Preparation of SHP2 phosphatase inhibitors and its applications

Abstract

The present invention has disclosed SHP2 phosphatase inhibitors and its applications. Specifically, the present invention has disclosed the compounds shown in the general formula (I), methods of preparation thereof, and pharmaceutical compositions containing the compound, and their use as tyrosine phosphatase SHP-2 inhibitors in the treatment of leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, pancreatic cancer, head and neck squamous cell carcinoma, stomach cancer, liver cancer, anaplastic large cell lymphoma, and glioblastoma, wherein each substituent in general formula (I)k is as defined in the specification.

Claims

1. A compound represented by general formula (I) and general formula (II) or its prodrug, stable isotope derivative, pharmaceutically acceptable salt, polymorph or isomer, ##STR00226## Wherein: Each L.sub.1 is, at each occurrence, independently selected from bond, O, CH.sub.2, NH, CO, S(O).sub.m, or S; Each L.sub.2 is, at each occurrence, independently selected from bond, O, CH.sub.2, NH, CONH.sub.2, CO, S(O).sub.m, or S; Each Ar.sub.1, at each occurrence, is independently selected from a 6-membered heteroaryl or a 10-membered heteroaryl; Each Ar.sub.1 at each occurrence is independently optionally substituted or unsubstituted by 1 or 2 R.sub.19S; Each Ar.sub.2 is, at each occurrence, independently selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, 3-membered to 10-membered cycloalkyl, 5-membered to 10-membered heterocyclic alkyl; and each heteroaryl and heterocyclic alkyl at each occurrence independently comprises, 1, 2, 3, or 4 heteroatoms selected from N, O, or S; Each Ar.sub.2 at each occurrence is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5, or 6 R.sub.19S; Each Ar.sub.3 is, at each occurrence, independently selected from H, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, 3-membered to 10-membered cycloalkyl, 5-membered to 10-membered heterocyclic alkyl; and each heteroaryl and heterocyclic alkyl is, at each occurrence, independently comprises 1, 2, 3, or 4 heteroatoms selected from N, O, or S; Each Ar.sub.3 at each occurrence is independently optionally substituted or unsubstituted by 1, 2, 3, 4, or 6 R.sub.19S; Each R.sub.19 is, at each occurrence, independently selected from deuterium, halogen, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkylidene-(halogen).sub.1-3, C.sub.1-6 heteroalkyl, CN, OR.sub.10, C.sub.1-6 alkylidene-(OR.sub.10).sub.1-3, OC.sub.1-6 alkylidene-(halogen).sub.1-3, SR.sub.10, SC.sub.1-6 alkylidene-(halogen).sub.1-3, NR.sub.10R.sub.11, C.sub.1-6 alkylidene-NR.sub.10R.sub.11, C(?O)R.sub.10, C(?O)OR.sub.10, OC(?O)R.sub.10, C(?O)NR.sub.10R.sub.11, NR.sub.10C(?O)R.sub.11, S(O).sub.2NR.sub.10R.sub.11, or C.sub.3-6 carbocyclyl; Each R.sub.19 is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, oxo, OR.sub.10, NR.sub.10R.sub.11, CN, C(?O)R.sub.10, C(?O)OR.sub.10, OC(?O)R.sub.10, C(?O)NR.sub.10R.sub.11, NR.sub.10C(?O)R.sub.11, or S(O).sub.2NR.sub.6R.sub.11; Each R.sub.10 and R.sub.11 is, at each occurrence, independently selected from hydrogen, deuterium, or C.sub.1-6 alkyl, and each R.sub.10 and R.sub.11 is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5, or 6 substituents of R.sub.19; Or, R.sub.10, R.sub.11 and the N atoms attached to the R.sub.10 and R.sub.11 together form a 3-membered and 10-membered heterocyclic ring, which can further comprise 1, 2, 3, or 4 heteroatoms selected from N, O, S, S(?O), S(?O), or S(?O).sub.2, and the stated 3-membered and 10-membered heterocyclic ring is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5, or 6 R.sub.20s; Each R.sub.20 is, at each occurrence, independently selected from deuterium, halogen, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkylidene-(halogen).sub.1-3, C.sub.1-6 heteroalkyl, CN, OC.sub.1-6, C.sub.1-6 alkylidene-(OC.sub.1-6).sub.1-3, OC.sub.1-6 alkylidene-(halogen).sub.1-3, SC.sub.1-6, SC.sub.1-6 alkylidene-(halogen).sub.1-3, or C.sub.3-6 carbocyclyl; Each X.sub.8 is, at each occurrence, independently selected from CR.sub.4R.sub.5, SiR.sub.4R.sub.5, NH, or O; Each X.sub.9 is, at each occurrence, independently selected from CR.sub.6 or NH, wherein, one of X.sub.7 and X.sub.8 must be carbon atom; Each R.sub.1 is, at each occurrence, independently selected from H, deuterium, or C.sub.1-6 alkyl; Each R.sub.2 is, at each occurrence, independently selected from H, deuterium, OH, or CH.sub.2NH.sub.2; Each R.sub.3, R.sub.7 and R.sub.8 is, at each occurrence, independently selected from H or deuterium; Each R.sub.4 is, at each occurrence, independently selected from H, deuterium, OH, or C.sub.0-3NR.sub.12R.sub.13; Each R.sub.5 is, at each occurrence, independently selected from H, deuterium, OH, or C.sub.1-6 alkyl; C.sub.1-6 alkyl comprises 1, 2, 3, 4, 5, or 6 deuteriums, OH, methyl, OCH.sub.3, and 5-membered to 10-membered heteroaryl; Each R.sub.6 is, at each occurrence, independently selected from H, deuterium, or NH.sub.2; Two of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, and R.sub.8 can connect each other in the following manner: R1 and R2 can be connected by CH.sub.2NHCH.sub.2 to form a fused bicyclic structure, R.sub.1 and R.sub.6 can be connected by an alkylidene group to form a bridged bicyclic structure, R.sub.2 and R.sub.3 can be connected by an NH.sub.2-substituted alkylidene to form a spiro, R.sub.4 and R.sub.5 can be connected to form a C.sub.3-12 cycloalkyl, a C.sub.3-12 heterocyclic alkyl, a C.sub.3-12 bicyclic alkyl, or a C.sub.3-12 heterobicyclic alkyl, wherein, the heterocyclic alkyl and the heterobicyclic alkyl of C.sub.3-12, at each occurrence, independently comprise 1, 2, 3, or 4 heteroatoms selected from N, O, or S, and wherein each of C.sub.3-12 cycloalkyl, C.sub.3-12 heterocyclic alkyl, C.sub.3-12 bicyclic alkyl, and C.sub.3-12 heterobicyclic alkyl is, at each occurrence, independently optionally is substituted by deuterium, halogen, OH, CH.sub.3, OCH.sub.3, or NH.sub.2 to form a spiro. R.sub.1 and R.sub.7 can form a bridged bicyclic structure through the connection of alkylidene, O and NH, R.sub.2 and R.sub.6 can form a bridged bicyclic structure through the connection of alkylidenes, R.sub.2 and R.sub.7 can form a bridged bicyclic structure through the connection of alkylidene and O, R.sub.4 and R.sub.6 can connect with each other to form a fused bicyclic structure through NHCH.sub.2 and NH.sub.2-substituted C.sub.3-12 cycloalkyl, Each of a, b, c, and d is, at each occurrence, independently selected from 0, or 1;

2. The compound of (I) according to claim 1, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein each Ar.sub.1 is independently selected from ##STR00227## ##STR00228## ##STR00229## ##STR00230## Each Ar.sub.1 is, at each occurrence, independently optionally substituted or unsubstituted by 1 or 2 R.sub.19S; Each R.sub.19 is independently selected, at each occurrence, from deuterium, halogen, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkylidene-(halogen).sub.1-3, C.sub.1-6 heteroalkyl, CN, OR.sub.10, C.sub.1-6 alkylidene-(OR 10).sub.1-3, OC.sub.1-6 alkylidene-(halogen).sub.1-3, SR.sub.10, SC.sub.1-6 alkylidene-(halogen).sub.1-3, NR.sub.10R.sub.11, C.sub.1-6 alkylidene-NR.sub.10R.sub.11, C(?O)R.sub.10, C(?O)OR.sub.10, OC(?O)R.sub.10, C(?O)NR.sub.10R.sub.11, NR.sub.10C(?O)R.sub.11, S(O).sub.2NR.sub.10R.sub.11, or C.sub.3-6 carbocyclic; Each R.sub.19 is independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, oxo, OR.sub.10, NR.sub.10R.sub.11, CN, C(?O)R.sub.10, C(?O)OR.sub.10, OC(?O)R.sub.10, C(?O)NR.sub.10R.sub.11, NR.sub.10C(?O)R.sub.11, or S(O).sub.2NR.sub.6R.sub.11; Each of R.sub.10 and R.sub.11 is independently selected, at each occurrence, from hydrogen, deuterium, or C.sub.1-6 alkyl, and each of R.sub.10 and R.sub.11 is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5, or 6 R.sub.19s; or R.sub.10, R.sub.11, and the atoms attached thereto form a 3-membered to 10-membered heterocyclic ring, and the stated 3-membered to 10-membered heterocyclic ring can further comprise 1, 2, 3, or 4 heteroatoms selected from N, O, S, S(?O), S(?O), or S(?O).sub.2, and the stated 3-membered to 10-membered heterocyclic ring is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5, or 6 R.sub.20S; Each R.sub.20 is independently selected, at each occurrence, from deuterium, halogen, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkylidene-(halogen).sub.1-3, C.sub.1-6 heteroalkyl, .CN, OC.sub.1-6, C.sub.1-6 alkylidene-(OC.sub.1-6).sub.1-3, OC.sub.1-6 alkylidene-(halogen).sub.1-3, SC.sub.1-6, SC.sub.1-6 alkylidene-(halogen).sub.1-3, or C.sub.3-6 carbocyclic;

3. In some embodiments, the compound of (I) described above, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, wherein the structure ##STR00231## is selected from the following: ##STR00232##

4. The compounds of (I) according to claim 1, pharmaceutically acceptable salts thereof, or a stereoisomers thereof, wherein Ar.sub.2 is, at each occurrence, independently selected of phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, 3-membered to 10-membered cycloalkyl, 5-membered to 10-membered heterocycloalkyl; Each of heteroaryl and heterocycloalkyl at each occurrence independently comprises 1, 2, 3, or 4 heteroatoms selected from N, O, or S; Each Ar.sub.3 is, at each occurrence, independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5 or 6 R.sub.19S; Each Ar.sub.3 is independently selected, at each occurrence, from H, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, 3-membered to 10-membered cycloalkyl, and 5-membered to 10-membered heterocyclic alkyl; Each of heteroaryl and heterocycloalkyl at each occurrence independently comprises 1, 2, 3, or 4 heteroatoms selected from N, O, or S; Each Ar.sub.2 is, at each occurrence, independently and optionally substituted or unsubstituted by 1, 2, 3, 4, 5, or 6 R.sub.19S; Each R.sub.19 is independently selected, at each occurrence, from deuterium, halogen, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkylidene-(halogen).sub.1-3, C.sub.1-6 heteroalkyl, CN, OR.sub.10, C.sub.1-6 alkylidene-(OR.sub.10).sub.1-3, OC.sub.1-6 alkylidene-(halogen).sub.1-3, SR.sub.10, SC.sub.1-6 alkylidene-(halogen).sub.1-3, NR.sub.10R.sub.11, C.sub.1-6 alkylidene-NR.sub.10R.sub.11, C(?O)R.sub.10, C(?O)OR.sub.10, OC(?O)R.sub.10, C(?O)NR.sub.10R.sub.11, NR.sub.10C(?O)R.sub.11, S(O).sub.2NR.sub.10R.sub.11, or C.sub.3-6 carbocyclic; Each R.sub.19 is independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, oxo, OR.sub.10, NR.sub.10R.sub.11, CN, C(?O)R.sub.10, C(?O)OR.sub.10, OC(?O)R.sub.10, C(?O)NR.sub.10R.sub.11, NR.sub.10C(?O)R.sub.11, or S(O).sub.2NR.sub.6R.sub.11; Each of R.sub.10 and R.sub.11 is independently selected, at each occurrence, from hydrogen, deuterium, or C.sub.1-6 alkyl, and each of R.sub.10 and R.sub.11 is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5, or 6 R.sub.19s; or R.sub.10, R.sub.11, and the atoms attached thereto form a 3-membered to 10-membered heterocyclic ring, and the stated 3-membered to 10-membered heterocyclic ring can further comprise 1, 2, 3, or 4 heteroatoms selected from N, O, S, S(?O), or S(?O).sub.2, and the stated 3-membered to 10-membered heterocyclic ring is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5, or 6 R.sub.20S; Each R.sub.20 is independently selected, at each occurrence, from deuterium, halogen, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkylidene-(halogen).sub.1-3, C.sub.1-6 heteroalkyl, .CN, OC.sub.1-6, C.sub.1-6 alkylidene-(OC.sub.1-6).sub.1-3, OC.sub.1-6 alkylidene-(halogen).sub.1-3, SC.sub.1-6, SC.sub.1-6 alkylidene-(halogen).sub.1-3, or C.sub.3-6 carbocyclic; Further preferably, each ##STR00233## is selected from the following structure: ##STR00234## ##STR00235##

5. The compounds according to claim 1 or its prodrug, stable isotope derivatives, pharmaceutically acceptable salts, polymorphs or isomers and mixtures thereof, which are selected from the following compounds: ##STR00236## ##STR00237## ##STR00238## ##STR00239## ##STR00240## ##STR00241## ##STR00242## ##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247## ##STR00248## ##STR00249## ##STR00250## ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265## ##STR00266## ##STR00267## ##STR00268## ##STR00269## ##STR00270## Or their prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, solvates, isomers and mixtures thereof.

