to 6-membered saturated heterocyclic groups containing 1 or 2 heteroatoms selected from O, N, or S, wherein the optional substituents are selected from C. 1-4 alkyl.

[0407] Other preferred embodiments include any of the Y portions shown in the following formulas:

[0408] [Chemical Formula 22]

[0409]

[0410] Where R 8 R 10 R 11 The same as d as defined above;

[0411] A more preferred embodiment includes any of the Y portions shown in the following formulas:

[0412] [Chemical Formula 23]

[0413]

[0414] Where R 8 and R 10 Same as defined above.

[0415] A more preferred embodiment includes any of the Y portions shown in the following formulas:

[0416] [Chemical Formula 24]

[0417]

[0418] A more preferred embodiment includes any of the Y portions shown in the following formulas:

[0419] [Chemical Formula 25]

[0420]

[0421] A particularly preferred embodiment includes any of the Y portions shown in the following formulas:

[0422] [Chemical Formula 26]

[0423]

[0424] The following are examples of preferred compounds of the present invention:

[0425] 2-(3,8-diazabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0426] 2-(4-(aminomethyl)-4-methylpiperidin-1-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0427] 2-(4-amino-4-methylpiperidin-1-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0428] 2-(exo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0429] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0430] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(7-chloro-2-ethylbenzo[d]thiazo-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0431] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(7-chloro-2-methylbenzo[d]thiazo-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0432] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0433] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(2-(tert-butyl)-4-chloro-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0434] 2-(exo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0435] (R)-2-(1-amino-8-azaspiro[4.5]decane-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0436] (S)-2-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0437] 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-2-(endo-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0438] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(endo-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0439] 2-(endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0440] 2-(endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0441] 2-(3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0442] (R)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(3-methylpiperazin-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0443] (S)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-2-(3-(hydroxymethyl)piperazin-1-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0444] (R)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-2-(3-(2-hydroxyethyl)piperazin-1-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0445] 2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0446] 2-(7-amino-3-oxa-9-azabicyclo[3.3.1]nonane-9-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0447] 2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0448] 2-(exo-8-amino-3-azabicyclo[3.2.1]octane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0449] 2-(endo-8-amino-3-azabicyclo[3.2.1]octane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0450] rac-2-((1S,2R,3R,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0451] 2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0452] 2-(3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0453] 2-(3,6-diazabicyclo[3.1.1]heptane-6-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0454] 2-(3,9-diazabicyclo[3.3.1]nonane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0455] 2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0456] 2-(2,5-diazabicyclo[2.2.2]octane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0457] 2-(exo-6-amino-3-azabicyclo[3.1.1]heptane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0458] 2-(endo-6-amino-3-azabicyclo[3.1.1]heptane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0459] 2-(5-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0460] 2-(exo-3-amino-9-azabicyclo[3.3.1]nonane-9-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0461] 2-(endo-3-amino-9-azabicyclo[3.3.1]nonane-9-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0462] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(1,8-diazaspiro[4.5]decane-8-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0463] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(piperazin-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0464] 2-(3,7-diazabicyclo[4.2.0]octane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0465] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(1,9-diazaspiro[5.5]undecane-9-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0466] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(1,7-diazaspiro[3.5]nonane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0467] (S)-2-(3-aminopyrrolidone-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0468] (R)-2-(3-aminopyrrolidone-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0469] (S)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(3-methylpiperazin-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0470] 2-((1S,2S,4R)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0471] (R)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(2-methylpiperazin-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0472] (S)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(2-methylpiperazin-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0473] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0474] 2-((3R,4S)-3-amino-4-fluoropyrrolidine-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0475] rac-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0476] 2-((3S,4S)-3-amino-4-fluoropyrrolidine-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0477] 2-(4-amino-3,3-difluoropyrrolidone-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0478] (S)-2-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0479] (R)-2-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0480] 2-((3R,4R)-3-amino-4-methylpyrrolidone-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0481] 2-((3R,4S)-3-amino-4-methylpyrrolidone-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0482] 2-(3-amino-3-(hydroxymethyl)pyrrolidone-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0483] 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0484] (R)-2-(3-(aminomethyl)pyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0485] 2-(1-Amino-3-azabicyclo[3.1.0]hexane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0486] 2-(6-amino-3-azabicyclo[3.1.0]hexane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0487] (S)-2-(3-(aminomethyl)pyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0488] 2-(4-(aminomethyl)-4-methoxypiperidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0489] 2-(4-(aminomethyl)-4-fluoropiperidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0490] 2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0491] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-3-methyl-5-(2-methyl-2H-indazol-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0492] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(7-chloro-2-methylbenzo[d]oxazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0493] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(7-chloro-2-ethylbenzo[d]oxazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0494] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0495] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(6,7-difluoro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0496] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(6-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0497] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-methoxy-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0498] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(7-chloro-1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0499] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0500] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2,7-dimethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0501] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(1H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0502] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0503] 2-(endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octane-8-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0504] 2-(3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0505] 2-(3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-yl)-5-(7-chloro-2-methylbenzo[d]thiazo-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0506] 2-(5-(2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,4-dichloro-2H-indazol-2-yl)-N,N-dimethylacetamide,

[0507] 3-(5-(2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,4-dichloro-2H-indazol-2-yl)-N,N-dimethylpropionamide,

[0508] 2-(6-(2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-7-chlorobenzo[d]thiazolyl)-N,N-dimethylacetamide,

[0509] 2-(3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0510] 2-(5-(2-(3,8-diazabicyclo[3.2.1]octane-8-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-chloro-2H-indazol-2-yl)-N,N-dimethylacetamide,

[0511] 2-(3,8-diazabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0512] 3-(5-(2-(3,8-diazabicyclo[3.2.1]octane-8-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-chloro-2H-indazol-2-yl)-N,N-dimethylpropionamide,

[0513] 3-(5-(2-(3,8-diazabicyclo[3.2.1]octane-8-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,4-dichloro-2H-indazol-2-yl)-N,N-dimethylpropionamide,

[0514] 2-(3,8-diazabicyclo[3.2.1]octane-8-yl)-5-(7-chloro-2-methylbenzo[d]thiazolyl-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0515] 2-(3,8-diazabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0516] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0517] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0518] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2,3-dimethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0519] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(7-chloro-2-methylbenzo[d]thiazolyl-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0520] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3-chloro-4-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0521] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0522] 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0523] 2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0524] 2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-5-(3-chloro-4-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0525] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(7-chlorobenzo[d]thiazolyl-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0526] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-ethyl-3-methoxy-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0527] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3,4-dichloro-2-(fluoromethyl)-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0528] 5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0529] 5-(7-chlorobenzo[d]thiazolyl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0530] 5-(3-chloro-4-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0531] 5-(7-chloro-2-methylbenzo[d]thiazolyl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0532] 2-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-5-(7-chlorobenzo[d]thiazolyl-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0533] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-3-(difluoromethyl)-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0534] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-ethyl-3-(hydroxymethyl)-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0535] 6-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0536] 6-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0537] 6-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-(7-chloro-2-methylbenzo[d]thiazolyl-6-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0538] 6-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0539] 6-(endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octane-8-yl)-3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0540] 6-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0541] 6-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0542] 3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0543] 3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0544] 3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0545] 3-(3-chloro-4-fluoro-2-methyl-2H-indazol-5-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0546] 6-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-3-(7-chlorobenzo[d]thiazolyl-6-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0547] 3-(7-chlorobenzo[d]thiazolyl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0548] 3-(7-chloro-2-methylbenzo[d]thiazolyl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0549] rac-6-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0550] rac-6-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0551] 6-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-(3,4-dichloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0552] 3-(3,4-dichloro-2-ethyl-2H-indazol-5-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0553] 2-((1R,2S,3R,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0554] 2-((1S,2R,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0555] 2-((1R,2R,3R,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0556] 2-((1S,2S,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0557] rac-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0558] rac-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-3-(7-chlorobenzo[d]thiazolyl-6-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0559] rac-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-((1S,4S,7S)-7-(methylamino)-2-azabicyclo[2.2.1]heptane-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0560] endo-6-[3-amino-8-azabicyclo[3.2.1]octane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0561] 3-(4-chloro-2-methyl-2H-indazol-5-yl)-6-{3,8-diazabicyclo[3.2.1]octane-8-yl}-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0562] 6-[(1R,3S)-1-amino-3-hydroxy-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0563] 6-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0564] exo-6-[3-amino-8-azabicyclo[3.2.1]octane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0565] 3-(4-chloro-2-methyl-2H-indazol-5-yl)-6-{2,7-diazaspiro[3.5]nonane-7-yl}-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0566] 6-[(1R)-1-amino-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0567] 6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0568] 6-[(1R,3R)-1-amino-3-fluoro-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0569] 3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-6-{3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-yl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0570] 3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-6-{3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-yl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0571] 6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0572] 6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0573] 6-[(1S,2R,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one,

[0574] 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0575] 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-(1,4-diazacycloheptane-1-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0576] rac-2-[(1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-yl]-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0577] rac-5-(4-chloro-2-methyl-2H-indazol-5-yl)-2-[(1R,6S)-3,9-diazabicyclo[4.2.1]nonane-9-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0578] rac-2-(4-aminoazacycloheptan-1-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0579] rel-2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0580] rel-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0581] rel-2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0582] rel-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0583] 5-(2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-chloro-2-ethyl-2H-indazole-3-carboxynitrile,

[0584] 6-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0585] 6-(endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octane-8-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0586] 6-((3R,4S)-4-amino-3-fluoropiperidin-1-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0587] 2-((1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0588] 2-(rac-(1R,2S,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0589] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-((1S,2S,4R)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0590] 2-((1R,2S,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0591] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0592] 2-((1R,2S,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-methyl-5-(3,4,7-trichloro-2-methyl-2H-indazol-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0593] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(5-chloro-3-methoxyquinoxalin-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0594] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(5-chloro-3-(dimethylamino)quinoxalin-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0595] 6-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0596] 2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0597] rac-2-((1R,2R,4S)-2-amino-2-methyl-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0598] 2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(3-chloro-4-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0599] rac-6-((1R,2R,4S)-2-amino-2-methyl-7-azabicyclo[2.2.1]heptane-7-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0600] 2-(endo-3-amino-8-azabicyclo[3.2.1]octane-8-yl)-5-(5-chloroquinoxalin-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0601] 3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-6-((1R,2R,4S)-2-(ethylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0602] 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-(2-methoxyethyl)-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one,

[0603] 3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-6-((1R,2R,4S)-2-(isopropylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,

[0604] 2-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(2-ethyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0605] 2-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(2-ethyl-4-fluoro-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0606] 2-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(7-chloro-2-ethyl-2H-indazol-6-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0607] 2-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(2-ethyl-2H-indazol-6-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0608] 2-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(2-ethyl-7-fluoro-2H-indazol-6-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0609] 2-[(endo)-3-amino-3-(difluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl]-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0610] 2-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(2-ethyl-7-fluoro-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0611] 2-[(3R,4S)-4-amino-3-fluoropiperidin-1-yl]-5-(7-chloro-1,3-benzothiazo-6-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0612] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-2-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-9-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0613] 5-(4-chloro-2-methyl-2H-indazol-5-yl)-2-[(1R,6S)-3,9-diazabicyclo[4.2.1]nonane-9-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0614] 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-{(1R,5R)-3,6-diazabicyclo[3.2.1]octane-3-yl}-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0615] 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-{(1S,5S)-3,6-diazabicyclo[3.2.1]octane-3-yl}-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0616] 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-[(1S,5R)-3,6-diazabicyclo[3.2.1]octane-6-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0617] 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-[(1R,5S)-3,6-diazabicyclo[3.2.1]octane-6-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0618] 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(4-chloro-7-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0619] 2-[(endo)-2-amino-2-methyl-7-azabicyclo[2.2.1]heptane-7-yl]-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0620] rac-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-{2,6-diazaspiro[3,4]octane-6-yl}-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0621] 2-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl]-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one,

[0622] 2-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl]-5-[8-chloro-2-(dimethylamino)quinolin-7-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, and

[0623] 2-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl]-5-[8-chloro-2-(methylamino)quinolin-7-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one.

[0624] Preparation method of compound (I)

[0625] Compound (I) can be prepared according to synthetic methods known to those skilled in the art.

[0626] According to another aspect of the present invention, a method for preparing a compound of formula (I) or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof is provided, the method comprising:

[0627] [Chemical Formula 27]

[0628]

[0629] (where P) 1 It is a protective base, L 1 L 2 and L 3 It is a leaving group, R 1 (As defined above for X). L 1 L 2 and L 3 It can be any of the following: chloride, bromide, and iodide.

[0630] (Step a)

[0631] In this step, compound (II) is protected to form compound (III).

[0632] The compound of formula (II) is commercially available or prepared using a similar method as described in the examples.

[0633] In compound (III), P 1Examples of protecting groups shown include ((2-trimethylsilyl)ethoxy)methyl (SEM) or tetrahydro-2H-pyran-2-yl (THP).

[0634] The method typically involves reacting a compound of formula (II) with ((2-trimethylsilyl)ethoxy)methyl chloride (SEMCl) at a suitable temperature, in a suitable solvent, and in a suitable base. Examples of suitable bases are sodium hydride, triethylamine, or N,N-diisopropylethylamine. Examples of suitable solvents are tetrahydrofuran or N,N-dimethylformamide. The amount of SEMCl used per mole of the compound of formula (II) is typically 1-10 moles, and preferably 1-5 moles. The amount of base used per mole of the compound of formula (II) is typically 1-100 moles, and preferably 1-10 moles.

[0635] The method typically involves reacting a compound of formula (II) with 3,4-dihydro-2H-pyran at a suitable temperature, in a suitable solvent, and in a suitable acid. Examples of suitable acids are p-toluenesulfonic acid monohydrate or camphorsulfonic acid. Examples of suitable solvents are tetrahydrofuran or dichloromethane. The amount of 3,4-dihydro-2H-pyran used per mole of the compound of formula (II) is typically 1-10 moles, and preferably 1-5 moles. The amount of acid used per mole of the compound of formula (II) is typically 0.001-100 moles, and preferably 0.01-10 moles.

[0636] The reaction temperature is typically 0-200°C, preferably room temperature to 150°C. The reaction time is typically 5 minutes to 7 days, preferably 30 minutes to 4 days.

[0637] The compound of formula (III) obtained therefrom may be subjected to subsequent steps after separation or purification by known methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or without separation or purification.

[0638] (Step b)

[0639] In this step, the compound of formula (III) is hydroxylated to produce the compound of formula (IV).

[0640] This method typically involves reacting a compound of formula (III) with a suitable base at a suitable temperature in a suitable solvent. Examples of suitable bases are sodium hydroxide or potassium hydroxide. Examples of suitable solvents are tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane with water.

[0641] For each mole of the compound represented by formula (III), the amount of base used is typically 0.1-100 moles, and preferably 1-20 moles.

[0642] The reaction temperature is typically 0-200°C, preferably room temperature to 150°C. The reaction time is typically 5 minutes to 7 days, preferably 30 minutes to 4 days.

[0643] The compound of formula (IV) obtained therefrom may be subjected to subsequent steps after separation or purification by known methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or without separation or purification.

[0644] (Step c)

[0645] In this step, the compound of formula (IV) reacts with an alkylating agent such as iodomethane to produce the compound of formula (V).

[0646] This method typically involves reacting a compound of formula (IV) with iodomethane and a suitable base at a suitable temperature in a suitable solvent. Examples of suitable bases are potassium carbonate or cesium carbonate. Examples of suitable solvents are N,N-dimethylformamide or N-methyl-2-pyrrolidone.

[0647] The amount of iodomethane used is typically 1-100 moles per mole of the compound represented by formula (IV), and preferably 1-20 moles. The amount of base used is typically 1-100 moles per mole of the compound represented by formula (IV), and preferably 1-20 moles.

[0648] The reaction temperature is typically 0-200℃, preferably 0-100℃. The reaction time is typically 5 minutes to 7 days, preferably 30 minutes to 4 days.

[0649] The compound of formula (V) obtained therefrom may be subjected to subsequent steps after separation or purification by known methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or without separation or purification.

[0650] [Chemical Formula 28]

[0651]

[0652] (where P) 1 P 2 It is a protective base, L 1 L 2 and L 3 It is a leaving group, where V represents a metal or metalloid residue (e.g., boric acid, pinacol boronic acid), and rings A and R... 1 R 8 R 9 R 10 R 11 X and d are as defined above.

[0653] (Step d)

[0654] In this step, the compound of formula (VI) reacts with alcohol P. 2 -OH reaction to produce compound of formula (VII).

[0655] The compounds of formula (VI) are commercially available or can be prepared using similar methods as described in the examples.

[0656] This method typically involves reacting a compound of formula (VI) with an alcohol, such as 4-methoxybenzyl alcohol, and a suitable base in a suitable solvent at a suitable temperature. Examples of suitable bases are potassium tert-butoxide or sodium tert-butoxide. Examples of suitable solvents are tetrahydrofuran or 1,4-dioxane.

[0657] The amount of alcohol used is typically 1-100 moles per mole of the compound represented by formula (VI), and preferably 1-20 moles. The amount of base used is typically 1-100 moles per mole of the compound represented by formula (VI), and preferably 1-20 moles.

[0658] The reaction temperature is typically 0-200℃, preferably 0-100℃. The reaction time is typically 5 minutes to 7 days, preferably 30 minutes to 4 days.

[0659] The compound of formula (VII) obtained therefrom may be subjected to subsequent steps after separation or purification by known methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or without separation or purification.

[0660] (Step e)

[0661] In this step, the compound of formula (VII) is halogenated to produce the compound of formula (VIII), wherein L 1 It is halogen.

[0662] This method typically involves reacting a compound of formula (VII) with a halogenating agent in a suitable solvent at a suitable temperature. Examples of halogenating agents are N-bromosuccinimide or N-iodosuccinimide. Examples of suitable solvents are tetrahydrofuran or N,N-dimethylformamide.

[0663] The amount of halogenating agent used is typically 1-100 moles per mole of the compound represented by formula (VII), and preferably 1-20 moles.

[0664] The reaction temperature is typically -78 to 100°C, preferably -20 to 100°C. The reaction time is typically 5 minutes to 7 days, preferably 30 minutes to 4 days.

[0665] The compound of formula (VIII) obtained therefrom may be subjected to subsequent steps after separation or purification by known methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or without separation or purification.

[0666] (Step f)

[0667] Complete this step in a similar manner to step a.

[0668] (Step g)

[0669] In this step, the compound of formula (IX) is coupled with the compound of formula (X) to produce the compound of formula (XI).

[0670] The compound of formula (X) is commercially available or can be prepared using a similar method as described in the examples.

[0671] This method typically involves reacting a compound of formula (IX) with a compound of formula (X) and a suitable catalyst, a suitable base, at a suitable temperature, and in a suitable solvent.

[0672] Examples of suitable catalysts are [1,1′-bis(diphenylphosphino)ferrocene]palladium(II), tetratriphenylphosphine palladium, or tris(dibenzylacetone)palladium(O) with a suitable ligand (e.g., triphenylphosphine, tri-tert-butylphosphine, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl). Another example of a suitable catalyst is (di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(ii). Examples of suitable bases are sodium carbonate, potassium carbonate, or potassium phosphate. Examples of suitable solvents are tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane with water.

[0673] The amount of compound (X) used per mole of the compound represented by formula (IX) is typically 1-100 moles, and preferably 1-20 moles. The amount of catalyst used per mole of the compound represented by formula (IX) is typically 0.0001-1 mole, and preferably 0.001-0.5 moles. The amount of ligand used per mole of the compound represented by formula (IX) is typically 0.0001-4 moles, and preferably 0.001-2 moles. The amount of base used per mole of the compound represented by formula (IX) is typically 0.1-10 moles, and preferably 1-5 moles.

[0674] The reaction temperature is typically 0-200°C, preferably room temperature to 150°C. The reaction time is typically 5 minutes to 7 days, preferably 30 minutes to 4 days.

[0675] The compound of formula (XI) obtained therefrom may be subjected to subsequent steps after separation or purification by known methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or without separation or purification.

[0676] (Step h)

[0677] In this step, the compound of formula (XI) is deprotected to produce the compound of formula (XII).

[0678] This method typically involves reacting a compound of formula (XI) with 2,3-dichloro-5,6-dicyano-p-benzoquinone in a suitable solvent at a suitable temperature. An example of a suitable solvent is dichloromethane.

[0679] The amount of 2,3-dichloro-5,6-dicyano-p-benzoquinone used is typically 1-100 moles per mole of the compound represented by formula (XI), and preferably 1-20 moles.

[0680] The reaction temperature is typically 0-200°C, preferably room temperature to 100°C. The reaction time is typically 5 minutes to 7 days, preferably 30 minutes to 4 days.

[0681] The compound of formula (XII) obtained therefrom may be subjected to subsequent steps after separation or purification by known methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or without separation or purification.

[0682] (Step i)

[0683] Complete this step in a similar manner to step c.

[0684] [Chemical Formula 29]

[0685]

[0686] (where P) 1 It is a protective base, L 1 L 2 It is a leaving group, R 1 R 2 R 3 R 4 R 5 R 6 R 7 Q, X, a, b, and c are defined as above.

[0687] (Step j)

[0688] In the step described, the compound of formula (V) is coupled with the compound of formula (XIV) to produce the compound of formula (XV).

[0689] Optionally, the reaction is carried out in the presence of an activator.

[0690] The compounds of formula (XIV) are commercially available or can be prepared using similar methods as described in the examples.

[0691] This method typically involves reacting a compound of formula (V) with a compound of formula (XIV) and a suitable base in a suitable solvent at a suitable temperature. An example of a suitable base is N,N-diisopropylethylamine. Examples of suitable solvents are N-methyl-2-pyrrolidone or N,N-dimethylformamide.

[0692] The amount of compound of formula (XIV) used is typically 1-100 moles, and preferably 1-10 moles, relative to each mole of the compound of formula (V). The amount of base used is typically 1-100 moles, and preferably 1-20 moles, relative to each mole of the compound of formula (V).

[0693] The reaction temperature is typically room temperature to 200°C, preferably room temperature to 150°C. The reaction time is typically 5 minutes to 7 days, preferably 30 minutes to 4 days.

[0694] The compound of formula (XV) obtained therefrom may be subjected to subsequent steps after separation or purification by known methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or without separation or purification.

[0695] [Chemical Formula 30]

[0696]

[0697] (where P) 1 It is a protective base, L 1 It is a leaving group, where V represents a metal or metalloid residue (e.g., boric acid or pinacol boronic acid ester), and rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 Q, X, a, b, c, and d are as defined above.

[0698] (Step k)

[0699] This step can be completed in a similar manner to step g.

[0700] [Chemical Formula 31]

[0701]

[0702] (where P) 1 It is a protective base, L 2 It is a leaving group, ring A, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 Q, X, a, b, c, and d are as defined above.

[0703] (Step 1)

[0704] This step can be completed in a similar manner to step j.

[0705] [Chemical Formula 32]

[0706]

[0707] (where P) 1 It is a protective base, ring A, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 Q, X, a, b, c, and d are as defined above.

[0708] (Step m)

[0709] In this step, the compound of formula (XVI) is deprotected to produce the compound of formula (I).

[0710] The method typically involves any suitable deprotection reaction, the conditions of which will depend on the nature of the protecting group. When the protecting group P 1When representing a ((2-trimethylsilyl)ethoxy)methyl group (SEM), the deprotection reaction typically involves using a suitable acid in a suitable solvent, followed by removal of the hydroxymethyl adduct formed during acid deprotection of the SEM protecting group with ethylenediamine or sodium hydroxide. For example, the acid may suitably include trifluoroacetic acid or hydrochloric acid, and the solvent may suitably include dichloromethane, chloroform, N,N-dimethylformamide, or methanol. Optionally, a solvent mixture, such as water and methanol, may be used. The second step involves vacuum concentration, followed by dissolution of the crude material in a suitable solvent, such as methanol, and treatment with a suitable scavenging agent, such as ethylenediamine or sodium hydroxide.

[0711] The amount of acid used is typically 1-100 moles per mole of the compound represented by formula (XVI), and preferably 1-20 moles. The amount of scavenger used is typically 1-100 moles per mole of the compound represented by formula (XVI), and preferably 1-20 moles.

[0712] The reaction temperature is typically 0-200°C, preferably room temperature to 100°C. The reaction time is typically 5 minutes to 7 days, preferably 30 minutes to 4 days.

[0713] When the protecting group is a tetrahydro-2H-pyran-2-yl group (THP), strong acids such as hydrochloric acid can be used in suitable solvents such as methanol at appropriate temperatures.

[0714] The amount of acid used is typically 1-100 moles per mole of the compound represented by formula (XVI), and preferably 1-20 moles.

[0715] The reaction temperature is typically 0-200°C, preferably room temperature to 100°C. The reaction time is typically 5 minutes to 7 days, preferably 30 minutes to 4 days.

[0716] The compound of formula (I) obtained therefrom can be separated and purified by known separation and purification methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography.

[0717] As a general method for preparing compounds of formula (I), deprotection can be completed according to the method described herein.

[0718] [Chemical Formula 33]

[0719]

[0720] (where L) 4 It is a leaving group, R 1 R 2 R 3 R 4 R 5 R 6 R7 R 8 R 9 R 10 R 11 Rings A, Q, a, b, c, and d are as defined above. 4 It can be any of, for example, bromide, iodide, and trifluoromethanesulfonate.

[0721] (Step n)

[0722] In this step, the compound of formula (XVII) is formylated to produce the compound of formula (XVIII).

[0723] This method typically involves reacting a compound of formula (XVII) with an organometallic reagent such as i-PrMgCl and a formylation agent such as N,N-dimethylformamide in a suitable solvent at an appropriate temperature. An example of a suitable solvent is tetrahydrofuran.

[0724] The amount of i-PrMgCl used is typically 1-10 moles per mole of the compound represented by formula (XVII), and preferably 1-5 moles. The amount of N,N-dimethylformamide used is typically 1-20 moles per mole of the compound represented by formula (XVII), and preferably 1-10 moles.

[0725] The reaction temperature is typically 0-100℃, preferably 0-60℃. The reaction time is typically 5 minutes to 7 days, preferably 30 minutes to 4 days.

[0726] The resulting compound of formula (XVIII) may be subjected to subsequent steps after separation or purification by known methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or without separation or purification.

[0727] (Step o)

[0728] In this step, compound (XVIII) is cyclized with compound (XIX) to produce compound (XX).

[0729] This method typically involves reacting a compound of formula (XVIII) with a compound of formula (XIX) and a suitable base in a suitable solvent at a suitable temperature. An example of a suitable base is piperidine. Examples of suitable solvents are N,N-dimethylformamide and isopropanol.

[0730] The amount of compound of formula (XVIII) used is typically 1-10 moles, and preferably 1-5 moles, relative to each mole of the compound represented by formula (XIX). The amount of base used is typically 1-10 moles, and preferably 1-5 moles, relative to each mole of the compound represented by formula (XIX).

[0731] The reaction temperature is typically 0-100℃, preferably 0-60℃. The reaction time is typically 5 minutes to 7 days, preferably 30 minutes to 4 days.

[0732] The compound of formula (XX) obtained therefrom may be subjected to subsequent steps after separation or purification by known methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or without separation or purification.

[0733] The compounds of formula (XIX) are known or prepared according to similar methods described in the literature.

[0734] (Step p)

[0735] In this step, compound (XX) is coupled with compound (XIV) to produce compound (XXI).

[0736] The compounds of formula (XIV) are commercially available or can be prepared using similar methods as described in the examples.

[0737] The method typically involves reacting a compound of formula (XX) with a compound of formula (XIV), an activator such as PyBOP, and a suitable base in a suitable solvent at a suitable temperature. Examples of suitable bases are DBU or N,N-diisopropylethylamine. Examples of suitable solvents are N-methyl-2-pyrrolidone or N,N-dimethylformamide.

