Pyrimidine-fused cyclic compound, preparation method therefor and application thereof

Abstract

Disclosed in the present disclosure are a pyrimidine-fused cyclic compound or a pharmaceutically acceptable salt, hydrate, prodrug, stereoisomer, solvate or isotope labeled compound thereof. Also provided in the present disclosure are a preparation method for the compound, a composition comprising the compound and a use of the compound for the preparation of a medicament for the prevention and/or treatment of a disease or condition associated with abnormal SHP2 activity. ##STR00001##

Claims

1. A compound selected from the group consisting of ##STR00757## and or a pharmaceutically acceptable salt thereof.

2. The compound or pharmaceutically acceptable salt thereof as defined in claim 1, wherein the compound is ##STR00758##

3. The compound or pharmaceutically acceptable salt thereof as defined in claim 1, wherein the compound is ##STR00759##

4. The compound or pharmaceutically acceptable salt thereof as defined in claim 1, wherein the compound is ##STR00760##

5. A pharmaceutical composition, comprising the compound or pharmaceutically acceptable salt thereof as defined in claim 1, and a pharmaceutically acceptable excipient.

6. A method for the treatment of a disease or condition associated with abnormal activity of SHP2 in a subject in need thereof, comprising administering the compound or the pharmaceutically acceptable salt thereof as defined in claim 1 to the subject, wherein the disease or condition is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma and glioblastoma.

7. A pharmaceutical preparation, comprising the compound or pharmaceutically acceptable salt thereof as defined in claim 1.

8. The pharmaceutical preparation as defined in claim 7, wherein the pharmaceutical preparation is adapted for oral administration, sublingual administration, subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, nasal administration, local topical administration or rectal administration; and/or, the pharmaceutical preparation is adapted to be administered once or multiple times a day.

9. A combination product comprising (i) the compound or pharmaceutically acceptable salt thereof as defined in claim 1; and (ii) another medicament, wherein the another medicament is selected from anticancer medicaments, tumor immune medicaments, antiallergic medicaments, antiemetic medicaments, analgesics, and cell protection medicaments.

10. A method for treatment of a disease or condition associated with abnormal activity of SHP2 in a subject in need thereof, comprising administering the pharmaceutical composition thereof as defined in claim 5 to the subject, wherein the disease or condition is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma and glioblastoma.

11. A method for the treatment of a disease or condition associated with abnormal activity of SHP2 in a subject in need thereof, comprising administering the pharmaceutical composition thereof as defined in claim 7 to the subject, wherein the disease or condition is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma and glioblastoma.

12. A method for the treatment of a disease or condition associated with abnormal activity of SHP2 in a subject in need thereof, comprising administering the pharmaceutical composition thereof as defined in claim 9 to the subject, wherein the disease or condition is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma and glioblastoma.

Description

DETAILED DESCRIPTION OF THE EMBODIMENT

(1) The present disclosure is further described by way of examples below, but the present disclosure is not limited to the scope of the described examples. The experimental methods without specific conditions in the following examples are selected according to the conventional methods and conditions or according to the product instruction.

(2) The starting materials used in the following examples can be purchased from chemical vendors e.g., Aldrich, TCI, Alfa Aesar, Bide, and Energy Chemical, or can be synthesized by known methods.

(3) In the following examples, the ice bath refers to −5° C. to 0° C., the room temperature refers to 10° C. to 30° C., and the reflux temperature generally refers to the solvent reflux temperature under normal pressure. Overnight reaction refers to a time of 8-15 hours. In the following examples, if the operating temperature is not specified, the operation is carried out at room temperature.

(4) In the following examples, the isolation and purification of the intermediates and final products are performed by normal phase or reversed-phase chromatography column separation or other suitable methods. Normal phase flash chromatography columns use ethyl acetate and n-hexane or methanol and dichloromethane as mobile phases. Reversed-phase preparative high-performance liquid chromatography (HPLC) uses C18 column and uses UV 214 nm and 254 nm for detection, of which the mobile phase is A (water and 0.1% formic acid) and B (acetonitrile), or mobile phase A (water and 0.1% ammonium bicarbonate) and B (acetonitrile).

(5) In each example: LCMS instrument: Pump Agilent 1260 UV detector: Agilent 1260 DAD Mass Spectrometer API 3000.

(6) Chromatography column: Waters sunfire C18, 4.6×50 mm, 5 m.

(7) Mobile phase: A-H.sub.2O (0.1% HCOOH); B-acetonitrile NMR.

(8) Instrument: Bruker Ascend 400M (H NMR: 400 MHz; .sup.13C NMR: 100 MHz).

Example 1

Preparation of Intermediate: 5-chloro-8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidine (B1)

Step 1:2-chloro-N-(2,2-dimethoxyethyl)-5-iodopyrimidin-4-amine

(9) ##STR00375##

(10) To a dry 2 L flask were successively added 2,4-dichloro-5-iodopyrimidine (110 g, 400 mmol), 2,2-dimethoxyethylamine (84 g, 800 mmol) and anhydrous ethanol (1.2 L). At 0° C. under nitrogen atmosphere, triethylamine (109 mL, 800 mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature for 10 hours. After the reaction was completed, the mixture was concentrated in vacuum, and the resulting concentrate was added with 1 L of water, and extracted with dichloromethane (3×300 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting brown-black solid was washed with anhydrous ethanol (3×50 mL) to obtain 2-chloro-N-(2,2-dimethoxyethyl)-5-iodopyrimidin-4-amine (110 g, yield: 78%) as a brown solid.

(11) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.35 (s, 1H), 4.58 (t, J=5.4 Hz, 1H), 3.47 (t, J=5.6 Hz, 2H), 3.29 (s, 6H) ppm; LC-MS: m/z 344.1 [M+H].sup.+.

Step 2: 8-iodoimidazo[1,2-c]pyrimidin-5-ol

(12) ##STR00376##

(13) To a dry 2 L flask were successively added 2-chloro-N-(2,2-dimethoxyethyl)-5-iodopyrimidin-4-amine (110 g, 317 mmol) and 800 mL of concentrated sulfuric acid. Under nitrogen atmosphere, the mixture was heated to 65° C. and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and slowly poured into ice water, and then the pH was adjusted to about 6.0 with 4 M NaOH solution, followed by extraction with ethyl acetate (3×300 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 8-iodoimidazo[1,2-c]pyrimidin-5-ol (70 g, yield 84.5%).

(14) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.80 (s, 1H), 7.92 (d, J=1.5 Hz, 1H), 7.60 (d, J=3.9 Hz, 1H), 7.40 (d, J=1.5 Hz, 1H); LC-MS: m/z 262.1 [M+H].sup.+

Step 3: 8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-ol

(15) ##STR00377##

(16) To a dry 250 mL three-neck flask were successively added 8-iodoimidazo[1,2-c]pyrimidin-5-ol (2.61 g, 10 mmol), cuprous iodide (190 mg, 1 mmol), 1,10-phenanthroline (360 mg, 2 mmol), 2,3-dichlorothiophenol (2.15 g, 12 mmol), potassium phosphate (4.2 g, 20 mmol) and 50 mL of dioxane. The mixture was heated for 3 hours under nitrogen atmosphere. After the reaction was completed, saturated NH.sub.4Cl solution (200 mL) was added, followed by extraction with ethyl acetate (3×200 mL). The organic phases were combined, dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (methanol:ethyl acetate with a gradient of 0 to 10%) to obtain 8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-ol (2.3 g, yield: 74%) as pale yellow solid.

(17) LC-MS: m/z 312.1 [M+H].sup.+.

Step 4: 5-chloro-8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidine (B1)

(18) ##STR00378##

(19) To a dry 100 mL single-necked flask were added 8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-ol (2.3 g, 7.3 mmol) and phosphorus oxychloride (30 mL) sequentially, and N,N-diisopropylethylamine (1 mL) was slowly added dropwise under nitrogen atmosphere. The mixture was then heated to 120° C. and stirred for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and then concentrated in vacuum, and the reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3×30 mL), and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography (methanol: ethyl acetate with a gradient of 0 to 10%) to obtain 5-chloro-8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidine (B1) as a white solid (660 mg, yield: 27.4%).

(20) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.18 (d, J=1.4 Hz, 1H), 8.07 (s, 1H), 7.76 (d, J=1.4 Hz, 1H), 7.52 (dd, J=8.0, 1.3 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.00 (dd, J=8.1, 1.2 Hz, 1H) ppm; LC-MS: m/z 330.1 [M+H].sup.+.

Example 2: Preparation of Intermediate: 5-chloro-8-iodoimidazo[1,2-c]pyrimidine (E1)

(21) ##STR00379##

(22) To a dry 250 mL single-necked flask were sequentially added 8-iodoimidazo[1,2-c]pyrimidin-5-ol (5 g, 19.1 mmol) and phosphorus oxychloride (50 mL), and N,N-diisopropylethylamine (1 mL) was slowly added dropwise under nitrogen atmosphere. The mixture was then heated to 120° C. and stirred for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated in vacuum, quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give a residue, which was purified by silica gel chromatography (methanol: ethyl acetate with a gradient of 0 to 10%) to obtain 5-chloro-8-iodoimidazo[1,2-c]pyrimidine E1 (1.6 g, yield: 29.8%).

(23) .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.28 (s, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H) ppm; LC-MS: m/z 280.1 [M+H].sup.+.

Example 3: Preparation of Intermediate: (R)-2-methyl-N—((R)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1A)

Step 1: Tert-Butyl (R)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decane-8-carboxylate

(24) ##STR00380##

(25) To a dry 100 mL single-necked flask were successively added tert-butyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate (2.53 g, 10 mmol), (R)-2-methylpropane-2-sulfinamide (1.45 g, 12 mmol), titanium tetraethoxide (6.84 g, 30 mmol) and 50 mL of tetrahydrofuran. The reaction solution was stirred under reflux for 4 hours. After cooling to room temperature, methanol (10 mL) was added followed by lithium borohydride (0.65 g, 30 mmol). The resulting mixture was stirred at room temperature for 3 hours. Methanol was slowly added to quench excess borohydride, followed by addition of brine. The resulting mixture was stirred for 15 minutes and then filtered through diatomite. The aqueous mixture was extracted with ethyl acetate (3×50 mL). The organic phases were combined, dried over MgSO.sub.4, filtered, and the volatiles were removed under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate: petroleum ether with a gradient 0 to 50%) to obtain tert-butyl (R)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decane-8-carboxylate as a white solid (2.86 g, yield: 80%).

(26) LC-MS: m/z 359.1 [M+H].sup.+.

Step 2: (R)-2-methyl-N—((R)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1A)

(27) ##STR00381##

(28) A solution of tert-butyl (R)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decane-8-carboxylate (2.86 g, 8 mmol) and concentrated sulfuric acid (2.0 mL, 32 mmol) in dioxane (50 mL) was stirred at room temperature for 2 hours. A saturated aqueous solution of Na.sub.2CO.sub.3 was added until pH reached 11, and the aqueous mixture was extracted with DCM (3×50 mL). The organic phases were combined, washed with brine, dried over Na.sub.2SO.sub.4, filtered, and the volatiles were removed under reduced pressure to obtain (R)-2-methyl-N—((R)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1A) as a white solid (1.86 g, yield: 90%)

(29) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 4.82 (d, J=7.5 Hz, 1H), 3.04 (d, J=7.6 Hz, 1H), 2.81 (ddd, J=12.1, 8.0, 4.0 Hz, 2H), 2.60-2.51 (m, 2H), 1.92-1.14 (m, 10H), 1.12 (s, 9H) ppm; LC-MS: m/z 259.1 [M+H].sup.+.

(30) According to the synthesis method of Example 3, the following intermediates C-1B, C-1C, C-D, C-1E, C-1F, C-1G and C-1H were obtained by carrying out the reaction with similar raw materials.

(31) TABLE-US-00003 No. Name Structure Analysis data C-1B (R)-2-methyl-N-((R)-7-azaspiro[3.5] nonan-1-yl)propane-2-sulfinamide .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.56 (t, J = 8.9 Hz, 1H), 3.51- 3.20 (m, 2H), 3.18-2.97 (m, 2H), 2.34 (d, J = 10.1 Hz, 1H), 2.06- 1.83 (m, 3H), 1.70 (dt, J = 26.3, 12.0 Hz, 3H), 1.52 (t, J = 10.0 Hz, 1H), 1.19 (s, 9H) ppm; LC-MS: m/z 244.1 [M + H].sup.+. C-1C (R)-2-methyl-N-(7-azaspiro[3.5]no- nan-2-yl)propan-2-sulfinamide LC-MS: m/z 244.1 [M + H].sup.+ C-1D (S)-2-methyl-N-((S)-8-azaspiro[4.5] decan-1-yl)propane-2-sulfinamide LC-MS: m/z 259.1 [M + H].sup.+ C-1E (R)-2-methyl-N-((7R)-2-azaspiro[4.4] nonan-7-yl)propane-2-sulfinamide LC-MS: m/z 245.1 [M + H].sup.+ C-1F (R)-1-methyl-N-((R)-3-azaspiro[5.5] undecan-7-yl)propane-2-sulfinamide LC-MS: m/z 169.1 [M + H].sup.+ C-1G (R)-N-((R)-azepan-4-yl)-2-methylpro- pane-2-sulfinamide LC-MS: m/z 219.1 [M + H].sup.+ C-1H (S)-2-methyl-N-((S)-7-azaspiro[3.5] nonan-1-yl)propane-2-sulfinamide LC-MS: m/z 245.2 [M + H].sup.+

Example 4: Preparation of Intermediate: (R)-2-methyl-N—((S)-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1H)

Step 1: 1-(tert-butyl)-4-methyl 4-(2-(benzyloxy)-1-hydroxyethyl)piperidine-1,4-dicarboxylate

(32) ##STR00389##

(33) Under the atmosphere of nitrogen, 1-tert-butyl-4-methylpiperidine-1,4-dicarboxylate (45 g, 180 mmol) and tetrahydrofuran (400 mL) were added to a dry 500 mL three-necked flask sequentially. The solution was then cooled to −78° C., and LiHMDS (261 mL, 261 mmol) was added dropwise. After the dropwise addition was completed, the temperature was raised to room temperature and the mixture was stirred at room temperature for 3 hours, and then cooled to −78° C., followed by slow addition of a solution of benzyloxyacetaldehyde (46 g, 300 mmol) in tetrahydrofuran (50 mL). The reaction solution was slowly warmed to room temperature and stirred for 2.5 hours. After the reaction was completed, saturated NH.sub.4Cl solution (200 mL) was added to quench the reaction, followed by extraction with ethyl acetate (3×200 mL). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 50%) to obtain 1-(tert-butyl)-4-methyl 4-(2-(benzyloxy)-1-hydroxyethyl)piperidine-1,4-dicarboxylate (52 g, yield: 73.3%).

(34) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.36-7.30 (m, 5H), 4.50 (s, 2H), 3.97 (s, 2H), 3.73-3.65 (m, 2H), 3.62 (s, 3H), 3.59-3.48 (m, 3H), 2.88 (d, J=6.2 Hz, 1H), 2.23 (dd, J=13.7, 2.7 Hz, 1H), 2.04-1.88 (m, 2H), 1.74 (d, J=14.7 Hz, 1H), 1.56 (d, J=4.2 Hz, 1H), 1.44 (s, 9H) ppm; LC-MS: m/z 294.1 [M+H].sup.+.

Step 2: Tert-Butyl 4-(2-(benzyloxy)-1-hydroxyethyl)-4-(hydroxymethyl)piperidine-1-carboxylate

(35) ##STR00390##

(36) 1-(tert-butyl)-4-methyl 4-(2-(benzyloxy)-1-hydroxyethyl)piperidine-1,4-dicarboxylate (51.4 g, 130 mmol) and tetrahydrofuran (500 mL), then LiBH.sub.4 (11.44 g, 520 mmol) was added to the solution, and the resulting mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction was quenched with saturated NaHCO.sub.3 (200 mL). The mixture was extracted with ethyl acetate (3×200 mL). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 50%) to obtain tert-butyl 4-(2-(benzyloxy)-1-hydroxyethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (27 g, yield: 57%).

(37) LC-MS: m/z 266.1 [M+H].sup.+.

Step 3: Tert-Butyl 4-(1,2-dihydroxyethyl)-4-(hydroxymethyl)piperidine-1-carboxylate

(38) ##STR00391##

(39) To a dry 500 mL single-necked flask were added tert-butyl 4-(2-(benzyloxy)-1-hydroxyethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (27 g, 74 mmol), methanol (270 mL) and Pd/C (20 g) and then the flask was purged with a hydrogen balloon three times. The mixture was stirred at room temperature for 12 hours. The reaction solution was filtered and concentrated to obtain tert-butyl 4-(1,2-dihydroxyethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (18.9 g, yield: 93%).

(40) LC-MS: m/z 176.1 [M+H].sup.+.

Step 4: Tert-Butyl 4-hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(41) ##STR00392##

(42) To a dry 500 mL single-necked flask were successively added tert-butyl 4-(1,2-dihydroxyethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (18.9 g, 69 mmol), triphenyl phosphine (25.2 g, 86.25 mmol) and tetrahydrofuran (350 mL). The reaction solution was cooled to 0° C., followed by addition of DEAD (12.46 mL, 86 mmol). The reaction solution was then warmed to room temperature and stirred for 5 hours. After the reaction was completed, saturated water (200 mL) was added to quench the reaction, followed by extraction with ethyl acetate (3×200 mL). The organic phases were combined and dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (methanol/dichloromethane with a gradient of 0 to 2%) to give tert-butyl 4-hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (13.2 g, yield: 74%).

(43) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.04 (dd, J=10.0, 4.6 Hz, 1H), 3.98-3.90 (m, 1H), 3.71-3.63 (m, 2H), 3.64-3.49 (m, 3H), 3.20 (dt, J=13.4, 6.3 Hz, 1H), 3.07 (ddd, J=13.2, 9.2, 3.5 Hz, 1H), 1.95 (d, J=5.2 Hz, 1H), 1.74-1.66 (m, 1H), 1.53-1.46 (m, 1H), 1.39 (s, 9H), 1.27-1.11 (m, 1H) ppm; LC-MS: m/z 202.1[M-56+H].sup.+.

Step 5: Tert-Butyl 4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(44) ##STR00393##

(45) To a dry 500 mL single-necked flask were added tert-butyl 4-hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (13.2 g, 51 mmol), dichloromethane (280 mL) and Dess-Martin oxidant (32.2 g, 76.5 mmol), and the mixture was stirred for 5 hours in an ice bath. After the reaction was completed, a saturated solution (200 mL) of NaHCO.sub.3:Na.sub.2S.sub.2O.sub.3 (1:1) was added. The organic phase was separated, and the aqueous phase was extracted with DCM (3×100 mL).

(46) The organic phases were combined, dried over Na.sub.2SO.sub.4 and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 40%) to obtain tert-butyl 4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (12 g, yield: 92.1%).

(47) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.05 (d, J=13.6 Hz, 4H), 3.87 (d, J=12.9 Hz, 2H), 3.09 (ddd, J=13.5, 9.8, 3.5 Hz, 2H), 1.73 (ddd, J=13.9, 9.8, 4.3 Hz, 2H), 1.53 (d, J=15.1 Hz, 2H), 1.46 (s, 9H) ppm; LC-MS: m/z 200.0 [M-56+H].sup.+.

Step 6: Tert-Butyl (S)-4-(((R)-tert-butylsulfinyl)amino)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(48) ##STR00394##

(49) Using the same synthesis method as Step 1 of Example 3 (intermediate C-1A), tert-butyl 4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate was subjected to reductive amination to obtain (S)-4-(((R)-tert-butylsulfinyl)amino)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate as a white solid.

(50) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.14 (dd, J=9.3, 6.2 Hz, 1H), 3.90 (d, J=13.8 Hz, 2H), 3.77 (s, 2H), 3.70 (dd, J=9.2, 5.3 Hz, 1H), 3.63 (q, J=6.1 Hz, 1H), 3.27 (d, J=6.4 Hz, 1H), 2.90 (t, J=12.4 Hz, 2H), 1.71 (dt, J=16.6, 7.9 Hz, 2H), 1.51 (s, 2H), 1.45 (s, 9H), 1.22 (s, 9H) ppm; LC-MS: m/z 361.1 [M-100].sup.+

Step 7: (R)-2-methyl-N—((S)-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1H)

(51) ##STR00395##

(52) Using the same synthesis method as Step 2 of Example 3 (intermediate C-1A), (S)-4-(((R)-tert-butylsulfinyl)amino)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate was subjected to deprotection of the Boc protecting group to obtain (R)-2-methyl-N—((S)-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1H) as a white solid.

(53) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 5.30 (s, 1H), 5.23 (d, J=8.9 Hz, 1H), 3.93 (dd, J=8.6, 7.2 Hz, 1H), 3.69 (d, J=8.6 Hz, 1H), 3.58 (d, J=8.6 Hz, 1H), 3.46 (dd, J=8.5, 7.0 Hz, 2H), 2.89-2.73 (m, 2H), 2.48-2.42 (m, 1H), 1.69-1.50 (m, 2H), 1.39-1.21 (m, 3H), 1.12 (s, 9H) ppm; LC-MS: m/z 261.1 [M+H].sup.+.

Example 5: Preparation of (R)-2-methyl-N—((R)-1-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1I)

Step 1: 3-methoxyprop-1-yne

(54) ##STR00396##

(55) To a stirred solution of prop-2-yn-1-ol (50 g, 892.8 mmol) in water (40 mL) was added 50% aqueous NaOH solution (98.2 g), and the reaction mixture was heated to 70° C. Dimethyl sulfate (67.4 g, 535.7 mmol) was slowly added to the reaction mixture below 70° C. The reaction mixture was stirred at 60° C. for 2 hours. The product was distilled from the reaction mixture at 60° C. and collected into a receiving flask cooled at −70° C. The distillate was dried over calcium chloride overnight and further distilled to obtain 3-methoxyprop-1-yne (30 g, yield: 48%) as a colorless liquid.

(56) .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 4.10 (d, J=2.0 Hz, 2H), 3.39 (s, 3H), 2.43 (t, J=2.0 Hz, 1H) ppm.

Step 2: 1-methoxy-1,2-propadiene

(57) ##STR00397##

(58) A suspension of potassium tert-butoxide (3.9 g, 35.7 mmol) and 3-methoxyprop-1-yne (50 g, 714.2 mmol) was stirred at 70° C. for 2 hours. The product was distilled from the reaction mixture at 50° C. and collected into a receiving cooled at −70° C. to obtain 1-methoxyprop-1,2-diene (35 g, yield: 70%) as a colorless liquid. The compound was dried over KOH and stored at 0° C.

(59) .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 6.76 (t, J=8.0 Hz, 1H), 5.48 (d, J=6.0 Hz, 2H), 3.41 (s, 3H) ppm

(60) Step 3: Tert-Butyl 4-hydroxy-4-(1-methoxyprop-1,2-dien-1-yl)piperidine-1-carboxylate

(61) ##STR00398##

(62) At −78° C., to a stirred solution of 1-methoxyprop-1,2-diene (0.527 g, 7.5 mmol) in THE (10 mL) was slowly added dropwise n-butyllithium (2.5 M in THF) (2.8 mL, 7.0 mmol), and the reaction solution was stirred at this temperature for 30 minutes. Then a solution of tert-butyl 4-carbonylpiperidine-1-carboxylate (1.0 g, 5.0 mmol) in THE (5 mL) was added to the reaction mixture, and further stirred at −78° C. for 4 hours. The reaction mixture was quenched with saturated aqueous NaHCO.sub.3 and extracted with ethyl acetate (3×10 mL). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl 4-hydroxy-4-(1-methoxyprop-1,2-dien-1-yl)piperidine-1-carboxylate (1.0 g, yield: 90%) as a brown gum.

Step 4: Tert-Butyl 4-methoxy-1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate

(63) ##STR00399##

(64) To a stirred solution of tert-butyl 4-hydroxy-4-(1-methoxyprop-1,2-dien-1-yl)piperidine-1-carboxylate (6.0 g, 22.3 mmol) in tert-butanol (60 mL) were added potassium tert-butoxide (12.5 g, 111.5 mmol) and dicyclohexyl-18-crown-6 (0.42 g, 1.1 mmol). The reaction mixture was stirred under reflux for 9 hours. The reaction mixture was cooled to 10° C., neutralized with 5% HCl (pH=7.0), and extracted with ethyl acetate (3×150 mL). The organic phases were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-methoxy-1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate, which was used in the next step without purification.

(65) .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 4.56 (s, 2H), 3.97 (s, 1H), 3.69 (s, 3H), 3.08 (s, 1H), 1.79-1.74 (m, 1H), 1.52 (s, 9H), 1.45-1.26 (m, 1H) ppm; LCMS: m/z 214 [M-55].sup.+

Step 5: Tert-Butyl 4-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

(66) ##STR00400##

(67) A mixture of tert-butyl 4-methoxy-1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate (38.0 g, 141.3 mmol) and p-TSA.H.sub.2O (29.6 g, 155.4 mmol) and acetone (400 mL) was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO.sub.3, and extracted with ethyl acetate (3×500 mL). The organic phases were combined, washed with brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl 4-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (25 g) as a brown gum, which was directly used in the next reaction.

(68) LCMS: m/z 278 [M+Na].sup.+.

Steps 6 and 7: Synthesis of (R)-2-methyl-N—((R)-1-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1I)

(69) ##STR00401##

(70) According to the same synthesis method as that of the intermediate C-1A in Example 3, the keto intermediate tert-butyl 4-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate was subjected to reductive amination, followed by deprotection of the Boc protecting group to obtain (R)-2-methyl-N—((R)-1-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1I).

(71) LCMS: m/z 261 [M+Na].sup.+.

Example 6: Preparation of (R)-2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1J)

Step 1: ethyl (S)-2-((tert-butyldimethylsilyl)oxy)propionate

(72) ##STR00402##

(73) To a solution of ethyl (S)-2-hydroxypropionate (30 g, 254 mmol) in dichloromethane (300 mL) was added imidazole (2.75 g, 304.9 mmol) and the solution was cooled to 0° C., followed by addition of tert-butyldimethylsilyl chloride (46.0 g, 304.9 mmol) in portions. The mixture was stirred at room temperature for 16 hours. After the completion of the reaction was confirmed by TLC analysis, the reaction mixture was quenched with water and extracted with dichloromethane (2×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain ethyl (S)-2-((tert-butyldimethylsilyl)oxy)propionate (50 g, yield: 84%) as a colorless liquid.

(74) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.32-4.27 (m, 1H), 4.21-4.12 (m, 2H), 1.37 (d, J=6.8 Hz, 3H), 1.27 (d, J=7.2 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 6H) ppm.

Step 2: (S)-2-((tert-butyldimethylsilyl)oxy)propanal

(75) ##STR00403##

(76) At −78° C., to a solution of ethyl (S)-2-((tert-butyldimethylsilyl)oxy)propionate (25 g, 107.6 mmol) in diethyl ether (500 mL) was slowly added dropwise diisobutylaluminum hydride (1M in hexane) (129 mL, 129.1 mmol), and stirred at −78° C. for 1 hour. After the completion of the reaction was confirmed by TLC analysis, the reaction mixture was warmed to −40° C., and the reaction was quenched with a saturated aqueous solution of Rochelle salt (1 L), followed by addition of diethyl ether (500 mL). The resulting mixture was stirred at room temperature for 2 hours and extracted with diethyl ether (200 mL). The organic phase was washed with saturated brine (250 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to obtain (S)-2-((tert-butyldimethylsilyl)oxy)propanal (19 g, yield: 94%).

(77) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.61 (s, 1H), 4.12-4.06 (m, 1H), 1.27 (d, J=6.8 Hz, 3H), 0.91 (s, 9H), 0.10 (s, 6H) ppm.

Step 3: 1-(tert-butyl) 4-ethyl 4-((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)piperidine-1,4-dicarboxylate

(78) ##STR00404##

(79) At 0° C., to a stirred solution of 1-(tert-butyl)-4-ethylpiperidine-1,4-dicarboxylate (30 g, 116.6 mmol) in THE (250 mL) was added lithium diisopropylamide (2M in THF) (93.3 mL, 186.6 mmol), and the solution was stirred at 0° C. for 30 minutes, followed by addition of (S)-2-((tert-butyldimethylsilyl)oxy)propanal (22 g, 116.6 mmol) in THF (50 mL). The resulting reaction mixture was stirred at 0° C. for 1 hour, and then kept at room temperature for 1 hour. After the completion of the reaction was confirmed by TLC analysis, the reaction mixture was quenched with saturated NH.sub.4Cl solution and extracted with ethyl acetate (2×250 mL). The organic phases were combined, washed with water (150 mL), brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column (60-120 mesh) chromatography, using 25% ethyl acetate in petroleum ether as eluent to obtain 1-(tert-butyl) 4-ethyl 4-((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)piperidine-1,4-dicarboxylate (17 g, yield: 32%) as a light red oil.

(80) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.29-4.09 (m, 2H), 3.96-3.94 (m, 2H), 3.86-3.80 (m, 1H), 3.56-3.54 (m, 1H), 2.86-2.76 (m, 2H), 2.46 (d, J=5.2 Hz, 1H), 2.16-2.13 (m, 1H), 2.13-2.04 (m, 1H), 1.77-1.60 (m, 2H), 1.46 (s, 9H), 1.29-1.24 (m, 3H), 1.12 (d, J=4 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H) ppm; LCMS: m/z 346 [M-100].sup.+.

Step 4: Tert-Butyl 4-((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate

(81) ##STR00405##

(82) To a stirred solution of 1-tert-butyl 4-ethyl 4-((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)piperidine-1,4-dicarboxylate (5 g, 11.21 mmol) in THE (50 mL) was added LiBH.sub.4 (0.73 g, 33.65 mmol) in portions, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was quenched with saturated NaHCO.sub.3 solution at 0° C. and stirred at room temperature for 15 minutes. The precipitated solid was filtered off, and the aqueous phase was extracted with ethyl acetate (2×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentered under reduced pressure to obtain a crude product, which was then purified by silica gel column (100-200 mesh) chromatography using 25% ethyl acetate in petroleum ether as eluent to obtain tert-butyl 4-((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate (3 g, yield: 66%).

(83) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.55 (t, J=4.8 Hz, 1H), 4.43 (d, J=6.4 Hz, 1H), 3.52-3.47 (m, 5H), 3.31-3.28 (m, 1H), 3.05-3.01 (m, 2H), 1.58-1.49 (m, 2H), 1.42-1.38 (m, 11H), 1.11 (d, J=6.4 Hz, 3H), 0.85 (m, 9H), 0.04 (s, 6H) ppm; LC-MS: m/z 404.3 [M+H].sup.+.

Step 5: Tert-Butyl 4-((2S)-1,2-dihydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate

(84) ##STR00406##

(85) To a solution of tert-butyl 4-((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate (25 g, 61.93 mmol) in THE (500 mL) was added tetrabutylammonium fluoride (1M in THF) (93 mL, 92.89 mmol), and the resulting reaction mixture was stirred at room temperature for 2 hours. After the completion of the reaction was confirmed by TLC analysis, the reaction mixture was quenched with saturated NaHCO.sub.3 solution and extracted with ethyl acetate (2×500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentered under reduced pressure to obtain a crude product, which was then purified by silica gel (60-120 mesh) column chromatography, using ethyl acetate in petroleum ether with a gradient of 70-90% as eluent to obtain tert-butyl 4-((2S)-1,2-dihydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate (12 g, yield: 67%) as a colorless liquid.

(86) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 4.72 (t, J=4.8 Hz, 1H), 4.61 (d, J=5.2 Hz, 1H), 4.50 (d, J=7.2 Hz, 1H), 3.72-3.68 (m, 1H), 3.53-3.44 (m, 4H), 3.11-2.98 (m, 3H), 1.68-1.53 (m, 2H), 1.42-1.35 (m, 11H), 1.10 (d, J=6.4 Hz, 3H) ppm; LC-MS: m/z 290.1 [M+H].sup.+.

Step 6: Tert-Butyl (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(87) ##STR00407##

(88) At 0° C., to a stirred suspension of NaH (60% in mineral oil) (1.45 g, 60.5 mmol) in THE (30 mL) was added a solution of tert-butyl 4-((2S)-1,2-dihydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate (5 g, 17.3 mmol) and p-toluenesulfonyl chloride (3.29 g, 17.3 mmol) in THE (20 mL), and the resulting reaction mixture was reacted at 0° C. for 3 hours. After the reaction was completed, the reaction mixture was quenched with saturated NH.sub.4Cl solution (250 mL) at −20° C. and extracted with ethyl acetate (2×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentered under reduced pressure to obtain a crude product, which was then purified by silica gel (100-200 mesh) column chromatography, using 40% ethyl acetate in petroleum ether as eluent to obtain tert-butyl (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (2.1 g, yield: 44%).

(89) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.83-3.62 (m, 5H), 3.43 (d, J=6.0, 1H), 3.07-2.97 (m, 2H), 1.72-1.55 (m, 3H), 1.51-1.42 (m, 11H), 1.33 (d, J=6.4 Hz, 3H) ppm; LC-MS: m/z 172.2 [M-100].sup.+.

Step 7: (S)-tert-butyl-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(90) ##STR00408##

(91) Tert-butyl (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (2.1 g, 7.74 mmol) was added to tetrahydrofuran (50 mL), and the solution was stirred for 1 hour. After the reaction was completed, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel (100-200 mesh) column chromatography using 30% ethyl acetate in petroleum ether as eluent, followed by flash chromatography using 0.1% formic acid and acetonitrile as eluent to obtain (S)-tert-butyl-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.2 g, yield: 57%).

(92) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.20 (d, J=9.5 Hz, 1H), 3.94-3.90 (m, 4H), 3.16-3.10 (m, 1H), 3.03-2.97 (m, 1H), 1.81-1.75 (m, 1H), 1.67-1.62 (m, 1H), 1.61-1.57 (m, 1H), 1.42-1.45 (m, 10H), 1.32 (d, J=6.0 Hz, 3H) ppm; LC-MS: m/z 214.1 [M-55].sup.+.

Step 8: Tert-Butyl (3S,4S)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(93) ##STR00409##

(94) To a solution of tert-butyl (S)-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.2 g, 4.46 mmol) in THE (15 mL) were added (R)-2-methylpropane-2-sulfinamide (1.07 g, 8.91 mmol) and titanium tetraethoxide (4.07 g, 17.84 mmol). The resulting reaction mixture was stirred at 90° C. for 20 hours. The reaction mixture was cooled to −4° C., MeOH (2 mL) was added, then LiBH.sub.4 (282 mg, 12.99 mmol) was added in portions and the resulting mixture was stirred at the same temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched with saturated brine at 0° C. and stirred at room temperature for 15 minutes, followed by filtration and extraction with ethyl acetate (2×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentered under reduced pressure to obtain a crude product, which was then purified by GRACE flash chromatography using 0.1% formic acid and acetonitrile as eluent to obtain tert-butyl (3S,4S)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.2 g, yield: 72%).

(95) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.20-4.15 (m, 1H), 3.90-3.84 (m, 2H), 3.63-3.59 (m, 1H), 3.49-3.43 (m, 1H), 3.31-3.29 (m, 1H), 2.95-2.81 (m, 2H), 1.90-1.71 (m, 2H), 1.49-1.40 (m, 11H), 1.25 (s, 9H), 1.19 (d, J=6.5 Hz, 3H) ppm; LC-MS: m/z 375.2 [M+H].sup.+.

Step 9: (R)-2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1J)

(96) ##STR00410##

(97) To a solution of tert-butyl (3S,4S)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.1 g, 2.936 mmol) in dichloromethane (10 mL) was dropwise added trifluoroacetic acid (1.12 mL, 14.68 mmol) and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by chromatography using 0.1% formic acid and acetonitrile to obtain (R)-2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1J) (850 mg, yield: 72%).

(98) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.40 (brs, D.sub.2O Exchangeable, 1H), 8.30 (brs, D.sub.2O Exchangeable, 1H), 5.28 (d, J=12.0 Hz, 1H), 4.13-4.09 (m, 1H), 3.77 (d, J=9.0 Hz, 1H), 3.50-3.45 (m, 2H), 3.29-3.26 (m, 1H), 3.19-3.15 (m, 1H), 2.94-2.85 (m, 2H), 1.87-1.80 (m, 2H), 1.69-1.59 (m, 2H), 1.17 (s, 9H), 1.08 (d, J=6.0 Hz, 3H) ppm; LC-MS: m/z 275.2 [M+H].sup.+.

Example 7: Preparation of Intermediate: (R)-2-methyl-N-((1R)-2-methyl-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1K)

Step 1: Tert-Butyl 2-methyl-1-oxo-8-azaspiro[4.5]decane-8-carboxylate

(99) ##STR00411##

(100) At 0° C. and under nitrogen atmosphere, to a 100 mL dry single-necked flask were added tert-butyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate (1 g, 3.95 mmol) and anhydrous tetrahydrofuran (15 mL), and LiHMDS (3.95 mL, 3.95 mmol) was then slowly added dropwise thereto. After stirring at 0° C. for 1 hour, iodomethane (0.25 mL, 3.95 mmol) was added thereto, and stirring was continued for 2 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (3×20 mL). The organic phases were combined, dried over Na.sub.2SO.sub.4, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 20%) to obtain tert-butyl 2-methyl-1-oxo-8-azaspiro[4.5]decane-8-carboxylate. LCMS: m/z 368.0 [M+H].sup.+.

Step 2 and Step 3: (R)-2-methyl-N-((1R)-2-methyl-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1K)

(101) ##STR00412##

(102) According to the same synthesis method as the intermediate C-1A in Example 3, the ketone intermediate tert-butyl 2-methyl-1-oxo-8-azaspiro[4.5]decane-8-carboxylate was subjected to reductive amination, followed by the deprotection of the Boc protecting group to obtain (R)-2-methyl-N-((1R)-2-methyl-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1K).

(103) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.07-4.97 (m, 1H), 3.32-3.20 (m, 1H), 3.01-2.84 (m, 2H), 2.81-2.61 (m, 2H), 2.20-2.11 (m, 1H), 2.02-1.34 (m, 8H), 1.25-1.20 (m, 9H), 1.06-0.99 (m, 3H) ppm; LCMS: m/z 273.0 [M+H].sup.+.

Example 8: Preparation of

(104) (R)—N—((R)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide (C-1L)

Step 1: Tert-Butyl 3,3-dimethyl-4-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

(105) ##STR00413##

(106) At −78° C. and under nitrogen atmosphere, to a solution of tert-butyl 4-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (5 g, 19.6 mmol) in THE (50 mL) was slowly added dropwise LiHMDS (1M in THF; 19.6 mL, 19.6 mmol) and the mixture was stirred at −78° C. for 2 hours. After the reaction mixture was warmed to room temperature, iodomethane (1.22 mL, 19.6 mmol) was added thereto in portions. The resulting reaction mixture was further stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (150 mL) and quenched with saturated NaHCO.sub.3 solution (150 mL), and extracted with ethyl acetate (2×300 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 15%) to obtain tert-butyl 3,3-dimethyl-4-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1 g, yield: 18%) and tert-butyl 3-methyl-4-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.7 g, yield: 14%)

(107) Tert-butyl 3,3-dimethyl-4-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate:

(108) .sup.1HNMR (400 MHz, CDCl.sub.3) δ 3.94 (brs, 2H), 3.89 (s, 2H), 3.16-3.10 (m, 2H), 1.70-1.61 (m, 4H), 1.48 (s, 9H), 1.14 (s, 6H) ppm; LCMS: m/z 306 [M+Na].sup.+.

(109) Tert-butyl 3-methyl-4-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate:

(110) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 4.38 (t, J=8.8 Hz, 1H), 3.96 (brs, 2H), 3.67 (t, J=9.6 Hz, 1H), 3.14-3.09 (m, 2H), 2.65-2.58 (m, 1H), 1.75-1.46 (m, 13H), 1.15 (d, J=7.2 Hz, 3H) ppm; LCMS: m/z 292 [M+Na].sup.+.