6. A pharmaceutical composition, which comprises a compound of formula (I) stated in claim 1, its pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, or isomer and mixture thereof.

7. A pharmaceutical preparation, which comprises a compound of formula (I) stated in claim 1, its pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, or isomer and its mixture thereof, or the pharmaceutical compositions stated in claim 5; wherein, the described preparation is any of tablet, capsule, injection, granule, powder, suppository, pill, cream, paste, gel, pulvis, oral solution, inhalation, suspension, dry suspension, patch, and lotion.

8. A compound of formula (I) stated in claim 1, or its pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, or its isomer and mixture thereof; Or, the pharmaceutical composition stated in claim 6; Or, the pharmaceutical preparation stated in claim 7; all above are used for the prevention and treatment of non-receptor protein tyrosine phosphatase-mediated or -dependent diseases or symptoms.

9. A compound of formula (I) stated in claim 1, or its pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, or its isomer and mixture thereof; Or, the pharmaceutical composition stated in claim 6; Or, the pharmaceutical preparation stated in claim 7; all above are used for the prevention and treatment of non-receptor protein tyrosine phosphatase-mediated or -dependent diseases or symptoms.

10. A compound of formula (I) stated in claim 1, or its pharmaceutically acceptable prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, or its isomer and mixture thereof; Or, the pharmaceutical preparation stated in claim 4 which is used for the prevention and treatment of non-receptor protein tyrosine phosphatase-mediated or -dependent diseases or symptoms.

11. The compound of general formula (I) stated in claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or atropisomer or mixture thereof; Or, its pharmaceutically acceptable salt thereof; Or, the use of the pharmaceutical compositions containing it in the prevention or treatment of Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, pancreatic cancer, head and neck squamous cell carcinoma, gastric cancer, liver cancer, anaplastic large cell lymphoma and glioblastoma.

Description

EXAMPLE 1

Preparation of 7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(2,3-dichloropheny l)quinazoline-2,4(1H,3H)-dione

[0262] ##STR00095##

[0263] Dissolve the compound 7-bromo-3-(2,3-dichlorophenyl)quinazoline-2,4(1H,3H)-dione (772 mg, 2 mmol) in 8 mL of toluene, add (3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane dihydrochloride (584 mg, 2.4 mmol), cesium carbonate (1.95 g, 6.0 mmol), and bis(dibenzylideneacetone)palladium (12 mg, 0.02 mmol), 2-dicyclohexylphosphonium-2,6-diisopropoxy-1,1-biphenyl (19 mg, 0.04 mmol).

[0264] Perform nitrogen substitution is 3 times, and react at 90? C. for 6 hours with stirring. After cooling to room temperature, the reaction solution is passed through a silica gel short column, rinse the column with ethyl acetate, and evaporate the solution to dryness under reduced pressure. The residue is purified by column chromatography to give the target product 1 (494 mg, yield 52%). 1H NMR (400 MHZ, DMSO-d.sub.6) ?: 11.51 (s, 1H), 7.83 (d, 1H), 7.51-7.45 (m, 2H), 7.31-7.26 (m, 2H), 6.83 (d, 1H), 4.10-4.07 (m, 1H), 3.89-3.45 (m, 4H), 3.32-3.25 (m, 2H), 2.91 (d, 1H), 1.77-1.32 (m, 6H), 1.13 (d, 3H); LC/MS(ESI): m/z=475.1[M+H].sup.+.

Embodiment 2

Preparation of (S)-7-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(2,3-dichlorophenyl)quinazoline-2,4(1H,3H)-dione

[0265] ##STR00096##

[0266] Compound 2 (415 mg, yield 45%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=461.1[M+H].sup.+.

Embodiment 3

Preparation of (S)-3-(2-amino-3-chloropyridine-4-yl)-7-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)q uinazoline-2,4(1H,3H)-dione

[0267] ##STR00097##

[0268] Compound 3 (222 mg, yield 25%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 11.23 (s, 1H), 7.82 (d, 1H), 7.51-7.45 (m, 1H), 7.30-7.26 (m, 1H), 6.85 (d, 1H), 6.64 (d, 1H), 5.87 (s, 2H), 4.12-4.08 (m, 1H), 3.89-3.45 (m, 5H), 3.32-3.25 (m, 2H), 2.82-2.74 (m, 1H), 1.74-1.29 (m, 6H); LC/MS(ESI): m/z=443.2[M+H].sup.+.

Embodiment 4

Preparation of (S)-7-(1-amino-1,3-dihydrospiro[indene-2,4-piperidine]-1-yl)-3-(2,3-dichlorophenyl) quinazoline-2,4(1H,3H)-dione

[0269] ##STR00098##

[0270] Compound 4 (548 mg, yield 54%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ?: 11.28 (s, 1H), 7.83 (d, 1H), 7.51-7.45 (m, 2H), 7.31-7.23 (m, 6H), 6.83 (d, 1H), 4.08-4.03 (m, 1H), 3.53-3.45 (m, 2H), 3.32-3.25 (m, 2H), 2.91-2.79 (m, 2H), 1.65-1.30 (m, 6H); LC/MS(ESI): m/z=507.1[M+H].sup.+.

Embodiment 5

Preparation of (S)-7-(5-Amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4-piperidine]-1-yl)-3-(2,3-dichlorophenyl)auinazoline-2.4(1H,3H)-dione

[0271] ##STR00099##

[0272] Compound 5 (498 mg, yield 49%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 11.50 (s, 1H), 8.28-8.23 (m, 2H), 7.83 (d, 1H), 7.51-7.45 (m, 2H), 7.31-7.23 (m, 3H), 6.83 (d, 1H), 4.03-3.95 (m, 1H), 3.52-3.45 (m, 2H), 3.32-3.25 (m, 2H), 2.71-2.63 (m, 2H), 1.61-1.29 (m, 6H); LC/MS(ESI): m/z=508.1[M+H].sup.+.

Embodiment 6

Preparation of (S)-7-(7-Amino-5,7-dihydrospiro [cyclopenta[c]pyridine-6,4-piperidine]-1-yl)-3-(2,3-dichlorophenyl)quinazoline-2,4(1H,3H)-dione

[0273] ##STR00100##

[0274] Compound 6 (437 mg, yield 43%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=508.1[M+H].sup.+.

Embodiment 7

Preparation of (S)-7-(5-Amino-5,7-dihydrospiro [cyclopenta[b]pyridine-6,4-piperidine]-1-yl)-3-(2,3-dichlorophenyl)quinazoline-2,4(1H,3H)-dione

[0275] ##STR00101##

[0276] Compound 7 (528 mg, yield 52%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=508.1[M+H].sup.+.

Embodiment 8

Preparation of (S)-7-(7-Amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4-piperidine]-1-yl)-3-(2,3-dichlorophenyl)quinazoline-2,4(1H,3H)-dione

[0277] ##STR00102##

[0278] Compound 8 (416 mg, yield 41%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=508.1[M+H].sup.+.

Embodiment 9

Preparation of (R)-7-(4-(1-aminoethyl)-4-methylpiperidine-1-yl)-3-(2,3-dichlorophenyl)quinazoline-2,4(1H,3H)-dione

[0279] ##STR00103##

[0280] Compound 9 (394 mg, yield 44%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=449.1[M+H].sup.+.

Embodiment 10

Preparation of 7-(4-(aminoethyl)-4-methylpiperidine-1-yl)-3-(2,3-dichlorophenyl)quinazoline-2,4(1 H,3H)-dione

[0281] ##STR00104##

[0282] Compound 10 (328 mg, yield 38%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 11.42 (s, 1H), 7.93 (s, 1H), 7.51-7.45 (m, 2H), 7.26 (d, 1H), 3.48-3.39 (m, 2H), 3.34-3.26 (m, 2H), 2.63 (s, 2H), 1.72-1.45 (m, 4H), 1.12 (s, 3H); LC/MS(ESI): m/z=433.1[M+H].sup.+.

Embodiment 11

Preparation of 7-(4-amino-4-methylpiperidine-1-yl)-3-(2,3-dichlorophenyl)quinazoline-2,4(1H,3H)-dione

[0283] ##STR00105##

[0284] Compound 11 (361 mg, yield 43%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 11.42 (s, 1H), 7.93 (s, 1H), 7.51-7.45 (m, 2H), 7.26 (d, 1H), 3.45-3.37 (m, 2H), 3.32-3.25 (m, 2H), 1.82-1.65 (m, 4H), 1.24 (s, 3H); LC/MS(ESI): m/z=421.1[M+H].sup.+.

Embodiment 12

Preparation of 7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(2,3-dichloropheny l)pteridine-2,4(1H,3H)-dione

[0285] ##STR00106##

[0286] Compound 12 (485 mg, yield 51%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=477.1[M+H].sup.+.

Embodiment 13

Preparation of (S)-7-(1-amino-1,3-dihydrospiro[indene-2,4-piperidine]-1-yl)-3-(2,3-dichlorophenyl) pteridine-2,4(1H,3H)-dione

[0287] ##STR00107##

[0288] Compound 13 (436 mg, yield 43%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 11.42 (s, 1H), 7.95 (s, 1H), 7.49-7.43 (m, 2H), 7.25 (d, 1H), 4.08-4.03 (m, 1H), 3.57-3.48 (m, 2H), 3.33-3.25 (m, 2H), 2.91-2.77 (m, 2H), 1.65-1.31 (m, 4H); LC/MS(ESI): m/z=509.1[M+H].sup.+.

Embodiment 14

Preparation of (S)-7-(5-Amino-5,7-dihydrospiro [cyclopenta[b]pyridine-6,4-piperidine]-1-yl)-3-(2,3-dichlorophenyl)pteridine-2,4(1 H,3H)-dione

[0289] ##STR00108##

[0290] Compound 14 (395 mg, yield 39%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=510.1[M+H].sup.+.

Embodiment 15

Preparation of (S)-7-(5-Amino-5,7-dihydrospiro [cyclopenta[c]pyridine-6,4-piperidine]-1-yl)-3-(2,3-dichlorophenyl)pteridine-2,4(1H,3H)-dione

[0291] ##STR00109##

[0292] Compound 15 (506 mg, yield 50%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=510.1[M+H].sup.+.

Embodiment 16

Preparation of (S)-7-(7-Amino-5,7-dihydrospiro [cyclopenta[c]pyridine-6,4-piperidine]-1-yl)-3-(2,3-dichlorophenyl)pteridine-2,4(1H,3H)-dione

[0293] ##STR00110##

[0294] Compound 16 (425 mg, yield 42%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=510.1[M+H].sup.+.

Embodiment 17

Preparation of 3-(2-amino-3-chloropyridine-4-yl)-7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pteridine-2,4(1H,3H)-dione

[0295] ##STR00111##

[0296] Compound 17 (222 mg, yield 29%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 11.35 (s, 1H), 7.95 (s, 1H), 7.83 (d, 1H), 7.30-7.26 (m, 1H), 5.93 (s, 2H), 4.10-4.07 (m, 1H), 3.89-3.45 (m, 4H), 3.32-3.24 (m, 2H), 2.92 (d, 1H), 1.77-1.32 (m, 6H), 1.14 (d, 3H); LC/MS(ESI): m/z=459.2[M+H].sup.+.

Embodiment 18

Preparation of (S)-7-(1-amino-1,3-dihydrospiro[indene-2,4-piperidine]-1-yl)-3-(2-amino-3-chlorop yridine-4-yl)pteridine-2,4(1H,3H)-dione

[0297] ##STR00112##

[0298] Compound 18 (222 mg, yield 21%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=491.2[M+H].sup.+.