[0738] The amount of compound (XVIII) used per mole of the compound represented by formula (XX) is typically 1-10 moles, and preferably 1-5 moles. The amount of PyBOP used per mole of the compound represented by formula (XX) is typically 1-10 moles, and preferably 1-5 moles. The amount of base used per mole of the compound represented by formula (XX) is typically 1-20 moles, and preferably 1-10 moles.

[0739] The reaction temperature is typically 0-100℃, preferably 0-60℃. The reaction time is typically 5 minutes to 7 days, preferably 30 minutes to 4 days.

[0740] The resulting compound of formula (XXI) may be subjected to subsequent steps after separation or purification by known methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or without separation or purification.

[0741] (Step q)

[0742] In this step, the compound of formula (XXI) is deprotected to produce the compound of formula (I-1).

[0743] The method typically involves reacting a compound of formula (XXI) with a suitable acid in a suitable solvent at a suitable temperature. An example of a suitable acid is trifluoromethanesulfonic acid. Examples of suitable solvents are dichloromethane or chloroform.

[0744] The amount of trifluoromethanesulfonic acid used is typically 1-100 moles per mole of the compound represented by formula (XXI), and preferably 1-20 moles.

[0745] The reaction temperature is typically 0-200℃, preferably 0-100℃. The reaction time is typically 5 minutes to 7 days, preferably 30 minutes to 4 days.

[0746] The compound of formula (I-1) obtained therefrom can be separated and purified by known separation and purification methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography.

[0747] As a general method for preparing compounds of formula (I-1), deprotection can be completed according to the method described in the text.

[0748] In any of the above steps, the protection of substituents and the removal or conversion of protecting groups can be appropriately carried out. For example, for functional groups such as amino, imino, hydroxyl, carboxyl, carbonyl, and amide, as well as functional groups with active protons such as indole, protecting agents can be used, or protecting groups can be introduced into said functional groups according to conventional methods. The protecting groups can then be removed in appropriate steps of each production method.

[0749] The protecting group is not specifically limited to an amino group or an imino group, as long as it has a protective function. Examples of such protecting groups include aralkyl groups, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, diphenylmethyl, triphenylmethyl, and cumyl; lower alkanoyl groups, such as formyl, acetyl, propionyl, butyryl, neopentyl, trifluoroacetyl, and trichloroacetyl; benzoyl; arylalkylyl groups, such as phenylacetyl and phenoxyacetyl; and lower alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and tert-butyl. Oxycarbonyl; aralkyloxocarbonyl groups, such as p-nitrobenzyloxocarbonyl and phenylethoxycarbonyl; lower alkylsilyl groups, such as trimethylsilyl and tert-butyldimethylsilyl; tetrahydropyranyl; trimethylsilylethoxymethyl; lower alkylsulfonyl groups, such as methanesulfonyl, ethanesulfonyl and tert-butylsulfonyl; lower alkylsulfinyl groups, such as tert-butylsulfinyl; arylsulfonyl groups, such as benzenesulfonyl and toluenesulfonyl; and imino groups, such as phthalimino. Specifically, trifluoroacetyl, acetyl, tert-butyloxocarbonyl, benzyloxocarbonyl, trimethylsilylethoxymethyl, cumyl, etc., are preferred.

[0750] The protecting group of the hydroxyl group is not particularly limited, as long as it has a protective function. Examples of the protecting group include lower alkyl groups, such as methyl, ethyl, propyl, isopropyl, and tert-butyl; lower alkylsilyl groups, such as trimethylsilyl and tert-butyldimethylsilyl; lower alkoxymethyl groups, such as methoxymethyl and 2-methoxyethoxymethyl; tetrahydropyranyl; trimethylsilylethoxymethyl; aralkyl groups, such as benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, and triphenylmethyl; and acyl groups, such as formyl, acetyl, and trifluoroacetyl. Specifically, methyl, methoxymethyl, tetrahydropyranyl, trimethylsilylethoxymethyl, tert-butyldimethylsilyl, and acetyl are preferred.

[0751] The protecting group of the carboxyl group is not particularly limited, as long as it has a protective function. Examples of such protecting groups include lower alkyl groups, such as methyl, ethyl, propyl, isopropyl, and tert-butyl; halo-lower alkyl groups, such as 2,2,2-trichloroethyl; lower alkenyl groups, such as allyl; trimethylsilylethoxymethyl; and aralkyl groups, such as benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, and triphenylmethyl. Specifically, methyl, ethyl, tert-butyl, allyl, benzyl, p-methoxybenzyl, and trimethylsilylethoxymethyl are preferred.

[0752] The protecting group of the carbonyl group is not particularly limited, as long as it has a protective function. Examples of such protecting groups include ethylene glycol ketals, trimethylene ketals, dimethyl ketals, ethylene glycol acetals, trimethylene acetals, dimethyl acetals, and similar ketals and acetals.

[0753] The protecting group is not particularly limited to an amide group or a functional group with an active proton, such as an indole protecting group, as long as it has a protective function. Examples of the protecting group include lower alkyl groups, such as methyl, ethyl, propyl, isopropyl, and tert-butyl; lower alkylsilyl groups, such as trimethylsilyl and tert-butyldimethylsilyl; lower alkoxymethyl groups, such as methoxymethyl and 2-methoxyethoxymethyl; tetrahydropyranyl; trimethylsilylethoxymethyl; aralkyl groups, such as benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, and triphenylmethyl; and acyl groups, such as formyl, acetyl, and trifluoroacetyl. Specifically, methyl, methoxymethyl, tetrahydropyranyl, trimethylsilylethoxymethyl, tert-butyldimethylsilyl, and acetyl are preferred.

[0754] The method for removing the protecting group can vary depending on the type of protecting group, the stability of the target compound (I), etc. For example, the following methods can be used: solvent decomposition using acid or base according to the method disclosed in the publication (Protective Groups in Organic Synthesis, 3rd edition, TW Green, John Wiley & Sons (1999)) or similar methods, i.e., a method involving reaction with 0.01 moles or a large excess of acid (preferably trifluoroacetic acid, formic acid or hydrochloric acid) or an equimolar to large excess of base (preferably potassium hydroxide or calcium hydroxide); chemical reduction using metal hydride complexes, etc.; or catalytic reduction using palladium-carbon catalysts, Raney nickel catalysts, etc.

[0755] The compounds of this invention can be easily separated and purified using commonly used separation and purification methods. Examples of such methods include solvent extraction, recrystallization, preparative reversed-phase high-performance liquid chromatography, column chromatography, and preparative thin-layer chromatography.

[0756] When the compounds of the present invention have isomers such as optical isomers, stereoisomers, rotational isomers, and tautomers, any isomer and mixtures thereof are included within the scope of the compounds of the present invention, unless otherwise stated. For example, when the compounds of the present invention have optical isomers, optical isomers isolated from racemic mixtures are also included within the scope of the compounds of the present invention, unless otherwise stated. Each of the isomers can be obtained as a single compound by known synthetic and separation methods (e.g., concentration, solvent extraction and column chromatography, recrystallization).

[0757] As described above, unless otherwise stated, the compounds of the present invention comprise all enantiomers and mixtures thereof. The compounds of the present invention can be mixtures of R and S enantiomers. Such mixtures can be mixtures containing 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 99% or more of the R isomer; mixtures containing 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 99% or more of the S isomer; etc.

[0758] Methods for chiral resolution include, for example: diastereomeric methods, in which a chiral resolving agent is applied to the compound of the present invention to form a salt, and one of the enantiomers is separated by the difference in solubility of the resulting salt; preferred crystallization methods, in which an enantiomer is added to a supersaturated solution of the racemic mixture as a seed crystal; and column chromatography, such as HPLC using a chiral column. Chiral resolving agents suitable for diastereomeric methods may be selected, for example, acidic resolving agents such as tartaric acid, malic acid, lactic acid, mandelic acid, 10-camphorsulfonic acid and their derivatives; and basic resolving agents such as strychnine, strychnine, quinine, and similar alkaloid compounds, amino acid derivatives, cinconidine, and α-methylbenzylamine. Not only can a single enantiomer of the compound of the present invention be obtained by obtaining the compound of the present invention in the form of an enantiomeric mixture and then performing chiral resolution as described above, but also a single enantiomer of the compound of the present invention can be obtained by obtaining an enantiomer of the compound of the present invention by the chiral resolution described above or by other methods and using it as a starting material for the synthesis of the compound of the present invention. Furthermore, a method for obtaining an enantiomer of the compound of the present invention or its starting material compound includes a method for preferentially obtaining an enantiomer by adjusting reaction conditions such as a catalyst in the reaction step for generating asymmetric carbon.

[0759] Compounds of formula (I) may optionally be converted into pharmaceutically acceptable salts. The compounds of the present invention or their salts may be in crystalline form. Mixtures of single crystals and polycrystalline forms are included within the scope of the compounds of the present invention or their salts. The crystals may be produced by crystallization according to crystallization methods known in the art. The compounds of the present invention or their salts may be solvates (e.g., hydrates) or non-solvents. Any of these forms are included within the scope of the compounds of the present invention or their salts. Using one or more isotopes (e.g., 2 H, 3 H, 14 C 35 S and 125 I) The labeled compounds are also included in the scope of the compounds of the present invention or their salts.

[0760] Salts of the compounds or intermediates thereof of this invention refer to common salts used in the field of organic chemistry. Examples of such salts include basic addition salts of a carboxyl group when the compound contains a carboxyl group, and acid addition salts of an amino or basic heterocyclic group when the compound contains an amino or basic heterocyclic group.

[0761] Examples of base addition salts include alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; ammonium salts; and organic amine salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, and N,N′-dibenzylethylenediamine salts.

[0762] Examples of acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, and perchlorates; organic acid salts such as acetates, formates, maleates, fumarates, tartrates, citrates, ascorbic acid salts, and trifluoroacetates; and sulfonates such as methanesulfonates, hydroxyethanesulfonates, benzenesulfonates, and p-toluenesulfonates.

[0763] Formula (I) also includes any prodrug of a compound of formula (I). A "prodrug" refers to any compound of formula (I) that is converted in vivo to a biologically active compound of formula (I). The prodrug can be prepared, for example, by replacing suitable functional groups present in a compound of formula (I) with certain groups known to those skilled in the art. In one embodiment, certain compounds of formula (I) may themselves serve as prodrugs for other compounds of formula (I). In one embodiment, formula (I) does not include prodrugs of compounds of formula (I) within its scope.

[0764] Due to their excellent SHP2 inhibitory activity, the compounds of the present invention or their salts can be used as pharmaceutical preparations for the prevention or treatment of SHP2-mediated diseases or conditions.

[0765] Examples of “SHP2-mediated diseases or conditions” include diseases or conditions whose incidence can be reduced by eliminating, suppressing, and / or inhibiting SHP2 function, and whose symptoms can be eliminated, alleviated, and / or completely cured. Such diseases may include those where SHP2 activity / presence / state is abnormal and associated with an abnormal RAS-ERK signaling pathway or receptor tyrosine kinase signaling pathway state, or those where SHP2 activity / presence / state is abnormal and associated with an abnormal immune response state. Examples of “SHP2-mediated diseases or conditions” include, but are not limited to, malignant tumors.

[0766] The types of malignant tumors to be treated with the compounds of the present invention or their salts are not particularly limited. Examples of such malignant tumors include head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, bile duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumors, osteosarcoma, soft tissue sarcoma, leukemia, myelodysplastic syndrome, chronic myelodysplastic disease, malignant lymphoma, multiple myeloma, skin cancer, brain tumors, mesothelioma, etc.

[0767] When the compounds of the present invention or their salts are used as pharmaceutical preparations, a pharmaceutically acceptable carrier may be added if desired to form a suitable dosage form for preventive and therapeutic purposes. Examples of dosage forms include oral preparations, injections, suppositories, ointments, patches, etc.; oral preparations are preferred. These dosage forms can be formed by methods conventionally known to those skilled in the art.

[0768] As pharmaceutically acceptable carriers, various conventional organic or inorganic carrier materials used as formulation materials can be incorporated as excipients, binders, disintegrants, lubricants, or coating agents in solid dosage forms; or as solvents, solubilizers, suspending agents, isotonic agents, pH adjusters / buffers, or soothing agents in liquid dosage forms. Furthermore, pharmaceutical additives such as preservatives, antioxidants, colorants, sweeteners, and stabilizers can be used if desired.

[0769] When preparing solid dosage forms for oral administration, excipients, binders, disintegrants, lubricants, colorants, sweeteners, etc., may be optionally added to the compounds of the present invention; and the resulting mixture may be formulated into tablets, coated tablets, granules, powders, capsules, etc., according to conventional methods.

[0770] When preparing injectable formulations, pH adjusters, buffers, stabilizers, isotonic agents, local anesthetics, etc., may be added to the compounds of the present invention as needed; and the resulting mixture may be formulated into subcutaneous, intramuscular, and intravenous injection formulations according to conventional methods.

[0771] In each of the aforementioned dosage unit forms, the amount of the compound of the invention incorporated depends on the patient's condition, dosage form, etc., when administering the compound. Generally, for oral, injectable, and suppository forms, the amount of the compound of the invention per dosage unit form is preferably 0.05-1000 mg, 0.01-500 mg, and 1-1000 mg, respectively.

[0772] The amount of active compound administered will depend on the mammal being treated, the severity of the patient or condition, the rate of administration, the disposal of the compound, and the prescribing physician's judgment. Effective doses are typically from about 0.001 to about 100 mg / kg body weight / day, preferably from about 0.01 mg to about 40 mg / kg / day, as a single dose or fractions. For example, for an adult (weight: 50 kg), the daily dose of the compound of the present invention can typically be from about 0.05 mg to about 5000 mg, and preferably from about 0.5 mg to about 2000 mg. In some cases, dose levels below the lower limit of the above range may be sufficient, while in others, larger doses may be used without causing any adverse side effects. Generally, the larger dose can be divided into several smaller doses for administration throughout the day. The total daily dose can be administered as a single dose or fractions. The total daily dose may fall outside the typical range based on the average human individual, for example, an individual weighing about 50 kg to about 70 kg. For individuals whose weight exceeds this range, such as infants and the elderly, the physician will be able to easily determine the dosage. Example

[0773] Synthesis method

[0774] The compounds listed below are prepared by methods similar to and / or analogous to the general operations described below.

[0775] The following synthetic procedures are provided to illustrate the methods used; for a given preparation or step, the precursor used need not be derived from an individual batch synthesized according to the steps described in the given description.

[0776] When a compound is described as a mixture of two diastereomers / epiromers, the configuration of the stereocenter is not specified and is represented by a straight line.

[0777] As those skilled in the art will understand, compounds synthesized using the illustrated strategy may exist as solvates, such as hydrates, and / or contain residual solvents or trace amounts of impurities. Compounds isolated as salts may be integer stoichiometric, i.e., single or disalts, or intermediate stoichiometric.

[0778] For example, depending on the acid used in the purification method, some compounds are separated as salts. Some compounds are separated as free bases.

[0779] Compounds containing a single stereocenter are typically isolated into single isomers using preparative chiral HPLC (as described in the General Methods section); at (or towards) the final stage of the synthetic sequence. In this case, stereochemistry is specified using “dummy” or “solid” wedges according to IUPAC. Unless otherwise stated, a straight line representing the stereocenter indicates that the compound exists as a mixture of two isomers.

[0780] Compounds containing a second stereocenter are typically resolved into single isomers using preparative achiral and / or chiral HPLC.

[0781] Optical isomers can be characterized by their optical activity (i.e., as + and - isomers or as d and l isomers). According to the nomenclature established by Cahn, Ingold, and Prelog, the stereocenter can also be designated as "R or S," see Jerry March, Advanced Organic Chemistry, 4th ed., John Wiley & Sons, New York, 1992, pp. 109-114, and also see Cahn, Ingold, and Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415.

[0782] Optical isomers can be separated by a variety of techniques, including chiral chromatography (chromatography on a chiral support), and these techniques are well known to those skilled in the art.

[0783] As an alternative to chiral chromatography, the optical isomers of basic compounds can be separated by forming diastereomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid. The diastereomeric salts are then preferentially crystallized and resolved, followed by salt dissociation to obtain a single enantiomer of the free base. Similarly, the optical isomers of acidic compounds can be separated by forming diastereomeric salts with chiral amines such as strychnine, cinconidine, and quinine.

[0784] Alternatively, enantiomeric separation can be achieved by covalently attaching an enantiomeric pure chiral auxiliary to the compound, followed by diastereomeric separation using conventional methods such as chromatography. The covalent bond is then cleaved to yield a suitable enantiomeric pure product. An example could be the preparation of menthol esters from acidic compounds.

[0785] When a compound of formula (I) exists in two or more optical isomers, one of the enantiomers in a pair may exhibit advantages over the other, for example, in terms of biological activity. Therefore, in some cases, it may be necessary to use only one of the one or more diastereomers in a pair as a therapeutic agent.

[0786] Therefore, the present invention provides compositions comprising compounds of formula (I) having one or more chiral centers, wherein at least 55% (e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) of the compound of formula (I) is present as a single optical isomer (e.g., an enantiomer or a diastereomer). In a general embodiment, 99% or more (e.g., substantially all) of the total amount of the compound of formula (I) may be present as a single optical isomer (e.g., an enantiomer or a diastereomer).

[0787] Compounds containing a double bond may have E (trans) or Z (cis) stereochemistry on the double bond. Substituents on a divalent cyclic or (partially) saturated group may have cis- or trans-configurations. When used in this text, the terms cis and trans are according to Chemical Abstracts nomenclature (J. Org. Chem. 1970, 35(9), 2849-2867) and refer to the position of the substituent on the cyclic group.

[0788] Of particular interest are stereochemically pure compounds of formula (I). When a compound of formula (I) is designated, for example, as R, this means that the compound is substantially free of the S isomer. If a compound of formula (I) is designated, for example, as E, this means that the compound is substantially free of the Z isomer. The terms cis, trans, R, S, E, and Z are well known to those skilled in the art.

[0789] The terms exo and endo refer to the stereochemistry of bridged bicyclic alkanes, such as substituted tropanes, as described in PAC, 1996, 68, 2193, Basic Terminology of Stereochemistry (IUPAC Recommendations 1996). If a substituent, such as an amino group, faces the highest-numbered bridge, it is described as exo; if it faces away from the highest-numbered bridge, it is described as endo. When there are two substituents on the same carbon atom, the terms exo and endo refer to the substituent with higher priority. The following figure illustrates how the graphical representation of aminotropane is defined in this patent.

[0790] [Chemical Formula 34]

[0791]

[0792] Example

[0793] The specific embodiments described in the following examples are intended to illustrate, but are not intended to limit, the invention. For example, compounds may be named using IUPAC rules, an automatic naming package such as AutoNom (MDL), or according to the chemical supplier's naming convention. In the examples, the following abbreviations are used.

[0794] [Math.1]

[0795] Acetyl group

[0796] aq. containing water

[0797] Boc tert-butyloxycarbonyl

[0798] Boc2O ditert-butyl dicarbonate

[0799] Butyllithium (BuLi)

[0800] t-BuOK potassium tert-butoxide

[0801] t-BuONa sodium tert-butoxide

[0802] Cbz carboxybenzyl

[0803] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0804] DCM dichloromethane

[0805] DIAD (Diisopropyl Azodicarbonate)

[0806] DIBAL-H Diisobutylaluminum Hydrogenation

[0807] DIPEA N,N-diisopropylethylamine

[0808] DMA N,N-dimethylacetamide

[0809] DME 1,2-dimethoxyethane

[0810] DMEAD di-2-methoxyethyl azodicarboxylate

[0811] DMF N,N-dimethylformamide

[0812] DMSO (dimethyl sulfoxide)

[0813] Et2O diethyl ether

[0814] EtOAc (ethyl acetate)

[0815] EtOH (ethanol)

[0816] h hours

[0817] HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylureonium hexafluorophosphate

[0818] HPLC (High Performance Liquid Chromatography)

[0819] IPA isopropanol

[0820] LDA (Lithium diisopropylamino)

[0821] i-PrMgCl isopropyl magnesium chloride

[0822] MeCN Acetonitrile

[0823] [Math.2]

[0824] MeOH (methanol)

[0825] min. minutes

[0826] MS mass spectrometry

[0827] MTBE tert-butyl methyl ether

[0828] NaOMe (sodium methoxide)

[0829] NBS N-bromosuccinimide

[0830] NCS N-chlorosuccinimide

[0831] NMP (N-methyl-2-pyrrolidone)

[0832] NMR (Nuclear Magnetic Resonance) Spectroscopy

[0833] PMB p-methoxybenzyl

[0834] PyBOP (benzotriazol-1-yloxy)tripyrrolidine phosphonium hexafluorophosphate

[0835] RT room temperature

[0836] Sat. saturated

[0837] SEM (2-(trimethylsilyl)ethoxy)methyl

[0838] SEMCl 2-(trimethylsilyl)ethoxymethyl chloride

[0839] TBAF Tetrabutylammonium Fluoride

[0840] TBSCl tert-butyldimethylchlorosilane

[0841] TEA Triethylamine

[0842] TBME tert-butyl methyl ether

[0843] TFA (trifluoroacetic acid)

[0844] THF Tetrahydrofuran

[0845] TLC (Thin Layer Chromatography)

[0846] TsCl p-Toluenesulfonyl chloride

[0847] Z-chloride benzyl chloroformate

[0848] Synthesis method

[0849] All starting materials and solvents were commercially available or prepared according to literature citations. Unless otherwise specified, all reactions were stirred. Organic solutions were routinely dried with anhydrous magnesium sulfate. Hydrogenation was carried out under the stated conditions or in a Parr hydrogenator or Thales H-cube flow reactor under a hydrogen balloon. Microwave reactions were performed using Biotage (registered trademark) Initiator, CEM Discover, and Smithcreator microwave reactors, heated to a constant temperature using variable power microwave radiation. Normal-phase column chromatography was routinely performed on pre-packed silica gel (230-400 mesh, 40-63 μm) columns in automated rapid chromatography systems such as the CombiFlash Companion or CombiFlash RF system. SCX was purchased from Supelco and treated with 1M hydrochloric acid before use. Unless otherwise specified, the reaction mixture to be purified was first diluted with MeOH and acidified with a few drops of AcOH. This solution was injected directly into the SCX and washed with MeOH. The desired substances were then eluted by washing with a solvent such as MeOH containing 1% NH3. Using Strata NH2 (55μm, NH2 ion-exchange silica gel columns were used for purification. The columns were directly loaded onto the NH2 column and eluted with a solvent such as methanol. Biotage (registered trademark) SNAP Ultra silica gel columns and Biotage (registered trademark) KP-NH SNAP silica gel columns were purchased from Biotage (registered trademark). Reverse-phase purification was performed using Biotage (registered trademark) SNAP Ultra C18 silica gel columns, also purchased from Biotage (registered trademark).

[0850] NMR data

[0851] 1 ¹H NMR spectra were obtained on a 400 MHz Bruker Avance III spectrometer, an AL400 (400 MHz; manufactured by JEOL), a Mercury 400 (400 MHz; manufactured by Agilent Technologies, Inc.), a 500 MHz Bruker Avance IIIHD NMR spectrometer, or a Bruker Avance NEO NMR spectrometer (400 MHz). The central peaks of chloroform-d, dimethyl sulfoxide-d6, or the internal standard tetramethylsilane can be used as references. For NMR data, when the number of attributed protons is less than the theoretical number of protons in the molecule, the inferred solvent and / or water peaks mask the significantly missing signal. Additionally, when spectra are obtained in proton NMR solvents, NH and / or OH protons are exchanged with the solvent, and therefore such signals are usually not observed.

[0852] Analytical and preparative LC-MS systems

[0853] Description of analytical LC-MS systems and methods

[0854] In the examples below, the compounds were characterized by mass spectrometry using the systems and operating conditions listed below. When atoms containing different isotopes are present and a single mass is reported, the mass reported by the compound is the monoisotopic mass (i.e., 35 Cl; 79 Br et al.

[0855] [Math.3]

[0856] Shimadzu Nexera

[0857] HPLC system: Shimadzu SIL-30AC autosampler / 2x Shimadzu LC-30AD pumps

[0858] Shimadzu LCMS-2020 Single Quadrupole Mass Spectrometer

[0859] Second detector: Shimadzu SPD-M20A diode array detector

[0860] MS Operating Conditions

[0861]

[0862] [Math.4]

[0863] Agilent 1290 Infinity II-6130LC-MS system

[0864] HPLC system: Agilent 1290 Infinity II

[0865] Mass spectrometer detector: Agilent 6130 single quadrupole

[0866] Second detector: Agilent 1290 Infinity II diode array detector

[0867] MS operating requirements:

[0868]

[0869]

[0870] Alternatively, measure the LCMS spectrum using an SQD manufactured by Waters Corporation under the following two conditions and display [M+H]. + value.

[0871] [Math.5]

[0872] MS detection: ESI positive

[0873] UV detection: 254nm

[0874] Column flow rate: 0.5 mL / min

[0875] Mobile phase: Water / acetonitrile (0.1% formic acid)

[0876] Injection volume: 1 μL

[0877] method

[0878] Column: Acguity BEH, 2.1×50mm, 1.7μm

[0879] gradient:

[0880]

[0881] Description of preparative LC-MS systems and methods

[0882] Preparative LC-MS is a standard and effective method for purifying small organic molecules, such as those described herein. The methods of liquid chromatography (LC) and mass spectrometry (MS) can be modified to provide better separation of crude substances and improved sample detection by MS. Optimization of preparative gradient LC methods will involve modifying the chromatographic column, volatile eluent and modifier, and the gradient. Methods for optimizing preparative LC-MS methods and then using them for compound purification are well known in the art. These methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC-MS; J Comb Chem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometer platform for the preparative purification and analytical analysis of compound libraries, J Comb Chem., 2003, 5(3), 322-9.

[0883] Several systems for purifying compounds by preparative LC-MS are described below; however, those skilled in the art will understand that alternative systems and methods can be used. From the information provided herein or by employing alternative chromatographic systems, those skilled in the art can purify the compounds described herein by preparative LC-MS.

[0884] Quality-oriented LC-MS purification system

[0885] Preparative LC-MS is a standard and effective method for purifying small organic molecules, such as those described herein. The methods of liquid chromatography (LC) and mass spectrometry (MS) can be modified to provide better separation of crude substances and improved detection of samples by MS. Optimization of preparative gradient LC methods will involve modifying the column, volatile eluent, and modifier, as well as the gradient. Methods for optimizing preparative LC-MS methods and then using them for compound purification are well known in the art. These methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC-MS; J Comb Chem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometer platform for the preparative purification and analytical analysis of compound libraries, J Comb Chem., 2003, 5(3), 322-9.

[0886] The following describes a system for purifying compounds by preparative LC-MS; however, those skilled in the art will understand that alternative systems and methods can be used. Specifically, normal-phase preparative LC methods can be used instead of the reversed-phase methods described herein. Most preparative LC-MS systems use reversed-phase LC and volatile acid modifiers because this method is highly effective for purifying small molecules and because the eluent is compatible with positive ion electrospray mass spectrometry. Other chromatographic solutions, such as normal-phase LC, alternative buffered mobile phases, basic modifiers, etc., as outlined in the analytical methods described above, can be used alternatively for purifying compounds.

[0887] [Math.6]

[0888] Agilent 1260LC-MS preparation system

[0889] hardware:

[0890] Autosampler: G2260A Prep ALS

[0891] Pumps: 2 x G1361A Prep Pumps for preparing the flow gradient; G1311C Quat Pump VL for pumping out the modifier from the preparation flow; and G1310B Iso Pump for replenishing the pump flow.

