KRAS MUTANT PROTEIN INHIBITORS

Abstract

The invention relates to a KRAS mutant protein inhibitor, a composition containing the inhibitor and the use thereof.

##STR00001##

Claims

1. A compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof, wherein, the compound is selected from: ##STR00680## ##STR00681## ##STR00682## ##STR00683## ##STR00684## ##STR00685## ##STR00686## ##STR00687## ##STR00688## ##STR00689## ##STR00690## ##STR00691## ##STR00692## ##STR00693## ##STR00694## ##STR00695## ##STR00696## ##STR00697## ##STR00698## ##STR00699## ##STR00700## ##STR00701## ##STR00702## ##STR00703## ##STR00704## ##STR00705## ##STR00706## ##STR00707## ##STR00708## ##STR00709## ##STR00710## ##STR00711## ##STR00712## ##STR00713## ##STR00714## ##STR00715## ##STR00716## ##STR00717## ##STR00718## ##STR00719## ##STR00720## ##STR00721## ##STR00722## ##STR00723## ##STR00724## ##STR00725## ##STR00726## ##STR00727## ##STR00728## ##STR00729## ##STR00730## ##STR00731## ##STR00732## ##STR00733## ##STR00734## ##STR00735## ##STR00736## ##STR00737## ##STR00738##

2. The compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 1, wherein, the compound is: ##STR00739##

3. The compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 1, wherein, the compound is: ##STR00740##

4. The compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 1, wherein, the compound is: ##STR00741##

5. The compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 1, wherein, the compound is: ##STR00742##

6. The compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 1, wherein, the compound is: ##STR00743##

7. A pharmaceutical composition comprising at least one compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 1, and at least one pharmaceutically acceptable excipient.

8. The pharmaceutical composition according to claim 7, wherein the compound is: ##STR00744##

9. The pharmaceutical composition according to claim 7, wherein the compound is: ##STR00745##

10. The pharmaceutical composition according to claim 7, wherein the compound is: ##STR00746##

11. The pharmaceutical composition according to claim 7, wherein the compound is: ##STR00747##

12. The pharmaceutical composition according to claim 7, wherein the compound is: ##STR00748##

13. A method of treating a subject having a cancer related to KRAS G12C mutant protein, said method comprising administering to the subject a therapeutically effective amount of at least one compound, stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 1.

14. The method according to claim 13, wherein, the cancer is selected from blood cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer or lung cancer.

15. The method according to claim 14, wherein, the blood cancer is selected from acute myeloid leukemia or acute lymphocytic leukemia; the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

16. The method according to claim 13, wherein the compound is: ##STR00749##

17. The method according to claim 13, wherein the compound is: ##STR00750##

18. The method according to claim 13, wherein the compound is: ##STR00751##

19. The method according to claim 13, wherein the compound is: ##STR00752##

20. The method according to claim 13, wherein the compound is: ##STR00753##

Description

METHODS OF PREPARATION

[0194] Compounds of the present invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The examples which outline specific synthetic route, and the generic schemes below are meant to provide guidance to the ordinarily skilled synthetic chemist, who will readily appreciate that the solvent, concentration, reagent, protecting group, order of synthetic steps, time, temperature, and the like can be modified as necessary, well within the skill and judgment of the ordinarily skilled artisan.

[0195] For instance, compounds of the present invention may be prepared according to the General Synthetic Schemes

[0196] General Synthetic Schemes:

##STR00212## ##STR00213##

[0197] As exemplified in General Synthetic Scheme, a compound such as 1, can be purchased or synthesized (CN104910158) and may be achiral, racemic, or enantiopure. In step-1, compounds such as 1 can be reacted with an amiding reagent such as ammonium hydroxide or ammonium acetate in a polar solvent such as ethanol to form an enamine such as compound 2. In step-2 the enamine can be reacted with 2-cyanoacetic acid to form an amide such as compound 3 by treatment with a condensation reagent such as HATU or EDCl/HOBT, or an acyl chloride. This reaction proceeds in a solvent such as dichloromethane or DMF in the presence of a base such as triethylamine or Hunig's base. In step-3 the amide intermediate cyclized with a cyclization agent to form the pyridinedione ring such as compound 4 in a solvent such as THF. Contemplated cyclization agents include, but are not limited to, bases such as potassium hexamethyldisilazide, potassium tert-butoxide, phosphazene bases, and sodium hydride. In step-4 the oxo groups of the pyridinedione are then converted to leaving groups using an activating agent to form compound 5. Contemplated activating agents include, but not limited to, thionyl chloride, triflic anhydride, phosphorus oxychloride, and phosphorus pentachloride. In step-5 the leaving group is then replaced with a L.sub.4-E(PG) group to form a substituted pyridinone such as compound 6 in a solvent such as acetonitrile and a base such as DIPEA, Each of E at each occurrence is independently selected from

##STR00214##

at each occurrence is independently optionally substituted by 1, 2, 3, 4, 5 or 6 R.sub.42; In step-6 the L.sub.3-R.sub.3 group can be introduced by substitution of LG to provide compounds such as 7, typically in THF with an appropriate base such as NaH or t-BuONa. At the same time L.sub.3-R.sub.3 could also be introduced by cross-coupling reaction with the appropriate L.sub.3-R.sub.3 reagent, for example in the presence of a palladium catalyst such as Pd.sub.2(dba).sub.3/BINAP in a solvent such as toluene with a base such as cesium carbonate or sodium tert-butoxide to provide compound 7. In step-8 L.sub.1-R.sub.1 could be introduced by cross-coupling reaction with the appropriate functionalized L.sub.1-R.sub.1 reagent, in the presence of a palladium catalyst such as Pd.sub.2(dba).sub.3/BINAP in a solvent such as toluene with a base such as cesium carbonate or sodium tert-butoxide to provide compound 9. In step-9 compounds such as 9 can be de-protected by treatment with acid, typically TFA in DCM or HCl in MeOH, to provide the amino compounds, the amino compounds was then acylated to provide compounds such as formula (I), typically by treatment with acryloyl chloride in DCM with TEA or DIPEA as base. In some cases the groups L.sub.1-R.sub.1 and L.sub.3-R.sub.3 may contain protecting groups, which can be removed by an additional step in the synthetic schemes, for example, the PG can be removed with appropriate de-protecting reagent, such as Pd/C/H2 (g), TFA in a solvent such as DCM.

[0198] Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, and reverse phase HPLC or Prep-TLC. If necessary, separation of the enantiomers of formula (I) may be carried out under standard methods known in the art such as chiral SFC or HPLC to afford single enantiomers.

Intermediate A

[0199] ##STR00215##

Intermediate B

[0200] ##STR00216##

Following procedures of WO2017201161 A1, Intermediate A was prepared from but-3-enenitrile in 3 steps. Intermediate B was prepared from 1,8-dibromonaphthalene in 1 step.

Example 1

4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (Compound 1)

[0201] ##STR00217##

Step 1. ethyl 5-amino-1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate

[0202] Into a 250 mL three neck bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (10.01 g, 38.26 mmol, 1.00 eq), NH.sub.4OAc (58.99 g, 76.53 mmol, 20.00 eq) and EtOH (150 mL). The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was filtered and concentrated under vacuum and the resulting residues was partitioned between ethyl acetate and 1 N NaOH aqueous. The aqueous layer was further extracted with dichloromethane (200 mL2) and the combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was recrystallized with diethyl ether and hexane to gi ye ethyl 5-amino-1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate (10.05 g) as off-white solid. LCMS: m/z=261 [M+1].sup.+

Step 2. ethyl 1-benzyl-5-(2-cyanoacetamido)-1,2,3,6-tetrahydropyridine-4-carboxylate

[0203] Into a 250-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 2-cyanoacetic acid (13.14 g, 154.48 mmol, 1.00 eq), DCM (130 mL), followed b y the added of oxalyl chloride (25.49 g, 200.82 mmol, 1.29 eq) in dropwise, and then DMF (0.1 mL) was added. The mixture was stirred for 3 h at 25 C. The resulting solution was concentrated under vacuum. This resulted in 14.01 g (crude product) of 2-cyanoacetylchloride which was used directly in the next step.

[0204] Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 5-amino-1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate (10.05 g, 38.60 mmol), TEA (23.44 g, 231.64 mmol, 6.00 eq), DCM (100 mL). The mixture was cooled to 0 C. an d then 2-cyanoacetylchloride (14.01 g, crude product) was added in dropwise. The resulting solution was stirred for further 2 hrs at room temperature. The reaction was then quenched by the addition of water (100 mL), extracted with dichloromethane (50 mL3), the organic layer was combined and washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum, the crude product was applied onto a silica gel column eluted with EtOAc/hexane (v/v=3/2). This resulted in 6.02 g (47%, yield) of ethyl 1-benzyl-5-(2-cyanoacetamido)-1,2,3,6-tetrahydropyridine-4-carboxylate as yellow solid. LCMS: m/z=328 [M+1].sup.+.

Step 3. 7-benzyl-2,4-dioxo-1,2,3,4,5,6,7,8-octahydro-1,7-naphthyridine-3-carbonitrile

[0205] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 1-benzyl-5-(2-cyanoacetamido)-1,2,3,6-tetrahydropyridine-4-carboxylate (6.02 g, 18.38 mmol, 1.00 eq), MeONa (2.98 g, 55.16 mmol, 3.00 eq) and MeOH (60 mL). The mixture was stirred for 2 hrs at 65 C. The resulting solution was concentrated under vacuum and the residue was dissolved in 40 mL water and adjusted pH to 6 with AcOH. The solid was collected by filtration, dried under vacuum to provide 3.00 g (58%, yield) of 7-benzyl-2,4-dioxo-1,2,3,4,5,6,7,8-octahydro-1,7-naphthyridine-3-carbonitrile as white solid. LCMS: m/z=282 [M+1].sup.+

Step 4. 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile

[0206] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 1-benzyl-5-(2-cyanoacetamido)-1,2,3,6-tetrahydropyridine-4-carboxylate (3.00 g, 9.16 mmol, 1.00 eq), POCl.sub.3 (30 mL), DIEA (1 mL). The mixture was heated to 80 C. and stir red for 1 h. The solution was concentrated under vacuum. The residue was applied onto a silica gel column eluted with EtOAc/hexane (v/v=3/2). This resulted in 2.10 g (47%, yield) of 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile as yellow oil. LCMS: m/z=31 9 [M+1].sup.+

Step 5. tert-butyl 4-(7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0207] Into a 100-mL round-bottom flask, was placed 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (2.10 g, 6.59 mmol, 1.00 eq), 2-(3-methylpiperazin-2-yl)acetonitrile (2.76 g, 19.83 mmol, 3.00 eq), DIEA (3.70 g, 26.30 mmol, 3.99 eq) and DMSO (20 mL), the mixture was stirred at room temperature for 2 hrs. This was followed by the added of Boc.sub.2O (2.87 g, 13.16 mmol, 1.99 eq) in three batches. The mixture was stirred at room temperature overnight. The reaction was then quenched by the addition of water (100 mL), extracted with EtOAc (100 m L3), the organic layers combined and washed with brine (150 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by silica gel column elute d with EtOAc/hexane (v/v=1/1). This resulted in 1.90 g (57%, yield) of tert-butyl 4-(7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate as yellow solid. LCMS: m/z=508 [M+1].sup.+

Step 6. tert-butyl 4-(7-benzyl-3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0208] Into a 20-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl 4-(7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (0.45 g, 0.88 mmol, 1.00 eq), Cs.sub.2CO.sub.3 (0.80 g, 2.46 mmol, 2.77 eq), RuPhos Pd G3 (0.18 g, 0.21 mmol, 0.24 eq), (S)-(1-methylpyrrolidin-2-yl)methanol (0.31 g, 2.69 mmol, 3.03 eq) and 1,4-dioxane (10 mL). The mixture was stirred at 90 C. for 1 h. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column eluted with EtOAc/hexane (v/v=7/3). This resulted in 0.20 g (38%, yield) of tert-butyl 4-(7-benzyl-3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate as yellow solid. LCMS: m/z=586 [M+1].sup.+.