Step 2: Tert-Butyl (S)-4-((tert-butylsulfinyl)imino)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

(111) ##STR00414##

(112) To a stirred solution of tert-butyl 3,3-dimethyl-4-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (2.0 g, 7.1 mmol) in THE (5.0 mL) were added (R)-2-methylpropane-2-sulfinamide (2.56 g, 21.2 mmol) and titanium tetraethoxide (8.05 g, 35.3 mmol). The resulting reaction mixture was stirred at 90° C. for 48 hours. The reaction mixture was quenched with methanol (10 mL) and diluted with ethyl acetate (50 mL), then filtered through diatomite. The crude product obtained by concentration was separated by reversed-phase flash chromatography using 0.1% formic acid and acetonitrile as eluent to obtain tert-butyl (S)-4-((tert-butylsulfinyl)imino)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decane-8-carboxy late (1.5 g, yield: 55%).

(113) .sup.1HNMR (400 MHz, CDCl.sub.3) δ 4.10-3.88 (brs, 2H), 3.80-3.72 (m, 2H), 3.04 (brs, 2H), 1.70-1.59 (m, 5H), 1.46-1.41 (m, 14H), 1.24-1.14 (m, 9H) ppm; LCMS: m/z 331 [M-55].sup.+.

Step 3: Tert-Butyl (R)-4-(((R)-tert-butylsulfinyl)amino)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decane-8-carboxylate and tert-butyl (S)-4-(((R)-tert-butylsulfinyl)amino)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

(114) ##STR00415##

(115) To a solution of tert-butyl (S)-4-((tert-butylsulfinyl)imino)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decane-8-carboxy late (1.5 g, 3.88 mmol) in a mixed solvent of MeOH and THE (3:1, 30 mL) was added NaBH.sub.4 (886 mg, 23.3 mmol) and then the mixture was heated to reflux and stirred for 16 hours. After cooling to room temperature, the reaction mixture was concentrated to 10 mL under reduced pressure, and then poured into ice water (100 mL) and stirred for 10 minutes. The resulting solid precipitate was removed by filtration, followed by extraction with ethyl acetate (3×50 mL). The combined organic phase was dried and concentrated. The crude product obtained was isolated and purified to obtain tert-butyl (R)-4-(((R)-tert-butylsulfinyl)amino)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (350 mg, yield: 23%), tert-butyl (S)-4-(((R)-tert-butylsulfinyl)amino)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (350 mg, yield: 23%) and a mixture of the two (400 mg, yield: 28%).

(116) Tert-butyl (S)-4-(((R)-tert-butylsulfinyl)amino)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decane-8-carboxylate: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.94 (brs, 2H), 3.61 (d, J=9.2 Hz, 1H), 3.54 (d, J=9.2 Hz, 1H), 3.22 (d, J=10 Hz, 1H), 3.07-3.00 (m, 3H), 1.54-1.49 (m, 4H), 1.45 (s, 9H), 1.24 (s, 9H), 1.21 (s, 3H), 1.03 (s, 3H) ppm; LCMS: m/z 411 [M+Na].sup.+; [α].sup.25.sub.D=+19.62 (c 0.25, MeOH); retention time: 1.835 min

(117) Tert-butyl (R)-4-(((R)-tert-butylsulfinyl)amino)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decane-8-carboxylate: .sup.1HNMR (400 MHz, CDCl.sub.3) δ 4.03-3.93 (m, 2H), 3.62-3.58 (m, 1H), 3.50-3.47 (m, 1H), 3.30 (brs, 1H), 3.11-2.96 (m, 3H), 1.91-1.76 (m, 2H), 1.54-1.56 (m, merged in DMSO, 2H) 1.43 (s, 9H), 1.25 (s, 9H), 1.03 (s, 3H), 0.99 (s, 3H) ppm; LCMS: m/z 411 [M+Na]; [α].sup.25.sub.D=−43.56 (c 0.25, MeOH); retention time: 2.009 min.

Step 4: (R)—N—((R)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide (C-1L)

(118) ##STR00416##

(119) Using the same synthetic method as Step 9 of Example 6 (intermediate C-1J), tert-butyl (R)-4-(((R)-tert-butylsulfinyl)amino)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decane-8-carboxylate was subjected to deprotection of the Boc protecting group to obtain (R)—N—((R)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide C-1L.

(120) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 4.92 (d, D.sub.2O Exchangeable, J=11.5 Hz, 1H), 3.50 (d, J=9.0 Hz, 1H), 3.43 (d, J=9.0 Hz, 1H), 3.20-3.14 (m, 2H), 3.09 (d, J=12.0, 1H), 3.00-2.89 (m, 2H), 1.92-1.86 (m, 1H), 1.82-1.80 (m, 2H), 1.73-1.70 (m, 1H), 1.19 (s, 9H), 0.97 (s, 3H), 0.94 (s, 3H) ppm; LCMS: m/z 289 [M+H].sup.+.

Example 9: Preparation of (R)—N—((S)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide (C-1M)

(121) ##STR00417##

(122) Using the same synthetic method as Step 9 of Example 6 (intermediate C-1J), tert-butyl (S)-4-(((R)-tert-butylsulfinyl)amino)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decane-8-carboxylate was subjected to deprotection of the Boc protecting group to obtain (R)—N—((S)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide C-1M.

(123) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.40 (brs, D.sub.2O Exchangeable, 1H), 8.40 (brs, D.sub.2O Exchangeable, 1H), 5.27 (d, J=11.0 Hz, 1H), 4.12-4.10 (m, 1H), 3.77 (d, J=8.5 Hz, 1H), 3.47-3.44 (m, 2H), 3.28-3.24 (m, 1H), 3.17-3.15 (m, 1H), 2.95-2.87 (m, 2H), 1.86-1.82 (m, 2H), 1.69-1.59 (m, 2H), 1.17 (s, 9H), 1.08 (d, J=6.0 Hz, 3H) ppm; LCMS: m/z 289 [M+H].sup.+.

Example 10: Preparation of Intermediate: (R)-2-methyl-N-((1R)-3-methyl-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1N)

Step 1: Tert-Butyl 4-allyl-4-formylpiperidine-1-carboxylate

(124) ##STR00418##

(125) To a dry 1 L flask were added tert-butyl 4-formylpiperidine-1-carboxylate (35.0 g, 164 mmol), lithium tert-butoxide (15.77 g, 197 mmol) and allyl bromide (11.54 mL, 189 mmol) and DMF (328 mL), and the mixture was stirred at 0° C. for 1 hour. After the reaction was completed, the mixture was poured into a separating funnel charged with saturated aqueous NH.sub.4Cl solution and H.sub.2O (1:1, 500 mL), and extracted with Et.sub.2O (5×50 mL). The organic phases were combined, dried over MgSO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 25%) to obtain tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate as a colorless oil (24 g, yield: 48%).

(126) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.52 (s, 1H), 5.53-5.76 (m, 1H), 4.96-5.19 (m, 2H), 3.80 (br.s., 2H), 2.97 (t, J=11.49 Hz, 2H), 2.26 (d, J=7.33 Hz, 2H), 1.95 (dt, J=13.71, 3.13 Hz, 2H), 1.38-1.58 (m, 11H) ppm.

Step 2: Tert-Butyl 4-allyl-4-(1-hydroxyallyl)piperidine-1-carboxylate

(127) ##STR00419##

(128) To a dry 1 L three-necked flask were added tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (24 g, 95 mmol) and THE (300 mL) sequentially, and the solution was cooled to −78° C., and vinylmagnesium bromide (1 M in THF, 118 mL, 118 mmol) was slowly added dropwise under nitrogen atmosphere. The resulting solution was slowly warmed to room temperature within 1 hour. After the reaction was completed, the mixture was poured into a separating funnel charged with saturated aqueous NH.sub.4Cl solution (250 mL), and extracted with EtOAc (4×50 mL). The organic phases were combined, dried over MgSO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-allyl-4-(1-hydroxyallyl)piperidine-1-carboxylate (26.7 g), which was used in the next step without further purification.

(129) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.05-5.83 (m, 2H), 5.32-5.21 (m, 2H), 5.12 (s, 1H), 5.08 (d, J=3.5 Hz, 1H), 4.05-3.97 (m, 1H), 3.71 (s, 2H), 3.12 (ddd, J=13.8, 10.4, 3.6 Hz, 2H), 2.33 (dd, J=14.3, 7.8 Hz, 1H), 2.20 (dd, J=14.3, 7.2 Hz, 1H), 1.60 (q, J=4.3 Hz, 2H), 1.57-1.50 (m, 2H), 1.45 (s, 9H) ppm.

Step 3: Tert-Butyl 4-acryloyl-4-allylpiperidine-1-carboxylate

(130) ##STR00420##

(131) To a dry 1 L three-necked flask were successively added tert-butyl 4-allyl-4-(1-hydroxyallyl)piperidine-1-carboxylate (26.7 g, 95 mmol), and Dess-Martin oxidant (44.3 g, 105 mmol) and anhydrous dichloromethane (380 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was poured into a separating funnel charged with a saturated aqueous solution of NaHCO.sub.3:Na.sub.2SO.sub.3 (1:1, 300 mL), and then extracted with DCM (4×50 mL). The organic phases were combined, dried over MgSO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid. The white solid was suspended in petroleum ether (250 mL) and sonicated for 20 minutes. The white suspension was filtered through a pad of diatomite, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-acryloyl-4-allylpiperidine-1-carboxylate (25 g, two-step yield: 94%) as a yellow oil.

(132) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.80 (dd, J=16.8, 10.3 Hz, 1H), 6.39 (dd, J=16.8, 1.9 Hz, 1H), 5.70 (dd, J=10.3, 1.9 Hz, 1H), 5.55 (ddt, J=17.5, 10.2, 7.4 Hz, 1H), 5.09-4.98 (m, 2H), 3.77 (s, 2H), 2.94 (s, 2H), 2.31 (d, J=7.4 Hz, 2H), 2.08 (d, J=13.8 Hz, 2H), 1.47-1.41 (m, 11H) ppm

Step 4: Tert-Butyl 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate

(133) ##STR00421##

(134) To a dry 1 L three-necked flask were added tert-butyl 4-acryloyl-4-allylpiperidine-1-carboxylate (25 g, 89.6 mmol), toluene (degassed, 850 mL), and a solution of Grubbs' second-generation catalyst (2.02 g, 2.38 mmol) in toluene (degassed, 100 mL). The resulting mixture was stirred at 85° C. for 45 minutes under nitrogen atmosphere. After the reaction was completed, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 40%) to obtain tert-butyl 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate (19 g, 83 mmol) as a brown solid. A solution of this compound and DDQ (565 mg, 2.49 mmol) in toluene (540 mL) was stirred at room temperature for 15 minutes. The resulting bright red solution was filtered through a pad of diatomite, followed by addition of charcoal (100 g), and the resulting suspension was stirred at room temperature for 2 hours. The mixture was filtered through a pad of diatomite and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 40%) to obtain tert-butyl 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate (12 g, yield: 53.3%) as a white solid.

Step 5: Tert-Butyl 3-methyl-1-oxo-8-azaspiro[4.5]decane-8-carboxylate

(135) ##STR00422##

(136) Under nitrogen atmosphere, to a 250 mL dry three-necked flask was added CuI (3.8 g, 20 mmol) and anhydrous tetrahydrofuran (100 mL) sequentially. The solution was cooled to −20° C., and MeLi (1.6 M in THF, 25 mL, 40 mmol) was slowly added dropwise to the solution. After the dropwise addition, the reaction solution was reacted at −20° C. until the solution was clear. At this temperature, a solution of tert-butyl 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate (2.51 g, 10 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise. After the reaction was completed, the mixture was poured into a separating funnel charged with saturated aqueous NH.sub.4Cl solution, and extracted with ethyl acetate (3×15 mL). The organic phases were combined, dried over MgSO.sub.4, filtered and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 50%) to obtain tert-butyl 3-methyl-1-oxo-8-azaspiro[4.5]decane-8-carboxylate (1.6 g, yield: 60%).

(137) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.92 (s, 1H), 3.81 (s, 1H), 3.55 (d, J=5.0 Hz, 1H), 3.13-3.04 (m, 1H), 2.96 (t, J=10.9 Hz, 1H), 2.56-2.46 (m, 1H), 2.31-2.21 (m, 2H), 1.94-1.75 (m, 2H), 1.62-1.49 (m, 1H), 1.45 (s, 9H), 1.41-1.35 (m, 2H), 1.15 (d, J=6.0 Hz, 3H), 0.90 (t, J=6.9 Hz, 3H) ppm.

Step 6 and Step 7: (R)-2-methyl-N-((1R)-3-methyl-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1N)

(138) ##STR00423##

(139) Using the same synthetic method as that of steps 8 and 9 of the intermediate C-1J, the ketone intermediate tert-butyl 3-methyl-1-oxo-8-azaspiro[4.5]decane-8-carboxylate was subjected to reductive amination and deprotection of the Boc protecting group to obtain (R)-2-methyl-N-((1R)-3-methyl-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1N).

(140) .sup.1H NMR (400 MHz, CDCl.sub.3) δ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 3.04-2.95 (m, 1H), 2.75 (s, 2H), 2.62-2.53 (m, 2H), 1.93-1.57 (m, 5H), 1.52-1.27 (m, 13H), 0.96 (d, J=6.5 Hz, 3H) ppm; LCMS: m/z 273 [M+H].sup.+.

Example 11: Preparation of Intermediate: (R)-2-methyl-N-((1R,3R)-3-hydroxy-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-10)

Step 1: Tert-Butyl (R)-3-((tert-butyldimethylsilyl)oxy)-1-oxo-8-azaspiro[4.5]decane-8-carboxylate

(141) ##STR00424##

(142) To a dry 100 mL three-necked flask were added CuCl (19 mg, 0.19 mmol), (s)-TolBlNAP (129 mg, 0.19 mmol), sodium tert-butoxide (18 mg, 0.19 mmol) and THF (9 mL). The mixture was stirred at room temperature for 30 minutes, followed by addition of a solution of B.sub.2Pin.sub.2 (1.78 g, 7.01 mmol) in THE (2.5 mL). The resulting mixture was stirred at room temperature for 10 minutes, followed by addition of a solution of tert-butyl 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate (1.60 g, 6.37 mmol) in THE (9 mL) and MeOH (0.53 mL, 12.74 mmol). The resulting mixture was stirred at room temperature for 16 hours. After the reaction was completed, H.sub.2O (20 mL) was added, followed by sodium perborate (4.84 g, 32 mmol), and the resulting mixture was vigorously stirred at room temperature for 1 hour. The resulting green suspension was filtered through a pad of diatomite, poured into a separating funnel charged with saturated aqueous NaHCO.sub.3 and saturated aqueous Na.sub.2SO.sub.3 (40 mL), and extracted with EtOAc (4×40 mL). The organic phases were combined, dried over MgSO.sub.4, filtered and the filtrate was concentrated under reduced pressure to obtain crude tert-butyl (R)-3-hydroxy-1-oxo-8-azaspiro[4.5]decane-8-carboxylate.

(143) In a 100 mL single-necked flask were added the crude tert-butyl (R)-3-hydroxy-1-oxo-8-azaspiro[4.5]decane-8-carboxylate (theoretical amount, 6.37 mmol), imidazole (650 mg, 9.56 mmol), TBSCl (1.20 g, 7.96 mmol) and DMF (16 mL) sequentially, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was poured into a separating funnel charged with saturated aqueous NH.sub.4Cl solution (30 mL), and extracted with ethyl acetate (5×50 mL). The organic phases were combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 40%) to obtain tert-butyl (R)-3-((tert-butyldimethylsilyl)oxy)-1-oxo-8-azaspiro[4.5]decane-8-carboxylate (1.26 g, yield: 51.6%) as a colorless oil

(144) LCMS: m/z 328 [M-56+H].sup.+.

Step 2: Tert-Butyl (1R,3R)-3-((tert-butyldimethylsilyl)oxy)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decane-8-carboxylate

(145) ##STR00425##

(146) Using the same synthetic method as that of Step 8 of the intermediate C-1J, the ketone intermediate (R)-3-((tert-butyldimethylsilyl)oxy)-1-oxo-8-azaspiro[4.5]decane-8-carboxylate was subjected to reductive amination to obtain tert-butyl (1R,3R)-3-((tert-butyldimethylsilyl)oxy)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decane-8-carboxylate (1.24 g, yield: 77%) as a white solid.

(147) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.23 (s, 1H), 3.84 (d, J=13.6 Hz, 2H), 3.24 (s, 1H), 2.77 (td, J=12.7, 12.0, 3.0 Hz, 2H), 2.27 (d, J=8.8 Hz, 1H), 1.72-1.54 (m, 5H), 1.38 (s, 9H), 1.19 (d, J=2.5 Hz, 3H), 1.14 (s, 9H), 0.80 (s, 9H), −0.03 (s, 6H) ppm; LCMS: m/z 488.9 [M+H].sup.+.

Step 3: (R)—N-((1R,3R)-3-hydroxy-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (C-10)

(148) ##STR00426##

(149) Under an ice bath, to a solution of tert-butyl (1R)-3-((tert-butyldimethylsilyl)oxy)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decane-8-carboxylate (49 mg, 0.1 mmol) in 1,4-dioxane (1 mL) was added concentrated sulfuric acid (0.023 mL, 0.4 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH of 12 with sodium hydroxide solution, and then extracted with DCM (4×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the volatiles were removed under reduced pressure to obtain (R)—N-((1R,3R)-3-hydroxy-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (C-10) (20 mg, yield: 70%). LC-MS: m/z 275 [M+H].sup.+.

Example 12: Preparation of Intermediate: (R)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine (C-1P)

Step 1: (1R,3R)-1-amino)-3-hydroxy-8-azaspiro[4.5]decane

(150) ##STR00427##

(151) At room temperature, to a solution of tert-butyl (1R,3R)-3-((tert-butyldimethylsilyl)oxy)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decane-8-carboxylate (100 mg, 0.2 mmol) in methanol (5 mL) was slowly added a solution of hydrogen chloride in 1,4-dioxane (4M, 2 mmol, 0.5 mL), and the reaction solution was heated at 40° C. for 1 hour. The mixture was concentrated under reduced pressure to obtain (1R,3R)-1-amino)-3-hydroxy-8-azaspiro[4.5]decane, which was directly used in the next reaction.

(152) LC-MS: m/z 171.0.

Step 2: Tert-Butyl (1R,3R)-1-((tert-butoxycarbonyl)amino)-3-hydroxy-8-azaspiro[4.5]decane-8-carboxylate (C-1P-b)

(153) ##STR00428##

(154) The above (1R,3R)-1-amino)-3-hydroxy-8-azaspiro[4.5]decane (0.2 mmol) was dissolved in tetrahydrofuran (10 mL), followed by addition of (Boc).sub.2O (109 mg, 0.5 mmol) and DIPEA (516 mg, 4.0 mmol), and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, saturated ammonium chloride was added to quench the reaction, followed by extraction with diethyl ether (5×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 50%) to obtain tert-butyl (1R,3R)-1-((tert-butoxycarbonyl)amino)-3-hydroxy-8-azaspiro[4.5]decane-8-carboxylate (C-1P-b) (60 mg, two-step yield: 80%).

(155) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.11 (s, 1H), 4.36 (s, 1H), 3.86-3.62 (m, 3H), 2.94 (t, J=11.7 Hz, 2H), 2.20-2.08 (m, 1H), 1.81 (d, J=8.5 Hz, 1H), 1.64-1.55 (m, 3H), 1.49-1.42 (m, 3H), 1.37 (d, J=4.9 Hz, 18H) ppm; LC-MS: m/z 393.2 [M+H].sup.+.

Step 3: Tert-Butyl (R)-1-((tert-butoxycarbonyl)amino)-3-oxo-8-azaspiro[4.5]decane-8-carboxylate

(156) ##STR00429##

(157) Tert-butyl (1R,3R)-1-((tert-butoxycarbonyl)amino)-3-hydroxy-8-azaspiro[4.5]decane-8-carboxylate (60 mg, 0.16 mmol) was dissolved in dichloromethane (5 mL) at 0° C., then Dess-Martin (76 mg, 0.18 mmol) was slowly added at 0° C., and the reaction solution was kept at 0° C. to further react for 2 hours. After the reaction was completed, water (4 mL) was added to quench the reaction, followed by extraction with dichloromethane (5×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 80%) to obtain tert-butyl (R)-1-((tert-butoxycarbonyl)amino)-3-oxo-8-azaspiro[4.5]decane-8-carboxylate (30 mg, yield: 50%).

(158) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.46 (d, J=9.4 Hz, 1H), 4.07 (d, J=7.0 Hz, 1H), 3.92 (s, 2H), 2.73 (t, J=12.7 Hz, 2H), 2.63 (dd, J=19.0, 8.1 Hz, 1H), 2.41 (d, J=18.3 Hz, 1H), 2.14-2.01 (m, 2H), 1.68 (td, J=12.9, 4.6 Hz, 1H), 1.59 (d, J=4.8 Hz, 1H), 1.39 (d, J=2.5 Hz, 18H), 1.26 (d, J=2.9 Hz, 1H) ppm; LC-MS: m/z 369.1 [M+H].sup.+.

Step 4: Tert-Butyl (R)-1-((tert-butoxycarbonyl)amino)-3,3-difluoro-8-azaspiro[4.5]decane-8-carboxylate

(159) ##STR00430##

(160) (R)-1-((Tert-butoxycarbonyl)amino)-3-oxo-8-azaspiro[4.5]decane-8-carboxylate (80 mg, 0.22 mmol) was dissolved in dichloromethane (10 mL), then DeoxoFluor (162 μL, 0.88 mmol) was added, and the reaction solution was stirred at 50° C. for 48 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution at 0° C., extracted with ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R)-1-((tert-butoxycarbonyl)amino)-3,3-difluoro-8-azaspiro[4.5]decane-8-carboxylate (46 mg, yield: 54%).

(161) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.49 (d, J=9.9 Hz, 1H), 3.92 (dd, J=24.5, 15.9 Hz, 3H), 2.87-2.68 (m, 2H), 2.58-2.42 (m, 1H), 2.21 (td, J=17.7, 16.8, 9.6 Hz, 1H), 2.06-1.86 (m, 2H), 1.60 (t, J=6.6 Hz, 1H), 1.38 (d, J=4.0 Hz, 21H) ppm; LC-MS: m/z 391.1 [M+H].sup.+

Step 5: (R)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine (C-1P)

(162) ##STR00431##

(163) To a solution of (R)-1-((tert-butoxycarbonyl)amino)-3,3-difluoro-8-azaspiro[4.5]decane-8-carboxylate (46 mg, 0.12 mmol) in methanol (5 mL) was slowly added a solution of hydrogen chloride in 1,4-dioxane (4 M, 1.2 mmol, 0.3 mL), and the reaction solution was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain (R)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine (C-1P). LC-MS: m/z 191.1 [M+H].sup.+.

Example 13: Preparation of Intermediate: 1-methyl-8-azaspiro[4.5]decan-1-amine (C-2A)

(164) Step 1: tert-butyl 1-hydroxy-1-methyl-8-azaspiro[4.5]decane-8-carboxylate

(165) ##STR00432##

(166) To a solution of tert-butyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate (500 mg, 2.0 mmol) in toluene (20 mL) was slowly added a solution of methyl magnesium bromide in tetrahydrofuran (1 M, 2.2 mmol, 2.2 mL) at 0° C., and the reaction solution was stirred at 0° C. for 1 hour. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution, and then extracted with ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 50%) to obtain tert-butyl 1-hydroxy-1-methyl-8-azaspiro[4.5]decane-8-carboxylate (410 mg, yield: 77%).

(167) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.16-4.04 (m, 2H), 3.12-2.56 (m, 2H), 1.98-1.49 (m, 8H), 1.49 (s, 9H), 1.42-1.29 (m, 2H), 1.16 (s, 3H) ppm; LC-MS: m/z 270.2 [M+H].sup.+.

Step 2: N-(1-methyl-8-azaspiro[4.5]decan-1-yl)acetamide

(168) ##STR00433##

(169) Tert-butyl 1-hydroxy-1-methyl-8-azaspiro[4.5]decane-8-carboxylate (410 mg, 1.52 mmol) was dissolved in acetonitrile (1.82 mL), followed by addition of concentrated sulfuric acid (1.56 mL) at 0° C., and then the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was poured into ice water, and then basified with aqueous NaOH (50%) solution to pH of 12, followed by extraction with ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product of N-(1-methyl-8-azaspiro[4.5]decan-1-yl)acetamide (260 mg, yield: 81%), which was directly used in the next step.

(170) LC-MS: m/z 211.0 [M+H].sup.+.

Step 3: 1-methyl-8-azaspiro[4.5]decan-1-amine (C-2A)

(171) ##STR00434##

(172) The crude product of N-(1-methyl-8-azaspiro[4.5]decan-1-yl)acetamide (260 mg, 1.23 mmol) was dissolved in 6 M hydrochloric acid (5 mL) at room temperature and the reaction solution was reacted under microwave heating at 120° C. for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and then lyophilized to obtain a crude product of 1-methyl-8-azaspiro[4.5]decan-1-amine C-2A (200 mg, yield: 97%), which was used in the next reaction without purification.

(173) LC-MS: m/z 169.1 [M+H].sup.+.

Example 14: Preparation of intermediate: 4-ethylpiperidin-4-amine (C-3A)

Step 1: methyl 1-benzyl-4-ethylpiperidine-4-carboxylate

(174) ##STR00435##

(175) At −78° C. under nitrogen atmosphere, to a solution of methyl 1-benzylpiperidine-4-carboxylate (1 g, 4.3 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise a solution of LDA in tetrahydrofuran (1 M, 5.1 mmol, 5.1 mL), and the reaction solution was stirred at −78° C. for 1 hour. Then iodoethane (795 mg, 5.1 mmol) in tetrahydrofuran (1 mL) was slowly added, and the reaction solution was further reacted at −78° C. for 4 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution, and then extracted with ethyl acetate (3×30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 50%) to obtain methyl 1-benzyl-4-ethylpiperidine-4-carboxylate (800 mg, yield: 71%).

(176) LC-MS: m/z 262.2 [M+H].sup.+.

Step 2: 1-benzyl-4-ethylpiperidine-4-carboxylic Acid

(177) ##STR00436##

(178) Methyl 1-benzyl-4-ethylpiperidine-4-carboxylate (800 mg, 3.23 mmol) was dissolved in an aqueous solution of ethanol (ethanol:water=4:1, 20 mL), followed by addition of NaOH (517 mg, 12.9 mmol), and then the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, then acidified with 1 N hydrochloric acid to pH of 3, and then extracted with ethyl acetate (3×30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the product 1-benzyl-4-ethylpiperidine-4-carboxylic acid (720 mg, yield: 90%), which was directly used in the next reaction.

(179) LC-MS: m/z 248.2 [M+H].sup.+.

Step 3: 1-methyl-8-azaspiro[4.5]decan-1-amine

(180) ##STR00437##

(181) 1-Benzyl-4-ethylpiperidine-4-carboxylic acid (250 mg, 1.0 mmol) was dissolved in tert-butanol (5 mL) at room temperature, followed by addition of triethylamine (306 mg, 3.0 mmol) and diphenyl azidophosphate (330 mg, 2.0 mmol), and then the reaction solution was refluxed for 8 hours. After the reaction was completed, water was added to quench the reaction, and the resulting mixture was extracted with ethyl acetate (3×30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 70%) to obtain 1-methyl-8-azaspiro[4.5]decan-1-amine (160 mg, yield: 50%).

(182) LC-MS: m/z 319.2 [M+H].sup.+.

Step 4: Tert-Butyl (4-ethylpiperidin-4-yl)carbamate

(183) ##STR00438##

(184) 1-Methyl-8-azaspiro[4.5]decan-1-amine (160 mg, 0.5 mmol) was dissolved in 10 mL of methanol at room temperature, followed by addition of Pd/C (16 mg, 10%). The reaction solution was reacted under hydrogen atmosphere for 16 hours, and then filtered through diatomite, washed with ethyl acetate, and concentrated under reduced pressure to obtain tert-butyl (4-ethylpiperidin-4-yl)carbamate (110 mg, yield: 95%), which was directly used in the next reaction.

(185) LC-MS: m/z 229.2 [M+H].sup.+.

Step 5: 4-ethylpiperidin-4-amine (C-3A)

(186) ##STR00439##

(187) Tert-butyl (4-ethylpiperidin-4-yl)carbamate (110 mg, 0.5 mmol) was dissolved in methanol (3 mL) at room temperature, followed by addition of a solution of hydrogen chloride in 1,4-dioxane (4 N, 5 mmol, 1.1 mL). The reaction solution was stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain the product 4-ethylpiperidin-4-amine (C-3A) (50 mg, yield: 95%), which was directly used in the next reaction.

(188) LC-MS: m/z 128.2 [M+H].sup.+.

Example 15: Preparation of Intermediate: tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate (C-4A)

Step 1: 1-benzoyl-4-methylpiperidine-4-carbonitrile

(189) ##STR00440##

(190) Under nitrogen atmosphere, to a 100 mL dry single-necked flask were added 4-methylpiperidine-4-carbonitrile (496 mg, 4 mmol), DCM (10 mL) and triethylamine (611 mg, 6 mmol), and benzoyl chloride (670 mg, 4.8 mmol) was slowly added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by TLC until the raw material was consumed. The reaction solution was quenched with 1N HCl solution, and then extracted with dichloromethane (3×20 mL). The organic phases were combined, dried over Na.sub.2SO.sub.4, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 40%) to obtain 1-benzoyl-4-methylpiperidine-4-carbonitrile (650 mg, yield: 70.72%).

(191) LC-MS: m/z 229 [M+H].sup.+.

Step 2: Tert-Butyl 1-benzoyl-((4-methylpiperidin-4-yl)methyl)carbamate

(192) ##STR00441##

(193) At 0° C. and under nitrogen atmosphere, to a 100 mL dry flask were added 1-benzoyl-4-methylpiperidine-4-carbonitrile (650 mg, 2.85 mmol), nickel chloride hexahydrate (135 mg, 0.67 mmol), di-tert-butyl dicarbonate (1.86 g, 8.54 mmol) and methanol (12 mL), and sodium borohydride (754 mg, 20 mmol). The reaction solution was stirred at room temperature for 12 hours, and the reaction was monitored by TLC until the raw material was consumed. After the reaction was completed, the reaction solution was concentrated and extracted with dichloromethane (3×20 mL). The organic phases were combined, and dried over Na.sub.2SO.sub.4. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 40%) to obtain tert-butyl 1-benzoyl-((4-methylpiperidin-4-yl)methyl)carbamate (620 mg, yield: 65.50%).

(194) LC-MS: m/z 333 [M+H].sup.+.

Step 3: Tert-Butyl ((4-methylpiperidin-4-yl)methyl)carbamate (C-4A)

(195) ##STR00442##

(196) To a 100 mL single-necked flask were added tert-butyl 1-benzoyl-((4-methylpiperidin-4-yl)methyl)carbamate (620 mg, 1.87 mmol), ethanol (8 mL) and 7N NaOH (2 mL), and then the mixture was heated to 90° C. under nitrogen atmosphere and stirred for 8 hours. After the mixture was cooled to room temperature, the mixture was filtered, diluted with water and extracted with ethyl acetate (3×20 mL). The organic phases were combined, and dried over Na.sub.2SO.sub.4. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 80%) to obtain tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate (C-4A) (300 mg, yield: 70.5%).

(197) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 3.97 (q, J=7.0 Hz, 2H), 2.80 (d, J=6.4 Hz, 2H), 2.65 (d, J=30.3 Hz, 2H), 1.38 (s, 9H), 1.27 (dd, J=16.2, 7.0 Hz, 2H), 1.10 (d, J=12.8 Hz, 2H), 0.81 (s, 3H) ppm; LC-MS: m/z 229 [M+H].sup.+.

Example 16: Preparation of Intermediate: tert-butyl ((4-phenylpiperidin-4-yl)methyl)carbamate (C-4B)

Step 1: Tert-Butyl 4-cyano-4-phenylpiperidine-1-carboxylate

(198) ##STR00443##

(199) At 0° C., to a solution of tert-butyl (2-chloroethyl)carbamate (2 g, 8.26 mmol) and 2-phenylacetonitrile (968 mg, 8.26 mmol) in anhydrous DMF (20 mL) was added NaH (60% dispersed in mineral oil, 1.6 g, 41.3 mmol) in portions. The reaction mixture was heated at 60° C. for 16 hours. After the reaction was completed, the reaction solution was quenched with ice water (30 mL), and then extracted (3×50 mL). The organic phases were combined, washed with saturated brine (2×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 40%) to obtain tert-butyl 4-cyano-4-phenylpiperidine-1-carboxylate (500 mg, yield: 21%).

(200) LCMS: m/z 187.2 [M-100].sup.+.

Step 2: Tert-Butyl 4-(aminomethyl)-4-phenylpiperidine-1-carboxylate

(201) ##STR00444##

(202) Tert-butyl 4-cyano-4-phenylpiperidine-1-carboxylate (0.5 g, 1.75 mmol) was dissolved in 20 mL of methanol, followed by addition of palladium on carbon (50 mg), and the reaction solution was reacted under hydrogen atmosphere for 16 hours. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain tert-butyl 4-(aminomethyl)-4-phenylpiperidine-1-carboxylate (0.4 g, yield: 80%).

(203) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38 (t, J=7.6 Hz, 2H), 7.30 (d, J=7.5 Hz, 2H), 7.24 (d, J=7.2 Hz, 1H), 3.75 (d, J=7.8 Hz, 2H), 3.04 (t, J=11.2 Hz, 2H), 2.58 (brs, 2H), 2.21 (d, J=13.9 Hz, 2H), 1.76-1.61 (m, 2H), 1.44 (s, 9H) ppm; LC-MS: m/z 191.0 [M-100].sup.+.

Step 3: (4-phenylpiperidin-4-yl)methanamine (C-4B)

(204) ##STR00445##

(205) Tert-butyl 4-(aminomethyl)-4-phenylpiperidine-1-carboxylate (0.4 g, 1.37 mmol) was dissolved in 10 mL of methanol, followed by addition of a solution of hydrogen chloride in 1,4-dioxane (4 M, 13.7 mmol) at room temperature. The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain (4-phenylpiperidin-4-yl)methanamine (C-4B) (0.25 g, yield: 95%), which was directly used in the next reaction.

(206) LC-MS: m/z 191.2 [M+H].sup.+.

Example 17: Preparation of Intermediate Sodium 6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridine-4-thiolate (F-1A)

Step 1: Tert-Butyl (6-chloropyridin-2-yl)carbamate

(207) ##STR00446##

(208) Under nitrogen atmosphere, to a dry 250 mL three-necked flask were added 6-chloropyridin-2-amine (8 g, 62.2 mmol) and THE (80 mL). The mixture was stirred at 0° C. for 10 minutes, followed by addition of NaHDMS (124.4 mL, 1.0 M in THF). The mixture was kept at 0° C., and a solution of di-tert-butyl dicarbonate (16.3 g, 74.7 mmol) in tetrahydrofuran (50 mL) was slowly added, and the reaction was continued at 0° C. for 4 hours. After the reaction was completed, H.sub.2O (40 mL) was added, followed by extraction with EtOAc (3×100 mL). The organic phases were combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 10%) to obtain tert-butyl (6-chloropyridin-2-yl)carbamate (7 g, yield: 49%).

(209) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.04 (s, 1H), 7.79-7.58 (m, 2H), 7.02 (dd, J=5.5, 2.9 Hz, 1H), 1.38 (s, 9H) ppm; LCMS: m/z 288.1 [M+H].sup.+.

Step 2: Tert-Butyl (5,6-dichloropyridin-2-yl)carbamate

(210) ##STR00447##

(211) To a dry 100 mL round bottom flask were added tert-butyl (6-chloropyridin-2-yl)carbamate (7 g, 30.6 mmol) and N,N-dimethylformamide (50 mL), and the mixture was stirred at room temperature for 10 minutes, followed by addition of N-chlorosuccinimide (4.50 g, 33.67 mmol). The mixture was reacted at 100° C. for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, followed by addition of H.sub.2O (50 mL) and extraction with ethyl acetate (3×80 mL). The organic phase was washed with saturated aqueous lithium chloride solution (2×40 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 5%) to obtain tert-butyl (5,6-dichloropyridin-2-yl)carbamate (5.3 g, yield: 65.8%).

(212) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.86 (d, J=8.7 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.24 (s, 1H), 1.51 (s, 9H); LCMS: m/z 207.1 [M-55].sup.+.

Step 3: Tert-Butyl (5,6-dichloro-4-iodopyridin-2-yl)carbamate

(213) ##STR00448##

(214) At −78° C. and under nitrogen atmosphere, to a dry 100 mL round bottom flask were slowly added tert-butyl (5,6-dichloropyridin-2-yl)carbamate (5.3 g, 20.14 mmol) and tetrahydrofuran (50 mL), followed by addition of n-butyllithium (44.3 mmol, 2.5M in THF) dropwise. The reaction solution was stirred at −78° C. for 1 hour, followed by slow dropwise addition of a solution of iodine (3.07 g, 24.17 mmol) in tetrahydrofuran (20 mL), and the reaction was continued at −78° C. for 3 hours. After the reaction was completed, H.sub.2O (50 mL) was added, followed by extraction with EtOAc (3×80 mL). The organic phases were combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 5%) to obtain tert-butyl (5,6-dichloro-4-iodopyridin-2-yl)carbamate (4.3 g, yield: 55%).

(215) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.44 (s, 1H), 8.36 (s, 1H), 1.46 (s, 9H) ppm; LCMS: m/z 334.1 [M-55].sup.+.

Step 4: methyl 3-((6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridin-4-yl)thio)propionate

(216) ##STR00449##

(217) To a dry 100 mL round bottom flask were added tert-butyl (5,6-dichloro-4-iodopyridin-2-yl)carbamate (3.2 g, 8.22 mmol), palladium acetate (92 mg, 0.41 mmol), Xantphos (285 mg, 0.49 mmol), DIPEA (2.12 g, 16.46 mmol) and 1,4-dioxane (30 mL) sequentially. The reaction mixture was stirred at 100° C. for 2 hours, followed by filtration and concentration under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 30%) to obtain methyl 3-((6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridin-4-yl)thio)propionate (3 g, yield: 96%).

(218) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.25 (s, 1H), 7.73 (s, 1H), 3.64 (s, 3H), 3.26 (t, J=6.9 Hz, 2H), 2.82 (t, J=6.9 Hz, 2H), 1.46 (s, 9H) ppm; LCMS: m/z 326.3[M-55].sup.+.

Step 5: Sodium 6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridine-4-thiolate (F-1A)

(219) ##STR00450##

(220) To a dry 100 mL round bottom flask were successively added methyl 3-((6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridin-4-yl)thio)propionate and tetrahydrofuran (30 mL). A solution of sodium ethoxide in ethanol (21%, 6 mL) was slowly added dropwise at room temperature, and the reaction solution was stirred at room temperature for 1 hour. After concentration under reduced pressure, dichloromethane (10 mL) was added, and a large amount of brown solid was precipitated out, followed by filtration. The filter cake was washed with dichloromethane, and dried to obtain sodium 6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridine-4-thiolate (F-1A)(2.1 g, yield: 84%).

(221) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.05 (s, 1H), 7.61 (s, 1H), 1.41 (s, 9H) ppm; LCMS: m/z 262.2 [M-55].sup.+.

(222) According to the synthesis method of Example 17, the following intermediates F-1B, F-1C, F-1D, F-1E, F-1F, F-1G, F-1H, F-1I, F-1J, F-1K, F-1L, F-1M, F-1N, F-10, F-1P were obtained by using similar intermediate raw materials.