[0892] UV detector: G1365C 1260MWD

[0893] MS detector: G6120B Quadrupole LC-MS

[0894] Stage Collectors: 2x G1364B 1260FC-PS

[0895] G1968D Active Splitter

[0896] software:

[0897] Agilent OpenLab C01.06

[0898] Agilent MS runtime requirements:

[0899]

[0900] [Math.7]

[0901] Pillar:

[0902] 1.Waters XBridge Prep C18 5m OBD 100x19mm

[0903] Commonly used in ammonium bicarbonate-based methods

[0904] 2.Waters SunFire Prep C18OBD 5m 100x19mm

[0905] Typically used in -TFA-based methods

[0906] 3.Waters XBridge Prep Phenyl 5m OBD 100x19mm

[0907] Commonly used in methods based on neutral pH ammonium acetate

[0908] 4.Supelco Ascentis RP-Amide 5m 100x21.2mm

[0909] Commonly used in formic acid-based methods

[0910] 5.Phenomenex Synergi Fusion-RP 4m 100x21.2mm

[0911] Commonly used in formic acid-based methods

[0912] Eluent:

[0913] Solvent A: Water

[0914] Solvent B: Acetonitrile

[0915] Solvent C: Selection of available modifiers:

[0916] 2.5% trifluoroacetic acid aqueous solution;

[0917] 2.5% formic acid aqueous solution;

[0918] 250 mM ammonium bicarbonate aqueous solution, pH 9.4;

[0919] 250mM ammonium acetate

[0920] Make up the solvent:

[0921] 90:10 methanol:water + 0.2% formic acid (for all chromatographic types)

[0922] method:

[0923] Based on the microanalysis, select the most suitable preparative chromatographic type. A typical practice is to run analytical LC-MS using the chromatographic type best suited to the compound structure (low or high pH). Once the microanalysis shows good chromatography, select the appropriate preparative method of the same type. Typical operating conditions for low-pH and high-pH chromatographic methods are:

[0924] Flow rate: 25 mL / min

[0925] Gradient: Typically, all gradients begin with a 0.4-minute step using 95% A + 5% B (containing additional modifier C). Then, depending on the microanalysis, a 6.6-minute gradient is selected to achieve good separation (e.g., 5%-50% B for earlier retained compounds; 35%-80% B for intermediate retained compounds, etc.).

[0926] Cleaning: At the end of the gradient, complete a 1.6-minute cleaning step.

[0927] Supplemental flow rate: 0.8 mL / min

[0928] Solvent:

[0929] All compounds are usually dissolved in 100% MeOH or 100% DMSO.

[0930] Based on the information provided, those skilled in the art can purify the compounds described herein using preparative LC-MS.

[0931] [Math.8]

[0932] Waters Fractionlynx System

[0933] hardware:

[0934] 2767 Dual Quantitative Loop Autosampler / Fractional Collector

[0935] 2525 Preparative Pump

[0936] CFO (column fluidic organiser) is used for column selection;

[0937] RMA (Waters Reagent Manager), used as a supplementary pump;

[0938] Waters ZQ Mass Spectrometer

[0939] Waters 2996 Photo Diode Array Detector

[0940] Waters ZQ Mass Spectrometer

[0941] software:

[0942] Masslynx 4.1

[0943] Waters MS Operating Conditions

[0944]

[0945] Alternatively, reversed-phase preparative HPLC column chromatography can be performed under the following conditions.

[0946] [Math.9]

[0947]

[0948] Chiral preparative chromatography

[0949] The compound examples were purified by HPLC using the method recommended in Snyder LR, Dolan JW, High-Performance Gradient Elution: The Practical Application of the Linear-Solvent-Strength Model, Wiley, Hoboken, 2007.

[0950] Chiral preparative chromatography

[0951] Preparative separation using chiral stationary phases (CSPs) is a natural technique for resolving mixtures of enantiomers. Similarly, it can be used for the separation of diastereomers and achiral molecules. Methods for optimizing preparative chiral separations using CSPs and then using them to purify compounds are well known in the art. These methods are described in Beesley TE, Scott R. PW; Chiral Chromatography; Wiley, Chichester, mid-1998.

[0952] Preparation of 1: 2-chloro-4-((4-methoxybenzyl)oxy)-7H-pyrrolo[2,3-d]pyrimidine

[0953] [Chemical Formula 35]

[0954]

[0955] Potassium tert-butoxide (5.97 g, 53.2 mmol) was added to a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 13.3 mmol) and 4-methoxybenzyl alcohol (1.99 mL, 16.0 mmol) in 1,4-dioxane (37.5 mL) under RT. The mixture was stirred under RT for 1 h. Saturated NH4Cl was added under RT. The precipitate was collected, washed with water and EtOAc, and dried under reduced pressure overnight at 50 °C to give the title compound (3.14 g). MS: [M+H] + =290, 292.

[0956] Preparation of 2:5-bromo-2-chloro-4-((4-methoxybenzyl)oxy)-7H-pyrrolo[2,3-d]pyrimidine

[0957] [Chemical Formula 36]

[0958]

[0959] NBS (2.12 g, 11.9 mmol) was added to a DMF (31.4 mL) solution of 2-chloro-4-((4-methoxybenzyl)oxy)-7H-pyrrolo[2,3-d]pyrimidine (3.14 g, 10.8 mmol) at -20 °C. The mixture was stirred at -20 °C for 30 min. Saturated sodium thiosulfate (30 mL) and EtOAc (15 mL) were added. The mixture was stirred at RT for 30 min. The precipitate was collected, washed with water, and dried under reduced pressure overnight at 50 °C to give the title compound (3.78 g). MS: [M+H] + =368, 370.

[0960] Preparation of 3: 5-bromo-2-chloro-4-((4-methoxybenzyl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl )-7H-pyrrolo[2,3-d]pyrimidine

[0961] [Chemical Formula 37]

[0962]

[0963] At 0 °C, sodium hydride (60%, in mineral oil, 0.26 g, 6.51 mmol) and SEMCl (1.14 mL, 6.51 mmol) were added to a DMF (40 mL) solution of 5-bromo-2-chloro-4-((4-methoxybenzyl)oxy)-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 5.43 mmol). The mixture was stirred at 0 °C for 1 h. Saturated NH4Cl was added, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 20–60% EtOAc / hexane) to give the title compound (2.68 g). MS: [M+H] + =498,500.

[0964] Preparation of 4:5-bromo-2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-4H-pyrrolo [2,3-d]pyrimidin-4-one

[0965] [Chemical Formula 38]

[0966]

[0967] To a solution of 5-bromo-2-chloro-4-((4-methoxybenzyl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1.6 g, 3.21 mmol) in DCM (30.4 mL), 2,3-dichloro-5,6-dicyano-p-benzoquinone (2.18 g, 9.62 mmol) and water (1.6 mL) were added. The mixture was stirred at RT for 3 days. CHCl3 and sat.NaHCO3 were added at RT. The mixture was filtered through diatomaceous earth and washed with CHCl3 and water. The filtrate was extracted with CHCl3, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0–60% EtOAc / hexane) to give the title compound (0.746 g). MS: [M+H] + =378, 380.

[0968] Preparation of 5: 5-bromo-2-chloro-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-4H- Pyrrolo[2,3-d]pyrimidin-4-one

[0969] [Chemical Formula 39]

[0970]

[0971] Under RT, K₂CO₃ (0.544 g, 3.94 mmol) and methyl iodoform (0.245 mL, 3.94 mmol) were added to a DMF solution of 5-bromo-2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (0.746 g, 1.97 mmol) in 7.46 mL. The mixture was stirred under RT for 30 min, poured into water, and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0–60% EtOAc / hexane) to give the title compound (0.7 g). MS: [M+H] + =392,394.

[0972] Preparation of 6:2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] Pyrimidine

[0973] [Chemical Formula 40]

[0974]

[0975] SEMCl (1.13 mL, 6.37 mmol) was added to a THF (10 mL) solution of a mixture of 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1 g, 3.18 mmol) and DIPEA (1.66 mL, 9.55 mmol). The mixture was stirred at RT for 2 h and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0–30% EtOAc / hexane) to give the title compound (1.5 g). MS: [M+H] + =444, 446.

[0976] Preparation of 7: 2-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-4H-pyrrolo [2,3-d]pyrimidin-4-one

[0977] [Chemical Formula 41]

[0978]

[0979] At RT, 4M KOH (1 mL, 4 mmol) was added to a solution of 1,4-dioxane (4 mL) of a mixture of 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (0.3 g, 0.67 mmol). The mixture was stirred overnight at 60 °C, cooled to RT, acidified with aq. HCl, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0–70% EtOAc / hexane) to give the title compound (0.17 g). MS: [M+H] + =426, 428.

[0980] Preparation 8: 2-Chloro-5-iodo-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-4H- Pyrrolo[2,3d]pyrimidin-4-one

[0981] [Chemical Formula 42]

[0982]

[0983] Iodomethane (0.05 mL, 0.79 mmol) was added to a 1 mL NMP solution of a mixture of 2-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (0.17 g, 0.40 mmol) and K₂CO₃ (0.11 g, 0.79 mmol). The mixture was stirred at RT for 3 h, diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0–50% EtOAc / hexane) to give the title compound (0.15 g). MS: [M+H] + =440, 442.

[0984] Preparation 9: [endo-3-(tert-butoxycarbonyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester

[0985] [Chemical Formula 43]

[0986]

[0987] At 0°C, in an ice bath, Z-chloride (0.69 mL, 4.9 mmol) was added to a suspension of (endo-8-azabicyclo[3.2.1]octane-3-yl)carbamate tert-butyl (1.0 g, 4.4 mmol) and TEA (1.2 equivalents, 5.3 mmol) in THF (5.0 mL) and DCM (3.0 mL). The ice bath was removed, and the mixture was stirred at RT for 1 h. At RT, Z-chloride (0.13 mL, 0.88 mmol) was added to the mixture, and the mixture was stirred at RT for another 3 h. Dilute aqueous HCl and EtOAc were added to the mixture, and the mixture was extracted with EtOAc (X3). The organic extract was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue (pale yellow oil, 1.7 g) was purified by silica gel column chromatography (gradient elution, 0-8% MeOH / CHCl3) to give the title compound (1.4 g, 4.0 mmol, 91% yield) as a colorless solid. MS: [M+H] + =361.

[0988] Preparation of 10: [endo-3-(tert-butoxycarbonyl)(methyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester

[0989] [Chemical Formula 44]

[0990]

[0991] At 0 °C, sodium hydride (60%, in mineral oil, 0.24 g, 5.99 mmol) was added to a DMF (5.0 mL) solution of [endo-3-(tert-butyloxycarbonyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (1.4 g, 4.0 mmol) and the mixture was stirred at 0 °C for 40 min. Iodimethane (0.50 mL, 7.99 mmol) was added to the mixture at 0 °C, and the ice bath was removed over 5 min. After stirring at RT for 30 min, sodium hydride (60%, in mineral oil, 32 mg, 0.799 mmol) and iodomethane (0.12 mL, 2.00 mmol) were added to the mixture, and the mixture was stirred at RT for another 30 min. Dilute aqueous citric acid and EtOAc were added to the mixture, and the mixture was extracted with EtOAc. The organic extract was washed with water and brine and dried over Na2SO4. The filtrate was concentrated to give a crude product (yellow oil, 1.7 g), which was purified by silica gel column chromatography (gradient elution, 0-70% EtOAc / hexane) to give the title compound (879 mg, 2.3 mmol, yield 58%) as a colorless oil. MS: [M+H] + =375.

[0992] Preparation of 11: (endo-8-azabicyclo[3.2.1]octane-3-yl)(methyl)carbamate tert-butyl ester

[0993] [Chemical Formula 45]

[0994]

[0995] [endo-3-(tert-Butoxycarbonyl)(methyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (875 mg, 2.3 mmol) and 10% Pd-C(M)Wet (500 mg) were suspended in MeOH (5.0 mL), and the mixture was replaced with H2. The mixture was stirred at RT for 3 h. The reaction mixture was applied to a diatomaceous earth mat, and the filtrate was concentrated. The residue was dissolved in MeOH and applied again to a diatomaceous earth mat, and the filtrate was concentrated to give the title compound (556 mg, 2.3 mmol, 99% yield) as a pale yellow oil-solid. MS: [M+H] + =241.

[0996] Preparation of 12:8-benzyl-3-methyl-8-azabicyclo[3.2.1]octane-3-ol

[0997] [Chemical Formula 46]

[0998]

[0999] In a MeCN-dry ice bath, a THF solution of methyl magnesium chloride (29.4 mL, 88.4 mmol) was added to a THF solution of 8-benzyl-8-azabicyclo[3.2.1]octane-3-one (4.28 g, 19.9 mmol) (47.0 mL), and the reaction mixture was stirred at the stated temperature for 30 min, followed by stirring at RT for 20 h. Sat. NH4Cl solution was added at 0 °C, and the mixture was extracted with EtOAc. The combined organic layers were washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (NH4 silica gel, gradient elution, 20–50% CHCl3 / hexane) to give the title compound (4.50 g). MS: [M+H] + =232.

[1000] Preparation of 13:N-(endo-8-benzyl-3-methyl-8-azabicyclo[3.2.1]octane-3-yl)acetamide

[1001] [Chemical Formula 47]

[1002]

[1003] At 0 °C, concentrated sulfuric acid (18 mL) was added dropwise over 15 min to a solution of 8-benzyl-3-methyl-8-azabicyclo[3.2.1]octane-3-ol (4.28 g, 18.48 mmol) in acetonitrile (26 mL), and the mixture was stirred at RT for 18 h. The reaction mixture was poured into ice (ca. 200 g) and alkalized with 5 mol / L sodium hydroxide solution (ca. 100 mL) (ca. pH 10). The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent was removed under reduced pressure. The residue was washed with diethyl ether and petroleum ether to give the title compound (2.45 g). MS: [M+H] + =273.

[1004] Preparation of 14: N-(endo-8-benzyl-3-methyl-8-azabicyclo[3.2.1]octane-3-yl)carbamate tert-butyl ester

[1005] [Chemical Formula 48]

[1006]

[1007] To N-(endo-8-benzyl-3-methyl-8-azabicyclo[3.2.1]octane-3-yl)acetamide, 6 mol / L hydrochloric acid (80 mL) was added, and the mixture was stirred at 140 °C for 11 days. At 0 °C, the reaction mixture was alkalized with 4 mol / L sodium hydroxide solution, and 1,4-dioxane (20 mL) and di-tert-butyl dicarbonate (3.93 g, 18.0 mmol) were added. The reaction mixture was stirred at 0 °C for 1 h, and then at RT for 18 h. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtering off the drying agent, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution, 0-10% MeOH / DCM) to give the title compound (3.05 g). MS: [M+H] + =331.

[1008] Preparation of 15:N-(endo-3-methyl-8-azabicyclo[3.2.1]octane-3-yl)tert-butyl carbamate

[1009] [Chemical Formula 49]

[1010]

[1011] Pd(OH)₂ / C (10 wt% Pd, 637 mg, 0.454 mmol) was added to a solution of N-(endo-8-benzyl-3-methyl-8-azabicyclo[3.2.1]octane-3-yl)carbamate tert-butyl ester (3.0 g, 9.08 mmol) in MeOH (20 mL), and the reaction mixture was hydrogenated at ambient pressure and RT for 24 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated. The residue was ground with diethyl ether to give the title compound (1.86 g). MS: [M+H] + =241.

[1012] Preparation of 16: rac-(1S,2R,3S,5R)-3-(benzylamino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-methyl tert-butyl ester

[1013] [Chemical Formula 50]

[1014]

[1015] Sodium triacetoxyborohydride (41 g, 193 mmol) was added in portions to a solution of (±)-2-fluoro-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (34.8 g, 129 mmol), acetic acid (11.0 mL, 192 mmol), and benzylamine (20 mL, 183 mmol) in dichloromethane (500 mL), and the mixture was stirred overnight at room temperature. The mixture was diluted with 10% sodium bicarbonate (500 mL) and then extracted with dichloromethane (3 x 500 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated under reduced pressure. The crude material was recrystallized from ethyl acetate:isohexane (800 mL, 1:3) to give the title compound (11.6 g). 1 HNMR (500MHz, DMSO-d6) δ: 7.39-7.27(m, 4H), 7.27-7.19(m, 1H), 4.51(br d, 1H), 4.38-4.21 (m, 1H), 4.13-4.04 (m, 1H), 3.83-3.65 (m, 2H), 2.80 (dd, 1H), 2.48-2. 33(m, 1H), 2.09(s, 1H), 2.03-1.88(m, 2H), 1.86-1.69(m, 2H), 1.56(d, 1H), 1.37(s, 9H).

[1016] The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography (gradient elution, 0-50% EtOAc / isohexane) to give the following compounds:

[1017] Preparation of 17: rac-(1S,2S,3S,5R)-3-(benzylamino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-methyl tert-butyl ester

[1018] [Chemical Formula 51]

[1019]

[1020] The title compound (3.8 g) was obtained. 1 H NMR (500MHz, DMSO-d6) δ: 7.42-7.28 (m, 4H), 7.29-7.18 (m, 1H), 4.68 (dt, 1H), 4.16-4.04 (m, 1H), 4.05-3.94 (m, 1H), 3.82 (dd, 1 H), 3.63(dd, 1H), 3.29-3.20(m, 1H), 2.44-2.31(m, 1H), 2.21-2.04(m, 2H), 1.97-1.87(m, 1H), 1.89-1.61(m, 3H), 1.39(s, 9H).

[1021] Preparation of 18: rac-(1S,2R,3R,5R)-3-(benzylamino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-methyl tert-butyl ester

[1022] [Chemical Formula 52]

[1023]

[1024] 14 g of colorless oil was obtained, which was purified by silica gel column chromatography (gradient elution, 0-50% EtOAc / isohexane) to give the title compound (11.9 g). 1 H NMR (500MHz, DMSO-d6) δ: 7.38-7.26 (m, 4H), 7.26-7.15 (m, 1H), 4.66 (dt, 1H), 4.48-4.24 (m, 1H), 4.19-4.0 6(m, 1H), 3.77(d, 1H), 3.72(d, 1H), 2.96-2.72(m, 1H), 1.95-1.64(m, 4H), 1.61-1.43(m, 3H), 1.38(s, 9H).

[1025] Preparation of 19: rac-(1S,2R,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1026] [Chemical Formula 53]

[1027]

[1028] 18.5 g (55.3 mmol) of rac-(1S,2R,3S,5R)-3-(benzylamino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 10% palladium on carbon (JM Type 39, 57.3% humidity) (4.0 g, 1.605 mmol) were dissolved in acetic acid / ethanol (1:3, 200 mL) and stirred at 1 bar hydrogen for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was treated with sodium bicarbonate slurry (10 g, 100 mL) and then extracted with chloroform / IPA (9:1, 3 x 100 mL). The combined organic phases were concentrated under reduced pressure to give the title compound (13.5 g). 1 H NMR (500MHz, DMSO-d6) δ: 4.39-4.15 (m, 2H), 4.07 (m, 1H), 3.11 (dd, 1H), 2.12-1.88 (m, 4H), 1.83-1.65 (m, 4H), 1.37 (s, 9H).

[1029] Preparation of 20: rac-(1S,2R,3R,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1030] [Chemical Formula 54]

[1031]

[1032] The title compound was prepared using rac-(1S,2R,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (11 g, 32.9 mmol) in a similar manner to that used for rac-(1S,2R,3R,5R)-3-(benzylamino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (11 g, 32.9 mmol) to give the title compound (8.25 g). 1 H NMR (500MHz, DMSO-d6) δ: 4.37 (dt, 2H), 4.38-4.33 (m, 1H), 4.16-4.09 (m, 1H), 2.95 (dddd, 1H), 1.88-1.76 (m, 3H), 1.66-1.46 (m, 4H), 1.41 (d, J=0.5Hz, 9H).

[1033] Preparation of 21: rac-(1S,2S,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[1034] [Chemical Formula 55]

[1035]

[1036] The title compound was prepared by means of rac-(1S,2R,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (6.0 g, 17.0 mmol) to give the title compound (4.0 g). 1 H NMR (500MHz, DMSO-d6) δ: 4.53 (dt, 1H), 4.13-4.03 (m, 1H), 4.03-3.91 (m, 1H), 3.64- 3.53(m, 1H), 2.50-2.40(m, 1H), 2.22-2.05(m, 1H), 1.97-1.49(m, 6H), 1.39(d, 9H).

[1037] Preparation of 22: rac-(1S,2R,3S,5R)-3-{[(benzyloxy)carbonyl]amino}-2-fluoro-8-azabicyclo [3.2.1] tert-butyl octane-8-carboxylate

[1038] [Chemical Formula 56]

[1039]

[1040] Benzyl chloroformate (10 mL, 70.0 mmol) was added to a cooled (0 °C) solution of rac-(1S,2R,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (13.5 g, 52.5 mmol) and DIPEA (27 mL, 155 mmol) in THF / DCM (375 mL: 1:4), and stirred overnight at room temperature. Water (400 mL) was added, and the mixture was extracted with dichloromethane (3 x 400 mL), and the combined organic phases were concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0–30% EtOAc / isohexane). The purified oil was further purified by silica gel column chromatography (gradient elution, 0–10% EtOAc / DCM) to give the title compound (19.5 g). 1 H NMR (500MHz, DMSO-d6) δ: 7.46-7.39 (m, 1H), 7.39-7.34 (m, 4H), 7.34-7.29 (m, 1H), 5.07 (d, 1H), 5.02 (d, 1H), 4.51 (br d, 1H), 4.38-4.20 (m, 1H), 4.16-4.06 (m, 1H), 3.64-3.49 (m, 1H), 2.23-2.11 ( m, 1H), 1.94-1.79 (m, 2H), 1.78-1.66 (m, 2H), 1.49-1.43 (m, 1H), 1.38 (s, 9H).

[1041] Preparation of 23: rac-(1S,2R,3R,5R)-3-{[(benzyloxy)carbonyl]amino}-2-fluoro-8-azabicyclo [3.2.1] tert-butyl octane-8-carboxylate

[1042] [Chemical Formula 57]

[1043]

[1044] The title compound was prepared by means of rac-(1S,2R,3S,5R)-3-{[(benzyloxy)carbonyl]amino}-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (8.25 g, 32.1 mmol) to give the title compound (10.9 g). 1 H NMR (500MHz, DMSO-d6) δ: 7.46-7.26 (m, 6H), 5.11-4.94 (m, 2H), 4.54 (dt, 1H), 4.43-4.26 (m, 1 H), 4.20-4.06(m, 1H), 3.92-3.72(m, 1H), 1.99-1.69(m, 3H), 1.70-1.48(m, 3H), 1.38(s, 9H).

[1045] Preparation of 24: rac-(1S,2S,3S,5R)-3-{[(benzyloxy)carbonyl]amino}-2-fluoro-8-azabicyclo [3.2.1] tert-butyl octane-8-carboxylate

[1046] [Chemical Formula 58]

[1047]

[1048] The title compound was prepared by means of rac-(1S,2R,3S,5R)-3-{[(benzyloxy)carbonyl]amino}-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (4.0 g, 15.5 mmol) to give the title compound (5.45 g). 1 H NMR (500MHz, DMSO-d6) δ: 7.41-7.35 (m, 4H), 7.35-7.28 (m, 1H), 7.14-6.93 (m, 1H), 5.23-4.89 (m, 2H), 4.85-4.65 (m, 1H), 4.2 2-4.07(m, 2H), 4.07-3.97(m, 1H), 2.29-2.17(m, 1H), 2.08-2.02(m, 1H), 1.99-1.79(m, 2H), 1.80-1.64(m, 2H), 1.40(s, 9H).

[1049] Preparation of 25: rac-N-[(1S,2S,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]carbamic acid benzyl ester

[1050] [Chemical Formula 59]

[1051]

[1052] A solution of 3.0 M hydrogen chloride in cyclopentyl methyl ether (130 mL, 390 mmol) was added to a solution of rac-(1S,2R,3S,5R)-3-{[(benzyloxy)carbonyl]amino}-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (14.5 g, 36.4 mmol) in tert-butyl methyl ether (15 mL), and the mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and then partitioned between dichloromethane (200 mL) and saturated sodium bicarbonate solution (200 mL). The organic layer was concentrated under reduced pressure and then purified by silica gel column chromatography (gradient elution, 0–10% (0.7 M ammonia / MeOH) / DCM) to give the title compound (6.0 g). 1H NMR (500MHz, DMSO-d6) δ: 7.41-7.28 (m, 5H), 7.28-7.20 (m, 1H), 5.10-4.97 (m, 2H), 4.29 (ddd, 1H), 3.69-3.51 (m, 1H), 3.41 ( dd, 1H), 3.37-3.29(m, 1H), 2.30-2.09(m, 1H), 2.10-1.97(m, 1H), 1.77-1.63(m, 2H), 1.64-1.47(m, 2H), 1.30-1.14(m, 1H).

[1053] Preparation of 26: rac-N-[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]carbamic acid benzyl ester hydrochloride

[1054] [Chemical Formula 60]

[1055]

[1056] A 3.0 M hydrogen chloride solution of cyclopentyl methyl ether (100 mL, 300 mmol) was added to a suspension of (±)-(1S,2S,3R,5R)-3-(((benzyloxy)carbonyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ether (10.9 g, 27.4 mmol) in tert-butyl methyl ether (15 mL) and dichloromethane (10 mL), and then stirred at room temperature for 18 h. The precipitate was collected by filtration to give the title compound (8.8 g). 1 H NMR (500MHz, DMSO-d6) δ: 10.28-9.22(m, 1H), 9.22-8.29(m, 1H), 7.74-7.59(m, 1H), 7.42-7.35(m, 4H), 7.35-7.29(m, 1H), 5.07(d , 1H), 5.04(d, 1H), 4.83(dt, 1H), 4.22-4.12(m, 1H), 3.99-3.92(m, 1H), 3.92-3.75(m, 1H), 2.08-1.86(m, 4H), 1.86-1.68(m, 2H).

[1057] Preparation of 27: rac-N-[(1S,2R,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]carbamic acid benzyl ester hydrochloride

[1058] [Chemical Formula 61]

[1059]

[1060] rdc-(1S,2S,3S,5R)-3-{[(benzyloxy)carbonyl]amino}-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (5.45 g, 14.26 mmol) was dissolved in dichloromethane (5 mL) and then stirred at room temperature for 4 h with a 3.0 M hydrogen chloride solution in cyclopentyl methyl ether (50 mL). TBME (ca 10 mL) was added dropwise while stirring until turbidity was maintained, and the mixture was then stirred overnight. The resulting precipitate was collected by filtration and washed with TBME (10 mL) and isohexane (10 mL) to give the title compound (3.9 g). 1 H NMR (500MHz, DMSO-d6) δ: 10.08-9.28(m, 2H), 7.46-7.14(m, 6H), 5.21-5.00(m, 3H), 4.27-4.15(m, 1H), 4.13-4.04( m, 1H), 3.96-3.88 (m, 1H), 2.42 (ddd, 1H), 2.36-2.26 (m, 1H), 2.16 (ddd, 1H), 2.04-1.90 (m, 2H), 1.89-1.78 (m, 1H).

[1061] Preparation of 28: N-[(1S,2S,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]benzyl carbamate (Rapidly eluted isomers)

[1062] [Chemical Formula 62]

[1063]

[1064] 5.82 g of rac-N-[(1S,2S,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]carbamate was dissolved in methanol (150 mL) and then purified by chiral preparative supercritical fluid chromatography (Lux A1 column, (21.2 mm x 250 mm, 5 μm); 40 °C, flow rate 50 mL / min, BPR 100 BarG, detection at 210 nm, injection volume 200 μL (30 mg), 35:65 MeOH:CO2 (0.2% v / v NH3)). The purified fractions were combined and then evaporated to give the title compound (2.58 g), which was used as the faster eluting enantiomeric compound. 1H NMR (500MHz, DMSO-d6) δ: 7.41-7.28 (m, 5H), 7.28-7.20 (m, 1H), 5.10-4.97 (m, 2H), 4.29 (ddd, 1H), 3.69-3.51 (m, 1H), 3.41 ( dd, 1H), 3.37-3.29(m, 1H), 2.30-2.09(m, 1H), 2.10-1.97(m, 1H), 1.77-1.63(m, 2H), 1.64-1.47(m, 2H), 1.30-1.14(m, 1H).

