HETEROCYCLIC COMPOUNDS AS INHIBITORS OF KRAS G12C

Abstract

Heterocyclic compounds or pharmaceutically acceptable salt thereof are provided as inhibitors of the KRAS G12C mutant, and compositions containing these compounds which may be used to treat various disease conditions associated with KRAS G12C, such as cancers.

Claims

1. A compound of Formula VIIA or a pharmaceutically acceptable salt thereof: ##STR00450## where ##STR00451## R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, halo, C.sub.0-6alkylene-CN, C.sub.0-6alkyleneNR.sup.19R.sup.20, C.sub.1-6alkoxy, hydroxy, C.sub.0-6alkylene-C(O)NH.sub.2, C.sub.0-6alkylene-C(O)NHC.sub.1-6 alkyl, C.sub.0-6alkylene-C(O)N(C.sub.1-6 alkyl).sub.2, C.sub.0-6alkylene-S(O).sub.2—C.sub.1-6alkyl, C.sub.0-6alkylene-S(O).sub.2NH.sub.2, C.sub.0-6alkylene-S(O).sub.2NHC.sub.1-6alkyl, C.sub.0-6alkylene-S(O).sub.2N(C.sub.1-6 alkyl).sub.2, C.sub.0-6alkylene-NHC(O)NH.sub.2, C.sub.0-6alkylene-NHC(O)NHC.sub.1-6alkyl, C.sub.0-6 alkylene-NR.sup.19C(O)N(C.sub.1-6 alkyl).sub.2, C.sub.1-6alkyl, C.sub.0-6 alkylene-NHC(O)OC.sub.1-6alkyl, C.sub.0-6 alkylene-C(O)—C.sub.1-6 alkyl, C.sub.1-6heteroalkyl, C.sub.0-6 alkylene-heterocyclyl, and C.sub.0-6 alkylene-heterocyclylalkyl; or R.sup.1 and R.sup.2, together with the carbon atom to which they are attached, can form a 3 to 6 membered carbocyclic ring; Z and Y are each independently N or CR.sup.3; W is N or CR.sup.6; W.sup.1 is N or CR.sup.3; W.sup.2 is N or CR.sup.4; Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4 and Z.sup.5 are each independently N or CR.sup.18; R.sup.3, R.sup.4 and R.sup.6 are each independently selected from the group consisting of H, OH, CN or halo, C.sub.1-6alkyl, C.sub.3-10cycloalkyl, C.sub.3-10heteroalkyl, C.sub.3-10heterocylcoalkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, NH—C.sub.1-6alkyl, N(C.sub.1-6alkyl).sub.2, C.sub.3-8cycloalkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, C.sub.2-6heterocyclyl, aryl and heteroaryl; R.sup.17 and R.sup.18 are each independently selected from the group consisting of halogen, CN, a branched or a linear C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 heterocycyl, —SC.sub.1-6 alkyl, —OC.sub.1-6 alkyl. —OC.sub.3-6 heterocycyl, —OC.sub.3-6 cycyl, NH—C.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, —SC.sub.3-6 heterocycyl, —SC.sub.3-6 cycyl, —S(O)C.sub.1-6 alkyl, —S(O).sub.2C.sub.1-6 alkyl, —S(O).sub.2NH.sub.2, —S(O).sub.2NHC.sub.1_.sub.6 alkyl, —S(O).sub.2N(C.sub.1-6 alkyl).sub.2, —P(O)(C.sub.1-6 alkyl).sub.2, C.sub.2-6 heterocyclyl, an C.sub.6-10 aryl and a C.sub.1-8heteroaryl; L.sub.3 is selected from the group consisting of —(CH.sub.2).sub.q, —(CH.sub.2).sub.qC(O)—, —O(CH.sub.2).sub.qC(O)—, —NR.sup.19(CH.sub.2).sub.qNR.sup.20—, —(CH.sub.2).sub.qNR.sup.20—, —O(CH.sub.2).sub.qO—, —(CH.sub.2).sub.qC(O)NR.sup.19—, —(CH.sub.2).sub.qC(S)NR.sup.19—, —(CH.sub.2).sub.qCHCF.sub.3NR.sup.19—, —(CH.sub.2).sub.qNR.sup.19C(O)—, —(CH.sub.2).sub.qNR.sup.19CHCF.sub.3—, —C(O)NR.sup.19(CH.sub.2).sub.q—, —CHCF.sub.3NR.sup.19(CH.sub.2).sub.q—, —C(S)NR.sup.19(CH.sub.2).sub.q—, —O(CH.sub.2).sub.qC(O)NR.sup.19—, —O(CH.sub.2).sub.qC(S)NR.sup.19—, —S(O).sub.v(CH.sub.2).sub.qC(O)—, —O(CH.sub.2).sub.qC(O)NR.sup.19—, —NR.sup.19C(O)(CH.sub.2).sub.qC(O)NR.sup.20, —C(O)NR.sup.19(CH.sub.2).sub.qC(O)NR.sup.20—, —C(O)NR.sup.19(CH.sub.2).sub.qNR.sup.20C(O)—, —NR.sup.19C(O)(CH.sub.2).sub.qNR.sup.20C(O)—, O(CH.sub.2).sub.qCNR.sup.19—, —S(O).sub.v(CH.sub.2).sub.qO—, —O(CH.sub.2).sub.qS(O).sub.v—, —S(O).sub.v(CH.sub.2).sub.q—, —(CH.sub.2).sub.qS(O).sub.v—, —S(O).sub.v(CH.sub.2).sub.qS(O).sub.v—, —NR.sup.19(CH.sub.2).sub.qC(O)NR.sup.20—, —NR.sup.19(CH.sub.2).sub.q—, —NR.sup.19C(O)(CH.sub.2).sub.q—, —NR.sup.19CHCF.sub.3(CH.sub.2).sub.q—, —NR.sup.19(CH.sub.2).sub.qO—, —(CH.sub.2).sub.rOC(O)(CH.sub.2).sub.q—, —OC(O)(CH.sub.2).sub.q—, —OC(O)(CH.sub.2).sub.qS(O).sub.v—, —NR.sup.19(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.r—, NR.sup.19C(O)(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.r—, —(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.rC(O)NR.sup.20—, —(CH.sub.2).sub.qNR.sup.19C(O)NR.sup.20(CH.sub.2).sub.r—, —(CH.sub.2).sub.qNR.sup.19C(S)NR.sup.20(CH.sub.2).sub.r—, —(CH.sub.2).sub.qNR.sup.19S(O).sub.2NR.sup.20(CH.sub.2).sub.r—, —(CH.sub.2).sub.qS(O).sub.v(CH.sub.2).sub.r—, —(CH.sub.2).sub.qS(O).sub.2NR.sup.20(CH.sub.2).sub.r—, —(CH.sub.2).sub.qNR.sup.19S(O).sub.v(CH.sub.2).sub.r—, —(CH.sub.2).sub.qSS(CH.sub.2).sub.r—, —(CH.sub.2).sub.qS(CH.sub.2).sub.r—, —(CH.sub.2).sub.qO(CH.sub.2).sub.r—, —(CH.sub.2).sub.qNR.sup.19(CH.sub.2).sub.r—, —(CH.sub.2).sub.qC≡C(CH.sub.2).sub.r—, —O(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.r—, —O(CH.sub.2).sub.qCH≡CH(CH.sub.2).sub.r—, —(CH.sub.2).sub.qCH≡CH(CH.sub.2).sub.rO—, —O(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.rO—, —O(CH.sub.2).sub.qCH≡CH(CH.sub.2).sub.rO—, —S(O).sub.v(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.r—, S(O).sub.v(CH.sub.2).sub.qCH≡CH(CH.sub.2).sub.r—, —(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.rS(O).sub.v—, (CH.sub.2).sub.qCH≡CH(CH.sub.2).sub.rS(O).sub.v—, —O(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.rS(O).sub.v—, —O(CH.sub.2).sub.qCH≡CH(CH.sub.2).sub.rS(O).sub.v—, —S(O).sub.v(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.rO—, S(O).sub.v(CH.sub.2).sub.qCH≡CH(CH.sub.2).sub.rO—, —C(CH.sub.2).sub.qS(CH.sub.2).sub.r —, —C(CH.sub.2).sub.qO(CH.sub.2).sub.r—, —C(O)NR.sup.19S(O).sub.2(CH.sub.2).sub.q—, and —(CH.sub.2).sub.qS(O).sub.2NR.sup.19C(O)—; or L.sub.3 is L.sub.4-L.sub.5-L.sub.6; L.sub.4 and L.sub.6 are each independently selected from the group consisting of —(CH.sub.2).sub.q—, —O(CH.sub.2).sub.q—, —S(CH.sub.2).sub.q—, —NR.sup.19(CH.sub.2).sub.q—, —(CH.sub.2).sub.qNR.sup.20—, —(CH.sub.2).sub.qO—, —(CH.sub.2).sub.qS—, —(CH.sub.2).sub.qC(O)—, —C(O)(CH.sub.2).sub.q—, —(CH.sub.2).sub.qC(O)NR.sup.19—, —NR.sup.19C(O)(CH.sub.2).sub.q—, —(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.r—, —O(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.r—, —(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.rO—, —S(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.r—, —(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.rS—, —O(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.rS—, and —S(CH.sub.2).sub.qCH═CH(CH.sub.2).sub.rO—; L.sup.5 is a C.sub.2-6 heterocyclyl, an C.sub.6-10 aryl or a C.sub.1-9 heteroaryl; each of the oxo group in L.sub.3, L.sub.4, L.sub.5 and L.sub.6 can be independently optionally replaced with a thiocarbonyl group (—C(S)—), an oxetane group, or an imine group (—C(═NR.sup.19)—) q and r are each independently an integer selected from 0 to 10; v is 0, 1 or 2; R.sup.19 and R.sup.20 are each independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.3-10 heteroalkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl or a C.sub.1-5 heteroaryl, and C.sub.2-6 heterocyclyl; or R.sup.19 and R.sup.20 can be connected to form a ring; Q is a moiety capable of forming a covalent bond with a nucleophile