Step 7. tert-butyl 4-(3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0209] Into a 50-mL round-bottom flask was placed tert-butyl 4-(7-benzyl-3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (0.20 g, 0.34 mmol, 1.00 eq), 10% Pd(OH).sub.2/C (50 mg) and MeOH (10 mL), purged and maintained with an atmosphere of hydrogen, stirred at room temperature for 6 hrs. The catalyst was removed by filtration. The filtrate was concentrated to give tert-butyl 4-(3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (120 mg, 71%, yield) as a yellow solid. LCMS: m/z=496 [M+1].sup.+

Step 8. tert-butyl 4-(3-cyano-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0210] Into a 20-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl 4-(3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (0.12 g, 0.24 mmol, 1.00 eq), Cs.sub.2CO.sub.3 (0.19 g, 0.58 mmol, 2.41 eq), RuPhos Pd G3 (40 mg, 0.05 mmol, 0.21 eq), 1-bromo-8-methylnaphthalene (0.16 g, 0.72 mmol, 3.00 eq) and 1,4-dioxane (6 mL). The mixture was stirred at 100 C. for 3 hrs. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column eluted with EtOAc/hexane (v/v=3/1). This resulted in 17 mg (11%, yield) of tert-butyl 4-(3-cyano-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate as yellow solid. LCMS: m/z=636 [M+1].sup.+

Step 9. 4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methyl pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile

[0211] Into a 50-mL round-bottom flask, was placed tert-butyl 4-(3-cyano-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (0.017 g, 26.74 umol), dichloromethane (5 mL), trifluoroacetic acid (3.05 mg, 26.74 umol). The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (5 mL), followed by the addition of DIEA (0.02 g, 154.75 umol). The reaction mixture was cooled to 0 C. and acryloyl chloride (0.004 g, 44.19 umol) was added. The reaction mixture was stirred at room temperature for 85 min. After the reaction was completed, the reaction mixture was concentrated under vacuum, the crude product was applied onto a C18 column eluted with CH.sub.3CN/H.sub.2O (0.5% NH.sub.4HCO.sub.3) (v/v=7/3), this afford 5 mg (26.57%, yield) of 4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile as brown solid. LCMS: m/z=590M+H.sup.+

[0212] .sup.1H NMR (400 MHz, CD.sub.3OD) 7.87-7.63 (m, 2H), 7.59-7.31 (m, 3H), 7.30-7.20 (m, 1H), 6.86 (s, 1H), 6.42-6.26 (m, 1H), 5.95-5.81 (m, 1H), 5.32-5.04 (m, 1H), 4.86-4.71 (m, 1H), 4.62 (s, 1H), 4.53-4.36 (m, 1H), 4.32-4.09 (m, 2H), 4.08-3.41 (m, 8H), 3.30-3.18 (m, 3H), 3.15 (t, J=7.0 Hz, 3H), 2.99 (dd, J=16.8, 6.7 Hz, 1H), 2.90 (s, 3H), 2.48-2.34 (m, 1H), 2.29-1.88 (m, 4H), 1.43-1.22 (m, 1H).

Example 2

(S)-4-(4-acryloylpiperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (Compound 2)

[0213] ##STR00218##

Step 1. tert-butyl 4-(7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate

[0214] Into a 50-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (3.50 g, 11.04 mmol), tert-butyl piperazine-1-carboxylate (4.28 g, 23.01 mmol), DIEA (12.50 g, 96.90 mmol), DMSO (15 mL). The reaction mixture was stirred at 80 C. for 4 hrs. The reaction was then quenched b y the addition of water (20 mL), extracted with Ethyl acetate (50 mL3), the organic layers w as combined and washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by C18 column eluted with ACN/H.sub.2O (v/v=1/1). This resulted in 485 mg of tert-butyl 4-(7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate as yellow solid. LCMS: m/z=468 [M+1].sup.+

Step 2. tert-butyl (S)-4-(7-benzyl-3-cyano-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate

[0215] Into a 20-mL sealed tube and maintained with an inert atmosphere of nitrogen, was placed tert-butyl 4-(7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate (485 mg, 1.04 mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (413 mg, 3.59 mmol), Ruphos Pd G3 (264 mg, 0.32 mmol), Cs.sub.2CO.sub.3 (1.09 g, 3.33 mmol), 1,4-dioxane (8 mL). The reaction mixture was stirred at 90 C. for 4 hrs. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by C18 column eluted with ACN/H.sub.2O (0.5% NH.sub.4HCO.sub.3) (v/v=3/4). This resulted in 402 mg of tert-butyl (S)-4-(7-benzyl-3-cyano-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate as yellow solid. LCMS: m/z=54 7 [M+1].sup.+

Step 3. tert-butyl (S)-4-(3-cyano-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate

[0216] Into a 25-mL round-bottom flask was placed tert-butyl (S)-4-(7-benzyl-3-cyano-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate (402 mg, 0.73 mmol), Pd(OH).sub.2 (103 mg, 0.74 mmol), EtOAc (20 mL), purged and maintained with an atmosphere of hydrogen. The reaction mixture was stirred at room temperature for 18 hrs. The reaction mixture was filtered and the filtrate was concentrated under vacuum. This resulted in 251 mg (74%) of tert-butyl (S)-4-(3-cyano-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate as yellow solid. LCMS: m/z=457 [M+1].sup.+

Step 4. tert-butyl (S)-4-(3-cyano-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate

[0217] Into a 20-mL sealed tube, purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (S)-4-(3-cyano-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate (251 mg, 0.55 mmol), 1-bromo-8-methylnaphthalene (336 mg, 1.52 mmol), RuPhos Pd G3 (217 mg, 0.26 mmol), Cs.sub.2CO.sub.3 (472 mg, 1.45 mmol), 1,4-dioxane (8 m L). The reaction mixture was stirred at 90 C. for 4 hrs. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by C18 column eluted with ACN/H.sub.2O (v/v=1/1). This resulted in 142 mg (74%) of tert-butyl (S)-4-(3-cyano-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate as yellow oil. LCMS: m/z=597[M+1].sup.+

Step 5. (S)-4-(4-acryloylpiperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile

[0218] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (S)-4-(3-cyano-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)meth oxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate (142 mg, 0.24 mmol), TFA (54 mg, 0.48 mmol), DCM (15 mL). The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under vacuum. The residue was dissolved by DCM (3 mL) in a 25-mL round-bottom flask, this was followed by the added of DIEA (402 mg, 3.11 mmol). The reaction mixture was cooled to 0 C. and acryloyl chloride (43 mg, 0.48 mmol) was added. The mixture stirred at room temperature for 0.5 h. The reaction was then quenched by the addition of water (10 mL), extracted with DCM (50 mL3), the organic layers was combined and washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtrated and concentrated un der vacuum. The residue was purified by silica gel column eluted with EtOAc/hexane (v/v=1/1). This resulted in 24 mg (15%) of (S)-4-(4-acryloylpiperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile as yellow solid. LCMS: m/z=551 [M+1]+

[0219] .sup.1H NMR (400 MHz, MeOD) 8.22 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.74 (d, J=6.5 Hz, 1H), 7.56-7.48 (m, 2H), 6.69 (dd, J=16.8, 10.6 Hz, 1H), 6.14 (dd, J=16.8, 1.9 Hz, 1H), 5.68 (dd, J=10.6, 1.9 Hz, 1H), 4.96 (s, 2H), 4.62 (dd, J=12.5, 3.0 Hz, 1H), 4.37-4.21 (m, 3H), 3.88-3.77 (m, 1H), 3.73-3.51 (m, 7H), 3.34 (s, 4H), 3.18-3.07 (m, 1H), 3.06-2.97 (m, 3H), 2.93 (t, J=5.9 Hz, 2H), 2.34-2.22 (m, 1H), 2.15-1.79 (m, 3H), 1.32-1.24 (m, 1H).

Example 3

4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (Compound 3)

[0220] ##STR00219##

Step 1. 7-benzyl-2-chloro-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-6,8-dihydro-5H-1,7-naphthyridine-3-carbonitrile

[0221] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2R,6S)-2,6-dimethylpiperazine (0.237 g, 2.08 mmol), 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (0.213 g, 669.39 umol), DIEA (0.373 g, 2.89 mmol), NMP (3 mL), the reaction mixture was stirred for 45 min at 80 C. The reaction mixture was concentrated under vacuum. The crude product was purified by C18 column eluted with ACN/H.sub.2O (v/v=3/1). This afford 230 mg (580.91 umol, 86.78%) of 7-benzyl-2-chloro-4-[(3S,5R)-3,5-dimeth ylpiperazin-1-yl]-6,8-dihydro-5H-1,7-naphthyridine-3-carbonitrile as yellow solid. LCMS: m/z=396 [M+1].sup.+.

Step 2. 7-benzyl-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-1,7-naphthyridine-3-carbonitrile

[0222] Into a 30 mL vial purged and maintained with an inert atmosphere of nitrogen was placed 7-benzyl-2-chloro-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-6,8-dihydro-5H-1,7-naphthyridine-3-carbonitrile (0.23 g, 580.91 umol), 1,4-Dioxane (5 mL), (S)-(1-methylpyrrolidin-2-yl)methanol (334.53 mg, 2.90 mmol), RuPhos Pd G3 (48.64 mg, 58.09 umol), Cs.sub.2CO.sub.3 (378.55 mg, 1.16 mmol), the reaction mixture was stirred for 16 hrs at 80 C. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel column eluted with DCM/MeOH (v/v=3/1). This of ford 220 mg (463.51 umol, 79.79%) of 7-benzyl-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-[[(2S)-1-m ethylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-1,7-naphthyridine-3-carbonitrile as light yellow solid. LCMS: m/z=475 [M+1].sup.+.

Step 3. 4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile

[0223] Into a 50-mL round bottom flask was placed 7-benzyl-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-1,7-naphthyridine-3-carbonitrile (0.22 g, 463.51 umol), Pd(OH).sub.2 (0.22 g, 1.57 mmol), ethyl acetate (6 mL), methanol (1 mL), purged and maintained with an atmosphere of hydrogen. the reaction mixture was stirred for 3 hrs at 60 C. The reaction mixture was filtered, the filtrate was evaporated to afford crude product 180 mg of 4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile as light yellow solid. LCMS: m/z=385 [M+1].sup.+.

Step 4. 4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-1,7-naphthyridine-3-carbonitrile

[0224] Into a 30 mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (0.18 g, crude product), 1-bromo-8-methylnaphthalene (0.207 g, 936.26 umol), RuPhos Pd G3 (0.04 g, 47.77 umol), Cesium carbonate (0.31 g, 951.45 umol) 1,4-Dioxa ne (5 mL), the reaction mixture was stirred for 16 hrs at 80 C. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel column eluted with EtOAc/Hexane (v/v=7/3). This afford 120 mg (228.70 umol, 48.86% yield) of 4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-1,7-naphthyridine-3-carbonitrile as light yellow solid. LCMS: m/z=525 [M+1].sup.+.