Embodiment 19

Preparation of (S)-3-(2-amino-3-chloropyridine-4-yl)-7-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyr idine-6,4-piperidine]-1-yl)pteridine-2,4(1H,3H)-dione

[0299] ##STR00113##

[0300] Compound 19 (244 mg, yield 23%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=492.2[M+H].sup.+.

Embodiment 20

Preparation of (S)-3-(2-amino-3-chloropyridine-4-yl)-7-(5-amino-5,7-dihydrospiro[cyclopenta[c]pyr idine-6,4-piperidine]-1-yl)pteridine-2,4(1H,3H)-dione

[0301] ##STR00114##

[0302] Compound 20 (202 mg, yield 19%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 11.50 (s, 1H), 7.95 (s, 1H), 7.83 (d, 1H), 7.30-7.26 (m, 1H), 5.84 (s, 2H), 4.03-3.96 (m, 1H), 3.52-3.45 (m, 2H), 3.32-3.25 (m, 2H), 2.73-2.65 (m, 2H), 1.61-1.30 (m, 6H); LC/MS(ESI): m/z=492.2[M+H].sup.+.

Embodiment 21

Preparation of (S)-3-(2-amino-3-chloropyridine-4-yl)-7-(7-amino-5,7-dihydrospiro[cyclopenta[c]pyr idine-6,4-piperidine]-1-yl)pteridine-2,4(1H,3H)-dione

[0303] ##STR00115##

[0304] Compound 21 (266 mg, yield 25%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=492.2[M+H].sup.+.

Embodiment 22

Preparation of (S)-3-(2-amino-3-chloropyridine-4-yl)-7-(7-amino-5,7-dihydrospiro[cyclopenta[b]pyr idine-6,4-piperidine]-1-yl)pteridine-2,4(1H,3H)-dione

[0305] ##STR00116##

[0306] Compound 22 (223 mg, yield 21%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=492.2[M+H].sup.+.

Embodiment 23

Preparation of 3-(2-amino-3-chloropyridine-4-yl)-7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pteridine-2,4(1H,3H)-dione

[0307] ##STR00117##

[0308] Compound 23 (280 mg, yield 26%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 11.35 (s, 1H), 7.95 (s, 1H), 7.88 (d, 1H), 7.30-7.26 (m, 1H), 5.23 (s, 1H), 4.10-4.07 (m, 1H), 3.89-3.45 (m, 4H), 3.32-3.24 (m, 2H), 2.92 (d, 1H), 2.53-2.46 (m, 1H), 1.77-1.32 (m, 6H), 1.14 (d, 3H), 0.81-0.77 (m, 2H), 0.57-0.52 (m, 2H); LC/MS(ESI): m/z=499.2[M+H].sup.+.

Embodiment 24

Preparation of (S)-7-(5-Amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4-piperidine-1-yl)-3-(3-ch loro-2-(cyclopropylamino)pyridine-4-yl)-pteridine-2,4(1H,3H)-dione

[0309] ##STR00118##

[0310] Compound 24 (356 mg, yield 31%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=532.2[M+H].sup.+.

Embodiment 25

Preparation of 7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(2,3-dichloropheny l)pyridinyl[2,3-d]pyrimidine-2,4(1H,3H)-dione

[0311] ##STR00119##

[0312] Compound 25 (443 mg, yield 43%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=477.1[M+H].sup.+.

Embodiment 26

Preparation of (S)-7-(5-Amino-5,7-dihydrospiro [cyclopenta[c]pyridine-6,4-piperidine]-1-yl)-3-(2,3-dichlorophenyl)pyridinyl[2,3-d]pyrimidine-2,4(1H,3H)-dione

[0313] ##STR00120##

[0314] Compound 26 (560 mg, yield 51%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 11.35 (s, 1H), 8.28-8.23 (m, 2H), 7.56-7.45 (m, 3H), 7.31-7.23 (m, 2H), 6.55 (d, 1H), 4.05-3.96 (m, 1H), 3.52-3.45 (m, 2H), 3.31-3.25 (m, 2H), 2.72-2.63 (m, 2H), 1.64-1.29 (m, 6H); LC/MS(ESI): m/z=509.1[M+H].sup.+.

Embodiment 27

Preparation of (S)-3-(2-amino-3-chloropyridine-4-yl)-7-(5-amino-5,7-dihydrospiro[cyclopenta[c]pyr idine-6,4-piperidine]-1-yl) pyridinyl[2,3-d]pyrimidine-2,4(1H,3H)-dione

[0315] ##STR00121##

[0316] Compound 27 (265 mg, yield 25%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=491.2[M+H].sup.+.

Embodiment 28

Preparation of (S)-7-(5-Amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4-piperidine-1-yl)-3-(3-ch loro-2-(cyclopropylamino)pyridine-4-yl)pyridinyl[2,3-d]pyrimidine-2,4(1H,3H)-dion e

[0317] ##STR00122##

[0318] Compound 28 (344 mg, yield 30%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=531.2[M+H].sup.+.

Embodiment 29

Preparation of (S)-7-(6-Amino-4,6-dihydrospiro[cyclopenta[b]thiazole-5,4-piperidine]-1-yl)-3-(2,3-dichlorophenyl)pteridine-2,4(1H,3H)-dione

[0319] ##STR00123##

[0320] Compound 29 (457 mg, yield 41%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=531.2[M+H].sup.+.

Embodiment 30

Preparation of (S)-7-(5-Amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4-piperidine-1-yl)-3-(7-ch lorobenzo[d]thiazol-6-yl)pteridine-2,4(1H,3H)-dione

[0321] ##STR00124##

[0322] Compound 30 (449 mg, yield 39%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=533.1[M+H].sup.+.

Embodiment 31

Preparation of 7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(7-chlorobenzo[d]t hiazol-6-yl)pteridine-2,4(1H,3H)-dione

[0323] ##STR00125##

[0324] Compound 31 (367 mg, yield 34%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 11.35 (s, 1H), 8.92 (s, 1H), 7.95 (s, 1H), 7.85 (d, 1H), 7.53 (d, 1H), 4.12-4.09 (m, 1H), 3.85-3.47 (m, 4H), 3.32-3.24 (m, 2H), 2.92 (d, 1H), 1.75-1.30 (m, 6H), 1.14 (d, 3H); LC/MS(ESI): m/z=500.1[M+H].sup.+.

Embodiment 32

Preparation of (S)-3-(2-amino-3-chloropyridine-4-yl)-7-(6-amino-4,6-dihydrospiro[cyclopenta[b]thi azole-5,4-piperidine]-1-yl)pteridine-2,4(1H,3H)-dione

[0325] ##STR00126##

[0326] Compound 32 (247 mg, yield 23%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=498.1[M+H].sup.+.

Embodiment 33

Preparation of N-(3-(7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2,4-dioxa-1,2-d ihydropteridine-3(4H)-yl)-2-chlorophenyl)-2-hydroxy-4-oxa-6,7,8,9-tetrahydro-4H-p yridinyl[1,2-a]pyrimidine-3-carboxamide

[0327] ##STR00127##

[0328] Compound 33 (448 mg, yield 32%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 12.31 (br s, 1H), 11.42 (s, 1H), 7.97 (s, 1H), 7.63-7.52 (m, 2H), 7.28-7.25 (m, 1H), 5.51 (br s, 3H), 4.13-4.10 (m, 1H), 3.93-3.45 (m, 8H), 2.95 (d, 1H), 2.74 (s, 2H), 1.85-1.41 (m, 8H), 1.14 (d, 3H); LC/MS(ESI): m/z=650.2[M+H].sup.+.

Embodiment 34

Preparation of N-(3-(7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2,4-dioxa-1,2-d ihydropyridinyl[3,2-d]pyrimidine-3(4H)-yl)-2-chlorophenyl)-2-hydroxy-4-oxa-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]pyrimidine-3-carboxamide

[0329] ##STR00128##

[0330] Compound 34 (406 mg, yield 29%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=649.2[M+H].sup.+.

Embodiment 35

Preparation of N-(3-(7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2,4-dioxa-1,2-d ihydropyridinyl[2,3-d]pyrimidine-3(4H)-yl)-2-chlorophenyl)-2-hydroxy-4-oxa-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]pyrimidine-3-carboxamide

[0331] ##STR00129##

[0332] Compound 35 (574 mg, yield 41%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=649.2[M+H].sup.+.

Embodiment 36

Preparation of N-(3-(7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2,4-dioxa-1,2-d ihydroquinazolin-3(4H)-yl)-2-chlorophenyl)-2-hydroxy-4-oxa-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]pyrimidine-3-carboxamide

[0333] ##STR00130##

[0334] Compound 36 (531 mg, yield 38%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=648.2[M+H].sup.+.

Embodiment 37

Preparation of N-(3-(7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2,4-dioxa-1,2-d ihydropteridine-3(4H)-yl)-2-chlorophenyl)-1-methyl-1H-pyrazole-3-carboxamide

[0335] ##STR00131##

[0336] Compound 37 (586 mg, yield 48%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 11.50 (s, 1H), 8.45 (d, 1H), 7.95 (s, 1H), 7.63-7.52 (m, 3H), 7.33-7.28 (m, 1H), 6.65 (d, 1H), 4.18 (s, 1H), 4.12-4.09 (m, 1H), 3.85-3.47 (m, 4H), 3.32-3.24 (m, 2H), 2.92 (d, 1H), 1.75-1.30 (m, 6H), 1.14 (d, 3H); LC/MS(ESI): m/z=566.2[M+H].sup.+.

Embodiment 38

Preparation of N-(3-(7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2,4-dioxa-1,2-d ihydropteridine-3(4H)-yl)-2-chlorophenyl)-1-methyl-1H-pyrazole-4-carboxamide

[0337] ##STR00132##

[0338] Compound 38 (525 mg, yield 43%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=566.2[M+H].sup.+.

Embodiment 39

Preparation of N-(3-(7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2,4-dioxa-1,2-d ihydropteridine-3(4H)-yl)-2-chlorophenyl) benzamide

[0339] ##STR00133##

[0340] Compound 39 (448 mg, yield 37%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=562.2[M+H].sup.+.

Embodiment 40

Preparation of N-(3-(7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2,4-dioxa-1,2-d ihydropteridine-3(4H)-yl)-2-chlorophenyl)pyrazine-2-carboxamide

[0341] ##STR00134##

[0342] Compound 40 (499 mg, yield 41%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 11.43 (s, 1H), 9.26 (s, 1H), 8.75 (d, 1H), 8.56 (s, 1H), 8.34 (d, 1H), 7.95 (s, 1H), 7.63-7.52 (m, 2H), 7.33-7.28 (m, 1H), 4.12-4.09 (m, 1H), 3.83-3.47 (m, 4H), 3.32-3.24 (m, 2H), 2.92 (d, 1H), 1.75-1.30 (m, 6H), 1.14 (d, 3H); LC/MS(ESI): m/z=564.2[M+H].sup.+.

Embodiment 41

Preparation of N-(3-(7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2,4-dioxa-1,2-d ihydropteridine-3(4H)-yl)-2-chlorophenyl) pyridine-2-carboxamide

[0343] ##STR00135##

[0344] Compound 41 (558 mg, yield 46%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=563.2[M+H].sup.+.

Embodiment 42

Preparation of N-(3-(7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2,4-dioxa-1,2-d ihydropteridine-3(4H)-yl)-2-chlorophenyl)pyrimidine-4-carboxamide

[0345] ##STR00136##

[0346] Compound 42 (389 mg, yield 32%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=564.2[M+H].sup.+.

Embodiment 43

Preparation of N-(3-(7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2,4-dioxa-1,2-d ihydropteridine-3(4H)-yl)-2-chlorophenyl)-1-methyl-1H-indole-7-carboxamide

[0347] ##STR00137##

[0348] Compound 43 (477 mg, yield 36%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=615.2[M+H].sup.+.

Embodiment 44

Preparation of N-(3-(7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-2,4-dioxa-1,2-d ihydropteridine-3(4H)-yl)-2-chlorophenyl)-1-methyl-1H-indazole-7-carboxamide

[0349] ##STR00138##

[0350] Compound 44 (545 mg, yield 41%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=616.2[M+H].sup.+.

Embodiment 45

Preparation of 7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(2-chloro-3-(pyrim idine-4-yl)phenyl)pteridine-2,4(1H,3H)-dione

[0351] ##STR00139##

[0352] Compound 45 (371 mg, yield 33%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 11.43 (s, 1H), 9.26 (s, 1H), 8.75 (d, 1H), 8.56 (s, 1H), 8.34 (d, 1H), 7.95 (s, 1H), 7.63-7.52 (m, 2H), 7.33-7.28 (m, 1H), 4.12-4.09 (m, 1H), 3.83-3.47 (m, 4H), 3.32-3.24 (m, 2H), 2.92 (d, 1H), 1.75-1.30 (m, 6H), 1.14 (d, 3H); LC/MS(ESI): m/z=521.2[M+H].sup.+.