2. A compound of Formula VIIA in which Q is any of the following moieties: ##STR00452##

3. The compound or a pharmaceutically acceptable salt thereof of claim 1 wherein the compound is selected from the group consisting of ##STR00453## ##STR00454## ##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459## ##STR00460## ##STR00461## ##STR00462## ##STR00463## ##STR00464## ##STR00465## ##STR00466## ##STR00467## ##STR00468## ##STR00469## ##STR00470## ##STR00471## ##STR00472## ##STR00473## ##STR00474## ##STR00475## ##STR00476## ##STR00477## ##STR00478## ##STR00479## ##STR00480## ##STR00481## ##STR00482## ##STR00483## ##STR00484## ##STR00485## ##STR00486## ##STR00487## ##STR00488## ##STR00489## ##STR00490## ##STR00491## ##STR00492## ##STR00493## ##STR00494## ##STR00495## ##STR00496## ##STR00497## ##STR00498## ##STR00499## ##STR00500## ##STR00501## ##STR00502## ##STR00503## ##STR00504## ##STR00505## ##STR00506## ##STR00507## ##STR00508## ##STR00509## ##STR00510## ##STR00511## ##STR00512## ##STR00513## ##STR00514## ##STR00515## ##STR00516## ##STR00517## ##STR00518## ##STR00519## ##STR00520## ##STR00521## ##STR00522## ##STR00523## ##STR00524## ##STR00525## ##STR00526## ##STR00527## ##STR00528## ##STR00529## ##STR00530## ##STR00531## ##STR00532## ##STR00533## ##STR00534## ##STR00535## ##STR00536## ##STR00537## ##STR00538## ##STR00539## ##STR00540## ##STR00541## ##STR00542## ##STR00543## ##STR00544## ##STR00545## ##STR00546## ##STR00547## ##STR00548## ##STR00549## ##STR00550## ##STR00551## ##STR00552## ##STR00553## ##STR00554## ##STR00555## ##STR00556## ##STR00557## ##STR00558## ##STR00559## ##STR00560## ##STR00561## ##STR00562## ##STR00563## ##STR00564## ##STR00565## ##STR00566## ##STR00567## ##STR00568## ##STR00569## ##STR00570## ##STR00571## ##STR00572## ##STR00573## ##STR00574## ##STR00575## ##STR00576## ##STR00577## ##STR00578## ##STR00579## ##STR00580## ##STR00581## ##STR00582## ##STR00583## ##STR00584## ##STR00585## ##STR00586## ##STR00587## ##STR00588## ##STR00589## ##STR00590## ##STR00591## ##STR00592## ##STR00593## ##STR00594## ##STR00595## ##STR00596## ##STR00597## ##STR00598##

4. A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof alone or together with a therapeutically effective amount of any other anticancer drug.

Description

EXAMPLE 1

(S)-2.SUP.4.-(4-Acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-2.SUP.2.,5-dione

[0204] ##STR00307##

Step 1 tert-butyl (E)-3-(3-amino-2-isopropylpyridin-4-yl)acrylate

[0205] ##STR00308##

[0206] To a stirred solution of 4-iodo-2-isopropylpyridin-3-amine (690 mg, 2.63 mmol), tert-butyl acrylate (505 mg, 3.95 mmol), tri-tolylphosphine (79 mg, 0.26 mmol) and TEA (399 mg, 3.95 mmol) in DMF (10 ml) was added Pd(OAc).sub.2 (58 mg, 0.26 mmol) under Ar. The resulting mixture was stirred at 100° C. for 3 h to give a black suspension. Water (20 mL) and EtOAc (50 mL) were then added. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=1:1) to give 600 mg of the title product as a yellow solid. MS (ES+): 262.8[M+1].sup.+.

Step 2 tert-butyl 3-(3-amino-2-isopropylpyridin-4-yl)propanoate

[0207] ##STR00309##

[0208] To a stirred solution of tert-butyl (E)-3-(3-amino-2-isopropylpyridin-4-yl)acrylate (600 mg, 2.3 mmol) in MeOH (10 ml) was added 10% Pd/C (100 mg) at room temperature. The reaction vessel was purged three times with H.sub.2 and the resulting mixture was stirred at 30° C. for 16 h. The mixture was then filtered and the filtrate was concentrated to give the title product as yellow oil. MS (ES+): 264.8[M+1].sup.+.

Step 3 tert-butyl 3-(3-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-2-isopropylpyridin-4-yl)propanoate

[0209] ##STR00310##

[0210] To a stirred solution of 2,6-dichloro-5-fluoronicotinamide (157 mg, 0.754 mmol) in THF (5 ml) was added oxalyl chloride (192 mg, 1.49 mmol) at room temperature under Ar. After the resulting mixture was stirred for 1 h at 80° C., the solvent was removed under reduced pressure. The residue was then diluted with 5 ml of THF and was added dropwise to a stirred solution of the product of Step 2 (100 mg, 0.378 mmol) at 0° C. After stirring for 1 h at 0° C., the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (PE:EtOAc=1:1) to give 168 mg of the title product as a white solid. MS (ES+): 499.0[M+1].sup.+.

Step 4 tert-butyl 3-(3-(7-chloro-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoate

[0211] ##STR00311##

[0212] To a stirred solution of the product of Step 3 (791 mg, 1.58 mmol) in THF (12 ml) was added KHMDS (1.0 M) (3.5 ml, 3.49 mmol) at room temperature under Ar. After stirring for 1 h at room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness to give 671 mg of pure product as a white solid. MS (ES+): 463.0[M+1].sup.+.

Step 5 tert-butyl 3-(3-(7-(2-amino-6-fluorophenyl)-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoate

[0213] ##STR00312##

[0214] To a stirred solution the product of Step 4 (210 mg, 0.453 mmol), 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (215 mg, 0.907 mmol) and KOAc (134 mg, 1.36 mmol) in dioxane (6 ml) and H.sub.2O (2 drops) was added Pd(dppf)Cl.sub.2.DCM (37 mg, 0.045 mmol) at room temperature under Ar. After stirring for 1.5 h at 80° C. to give a blank solution, the reaction mixture treated with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=1:2) to give 229 mg of the title product as a white solid. MS (ES+): 537.8[M+1].sup.+.

Step 6 3-(3-(7-(2-amino-6-fluorophenyl)-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoic acid

[0215] ##STR00313##

[0216] To a stirred solution of the product of Step 5 (229 mg, 0.426 mmol) in DCM (3 ml) was added TFA (1 ml) at room temperature under Ar. After stirring for 3 h at 25° C., the reaction mixture was concentrated to dryness to give 360 mg of the title product as yellow oil. MS (ES+): 482.0[M+1].sup.+.

Step 7 2.SUP.6.,3.SUP.6.-difluoro-2.SUP.4.-hydroxy-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-2.SUP.2.,5-dione

[0217] ##STR00314##

[0218] To a stirred solution of the product of Step 6 (360 mg, 0.74 mmol) and NMI (920 mg, 14.5 mmol) in DMF (20 ml) was added TCFH (628 mg, 3.74 mmol) at room temperature under Ar. The resulting mixture was stirred for 1 h at 25° C. and then quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel chromatography (DCM:MeOH=10:1) to give 160 mg of the title product as a yellow solid. MS (ES+): 463.8[M+1].sup.+

Step 8 tert-butyl (S)-4-(2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.2.,5-dioxo-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-2.SUP.4.-yl)-3-methylpiperazine-1-carboxylate

[0219] ##STR00315##

[0220] To a stirred solution of the product of Step 8 (160 mg, 0.344 mmol) and DIPEA (446 mg, 3.44 mmol) in CH.sub.3CN (3 ml) was added POCl.sub.3 (318 mg, 2.06 mmol) at room temperature under Ar. The resulting mixture was stirred for 1 h at 80° C. and then concentrated to dryness. The residue was dissolved in 3 ml of DMF and the resulted solution was treated with DIPEA (244 mg, 1.9 mmol) and tert-butyl (S)-3-methylpiperazine-1-carboxylate (140 mg, 0.68 mmol) at room temperature under Ar. After stirring for 2 h at 25° C., the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (EtOAc:MeOH=15:1) to give 33 mg of the title product as a yellow solid. MS (ES+): 646.0[M+1].sup.+.

Step 9 (S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-2.SUP.2.,5-dione

[0221] ##STR00316##

[0222] To a stirred solution of the product of Step 8 (30 mg, 0.046 mmol) in DCM (2 ml) was added TFA (0.5 ml) at room temperature under Ar. After stirring for 1 h at 25° C., the mixture was concentrated to dryness and diluted with 2 ml of DCM. The resulting solution was treated with DIPEA (24 mg, 0.186 mmol) and acryloyl chloride (5 mg, 0.046 mmol) at room temperature under Ar. The resulted mixture was stirred for 0.5 h at 25° C., the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (EtOAc:MeOH=15:1) to give 5.5 mg of the title product as a yellow solid. MS (ES+): 600.0[M+1].sup.+.

[0223] .sup.1HNMR Spectrum: (400 MHz, CD.sub.3OD) δ 8.43 (d, 1H), 8.24˜8.21 (m, 1H), 7.42˜7.33 (m, 2H), 7.00˜6.96 (m, 2H), 6.92˜6.90 (m, 1H), 6.2 (d, 1H), 5.72 (d, 1H), 5.22 (m, 1H), 3.98 (m, 3H), 3.52˜3.51 (m, 1H), 2.9 (m, 1H), 2.74˜2.67 (m, 2H), 2.35 (m, 1H), 2.14˜2.06 (m, 1H), 1.9 (m, 1H), 1.3˜1.1 (m, 6H), 0.36˜0.25 (m, 2H).