Step 5. 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile

[0225] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-1,7-naphthyridine-3-carbonitrile (0.12 g, 228.70 umol), DCM (8 mL), triethylamine (0.047 g, 464.48 umol), followed by the addition of acryloyl chloride (0.023 g, 254.12 umol), the reaction mixture was stirred for 80 min at room temperature. The reaction was quenched with H.sub.2O (50 mL), extracted with EtOAc (50 mL3), the organic layers was combined and washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The crude product was purified with HPLC (CH.sub.3CN/H.sub.2O (v/v=7/3), This afford 810 mg (1.40 mmol) of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile as off-white solid. LCMS: m/z=579 [M+1].sup.+

[0226] .sup.1H NMR (400 MHz, MeOD) 7.68-7.53 (m, 2H), 7.48-7.31 (m, 2H), 7.29-7.22 (m, 1H), 7.17 (d, J=7.1 Hz, 1H), 6.76 (dd, J=16.7, 10.6 Hz, 1H), 6.20 (dd, J=16.8, 1.9 Hz, 1H), 5.71 (dd, J=10.5, 1.9 Hz, 1H), 4.65-4.35 (m, 3H), 4.32-4.06 (m, 2H), 3.83-3.63 (m, 2H), 3.57-3.47 (m, 1H), 3.44-3.32 (m, 1H), 3.19-2.95 (m, 4H), 2.80 (s, 2H), 2.50-2.38 (m, 1H), 2.19-1.90 (m, 3H), 1.81 (s, 2H), 1.66 (s, 1H), 1.58-1.37 (m, 4H), 1.25-1.18 (m, 6H), 0.83 (t, J=6.8 Hz, 1H).

Example 4

(S)-4-((1-acryloylazetidin-3-yl)amino)-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (Compound 4)

[0227] ##STR00220##

Step 1. tert-butyl 3-((7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)amino)azetidine-1-carboxylate

[0228] Into a 50-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (3.20 g, 10.09 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (4.13 g, 24.03 mmol), DIEA (12.50 g, 96.57 mmol), DMSO (15 mL). The reaction mixture was stirred at 80 C. for 4 hrs. The reaction was then quenched by the addition of water (20 mL), extracted with Ethyl acetate (50 mL3), the organic layers was combined and washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by C18 column eluted with ACN/H.sub.2O (v/v=3/4). This resulted in 560 mg of tert-butyl 3-((7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)amino)azetidine-1-carboxylate as yellow solid. LCMS: m/z=454 [M+1]+

Step 2. tert-butyl (S)-3-((7-benzyl-3-cyano-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)amino)azetidine-1-carboxylate

[0229] Into a 20-mL sealed tube and maintained with an inert atmosphere of nitrogen, was placed t tert-butyl 3-((7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)amino)azetidine-1-carboxylate (560 mg, 1.23 mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (527 mg, 4.58 mmol), Ruphos Pd G.sub.3 (213 mg, 0.25 mmol), Cs.sub.2CO.sub.3 (1.08 g, 3.31 mmol), 1,4-dioxane (8 mL). The reaction mixture was stirred at 90 C. for 4 hrs. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by C18 column eluted with ACN/H.sub.2O (0.5%) NH.sub.4HCO.sub.3 (v/v=3/4). This resulted in 590 mg of tert-butyl (S)-3-((7-benzyl-3-cyano-2-((1-methylpyrrolidin-2-yl) methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)amino)azetidine-1-carboxylate as yellow solid. LCMS: m/z=533 [M+1].sup.+

Step 3. tert-butyl (S)-3-((3-cyano-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)amino)azetidine-1-carboxylate

[0230] Into a 50-mL round-bottom flask was placed tert-butyl (S)-3-((7-benzyl-3-cyano-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)amino) azetidine-1-carboxylate (590 m g, 1.11 mmol), Pd(OH).sub.2 (489 mg, 3.48 mmol), MeOH (20 mL), purged and maintained with an atmosphere of hydrogen. The reaction mixture was stirred at room temperature for 8 hrs. The reaction mixture was filtered and the filtrate was concentrated under vacuum. This resulted in 440 mg of tert-butyl (S)-3-((3-cyano-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)amino)azetidine-1-carboxylate as yellow solid. LCMS: m/z=443 [M+1].sup.+

Step 4. tert-butyl (S)-3-((3-cyano-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)amino)azetidine-1-carboxylate

[0231] Into a 20-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (S)-3-((3-cyano-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)amino)azetidine-1-carboxylate (440 mg, 0.99 mmol), 1-bromo-8-methylnaphthalene (203 m g, 0.92 mmol), Ruphos Pd G3 (184 mg, 0.22 mmol), Cs.sub.2CO.sub.3 (312 mg, 0.96 mmol), dioxane (8 mL). The reaction mixture was stirred at 90 C. for 4 hrs. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by C18 column eluted with ACN/H.sub.2O (v/v=5/4). This resulted in 145 mg of tert-butyl (S)-3-((3-cyano-7-(8-methylnaphthalen-1-yl)-2-((1-m ethylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)amino) azetidine-1-carboxylate as yellow oil. LCMS: m/z=583 [M+1].sup.+.

Step 5. (S)-4-((1-acryloylazetidin-3-yl)amino)-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile

[0232] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (S)-3-((3-cyano-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)meth oxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)amino)azetidine-1-carboxylate (141 mg, 0.24 mmol), T FA (27 mg, 0.24 mmol), DCM (15 mL). The reaction mixture was stirred at room temperature f or 2 hrs. The reaction mixture was concentrated under vacuum. The residue was dissolved by D CM (3 mL) in a 25-mL round-bottom flask, followed by the addition of DIEA (402 mg, 3.11 m mol). The reaction mixture was cooled to 0 C. and acryloyl chloride (21 mg, 0.23 mmol) was added. The mixture stirred at room temperature for 0.5 h. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with DCM (50 mL3), the organic layers combined and washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtrated an d concentrated under vacuum. The residue was purified by silica gel column eluted with EtOAc/hexane (v/v=3/4). This resulted in 10 mg (15%) of (S)-4-((1-acryloylazetidin-3-yl)amino)-7-(8-m ethylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile as yellow solid. LCMS: m/z=537 [M+H].sup.+.

[0233] .sup.1H NMR (400 MHz, MeOD) 8.34 (d, J=8.9 Hz, 1H), 7.98-7.79 (m, 2H), 7.56-7.42 (m, 3H), 6.46-6.20 (m, 2H), 5.76 (dd, J=10.1, 2.1 Hz, 1H), 4.78-4.59 (m, 1H), 4.54-3.95 (m, 6H), 3.51 (s, 2H), 3.28-2.73 (m, 5H), 2.64 (s, 2H), 2.23-1.82 (m, 4H), 1.81-1.53 (m, 2H), 1.31 (s, 4H).

Example 5

4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (Compound 5)

[0234] ##STR00221##

Step 1. tert-butyl (2R)-4-(7-benzyl-2-chloro-3-cyano-6,8-dihydro-5H-1,7-naphthyridin-4-yl)-2-methyl-piperazine-1-carboxylate

[0235] Into a 100-mL round-bottom flask was placed 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (1.05 g, 3.28 mmol), (R)-1-N-Boc-2-methylpiperazine (1 g, 4.99 mmol), NMP (10 mL), N,N-Diisopropylethylamine (1.25 g, 9.64 mmol), the reaction mixture was warmed to 80 C. and stirred for 30 min, another batch of (R)-1-N-Boc-2-methylpiperazine (252 mg) was added. The reaction mixture was stirred further for 80 min. The reaction was quenched with H.sub.2O (50 mL), extracted with EtOAc (50 mL2), dried over Na.sub.2SO.sub.4, filtrated and concentrated un der vacuum. The residue was purified by silica gel column eluted with EtOAc/hexane (v/v=5/1). The fraction was concentrated to afford tert-butyl (2R)-4-(7-benzyl-2-chloro-3-cyano-6,8-dihydro-5H-1,7-naphthyridin-4-yl)-2-methyl-piperazine-1-carboxylate (541 mg, 1.12 mmol, 34.18% yield) as yellow solid. LCMS: m/z=482 [M+1]+

Step 2. tert-butyl (2R)-4-[7-benzyl-3-cyano-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-1,7-naphthyridin-4-yl]-2-methyl-piperazine-1-carboxylate

[0236] Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl (2R)-4-(7-benzyl-2-chloro-3-cyano-6,8-dihydro-5H-1,7-naphthyridin-4-yl)-2-methyl-piperazine-1-carboxylate (0.541 g, 1.12 mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (0.526 g, 4.57 mmol), RuPhosPdG3 (0.182 g, 217.35 umol), Cs.sub.2CO.sub.3 (1.08 g, 3.31 mmol), 1,4-Dioxane (0.01 L). The reaction mixture was warmed to 100 C. and stirred for 80 min. The mixture was evaporated under vacuum and applied onto a silica gel column, eluted with EtOAc/hexane (v/v=1/1), to afford ter t-butyl (2R)-4-[7-benzyl-3-cyano-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-1,7-naphthyridin-4-yl]-2-methyl-piperazine-1-carboxylate (511 mg, 911.31 umol, 81.20%). LCMS: m/z=561 [M+1].sup.+

Step 3. tert-butyl (2R)-4-[3-cyano-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl]-2-methyl-piperazine-1-carboxylate

[0237] Into a 50-mL 3-neck round bottom flask was placed tert-butyl (2R)-4-[7-benzyl-3-cyano-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-1,7-naphthyridin-4-yl]-2-methyl-piperazine-1-carboxylate (0.511 g, 911.31 umol), EtOAc (10 mL), Pd(OH).sub.2 (0.522 g, 3.72 mmol), was purged a nd maintained with an atmosphere of hydrogen. The reaction mixture was warmed to 60 C. and stirred for 2 hrs. The reaction mixture was filtered, the filter cake was washed with EtOAc (10 mL2), the filtrate was concentrated under vacuum to afford tert-butyl (2R)-4-[3-cyano-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl]-2-methyl-piperazine-1-carboxylate (410 mg, 871.22 umol, 95.6% yield) as yellow solid. LCMS: m/z=471 [M+1].sup.+

Step 4. tert-butyl (2R)-4-[3-cyano-7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-1,7-naphthyridin-4-yl]-2-methyl-piperazine-1-carboxylate

[0238] Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl (2R)-4-[3-cyano-2-[[(2 S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl]-2-methyl-piperazine-1-carboxylate (0.41 g, 871.22 umol), 1-bromo-8-methylnaphthalene (0.427 g, 1.93 mmol), RuPhos Pd G3 (0.213 g, 254.37 umol), Cs.sub.2CO.sub.3 (0.984 g, 3.02 mmol), dioxane (5 mL). The reaction stirred for 16 hrs at 100 C. The mixture was concentrated under vacuum, the residue was purified by silica gel column, eluted with EtOAc/hexane (v/v=3/1). The fraction was concentrated to afford tert-butyl (2R)-4-[3-cyano-7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methy 1pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-1,7-naphthyridin-4-yl]-2-methyl-piperazine-1-carboxylate (199 mg, 325.81 umol, 37.4% yield) as yellow solid. LCMS: m/z=611 [M+1].sup.+

Step 5. 4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile

[0239] Into a 50-mL round bottom flask was placed tert-butyl (2R)-4-[3-cyano-7-(8-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-1,7-naphthyridin-4-yl]-2-methyl-piperazine-1-carboxylate (0.199 g, 325.81 umol), DCM (5 mL), TFA (2 mL), the reaction mixture was stirred for 2 hrs at room temperature. After the reaction was completed, the reaction mixture was concentrated under vacuum. The residue was dissolved in dichloromethane (5 mL), this was followed by the added of DIEA (0.118 g, 913.01 umol). Then cooled to 0 C. and acryloyl chloride (0.028 g, 309.36 umol) was added in dropwise. The reaction mixture was stirred for 15 min at room temperature. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with DCM (50 mL3), the organic layers combined and washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The crude product was purified with HPLC eluted with ACN/H.sub.2O (0.5%) NH.sub.4HCO.sub.3 (v/v=1/1). This resulted in (58 mg, 32.72% yield) of 4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile as yellow solid. LCMS: m/z=565 [M+1].sup.+.