Embodiment 46

Preparation of 7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(2-chloro-3-(pyridi ne-3-yl)phenyl)pteridine-2,4(1H,3H)-dione

[0353] ##STR00140##

[0354] Compound 46 (460 mg, yield 41%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=520.2[M+H].sup.+.

Embodiment 47

Preparation of 7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(2-chloro-3-(pyrazi ne-2-yl)phenyl)pteridine-2,4(1H,3H)-dione

[0355] ##STR00141##

[0356] Compound 47 (483 mg, yield 43%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=521.2[M+H].sup.+.

Embodiment 48

Preparation of 7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(2-chloro-3-(1-met hyl-1H-pyrazole-3-yl)phenyl)pteridine-2,4(1H,3H)-dione

[0357] ##STR00142##

[0358] Compound 48 (327 mg, yield 29%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=523.2[M+H].sup.+.

Embodiment 49

Preparation of 7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(2-chloro-3-(pyrim idine-4-amino)phenyl)pteridine-2,4(1H,3H)-dione

[0359] ##STR00143##

[0360] Compound 49 (347 mg, yield 30%) is obtained in a similar manner to Embodiment 1. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 11.36 (s, 1H), 8.95 (s, 1H), 8.35 (d, 1H), 7.97-7.95 (m, 2H), 7.43-7.32 (m, 2H), 7.13-7.08 (m, 1H), 5.93 (s, 1H), 4.12-4.09 (m, 1H), 3.81-3.45 (m, 4H), 3.30-3.22 (m, 2H), 2.89 (d, 1H), 1.73-1.29 (m, 6H), 1.14 (d, 3H); LC/MS(ESI): m/z=536.2[M+H].sup.+.

Embodiment 50

Preparation of 7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(2-chloro-3-(pyridi ne-2-amino)phenyl)pteridine-2,4(1H,3H)-dione

[0361] ##STR00144##

[0362] Compound 50 (311 mg, yield 27%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=535.2[M+H].sup.+.

Embodiment 51

Preparation of 7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(2-chloro-3-(pyrazi ne-2-amino)phenyl)pteridine-2,4(1H,3H)-dione

[0363] ##STR00145##

[0364] Compound 51 (405 mg, yield 35%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=536.2[M+H].sup.+.

Embodiment 52

Preparation of 7-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(2-chloro-3-(pyrim idine-2-amino)phenyl)pteridine-2,4(1H,3H)-dione

[0365] ##STR00146##

[0366] Compound 52 (474 mg, yield 41%) is obtained in a similar manner to Embodiment 1. LC/MS(ESI): m/z=536.2[M+H].sup.+.

##STR00147## ##STR00148## ##STR00149##

Embodiment 63

Preparation of (3S,4S)-8-(2-((2-chloro-3-(1-methyl-1H-pyrazole-3-yl)phenyl)mercapto)pteridine-6-y 1)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0367] ##STR00150##

[0368] Dissolve the compound 3-(1-methyl-1H-pyrazole-3-yl)-2-chloro-thiophenol (674 mg, 3 mmol) in 8 mL of N,N-dimethylacetamide, add 2,6-dichloropteridine (720 mg, 3.6 mmol), potassium hydroxide (336 mg, 6.0 mmol) and cuprous oxide (215 mg, 1.5 mmol). Perform nitrogen substitution 3 times, and react at 60?C for 8 hours with stirring. After cooling to room temperature, the reaction solution is diluted with water and, extracted with ethyl acetate. The obtained organic phase is washed with water and saturated brine, dried with anhydrous sodium sulfate, and the organic phase is evaporated to dryness under reduced pressure to give the intermediate 6-chloro-(2-((2-chloro-3-(1-methyl-1H-pyrazole-3-yl)phenyl)mercapto)pteridine (619 mg, 53% yield). LC/MS(ESI): m/z=389.0[M+H].sup.+.

[0369] Dissolve the compound 6-chloro-(2-((2-chloro-3-(1-methyl-1H-pyrazole-3-yl)phenyl)mercapto)pteridine (584 mg, 1.5 mmol) in 10 mL of N,N-dimethylformamide, add (3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane dihydrochloride (438 mg, 1.8 mmol) and cesium carbonate (1.95 g, 6.0 mmol), react at 120? C. for 12 hours under stirring. After cooling to room temperature, the reaction solution is diluted with water and extracted with ethyl acetate. The obtained organic phase is washed with water and saturated brine, dried with anhydrous sodium sulfate, and the organic phase is evaporated to dryness under reduced pressure. The residue is purified by column chromatography to give the target product 63 (282 mg, 36% yield). 1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.41 (s, 1H), 8.34 (s, 1H), 7.78 (d, 1H), 7.51 (d, 1H), 7.23 (t, 1H), 6.84 (d, 1H), 6.60 (d, 1H), 4.13-4.09 (m, 1H), 3.95-3.45 (m, 7H), 3.32-3.25 (m, 2H), 2.90 (d, 1H), 1.75-1.30 (m, 6H), 1.14 (d, 3H); LC/MS(ESI): m/z=523.2[M+H].sup.+.

Embodiment 64

Preparation of (3S,4S)-8-(6-((2-chloro-3-(1-methyl-1H-pyrazole-3-yl)phenyl)mercapto)pteridine-2-y 1)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0370] ##STR00151##

[0371] Dissolve 2,6-dichloropteridine (0.72 g, 3.6 mmol) in 10 mL of dichloromethane, add (3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane dihydrochloride (0.73 g, 3 mmol) and triethylamine (0.91 g, 9 mmol), stir overnight at room temperature. The reaction solution is diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate, and the organic phase is evaporated to dryness under reduced pressure. The residue is purified by column chromatography to give the compound (3S,4S)-8-(6-chloropteridine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (0.65 g, 65% yield). LC/MS(ESI): m/z=335.1[M+H].sup.+.

[0372] Dissolve the compound (3S,4S)-8-(6-chloropteridine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (502 mg, 1.5 mmol) in 8 mL of 1,4-dioxane, add 3-(1-methyl-1H-pyrazole-3-yl)-2-chloro-thiophenol (405 mg, 1.8 mmol), potassium tert-butoxide (335 mg, 3.0 mmol), and cuprous iodide (29 mg, 0.15 mmol), perform nitrogen substitution 3 times, and reflux for 16 hours under stirring. After cooling to room temperature, the reaction solution is passed through a silica gel short column, rinse the column with ethyl acetate, and evaporate the solution to dryness under reduced pressure. The residue is purified by column chromatography to give the target product 64 (377 mg, 48% yield). 1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.71 (s, 1H), 8.43 (s, 1H), 7.78 (d, 1H), 7.51 (d, 1H), 7.23 (t, 1H), 6.85 (d, 1H), 6.58 (d, 1H), 4.13-4.09 (m, 1H), 3.95-3.44 (m, 7H), 3.34-3.25 (m, 2H), 2.92 (d, 1H), 1.75-1.31 (m, 6H), 1.15 (d, 3H); LC/MS(ESI): m/z=523.2[M+H].sup.+.

Embodiment 65

Preparation of (3S,4S)-8-(2-((2-chloro-3-(1-methyl-1H-pyrazole-3-yl)phenyl)mercapto)pyridinyl[3,2-d]pyrimidine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0373] ##STR00152##

[0374] Compound 65 (328 mg, 42% yield, which is the yield of the last step, the same below) is obtained in a similar manner to that of Embodiment 63. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.42 (s, 1H), 7.93 (d, 1H), 7.78 (d, 1H), 7.51 (d, 1H), 7.23 (t, 1H), 6.88-6.75 (m, 2H), 6.59 (d, 1H), 4.13-4.09 (m, 1H), 3.94-3.45 (m, 7H), 3.31-3.25 (m, 2H), 2.91 (d, 1H), 1.75-1.30 (m, 6H), 1.15 (d, 3H); LC/MS(ESI): m/z=522.2[M+H].sup.+.

Embodiment 66

Preparation of (3S,4S)-8-(2-((2-chloro-3-(1-ethyl-1H-pyrazole-3-yl)phenyl)mercapto)pteridine-6-yl)-3-methyl yl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0375] ##STR00153##

[0376] Compound 66 (322 mg, yield 40%) is obtained in a similar manner to Embodiment 63. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.42 (s, 1H), 8.34 (s, 1H), 7.75 (d, 1H), 7.51 (d, 1H), 7.23 (t, 1H), 6.83 (d, 1H), 6.56 (d, 1H), 4.13-4.09 (m, 1H), 3.95-3.44 (m, 6H), 3.32-3.25 (m, 2H), 2.90 (d, 1H), 1.73-1.31 (m, 6H), 1.28 (t, 3H), 1.13 (d, 3H); LC/MS(ESI): m/z=537.2[M+H].sup.+.

Embodiment 67

Preparation of (3S,4S)-8-(6-((2-chloro-3-(1-ethyl-1H-pyrazole-3-yl)phenyl)mercapto)pteridine-2-yl)-3-methyl yl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0377] ##STR00154##

[0378] Compound 67 (362 mg, yield 45%) is obtained in a similar manner to Embodiment 64. LC/MS(ESI): m/z=537.2[M+H].sup.+.

Embodiment 68

Preparation of (3S,4S)-8-(2-((2-chloro-3-(1-ethyl-1H-pyrazole-3-yl)phenyl)mercapto)pyridinyl[3,2-d]pyrimidine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0379] ##STR00155##

[0380] Compound 68 (305 mg, yield 38%) is obtained in a similar manner to Embodiment 63. LC/MS(ESI): m/z=536.2[M+H].sup.+.

Embodiment 69

Preparation of (3S,4S)-8-(2-((2-chloro-3-(1-isopropyl-1H-pyrazole-3-yl)phenyl)mercapto)pteridine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0381] ##STR00156##

[0382] Compound 69 (305 mg, yield 37%) is obtained in a similar manner to Embodiment 63. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.42 (s, 1H), 8.34 (s, 1H), 7.76 (s, 1H), 7.51 (d, 1H), 7.23 (t, 1H), 6.83 (d, 1H), 6.55 (d, 1H), 4.14-4.07 (m, 2H), 3.93-3.45 (m, 4H), 3.32-3.25 (m, 2H), 2.90 (d, 1H), 1.73-1.30 (m, 12H), 1.14 (d, 3H); LC/MS(ESI): m/z=551.2[M+H].sup.+.

Embodiment 70

Preparation of (3S,4S)-8-(6-((2-chloro-3-(1-isopropyl-1H-pyrazole-3-yl)phenyl)mercapto)pteridine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0383] ##STR00157##

[0384] Compound 70 (380 mg, yield 46%) is obtained in a similar manner to Embodiment 64. LC/MS(ESI): m/z=551.2[M+H].sup.+.

Embodiment 71

Preparation of (3S,4S)-8-(2-((2-chloro-3-(1-isopropyl-1H-pyrazole-3-yl)phenyl)mercapto)pyridinyl[3,2-d]pyrimidine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0385] ##STR00158##

[0386] Compound 71 (288 mg, yield 35%) is obtained in a similar manner to Embodiment 63. LC/MS(ESI): m/z=550.2[M+H].sup.+.

Embodiment 72

Preparation of (3S,4S)-8-(2-((2-chloro-3-(pyrazine-2-yl)phenyl)mercapto)pteridine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0387] ##STR00159##

[0388] Compound 72 (273 mg, yield 35%) is obtained in a similar manner to Embodiment 63. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.81 (s, 1H), 8.75 (s, 2H), 8.43 (s, 1H), 8.34 (s, 1H), 7.51 (d, 1H), 7.21 (t, 1H), 6.86 (d, 1H), 4.13-4.09 (m, 1H), 3.94-3.75 (m, 2H), 3.65 (d, 1H), 3.47 (d, 1H), 3.32-3.25 (m, 2H), 2.90 (d, 1H), 1.75-1.33 (m, 6H), 1.14 (d, 3H); LC/MS(ESI): m/z=521.2[M+H].sup.+.

Embodiment 73

Preparation of (3S,4S)-8-(6-((2-chloro-3-(pyrazine-2-yl)phenyl)mercapto)pteridine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0389] ##STR00160##

[0390] Compound 73 (328 mg, yield 42%) is obtained in a similar manner to Embodiment 64. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.82-8.80 (m, 2H), 8.75 (s, 2H), 8.43 (s, 1H), 7.51 (d, 1H), 7.23 (t, 1H), 7.05 (d, 1H), 4.13-4.09 (m, 1H), 3.94-3.43 (m, 4H), 3.32-3.23 (m, 2H), 2.91 (d, 1H), 1.79-1.33 (m, 6H), 1.15 (d, 3H); LC/MS(ESI): m/z=521.2[M+H].sup.+.