EXAMPLE 2

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0224] ##STR00317##

Step 1 2.SUP.6.,3.SUP.6.-difluoro-2.SUP.4.-hydroxy-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0225] ##STR00318##

[0226] To a stirred solution of the product of Step 7 of Example 1 (6.7 g, 14.5 mmol) in DME (140 ml) was added Borane-methyl sulfide complex (10.0 M, 5.78 ml, 5.78 mmol) at 0° C. under Ar. The reaction mixture was stirred for 2 h at 45° C. and then quenched with MeOH at 0° C. After stirring for 2 h, water was added and the reaction mixture extracted with EtOAc. The organic was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel chromatography (EA:PE=4:1) to give 3.5 g of pure product. MS (ES+): 450.0 [M+1].sup.+.

Step 2 tert-butyl (S)-4-(2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.2.-oxo-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-2.SUP.4.-yl)-3-methylpiperazine-1-carboxylate

[0227] ##STR00319##

[0228] To a stirred solution of the product of Step 1 (2 g, 4.3 mmol) and DIPEA (5.74 g, 44.5 mmol) in CH.sub.3CN (20 ml) was added POCl.sub.3 (4.09 g, 26.7 mmol) at rt under Ar. The mixture was stirred for 0.5 h at 80° C., and then was concentrated to dryness. The residue was dissolved in 20 ml of DMF and the resulting solution was treated with DIPEA (2.87 g, 22.3 mmol) and tert-butyl (S)-3-methylpiperazine-1-carboxylate (1.78 g, 8.9 mmol) at 0° C. After stirring for 5 min at 0, the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc:MeOH=15:1) to give 1.54 g of the title product as a yellow solid. MS (ES+): 632.0 [M+1].sup.+.

Step 3 (S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0229] ##STR00320##

[0230] To a stirred solution of the product of Step 2 (2 g, 3.17 mmol) in DCM (20 ml) was added TFA (20 ml) at rt under Ar. The resulting mixture was stirred for 0.5 h at rt and then was concentrated to dryness. The residue was dissolved in 40 ml of DCM and the resulted solution was treated with DIPEA (4.1 g, 31.7 mmol) and acryloyl chloride (240 mg, 2.69 mmol) at 0° C. After stirring for 5 min at 0° C., the reaction was completed, the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc:MeOH=15:1) to provide 1.38 g of the title product as a yellow solid. MS (ES+): 586.0 [M+1].sup.+

[0231] .sup.1HNMR Spectrum: (400 MHz, CDCl3) δ 8.62 (d, 1H), 7.85 (dd, 1H), 7.25-7.21 (m, 2H), 6.59-6.40 (m, 3H), 5.84 (d, 1H), 5.36 (m, 1H), 4.8-3.2 (m, 7H), 3.32 (d, 1H), 3.1-2.79 (m, 3H), 2.38-2.0 (m, 3H), 1.63-1.52 (m, 3H), 1.47-1.25 (m, 5H), 1.03-0.78 (d, 3H).

EXAMPLE 2A and 2B

[0232] Separation of Example 2: Example 2 was separated using Daicel CHIRALPAK® IA 250*20 mm, 5 μm, at room temperature, using Hex:EtOH=60:40 as eluent with a flow rate of 15 mL/min and a UV detector at 214 nm.

[0233] Example 2A: retention time: 4.6 min, MS (ESI, m/e): 586 [M+1].sup.+.

[0234] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.47 (d, J=5.0 Hz, 1H), 8.25 (d, J=9.6 Hz, 1H), 7.39-7.22 (m, 2H), 6.87 (m, 1H), 6.69 (d, J=8.2 Hz, 1H), 6.62-6.53 (t, 1H), 6.21 (d, J=16.5 Hz, 1H), 5.78 (d, J=10.7 Hz, 1H), 4.84 (m, 2H), 4.51 (d, J=13.9 Hz, 1H), 4.33-3.98 (m, 3H), 3.57 (m, 2H), 3.31-3.11 (m, 2H), 2.80 (m, 2H), 2.42 (m, 1H), 2.20 (m, 1H), 2.04-1.84 (m, 1H), 1.43-1.20 (m, 3H), 1.08 (d, J=6.4 Hz, 3H), 0.88 (d, J=6.7 Hz, 3H).

[0235] Example 2B: retention time: 5.7 min, MS (ESI, m/e): 586 [M+1].sup.+.

[0236] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.47 (m, 2H), 7.38-7.22 (m, 2H), 6.89 (m, 1H), 6.69 (d, J=8.2 Hz, 1H), 6.63-6.51 (t, 1H), 6.23 (m, 1H), 5.78 (d, J=10.3 Hz, 1H), 5.13 (s, 1H), 4.80 (d, J=6.6 Hz, 1H), 4.31-3.70 (m, 6H), 3.23 (m, 1H), 2.93 (m, 1H), 2.80 (m, 2H), 2.60-2.44 (m, 1H), 2.18 (m, 1H), 1.90 (m, 1H), 1.29-1.18 (m, 3H), 1.12 (d, J=7.0 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H).

EXAMPLE 3

(S)-2-(1-acryloyl-4-(2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.2.,5-dioxo-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-2.SUP.4.-yl)piperazin-2-yl)acetonitrile

[0237] ##STR00321##

Step 1 benzyl (S)-4-(1-(4-(3-(tert-butoxy)-3-oxopropyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0238] ##STR00322##

[0239] Starting from the product of Step 4 of Example 1 (150 mg, 0.325 mmol) and (S)-benzyl 2-(cyanomethyl)piperazine-1-carboxylate hydrochloride (192 mg, 0.649 mmol), the title product (256 mg) was obtained by following the conditions described in Step 8 of Example 1. MS (ESI+): 703.9[M+H].sup.+

Step 2 benzyl (2S)-4-(7-(2-amino-6-fluorophenyl)-1-(4-(3-(tert-butoxy)-3-oxopropyl)-2-isopropylpyridin-3-yl)-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0240] ##STR00323##

[0241] Starting from the product of Step 1 (217 mg, 0.308 mmol), 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (146 mg, 0.616 mmol), the title product (158 mg) was obtained as a yellow solid by following the conditions described in Step 5 of Example 1. MS (ESI+): 779.0[M+H].sup.+.

Step 3 3-(3-(7-(2-amino-6-fluorophenyl)-4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-6-fluoro-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoic acid

[0242] ##STR00324##

[0243] Starting from the product of Step 2 (158 mg, 0.203 mmol), the title product (152 mg) was obtained as a yellow solid by following the conditions described in Step 6 of Example 1. MS (ESI+): 722.9[M+H].sup.+.

Step 4 benzyl (S)-2-(cyanomethyl)-4-(2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.2.,5-dioxo-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-2.SUP.4.-yl)piperazine-1-carboxylate

[0244] ##STR00325##

[0245] Starting from the product of Step 3 (152 mg, 0.211 mmol), the title product (96 mg) was obtained as a yellow solid by following the conditions described in Step 7 of Example 1. MS (ES+): 704.9[M+H].sup.+.

Step 5 (S)-2-(4-(2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.2.,5-dioxo-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-2.SUP.4.-yl)piperazin-2-yl)acetonitrile

[0246] ##STR00326##

[0247] To a stirred solution of the product of Step 4 (70 mg, 0.099 mmol) in MeOH (4 ml) was added 10% Pd/C (70 mg) at rt. The resulting mixture was attired for 1.5 h at 30° C. under H.sub.2. The reaction mixture was filtered and concentrated to give the title product as a yellow solid (48 mg). MS (ES+): 570.9[M+H].sup.+.

Step 6 (S)-2-(1-acryloyl-4-(2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.2.,5-dioxo-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-2.SUP.4.-yl)piperazin-2-yl)acetonitrile

[0248] ##STR00327##

[0249] To a stirred solution of the product of Step 7 (48 mg, 0.084 mmol) and DIPEA (44 mg, 0.341 mmol) in DCM (1 ml) was added acryloyl chloride (8 mg, 0.084 mmol) at 5˜10° C. After stirring for 1 h at rt, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (EtOAc:MeOH=10:1) to give 9 mg of the title product as a yellow solid. MS (ES+): 625.0[M+H].sup.+.

[0250] .sup.1HNMR Spectrum: (400 MHz, CDCl.sub.3) δ 8.92 (s, 1H), 8.54˜8.53 (d, J=4.4 Hz, 1H), 7.99˜7.96 (m, 1H), 7.52˜7.21 (m, 3H), 7.01 (m, 1H), 6.62 (m, 1H), 6.48 (m, 1H), 5.90˜5.88 (d, J=11.2 Hz, 1H), 5.0˜3.7 (m, 7H), 3.0˜2.8 (m, 5H), 2.61 (m, 1H), 2.33 (m, 1H), 1.32˜1.25 (m, 3H), 1.08˜1.06 (m, 3H).

EXAMPLE 4

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-4-methyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0251] ##STR00328##

[0252] To a stirred solution of Example 2 (50 mg, 0.085 mmol) and Cs.sub.2CO.sub.3 (111 mg, 0.342 mmol) in DMF (2 ml) was added CH.sub.3I (42 mg, 0.299 mmol) at rt. After stirring for 5 h at 40° C., the reaction mixture was treated with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (EA:MeOH=15:1) to obtain 15 mg of the title product as a yellow solid. MS (ES+): 599.9 [M+1].sup.+.