[0240] .sup.1H NMR (400 MHz, MeOD) 7.77-7.63 (m, 2H), 7.49-7.30 (m, 3H), 7.29-7.21 (m, 1H), 6.90-6.75 (m, 1H), 6.26 (dd, J=16.0, 4.3 Hz, 1H), 5.85-5.76 (m, 1H), 4.75 (dd, J=12.5, 3.0 Hz, 1H), 4.46 (dd, J=12.5, 8.3 Hz, 2H), 4.33-4.15 (m, 1H), 4.10-3.89 (m, 2H), 3.88-3.65 (m, 4H), 3.66-3.36 (m, 4H), 3.30-3.11 (m, 6H), 2.96-2.82 (m, 4H), 2.49-2.31 (m, 1H), 2.28-1.91 (m, 3H), 1.50-1.28 (m, 3H).

Example 6

4-((S)-4-acryloyl-3-methylpiperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (Compound 6)

[0241] ##STR00222##

Step 1. tert-butyl (S)-4-(7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-methylpiperazine-1-carboxylate

[0242] Into a 25-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (3.14 g, 9.91 mmol), tert-butyl (S)-2-methylpiperazine-1-carboxylate (4.06 g, 20.27 mmol), DIEA (12.48 g, 96.56 mmol), DMSO (15 mL). The reaction mixture was stirred at 80 C. for 4 hrs. The reaction was then quenched by the addition of water (20 mL), extracted with EtOAc (50 mL3), the organic lay ers was combined and washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by C18 column eluted with ACN/H.sub.2O (v/v=4/5). This resulted in 613 mg of tert-butyl (S)-4-(7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-methylpiperazine-1-carboxylate as yellow solid. LCMS: m/z=482 [M+1].sup.+

Step 2. tert-butyl (S)-4-(7-benzyl-3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-methylpiperazine-1-carboxylate

[0243] Into a 30 mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (S)-4-(7-benzyl-2-chloro-3-cyano-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-methylpiperazine-1-carboxylate (613 mg, 1.27 mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (468 mg, 4.06 mmol), Ruphos Pd G3 (351 mg, 0.42 mmol), Cs.sub.2CO.sub.3 (1.28 g, 3.92 mmol), 1,4-dioxane (8 mL). The reaction mixture was stirred at 90 C. for 4 hrs. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by C18 column eluted with ACN/H.sub.2O (0.5% N H4HCO.sub.3) (v/v=3/4). This resulted in 364 mg of tert-butyl (S)-4-(7-benzyl-3-cyano-2-(((S)-1-meth ylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-methylpiperazine-1-carboxylate as yellow solid. LCMS: m/z=561 [M+H].sup.+

Step 3. tert-butyl (S)-4-(3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-methylpiperazine-1-carboxylate

[0244] Into a 50 mL round-bottom flask, was placed tert-butyl (S)-4-(7-benzyl-3-cyano-2-(((S)-1-meth ylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-methylpiperazine-1-carboxylate (364 mg, 0.65 mmol), Pd(OH).sub.2 (723 mg, 5.15 mmol), EtOAc (20 mL), purged and maintained with an atmosphere of hydrogen. The reaction mixture was stirred at room temperature for 8 hrs. The reaction mixture was filtered and the filtrate was concentrated under vacuum. This resulted in 216 mg of tert-butyl (S)-4-(3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-methylpiperazine-1-carboxylate as yellow solid. LCMS: m/z=471 [M+1].sup.+

Step 4. tert-butyl (S)-4-(3-cyano-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-methylpiperazine-1-carboxylate

[0245] Into a 30 mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (S)-4-(3-cyano-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-methylpiperazine-1-carboxylate (216 mg, 0.46 mmol), 1-bromo-8-methylnaphthalene (375 mg, 1.70 mmol), Ruphos Pd G3 (391 mg, 0.47 mmol), Cs.sub.2CO.sub.3 (452 mg, 1.39 mmol), 1,4-dioxane (8 mL). The reaction mixture was stirred at 90 C. for 4 hrs. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by C18 column eluted with A CN/H.sub.2O (v/v=5/4). This resulted in 145 mg of tert-butyl (S)-4-(3-cyano-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-methylpiperazine-1-carboxylate as yellow oil. LCMS: m/z=611 [M+1].sup.+

Step 5. 4-((S)-4-acryloyl-3-methylpiperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile

[0246] Into a 50 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (S)-4-(3-cyano-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)-2-methylpiperazine-1-carboxylate (86 mg, 0.14 mmol), TFA (1.54 g, 13.51 mmol), DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under vacuum. The residue was dissolved by DCM (3 mL) in 25-mL round-bottom flask. TEA (873 mg, 8.63 mmol) was added. The react ion mixture was cooled to 0 C. and acryloyl chloride (12 mg, 0.14 mmol) was added. The mixture stirred at room temperature for 0.5 h. The reaction was then quenched by the addition of water (50 mL). The resulting solution was extracted with DCM (50 mL3), the organic layers combined and washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by silica gel column eluted with EtOAc/hexane (v/v=3/4). This resulted in 31 mg of 4-((S)-4-acryloyl-3-methylpiperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile as yellow solid. LCMS: m/z=565 [M+1].sup.+

[0247] .sup.1H NMR (400 MHz, MeOD) 8.33 (d, J=8.4 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.82 (d, J=6.6 Hz, 1H), 7.67-7.58 (m, 2H), 6.79 (dd, J=16.7, 10.7 Hz, 1H), 6.25 (dd, J=16.8, 1.7 Hz, 1H), 5.79 (dd, J=10.7, 1.8 Hz, 1H), 5.10-4.94 (m, 2H), 4.85-4.81 (m, 1H), 4.77 (dd, J=12.5, 3.0 Hz, 1H), 4.48-4.37 (m, 2H), 4.33 (s, 2H), 3.97-3.87 (m, 1H), 3.84-3.71 (m, 5H), 3.56-3.38 (m, 3H), 3.31-3.19 (m, 2H), 3.17-3.05 (m, 4H), 3.04-2.91 (m, 1H), 2.54-2.32 (m, 1H), 2.28-1.92 (m, 3H), 1.43-1.25 (m, 3H).

[0248] The following examples were synthesized using the above procedure or modification procedure using the corresponding Intermediate.