[1065] Preparation of 29: N-[(1R,2R,3R,5S)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]carbamate (Slow-eluting isomers)

[1066] [Chemical Formula 63]

[1067]

[1068] 5.82 g of rac-N-[(1S,2S,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]carbamate was dissolved in 150 mL of methanol and then purified by chiral preparative supercritical fluid chromatography (Lux A1 column, (21.2 mm x 250 mm, 5 μm); 40 °C; flow rate 50 mL / min; BPR 100 BarG, detection at 210 nm; injection volume 200 μL (30 mg); 35:65 MeOH:CO2 (0.2% v / v NH3)). The purified fractions were combined and then evaporated to give the title compound (2.99 g). 1 H NMR (500MHz, DMSO-d6) δ: 7.41-7.28 (m, 5H), 7.28-7.20 (m, 1H), 5.10-4.97 (m, 2H), 4.29 (ddd, 1H), 3.69-3.51 (m, 1H), 3.41 ( dd, 1H), 3.37-3.29(m, 1H), 2.30-2.09(m, 1H), 2.10-1.97(m, 1H), 1.77-1.63(m, 2H), 1.64-1.47(m, 2H), 1.30-1.14(m, 1H).

[1069] Preparation of 30: N-[(1S,2S,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]benzyl carbamate hydrochloride

[1070] [Chemical Formula 64]

[1071]

[1072] The rapidly eluted isomer N-[(1S,2S,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]carbamate (3.8 g) was dissolved in dichloromethane (10 mL) and then treated with a cyclopentylmethyl ether solution of 3.0 M hydrogen chloride (10 mL, 30.0 mmol) to give a white solid, which was recrystallized in acetonitrile (50 mL) to give the title compound (2.2 g). 1 H NMR (500MHz, DMSO-d6) δ: 9.34 (br s, 2H), 7.76-7.56 (m, 1H), 7.45-7.27 (m, 5H), 5.09 (d, 1H), 5.04 (d, 1H), 4.95-4.77 (m, 1H), 4.17-4.06 (m , 1H), 3.98-3.87(m, 1H), 3.77-3.60(m, 1H), 2.33(ddd, 1H), 2.18(q, 1H), 2.03-1.89(m, 3H), 1.79(d, 1H).

[1073] Preparation of 31: N-[(1R,2R,3R,5S)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]benzyl carbamate hydrochloride

[1074] [Chemical Formula 65]

[1075]

[1076] The slow-eluting isomer N-[(1R,2R,3R,5S)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]carbamate (3.8 g) was dissolved in dichloromethane (10 mL) and then treated with a cyclopentylmethyl ether solution of 3.0 M hydrogen chloride (10 mL, 30.0 mmol) to give a white solid, which was recrystallized in acetonitrile (50 mL) to give the title compound (3.2 g). 1 HNMR (500MHz, DMSO-d6) δ: 9.34 (br s, 2H), 7.76-7.56 (m, 1H), 7.45-7.27 (m, 5H), 5.09 (d, 1H), 5.04 (d, 1H), 4.95-4.77 (m, 1H), 4.17-4.06 (m , 1H), 3.98-3.87(m, 1H), 3.77-3.60(m, 1H), 2.33(ddd, 1H), 2.18(q, 1H), 2.03-1.89(m, 3H), 1.79(d, 1H).

[1077] Preparation of 32:N-[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]benzyl carbamate (Rapidly eluted isomers)

[1078] [Chemical Formula 66]

[1079]

[1080] 8.8 g of rac-N-[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]carbamate was dissolved in methanol (50 mg / mL). -1 The fraction was then purified by chiral preparative supercritical fluid chromatography (Lux C2 (4.6 mm x 250 mm, 5 μm); 40 °C, flow rate 50 mL / min, BPR 100 BarG, detection at 210 nm, injection volume 500 μL (25 mg), 35:65 EtOH:CO2 (0.2% v / v NH3)). The purified fractions were combined and then evaporated to give the title compound (4.04 g) as the faster eluting enantiomer. 1 ¹H NMR (500 MHz, DMSO-d⁶) δ: 8.08–7.57 (m, 2), 7.53 (d, 1H), 7.41–7.28 (m, 5H), 5.04 (d, 1H), 5.02 (d, 1H), 4.67 (dt, 1H), 3.99–3.89 (m, 1H), 3.85–3.67 (m, 2H), 1.97–1.59 (m, 6H). (The compound was separated as a partial hydrochloride salt.)

[1081] Preparation of 33: N-[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]benzyl carbamate (Slow-wash enantiomers)

[1082] [Chemical Formula 67]

[1083]

[1084] 8.8 g of rac-N-[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]carbamate was dissolved in methanol (50 mg / mL). -1 The fraction was then purified by chiral preparative supercritical fluid chromatography (Lux C2 (4.6 mm x 250 mm, 5 μm); 40 °C, flow rate 50 mL / min, BPR 100 BarG, detection at 210 nm, injection volume 500 μL (25 mg), 35:65 EtOH:CO2 (0.2% v / v NH3)). The purified fractions were combined and then evaporated to give the title compound (4.01 g) as the slower-eluting enantiomer. 1¹H NMR (500MHz, DMSO-d6) δ: 7.47–7.28 (m, 6H), 5.97–4.75 (m, 2H), 5.08–4.99 (m, 2H), 4.52 (dt, 1H), 3.82–3.72 (m, 1H), 3.73–3.65 (m, 2H), 3.59–3.51 (m, 1H), 1.85–1.72 (m, 2H), 1.72–1.50 (m, 3H). (The compound was separated as a partial hydrochloride salt.)

[1085] Preparation of 34: N-[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]benzyl carbamate hydrochloride

[1086] [Chemical Formula 68]

[1087]

[1088] A portion of the HCl salt of ((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl)carbamate (the enantiomer eluted more quickly) (4.0 g, 13.65 mmol) was slurried in a minimal amount of dichloromethane (10 mL) and tert-butyl methyl ether (50 mL), and then treated with a cyclopentyl methyl ether solution of 3 M hydrogen chloride (7 mL, 21.00 mmol). The mixture was slurried overnight and then collected by filtration to give the title compound (4.19 g). 1 H NMR (500MHz, DMSO-d6) δ: 10.3-8.10 (brm, 2H), 7.65 (d, 1H), 7.46-7.24 (m, 5H), 5.18-4.94 (m, 2H), 4. 82(d, J=47.7Hz, 1H), 4.25-4.09(m, 1H), 3.99-3.90(m, 1H), 3.90-3.75(m, 1H), 2.08-1.73(m, 6H).[α] 20 D =15.47° (c1.00, MeOH).

[1089] Preparation of 35:N-[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]benzyl carbamate hydrochloride

[1090] [Chemical Formula 69]

[1091]

[1092] ((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl)benzyl carbamate (slow-eluting isomer) (4.0 g, 13.65 mmol) was slurried in a minimal amount of dichloromethane (10 mL) and tert-butyl methyl ether (50 mL), and then treated with a 3M hydrogen chloride solution of cyclopentyl methyl ether (7 mL, 21.00 mmol). The mixture was slurried overnight and then collected by filtration to give the title compound (4.23 g). 1 H NMR (500MHz, DMSO-d6) δ: 10.3-8.10 (br m, 2H), 7.65 (d, 1H), 7.46-7.24 (m, 5H), 5.18-4.94 (m, 2H), 4.82 (d, J=47.7Hz, 1H) , 4.25-4.09(m, 1H), 3.99-3.90(m, 1H), 3.90-3.75(m, 1H), 2.08-1.73(m, 6H).[α] 20 D = -11.88° (c 1.05, MeOH).

[1093] Preparation of 36: N-[(1S,2R,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]benzyl carbamate Hydrochloride (rapidly eluted isomer)

[1094] [Chemical Formula 70]

[1095]

[1096] 3.83 g of rac-N-[(1S,2R,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]carbamate was dissolved in methanol (50 mg mL⁻¹) and then purified by chiral preparative supercritical fluid chromatography (Lux A1 (4.6 mm x 250 mm, 5 μm); 40 °C, flow rate 50 mL / min, BPR 125 BarG, detection at 210 nm, injection volume 1000 μL (50 mg), 50:50 MeOH:CO₂ (0.7% v / v DEA)). N-[(1S,2R,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl]carbamate was used as a faster eluting enantiomeric fraction. The purified fractions were combined and then evaporated. The residue was then dissolved in dichloromethane (5 mL) and added dropwise to a mixture of stirred tert-butyl methyl ether (20 mL) and isohexane (20 mL) and cyclopentyl methyl ether solution of 3.0 M hydrogen chloride (2 mL, 6.00 mmol) to obtain a solid, which was recrystallized in acetonitrile (15 mL) to give the title compound (1.15 g). 1H NMR (500MHz, DMSO-d6) δ: 9.82-9.29 (m, 2H), 7.62-6.86 (m, 6H), 5.25-4.87 (m, 3H), 4.29-4.13 (m, 1H), 4.13-4.00 (m, 1H), 3.98 -3.85 (m, 1H), 2.42 (ddd, J=14.1, 9.7, 4.7Hz, 1H), 2.33-2.23 (m, 1H), 2.22-2.11 (m, 1H), 2.03-1.86 (m, 2H), 1.87-1.73 (m, 1H).

[1097] Preparation of 37: N-[(1R,2S,3R,5S)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]benzyl carbamate Hydrochloride (slow-eluting isomer)

[1098] [Chemical Formula 71]

[1099]

[1100] rac-N-[(1S,2R,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]carbamate was subjected to chiral preparative supercritical fluid chromatography (as described above) and separated as a slow-eluting enantiomeric compound. The purified fractions were combined and then evaporated. The residue was then dissolved in dichloromethane (5 mL), diluted with tert-butyl methyl ether (20 mL), and treated with a cyclopentyl methyl ether solution of 3.0 M hydrogen chloride (2 mL, 6.00 mmol) to give a viscous suspension. The suspension was diluted with isohexane (30 mL), stirred for 18 h, and collected by filtration to give the title compound (1.5 g). 1 H NMR (500MHz, DMSO-d6) δ: 9.82-9.29 (m, 2H), 7.62-6.86 (m, 6H), 5.25-4.87 (m, 3H), 4.29-4.13 (m, 1H), 4.13-4.00 (m, 1H), 3.98 -3.85 (m, 1H), 2.42 (ddd, J=14.1, 9.7, 4.7Hz, 1H), 2.33-2.23 (m, 1H), 2.22-2.11 (m, 1H), 2.03-1.86 (m, 2H), 1.87-1.73 (m, 1H).

[1101] Preparation of 38:((1R,2R,4S)-7-azabicyclo[2.2.1]heptane-2-yl)tert-butyl carbamate

[1102] [Chemical Formula 72]

[1103]

[1104] Step 1

[1105] 36 mg of rac-((1S,2S,4R)-7-azabicyclo[2.2.1]heptane-2-yl)carbamate tert-butyl hydrochloride was dissolved in DCM (2.89 mL). TEA (0.040 mL) and benzyl chloroformate (0.025 mL) were added to the solution at RT, followed by stirring at RT for 1 h. The solvent was evaporated off, and chloroform and water were added. The mixture was extracted twice with chloroform and washed with water and saturated brine. The solvent was evaporated off, and the residue was purified by silica gel column chromatography (gradient elution: hexane / EtOAc) to give rac-(1S,2S,4R)-2-((tert-butyloxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carbamate benzyl ester.

[1106] rac-(1S,2S,4R)-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylic acid benzyl ester was obtained as a 10 mg / mL ethanol solution and separated under the following conditions.

[1107] Column: Daicel Chiralpak IC 2.0x25cm

[1108] Mobile phase: hexane / 2-propanol = 85 / 15

[1109] Flow rate: 12.5 mL / min

[1110] Retention times of each isomer:

[1111] (1R,2R,4S)-2-((tert-Butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylic acid benzyl ester: 16.93 min

[1112] (1S,2S,4R)-2-((tert-Butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylic acid benzyl ester: 23.82 min.

[1113] Chiral analysis conditions:

[1114] Column: CHIRALPAK IC 4.6x150mm

[1115] Mobile phase: hexane / 2-propanol = 85 / 15

[1116] Flow rate: 1.0 mL / min

[1117] Retention times of each isomer:

[1118] (1R,2R,4S)-2-((tert-Butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylic acid benzyl ester: 6.972 min

[1119] (1S,2S,4R)-2-((tert-Butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylic acid benzyl ester: 9.895 min.

[1120] Step 2

[1121] (1R,2R,4S)-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate (93 g) and 10% Pd / C (10 g) were suspended in methanol (1.0 L). The mixture was stirred at RT for 5 h under a hydrogen atmosphere (50 psi). The reaction solution was filtered, and the filtrate was concentrated to give the title compound. MS: [M+H] + =213. 1 H-NMR(DMSO-d6)δ: 6.96-6.92(1H,m), 3.63-3.56(1H,m), 3.41-3.38(1H,m), 3.35-3.32(1H,m), 1.79-1.72(1H,m), 1.67-1.61(1H,m), 1.42-1.30(11H,m), 1.27-1.19(1H,m), 0.98-0.93(1H,m).

[1122] Preparation of 39:((1S,2S,4R)-7-azabicyclo[2.2.1]heptane-2-yl)tert-butyl carbamate

[1123] [Chemical Formula 73]

[1124]

[1125] Except for replacing (1R,2R,4S)-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate with (1S,2S,4R)-2-((tert-butoxycarbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate in step 1 of preparation 38, the title compound was obtained according to step 2 of preparation 38. MS: [M+H] + =213. 1 H-NMR(DMSO-d6)δ: 6.97-6.93(1H,m), 3.63-3.57(1H,m), 3.42-3.38(1H,m), 3.36-3.32(1H,m), 1.79-1.72(1H,m), 1.67-1.61(1H,m), 1.43-1.30(11H,m), 1.28-1.20(1H,m), 0.99-0.92(1H,m).

[1126] Preparation of 40:1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid benzyl ester

[1127] [Chemical Formula 74]

[1128]

[1129] To a mixture of 11.7 g (50 mmol) of 4-oxopiperidinium-1-carboxylate and 12.1 g (55 mmol) of trimethylsulfoxonium iodide in 200 mL of DME, potassium tert-butoxide (6.17 g, 55 mmol) was added and the mixture was stirred at 100 °C for 5 h. Water was added at RT, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, EtOAc:hexane = 1:5 to 1:2) to give the title compound (7.58 g). MS: [M+H] + =248.

[1130] Preparation of 41: 4-(azidomethyl)-4-methoxypiperidine-1-carboxylic acid benzyl ester

[1131] [Chemical Formula 75]

[1132]

[1133] To a solution of 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (1.24 g, 5.0 mmol) in MeOH (30 mL) and water (6 mL), sodium azide (1.63 g, 25 mmol) and NH4Cl (535 mg, 10 mmol) were added, and the mixture was stirred at 90 °C for 14 h. The solvent was removed under reduced pressure, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. At 0 °C, a THF solution (15 mL) of the residue was added to sodium hydride (55%, in mineral oil, 262 mg, 6.0 mmol), and stirred for 15 min. Then, iodomethane (0.40 mL, 6.5 mmol) was added, and the mixture was stirred at RT for 15 h. At 0 °C, Sat. NH4Cl was added, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, EtOAc:hexane = 1:5 to 1:2) to give the title compound (1.16 g). MS: [M+H] + =305.

[1134] Preparation of 42: 4-(((tert-Butoxycarbonyl)amino)methyl)-4-methoxypiperidine-1-carboxylic acid benzyl ester

[1135] [Chemical Formula 76]

[1136]

[1137] Triphenylphosphine (1.84 g, 7.0 mmol) was added to a solution of 4-(azidomethyl)-4-methoxypiperidine-1-carboxylic acid benzyl ester (1.07 g, 3.5 mmol) in THF (15 mL) and water (0.63 mL, 35 mmol) at RT, and the mixture was stirred at 45 °C for 15 h. At 0 °C, the mixture was added to 2 M NaOH (3.5 mL, 7.0 mmol) and di-tert-butyl dicarbonate (918 mg, 4.2 mmol), and stirred at RT for 2 h. The mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, EtOAc:hexane = 1:3 to 2:3) to give the title compound (1.32 g). MS: [M+H] + =379.

[1138] Preparation of 43:((4-methoxypiperidin-4-yl)methyl)tert-butyl carbamate

[1139] [Chemical Formula 77]

[1140]

[1141] To a THF (15 mL) solution of 1.14 g (3.0 mmol) of benzyl 4-(((tert-Butoxycarbonyl)amino)methyl)-4-methoxypiperidine-1-carboxylate, 10% palladium on carbon (46.7% wet, 280 mg, 0.12 mmol) was added, and the mixture was stirred for 6 h under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the solvent was removed under reduced pressure to give the title compound (742 mg). MS: [M+H] + =245.

[1142] Preparation of 44: 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylic acid benzyl ester

[1143] [Chemical Formula 782]

[1144]

[1145] At -10 °C, a solution of 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2.47 g, 10.0 mmol) in DCM (15 mL) was added, followed by a solution of pyridine hydrofluoride (2.0 mL, 14 mmol) in DCM (5 mL), and the mixture was stirred at RT for 2 h. The mixture was extracted with EtOAc by adding Sat. NaHCO3 at 0 °C. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, EtOAc∶CHCl3 = 1∶10 to 1∶3) to give the title compound (1.71 g). MS: [M+H] + =268.

[1146] Preparation of 45: 4-(azidomethyl)-4-fluoropiperidine-1-carboxylic acid benzyl ester

[1147] [Chemical Formula 79]

[1148]

[1149] At RT, Et3N (1.68 mL, 12 mmol) and methanesulfonyl chloride (0.56 mL, 7.2 mmol) were added to a DCM (20 mL) solution of 4-fluoro-4-(hydroxymethyl)piperidin-1-carboxylate (1.60 g, 6.0 mmol) and stirred for 1 h. Water was added at 0 °C, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Sodium azide (1.94 g, 30 mmol) was added to a DMF solution (15 mL) of the residue, and stirred at 110 °C for 48 h. Water was added at RT, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, EtOAc:hexane = 1:5 to 1:2) to give the title compound (1.20 g). MS: [M+H] + =293.

[1150] Preparation of 46: 4-(((tert-Butoxycarbonyl)amino)methyl)-4-fluoropiperidine-1-carboxylic acid benzyl ester

[1151] [Chemical Formula 80]

[1152]

[1153] Triphenylphosphine (1.84 g, 7.0 mmol) was added to a solution of 4-(azidomethyl)-4-fluoropiperidine-1-carboxylic acid benzyl ester (1.02 g, 3.5 mmol) in THF (15 mL) and water (0.63 mL, 35 mmol) at RT, and the mixture was stirred at 45 °C for 15 h. At 0 °C, 2 M NaOH (3.5 mL, 7.0 mmol) and di-tert-butyl dicarbonate (918 mg, 4.2 mmol) were added to the mixture, and the mixture was stirred at RT for 6 h. The mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, EtOAc:hexane = 1:3 to 2:3) to give the title compound (1.24 g). MS: [M+H] + =367.

[1154] Preparation of 47:((4-fluoropiperidin-4-yl)methyl)tert-butyl carbamate

[1155] [Chemical Formula 81]

[1156]

[1157] To a solution of 1.10 g (3.0 mmol) of benzyl 4-(((tert-Butoxycarbonyl)amino)methyl)-4-fluoropiperidine-1-carboxylate in 15 mL of THF and 15 mL of MeOH, 10% palladium on carbon (46.7% wet, 345 mg, 0.15 mmol) was added, and the mixture was stirred for 8 h under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the solvent was removed under reduced pressure to give the title compound (718 mg). MS: [M+H] + =233.

[1158] Preparation of 48:2-methyl-N-((R)-8-azaspiro[4.5]decane-1-yl)propane-2-sulfinamide

[1159] [Chemical Formula 82]

[1160]

[1161] TFA (0.20 mL, 2.6 mmol) was added to a CHCl3 (1 mL) solution of (1R)-1-((tert-butylsulfinyl)amino)-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (0.10 g, 0.28 mmol) prepared according to the method described in WO2016203405. The mixture was stirred at RT for 2 h. Volatiles were removed under reduced pressure, and the resulting crude 2-methyl-N-((R)-8-azaspiro[4.5]decane-1-yl)propane-2-sulfinamide salt was used without further purification. MS: [M+H] + =259.

[1162] Preparation of 49: (S)-2-oxa-8-azaspiro[4.5]decane-4-amine

[1163] [Chemical Formula 83]

[1164]

[1165] At RT, a solution of 1,4-dioxane (0.70 mL, 2.8 mmol) of 4M HCl was added to a MeOH solution of (4S)-4-((tert-butylsulfinyl)amino)-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (0.10 g, 0.28 mmol) prepared according to the method described in WO2016203405. The mixture was stirred at 50 °C for 30 min and cooled to RT. Volatiles were removed under reduced pressure, and the residue was azeotropically treated with toluene. The resulting crude (S)-2-oxa-8-azaspiro[4.5]decane-4-amine salt was used without further purification. MS: [M+H] + =157.

[1166] Preparation of 50: (1R,3R)-3-fluoro-8-azaspiro[4.5]decane-1-amine dihydrochloride

[1167] [Chemical Formula 84]

[1168]

[1169] Step 1: (1R,3S)-1-(1,1-dimethylethylsulfinamide)-3-hydroxy-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[1170] N-((1R,3S)-3-hydroxy-8-azaspiro[4.5]decane-1-yl)-2-methylpropane-2-sulfinamide (950 mg, 3.46 mmol) was dissolved in THF (5 mL), and Boc₂O (754 mg, 3.46 mmol) was added. The solution was stirred at 50 °C for 4 hours and then concentrated. The crude substance was purified by silica gel chromatography (12 g column, 0-10% MeOH / DCM) to give (1R,3S)-1-(1,1-dimethylethylsulfinamide)-3-hydroxy-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (210 mg, 0.53 mmol, yield 15%) as a colorless solid. MS: [M+Na] + =397.

[1171] Step 2: (1R,3R)-1-(1,1-dimethylethylsulfinylamino)-3-fluoro-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[1172] (1R,3S)-1-(1,1-dimethylethylsulfinylamino)-3-hydroxy-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (200 mg, 0.53 mmol) was dissolved in DCM (2.5 mL), and the solution was cooled to 0 °C. Deoxofluor (50 wt% toluene solution) (0.35 mL, 0.934 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 hours. Another portion of Deoxofluor (50 wt% toluene solution) (0.35 mL, 0.934 mmol) was added, and the reaction mixture was stirred at 0 °C for 3 hours, then stirred at ambient temperature for 30 minutes. The reaction was quenched with a saturated aqueous solution of NaHCO3 (5 mL), and the mixture was stirred for 15 minutes. The organic phase was separated, and the aqueous phase was further extracted with DCM (2 x 10 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated to give a crude product as an orange oil. The crude product was purified by silica gel chromatography (4 g column, 0-10% MeOH / DCM) to give (1R,3R)-1-(1,1-dimethylethylsulfinylamino)-3-fluoro-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (135 mg, 0.32 mmol, yield 60%) as a pale yellow gel. MS: [M+Na] + =399.

[1173] Step 3: (1R,3R)-3-fluoro-8-azaspiro[4.5]decane-1-amine dihydrochloride

[1174] 1.0 mL of HCl (4 M dioxane solution) was added to (1R,3R)-1-(1,1-dimethylethylsulfinylamino)-3-fluoro-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (130 mg, 0.345 mmol), and the mixture was stirred at room temperature. Another 1.0 mL of HCl (4 M dioxane solution) was added, and the reaction mixture was stirred at room temperature for 1 hour and 30 minutes. The mixture was concentrated to give an orange solid. The crude product was used directly in the following steps.

[1175] Preparation of 51:(3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride

[1176] [Chemical Formula 85]

[1177]

[1178] Step 1: Ethyl (2S)-2-[(tert-butyldimethylsilyl)oxy]propionate

[1179] Ethyl (2S)-2-hydroxypropionate (95.0 g, 0.8 mol) in the reaction mixture DCM (1 L) was cooled to 0 °C, and then imidazole (81.6 g, 1.2 mol) and TBSCl (133.3 g, 0.88 mol) were added. The mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was poured into water (1.0 L), extracted with DCM (2 x 500 mL), washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1-20 / 1) to give the product (180.0 g, 97%) as a colorless oil. 1 H NMR (500MHz, CDCl3) δ: 4.33 (s, 1H), 4.22 (s, 2H), 1.44 (d, 3H), 1.32 (t, 3H), 0.97 (s, 9H), 0.15 (s, 6H).

[1180] Step 2: (2S)-2-[(tert-butyldimethylsilyl)oxy]propionaldehyde

[1181] A toluene solution (800 mL) of ethyl (2S)-2-[(tert-butyldimethylsilyl)oxy]propionate (131.0 g, 0.56 mol) was cooled to -60 °C, and DIBAL-H (1.5 M, 560 mL, 0.85 mol) was added dropwise. The mixture was then stirred at -60 °C for 2 h. The reaction mixture was poured into water (800 mL), extracted with EtOAc (2 x 500 mL), washed with brine, dried over Na₂SO₄, and concentrated under vacuum to obtain the crude product. No purification was required, and this crude product was used in the next step.

[1182] Step 3: 4-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-1-hydroxypropyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

[1183] A solution of diisopropylamine (65.0 g, 0.64 mol) in THF (400 mL) was cooled to -20 °C. n-BuLi (2.5 M, 224 mL, 0.56 mol) was added dropwise, and the mixture was stirred at -10 °C for 1 h. At -10 °C, a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (110.0 g, 0.43 mol) in THF (200 mL) was added dropwise, and the mixture was stirred at N2 atmosphere from -10 °C to ambient temperature for 1 h. At -10 °C, a solution of (2S)-2-[(tert-butyldimethylsilyl)oxy]propionaldehyde (120.0 g, 0.64 mol) in THF (200 mL) was added dropwise, and the mixture was stirred from -10 °C to 0 °C for 2 h. The reaction mixture was poured into sat.NH4Cl (1 L) and extracted with EtOAc (2 x 500 mL). The combined EtOAc phases were washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1 to 30 / 1 to 20 / 1) to give the product (70.0 g, 37%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ: 4.29-4.09 (m, 2H), 4.06-3.88 (m, 2H), 3.79 (d, 1H), 3.60-3.48 (m, 1H), 2.78 (s, 2H), 2.66-2.25 ( m, 1H), 2.24-1.94 (m, 2H), 1.74 (m, 2H), 1.50-1.37 (m, 9H), 1.34-1.18 (m, 5H), 1.12 (d, 3H), 0.91 (s, 10H), 0.04 (s, 6H).

[1184] Step 4: 4-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-1-hydroxypropyl]-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester

[1185] At 0 °C, LiBH4 (2 M, 118 mL, 0.236 mol) was added to a THF solution of 4-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-1-hydroxypropyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (70.0 g, 0.157 mol) in 700 mL of water and stirred at ambient temperature overnight. The mixture was poured into water (500 mL), stirred at ambient temperature for 20 min, extracted with EtOAc (2 x 300 mL), washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain crude product (60.0 g). No purification was required, and it was used in the next step.

[1186] Step 5: 4-[(2S)-1,2-dihydroxypropyl]-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester

[1187] To a cooled (0°C) THF solution of 600 mL of 4-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-1-hydroxypropyl]-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (60.0 g, 0.149 mol), TBAF (1 M, 223 mL, 0.223 mol) was added, and the mixture was stirred at ambient temperature for 2 h. NaHCO3 (aq. 600 mL) was added, and the mixture was stirred at ambient temperature for 10 min. Extraction was performed with EtOAc (2 x 300 mL), washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 50 / 1 to 30 / 1) to obtain the product (37.0 g, 86%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ: 4.02-3.87 (m, 1H), 3.74 (m, 4H), 3.36 (d, 4H), 3.10 (s, 2H), 1.66 (s, 3H), 1.40 (s, 10H), 1.31 (s, 3H).