[0253] .sup.1HNMR Spectrum: (400 MHz, CDCl.sub.3) δ 8.54-8.53 (d, J=4 Hz, 1H), 7.88-7.76 (m, 1H), 7.40-7.26 (q, 1H), 7.09-7.05 (m, 2H), 6.93-6.89 (t, 1H), 6.65 (s, 1H), 6.44-6.39 (d, J=20 Hz, 1H), 5.83-5.80 (d, J=12 Hz, 1H), 5.51-4.57 (m, 2H), 4.28-3.17 (m, 4H), 2.95-2.86 (m, 3H), 2.66-2.63 (d, J=12 Hz, 1H), 2.48-2.42 (m, 5H), 1.89 (s, 1H), 1.46-1.44 (d, J=8 Hz, 2H), 1.38-1.22 (t, 5H), 1.15-0.86 (m, 3H).

EXAMPLE 5

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4,6-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphane-2.SUP.2.,5-dione

[0254] ##STR00329##

Step 1 2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.,2.SUP.3.,2.SUP.4.-tetrahydro-4,6-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphane-2.SUP.2.,2.SUP.4.,5-trione

[0255] ##STR00330##

[0256] To a stirred solution of the product of Step 6 of Example 1 (408 mg, 0.85 mmol) and TEA (430.06 mg, 4.25 mmol) in toluene (15 ml) was added diphenylphosphoryl azide (701.76 mg, 2.55 mmol). After the mixture was stirred at 75° C. for 1 h, water (5 ml) and EtOAc (3 ml) were added. The mixture was stirred for 0.5 h, and the resulting solid was collected by filtration and dried to get 180 mg of the title product as a yellow solid. MS (ES+): 478.9[M+1].sup.+.

Step 2 (S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4,6-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphane-2.SUP.2.,5-dione

[0257] ##STR00331##

[0258] Starting from the product of Step 1, the title product was obtained as a yellow solid by following the reaction conditions described for Step 8 and Step 9 of Example 1. MS (ES+): 614.9[M+1].sup.+

[0259] .sup.1HNMR Spectrum: (400 MHz, CDCl3) δ 11.23 (s, 1H), 8.59 (s, 1H), 7.89 (s, 1H), 7.43 (s, 1H), 7.19 (s, 1H), 7.03 (s, 1H), 6.63 (s, 1H), 6.44-6.40 (d, J=16, 1H), 5.84-5.81 (d, J=12, 1H), 4.77 (s, 2H), 4.12-3.75 (m, 2H), 3.65 (m, 2H), 3.22 (m, 2H), 2.66 (m, 1H), 1.43 (m, 5H), 1.32 (m, 3H), 1.02 (m, 3H).

EXAMPLE 6A and 6B

[0260] 2.sup.6,3.sup.6-difluoro-2.sup.4-((2S,5R)-4-(2-fluoroacryloyl)-2,5-dimethylpiperazin-1-yl)-1.sup.2-isopropyl-2.sup.1,2.sup.2-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.sup.2-one

##STR00332##

Step 1 tert-butyl (2R,5S)-4-(2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.2.-oxo-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-2.SUP.4.-yl)-2,5-dimethylpiperazine-1-carboxylate

[0261] ##STR00333##

[0262] To a stirred solution of the product of Step 1 of Example 2 (120 mg, 0.27 mmol) in CH.sub.3CN (18 ml) were added DIPEA (345 mg, 2.7 mmol) and POCl.sub.3 (414 mg, 2.7 mmol). The mixture was stirred at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DMF (1 ml). The resulted solution was treated with DIEA (172 mg, 1.4 mmol) and (2R,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate (64 mg, 0.3 mmol) at 0° C. After stirring for 10 min at at 0° C., the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to get 182 mg of the title compound as a yellow solid. MS (ES+): 645.9[M+1].sup.+

Step 2 24-((2S,5R)-2,5-dimethylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0263] ##STR00334##

[0264] To a stirred solution of the product of the Step 1(182 mg, 0.28 mmol) in DCM (1 ml) was added TFA (1 ml). After stirring at rt for 1 h, the reaction mixture was concentrated, basified to pH 7-8 with NaHCO.sub.3(aq.) and extracted with EA. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to get 141 mg of the target compound as a yellow solid. MS (ES+): 545.9[M+1].sup.+.

Step 3 2.SUP.6.,3.SUP.6.-difluoro-2.SUP.4.-((2S,5R)-4-(2-fluoroacryloyl)-2,5-dimethylpiperazin-1-yl)-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0265] ##STR00335##

[0266] To a solution of the product of the step 2 (70 mg, 0.13 mmol) in DCM (3 ml) were added 2-fluoroprop-2-enoic acid (9.37 mg, 0.1 mmol), DIPEA (84 mg, 0.65 mmol) and T3P (124 mg, 0.39 mmol). After stirring at rt for 10 min, the reaction was quenched with saturated aqueous NaHCO.sub.3(15 ml) and extracted with DCM. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (MeOH/EA=5%) to give rise to 15.5 mg of Example 6A (fast eluting) as a yellow solid, MS (ES+): 617.9[M+1].sup.+, and 15.2 mg of Example 6B (slow eluting) as a yellow solid, MS (ES+): 617.9[M+1].sup.+.

[0267] .sup.1HNMR Spectrum (Example 6A): (400 MHz, CDCl.sub.3) δ 8.47-8.46 (d, J=4 Hz, 2H), 7.34-7.26 (m, 2H), 6.72-6.54 (m, 2H), 5.37-5.32 (m, 2H), 4.87-4.88 (m, 2H), 4.75-4.25 (m, 1H), 4.12-4.01 (m, 2H), 3.78-3.63 (m, 1H), 3.17 (s, 1H), 2.84 (m, 1H), 2.76-2.73 (m, 1H), 2.45 (m, 1H), 2.12-1.93 (m, 2H), 1.27-1.09 (m, 10H), 0.84-0.82 (d, J=8 Hz, 3H).

[0268] .sup.1HNMR Spectrum (Example 6B): (400 MHz, CDCl.sub.3) δ 8.47-8.45 (d, J=4 Hz, 1H), 8.11 (m, 1H), 7.33-7.24 (m, 2H), 6.71-6.55 (m, 2H), 5.37-5.32 (d, J=20 Hz, 2H), 4.88-4.61 (m, 3H), 4.52-4.11 (m, 1H), 3.88-3.46 (m, 2H), 3.25 (m, 1H), 2.89-2.73 (m, 2H), 2.57 (m, 1H), 2.18-1.91 (m, 2H), 1.50-1.48 (d, J=8 Hz, 2H), 1.38-1.25 (m, 4H), 1.08-1.06 (d, J=8 Hz, 3H), 0.93-0.91 (d, J=8 Hz, 3H).

EXAMPLE 7A and 7B

2.SUP.4.-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0269] ##STR00336##

[0270] To a stirred solution of the product of Step 2 of Example 6A and 6B (0.07 g, 0.128 mmol), acrylic acid (0.007 g, 0.103 mmol) and DIPEA (0.083 g, 0.642 mmol) in DCM (3 ml) was added T3P (0.123 g, 0.385 mmol). After stirring at rt for 0.5 h under Ar, the reaction was quenched with NaHCO.sub.3(aq.) and extracted with DCM, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (MeOH:EA=7.5%) to give 9.8 mg of Example 7A (fast eluting) as a yellow solid, MS (ES+): 599.9[M+1].sup.+, and 9.8 mg of Example 7B (slow eluting) as a yellow solid, MS (ES+): 599.9[M+1].sup.+.

[0271] .sup.1HNMR Spectrum (Example 7A): (400 MHz, CDCl.sub.3) δ 8.49 (m, 2H), 7.34-7.26 (m, 1H), 6.86-6.70 (m, 2H), 6.59-6.55 (m, 1H), 6.22-6.17 (m, 1H), 5.77-5.74 (m, 1H), 4.97-4.87 (m, 2H), 4.75-4.25 (m, 1H), 4.07-3.86 (m, 4H), 2.84-2.66 (m, 3H), 2.13-1.78 (m, 3H), 1.36-1.24 (d, 2H), 1.18 (d, 1H), 1.17-1.06 (m, 3H), 0.88-0.78 (d, 4H).

[0272] .sup.1HNMR Spectrum (Example 7B): (400 MHz, CDCl.sub.3) δ 8.46-8.45 (d, J=4 Hz, 1H), 8.12-8.06 (m, 1H), 7.33-7.26 (m, 2H), 6.87-6.55 (m, 3H), 6.21-6.16 (m, 1H), 5.78-5.75 (m, 1H), 4.89-4.47 (m, 4H), 4.27-3.56 (m, 3H), 2.84-2.78 (m, 2H), 2.46-1.87 (m, 2H), 1.48-1.45 (m, 3H), 1.32-1.28 (m, 3H), 1.10-1.06 (m, 3H), 0.92-0.78 (m, 3H).

EXAMPLE 8

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-8-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphan-2.SUP.2.-one

[0273] ##STR00337##

Step 1 methyl 3-(3-amino-2-isopropylpyridin-4-ylthio)propanoate

[0274] ##STR00338##

[0275] The mixture of 4-iodo-2-isopropylpyridin-3-amine (625 mg, 2.385 mmol), methyl 3-sulfanylpropanoate (716 mg, 5.964 mmol), DIPEA (1.231 g, 9.542 mmol), Pd.sub.2(dba).sub.3 (437 mg, 0.477 mmol) and Xantphos (552 mg, 0.954 mmol) in 1,4-Dioxane (15 ml) was stirred for 2 h at 80° C. under Ar. The reaction mixture was treated with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA:PE=1:1) to give 582 mg of the title product as a yellow solid. MS (ES+): 255 [M+1].sup.+.

Step 2 methyl 3-(3-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-2-isopropylpyridin-4-ylthio)propanoate

[0276] ##STR00339##

[0277] Starting with 2,6-dichloro-5-fluoronicotinamide and the product of Step 1, the title product was obtained as a yellow solid by following the procedure described in Step 3 of Example 1. MS (ES+): 489 [M+1].sup.+

Step 3 methyl 3-(3-(7-chloro-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-ylthio)propanoate

[0278] ##STR00340##

[0279] The mixture of the product of Step 2 (900 mg, 1.844 mmol) and K.sub.2CO.sub.3 (509 mg, 3.689 mmol) in DMF (15 ml) was stirred for 18 h at rt. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to give 804 mg of the title product as a yellow solid. MS (ES+): 453 [M+1].sup.+.