TABLE-US-00001 Com- MS: pound Structure IUPAC Name (M + H).sup.+ 7 [00223] 4-((3R,5S)-4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 597 8 [00224] 7-(8-chloronaphthalen-1-yl)-4- ((3R,5S)-4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 617 9 [00225] 7-(8-chloro-7-fluoronaphthalen-1-yl)- 4-((3R,5S)-4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 635 10 [00226] 7-(7,8-difluoronaphthalen-1-yl)-4- ((3R,5S)-4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 619 11 [00227] 7-(7-fluoro-8-methylnaphthalen-1-yl)- 4-((3R,5S)-4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 615 12 [00228] 4-((3R,5S)-4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-7-(3-methyl- 2-(trifluoromethyl)phenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 615 13 [00229] 7-(3-fluoro-2- (trifluoromethyl)phenyl)-4-((3R,5S)- 4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 619 14 [00230] 7-(3-chloro-2- (trifluoromethyl)phenyl)-4-((3R,5S)- 4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 635 15 [00231] 7-(3-chloro-2- (trifluoromethyl)phenyl)-4-((3R,5S)- 4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-2-(((R)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 635 16 [00232] 7-(7,8-dichloronaphthalen-1-yl)-4- ((3R,5S)-4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 651 17 [00233] 7-(6,7-difluoronaphthalen-1-yl)-4- ((3R,5S)-4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 619 18 [00234] 4-((3R,5S)-4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(2- (trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 601 19 [00235] 4-((3R,5S)-4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-7-(6- hydroxynaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 599 20 [00236] 4-((3R,5S)-4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-7- (isoquinolin-5-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 584 21 [00237] 4-((3R,5S)-4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-7-(5-methyl- 1H-indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 587 22 [00238] 4-((3R,5S)-4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-7-(6-methyl- 1H-indazol-7-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 587 23 [00239] 7-(1,6-dimethyl-1H-indazol-7-yl)-4- ((3R,5S)-4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 601 24 [00240] 7-(1,5-dimethyl-1H-indazol-4-yl)-4- ((3R,5S)-4-(2-fluoroacryloyl)-3,5- dimethylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 601 25 [00241] 4-((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 583 26 [00242] 7-(8-chloronaphthalen-1-yl)-4-((S)-4- (2-fluoroacryloyl)-3-methylpiperazin- 1-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 603 27 [00243] 7-(8-chloro-7-fluoronaphthalen-1-yl)- 4-((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 621 28 [00244] 7-(7,8-difluoronaphthalen-1-yl)-4- ((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 605 29 [00245] 7-(7-fluoro-8-methylnaphthalen-1-yl)- 4-((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 601 30 [00246] 4-((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(3-methyl-2- (trifluoromethyl)phenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 601 31 [00247] 7-(3-fluoro-2- (trifluoromethyl)phenyl)-4-((S)-4-(2- fluoroacryloyl)-3-methylpiperazin-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 605 32 [00248] 7-(3-chloro-2- (trifluoromethyl)phenyl)-4-((S)-4-(2- fluoroacryloyl)-3-methylpiperazin-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 621 33 [00249] 7-(3-chloro-2- (trifluoromethyl)phenyl)-4-((S)-4-(2- fluoroacryloyl)-3-methylpiperazin-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 621 34 [00250] 7-(7,8-dichloronaphthalen-1-yl)-4- ((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 637 35 [00251] 7-(6,7-difluoronaphthalen-1-yl)-4- ((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 605 36 [00252] 4-((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(2- (trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 587 37 [00253] 4-((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(6- hydroxynaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 585 38 [00254] 4-((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(isoquinolin- 5-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 570 39 [00255] 4-((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(5-methyl- 1H-indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 573 40 [00256] 4-((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(6-methyl- 1H-indazol-7-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 573 41 [00257] 7-(1,6-dimethyl-1H-indazol-7-yl)-4- ((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 587 42 [00258] 7-(1,5-dimethyl-1H-indazol-4-yl)-4- ((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 587 43 [00259] 4-((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 583 44 [00260] 7-(8-chloronaphthalen-1-yl)-4-((R)-4- (2-fluoroacryloyl)-3-methylpiperazin- 1-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 603 45 [00261] 7-(8-chloro-7-fluoronaphthalen-1-yl)- 4-((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 621 46 [00262] 7-(7,8-difluoronaphthalen-1-yl)-4- ((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 605 47 [00263] 7-(7-fluoro-8-methylnaphthalen-1-yl)- 4-((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 601 48 [00264] 4-((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(3-methyl-2- (trifluoromethyl)phenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 601 49 [00265] 7-(3-fluoro-2- (trifluoromethyl)phenyl)-4-((R)-4-(2- fluoroacryloyl)-3-methylpiperazin-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 605 50 [00266] 7-(3-chloro-2- (trifluoromethyl)phenyl)-4-((R)-4-(2- fluoroacryloyl)-3-methylpiperazin-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 621 51 [00267] 7-(3-chloro-2- (trifluoromethyl)phenyl)-4-((R)-4-(2- fluoroacryloyl)-3-methylpiperazin-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 621 52 [00268] 7-(7,8-dichloronaphthalen-1-yl)-4- ((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 637 53 [00269] 7-(6,7-difluoronaphthalen-1-yl)-4- ((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 605 54 [00270] 4-((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(2- (trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 587 55 [00271] 4-((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(6- hydroxynaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 585 56 [00272] 4-((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(isoquinolin- 5-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 570 57 [00273] 4-((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(5-methyl- 1H-indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 573 58 [00274] 4-((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(6-methyl- 1H-indazol-7-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 573 59 [00275] 7-(1,6-dimethyl-1H-indazol-7-yl)-4- ((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 587 60 [00276] 7-(1,5-dimethyl-1H-indazol-4-yl)-4- ((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 587 61 [00277] (R)-4-(4-acryloylpiperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 551 62 [00278] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((R)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 579 63 [00279] 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 579 64 [00280] 4-((S)-4-acryloyl-2-methylpiperazin- 1-yl)-7-(8-methylnaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 565 65 [00281] (S)-4-(2-acryloyl-2,7- diazaspiro[3.5]nonan-7-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 591 66 [00282] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(4- chlorophenyl)-2-(3- morpholinopropoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 590 67 [00283] (S)-7-(2-(1H-pyrazol-4-yl)phenyl)-4- (4-acryloyl-3-(cyanomethyl)piperazin- 1-yl)-2-(3-morpholinopropoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 622 68 [00284] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(2,3- difluoro-6-hydroxyphenyl)-2-(3- morpholinopropoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 608 69 [00285] 4-(4-acryloylpiperazin-1-yl)-7-(3- chloro-6-fluoro-2-hydroxyphenyl)-2- (3-(dimethylamino)propoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 543 70 [00286] 4-(4-acryloylpiperazin-1-yl)-7-(2- chloro-5-hydroxyphenyl)-2-(3- (dimethylamino)propoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 525 71 [00287] 4-(4-acryloylpiperazin-1-yl)-7-(2,3- dichloro-5-hydroxyphenyl)-2-(3- (dimethylamino)propoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 559 72 [00288] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- amino-6-fluorophenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 520 73 [00289] (S)-4-(4-acryloylpiperazin-1-yl)-7-(5- hydroxy-2-(trifluoromethoxy)phenyl)- 2-((1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 587 74 [00290] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- hydroxy-5-(trifluoromethoxy)phenyl)- 2-((1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 587 75 [00291] (S)-4-(4-acryloylpiperazin-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)-7-(2- (trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 555 76 [00292] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- fluoro-6-(trifluoromethyl)phenyl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 573 77 [00293] (S)-4-(4-acryloylpiperazin-1-yl)-7-(3- fluoro-2-(trifluoromethyl)phenyl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 573 78 [00294] (S)-4-(4-acryloylpiperazin-1-yl)-7-(3- chloro-2-(trifluoromethyl)phenyl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 589 79 [00295] (S)-4-(4-acryloylpiperazin-1-yl)-7-(4- fluoro-2-(trifluoromethyl)phenyl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 573 80 [00296] (S)-4-(4-acryloylpiperazin-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)-7-(2- (trifluoromethyl)pyridin-3-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 556 81 [00297] (S)-4-(4-acryloylpiperazin-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)-7-(3- (trifluoromethyl)pyridin-4-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 556 82 [00298] (S)-4-(4-acryloylpiperazin-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)-7-(4- (trifluoromethyl)pyridin-3-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 556 83 [00299] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(3- (trifluoromethyl)pyridin-2-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 584 84 [00300] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(3-methyl- 2-(trifluoromethyl)phenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 597 85 [00301] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(3-chloro- 5-methyl-1H-indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 603 86 [00302] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(5-methyl- 1H-indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 569 87 [00303] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(1,5- dimethyl-1H-indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 583 88 [00304] (S)-4-(4-acryloylpiperazin-1-yl)-7-(5- chloro-1H-indazol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 561 89 [00305] (S)-4-(4-acryloylpiperazin-1-yl)-7-(5- fluoro-1H-indazol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 545 90 [00306] (S)-4-(4-acryloylpiperazin-1-yl)-7-(5- chloro-6-fluoro-1H-indazol-4-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile 579 91 [00307] (S)-4-(4-acryloylpiperazin-1-yl)-7-(3- fluoro-5-methyl-1H-indazol-4-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 559 92 [00308] (S)-4-(4-acryloylpiperazin-1-yl)-7-(5- methyl-1H-indol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 540 93 [00309] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(5-methyl- 1H-benzo[d]imidazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 569 94 [00310] (S)-4-(4-acryloylpiperazin-1-yl)-7-(5- chloro-6-methyl-1H-indazol-4-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 575 95 [00311] (S)-4-(4-acryloylpiperazin-1-yl)-7-(5- methyl-1H-pyrazolo[3,4-b]pyridin-4- yl)-2-((1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 542 96 [00312] (S)-4-(4-acryloylpiperazin-1-yl)-7-(6- methyl-2-oxo-2,3- dihydrooxazolo[4,5-b]pyridin-7-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 559 97 [00313] (S)-4-(4-acryloylpiperazin-1-yl)-7-(5- chloro-6-fluoro-1H-indazol-4-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 579 98 [00314] (S)-4-(4-acryloylpiperazin-1-yl)-7-(5- cyclopropyl-1H-indazol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 567 99 [00315] (S)-4-(4-acryloylpiperazin-1-yl)-7-(3- cyano-5-methyl-1H-indazol-4-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 566 100 [00316] (S)-4-(4-acryloylpiperazin-1-yl)-7-(5- methyl-3-(trifluoromethyl)-1H- indazol-4-yl)-2-((1-methylpyrrolidin- 2-yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 609 101 [00317] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- fluoro-5-methyl-1H-indol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 558 102 [00318] (R)-4-(4-acryloylpiperazin-1-yl)-7-(5- methoxy-1H-indazol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 557 103 [00319] (R)-4-(4-acryloylpiperazin-1-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 7-(5-(trifluoromethyl)-1H-indazol-4- yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 595 104 [00320] (S,E)-4-(4-(3- (dimethylamino)acryloyl)piperazin-1- yl)-7-(5-methyl-1H-indazol-4-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 584 105 [00321] (S,E)-4-(4-(3- cyclopropylacryloyl)piperazin-1-yl)- 7-(5-methyl-1H-indazol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 581 106 [00322] (S,E)-7-(5-methyl-1H-indazol-4-yl)-4- (4-(2-methylbut-2-enoyl)piperazin-1- yl)-2-((1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 569 107 [00323] (S,E)-4-(4-(3- cyanoacryloyl)piperazin-1-yl)-7-(5- methyl-1H-indazol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 566 108 [00324] (S)-7-(5-methyl-1H-indazol-4-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 4-(4-(1,2,3,6-tetrahydropyridine-4- carbonyl)piperazin-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 596 109 [00325] (S,E)-7-(5-methyl-1H-indazol-4-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 4-(4-(3-morpholinoacryloyl)piperazin- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 626 110 [00326] (S)-7-(5-methyl-1H-indazol-4-yl)-4- (4-(1-methyl-2,5-dihydro-1H-pyrrole- 3-carbonyl)piperazin-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 596 111 [00327] (S,E)-4-(4-(3-cyano-7-(5-methyl-1H- indazol-4-yl)-2-((1-methylpyrrolidin- 2-yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridin-4-yl)piperazin-1-yl)-4- oxobut-2-enoic acid; 585 112 [00328] (S,E)-N-(3-(4-(3-cyano-7-(5-methyl- 1H-indazol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridin-4- yl)piperazin-1-yl)-3-oxoprop-1-en-1- yl)acetamide; 598 113 [00329] (S,E)-4-(4-(5-aminopent-2- enoyl)piperazin-1-yl)-7-(5-methyl- 1H-indazol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 584 114 [00330] (S,E)-4-(4-(4-(3,3-difluoroazetidin-1- yl)but-2-enoyl)piperazin-1-yl)-7-(5- methyl-1H-indazol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 646 115 [00331] (S)-4-(4-(2-chloroacryloyl)piperazin- 1-yl)-7-(5-methyl-1H-indazol-4-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 575 116 [00332] (S,E)-7-(5-methyl-1H-indazol-4-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 4-(4-(4,4,4-trifluorobut-2- enoyl)piperazin-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 609 117 [00333] 7-(8-methylnaphthalen-1-yl)-4-(4- ((Z)-3-(1-methylpyrrolidin-2- yl)acryloyl)piperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 634 118 [00334] 4-((1R,5S)-3-acryloyl-3,8- diazabicyclo[3.2.1]octan-8-yl)-7-(8- methylnaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 577 119 [00335] 4-(5-acryloyl-2,5- diazabicyclo[4.1.0]heptan-2-yl)-7-(8- methylnaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 563 120 [00336] (S)-4-(5-acryloyl-2-oxa-5,8- diazaspiro[3.5]nonan-8-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 593 121 [00337] (S)-4-(4-acryloyl-3,3- dimethylpiperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 579 122 [00338] (R)-4-((1-acryloylazetidin-3- yl)amino)-7-(8-methylnaphthalen-1- yl)-2-((1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 537 123 [00339] (S)-4-(6-acryloyl-2,6- diazaspiro[3.3]heptan-2-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 563 124 [00340] (S)-4-(4-acryloyl-4,7- diazaspiro[2.5]octan-7-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 577 125 [00341] 4-(4-acryloyl-3- (hydroxymethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 581 126 [00342] (S)-4-(4-acryloylpiperazin-1-yl)-7-(5- methyl-1H-indazol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 541 127 [00343] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- fluoro-6-hydroxyphenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 521 128 [00344] 4-((S)-4-acryloyl-2-methylpiperazin- 1-yl)-7-(2-fluoro-6-methoxyphenyl)- 2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 549 129 [00345] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(2- fluoro-6-methoxyphenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 574 130 [00346] 4-((3R,5S)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(2-fluoro-6- methylphenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 547 131 [00347] 4-((3R,5S)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(2-fluoro-6- methylphenyl)-2-(2- morpholinoethoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 563 132 [00348] 4-((3R,5S)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(2,4- difluorophenyl)-2-(2- morpholinoethoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 567 133 [00349] 4-((3R,5S)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-2-(2- (dimethylamino)ethoxy)-7-(4-fluoro- 2-(trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 575 134 [00350] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(2- fluoro-5-hydroxyphenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 560 135 [00351] 2-(4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-3- cyano-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,8-dihydro-1,7- naphthyridin-7(6H)-yl)-3- fluorobenzenesulfonamide; 623 136 [00352] (S)-2-(4-(4-acryloylpiperazin-1-yl)-3- cyano-2-((1-methylpyrrolidin-2- yl)methoxy)-5,8-dihydro-1,7- naphthyridin-7(6H)-yl)-3- fluorobenzamide; 548 137 [00353] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- cyano-6-hydroxyphenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 528 138 [00354] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- chloro-5-hydroxyphenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 537 139 [00355] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- hydroxy-6-methoxyphenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 533 140 [00356] 4-(4-acryloyl-3-cyclopropylpiperazin- 1-yl)-7-(8-methylnaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 591 141 [00357] 4-(5-acryloylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-7-(8- methylnaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 577 142 [00358] 4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(2- fluorophenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 544 143 [00359] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- chlorophenyl)-2-((1-methylpyrrolidin- 2-yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 521 144 [00360] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- cyclopropylphenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 527 145 [00361] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- hydroxyphenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 503 146 [00362] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- cyanophenyl)-2-((1-methylpyrrolidin- 2-yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 512 147 [00363] (S)-4-(4-acryloylpiperazin-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)-7-(2- (trifluoromethoxy)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 571 148 [00364] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(3- hydroxynaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 592 149 [00365] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 590 150 [00366] (S)-4-(4-acryloylpiperazin-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)-7- (naphthalen-1-yl)-5,6,7,8-tetrahydro- 1,7-naphthyridine-3-carbonitrile; 537 151 [00367] (S)-4-(4-acryloylpiperazin-1-yl)-7-(3- (difluoromethyl)naphthalen-1-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 587 152 [00368] (S)-4-(4-acryloylpiperazin-1-yl)-7-(3- (difluoromethyl)isoquinolin-1-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 588 153 [00369] (S)-4-(4-acryloylpiperazin-1-yl)-7-(3- aminoisoquinolin-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 553 154 [00370] (S)-4-(4-acryloylpiperazin-1-yl)-7-(3- aminonaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 552 155 [00371] (S)-4-(4-acryloylpiperazin-1-yl)-7-(4- fluoro-3-hydroxynaphthalen-1-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 571 156 [00372] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- fluoro-3-hydroxynaphthalen-1-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 571 157 [00373] (S)-4-(4-acryloylpiperazin-1-yl)-7-(8- fluoronaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 555 158 [00374] (S)-4-(4-acryloylpiperazin-1-yl)-7-(8- chloro-7-fluoronaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 589 159 [00375] (S)-4-(4-acryloylpiperazin-1-yl)-7-(8- cyanonaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 562 160 [00376] 4-(4-acryloylpiperazin-1-yl)-7-(8- cyclopropylnaphthalen-1-yl)-2-(2- (dimethylamino)ethoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 551 161 [00377] 4-(4-acryloylpiperazin-1-yl)-2-(2- (dimethylamino)ethoxy)-7-(8- (trifluoromethyl)naphthalen-1-yl)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 579 162 [00378] (S)-4-(4-acryloylpiperazin-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)-7-(8- (trifluoromethyl)naphthalen-1-yl)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 605 163 [00379] 4-(4-acryloylpiperazin-1-yl)-2-(2- (dimethylamino)ethoxy)-7- (isoquinolin-4-yl)-5,6,7,8-tetrahydro- 1,7-naphthyridine-3-carbonitrile; 512 164 [00380] 4-(4-acryloylpiperazin-1-yl)-2-(2- (dimethylamino)ethoxy)-7-(quinolin- 4-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 512 165 [00381] 4-(4-acryloylpiperazin-1-yl)-2-(2- (dimethylamino)ethoxy)-7- (isoquinolin-8-yl)-5,6,7,8-tetrahydro- 1,7-naphthyridine-3-carbonitrile; 512 166 [00382] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- chloronaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 610 167 [00383] (S)-4-(4-acryloylpiperazin-1-yl)-7-(7- fluoro-8-methylnaphthalen-1-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 