(223) TABLE-US-00004 Intermediate Name Structure Analysis data F-1B sodium 2-amino-3-chloropyridine-4-thiolate .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.06 (d, J = 3.1 Hz, 1H), 6.51 (d, J = 5.2 Hz, 1H) ppm; LCMS: m/z 161.0 [M + H].sup.+. F-1C sodium 2-amino-5-chloropyridine-4-thiolate .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.88 (s, 1H), 7.49 (d, J = 5.3 Hz, 1H), 7.09 (d, J = 5.3 Hz, 1H) ppm; LCMS: m/z 161.0 [M + H].sup.+. F-1D sodium 2-chloropyridine-3-thiolate .sup.1H NMR (400 MHz, DMSO-d.sub.6 ) δ 7.57 (dd, J = 7.7, 1.5 Hz, 1H), 7.45 (d, J = 3.5 Hz, 1H), 6.69 (dd, J = 7.6, 4.4 Hz, 1H) ppm; LCMS: m/z 146.0 [M + H].sup.+. F-1E sodium 2-methylpyridine-3-thiolate .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.59-7.46 (m, 1H), 7.32 (dd, J = 7.7, 1.4 Hz, 1H), 6.53 (dd, J = 7.7, 4.6 Hz, 1H), 2.36 (s, 3H) ppm; LCMS: m/z 126.0 [M + H].sup.+. F-1F sodium quinoline-4-thiolate .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.79 (d, J = 4.6 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.74-7.64 (m, 2H), 7.30 (d, J = 4.6 Hz, 1H) ppm; LCMS: m/z 162.0 [M + H].sup.+. F-1G sodium 2,3-dichloropyridine-4-thiolate .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.31 (d, J = 5.3 Hz, 1H), 7.07 (d, J = 5.3 Hz, 1H) ppm; LCMS: m/z 180.0 [M + H].sup.+. F-1H sodium 3-chloropyridine-4-thiolate .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.88 (s, 1H), 7.49 (d, J = 5.3 Hz, 1H), 7.09 (d, J = 5.3 Hz, 1H) ppm; LCMS: m/z 146.0 [M + H].sup.+. F-1I sodium benzo[d]thiazole-7-thiolate LCMS: m/z 146.0 [M + H].sup.+. F-1J sodium 2-(trifluoromethyl)pyridine-3-thiolate LCMS: m/z 146.0 [M ' H].sup.+. F-1K sodium 3-(trifluoromethyl)pyridine-4-thiolate 0 .sup.1HNMR (400 MHz, D.sub.2O) δ 8.24 (s, 1H), 7.84 (d, J = 5.6 Hz, 1H), 7.31 (d, J = 5.6 Hz, 1H) ppm; LCMS: m/z 146.0 [M + H].sup.+. F-1L sodium 6-amino-2-chloropyridine-3-thiolate .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.29 (d, J = 8.1 Hz, 1H), 6.03 (d, J = 7.8 Hz, 1H), 5.21 (brs, 2H) ppm; LCMS: m/z 160.0 [M + H].sup.+. F-1M sodium thiazole-2-thiolate .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.95 (d, J = 3.7 Hz, 1H), 6.52 (d, J = 3.7 Hz, 1H) ppm; LCMS: m/z 118.0 [M + H].sup.+. F-1N sodium 1-methyl-1H-benzo[d]imidazole-4-thi- olate LCMS: m/z 165.0 [M + H].sup.+. F-1O sodium 2,3-dihydrobenzofuran-4-thiolate LCMS: m/z 153.0 [M ' H].sup.+. F-1P sodium 1H-pyrrolo[2,3-b]pyridine-4-thiolate .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.21 (d, J = 2.6 Hz, 1H), 7.50 (d, J = 3.5 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 6.38 (d, J = 3.5 Hz, 1H), 3.62 (s, 3H) ppm; LCMS: m/z 165.0 [M + H].sup.+.

Example 18: Preparation of Intermediate: Sodium 3-chloro-2-methylpyridine-4-thiolate (F-1Q)

Step 1: methyl 3-((3-chloro-2-methylpyridin-4-yl)thio)propionate

(224) The intermediate methyl 3-((2,3-dichloropyridin-4-yl)thio)propionate obtained from the synthesis of intermediate F-1G was used in the following reaction.

(225) ##STR00466##

(226) Under nitrogen atmosphere, to a dry 100 mL round bottom flask were added methyl 3-((2,3-dichloropyridin-4-yl)thio)propionate (500 mg, 1.88 mmol), Pd(PPh.sub.3).sub.4 (217 mg, 0.188 mmol), trimethylcyclotriboroxane (354 mg, 2.82 mmol), potassium carbonate (389 mg, 2.82 mmol) and 1,4-dioxane (10 mL). The reaction mixture was heated and stirred at 100° C. under nitrogen atmosphere for 6 hours. The residue obtained by filtration and concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 40%) to obtain methyl 3-((3-chloro-2-methylpyridin-4-yl)thio)propionate (320 mg, yield: 69%).

Step 2: sodium 3-chloro-2-methylpyridine-4-thiolate (F-1Q)

(227) ##STR00467##

(228) To a dry 100 mL round bottom flask were added methyl 3-((3-chloro-2-methylpyridin-4-yl)thio)propionate (320 mg, 1.30 mmol) and tetrahydrofuran (10 mL) sequentially, and a solution of sodium ethoxide in ethanol (21%, 2 mL) was slowly added dropwise at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, followed by addition of dichloromethane (10 mL), and a large amount of brown solid was precipitated. The mixture was filtered and the filter cake was washed with dichloromethane, and dried to obtain sodium 3-chloro-2-methylpyridine-4-thiolate F-1Q (200 mg, yield: 85%).

(229) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.37 (d, J=4.8 Hz, 1H), 6.97 (d, J=4.8 Hz, 1H), 2.31 (s, 3H) ppm; LCMS: m/z 160.0 [M+H].sup.+.

(230) According to the synthesis method of Example 18, the following intermediate F-1R was obtained by using similar intermediate raw materials.

(231) TABLE-US-00005 Inter- me- diate Name Structure Analysis data F-1R sodium 3-chloro-2-cyclo- propylpyridine- 4-thiolate LCMS: m/z 186.0 [M + H].sup.+.

Example 19: Preparation of Intermediate: Sodium 6-((tert-butoxycarbonyl)amino)-3-chloro-2-methylpyridine-4-thiolate (F-1S)

Step 1: methyl 3-((6-((tert-butoxycarbonyl)amino)-3-chloro-2-methylpyridin-4-yl)thio)propionate

(232) The intermediate methyl 3-((6-(((tert-butoxycarbonyl)amino)-2,3-dichloropyridin-4-yl)thio)propionate obtained from the synthesis of intermediate F-1A was used in the following reaction.

(233) ##STR00469##

(234) Under nitrogen atmosphere, to a dry 100 mL round bottom flask were successively added methyl 3-((6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridin-4-yl)thio)propionate (600 mg, 1.57 mmol), [1,1′-bis(tert-butylphosphino)ferrocene]palladium dichloride (103 mg, 0.157 mmol), trimethylcyclotriboroxane (301 mg, 2.4 mmol), potassium carbonate (331 mg, 2.4 mmol), 1,4-dioxane (10 mL) and water (1 mL). The reaction mixture was heated and stirred at 100° C. under nitrogen atmosphere for 6 hours. The residue obtained by filtration and concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 40%) to obtain methyl 3-((6-((tert-butoxycarbonyl)amino)-3-chloro-2-methylpyridin-4-yl)thio)propionate (420 mg, yield: 74%).

(235) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.90 (s, 1H), 7.64 (s, 1H), 3.64 (s, 3H), 3.21 (t, J=6.9 Hz, 2H), 2.80 (t, J=6.9 Hz, 2H), 1.46 (s, 9H) ppm; LCMS: m/z 361.1 [M+H].sup.+.

Step 2: Sodium 6-((tert-butoxycarbonyl)amino)-3-chloro-2-methylpyridine-4-thiolate (F-1S)

(236) ##STR00470##

(237) To a dry 100 mL round-bottom flask were added methyl 3-((6-((tert-butoxycarbonyl)amino)-3-chloro-2-methylpyridin-4-yl)thio)propionate (420 mg, 1.17 mmol) and tetrahydrofuran (10 mL) sequentially. A solution of sodium ethoxide in ethanol (21%, 2 mL) was then slowly added dropwise at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, followed by addition of dichloromethane (10 mL), and a large amount of brown solid was precipitated. The mixture was filtered and the filter cake was washed with dichloromethane, and dried to obtain sodium 6-((tert-butoxycarbonyl)amino)-3-chloro-2-methylpyridine-4-thiolate (F-1S) (320 mg, yield: 92%).

(238) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.87 (s, 1H), 7.63 (s, 1H), 3.64 (s, 3H), 1.46 (s, 9H) ppm; LCMS: m/z 275.0 [M+H].sup.+.

Example 20: Preparation of Intermediate: 3-amino-2-chlorobenzenethiol Hydrochloride (F-2A)

Step 1: 2-chloro-3-aminophenyl Tert-Butyl Sulfide

(239) ##STR00471##

(240) Under nitrogen atmosphere, to a dry 100 mL round bottom flask were added 2-chloro-3-fluoroaniline (5 g, 34.3 mmol) and N-methylpyrrolidone (50 mL) sequentially, followed by 2-methylpropane-2-thiol (8.66 g, 96.04 mmol) and cesium carbonate (22.36 g, 68.6 mmol), and the reaction mixture was heated and stirred at 120° C. for 16 hours. After cooling to room temperature, the reaction solution was diluted with 60 mL of ethyl acetate, washed successively with saturated lithium chloride aqueous solution (30 mL), water (30 mL) and saturated sodium chloride aqueous solution (30 mL), and then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-chloro-3-aminophenyl tert-butyl sulfide (6.04 g, yield: 82%).

(241) LCMS: m/z 216.1 [M+H].sup.+.

Step 2: 3-amino-2-chlorobenzenethiol Hydrochloride (F-2A)

(242) ##STR00472##

(243) To a dry 100 mL round bottom flask were added 2-chloro-3-aminophenyl tert-butyl sulfide (6.04 g, 28 mmol) and concentrated hydrochloric acid (50 mL), and the reaction mixture was heated and stirred at 45° C. for 8 hours. After cooling to room temperature naturally, the reaction solution was further cooled to 0° C., and a large amount of white solid was precipitated. The mixture was filtered and the filter cake was washed successively with concentrated hydrochloric acid and petroleum ether to obtain 3-amino-2-chlorobenzenethiol hydrochloride F-2A (4.9 g, yield: 90%).

(244) LCMS: m/z 160.0 [M+H].sup.+.

Example 21: Preparation of Compound: 1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-4-methylpiperidin-4-amine

(245) Step 1: Tert-Butyl (1-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-4-methylpiperidin-4-yl)carbamate

(246) ##STR00473##

(247) Under nitrogen atmosphere, to a dry 50 mL single-necked flask were added 5-chloro-8-iodoimidazo[1,2-c]pyrimidine (E1) (50 mg, 0.18 mmol), tert-butyl (4-methylpiperidine-4-yl)carbamate (77 mg, 0.36 mmol), DIEA (46 mg, 0.36 mmol) and NMP (5 mL), and then the reaction solution was stirred at 90° C. for 2 hours. After the reaction was completed, the resulting residue was poured into water (10 mL), stirred at room temperature for 5 minutes, and then extracted with ethyl acetate (3×50 mL). The organic phases were combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 80%) to obtain tert-butyl (1-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-4-methylpiperidin-4-yl)carbamate (70 mg, yield: 43%) as a pale yellow solid.

(248) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.89 (d, J=1.5 Hz, 1H), 7.62 (d, J=1.4 Hz, 1H), 3.49 (d, J=13.4 Hz, 2H), 3.21 (ddd, J=13.3, 10.8, 2.6 Hz, 2H), 2.18 (d, J=13.9 Hz, 2H), 1.65 (ddd, J=14.1, 10.7, 3.8 Hz, 2H), 1.40 (s, 9H), 1.28 (s, 3H) ppm; LCMS: m/z 458.1 [M+H].sup.+.

Step 2: Tert-Butyl (1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-4-methylpiperidin-4-yl) carbamate

(249) ##STR00474##

(250) To a dry 50 mL three-necked flask were added tert-butyl (1-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-4-methylpiperidin-4-yl)carbamate (70 mg, 0.15 mmol), cuprous iodide (3 mg, 0.015 mmol), 1,10-phenanthroline (6 mg, 0.030 mmol), 2,3-dichlorothiophenol (32 mg, 0.18 mmol), potassium phosphate (66 mg, 0.30 mmol) and 5 mL of dioxane sequentially. The mixture was heated for 3 hours under nitrogen atmosphere. After the reaction was completed, saturated NH.sub.4Cl solution (10 mL) was added, followed by extraction with ethyl acetate (3×50 mL). The organic phases were combined, dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 60%) to obtain tert-butyl (1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-4-methylpiperidin-4-yl) carbamate (30 mg, yield: 39%) as a pale yellow solid.

(251) LC-MS: m/z 508.1 [M+H].sup.+.

Step 3: 1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-4-methylpiperidin-4-amine

(252) ##STR00475##

(253) To a dry 50 mL round bottom flask was added a solution of tert-butyl (1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-4-methylpiperidin-4-yl) carbamate (30 mg, 0.059 mmol) and hydrogen chloride in 1,4-dioxane (7 M, 5 mL), and the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by high-performance liquid chromatography to obtain the product 1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-4-methylpiperidin-4-amine (15 mg, yield: 62%).

(254) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.84 (d, J=1.3 Hz, 1H), 7.55 (d, J=1.2 Hz, 1H), 7.41 (dd, J=8.0, 1.2 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.69 (dd, J=8.1, 1.2 Hz, 1H), 3.60 (t, J=4.2 Hz, 4H), 1.73-1.60 (m, 4H), 1.19 (s, 3H) ppm; LC-MS: m/z 408.1 [M+H].sup.+.

(255) Using the synthesis method of Example 21, the following compounds were synthesized using commercially available or self-synthesized amines:

Example 22: 8-((2,3-dichlorophenyl)thio)-5-(1,8-diazaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidine

(256) ##STR00476##

(257) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.72 (d, J=8.1 Hz, 1H), 3.79 (ddd, J=13.9, 7.1, 3.7 Hz, 2H), 3.49 (ddd, J=12.8, 8.0, 3.4 Hz, 2H), 3.19 (t, J=6.9 Hz, 2H), 2.04 (ddd, J=12.3, 8.1, 3.5 Hz, 2H), 1.93 (dt, J=20.5, 6.5 Hz, 6H) ppm; LC-MS: m/z 434.1 [M+H].sup.+.

Example 23: Preparation of Compound: 8-((2,3-dichlorophenyl)thio)-5-(piperidin-1-yl)imidazo[1,2-c]pyrimidine

(258) ##STR00477##

(259) To a dry 50 mL single-necked flask were added 5-chloro-8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidine (B1) (50 mg, 0.15 mmol) and piperidine (20 mg, 0.23 mmol), DIEA (39 mg, 0.3 mmol) and NMP (5 mL) sequentially, and then the reaction solution was stirred at 90° C. for 2 hours. After the reaction was completed, the resulting residue was poured into water (100 mL), stirred at room temperature for 5 minutes, and then extracted with ethyl acetate (3×50 mL). The organic phases were combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 80%) and high-performance liquid chromatography to obtain the product tert-butyl ((1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)pyrrolidine-3-yl)methy 1)carbamate (20 mg, yield: 35%).

(260) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.83 (d, J=1.4 Hz, 1H), 7.55 (d, J=1.4 Hz, 1H), 7.41 (dd, J=8.0, 1.3 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.69 (dd, J=8.1, 1.3 Hz, 1H), 3.50 (d, J=5.6 Hz, 4H), 1.79-1.63 (m, 6H) ppm; LC-MS: m/z 378.7 [M+H].sup.+.

(261) Using the synthesis method of Example 23, the following compounds were synthesized:

Example 24: 8-((2,3-dichlorophenyl)thio)-5-(3,5-dimethylpiperazin-1-yl)imidazo[1,2-c]pyrimidine

(262) ##STR00478##

(263) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.23 (s, 1H), 8.03 (s, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.55 (d, J=1.2 Hz, 1H), 7.44-7.37 (m, 1H), 7.12 (t, J=8.1 Hz, 1H), 6.69 (dd, J=8.1, 1.1 Hz, 1H), 3.89 (d, J=12.0 Hz, 2H), 3.02 (d, J=6.6 Hz, 2H), 2.72-2.59 (m, 2H), 1.05 (t, J=6.0 Hz, 7H) ppm; LC-MS: m/z 407.7 [M+H].sup.+.

Example 25: 8-((2,3-dichlorophenyl)thio)-5-(4-methylpiperazin-1-yl)imidazo[1,2-c]pyrimidine

(264) ##STR00479##

(265) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.20 (s, 1H), 8.04 (s, 1H), 7.91 (d, J=1.4 Hz, 1H), 7.57 (d, J=1.4 Hz, 1H), 7.41 (dd, J=8.0, 1.2 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.70 (dd, J=8.1, 1.2 Hz, 1H), 3.59-3.50 (m, 4H), 2.59-2.53 (m, 4H), 2.27 (s, 3H) ppm; LC-MS: m/z 393.8 [M+H].sup.+.

Example 26: (1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-4-phenylpiperidin-4-yl) methanamine

(266) ##STR00480##

(267) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.00 (s, 1H), 7.88 (s, 1H), 7.54 (s, 1H), 7.50-7.33 (m, 5H), 7.28 (t, J=6.8 Hz, 1H), 7.10 (t, J=8.0 Hz, 1H), 6.67 (d, J=8.1 Hz, 1H), 3.77 (d, J=12.5 Hz, 2H), 3.31-3.22 (m, 2H), 3.09 (s, 1H), 2.82 (s, 1H), 2.32 (s, 2H), 2.06 (t, J=10.3 Hz, 2H); LC-MS: m/z 484.7 [M+H].sup.+.

Example 27: (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine

(268) ##STR00481##

(269) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.4 Hz, 1H), 7.42 (dd, J=8.0, 1.3 Hz, 1H), 7.12 (t, J=8.1 Hz, 1H), 6.69 (dd, J=8.1, 1.4 Hz, 1H), 3.93 (t, J=14.9 Hz, 2H), 3.31 (d, J=19.3 Hz, 2H), 3.28-3.16 (m, 3H), 2.252.06 (m, 2H), 1.90 (dd, J=32.1, 11.8 Hz, 2H), 1.61-1.45 (m, 2H) ppm; LC-MS: m/z 484.1 [M+H].sup.+.

Example 28: (R)-3-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-azaspiro[5.5]undecan-7-amine

(270) ##STR00482##

(271) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.82 (d, J=1.2 Hz, 1H), 7.56 (d, J=1.2 Hz, 1H), 7.41 (dd, J=8.0, 1.2 Hz, 1H), 7.12 (t, J=8.1 Hz, 1H), 6.68 (dd, J=8.1, 1.2 Hz, 1H), 3.80 (d, J=4.8 Hz, 2H), 3.33 (dd, J=29.0, 11.6 Hz, 2H), 2.77 (d, J=5.2 Hz, 1H), 2.04 (dd, J=30.0, 14.7 Hz, 2H), 1.85-1.12 (m, 10H) ppm; LC-MS: m/z 461.7 [M+H].sup.+.

Example 29: 1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-4-ethylpiperidin-4-amine

(272) ##STR00483##

(273) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.88 (d, J=1.5 Hz, 1H), 7.58 (d, J=1.4 Hz, 1H), 7.42 (dd, J=8.0, 1.3 Hz, 1H), 7.12 (t, J=8.1 Hz, 1H), 6.70 (dd, J=8.1, 1.4 Hz, 1H), 3.71-3.64 (m, 4H), 1.90-1.73 (m, 4H), 1.69 (q, J=7.3 Hz, 2H), 0.93 (t, J=7.5 Hz, 3H) ppm; LC-MS: m/z 422.1 [M+H].sup.+.

Example 30: 8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-1-methyl-8-azaspiro[4. 5]decan-1-amine

(274) ##STR00484##

(275) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.33 (s, 1H), 7.83 (s, 1H), 7.56 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.17-7.08 (m, 1H), 6.69 (d, J=8.2 Hz, 1H), 4.08-3.93 (m, 2H), 3.18-3.04 (m, 2H), 3.04-2.94 (m, 1H), 2.45 (s, 1H), 1.90-1.29 (m, 8H), 0.95 (t, J=6.3 Hz, 3H) ppm; LC-MS: m/z 462.1[M+H].sup.+.

Example 31: Preparation of Compound: 1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)pyrrolidin-3-amine

Step 1: Tert-Butyl (1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)pyrrolidin-3-yl)carbamate

(276) ##STR00485##

(277) Using the same method as that of Example 23, B1 was substituted by a corresponding amine to obtain tert-butyl (1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)pyrrolidin-3-yl)carbamate.

(278) LC-MS: m/z 424.1[M+H].sup.+.

Step 1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)pyrrolidine-3-amine

(279) ##STR00486##

(280) Using the same method as that of Step 3 in Example 21, tert-butyl (1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)pyrrolidine-3-yl)carba mate was subjected to deprotection of the Boc protecting group to obtain compound 1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)pyrrolidine-3-amine.

(281) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.18 (s, 1H), 7.93 (d, J=1.1 Hz, 1H), 7.46 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 4.14 (d, J=9.3 Hz, 1H), 4.05 (d, J=5.9 Hz, 1H), 3.82 (d, J=11.2 Hz, 3H), 2.24 (d, J=7.3 Hz, 1H), 2.02 (s, 1H) ppm; LC-MS: m/z 379.9 [M+H].sup.+.

(282) Using the synthesis method of Example 31, the following compounds were synthesized:

Example 32: 1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-amine

(283) ##STR00487##

(284) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.39 (s, 1H), 8.03 (s, 1H), 7.86 (s, 1H), 7.57 (s, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.69 (d, J=8.1 Hz, 1H), 4.00 (d, J=13.0 Hz, 2H), 3.13 (d, J=11.5 Hz, 2H), 2.02-1.86 (m, 3H), 1.62 (dd, J=21.0, 9.8 Hz, 2H), 1.23 (s, 1H); LC-MS: m/z 394.7 [M+H].sup.+.

Example 33: (1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)pyrrolidin-3-yl)methan amine

(285) ##STR00488##

(286) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.17 (d, J=1.6 Hz, 1H), 7.91 (s, 1H), 7.45 (d, J=1.5 Hz, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 4.04 (ddd, J=11.5, 8.9, 5.5 Hz, 2H), 3.94-3.86 (m, 1H), 3.72 (dd, J=10.8, 7.6 Hz, 2H), 2.93 (d, J=7.2 Hz, 2H), 2.16 (dq, J=11.9, 6.2 Hz, 1H), 1.79 (dq, J=12.3, 8.3 Hz, 1H) ppm; LC-MS: m/z 394.1 [M+H].sup.+.

Example 34: (1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-4-methylpiperidin-4-yl) methanamine

(287) ##STR00489##

(288) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.83 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.4 Hz, 1H), 7.42 (dd, J=8.0, 1.3 Hz, 1H), 7.12 (t, J=8.1 Hz, 1H), 6.69 (dd, J=8.1, 1.3 Hz, 1H), 3.68 (dt, J=13.7, 4.6 Hz, 2H), 3.44 (td, J=9.6, 4.8 Hz, 2H), 2.76 (s, 2H), 1.70 (ddd, J=13.3, 9.2, 3.7 Hz, 2H), 1.62-1.49 (m, 2H), 1.08 (s, 3H) ppm; LC-MS: m/z 422.1 [M+H].sup.+.

Example 35: (1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)methanamine

(289) ##STR00490##

(290) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.30 (s, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 7.57 (s, 1H), 7.42 (d, J=7.7 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 4.05 (d, J=13.2 Hz, 2H), 3.07 (t, J=12.3 Hz, 2H), 2.75 (d, J=5.9 Hz, 2H), 1.88 (d, J=11.8 Hz, 3H), 1.53-1.35 (m, 2H) ppm; LC-MS: m/z 409.8 [M+H].sup.+.

Example 36: 2-(1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)ethan-1-amine

(291) ##STR00491##

(292) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.56 (d, J=1.2 Hz, 1H), 7.41 (dd, J=8.0, 1.2 Hz, 1H), 7.12 (t, J=8.1 Hz, 1H), 6.69 (dd, J=8.1, 1.2 Hz, 1H), 4.02 (d, J=12.9 Hz, 2H), 3.03 (t, J=12.0 Hz, 2H), 2.87-2.78 (m, 2H), 1.82 (d, J=12.5 Hz, 2H), 1.70 (s, 1H), 1.55 (dd, J=14.7, 6.9 Hz, 2H), 1.40 (dd, J=21.6, 11.5 Hz, 2H) ppm; LC-MS: m/z 422.7 [M+H].sup.+.

Example 37: Synthesis of Compound: (S)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

Step 1: (R)—N—((S)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide

(293) ##STR00492##

(294) Using the same method as that of Example 23, B1 was substituted by a corresponding amine to obtain (R)—N—((S)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide.

(295) LC-MS: m/z 554.1 [M+H].sup.+.

Step 2: (S)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

(296) ##STR00493##

(297) Under nitrogen atmosphere, to a 50 mL single-necked flask were added (R)—N—((S)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide (70 mg, 0.13 mmol) and methanol (0.5 mL), followed by dropwise addition of a solution of hydrogen chloride in 1,4-dioxane (0.05 mL, 4 M) at room temperature, and the mixture was stirred and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, filtered and concentrated under reduced pressure to obtain a residue, which was purified by high performance liquid chromatography to obtain (S)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (10 mg, yield: 17%).

(298) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.83 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.4 Hz, 1H), 7.42 (dd, J=8.0, 1.4 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.69 (dd, J=8.1, 1.4 Hz, 1H), 4.00 (dd, J=8.8, 6.4 Hz, 1H), 3.87-3.71 (m, 2H), 3.66 (d, J=8.5 Hz, 1H), 3.29-3.27 (m, 1H), 3.17 (t, J=5.8 Hz, 2H), 1.92-1.76 (m, 2H), 1.57 (dd, J=12.5, 5.8 Hz, 2H), 1.24 (d, J=3.2 Hz, 1H) ppm; LC-MS: m/z 450.1 [M+H].sup.+.

(299) According to the synthesis method of Example 37, the following compounds were synthesized:

Example 38: (R)-1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)azepan-4-amine

(300) ##STR00494##

(301) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.39 (s, 1H), 7.95 (s, 2H), 7.48 (s, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 4.03-3.89 (m, 2H), 3.81-3.61 (m, 2H), 3.20 (s, 1H), 2.15 (s, 1H), 1.95 (d, J=14.1 Hz, 4H), 1.56 (d, J=10.7 Hz, 1H) ppm; LC-MS: m/z 409.8 [M+H].sup.+.

Example 39: (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decan-4-amine

(302) ##STR00495##

(303) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.18 (s, 1H), 8.03 (s, 1H), 7.84 (s, 1H), 7.56 (s, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.12 (t, J=8.1 Hz, 1H), 6.70 (d, J=8.1 Hz, 1H), 3.94 (t, J=13.7 Hz, 2H), 3.54 (d, J=8.7 Hz, 1H), 3.45 (d, J=8.7 Hz, 1H), 3.32 (d, J=12.2 Hz, 2H), 2.68 (s, 1H), 1.98-1.88 (m, 2H), 1.65 (s, 2H), 1.02 (s, 3H), 0.95 (s, 3H); LC-MS: m/z 479.7 [M+H].sup.+.

Example 40: (S)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decan-4-amine

(304) ##STR00496##

(305) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.84 (s, 1H), 7.56 (s, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.69 (d, J=8.1 Hz, 1H), 3.94 (t, J=14.1 Hz, 2H), 3.54 (d, J=8.7 Hz, 1H), 3.45 (d, J=8.7 Hz, 1H), 3.35-3.25 (m, 2H), 2.69 (s, 1H), 1.98-1.85 (m, 2H), 1.71-1.59 (m, 2H), 1.03 (s, 3H), 0.95 (s, 3H); LC-MS: m/z 479.7 [M+H].sup.+.

Example 41: (1R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2-methyl-8-azaspiro[4.5]decan-1-amine

(306) ##STR00497##

(307) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.81 (dd, J=7.4, 1.6 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.41 (dd, J=8.0, 1.4 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.68 (dd, J=8.1, 1.4 Hz, 1H), 3.95 (d, J=11.9 Hz, 2H), 3.12 (t, J=12.0 Hz, 2H), 2.89 (d, J=5.8 Hz, 1H), 2.08-1.44 (m, 9H), 1.00 (dd, J=31.0, 6.6 Hz, 3H) ppm; LC-MS: m/z 462.1 [M+H].sup.+.

Example 42: (1R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine

(308) ##STR00498##

(309) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.12 (t, J=8.1 Hz, 1H), 6.69 (d, J=8.1 Hz, 1H), 3.99-3.80 (m, 2H), 3.24-2.98 (m, 3H), 2.27-1.14 (m, 9H), 1.04-0.95 (m, 3H) ppm; LC-MS: m/z 462.1 [M+H].sup.+.

Example 43: (2R,4R)-4-amino-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-2-ol

(310) ##STR00499##

(311) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.37 (s, 1H), 8.04 (s, 1H), 7.81 (s, 1H), 7.57 (s, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.68 (d, J=8.0 Hz, 1H), 4.15 (d, J=6.5 Hz, 1H), 3.91 (d, J=14.3 Hz, 2H), 3.22 (s, 2H), 2.93 (t, J=7.3 Hz, 1H), 2.27-2.20 (m, 1H), 1.89-1.66 (m, 5H), 1.54 (dt, J=13.4, 6.7 Hz, 1H), 1.35 (d, J=12.9 Hz, 1H) ppm; LC-MS: m/z 465.7 [M+H].sup.+.

Example 44: (3S,4S)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(312) ##STR00500##

(313) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.84 (s, 1H), 7.56 (s, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 4.15-4.06 (m, 1H), 3.73 (s, 2H), 3.56 (d, J=8.5 Hz, 1H), 3.42-3.27 (m, 3H), 3.05 (d, J=4.8 Hz, 1H), 1.91 (dt, J=39.6, 9.8 Hz, 2H), 1.67 (dd, J=25.7, 13.7 Hz, 2H), 1.12 (d, J=6.4 Hz, 3H) ppm; LC-MS: m/z 463.7 [M+H].sup.+.

Example 45: (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-1-oxa-8-azaspiro[4.5]decan-4-amine

(314) ##STR00501##

(315) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.95 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 7.20 (d, J=6.4 Hz, 1H), 6.95 (t, J=6.4 Hz, 1H), 6.70 (d, J=6.4 Hz, 1H), 4.00-3.85 (m, 4H), 3.46 (t, J=8.8 Hz, 2H), 3.20 (t, J=5.2 Hz, 1H), 2.39-2.35 (m, 1H), 1.94-1.89 (m, 2H), 1.80-1.74 (m, 2H), 1.68-1.65 (m, 1H) ppm; LCMS: m/z 450.1 [M+H].sup.+.

Example 46: Synthesis of Compound: (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-N-methyl-8-azaspiro[4.5]decan-1-amine

Step 1: (R)—N—((R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide

(316) ##STR00502##

(317) Using the same method as that of Example 23, B1 was substituted by an amine to obtain (R)—N—((R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (70 mg, yield: 80%). LC-MS: m/z 552.1 [M+H].sup.+.

Step 2: (R)—N—((R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-N,2-dimethylpropane-2-sulfinamide

(318) ##STR00503##

(319) To a dry 50 mL round bottom flask were added (R)—N—((R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-N,2-dimethylpropane-2-sulfinamide (70 mg, 0.13 mmol) and DMF (5 mL), followed by slow addition of NaH (10.4 mg, 0.26 mmol) at 0° C. The mixture was stirred at 0° C. for 10 minutes, and then CH.sub.3I (28 mg, 0.20 mmol) was slowly added at 0° C., and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (10 mL) was added to quench the reaction, followed by extraction with ethyl acetate (3×10 mL). The organic phases were combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to obtain a residue, which was then purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 80%) to obtain (R)—N—((R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-N,2-dimethylpropane-2-sulfinamide (50 mg, yield: 49%).

(320) LC-MS: m/z 566.1 [M+H].sup.+.

Step 3: (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-N-methyl-8-azaspiro[4.5]decan-1-amine

(321) ##STR00504##

(322) Using the same method as that of Step 2 in Example 37, (R)—N—((R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-N,2-dimethylpropane-2-sulfinamide was subjected to the removal of the sulfinyl group to obtain (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-N-methyl-8-azaspiro [4.5]decan-1-amine.

(323) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.30 (s, 1H), 8.03 (s, 1H), 7.82 (s, 1H), 7.55 (s, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.69 (d, J=8.1 Hz, 1H), 3.87 (d, J=13.2 Hz, 2H), 3.22 (dd, J=22.1, 10.8 Hz, 2H), 2.56 (t, J=7.3 Hz, 1H), 2.35 (s, 3H), 1.89 (ddd, J=33.1, 16.7, 7.8 Hz, 4H), 1.72-1.33 (m, 6H) ppm; LC-MS: m/z 461.7 [M+H].sup.+.

Example 47: (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

Step 1: (R)—N—((R)-8-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide

(324) ##STR00505##

(325) To a dry 50 mL single-necked flask were added 5-chloro-8-iodoimidazo[1,2-c]pyrimidine (E1) (50 mg, 0.18 mmol), (R)-2-methyl-N—((R)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1A) (93 mg, 0.36 mmol), DIEA (46 mg, 0.36 mmol) and NMP (5 mL), and the reaction mixture was stirred at 90° C. for 2 hours. After the reaction was completed, the obtained residue was poured into water (10 mL), stirred at room temperature for 5 minutes, and then extracted with ethyl acetate (3×20 mL). The combined organic phase was dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 80%) to obtain (R)—N—((R)-8-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide as a pale yellow solid (80 mg, yield: 88%).

(326) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.79 (d, J=1.4 Hz, 1H), 7.64 (d, J=1.4 Hz, 1H), 4.97 (d, J=8.0 Hz, 1H), 3.77-3.65 (m, 2H), 3.23-3.13 (m, 1H), 3.04 (dd, J=30.0, 11.5 Hz, 2H), 2.03-1.78 (m, 4H), 1.67-1.31 (m, 6H), 1.13 (s, 9H) ppm; LC-MS: m/z 502.1 [M+H].sup.+.

Step 2: (R)—N—((R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide

(327) ##STR00506##

(328) To a dry 50 mL three-necked flask were added (R)—N—((R)-8-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (80 mg, 0.16 mmol), cuprous iodide (3 mg, 0.016 mmol), 1,10-phenanthroline (6 mg, 0.032 mmol), 2,3-dichlorothiophenol (34 mg, 0.192 mmol), potassium phosphate (68 mg, 0.32 mmol) and 10 mL of dioxane sequentially. The mixture was heated for 3 hours under nitrogen atmosphere. After the reaction was completed, saturated NH.sub.4Cl solution (50 mL) was added, followed by extraction with ethyl acetate (3×20 mL). The organic phases were combined, dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (methanol/ethyl acetate with a gradient of 0 to 10%) to obtain (R)—N—((R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide as a pale yellow solid (60 mg, yield: 68%).

(329) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.76 (d, J=1.4 Hz, 1H), 7.56 (d, J=1.4 Hz, 1H), 7.40 (dd, J=8.0, 1.3 Hz, 1H), 7.11 (t, J=8.0 Hz, 1H), 6.68 (dd, J=8.1, 1.3 Hz, 1H), 5.00 (d, J=8.1 Hz, 1H), 3.94 (dd, J=12.8, 3.4 Hz, 2H), 3.26-3.14 (m, 3H), 2.08-1.84 (m, 4H), 1.69-1.36 (m, 6H), 1.14-1.11 (m, 9H) ppm; LC-MS: m/z 552.1 [M+H].sup.+.

Step 3: (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(330) ##STR00507##

(331) To a dry 50 mL round bottom flask were added (R)—N—((R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (Example 17-2) (60 mg, 0.11 mmol) and a solution of hydrogen chloride in 1,4-dioxane (7 M, 5 mL), and the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by reversed-phase high-performance liquid chromatography to obtain the product (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (25 mg, yield: 51%).

(332) .sup.1H NMR (400 MHz, CD.sub.3OD-d.sub.4) δ 8.54 (s, 2H), 8.04 (s, 1H), 7.81 (s, 1H), 7.58 (s, 1H), 7.33 (dd, J=8.0, 1.3 Hz, 1H), 7.05 (t, J=8.0 Hz, 1H), 6.68 (dd, J=8.1, 1.3 Hz, 1H), 4.03 (t, J=14.7 Hz, 2H), 3.38 (s, 2H), 2.27 (d, J=5.4 Hz, 1H), 1.97-1.63 (m, 9H) ppm; LC-MS: m/z 448.1 [M+H].sup.+.

(333) According to the synthesis method of Example 47, using commercially available raw materials or self-synthesized intermediates, the following compounds were synthesized:

Example 48: (R)-7-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-7-azaspiro[3.5]nonan-1-amine

(334) ##STR00508##

(335) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.34 (s, 1H), 8.02 (s, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.12 (t, J=8.1 Hz, 1H), 6.69 (d, J=7.9 Hz, 1H), 3.91 (d, J=13.2 Hz, 1H), 3.84-3.73 (m, 1H), 3.18-3.08 (m, 3H), 2.13 (q, J=8.0 Hz, 1H), 1.83 (td, J=10.7, 8.5, 4.2 Hz, 2H), 1.80-1.69 (m, 3H) ppm; LC-MS: m/z 434.1 [M+H].sup.+.

Example 49: 7-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-7-azaspiro[3.5]nonan-2-amine

(336) ##STR00509##

(337) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.01 (s, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.41 (dd, J=8.0, 1.4 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.69 (dd, J=8.1, 1.4 Hz, 1H), 3.50 (d, J=10.2 Hz, 2H), 3.41 (s, 2H), 2.71-2.64 (m, 1H), 2.36-2.30 (m, 1H), 2.21 (s, 2H), 1.81 (d, J=26.6 Hz, 5H) ppm; LC-MS: m/z 434.1 [M+H].sup.+.

Example 50: (7R)-2-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2-azaspiro[4.4]nonan-7-ylamine

(338) ##STR00510##

(339) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.36 (brs, 1H), 8.18 (s, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.43 (s, 1H), 7.38 (d, J=6.0 Hz, 1H), 7.11 (t, J=6.4 Hz, 1H), 6.64 (d, J=6.0 Hz, 1H), 3.96-3.74 (m, 4H), 3.53-3.51 (m, 1H), 2.00-1.60 (m, 8H) ppm; LCMS: m/z 434.2[M+H].sup.+.

Example 51: (R)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decan-4-amine

(340) ##STR00511##

(341) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.17 (s, 2H), 8.08 (s, 1H), 7.90 (s, 1H), 7.65 (s, 1H), 5.67 (s, 1H), 4.09-3.93 (m, 2H), 3.61 (dd, J=14.2, 9.1 Hz, 4H), 3.10 (d, J=5.4 Hz, 1H), 2.35 (d, J=15.8 Hz, 3H), 2.03-1.71 (m, 4H), 1.16 (s, 3H), 1.07 (s, 3H) ppm; LCMS: m/z 474.1 [M+H].sup.+.

Example 52: (S)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(342) ##STR00512##

(343) .sup.1H NMR (DMSO-d.sub.6) δ 8.43 (s, 1H), 8.02 (s, 1H), 7.79-7.80 (d, 1H), 7.56-7.57 (d, 1H), 7.40-7.42 (d, 1H), 7.11-7.15 (t, 1H), 6.68-6.71 (d, 1H), 3.88 (t, 2H), 3.24 (t, 2H), 3.01 (t, 1H), 1.60-1.90 (m, 5H), 1.30-1.59 (m, 5H) ppm; LC-MS: m/z 448.1 [M+H].sup.+.

Example 53: (R)-8-(8-((2-chlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(344) ##STR00513##

(345) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.97 (s, 1H), 7.80 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.4 Hz, 1H), 7.49 (dd, J=7.7, 1.6 Hz, 1H), 7.15 (dtd, J=19.6, 7.4, 1.6 Hz, 2H), 6.76 (dd, J=7.7, 1.7 Hz, 1H), 3.93-3.80 (m, 2H), 3.21 (td, J=11.2, 2.7 Hz, 2H), 3.00 (s, 1H), 2.05-1.75 (m, 4H), 1.75-1.35 (m, 6H) ppm; LCMS: m/z 414.1 [M+H].sup.+.

Example 54: (R)-8-(8-((3-chlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(346) ##STR00514##

(347) .sup.1H NMR (CD.sub.3OD-d.sub.4) δ 7.96 (s, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 7.23-7.27 (m, 3H), 7.14-7.16 (m, 1H), 3.83 (m, 2H), 3.24 (m, 2H), 2.89 (m, 1H), 1.77-1.83 (m, 4H), 1.51-1.62 (m, 2H), 1.354-1.46 (m, 4H) ppm; LCMS: m/z 414.1 [M+H].sup.+.