Step 4 methyl 3-(3-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-ylthio)propanoate

[0280] ##STR00341##

[0281] Starting with the product of Step 3 and 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, the title product was obtained as a yellow solid by following the procedure described in Step 5 of Example 1. MS (ES+): 527.8 [M+1].sup.+

Step 5 3-(3-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-ylthio)propanoic acid

[0282] ##STR00342##

[0283] A mixture of the product of Step 4 (300 mg, 28.8 mmol) in 6 N HCl/THF (30 ml/5 ml) was stirred overnight at rt. The pH of reaction mixture was adjusted to 5-6 with NaHCO.sub.3(aq.) and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to give 360 mg of the title product as a brown solid. MS (ES+): 513.8 [M+1].sup.+.

Step 6 2.SUP.6.,3.SUP.6.-difluoro-12-isopropyl-2.SUP.1.,2.SUP.2.,2.SUP.3.,2.SUP.4.-tetrahydro-8-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphane-2.SUP.2.,2.SUP.4.,5-trione

[0284] ##STR00343##

[0285] To a stirred solution of the product of Step 5 (360 mg, 0.70 mmol) in DCE (12 ml) was added T3P in EtOAc (50% wt, 2.2 g, 3.5 mmol) at rt under Ar. The mixture was stirred overnight at 55° C. The pH of reaction mixture was adjusted to 5-6 with NaHCO.sub.3(aq.) and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (EA:MeOH=15:1) to give 130 mg of the title product as a yellow solid. MS (ES+): 495.8 [M+1].sup.+

Step 7 2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.,2.SUP.3.,2.SUP.4.-tetrahydro-8-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphane-2.SUP.2.,2.SUP.4.-dione

[0286] ##STR00344##

[0287] To a stirred the product of Step 6 (130 mg, 0.26 mmol) in THF (7 ml) was added borane-tetrahydrofuran complex in THF (1.0 M, 1.3 ml, 1.3 mmol) at 0° C. under Ar. After stirring for 1 h at rt, additional borane-tetrahydrofuran complex in THF (1.0 M, 0.8 ml, 0.8 mmol) was added at 0° C. under Ar. The mixture was stirred for another 1 h at rt, and then quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (EA:MeOH=15:1) to give 69 mg of the title product as a white solid. MS (ES+): 481.9 [M+1].sup.+.

Step 8 tert-butyl (S)-4-(2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.2.-oxo-2.SUP.1.,2.SUP.2.-dihydro-8-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphane-2.SUP.4.-yl)-3-methylpiperazine-1-carboxylate

[0288] ##STR00345##

[0289] Starting with the product of Step 7 and 3 tert-butyl (S)-3-methylpiperazine-1-carboxylate, the title product was obtained as a yellow solid by following the procedure described in Step 2 of Example 2. MS (ES+): 663.8 [M+1].sup.+.

Step 9 (S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-8-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphan-2.SUP.2.-one

[0290] ##STR00346##

[0291] Starting with the product of Step 8, the title product was obtained as a yellow solid by following the procedure described in Step 3 of Example 2. MS (ES+): 617.8 [M+1].sup.+.

[0292] .sup.1HNMR Spectrum: (400 MHz, CDCl.sub.3) δ 8.53-8.52 (d, J=4 Hz, 1H), 7.83 (m, 1H), 7.26-7.21 (m, 1H), 7.15-7.13 (d, J=8 Hz, 1H), 6.64 (s, 2H), 6.42-6.38 (m, 3H), 5.82-5.80 (d, J=8 Hz, 1H), 4.98-4.41 (m, 2H), 4.38-3.61 (m, 3H), 3.47-3.32 (m, 3H), 3.14-3.02 (m, 3H), 2.78 (m, 1H), 2.22 (m, 1H), 2.07-1.68 (m, 3H), 1.64-1.55 (m, 2H), 1.39-1.37 (d, J=8 Hz, 2H), 1.01-0.99 (d, J=8 Hz, 3H).

EXAMPLE 9

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0293] ##STR00347##

Step 1 2-isopropyl-4-((4-methoxybenzyl)thio)pyridin-3-amine

[0294] ##STR00348##

[0295] A mixture of 4-iodo-2-isopropylpyridin-3-amine (320 mg, 1.2 mmol), (4-methoxyphenyl)methanethiol (376 mg, 2.4 mmol), DIPEA (630 mg, 4.9 mmol), Xantphos (283 mg, 0.49 mmol) and Pd.sub.2(dba).sub.3 (224 mg, 0.24 mmol) in dioxane (10 ml) was stirred at 90° C. for 2 h. The reaction was quenched with water at rt and extracted with EA. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=5:1) to give 382 mg of the title product as a yellow solid. MS (ES+): 288.8 [M+1].sup.+.

Step 2 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-((4-methoxybenzyl)thio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

[0296] ##STR00349##

[0297] Starting from the product of Step 1 and 2,6-dichloro-5-fluoronicotinamide, the title product was obtained as a white solid by following the procedures described in Step 3 and Step 4 of Example 1. MS (ES+): 486.9[M+1].sup.+.

Step 3 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-mercaptopyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

[0298] ##STR00350##

[0299] To a stirred solution of the product of Step 2 (538 mg, 1.1 mmol) in TFA (12 ml) was added trifluoromethanesulfonic anhydride (620.7 mg, 2.2 mmol, dissolved in 1 ml of TFA) at rt under Ar. The mixture was stirred for 2.5 h at 80° C. and was concentrated to dryness. The residue was dissolved in DMF (12 ml) and the resulted solution was treated with TEA (2.0 g, 19.8 mmol) and tert-Butyl bromoacetate (171.6 mg, 0.88 mmol, dissolved in 1 ml of DMF). After stirring for 30 min, water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1) to obtain 144 mg of the title product as a yellow solid. MS (ES+): 480.9[M+1].sup.+.

Step 4 2.SUP.6.,3.SUP.6.-difluoro-2.SUP.4.-hydroxy-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-2.SUP.2.,5-dione

[0300] ##STR00351##

[0301] Starting with the product of Step 3 and 3-fluoro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, the title product was obtained as a white solid by following the procedures described in Step 5 and Step 6 and Step 7 of Example 1. MS (ES+): 481.8[M+1].sup.+.

Step 5 (S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0302] ##STR00352##

[0303] Starting from the product of Step 4, the title product was obtained as a yellow solid by following the procedures described in Step 7, Step 8 and Step 9 of Example 8. MS (ES+): 604.1 [M+1].sup.+.

[0304] .sup.1HNMR Spectrum: (400 MHz, DMSO-d.sub.6) δ 8.54-8.50 (m, 1H), 8.48-8.47 (d, J=4 Hz, 1H), 8.34-8.32 (m, 1H), 7.62-7.60 (m, 1H), 7.46-7.42 (m, 1H), 7.35-7.25 (m, 2H), 6.88-6.84 (m, 1H), 6.70-6.68 (m, 1H), 6.65-6.60 (t, 1H), 6.23-6.19 (d, J=16 Hz, 1H), 5.79-5.76 (m, 1H), 4.24 (m, 1H), 4.31-4.20 (m, 1H), 3.99-3.95 (m, 2H), 3.63-3.60 (m, 2H), 3.01-2.93 (m, 3H), 2.91-2.80 (m, 1H), 2.57-2.54 (m, 1H), 1.43 (m, 1H), 1.24 (m, 3H), 1.16-1.13 (m, 2H), 1.12-1.11 (m, 3H), 0.91-0.89 (d, J=8 Hz, 3H).

EXAMPLE 10

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-3.SUP.6.-chloro-2.SUP.6.-fluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0305] ##STR00353##

Step 13-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0306] ##STR00354##

[0307] A mixture of 2-bromo-3-chloroaniline (10 g, 48.43 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (15.99 g, 62.96 mmol), potassium acetate (14.26 g, 145.29 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.54 g, 4.84 mmol) in 1,4-dioxane (150 ml) was stirred for 14 h at 105° C. under Ar. The mixture was cooled to rt and filtered through a layer of celite, the filter cake was washed with EtOAc. The filtrate was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to get 17.51 g of crude product as black oil.

Step 2 tert-butyl 3-(3-(7-(2-amino-6-chlorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoate

[0308] ##STR00355##

[0309] To a stirred solution of the product of Step 4 of Example 1 and potassium acetate (0.64 g, 6.48 mmol) in 1,4-dioxane (40 ml) were added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.18 g, 0.22 mmol) and H.sub.2O (1 ml). The resulting mixture was stirred for 2 h at 80° C. under Ar. Water was added and the reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA:PE=1:1) to give 2.39 g of the title product as yellow oil. MS (ES+): 553.8 [M+1].sup.+.

Step 3 3-(3-(7-(2-amino-6-chlorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoic acid

[0310] ##STR00356##

[0311] A mixture of the product of Step 2 (600 mg, 1.085 mmol) in TFA (6 ml) was stirred for 0.5 h at rt. The reaction mixture was concentrated to dryness to give 859 mg of the title product as brown oil. MS (ES+): 497.8[M+1].sup.+.

Step 4 3.SUP.6.-chloro-2.SUP.6.-fluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.,2.SUP.3.,2.SUP.4.-tetrahydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-2.SUP.2.,2.SUP.4.,5-trione

[0312] ##STR00357##

[0313] To a stirred solution of the product of Step 3 (590 mg, 1.18 mmol) in DCE (30 ml) was added T3P (3.78 g, 5.93 mmol) at rt under Ar. After stirring for 1 h at 50° C., the reaction was quenched with sat. NaHCO.sub.3(aq.) and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel column chromatography (MeOH/EA=2%) to give 165 mg of the title product as a yellow solid. MS (ES+): 479.8 [M+1].sup.+.