Embodiment 74

Preparation of (3S,4S)-8-(2-((2-chloro-3-(pyrazine-2-yl)phenyl)mercapto)pyridinyl[3,2-d]pyrimidin e-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0391] ##STR00161##

[0392] Compound 74 (288 mg, yield 37%) is obtained in a similar manner to Embodiment 63. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.81 (s, 1H), 8.75 (s, 2H), 8.43 (s, 1H), 7.91 (d, 1H), 7.51 (d, 1H), 7.21 (t, 1H), 6.86-6.79 (m, 2H), 4.13-4.09 (m, 1H), 3.94-3.75 (m, 2H), 3.65 (d, 1H), 3.47 (d, 1H), 3.32-3.25 (m, 2H), 2.90 (d, 1H), 1.75-1.33 (m, 6H), 1.14 (d, 3H); LC/MS(ESI): m/z=520.2[M+H].sup.+.

Embodiment 75

Preparation of (3S,4S)-8-(2-((2-chloro-3-(pyrimidine-4-yl)phenyl)mercapto)pteridine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0393] ##STR00162##

[0394] Compound 75 (320 mg, yield 41%) is obtained in a similar manner to Embodiment 63. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ?: 9.24 (s, 1H), 8.85 (d, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 8.12 (d, 1H), 7.50 (d, 1H), 7.21 (t, 1H), 6.86 (d, 1H), 4.13-4.09 (m, 1H), 3.94-3.75 (m, 2H), 3.65 (d, 1H), 3.47 (d, 1H), 3.32-3.25 (m, 2H), 2.91 (d, 1H), 1.77-1.33 (m, 6H), 1.14 (d, 3H); LC/MS(ESI): m/z=521.2[M+H].sup.+.

Embodiment 76

Preparation of (3S,4S)-8-(6-((2-chloro-3-(pyrimidine-4-yl)phenyl)mercapto)pteridine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0395] ##STR00163##

[0396] Compound 76 (295 mg, yield 37%) is obtained in a similar manner to Embodiment 2. LC/MS(ESI): m/z=521.2[M+H].sup.+.

Embodiment 77

Preparation of (3S,4S)-8-(2-((2-chloro-3-(pyrimidine-4-yl)phenyl)mercapto)pyridinyl[3,2-d]pyrimid ine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0397] ##STR00164##

[0398] Compound 77 (350 mg, yield 45%) is obtained in a similar manner to Embodiment 63. LC/MS(ESI): m/z=520.2[M+H].sup.+.

Embodiment 78

Preparation of (3S,4S)-8-(2-((2-chloro-3-(pyrimidine-3-yl)phenyl)mercapto)pteridine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0399] ##STR00165##

[0400] Compound 78 (327 mg, yield 42%) is obtained in a similar manner to Embodiment 63. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.87 (s, 1H), 8.71 (d, 1H), 8.34-8.30 (m, 3H), 7.55-7.51 (m, 2H), 7.22 (t, 1H), 7.04 (d, 1H), 4.13-4.08 (m, 1H), 3.94-3.45 (m, 4H), 3.31-3.25 (m, 2H), 2.91 (d, 1H), 1.78-1.31 (m, 6H), 1.15 (d, 3H); LC/MS(ESI): m/z=520.2[M+H].sup.+.

Embodiment 79

Preparation of (3S,4S)-8-(6-((2-chloro-3-(pyrimidine-4-yl)phenyl)mercapto)pteridine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0401] ##STR00166##

[0402] Compound 79 (273 mg, yield 35%) is obtained in a similar manner to Embodiment 64. LC/MS(ESI): m/z=520.2[M+H].sup.+.

Embodiment 80

Preparation of (3S,4S)-8-(2-((2-chloro-3-(pyrimidine-4-yl)phenyl)mercapto)pyridinyl[3,2-d]pyrimid ine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0403] ##STR00167##

[0404] Compound 80 (295 mg, yield 38%) is obtained in a similar manner to Embodiment 63. LC/MS(ESI): m/z=519.2[M+H].sup.+.

Embodiment 81

Preparation of N-(3-((6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pteridine-2-yl) mercapto)-2-chlorophenyl)pyrimidine-4-carboxamide

[0405] ##STR00168##

[0406] Compound 81 (320 mg, yield 41%) is obtained in a similar manner to Embodiment 63. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ?: 9.88 (s, 1H), 9.31 (s, 1H), 9.01 (d, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 8.31 (s, 2H), 8.21 (d, 1H), 7.75 (d, 1H), 7.42 (t, 1H), 7.15 (d, 1H), 4.15-4.11 (m, 1H), 3.93-3.45 (m, 4H), 3.33-3.21 (m, 2H), 2.90 (d, 1H), 1.75-1.31 (m, 6H), 1.15 (d, 3H); LC/MS(ESI): m/z=564.2[M+H].sup.+.

Embodiment 82

Preparation of N-(3-((2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pteridine-6-yl) mercapto)-2-chlorophenyl)pyrimidine-4-carboxamide

[0407] ##STR00169##

[0408] Compound 82 (295 mg, yield 37%) is obtained in a similar manner to Embodiment 64. LC/MS(ESI): m/z=564.2[M+H].sup.+.

Embodiment 83

Preparation of N-(3-((6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyridinyl[3,2-d]pyrimidine-2-yl)mercapto)-2-chlorophenyl)pyrimidine-4-carboxamide

[0409] ##STR00170##

[0410] Compound 83 (350 mg, yield 45%) is obtained in a similar manner to Embodiment 63. LC/MS(ESI): m/z=563.2[M+H].sup.+.

Embodiment 84

Preparation of N-(3-((6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pteridine-2-yl) mercapto)-2-chlorophenyl)pyrazine-2-carboxamide

[0411] ##STR00171##

[0412] Compound 84 (313 mg, yield 37%) is obtained in a similar manner to Embodiment 63. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 9.70 (s, 1H), 9.51 (s, 1H), 8.81 (d, 1H), 8.55-8.52 (m, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 7.75 (d, 1H), 7.42 (t, 1H), 7.14 (d, 1H), 4.15-4.11 (m, 1H), 3.93-3.45 (m, 4H), 3.33-3.21 (m, 2H), 2.90 (d, 1H), 1.75-1.31 (m, 6H), 1.15 (d, 3H); LC/MS(ESI): m/z=564.2[M+H].sup.+.

Embodiment 85

Preparation of N-(3-((2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pteridine-6-yl) mercapto)-2-chlorophenyl)pyrazine-2-carboxamide

[0413] ##STR00172##

[0414] Compound 85 (337 mg, yield 40%) is obtained in a similar manner to Embodiment 64. LC/MS(ESI): m/z=564.2[M+H].sup.+.

Embodiment 86

Preparation of N-(3-((6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyridinyl[3,2-d]pyrimidine-2-yl)mercapto)-2-chlorophenyl)pyrazine-2-carboxamide

[0415] ##STR00173##

[0416] Compound 76 (346 mg, yield 41%) is obtained in a similar manner to Embodiment 63. LC/MS(ESI): m/z=563.2[M+H].sup.+.

Embodiment 87

Preparation of N-(3-((6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pteridine-2-yl) mercapto)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]p yrimidine-3-carboxamide

[0417] ##STR00174##

[0418] Compound 87 (341 mg, yield 35%) is obtained in a similar manner to Embodiment 63. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 12.3 (br s, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 8.24 (s, 1H), 7.23 (s, 1H), 6.63 (d, 1H), 5.51 (br s, 3H), 4.13-4.10 (m, 1H), 3.93-3.45 (m, 8H), 2.95 (d, 1H), 2.74 (s, 2H), 1.85-1.41 (m, 8H), 1.14 (d, 3H); LC/MS(ESI): m/z=650.2[M+H].sup.+.

Embodiment 88

Preparation of N-(3-((2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pteridine-6-yl) mercapto)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]p yrimidine-3-carboxamide

[0419] ##STR00175##

[0420] Compound 88 (389 mg, yield 40%) is obtained in a similar manner to Embodiment 64. LC/MS(ESI): m/z=650.2[M+H].sup.+.

Embodiment 89

Preparation of N-(3-((6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyridinyl[3,2-d]pyrimidine-2-yl)mercapto)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]pyrimidine-3-carboxamide

[0421] ##STR00176##

[0422] Compound 79 (369 mg, yield 38%) is obtained in a similar manner to Embodiment 63. LC/MS(ESI): m/z=649.2[M+H].sup.+.

Embodiment 90

Preparation of (3S,4S)-8-(6-((2-chloro-3-(1-methyl-1H-pyrazole-3-yl)phenyl)mercapto)pyridinyl[3,2-b]pyrimidine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0423] ##STR00177##

[0424] Compound 90 (281 mg, yield 36%) is obtained in a similar manner to Embodiment 64. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.43 (s, 1H), 7.96 (d, 1H), 7.78 (d, 1H), 7.49-7.23 (m, 3H), 6.88 (d, 1H), 6.59 (d, 1H), 4.13-3.45 (m, 8H), 3.30-3.25 (m, 2H), 2.91 (d, 1H), 1.75-1.30 (m, 6H), 1.15 (d, 3H); LC/MS(ESI): m/z=522.2[M+H].sup.+.

Embodiment 91

Preparation of (3S,4S)-8-(2-((2-chloro-3-(1-methyl-1H-pyrazole-3-yl)phenyl)mercapto)pyridinyl[2,3-b]pyrazine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0425] ##STR00178##

[0426] Compound 91 (235 mg, yield 30%) is obtained in a similar manner to Embodiment 63. LC/MS(ESI): m/z=522.2[M+H].sup.+.

Embodiment 92

Preparation of (3S,4S)-8-(6-((2-chloro-3-(1-methyl-1H-pyrazole-3-yl)phenyl)mercapto)pyridinyl[2,3-b]pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0427] ##STR00179##

[0428] Compound 92 (211 mg, yield 27%) is obtained in a similar manner to Embodiment 64. LC/MS(ESI): m/z=522.2[M+H].sup.+.

Embodiment 93

Preparation of (3S,4S)-8-(6-((2-chloro-3-(1-methyl-1H-pyrazole-3-yl)hydroxy)phenyl)mercapto)pter idine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0429] ##STR00180##

[0430] Compound 93 (315 mg, yield 39%) is obtained in a similar manner to Embodiment 65. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ?: 8.43-8.40 (m, 2H), 7.78 (d, 1H), 7.03-6.55 (m, 4H), 4.14-3.45 (m, 8H), 3.32-3.25 (m, 2H), 2.91 (d, 1H), 1.75-1.30 (m, 6H), 1.14 (d, 3H); LC/MS(ESI): m/z=539.2[M+H].sup.+.

Embodiment 94

Preparation of (3S,4S)-8-(2-((2-chloro-3-(1-methyl-1H-pyrazole-3-yl)hydroxy)phenyl)mercapto)pter idine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0431] ##STR00181##

[0432] Compound 94 (331 mg, yield 41%) is obtained in a similar manner to Embodiment 63. LC/MS(ESI): m/z=539.2[M+H].sup.+.

Embodiment 95

Preparation of (3S,4S)-8-(2-((2-chloro-3-(1-methyl-1H-pyrazole-3-yl)hydroxy)phenyl)mercapto)pyri dinyl[3,2-d]pyrimidine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0433] ##STR00182##

[0434] Compound 95 (282 mg, yield 35%) is obtained in a similar manner to Embodiment 63. LC/MS(ESI): m/z=538.2[M+H].sup.+.

Embodiment 96

Preparation of N-(3-((2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyridinyl[3,2-d]pyrimidine-6-yl)mercapto)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]pyrimidine-3-carboxamide

[0435] ##STR00183##

[0436] Compound 96 (379 mg, yield 39%) is obtained in a similar manner to Embodiment 64. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 12.1 (br s, 1H), 8.43 (s, 1H), 7.94-7.76 (m, 2H), 7.33-7.24 (m, 2H), 6.67 (d, 1H), 5.52 (br s, 3H), 4.13-4.10 (m, 1H), 3.93-3.45 (m, 8H), 2.93 (d, 1H), 2.71 (s, 2H), 1.83-1.35 (m, 8H), 1.14 (d, 3H); LC/MS(ESI): m/z=649.2[M+H].sup.+.

Embodiment 97

Preparation of N-(3-((6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyridinyl[2,3-b]pyrazine-2-yl)mercapto)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-p yridinyl[1,2-a]pyrimidine-3-carboxamide

[0437] ##STR00184##

[0438] Compound 97 (340 mg, yield 35%) is obtained in a similar manner to Embodiment 63. LC/MS(ESI): m/z=649.2[M+H].sup.+.

Embodiment 98

Preparation of N-(3-((2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyridinyl[2,3-b]pyrazine-6-yl)mercapto)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-p yridinyl[1,2-a]pyrimidine-3-carboxamide

[0439] ##STR00185##

[0440] Compound 98 (315 mg, yield 33%) is obtained in a similar manner to Embodiment 64. LC/MS(ESI): m/z=649.2[M+H].sup.+.