Example 55: (R)-8-(8-((4-chlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(348) ##STR00515##

(349) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.91 (s, 1H), 7.79-7.75 (m, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 3.91-3.71 (m, 2H), 3.18 (t, J=12.3 Hz, 2H), 3.00 (s, 1H), 2.05-1.66 (m, 5H), 1.64-1.34 (m, 5H) ppm; LCMS: m/z 414.1 [M+H].sup.+.

Example 56: (R)-8-(8-((2,6-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(350) ##STR00516##

(351) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.75 (s, 1H), 7.66 (s, 1H), 7.64 (s, 1H), 7.60 (s, 1H), 7.51 (t, J=8.1 Hz, 1H), 7.09 (s, 1H), 3.64 (s, 2H), 3.04 (q, J=12.4 Hz, 2H), 2.74 (t, J=7.2 Hz, 1H), 1.89-1.74 (m, 4H), 1.52 (s, 2H), 1.42-1.24 (m, 4H) ppm; LCMS: m/z 450.0 [M+H].sup.+.

Example 57: (R)-8-(8-((2,4-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(352) ##STR00517##

(353) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.00 (s, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.69 (d, J=2.3 Hz, 1H), 7.56 (d, J=1.4 Hz, 1H), 7.20 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 3.94-3.79 (m, 2H), 3.20 (q, J=11.9 Hz, 2H), 2.77 (t, J=7.3 Hz, 1H), 1.90-1.77 (m, 4H), 1.67-1.52 (m, 2H), 1.37 (td, J=27.0, 26.1, 12.9 Hz, 4H) ppm; LCMS: m/z 450.0 [M+H].sup.+.

Example 58: (R)-8-(8-((2,5-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(354) ##STR00518##

(355) .sup.1H NMR (CD.sub.3OD-d.sub.4) δ 8.02 (s, 1H), 7.82 (s, 1H), 7.52-7.58 (m, 2H), 7.22-7.25 (m, 1H), 6.71 (s, 1H), 3.88-3.89 (m, 2H), 3.22-3.24 (m, 2H), 2.81-2.83 (m, 1H), 1.77-1.83 (m, 4H), 1.51-1.62 (m, 2H), 1.354-1.46 (m, 4H) ppm; LCMS: m/z 450.0 [M+H].sup.+.

Example 59: (R)-8-(8-((2-isopropylphenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]deca n-1-amine

(356) ##STR00519##

(357) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.76 (s, 1H), 7.58 (s, 2H), 7.37 (d, J=7.7 Hz, 1H), 7.24 (s, 1H), 7.06 (d, J=6.1 Hz, 2H), 3.73 (s, 2H), 3.52 (s, 1H), 3.11 (d, J=12.8 Hz, 2H), 2.76 (s, 1H), 1.83 (d, J=31.7 Hz, 4H), 1.58 (d, J=42.0 Hz, 2H), 1.36 (s, 4H), 1.24 (d, J=7.0 Hz, 6H) ppm; LCMS: m/z 423.2 [M+H].sup.+.

Example 60: (R)-8-(8-((2-methoxyphenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(358) ##STR00520##

(359) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.77 (s, 1H), 7.73 (s, 1H), 7.58 (s, 1H), 7.19 (t, J=7.9 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 6.82-6.69 (m, 2H), 3.87 (s, 3H), 3.77 (d, J=12.4 Hz, 2H), 3.17 (s, 2H), 2.97 (s, 2H), 1.97 (s, 1H), 1.77-1.30 (m, 9H) ppm; LCMS: m/z 410.1 [M+H].sup.+.

Example 61: Methyl (R)-2-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)benzoate

(360) ##STR00521##

(361) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.38 (s, 1H), 7.95 (dd, J=7.8, 1.6 Hz, 1H), 7.78 (d, J=1.5 Hz, 1H), 7.53 (d, J=1.4 Hz, 1H), 7.30 (td, J=7.7, 1.6 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 6.77 (d, J=8.1 Hz, 1H), 3.91 (s, 3H), 3.85 (d, J=13.4 Hz, 2H), 3.23 (d, J=12.8 Hz, 2H), 2.97 (t, J=7.0 Hz, 1H), 1.97 (d, J=7.0 Hz, 2H), 1.82-1.40 (m, 8H) ppm; LC-MS: m/z 438.1 [M+H].sup.+.

Example 62: (R)-8-(8-((4-aminophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(362) ##STR00522##

(363) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.71 (s, 1H), 7.61 (s, 1H), 7.24 (d, J=7.5 Hz, 2H), 7.13 (s, 1H), 6.58 (d, J=7.5 Hz, 2H), 5.48 (s, 2H), 3.60 (s, 2H), 3.17 (s, 2H), 3.04-3.01 (m, 1H), 1.40 (s, 10H) ppm; LC-MS: m/z 396.2 [M+H].sup.+.

Example 63: (R)-8-(8-((3-amino-2-chlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(364) ##STR00523##

(365) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.31 (s, 2H), 7.85 (s, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 6.80 (t, J=7.9 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 5.94 (d, J=7.8 Hz, 1H), 5.50 (s, 2H), 3.84 (t, J=13.1 Hz, 2H), 3.17 (s, 2H), 3.04 (s, 1H), 2.00 (q, J=7.2 Hz, 2H), 1.83-1.37 (m, 10H) ppm; LC-MS: m/z 429.1 [M+H].sup.+.

Example 64: (R)-8-(8-((3-(trifluoromethyl)phenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(366) ##STR00524##

(367) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.31 (s, 2H), 8.00 (s, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.59-7.52 (m, 1H), 7.47 (dd, J=16.9, 9.2 Hz, 5H), 3.84 (t, J=13.0 Hz, 2H), 3.22 (d, J=13.1 Hz, 2H), 2.98 (s, 1H), 1.79 (d, J=13.8 Hz, 5H), 1.60-1.36 (m, 5H) ppm; LC-MS: m/z 448.1 [M+H].sup.+.

Example 65: (R)—N-(4-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio) phenyl)acetamide

(368) ##STR00525##

(369) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.04 (d, J=5.3 Hz, 1H), 8.35 (s, 1H), 7.74 (s, 1H), 7.61 (d, J=13.9 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 3.73 (t, J=12.0 Hz, 2H), 3.12 (s, 2H), 2.97 (s, 1H), 2.02 (s, 3H), 1.96 (s, 1H), 1.74 (dt, J=53.1, 26.6 Hz, 5H), 1.50 (d, J=35.3 Hz, 4H) ppm; LC-MS: m/z 396.2 [M+H].sup.+.

Example 66: (R)-5-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)-1,3,4-thiadiazol-2-amine

(370) ##STR00526##

(371) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.33 (s, 1H), 7.96 (s, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.4 Hz, 1H), 7.33 (s, 2H), 3.83 (td, J=11.2, 9.7, 4.9 Hz, 2H), 3.20 (s, 2H), 3.05 (d, J=6.9 Hz, 1H), 1.99 (t, J=6.5 Hz, 1H), 1.86-1.69 (m, 4H), 1.62-1.38 (m, 5H) ppm; LC-MS: m/z 403.1 [M+H].sup.+.

Example 67: (R)-8-(8-((1-methyl-1H-imidazol-2-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(372) ##STR00527##

(373) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.76 (d, J=1.5 Hz, 1H), 7.60 (dd, J=6.8, 1.4 Hz, 1H), 7.39 (d, J=1.1 Hz, 1H), 7.35 (d, J=7.0 Hz, 1H), 7.00 (d, J=1.1 Hz, 1H), 3.80 (d, J=2.6 Hz, 3H), 3.63 (d, J=10.4 Hz, 2H), 3.08 (t, J=12.2 Hz, 2H), 2.73 (t, J=7.3 Hz, 1H), 1.90-1.67 (m, 4H), 1.65-1.51 (m, 2H), 1.50-1.29 (m, 4H) ppm; LC-MS: m/z 384.1 [M+H].sup.+.

Example 68: (R)-8-(8-(naphthalen-1-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(374) ##STR00528##

(375) .sup.1H NMR (CD.sub.3D-d.sub.4) δ 8.35-8.40 (m, 2H), 7.99-8.02 (m, 1H), 7.89-7.91 (m, 1H), 7.76 (m, 1H), 7.57-7.64 (m, 4H), 7.43-7.47 (m, 2H), 3.73 (m, 2H), 3.11 (m, 2H), 2.95 (m, 1H), 1.71-2.05 (m, 4H), 1.35-1.68 (m, 6H) ppm; LC-MS: m/z 430.2 [M+H].sup.+.

Example 69: (R)-8-(8-(thiazol-2-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(376) ##STR00529##

(377) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.35 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.69 (d, J=3.3 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=3.3 Hz, 1H), 3.89 (d, J=4.1 Hz, 2H), 3.25 (t, J=12.2 Hz, 2H), 3.07 (s, 1H), 2.32-2.25 (m, 2H), 2.06-1.69 (m, 5H), 1.65-1.40 (m, 5H) ppm; LC-MS: m/z 387.1 [M+H].sup.+.

Example 70: (R)-8-(8-(oxazol-2-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(378) ##STR00530##

(379) .sup.1H NMR (CD.sub.3OD-d.sub.4) δ 8.12 (s, 1H), 8.04 (s, 1H), 7.80 (s, 1H), 7.60 (s, 1H), 7.22 (s, 1H), 3.86 (m, 2H), 3.22 (m, 2H), 2.98 (m, 1H), 1.71-2.05 (m, 4H), 1.35-1.68 (m, 6H) ppm; LC-MS: m/z 371.1 [M+H].sup.+.

Example 71: Synthesis of Compound: (R)—N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)-2-chlorophenyl)acrylamide

Step 1: N-(2-chloro-3-((5-((R)-1-(((R)-tert-butylsulfinyl)amino)-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)phenyl)acrylamide

(380) ##STR00531##

(381) The intermediate (R)—N—((R)-8-(8-((3-amino-2-chlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide obtained from the synthesis of Example 63 was used in the following reaction.

(382) To a 100 mL round bottom flask was added (R)—N—((R)-8-(8-((3-amino-2-chlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (60 mg, 0.11 mmol), triethylamine (22 mg, 0.22 mmol) and dichloromethane (5 mL), followed by slow addition of acryloyl chloride (23 mg, 0.22 mmol) to the reaction solution at 0° C. After the addition, the reaction solution was allowed to react at room temperature for 2 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, and then the mixture was extracted with ethyl acetate (3×20 mL). The organic phase was washed with water (20 mL×1) and saturated brine (20 mL×1) sequentially. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, followed by purification by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain a crude product of N-(2-chloro-3-((5-((R)-1-(((R)-tert-butylsulfinyl)amino)-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)phenyl)acrylamide (30 mg, yield: 46%).

(383) LC-MS: m/z 587.2 [M+H].sup.+.

Step 2: (R)—N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)-2-chlorophenyl)acrylamide

(384) ##STR00532##

(385) According to the same method as that of Step 2 in Example 37, (R)—N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)-2-chlorophenyl)acrylamide was obtained by the removal of the sulfinyl group.

(386) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.86 (s, 1H), 7.99 (s, 1H), 7.80 (s, 1H), 7.57 (s, 1H), 7.49 (s, 1H), 7.10 (t, J=8.0 Hz, 1H), 6.72-6.51 (m, 2H), 6.29 (d, J=16.9 Hz, 1H), 5.81 (d, J=10.3 Hz, 1H), 3.87 (dd, J=14.9, 10.9 Hz, 2H), 3.20 (s, 2H), 3.01 (t, J=6.8 Hz, 1H), 2.05-1.34 (m, 10H) ppm; LC-MS: m/z 482.8 [M+H].sup.+.

(387) According to the synthesis method of Example 71, the following compounds were synthesized:

Example 72: (R)—N.SUP.1.-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)

(388) ##STR00533##

(389) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.00 (s, 1H), 7.80 (s, 1H), 7.57 (s, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.62 (d, J=8.2 Hz, 1H), 5.49 (s, 1H), 3.86 (d, J=12.7 Hz, 2H), 3.81 (s, 3H), 3.23 (t, J=12.7 Hz, 2H), 3.11 (s, 3H), 3.02 (d, J=6.8 Hz, 1H), 2.05-1.75 (m, 5H), 1.54 (dd, J=41.2, 13.2 Hz, 5H) ppm; LC-MS: m/z 528.2[M+H].sup.+.

Example 73: Synthesis of Compound: (R)—N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-carboxamide

Step 1: ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate

(390) ##STR00534##

(391) To a solution of pyridine-2-amine (940 mg, 10 mmol) in xylene (10 mL) was added triethyl methanetricarboxylate (4.64 g, 20 mmol) under nitrogen atmosphere. The mixture was stirred at 140° C. for 4 hours. The reaction was monitored by TLC until the raw material was consumed. The reaction mixture was filtered and washed with ethyl acetate to obtain ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1.95 g, yield: 83%).

(392) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.47 (s, 1H), 8.93 (dd, J=7.4, 1.5 Hz, 1H), 8.19 (ddd, J=8.6, 7.1, 1.6 Hz, 1H), 7.43-7.34 (m, 2H), 4.15 (q, J=7.1 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H) ppm; LCMS: m/z 235 [M+H].sup.+.

Step 2: N-(2-chloro-3-((5-((R)-1-(((R)-tert-butylsulfinyl)amino)-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)phenyl)-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-carboxamide

(393) The intermediate (R)—N—((R)-8-(8-((3-amino-2-chlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide obtain from the synthesis of Example 63 was used in the following reaction.

(394) ##STR00535##

(395) Under nitrogen atmosphere, to a solution of ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (40 mg, 0.169 mmol) in DMF (2 mL) was added (R)—N—((R)-8-(8-((3-amino-2-chlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (60 mg, 0.113 mmol). The mixture was reacted under microwave at 160° C. for 1 hour. After the mixture was cooled to room temperature, the mixture was filtered, diluted with water, extracted with ethyl acetate (20 mL×3), and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain N-(2-chloro-3-((5-((R)-1-(((R)-tert-butylsulfinyl)amino)-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)phenyl)-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-carboxamide (20 mg, yield 21.7%).

(396) LCMS: m/z 721 [M+H].sup.+.

Step 3: (R)—N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-carboxamide

(397) ##STR00536##

(398) According to the same method as that of Step 2 in Example 37, (R)—N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-carboxamide was obtained by the removal of the sulfinyl group.

(399) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.68 (s, 1H), 8.43 (s, 1H), 7.94 (s, 1H), 7.79 (s, 1H), 7.63 (d, J=34.6 Hz, 2H), 7.03 (d, J=8.2 Hz, 1H), 6.61-6.51 (m, 1H), 6.40 (d, J=8.2 Hz, 1H), 6.00 (d, J=6.9 Hz, 1H), 5.45 (s, 1H), 3.94-3.80 (m, 2H), 3.23 (s, 2H), 3.05 (s, 1H), 2.09-1.34 (m, 10H) ppm; LC-MS: m/z 617.1 [M+H].sup.+.

Example 74: Synthesis of Compound (R)—N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-carboxamide

Step 1: ethyl 2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylate

(400) ##STR00537##

(401) To a 100 mL round bottom flask was added ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (obtained from step 1 of Example 69) (1 g, 4.12 mmol), methanol (25 mL) and 10% Pd/C (862 mg). The mixture was stirred at room temperature under hydrogen atmosphere (hydrogen balloon) for 2.5 hours. The reaction was monitored by TLC until the raw materials were consumed. The reaction mixture was filtered through diatomite and concentrated in vacuum to obtain ethyl 2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (700 mg, yield: 69.4%).

(402) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.39 (s, 1H), 4.09 (q, J=7.1 Hz, 2H), 3.66 (t, J=6.0 Hz, 2H), 2.77 (t, J=6.4 Hz, 2H), 1.88-1.80 (m, 2H), 1.78-1.71 (m, 2H), 1.19 (t, J=7.1 Hz, 3H) ppm; LCMS: m/z [M+H].sup.+.

(403) (R)—N-(3-((5-(1-Amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-carboxamide was obtained using the same method as that of Step 2 and Step 3 in Example 73.

(404) ##STR00538##

(405) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.31 (s, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.81-7.72 (m, 2H), 7.58 (s, 1H), 3.86 (dd, J=30.5, 16.1 Hz, 4H), 3.29-3.15 (m, 4H), 2.85-2.78 (m, 1H), 2.11-1.61 (m, 14H); LC-MS: m/z 621.1 [M+H].sup.+.

Example 75: Synthesis of (R)-8-(8-(2,3-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

Step 1: (R)—N—((R)-8-(8-(2,3-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide

(406) ##STR00539##

(407) To a 20 mL sealed tube were sequentially added (R)—N—((R)-8-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (60 mg, 0.12 mmol), 1,4-dioxane (2 mL), purified water (0.5 mL), (2,3-dichlorophenyl)boronic acid (50 mg, 0.24 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (9 mg, 0.012 mmol) and potassium carbonate (50 mg, 0.36 mmol) at room temperature. The reaction system was bubbled with nitrogen for one minute. The sealed tube was heated to 80° C., and the reaction continued for 6 hours. After the reaction was completed, 20 mL of water was added to the reaction solution and extracted with ethyl acetate (50 mL×3). The organic phase was sequentially washed with water (20 mL×1) and saturated saline (20 mL×1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain a crude product of (R)—N—((R)-8-(8-(2,3-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (30 mg, yield: 48%) as a pale yellow solid.

(408) LC-MS: m/z 520.1 [M+H].sup.+.

Step 2: (R)-8-(8-(2,3-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(409) ##STR00540##

(410) According to the same method as that of Step 2 in Example 37, (R)—N—((R)-8-(8-(2,3-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide was subjected to the removal of the sulfinyl group to obtain (R)-8-(8-(2,3-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine.

(411) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.35 (s, 1H), 7.75 (s, 3H), 7.60 (s, 1H), 7.49 (s, 1H), 3.79 (s, 2H), 3.21-3.12 (m, 2H), 2.93 (s, 1H), 1.82 (s, 5H), 1.46 (s, 7H) ppm; LCMS: m/z 416.1 [M+H].sup.+.

Example 76: Synthesis of Compound: (R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

Step 1: (R)—N—((R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide

(412) ##STR00541##

(413) Under nitrogen atmosphere, to a 100 mL single-necked flask were sequentially added the crude (R)—N—((R)-8-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (100 mg, 0.20 mmol), sodium 2-amino-3-chloropyridine-4-thiolate (43 mg, 0.26 mmol), Pd.sub.2(dba).sub.3 (20 mg, 0.02 mmol), Xantphos (23 mg, 0.040 mmol), DIPEA (52 mg, 0.40 mmol) and 1,4-dioxane (10 mL). The mixture was heated at 100° C. and stirred for 6 hours under nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature, filtered and concentrated under reduced pressure to obtain a residue, which was purified by silica gel chromatography (ethyl acetate/methanol with a of 0 to 30% gradient) to obtain (R)—N—((R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (40 mg, yield: 37%).

(414) LC-MS: m/z 534.2 [M+H].sup.+.

Step 2: (R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(415) ##STR00542##

(416) According to the same method as that of Step 2 in Example 37, (R)—N—((R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide was subjected to the removal of the sulfinyl group to obtain (R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine.

(417) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.32 (d, J=6.9 Hz, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.58 (d, J=1.4 Hz, 1H), 7.54 (d, J=5.4 Hz, 1H), 6.35 (s, 1H), 5.78 (d, J=5.4 Hz, 1H), 3.89 (t, J=12.5 Hz, 2H), 3.29-3.17 (m, 3H), 3.00 (s, 1H), 1.97 (s, 1H), 1.89-1.33 (m, 6H) ppm; LCMS: m/z 430.1 [M+H].sup.+.

(418) According to the synthesis method of Example 76, the following compounds were synthesized:

Example 77: (R)-8-(8-((3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(419) ##STR00543##

(420) .sup.1H NMR (CD.sub.3OD-d.sub.4) δ 8.54 (s, 1H), 8.35 (s, 1H), 8.15-8.16 (m, 1H), 8.09 (s, 1H), 7.83-7.84 (m, 1H), 7.57-7.58 (m, 1H), 6.67-6.68 (m, 1H), 3.92 (m, 2H), 3.26 (m, 2H), 3.00 (m, 1H), 1.71-2.05 (m, 4H), 1.35-1.68 (m, 6H) ppm; LCMS: m/z 415.1 [M+H].sup.+.

Example 78: (R)-8-(8-((3-(trifluoromethyl)pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(421) ##STR00544##

(422) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.82 (s, 1H), 8.41 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.10 (s, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 6.90 (d, J=5.4 Hz, 1H), 3.93 (s, 2H), 3.28-3.20 (m, 2H), 2.94 (s, 1H), 1.90-1.32 (m, 10H); LCMS: m/z 449.1 [M+H].sup.+.

Example 79: (3S,4S)-8-(8-((2-amino-5-chloro-pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(423) ##STR00545##

(424) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.05 (s, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.62 (d, J=1.3 Hz, 1H), 5.91 (s, 2H), 5.65 (s, 1H), 4.13 (d, J=5.2 Hz, 1H), 3.77 (d, J=8.5 Hz, 3H), 3.60 (d, J=8.6 Hz, 1H), 3.40 (s, 1H), 3.14 (s, 1H), 1.81 (dd, J=82.1, 33.6 Hz, 5H), 1.14 (d, J=6.3 Hz, 3H) ppm; LC-MS: m/z 462.1 [M+H].sup.+.

Example 80: (3S,4S)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(425) ##STR00546##

(426) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.14 (s, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 7.63 (s, 1H), 5.82 (s, 2H), 5.51 (s, 1H), 4.26-4.18 (m, 1H), 3.88 (t, J=13.0 Hz, 3H), 3.70 (d, J=8.9 Hz, 1H), 3.42 (d, J=4.3 Hz, 1H), 3.27 (s, 2H), 2.31 (s, 3H), 1.99 (d, J=10.0 Hz, 2H), 1.80 (d, J=13.5 Hz, 1H), 1.69 (d, J=12.8 Hz, 1H), 1.23 (d, J=6.4 Hz, 3H) ppm; LC-MS: m/z 459.8 [M+H].sup.+.

Example 81: (R)-8-(8-((3-chloro-2-cyclopropylpyrimidin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(427) ##STR00547##

(428) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.06 (s, 1H), 7.97 (d, J=5.3 Hz, 1H), 7.82 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.4 Hz, 1H), 6.40 (d, J=5.3 Hz, 1H), 3.91 (t, J=13.1 Hz, 2H), 3.25 (t, J=11.7 Hz, 2H), 3.02 (t, J=6.6 Hz, 1H), 2.03-1.65 (m, 5H), 1.67-1.37 (m, 5H), 1.04 (ddt, J=8.0, 5.6, 2.4 Hz, 2H), 0.97 (dq, J=6.9, 4.2, 3.4 Hz, 2H) ppm; LCMS: m/z 455.1 [M+H].sup.+.

Example 82: (R)-8-(8-((3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(429) ##STR00548##

(430) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.35-8.29 (m, 1H), 8.07 (s, 1H), 8.02 (d, J=5.4 Hz, 1H), 7.83 (s, 1H), 7.57 (d, J=1.4 Hz, 1H), 6.50 (d, J=5.3 Hz, 1H), 3.91 (t, J=12.9 Hz, 2H), 3.26 (t, J=12.3 Hz, 2H), 3.01 (s, 1H), 2.55 (s, 3H), 2.02-1.77 (m, 4H), 1.75-1.38 (m, 6H) ppm; LCMS: m/z 429.1 [M+H].sup.+.

Example 83: (R)-8-(8-((2-amino-5-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(431) ##STR00549##

(432) .sup.1H NMR (CD.sub.3OD-d.sub.4) δ 8.38 (s, 1H), 8.04 (s, 1H), 7.82-7.84 (m, 2H), 7.61 (m, 1H), 5.93 (s, 2H), 5.66 (m, 1H), 3.87-3.93 (m, 2H), 3.21-3.28 (m, 2H), 2.98 (m, 1H), 1.71-2.05 (m, 4H), 1.35-1.68 (m, 6H) ppm; LCMS: m/z 430.1 [M+H].sup.+.

Example 84: (R)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(433) ##STR00550##

(434) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.10 (s, 1H), 8.00 (d, J=5.3 Hz, 1H), 7.83 (d, J=1.5 Hz, 1H), 7.59 (d, J=1.4 Hz, 1H), 6.72 (d, J=5.3 Hz, 1H), 4.03-3.87 (m, 2H), 3.27 (d, J=13.6 Hz, 2H), 3.14 (t, J=6.3 Hz, 1H), 2.05 (q, J=6.4 Hz, 1H), 1.87-1.42 (m, 9H) ppm; LCMS: m/z 449.1 [M+H].sup.+.

Example 85: (R)-8-(8-((2-methylpyridin-3-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(435) ##STR00551##

(436) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.25 (dd, J=4.7, 1.5 Hz, 1H), 7.89 (s, 1H), 7.79 (d, J=1.4 Hz, 1H), 7.56 (d, J=1.4 Hz, 1H), 7.23 (dd, J=7.9, 1.5 Hz, 1H), 7.06 (dd, J=7.9, 4.7 Hz, 1H), 3.89-3.70 (m, 2H), 3.17 (dd, J=22.2, 10.5 Hz, 2H), 2.80 (t, J=7.2 Hz, 1H), 2.60 (s, 3H), 1.88-1.20 (m, 10H) ppm; LCMS: m/z 395.2 [M+H].sup.+.

Example 86: (R)-8-(8-((2-(trifluoromethyl)pyridin-3-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(437) ##STR00552##

(438) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.52 (s, 1H), 8.35 (s, 1H), 7.75 (s, 1H), 7.21 (d, J=8.2 Hz, 2H), 6.52 (d, J=8.4 Hz, 2H), 5.39 (s, 2H), 4.69 (s, 2H), 2.87 (s, 1H), 1.93-1.30 (m, 10H) ppm; LCMS: m/z 449.1 [M+H].sup.+.

Example 87: (R)-8-(8-((2-chloropyridin-3-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(439) ##STR00553##

(440) .sup.1H NMR (CD.sub.3OD-d.sub.4) δ 8.38 (s, 1H), 8.16-8.18 (m, 1H), 8.06 (s, 1H), 7.81 (m, 2H), 7.23 (m, 1H), 7.14-7.22 (m, 2H), 3.88 (m, 2H), 3.23 (m, 2H), 2.97 (m, 1H), 1.71-2.05 (m, 4H), 1.35-1.68 (m, 6H) ppm; LCMS: m/z 415.1 [M+H].sup.+.

Example 88: (R)-8-(8-((6-amino-2-chloropyridin-3-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(441) ##STR00554##

(442) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.33 (s, 1H), 7.74 (d, J=1.4 Hz, 1H), 7.61 (d, J=1.4 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.40 (s, 1H), 6.73 (s, 2H), 6.38 (d, J=8.4 Hz, 1H), 3.68 (d, J=12.5 Hz, 3H), 3.10 (s, 2H), 2.97 (t, J=6.8 Hz, 1H), 2.01-1.31 (m, 10H) ppm. LC-MS: m/z 431.1 [M+H].sup.+.

Example 89: (R)-8-(8-(benzo[d]thiazol-7-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(443) ##STR00555##

(444) .sup.1HNMR(CD.sub.3OD-d.sub.4) δ 9.43 (m, 1H), 8.35 (s, 3H), 8.00-8.02 (m, 1H), 7.88 (s, 1H), 7.76 (m, 1H), 7.56-7.58 (m, 1H), 7.47-7.51 (m, 1H), 7.38-7.40 (m, 1H), 3.80 (m, 2H), 3.17 (m, 2H), 2.98 (m, 1H), 1.71-2.05 (m, 4H), 1.35-1.68 (m, 6H) ppm; LC-MS: m/z 437.1 [M+H].sup.+.

Example 90: (R)-8-(8-(phenylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(445) ##STR00556##

(446) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.31 (s, 1H), 7.83 (s, 1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.25 (tq, J=14.0, 7.4 Hz, 5H), 3.84-3.70 (m, 2H), 3.16 (d, J=12.4 Hz, 2H), 3.01 (t, J=6.8 Hz, 1H), 1.97 (dd, J=13.2, 7.2 Hz, 1H), 1.86-1.26 (m, 9H) ppm; LCMS: m/z 380.1 [M+H].sup.+.

Example 91: (R)-8-(8-((1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(447) ##STR00557##

(448) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.97 (d, J=5.1 Hz, 1H), 7.80 (s, 1H), 7.61-7.49 (m, 2H), 6.56-6.39 (m, 2H), 3.84 (d, J=22.6 Hz, 5H), 3.22 (t, J=12.5 Hz, 2H), 2.98 (t, J=6.9 Hz, 1H), 2.03-1.33 (m, 10H) ppm; LC-MS: m/z 433.9 [M+H].sup.+.

Example 92: (R)-8-(8-((2,3-dihydrobenzofuran-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(449) ##STR00558##

(450) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.72 (s, 1H), 7.62 (s, 1H), 7.46 (s, 1H), 7.39 (s, 1H), 7.27 (d, J=8.2 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 4.54 (t, J=8.7 Hz, 2H), 3.69 (t, J=11.9 Hz, 2H), 3.11 (dt, J=29.5, 12.5 Hz, 6H), 1.99 (s, 1H), 1.87-1.36 (m, 9H) ppm; LC-MS: m/z 422.1 [M+H].sup.+.

Example 93: (R)-8-(8-(quinolin-4-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(451) ##STR00559##

(452) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.52 (d, J=4.8 Hz, 1H), 8.26 (dd, J=8.4, 1.3 Hz, 1H), 8.12 (s, 1H), 8.04 (dd, J=8.5, 1.2 Hz, 1H), 7.89-7.79 (m, 2H), 7.73 (ddd, J=8.2, 6.8, 1.3 Hz, 1H), 7.56 (d, J=1.4 Hz, 1H), 6.82 (d, J=4.8 Hz, 1H), 3.91 (dd, J=15.3, 11.3 Hz, 2H), 3.37-3.16 (m, 2H), 3.05 (t, J=6.5 Hz, 1H), 2.10-1.65 (m, 5H), 1.67-1.38 (m, 5H) ppm; LC-MS: m/z 431.2 [M+H].sup.+.

Example 94: (1R)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine

(453) ##STR00560##

(454) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.32 (s, 1H), 8.09 (d, J=6.5 Hz, 1H), 8.00 (d, J=5.3 Hz, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 6.71 (d, J=5.3 Hz, 1H), 4.03-3.85 (m, 2H), 3.26-3.15 (m, 2H), 2.98 (d, J=21.9 Hz, 1H), 2.14 (dd, J=25.3, 11.9 Hz, 2H), 1.87 (dd, J=41.5, 14.7 Hz, 3H), 1.43 (dd, J=32.2, 18.7 Hz, 2H), 1.28 (dd, J=18.2, 8.7 Hz, 1H), 1.12 (d, J=12.5 Hz, 1H), 1.05-0.93 (m, 3H) ppm; LC-MS: m/z 462.8 [M+H].sup.+.

Example 95: (1R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-meth yl-8-azaspiro[4.5]decan-1-amine

(455) ##STR00561##

(456) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.36 (s, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.63-7.49 (m, 2H), 6.34 (s, 2H), 5.78 (d, J=5.4 Hz, 1H), 3.98-3.83 (m, 2H), 3.18 (dd, J=27.6, 14.3 Hz, 2H), 3.06-2.94 (m, 1H), 2.23-2.07 (m, 2H), 1.96-1.89 (m, 1H), 1.86-1.67 (m, 2H), 1.51-1.33 (m, 2H), 1.33-1.20 (m, 1H), 1.21-1.09 (m, 1H), 1.08-0.94 (m, 3H) ppm; LC-MS: m/z 443.8 [M+H].sup.+.

Example 96: (1R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-m ethyl-8-azaspiro[4.5]decan-1-amine

(457) ##STR00562##

(458) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.33 (s, 1H), 8.06 (s, 1H), 7.84 (s, 1H), 7.61 (s, 1H), 6.33 (s, 2H), 5.62 (s, 1H), 4.00-3.86 (m, 2H), 3.17 (d, J=13.0 Hz, 1H), 3.07-2.95 (m, 1H), 2.25-2.07 (m, 2H), 1.94 (dd, J=12.0, 8.2 Hz, 2H), 1.79 (dd, J=28.2, 13.0 Hz, 2H), 1.45 (dd, J=33.4, 19.7 Hz, 2H), 1.34-1.11 (m, 2H), 1.01 (dd, J=18.3, 10.3 Hz, 3H); LCMS: m/z 447.8 [M+H].sup.+.

Example 97: (S)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

(459) ##STR00563##

(460) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.19 (s, 1H), 8.10 (s, 1H), 8.00 (d, J=5.3 Hz, 1H), 7.86 (s, 1H), 7.58 (s, 1H), 6.72 (d, J=5.3 Hz, 1H), 4.02 (dd, J=8.8, 6.4 Hz, 1H), 3.85 (dd, J=17.4, 13.7 Hz, 2H), 3.72 (dd, J=21.2, 8.6 Hz, 2H), 3.43 (dd, J=9.0, 4.8 Hz, 2H), 3.25 (dd, J=15.2, 9.6 Hz, 2H), 1.98-1.86 (m, 1H), 1.85-1.73 (m, 1H), 1.61 (s, 2H); LC-MS: m/z 451.7 [M+H].sup.+.

Example 98: (S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

(461) ##STR00564##

(462) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.14 (s, 1H), 8.04 (s, 1H), 7.83 (s, 1H), 7.60 (s, 1H), 7.55 (d, J=5.4 Hz, 1H), 6.35 (s, 2H), 5.78 (d, J=5.4 Hz, 1H), 4.10 (dd, J=9.9, 6.0 Hz, 1H), 3.92-3.76 (m, 4H), 3.69 (dd, J=10.1, 3.1 Hz, 1H), 3.53 (s, 1H), 3.24 (d, J=10.8 Hz, 1H), 1.99-1.83 (m, 2H), 1.73 (d, J=12.0 Hz, 2H), 1.24 (d, J=6.4 Hz, 1H) ppm; LC-MS: m/z 431.8 [M+H].sup.+.

Example 99: (3S,4S)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(463) ##STR00565##

(464) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.17 (s, 1H), 8.10 (s, 1H), 8.00 (d, J=5.3 Hz, 1H), 7.87 (s, 1H), 7.57 (d, J=1.0 Hz, 1H), 6.72 (d, J=5.3 Hz, 1H), 4.12 (dt, J=12.1, 6.1 Hz, 1H), 3.85-3.67 (m, 3H), 3.57 (d, J=8.5 Hz, 1H), 3.41 (dd, J=26.4, 9.0 Hz, 2H), 3.06 (d, J=4.9 Hz, 1H), 1.99-1.81 (m, 2H), 1.68 (dd, J=27.9, 14.6 Hz, 2H), 1.13 (d, J=6.4 Hz, 3H) ppm; LC-MS: m/z 464.8 [M+H].sup.+.

Example 100: (3S,4S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(465) ##STR00566##

(466) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.21 (s, 1H), 8.02 (s, 1H), 7.84 (s, 1H), 7.61-7.50 (m, 2H), 6.34 (s, 2H), 5.79 (d, J=5.4 Hz, 1H), 4.11 (dt, J=12.3, 6.3 Hz, 1H), 3.73 (d, J=8.5 Hz, 3H), 3.56 (d, J=8.5 Hz, 1H), 3.38-3.26 (m, 2H), 3.05 (d, J=4.9 Hz, 1H), 1.99-1.81 (m, 2H), 1.67 (dd, J=26.4, 15.3 Hz, 2H), 1.18-1.02 (m, 3H) ppm; LC-MS: m/z 445.8 [M+H].sup.+.

Example 101: 4-((5-(4-amino-4-methylpiperidin-1-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)-3-chloropyridine-2-amine

(467) ##STR00567##

(468) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.00 (s, 1H), 7.83 (s, 1H), 7.54 (d, J=5.8 Hz, 2H), 6.29 (s, 2H), 5.79 (d, J=5.4 Hz, 1H), 3.60 (d, J=4.3 Hz, 4H), 1.77-1.53 (m, 4H), 1.19 (s, 3H) ppm; LC-MS: m/z 390.1 [M+H].sup.+.

Example 102: (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-aza spiro[4.5]decan-1-amine

(469) ##STR00568##

(470) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.05 (s, 1H), 7.85 (d, J=1.5 Hz, 1H), 7.60 (d, J=1.4 Hz, 1H), 6.32 (s, 2H), 5.62 (s, 1H), 3.90 (dd, J=13.2, 8.5 Hz, 2H), 3.23 (q, J=11.9, 11.0 Hz, 2H), 2.77 (t, J=7.3 Hz, 1H), 1.90-1.77 (m, 4H), 1.67-1.53 (m, 2H), 1.45-1.28 (m, 4H) ppm; LCMS: m/z 466.1 [M+H].sup.+.

Example 103: (R)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(471) ##STR00569##

(472) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.88 (s, 4H), 7.66 (d, J=11.1 Hz, 1H), 5.81 (s, 1H), 3.96 (t, J=13.9 Hz, 2H), 3.37-3.23 (m, 3H), 2.42 (s, 3H), 2.14-2.05 (m, 1H), 1.88-1.46 (m, 9H); LC-MS: m/z 443.8 [M+H].sup.+.

Example 104: (S)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

(473) ##STR00570##

(474) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.17 (d, J=4.9 Hz, 3H), 7.91 (s, 1H), 7.68 (s, 1H), 5.81 (s, 1H), 4.13 (dd, J=10.4, 5.8 Hz, 1H), 3.90 (d, J=9.0 Hz, 3H), 3.80 (d, J=9.0 Hz, 1H), 3.74 (dd, J=10.3, 2.6 Hz, 1H), 3.63 (s, 1H), 3.40 (dd, J=12.6, 8.6 Hz, 1H), 3.30 (dd, J=12.6, 9.4 Hz, 1H), 2.42 (s, 3H), 1.95-1.81 (m, 2H), 1.75 (d, J=10.3 Hz, 2H); LC-MS: m/z 445.8 [M+H].sup.+.

Example 105: (S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

(475) ##STR00571##

(476) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.16 (s, 1H), 8.07 (s, 1H), 7.87 (s, 1H), 7.63 (s, 1H), 6.33 (s, 2H), 5.62 (s, 1H), 4.06 (dd, J=9.6, 6.2 Hz, 1H), 3.93-3.74 (m, 4H), 3.56 (dd, J=9.5, 4.0 Hz, 1H), 3.26 (s, 3H), 1.98-1.80 (m, 2H), 1.67 (s, 2H) ppm; LC-MS: m/z 466.6 [M+H].sup.+.

Example 106: (3S,4S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(477) ##STR00572##

(478) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.18 (s, 3H), 8.08 (s, 1H), 7.87 (s, 1H), 7.65 (s, 1H), 6.35 (s, 2H), 5.64 (s, 1H), 4.31-4.16 (m, 1H), 4.03-3.83 (m, 3H), 3.71 (d, J=9.0 Hz, 1H), 3.46 (s, 1H), 3.24 (d, J=11.2 Hz, 2H), 2.03 (t, J=12.3 Hz, 2H), 1.75 (dd, J=41.2, 13.7 Hz, 2H), 1.24 (d, J=6.5 Hz, 3H); LCMS: m/z 479.7 [M+H].sup.+.

Example 107: (3S,4S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-m ethyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(479) ##STR00573##

(480) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.06 (s, 1H), 8.01 (d, J=5.3 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H), 7.56 (d, J=1.4 Hz, 1H), 6.50 (d, J=5.3 Hz, 1H), 4.15-4.05 (m, 1H), 3.74-3.66 (m, 5H), 3.45-3.42 (m, 1H), 3.03 (d, J=4.9 Hz, 1H), 2.55 (s, 3H), 2.00-1.60 (m, 4H), 1.12 (d, J=6.4 Hz, 3H) ppm; LC-MS: m/z 445.2 [M+H].sup.+.