[1188] Step 6: (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[1189] To a chilled THF (400 mL) solution of tert-butyl 4-[(2S)-1,2-dihydroxypropyl]-4-(hydroxymethyl)piperidin-1-carboxylate (37.0 g, 0.127 mol), NaH (17.8 g, 0.44 mol) was added in portions, followed by a THF (200 mL) solution of TsCl (25.5 g, 0.134 mol). The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into ice and NH4Cl (aq. 600 mL), extracted with EtOAc (3 x 400 mL), washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 50 / 1 to 30 / 1) to give the product (20.0 g, 58%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ: 3.94-3.57 (m, 4H), 3.45 (d, 1H), 2.96 (s, 2H), 1.70 (s, 3H), 1.42 (s, 10H), 1.29 (m, 4H).

[1190] Step 7: (3S)-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[1191] DMP (37.5 g, 0.088 mol) was added in portions to a cold DCM (200 mL) solution of (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (20.0 g, 0.074 mol). The reaction mixture was stirred at ambient temperature for 1 h, poured into NaHCO3 (aq.), extracted with DCM, washed with brine, dried over Na2SO4, and concentrated under vacuum to give the product (19.0 g, 95%) as a yellow oil. This was used directly in the next step.

[1192] Step 8: (3S,4S)-3-methyl-4-[(2-methylpropane-2-sulfinyl)amino]-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[1193] To a THF (250 mL) solution of (3S)-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (11.0 g, 0.04 mol), (R)-2-methylpropane-2-sulfinamide (9.9 g, 0.08 mol) and Ti(OEt)4 (36.5 g, 0.16 mol) were added, and the reaction mixture was stirred overnight at 75 °C. The reaction mixture was cooled to -10 °C, and LiBH4 (2 M, 30 mL, 0.06 mol) was added dropwise, followed by stirring at -10 °C for 1 h. The reaction mixture was poured into ice and NH4Cl (aq. 300 mL) and EtOAc (300 mL), stirred at ambient temperature for 20 min, and then filtered through diatomaceous earth. The reaction mixture was extracted with EtOAc (2 x 300 mL), washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1 to 5 / 1 to 3 / 1 to 2 / 1) to give the product (7.0 g, 47%). 1 H NMR (400MHz, DMSO-d6) δ: 5.07 (d, J=11.0Hz, 1H), 4.06 (s, 1H), 3.74 (m, 3H), 3.37 (d, 3H), 2.84 (s, 2H), 1.69-1.50 (m, 2H), 1.39 (s, 11H), 1.15 (s, 9H), 1.06 (m, 3H).

[1194] Step 9: (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride

[1195] To a solution of (3S,4S)-3-methyl-4-[(2-methylpropane-2-sulfinyl)amino]-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (5.8 g, 15.5 mmol) in MeOH (20 mL), HCl / dioxane (4 M, 39 mL, 155 mmol) was added, and the mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to ambient temperature and concentrated under vacuum. The crude product was dissolved in water (50 mL) and extracted with EtOAc (3 x 40 mL). The aqueous phase was lyophilized to give the HCl salt of the product (4.0 g) as a yellow solid. MS: [M+H] + =171. 1 H NMR (400MHz, DMSO-d6) δ: 4.44 (m, 1H), 4.05-3.88 (m, 2H), 3.67 (s, 1H), 3.58-3.39 (m, 2H), 3.22-3.01 (m, 2H), 1.98 (m, 4H), 1.34 (s, 3H).

[1196] Preparation of 52: N-((1R,3S)-3-hydroxy-8-azaspiro[4.5]decane-1-yl)-2-methylpropane-2-sulfinyl amine

[1197] [Chemical Formula 86]

[1198]

[1199] Step 1: 4-Formyl-4-(prop-2-en-1-yl)piperidin-1-carboxylic acid tert-butyl ester

[1200] A THF (3 L) solution of tert-butyl 4-formylpiperidin-1-carboxylate (300.0 g, 1.40 mol) was cooled to -25 °C, and allyl bromide (187.7 g, 1.55 mol) was added. Then, t-BuOK (173.0 g, 1.55 mol) was added in portions, and the mixture was stirred at -25 °C to -15 °C for 45 min. The reaction mixture was poured into ice and NH4Cl (aq. 3 L), extracted with EtOAc (2 x 2 L), washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1 to 20 / 1 to 10 / 1) to give the product (210.0 g, 60%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ: 9.48 (s, 1H), 5.58 (s, 1H), 5.03 (s, 2H), 3.76 (s, 2H), 2.90 (s, 2H), 2.21 (s, 2H), 1.89 (s, 2H), 1.43 (s, 9H).

[1201] Step 2: 4-(1-hydroxypropyl-2-en-1-yl)-4-(propyl-2-en-1-yl)piperidin-1-carboxylic acid tert-butyl ester

[1202] A THF solution (2.5 L) of tert-butyl 4-formyl-4-(prop-2-en-1-yl)piperidin-1-carboxylate (250.0 g, 0.99 mol) was cooled to -60 °C, and vinyl magnesium bromide (1.18 L, 1.18 mol) was added. The mixture was then stirred at ambient temperature for 1 h. The mixture was poured into NH4Cl (aq. 3 L), extracted with EtOAc (2 x 2 L), washed with brine, and dried over Na2SO4 to give the product (270.0 g, 97%) as a brown oil. 1 H NMR (400MHz, CDCl3) δ: 6.00-5.78 (m, 2H), 5.28-5.15 (m, 2H), 5.11-4.99 (m, 2H), 3.98 (d, 1H), 3.79-3 .56(m, 2H), 3.09(s, 2H), 2.24(ddd, 7.5Hz, 2H), 1.86(d, 1H), 1.65-1.49(m, 2H), 1.45-1.38(m, 11H).

[1203] Step 3: 4-(prop-2-en-1-yl)-4-(prop-2-enyl)piperidin-1-carboxylic acid tert-butyl ester

[1204] A solution of tert-butyl 4-(1-hydroxypropyl-2-en-1-yl)-4-(propyl-2-en-1-yl)piperidin-1-carboxylic acid (286.0 g, 1.01 mol) in DCM (1.5 L) was cooled to 0 °C, and DMP (471.0 g, 1.1 mol) was added. The mixture was stirred at ambient temperature for 2 h. The reaction mixture was poured into NaHCO3 / Na2SO3 (1:1, 2 L) and extracted with DCM (1 L). The combined DCM phases were washed with brine, dried over Na2SO4, and concentrated under vacuum to give a crude product (840.0 g) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ: 6.88-6.70 (m, 1H), 6.37 (d, 1H), 5.68 (d, 1H), 5.55 (d, 1H) , 5.02(t, 2H), 3.74(s, 2H), 2.93(s, 2H), 2.28(s, 2H), 2.06(s, 2H), 1.43(s, 11H).

[1205] Step 4: tert-butyl 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate

[1206] To a toluene (3 L) solution of tert-butyl 4-(prop-2-en-1-yl)-4-(prop-2-enoyl)piperidin-1-carboxylate (256.0 g, 0.91 mol), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinediyl](benzylidene)(tricyclohexylphosphine)ruthenium(II) (31.1 g, 0.037 mol) was added, and the mixture was stirred at 85 °C for 3 h. The reaction mixture was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1 to 30 / 1 to 15 / 1) to give the product (370.0 g) as a brown solid. 1 H NMR (400MHz, CDCl3) δ: 7.64 (s, 1H), 6.16 (s, 1H), 4.08 (s, 2H), 2.90 (s, 2H), 2.60 (s, 2H), 1.72 (m, 2H), 1.46 (s, 9H), 1.25 (s, 2H).

[1207] Step 5: (3R)-3-hydroxy-1-oxo-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[1208] A mixture of CuCl (1.55 g, 0.0156 mol), (S)-TolBINAP (10.6 g, 0.0156 mol), and t-BuONa (1.5 g, 0.0156 mol) in THF (900 mL) was stirred at ambient temperature for 30 min. A solution of bis(pinacol)diboron (145.3 g, 0.572 mol) in THF (400 mL) was added, and the mixture was stirred at ambient temperature for 15 min. A solution of 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylic acid tert-butyl ester (130.0 g, 0.52 mol) in THF (200 mL) and MeOH (33.3 g, 1.04 mol) was added, and the reaction mixture was stirred at ambient temperature overnight. Water (1.6 L) and NaBO3 (400.0 g, 2.6 mol) were added, and the reaction mixture was stirred at ambient temperature for 1 h. The mixture was filtered, extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1 to 10 / 1 to 3 / 1) to give the product (100.0 g, 71%) as a brown solid. 1 H NMR (400MHz, CDCl3) δ: 4.61 (s, 1H), 3.88 (s, 2H), 3.03 (m, 2H), 2.65 (s, 1H), 2.38 (s, 1H), 2.19 (s, 3H), 1.73 (m, 4H), 1.44 (s, 9H).

[1209] Step 6: (3R)-3-[(tert-butyldimethylsilyl)oxy]-1-oxo-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[1210] To a DMF (1.0 L) solution of (3R)-3-hydroxy-1-oxo-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (110.0 g, 0.4 mol), imidazole (41.0 g, 0.6 mol) and TBSCl (73.3 g, 0.48 mol) were added, and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was poured into water (5 L), extracted with EtOAc (2 x 2 L), washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1 to 10 / 1 to 3 / 1) to give the product (120.0 g, 78%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ: 4.49 (s, 1H), 3.88 (s, 2H), 2.97 (s, 2H), 2.52 (s, 1H), 2 .21(s, 2H), 2.06(s, 2H), 1.66(s, 4H), 1.43(s, 9H), 0.87(s, 9H), 0.03(s, 6H).

[1211] Step 7: (1R,3R)-3-[(tert-butyldimethylsilyl)oxy]-1-[(2-methylpropane-2-sulfinyl)amino]-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[1212] To a THF (1.3 L) solution of (3R)-3-[(tert-butyldimethylsilyl)oxy]-1-oxo-8-azaspiro[4.5]decane-8-carboxylate (80.0 g, 0.2 mol), (R)-2-methylpropane-2-sulfinamide (50.6 g, 0.4 mol) and Ti(OEt)4 (182.5 g, 0.8 mol) were added, and the mixture was stirred overnight at 65 °C. The reaction mixture was cooled to -60 °C, and LiBH4 (2 M, 300 mL, 0.6 mol) was added dropwise, followed by stirring overnight at -60 °C. The reaction mixture was poured into NH4Cl (aq. 2 L), extracted with EtOAc (2 x 1 L), washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1 to 3 / 1) to give the product (120.0 g) as a yellow oil. ¹H NMR (400 MHz, CDCl3) δ: 4.30 (s, 1H), 3.94 (s, 2H), 3.58 (s, 1H), 3.28 (s, 1H), 2.82 (s, 2H), 2.30 (s, 1H), 1.76 (m, 7H), 1.38 (s, 9H), 1.19 (s, 9H), 0.85 (s, 9H), 0.01 (s, 6H).

[1213] Step 8: (1R,3R)-3-hydroxy-1-[(2-methylpropane-2-sulfinyl)amino]-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[1214] To a solution of (1R,3R)-3-[(tert-butyldimethylsilyl)oxy]-1-[(2-methylpropane-2-sulfinyl)amino]-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (135.0 g, 0.276 mol) in THF (800 mL), TBAF (553 mL, 0.553 mol) was added, and the mixture was stirred at ambient temperature for 4 h. The reaction mixture was poured into water (1 L), extracted with EtOAc (2 x 500 mL), washed with brine, dried over Na2SO4, and concentrated under vacuum to give a crude product (100.0 g, 97%) as a yellow oil. No purification was required, and it was used in the next step. 1 H NMR (400MHz, DMSO-d6) δ: 5.05 (s, 1H), 4.67 (s, 1H), 4.04 (s, 1H), 3.82 (s, 2H), 3.05 (s, 1 H), 2.74 (br, s, 2H), 2.10 (m, 1H), 1.67 (m, 4H), 1.42 (m, 11H), 1.24 (s, 2H), 1.09 (m, 9H).

[1215] Step 9: (1R,3S)-3-(isoquinoline-1-carbonyloxy)-1-[(2-methylpropane-2-sulfinyl)amino]-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[1216] To a THF (1 L) solution of (1R,3R)-3-hydroxy-1-[(2-methylpropane-2-sulfinyl)amino]-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (120.0 g, 0.32 mol), isoquinoline-1-carboxylic acid (166.6 g, 0.96 mol), DIAD (97.1 g, 0.48 mol), and TPP (125.9 g, 0.48 mol) were added, and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was poured into NaHCO3 (aq. 2 L), extracted with EtOAc (2 x 1 L), washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain a crude product. This crude product was purified by silica gel column chromatography (DCM / EtOAc = 50 / 1 to 20 / 1 to DCM / MeOH = 20 / 1) to obtain a product (120.0 g, 71%) as a yellow solid. MS: [M+H] + =530. 1 H NMR (400MHz, DMSO-d6) δ: 8.59 (s, 1H), 8.40 (s, 1H), 8.04 (s, 2H), 7.83 (d, 2H), 5.48 (s, 1H), 5.23 (s, 1H), 3.85 (s, 2H), 3.50 ( s, 1H), 2.77 (s, 2H), 2.49-2.38 (m, 1H), 2.14 (d, 2H), 1.73 (s, 2H), 1.47 (s, 1H), 1.38 (s, 9H), 1.25 (s, 3H), 1.15-1.11 (m, 9H).

[1217] Step 10: (1R,3S)-3-hydroxy-1-[(2-methylpropane-2-sulfinyl)amino]-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[1218] To a solution of (1R,3S)-3-(isoquinoline-1-carbonyloxy)-1-[(2-methylpropane-2-sulfinyl)amino]-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (120.0 g, 0.227 mol) in THF / H2O (1 / 1, 1 L), LiOH·H2O (92.9 g, 2.27 mol) was added, and the mixture was stirred at ambient temperature for 2 h. The reaction mixture was poured into NH4Cl (aq. 2 L), extracted with EtOAc (2 x 1 L), washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain a crude product. This crude product was crystallized from EtOAc / hexane to give a product (64.0 g, 75%) as a white solid. MS: [M+H-Boc] + =275. 1 H NMR (400MHz, DMSO-d6) δ: 4.97 (s, 1H), 4.51 (s, 1H), 4.06 (s, 1H), 3.82 (s, 2H), 3.39 (s, 1H) ), 2.74(s, 2H), 1.99(s, 1H), 1.81(s, 3H), 1.39(s, 11H), 1.28-1.16(m, 1H), 1.11(s, 9H).

[1219] Step 11: N-[(1R,3S)-3-hydroxy-8-azaspiro[4.5]decane-1-yl]-2-methylpropane-2-sulfinamide

[1220] TFA (195.3 g, 1.71 mol) was added to a DCM solution of (1R,3S)-3-hydroxy-1-[(2-methylpropane-2-sulfinyl)amino]-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (64.0 g, 0.171 mol) in 600 mL, and the mixture was stirred at ambient temperature for 2 h. The reaction mixture was poured into water (2 L), extracted with Et2O (5 x 300 mL) to remove impurities, and then the pH was adjusted to pH 8 with NaHCO3 (aq.). The water was freeze-dried to give the product (50.0 g) as a colorless oil. MS: [M+H] + =275. 1 H NMR (400MHz, DMSO-d6) δ: 5.13 (d, 1H), 4.83 (br, s, 3H), 4.08 (s, 1H), 3.44 (m, 1H), 3 .15(m, 2H), 2.78(m, 2H), 2.01-1.64(m, 4H), 1.40(m, 2H), 1.25(m, 1H), 1.15(s, 9H).

[1221] Preparation of 53: 5-bromo-4-chloro-2-methyl-2H-indazole

[1222] [Chemical Formula 87]

[1223]

[1224] Trimethyloxonium tetrafluoroborate (9.58 g, 64.8 mmol) was added to a suspension of 5-bromo-4-chloro-1H-indazole (10.0 g, 43.2 mmol) in EtOAc (200 mL) under RT. The mixture was stirred at RT for 20 h, quenched with sat. NaHCO3, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0–50% EtOAc / hexane) to give the title compound (9.16 g). MS: [M+H] + =245, 247.

[1225] Preparation of 54: 5-bromo-4-chloro-2-ethyl-2H-indazole

[1226] [Chemical Formula 88]

[1227]

[1228] Triethyloxonium hexafluorophosphate (8.04 g, 32.4 mmol) was added to a suspension of 5-bromo-4-chloro-1H-indazole (5.0 g, 21.6 mmol) in EtOAc (100 mL) under RT. The mixture was stirred overnight at RT, quenched with sat. NaHCO3, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0–50% EtOAc / hexane) to give the title compound (5.05 g). MS: [M+H] + =259,261.

[1229] Preparation of 55: 5-bromo-2-(tert-butyl)-4-chloro-2H-indazole

[1230] [Chemical Formula 89]

[1231]

[1232] Under RT, tert-butyl acetate (4.7 g, 40 mmol) and methanesulfonic acid (0.38 g, 4.0 mmol) were added to a toluene suspension (8.0 mL) of 5-bromo-4-chloro-1H-indazole (0.93 g, 4.0 mmol).

[1233] The mixture was stirred at 95 °C for 1 day. Tert-butyl acetate (4.7 g, 40 mmol) and methanesulfonic acid (0.38 g, 4.0 mmol) were added to the mixture, and the mixture was stirred for another 1 day. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0–20% EtOAc / hexane) to give the title compound (1.1 g). MS: [M+H] + =287, 289.

[1234] Preparation of 56: 5-bromo-2-methyl-2H-indazole

[1235] [Chemical Formula 90]

[1236]

[1237] The title compound was prepared from 5-bromo-1H-indazole using a similar method to that used for 5-bromo-4-chloro-2-methyl-2H-indazole. MS: [M+H] + =211, 213.

[1238] Preparation of 57: 5-bromo-4-fluoro-2-methyl-2H-indazole

[1239] [Chemical Formula 91]

[1240]

[1241] The title compound was prepared from 5-bromo-4-fluoro-1H-indazole using a similar method to that used for 5-bromo-4-chloro-2-methyl-2H-indazole. MS: [M+H] + =229,231.

[1242] Preparation of 58: 5-bromo-6-fluoro-2-methyl-2H-indazole

[1243] [Chemical Formula 92]

[1244]

[1245] The title compound was prepared from 5-bromo-6-fluoro-1H-indazole using a similar method to that used for 5-bromo-4-chloro-2-methyl-2H-indazole. MS: [M+H] + =229,231.

[1246] Preparation of 59: 5-bromo-4-methoxy-2-methyl-2H-indazole

[1247] [Chemical Formula 93]

[1248]

[1249] The title compound was prepared from 5-bromo-4-methoxy-1H-indazole using a similar method to that used for 5-bromo-4-chloro-2-methyl-2H-indazole. MS: [M+H] + =241, 243.

[1250] Preparation of 60: 1-(5-bromo-4-chloro-2H-indazol-2-yl)-2-methylpropane-2-ol

[1251] [Chemical Formula 94]

[1252]

[1253] Under RT, K₂CO₃ (1.19 g, 8.64 mmol) and isobutylene oxide (0.58 mL, 6.48 mmol) were added to a DMF solution (10 mL) of 5-bromo-4-chloro-1H-indazole (1.0 g, 4.32 mmol). The mixture was stirred at 100 °C for 2 h, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 10–20% EtOAc / hexane) to give the title compound (0.55 g). MS: [M+H] + =303, 305.

[1254] Preparation of 61: 5-bromo-4-chloro-2,7-dimethyl-2H-indazole

[1255] [Chemical Formula 95]

[1256]

[1257] Under RT, tert-butyl nitrite (2.5 g, 25 mmol) was added to a mixture of 4-bromo-3-chloro-2,6-dimethylaniline (4.8 g, 20 mmol), potassium acetate (3.1 g, 31 mmol), acetic acid (1.8 g, 29 mmol), and toluene (61 mL). The mixture was stirred overnight at 45 °C. EtOAc (40 mL) and 1 M NaOH aq. (40 mL) were added to the mixture. The separated organic layer was washed with brine and concentrated under vacuum. The residue was suspended in toluene and heptane. The precipitate was collected and dried under reduced pressure at 50 °C to give a mixture of 5-bromo-4-chloro-7-methyl-1H-indazole and 5-bromo-6-chloro-7-methyl-1H-indazole (3.4 g). MS: [M+H] + =245, 247.

[1258] The title compound was prepared from a mixture of 5-bromo-4-chloro-2-methyl-2H-indazole using a similar method to that used for 5-bromo-4-chloro-7-methyl-1H-indazole. MS: [M+H]+ =259,261

[1259] Preparation of 62: 5-bromo-3,4-dichloro-2-methyl-2H-indazole

[1260] [Chemical Formula 96]

[1261]

[1262] At 0 °C, NCS (2.99 g, 22.4 mmol) was added to a DMF solution (50 mL) of 5-bromo-4-chloro-2-methyl-2H-indazole (5 g, 20.3 mmol). The mixture was stirred overnight at RT. Water (150 mL) was added at RT. The mixture was stirred at RT for 1 h. The precipitate was collected, washed with water, and dried under reduced pressure at 60 °C for 3 h to give the title compound (5.63 g). MS: [M+H] + =279,281.

[1263] Preparation of 63: 5-bromo-4-chloro-2,3-dimethyl-2H-indazole

[1264] [Chemical Formula 97]

[1265]

[1266] At -78 °C, LDA (1.08 M THF solution, 2.26 mL, 2.44 mmol) was added to 10 mL of a THF solution of 5-bromo-4-chloro-2-methyl-2H-indazole (500 mg, 2.03 mmol). The mixture was stirred at 0 °C for 30 min and then cooled to -78 °C. Iodomethane (0.190 mL, 3.05 mmol) was added at -78 °C. The mixture was stirred at -78 °C for 2 h, quenched with sat.NH4Cl, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-60% EtOAc / hexane) to give the title compound (442 mg). MS: [M+H] + =259,261.

[1267] Preparation of 64: 2-(5-bromo-4-chloro-2H-indazol-2-yl)-M,N-dimethylacetamide

[1268] [Chemical Formula 98]

[1269]

[1270] Step 1

[1271] At RT, DMEAD (759 mg, 3.24 mmol) and triphenylphosphine (850 mg, 3.24 mmol) were added to a THF (10 mL) solution of 5-bromo-4-chloro-1H-indazole (500 mg, 2.16 mmol) and methyl glycolate (0.25 mL, 3.24 mmol). The mixture was stirred at RT for 2 h. The reaction solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (gradient elution, 20–40% EtOAc / hexane) to give methyl 2-(5-bromo-4-chloro-2H-indazole-2-yl)acetate (190 mg). MS: [M+H] + =303, 305.

[1272] Step 2

[1273] At RT, an aqueous solution of LiOH (90 mg, 3.76 mmol) in 0.95 mL was added to a THF solution of methyl 2-(5-bromo-4-chloro-2H-indazol-2-yl)acetate (190 mg, 0.63 mmol) in 1.9 mL. The mixture was stirred at RT for 20 min, diluted with MTBE, and 2 M NaOH was added. The aqueous layer was added with 6 M HCl and extracted three times with CHCl3. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give 2-(5-bromo-4-chloro-2H-indazol-2-yl)acetic acid (140 mg). MS: [M+H] + =289,291.

[1274] Step 3

[1275] Under RT, TEA (0.27 mL, 1.93 mmol), HATU (276 mg, 0.73 mmol), and dimethylamine hydrochloride (59 mg, 0.73 mmol) were added to a solution of 2-(5-bromo-4-chloro-2H-indazol-2-yl)acetic acid (140 mg, 0.48 mmol) in THF (1.4 mL). The mixture was stirred at 50 °C for 1 h. The reaction solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (gradient elution, 40–100% EtOAc / hexane) to give the title compound (125 mg). MS: [M+H] + =316, 318.

[1276] Preparation of 65: 6-bromo-7-chloro-2,3-dihydro-1,3-benzothiazol-2-thione

[1277] [Chemical Formula 99]

[1278]

[1279] A DMF solution (100 mL) of a mixture of 4-bromo-2,3-dichloroaniline (10.0 g, 41.5 mmol) and potassium ethyl xanthate (15.0 g, 93.4 mmol) was stirred at 120 °C for 18 h. The mixture was quenched with 2 M aq HCl (80 mL) and water (400 mL). The mixture was filtered and washed with water to give the title compound (1.13 g). 1 H-NMR (400MHz, DMSO-d6) δ: 14.10 (1H, s), 7.78 (1H, d), 7.19 (1H, d).

[1280] Preparation of 66: 6-bromo-7-chloro-1,3-benzothiazole

[1281] [Chemical Formula 100]

[1282]

[1283] A round-bottom flask packed with 6-bromo-7-chloro-2,3-dihydro-1,3-benzothiazol-2-thione (1.13 g, 40.3 mmol), iron powder (12.4 g, 221.5 mmol), and acetic acid (200 mL) was stirred at 120 °C (with a mechanical stirrer) for 2 h. Then, iron powder (24.8 g, 443.0 mmol) was added, and the mixture was stirred at 120 °C for 2 h. Further iron powder (12.4 g, 221.5 mmol) was added, and the reaction was stirred at 120 °C for 15 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by recrystallization from EtOAc followed by silica gel column chromatography (10% EtOAc / Petrol) to give the title compound (0.27 g). MS: [M+H] + =248.

[1284] Preparation of 67: N-(4-bromo-3-chloro-2-fluorophenyl)acetamide

[1285] [Chemical Formula 101]

[1286]

[1287] After 1.5 h, acetic anhydride (11.05 mL, 117 mmol) was added to DCM (250 mL) containing 25 g (111 mmol) of 4-bromo-3-chloro-2-fluoroaniline and 48.5 mL (278 mmol) of DPEA, which was cooled in an ice bath. The reaction mixture was heated to RT and stirred for 24 h. The mixture was washed with HCl (1 M, 250 mL), NaHCO3 (150 mL), and water (100 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution, 0-40% EtOAc / Petrol) to give the title compound (23.8 g). 1 H-NMR (500MHz, DMSO-d6) δ: 9.97 (s, 1H), 7.95-7.77 (m, 1H), 7.56 (dd, 1H), 2.10 (s, 3H).

[1288] Preparation of 68: 6-bromo-7-chloro-2-methyl-1,3-benzothiazole

[1289] [Chemical Formula 102]

[1290]

[1291] Lawrence's reagent (1.53 g, 2.26 mmol) was added to a xylene (9.86 mL) solution of N-(4-bromo-3-chloro-2-fluorophenyl)acetamide (1.0 g, 3.77 mmol). The reaction mixture was heated to 110 °C and maintained for 18 h. Cesium carbonate (4.11 g, 7.55 mmol) was added, and the mixture was stirred at 110 °C for 18 h. The reaction mixture was cooled to RT and diluted with water (500 mL) and ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution, 0–20% EtOAc / Petrol) to give the title compound (0.97 g). 1 H-NMR (400MHz, DMSO-d6) δ: 7.85 (2H, d), 2.83 (3H, s).

[1292] Preparation of 69: 6-bromo-7-chloro-2-ethylbenzo[d]thiazole

[1293] [Chemical Formula 103]

[1294]

[1295] The title compound was prepared from propionyl chloride using a similar method to that used for 6-bromo-7-chloro-2-methyl-1,3-benzothiazole. MS: [M+H] +=211, 213.