Step 5 3.SUP.6.-chloro-2.SUP.6.-fluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.,2.SUP.3.,2.SUP.4.-tetrahydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-2.SUP.2.,2.SUP.4.-dione

[0314] ##STR00358##

[0315] Starting from the product of Step 4, the title compound was obtained as a yellow solid by following the reaction conditions described in Step 1 of Example 2. MS (ES+): 465.8 [M+1].sup.+.

Step 6 (S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-3.SUP.6.-chloro-2.SUP.6.-fluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0316] ##STR00359##

[0317] Starting from the product of Step 5, the title product was obtained as a yellow solid by following the procedures described in Step 2, and Step 3 of Example 2. MS (ES+): 601.8 [M+1].sup.+.

[0318] .sup.1HNMR Spectrum: (400 MHz, CDCl.sub.3) δ 8.58-8.57 (d, J=4 Hz, 1H), 7.93-7.87 (m, 1H), 7.26-7.15 (m, 2H), 6.88-6.86 (d, J=8 Hz, 1H), 6.73-6.71 (d, J=8 Hz, 1H), 6.60 (s, 1H), 6.44-6.40 (m, 1H), 5.84-5.81 (d, J=12 Hz, 1H), 5.46-5.30 (m, 1H), 4.78-4.23 (m, 4H), 3.85-3.39 (m, 3H), 2.91-2.71 (m, 3H), 2.30-1.94 (m, 2H), 1.68-1.58 (m, 3H), 1.39-1.37 (d, J=8 Hz, 2H), 1.29-1.26 (m, 3H), 1.06-1.04 (d, J=8 Hz, 3H).

EXAMPLE 11

(S)-2.SUP.6.,3.SUP.6.-difluoro-2.SUP.4.-(4-(2-fluoroacryloyl)-2-methylpiperazin-1-yl)-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0319] ##STR00360##

[0320] To a stirred solution of the product of Step 2 od Example 2 and 2-fluoroacrylic acid, the title compound was obtained as a yellow solid by following the reaction conditions described in Step 2 and Step 3 of Example 6A and 6B. MS (ES+): 603.9[M+1].sup.+.

[0321] .sup.1HNMR Spectrum: (400 MHz, DMSO-d.sub.6) δ 8.47-8.45 (m, 2H), 7.73-7.25 (m, 2H), 6.70-6.55 (m, 2H), 5.41-5.36 (m, 3H), 4.8-4.79 (m, 1H), 4.50-3.45 (m, 6H), 2.80-2.78 (m, 2H), 2.51-2.44 (m, 2H), 2.23-2.22 (m, 1H), 1.98-1.88 (m, 1H), 1.40-0.08 (m, 11H).

EXAMPLE 12

(S)-4-acetyl-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0322] ##STR00361##

[0323] To a stirred solution of Example 2 (50 mg, 0.085 mmol) and DIPEA (58 mg, 0.45 mmol) in DCM (2 ml) was added acetyl chloride (17.6 mg, 0.22 mmol) at rt. After stirring for 2 h at 40° C., the reaction was quenched with sat.NaHCO.sub.3(aq.) and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (EA:MeOH=5:1) to obtain 21 mg of the title product as a yellow solid. MS (ES+): 627.9 [M+1].sup.+.

[0324] .sup.1HNMR Spectrum: (400 MHz, CDCl3) δ 8.49-8.48 (d, J=4 Hz, 1H), 7.88-7.83 (t, 1H), 7.47 (q, 1H), 7.18 (t, 1H), 6.99 (t, 2H), 6.62 (s, 1H), 6.43 (d, 1H), 5.84-5.81 (d, J=12 Hz, 1H), 5.13-4.37 (m, 2H), 4.26-3.28 (m, 5H), 3.26-2.66 (m, 3H), 2.65-2.36 (m, 2H), 2.04 (s, 1H), 1.43-1.41 (d, J=8 Hz, 2H), 1.31-1.18 (m, 8H), 1.01-0.99 (d, J=8 Hz, 3H).

EXAMPLE 13

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-N,N-dimethyl-2.SUP.2.-oxo-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-4-carboxamide

[0325] ##STR00362##

[0326] To a stirred solution of Example 2 (50 mg, 0.085 mmol) in DCE (3 ml) were added dimethylcarbamic chloride (18 mg, 0.171 mmol), DIEA (33 mg, 0.256 mmol) and DMAP (10 mg, 0.085 mmol). The resulting mixture was stirred overnight at 80° C. and then quenched with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (MeOH/EA=1:9) to get 24.5 mg of the title product as a yellow solid. MS (ES+): 656.9 [M+1].sup.+.

[0327] .sup.1HNMR Spectrum: (400 MHz, CDCl.sub.3) δ 8.52 (s, 1H), 7.88-7.86 (d, J=8 Hz, 1H), 7.36 (s, 1H), 7.21 (s, 1H), 7.07-7.05 (d, J=8 Hz, 2H), 6.64-6.63 (d, J=4 Hz, 1H), 6.44-6.40 (d, J=16 Hz, 1H), 5.84-5.81 (m, 1H), 4.82-4.80 (m, 1H), 4.78-3.56 (m, 4H), 3.20 (s, 1H), 2.89 (s, 1H), 2.80-2.76 (d, J=16 Hz, 2H), 2.49 (s, 3H), 1.46 (m, 3H), 1.40-1.25 (m, 9H), 1.08-0.97 (m, 5H).

EXAMPLE 14

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-4-nicotinoyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0328] ##STR00363##

[0329] To a stirred solution of Example 2 (35 mg, 0.060 mmol) in NMP (3 ml) were added pyridine-3-carboxylic acid (29 mg, 0.239 mmol), 2-Chloro-1,3-dimethylimidazolidinium hexafluorophosphate (99 mg, 0.359 mmol) and DIPEA (46 mg, 0.359 mmol) at rt. After stirring at 80° C. overnight, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (MeOH/EA=1:9) to get 5.8 mg of the title product as a yellow solid. MS (ES+): 690.8 [M+1].sup.+

[0330] .sup.1HNMR Spectrum: (400 MHz, CDCl.sub.3) δ 8.52-8.48 (m, 2H), 8.34 (s, 1H), 7.90-7.85 (m, 1H), 7.44-7.42 (d, J=8 Hz, 1H), 7.11 (s, 1H), 7.07-7.03 (m, 3H), 6.78 (s, 1H), 6.68 (s, 1H), 6.62-6.58 (m, 1H), 6.44-6.40 (d, J=16 Hz, 1H), 5.85-5.82 (d, J=12 Hz, 1H), 5.34-4.81 (m, 1H), 4.81-4.16 (m, 2H), 4.11-3.93 (m, 3H), 3.75-3.32 (m, 3H), 2.81-2.64 (m, 3H), 2.29-2.02 (m, 2H), 1.15-0.73 (m, 9H).

EXAMPLE 15

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-4-(2-hydroxy-2-methylpropanoyl)-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0331] ##STR00364##

[0332] To a stirred solution of Example 2 (40 mg, 0.0816 mmol), 2-hydroxy-2-methylpropanoic acid (25.6 mg, 0.245 mmol) and DIPEA (8064 mg, 0.49 mmol) in NMP (2 ml) was added CIP (45.6 mg, 0.164 mmol) at rt. The resulting mixture was stirred for 4 h at 50° C. and then quenched with water. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (EA:MeOH=5:1) to obtain 9 mg of the title product as a yellow solid. MS (ES+): 671.8 [M+1].sup.+.

[0333] .sup.1HNMR Spectrum: (400 MHz, CDCl.sub.3) δ 8.52-8.50 (d, J=8 Hz, 1H), 7.85 (m, 1H), 7.44 (m, 1H), 7.20 (m, 1H), 7.16-7.04 (m, 2H), 6.62-6.55 (dd, 1H), 6.44-6.39 (d, J=20 Hz, 1H), 5.82-5.74 (m, 1H), 4.74 (s, 1H), 4.55-4.15 (m, 1H), 4.03-3.82 (m, 1H), 3.82-3.48 (m, 2H), 3.49 (s, 1H), 2.82 (m, 1H), 2.54-2.37 (m, 2H), 1.81 (s, 1H), 1.65 (s, 1H), 1.54-1.41 (m, 8H), 0.99-0.97 (d, J=8 Hz, 3H), 0.90-0.76 (m, 8H).

EXAMPLE 16

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-4-methyl-2.SUP.1.,2.SUP.2.-dihydro-4,6-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphane-2.SUP.2.,5-dione

[0334] ##STR00365##

[0335] To a stirred solution of the product of example 5 (5.2 mg, 0.007 mmol) and cesium carbonate (27.5 mg, 0.084 mmol) in DMF (0.9 ml) was added iodomethane (48.0 mg, 0.336 mmol). The mixture was stirred at rt overnight, and then was quenched with water and extracted with EA. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to get 3.7 mg of the title product as a yellow solid. MS (ES+): 628.8[M+1].sup.+.

[0336] .sup.1HNMR Spectrum: (400 MHz, CDCl.sub.3) δ 8.57-8.56 (d, J=4 Hz, 1H), 7.85-7.83 (d, J=8 Hz, 1H), 7.52 (m, 1H), 7.16-7.11 (m, 3H), 6.65 (s, 1H), 6.44-6.40 (m, 1H), 5.84-5.81 (d, J=12 Hz, 1H), 5.36-5.33 (m, 1H), 4.78-4.46 (m, 3H), 4.21 (m, 1H), 4.01-3.64 (m, 1H), 3.58-3.20 (m, 1H), 3.12 (m, 4H), 2.85 (m, 1H), 2.62 (m, 1H), 2.21 (m, 1H), 2.01 (m, 1H), 1.47-1.41 (m, 3H), 1.29-1.25 (m, 4H), 1.01 (m, 3H).