Example 108: (S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decan-4-amine

(481) ##STR00574##

(482) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.23 (s, 1H), 8.06 (s, 1H), 7.88 (s, 1H), 7.61 (s, 1H), 6.34 (s, 2H), 5.64 (s, 1H), 3.95 (d, J=14.3 Hz, 2H), 3.55 (s, 1H), 3.44 (s, 1H), 3.31 (d, J=11.5 Hz, 2H), 2.69 (s, 1H), 1.94 (d, J=12.4 Hz, 2H), 1.66 (t, J=11.9 Hz, 2H), 1.06-0.99 (m, 3H), 0.94 (d, J=14.9 Hz, 3H); LC-MS: m/z 493.7 [M+H].sup.+.

Example 109: (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decan-4-amine

(483) ##STR00575##

(484) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (s, 2H), 7.89 (s, 1H), 7.64 (s, 1H), 6.33 (s, 1H), 5.63 (s, 1H), 4.03 (s, 2H), 3.59 (d, J=14.4 Hz, 2H), 3.38 (s, 2H), 3.09 (s, 1H), 1.83 (s, 4H), 1.16 (s, 3H), 1.07 (s, 3H); LC-MS: m/z 493.7 [M+H].sup.+.

Example 110: (S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decan-4-amine

(485) ##STR00576##

(486) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.16 (s, 1H), 8.02 (s, 1H), 7.84 (s, 1H), 7.61-7.51 (m, 2H), 6.33 (s, 2H), 5.80 (d, J=5.4 Hz, 1H), 4.00-3.88 (m, 2H), 3.55 (d, J=8.7 Hz, 1H), 3.46 (d, J=8.8 Hz, 1H), 3.32-3.27 (m, 2H), 2.73 (s, 1H), 1.98-1.86 (m, 2H), 1.68 (s, 2H), 1.00 (d, J=29.6 Hz, 6H); LC-MS: m/z 459.8 [M+H].sup.+.

Example 111: (R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,3-dimethyl-1-oxa-8-azaspiro[4.5]decan-4-amine

(487) ##STR00577##

(488) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (s, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 7.55 (d, J=5.4 Hz, 1H), 6.33 (s, 2H), 5.80 (d, J=5.3 Hz, 1H), 4.01-3.91 (m, 2H), 3.56 (d, J=8.8 Hz, 1H), 3.48 (d, J=8.9 Hz, 1H), 3.32-3.26 (m, 2H), 2.80 (s, 1H), 1.97-1.88 (m, 2H), 1.70 (d, J=12.3 Hz, 2H), 1.06 (s, 3H), 0.99 (s, 3H); LC-MS: m/z 459.8 [M+H].sup.+.

Example 112: Synthesis of (R)-8-(8-((3-chloro-2-methoxypyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

Step 1: methyl ((R)-1-((R)-tert-butylsulfinyl)amino)-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimi dine-8-yl)thio)propionate

(489) ##STR00578##

(490) Under nitrogen atmosphere, to a 100 mL single-necked flask were successively added (R)—N—((R)-8-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (500 mg, 1.0 mmol), methyl mercaptopropionate (132 mg, 1.1 mmol), Pd.sub.2(dba).sub.3 (46 mg, 0.05 mmol), Xantphos (58 mg, 0.10 mmol), DIPEA (258 mg, 2.0 mmol) and 1,4-dioxane (30 mL). The mixture was heated at 100° C. and stirred for 4 hours under nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature, filtered and concentrated under reduced pressure to obtain a residue, which was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 30%) to obtain methyl ((R)-1-((R)-tert-butylsulfinyl)amino)-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimi dine-8-yl)thio)propionate (380 mg, yield: 77%).

(491) LCMS: m/z 494.2 [M+H].sup.+.

Step 2: sodium ((R)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-thiolate

(492) ##STR00579##

(493) To a dry 100 mL round bottom flask were successively added methyl ((R)-1-((R)-tert-butylsulfinyl)amino)-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)propionate (380 mg, 0.77 mmol) and tetrahydrofuran (20 mL), followed by slow addition of a solution of sodium ethoxide in ethanol (21%, 3 mL) at room temperature. The reaction solution was stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain a crude product of sodium ((R)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-thiolate, which was not purified.

(494) LC-MS: m/z 408.2 [M+H].sup.+.

Step 3: (R)—N—((R)-8-(8-((3-chloro-2-methoxypyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide

(495) ##STR00580##

(496) Under nitrogen atmosphere, to a 100 mL single-necked flask were added the crude product of sodium ((R)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-thiolate (100 mg, 0.23 mmol), 3-chloro-4-iodo-2-methoxypyridine (71 mg, 0.26 mmol), Pd.sub.2(dba).sub.3 (22 mg, 0.024 mmol), Xantphos (28 mg, 0.048 mmol), DIPEA (62 mg, 0.48 mmol) and 1,4-dioxane (10 mL). The reaction solution was heated to 100° C. and stirred for 4 hours under nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature, filtered and concentrated under reduced pressure to obtain a residue, which was purified by silica gel chromatography (ethyl acetate/methanol with a gradient of 0 to 30%) to obtain (R)—N—((R)-8-(8-((3-chloro-2-methoxypyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide) (51 mg, yield: 40%).

(497) LCMS: m/z 549.2 [M+H].sup.+.

Step 4: (R)-8-(8-((3-chloro-2-methoxypyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(498) ##STR00581##

(499) Under nitrogen atmosphere, to a 100 mL single-necked flask were sequentially added (R)—N—((R)-8-(8-((3-chloro-2-methoxypyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (40 mg, 0.09 mmol) and methanol (2.3 mL), and a solution of hydrogen chloride in 1,4-dioxane (0.23 mL, 4M) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, filtered and concentrated under reduced pressure to obtain a residue, which was purified by high performance liquid chromatography to obtain (R)-8-(8-((3-chloro-2-methoxypyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (15 mg, yield: 37%).

(500) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.05 (s, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.77 (d, J=5.5 Hz, 1H), 7.56 (d, J=1.5 Hz, 1H), 6.28 (d, J=5.5 Hz, 1H), 3.93 (s, 3H), 3.88 (d, J=9.4 Hz, 2H), 3.23 (d, J=11.6 Hz, 2H), 2.76 (t, J=7.2 Hz, 1H), 1.80 (d, J=11.4 Hz, 4H), 1.66-1.52 (m, 2H), 1.44-1.29 (m, 4H). LCMS: m/z 445.1 [M+H].sup.+.

(501) According to the synthesis method of Example 112, the following compounds were synthesized:

Example 113: Methyl (R)-3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)propionate

(502) ##STR00582##

(503) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.73 (d, J=2.7 Hz, 2H), 7.64 (d, J=1.3 Hz, 1H), 3.70 (d, J=4.0 Hz, 2H), 3.56 (s, 3H), 3.26 (t, J=7.0 Hz, 2H), 3.15-3.04 (m, 3H), 2.61 (t, J=7.0 Hz, 2H), 2.05-1.68 (m, 5H), 1.66-1.37 (m, 5H) ppm; LC-MS: m/z 390.1 [M+H].sup.+.

Example 114: (R)-8-(8-((3-chloro-2-fluoropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(504) ##STR00583##

(505) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.10 (s, 1H), 7.86-7.80 (m, 2H), 7.58 (d, J=1.4 Hz, 1H), 6.66 (d, J=5.4 Hz, 1H), 3.95 (d, J=12.7 Hz, 2H), 3.28 (s, 2H), 2.95 (s, 1H), 1.97-1.80 (m, 4H), 1.66 (d, J=32.2 Hz, 2H), 1.56-1.41 (m, 4H) ppm; LCMS: m/z 434.1 [M+H].sup.+.

Example 115: (R)-8-(8-((3-chloro-2-(dimethylamino)pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(506) ##STR00584##

(507) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.79 (d, J=5.3 Hz, 1H), 7.56 (d, J=1.4 Hz, 1H), 6.15 (d, J=5.3 Hz, 1H), 3.98-3.79 (m, 2H), 3.23 (d, J=11.6 Hz, 3H), 2.90 (s, 6H), 2.77 (t, J=7.3 Hz, 1H), 1.83-1.74 (m, 7H), 1.69-1.51 (m, 3H), 1.49-1.27 (m, 5H) ppm; LCMS: m/z 458.2 [M+H].sup.+.

Example 116: (R)-4-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)indoline-2,3-dione

(508) ##STR00585##

(509) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.28 (s, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.58 (s, 1H), 7.24 (t, J=8.0 Hz, 1H), 6.58 (d, J=7.7 Hz, 2H), 6.21 (d, J=8.3 Hz, 1H), 3.90 (s, 3H), 3.24 (s, 3H), 2.97 (s, 1H), 1.69 (d, J=93.3 Hz, 9H) ppm; LC-MS: m/z 449.1 [M+H].sup.+.

Example 117: Synthesis of Compound: (R)-8-(8-((3-chloropyridazin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

Step 1: (R)—N—((R)-8-(8-((3-chloropyridazin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide

(510) ##STR00586##

(511) Under nitrogen atmosphere, to a 100 mL single-necked flask were sequentially added the crude product of sodium ((R)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-thiolate (50 mg, 0.12 mmol), 3,4-dichloropyridazine (19 mg, 0.13 mmol) and acetonitrile (3 mL), followed by DIPEA (31 mg, 0.24 mmol), and the reaction solution was heated to 80° C. and stirred for 16 hours. After the reaction solution was cooled, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate/methanol with a gradient of 0 to 30%) to obtain (R)—N—((R)-8-(8-((3-chloropyridazin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (10 mg, yield: 16%).

(512) LCMS: m/z 520.2 [M+H].sup.+.

Step 2: (R)-8-(8-((3-chloropyridazin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(513) ##STR00587##

(514) Under nitrogen atmosphere, to a 50 mL single-necked flask were sequentially added (R)—N—((R)-8-(8-((3-chloropyridazin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (10 mg, 0.02 mmol) and methanol (0.5 mL), and a solution of hydrogen chloride in 1,4-dioxane (0.05 mL, 4M) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, filtered and concentrated under reduced pressure to obtain a residue, which was then purified by high performance liquid chromatography to obtain (R)-8-(8-((3-chloropyridazin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (2 mg, yield: 24%).

(515) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.79 (d, J=5.4 Hz, 1H), 8.36 (s, 2H), 8.12 (s, 1H), 7.84 (s, 1H), 7.58 (s, 1H), 7.01 (d, J=5.4 Hz, 1H), 3.88 (d, J=9.4 Hz, 2H), 3.23 (d, J=11.6 Hz, 2H), 2.76 (t, J=7.2 Hz, 1H), 1.70-1.32 (m, 9H); LCMS: m/z 416.1 [M+H].sup.+.

(516) According to the synthesis method of Example 117, the following compounds were synthesized:

Example 118: (R)-8-(8-((2-chloropyrimidin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(517) ##STR00588##

(518) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.37 (d, J=5.5 Hz, 1H), 8.29 (s, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.61 (d, J=1.2 Hz, 1H), 7.06 (d, J=5.5 Hz, 1H), 3.93 (t, J=12.9 Hz, 2H), 3.25 (s, 2H), 3.09 (s, 1H), 2.03 (s, 1H), 1.81 (dd, J=19.3, 13.3 Hz, 4H), 1.65-1.46 (m, 5H) ppm; LCMS: m/z 416.1 [M+H].sup.+.

Example 119: Preparation of Compound (R)-8-(8-(pyridin-2-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

Step 1: (R)-2-methyl-N—(R)-8-(8-(pyridin-2-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide

(519) ##STR00589##

(520) Under nitrogen atmosphere, to a 100 mL single-necked flask were sequentially added (R)—N—((R)-8-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-met hylpropane-2-sulfinamide (50 mg, 0.10 mmol), pyridine-2-thiol (13 mg, 0.12 mmol), Cu (OTf).sub.2 (4 mg, 0.01 mmol), BINAM (3 mg, 0.01 mmol) and 1,4-dioxane (3 mL), followed by cesium carbonate (65 mg, 0.2 mmol). The reaction solution was heated to 100° C. and stirred for 16 hours. After the reaction solution was cooled, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate/methanol with a gradient of 0 to 50%) to obtain (R)-2-methyl-N—(R)-8-(8-(pyridin-2-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (20 mg, yield: 41%).

(521) LCMS: m/z 485.2 [M+H].sup.+.

Step 2: (R)-8-(8-(pyridin-2-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(522) ##STR00590##

(523) Using the same method as that of Step 2 in Example 37, (R)-2-methyl-N—(R)-8-(8-(pyridin-2-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide was subjected to the removal of the sulfinyl group to obtain (R)-8-(8-(pyridin-2-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine.

(524) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.34 (d, J=3.1 Hz, 2H), 8.02 (s, 1H), 7.78 (s, 1H), 7.63-7.48 (m, 2H), 7.11 (dd, J=7.3, 4.9 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 3.86 (t, J=13.0 Hz, 2H), 3.22 (t, J=12.4 Hz, 2H), 3.03 (t, J=6.5 Hz, 1H), 2.04-1.35 (m, 10H) ppm; LCMS: m/z 381.2 [M+H].sup.+.

(525) According to the synthesis method of Example 119, the following compounds were synthesized:

Example 120: (R)-8-(8-(pyridazin-3-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(526) ##STR00591##

(527) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.97 (d, J=4.8 Hz, 1H), 8.09 (s, 1H), 7.80 (s, 1H), 7.58 (s, 1H), 7.48 (dd, J=8.9, 4.9 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 3.90 (s, 2H), 3.25 (d, J=12.2 Hz, 3H), 3.18 (s, 1H), 1.86-1.46 (m, 9H); LCMS: m/z 382.1 [M+H].sup.+.

Example 121: (R)-8-(8-(pyrazin-2-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(528) ##STR00592##

(529) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.41 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.79 (s, 1H), 7.58 (s, 1H), 3.89 (t, J=12.8 Hz, 2H), 3.24 (d, J=12.2 Hz, 2H), 2.06-1.46 (m, 9H); LCMS: m/z 382.1 [M+H].sup.+.

Example 122: Preparation of Compound 8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-1-methyl-8-azaspiro[4.5]decan-1-amine

Step 1: 8-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-1-methyl-8-azaspiro[4.5]decan-1-amine

(530) ##STR00593##

(531) To a solution of 5-chloro-8-iodoimidazo[1,2-c]pyrimidine (56 mg, 0.2 mmol) in anhydrous DMF (10 mL) was added 1-methyl-8-azaspiro[4.5]decan-1-amine (40 mg, 0.24 mmol) at 0° C., followed by diisopropylethylamine (51.6 mg, 0.4 mmol), and the reaction mixture was stirred at 0° C. for 1 hour. After the reaction was completed, the reaction solution was directly used in the next reaction.

(532) LCMS: m/z 412.0 [M+H].sup.+.

Step 2: Tert-Butyl (8-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-1-methyl-8-azaspiro[4.5]decan-1-yl)carbamate

(533) ##STR00594##

(534) To the solution obtained in the previous step was added (Boc).sub.2O (87 mg, 0.4 mmol), followed by diisopropylethylamine (51.6 mg, 0.4 mmol), and the reaction solution was stirred at room temperature for 4 hours. After the reaction was completed, water was added to quench the reaction, followed by extraction with ethyl acetate (3×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 30%) to obtain tert-butyl (8-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-1-methyl-8-azaspiro[4.5]decan-1-yl)carbamate (15 mg, two-step yield: 7%).

(535) LC-MS: m/z=512.0 [M+H].sup.+.

Step 3: Tert-Butyl (8-(8-((6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-methyl-8-azaspiro[4.5]decan-1-yl)carbamate

(536) ##STR00595##

(537) According to the synthesis method of step 1 in Example 76, tert-butyl (8-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-1-methyl-8-azaspiro[4.5]decan-1-yl)carbamate and sodium 6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridine-4-thiolate were subjected to coupling reaction to obtain tert-butyl (8-(8-((6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-methyl-8-azaspiro[4.5]decan-1-yl)carbamate (4 mg, yield: 15%). LC-MS: m/z 678.2 [M+H].sup.+.

Step 4: 4-((5-(1-amino-1-methyl-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)-5,6-dichloropyridin-2-amine

(538) ##STR00596##

(539) According to the synthesis method of step 3 in Example 21, tert-butyl (8-(8-((6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-methyl-8-azaspiro[4.5]decan-1-yl)carbamate was subjected to deprotection of the Boc protecting group to obtain 4-((5-(1-amino-1-methyl-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)-5,6-dichloropyridin-2-amine (2 mg, yield: 60%).

(540) .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 8.10 (s, 1H), 7.87 (s, 1H), 7.64 (s, 1H), 6.42 (s, 2H), 5.63 (s, 1H), 4.06 (s, 2H), 3.18 (t, J=12.4 Hz, 2H), 1.96-1.37 (m, 9H), 1.26 (s, 3H), 0.98-0.84 (m, 1H) ppm; LC-MS: m/z=478.2 [M+H].sup.+.

(541) According to the synthesis method of Example 122, the following compounds were synthesized:

Example 123: (R)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine

(542) ##STR00597##

(543) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.19 (s, 2H), 8.07 (s, 1H), 7.84 (s, 1H), 7.65 (s, 1H), 5.65 (s, 1H), 3.99 (t, J=15.1 Hz, 2H), 3.62-3.55 (m, 3H), 2.74-2.63 (m, 2H), 2.44-2.33 (m, 5H), 2.01 (t, J=11.8 Hz, 1H), 1.85-1.60 (m, 3H) ppm; LC-MS: m/z=480.2 [M+H].sup.+.

Example 124: Preparation of Compound (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine

Step 1 and Step 2: 5,6-dichloro-4-((5-chloroimidazo[1,2-c]pyrimidin-8-yl)thio)pyridin-2-amine

(544) ##STR00598##

(545) According to the synthesis method of Step 3 and Step 4 in Example 1, 8-iodoimidazo[1,2-c]pyrimidin-5-phenol and sodium 6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridine-4-thiolate were subjected to coupling and halogenation reaction to obtain 5,6-dichloro-4-((5-chloroimidazo[1,2-c]pyrimidin-8-yl)thio)pyridin-2-amine.

(546) LC-MS: m/z 347.9 [M+H].sup.+

Step 3: (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine

(547) ##STR00599##

(548) According to the synthesis method of Example 23, 5,6-dichloro-4-((5-chloroimidazo[1,2-c]pyrimidin-8-yl)thio)pyridin-2-amine was substituted by (R)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine to obtain (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine.

(549) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.35 (s, 2H), 8.06 (s, 1H), 7.86 (s, 1H), 7.61 (s, 1H), 6.31 (s, 2H), 5.62 (s, 1H), 3.92 (d, J=14.9 Hz, 2H), 3.21 (d, J=12.8 Hz, 3H), 3.07 (t, J=8.1 Hz, 2H), 2.12-1.98 (m, 3H), 1.91 (d, J=12.4 Hz, 2H), 1.47 (t, J=16.6 Hz, 3H) ppm; LC-MS: m/z 501.7 [M+H].sup.+.

Example 1-2: Preparation of Intermediate: 5-chloro-8-iodo-[1,2,4]triazolo[4,3-c]pyrimidine (E-1)

Step 1: 2-chloro-4-hydrazino-5-iodopyrimidine

(550) ##STR00600##

(551) To a dry 100 mL flask were added 2,4-dichloro-5-iodopyrimidine (25 g, 91 mmol) and anhydrous ethanol (20 mL), followed by slow addition of hydrazine hydrate (13.66 g, 272.9 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours, during which a large amount of solid was precipitated. The mixture was filtered and the filter cake was washed with ethanol, and dried in vacuum to obtain 2-chloro-4-hydrazino-5-iodopyrimidine as a brown solid (20 g, yield: 81%).

(552) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.29 (s, 1H), 6.67 (s, 1H), 4.08 (s, 2H) ppm; LC-MS: m/z 271.1 [M+H].sup.+.

Step 2: 5-chloro-8-iodo-[1,2,4]triazolo[4,3-c]pyrimidine

(553) ##STR00601##

(554) To a dry 50 mL sealed tube were sequentially added 2-chloro-4-hydrazino-5-iodopyrimidine (10 g, 37 mmol) and trimethyl orthoformate (3.92 g, 37 mmol). Under nitrogen atmosphere, the mixture was heated to 80° C. and stirred for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature. The mixture was slowly poured into saturated sodium bicarbonate solution, and extracted with ethyl acetate (3×100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the product, which was then isolated by silica gel column chromatography (ethyl acetate: petroleum ether=1:1) to obtain 5-chloro-8-iodo-[1,2,4]triazolo[4,3-c]pyrimidine (5.7 g, yield: 55%).

(555) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.69 (s, 1H), 8.28 (s, 1H) ppm; LC-MS: m/z 280.1 [M+H].sup.+.

Example 2-2: Preparation of intermediate: (R)-2-methyl-N—((R)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1A-2)

Step 1: Tert-Butyl (R)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decane-8-carboxylate

(556) ##STR00602##

(557) To a 100 mL single-necked flask were sequentially added tert-butyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate (2.53 g, 10 mmol) and titanium tetraethoxide (6.84 g, 30 mmol) and 50 mL of tetrahydrofuran, and the reaction mixture was stirred under reflux for 4 hours. After the mixture was cooled to room temperature, methanol (10 mL) was added followed by lithium borohydride (0.65 g, 30 mmol). The resulting mixture was stirred at room temperature for 3 hours.

(558) Methanol was slowly added to quench excess borohydride, followed by addition of brine. The resulting mixture was stirred for 15 minutes and then filtered through diatomite. The aqueous mixture was extracted with ethyl acetate (3×50 mL). The organic phases were combined, dried over MgSO.sub.4, filtered, and the volatiles were removed under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate: petroleum ether with a gradient of 0 to 50%) to obtain tert-butyl (R)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decane-8-carboxylate as a white solid (2.86 g, yield: 80%).

(559) LC-MS: m/z 359.1 [M+H].sup.+.

Step 2: (R)-2-methyl-N—((R)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1A-2)

(560) ##STR00603##

(561) A solution of tert-butyl (R)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decane-8-carboxylate (2.86 g, 8 mmol) and concentrated sulfuric acid (2.0 mL, 32 mmol) in dioxane (50 mL) was stirred at room temperature for 2 hours. Saturated aqueous solution of Na.sub.2CO.sub.3 was then added until the pH of the mixture reached 11, and the aqueous mixture was extracted with DCM (3×50 mL). The organic phases were combined, washed with brine, dried over Na.sub.2SO.sub.4, filtered, and the volatiles were removed under reduced pressure to obtain (R)-2-methyl-N—((R)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1A-2) as a white solid (1.86 g, yield: 90%).

(562) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 4.82 (d, J=7.5 Hz, 1H), 3.04 (d, J=7.6 Hz, 1H), 2.81 (ddd, J=12.1, 8.0, 4.0 Hz, 2H), 2.60-2.51 (m, 2H), 1.92-1.14 (m, 10H), 1.12 (s, 9H) ppm; LC-MS: m/z 259.1 [M+H].sup.+.

(563) According to the synthesis method of Example 2, the following intermediates C-1B-2, C-1C-2, C-1D-2, C-1E-2, C-1F-2, C-1G-2, C-1H-2 were obtained by using similar raw materials.

(564) TABLE-US-00006 No. Name Structure Analysis data C-1B-2 (R)-2-methyl-N-((R)-7-aza- spiro[3.5]nonan-1-yl)propane- 2-sulfinamide 04 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.56 (t, J = 8.9 Hz, 1H), 3.51- 3.20 (m, 2H), 3.18-2.97 (m, 2H), 2.34 (d, J = 10.1 Hz, 1H), 2.06-1.83 (m, 3H), 1.70 (dt, J = 26.3, 12.0 Hz, 3H), 1.52 (t, J = 10.0 Hz, 1H), 1.19 (s, 9H) ppm; LC-MS: m/z 244.1 [M + H].sup.+. C-1C- 2 (R)-2-methyl-N-(7-azaspiro [3.5]nonan-2-yl)propane- 2-sulfinamide 05 LC-MS: m/z 244.1 [M + H].sup.+ C-1D- 2 (S)-2-methyl-N-((S)-8-azaspi- ro[4.5]decan-1-yl)propane- 2-sulfinamide 06 LC-MS: m/z 259.1 [M + H].sup.+ C-1E-2 (R)-2-methyl-N-((7R)-2-aza- spiro[4.4]nonan-7-yl)pro- pane-2-sulfinamide 07 LC-MS: m/z 245.1 [M + H].sup.+ C-1F-2 (R)-2-methyl-N-((R)-3-aza- spiro[5.5]undecan-7-yl)pro- pane-2-sulfinamide 08 LC-MS: m/z 169.1 [M + H].sup.+ C-1G- 2 (R)-N-((R)-azepan-4-yl)-2- methylpropan-2-sulfinamide 09 LC-MS: m/z 219.1 [M + H].sup.+ C-1H- 2 (S)-2-methyl-N-((S)-7-azaspi- ro[3.5]nonan-1-yl)propane- 2-sulfinamide 0 LC-MS: m/z 245.2 [M + H].sup.+

Example 3-2: Preparation of Intermediate: (R)-2-methyl-N—((S)-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-11-2)

Step 1: 1-(tert-butyl) 4-methyl 4-(2-(benzyloxy)-1-hydroxyethyl)piperidine-1,4-dicarboxylate

(565) ##STR00611##

(566) Under nitrogen atmosphere, to a dry 500 mL three-necked flask were sequentially added 1-(tert-butyl) 4-methyl piperidine-1,4-dicarboxylate (45 g, 180 mmol) and tetrahydrofuran (400 mL). The solution was cooled to −78° C., and LiIMDS (261 mL, 261 mmol) was added dropwise. After the dropwise addition, the mixture was warmed to room temperature, stirred at room temperature for 3 hours, and then cooled to −78° C. again, followed by slow addition of a solution of benzyloxyacetaldehyde (46 g, 300 mmol) in tetrahydrofuran (50 mL). The reaction solution was slowly warmed to room temperature and stirred for 2.5 hours. After the reaction was completed, saturated NH.sub.4Cl solution (200 mL) was added to quench the reaction, followed by extraction with ethyl acetate (3×200 mL). The organic phases were combined, dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 50%) to obtain 1-(tert-butyl) 4-methyl 4-(2-(benzyloxy)-1-hydroxyethyl)piperidine-1,4-dicarboxylate (52 g, yield: 73.3%).

(567) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.36-7.30 (m, 5H), 4.50 (s, 2H), 3.97 (s, 2H), 3.73-3.65 (m, 2H), 3.62 (s, 3H), 3.59-3.48 (m, 3H), 2.88 (d, J=6.2 Hz, 1H), 2.23 (dd, J=13.7, 2.7 Hz, 1H), 2.04-1.88 (m, 2H), 1.74 (d, J=14.7 Hz, 1H), 1.56 (d, J=4.2 Hz, 1H), 1.44 (s, 9H) ppm; LC-MS: m/z 294.1 [M+H].sup.+.

Step 2: Tert-Butyl 4-(2-(benzyloxy)-1-hydroxyethyl)-4-(hydroxymethyl)piperidine-1-carboxylate

(568) ##STR00612##

(569) To a dry 500 mL three-necked flask were sequentially added 1-(tert-butyl) 4-methyl 4-(2-(benzyloxy)-1-hydroxyethyl)piperidine-1,4-dicarboxylate (51.4 g, 130 mmol) and tetrahydrofuran (500 mL), and LiBH.sub.4 (11.44 g, 520 mmol) was then added to the solution. The mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction was quenched with saturated NaHCO.sub.3 (200 mL), followed by extraction with ethyl acetate (3×200 mL). The organic phases were combined, dried over Na.sub.2SO.sub.4, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 50%) to obtain tert-butyl 4-(2-(benzyloxy)-1-hydroxyethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (27 g, yield: 57%).

(570) LC-MS: m/z 266.1 [M+H].sup.+.

Step 3: Tert-Butyl 4-(1,2-dihydroxyethyl)-4-(hydroxymethyl)piperidine-1-carboxylate

(571) ##STR00613##

(572) To a dry 500 mL single-necked flask were sequentially added tert-butyl 4-(2-(benzyloxy)-1-hydroxyethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (27 g, 74 mmol), methanol (270 mL) and Pd/C (20 g). The flask was purged with hydrogen using a hydrogen balloon three times, and the mixture was stirred at room temperature for 12 hours. The reaction solution was filtered and concentrated to obtain tert-butyl 4-(1,2-dihydroxyethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (18.9 g, yield: 93%).

(573) LC-MS: m/z 176.1 [M+H].sup.+.

Step 4: Tert-Butyl 4-hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(574) ##STR00614##

(575) To a dry 500 mL single-necked flask were sequentially added tert-butyl 4-(1,2-dihydroxyethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (18.9 g, 69 mmol), triphenyl phosphine (25.2 g, 86.25 mmol) and tetrahydrofuran (350 mL), and the reaction solution was cooled to 0° C., followed by addition of DEAD (12.46 mL, 86 mmol). The mixture was then warmed to room temperature and stirred for 5 hours. After the reaction was completed, water (200 mL) was added to quench the reaction, followed by extraction with ethyl acetate (3×200 mL). The organic phases were combined and dried over Na.sub.2SO.sub.4, filtered, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (methanol/dichloromethane with a gradient of 0 to 2%) to obtain tert-butyl 4-hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (13.2 g, yield: 74%).

(576) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.04 (dd, J=10.0, 4.6 Hz, 1H), 3.98-3.90 (m, 1H), 3.71-3.63 (m, 2H), 3.64-3.49 (m, 3H), 3.20 (dt, J=13.4, 6.3 Hz, 1H), 3.07 (ddd, J=13.2, 9.2, 3.5 Hz, 1H), 1.95 (d, J=5.2 Hz, 1H), 1.74-1.66 (m, 1H), 1.53-1.46 (m, 1H), 1.39 (s, 9H), 1.27-1.11 (m, 1H) ppm; LC-MS: m/z 202.1[M-56+H].sup.+.

Step 5: Tert-Butyl 4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(577) ##STR00615##

(578) To a dry 500 mL single-necked flask were sequentially added tert-butyl 4-hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (13.2 g, 51 mmol), dichloromethane (280 mL) and Dess-Martin oxidant (32.2 g, 76.5 mmol), and the mixture was stirred for 5 hours in an ice bath. After the reaction was completed, a saturated solution (200 mL) of NaHCO.sub.3:Na.sub.2S.sub.2O.sub.3 (1:1) was added, the organic phase was separated, and the aqueous phase was extracted with DCM (3×100 mL). The organic phases were combined, dried over Na.sub.2SO.sub.4 and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 40%) to obtain tert-butyl 4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (12 g, yield: 92.1%).

(579) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.05 (d, J=13.6 Hz, 4H), 3.87 (d, J=12.9 Hz, 2H), 3.09 (ddd, J=13.5, 9.8, 3.5 Hz, 2H), 1.73 (ddd, J=13.9, 9.8, 4.3 Hz, 2H), 1.53 (d, J=15.1 Hz, 2H), 1.46 (s, 9H) ppm; LC-MS: m/z 200.0 [M-56+H].sup.+.

Step 6: Tert-Butyl (S)-4-((R)-1,1-dimethylethylsulfinamido)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(580) ##STR00616##

(581) According to the synthesis method of step 1 in Example 2 (intermediate C-1A-2), tert-butyl 4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate was subjected to reductive amination to obtain tert-butyl (S)-4-((R)-1,1-dimethylethylsulfinamido)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate as a white solid.

(582) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.14 (dd, J=9.3, 6.2 Hz, 1H), 3.90 (d, J=13.8 Hz, 2H), 3.77 (s, 2H), 3.70 (dd, J=9.2, 5.3 Hz, 1H), 3.63 (q, J=6.1 Hz, 1H), 3.27 (d, J=6.4 Hz, 1H), 2.90 (t, J=12.4 Hz, 2H), 1.71 (dt, J=16.6, 7.9 Hz, 2H), 1.51 (s, 2H), 1.45 (s, 9H), 1.22 (s, 9H) ppm; LC-MS: m/z 361.1 [M-100].sup.+.

Step 7: (R)-2-methyl-N—((S)-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1I-2)

(583) ##STR00617##

(584) According to the synthesis method of Step 2 of Example 2 (intermediate C-1A-2), tert-butyl (S)-4-((R)-1-methylethylsulfinamido)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate was subjected to the removal of the Boc protecting group to obtain (R)-2-methyl-N—((S)-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1I-2) as a white solid.

(585) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 5.30 (s, 1H), 5.23 (d, J=8.9 Hz, 1H), 3.93 (dd, J=8.6, 7.2 Hz, 1H), 3.69 (d, J=8.6 Hz, 1H), 3.58 (d, J=8.6 Hz, 1H), 3.46 (dd, J=8.5, 7.0 Hz, 2H), 2.89-2.73 (m, 2H), 2.48-2.42 (m, 1H), 1.69-1.50 (m, 2H), 1.39-1.21 (m, 3H), 1.12 (s, 9H) ppm; LC-MS: m/z 261.1 [M+H].sup.+.

Example 4-2: Preparation of (R)-2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1J-2) (same as Example 6-2)

Step 1: ethyl (S)-2-((tert-butyldimethylsilyl)oxy)propionate

(586) ##STR00618##

(587) To a solution of ethyl (S)-2-hydroxypropionate (30 g, 254 mmol) in dichloromethane (300 mL) was added imidazole (2.75 g, 304.9 mmol), and the solution was cooled to 0° C. To this solution, tert-butyldimethylsilyl chloride (46.0 g, 304.9 mmol) was added in portions, and the resulting mixture was stirred at room temperature for 16 hours. After the completion of the reaction was confirmed by TLC analysis, the reaction mixture was quenched with water and extracted with dichloromethane (2×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain ethyl (S)-2-((tert-butyldimethylsilyl)oxy)propionate as a colorless liquid (50 g, yield 84%).

(588) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.32-4.27 (m, 1H), 4.21-4.12 (m, 2H), 1.37 (d, J=6.8 Hz, 3H), 1.27 (d, J=7.2 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 6H) ppm.

Step 2: (S)-2-((tert-butyldimethylsilyl)oxy)propanal

(589) ##STR00619##

(590) At −78° C., to a solution of ethyl (S)-2-((tert-butyldimethylsilyl)oxy)propionate (25 g, 107.6 mmol) in diethyl ether (500 mL) was slowly added dropwise diisobutylaluminum hydride (1 M in hexane) (129 mL, 129.1 mmol), and the resulting mixture was stirred at −78° C. for 1 hour. After the completion of the reaction was confirmed by TLC analysis, the reaction mixture was slowly warmed to −40° C., and then quenched with a saturated aqueous solution of Rochelle salt (1 L), followed by addition of diethyl ether (500 mL). The resulting mixture was stirred at room temperature for 2 hours, and then extracted with diethyl ether (200 mL). The organic phase was washed with saturated brine (250 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to obtain (S)-2-((tert-butyldimethylsilyl)oxy)propanal (19 g, yield: 94%).

(591) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.61 (s, 1H), 4.12-4.06 (m, 1H), 1.27 (d, J=6.8 Hz, 3H), 0.91 (s, 9H), 0.10 (s, 6H) ppm.

Step 3: 1-(tert-butyl) 4-ethyl 4-((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)piperidine-1,4-dicarboxylate

(592) ##STR00620##

(593) At 0° C., to a stirred solution of 1-(tert-butyl)-4-ethyl piperidine-1,4-dicarboxylate (30 g, 116.6 mmol) in THE (250 mL) was added lithium diisopropylamide (2M in THF) (93.3 mL, 186.6 mmol), and the solution was stirred at 0° C. for 30 minutes, followed by addition of a solution of (S)-2-((tert-butyldimethylsilyl)oxy)propanal (22 g, 116.6 mmol) in THF (50 mL). The resulting reaction mixture was stirred at 0° C. for 1 hour, and then kept at room temperature for 1 hour. After the completion of the reaction was confirmed by TLC analysis, the reaction mixture was quenched with saturated NH.sub.4Cl solution and extracted with ethyl acetate (2×250 mL). The organic phases were combined, washed with water (150 mL), and brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (60-120 mesh) column chromatography, using 25% ethyl acetate in petroleum ether as eluent to obtain 1-(tert-butyl) 4-ethyl 4-((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)piperidine-1,4-dicarboxylate (17 g, yield: 32%) as a light red oil.

(594) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.29-4.09 (m, 2H), 3.96-3.94 (m, 2H), 3.86-3.80 (m, 1H), 3.56-3.54 (m, 1H), 2.86-2.76 (m, 2H), 2.46 (d, J=5.2 Hz, 1H), 2.16-2.13 (m, 1H), 2.13-2.04 (m, 1H), 1.77-1.60 (m, 2H), 1.46 (s, 9H), 1.29-1.24 (m, 3H), 1.12 (d, J=4 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H) ppm; LCMS: m/z 346 [M-100].sup.+.

Step 4: Tert-Butyl ((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate

(595) ##STR00621##

(596) To a stirred solution of 1-(tert-butyl) 4-ethyl 4-((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)piperidine-1,4-dicarboxylate (5 g, 11.21 mmol) in THE (50 mL) was added LiBH.sub.4 (0.73 g, 33.65 mmol) in portions, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was quenched with saturated NaHCO.sub.3 solution at 0° C. and stirred at room temperature for 15 minutes. The precipitated solid was filtered off, and the aqueous phase was extracted with ethyl acetate (2×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by silica gel (100-200 mesh) column chromatography using 25% ethyl acetate in petroleum ether as eluent to obtain tert-butyl ((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate (3 g, yield: 66%).

(597) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.55 (t, J=4.8 Hz, 1H), 4.43 (d, J=6.4 Hz, 1H), 3.52-3.47 (m, 5H), 3.31-3.28 (m, 1H), 3.05-3.01 (m, 2H), 1.58-1.49 (m, 2H), 1.42-1.38 (m, 11H), 1.11 (d, J=6.4 Hz, 3H), 0.85 (m, 9H), 0.04 (s, 6H) ppm; LC-MS: m/z 404.3 [M+H].sup.+.

Step 5: Tert-Butyl 4-((2S)-1,2-dihydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate

(598) ##STR00622##

(599) To a solution of tert-butyl ((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate (25 g, 61.93 mmol) in THE (500 mL) was added tetrabutylammonium fluoride (1M in THF) (93 mL, 92.89 mmol), and the resulting reaction mixture was stirred at room temperature for 2 hours. After the completion of the reaction was confirmed by TLC analysis, the reaction mixture was quenched with saturated NaHCO.sub.3 solution and extracted with ethyl acetate (2×500 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by silica gel (60-120 mesh) column chromatography using ethyl acetate in petroleum ether with a gradient of 70-90% as eluent to obtain tert-butyl 4-((2S)-1,2-dihydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate (12 g, yield: 67%) as a colorless liquid.

(600) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 4.72 (t, J=4.8 Hz, 1H), 4.61 (d, J=5.2 Hz, 1H), 4.50 (d, J=7.2 Hz, 1H), 3.72-3.68 (m, 1H), 3.53-3.44 (m, 4H), 3.11-2.98 (m, 3H), 1.68-1.53 (m, 2H), 1.42-1.35 (m, 11H), 1.10 (d, J=6.4 Hz, 3H) ppm; LC-MS: m/z 290.1 [M+H].sup.+.

Step 6: Tert-Butyl (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(601) ##STR00623##

(602) At 0° C., to a stirred suspension of NaH (60% in mineral oil) (1.45 g, 60.5 mmol) in THE (30 mL) was added a solution of tert-butyl 4-((2S)-1,2-dihydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate (5 g, 17.3 mmol) and p-toluenesulfonyl chloride (3.29 g, 17.3 mmol) in THE (20 mL), and the resulting reaction mixture was allowed to react at 0° C. for 3 hours. After the reaction was completed, the reaction mixture was quenched with saturated NH.sub.4Cl solution (250 mL) at −20° C. and extracted with ethyl acetate (2×50 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by silica gel (100-200 mesh) column chromatography, using 40% ethyl acetate in petroleum ether as eluent to obtain tert-butyl (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (2.1 g, yield: 44%).

(603) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.83-3.62 (m, 5H), 3.43 (d, J=6.0, 1H), 3.07-2.97 (m, 2H), 1.72-1.55 (m, 3H), 1.51-1.42 (m, 11H), 1.33 (d, J=6.4 Hz, 3H) ppm; LC-MS: m/z 172.2 [M-100].sup.+.