[1296] Preparation of 70: 2-(6-bromo-7-chlorobenzo[d]thiazolyl-2-yl)-N,N-dimethylacetamide

[1297] [Chemical Formula 104]

[1298]

[1299] Step 1

[1300] Under RT, TEA (5.58 mL, 40.1 mmol) and 3-tert-butoxy-3-oxopropionic acid (3.09 mL, 20.0 mmol) were added to a DMA (30 mL) solution of 4-bromo-3-chloro-2-fluoro-aniline (3 g, 13.4 mmol) and HATU (10.2 g, 26.7 mmol). The mixture was stirred at 50 °C for 1 h, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 30–70% EtOAc / hexane) to give tert-butyl 3-(4-bromo-3-chloro-2-fluoro-phenylamino)-3-oxopropionic acid (3.35 g).

[1301] Step 2

[1302] At RT, Lawson's reagent (1.32 g, 3.27 mmol) was added to a toluene suspension (20 mL) of tert-butyl 3-(4-bromo-3-chloro-2-fluoro-phenylamino)-3-oxo-propionate (2 g, 5.47 mmol). The mixture was stirred at 110 °C for 3 h. Cs₂CO₃ (3.56 g, 10.9 mmol) was added. The mixture was stirred at 110 °C for 19 h, cooled to RT, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0–20% EtOAc / CHCl₃) to give tert-butyl 2-(6-bromo-7-chlorobenzo[d]thiazol-2-yl)acetate (983 mg).

[1303] Step 3

[1304] Under RT, TFA (2.5 mL, 32 mmol) was added to a CHCl3 solution (500 mg, 1.38 mmol) of tert-butyl 2-(6-bromo-7-chlorobenzo[d]thiazol-2-yl)acetate (500 mg, 1.38 mmol). The mixture was stirred at 60 °C for 1 h. The reaction solution was concentrated under vacuum, and the residue was suspended in hexane. The precipitate was collected, washed with hexane, and dried under reduced pressure at 60 °C for 3 h to give 2-(6-bromo-7-chlorobenzo[d]thiazol-2-yl)acetic acid (200 mg). MS: [M+H] + =306, 308.

[1305] Step 4

[1306] At RT, TEA (0.45 mL, 3.26 mmol), propylphosphonic anhydride (1.6 M THF solution, 0.82 mL, 1.30 mmol), and dimethylamine (2.0 M THF solution, 0.65 mL, 1.30 mmol) were added to a solution of 2-(6-bromo-7-chlorobenzo[d]thiazol-2-yl)acetic acid (200 mg, 0.65 mL, 1.30 mmol) in 4 mL of THF. The mixture was stirred at RT for 10 min. The reaction solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (gradient elution, 80–100% EtOAc / hexane) to give the title compound (168 mg). MS: [M+H] + =333, 335.

[1307] Preparation of 71: N-(4-bromo-3-chloro-2-hydroxyphenyl)acetamide

[1308] [Chemical Formula 105]

[1309]

[1310] A suspension of N-(4-bromo-3-chloro-2-fluoro-phenyl)acetamide (1.0 g, 3.8 mmol), cesium carbonate (2.0 equivalent, 7.5 mmol), and NMP (6.0 mL) was irradiated in a microwave initiator (Biotage) at 150 °C for 5 h. NMP (15 mL) was added to the mixture, and the mixture was then irradiated in a microwave initiator at 150 °C for another 5 h. The reaction mixture was diluted with EtOAc and water, and acidified with 5N HCl aqueous solution to adjust the pH to 1–2. The mixture was extracted with EtOAc (X3), and the organic extract was washed with brine and dried over Na2SO4. The crude mixture (1.20 g, brown oil) was concentrated and purified by column chromatography (gradient elution, 5–70% EtOAc / hexane) to give the title compound (425 mg, 1.61 mmol, 43% yield) as a yellow solid. MS: [M+H] + =264,266.

[1311] Preparation of 72: 6-bromo-7-chloro-2-methylbenzo[d]oxazole

[1312] [Chemical Formula 106]

[1313]

[1314] To a THF solution (30 mL) of N-(4-bromo-3-chloro-2-hydroxyphenyl)acetamide (1.09 g, 4.12 mmol) and triphenylphosphine (1.62 g, 6.18 mmol), diisopropyl azodicarbonate (1.21 mL, 6.18 mmol) was added, and the mixture was heated in an oil bath at 50 °C for 2 h 45 min. The reaction mixture was concentrated to give a crude oil (4.30 g, brown oil), which was purified by column chromatography (gradient elution, 5-70% EtOAc / hexane), then suspended in hexane and collected by filtration to give the title compound (908 mg, 3.68 mmol, 89% yield) as a colorless solid. MS: [M+H] + =246, 248.

[1315] Preparation of 73: N-(4-bromo-3-chloro-2-fluorophenyl)propionamide

[1316] [Chemical Formula 107]

[1317]

[1318] At 0 °C, TEA (2.0 equivalent, 44.6 mmol) and propionyl chloride (2.34 mL, 26.7 mmol) were added to a DCM (40 mL) solution of 4-bromo-3-chloro-2-fluoroaniline (5.00 g, 22.3 mmol). The ice-water bath was removed, and the mixture was stirred at RT for 17 h. At RT, propionyl chloride (0.779 mL, 8.92 mmol) was added to the mixture. After stirring at RT for 45 min, water was added to the mixture. The mixture was extracted with EtOAc (X2), and the organic extract was washed with water, dilute NH4Cl aqueous solution, NaHCO3aq., and brine, and dried over Na2SO4. The concentrated crude mixture was suspended in hexane-EtOAc (4 / 1) and collected by Kiriyama-roshi (No. 4) to give the title compound (4.22 g, 15.0 mmol, yield 67%) as a colorless needle. The filtrate (orange solid, 2.23 g) was purified by column chromatography (gradient elution, 5–40% EtOAc / hexane) to give the title compound (1.33 g, 4.74 mmol, 21% yield) as a colorless needle-like substance. MS: [M+H] + =280, 282.

[1319] Preparation of 74: N-(4-bromo-3-chloro-2-hydroxyphenyl)propionamide

[1320] [Chemical Formula 108]

[1321]

[1322] A suspension of N-(4-bromo-3-chloro-2-fluoro-phenyl)propionamide (2.50 g, 8.91 mmol) and cesium carbonate (5.80 g, 17.8 mmol) in NMP (15 mL) was irradiated in a microwave initiator (Biotage) at 150 °C for 5 h. NMP (15 mL) was added to the mixture, and the mixture was irradiated again in a microwave initiator at 150 °C for 5 h. The reaction mixture was diluted with EtOAc and water, and acidified with 5N HCl aqueous solution to adjust the pH to 1–2. The mixture was extracted with EtOAc (X3), and the organic extract was washed with brine and dried over Na2SO4. The crude mixture (5.90 g, brown oil) was concentrated and purified by column chromatography (gradient elution, 5–100% EtOAc / hexane) to give the title compound (1.27 g, 4.56 mmol, 51% yield). MS: [M+H] + =278, 280.

[1323] Preparation of 75: 6-bromo-7-chloro-2-ethylbenzo[d]oxazole

[1324] [Chemical Formula 109]

[1325]

[1326] To a solution of N-(4-bromo-3-chloro-2-hydroxyphenyl)propionamide (607 mg, 2.18 mmol) and triphenylphosphine (857 mg, 3.27 mmol) in THF (10 mL), diisopropyl azodicarbonate (0.642 mL, 3.27 mmol) was added, and the mixture was heated in an oil bath at 50 °C for 1 h 45 min. The reaction mixture was concentrated to give a crude oil (2.38 g, brown oil), which was purified by column chromatography (gradient elution, 5-50% EtOAc / hexane) to give the title compound (525 mg, 2.02 mmol, 92% yield) as a pale yellow solid. MS: [M+H] + =260, 262.

[1327] Preparation of 76: 6-bromo-7-chloro-1-methyl-1H-benzo[d][1,2,3]triazole

[1328] [Chemical Formula 110]

[1329]

[1330] At RT, triphenylphosphine (542 mg, 2.06 mmol), MeOH (0.084 mL, 2.06 mmol), and DMEAD (484 mg, 2.06 mmol) were added to a THF (8 mL) solution of 6-bromo-7-chloro-1H-benzo[d][1,2,3]triazole (400 mg, 1.72 mmol). The mixture was stirred at RT for 2 h. The reaction solution was then concentrated under vacuum, and the residue was purified by silica gel column chromatography (gradient elution, 10–40% EtOAc / hexane). The fraction containing the target product was collected and concentrated under vacuum. The residue was purified by NH silica gel column chromatography (gradient elution, 0–20% EtOAc / hexane) to give the title compound (152 mg). 1 H-NMR (CDCl3) δ: 7.82 (1H, d, J = 8.8Hz), 7.58 (1H, d, J = 8.8Hz), 4.57 (3H, s). MS: [M+H] + =246, 248.

[1331] Preparation of 77: 5-bromo-4-chloro-2-methyl-2H-benzo[d][1,2,3]triazole

[1332] [Chemical Formula 111]

[1333]

[1334] At RT, triphenylphosphine (542 mg, 2.06 mmol), MeOH (0.084 mL, 2.06 mmol), and DMEAD (484 mg, 2.06 mmol) were added to an 8 mL THF solution of 6-bromo-7-chloro-1H-benzo[d][1,2,3]triazole (400 mg, 1.72 mmol). The mixture was stirred at RT for 2 h. The reaction solution was then concentrated under vacuum, and the residue was purified by silica gel column chromatography (gradient elution, 10–40% EtOAc / hexane). The fraction containing the target product was collected and concentrated under vacuum. The residue was purified by NH silica gel column chromatography (gradient elution, 0–20% EtOAc / hexane) to give the title compound (160 mg). 1 H-NMR (CDCl3) δ: 7.66 (1H, d, J = 9.0Hz), 7.57 (1H, d, J = 9.0Hz), 4.54 (3H, s). MS: [M+H] + =246, 248.

[1335] Preparation of 78: 5-bromo-3-chloro-4-fluoro-2-methyl-2H-indazole

[1336] [Chemical Formula 112]

[1337]

[1338] The title compound was prepared from 5-bromo-4-fluoro-2-methyl-2H-indazole using a similar method. MS: [M+H] + =263, 265.

[1339] Preparation of 79: 5-bromo-4-chloro-2-ethyl-2H-indazole-3-carboxaldehyde

[1340] [Chemical Formula 113]

[1341]

[1342] At -78 °C, LDA (1.08 M hexane-THF solution, 5.8 mL, 6.3 mmol) was added to a THF solution of 5-bromo-4-chloro-2-ethyl-2H-indazole (1.1 g, 4.1 mmol) in 8.3 mL of THF. The mixture was stirred at 0 °C for 30 min. N,N-dimethylformamide (0.61 g, 8.3 mmol) was added at 0 °C. The mixture was stirred overnight at RT, quenched with sat. NH4Cl aq., and extracted with EtOAc. The organic layer was washed with brine and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-40% EtOAc / hexane) to give the title compound (772 mg). MS: [M+H] + =287, 289.

[1343] Preparation of 80: 5-bromo-4-chloro-2-ethyl-3-methoxy-2H-indazole

[1344] [Chemical Formula 114]

[1345]

[1346] At -78°C, LDA (1.08 M THF solution, 2.14 mL, 2.31 mmol) was added to a THF solution of 5-bromo-4-chloro-2-ethyl-2H-indazole (500 mg, 1.92 mmol) in 10 mL of THF. The mixture was stirred at 0°C for 30 min. N-fluorobenzenesulfonamide (850 mg, 2.69 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 h, quenched with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-60% EtOAc / hexane) to give 5-bromo-4-chloro-2-ethyl-3-fluoro-2H-indazole (185 mg). MS: [M+H] + =277, 279.

[1347] At RT, NaOMe (28% MeOH solution, 0.472 mL, 1.97 mmol) was added to a THF (3 mL) solution of 5-bromo-4-chloro-2-ethyl-3-fluoro-2H-indazole (183 mg, 0.659 mmol). The mixture was stirred at 60 °C for 4 h, cooled to RT, poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-60% EtOAc / hexane) to give the title compound (166 mg). MS: [M+H] + =289,291.

[1348] Preparation of 81: 5-bromo-3,4-dichloro-2-(fluoromethyl)-2H-indazole

[1349] [Chemical Formula 115]

[1350]

[1351] A mixture of 5-bromo-4-chloro-1H-indazole (1.00 g, 4.32 mmol), p-fluoromethyl toluenesulfonate (0.970 g, 4.75 mmol), Cs₂CO₃ (1.68 g, 5.18 mmol), and NMP (10 mL) was stirred at 60 °C for 11 h, cooled to RT, poured into water, and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-60% EtOAc / hexane) to give 5-bromo-4-chloro-2-(fluoromethyl)-2H-indazole (346 mg). MS: [M+H] + =263, 265.

[1352] At 0 °C, NCS (210 mg, 1.57 mmol) was added to a DMF (4 mL) solution of 5-bromo-4-chloro-2-(fluoromethyl)-2H-indazole (378 mg, 1.43 mmol). The mixture was stirred at RT for 44 h. NCS (40 mg, 0.299 mmol) was added at RT. The mixture was stirred at RT for 24 h, poured into water, and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 10–35% EtOAc / hexane) to give the title compound (401 mg). MS: [M+H] + =297,299.

[1353] Preparation of 82: 4-chloro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-2H-indazole

[1354] [Chemical Formula 116]

[1355]

[1356] A solution (12.14 g, 49.45 mmol) of a complex of 5-bromo-4-chloro-2-methyl-2H-indazole (12.14 g, 49.45 mmol), bis(pinacolyl)diboron (18.83 g, 74.18 mmol), [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) with dichloromethane (4.038 g, 4.945 mmol), and potassium acetate (9.706 g, 98.90 mmol) in 1,4-dioxane (120 mL) was degassed, packed with nitrogen, and stirred at 120 °C for 5 h. The reaction mixture was cooled to RT, filtered through a diatomaceous earth mat, and washed with EtOAc. The filtrate was concentrated under vacuum. The residue was purified by NH4Cl column chromatography (gradient elution, 0-70% EtOAc / hexane) to give the title compound (14.36 g). MS: [M+H] + =293,295.

[1357] Using a method similar to that described in Preparation 82, the compounds in Table 1 below are prepared starting from suitable substituted aryl halides (synthesized as described above, with any significant variations shown below).

[1358] Table 1

[1359]

[1360]

[1361]

[1362] Preparation of 83: 2-(3,4-dichloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-2H-indyl (2-azolyl)-N,N-dimethylacetamide

[1363] [Chemical Formula 117]

[1364]

[1365] Under RT, NCS (48 mg, 0.36 mmol) was added to a solution of 2-(4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboroncyclopentan-2-yl)-2H-indazol-2-yl)-N,N-dimethylacetamide (109 mg, 0.30 mmol) in MeCN (2.18 mL). The mixture was stirred at 50 °C for 18 h. The reaction solution was then concentrated under vacuum, and the residue was purified by silica gel column chromatography (gradient elution, 0-20% MeOH / CHCl3) to give the title compound (71 mg). MS: [M+H] + =398,400.

[1366] Preparation of 84: 3-(4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-2H-indazole-2- )-N,N-dimethylpropionamide

[1367] [Chemical Formula 118]

[1368]

[1369] Step 1

[1370] Under RT, K₂CO₃ (1.19 g, 8.64 mmol) and tert-butyl 3-bromopropionate (1.44 mL, 8.64 mmol) were added to a DMF (10 mL) solution of 5-bromo-4-chloro-1H-indazole (1 g, 4.32 mmol). The mixture was stirred at 100 °C for 2 h, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 5–30% EtOAc / hexane) to give tert-butyl 3-(5-bromo-4-chloro-2H-indazole-2-yl)propionate (599 mg). MS: [M+H] + =361, 363.

[1371] Step 2

[1372] A 1,4-dioxane solution (6 mL) of a mixture of tert-butyl 3-(5-bromo-4-chloro-2H-indazole-2-yl)propionate (599 mg, 1.67 mmol), bis(pinacolyl)diboron (634 mg, 2.50 mmol), a complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (109 mg, 0.133 mmol), and potassium acetate (327 g, 3.33 mmol) was degassed, purged with nitrogen, and stirred at 120 °C for 5 h. The reaction mixture was cooled to RT, filtered through a diatomaceous earth filter, and washed with EtOAc. The filtrate was concentrated under vacuum. The residue was purified by NH4Cl column chromatography (gradient elution, 10-30% EtOAc / hexane) to give tert-butyl 3-(4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-2H-indazol-2-yl)propionate (553 g). MS: [M+H + =406, 408.

[1373] Step 3

[1374] At RT, TFA (1 mL, 13.0 mmol) was added to a CHCl3 (2 mL) solution of tert-butyl 3-(4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboroncyclopentan-2-yl)-2H-indazol-2-yl)propionate (200 mg, 0.492 mmol). The mixture was stirred at 60 °C for 1 h, diluted with water, and extracted with CHCl3. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was diluted with THF (4 mL). At RT, TEA (0.685 mL, 4.92 mmol), propylphosphonic anhydride (1.6 M THF solution, 0.92 mL, 1.48 mmol), and dimethylamine (2.0 M THF solution, 0.98 mL, 1.97 mmol) were added to the mixture. The mixture was stirred at RT for 30 min. The reaction solution was then concentrated under vacuum, and the residue was purified by silica gel column chromatography (gradient elution, 0-10% MeOH / CHCl3) to give the title compound (116 mg). MS: [M+H] + =378, 380.

[1375] Preparation of 85: 3,4-dichloro-2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-2H- Indazole

[1376] [Chemical Formula 119]

[1377]

[1378] Step 1

[1379] Under RT, NCS (99 mg, 0.738 mmol) was added to a MeCN (5 mL) solution of tert-butyl 3-(4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-2H-indazole-2-yl)propionate (250 mg, 0.615 mmol). The mixture was stirred at 60 °C for 12 h. The reaction solution was then concentrated under vacuum, and the residue was purified by silica gel column chromatography (gradient elution, 10-20% EtOAc / hexane) to give tert-butyl 3-(3,4-dichloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-2H-indazole-2-yl)propionate (164 mg). MS: [M+H] + =441, 443.

[1380] Step 2

[1381] At RT, TFA (1 mL, 13.0 mmol) was added to a CHCl3 (1 mL) solution of tert-butyl 3-(3,4-dichloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronacyclopentan-2-yl)-2H-indazol-2-yl)propionate (164 mg, 0.372 mmol). The mixture was stirred at 70 °C for 10 min, diluted with water, and extracted with CHCl3. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was diluted with THF (2.58 mL). At RT, TEA (0.233 mL, 1.68 mmol), propylphosphonic anhydride (1.6 M THF solution, 0.420 mL, 0.670 mmol), and dimethylamine (2.0 M THF solution, 0.34 mL, 0.670 mmol) were added to the mixture. The mixture was stirred at RT for 30 min. The reaction solution was then concentrated under vacuum, and the residue was purified by silica gel column chromatography (gradient elution, 0-10% MeOH / CHCl3) to give the title compound (128 mg). MS: [M+H] + =412, 414.

[1382] Preparation of 86: 2-chloro-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-4-((4-methoxybenzyl)oxy)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

[1383] [Chemical Formula 120]

[1384]

[1385] A mixture of 5-bromo-2-chloro-4-((4-methoxybenzyl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2.68 g, 5.37 mmol), 4-chloro-2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-2H-indazole (2.47 g, 6.45 mmol), K3PO4 (2.28 g, 10.7 mmol), a complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (0.439 g, 0.537 mmol), 1,4-dioxane (53.6 mL), and water (5.36 mL) was stirred at 120 °C for 1 h, cooled to RT, poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / hexane) to give the title compound (1.7 g). MS: [M+H] + =598,600.

[1386] Preparation of 87: 2-chloro-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-7-((2-(trimethylsilyl)ethoxy) methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[1387] [Chemical Formula 121]

[1388]

[1389] To a solution of 2-chloro-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-4-((4-methoxybenzyl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1.7 g, 2.84 mmol) in DCM (32.3 mL), 2,3-dichloro-5,6-dicyano-p-benzoquinone (1.93 g, 8.52 mmol) and water (1.7 mL) were added. The mixture was stirred overnight at RT. CHCl3 and sat.NaHCO3 were added at RT. The mixture was filtered through a diatomaceous earth mat and washed with CHCl3 and water. The filtrate was extracted with CHCl3, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / hexane) to give the title compound (0.713 g). MS: [M+H] + =478, 480.

[1390] Preparation of 88: 2-chloro-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-7-((2-(trimethylsilyl)) (ethoxy)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[1391] [Chemical Formula 122]

[1392]

[1393] At RT, K₂CO₃ (0.412 g, 2.98 mmol) and methyl iodo[2,3-d]pyrimidin-4-one (0.713 g, 1.49 mmol) were added to a DMF solution (7.13 mL) containing 2-chloro-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (0.713 g, 1.49 mmol). The mixture was stirred at RT for 30 min, poured into water, and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / hexane) to give the title compound (0.717 g). MS: [M+H] + =492,494.

[1394] The compounds in Table 2 below were prepared using a method similar to that described in Preparations 86-88, starting with appropriately substituted aryl borate esters (using any significant variations shown below, synthesized as described above).

[1395] [Table 2]

[1396] Table 2

[1397]

[1398]

[1399] Preparation of 89: 2-chloro-5-(4-chloro-2-methyl-2H-indazol-5-yl)-4-((4-methoxybenzyl)oxy)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

[1400] [Chemical Formula 123]

[1401]

[1402] The title compound was prepared from 4-chloro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboranecyclopentan-2-yl)-2H-indazole using a similar method to that used for 2-chloro-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-4-((4-methoxybenzyl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine. MS: [M+H] + =584,586.

[1403] Preparation of 90: 2-chloro-5-(4-chloro-2-methyl-2H-indazol-5-yl)-7-((2-(trimethylsilyl)ethoxy) methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[1404] [Chemical Formula 124]

[1405]

[1406] The title compound was prepared from 2-chloro-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one using a similar method. MS: [M+H] + =464, 466.

[1407] Preparation of 91: 2-chloro-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-7-((2-(trimethylsilyl)) (ethoxy)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[1408] [Chemical Formula 125]

[1409]

[1410] A mixture of 2-chloro-5-iodo-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (150 mg, 0.341 mmol), 4-chloro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-2H-indazole (171 mg, 0.409 mmol), K2CO3 (110 mg, 0.798 mmol), a complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (27.8 mg, 0.0341 mmol), 1,4-dioxane (2.5 mL), and water (0.5 mL) was stirred at 70 °C for 2 h, cooled to RT, poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / hexane) to give the title compound (90 mg). MS: [M+H] + =478, 480.

[1411] Preparation of 92: (endo-8-(5-bromo-3-methyl-4-oxo-7-((2-(trimethylsilyl)ethoxy)methyl)- 4,7-Dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-8-azabicyclo[3.2.1]octane-3-yl)tert-butyl carbamate

[1412] [Chemical Formula 126]

[1413]

[1414] A mixture of 5-bromo-2-chloro-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (0.700 g, 1.78 mmol), endo-(8-azabicyclo[3.2.1]octane-3-yl)carbamate tert-butyl ester (1.21 g, 5.34 mmol), DIPEA (3.10 mL, 17.8 mmol), and NMP (1 mL) was stirred at 120 °C for 30 min and cooled to RT. Water was added, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / hexane) to give the title compound. MS: [M+H] + =581,583.

[1415] Preparation of 93: (endo-8-(5-iodo-3-methyl-4-oxo-7-((2-(trimethylsilyl)ethoxy)methyl)- 4,7-Dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-8-azabicyclo[3.2.1]octane-3-yl)tert-butyl carbamate

[1416] [Chemical Formula 127]

[1417]

[1418] A mixture of 5-iodo-2-chloro-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (2.00 g, 4.55 mmol), endo-(8-azabicyclo[3.2.1]octane-3-yl)carbamate tert-butyl ester (1.24 g, 5.46 mmol), DIPEA (1.58 mL, 9.10 mmol), and NMP (10 mL) was stirred at 120 °C for 8 h and cooled to RT. Water was added, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0–80% EtOAc / hexane) to give the title compound (2.41 g). MS: [M+H] + =630.

[1419] Using a method similar to that described in Preparation 93, starting with suitable substituted amines, the compounds in Table 3 below were prepared (synthesized as described above, with any significant variations shown below).

[1420] Table 3

[1421]

[1422]

[1423] Preparation of 94: ((1R,2R,4S)-7-(5-iodo-3-methyl-4-oxo-7-((2-trimethylsilyl)ethoxy)methyl (2,3-d)pyrimidin-2-yl)-7-azabicyclo[2.2.1]heptane-2-yl)(methyl)amino tert-butyl formate

[1424] [Chemical Formula 128]

[1425]

[1426] At 0 °C, NaH (60%, in mineral oil, 64.9 mg, 1.62 mmol) was added to a THF (15 mL) solution of ((1R,2R,4S)-7-(5-iodo-3-methyl-4-oxo-7-((2-trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-7-azabicyclo[2.2.1]heptane-2-yl)carbamate (500 mg, 0.812 mmol). The mixture was stirred at 0 °C for 15 min. Iodomethane (0.101 mL, 1.62 mmol) was added at 0 °C. The mixture was stirred overnight at RT, poured into sat.NH4Cl, and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 30-50% EtOAc / hexane) to give the title compound (493 mg). MS: [M+H]+ =630.

[1427] Preparation of 95: 3-bromo-4,6-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4- d]Pyrimidine

[1428] [Chemical Formula 129]

[1429]

[1430] At RT, SEMCl (0.794 mL, 4.47 mmol) was added to a mixture of 3-bromo-4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (1.00 g, 3.73 mmol) and DIPEA (1.95 mL, 11.2 mmol) in DCM (10 mL). The mixture was stirred at RT for 1 h and purified by silica gel column chromatography (gradient elution, 0–15% EtOAc / hexane) to give the title compound (1.12 g). MS: [M+H] + =397,399.

[1431] Preparation of 96: 3-bromo-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazol [3,4-d]pyrimidin-4-one

[1432] [Chemical Formula 130]

[1433]

[1434] At RT, 5 M NaOH (5.06 mL, 25.3 mmol) was added to a THF (10 mL) solution of 3-bromo-4,6-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (1.12 g, 2.81 mmol). The mixture was stirred at RT for 7 h, diluted with 2-methyltetrahydrofuran, acidified with 6 M HCl, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give the title compound (1.05 g). MS: [M+H] + =379, 381.

[1435] Preparation of 97: 3-bromo-6-chloro-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H- Pyrazolo[3,4-d]pyrimidin-4-one

[1436] [Chemical Formula 131]

[1437]

[1438] At RT, iodomethane (0.344 mL, 5.53 mmol) was added to a DMF (10 mL) solution of a mixture of 3-bromo-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1.05 g, 2.77 mmol) and K₂CO₃ (0.764 g, 5.53 mmol). The mixture was stirred at RT for 30 min, diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0–50% EtOAc / hexane) to give the title compound (0.780 g). MS: [M+H] + =393,395.

[1439] Preparation of 98: 3-bromo-4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

[1440] [Chemical Formula 132]

[1441]

[1442] 3-Bromo-4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (4.55 g, 17.0 mmol), 3,4-dihydro-2H-pyran (4.62 mL, 51.0 mmol), and p-toluenesulfonic acid monohydrate (0.646 g, 3.40 mmol) were dissolved in THF (74 mL) and heated at 70 °C for 2 h. The solvent was removed under vacuum, and the solid residue was ground at 40 °C in Et₂O (30 mL) for 2 h. The resulting suspension was slowly cooled to room temperature. The solid was collected by filtration and washed with Et₂O. The wet solid was dried in a vacuum drying oven at 50 °C to give the title compound (4.8 g). MS: [M+H] + =353, 355.

[1443] Preparation of 99: 3-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine- 4-keto

[1444] [Chemical Formula 133]

[1445]

[1446] At 0 °C, 27 mL of 5 M NaOH was added to a 54 mL THF solution of 3-bromo-4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (5.42 g, 15.4 mmol). The mixture was stirred overnight at RT. The mixture was diluted with 2-methyltetrahydrofuran, acidified with 6 M HCl, and extracted with 2-methyltetrahydrofuran. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give the title compound (5.14 g). MS: [M+H] + =333, 335.