569 168 [00384] (S)-4-(4-acryloylpiperazin-1-yl)-7- (7,8-difluoronaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 573 169 [00385] (S)-4-(4-acryloylpiperazin-1-yl)-7- (6,7-difluoroisoquinolin-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 574 170 [00386] (S)-4-(4-acryloylpiperazin-1-yl)-7- (7,8-dichloronaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 605 171 [00387] (S,E)-4-(4-(4-fluorobut-2- enoyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 583 172 [00388] (S,E)-4-(4-(4-methoxybut-2- enoyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 595 173 [00389] (S,E)-4-(4-(4-hydroxybut-2- enoyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 581 174 [00390] (S,E)-4-(4-(4-(3-fluoroazetidin-1- yl)but-2-enoyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 638 175 [00391] (S)-4-(4-(2-fluoroacryloyl)piperazin- 1-yl)-7-(8-methylnaphthalen-1-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 569 176 [00392] (S)-7-(8-methylnaphthalen-1-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 4-(4-(2- (trifluoromethyl)acryloyl)piperazin-1- yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 619 177 [00393] (S)-4-(4-(2-fluoroacryloyl)piperazin- 1-yl)-7-(8-methylnaphthalen-1-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 569 178 [00394] (S)-7-(8-chloronaphthalen-1-yl)-4-(4- (2-fluoroacryloyl)piperazin-1-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 589 179 [00395] (S)-7-(8-chloro-7-fluoronaphthalen-1- yl)-4-(4-(2-fluoroacryloyl)piperazin- 1-yl)-2-((1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 607 180 [00396] (S)-7-(7,8-difluoronaphthalen-1-yl)-4- (4-(2-fluoroacryloyl)piperazin-1-yl)- 2-((1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 591 181 [00397] (S)-7-(7-fluoro-8-methylnaphthalen-1- yl)-4-(4-(2-fluoroacryloyl)piperazin- 1-yl)-2-((1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 587 182 [00398] (S)-4-(4-(2-fluoroacryloyl)piperazin- 1-yl)-7-(3-methyl-2- (trifluoromethyl)phenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 587 183 [00399] (S)-7-(3-fluoro-2- (trifluoromethyl)phenyl)-4-(4-(2- fluoroacryloyl)piperazin-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 591 184 [00400] (S)-7-(3-chloro-2- (trifluoromethyl)phenyl)-4-(4-(2- fluoroacryloyl)piperazin-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 607 185 [00401] (R)-7-(3-chloro-2- (trifluoromethyl)phenyl)-4-(4-(2- fluoroacryloyl)piperazin-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 607 186 [00402] (S)-7-(7,8-dichloronaphthalen-1-yl)-4- (4-(2-fluoroacryloyl)piperazin-1-yl)- 2-((1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 623 187 [00403] (S)-7-(6,7-difluoronaphthalen-1-yl)-4- (4-(2-fluoroacryloyl)piperazin-1-yl)- 2-((1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 591 188 [00404] (S)-4-(4-(2-fluoroacryloyl)piperazin- 1-yl)-2-((1-methylpyrrolidin-2- yl)methoxy)-7-(2- (trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 573 189 [00405] (S)-4-(4-(2-fluoroacryloyl)piperazin- 1-yl)-7-(6-hydroxynaphthalen-1-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 571 190 [00406] (S)-4-(4-(2-fluoroacryloyl)piperazin- 1-yl)-7-(isoquinolin-5-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 556 191 [00407] (S)-4-(4-(2-fluoroacryloyl)piperazin- 1-yl)-7-(5-methyl-1H-indazol-4-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 559 192 [00408] (S)-4-(4-(2-fluoroacryloyl)piperazin- 1-yl)-7-(6-methyl-1H-indazol-7-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 559 193 [00409] (S)-7-(1,6-dimethyl-1H-indazol-7-yl)- 4-(4-(2-fluoroacryloyl)piperazin-1- yl)-2-((1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 573 194 [00410] (S)-7-(1,5-dimethyl-1H-indazol-4-yl)- 4-(4-(2-fluoroacryloyl)piperazin-1- yl)-2-((1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 573 195 [00411] 7-(7-fluoro-1-oxo-1,2- dihydroisoquinolin-8-yl)-4-((R)-4-(2- fluoroacryloyl)-3-methylpiperazin-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 604 196 [00412] 4-((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(6-methyl-2- oxo-2,3-dihydrobenzo[d]oxazol-7-yl)- 2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 590 197 [00413] 4-((R)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(6-methyl- 1H-benzo[d]imidazol-7-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 573 198 [00414] 7-(7-fluoro-1-oxo-1,2- dihydroisoquinolin-8-yl)-4-((S)-4-(2- fluoroacryloyl)-3-methylpiperazin-1- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 604 199 [00415] 4-((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(6-methyl-2- oxo-2,3-dihydrobenzo[d]oxazol-7-yl)- 2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 590 200 [00416] 4-((S)-4-(2-fluoroacryloyl)-3- methylpiperazin-1-yl)-7-(6-methyl- 1H-benzo[d]imidazol-7-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 573 201 [00417] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((R)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 590 202 [00418] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)-7- (2-(trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 594 203 [00419] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(2,3- dichlorophenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 594 204 [00420] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(3- hydroxynaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 592 205 [00421] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(5- methyl-1H-indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 580 206 [00422] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(2- fluoro-6-hydroxyphenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 560 207 [00423] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(2- methyl-6-(trifluoromethyl)phenyl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 608 208 [00424] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(5- chloro-6-fluoro-1H-indazol-4-yl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile 618 209 [00425] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(5- cyclopropyl-1H-indazol-4-yl)-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 606 210 [00426] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(2- fluoro-6-methylphenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 558 211 [00427] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(2- chloro-6-methylphenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 574 212 [00428] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(2- (trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 583 213 [00429] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(2,3- dichlorophenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 583 214 [00430] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(3- hydroxynaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 581 215 [00431] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(5-methyl- 1H-indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 569 216 [00432] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(2-fluoro-6- hydroxyphenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 549 217 [00433] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(2-methyl- 6-(trifluoromethyl)phenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 597 218 [00434] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(5-chloro- 6-fluoro-1H-indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile 607 219 [00435] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(5- cyclopropyl-1H-indazol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 595 220 [00436] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(2-fluoro-6- methylphenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 547 221 [00437] 4-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-7-(2-chloro- 6-methylphenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 563 222 [00438] (S)-4-(4-acryloylpiperazin-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)-7-(2- (trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 555 223 [00439] (S)-4-(4-acryloylpiperazin-1-yl)-7- (2,3-dichlorophenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 555 224 [00440] (S)-4-(4-acryloylpiperazin-1-yl)-7-(3- hydroxynaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 553 225 [00441] (S)-4-(4-acryloylpiperazin-1-yl)-7-(5- methyl-1H-indazol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 541 226 [00442] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- fluoro-6-hydroxyphenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 521 227 [00443] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- methyl-6-(trifluoromethyl)phenyl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 569 228 [00444] (S)-4-(4-acryloylpiperazin-1-yl)-7-(5- chloro-6-fluoro-1H-indazol-4-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile 579 229 [00445] (S)-4-(4-acryloylpiperazin-1-yl)-7-(5- cyclopropyl-1H-indazol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 567 230 [00446] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- fluoro-6-methylphenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 519 231 [00447] (S)-4-(4-acryloylpiperazin-1-yl)-7-(2- chloro-6-methylphenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 535 232 [00448] 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 579 233 [00449] 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(2- (trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 583 234 [00450] 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(2,3- dichlorophenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 583 235 [00451] 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(3- hydroxynaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 581 236 [00452] 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(5-methyl- 1H-indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 569 237 [00453] 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(2-fluoro-6- hydroxyphenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 549 238 [00454] 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(2-methyl- 6-(trifluoromethyl)phenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 597 239 [00455] 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(5-chloro- 6-fluoro-1H-indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile 607 240 [00456] 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(5- cyclopropyl-1H-indazol-4-yl)-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 595 241 [00457] 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(2-fluoro-6- methylphenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 547 242 [00458] 4-((2S,5R)-4-acryloyl-2,5- dimethylpiperazin-1-yl)-7-(2-chloro- 6-methylphenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 563 243 [00459] 4-((S)-4-acryloyl-2-methylpiperazin- 1-yl)-7-(8-methylnaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 565 244 [00460] 4-((S)-4-acryloyl-2-methylpiperazin- 1-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(2- (trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 569 245 [00461] 4-((S)-4-acryloyl-2-methylpiperazin- 1-yl)-7-(2,3-dichlorophenyl)-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 569 246 [00462] 4-((S)-4-acryloyl-2-methylpiperazin- 1-yl)-7-(3-hydroxynaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 567 247 [00463] 4-((S)-4-acryloyl-2-methylpiperazin- 1-yl)-7-(5-methyl-1H-indazol-4-yl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 555 248 [00464] 4-((S)-4-acryloyl-2-methylpiperazin- 1-yl)-7-(2-fluoro-6-hydroxyphenyl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 535 249 [00465] 4-((S)-4-acryloyl-2-methylpiperazin- 1-yl)-7-(2-methyl-6- (trifluoromethyl)phenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 583 250 [00466] 4-((S)-4-acryloyl-2-methylpiperazin- 1-yl)-7-(5-chloro-6-fluoro-1H- indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile 593 251 [00467] 4-((S)-4-acryloyl-2-methylpiperazin- 1-yl)-7-(5-cyclopropyl-1H-indazol-4- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 581 252 [00468] 4-((S)-4-acryloyl-2-methylpiperazin- 1-yl)-7-(2-fluoro-6-methylphenyl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 533 253 [00469] 4-((S)-4-acryloyl-2-methylpiperazin- 1-yl)-7-(2-chloro-6-methylphenyl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 549 254 [00470] (S)-4-(6-acryloyl-2,6- diazaspiro[3.3]heptan-2-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 563 255 [00471] (S)-4-(6-acryloyl-2,6- diazaspiro[3.3]heptan-2-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)-7-(2- (trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 567 256 [00472] (S)-4-(6-acryloyl-2,6- diazaspiro[3.3]heptan-2-yl)-7-(2,3- dichlorophenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 567 257 [00473] (S)-4-(6-acryloyl-2,6- diazaspiro[3.3]heptan-2-yl)-7-(3- hydroxynaphthalen-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 565 258 [00474] (S)-4-(6-acryloyl-2,6- diazaspiro[3.3]heptan-2-yl)-7-(5- methyl-1H-indazol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 553 259 [00475] (S)-4-(6-acryloyl-2,6- diazaspiro[3.3]heptan-2-yl)-7-(2- fluoro-6-hydroxyphenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 533 260 [00476] (S)-4-(6-acryloyl-2,6- diazaspiro[3.3]heptan-2-yl)-7-(2- methyl-6-(trifluoromethyl)phenyl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 581 261 [00477] (S)-4-(6-acryloyl-2,6- diazaspiro[3.3]heptan-2-yl)-7-(5- chloro-6-fluoro-1H-indazol-4-yl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile 591 262 [00478] (S)-4-(6-acryloyl-2,6- diazaspiro[3.3]heptan-2-yl)-7-(5- cyclopropyl-1H-indazol-4-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 579 263 [00479] (S)-4-(6-acryloyl-2,6- diazaspiro[3.3]heptan-2-yl)-7-(2- fluoro-6-methylphenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 531 264 [00480] (S)-4-(6-acryloyl-2,6- diazaspiro[3.3]heptan-2-yl)-7-(2- chloro-6-methylphenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 547 265 [00481] (S)-4-((1-acryloylazetidin-3- yl)amino)-2-((1-methylpyrrolidin-2- yl)methoxy)-7-(2- (trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 541 266 [00482] (S)-4-((1-acryloylazetidin-3- yl)amino)-7-(2,3-dichlorophenyl)-2- ((1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 541 267 [00483] (S)-4-((1-acryloylazetidin-3- yl)amino)-7-(3-hydroxynaphthalen-1- yl)-2-((1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 539 268 [00484] (S)-4-((1-acryloylazetidin-3- yl)amino)-7-(5-methyl-1H-indazol-4- yl)-2-((1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 527 269 [00485] (S)-4-((1-acryloylazetidin-3- yl)amino)-7-(2-fluoro-6- hydroxyphenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 507 270 [00486] (S)-4-((1-acryloylazetidin-3- yl)amino)-7-(2-methyl-6- (trifluoromethyl)phenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 555 271 [00487] (S)-4-((1-acryloylazetidin-3- yl)amino)-7-(5-chloro-6-fluoro-1H- indazol-4-yl)-2-((1-methylpyrrolidin- 2-yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile 565 272 [00488] (S)-4-((1-acryloylazetidin-3- yl)amino)-7-(5-cyclopropyl-1H- indazol-4-yl)-2-((1-methylpyrrolidin- 2-yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 553 273 [00489] (S)-4-((1-acryloylazetidin-3- yl)amino)-7-(2-fluoro-6- methylphenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 505 274 [00490] (S)-4-((1-acryloylazetidin-3- yl)amino)-7-(2-chloro-6- methylphenyl)-2-((1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 521 275 [00491] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(2- (trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 569 276 [00492] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(2,3-dichlorophenyl)-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 569 277 [00493] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(3-hydroxynaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 567 278 [00494] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(5-methyl-1H-indazol-4-yl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 555 279 [00495] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(2-fluoro-6-hydroxyphenyl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 535 280 [00496] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(2-methyl-6- (trifluoromethyl)phenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 583 281 [00497] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(5-chloro-6-fluoro-1H- indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile 593 282 [00498] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(5-cyclopropyl-1H-indazol-4- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 581 283 [00499] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(2-fluoro-6-methylphenyl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 533 284 [00500] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(2-chloro-6-methylphenyl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 549 285 [00501] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-7-(2- (trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 569 286 [00502] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(2,3-dichlorophenyl)-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 569 287 [00503] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(3-hydroxynaphthalen-1-yl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 567 288 [00504] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(5-methyl-1H-indazol-4-yl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 555 289 [00505] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(2-fluoro-6-hydroxyphenyl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 535 290 [00506] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(2-methyl-6- (trifluoromethyl)phenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 583 291 [00507] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(5-chloro-6-fluoro-1H- indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile 593 292 [00508] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(5-cyclopropyl-1H-indazol-4- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 581 293 [00509] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(2-fluoro-6-methylphenyl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 533 294 [00510] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(2-chloro-6-methylphenyl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 549 295 [00511] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- (dimethylamino)ethoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 564 296 [00512] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(3- (dimethylamino)propoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 578 297 [00513] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(3- (piperidin-1-yl)propoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 618 298 [00514] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(3- morpholinopropoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 620 299 [00515] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((1- (2-methoxyethyl)piperidin-4-yl)oxy)- 7-(8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 634 300 [00516] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpiperidin-4-yl)oxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 590 301 [00517] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(3- (dimethylamino)azetidin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 575 302 [00518] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2- (((3R,4R)-4-methoxy-1- methylpyrrolidin-3-yl)oxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 606 303 [00519] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((S)- 3-fluoro-1-methylpiperidin-3- yl)methoxy)-7-(8-methylnaphthalen- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 622 304 [00520] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((4- fluoro-1-methylpiperidin-4- yl)methoxy)-7-(8-methylnaphthalen- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 622 305 [00521] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((R)- 3-fluoro-1-methylpiperidin-3- yl)methoxy)-7-(8-methylnaphthalen- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 622 306 [00522] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((4- fluoro-1-methylpiperidin-4- yl)methoxy)-7-(8-methylnaphthalen- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 622 307 [00523] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((2- methyl-1,2,3,4-tetrahydroisoquinolin- 5-yl)oxy)-7-(8-methylnaphthalen-1- yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 638 308 [00524] (S)-4-(3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2-(2- (dimethylamino)ethoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 582 309 [00525] (S)-4-(3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2-(3- (dimethylamino)propoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 596 310 [00526] (S)-4-(3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(3- (piperidin-1-yl)propoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 636 311 [00527] (S)-4-(3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(3- morpholinopropoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 638 312 [00528] (S)-4-(3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2-((1- (2-methoxyethyl)piperidin-4-yl)oxy)- 7-(8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 652 313 [00529] (S)-4-(3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpiperidin-4-yl)oxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 608 314 [00530] (S)-4-(3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2-(3- (dimethylamino)azetidin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 593 315 [00531] 4-((S)-3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2- (((3R,4R)-4-methoxy-1- methylpyrrolidin-3-yl)oxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 624 316 [00532] 4-((S)-3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2-(((S)- 3-fluoro-1-methylpiperidin-3- yl)methoxy)-7-(8-methylnaphthalen- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile 640 317 [00533] (S)-4-(3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2-((4- fluoro-1-methylpiperidin-4- yl)methoxy)-7-(8-methylnaphthalen- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 640 318 [00534] 4-((S)-3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2- (((R)-3-fluoro-1-methylpiperidin-3- yl)methoxy)-7-(8-methylnaphthalen- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 640 319 [00535] (S)-4-(3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2-((4- fluoro-1-methylpiperidin-4- yl)methoxy)-7-(8-methylnaphthalen- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 640 320 [00536] (S)-4-(3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2-((2- methyl-1,2,3,4-tetrahydroisoquinolin- 