Step 7: tert-butyl (S)-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(604) ##STR00624##

(605) Tert-butyl (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (2.1 g, 7.74 mmol) was added to tetrahydrofuran (50 mL), followed by addition of Dess-Martin oxidant (4.26 g, 10.06 mmol), and the mixture was stirred for 1 hour. After the reaction was completed, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel (100-200 mesh) column chromatography using 30% ethyl acetate in petroleum ether as eluent, followed by flash chromatography with 0.1% formic acid and acetonitrile as eluent to obtain tert-butyl (S)-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.2 g, yield: 57%).

(606) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.20 (d, J=9.5 Hz, 1H), 3.94-3.90 (m, 4H), 3.16-3.10 (m, 1H), 3.03-2.97 (m, 1H), 1.81-1.75 (m, 1H), 1.67-1.62 (m, 1H), 1.61-1.57 (m, 1H), 1.42-1.45 (m, 10H), 1.32 (d, J=6.0 Hz, 3H) ppm; LC-MS: m/z 214.1 [M-55].sup.+

Step 8: Tert-Butyl (3S,4S)-4-((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(607) ##STR00625##

(608) To a stirred solution of tert-butyl (S)-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.2 g, 4.46 mmol) in THE (15 mL) were added (R)-2-methylpropane-2-sulfinamide (1.07 g, 8.91 mmol) and titanium tetraethoxide (4.07 g, 17.84 mmol). The resulting reaction mixture was stirred at 90° C. for 20 hours. The reaction mixture was cooled to −4° C., followed by addition of MeOH (2 mL). LiBH.sub.4 (282 mg, 12.99 mmol) was then added thereto in portions and the resulting mixture was stirred at the same temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched with saturated brine at 0° C., stirred at room temperature for 15 minutes, filtered and extracted with ethyl acetate (2×50 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by flash chromatography using 0.1% formic acid and acetonitrile as eluent to obtain tert-butyl (3S,4S)-4-((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.2 g, yield: 72%).

(609) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.20-4.15 (m, 1H), 3.90-3.84 (m, 2H), 3.63-3.59 (m, 1H), 3.49-3.43 (m, 1H), 3.31-3.29 (m, 1H), 2.95-2.81 (m, 2H), 1.90-1.71 (m, 2H), 1.49-1.40 (m, 11H), 1.25 (s, 9H), 1.19 (d, J=6.5 Hz, 3H) ppm; LC-MS: m/z 375.2 [M+H].sup.+.

Step 9: (R)-2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1J-2)

(610) ##STR00626##

(611) To a solution of tert-butyl (3S,4S)-4-((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.1 g, 2.936 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.12 mL, 14.68 mmol) dropwise, and the mixture was stirred at room temperature for 6 hours. After of the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by chromatography with 0.1% formic acid and acetonitrile to obtain (R)-2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1J-2) (850 mg, yield: 72%).

(612) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.40 (brs, D.sub.2O Exchangeable, 1H), 8.30 (brs, D.sub.2O Exchangeable, 1H), 5.28 (d, J=12.0 Hz, 1H), 4.13-4.09 (m, 1H), 3.77 (d, J=9.0 Hz, 1H), 3.50-3.45 (m, 2H), 3.29-3.26 (m, 1H), 3.19-3.15 (m, 1H), 2.94-2.85 (m, 2H), 1.87-1.80 (m, 2H), 1.69-1.59 (m, 2H), 1.17 (s, 9H), 1.08 (d, J=6.0 Hz, 3H) ppm; LC-MS: m/z 275.2 [M+H].sup.+.

Example 5-2: Preparation of (R)-2-methyl-N-((3R,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide and (R)-2-methyl-N-((3R,4R)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1K-2)

Step 1: Tert-Butyl (R)-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(613) ##STR00627##

(614) According to the method of above Example 4, (R)-2-((tert-butyldimethylsilyl)oxo)propanal was used as raw material to obtain tert-butyl(R)-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

Step 2: tert-butyl (3R,4S)-4-((R)-1,1-dimethylethylsulfinamido)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate and tert-butyl (3R,4R)-4-((R)-1,1-dimethylethylsulfinamido)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(615) ##STR00628##

(616) To a stirred solution of tert-butyl (R)-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.97 g, 3.71 mmol) in THE (5 mL) were added (R)-2-methylpropane-2-sulfinamide (0.873 g, 7.2 mmol) and titanium tetraethoxide (3.36 mL, 14.74 mmol). The resulting reaction mixture was stirred at 90° C. for 18 hours, and then cooled to −4° C., followed by addition of MeOH (5 mL). LiBH.sub.4 (80 mg, 3.71 mmol) was then added in portions and the resulting mixture was stirred at −4° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched with saturated brine at 0° C. and stirred at room temperature for 15 minutes, followed by filtration and extraction with ethyl acetate (2×50 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by flash chromatography using 0.1% formic acid and acetonitrile as eluent to obtain tert-butyl (3R,4S)-4-((R)-1,1-dimethylethylsulfinamido)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate and tert-butyl (3R,4R)-4-((R)-1,1-dimethylethylsulfinamido)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.5 g, yield: 36%).

Step 3: (R)-2-methyl-N-((3R,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide and (R)-2-methyl-N-((3R,4R)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1K-2)

(617) ##STR00629##

(618) According to the method of step 9 of Example 4-2, a mixture of (R)-2-methyl-N-((3R,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide and (R)-2-methyl-N-((3R,4R)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide was obtained. The crude product was then purified by flash chromatography using 0.1% formic acid and acetonitrile as eluent to obtain (R)-2-methyl-N-((3R,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (119 g, yield: 24%) and (R)-2-methyl-N-((3R,4R)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfin amide (154 mg, yield: 31%).

(619) (R)-2-methyl-N-((3R,4S)-3-Methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ 5.45 (d, D.sub.2O Exchangeable, J=11.0 Hz, 1H), 3.78 (d, J=9.0 Hz, 1H), 3.64-3.59 (m, 2H), 3.27-3.25 (m, 1H), 3.17-3.14 (m, 1H), 2.88-2.76 (m, 3H), 1.90-1.85 (m, 1H), 1.82-1.76 (m, 1H), 1.59-1.51 (m, 2H), 1.18-1.17 (m, 12H) ppm; LC-MS: m/z 275.2 [M+H].sup.+.

(620) (R)-2-methyl-N-((3R,4R)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide:

(621) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ 5.04 (d, D.sub.2O Exchangeable, J=10.5 Hz, 1H), 4.45-4.11 (m, 1H), 3.48 (d, J=8.5 Hz, 1H), 3.50-3.46 (m, 1H), 3.43 (d, J=9.0 Hz, 1H), 3.14-3.12 (m, 1H), 3.04-3.02 (m, 1H), 3.91-3.87 (m, 2H), 1.73-1.68 (m, 2H), 1.62-1.56 (m, 2H), 1.17 (s, 9H), 1.14 (d, J=6.5 Hz, 3H) ppm; LC-MS: m/z 275.2 [M+H].sup.+.

Example 6-2: Synthesis of (R)-2-methyl-N-(4-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1L-2)

Step 1: (R,Z)—N-(8-benzoyl-2-oxa-8-azaspiro[4.5]decan-4-ylidene)-2-methylpropane-2-sulfinamide

(622) ##STR00630##

(623) According to the method of Example 3-2, (R,Z)—N-(8-benzoyl-2-oxa-8-azaspiro[4.5]decan-4-ylidene)-2-methylpropane-2-sulfinamide was obtained.

(624) LC-MS: m/z 363.2 [M+H].sup.+.

Step 2: (R)—N-(8-benzoyl-4-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide

(625) ##STR00631##

(626) (R,Z)—N-(8-Benzoyl-2-oxa-8-azaspiro[4.5]decan-4-ylidene)-2-methylpropane-2-sulfinamide (200 mg, 0.552 mmol) was dissolved in toluene (5 mL). The solution was cooled to 0° C., and a solution of methylmagnesium bromide (1.1 mL, 3.32 mmol) was then slowly added dropwise thereto. The reaction mixture was then stirred at room temperature for 2.5 hours. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and rotary-evaporated under reduced pressure. The crude product was separated with a preparative plate (20% ethyl acetate in petroleum ether) to obtain (R)—N-(8-benzoyl-4-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide (20 mg, yield: 10%).

(627) LC-MS: m/z 379.2 [M+H].sup.+.

Step 3: 2-methyl-N—((S)-4-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (C-1L-2)

(628) ##STR00632##

(629) (R)—N-(8-Benzoyl-4-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropa ne-2-sulfinamide (100 mg, 0.26 mmol) was dissolved in tetrahydrofuran (5 mL), and cooled to 0° C., followed by slow addition of 4 N NaOH (0.65 mL, 2.6 mmol). The reaction solution was then stirred at room temperature for 2.5 hours. The reaction solution was extracted with ethyl acetate (5×10 mL). The organic phases were combined, dried over MgSO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-methyl-N—((S)-4-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (50 mg, yield: 70%), which was directly used in the next reaction.

(630) LC-MS: m/z 275.2 [M+H].sup.+.

Example 7-2: (R)—N,2-dimethyl-N—((R)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1M-2)

Step 1: Tert-Butyl (R)-1-((R)—N,2-dimethylpropane-2-ylsulfinamido)-8-azaspiro[4.5]decane-8-carboxylate

(631) ##STR00633##

(632) Tert-butyl (R)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decane-8-carboxylate (500 mg, 1.39 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to 0° C., followed by slow addition of NaH (54 mg, 2.23 mmol). Iodomethane (396 mg, 2.79 mmol) was then added and the reaction solution was stirred at room temperature overnight. The reaction solution was quenched with water, and then extracted with ethyl acetate (3×10 mL). The organic phases were combined, dried over MgSO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by a silica gel column (50% ethyl acetate in petroleum ether) to obtain tert-butyl (R)-1-((R)—N,2-dimethylpropane-2-ylsulfinamido)-8-azaspiro[4.5]decane-8-carboxylat e (400 mg, yield: 80%).

(633) LC-MS: m/z 373.2 [M+H].sup.+.

Step 2: (R)—N,2-dimethyl-N—((R)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1M-2)

(634) ##STR00634##

(635) According to the method of step 9 in Example 4-2, (R)—N,2-dimethyl-N—((R)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide was obtained.

(636) LC-MS: m/z 273.2 [M+H].sup.+.

Example 8-2: Preparation of Intermediate: (R)-2-methyl-N-((1R)-3-methyl-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1N-2)

Step 1: Tert-Butyl 4-allyl-4-formylpiperidine-1-carboxylate

(637) ##STR00635##

(638) To a dry 1 L flask were sequentially added tert-butyl 4-formylpiperidine-1-carboxylate (35.0 g, 164 mmol), lithium tert-butoxide (15.77 g, 197 mmol) and allyl bromide (11.54 mL, 189 mmol) and DMF (328 mL), and the mixture was stirred at 0° C. for 1 hour. After the reaction was completed, the mixture was poured into a separating funnel charged with saturated aqueous NH.sub.4Cl solution (50%, 500 mL), and extracted with Et.sub.2O (5×50 mL). The organic phases were combined, dried over MgSO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 25%) to obtain tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate as a colorless oil (24 g, yield: 48%).

(639) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.52 (s, 1H), 5.53-5.76 (m, 1H), 4.96-5.19 (m, 2H), 3.80 (br.s., 2H), 2.97 (t, J=11.49 Hz, 2H), 2.26 (d, J=7.33 Hz, 2H), 1.95 (dt, J=13.71, 3.13 Hz, 2H), 1.38-1.58 (m, 11H) ppm.

(640) Step 2: tert-butyl 4-allyl-4-(1-hydroxyallyl)piperidine-1-carboxylate (C-1N-c-2)

(641) ##STR00636##

(642) To a 1 L dry three-necked flask were sequentially added tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (24 g, 95 mmol) and THE (300 mL). The solution was cooled to −78° C., and vinyl magnesium bromide (1 M in THF, 118 mL, 118 mmol) was slowly added dropwise under nitrogen atmosphere. The resulting solution was slowly warmed to room temperature within 1 hour. After the reaction was completed, the mixture was poured into a separating funnel charged with saturated aqueous NH.sub.4Cl solution (250 mL), and extracted with EtOAc (4×50 mL). The organic phases were combined, dried over MgSO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-allyl-4-(1-hydroxyallyl)piperidine-1-carboxylate, which was used in the next step without further purification.

(643) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.05-5.83 (m, 2H), 5.32-5.21 (m, 2H), 5.12 (s, 1H), 5.08 (d, J=3.5 Hz, 1H), 4.05-3.97 (m, 1H), 3.71 (s, 2H), 3.12 (ddd, J=13.8, 10.4, 3.6 Hz, 2H), 2.33 (dd, J=14.3, 7.8 Hz, 1H), 2.20 (dd, J=14.3, 7.2 Hz, 1H), 1.60 (q, J=4.3 Hz, 2H), 1.57-1.50 (m, 2H), 1.45 (s, 9H) ppm.

Step 3: Tert-Butyl 4-acryloyl-4-allylpiperidine-1-carboxylate

(644) ##STR00637##

(645) To a dry three-necked flask were sequentially added 4-allyl-4-(1-hydroxyallyl)piperidine-1-carboxylate (26.7 g, 95 mmol), Dess-Martin oxidant (44.3 g, 105 mmol) and anhydrous dichloromethane (380 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was poured into a separating funnel charged with a saturated aqueous solution of NaHCO.sub.3:Na.sub.2SO.sub.3 (1:1, 300 mL), and then extracted with DCM (4×50 mL). The organic phases were combined, dried over MgSO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid. The white solid was suspended in petroleum ether (250 mL) and sonicated for 20 minutes. The white suspension was filtered through a pad of diatomite and removed under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-acryloyl-4-allylpiperidine-1-carboxylate (25 g, two-step yield: 94%).

(646) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.80 (dd, J=16.8, 10.3 Hz, 1H), 6.39 (dd, J=16.8, 1.9 Hz, 1H), 5.70 (dd, J=10.3, 1.9 Hz, 1H), 5.55 (ddt, J=17.5, 10.2, 7.4 Hz, 1H), 5.09-4.98 (m, 2H), 3.77 (s, 2H), 2.94 (s, 2H), 2.31 (d, J=7.4 Hz, 2H), 2.08 (d, J=13.8 Hz, 2H), 1.47-1.41 (m, 11H) ppm.

Step 4: Tert-Butyl 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate

(647) ##STR00638##

(648) To a 1 L dry three-necked flask were sequentially added tert-butyl 4-acryloyl-4-allylpiperidine-1-carboxylate (25 g, 89.6 mmol), toluene (degassed, 850 mL) and a solution of Grubbs II Catalyst (2.02 g, 2.38 mmol) in toluene (degassed, 100 mL). The resulting mixture was stirred at 85° C. for 45 minutes under nitrogen atmosphere. After the reaction was completed, the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0-40%) to obtain tert-butyl 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate (19 g, 83 mmol) as a brown solid. A solution of the compound and DDQ (565 mg, 2.49 mmol) in toluene (540 mL) was stirred at room temperature for 15 minutes. The resulting bright red solution was filtered through a pad of diatomite, followed by addition of activated carbon (100 g), and the resulting suspension was stirred at room temperature for 2 hours. The mixture was filtered through a pad of diatomite and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0-40%) to obtain tert-butyl 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate (12 g, yield: 53.3%) as a white solid.

Step 5: Tert-Butyl 3-methyl-1-oxo-8-azaspiro[4.5]decane-8-carboxylate

(649) ##STR00639##

(650) Under nitrogen atmosphere, to a 250 mL dry three-necked flask were sequentially added CuI (3.8 g, 20 mmol) and anhydrous tetrahydrofuran (100 mL). The solution was cooled to −20° C., and MeLi (1.6 M in THF, 25 mL, 40 mmol) was slowly added dropwise to the solution. After the dropwise addition, the reaction solution was allowed to react at −20° C. until the solution was clear. At −20° C., a solution of tert-butyl 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate (2.51 g, 10 mmol) in tetrahydrofuran (20 mL) was then slowly added dropwise. After the reaction was completed, the mixture was poured into a separating funnel charged with saturated aqueous NH.sub.4Cl solution, and extracted with ethyl acetate (3×15 mL). The organic phases were combined, dried over MgSO.sub.4, filtered and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 50%) to obtain tert-butyl 3-methyl-1-oxo-8-azaspiro[4.5]decane-8-carboxylate (1.6 g, yield: 60%).

(651) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.92 (s, 1H), 3.81 (s, 1H), 3.55 (d, J=5.0 Hz, 1H), 3.13-3.04 (m, 1H), 2.96 (t, J=10.9 Hz, 1H), 2.56-2.46 (m, 1H), 2.31-2.21 (m, 2H), 1.94-1.75 (m, 2H), 1.62-1.49 (m, 1H), 1.45 (s, 9H), 1.41-1.35 (m, 2H), 1.15 (d, J=6.0 Hz, 3H), 0.90 (t, J=6.9 Hz, 3H) ppm.

Step 6 and Step 7: (R)-2-methyl-N-((1R)-3-methyl-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1N-2)

(652) ##STR00640##

(653) According to the synthesis method of step 8 and step 9 of the intermediate C-1J-2, the ketone intermediate tert-butyl 3-methyl-1-oxo-8-azaspiro[4.5]decane-8-carboxylate was subjected to reductive amination and removal of the Boc protecting group to obtain (R)-2-methyl-N-((1R)-3-methyl-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1N-2).

(654) .sup.1H NMR (400 MHz, CDCl.sub.3) δ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 3.04-2.95 (m, 1H), 2.75 (s, 2H), 2.62-2.53 (m, 2H), 1.93-1.57 (m, 5H), 1.52-1.27 (m, 13H), 0.96 (d, J=6.5 Hz, 3H) ppm; LCMS: m/z 273 [M+H].sup.+.

Example 9-2: Preparation of Intermediate: Tert-Butyl ((4-methylpiperidin-4-yl)methyl)carbamate (C-4A-2)

Step 1: 1-benzoyl-4-methylpiperidine-4-carbonitrile

(655) ##STR00641##

(656) Under nitrogen atmosphere, to a 100 mL dry single-necked flask were sequentially added 4-methylpiperidine-4-carbonitrile (496 mg, 4 mmol), DCM (10 mL) and triethylamine (611 mg, 6 mmol), and benzoyl chloride (670 mg, 4.8 mmol) was then slowly added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by TLC until the raw materials were consumed. The reaction solution was quenched with 1N HCl solution, and extracted with dichloromethane (3×20 mL). The organic phases were combined, and dried over Na.sub.2SO.sub.4. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 40%) to obtain 1-benzoyl-4-methylpiperidine-4-carbonitrile (650 mg, yield: 70.72%).

(657) LC-MS: m/z 229 [M+H].sup.+.

Step 2: Tert-Butyl 1-benzoyl-((4-methylpiperidin-4-yl)methyl)carbamate

(658) ##STR00642##

(659) At 0° C. and under nitrogen atmosphere, to a 100 mL dry flask were sequentially added 1-benzoyl-4-methylpiperidine-4-carbonitrile (650 mg, 2.85 mmol), nickel chloride hexahydrate (135 mg, 0.67 mmol), di-tert-butyl dicarbonate (1.86 g, 8.54 mmol) and methanol (12 mL), followed by sodium borohydride (754 mg, 20 mmol). The reaction solution was then stirred at room temperature for 12 hours, and the reaction was monitored by TLC until the raw materials were consumed. After the reaction was completed, the reaction solution was concentrated and extracted with dichloromethane (3×20 mL). The organic phases were combined, and dried over Na.sub.2SO.sub.4. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 40%) to obtain tert-butyl 1-benzoyl-((4-methylpiperidin-4-yl)methyl)carbamate (620 mg, yield: 65.50%).

(660) LC-MS: m/z 333 [M+H].sup.+.

Step 3: Tert-Butyl ((4-methylpiperidin-4-yl)methyl)carbamate (C-4A-2)

(661) ##STR00643##

(662) To a 100 mL single-necked flask were sequentially added tert-butyl 1-benzoyl-((4-methylpiperidin-4-yl)methyl)carbamate (620 mg, 1.87 mmol), ethanol (8 mL) and 7N NaOH (2 mL), then the mixture was heated to 90° C. under nitrogen atmosphere and stirred for 8 hours. After the mixture was cooled to room temperature, the mixture was filtered, diluted with water and extracted with ethyl acetate (3×20 mL). The organic phases were combined, and dried over Na.sub.2SO.sub.4. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 80%) to obtain tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate (C-4A-2) (300 mg, yield: 70.5%).

(663) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 3.97 (q, J=7.0 Hz, 2H), 2.80 (d, J=6.4 Hz, 2H), 2.65 (d, J=30.3 Hz, 2H), 1.38 (s, 9H), 1.27 (dd, J=16.2, 7.0 Hz, 2H), 1.10 (d, J=12.8 Hz, 2H), 0.81 (s, 3H) ppm; LC-MS: m/z 229 [M+H].sup.+.

Example 10-2: Preparation of Intermediate: Tert-Butyl ((4-phenylpiperidin-4-yl)methyl)carbamate (C-4B-2)

Step 1: Tert-Butyl 4-cyano-4-phenylpiperidine-1-carboxylate

(664) ##STR00644##

(665) At 0° C., to a solution of tert-butyl (2-chloroethyl)carbamate (2 g, 8.26 mmol) and 2-phenylacetonitrile (968 mg, 8.26 mmol) in anhydrous DMF (20 mL) was added NaH (60% dispersed in mineral oil, 1.6 g, 41.3 mmol) in portions. The reaction mixture was heated at 60° C. for 16 hours. After the reaction was completed, the mixture was quenched with ice water (30 mL), and then extracted (3×50 mL). The organic phases were combined, washed with saturated brine (2×50 mL), then dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 40%) to obtain tert-butyl 4-cyano-4-phenylpiperidine-1-carboxylate (500 mg, yield: 21%).

(666) LCMS: m/z 187.2 [M-100].sup.+.

Step 2: Tert-Butyl 4-(aminomethyl)-4-phenylpiperidine-1-carboxylate

(667) ##STR00645##

(668) Tert-butyl 4-cyano-4-phenylpiperidine-1-carboxylate (0.5 g, 1.75 mmol) was dissolved in 20 mL of methanol, followed by addition of palladium on carbon (50 mg), and the reaction solution was allowed to react under hydrogen atmosphere for 16 hours. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain tert-butyl 4-(aminomethyl)-4-phenylpiperidine-1-carboxylate (0.4 g, yield: 80%).

(669) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38 (t, J=7.6 Hz, 2H), 7.30 (d, J=7.5 Hz, 2H), 7.24 (d, J=7.2 Hz, 1H), 3.75 (d, J=7.8 Hz, 2H), 3.04 (t, J=11.2 Hz, 2H), 2.58 (brs, 2H), 2.21 (d, J=13.9 Hz, 2H), 1.76-1.61 (m, 2H), 1.44 (s, 9H) ppm; LC-MS: m/z 191.0 [M-100].sup.+.

Step 2: (4-phenylpiperidin-4-yl)methanamine (C-4B-2)

(670) ##STR00646##

(671) Tert-butyl 4-(aminomethyl)-4-phenylpiperidine-1-carboxylate (0.4 g, 1.37 mmol) was dissolved in 10 mL of methanol, followed by addition of a solution of hydrogen chloride in 1,4-dioxane (4 M, 13.7 mmol) at room temperature. The reaction solution was allowed to react at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product of (4-phenylpiperidin-4-yl)methanamine (C-4B-2) (0.25 g, yield: 95%), which was directly used in the next reaction.

(672) LC-MS: m/z 191.2 [M+H].sup.+.

Example 11-2: Preparation of Intermediate: 6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridine-4-thiol (F-1A-2)

Step 1: Tert-Butyl (6-chloropyridin-2-yl)carbamate

(673) ##STR00647##

(674) Under nitrogen atmosphere, to a dry 250 mL three-necked flask were added 6-chloropyridin-2-amine (8 g, 62.2 mmol) and THE (80 mL), and the mixture was stirred at 0° C. for 10 minutes, followed by addition of NaHDMS (124.4 mL, 1.0 M in THF). The mixture was kept at 0° C., a solution of di-tert-butyl dicarbonate (16.3 g, 74.7 mmol) in tetrahydrofuran (50 mL) was slowly added, and the reaction was continued at 0° C. for 4 hours. After the reaction was completed, H.sub.2O (40 mL) was added, followed by extraction with EtOAc (3×100 mL). The organic phases were combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 10%) to obtain tert-butyl (6-chloropyridin-2-yl)carbamate (7 g, yield: 49%).

(675) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.04 (s, 1H), 7.79-7.58 (m, 2H), 7.02 (dd, J=5.5, 2.9 Hz, 1H), 1.38 (s, 9H) ppm; LCMS: m/z 288.1 [M+H].sup.+.

Step 2: Tert-Butyl (5,6-dichloropyridin-2-yl)carbamate

(676) ##STR00648##

(677) To a dry 100 mL round bottom flask were added tert-butyl (6-chloropyridin-2-yl)carbamate (7 g, 30.6 mmol) and N,N-dimethylformamide (50 mL), and the mixture was stirred at room temperature for 10 minutes, followed by addition of N-chlorosuccinimide (4.50 g, 33.67 mmol). The mixture was allowed to react at 100° C. for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, followed by addition of H.sub.2O (50 mL) and extraction with ethyl acetate (3×80 mL), and then washed with saturated aqueous lithium chloride solution (2×40 mL). The organic phase was dried over MgSO.sub.4, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 5%) to obtain tert-butyl (5,6-dichloropyridin-2-yl)carbamate (5.3 g, yield: 65.8%).

(678) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.86 (d, J=8.7 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.24 (s, 1H), 1.51 (s, 9H); LCMS: m/z 207.1 [M-55].sup.+.

Step 3: Tert-Butyl (5,6-dichloro-4-iodopyridin-2-yl)carbamate

(679) ##STR00649##

(680) Under nitrogen atmosphere, to a dry 100 mL round bottom flask were added tert-butyl (5,6-dichloropyridin-2-yl)carbamate (5.3 g, 20.14 mmol) and tetrahydrofuran (50 mL). n-Butyllithium (44.3 mmol, 2.5M in THF) was slowly added dropwise at −78° C., and the reaction solution was further stirred at −78° C. for 1 hour. A solution of iodine (3.07 g, 24.17 mmol) in tetrahydrofuran (20 mL) was then slowly added dropwise, and the reaction was continued at −78° C. for 3 hours. After the reaction was completed, H.sub.2O (50 mL) was added, followed by extraction with EtOAc (3×80 mL). The organic phases were combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 5%) to obtain tert-butyl (5,6-dichloro-4-iodopyridin-2-yl)carbamate (4.3 g, yield: 55%).

(681) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.44 (s, 1H), 8.36 (s, 1H), 1.46 (s, 9H) ppm; LCMS: m/z 334.1 [M-55].sup.+.

Step 4: methyl 3-((6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridin-4-yl)thio)propionate

(682) ##STR00650##

(683) To a dry 100 mL round bottom flask were sequentially added tert-butyl (5,6-dichloro-4-iodopyridin-2-yl)carbamate (3.2 g, 8.22 mmol), palladium acetate (92 mg, 0.41 mmol), Xantphos (285 mg, 0.49 mmol), DIPEA (2.12 g, 16.46 mmol) and 1,4-dioxane (30 mL). The reaction mixture was heated and stirred at 100° C. for 2 hours, then filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0-30%) to obtain methyl 3-((6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridin-4-yl)thio)propionate (3 g, yield: 96%).

(684) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.25 (s, 1H), 7.73 (s, 1H), 3.64 (s, 3H), 3.26 (t, J=6.9 Hz, 2H), 2.82 (t, J=6.9 Hz, 2H), 1.46 (s, 9H) ppm; LCMS: m/z 326.3[M-55].sup.+.

Step 5: 6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridine-4-thiol (F-1A-2)

(685) ##STR00651##

(686) To a dry 100 mL round bottom flask were sequentially added methyl 3-((6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridin-4-yl)thio)propionate and tetrahydrofuran (30 mL), and a solution of sodium ethoxide in ethanol (21%, 6 mL) was then slowly added dropwise at room temperature. The reaction solution was stirred at room temperature for 1 hour and then concentrated under reduced pressure, followed by addition of dichloromethane (10 mL), and a large amount of brown solid was precipitated. The mixture was filtered, and the filter cake was washed with dichloromethane, and dried to obtain sodium 6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridine-4-thiolate, which was acidified with 1N HCl to pH of 3. The mixture was directly concentrated under reduced pressure, and the obtained crude product of F-1A-2 (2.1 g) was directly used in the next reaction.

(687) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.05 (s, 1H), 7.61 (s, 1H), 1.41 (s, 9H) ppm; LCMS: m/z 262.2 [M-55].sup.+.

(688) According to the synthesis method of Example 11-2, the following intermediates F-1B-2, F-1C-2, F-1D-2, F-1E-2, F-1F-2, F-1G-2, F-1H-2, F-1I-2, F-1J-2, F-1K-2 were obtained by using similar intermediate raw materials.

(689) TABLE-US-00007 Intermedi- ate Name Structure Analysis data F-1B-2 2-amino-3-chloropyridine-4-thiol .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.06 (d, J = 3.1 Hz, 1H), 6.51 (d, J = 5.2 Hz, 1H) ppm; LCMS: m/z 161.0 [M + H].sup.+. F-1C-2 2-amino-5-chloropyridin-4-thiol .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.88 (s, 1H), 7.49 (d, J = 5.3 Hz, 1H), 7.09 (d, J = 5.3 Hz, 1H) ppm; LCMS: m/z 161.0 [M + H].sup.+. F-1D-2 2-chloropyridine-3-thiol .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.57 (dd, J = 7.7, 1.5 Hz, 1H), 7.45 (d, J = 3.5 Hz, 1H), 6.69 (dd, J = 7.6, 4.4 Hz, 1H) ppm; LCMS: m/z 146.0 [M + H].sup.+. F-1E-2 2-methylpyridine-3-thiol .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.59-7.46 (m, 1H), 7.32 (dd, J = 7.7, 1.4 Hz, 1H), 6.53 (dd, J = 7.7, 4.6 Hz, 1H), 2.36 (s, 3H) ppm; LCMS: m/z 126.0 [M + H].sup.+. F-1F-2 quinoline-4-thiol .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.79 (d, J = 4.6 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.74-7.64 (m, 2H), 7.30 (d, J = 4.6 Hz, 1H) ppm; LCMS: m/z 162.0 [M + H].sup.+. F-1G-2 2,3-dichloropyridine-4-thiol .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.31 (d, J = 5.3 Hz, 1H), 7.07 (d, J = 5.3 Hz, 1H) ppm; LCMS: m/z 180.0 [M + H].sup.+. F-1H-2 3-chloropyridine-4-thol .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.88 (s, 1H), 7.49 (d, J = 5.3 Hz, 1H), 7.09 (d, J = 5.3 Hz, 1H) ppm; LCMS: m/z 146.0. F-1I-2 2-(trifluoromethyl)pyridin-3-thiol LCMS: m/z 180.0. F-1J-2 3-(trifluoromethyl)pyridine-4-thiol 0 .sup.1HNMR (400 MHz, D.sub.2O) δ 8.24 (s, 1H), 7.84 (d, J = 5.6 Hz, 1H), 7.31 (d, J = 5.6 Hz, 1H) ppm; LCMS: m/z 146.0. F-1K-2 6-amino-2-chloropyridin-3-thiol .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.29 (d, J = 8.1 Hz, 1H), 6.03 (d, J = 7.8 Hz, 1H), 5.21 (brs, 2H) ppm; LCMS: m/z 160.0.

Example 12-2: Preparation of Intermediate: 3-chloro-2-methylpyridine-4-thiol (F-1L-2)

Step 1: Methyl 3-((3-chloro-2-methylpyridin-4-yl)thio)propionate

(690) The intermediate methyl 3-((2,3-dichloropyridin-4-yl)thio)propionate obtained from the synthesis of intermediate F-1G-2 was used in the following reaction.

(691) ##STR00662##

(692) Under nitrogen atmosphere, to a dry 100 mL round bottom flask were successively added methyl 3-((2,3-dichloropyridin-4-yl)thio)propionate (500 mg, 1.88 mmol), Pd(PPh.sub.3).sub.4 (217 mg, 0.188 mmol), trimethylcyclotriboroxane (354 mg, 2.82 mmol), potassium carbonate (389 mg, 2.82 mmol) and 1,4-dioxane (10 mL). The reaction mixture was heated and stirred at 100° C. under nitrogen atmosphere for 6 hours. The residue obtained by filtration and concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 40%) to obtain methyl 3-((3-chloro-2-methylpyridin-4-yl)thio)propionate (320 mg, yield: 69%).

Step 2: 3-chloro-2-methylpyridine-4-thiol (F-1L-2)

(693) ##STR00663##

(694) To a dry 100 mL round bottom flask were sequentially added methyl 3-((3-chloro-2-methylpyridin-4-yl)thio)propionate (320 mg, 1.30 mmol) and tetrahydrofuran (10 mL), and a solution of sodium ethoxide in ethanol (21%, 2 mL) was slowly added dropwise at room temperature. The reaction solution was stirred at room temperature for 1 hour, and then concentrated under reduced pressure, followed by addition of dichloromethane (10 mL), and a large amount of brown solid was precipitated. The mixture was filtered, and the filter cake was washed with dichloromethane and dried to obtain sodium 3-chloro-2-methylpyridine-4-thiolate, which was acidified with 1N HCl to pH of 3. The mixture was directly rotary-evaporated to dryness under reduced pressure to obtain a crude product of F-1L-2 (200 mg), which was directly used in the next reaction.

(695) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.37 (d, J=4.8 Hz, 1H), 6.97 (d, J=4.8 Hz, 1H), 2.31 (s, 3H) ppm; LCMS: m/z 160.0 [M+H].sup.+.

Example 13-2: Preparation of Intermediate: Sodium 6-((tert-butoxycarbonyl)amino)-3-chloro-2-methylpyridine-4-thiolate (F-1M-2)

Step 1: Methyl 3-((6-((tert-butoxycarbonyl)amino)-3-chloro-2-methylpyridin-4-yl)thio)propionate

(696) Methyl 3-((6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridin-4-yl)thio)propionate obtained from the synthesis of intermediate F-1A-2 was used in the following reaction.

(697) ##STR00664##

(698) Under nitrogen atmosphere, to a dry 100 mL round bottom flask were added methyl 3-((6-((tert-butoxycarbonyl)amino)-2,3-dichloropyridin-4-yl)thio)propionate (600 mg, 1.57 mmol), [1,1′-bis(tert-butylphosphino)ferrocene]palladium dichloride (103 mg, 0.157 mmol), trimethylcyclotriboroxane (301 mg, 2.4 mmol), potassium carbonate (331 mg, 2.4 mmol), 1,4-dioxane (10 mL) and water (1 mL). The reaction mixture was heated and stirred at 100° C. under nitrogen atmosphere for 6 hours. The residue obtained by filtration and concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 40%) to obtain methyl 3-((6-((tert-butoxycarbonyl)amino)-3-chloro-2-methylpyridin-4-yl)thio)propionate (420 mg, yield: 74%).

(699) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.90 (s, 1H), 7.64 (s, 1H), 3.64 (s, 3H), 3.21 (t, J=6.9 Hz, 2H), 2.80 (t, J=6.9 Hz, 2H), 1.46 (s, 9H) ppm; LCMS: m/z 361.1 [M+H].sup.+.

Step 2: sodium 6-((tert-butoxycarbonyl)amino)-3-chloro-2-methylpyridine-4-thiolate (F-1M-2)

(700) ##STR00665##

(701) To a dry 100 mL round bottom flask were sequentially added methyl 3-((6-((tert-butoxycarbonyl)amino)-3-chloro-2-methylpyridin-4-yl)thio)propionate (420 mg, 1.17 mmol) and tetrahydrofuran (10 mL), and a solution of sodium ethoxide in ethanol (21%, 2 mL) was then slowly added dropwise at room temperature. The reaction solution was stirred at room temperature for 1 hour, and then concentrated under reduced pressure, followed by addition of dichloromethane (10 mL), and a large amount of brown solid was precipitated. The mixture was filtered, washed with dichloromethane and dried to obtain sodium 6-((tert-butoxycarbonyl)amino)-3-chloro-2-methylpyridine-4-thiolate, which was acidified with 1N HCl to pH of 3. The mixture was directly concentrated under reduced pressure, and the obtained crude product of F-1M-2 (320 mg) was directly used in the next reaction.

(702) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.87 (s, 1H), 7.63 (s, 1H), 3.64 (s, 3H), 1.46 (s, 9H) ppm; LCMS: m/z 275.0.

Example 14-2: Preparation of Intermediate: 3-amino-2-chlorobenzenethiol hydrochloride (F-1N-2)

Step 1: 2-chloro-3-aminophenyl Tert-Butyl Sulfide

(703) ##STR00666##

(704) Under nitrogen atmosphere, to a dry 100 mL round bottom flask were sequentially added 2-chloro-3-fluoroaniline (5 g, 34.3 mmol) and N-methylpyrrolidone (50 mL), followed by 2-methylpropane-2-thiol (8.66 g, 96.04 mmol) and cesium carbonate (22.36 g, 68.6 mmol), and the reaction mixture was heated and stirred at 120° C. for 16 hours. After cooling to room temperature, the reaction solution was diluted with 60 mL of ethyl acetate and sequentially washed with saturated lithium chloride aqueous solution (30 mL), water (30 mL) and saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-chloro-3-aminophenyl tert-butyl sulfide (6.04 g, yield: 82%).

(705) LCMS: m/z 216.1 [M+H].sup.+.

Step 2: 3-amino-2-chlorobenzenethiol Hydrochloride (F-1N-2)

(706) ##STR00667##

(707) To a dry 100 mL round bottom flask were sequentially added 2-chloro-3-aminophenyl tert-butyl sulfide (6.04 g, 28 mmol) and concentrated hydrochloric acid (50 mL), and the reaction mixture was heated and stirred at 45° C. for 8 hours. After naturally cooling to room temperature, the reaction solution was further cooled to 0° C., during which a large amount of white solid was precipitated. The mixture was filtered, and the filter cake was washed with concentrated hydrochloric acid and petroleum ether to obtain 3-amino-2-chlorobenzenethiol hydrochloride F-1N-2 (4.9 g, yield: 90%).

(708) LCMS: m/z 160.0 [M+H].sup.+.

Example 15-2: Preparation of Compound 1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperidin-4-amine

Step 1: Tert-Butyl (1-(8-iodo-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperidin-4-yl)carbamate

(709) ##STR00668##

(710) Under nitrogen protection, to a dry 50 mL single-necked flask were added 5-chloro-8-iodo-[1,2,4]triazolo[4,3-c]pyrimidine (E1) (50 mg, 0.18 mmol), tert-butyl (4-methylpiperidin-4-yl)carbamate (77 mg, 0.36 mmol), DIEA (46 mg, 0.36 mmol) and NMP (5 mL), and then the reaction solution was stirred at 90° C. for 2 hours. After the reaction was completed, the obtained residue was poured into water (10 mL), stirred at room temperature for 5 minutes, and then extracted with ethyl acetate (3×50 mL). The organic phases were combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 80%) to obtain tert-butyl (1-(8-iodo-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperidin-4-yl)carbamate as a pale yellow solid (60 mg, yield: 73%).

(711) LCMS: m/z 459.1 [M+H].sup.+.

Step 2: Tert-Butyl (1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperidin-4-yl)carbamate

(712) ##STR00669##

(713) To a dry 50 mL three-necked flask were sequentially added tert-butyl (1-(8-iodo-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperidin-4-yl)carbamate (60 mg, 0.13 mmol), cuprous iodide (3 mg, 0.013 mmol), 1,10-phenanthroline (5 mg, 0.026 mmol), 2,3-dichlorothiophenol (36 mg, 0.2 mmol), potassium phosphate (60 mg, 0.26 mmol) and 5 mL of dioxane. The mixture was heated for 3 hours under nitrogen atmosphere. After the reaction was completed, saturated NH.sub.4Cl solution (10 mL) was added, followed by extraction with ethyl acetate (3×50 mL). The organic phases were combined, dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 60%) to obtain tert-butyl (1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperid in-4-yl)carbamate as a pale yellow solid (25 mg, yield: 38%).