EXAMPLE 17

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphan-2.SUP.2.-one

[0337] ##STR00366##

Step 1 2-bromo-6-isopropylaniline

[0338] ##STR00367##

[0339] To a solution of 2-isopropylaniline (1.00 g, 7.4 mmol) in benzene (40.0 mL) was added NBS (1.31 g, 7.4 mmol) all at once. After stirring at rt overnight. The volume of the reaction mixture was deduced by one quarter under reduced pressure and the solid was removed by filtration. The filtrate was concentrated and pentane was added with ice followed by 0.4 mL acetic anhydride. After about 15 min, solid was filtered off. Pentane solution was separated from filtrate, washed with NH.sub.4OH, and concentrated. The residue was distilled at 83° C. under 0.2 mmHg to give title compound (600.0 mg).

[0340] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.22 (d, 1H), 7.04 (d, 1H), 6.53-6.49 (t, 1H), 4.98 (s, 2H), 3.07-3.03 (m, 1H), 6.15 (d, 6H).

Step 2 tert-butyl (E)-3-(2-amino-3-isopropylphenyl)acrylate

[0341] ##STR00368##

[0342] A solution of 2-bromo-6-isoproplyaniline (50.0 mg, 4.70 mmol), tert-butyl acrylate (59.6 mg, 0.467 mmol), K.sub.2CO.sub.3 (64.0 mg, 0.46 mmol) and Pd(OAc).sub.2 (10.0 mg, 0.045 mmol), tri-o-tolylphosphane (28.0 mg, 0.093 mmol) in DMF (15 mL) was heated at 100° C. under Ar atmosphere for 2 h. The reaction was quenched with water and extracted with EtOAc (10 mL×2). The combined organic phase was dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by silica gel chromatography eluted with a gradient of EtOAc/Hexane (0-10%) to afford title compound (40 mg). MS (ESI+): 262.1 [M+1].sup.+.

[0343] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.86 (d, 1H), 7.27 (d, 1H), 7.07 (d, 1H), 6.58-6.54 (t, 1H), 6.21 (d, 1H), 5.23 (s, 2H), 3.06-3.00 (m, 1H), 1.48 (s, 9H), 1.13 (d, 6H).

Step 3 tert-butyl-(E)-3-(2-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-3-isopropylphenyl)acrylate

[0344] ##STR00369##

[0345] Starting with 2,6-dichloro-5-fluoronicotinamide and the product of Step 2, the title product was obtained as a yellow solid by following the procedure described in Step 3 of Example 1. MS (ESI+): 496.1 [M+1].sup.+.

[0346] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.37 (s, 1H), 9.60 (s, 1H), 8.52 (d, 1H), 7.72-7.66 (m, 2H), 7.44 (d, 1H), 7.38-7.34 (t, 1H), 6.47 (d, 1H), 3.31-3.12 (m, 1H), 1.47 (s, 9H), 1.17 (d, 6H).

Step 4 tert-butyl-(E)-3-(2-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)acrylate

[0347] ##STR00370##

[0348] Starting with the product od Step 3, the title product was obtained as a yellow solid by following the procedure described in Step 3 of Example 8.

[0349] .sup.1HNMR (400 MHz, CDCl3-d1): δ 8.55 (s, 1H), 8.24 (d, 1H), 7.64-7.62 (dd, 1H), 7.55-7.50 (m, 2H), 7.25 (d, 1H), 6.36 (d, 1H), 2.58-2.54 (m, 1H), 1.45 (s, 9H), 1.18 (d, 3H), 1.07 (d, 3H).

Step 5 2-fluoro-6-nitrophenyl trifluoromethanesulfonate

[0350] ##STR00371##

[0351] To a solution of 2-fluoro-6-nitrophenol (10.0 g, 63.69 mmol) in DCM (200.0 mL) cooled at 0° C., were added pyridine (6.15 mL, 76.43 mmol) and Tf.sub.2O (12.86 mL, 76.43 mmol). After stirring for 2 h, the reaction was quenched with NaHCO.sub.3(aq) and extracted with DCM. The DCM layer was washed with 1N HCl, dried over MgSO.sub.4 and concentrated to give the crude title compound (17.0 g).

[0352] .sup.1HNMR (400 MHz, CDCl.sub.3): δ 8.00-7.97 (m, 1H), 7.64-7.54 (m, 2H).

Step 6 2-(2-fluoro-6-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0353] ##STR00372##

[0354] To a solution of the product of Step 5 (290.0 mg, 1.0 mmol) in dioxane (3.0 mL), was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (381.0 mg, 1.50 mmol), KOAc (295.0 mg, 3.0 mmol) and Pd(dppf)Cl.sub.2 (82.0 mg, 0.1 mmol) and 4 drops of water. After stirring at 80° C. for 2.5 h, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated and the residue was purified by silica gel chromatography eluted with a gradient of EtOAc/Hexane (0-20%) to afford the title compound (250.0 mg).

[0355] .sup.1HNMR (400 MHz, CDCl3): δ 8.03 (d, 1H), 7.56-7.50 (m, 1H), 7.39-7.35 (t, 1H), 1.45 (s, 12H).

Step 7 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0356] ##STR00373##

[0357] To a solution of 2-(2-fluoro-6-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.49 g, 9.32 mmol) in EtOAc (40 mL) was added 10% Pd/C (992 mg, 0.93 mmol) under nitrogen atmosphere. The mixture was then stirred under H.sub.2 atmosphere at rt for 16.5 h. The solution was filtered through a pad of celite, and the pad was washed with ethyl acetate. The filtrate was concentrated to give the title compound (2.2 g). MS (ESI+): 238.1 [M+1].sup.+.

Step 8 tert-butyl-(E)-3-(2-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)acrylate

[0358] ##STR00374##

[0359] To a solution of the product of Step 4 (100.0 mg, 0.218 mmol) and Step 7 (155.0 mg, 0.654 mmol) in dioxane (3.0 mL), were added K.sub.2CO.sub.3 (60.0 mg, 0.436 mmol) and Pd(dppf)Cl.sub.2 (18.0 mg, 0.022 mmol) under Ar atmosphere. After stirring at 80° C. for 2 h, the reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL×2). The combined extracts were dried over Na.sub.2SO.sub.4, filtrated and concentrated. The residue was purified by silica gel chromatography eluted with a gradient of EtOAc/Hexane (0-20%) to afford the title compound (120 mg). MS (ESI+): 479.1 [M−55].sup.+.

Step 9 tert-butyl-3-(2-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)propanoate

[0360] ##STR00375##

[0361] To a solution of the product of Step 8 (120.0 mg, 0.225 mmol) in MeOH (5 mL) and 7M NH.sub.3/MeOH (0.05 mL) was added Pd/C (24 mg, 0.023 mmol). The mixture was stirred at rt for 2 hour and then filtered through a pad of celite and the filtrate was concentrated to afford the title compound (118.0 mg). MS (ESI+): 481.1 [M−55].sup.+.

Step 10 3-(2-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)propanoic acid

[0362] ##STR00376##

[0363] To a solution of 4N HCl/dioxane (4.0 mL) was the product of Step 9 (118.0 mg, 0.22 mmol) at 0° C. After stirring at 0° C. for 10 min, the reaction mixture was kept at rt. for 2 h. The reaction mixture was concentrated to dryness for to afford the crude title compound (100.0 mg). MS (ESI+): 481.1 [M+1].sup.+.

Step 11 2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.,2.SUP.3.,2.SUP.4.-tetrahydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphane-2.SUP.2.,2.SUP.4.,5-trione

[0364] ##STR00377##

[0365] Starting with the product of Step 10, the title product was obtained as a yellow solid by following the procedure described in Step 7 of Example 1. MS (ESI+): 463.1 [M+1].sup.+.

Step 122.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.,2.SUP.3.,2.SUP.4.-tetrahydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphane-2.SUP.2.,2.SUP.4.-dione

[0366] ##STR00378##

[0367] Starting with the product of Step 11, the title product was obtained as a yellow solid by following the procedure described in Step 1 of Example 2. MS (ESI+): 449.1 [M+1].sup.+.

Step 13(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphan-2.SUP.2.-one

[0368] ##STR00379##

[0369] To a solution of the product Step 12 (10.0 mg, 0.022 mmol) and DIPEA (28.4 mg, 0.22 mmol) in CH.sub.3CN (1.0 mL) was added POCl.sub.3 (20 mg, 0.134 mmoL) at rt under Ar. After stirring at 80° C. for 1 hour, the reaction mixture was then concentrated to dryness. The residue was dissolved in DMF (1.0 mL) and the resulted solution was treated with DIPEA (28.4 mg, 0.22 mmol) and Intermediate 2 (13.0 mg, 0.044 mmol). After stirring at rt overnight, EtOAc (10 mL) was added and the EtOAc layer was washed with water (8 mL×3), brine (8 mL×2), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by silica gel chromatography eluted with a gradient of MeOH/DCM (0-5%) to afford the title compound (6.0 mg). MS (ESI+): 585.1 [M+1].sup.+.

[0370] .sup.1HNMR (400 MHz, CDCl.sub.3): δ 7.88-7.81 (m, 1H), 7.41-7.37 (t, 1H), 7.29-7.20 (m, 3H), 7.69-7.59 (m, 1H), 6.55-6.47 (m, 2H), 6.43-6.39 (m, 1H), 5.82 (d, 1H), 4.87-4.73 (m, 1H), 4.68-4.56 (m, 1H), 4.18-4.13 (m, 1H), 3.97-3.87 (m, 1H), 3.78-3.68 (m, 1H), 3.56-3.36 (m, 1H), 3.30-3.23 (m, 1H), 3.00-2.94 (m, 1H), 2.88-2.84 (m, 1H), 2.67-2.61 (m, 1H), 2.41-2.31 (m, 2H), 2.03-1.99 (m, 2H), 1.23-1.22 (m, 3H), 1.21-1.20 (m, 3H), 0.95-0.94 (m, 3H).