5-3,4-7-(8-methylnaphthalen-1-yl)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 656 321 [00537] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(5- chloro-6-fluoro-1H-indazol-4-yl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 618 322 [00538] 7-(5-chloro-6-fluoro-1H-indazol-4- yl)-4-((S)-3-(cyanomethyl)-4-(2- fluoroacryloyl)piperazin-1-yl)-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 636 323 [00539] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((S)- 5,5-dimethylpyrrolidin-2- yl)methoxy)-7-(8-methylnaphthalen- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 604 324 [00540] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- (3,3-difluoropyrrolidin-1-yl)ethoxy)- 7-(8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 626 325 [00541] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2-(3- methoxypyrrolidin-1-yl)ethoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 620 326 [00542] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(3-(3- methoxypyrrolidin-1-yl)propoxy)-7- (8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 634 327 [00543] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((R)-1-((R)- 1-methylpyrrolidin-2-yl)ethoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 604 328 [00544] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((R)-1- methylpyrrolidin-3-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 590 329 [00545] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((S)-1- methylpyrrolidin-3-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 590 330 [00546] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((R)- pyrrolidin-3-yl)methoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 576 331 [00547] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((1- cyclohexylpyrrolidin-3-yl)methoxy)- 7-(8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 658 332 [00548] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((S)- 1-(2-methoxyethyl)pyrrolidin-2- yl)methoxy)-7-(8-methylnaphthalen- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 634 333 [00549] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((S)- 1-isopropylpyrrolidin-2-yl)methoxy)- 7-(8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 618 334 [00550] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpyrrolidin-3-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 590 335 [00551] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((1- (2-hydroxyethyl)pyrrolidin-3- yl)methoxy)-7-(8-methylnaphthalen- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 620 336 [00552] 2-(3-(((4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-3- cyano-7-(8-methylnaphthalen-1-yl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)-N,N- dimethylacetamide; 661 337 [00553] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((1- (2-methoxyethyl)pyrrolidin-3- yl)methoxy)-7-(8-methylnaphthalen- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 634 338 [00554] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((R)- 1-((R)-3-methoxypyrrolidin-1- yl)propan-2-yl)oxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 634 339 [00555] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((R)- 1-((S)-3-methoxypyrrolidin-1- yl)propan-2-yl)oxy)-7-(8-methyl-4 a,8a-dihydronaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 636 340 [00556] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((R)- 1-((S)-3-hydroxypyrrolidin-1- yl)propan-2-yl)oxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 620 341 [00557] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((S)-5- oxopyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 590 342 [00558] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(pyrrolidin- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 546 343 [00559] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpyrrolidin-3-yl)oxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 576 344 [00560] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((R)-1- (pyrrolidin-1-yl)propan-2-yl)oxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 604 345 [00561] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2-(3- fluoropyrrolidin-1-yl)ethoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 608 346 [00562] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(3- (pyrrolidin-1-yl)propoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 604 347 [00563] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2- (((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 608 348 [00564] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2- (((2S,4S)-4-methoxy-1- methylpyrrolidin-2-yl)methoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 620 349 [00565] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((S)- 1,2-dimethylpyrrolidin-2- yl)methoxy)-7-(8-methylnaphthalen- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 604 350 [00566] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((S)- 1-isopropylpyrrolidin-2-yl)methoxy)- 7-(8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 618 351 [00567] 2-(3-(3-azabicyclo[3.1.0]hexan-3- yl)propoxy)-4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 616 352 [00568] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(3- ((3R,4S)-3,4-difluoropyrrolidin-1- yl)propoxy)-7-(8-methylnaphthalen-1- yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 640 353 [00569] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2- (((2S,4R)-4-hydroxy-1- methylpyrrolidin-2-yl)methoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 606 354 [00570] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((1- benzylpyrrolidin-3-yl)methoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 666 355 [00571] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(3- (dimethylamino)pyrrolidin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 589 356 [00572] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpiperidin-4-yl)oxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 590 357 [00573] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(3- (piperidin-1-yl)propoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 618 358 [00574] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((R)-1- methylpiperidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 604 359 [00575] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(((S)-1- methylpiperidin-3-yl)oxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 590 360 [00576] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpiperidin-3-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 604 361 [00577] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(2-(4- methylpiperidin-1-yl)ethoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 618 362 [00578] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- ((S)-3-methoxypiperidin-1-yl)ethoxy)- 7-(8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 634 363 [00579] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((1- cyclopropylpiperidin-4-yl)oxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 616 364 [00580] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2-(4- methoxypiperidin-1-yl)ethoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 634 365 [00581] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- (4,4-difluoropiperidin-1-yl)ethoxy)-7- (8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 640 366 [00582] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((6- oxopiperidin-2-yl)methoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 604 367 [00583] 2-(2-((1S,4R)-2- azabicyclo[2.2.1]heptan-2-yl)ethoxy)- 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 616 368 [00584] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(4- (dimethylamino)piperidin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 603 369 [00585] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- ((S)-3-fluoropiperidin-1-yl)ethoxy)-7- (8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 622 370 [00586] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((R)- 1-(ethyl(methyl)amino)propan-2- yl)oxy)-7-(8-methylnaphthalen-1-yl)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 592 371 [00587] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- (dimethylamino)ethoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 564 372 [00588] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((1- (methylamino)propan-2-yl)oxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 564 373 [00589] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- (dimethylamino)propoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 578 374 [00590] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- ((2- methoxyethyl)(methyl)amino)ethoxy)- 7-(8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile 608 375 [00591] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- (dimethylamino)-2-methylpropoxy)-7- (8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 592 376 [00592] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- hydroxyethoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 537 377 [00593] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2,3- dihydroxypropoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 567 378 [00594] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- (diethylamino)ethoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 592 379 [00595] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((R)- 1-(dimethylamino)butan-2-yl)oxy)-7- (8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 592 380 [00596] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- (dimethylamino)-3-hydroxyl)ropoxy)- 7-(8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 594 381 [00597] (S)-N-(2-((4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-3- cyano-7-(8-methylnaphthalen-1-yl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-2- yl)oxy)ethyl)acetamide; 578 382 [00598] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- ((2- hydroxyethyl)(methyl)amino)ethoxy)- 7-(8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 594 383 [00599] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(4- (dimethylamino)butoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 592 384 [00600] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(3- hydroxypropoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 551 385 [00601] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2- morpholino-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 562 386 [00602] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(2- morpholinoethoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 606 387 [00603] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(3- morpholinopropoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 620 388 [00604] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((4- morpholinobutan-2-yl)oxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 634 389 [00605] 2-(3-((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5- yl)propoxy)-4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 632 390 [00606] 2-(3-((1R,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5- yl)propoxy)-4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 632 391 [00607] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- hydroxy-3-morpholinopropoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 636 392 [00608] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(3- (morpholinomethyl)phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 652 393 [00609] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((R)- 4-methylmorpholin-2-yl)methoxy)-7- (8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 606 394 [00610] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((S)- 4-methylmorpholin-2-yl)methoxy)-7- (8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 606 395 [00611] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((4- methylmorpholin-3-yl)methoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 606 396 [00612] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- (1,1-dioxidothiomorpholino)ethoxy)- 7-(8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 654 397 [00613] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((R)- 2-hydroxy-3-morpholinopropoxy)-7- (8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 636 398 [00614] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((3- morpholinopropyl)amino)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 619 399 [00615] (S)-2-(3-(1,4-oxazepan-4- yl)propoxy)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 634 400 [00616] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(3- (dimethylamino)propoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 578 401 [00617] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(2- (piperidin-1-yl)ethoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 604 402 [00618] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((1- hydroxy-3-morpholinopropan-2- yl)oxy)-7-(8-methylnaphthalen-1-yl)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 636 403 [00619] 2-((1-(4-acetylpiperazin-1-yl)propan- 2-yl)oxy)-4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 661 404 [00620] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((4- methylpiperazin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 605 405 [00621] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((1,4- dimethylpiperazin-2-yl)methoxy)-7- (8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 619 406 [00622] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(4- methylpiperazin-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 575 407 [00623] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(3-(4- methylpiperazin-1-yl)propoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 633 408 [00624] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(3- (dimethylamino)azetidin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 575 409 [00625] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(2- (3,3-difluoroazetidin-1-yl)ethoxy)-7- (8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 612 410 [00626] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(2-(pyridin- 2-yl)ethoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 598 411 [00627] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- (tetrahydro-2H-pyran-4-yl)piperidin- 4-yl)oxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 660 412 [00628] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((1- (2- (cyclopropylmethoxy)ethyl)piperidin- 4-yl)oxy)-7-(8-methylnaphthalen-1- yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 674 413 [00629] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((1- (1,3-difluoropropan-2-yl)piperidin-4- yl)oxy)-7-(8-methylnaphthalen-1-yl)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile 654 414 [00630] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- (pyridin-2-ylmethyl)piperidin-4- yl)oxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 667 415 [00631] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- methylpiperidin-4-yl)thio)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 606 416 [00632] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((1- (2-hydroxy-2-methylpropyl)piperidin- 4-yl)oxy)-7-(8-methylnaphthalen-1- yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 648 417 [00633] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((1- (2-methoxyethyl)piperidin-4-yl)oxy)- 7-(8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 634 418 [00634] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((1- (1,3-difluoropropan-2-yl)piperidin-4- yl)oxy)-7-(8-methylnaphthalen-1-yl)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 654 419 [00635] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1- (pyridin-2-ylmethyl)piperidin-4- yl)oxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 667 420 [00636] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(3- (bis(methyl-d3)amino)azetidin-1-yl)- 7-(8-methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 581 421 [00637] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(2- (pyrimidin-2-yl)ethoxy)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 599 422 [00638] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(3- (dimethylamino)azetidin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 575 423 [00639] (S)-N-(4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-3- cyano-7-(8-methylnaphthalen-1-yl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-2- yl)methanesulfonamide; 570 424 [00640] (S)-N-(4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-3- cyano-7-(8-methylnaphthalen-1-yl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-2- yl)cyclopropanesulfonamide; 596 425 [00641] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(3- (aziridin-1-yl)azetidin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 573 426 [00642] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(2-(pyridin- 2-yl)ethoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 598 427 [00643] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((3- fluoropyridin-2- yl)methoxy)methoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 632 428 [00644] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((1- methyl-1H-pyrazol-5-yl)oxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 573 429 [00645] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(7- methyl-2,7-diazaspiro[3.5]nonan-2- yl)-7-(8-methylnaphthalen-1-yl)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 615 430 [00646] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(7-oxa-2- azaspiro[3.5]nonan-2-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 602 431 [00647] (S)-2-(2-(1H-imidazol-1-yl)ethoxy)-4- (4-acryloyl-3-(cyanomethyl)piperazin- 1-yl)-7-(8-methylnaphthalen-1-yl)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 587 432 [00648] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2- (((2S,4R)-4-methoxy-1- methylpyrrolidin-2-yl)methoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 620 433 [00649] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2- (((2S,4S)-4-methoxy-1- methylpyrrolidin-2-yl)methoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 620 434 [00650] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2- (((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 608 435 [00651] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2- (dimethylphosphoryl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 553 436 [00652] (S)-2-(2-(1H-1,2,4-triazol-1- yl)ethoxy)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 588 437 [00653] (S)-2-(2-(1H-benzo[d]imidazol-1- yl)ethoxy)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 637 438 [00654] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(pyridin-2- ylmethoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 584 439 [00655] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-(pyridazin- 3-ylmethoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 585 440 [00656] (S)-4-(4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2- (morpholine-4-carbonyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 590 441 [00657] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2- (((2S,4S)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 608 442 [00658] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-(((S)- 4,4-difluoro-1-methylpyrrolidin-2- yl)methoxy)-7-(8-methylnaphthalen- 1-yl)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 626 443 [00659] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-2-((1,3,3- trimethylazetidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 604 444 [00660] 2-(((2S)-1-azabicyclo[2.2.1]heptan-2- yl)methoxy)-4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 602 445 [00661] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-2-((2,2- difluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(8- methylnaphthalen-1-yl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3- carbonitrile; 652 446 [00662] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(3- fluoro-2-(trifluoromethyl)phenyl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 612 447 [00663] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(3- chloro-2-(trifluoromethyl)phenyl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 628 448 [00664] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(6- methyl-hyl-1H-indazol-7-yl)-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 580 449 [00665] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(1,6- dimethyl-1H-indazol-7-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 594 450 [00666] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(1,5- dimethyl-1H-indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 594 451 [00667] 4-((S)-4-acryloyl-3- (cyanomethyl)piperazin-1-yl)-7-(5- methyl-1H-indazol-4-yl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 580 452 [00668] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(3-fluoro-2- (trifluoromethyl)phenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 587 453 [00669] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(3-chloro-2- (trifluoromethyl)phenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 603 454 [00670] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(6-methyl-1H-indazol-7-yl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 555 455 [00671] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(1,6-dimethyl-1H-indazol-7- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 569 456 [00672] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(1,5-dimethyl-1H-indazol-4- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 569 457 [00673] 4-((R)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(5-methyl-1H-indazol-4-yl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 555 458 [00674] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(3-fluoro-2- (trifluoromethyl)phenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 587 459 [00675] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(3-chloro-2- (trifluoromethyl)phenyl)-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydro-1,7-naphthyridine- 3-carbonitrile; 603 460 [00676] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(6-methyl-1H-indazol-7-yl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 555 461 [00677] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(1,6-dimethyl-1H-indazol-7- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; 569 462 [00678] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(1,5-dimethyl-1H-indazol-4- yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile; or 569 463 [00679] 4-((S)-4-acryloyl-3-methylpiperazin- 1-yl)-7-(5-methyl-1H-indazol-4-yl)-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydro-1,7- naphthyridine-3-carbonitrile. 555