Embodiment 99

Preparation of (3S,4S)-8-(2-((2-chloro-3-(1-methyl-1H-pyrazole-3-yl)phenyl)mercapto)pyrimidine-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0441] ##STR00186##

[0442] Dissolve compound 3-(1-methyl-1H-pyrazole-3-yl)-2-chloro-thiophenol (674 mg, 3 mmol) in 8 mL of ethanol, add 2-chloro-iodopyrimidine (864 mg, 3.6 mmol) and sodium ethoxide (408 mg, 6.0 mmol). Stir the reaction mixture and reflux overnight. After cooling to room temperature, the reaction solution is diluted with water and extracted with ethyl acetate. The obtained organic phase is washed with water and saturated brine, dried with anhydrous sodium sulfate, and the organic phase is evaporated to dryness under reduced pressure to give the intermediate 2-((2-chloro-3-(1-methyl-1H-pyrazole-3-yl)phenyl)mercapto)-5-iodopyrimidine (304 mg, 43% yield). LC/MS(ESI): m/z=471.2[M+H].sup.+.

[0443] Dissolve the compound 2-((2-chloro-3-(1-methyl-1H-pyrazole-3-yl)phenyl) mercapto)-5-iodopyrimidine (506 mg, 1.5 mmol) in 10 mL of N,N-dimethylformamide, add (3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane dihydrochloride (438 mg, 1.8 mmol) and potassium carbonate (829 mg, 6.0 mmol), stir at 120? ? C. for 6 hours. After cooling to room temperature, the reaction solution is diluted with water and extracted with ethyl acetate. The obtained organic phase is washed with water and saturated brine, dried with anhydrous sodium sulfate, and the organic phase is evaporated to dryness under reduced pressure. The residue is purified by column chromatography to give the target product 99 (304 mg, 43% yield). 1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.31 (s, 2H), 7.78 (d, 1H), 7.51 (d, 1H), 7.23 (t, 1H), 6.83 (d, 1H), 6.60 (d, 1H), 4.13-4.09 (m, 1H), 3.92-3.75 (m, 5H), 3.65 (d, 1H), 3.47 (d, 1H), 3.32-3.25 (m, 2H), 2.90 (d, 1H), 1.77-1.32 (m, 6H), 1.13 (d, 3H); LC/MS(ESI): m/z=471.2[M+H].sup.+.

Embodiment 100

Preparation of (3S,4S)-8-(2-((2-chloro-3-(1-ethyl-1H-pyrazole-3-yl)phenyl)mercapto)pyrimidine-5-y l)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0444] ##STR00187##

[0445] Compound 100 (327 mg, 45% yield, which is the yield of the last step, the same below) is obtained by a method similar to that of Embodiment 99. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.31 (s, 2H), 7.72 (d, 1H), 7.51 (d, 1H), 7.23 (t, 1H), 6.83 (d, 1H), 6.58 (d, 1H), 4.13-4.09 (m, 1H), 3.94-3.77 (m, 5H), 3.65 (d, 1H), 3.47 (d, 1H), 3.32-3.25 (m, 2H), 2.90 (d, 1H), 1.77-1.33 (m, 6H), 1.28 (t, 3H), 1.13 (d, 3H); LC/MS(ESI): m/z=485.2[M+H].sup.+.

Embodiment 101

Preparation of (3S,4S)-8-(2-((2-chloro-3-(1-isopropyl-1H-pyrazole-3-yl)phenyl)mercapto)pyrimidine-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0446] ##STR00188##

[0447] Compound 101 (381 mg, yield 51%) is obtained in a similar manner to Embodiment 99. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.31 (s, 2H), 7.70 (s, 1H), 7.51 (d, 1H), 7.23 (t, 1H), 6.83 (d, 1H), 6.54 (d, 1H), 4.14-4.07 (m, 2H), 3.92-3.75 (m, 5H), 3.65 (d, 1H), 3.47 (d, 1H), 3.32-3.25 (m, 2H), 2.90 (d, 1H), 1.77-1.32 (m, 12H), 1.13 (d, 3H); LC/MS(ESI): m/z=499.2[M+H].sup.+.

Embodiment 102

Preparation of N-(3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrimidine-2-y l)mercapto)-2-chlorobenzene)-2-hydroxyl-4-oxa-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]pyrimidine-3-carboxamide

[0448] ##STR00189##

[0449] Dissolve the compound 3-amino-2-chloro-thiophenol (3.19 g, 20 mmol) in 60 mL of dimethyl sulfoxide, add 2-chloro-5-iodopyrimidine (4.8 g, 20 mmol) and carbonic acid Cesium (13.0 g, 40 mmol), heat to 80? C. and stir for 6 hours. After cooling to room temperature, the reaction solution is diluted with water and extracted with ethyl acetate. The obtained organic phase is washed with water and saturated brine, dried with anhydrous sodium sulfate, and the organic phase is evaporated to dryness under reduced pressure. The residue is purified by column chromatography to give the compound 2-chloro-3-((5-iodopyrimidine-2-yl)mercapto)aniline (2.45 g, 45% yield). LC/MS(ESI): m/z=272.0[M+H].sup.+.

[0450] Dissolve compound 2-hydroxy-4-oxo-pyridinyl[1,2-a]pyrimidine-3-carboxylic acid ethyl ester (408 mg, 1.5 mmol) and compound 2-chloro-3-((5-iodopyrimidine-2-yl) mercapto)aniline (429 mg, 1.8 mmol) in 5 mL of chlorobenzene, heat to 130? C. and stir for 5 hours, then cool to room temperature, filter. After drying, compound N-(2-chloro-3-((5-iodopyrimidine-2-yl)mercapto)phenyl)-2-hydroxyl-4-oxa-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]pyrimidine-3-carboxamide is obtained(474 mg, 68% yield). LC/MS(ESI): m/z=464.0[M+H].sup.+.

[0451] Dissolve the compound N-(2-chloro-3-((5-iodopyrimidine-2-yl)mercapto)phenyl)-2-hydroxyl-4-oxa-6,7,8,9-tetrah ydro-4H-pyridinyl[1,2-a]pyrimidine-3-carboxamide (464 mg, 1 mmol) in 4 mL of N,N-dimethylformamide, add (3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane dihydrochloride (292 mg, 1.2 mmol) and potassium carbonate (553 mg, 4.0 mmol), stir at 120? C. for 8 hours. After cooling to room temperature, the reaction solution is diluted with water and extracted with ethyl acetate. The obtained organic phase is washed with water and saturated brine, dried with anhydrous sodium sulfate, and the organic phase is evaporated to dryness under reduced pressure. The residue is then purified by column chromatography to give the target product 102 (191 mg, 32% yield). 1H NMR (400 MHZ, DMSO-d.sub.6) ?: 12.5 (br s, 1H), 8.35-8.23 (m, 3H), 7.23 (s, 1H), 6.58 (d, 1H), 5.54 (br s, 3H), 4.13-4.09 (m, 1H), 3.92-3.55 (m, 7H), 3.32-3.25 (m, 3H), 2.92 (d, 1H), 1.82-1.43 (m, 8H), 1.13 (d, 3H); LC/MS(ESI): m/z=598.2[M+H].sup.+.

Embodiment 103

Preparation of (3S,4S)-8-(2-((2-chloro-3-(pyrimidine-5-yl)phenyl)mercapto)pyrimidine-5-yl)-3-meth yl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0452] ##STR00190##

[0453] Compound 103 (205 mg, yield 38%) is obtained in a similar manner to Embodiment 99. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 9.22 (s, 1H), 8.89 (s, 2H), 8.31 (s, 2H), 7.50 (d, 1H), 7.21 (t, 1H), 6.86 (d, 1H), 4.13-4.09 (m, 1H), 3.94-3.75 (m, 5H), 3.65 (d, 1H), 3.47 (d, 1H), 3.32-3.25 (m, 2H), 2.90 (d, 1H), 1.77-1.33 (m, 3H), 1.13 (d, 3H); LC/MS(ESI): m/z=469.1 [M+H].sup.+.

Embodiment 104

Preparation of (3S,4S)-8-(2-((2-chloro-3-(pyrazine-2-yl)phenyl)mercapto)pyrimidine-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0454] ##STR00191##

[0455] Compound 104 (189 mg, yield 35%) is obtained in a similar manner to Embodiment 102. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.81 (s, 1H), 8.75 (s, 2H), 8.31 (s, 2H), 7.50 (d, 1H), 7.21 (t, 1H), 6.86 (d, 1H), 4.13-4.09 (m, 1H), 3.94-3.75 (m, 5H), 3.65 (d, 1H), 3.47 (d, 1H), 3.32-3.25 (m, 2H), 2.90 (d, 1H), 1.77-1.33 (m, 3H), 1.13 (d, 3H); LC/MS(ESI): m/z=469.1 [M+H].sup.+.

Embodiment 105

Preparation of (3S,4S)-8-(2-((2-chloro-3-(pyridine-3-yl)phenyl)mercapto)pyrimidine-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0456] ##STR00192##

[0457] Compound 105 (327 mg, yield 42%) is obtained in a similar manner to Embodiment 93. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.85 (s, 1H), 8.70 (d, 1H), 8.32-8.30 (m, 3H), 7.53-7.50 (m, 2H), 7.21 (t, 1H), 6.86 (d, 1H), 4.13-4.09 (m, 1H), 3.94-3.75 (m, 5H), 3.65 (d, 1H), 3.47 (d, 1H), 3.32-3.25 (m, 2H), 2.90 (d, 1H), 1.77-1.33 (m, 3H), 1.13 (d, 3H); LC/MS(ESI): m/z=468.2[M+H].sup.+.

Embodiment 106

Preparation of (3S,4S)-8-(2-((2-chloro-3-(pyrimidine-4-yl)phenyl)mercapto)pyrimidine-5-yl)-3-meth yl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0458] ##STR00193##

[0459] Compound 106 (216 mg, yield 40%) is obtained in a similar manner to Embodiment 102. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 9.23 (s, 1H), 8.85 (d, 1H), 8.31 (s, 2H), 8.12 (d, 1H), 7.50 (d, 1H), 7.21 (t, 1H), 6.86 (d, 1H), 4.13-4.09 (m, 1H), 3.94-3.75 (m, 5H), 3.65 (d, 1H), 3.47 (d, 1H), 3.32-3.25 (m, 2H), 2.90 (d, 1H), 1.77-1.33 (m, 3H), 1.13 (d, 3H); LC/MS(ESI): m/z=469.1[M+H].sup.+.

Embodiment 107

Preparation of (3S,4S)-8-(2-((2-chloro-3-(pyridine-3-amino)phenyl)mercapto)pyrimidine-5-yl)-3-me thyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0460] ##STR00194##

[0461] Dissolve compound 3-(pyridine-4-amino)-2-chloro-thiophenol (592 mg, 2.5 mmol) in 6 mL of methanol, add 2-chloro-5-iodopyrimidine (720 mg, 3 mmol) and potassium carbonate (830 mg, 6.0 mmol), stir and reflux for 5 hours. After cooling to room temperature, the reaction solution is evaporated to dryness under reduced pressure. The residue is purified by column chromatography to give the compound N-(2-chloro-3-((5-iodopyrimidine-2-yl) mercapto) phenyl) pyridine-3-amine (463 mg, 53% yield). LC/MS(ESI): m/z=349.0[M+H].sup.+.

[0462] Dissolve compound N-(2-chloro-3-((5-iodopyrimidine-2-yl)mercapto)phenyl)pyridine-3-amine(419 mg, 1.2 mmol) in 5 mL of N-methylpyrrolidone, add (3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane dihydrochloride (365 mg, 1.5 mmol) and triethylamine (486 mg, 4.8 mmol), stir and react overnight at 120? C. After cooling to room temperature, the reaction solution is diluted with water and extracted with ethyl acetate. The obtained organic phase is washed with water and saturated brine, dried with anhydrous sodium sulfate, and the organic phase is evaporated to dryness under reduced pressure. The residue is then purified by column chromatography to give the target product 107 (203 mg, 35% yield). 1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.43 (s, 1H), 8.32-8.25 (m, 3H), 7.63-7.03 (m, 5H), 6.05 (s, 1H), 4.13-4.09 (m, 1H), 3.94-3.75 (m, 5H), 3.65 (d, 1H), 3.46 (d, 1H), 3.33-3.25 (m, 2H), 2.90 (d, 1H), 1.77-1.34 (m, 3H), 1.13 (d, 3H); LC/MS(ESI): m/z=483.2 [M+H].sup.+.