(714) LC-MS: m/z 510.1 [M+H].sup.+.

Step 3: 1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperidin-4-amine

(715) ##STR00670##

(716) To a dry 50 mL round bottom flask were sequentially added tert-butyl (1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperid in-4-yl)carbamate (25 mg, 0.049 mmol) and a solution of hydrogen chloride in 1,4-dioxane (7 M, 5 mL), and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, saturated NaHCO.sub.3 solution (10 mL) was added, followed by extraction with ethyl acetate (3×50 mL). The organic phases were combined, dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by high-performance liquid chromatography to obtain the product 1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperidin-4-amine (10 mg, yield: 49%).

(717) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.42 (s, 1H), 8.00 (s, 1H), 7.42 (t, J=8.4 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.80 (t, J=15.0 Hz, 1H), 3.78 (dd, J=35.6, 5.8 Hz, 4H), 1.75 (s, 4H), 1.26 (s, 3H) ppm; LC-MS: m/z 410.1 [M+H].sup.+.

(718) According to the synthesis method of Example 15-2, the following compounds were synthesized:

Example 16-2: 1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)piperidin-4-amine

(719) ##STR00671##

(720) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.45 (s, 1H), 8.31 (s, 1H), 8.02 (s, 1H), 7.44 (d, J=6.9 Hz, 1H), 7.14 (t, J=8.1 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 4.18 (d, J=13.5 Hz, 2H), 3.44 (d, J=7.1 Hz, 1H), 3.27 (s, 2H), 1.99 (d, J=10.9 Hz, 2H), 1.68 (d, J=9.9 Hz, 2H) ppm; LC-MS: m/z 395.0 [M+H].sup.+.

Example 17-2: (1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-phenylpiperidin-4-yl)methanamine

(721) ##STR00672##

(722) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.42 (s, 1H), 7.99 (s, 1H), 7.46 (dt, J=22.1, 7.5 Hz, 5H), 7.33 (t, J=6.8 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 3.97 (d, J=14.4 Hz, 2H), 3.45-3.37 (m, 2H), 2.98 (s, 2H), 2.38 (d, J=14.8 Hz, 2H), 2.06 (t, J=10.4 Hz, 2H) ppm; LC-MS: m/z 485.1 [M+H].sup.+.

Example 18-2: (1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)pyrrolidin-3-yl) methanamine

(723) ##STR00673##

(724) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.49 (s, 1H), 7.92 (s, 1H), 7.86 (brs, 2H), 8.42 (d, J=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 4.16-3.93 (m, 4H), 3.77-3.72 (m, 1H), 3.01-2.97 (m, 1H), 2.66-2.58 (m, 1H), 2.25-2.18 (m, 2H), 1.88-1.76 (m, 1H) ppm; LC-MS: m/z 395.1 [M+H].sup.+.

Example 19-2: (1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperid in-4-yl)methanamine

(725) ##STR00674##

(726) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.38 (s, 1H), 7.98 (s, 1H), 7.43 (dd, J=8.0, 1.3 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.82 (dd, J=8.1, 1.3 Hz, 1H), 3.92-3.78 (m, 2H), 3.64-3.55 (m, 2H), 2.56 (s, 2H), 1.67 (ddd, J=13.2, 9.4, 3.7 Hz, 2H), 1.53-1.41 (m, 2H), 1.01 (s, 3H) ppm; LC-MS: m/z 423.1 [M+H].sup.+.

Example 20-2: 2-(1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)piperidin-4-yl) ethan-1-amine

(727) ##STR00675##

(728) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.39 (s, 1H), 8.00 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H), 4.20 (d, J=13.3 Hz, 4H), 3.20 (d, J=12.5 Hz, 2H), 2.83 (t, J=7.7 Hz, 1H), 1.82 (d, J=12.7 Hz, 2H), 1.59-1.49 (m, 2H), 1.39-1.33 (m, 2H), 1.23 (s, 2H) ppm; LC-MS: m/z 424.1 [M+H].sup.+.

Example 21-2: 8-((2,3-dichlorophenyl)thio)-5-(3,5-dimethylpiperazin-1-yl)-[1,2,4]triazolo[4,3-c]pyrimidine

(729) ##STR00676##

(730) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (s, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.14 (t, J=8.1 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 4.12 (d, J=12.6 Hz, 2H), 3.23 (s, 2H), 2.94 (s, 2H), 1.15 (d, J=5.9 Hz, 6H) ppm; LC-MS: m/z 410.1 [M+H].sup.+.

Example 22-2: 8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-1,8-diazaspiro[4.5]decane

(731) ##STR00677##

(732) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.47 (s, 1H), 8.02 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 3.97 (ddd, J=14.1, 6.6, 3.9 Hz, 2H), 3.62 (ddd, J=13.3, 8.9, 3.3 Hz, 2H), 3.30 (t, J=6.7 Hz, 2H), 2.10 (ddd, J=13.1, 8.8, 3.7 Hz, 2H), 2.00 (p, J=6.3 Hz, 6H) ppm; LC-MS: m/z 435.1 [M+H].sup.+.

Example 23-2: 4-((5-(4-amino-4-methylpiperidin-1-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)thio)-3-chloropyridine-2-amine

(733) ##STR00678##

(734) .sup.1H NMR (400 MHz, CD.sub.3OD-d.sub.4) δ 9.24 (s, 1H), 7.94 (s, 1H), 7.42-7.44 (d, J=5.2 Hz, 1H), 5.93-5.94 (d, J=5.6 Hz, 1H), 3.97-4.02 (d, J=14 Hz, 2H), 3.58-3.60 (t, J=10.4 Hz, 2H), 1.92-1.98 (m, 4H), 1.44 (s, 3H) ppm; LC-MS: m/z 391.1[M+H].sup.+.

Example 24-2: (R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

Step 1: (R)—N—((R)-8-(8-iodine-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide

(735) ##STR00679##

(736) To a dry 50 mL single-necked flask were sequentially added 5-chloro-8-iodo-[1,2,4]triazolo[4,3-c]pyrimidine (E1) (50 mg, 0.18 mmol), (R)-2-methyl-N—((R)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (C-1A) (93 mg, 0.36 mmol), DIEA (46 mg, 0.36 mmol) and NMP (5 mL), and then the reaction mixture was stirred at 90° C. for 2 hours. After the reaction was completed, the obtained residue was poured into water (10 mL) and stirred at room temperature for 5 minutes, followed by extraction with ethyl acetate (3×20 mL). The organic phases were combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 80%) to obtain (R)—N—((R)-8-(8-iodo-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide as a pale yellow solid (80 mg, yield: 88%).

(737) LC-MS: m/z 503.1 [M+H].sup.+.

Step 2: (R)—N—((R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-aza spiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide

(738) ##STR00680##

(739) To a dry 50 mL three-necked flask were sequentially added (R)—N—((R)-8-(8-iodo-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (80 mg, 0.16 mmol), cuprous iodide (3 mg, 0.016 mmol), 1,10-phenanthroline (6 mg, 0.032 mmol), 2,3-dichlorothiophenol (34 mg, 0.192 mmol), potassium phosphate (68 mg, 0.32 mmol) and 10 mL of dioxane, and the mixture was heated for 3 hours under nitrogen atmosphere. After the reaction was completed, saturated NH.sub.4Cl solution (50 mL) was added, followed by extraction with ethyl acetate (3×20 mL). The organic phases were combined, dried over Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (methanol/ethyl acetate with a gradient of 0 to 10%) to obtain (R)—N—((R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-aza spiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide as a pale yellow solid (60 mg, yield: 68%).

(740) LC-MS: m/z 553.1 [M+H].sup.+.

Step 3: (R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(741) ##STR00681##

(742) To a dry 50 mL round bottom flask were sequentially added (R)—N—((R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-aza spiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (60 mg, 0.11 mmol) and a solution of hydrogen chloride in 1,4-dioxane (7 M, 5 mL), and the reaction solution was allowed to react at room temperature for 1 hour. The reaction solution was evaporated under reduced pressure, and the resulting crude product was purified by reversed-phase high-performance liquid chromatography to obtain the product (R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (20 mg, yield: 46%).

(743) .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 9.15 (s, 1H), 7.90 (s, 1H), 7.23 (d, J=8.0 Hz, J=1.6 Hz, 1H), 6.97 (t, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, J=1.6 Hz, 1H), 4.03-4.11 (m, 2H), 3.32-3.40 (m, 2H), 3.16 (t, J=6.8 Hz, 1H), 2.11-2.14 (m, 1H), 1.51-1.84 (m, 9H) ppm; LC-MS: m/z 451.1 [M+H].sup.+.

(744) According to the synthesis method of Example 24-2, the following compounds were synthesized:

Example 25-2: (S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(745) ##STR00682##

(746) .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 9.27 (s, 1H), 8.55 (s, 2H), 8.02 (s, 1H), 7.35 (dd, J=8.0, 1.3 Hz, 1H), 7.08 (t, J=8.1 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 4.19 (s, 3H), 3.51-3.48 (m, 2H), 3.21 (s, 1H), 3.15 (s, 1H), 2.31-2.14 (m, 1H), 2.03-1.78 (m, 7H), 1.63 (s, 2H) ppm; LC-MS: m/z 449.1 [M+H].sup.+.

Example 26-2: (S)-7-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-7-azaspiro[3.5]nonan-1-amine

(747) ##STR00683##

(748) .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 9.15 (s, 1H), 8.34 (brs, 2H), 7.90 (s, 1H), 7.23 (dd, J=8.0 Hz, J=1.6 Hz, 1H), 6.96 (t, J=8.0 Hz, 1H), 6.74 (dd, J=8.0 Hz, J=1.6 Hz, 1H), 4.11 (d, J=12.0 Hz, 1H), 4.00 (d, J=13.2 Hz, 1H), 3.44-3.40 (m, 1H), 3.35-3.28 (m, 1H), 2.33-2.29 (m, 1H), 2.03-1.95 (m, 2H), 1.91-1.87 (m, 2H), 1.80-1.70 (m, 3H) ppm; LC-MS: m/z 435.1 [M+H].sup.+.

Example 27-2: 7-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-7-azaspiro[3.5]nonan-2-amine

(749) ##STR00684##

(750) .sup.1H NMR (400 MHz, methanol-d.sub.4) δ 9.28 (s, 1H), 8.01 (s, 1H), 7.34 (dd, J=8.0, 1.4 Hz, 1H), 7.08 (t, J=8.0 Hz, 1H), 6.84 (dd, J=8.1, 1.4 Hz, 1H), 3.90-3.83 (m, 1H), 3.76 (t, J=5.7 Hz, 2H), 3.72-3.66 (m, 2H), 2.45 (s, 2H), 2.05 (t, J=10.6 Hz, 2H), 1.95 (t, J=5.7 Hz, 1H), 1.91 (t, J=5.7 Hz, 1H) ppm; LC-MS: m/z 435.1 [M+H].sup.+.

Example 28-2: (4R)-2-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)octahydrocyclopenta[c]pyrrol-4-amine

(751) ##STR00685##

(752) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.55 (s, 1H), 7.86 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 6.73 (d, J=8.1 Hz, 1H), 4.10-4.04 (m, 2H), 3.53 (s, 1H), 3.16 (d, J=4.8 Hz, 1H), 2.79 (s, 1H), 1.86-1.78 (m, 2H), 1.55 (d, J=8.5 Hz, 2H) ppm; LC-MS: m/z 421.1 [M+H].sup.+.

Example 29-2: (R)-3-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-azaspiro[5.5]undecan-7-amine

(753) ##STR00686##

(754) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.37 (s, 1H), 7.98 (s, 1H), 7.43 (d, J=7.2 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 3.99 (d, J=13.5 Hz, 2H), 3.59-3.51 (m, 2H), 2.82 (d, J=4.6 Hz, 1H), 2.14-1.11 (m, 14H) ppm; LC-MS: m/z 464.1 [M+H].sup.+.

Example 30-2: (R)-1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)azepan-4-amine

(755) ##STR00687##

(756) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.41 (s, 1H), 7.93 (s, 1H), 7.43 (d, J=7.4 Hz, 1H), 7.14 (t, J=8.1 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 4.15-3.99 (m, 2H), 3.84 (ddd, J=52.8, 16.3, 7.7 Hz, 2H), 3.21 (s, 31), 2.01 (dd, J=56.3, 34.4 Hz, 51-), 1.65-1.47 (m, 1H) ppm; LC-MS: m/z 410.1 [M+H].sup.+.

Example 31-2: (S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

(757) ##STR00688##

(758) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.39 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.47-7.39 (m, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 4.00 (dd, J=8.8, 6.5 Hz, 2H), 3.73 (d, J=8.5 Hz, 1H), 3.66 (d, J=8.5 Hz, 1H), 3.54-3.46 (m, 2H), 3.39 (dd, J=8.9, 5.0 Hz, 2H), 3.21-3.17 (m, 1H), 1.92-1.75 (m, 2H), 1.64-1.53 (m, 2H) ppm; LC-MS: m/z 450.7 [M+H].sup.+.

Example 32-2: (R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-N-methyl-8-azaspiro[4.5]decan-1-amine

(759) ##STR00689##

(760) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.38 (s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.14 (t, J=8.1 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 4.08 (d, J=14.0 Hz, 2H), 2.64 (d, J=21.8 Hz, 1H), 2.37 (s, 3H), 2.06-1.14 (m, 12H) ppm; LC-MS: m/z 463.1 [M+H].sup.+.

Example 33-2: (1R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine

(761) ##STR00690##

(762) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.38 (d, J=3.5 Hz, 1H), 8.37 (s, 1H), 8.00 (d, J=1.0 Hz, 1H), 7.44 (d, J=7.1 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.81 (dd, J=8.1, 1.1 Hz, 1H), 4.15-4.04 (m, 2H), 3.06-2.93 (m, 2H), 2.15 (dd, J=19.1, 11.5 Hz, 2H), 2.01-1.26 (m, 8H), 1.06-0.99 (m, 3H) ppm; LC-MS: m/z 464.1 [M+H].sup.+.

Example 34-2: 8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(763) ##STR00691##

(764) .sup.1H NMR (CD.sub.3OD-d.sub.4) δ 9.31 (s, 1H), 8.49 (s, 1H), 8.02 (s, 1H), 7.34-7.37 (m, 1H), 7.07-7.11 (m, 1H), 6.86-6.88 (m, 1H), 4.19-4.21 (m, 2H), 4.10-4.12 (m, 2H), 3.85-3.94 (m, 2H), 3.37 (m, 1H), 3.18 (m, 1H), 2.04 (m, 2H), 1.80 (m, 2H), 1.38 (s, 3H) ppm; LC-MS: m/z 465.1 [M+H].sup.+.

Example 35-2: (3S,4S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methy 1-2-oxa-8-azaspiro[4.5]decan-4-amine

(765) ##STR00692##

(766) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.40 (s, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.44 (d, J=7.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.82 (d, J=7.2 Hz, 1H), 4.12 (s, 1H), 3.89 (d, J=6.8 Hz, 2H), 3.74 (d, J=8.6 Hz, 1H), 3.59-3.49 (m, 3H), 3.08 (d, J=4.8 Hz, 1H), 1.96-1.81 (m, 2H), 1.73 (s, 2H), 1.13 (d, J=6.4 Hz, 3H) ppm; LC-MS: m/z 466.1 [M+H].sup.+.

Example 36-2: (3R,4R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidine-5-yl)-3-meth yl-2-oxa-8-azaspiro[4.5]decan-4-amine

(767) ##STR00693##

(768) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.31 (s, 1H), 7.95 (s, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.11 (t, J=8.1 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 4.68-4.53 (m, 4H), 3.17-3.08 (m, 1H), 1.89 (s, 2H), 1.71-1.61 (m, 4H), 1.13 (d, J=6.5 Hz, 3H); LC-MS: m/z 465.1 [M+H].sup.+.

Example 37-2: 1-(8-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperidin-4-a mine

Step 1: Tert-Butyl (1-(8-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperidine-4-yl)carbamate

(769) ##STR00694##

(770) At room temperature, to a 20 mL sealed tube were sequentially added tert-butyl (1-(8-iodo-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperidine-4-yl)carbamate (55 mg, 0.12 mmol) 1,4-dioxane (2 mL), purified water (0.5 mL), (2,3-dichlorophenyl)boronic acid (50 mg, 0.24 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (9 mg, 0.012 mmol) and potassium carbonate (50 mg, 0.36 mmol). The reaction mixture was bubbled with nitrogen for one minute, and then the sealed tube was heated to 80° C., and the reaction continued for 6 hours. After the reaction was completed, 20 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (50 mL×3). The organic phase was sequentially washed with water (20 mL×1) and saturated saline (20 mL×1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (petroleum ether: ethyl acetate=1:1) to obtain a crude product of tert-butyl (1-(8-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperidine-4-yl)carbamate (33 mg, yield: 57%) as a pale yellow solid.

(771) LC-MS: m/z 477.1 [M+H].sup.+.

Step 2: 1-(8-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperidine-4-amine

(772) ##STR00695##

(773) According to the method of step 3 of Example 15-2, tert-butyl (1-(8-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperidin-4-yl)carbamate was subjected to the removal of 1-tert-butoxycarbonyl group to obtain 1-(8-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4-methylpiperidine-4-amine.

(774) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.38 (s, 1H), 7.79-7.72 (m, 2H), 7.56-7.46 (m, 2H), 3.68 (t, J=5.3 Hz, 4H), 1.76-1.51 (m, 4H), 1.18 (s, 3H) ppm; LC-MS: m/z 377.1 [M+H].sup.+.

Example 38-2: Synthesis of (R)-8-(8-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

Step 1: (R)—N—((R)-8-(8-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro decan-1-yl)-2-methylpropane-2-sulfinamide

(775) ##STR00696##

(776) At room temperature, to a 20 mL sealed tube were sequentially added (R)—N—((R)-8-(8-iodo-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (60 mg, 0.12 mmol), 1,4-dioxane (2 mL), purified water (0.5 mL), (2,3-dichlorophenyl)boronic acid (50 mg, 0.24 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (9 mg, 0.012 mmol) and potassium carbonate (50 mg, 0.36 mmol). The reaction mixture was bubbled with nitrogen for one minute, and then the sealed tube was heated to 80° C., and the reaction continued for 6 hours. After the reaction was completed, 20 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (50 mL×3). The organic phase was sequentially washed with water (20 mL×1) and saturated saline (20 mL×1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (petroleum ether: ethyl acetate=1:1) to obtain a crude product of (R)—N—((R)-8-(8-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro decan-1-yl)-2-methylpropane-2-sulfinamide (30 mg, yield: 48%) as a pale yellow solid.

(777) LC-MS: m/z 521.1 [M+H].sup.+.

Step 2: (R)-8-(8-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(778) ##STR00697##

(779) According to the method of step 3 of Example 24-2, (R)—N—((R)-8-(8-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro decan-1-yl)-2-methylpropane-2-sulfinamide was subjected to the removal of the sulfinyl group to obtain (R)-8-(8-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine.

(780) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.35 (s, 1H), 7.81-7.71 (m, 2H), 7.58-7.45 (m, 2H), 3.99 (t, J=13.6 Hz, 2H), 3.35 (dd, J=22.9, 10.6 Hz, 2H), 3.06 (t, J=6.2 Hz, 1H), 2.09-1.35 (m, 10H) ppm; LC-MS: m/z 417.1 [M+H].sup.+.

(781) According to the synthesis method of Example 24-2, the following compounds were synthesized:

Example 39-2: methyl (R)-3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)thio) propionate

(782) ##STR00698##

(783) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.32 (s, 1H), 8.34 (s, 1H) 7.71 (s, 1H), 3.88 (t, J=13.3 Hz, 2H), 3.57 (s, 3H), 3.24 (t, J=7.0 Hz, 4H), 3.08 (t, J=6.3 Hz, 1H), 2.68-2.59 (m, 2H), 2.03-1.39 (m, 10H) ppm; LC-MS: m/z 391.1 [M+H].sup.+.

Example 40-2: (R)-8-(8-(phenylthio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-a mine

(784) ##STR00699##

(785) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.34 (s, 1H), 7.84 (d, J=17.0 Hz, 1H), 7.33-7.19 (m, 5H), 3.98 (dd, J=27.7, 14.8 Hz, 2H), 3.32 (d, J=12.8 Hz, 2H), 3.02 (t, J=6.4 Hz, 1H), 2.01-1.39 (m, 10H) ppm; LC-MS: m/z 381.1 [M+H].sup.+.

Example 41-2: (R)-8-(8-((2-chlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]d ecan-1-amine

(786) ##STR00700##

(787) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.37 (s, 1H), 7.96 (s, 1H), 7.50 (dd, J=7.7, 1.4 Hz, 1H), 7.16 (dtd, J=21.0, 7.5, 1.5 Hz, 2H), 6.87 (dd, J=7.8, 1.6 Hz, 1H), 4.07 (dd, J=15.4, 11.3 Hz, 2H), 3.39 (dtd, J=13.7, 7.7, 3.1 Hz, 2H), 3.05 (s, 1H), 2.00 (q, J=7.9 Hz, 1H), 1.92-1.36 (m, 9H) ppm; LC-MS: m/z 415.1 [M+H].sup.+.

Example 42-2: (R)-8-(8-((4-chlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(788) ##STR00701##

(789) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.34 (s, 1H), 7.92 (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 7.27 (d, J=8.6 Hz, 2H), 4.12-3.92 (m, 2H), 3.35 (tt, J=13.8, 3.4 Hz, 2H), 3.04 (d, J=7.0 Hz, 1H), 1.99 (t, J=5.3 Hz, 1H), 1.92-1.33 (m, 9H) ppm; LC-MS: m/z 415.1 [M+H].sup.+.

Example 43-2: (R)-8-(8-((2,4-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(790) ##STR00702##

(791) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.38 (s, 1H), 7.98 (s, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.20 (dd, J=8.6, 2.3 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 4.05 (dd, J=12.3, 6.8 Hz, 2H), 2.76 (t, J=7.3 Hz, 1H), 1.94-1.75 (m, 4H), 1.66-1.53 (m, 2H), 1.45-1.27 (m, 4H) ppm; LC-MS: m/z 449.1 [M+H].sup.+.

Example 44-2: (R)-8-(8-((2,6-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(792) ##STR00703##

(793) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.31 (s, 1H), 7.62 (d, J=8.1 Hz, 2H), 7.48 (dd, J=8.7, 7.5 Hz, 1H), 7.34 (s, 1H), 3.82 (s, 2H), 3.21 (td, J=11.7, 11.3, 9.1 Hz, 2H), 2.72 (t, J=7.3 Hz, 1H), 1.85 (ddt, J=11.8, 7.6, 3.9 Hz, 1H), 1.77 (td, J=12.6, 11.4, 7.3 Hz, 3H), 1.64-1.49 (m, 2H), 1.42-1.25 (m, 4H) ppm; LC-MS: m/z 449.1 [M+H].sup.+.

Example 45-2: (R)-8-(8-((2-isopropylphenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(794) ##STR00704##

(795) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.34 (s, 1H), 7.71 (s, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.22 (ddd, J=8.0, 5.5, 3.1 Hz, 1H), 7.07-7.02 (m, 2H), 3.95 (dd, J=11.9, 6.8 Hz, 2H), 3.57-3.47 (m, 1H), 3.32-3.21 (m, 2H), 2.75 (t, J=7.3 Hz, 1H), 1.89-1.75 (m, 4H), 1.651.50 (m, 2H), 1.44-1.29 (m, 4H), 1.27 (d, J=6.8 Hz, 6H) ppm; LC-MS: m/z 423.1 [M+H].sup.+.

Example 46-2: (R)-8-(8-((2-methoxyphenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(796) ##STR00705##

(797) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.30 (s, 1H), 7.75 (s, 1H), 7.17 (ddd, J=8.5, 6.1, 2.8 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 6.80-6.74 (m, 2H), 3.96 (dd, J=12.5, 8.4 Hz, 4H), 3.86 (s, 3H), 3.35-3.27 (m, 2H), 2.75 (t, J=7.2 Hz, 1H), 1.90-1.76 (m, 2H), 1.65-1.15 (m, 8H) ppm; LC-MS: m/z 411.1 [M+H].sup.+.

Example 47-2: methyl (R)-2-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)thio) benzoate

(798) ##STR00706##

(799) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.35 (s, 1H), 7.96 (dd, J=8.2, 5.3 Hz, 2H), 7.33 (t, J=7.7 Hz, 1H), 7.24 (t, J=7.4 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 4.04 (dd, J=12.3, 7.8 Hz, 2H), 3.92 (s, 3H), 3.39 (d, J=10.5 Hz, 2H), 2.78 (t, J=7.2 Hz, 1H), 1.89-1.29 (m, 10H); LC-MS: m/z 439.1 [M+H].sup.+.

Example 48-2: (R)—N-(4-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl) thio)phenyl)acetamide

(800) ##STR00707##

(801) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.03 (s, 1H), 9.32 (s, 1H), 8.33 (s, 1H), 7.72 (s, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 3.93 (t, J=11.8 Hz, 2H), 3.29 (s, 2H), 2.94 (s, 1H), 2.02 (s, 3H), 1.96 (s, 1H), 1.77 (t, J=11.4 Hz, 3H), 1.67 (s, 1H), 1.57 (d, J=17.2 Hz, 2H), 1.50-1.32 (m, 3H) ppm; LC-MS: m/z 396.2 [M+H].sup.+.

Example 49-2: (R)-8-(8-((4-aminophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(802) ##STR00708##

(803) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.26 (d, J=15.3 Hz, 1H), 8.37 (s, 1H), 7.23 (dd, J=33.3, 27.4 Hz, 3H), 6.55 (t, J=20.4 Hz, 2H), 3.78 (dd, J=35.2, 22.6 Hz, 4H), 3.26-3.16 (m, 2H), 3.01 (t, J=6.5 Hz, 1H), 1.98 (d, J=10.5 Hz, 1H), 1.89-1.19 (m, 9H) ppm; LC-MS: m/z 396.1 [M+H].sup.+.

Example 50-2: (R)-8-(8-((3-amino-2-chlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(804) ##STR00709##

(805) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.35 (s, 1H), 8.32 (s, 1H), 7.87 (s, 1H), 6.80 (t, J=7.9 Hz, 1H), 6.59 (d, J=7.1 Hz, 1H), 6.01 (d, J=6.9 Hz, 1H), 5.51 (s, 2H), 4.03 (t, J=12.0 Hz, 2H), 3.39 (s, 2H), 2.96 (t, J=6.7 Hz, 1H), 1.96-1.44 (m, 10H) ppm; LC-MS: m/z 430.1 [M+H].sup.+.

Example 51-2: (R)—N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl) thio)-2-chlorophenyl)acrylamide

(806) ##STR00710##

(807) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.86 (s, 1H), 9.38 (s, 1H), 8.34 (s, 1H), 7.97 (s, 1H), 7.53 (d, J=7.7 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.71-6.59 (m, 2H), 6.29 (dd, J=17.1, 1.8 Hz, 1H), 5.83-5.77 (m, 1H), 4.13-4.03 (m, 2H), 3.53 (s, 2H), 2.94 (s, 1H), 1.92-1.40 (m, 10H) ppm; LC-MS: m/z 484.1 [M+H].sup.+.

Example 52-2: (R)-8-(8-(pyridin-2-ylthio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(808) ##STR00711##

(809) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.36 (s, 1H), 8.36 (d, J=4.7 Hz, 1H), 7.96 (s, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.13 (d, J=2.3 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 4.10-3.90 (m, 2H), 3.40 (d, J=11.0 Hz, 2H), 2.82 (s, 1H), 1.59 (ddd, J=23.4, 10.6, 4.0 Hz, 10H) ppm; LC-MS: m/z 382.1 [M+H].sup.+.

Example 53-2: (R)-8-(8-((3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(810) ##STR00712##

(811) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.41 (s, 1H), 8.56 (s, 1H), 8.28 (s, 1H), 8.19 (d, J=5.3 Hz, 1H), 8.04 (s, 1H), 6.84 (d, J=5.3 Hz, 1H), 4.11 (t, J=12.3 Hz, 2H), 3.43 (s, 2H), 3.00 (t, J=6.7 Hz, 1H), 1.99-1.43 (m, 10H) ppm; LC-MS: m/z 416.1 [M+H].sup.+.

Example 54-2: (R)-8-(8-((2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(812) ##STR00713##

(813) .sup.1HNMR (CD.sub.3OD-d.sub.4) δ 9.42 (s, 1H), 8.34 (s, 1H), 8.03-8.05 (m, 2H), 6.88-6.89 (m, 1H), 4.11-4.12 (m, 2H), 3.44-3.47 (m, 2H), 2.89 (m, 1H), 1.71-2.05 (m, 4H), 1.35-1.68 (m, 6H) ppm; LC-MS: m/z 449.8 [M+H].sup.+.

Example 55-2: (R)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(814) ##STR00714##

(815) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.41 (s, 1H), 8.31 (s, 1H), 8.05 (d, J=5.4 Hz, 1H), 8.02 (s, 1H), 6.67 (d, J=5.3 Hz, 1H), 4.10 (t, J=12.9 Hz, 2H), 3.46-3.40 (m, 2H), 3.01 (s, 1H), 1.99 (s, 1H), 1.88-1.66 (m, 4H), 1.65-1.39 (m, 5H) ppm; LC-MS: m/z 430.1 [M+H].sup.+.

Example 56-2: (R)-8-(8-((3-chloro-2-(dimethylamino)pyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(816) ##STR00715##

(817) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.38 (s, 1H), 7.98 (d, J=4.2 Hz, 1H), 7.82 (d, J=5.3 Hz, 1H), 6.31 (d, J=5.3 Hz, 1H), 4.16-3.94 (m, 2H), 3.41 (dd, J=15.8, 12.6 Hz, 2H), 2.91 (s, 6H), 2.84 (dd, J=13.1, 5.9 Hz, 1H), 1.90-1.36 (m, 10H) ppm; LC-MS: m/z 459.1 [M+H].sup.+.

Example 57-2: (R)-8-(8-((2-amino-5-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(818) ##STR00716##

(819) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.45 (s, 1H), 8.37 (s, 1H), 7.99 (s, 1H), 6.56 (s, 1H), 5.78 (s, 2H), 5.59 (s, 1H), 3.98 (s, 2H), 3.72 (s, 1H), 3.63 (d, J=8.3 Hz, 1H), 3.12 (s, 1H), 1.67 (d, J=79.0 Hz, 10H) ppm; LC-MS: m/z 432.1 [M+H].sup.+.

Example 58-2: (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(820) ##STR00717##

(821) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.46 (s, 1H), 8.30 (s, 1H), 8.03 (s, 1H), 6.31 (s, 2H), 5.71 (s, 1H), 4.11 (t, J=12.1 Hz, 2H), 3.44 (d, J=12.4 Hz, 2H), 2.92 (d, J=7.5 Hz, 1H), 1.96-1.77 (m, 4H), 1.70-1.64 (m, 2H), 1.56-1.40 (m, 4H).

(822) LC-MS: m/z 465.1 [M+H].sup.+.

Example 59-2: (R)-8-(8-((2-methylpyridin-3-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro decan-1-amine

(823) ##STR00718##

(824) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.35 (s, 1H), 8.26 (dd, J=4.7, 1.5 Hz, 1H), 7.91 (d, J=3.0 Hz, 1H), 7.31 (dd, J=8.0, 1.4 Hz, 1H), 7.07 (dd, J=7.9, 4.7 Hz, 1H), 4.05-3.94 (m, 2H), 3.30 (s, 3H), 2.80 (t, J=7.3 Hz, 1H), 2.61 (s, 3H), 1.89-1.25 (m, 10H) ppm; LC-MS: m/z 449.8 [M+H].sup.+.

Example 60-2: (R)-8-(8-((2-(trifluoromethyl)pyridin-3-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(825) ##STR00719##

(826) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.38 (s, 1H), 8.49 (d, J=4.5 Hz, 1H), 8.36 (s, 1H), 8.02 (s, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.46 (dd, J=8.3, 4.5 Hz, 1H), 4.08 (s, 2H), 2.94 (s, 2H), 1.98 (dd, J=14.4, 7.7 Hz, 2H), 1.88-1.64 (m, 4H), 1.52 (d, J 42.8 Hz, 6H) ppm; LC-MS: m/z 450.1 [M+H].sup.+.

Example 61-2: (R)-8-(8-(naphthalen-1-ylthio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(827) ##STR00720##

(828) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.33 (s, 1H), 8.39 (d, J=8.2 Hz, 1H), 8.27 (d, J=11.7 Hz, 1H), 8.00 (d, J=7.7 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.73 (s, 1H), 7.69-7.59 (m, 2H), 7.47 (d, J=7.1 Hz, 1H), 7.44-7.38 (m, 1H), 4.03-3.92 (m, 2H), 3.28 (s, 2H), 2.97 (s, 1H), 1.68 (dt, J=107.3, 31.9 Hz, 10H) ppm; LC-MS: m/z 431.2 [M+H].sup.+.

Example 62-2: (R)-8-(8-(quinolin-4-ylthio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(829) ##STR00721##

(830) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.40 (s, 1H), 8.54 (d, J=4.7 Hz, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.11-7.99 (m, 2H), 7.85 (t, J=7.6 Hz, 1H), 7.74 (t, J=7.6 Hz, 1H), 6.95 (d, J=4.7 Hz, 1H), 4.19-3.99 (m, 2H), 3.43 (dd, J=17.3, 8.7 Hz, 2H), 2.88 (t, J=7.0 Hz, 1H), 1.94-1.37 (m, 10H) ppm; LC-MS: m/z 432.2 [M+H].sup.+.

Example 63-2: (R)-8-(8-((1-methyl-1H-imidazol-2-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(831) ##STR00722##

(832) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.33 (s, 1H), 7.54 (s, 1H), 7.37 (d, J=1.2 Hz, 1H), 6.97 (d, J=1.2 Hz, 1H), 3.85 (d, J=2.4 Hz, 5H), 3.29-3.20 (m, 2H), 2.73 (t, J=7.3 Hz, 1H), 1.87-1.71 (m, 4H), 1.63-1.49 (m, 2H), 1.42-1.25 (m, 4H) ppm; LC-MS: m/z 385.2 [M+H].sup.+.

Example 64-2: (1R)-8-(8-((2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine

(833) ##STR00723##

(834) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.41 (s, 1H), 8.25 (s, 1H), 8.04 (d, J=5.3 Hz, 1H), 8.02 (s, 1H), 6.67 (d, J=5.3 Hz, 1H), 4.02-3.96 (m, 2H), 3.73 (d, J=8.4 Hz, 1H), 3.64 (d, J=8.5 Hz, 1H), 3.52 (d, J=10.0 Hz, 2H), 3.18-3.09 (m, 3H), 2.56 (s, 3H), 1.84 (dd, J=40.8, 9.5 Hz, 2H), 1.57 (d, J=12.5 Hz, 2H) ppm; LC-MS: m/z 434.1 [M+H].sup.+.

Example 65-2: (1R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine

(835) ##STR00724##

(836) .sup.1H NMR (CD.sub.3OD-d.sub.4) δ 9.37 (s, 1H), 7.98 (s, 1H), 7.57 (s, 1H), 6.36 (m, 2H), 5.93 (m, 1H), 4.16 (m, 2H), 3.44 (m, 2H), 3.10 (m, 1H), 2.42 (m, 1H), 1.31-2.13 (m, 8H), 1.01-1.05 (m, 3H) ppm; LC-MS: m/z 445.1 M+H].sup.+.

Example 66-2: (1R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine

(837) ##STR00725##

(838) .sup.1H NMR (CD.sub.3OD-d.sub.4) δ 9.45-9.46 (m, 1H), 8.04 (s, 1H), 6.32 (m, 2H), 5.74 (m, 1H), 4.14-4.17 (m, 2H), 3.45 (m, 2H), 3.14 (m, 2H), 1.45-2.41 (m, 8H), 1.02-1.05 (m, 3H) ppm; LC-MS: m/z 479.1 M+H).sup.+.

Example 67-2: (S)-8-(8-((2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

(839) ##STR00726##

(840) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.43 (s, 1H), 8.08-7.99 (m, 2H), 6.88 (d, J=5.3 Hz, 1H), 4.08-3.95 (m, 3H), 3.75-3.66 (m, 2H), 3.51 (d, J=13.6 Hz, 2H), 3.24-3.15 (m, 2H), 1.93-1.75 (m, 2H), 1.60 (d, J=13.1 Hz, 2H), 1.32 (s, 2H) ppm; LC-MS: m/z 452.1 [M+H].sup.+.

Example 68-2: (S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

(841) ##STR00727##

(842) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.38 (s, 1H), 8.28 (s, 1H), 7.97 (s, 1H), 7.57 (d, J=5.4 Hz, 1H), 6.34 (s, 2H), 5.95 (d, J=5.4 Hz, 1H), 3.97 (tt, J=13.8, 5.4 Hz, 3H), 3.72 (d, J=8.5 Hz, 1H), 3.64 (d, J=8.4 Hz, 1H), 3.49 (dq, J=10.7, 4.4, 2.9 Hz, 2H), 3.14 (t, J=5.9 Hz, 2H), 1.93-1.74 (m, 2H), 1.57 (dt, J=14.0, 4.3 Hz, 2H) ppm; LC-MS: m/z 433.1 [M+H].sup.+.

Example 69-2: (S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

(843) ##STR00728##

(844) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.41 (s, 1H), 8.25 (s, 1H), 8.04 (d, J=5.3 Hz, 1H), 8.02 (s, 1H), 6.67 (d, J=5.3 Hz, 1H), 4.02-3.96 (m, 2H), 3.73 (d, J=8.4 Hz, 1H), 3.64 (d, J=8.5 Hz, 1H), 3.52 (d, J=10.0 Hz, 2H), 3.18-3.09 (m, 3H), 2.56 (s, 3H), 1.84 (dd, J=40.8, 9.5 Hz, 2H), 1.57 (d, J=12.5 Hz, 2H) ppm; LC-MS: m/z 434.1 M+H].sup.+.

Example 70-2: (S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

(845) ##STR00729##

(846) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.47 (s, 1H), 8.25 (s, 1H), 8.04 (s, 1H), 6.30 (s, 2H), 5.71 (s, 1H), 4.09-3.92 (m, 4H), 3.73 (d, J=8.4 Hz, 1H), 3.65 (d, J=8.4 Hz, 1H), 3.49 (s, 2H), 3.16 (d, J=6.6 Hz, 1H), 1.88 (d, J=10.0 Hz, 2H), 1.59 (s, 2H) ppm; LC-MS: m/z 468 [M+H].sup.+.

Example 71-2: (3S,4S)-8-(8-((2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(847) ##STR00730##

(848) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.38 (s, 1H), 8.09-7.93 (m, 2H), 6.84 (d, J=5.3 Hz, 1H), 4.10 (q, J=6.1 Hz, 2H), 3.91 (dd, J=13.8, 5.5 Hz, 4H), 3.56 (m, 1H), 2.98 (d, J=5.0 Hz, 1H), 1.98-1.55 (m, 4H), 1.10 (d, J=6.3 Hz, 3H) ppm; LC-MS: m/z 466.1 [M+H].sup.+.

Example 72-2: (3S,4S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(849) ##STR00731##

(850) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.41 (s, 1H), 8.04 (d, J=5.4 Hz, 1H), 8.01 (s, 1H), 6.67 (d, J=5.3 Hz, 1H), 4.12-4.06 (m, 1H), 3.86 (s, 2H), 3.69 (d, J=8.4 Hz, 1H), 3.60 (dd, J=21.1, 9.5 Hz, 2H), 3.52 (d, J=8.5 Hz, 1H), 2.96 (d, J=4.9 Hz, 1H), 2.56 (s, 3H), 1.88 (d, J=48.6 Hz, 2H), 1.64 (s, 2H), 1.08 (dd, J=15.3, 6.5 Hz, 3H) ppm; LC-MS: m/z 446.1 [M+H].sup.+.