[1447] Preparation of 100: 3-bromo-6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3, [4-d]pyrimidin-4-one

[1448] [Chemical Formula 134]

[1449]

[1450] Iodomethane (4.78 mL, 76.7 mmol) was added to a solution of 3-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (12.8 g, 38.4 mmol) and K₂CO₃ (10.6 g, 76.7 mmol) in 256 mL of NMP under RT. The mixture was stirred at RT for 1 h, diluted with EtOAc, washed with water (x2) and brine, dried over Na₂SO₄, filtered, and then concentrated under vacuum to give the title compound (9.08 g). MS: [M+H] + =347,349.

[1451] Preparation of 101: 9-(3-bromo-5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-di Hydrogen-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3,9-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester

[1452] [Chemical Formula 135]

[1453]

[1454] A mixture of 3-bromo-6-chloro-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (780 mg, 1.981 mmol), tert-butyl 3,9-diazabicyclo[3.3.1]nonane-3-carboxylate (0.89 g, 3.9620 mmol), DIPEA (1.72 mL, 9.90 mmol), and NMP (8 mL) was stirred at 120 °C for 5 h, cooled to RT, poured into water, and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / hexane) to give the title compound (1.10 g). MS: [M+H] + =583, 585.

[1455] Using a method similar to that described in Preparation 101, compounds in Table 4 below were prepared starting with suitable substituted amines (synthesized as described above, with any significant variations shown below).

[1456] Table 4

[1457]

[1458]

[1459] Preparation of 102: rac-((1S,4S,7S)-2-(5-iodo-3-methyl-4-oxo-7-((2-(trimethylsilyl)ethyl) (oxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-7-yl)(methyl tert-butyl carbamate

[1460] [Chemical Formula 136]

[1461]

[1462] Using a similar method to that described in Preparation 94, tert-butyl rac-((1S,4S,7S)-2-(5-iodo-3-methyl-4-oxo-7-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-7-yl)carbamate was prepared from rac-((1S,4S,7S)-2-(5-iodo-3-methyl-4-oxo-7-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-7-yl)(methyl)carbamate. MS: [M+H] + =630.

[1463] Preparation of 103: ((1R,2R,4S)-7-(3-bromo-5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5- Dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-7-azabicyclo[2.2.1]heptane-2-yl)(methyl)carbamate tert-butyl ester

[1464] [Chemical Formula 137]

[1465]

[1466] At 0 °C, sodium hydride (60%, in mineral oil, 230 mg, 5.70 mmol) was added to a THF (30 mL) solution of ((1R,2R,4S)-7-(3-bromo-5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-7-azabicyclo[2.2.1]heptane-2-yl)carbamate (1.5 g, 2.90 mmol). The mixture was stirred at 0 °C for 15 min. Iodomethane (0.360 mL, 5.70 mmol) was added at 0 °C. The mixture was stirred overnight at RT, poured into Sat. NH4Cl, and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 20-50% EtOAc / hexane) to give the title compound (1.37 g). MS: [M+H] + =537,539.

[1467] Preparation of 104: 6-hydrazino-2-hydroxy-3-methyl-3,4-dihydropyrimidin-4-one

[1468] [Chemical Formula 138]

[1469]

[1470] At room temperature, hydrazine-H₂O (49.7 mL, 507 mmol) was added to a suspension of 6-chloro-2-hydroxy-3-methylpyrimidin-4(3H)-one (27.15 g, 169 mmol) in EtOH (250 mL). The resulting suspension was stirred at 80 °C for 18 h. The reaction mixture was cooled to room temperature and then kept in an ice bath at 0 °C for 1 h. The grayish-white precipitate was collected and washed with cold EtOH (2 x 100 mL). MS: [M+H] + =157.

[1471] Preparation of 105: 2-hydroxy-6-[(E)-2-[(4-methoxyphenyl)methylene]hydrazine-1-yl]-3-methyl-3,4-di Hydropyrimidine-4-one

[1472] [Chemical Formula 139]

[1473]

[1474] 4-Methoxybenzaldehyde (11.68 mL, 96 mmol) was slowly added to a methanol (250 mL) suspension of 6-hydrazino-2-hydroxy-3-methyl-3,4-dihydropyrimidin-4-one (10 g, 64.0 mmol), and the mixture was stirred for 3 hours, then filtered. The precipitate was washed with MeOH (3 x 100 mL), transferred to a flask, and stirred overnight with 3:1 DCM / EtOAc (400 mL). The precipitate was filtered and dried on a sintering plate to give the title compound (9.56 g, 31.7 mmol, yield 49.5%) as a colorless solid. MS: [M+H] + =275.

[1475] Preparation of 106: 4-chloro-2-methyl-2H-indazole-5-carboxaldehyde

[1476] [Chemical Formula 140]

[1477]

[1478] Under a nitrogen atmosphere, a solution of 5-bromo-4-chloro-2-methyl-2H-indazole (8.78 g, 35.8 mmol) in THF (60 mL) was slowly added over 10 minutes to a three-necked flask containing i-PrMgCl·LiCl (55 mL, 71.5 mmol). The reaction mixture was stirred at 30 °C for 4 hours, and then DMF (13.84 mL, 179 mmol) was slowly added. The reaction mixture was stirred at 30 °C for 1 hour, and then MeOH (40 mL) was added over 10 minutes. The mixture was allowed to stand overnight at room temperature. The mixture was concentrated under vacuum, and the residue was dissolved in a mixture of EtOAc (150 mL), DCM (10 mL), and MeOH (10 mL). The solution was washed with water (100 mL) and brine (100 mL). The organic phase was separated, and the aqueous phase was extracted again with EtOAc (100 mL). The combined organic phases were then washed with water (2 x 100 mL), dried (MgSO4), filtered, and concentrated to give a crude product. This crude product was ground with 4:1 isohexane / EtOAc (4 x 25 mL), and the solid was filtered off. It was then ground again with 4:1 isohexane / EtOAc (2 x 25 mL) to give 4-chloro-2-methyl-2H-indazole-5-carboxaldehyde (1.17 g, 5.89 mmol, yield 16.48%) as a light brown solid. MS: [M+H] + =195.

[1479] Preparation of 107: 4-chloro-2-ethyl-2H-indazole-5-carboxaldehyde

[1480] [Chemical Formula 141]

[1481]

[1482] 4-Chloro-2-ethyl-2H-indazole-5-carboxaldehyde was prepared from 5-bromo-4-chloro-2-ethyl-2H-indazole using a method similar to that described in preparation 106. MS: [M+H] + =209.

[1483] Preparation of 108:3,4-dichloro-2-methyl-2H-indazole-5-carboxaldehyde

[1484] [Chemical Formula 142]

[1485]

[1486] 3,4-Dichloro-2-methyl-2H-indazole-5-carboxaldehyde was prepared from 5-bromo-3,4-dichloro-2-methyl-2H-indazole using a method similar to that described in preparation 106. MS: [M+H] + =229.

[1487] Preparation of 109: 3-(4-chloro-2-methyl-2H-indazol-5-yl)-6-hydroxy-2-[(4-methoxyphenyl)methyl]-5- Methyl-2H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one

[1488] [Chemical Formula 143]

[1489]

[1490] A suspension of 2-hydroxy-6-[(E)-2-[(4-methoxyphenyl)methylene]hydrazino-1-yl]-3-methyl-3,4-dihydropyrimidin-4-one (2.013 g, 7.34 mmol) and 4-chloro-2-methyl-2H-indazole-5-carboxaldehyde (1.5 g, 7.71 mmol) in DMF / IPA (2:1, 55 mL) was stirred at room temperature. Piperidine (0.763 mL, 7.71 mmol) was added in one dose, and the reaction mixture was stirred overnight at 35 °C. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (2 x 100 mL) and DCM solution of 10% MeOH (2 x 100 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (80 g column, 0–3% MeOH / DCM) to give the title compound (932 mg, 2.0 mmol, yield 27.3%) as a pale orange solid. MS: [M+H] + =451. 1H NMR (500MHz, DMSO-d6) δ: 11.74 (s, 1H), 8.65 (s, 1H), 7.70 (dd, J=8.8, 1.0Hz, 1H), 7.23 (d, J=8.8Hz, 1H), 6.94 (d, J=8.7 Hz, 2H), 6.80 (d, J=8.7Hz, 2H), 5.08 (d, J=15.1Hz, 1H), 4.99 (d, J=15.1Hz, 1H), 4.25 (s, 3H), 3.69 (s, 3H), 3.10 (s, 3H).

[1491] Preparation of 110: 3-(4-chloro-2-ethyl-2H-indazol-5-yl)-6-hydroxy-2-[(4-methoxyphenyl)methyl]-5- Methyl-2H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one

[1492] [Chemical Formula 144]

[1493]

[1494] Using a similar method to that described in preparation 109, 3-(4-chloro-2-ethyl-2H-indazole-5-yl)-6-hydroxy-2-[(4-methoxyphenyl)methyl]-5-methyl-2H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one was prepared starting from 2-hydroxy-6-[(E)-2-[(4-methoxyphenyl)methyl]-5-methyl-2H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one. MS: [M+H] + =465. 1 H NMR (500MHz, DMSO-d6) δ: 11.73 (s, 1H), 8.70 (s, 1H), 7.71 (dd, J=8.8, 0.7Hz, 1H), 7.23 (d, J=8.8Hz, 1H), 6.96 (d, J=8.7Hz, 2H), 6.81 (d , J=8.7Hz, 2H), 5.09 (d, J=15.1Hz, 1H), 5.00 (d, J=15.1Hz, 1H), 4.54 (q, J=7.3Hz, 2H), 3.69 (s, 3H), 3.10 (s, 3H), 1.55 (t, J=7.3Hz, 3H).

[1495] Preparation of 111: 3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-6-hydroxy-2-[(4-methoxyphenyl)methyl] ]-5-methyl-2H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one

[1496] [Chemical Formula 145]

[1497]

[1498] Using a similar method to that described in preparation 109, 3-(3,4-dichloro-2-methyl-2H-indazole-5-yl)-6-hydroxy-2-[(4-methoxyphenyl)methyl]-5-methyl-2H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one was prepared starting from 2-hydroxy-6-[(E)-2-[(4-methoxyphenyl)methyl]-5-methyl-2H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one. MS: [M+H] + =485.

[1499] 1 H NMR (500MHz, DMSO-d6) δ: 11.76 (s, 1H), 7.72 (d, J = 8.8Hz, 1H), 7.26 (d, J = 8.8Hz, 1H), 6.96 (d, J = 8.7Hz, 2H), 6 .81 (d, J=8.7Hz, 2H), 5.08 (d, J=15.1Hz, 1H), 5.01 (d, J=15.1Hz, 1H), 4.19 (s, 3H), 3.69 (s, 3H), 3.10 (s, 3H).

[1500] General Method 1: 8-(5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-4-oxo-7-((2-(trimethyl) Silyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-3-carboxylate

[1501] [Chemical Formula 146]

[1502]

[1503] A mixture of 2-chloro-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (100 mg, 0.209 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (88.7 mg, 0.418 mmol), DIPEA (0.109 mL, 0.627 mmol), and NMP (2 mL) was stirred at 120 °C for 8 h, cooled to RT, diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / hexane) to give the title compound (140 mg). MS: [M+H] + =654,656.

[1504] Using a method similar to that described in General Method 1, the compounds in Table 5 below were prepared starting from appropriately substituted and protected pyrrolopyrimidinones and different amines (synthesized as described above, with any significant variations shown below).

[1505]

[1506]

[1507]

[1508]

[1509]

[1510]

[1511]

[1512]

[1513]

[1514]

[1515]

[1516]

[1517]

[1518]

[1519]

[1520]

[1521]

[1522]

[1523]

[1524]

[1525]

[1526]

[1527]

[1528] General Method 2: 9-(5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-4-oxo-7-((2-(trimethyl) Silyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-3,9-diazabicyclo[3.3.1] tert-butyl nonane-3-carboxylate

[1529] [Chemical Formula 147]

[1530]

[1531] 9-(5-iodo-3-methyl-4-oxo-7-((2-trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-3,9-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (500 mg, 0.794 mmol), 4-chloro-2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)- A mixture of 2H-indazole (365 mg, 1.19 mmol), K3PO4 (337 mg, 1.58 mmol), the complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (64.8 mg, 0.0794 mmol), 1,4-dioxane (8 mL), and water (2 mL) was stirred at 70 °C for 2 h, cooled to RT, poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / hexane) to give the title compound (375 mg). MS: [M+H] + =682,684.

[1532] Using a method similar to that described in General Method 2, starting with appropriately substituted and protected pyrrolopyrimidinones, and utilizing different boronic esters or boronic acids, the compounds in Table 6 below were prepared (synthesized as described above, with any significant variations shown below).

[1533]

[1534]

[1535]

[1536]

[1537]

[1538]

[1539]

[1540]

[1541]

[1542]

[1543]

[1544]

[1545]

[1546]

[1547]

[1548] Preparation of 112: ((1R,2R,4S)-7-(5-(4-chloro-3-(difluoromethyl)-2-ethyl-2H-indazole-5-yl)-3-methyl 4-oxo-7-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-2- tert-butyl heptane-2-yl)-7-azabicyclo[2.2.1]-2-yl)carbamate

[1549] [Chemical Formula 148]

[1550]

[1551] To a solution of ((1R,2R,4S)-7-(5-(4-chloro-2-ethyl-3-formyl-2H-indazol-5-yl)-3-methyl-4-oxo-7-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-7-azabicyclo[2.2.1]heptane-2-yl)carbamate tert-butyl ester (220 mg, 0.32 mmol) in 1,2-dichloroethane (1.3 mL), bis(2-methoxyethyl)aminosulfur trifluoride (290 mg, 1.3 mmol) was added. The mixture was stirred overnight at 50 °C. The mixture was quenched with sat. NaHCO3 and extracted with EtOAc. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-80% EtOAc / hexane) to give the title compound (54 mg). MS: [M+H] + =718, 720.

[1552] Preparation of 113: ((1R,2R,4S)-7-(5-(4-chloro-2-ethyl-3-(hydroxymethyl)-2H-indazole-5-yl)-3-methyl 4-oxo-7-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-2- tert-butyl heptane-2-yl)-7-azabicyclo[2.2.1]-2-yl)carbamate

[1553] [Chemical Formula 149]

[1554]

[1555] Sodium borohydride (21 mg, 0.56 mmol) was added to a methanol solution (3.0 mL) of ((1R, 2R, 4S)-7-(5-(4-chloro-2-ethyl-3-formyl-2H-indazol-5-yl)-3-methyl-4-oxo-7-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-7-azabicyclo[2.2.1]heptane-2-yl)carbamate (240 mg, 0.34 mmol). The mixture was stirred at RT for 1 h. The mixture was quenched with sat. NH4Cl aq. and extracted with EtOAc. The organic layer was washed with water and brine and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-10% MeOH / CHCl3) to give the title compound (215 mg). MS: [M+H] + =698,700.

[1556] Preparation of 114: ((1R,2R,4S)-7-(5-(4-chloro-3-cyano-2-ethyl-2H-indazol-5-yl)-3-methyl-4- oxo-7-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-7- Azabicyclo[2.2.1]heptane-2-yl)tert-butyl carbamate

[1557] [Chemical Formula 150]

[1558]

[1559] To an ethanol (0.9 mL) solution of a mixture of ((1R,2R,4S)-7-(5-(4-chloro-2-ethyl-3-formyl-2H-indazol-5-yl)-3-methyl-4-oxo-7-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-7-azabicyclo[2.2.1]heptane-2-yl)carbamate (314 mg, 0.45 mmol) and sodium carbonate (75 mg, 0.71 mmol), hydroxylamine hydrochloride (49 mg, 0.71 mmol) was added. The mixture was stirred overnight at RT. The mixture was diluted with EtOAc, washed with water and brine, and concentrated under vacuum. To the residue, acetonitrile (2.4 mL) and copper(II) acetate (8.1 mg, 0.045 mmol) were added. The mixture was stirred at 80 °C for 5 h, then concentrated under vacuum. The residue was purified by NH-silica gel chromatography (gradient elution, 0-10% MeOH / CHCl3) to give the title compound (245 mg). MS: [M+H] + =693,695.

[1560] General Method 3: 9-(3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-4-oxo-1-((2-(trimethyl) Silyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3,9-diazabicyclo[3.3.1] tert-butyl nonane-3-carboxylate

[1561] [Chemical Formula 151]

[1562]

[1563] 9-(3-bromo-5-methyl-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3,9-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (300 mg, 0.475 mmol), 4-chloro-2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)- A mixture of 2H-indazole (315 mg, 1.02 mmol), K3PO4 (327 mg, 1.54 mmol), the complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (41.9 mg, 0.0514 mmol), 1,4-dioxane (6 mL), and water (1.5 mL) was stirred at 90 °C for 2 h, cooled to RT, poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc / hexane) to give the title compound (200 mg). MS: [M+H] + =683,685.

[1564] Using a method similar to that described in General Method 3, the compounds in Table 7 below were prepared starting from appropriately substituted, protected pyrrolopyrimidinones and different boronic esters or boronic acids (synthesized as described above, with any significant variations shown below).

[1565]

[1566]

[1567]

[1568]

[1569]

[1570]

[1571] Preparation of 115: ((1R,2R,4S)-7-(3-(3,4-dichloro-2-ethyl-2H-indazol-5-yl)-5-methyl-4-oxo 1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-7-azabicyclo [2.2.1] Heptane-2-yl) tert-butyl carbamate

[1572] [Chemical Formula 152]

[1573]

[1574] At RT, NCS (36 mg, 0.270 mmol) was added to a DMF (1.4 mL) solution of ((1R,2R,4S)-7-(3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-7-azabicyclo[2.2.1]heptane-2-yl)carbamate (140 mg, 0.225 mmol). The mixture was stirred at 60 °C for 5 h. The reaction mixture was cooled to RT and treated at RT with NCS (15 mg, 0.112 mmol). The mixture was stirred at 60 °C for 1 h, diluted with water, and extracted with EtOAc. The organic layer was washed with water (x3) and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 50-80% EtOAc / hexane) to give the title compound (81 mg). MS: [M+H] + =657,659.

[1575] Preparation of 116: ((1R,2R,4S)-7-(3-(3,4-dichloro-2-ethyl-2H-indazol-5-yl)-5-methyl-4-oxo 1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-7-azabicyclo [2.2.1] Heptane-2-yl)(methyl)carbamate tert-butyl ester

[1576] [Chemical Formula 153]

[1577]

[1578] At RT, NCS (55.6 mg, 0.417 mmol) was added to a DMF solution (1.4 mL) of ((1R,2R,4S)-7-(3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-7-azabicyclo[2.2.1]heptane-2-yl)(methyl)carbamate (177 mg, 0.278 mmol). The mixture was stirred at 60 °C for 30 min, diluted with water, and extracted with EtOAc. The organic layer was washed with water (x3) and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 40-80% EtOAc / hexane) to give the title compound (115 mg). MS: [M+H] + =671, 673.

[1579] General Method 4: N-[endo-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-2-[(4-methoxyphenyl)methyl] ]-5-methyl-4-oxo-2H , 4H , 5H-pyrazolo[3,4-d]pyrimidin-6-yl]-8-azabicyclo[3.2.1]octane-3- [B] tert-butyl carbamate

[1580] [Chemical Formula 154]

[1581]

[1582] DBU (0.0677 mL, 0.45 mmol) was added dropwise at ambient temperature to a solution of 3-(4-chloro-2-methyl-2H-indazol-5-yl)-6-hydroxy-2-[(4-methoxyphenyl)methyl]-5-methyl-2H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (135 mg, 0.3 mmol) and PyBOP (172 mg, 0.33 mmol) in DMF (2.5 mL). The mixture was stirred for 10 minutes and then treated with N-(endo-8-azabicyclo[3.2.1]octane-3-yl)carbamate tert-butyl ester (102 mg, 0.45 mmol). The mixture was stirred overnight and kept for 20 hours – some starting material remained. The mixture was then treated with water (40 mL). The fine precipitate was then extracted into EtOAc (50 mL), and the organic layer was washed (2 x 20 mL), dried (Na₂SO₄), and concentrated under vacuum. The crude product was purified by silica gel chromatography (12 g column, 0-100% EtOAc / isohexane) to give the title compound (128 mg, 0.19 mmol, yield 65%) as a clear, colorless glassy substance. MS: [M+H] + =659.

[1583] Using a method similar to that described in General Method 4, the compounds in Table 8 below were prepared starting from appropriately substituted, protected pyrrolopyrimidinones and different amines (synthesized as described above, with any significant variations shown below).

[1584]

[1585]

[1586]

[1587] General Method 5: 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5- (4-Chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-3H,4H,7H- Pyrrolo[2,3-d]pyrimidin-4-one

[1588] [Chemical Formula 155]

[1589]

[1590] A solution of 2-chloro-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (250 mg, 0.51 mmol), (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine dihydrochloride (148 mg, 0.61 mmol), and triethylamine (0.21 mL, 1.52 mmol) in NMP (1 mL) was heated at 100 °C for 2 h. The mixture was cooled to ambient temperature and partitioned between EtOAc and water for phase separation. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with 50% saturated brine, then washed with brine, dried (MgSO4 + hydrophobic glass frit), and concentrated. The residue was purified by reversed-phase C18 silica gel chromatography and eluted with 5-100% MeCN / H2O containing 0.1% TFA to give the title compound as the TFA salt (256 mg, 0.346 mmol, 68%). 1 H NMR (400MHz, DMSO-d6) δ: 8.48 (1H, s), 7.98 (3H, s), 7.54 (1H, dd), 7.31 (1H, d), 7.2 5(1H, s), 5.48(2H, s), 4.50(2H, q), 4.29-4.18(1H, m), 3.70-3.66(1H, m), 3.62(2H, t), 3.53-3.33 (7H, m), 3.03-2.73 (2H, m), 1.98-1.86 (2H, m), 1.82-1.77 (1H, m), 1.6 6(1H,d), 1.53(3H,t), 1.24(3H,d), 0.93-0.82(2H,m), 0.02-0.08(9H,m).MS: [M+H] + =626.

[1591] Using a method similar to that described in General Method 5, the compounds in Table 9 below were prepared starting from appropriately substituted, protected pyrrolopyrimidinones and different amines (synthesized as described above, with any significant variations shown below).

[1592] Table 9

[1593]

[1594] General methods for preparing compounds of formula (I)

[1595] The following methods are used to explain the general methods used in the preparation of Examples 1-135 listed in Table 10 below.

[1596] Method 1: 2-(3,8-diazabicyclo[3.2.1]octane-8-yl)-5-(4-chloro-2-methyl-2H-indazole-5-) 3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[1597] [Chemical Formula 156]

[1598]

[1599] TFA (2 mL) was added to a CHCl3 (2 mL) solution of 8-(5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-4-oxo-7-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (140 mg, 0.214 mmol) at RT. The mixture was stirred at RT for 3 h and concentrated under vacuum. The residue was dissolved in MeOH (4 mL). 4 M NaOH (1 mL) was added at RT. The mixture was stirred at RT for 1 h, poured into water, and extracted with CHCl3-MeOH. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by NH silica gel column chromatography (gradient elution, 0-10% MeOH / CHCl3). The fraction was concentrated under vacuum and purified by r-HPLC. The fraction was alkalized with sat.NaHCO3 and extracted with CHCl3-MeOH. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give the title compound (24 mg).

[1600] Method 2: 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)- 7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[1601] [Chemical Formula 157]

[1602]

[1603] A mixture of ((1R,2R,4S)-7-(5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-4-oxo-7-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-7-azabicyclo[2.2.1]heptane-2-yl)(methyl)carbamate tert-butyl ester (150 mg, 0.219 mmol) and TFA (3 mL) was stirred at RT for 2 h and concentrated under vacuum. The residue was purified by NH silica gel column chromatography (gradient elution, 0-15% MeOH / CHCl3). The residue was dissolved in MeOH (3 mL). Ethylenediamine (0.2 mL, 2.99 mmol) was added at RT. The mixture was stirred at RT for 2 h and concentrated under vacuum. After concentration, the residue was purified by r-HPLC. The fraction obtained was purified by Vari-Pure and concentrated under vacuum. The resulting solid was suspended in EtOAc-hexane. The precipitate was collected and dried under reduced pressure at 60 °C to give the title compound (48 mg).

[1604] Method 3: 6-(3,9-diazabicyclo[3.3.1]nonane-9-yl)-3-(3,4-dichloro-2-methyl-2H-indazole- 5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1605] [Chemical Formula 158]

[1606]

[1607] At RT, a solution of 1,4-dioxane in 4M HCl (2 mL, 8 mmol) was added to a MeOH solution (1 mL) of a mixture of 9-(3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3,9-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (120 mg, 0.182 mmol) and tert-butyl ester (120 mg, 0.182 mmol). The mixture was stirred at RT for 2 h and concentrated under vacuum. The residue was purified by r-HPLC. The resulting fraction was purified by Vari-Pure and concentrated under vacuum. The resulting solid was suspended in EtOAc-hexane. The precipitate was collected and dried under reduced pressure at 60 °C to give the title compound (38 mg).

[1608] Method 4: rac-2-((1S,2R,3R,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl)-5- (4-Chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[1609] [Chemical Formula 159]

[1610]

[1611] TFA (0.5 mL) was added to a CHCl3 solution (129 mg, 0.179 mmol) of rac-((1S,2R,3R,5R)-8-(5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-4-oxo-7-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl)carbamate (0.5 mL) at RT. The mixture was stirred at RT for 6 h and concentrated under vacuum. The residue was purified by silica gel column chromatography (gradient elution, 0-10% MeOH / CHCl3). The fraction was concentrated under vacuum to give rac-((1S,2R,3R,5R)-8-(5-(4-chloro-2-methyl-2H-indazol-5-yl)-7-(hydroxymethyl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl) benzyl carbamate (106 mg, 0.17 mmol, 95% yield).

[1612] The residue (106 mg, 0.17 mmol) was dissolved in MeOH (0.40 mL) and THF (0.40 mL). Ethylenediamine (0.2 mL, 2.99 mmol) was added at RT. The mixture was stirred at RT for 1 h and concentrated under vacuum. The residue was purified by NH silica gel column chromatography (gradient elution, 0-10% MeOH / CHCl3). The fraction was concentrated under vacuum to give rac-((1S,2R,3R,5R)-8-(5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl) benzyl carbamate (97 mg, 0.16 mmol, 96% yield).

[1613] Under RT and N2 atmosphere, palladium(II) acetate (18 mg, 0.082 mmol) was added to a suspension of residue (97 mg, 0.16 mmol), triethylsilane (0.42 mL, 2.6 mmol), and triethylamine (0.073 mL, 0.52 mmol) in CH2Cl2 (2.0 mL), and the suspension was stirred at RT for 2.5 h. The solid was removed by filtration through a diatomaceous earth mat. The filtrate was concentrated to obtain a crude oil-solid, which was purified by NH silica gel column chromatography (gradient elution, 0-15% MeOH / CHCl3) to obtain a crude solid-oil. The crude solid-oil was purified by r-HPLC. The obtained fraction was concentrated, and the almost concentrated residue was alkalized with 1N NaOH and extracted with CHCl3 to give the title compound (27 mg, 0.059 mmol, yield 36%).

[1614] Method 5: 2-((1R,2S,3R,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl)-5-(4- Chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[1615] [Chemical Formula 160]

[1616]

[1617] ((1R,2S,3R,5S)-8-(5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-4-oxo-7-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl)carbamate (61 mg, 0.085 mmol) was dissolved in methanesulfonic acid (1.0 mL) and stirred at RT for 3 h. At 0 °C, the mixture was poured into a saturated aqueous solution of NaHCO3 and extracted with CHCl3. The organic layer was concentrated under vacuum. The residue was dissolved in THF (1 mL). At 0 °C, 5 M NaOH aq. (0.085 mL, 0.43 mmol) was added to the mixture and stirred at RT for 1 h. The mixture was then evaporated under vacuum. The residue was purified by NH silica gel column chromatography (gradient elution, 0-10% MeOH / CHCl3) to give the title compound (35 mg).