Embodiment 108

Preparation of (3S,4S)-8-(2-((2-chloro-3-(pyrimidine-2-amino)phenyl)mercapto)pyrimidine-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0463] ##STR00195##

[0464] Compound 108 (186 mg, yield 32%) is obtained in a similar manner to Embodiment 107. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.45 (d, 2H), 8.30-8.22 (m, 3H), 7.52-7.03 (m, 3H), 6.17 (s, 1H), 4.14-4.09 (m, 1H), 3.95-3.75 (m, 5H), 3.65 (d, 1H), 3.46 (d, 1H), 3.33-3.25 (m, 2H), 2.92 (d, 1H), 1.77-1.34 (m, 3H), 1.13 (d, 3H); LC/MS(ESI): m/z=484.2 [M+H].sup.+.

Embodiment 109

Preparation of (3S,4S)-8-(2-((2-chloro-3-(pyrazine-2-amino)phenyl)mercapto)pyrimidine-5-yl)-3-me thyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0465] ##STR00196##

[0466] Compound 109 (174 mg, yield 30%) is obtained in a similar manner to Embodiment 107. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.40-8.35 (m, 3H), 8.28 (s, 2H), 7.52-7.09 (m, 3H), 6.23 (s, 1H), 4.14-4.09 (m, 1H), 3.92-3.75 (m, 5H), 3.64 (d, 1H), 3.46 (d, 1H), 3.35-3.25 (m, 2H), 2.92 (d, 1H), 1.77-1.34 (m, 3H), 1.13 (d, 3H); LC/MS(ESI): m/z=484.2 [M+H].sup.+.

Embodiment 110

Preparation of (3S,4S)-8-(2-((2-chloro-3-(pyrimidine-4-amino)phenyl)mercapto)pyrimidine-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0467] ##STR00197##

[0468] Compound 110 (186 mg, yield 32%) is obtained in a similar manner to Embodiment 107. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.43 (s, 1H), 8.40 (d, 1H), 8.29 (s, 2H), 7.52-6.93 (m, 4H), 6.05 (s, 1H), 4.13-4.09 (m, 1H), 3.94-3.75 (m, 5H), 3.65 (d, 1H), 3.46 (d, 1H), 3.33-3.24 (m, 2H), 2.88 (d, 1H), 1.79-1.34 (m, 3H), 1.13 (d, 3H); LC/MS(ESI): m/z=484.2 [M+H].sup.+.

Embodiment 111

Preparation of (3S,4S)-8-(5-((2-chloro-3-(1-methyl-1H-pyrazole-3-yl)phenyl)mercapto)pyrimidine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0469] ##STR00198##

[0470] Dissolve compound (3S,4S)-8-(5-chloropyrimidine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (1.13 g, 4 mmol) in 10 mL of 1,4-dioxane, add compound 3-(1-methyl-1H-pyrazole-3-yl)-2-chloro-thiophenol (1.08 g, 4.8 mmol), potassium tert-butoxide (0.67 g, 6.0 mmol), and cuprous iodide (76 mg, 0.4 mmol). Perform nitrogen substitution 3 times. Stir the reaction mixture and reflux for 24 hours. After cooling to room temperature, the reaction solution is passed through a silica gel short column, rinse the column with ethyl acetate, and evaporate the solution to dryness under reduced pressure. The residue is purified by column chromatography to give compound 111 (810 mg, 43% yield). 1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.33 (s, 2H), 7.77 (d, 1H), 7.51 (d, 1H), 7.23 (t, 1H), 6.83 (d, 1H), 6.58 (d, 1H), 4.13-4.09 (m, 1H), 3.94-3.75 (m, 5H), 3.63 (d, 1H), 3.47 (d, 1H), 3.34-3.25 (m, 2H), 2.92 (d, 1H), 1.77-1.32 (m, 6H), 1.15 (d, 3H); LC/MS(ESI): m/z=471.2[M+H].sup.+.

Embodiment 112

Preparation of (3S,4S)-8-(5-((2-chloro-3-(1-ethyl-1H-pyrazole-3-yl)phenyl)mercapto)pyrimidine-2-y l)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0471] ##STR00199##

[0472] Compound 112 (912 mg, yield 47%) is obtained in a similar manner to Embodiment 111. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.32 (s, 2H), 7.77 (d, 1H), 7.52 (d, 1H), 7.23 (t, 1H), 6.85 (d, 1H), 6.57 (d, 1H), 4.13-4.09 (m, 1H), 3.98-3.77 (m, 5H), 3.65 (d, 1H), 3.49 (d, 1H), 3.34-3.25 (m, 2H), 2.90 (d, 1H), 1.78-1.33 (m, 6H), 1.28 (t, 3H), 1.15 (d, 3H); LC/MS(ESI): m/z=485.2[M+H].sup.+.

Embodiment 113

Preparation of (3S,4S)-8-(5-((2-chloro-3-(1-isopropyl-1H-pyrazole-3-yl)phenyl)mercapto)pyrimidine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0473] ##STR00200##

[0474] Compound 113 (799 mg, yield 40%) is obtained in a similar manner to Embodiment 111. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.32 (s, 2H), 7.78 (s, 1H), 7.51 (d, 1H), 7.23 (t, 1H), 6.83 (d, 1H), 6.57 (d, 1H), 4.14-4.07 (m, 2H), 3.97-3.74 (m, 5H), 3.64 (d, 1H), 3.47 (d, 1H), 3.34-3.25 (m, 2H), 2.90 (d, 1H), 1.79-1.32 (m, 12H), 1.15 (d, 3H); LC/MS(ESI): m/z=499.2[M+H].sup.+.

Embodiment 114

Preparation of N-(3-((2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrimidine-5-y l)mercapto)-2-chlorophenyl)-2-hydroxyl-4-oxo-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]pyrimidine-3-carboxamide

[0475] ##STR00201##

[0476] Dissolve compound (3S,4S)-8-(5-chloropyrimidine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (565 mg, 2 mmol) in 6 mL of 1,4-dioxane, add the compound N-(2-chloro-3-mercaptophenyl)-2-hydroxyl-4-oxo-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]pyrimidine-3-carboxamide (504 mg, 2.4 mmol), potassium tert-butoxide (335 mg, 3 mmol), and cuprous iodide (38 mg, 0.2 mmol). Perform nitrogen substitution 3 times. Stir the mixture and reflux for 24 hours. The reaction mixture is refluxed and stirred for 24 hours. After cooling to room temperature, the reaction solution is passed through a silica gel short column, rinse the column with ethyl acetate, and evaporate the solution to dryness under reduced pressure. The residue is purified by column chromatography to give compound 114 (538 mg, yield 45%). 1H NMR (400 MHz, DMSO-d.sub.6) ?: 12.7(br s, 1H), 8.35-8.23 (m, 3H), 7.24 (s, 1H), 6.59 (d, 1H), 5.52 (br s, 3H), 4.13-4.09 (m, 1H), 3.92-3.55 (m, 7H), 3.32-3.25 (m, 3H), 2.93 (d, 1H), 1.87-1.35 (m, 8H), 1.15 (d, 3H); LC/MS(ESI): m/z=598.2[M+H].sup.+.

Embodiment 115

Preparation of (3S,4S)-8-(5-((2-chloro-3-(pyrimidine-5-yl)phenyl)mercapto)pyrimidine-2-yl)-3-meth yl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0477] ##STR00202##

[0478] Compound 115 (441 mg, yield 47%) is obtained in a similar manner to the last step of Embodiment 114. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 9. 22 (s, 1H), 8. 90 (s, 2H), 8. 33 (s, 2H), 7.51 (d, 1H), 7.21 (t, 1H), 7. 06 (d, 1H), 4. 13-4.09 (m, 1H), 3.9 4-3.45 (m, 7H), 3.3 4-3.25 (m, 2H), 2.90 (d, 1H), 1. 81-1.33 (m, 3H), 1. 13 (d, 3H); LC/MS(ESI): m/z=469.1[M+H].sup.+.

Embodiment 116

Preparation of (3S,4S)-8-(5-((2-chloro-3-(pyrazine-2-yl)phenyl)mercapto)pyrimidine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0479] ##STR00203##

[0480] Compound 116 (422 mg, yield 45%) is obtained in a similar manner to the last step of Embodiment 114. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.80 (s, 1H), 8.75 (s, 2H), 8.32 (s, 2H), 7.51 (d, 1H), 7.23 (t, 1H), 7.05 (d, 1H), 4.13-4.09 (m, 1H), 3.94-3.43 (m, 7H), 3.32-3.23 (m, 2H), 2.91 (d, 1H), 1.79-1.33 (m, 3H), 1.15 (d, 3H); LC/MS(ESI): m/z=469.1[M+H].sup.+.

Embodiment 117

Preparation of (3S,4S)-8-(5-((2-chloro-3-(pyridine-3-yl)phenyl)mercapto)pyrimidine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0481] ##STR00204##

[0482] Compound 117 (393 mg, yield 42%) is obtained in a similar manner to the last step of Embodiment 114. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.87 (s, 1H), 8.71 (d, 1H), 8.34-8.30 (m, 3H), 7.55-7.51 (m, 2H), 7.22 (t, 1H), 7.04 (d, 1H), 4.13-4.08 (m, 1H), 3.94-3.45 (m, 7H), 3.31-3.25 (m, 2H), 2.91 (d, 1H), 1.78-1.31 (m, 3H), 1.15 (d, 3H); LC/MS(ESI): m/z=468.2[M+H].sup.+.

Embodiment 118

Preparation of (3S,4S)-8-(5-((2-chloro-3-(pyrimidine-4-yl)phenyl)mercapto)pyrimidine-2-yl)-3-meth yl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0483] ##STR00205##

[0484] Compound 118 (431 mg, yield 46%) is obtained in a similar manner to the last step of Embodiment 114. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 9.25 (s, 1H), 8.86 (d, 1H), 8.32 (s, 2H), 8.12 (d, 1H), 7.51 (d, 1H), 7.22 (t, 1H), 7.06 (d, 1H), 4.13-4.10 (m, 1H), 3.94-3.45 (m, 7H), 3.32-3.25 (m, 2H), 2.90 (d, 1H), 1.78-1.31 (m, 3H), 1.15 (d, 3H);

[0485] LC/MS(ESI): m/z=469.1 [M+H].sup.+.

Embodiment 119

Preparation of (3S,4S)-8-(5-((2-chloro-3-(pyridine-3-amino)phenyl)mercapto)pyrimidine-2-yl)-3-me thyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0486] ##STR00206##

[0487] Compound 119 (347 mg, yield 36%) is obtained in a similar manner to the last step of Embodiment 114. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.43 (s, 1H), 8.35-8.25 (m, 3H), 7.58-6.89 (m, 5H), 6.11 (s, 1H), 4.13-4.09 (m, 1H), 3.94-3.45 (m, 7H), 3.33-3.25 (m, 2H), 2.91 (d, 1H), 1.76-1.32 (m, 3H), 1.15 (d, 3H); LC/MS(ESI): m/z=483.2 [M+H].sup.+.

Embodiment 120

Preparation of (3S,4S)-8-(5-((2-chloro-3-(pyrimidine-2-amino)phenyl)mercapto)pyrimidine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0488] ##STR00207##

[0489] Compound 120 (386 mg, yield 40%) is obtained in a similar manner to the last step of Embodiment 114. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.46 (d, 2H), 8.33 (s, 2H), 8.05 (d, 1H), 7.32-6.95 (m, 3H), 6.15 (s, 1H), 4.14-4.10 (m, 1H), 3.95-3.45 (m, 7H), 3.33-3.25 (m, 2H), 2.93 (d, 1H), 1.75-1.31 (m, 3H), 1.15 (d, 3H); LC/MS(ESI): m/z=484.2 [M+H].sup.+.

Embodiment 121

Preparation of (3S,4S)-8-(5-((2-chloro-3-(pyrazine-2-amino)phenyl)mercapto)pyrimidine-2-yl)-3-me thyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0490] ##STR00208##

[0491] Compound 121 (405 mg, yield 42%) is obtained in a similar manner to the last step of Embodiment 114. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.41-8.35 (m, 3H), 8.31 (s, 2H), 7.41-6.94 (m, 3H), 6.21 (s, 1H), 4.14-4.10 (m, 1H), 3.92-3.75 (m, 5H), 3.64 (d, 1H), 3.46 (d, 1H), 3.35-3.25 (m, 2H), 2.92 (d, 1H), 1.75-1.31 (m, 3H), 1.15 (d, 3H); LC/MS(ESI): m/z=484.2 [M+H].sup.+.