Example 73-2: (3S,4S)-8-(8-((2-amino-5-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-y 1)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(851) ##STR00732##

(852) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.41 (s, 1H), 7.99 (s, 1H), 7.82 (s, 1H), 5.83 (s, 2H), 5.76 (s, 1H), 4.14 (p, J=6.3 Hz, 2H), 3.96 (ddd, J=15.1, 10.0, 5.1 Hz, 4H), 3.60 (s, 1H), 3.14 (d, J=5.0 Hz, 1H), 1.97-1.62 (m, 4H), 1.13 (t, J=5.9 Hz, 3H) ppm; LC-MS: m/z 447.1 [M+H].sup.+.

Example 74-2: (3S,4S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-y 1)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(853) ##STR00733##

(854) .sup.1H NMR (CD.sub.3D-d.sub.4) δ 9.39 (s, 1H), 7.97 (s, 1H), 7.57 (s, 1H), 6.35 (m, 2H), 5.95 (m, 1H), 4.09-4.11 (m, 1H), 3.86-3.90 (m, 2H), 3.70-3.72 (m, 1H), 3.54-3.62 (m, 3H), 3.00-3.02 (m, 1H), 1.93-1.95 (m, 1H), 1.80-1.83 (m, 1H), 1.60-1.70 (m, 2H), 1.10-1.12 (m, 3H) ppm; LC-MS: m/z 447.1 [M+H].sup.+.

Example 75-2: (3S,4S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(855) ##STR00734##

(856) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.49 (s, 1H), 8.06 (s, 1H), 6.31 (s, 2H), 5.71 (s, 1H), 4.26-4.19 (m, 1H), 4.06 (s, 2H), 3.88 (d, J=9.1 Hz, 1H), 3.71 (d, J=8.8 Hz, 1H), 3.57-3.37 (m, 4H), 1.91 (s, 2H), 1.69 (s, 2H), 1.21 (d, J=6.4 Hz, 3H) ppm; LC-MS: m/z 481.1 [M+H].sup.+.

Example 76-2: (3R,4S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(857) ##STR00735##

(858) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.41 (d, J=5.4 Hz, 1H), 8.04 (d, J=5.3 Hz, 1H), 8.01 (s, 1H), 6.67 (d, J=5.2 Hz, 1H), 4.12 (dd, J=33.3, 13.6 Hz, 2H), 3.73 (dd, J=23.6, 8.8 Hz, 2H), 3.39 (dd, J=16.2, 10.4 Hz, 2H), 3.30 (s, 1H), 2.54 (d, J=16.4 Hz, 3H), 2.42 (d, J=8.2 Hz, 1H), 1.93-1.81 (m, 2H), 1.50 (d, J=13.5 Hz, 2H), 1.21 (d, J=6.0 Hz, 3H) ppm; LC-MS: m/z 446.1 [M+H].sup.+.

Example 77-2: (3R,4R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-y 1)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(859) ##STR00736##

(860) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.35 (s, 1H), 7.95 (s, 1H), 7.55 (d, J=5.4 Hz, 1H), 6.27 (s, 2H), 5.95 (d, J=5.4 Hz, 1H), 4.08 (p, J=6.3 Hz, 2H), 3.85-3.81 (m, 2H), 3.55 (s, 2H), 2.95 (d, J=5.0 Hz, 1H), 1.99-1.56 (m, 5H), 1.09 (d, J=6.4 Hz, 3H) ppm; LC-MS: m/z 447.1 [M+H].sup.+.

Example 78-2: 1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-4-methylpiperidin-4-amine

(861) ##STR00737##

(862) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.48 (s, 1H), 8.23 (s, 1H), 7.40 (dd, J=8.0, 1.2 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.74 (dd, J=8.1, 1.2 Hz, 1H), 4.54-4.30 (m, 2H), 4.15-3.94 (m, 2H), 1.76-1.48 (m, 4H), 1.18 (s, 3H) ppm; LC-MS: m/z 409.1 [M+H].sup.+.

Example 79-2: (R)-1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)azepan-4-amine

(863) ##STR00738##

(864) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.47 (s, 1H), 8.21 (s, 1H), 7.41 (d, J=7.5 Hz, 1H), 7.13 (t, J=8.1 Hz, 1H), 6.74 (d, J=7.9 Hz, 1H), 4.15 (dd, J=90.0, 47.9 Hz, 4H), 3.21 (s, 2H), 2.22 (s, 1H), 1.94 (d, J=56.0 Hz, 5H), 1.61 (d, J=12.2 Hz, 1H) ppm; LC-MS: m/z 408.7 [M+H].sup.+.

Example 80-2: (R)-3-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-3-azaspiro[4.5]undecan-7-amine

(865) ##STR00739##

(866) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.49 (s, 1H), 8.24 (s, 1H), 7.42 (d, J=7.1 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 4.84 (s, 2H), 3.67-3.53 (m, 2H), 2.89 (d, J=4.3 Hz, 1H), 1.98 (dd, J=24.0, 13.1 Hz, 2H), 1.48 (ddd, J=74.9, 37.6, 6.9 Hz, 12H) ppm; LC-MS: m/z 462.7 [M+H].sup.+.

Example 81-2: (3R,4S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(867) ##STR00740##

(868) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.48 (d, J=6.0 Hz, 1H), 8.23 (d, J=6.3 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.12 (t, J=8.1 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 4.95 (dd, J=37.1, 13.4 Hz, 2H), 3.76 (dd, J=26.2, 8.9 Hz, 2H), 3.44 (d, J=7.8 Hz, 1H), 2.42 (d, J=8.1 Hz, 1H), 1.82 (t, J=11.6 Hz, 2H), 1.50 (d, J=13.6 Hz, 2H), 1.28-1.17 (m, 5H) ppm; LC-MS: m/z 465.1 [M+H].sup.+.

Example 82-2: (S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

(869) ##STR00741##

(870) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.48 (s, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 7.41 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.72 (dd, J=8.0 Hz, J=1.6 Hz, 1H), 4.76 (t, J=16.0 Hz, 2H), 4.06 (dd, J=9.6 Hz, 2.4 Hz, 1H), 3.81 (s, 2H), 3.67-3.54 (m, 3H), 3.35 (t, J=4.8 Hz, 1H), 1.87-1.81 (m, 2H), 1.68-1.65 (m, 2H) ppm; LC-MS: m/z 451.1 [M+H].sup.+.

Example 83-2: (3R,4R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-3-meth yl-2-oxa-8-azaspiro[4.5]decan-4-amine

(871) ##STR00742##

(872) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.48 (s, 1H), 8.23 (s, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.12 (t, J=8.1 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 4.45 (d, J=13.1 Hz, 2H), 4.11-4.05 (m, 2H), 3.96-3.80 (m, 2H), 2.96 (d, J=5.1 Hz, 1H), 2.01-1.93 (m, 2H), 1.78-1.56 (m, 4H), 1.09 (d, J=6.4 Hz, 3H); LC-MS: m/z 465.1 [M+H].sup.+.

Example 84-2: (R)-8-(8-(phenylthio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(873) ##STR00743##

(874) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.49 (s, 1H), 8.17 (s, 1H), 7.29-7.24 (m, 2H), 7.18 (dd, J=12.1, 7.2 Hz, 3H), 4.86 (t, J=11.7 Hz, 2H), 3.44 (t, J=12.5 Hz, 2H), 3.01 (t, J=6.7 Hz, 1H), 1.97 (dd, J=12.7, 7.3 Hz, 1H), 1.85-1.41 (m, 9H) ppm; LC-MS: m/z 381.2 [M+H].sup.+.

Example 85-2: (R)-8-(8-((2-methoxyphenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(875) ##STR00744##

(876) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.48 (s, 1H), 8.34 (s, 1H), 8.10 (s, 1H), 7.14 (t, J=7.8 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.75 (t, J=7.6 Hz, 1H), 6.64 (d, J=7.7 Hz, 2H), 4.87 (d, J=12.5 Hz, 3H), 3.88 (s, 2H), 2.93 (d, J=7.2 Hz, 1H), 2.02-1.92 (m, 2H), 1.82-1.37 (m, 8H) ppm; LC-MS: m/z 411.1 [M+H].sup.+.

Example 86-2: (R)-8-(8-((4-aminophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(877) ##STR00745##

(878) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.52 (s, 1H), 8.35 (s, 1H), 7.75 (s, 1H), 7.21 (d, J=8.2 Hz, 2H), 6.52 (d, J=8.4 Hz, 2H), 5.39 (s, 2H), 4.69 (s, 2H), 2.87 (s, 1H), 1.93-1.30 (m, 10H) ppm; LC-MS: m/z 396.2 [M+H].sup.+.

Example 87-2: (R)-8-(8-((3-(trifluoromethyl)phenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-8-aza spiro[4.5]decan-1-amine

(879) ##STR00746##

(880) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.47 (d, J=10.2 Hz, 1H), 8.22 (d, J=11.4 Hz, 1H), 7.57 (s, 1H), 7.54-7.36 (m, 3H), 4.97-4.72 (m, 2H), 3.47 (t, J=9.7 Hz, 2H), 2.72 (t, J=7.5 Hz, 1H), 1.83-1.26 (m, 10H); LC-MS: m/z 449.1 [M+H].sup.+.

Example 88-2: (R)-8-(8-(pyridin-3-ylthio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(881) ##STR00747##

(882) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.49 (s, 1H), 8.36 (s, 1H), 8.17 (s, 1H), 7.27 (d, J=7.6 Hz, 2H), 7.23-7.13 (m, 3H), 4.86 (t, J=12.3 Hz, 2H), 3.47 (d, J=2.6 Hz, 2H), 2.96 (t, J=7.0 Hz, 1H), 1.98 (q, J=5.7, 4.2 Hz, 1H), 1.92-1.34 (m, 9H) ppm; LC-MS: m/z 382.2 [M+H].sup.+.

Example 89-2: (R)-8-(8-((3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(883) ##STR00748##

(884) .sup.1H NMR (CD.sub.3D-d.sub.4) δ 8.50-8.54 (m, 2H), 8.37 (s, 1H), 8.26 (m, 1H), 8.16-8.17 (s, 1H), 6.79-6.80 (m, 1H), 4.94 (m, 2H), 3.48-3.53 (m, 2H), 2.91 (m, 1H), 1.71-2.05 (m, 4H), 1.35-1.68 (m, 6H) ppm; LC-MS: m/z 416.1 [M+H].sup.+.

Example 90-2: (R)-8-(8-((3-(trifluoromethyl)pyridin-4-yl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(885) ##STR00749##

(886) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.82 (s, 1H), 8.49 (s, 1H), 8.42 (d, J=5.5 Hz, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 7.01 (d, J=5.5 Hz, 1H), 4.96 (s, 2H), 3.51 (t, J=11.8 Hz, 3H), 2.96 (t, J=7.0 Hz, 1H), 2.02-1.35 (m, 10H) ppm; LC-MS: m/z 450.1 [M+H].sup.+.

Example 91-2: (R)-8-(8-((2-chloropyridin-3-yl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(887) ##STR00750##

(888) .sup.1H NMR (CD.sub.3OD-d.sub.4) δ 8.49 (m, 1H), 8.36 (s, 1H), 8.26 (m, 1H), 8.16-8.18 (s, 1H), 7.20-7.23 (m, 2H), 4.96-4.94 (m, 2H), 3.50-3.46 (m, 2H), 2.96-2.90 (m, 1H), 1.71-2.05 (m, 4H), 1.35-1.68 (m, 6H) ppm. LC-MS: m/z 416.1 [M+H].sup.+.

Example 92-2: (R)-8-(8-((2-methylpyridin-3-yl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-8-azaspiro decan-1-amine

(889) ##STR00751##

(890) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.50 (s, 1H), 8.24-8.22 (m, 1H), 8.21 (s, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.04 (dd, J=7.9, 4.5 Hz, 1H), 3.52-3.44 (m, 2H), 3.18-3.10 (m, 3H), 2.59 (s, 3H), 2.04 (s, 1H), 1.86-1.35 (m, 9H) ppm. LC-MS: m/z 396.1 [M+H].sup.+.

Example 93-2: (R)-8-(8-((6-amino-2-chloropyridin-3-yl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(891) ##STR00752##

(892) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.52 (s, 1H), 7.98 (s, 1H), 7.40 (d, J=8.5 Hz, 1H), 6.61 (s, 2H), 6.33 (d, J=8.5 Hz, 1H), 4.78 (s, 2H), 3.16 (d, J=5.0 Hz, 1H), 3.04 (s, 1H), 2.67 (s, 2H), 1.82-1.40 (m, 10H) ppm; LC-MS: m/z 431.2 [M+H].sup.+.

Example 94-2: (R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(893) ##STR00753##

(894) .sup.1H NMR (CD.sub.3OD-d.sub.4) δ 8.48 (s, 1H), 8.20 (s, 1H), 7.55 (s, 1H), 6.36 (s, 2H), 5.87 (m, 1H), 4.90 (m, 2H), 3.45-3.48 (m, 2H), 2.74-2.76 (m, 1H), 1.76-1.83 (m, 4H), 1.51-1.63 (m, 2H), 1.35-1.46 (m, 4H) ppm; LC-MS: m/z 431.1 M+H].sup.+.

Example 95-2: (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine

(895) ##STR00754##

(896) .sup.1H NMR (400 MHz, CD.sub.3OD-d.sub.4) δ 8.25 (s, 1H), 8.09 (s, 1H), 5.64 (s, 1H), 5.06 (s, 2H), 3.45-3.37 (m, 2H), 2.73 (t, J=7.5 Hz, 1H), 1.97-1.67 (m, 5H), 1.54 (dd, J=11.6, 5.0 Hz, 2H), 1.46-1.31 (m, 3H) ppm; LC-MS: m/z 467.1 M+H].sup.+.

Example 96-2: (S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

(897) ##STR00755##

(898) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.50 (s, 1H), 8.24 (d, J=3.4 Hz, 2H), 8.03 (d, J=5.3 Hz, 1H), 6.61 (d, J=5.4 Hz, 1H), 4.02-3.97 (m, 2H), 3.78 (s, 2H), 3.69 (s, 2H), 3.17 (s, 3H), 2.55 (s, 3H), 1.80 (d, J=27.7 Hz, 2H), 1.59 (s, 2H) ppm; LC-MS: m/z 434.1 [M+H].sup.+.

Example 97-2: (3S,4S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(899) ##STR00756##

(900) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.48 (s, 1H), 8.23 (s, 1H), 8.01 (d, J=5.3 Hz, 1H), 6.59 (d, J=5.4 Hz, 1H), 4.60 (d, J=13.5 Hz, 2H), 4.13 (d, J=5.9 Hz, 1H), 3.75 (dd, J=21.8, 9.9 Hz, 4H), 3.14 (d, J=19.8 Hz, 1H), 2.54 (s, 3H), 1.97-1.60 (m, 4H), 1.13 (d, J=6.4 Hz, 3H) ppm; LC-MS: m/z 446.1 [M+H].sup.+.

Examples 125-127: Pharmacological Related Examples

Example 125: SHP2 Enzyme Activity Inhibition Experiment

(901) Compound powders were dissolved in DMSO to prepare mother liquor.

(902) During the experiment, the stock solutions of the compounds were subjected to 3-fold gradient dilution with DMSO, and 10 different test concentrations of each compound were set. 1 μL of each concentration of the compounds was transferred into the wells of detection plates (Corning, Costar 3915), setting two duplicates for each concentration. The protein used was the activated protein SHP.sup.2E76A with amino acid mutation at position 76 of the protein, and the substrate used was DiFMUP (Invitrogen, E12020). SHP2.sup.E76A protein and substrate were diluted with buffer (0.1 M NaAc (pH 7.2), 0.02% Tween 20, 0.1% BSA, 1 mM EDTA, 5 mM DTT) to a concentration of 1.2 nM and 20 M, respectively. 50 L of enzyme solution was added to the detection wells, followed by 50 L of substrate. On the Spectra max i3 (Molecular Devices) instrument, the fluorescence signal was recorded (Ex 358 nm/Em 455 nm) every minute, from which the product accumulation rate was calculated to characterize the enzyme activity. GraphPad Prism 5 was used for nonlinear regression analysis, and the curve of enzyme activity versus compound concentration was fitted by the equation Y=Bottom+(Top-Bottom)/(1+10{circumflex over ( )}((Log IC.sub.50−X)*HillSlope)) to calculate the IC.sub.50 value of each compound.

(903) Results

(904) Tables 1.1 and 1.2 below show the IC.sub.50 values of some compounds of the present disclosure.

(905) The letter “A” refers to IC.sub.50 less than 100 nM.

(906) The letter “B” refers to IC.sub.50 ranging from 100 nM to 1000 nM.

(907) The letter “C” refers to IC.sub.50 ranging from 1000 nM to 10000 nM.

(908) TABLE-US-00008 TABLE 1.1 Compound IC.sub.50 1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-4-methylpiperidin- B 4-amine 1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-amine B (R)-1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)azepan-4-amine B (1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)pyrrolidin-3-yl) B methanamine (1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-4-methylpiperidin- A 4-yl)methanamine (1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl) B methanamine (R)-7-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-7-azaspiro B [3.5]nonan-1-amine 7-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-7-azaspiro[3.5] B nonan-2-amine (S)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2-oxa-8-azaspiro A [4.5]decan-4-amine (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-1-oxa-8-azaspiro B [4.5]decan-4-amine (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro A [4.5]decan-1-amine (1R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2-methyl-8- A azaspiro[4.5]decan-1-amine (1R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-methyl-8- A azaspiro[4.5]decan-1-amine (4R)-4-amino-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8- A azaspiro[4.5]decan-2-ol (3S,4S)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-methyl- A 2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- A 5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (R)-8-(8-(2,3-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro B [4.5]decan-1-amine (R)-8-(8-(phenylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine B (R)-8-(8-((2-chlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro A [4.5]decan-1-amine (R)-8-(8-((2,4-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro B [4.5]decan-1-amine (R)-8-(8-((2-isopropylphenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro B [4.5]decan-1-amine (R)-8-(8-((2-methoxyphenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro A [4.5]decan-1-amine (R)-8-(8-((3-amino-2-chlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro B [4.5]decan-1-amine (R)-N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl) B thio)-2-chlorophenyl)acrylamide (R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8- A azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro B [4.5]decan-1-amine (R)-8-(8-((3-(trifluoromethyl)pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8- A azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-fluoropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8- A azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-methoxypyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)- A 8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-cyclopropylpyrimidin-4-yl)thio)imidazo[1,2-c]pyrimidin- A 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8- A azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-(dimethylamino)pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- A 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-amino-5-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8- A azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)- A 8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro A [4.5]decan-1-amine (R)-8-(8-((2-methylpyridin-3-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro A [4.5]decan-1-amine (R)-8-(8-((2-(trifluoromethyl)pyridin-3-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8- A azaspiro[4.5]decan-1-amine (R)-8-(8-((2-chloropyridin-3-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro A [4.5]decan-1-amine (R)-8-(8-((6-amino-2-chloropyridin-3-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8- A azaspiro[4.5]decan-1-amine (R)-8-(8-((2-chloropyrimidin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro A [4.5]decan-1-amine (R)-8-(8-((3-chloropyridazin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro B [4.5]decan-1-amine (R)-8-(8-(benzo[d]thiazol-7-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro B [4.5]decan-1-amine (R)-8-(8-((1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- A 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2,3-dihydrobenzofuran-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8- B azaspiro[4.5]decan-1-amine (R)-8-(8-(naphthalen-1-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5] A decan-1-amine (R)-8-(8-(quinolin-4-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan- A 1-amine (R)-4-((5-(1-amino-8-azaspiro[1,2-c]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl) B thio)indoline-2,3-dione 4-((5-(4-amino-4-methylpiperidin-1-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)-3- B chloropyridin-2-amine (1R)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3- A methyl-8-azaspiro[4.5]decan-1-amine (1R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3- A methyl-8-azaspiro[4.5]decan-1-amine (S)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2-oxa-8- A azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)- A 3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)- A 2-oxa-8-azaspiro[4.5]decan-4-amine (S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-2- A oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3- A methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)- A 3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-4-phenylpiperidin- B 4-yl)methanamine Methyl B (R)-2-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio) benzoate (R)-N.sup.1-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl) B thio)-2-chlorophenyl)-N.sup.2,N.sup.2-dimethyloxalamide (R)-N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-c]pyrimidin-8-yl) B thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidin-3-carboxamide (R)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- A 5-yl)-8-azaspiro[1,2-c]decan-1-amine (1R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)- A 3-methyl-8-azaspiro[4.5]decan-1-amine (S)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- A 5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((2-amino-5-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)- A 3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2-c] A pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)- A 3,3-difluoro-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- A 5-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine (R)-3-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-azaspiro B [5.5]undecan-7-amine (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,3-dimethyl- B 1-oxa-8-azaspiro[4.5]decan-4-amine (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,3-difluoro- A 8-azaspiro[4.5]decan-1-amine

(909) TABLE-US-00009 TABLE 1.2 Compound IC.sub.50 1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- B 5-yl)-4-methylpiperidin-4-amine 1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5- C yl)piperidin-4-amine (1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5- A yl)-4-phenylpiperidin-4-yl)methanamine 8-((2,3-dichlorophenyl)thio)-5-(3,5-dimethylpiperazin-1-yl)- C [1,2,4]triazolo[4,3-c]pyrimidine (R)-1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- B 5-yl)azepan-4-amine (1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5- B yl)pyrrolidin-3-yl)methanamine (1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5- A yl)-4-methylpiperidin-4-yl)methanamine 2-(1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- C 5-yl)piperidin-4-yl)ethan-1-amine (S)-7-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- C 5-yl)-7-azaspiro[3.5]nonan-1-amine 7-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5- C yl)-7-azaspiro[3.5]nonan-2-amine 8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5- C yl)-1,8-diazaspiro[4.5]decane (4R)-2-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- C 5-yl)octahydrocyclopenta[c]pyrrol-4-amine (R)-3-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- B 5-yl)-3-azaspiro[5.5]undecan-7-amine (S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- A 5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- A 5-yl)-8-azaspiro[4.5]decan-1-amine (S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- C 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- C 5-yl)-N-methyl-8-azaspiro[4.5]decan-1-amine (1R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- A 5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (3S,4S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3- A c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3R,4R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3- C c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine 8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5- C yl)-4-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine 1-(8-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-4- C methylpiperidin-4-amine (R)-8-(8-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5- C yl)-8-azaspiro[4.5]decan-1-amine Methyl (R)-3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)- C [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)thio)propionate (R)-8-(8-(phenylthio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8- C azaspiro[4.5]decan-1-amine (R)-8-(8-((2-chlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- B 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((4-chlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- C 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2,4-dichlorophenyl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2,6-dichlorophenyl)thio)-[1,2,4]triazolo[4,3- C c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-isopropylphenyl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-methoxyphenyl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine Methyl (R)-2-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)- C [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)thio)benzoate (R)-8-(8-((4-aminophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- C 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-amino-2-chlorophenyl)thio)-[1,2,4]triazolo[4,3- A c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)-[1,2,4] B triazolo[4,3-c]pyrimidin-8-yl)thio)-2-chlorophenyl)acrylamide (R)-N-(4-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)-[1,2,4] C triazolo[4,3-c]pyrimidin-8-yl)thio)phenyl)acetamide (R)-8-(8-(pyridin-2-ylthio)-[1,2,4]triazolo[4,3-c]pyrimidin-5- C yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo A [4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-(dimethylamino)pyridin-4-yl)thio)- B [1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-amino-5-chloropyridin-4-yl)thio)-[1,2,4]triazolo C [4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4] A triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- A c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-methylpyridin-3-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-(trifluoromethyl)pyridin-3-yl)thio)-[1,2,4]triazolo B [4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-(naphthalen-1-ylthio)-[1,2,4]triazolo[4,3-c]pyrimidin- A 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-(quinolin-4-ylthio)-[1,2,4]triazolo[4,3-c]pyrimidin-5- A yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((1-methyl-1H-imidazol-2-yl)thio)-[1,2,4]triazolo[4,3- C c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine 4-((5-(4-amino-4-methylpiperidin-1-yl)-[1,2,4]triazolo[4,3- B c]pyrimidin-8-yl)thio)-3-chloropyridin-2-amine (1R)-8-(8-((2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- A c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (1R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo A [4,3-c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (1R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo A [4,3-c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (S)-8-(8-((2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (S)-8-(8-(3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo A [4,3-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- A c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo A [4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((2-amino-5-chloropyridin-4-yl)thio)-[1,2,4]triazolo A [4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo A [4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo A [4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3R,4S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo A [4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3R,4R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo C [4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine 1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5- C yl)-4-methylpiperidin-4-amine (R)-8-(8-((6-amino-2-chloropyridin-3-yl)thio)-[1,2,4]triazolo[1,5- C c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (3R,4S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5- B c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (R)-8-(8-((3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[1,5-c] C pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo B [1,5-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8((2-chloropyridin-3-yl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin- B 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-(pyridin-3-ylthio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-8- C azaspiro[4.5]decan-1-amine (R)-8-(8-((2-methoxyphenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5- B yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8((4-aminophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)- C 8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-(trifluoromethyl)pyridin-4-yl)thio)-[1,2,4]triazolo[1,5- C c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[1,5- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8((2-methylpyridin-3-yl)thio)-[1,2,4]triazolo]1,5-c]pyrimidin- C 5-yl)-8-azaspiro[4.5]decan-1-amine (S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin- B 5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine 3-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5- B yl)-3-azaspiro[5.5]undecan-7-amine 1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5- B yl)azepan-4-amine (R)-8-(8-(phenylthio)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-8- C azaspiro[4.5]decan-1-amine (3R,4R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5- C c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo[1,5- C c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo B [1,5-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

Example 126: Phosphorylated Protein Kinase (p-ERK) Cell Experiment

(910) The inhibitory activities of the compounds on the phosphorylation level of intracellular protein kinase (ERK) were determined by AlphaLISA method.

(911) Firstly, the cells were treated with the compounds. The compounds to be tested were subjected to 3-fold dilution with 100% DMSO, and a total of 9 different concentration gradients were set. MOLM13 cells were then seeded into 96-well plates at a density of 30,000 cells per well in a volume of 100 L per well. 0.5 L of DMSO or the test compounds with different concentrations was then transferred into each well, setting two duplicates for each concentration, and the final concentration of DMSO was controlled at 0.5%.

(912) Secondly, the cells were lysed. After 2 hours of cell treatment, the medium was removed, and the cells were washed 3 times with phosphate buffered saline. 50 L of freshly prepared lysis buffer was added to each well, and the plates were shaken and kept at room temperature for 10 minutes.

(913) Thirdly, the phosphorylated extracellular signal-regulated kinase (p-ERK) was detected by AlphaLISA@ SureFire® Ultra™ p-ERK 1/2 (Thr202/Tyr204) kit (Perkin Elmer, ALSU-PERK-A10K). 10 L of the above lysate was transferred to a 384-well plate (Perkin Elmer, 6005350), and the phosphorylation level of the extracellular signal-regulated kinase of the sample was detected according to the product instructions. The signal was read using AlphaScreen detector on Spectra max i3 (Molecular Devices). The percentage of inhibition (%) was calculated by the following formula:
Inhibition percentage(%)=(1−p-ERK signal of compound-treated cells/p-ERK signal of DMSO-treated cells)*100

(914) Results

(915) Tables 2.1 and 2.2 below show the IC.sub.50 values of some compounds of the present disclosure.

(916) The letter “A” refers to IC.sub.50 less than 100 nM.

(917) The letter “B” refers to IC.sub.50 ranging from 100 nM to 1000 nM.

(918) The letter “C” refers to IC.sub.50 ranging from 1000 nM to 10000 nM.

(919) TABLE-US-00010 TABLE 2.1 Compound IC.sub.50 (R)-7-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)- B 7-azaspiro[3.5]nonan-1-amine (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)- B 1-oxa-8-azaspiro[4.5]decan-4-amine (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)- B 8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-methoxyphenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8- B azaspiro[4.5]decan-1-amine (R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)- B 8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-methoxypyridin-4-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-(dimethylamino)pyridin-4-yl)thio)imidazo B [1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-amino-5-chloropyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- B 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-(trifluoromethyl)pyridin-3-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8((2-chloropyridin-3-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)- B 8-azaspiro[4.5]decan-1-amine (R)-8-(8-(naphthalen-1-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8- B azaspiro[4.5]decan-1-amine (R)-8-(8-(quinolin-4-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8- B azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-fluoropyridin-4-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (1R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5- B yl)-2-methyl-8-azaspiro[4.5]decan-1-amine (1R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5- A yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (S)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- B 5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (R)-8-(8-((1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thio)imidazo B [1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloropyridazin-4-yl)thio)imidazo[1,2-c]pyrimidin- B 5-yl)-8-azaspiro[4.5]decan-1-amine (4R)-4-amino-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-2-ol (3S,4S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (R)-N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2- B c]pyrimidin-8-yl)thio)-2-chlorophenyl)acrylamide (3S,4S)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5- B yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1R)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- A 5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (1R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-(trifluoromethyl)pyridin-4-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5- B yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo A [1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (S)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo B [1,2-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((2-amino-5-chloro-pyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio) A imidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5] decan-4-amine (R)-N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2- A c]pyrimidin-8-yl)hio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9- tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-carboxamide (R)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo A [1,2-c]pyrimidin-5-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine

(920) TABLE-US-00011 TABLE 2.2 Compound name IC.sub.50 1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- C 5-yl)-4-methylpiperidin-4-amine (1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- C 5-yl)pyrrolidin-3-yl)methanamine (1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- B 5-yl)-4-methylpiperidin-4-yl)methanamine (R)-3-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3- C c]pyrimidin-5-yl)-3-azaspiro[5.5]undecan-7-amine (S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (1R)-8-(8-(((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3- A c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (3S,4S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (R)-8-(8-((2-chlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- B 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-amino-2-chlorophenyl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)-[1,2,4]triazolo C [4,3-c]pyrimidin-8-yl)thio)-2-chlorophenyl)acrylamide (R)-8-(8-((3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4] B triazolo[4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- C c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-(trifluoromethyl)pyridin-3-yl)thio)-[1,2,4]triazolo[4,3- C c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine 4-((5-(4-amino-4-methylpiperidin-1-yl)-[1,2,4]triazolo[4,3- C c]pyrimidin-8-yl)thio)-3-chloropyridin-2-amine (1R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo A [4,3-c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo B [4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4- amine (R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[1,5- C c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo B [1,5-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin- C 5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

Example 127: MOLM-13 Cell Proliferation Experiment

(921) MOLM-13 cells suspended in medium (RPMI-1640, containing 10% FBS and 1% Penicillin-Streptomycin, Gibco) were seeded on 384-well plates at 800 cells (40 μL/well). The cells were immediately treated with the test compounds at concentration of 50, 16.67, 5.56, 1.85, 0.617, 0.206, 0.069, 0.023, 0.0076 P M. After 3 days, 5 L of CellTiter-Glo reagent (Promega, ZG7572) was added to each well, and the plates were kept at room temperature in the dark for 10 minutes. The fluorescence signal was detected by Spectra max i3 (Molecular Devices). The relative growth rate of the treated cells was compared with that of DMSO control.

(922) Results

(923) Tables 3.1 and 3.2 below show the IC.sub.50 values of some compounds of the present disclosure.

(924) The letter “A” refers to IC.sub.50 less than 100 nM.

(925) The letter “B” refers to IC.sub.50 ranging from 100 nM to 1000 nM.

(926) The letter “C” refers to IC.sub.50 ranging from 1000 nM to 10000 nM.

(927) TABLE-US-00012 TABLE 3.1 Compound name IC.sub.50 1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-4- B methylpiperidin-4-amine (1-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-4- B methylpiperidin-4-yl)methanamine (R)-7-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)- B 7-azaspiro[3.5]nonan-1-amine (S)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)- B 2-oxa-8-azaspiro[4.5]decan-4-amine (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)- B 8-azaspiro[4.5]decan-1-amine (1R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)- B 2-methyl-8-azaspiro[4.5]decan-1-amine (1R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)- B 3-methyl-8-azaspiro[4.5]decan-1-amine (4R)-4-amino-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-2-ol (3S,4S)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5- A yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio) A imidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5] decan-4-amine (3S,4S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (R)-8-(8-(phenylthio)imidazo[1,2-c]pyrimidin-5-yl)-8- B azaspiro[4.5]decan-1-amine (R)-8-(8-((2-methoxyphenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8- B azaspiro[4.5]decan-1-amine (R)-8-(8-((3-amino-2-chlorophenyl)thio)imidazo[1,2-c]pyrimidin- B 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2- B c]pyrimidin-8-yl)thio)-2-chlorophenyl)acrylamide (R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5- B yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-(trifluoromethyl)pyridin-4-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-fluoropyridin-4-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-methoxypyridin-4-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-cyclopropylpyrimidin-4-yl)thio)imidazo B [1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-(dimethylamino)pyridin-4-yl)thio)imidazo B [1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-amino-5-chloropyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- A 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8((2-methylpyridin-3-yl)thio)imidazo[1,2-c]pyrimidin-5- B yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-(trifluoromethyl)pyridin-3-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8((2-chloropyridin-3-yl)thio)imidazo[1,2-c]pyrimidin-5- B yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloropyridazin-4-yl)thio)imidazo[1,2-c]pyrimidin- B 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thio)imidazo B [1,2-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-(naphthalen-1-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8- B azaspiro[4.5]decan-1-amine (R)-8-(8-(quinolin-4-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8- A azaspiro[4.5]decan-1-amine (1R)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- A 5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (3S,4S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (S)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- B 5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2- A c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5- B yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine Methyl (R)-2-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo B [1,2-c]pyrimidin-8-yl)thio)benzoate (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine (S)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo B [1,2-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((6-amino-3-chloro-pyridin-4-yl)thio)imidazo[1,2- B c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (S)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo A [1,2-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (R)-N1-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2- B c]pyrimidin-8-yl)thio)-2-chlorophenyl)-N.sup.2,N.sup.2-dimethyloxalamide (R)-N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)imidazo[1,2- B c]pyrimidin-8-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9- tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-carboxamide

(928) TABLE-US-00013 TABLE 3.2 Compound name IC.sub.50 1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- C 5-yl)-4-methylpiperidin-4-amine (1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5- B yl)-4-phenylpiperidin-4-yl)methanamine (R)-1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- C 5-yl)azepan-4-amine (1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5- C yl)pyrrolidin-3-yl)methanamine (1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5- C yl)-4-methylpiperidin-4-yl)methanamine (R)-3-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- C 5-yl)-3-azaspiro[5.5]undecan-7-amine (S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- B 5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- B 5-yl)-8-azaspiro[4.5]decan-1-amine (1R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3- A c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (3S,4S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (R)-8-(8-((2-chlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5- B yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2,4-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- C 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-isopropylphenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- C 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-methoxyphenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5- B yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-amino-2-chlorophenyl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-N-(3-((5-(1-amino-8-azaspiro[4.5]decan-8-yl)-[1,2,4]triazolo B [4,3-c]pyrimidin-8-yl)thio)-2-chlorophenyl)acrylamide (R)-8-(8-((3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo B [4,3-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8((2-methylpyridin-3-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- C 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-(trifluoromethyl)pyridin-3-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-(naphthalen-1-ylthio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)- B 8-azaspiro[4.5]decan-1-amine 4-((5-(4-amino-4-methylpiperidin-1-yl)-[1,2,4]triazolo[4,3- C c]pyrimidin-8-yl)thio)-3-chloropyridin-2-amine (1R)-8-(8-((2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (1R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (1R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo A [4,3-c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (S)-8-(8-((2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo[4,3- B c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo C [4,3-c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- C c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((2-amino-5-chloropyridin-4-yl)thio)-[1,2,4]triazolo C [4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4- amine (3S,4S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo B [4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4- amine (3S,4S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4] B triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5] decan-4-amine (R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[1,5- B c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[1,5- C c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo B [1,5-c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8((2-chloropyridin-3-yl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin- C 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8((2-methoxyphenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5- C yl)-8-azaspiro[4.5]decan-1-amine (S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin- B 5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine 3-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5- C yl)-3-azaspiro[5.5]undecan-7-amine 1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[1,5-c]pyrimidin-5- C yl)azepan-4-amine (3S,4S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo C [1,5-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4- amine

(929) The applicant has tested the compound SHP099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine) disclosed in WO2015/107493A1 or literature (Nature 2016, 535, 148-152) according to the same test method as the SHP2 enzyme activity inhibition experiment described in Example 125, the phosphorylated protein kinase (p-ERK) cell experiment described in Example 126 and the MOLM-13 cell proliferation experiment described in Example 127. Table 4 below lists the comparative experimental data between the compounds obtained in some examples of the present disclosure and SHP099. After comparison, it is found that the pyrimidine-fused compounds of the present disclosure have more superior activities.

(930) TABLE-US-00014 TABLE 4 SHP2 MOLM-13 enzyme cell activity p-ERK prolifera- IC.sub.50 IC.sub.50 tion IC.sub.50 Compound name (μm) (μm) (μm) SHP099: 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2- 0.33 2.07 1.37 amine) (R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- 0.02 0.41 0.27 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)- 0.057 0.159 0.042 8-azaspiro[4.5]decan-1-amine (R)-8-(8-((2-methoxyphenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-8- 0.083 0.469 0.210 azaspiro[4.5]decan-1-amine (3S,4S)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo 0.016 0.043 0.042 [1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (R)-8-(8-((2-amino-5-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- 0.025 0.032 0.043 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-(naphthalen-1-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro 0.028 0.49 0.15 [4.5]decan-1-amine (R)-8-(8-(quinolin-4-ylthio)imidazo[1,2-c]pyrimidin-5-yl)-8-azaspiro 0.02 0.031 0.099 [4.5]decan-1-amine (R)-8-(8-((3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2- 0.04 0.18 0.058 c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (1R)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3- 0.011 0.053 0.14 methyl-8-azaspiro[4.5]decan-1-amine (4R)-4-amino-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin- 0.009 0.028 0.042 5-yl)-8-azaspiro[4.5]decan-2-ol (1R)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2- 0.032 0.059 0.054 c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (3S,4S)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- 0.005 0.035 0.038 5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2- 0.02 0.15 0.076 c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2- 0.009 0.028 0.054 c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((2,3-dichlorophenyl)thio)imidazo[1,2-c]pyrimidin-5- 0.008 0.103 0.068 yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2- 0.01 0.047 0.05 c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1R)-8-(8-((2,3-dichloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin- 0.008 0.034 0.028 5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2- 0.035 0.062 0.15 c]pyrimidin-5-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2- 0.017 0.037 0.21 c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (S)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2- 0.034 0.16 0.34 c]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((2-amino-5-chloro-pyridin-4-yl)thio)imidazo[1,2-c] 0.021 0.094 0.18 pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)imidazo[1,2- 0.015 0.019 0.050 c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo 0.016 0.043 0.042 [1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (R)-8-(8-((6-amino-3-chloro-2-methyl-pyridin-4-yl)thio)imidazo[1,2- 0.026 0.097 0.15 c]pyrimidin-5-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)imidazo[1,2- 0.012 0.009 0.016 c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (1-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)- 0.04 0.17 1.355 4-methylpiperidin-4-yl)methanamine (S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- 0.02 0.168 0.892 5-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (1R)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- 0.004 0.064 0.059 5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (3S,4S)-8-(8-((2,3-dichlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- 0.003 0.195 0.158 5-yl)-3-methyl-2-oxa-8-azaspiro[4. 5]decan-4-amine (R)-8-(8-((2-chlorophenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)- 0.140 0.548 0.485 8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-amino-2-chlorophenyl)thio)-[1,2,4]triazolo[4,3- 0.025 0.245 0.389 c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin- 0.1 0.357 0.324 5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo[4,3- 0.027 0.177 0.232 c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- 0.02 0.750 0.303 c]pyrimidin-5-yl)-8-azaspiro[4.5]decan-1-amine (1R)-8-(8-((6-amino-2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3- 0.002 0.047 0.017 c]pyrimidin-5-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine (3S,4S)-8-(8-((2,3-dichloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c] 0.005 0.161 0.133 pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((3-chloro-2-methylpyridin-4-yl)thio)-[1,2,4]triazolo 0.017 0.369 0.277 [4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3S,4S)-8-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo 0.013 0.335 0.102 [4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

(931) The above examples are preferred embodiments of the present disclosure, but the embodiments of the present disclosure are not limited by the above examples.

(932) Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principles of the present disclosure shall be equivalent alternatives, and shall be included in the protection scope of the present invention.