[1618]

[1619]

[1620]

[1621]

[1622]

[1623]

[1624]

[1625]

[1626]

[1627]

[1628]

[1629]

[1630]

[1631]

[1632]

[1633]

[1634]

[1635]

[1636]

[1637]

[1638]

[1639]

[1640]

[1641]

[1642]

[1643]

[1644]

[1645]

[1646]

[1647]

[1648]

[1649]

[1650]

[1651]

[1652]

[1653]

[1654]

[1655]

[1656]

[1657]

[1658]

[1659]

[1660]

[1661]

[1662]

[1663]

[1664]

[1665] The following methods are used to explain the general methods used to prepare the examples listed in Table 11 below.

[1666] Method 6: endo-6-[3-amino-8-azabicyclo[3.2.1]octane-8-yl]-3-(4-chloro-2-methyl-2H-indyl] (-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one

[1667] [Chemical Formula 161]

[1668]

[1669] Trifluoromethanesulfonic acid (2 mL, 22.5 mmol) was added dropwise to a solution of N-[endo-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-2-[(4-methoxyphenyl)methyl]-5-methyl-4-oxo-2H,4H,5H-pyrazolo[3,4-d]pyrimidin-6-yl]-8-azabicyclo[3.2.1]octane-3-yl]carbamate tert-butyl ester (100 mg, 0.15 mmol) in TFA (0.935 mL, 12.14 mmol) and DCM (10 mL). The resulting purple mixture was stirred at RT for 1 hour and 30 minutes, then evaporated under vacuum to a red liquid, which was added dropwise to saturated sodium carbonate (50 mL). The aqueous layer was extracted with DCM (2 x 50 mL), and the organic layer was recovered by a Phase Separator and evaporated under vacuum. The crude product was purified by silica gel column chromatography (4 g column, 0-10% MeOH / DCM) to obtain the first batch of crude product (38 mg). The crude product was purified by preparative HPLC to obtain the title compound (15 mg, 0.03 mmol, yield 22%) as a transparent colorless solid.

[1670] Method 7: 6-[(1R,3S)-1-amino-3-hydroxy-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one

[1671] [Chemical Formula 162]

[1672]

[1673] N-[(1R,3S)-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-2-[(4-methoxyphenyl)methyl]-5-methyl-4-oxo-2H,4H,5H-pyrazolo[3,4-d]pyrimidin-6-yl]-3-hydroxy-8-azaspiro[4,5]decane-1-yl]-2-methylpropane-2-sulfinamide (123 mg, 0.17 mmol) was dissolved in methanol (0.2 mL, 4.94 mmol), and then HCl (4 M 1,4-dioxane solution) (0.435 mL, 1.74 mmol) was added. The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was concentrated to give a very light brown solid. DCM (2 mL) and trifluoromethanesulfonic acid (0.154 mL, 1.739 mmol) were added to the solid, and the resulting purple solution was stirred at room temperature for 2 hours. The mixture was loaded onto an SCX (~5 g) and eluted with DCM and MeOH, followed by elution with a 0.7 M NH3 MeOH solution. The NH3 MeOH solution was fractionally concentrated to give the title compound (70 mg, 0.14 mmol, 81% yield).

[1674] Method 8: 6-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl- 2H-Indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one

[1675] [Chemical Formula 163]

[1676]

[1677] 6-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-2-[(4-methoxyphenyl)methyl]-5-methyl-2H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (145 mg, 0.25 mmol) was dissolved in DCM (2 mL), and trifluoromethanesulfonic acid (0.22 mL, 2.46 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was loaded onto an SCX (~5 g) and eluted with DCM, MeOH, and then with a MeOH solution of 0.7 M NH3. The MeOH solution of NH3 was fractionally concentrated to give the title compound (83 mg, 0.18 mmol, 72% yield).

[1678] The title compounds in Table 11 can be directly separated as free bases or as suitable salts without further purification, using methods similar to and / or analogous to those described in methods 6-8. Alternatively, the compounds can be purified (e.g., using quality-oriented preparative HPLC, chromatography, crystallization, or preparation). In some cases, the compounds are separated as hydrochloride salts; the compounds are separated by treating a solution of the final compound (e.g., a MeOH solution) with excess HCl (Et₂O solution of 2N HCl) and then evaporating to dryness.

[1679]

[1680]

[1681]

[1682]

[1683]

[1684] Example 149: 6-[(1S,2R,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl]-3- (4-Chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one

[1685] Step 1: N-[(1S,2R,3S,5R)-8-[3-bromo-5-methyl-1-(oxacyclohexane-2-yl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-6-yl]-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl] benzyl carbamate

[1686] [Chemical Formula 164]

[1687]

[1688] A solution of 3-bromo-6-chloro-5-methyl-1-(oxacyclohexane-2-yl)-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one (0.15 g, 0.43 mmol), N-[(1S,2S,3S,5R)-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]carbamate (0.144 g, 0.52 mmol), and diisopropylethylamine (0.38 mL, 2.16 mmol) in NMP (10 mL) was heated at 130 °C for 30 min. The reaction mixture was cooled to ambient temperature, diluted with TBME / DCM 1:1 (20 mL), and washed with 1 M LiCl aqueous solution (2 x 10 mL). The aqueous layers were combined and extracted with 10 mL DCM. The combined organic extracts were washed with HCl (1M, 10 mL), dried (MgSO4), and concentrated under reduced pressure to give N-[(1S,2R,3S,5R)-8-[3-bromo-5-methyl-1-(oxecyclohexane-2-yl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-6-yl]-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]benzyl carbamate (310 mg, 0.40 mmol, 94% yield) as a grayish-white solid. MS: [M+H] + =591.

[1689] Step 2: N-[(1S,2R,3S,5R)-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1-(oxacyclohexane-2-yl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-6-yl]-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl] benzyl carbamate

[1690] [Chemical Formula 165]

[1691]

[1692] 0.3 g (0.51 mmol) of N-[(1S,2R,3S,5R)-8-[3-bromo-5-methyl-1-(oxacyclohexane-2-yl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-6-yl]-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl] benzyl carbamate, 4-chloro-2-methyl-5-(4,4,5-yl)-(oxacyclohexane-2 ... A mixture of 1,4-dioxane (0.18 g, 0.61 mmol), Na₂CO₃ (0.16 g, 1.53 mmol), and PdCl₂ (dppf).DCM (0.042 g, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.6 mL) was degassed under a nitrogen stream. The reaction mixture was heated to 100 °C and held for 2 h. Once cooled to ambient temperature, the reaction mixture was partitioned with 2 mL of water and 10 mL of DCM, the organic layer was separated, dried over MgSO₄, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (12 g column, 0-10% MeOH / DCM) to give the product as a brown solid. The crude product was purified by silica gel chromatography (12 g gold column, 2–4% (0.7 M ammonia / MeOH) / DCM) to give N-[(1S,2R,3S,5R)-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1-(oxecyclohexane-2-yl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-6-yl]-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl] benzyl carbamate (0.07 g, 0.10 mmol, yield 20%) as a white powder. MS: [M+H] + =675.

[1693] Step 3: 6-[(1S,2R,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one

[1694] [Chemical Formula 166]

[1695]

[1696] A TFA solution (1.04 mL, 13.5 mmol) of N-[(1S,2R,3S,5R)-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1-(oxacyclohexane-2-yl)-4-oxo-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-6-yl]-2-fluoro-8-azabicyclo[3.2.1]octane-3-yl]benzyl carbamate (0.07 g, 0.10 mmol) was treated with trifluoromethanesulfonic acid (0.11 mL, 1.24 mmol) and stirred at RT for 5 min. The reaction mixture was quenched by adding it dropwise to a saturated aqueous sodium carbonate solution (10 mL), then diluted with 0.1 M LiCl (50 mL) and extracted with DCM (3 x 20 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (4g gold column, 0-10% (0.7M ammonia / MeOH) / DCM) to obtain 6-[(1S,2R,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one as a colorless glassy substance. The product was treated with 5 mL of 2 M HCl in ether, sonicated for 10 min, and filtered to give 6-[(1S,2R,3S,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one hydrochloride (10 mg, 0.02 mmol, yield 19%) as a white powder. MS: [M+H] + =457.

[1697] 1 H NMR (500MHz, methanol-d4) δ: 8.48 (s, 1H), 7.64 (dd, J=8.8, 0.9Hz, 1H), 7.47 (d, J=8.8Hz, 1H), 4. 75-4.68 (m, 1H), 4.64 (dd, J=16.7, 7.7Hz, 1H), 4.49 (t, J=7.8Hz, 1H), 4.30 (s, 3H), 3.75-3. 65 (m, 1H), 3.60 (s, 3H), 2.91 (q, J=11.5, 11.1Hz, 1H), 2.48 (d, J=11.8Hz, 1H), 2.12 (dq, J= 12.5, 6.4Hz, 1H), 1.91 (dt, J=14.4, 8.0Hz, 1H), 1.68 (t, J=10.0Hz, 1H), 1.44-1.35 (m, 1H).

[1698] Method 9: 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(4- Chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one

[1699] [Chemical Formula 167]

[1700]

[1701] TFA (1 mL) was added to a solution of 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one (256 mg, 1.82 mmol) in DCM (1 mL), and the mixture was stirred at RT for 18 h. The mixture was concentrated and azeotropically treated twice with toluene. MeOH (2 mL) and ethylenediamine (0.23 mL, 3.46 mmol) were added to the residue, and the mixture was stirred at RT for 5 h. The reaction mixture was concentrated, suspended in MeOH, and the solids were collected by filtration to give the title compound (24 mg, 0.048 mmol, 14%).

[1702] The compounds shown in Table 12 are prepared using methods similar to those described in Method 9. The compounds can be separated directly by grinding / precipitation from solution, or they can be purified (e.g., using quality-oriented preparative HPLC, chromatography, crystallization). In some cases, the compounds are separated as hydrochloride salts; the compounds are separated by treating the final compound solution (e.g., MeOH solution) with excess HCl (Et₂O solution of 2N HCl) and then evaporating to dryness.

[1703]

[1704]

[1705] Examples 155 and 156

[1706] rel-2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-ethyl- 2H-Indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Example 155) and rel-2- ((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)- 3-Methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (Example 156)

[1707] [Chemical Formula 168]

[1708]

[1709] The rac-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one was dissolved in a 2.0 mg / mL ethanol / DMSO / CHCl3 = 1 / 1 / 3 solution, and the separation was completed under the following conditions.

[1710] Column: Daicel Chiralpak IG 2x25cm

[1711] Mobile phase: hexane / 2-propanol = 40 / 60

[1712] Flow rate: 25 mL / min

[1713] Retention times of each isomer:

[1714] rel-2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one: 8.15 min

[1715] rel-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one: 13.5 min.

[1716] Chiral analysis conditions:

[1717] Column: CHIRALPAK IG 4.6x150mm

[1718] Mobile phase: hexane / 2-propanol = 40 / 60

[1719] Flow rate: 1.0 mL / min

[1720] Retention times of each isomer:

[1721] rel-2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one: 7.406 min. MS: [M+H] + =438, 440. 1H-NMR (DMSO-d6) δ: 11.49 (1H, br s), 8.42 (1H, s), 7.47 (1H, dd, J = 9.0, 0.7Hz), 7.30 (1H, d, J = 9.0Hz), 6.87 (1H, s), 4.46 (2H, q, J = 7.3Hz), 3.86-3.66 (2H, m), 3.30-3 .26(3H,m), 3.17-3.14(1H,m), 3.04-2.98(1H,m), 2.18-2.11(1H,m), 2.01-1.82(3H,m), 1.51(3H,t,J=7.1Hz), 1.40-1.31(1H,m).

[1722] rel-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one: 11.246 min. MS: [M+H] + =438, 440. 1 H-NMR (DMSO-d6) δ: 11.49 (1H, br s), 8.42 (1H, s), 7.47 (1H, dd, J = 9.0, 0.7Hz), 7.30 (1H, d, J = 9.0Hz), 6.87 (1H, s), 4.46 (2H, q, J = 7.3Hz), 3.86-3.66 (2H, m), 3.30-3 .26(3H,m), 3.17-3.14(1H,m), 3.04-2.98(1H,m), 2.18-2.11(1H,m), 2.01-1.82(3H,m), 1.51(3H,t,J=7.1Hz), 1.40-1.31(1H,m).

[1723] Example 157: rel-2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4- Chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[1724] [Chemical Formula 169]

[1725]

[1726] Step 1

[1727] rac-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (200 mg, 0.472 mmol) was dissolved in CHCl3 / MeOH = 4 / 1 (5.0 mL). Di-tert-butyl dicarbonate dissolved in CHCl3 (1.0 mL) was added at 0 °C, followed by stirring at RT for 3 h. The solvent was removed by distillation, and the residue was purified by NH silica gel column chromatography (gradient elution, 0-10% MeOH / EtOAc) to give rac-((1S,4S,7S)-2-(5-(4-chloro-2-methyl-2H-...

Claims

1. Compound of formula (I): [Chemical formula 1] or a tautomer or a pharmaceutically acceptable salt thereof, wherein: X is CH or N; R 1 is -CH3; R 2 and R 3 independently selected from hydrogen and C 1-4 alkyl; Q is C or N; When Q is C, then: (i)R 4 It is amino, amino C 1-4 Alkyl or single C 1-4 Alkylamino; R 5 It is hydrogen, C 1-4 Alkyl, halogen, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or C 1-4 Alkoxy C 1-4 Alkyl; or (ii) R 4 and R 5 Together with Q, it forms a 4-6 membered ring, which may optionally contain independently selected from N, O, S, NH, C(O) and S(O) m 1 to 3 heteroatoms or groups, and R 4 and R 5 The ring formed may be unsubstituted or substituted by 1-4 groups independently selected from: amino, halogen, halogenated C 1-4 Alkyl, hydroxy, methoxy, methylamino and C 1-4 alkyl, and m is selected from 1 and 2; and When Q is N, then: R 4 does not exist; and R 5 It is hydrogen; R 6 and R 7 Independently selected from C 1-4 Alkyl and hydroxy, provided that when Q is N, then R 6 or R 7 Not hydroxyl; Or, choose R 2 , R 3 , R 6 and R 7 Any two groups together form a 1-3 membered bridging group, the bridging group is selected from C 1-3 Alkylene, C 2-3 Alkenylene, Methylene-NR q -methylene and methylene-O-methylene, wherein the bridging group is optionally selected from C 1-4 alkyl, hydroxyl and halogen groups, and R q Selected from hydrogen and C 1-4 alkyl; Or, R 4 and R 7 Forming a 4-6 membered ring containing a N atom; Or, R 5 and R 7 Forming 3-6 membered rings; Or, R 6 and R 7 Forming direct bonds; a is selected from 0, 1 and 2; b is selected from 0, 1 and 2; c is selected from 0, 1 and 2; Or, Q is C, c is 2, R 4 is hydrogen, and the two R 7 Connect to form a 4-6 membered nitrogen-containing ring; Ring A is: (i) a five-membered nitrogen-containing aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains 1 or 2 additional heteroatoms selected from N, O and S, or (ii) a six-membered nitrogen-containing aromatic heterocycle, wherein the heterocycle optionally contains 1 or 2 additional heteroatoms selected from N, O and S, R 8 Selected from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl and halogen; R 9 is selected from hydrogen and halogen; R 10 It is chlorine; R 11 independently selected from halogen, cyano, cyano C 1-4 alkyl, hydroxy, oxo (=O), C optionally substituted by a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms selected from O, N and S 1-4 Alkyl, haloC 1-4 Alkyl, C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Alkyl sulfone, amino, mono-C 1-4 Alkylamino, di-C 1-4 Alkylamino, amino C 1-4 Alkyl, -C 1-4 Alkylene-C(=O)NH (2-q) (C 1-6 alkyl) q ), -C 1-4 Alkylene-NHC(=O)C 1-6 Alkyl, Sulfonamide, Sulfonamide C 1-4 Alkyl, 3-6 membered cycloalkyl, C substituted by 3-6 membered cycloalkyl 1-4 alkyl, a 5- or 6-membered unsaturated heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from O, N and S, and an optionally substituted 4-6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N and S, wherein the optional substituents are selected from C 1-4 alkyl; q is selected from 0, 1 and 2; and d is selected from 0, 1 and 2.

2. The compound according to claim 1 or its tautomer or pharmaceutically acceptable salt, wherein R 2 , R 3 , R 6 and R 7 Any two groups together form a 1-3 membered bridging group, the bridging group is selected from C 1-3 Alkylene, C 2-3 Alkenylene, Methylene-NR q -methylene and methylene-O-methylene, wherein the bridging group is optionally selected from C 1-4 alkyl, hydroxyl and halogen groups, and R q Selected from hydrogen and C 1-4 alkyl.

3. The compound according to claim 1 or 2, or its tautomer or pharmaceutically acceptable salt, wherein Q is C.

4. The compound according to claim 1 or its tautomer or pharmaceutically acceptable salt, wherein R 4 It is amino, amino C 1-4 Alkyl or single C 1-4 Alkylamino; and R 5 It is hydrogen, C 1-4 Alkyl, halogen, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or C 1-4 Alkoxy C 1-4 alkyl.

5. The compound according to claim 1 or its tautomer or pharmaceutically acceptable salt, wherein R 4 and R 5 Together with Q, it forms a 4-6 membered ring, which may optionally contain independently selected from N, O, S, NH, C(O) and S(O) m 1 to 3 heteroatoms or groups, and R 4 and R 5 The ring formed may be unsubstituted or substituted by 1-4 groups independently selected from amino, halogen, halogenated C 1-4 Alkyl, hydroxy, methoxy, methylamino and C 1-4 and m is selected from 1 and 2.

6. The compound according to claim 1 or 2, or a tautomer or a pharmaceutically acceptable salt thereof, wherein Q is N.

7. The compound according to claim 1, or a tautomer or a pharmaceutically acceptable salt thereof, wherein X is CH.

8. The compound according to claim 1, or a tautomer or a pharmaceutically acceptable salt thereof, wherein X is N.

9. The compound according to claim 1 or its tautomer or pharmaceutically acceptable salt, wherein the compound is selected from: 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(4-amino-4-methylpiperidin-1-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(exo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(7-chloro-2-ethylbenzo[d]thiazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(7-chloro-2-methylbenzo[d]thiazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(2-(tert-butyl)-4-chloro-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(exo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (R)-2-(1-amino-8-azaspiro[4.5]decane-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (S)-2-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-2-(endo-3-(methylamino)-8-azabicyclo[3.2.1]octan-8-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(endo-3-(methylamino)-8-azabicyclo[3.2.1]octan-8-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (R)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(3-methylpiperazin-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(7-amino-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(exo-8-amino-3-azabicyclo[3.2.1]octan-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-8-amino-3-azabicyclo[3.2.1]octan-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(3,9-diazabicyclo[3.3.1]nonan-9-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(3,6-diazabicyclo[3.1.1]heptane-6-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(2,5-diazabicyclo[2.2.2]octan-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(exo-6-amino-3-azabicyclo[3.1.1]heptane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-6-amino-3-azabicyclo[3.1.1]heptane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(5-amino-2-azabicyclo[2.2.1]heptan-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(exo-3-amino-9-azabicyclo[3.3.1]nonan-9-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-9-azabicyclo[3.3.1]nonan-9-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(1,8-diazaspiro[4.5]decane-8-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(piperazin-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(3,7-diazabicyclo[4.2.0]octan-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(1,9-diazaspiro[5.5]undecane-9-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(1,7-diazaspiro[3.5]nonan-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (S)-2-(3-aminopyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (R)-2-(3-aminopyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (S)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(3-methylpiperazin-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1S,2S,4R)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (R)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(2-methylpiperazin-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (S)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-(2-methylpiperazin-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, rac-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (S)-2-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (R)-2-(3-amino-3-methylpyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((3R,4R)-3-amino-4-methylpyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((3R,4S)-3-amino-4-methylpyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(3-amino-3-(hydroxymethyl)pyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (R)-2-(3-(aminomethyl)pyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(1-amino-3-azabicyclo[3.1.0]hexane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(6-amino-3-azabicyclo[3.1.0]hexane-3-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (S)-2-(3-(aminomethyl)pyrrolidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(4-(Aminomethyl)-4-methoxypiperidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(4-(Aminomethyl)-4-fluoropiperidin-1-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(3,9-diazabicyclo[3.3.1]nonan-9-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(7-chloro-2-methylbenzo[d]oxazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(7-chloro-2-ethylbenzo[d]oxazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(7-chloro-1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2,7-dimethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(1H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octan-8-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-5-(7-chloro-2-methylbenzo[d]thiazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(5-(2-(3,9-diazabicyclo[3.3.1]nonan-9-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,4-dichloro-2H-indazol-2-yl)-N,N-dimethylacetamide, 3-(5-(2-(3,9-diazabicyclo[3.3.1]nonan-9-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,4-dichloro-2H-indazol-2-yl)-N,N-dimethylpropanamide, 2-(6-(2-(3,9-diazabicyclo[3.3.1]nonan-9-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-7-chlorobenzo[d]thiazol-2-yl)-N,N-dimethylacetamide, 2-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(5-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-chloro-2H-indazol-2-yl)-N,N-dimethylacetamide, 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 3-(5-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-chloro-2H-indazol-2-yl)-N,N-dimethylpropanamide, 3-(5-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,4-dichloro-2H-indazol-2-yl)-N,N-dimethylpropanamide, 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(7-chloro-2-methylbenzo[d]thiazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2,3-dimethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(7-chloro-2-methylbenzo[d]thiazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(3,9-diazabicyclo[3.3.1]nonan-9-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(7-chlorobenzo[d]thiazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-ethyl-3-methoxy-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3,4-dichloro-2-(fluoromethyl)-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(7-chlorobenzo[d]thiazol-6-yl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(7-chloro-2-methylbenzo[d]thiazol-6-yl)-3-methyl-2-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-(3,9-diazabicyclo[3.3.1]nonan-9-yl)-5-(7-chlorobenzo[d]thiazol-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-3-(difluoromethyl)-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-ethyl-3-(hydroxymethyl)-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-(3,9-diazabicyclo[3.3.1]nonan-9-yl)-3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-(7-chloro-2-methylbenzo[d]thiazol-6-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octan-8-yl)-3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(3,9-diazabicyclo[3.3.1]nonan-9-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(3,9-diazabicyclo[3.3.1]nonan-9-yl)-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(3,9-diazabicyclo[3.3.1]nonan-9-yl)-3-(7-chlorobenzo[d]thiazol-6-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 3-(7-chlorobenzo[d]thiazol-6-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 3-(7-chloro-2-methylbenzo[d]thiazol-6-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, rac-6-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, rac-6-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-(3,4-dichloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 3-(3,4-dichloro-2-ethyl-2H-indazol-5-yl)-5-methyl-6-((1R,2R,4S)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, rac-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, rac-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-3-(7-chlorobenzo[d]thiazol-6-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, rac-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-((1S,4S,7S)-7-(methylamino)-2-azabicyclo[2.2.1]heptane-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, endo-6-[3-amino-8-azabicyclo[3.2.1]octan-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, 3-(4-chloro-2-methyl-2H-indazol-5-yl)-6-{3,8-diazabicyclo[3.2.1]octan-8-yl}-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, 6-[(1R,3S)-1-amino-3-hydroxy-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, 6-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, exo-6-[3-amino-8-azabicyclo[3.2.1]octan-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, 3-(4-chloro-2-methyl-2H-indazol-5-yl)-6-{2,7-diazaspiro[3.5]nonan-7-yl}-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, 6-[(1R)-1-amino-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, 6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, 6-[(1R,3R)-1-amino-3-fluoro-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, 3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-6-{3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, 3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-6-{3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, 6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, 6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-(1,4-diazepan-1-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, rac-2-[(1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octan-8-yl]-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, rac-5-(4-chloro-2-methyl-2H-indazol-5-yl)-2-[(1R,6S)-3,9-diazabicyclo[4.2.1]nonan-9-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, rac-2-(4-aminoazepan-1-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, rel-2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, rel-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, rel-2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, rel-2-((1S,4S,7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-chloro-2-ethyl-2H-indazole-3-carbonitrile, 6-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(endo-3-amino-3-methyl-8-azabicyclo[3.2.1]octan-8-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 2-(rac-(1R,2S,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-2-((1S,2S,4R)-2-(methylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,2S,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,2S,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-methyl-5-(3,4,7-trichloro-2-methyl-2H-indazol-5-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(5-chloro-3-methoxyquinoxalin-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(5-chloro-3-(dimethylamino)quinoxalin-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, rac-2-((1R,2R,4S)-2-amino-2-methyl-7-azabicyclo[2.2.1]heptane-7-yl)-5-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 2-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-yl)-5-(3-chloro-4-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, rac-6-((1R,2R,4S)-2-amino-2-methyl-7-azabicyclo[2.2.1]heptane-7-yl)-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 2-(endo-3-amino-8-azabicyclo[3.2.1]octan-8-yl)-5-(5-chloroquinoxalin-6-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-6-((1R,2R,4S)-2-(ethylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 2-((1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-5-(4-chloro-2-(2-methoxyethyl)-2H-indazol-5-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-6-((1R,2R,4S)-2-(isopropylamino)-7-azabicyclo[2.2.1]heptane-7-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 2-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(7-chloro-2-ethyl-2H-indazol-6-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, 2-[(endo)-3-amino-3-(difluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl]-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-methyl-2H-indazol-5-yl)-2-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-9-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-methyl-2H-indazol-5-yl)-2-[(1R,6S)-3,9-diazabicyclo[4.2.1]nonan-9-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-{(1R,5R)-3,6-diazabicyclo[3.2.1]octan-3-yl}-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-{(1S,5S)-3,6-diazabicyclo[3.2.1]octan-3-yl}-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-[(1S,5R)-3,6-diazabicyclo[3.2.1]octan-6-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, 5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-[(1R,5S)-3,6-diazabicyclo[3.2.1]octan-6-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(4-chloro-7-fluoro-2-methyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, 2-[(endo)-2-amino-2-methyl-7-azabicyclo[2.2.1]heptan-7-yl]-5-(4-chloro-2-methyl-2H-indazol-5-yl)-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, rac-5-(4-chloro-2-ethyl-2H-indazol-5-yl)-2-{2,6-diazaspiro[3.4]octan-6-yl}-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, 2-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl]-5-[8-chloro-2-(dimethylamino)quinolin-7-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one, and 2-[(1R,2R,4S)-2-Amino-7-azabicyclo[2.2.1]heptan-7-yl]-5-[8-chloro-2-(methylamino)quinolin-7-yl]-3-methyl-3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one.

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a tautomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

11. Use of the pharmaceutical composition according to claim 10 in the preparation of a drug for preventing or treating a disease or condition mediated by SHP2, wherein the disease or condition mediated by SHP2 is cancer.

12. The method of claim 11, wherein the cancer is selected from the group consisting of head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, bile duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumors, osteosarcoma, soft tissue sarcoma, leukemia, myelodysplastic syndrome, chronic myeloproliferative disease, malignant lymphoma, multiple myeloma, skin cancer, brain tumor or mesothelioma.

13. Use of a compound according to any one of claims 1 to 9 or a tautomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease or condition mediated by SHP2, wherein the disease or condition mediated by SHP2 is cancer.

14. The method of claim 13, wherein the cancer is selected from the group consisting of head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, bile duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, osteosarcoma, soft tissue sarcoma, leukemia, myelodysplastic syndrome, chronic myeloproliferative disease, malignant lymphoma, multiple myeloma, skin cancer, brain tumor or mesothelioma.

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