Embodiment 122

Preparation of (3S,4S)-8-(5-((2-chloro-3-(pyrimidine-4-amino)phenyl)mercapto)pyrimidine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0492] ##STR00209##

[0493] Compound 122 (424 mg, yield 44%) is obtained in a similar manner to the last step of Embodiment 114. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ?: 8.43 (s, 1H), 8.41 (d, 1H), 8.31 (s, 2H), 7.64-6.93 (m, 4H), 6.12 (s, 1H), 4.15-4.11 (m, 1H), 3.93-3.45 (m, 7H), 3.33-3.23 (m, 2H), 2.90 (d, 1H), 1.74-1.31 (m, 3H), 1.15 (d, 3H); LC/MS(ESI): m/z=484.2 [M+H].sup.+.

Embodiment 123

[0494] Preparation N-(3-((2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl I)pyrimidine-5-yl)mercapto)-2-chlorophenyl)pyrimidine-2-carboxamide of

##STR00210##

[0495] The subsequent two steps are similar to the last two steps of Embodiment 114 and performed to give compound 123 (266 mg, yield 52%). 1H NMR (400 MHZ, DMSO-d.sub.6) ?: 9.93 (s, 1H), 8.91 (d, 2H), 8.31 (s, 2H), 7.64-6.93 (m, 4H), 4.15-4.11 (m, 1H), 3.93-3.45 (m, 7H), 3.33-3.23 (m, 2H), 2.90 (d, 1H), 1.74-1.31 (m, 3H), 1.15 (d, 3H); LC/MS(ESI): m/z=512.2 [M+H].sup.+.

Embodiment 124

[0496] Preparation N-(3-((2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl of 1)pyrimidine-5-yl)mercapto)-2-chlorophenyl)pyrimidine-4-carboxamide

##STR00211##

[0497] Compound 124 (282 mg, yield 55%) is obtained in a similar manner to Embodiment 123 (the raw material is changed to pyrimidine-4-carboxylic acid). 1H NMR (400 MHZ, DMSO-d.sub.6) ?: 9.88 (s, 1H), 9.31 (s, 1H), 9.01 (d, 1H), 8.31 (s, 2H), 8.21 (d, 1H), 7.75 (d, 1H), 7.42 (t, 1H), 7.15 (d, 1H), 4.15-4.11 (m, 1H), 3.93-3.45 (m, 7H), 3.33-3.23 (m, 2H), 2.90 (d, 1H), 1.74-1.31 (m, 3H), 1.15 (d, 3H); LC/MS(ESI): m/z=512.2 [M+H].sup.+.

Embodiment 125

Preparation of N-(3-((2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrimidine-5-yl)mercapto)-2-chlorophenyl)pyridine-2-carboxamide

[0498] ##STR00212##

[0499] Compound 125 (245 mg, yield 48%) is obtained in a similar manner to Embodiment 123 (the raw material is changed to pyridine-2-carboxylic acid). 1H NMR (400 MHZ, DMSO-d.sub.6) ?: 10.02 (s, 1H), 8.61-8.59 (m, 1H), 8.32-8.30 (m, 3H), 7.75-7.55 (m, 3H), 7.44-7.39 (m, 1H), 7.14-7.03 (m, 1H), 4.15-4.11 (m, 1H), 3.93-3.45 (m, 7H), 3.32-3.21 (m, 2H), 2.90 (d, 1H), 1.73-1.30 (m, 3H), 1.15 (d, 3H); LC/MS(ESI): m/z=511.2 [M+H].sup.+.

Embodiment 126

Preparation of N-(3-((2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrimidine-5-yl)mercapto)-2-chlorophenyl)pyrazine-2-carboxamide

[0500] ##STR00213##

[0501] Compound 126 (261 mg, yield 51%) is obtained in a similar manner to Embodiment 123 (the raw material is changed to pyrazine-2-carboxylic acid). 1H NMR (400 MHZ, DMSO-d.sub.6) ?: 9.68 (s, 1H), 9.51 (s, 1H), 8.81 (d, 1H), 8.55-8.52 (m, 1H), 8.31 (s, 2H), 7.71-7.62 (m, 1H), 7.43-7.39 (m, 1H), 7.15 (d, 1H), 4.15-4.11 (m, 1H), 3.93-3.45 (m, 7H), 3.33-3.23 (m, 2H), 2.90 (d, 1H), 1.74-1.31 (m, 3H), 1.15 (d, 3H); LC/MS(ESI): m/z=512.2 [M+H].sup.+.

Embodiment 127

Preparation of (3S,4S)-8-(3-((2-chloro-3-(1-ethyl-1H-pyrazole-3-yl)phenyl)mercapto)pyridazine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0502] ##STR00214##

[0503] Compound 127 (320 mg, 44% yield, which is the yield of the last step, the same below) is obtained by a method similar to that of Embodiment 114. LC/MS(ESI): m/z=486.2[M+H].sup.+.

Embodiment 128

Preparation of (3S,4S)-8-(3-((2-chloro-3-(1-ethyl-1H-pyrazole-3-yl)phenyl)mercapto)-tetrazine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0504] ##STR00215##

[0505] Compound 128 (358 mg, 49% yield, which is the yield of the last step, the same below) is obtained by a method similar to that of Embodiment 114. LC/MS(ESI): m/z=488.2[M+H].sup.+.

Embodiment 129

Preparation of (3S,4S)-8-(3-((2-chloro-3-(1-ethyl-1H-pyrazole-3-yl)phenyl)mercapto)-1,2,4-triazine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0506] ##STR00216##

[0507] Compound 129 (350 mg, 48% yield, which is the yield of the last step, the same below) is obtained by a method similar to that of Embodiment 114. LC/MS(ESI): m/z=487.2[M+H].sup.+.

Embodiment 130

Preparation of N-(3-((2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-1,2,4-triazine-6-yl)mercapto)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]pyrimidine-3-carboxamide

[0508] ##STR00217##

[0509] Compound 130 (299 mg, 41% yield, which is the yield of the last step, the same below) is obtained by a method similar to that of Embodiment 123. LC/MS(ESI): m/z=600.2[M+H].sup.+.

Embodiment 131

Preparation of (3S,4S)-8-(6-((2-chloro-3-(1-ethyl-1H-pyrazole-3-yl)phenyl)mercapto)-1,2,4-triazine-3-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0510] ##STR00218##

[0511] Compound 131 (283 mg, yield 39%, this is the yield of the last step, the same below) is obtained by a method similar to that of Embodiment 123. LC/MS(ESI): m/z=487.2[M+H].sup.+.

Embodiment 132

Preparation of (3S,4S)-8-(3-((2-chloro-3-(pyrazine-2-yl)phenyl)mercapto)pyridazine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0512] ##STR00219##

[0513] Compound 132 (200 mg, yield 37%) is obtained in a similar manner to Embodiment 118. LC/MS(ESI): m/z=470.1[M+H].sup.+.

Embodiment 133

Preparation of (3S,4S)-8-(3-((2-chloro-3-(pyrazine-2-yl)phenyl)mercapto)-tetrazine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0514] ##STR00220##

[0515] Compound 133 (211 mg, yield 39%) is obtained in a similar manner to Embodiment 118. LC/MS(ESI): m/z=472.1[M+H].sup.+.

Embodiment 134

Preparation of (3S,4S)-8-(3-((2-chloro-3-(pyrazine-2-yl)phenyl)mercapto)-1,2,4-triazine-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0516] ##STR00221##

[0517] Compound 134 (227 mg, yield 42%) is obtained in a similar manner to Embodiment 114. LC/MS(ESI): m/z=471.1[M+H].sup.+.

Embodiment 135

Preparation of (3S,4S)-8-(6-((2-chloro-3-(pyrazine-2-yl)phenyl)mercapto)-1,2,4-triazine-3-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

[0518] ##STR00222##

[0519] Compound 135 (384 mg, yield 41%) is obtained in a similar manner to the last step of Embodiment 114. LC/MS(ESI): m/z=471.1[M+H].sup.+.

Embodiment 136

Preparation of N-(3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyridazine-3-yl) mercapto)-2-chlorophenyl)-2-hydroxy-4-oxa-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]pyrimidine-3-carboxamide

[0520] ##STR00223##

[0521] Compound 136 (197 mg, yield 32%) is obtained in a similar manner to Embodiment 117. LC/MS(ESI): m/z=499.1[M+H].sup.+.

Embodiment 137

Preparation of N-(3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)s-tetrazine-3-yl) mercapto)-2-chlorophenyl)-2-hydroxy-4-oxa-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]pyrimidine-3-carboxamide

[0522] ##STR00224##

[0523] Compound 137 (159 mg, yield 25%) is obtained in a similar manner to Embodiment 117. LC/MS(ESI): m/z=601.1[M+H].sup.+.

Embodiment 138

Preparation of N-(3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-1,2,4-triazine-3-yl)mercapto)-2-chlorobenzene)-2-hydroxy-4-oxa-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]pyrimidine-3-carboxamide

[0524] ##STR00225##

[0525] Compound 138 (178 mg, yield 29%) is obtained in a similar manner to Embodiment 117. LC/MS(ESI): m/z=600.1[M+H].sup.+.

Embodiment 139

Biological Activity Test of Embodiment 139

[0526] The following further describes and explains the present invention in combination with test examples, but these examples are not meant to limit the scope of the present invention. SHP2 allosteric inhibition experiment

Determination of Compound's Inhibitory Effect on SHP2 Kinase Activity

[0527] The purpose of this test is to measure the ability of the compounds to inhibit the allosteric activity of the SHP2 full-length protein. Experimental equipment: a centrifuge (5810R) is purchased from Eppendorf Company; pipettes are purchased from Eppendorf Company and Rainin Company, and microplate readers are purchased from BioTek Company of the United States, SynergyH1 multimode microplate reader.

[0528] Experimental method: Homogeneous Full Length SHP-2 Assay Kit (BPS Bioscience, #79330) is used to detect SHP2 activity in vitro. First, add 18 ?L of Master Mix to 96-well low-adsorption microplate (NUNC, #267342), that is, 0.5 ?L of SHP-2 activating Peptide and 5 mM DTT are included in the reaction buffer with a final concentration of 1?. After centrifugation, add 5 ?L of the compound to be tested in DMSO (final DMSO content is 1% (V/V) in each well: dissolve the compound to be tested in DMSO to 1 mM, conduct triple dilution with a total of 10 concentration levels ranging from 1 ?M to 0.05 nM in the reaction buffer. After diluting SHP2 in 1? reaction buffer to a final concentration of 0.06 nM, add it to the reaction microwell plate, 2 ?L per well. Set a full activity control (compound plus DMSO only) and a full inhibition control (without SHP-2) on the reaction plate, and incubate the reaction mixture at room temperature for 60 minutes after centrifugation.

[0529] After incubation, add 25 ?L of Substrate solution to each well, containing Substrate with a final concentration of 10 ?M and DTT with a final concentration of 5 mM, and after centrifugation, continue to incubate at room temperature for 30 minutes. After the reaction, set the excitation wavelength at 340 nm, the emission wavelength at 455 nM, and the gain value to 75 on the Synergy H1 microplate reader (Biotek) for reading.

Experimental Data Processing Method

[0530] Take the full activity control and full inhibition control as the values of Max and Min, and calculate the percentage inhibition rate of the wells treated with the compound based on the positive control wells (DMSO control wells) and negative control wells (no kinase added) on the reaction plate, (inhibition rate percentage=100?[(test compound?Min average value)/(Max average value?Min average value)]?100%. IC.sub.50 values of test compounds are calculated by fitting percentage of inhibition and ten-point concentration data to a 4-parameter nonlinear logic formula using GraphPad prism.

Experimental Conclusion

[0531] By following the above protocol, the tested compounds of the present invention exhibited the biological activities shown in Table 1 in the SHP2 kinase activity test. Where A represents IC.sub.50?10 nM; B represents 10<IC.sub.50?100 nM; C represents 100<IC.sub.50?1000 nM; D represents 1000<IC.sub.50 nM.

IC.SUB.50 .Values of Compounds Inhibiting SHP2

[0532]

TABLE-US-00001 No. IC.sub.50 1 A 2 A 3 A 4 A 5 A 6 A 7 A 8 A 9 B 10 B 11 B 12 B 13 B 14 B 15 B 16 B 17 A 18 A 19 A 20 A 21 A 22 A 23 A 24 A 25 A 26 A 27 A 28 A 63 A 64 A 65 A 66 A 67 A 68 A 69 A 70 A 71 A 72 A 73 A 74 A 75 A 76 A 77 A 78 A 79 A 80 A 81 A 82 A 83 A 84 A 85 A 86 A 87 A 88 A 89 A 90 A 91 A 92 A 93 A 94 A 95 A 96 A 97 A 98 A 99 A 100 A 101 A 102 A 103 A 104 A 105 A 106 A 107 B 108 B 109 B 110 B 111 B 112 B 113 B 114 B 115 A 116 A 117 A 118 A 119 A 120 A 121 A 122 A 123 A 124 A 125 A 126 A 127 A 128 A 129 A 130 A 131 A 132 A 133 A 134 A 135 A 136 A 137 A 138 A