PHARMACOLOGICAL TESTING

1. SOS1 Catalyzed Nucleotide Exchange Assay

[0249] HIS-KRAS (G12C, aa 2-185, Sino biological) was diluted to 5 M in EDTA buffer (20 mM HEPES, pH 7.4, 50 mM NaCl, 10 mM EDTA, 0.01% (v/v) Tween-20) and incubated for 30 min at 25 C. The EDTA pretreated HIS-KRAS (G12C) was diluted to 12 nM in assay buffer (25 mM HEPES, pH 7.4, 120 mM NaCl, 5 mM MgCl.sub.2, 1 mM DTT, 0.01% (v/v) Tween 20, 0.1% (w/v) BSA) containing 120 nM GDP (Sigma) and MAb Anti 6HIS-Tb cryptate Gold (Cisbio) and incubated for 1 hour at 25 C. to prepare GDP-loaded HIS-KRAS (G12C). The GDP-loaded HIS-KRAS (G12C) was pre-incubation with diluted compounds in a 384-well plate (Greiner) for 1 hour, then purified SOS1 ExD (Flag tag, aa 564-1049) and BODIPY FL GTP (Invitrogen) were added to the assay wells (Final concentration: 3 nM HIS-KRAS (G12C), 2 M SOS1 ExD, 80 nM BODIPY FL GTP, 21 ng/mL MAb Anti 6HIS-Tb cryptate Gold) and incubated for 4 hours at 25 C. TR-FRET signals were then read on Tecan Spark multimode microplate reader. The parameters were F486: Excitation 340 (35) nm, Emission 486 (10) nm, Lag time 100 las, Integration time 200 las; F515: Excitation 340 (35) nm, Emission 515 (10) nm, Lag time 100 las, Integration time 200 las. TR-FRET ratios for each individual wells were calculated by equation: TR-FRET ratio=(Signal F515/Signal F486)*10000. Then the data were analyzed using a 4-parameter logistic model to calculate IC.sub.50 values. The results of the SOS1 catalyzed nucleotide exchange assay are in the following Table:

TABLE-US-00002 SOS1 catalyzed nucleotide Compound exchange IC.sub.50(nM) Compound 1 53.07 Compound 2 >1000 Compound 3 >1000 Compound 4 >1000 Compound 5 >1000 Compound 6 >1000

[0250] It can be seen from the Table that the representative compound of the present invention had inhibitory activity in the SOS1 catalyzed nucleotide exchange assay.