EXAMPLE 18

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphane-2.SUP.2.,5-dione

[0371] ##STR00380##

[0372] Starting with the product of Step 11 of Example 17 and Intermediate 2, the title product was obtained as a yellow solid by following the procedure described in Step 13 of Example 17. MS (ESI+): 599.1 [M+1].sup.+.

[0373] .sup.1HNMR (400 MHz, CDCl3-d1): δ 7.89-7.80 (m, 1H), 7.73-7.70 (m, 1H), 7.53-7.33 (m, 4H), 7.16-7.10 (m, 1H), 7.03-6.97 (m, 1H), 6.86-6.77 (m, 1H), 6.69-6.51 (m, 1H), 6.45-6.38 (m, 1H), 5.84-5.81 (m, 1H), 4.33-3.98 (m, 4H), 3.77-3.60 (m, 2H), 3.09-2.98 (m, 1H), 2.93-2.85 (m, 1H), 2.82-2.76 (m, 1H), 2.63-2.57 (m, 1H), 2.37-2.33 (m, 1H), 2.22-2.20 (m, 1H), 1.22-1.06 (m, 6H), 0.90-0.89 (m, 3H).

EXAMPLE 19

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-4-methyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphan-2.SUP.2.-one

[0374] ##STR00381##

[0375] To a solution of the product of Example 17 (25 mg, 0.043 mmol) in DMF (1.0 mL) were added K.sub.2CO.sub.3 (11.8 mg, 0.086 mmol) and CH.sub.3I (18.2 mg, 0.13 mmol). After the reaction mixture was stirred at 40° C. for 3 h, and additional CH.sub.3I (36.4 mg, 0.26 mmol) was added and the reaction mixture was stirred at rt overnight. Water (5 mL) was added and the mixture was extracted with EtOAc (10 mL). The organic layer was washed with water (5 mL×3), brine (5 mL), dried over Na.sub.2SO.sub.4, and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography eluted with a gradient of MeOH/DCM (0-3%) to afford the title compound (10 mg, 39% yield). MS (ESI+): 599.1 [M+1].sup.+.

[0376] .sup.1HNMR (400 MHz, CDCl3-d1): δ 7.75-7.73 (m, 1H), 7.34-26 (m, 3H), 7.14-7.12 (m, 1H), 7.02-7.00 (m, 1H), 6.88-6.83 (m, 1H), 6.68-6.54 (m, 1H), 6.41 (d, 1H), 5.81 (d, 1H), 5.40-5.33 (m, 1H), 4.90-4.75 (m, 1H), 4.68-4.50 (m, 1H), 4.19-4.14 (m, 1H), 3.98-3.86 (m, 1H), 3.81-3.71 (m, 1H), 3.59-3.50 (m, 1H), 3.46-3.38 (m, 1H), 3.26-3.12 (m, 1H), 3.06-3.00 (m, 1H), 2.81-2.74 (m, 1H), 2.59-2.54 (m, 1H), 2.44-2.42 (m, 4H), 1.94-1.85 (m, 1H), 1.25-1.23 (m, 3H), 0.98-0.96 (m, 3H).

EXAMPLE 20

2.SUP.4.-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphan-2.SUP.2.-one

[0377] ##STR00382##

Step 1 2.SUP.4.-((2S,5R)-4-(3-chloropropanoyl)-2,5-dimethylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphan-2.SUP.2.-one

[0378] ##STR00383##

[0379] Starting from the product of Step 12 of Example 17 (25 mg) and Intermediate 4 (46 mg), the title product was obtained as a yellow solid by following the procedure described in Step 13 of Example 17. MS (ESI+): 635.1 [M+1].sup.+.

Step 2 2.SUP.4.-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphan-2.SUP.2.-one

[0380] ##STR00384##

[0381] To a solution of the product of Step 1 (20 mg) in CH.sub.3CN (1.0 mL) was added Et.sub.3N (112.7 mg). After stirring at 80° C. for 12 h, the reaction mixture was diluted with EtOAc (10 mL) and washed with water (8 mL×2), brine (8 mL), and dried over Na.sub.2SO.sub.4. The solution was concentrated to afford the title compound (20 mg). MS (ESI+): 599.1 [M+1].sup.+.

EXAMPLE 20A and 20B

[0382] Example 20 (˜20 mg) was separated by silica gel chromatography eluted with a gradient of MeOH/DCM (0-5%) to afford Example 20A (8 mg, fast eluted) and Example 20B (7.0 mg, slow eluted) as yellow solid.

[0383] Example 20A: .sup.1HNMR (400 MHz, CDCl): δ 7.83-7.78 (m, 1H), 7.41-7.38 (m, 1H), 7.28-7.20 (m, 3H), 6.61-6.47 (m, 3H), 6.44-6.35 (t, 1H), 5.81-5.78 (m, 1H), 5.12-5.10 (m, 1H), 5.01-4.97 (m, 1H), 4.41-4.30 (m, 1H), 4.15-4.08 (m, 1H), 4.00-3.00 (m, 2H), 3.72-3.64 (m, 1H), 3.32-3.29 (m, 1H), 3.01-2.96 (m, 1H), 2.89-2.82 (m, 1H), 2.66-2.58 (m, 1H), 2.44-2.32 (m, 2H), 2.02-1.99 (m, 1H), 1.40-1.39 (m, 3H), 1.22-1.17 (m, 6H), 0.91-0.89 (m, 3H).

[0384] MS (ESI+): 599.1 [M+1].sup.+.

[0385] Example 20B: .sup.1HNMR (400 MHz, CDCl): δ 7.89-7.82 (m, 1H), 7.40-7.36 (m, 1H), 7.28-7.19 (m, 3H), 6.66-6.55 (m, 1H), 6.53-6.40 (m, 3H), 5.83-5.78 (m, 1H), 5.20-5.13 (m, 1H), 4.94-4.88 (m, 1H), 4.80-4.74 (m, 1H), 4.54-4.46 (m, 1H), 4.44-4.39 (m, 1H), 3.74-3.63 (m, 2H), 3.58-3.53 (m, 1H), 3.31-3.26 (m, 1H), 3.22-3.19 (m, 1H), 3.00-2.95 (m, 1H), 2.89-2.84 (m, 1H), 2.64-2.58 (m, 1H), 2.38-2.33 (m, 1H), 2.00-1.97 (m, 1H), 1.64-1.62 (m, 3H), 1.50-1.48 (m, 3H), 1.22-1.17 (m, 3H), 1.00-0.96 (m, 3H).

[0386] MS (ESI+): 599.1 [M+1].sup.+.

EXAMPLE 21

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphane-2.SUP.2.,5-dione

[0387] ##STR00385##

Step 1 tert-butyl 3-((3-bromo-2-nitrophenyl)amino)propanoate

[0388] ##STR00386##

[0389] A solution of 1-bromo-3-fluoro-2-nitrobenzene (0.6918 g, 3.145 mmol), tert-butyl 3-aminopropanoate hydrochloride (0.6436 g, 3.543 mmol) and DIPEA (1.55 mL, 9.38 mmol) in 15 mL DMA was stirred for 23 h at 80° C. Water (80 mL) was added and the mixture was extracted with EtOAc (4×20 mL). The combined organic layer was washed with water (3×20 mL), brine, dried over Na.sub.2SO.sub.4, filtered, concentrated to give the title compound as a yellow oil (1.0 g).

[0390] .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.15 (t, J=8.2 Hz, 1H), 6.96 (dd, J=7.8, 0.9 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 5.84 (s, 1H), 3.46 (dd, J=12.3, 6.3 Hz, 2H), 2.55 (t, J=6.5 Hz, 2H), 1.47 (s, 9H).

Step 2 tert-butyl 3-((3-bromo-2-nitrophenyl)(tert-butoxycarbonyl)amino)propanoate

[0391] ##STR00387##

[0392] To a solution of the product od Step 1 (0.4405 g, 1.276 mmol), 4-dimethylaminopyridine (0.1614 g, 1.321 mmol) and DIPEA (0.86 mL, 5.22 mmol) in 5 mL dry DMF was added di-tert-butyl dicarbonate (1.20 mL, 5.22 mmol) at rt. The reaction mixture was stirred for 23 h at 80° C.

[0393] Water (80 mL) was added and the reaction mixture was extracted with EtOAc (4×20 mL). The combined organic layer was washed with water (3×20 mL), brine, dried over Na.sub.2SO.sub.4, filtered, concentrated. The residue was purified by silica gel column chromatography (eluent: EtOAc:Hexanes/0:100 to 10:90) to give the title compound (0.3688 g) as a brown oil. MS (ESI+): 467.1, 469.1 [M+23].sup.+.

Step 3 tert-butyl 3-((tert-butoxycarbonyl)(2-nitro-3-(prop-1-en-2-yl)phenyl)amino)propanoate

[0394] ##STR00388##

[0395] A mixture of the product of Step 2 (0.36 g, 1.04 mmol), isopropenylboronic acid pinacol ester (0.45 mL, 2.39 mmol), tetrakis(triphenylphosphine)palladium (0.0956 g, 0.0827 mmol) and K.sub.2CO.sub.3 (0.4138 g, 2.994 mmol) in 20 mL 1,4-dioxane and 4 mL H.sub.2O was stirred for 3 h at 80° C. under Argon. EtOAc (20 mL) and 20 mL brine were added. The organic layer was dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by silica gel column chromatography eluted with a gradient of petroleum ether/EtOAc (100:0 to 90:10) to give the title compound (0.2838 g) as a red oil. MS (ESI+): 429.2 [M+23].sup.+.

Step 4 tert-butyl 3-((2-amino-3-isopropylphenyl)(tert-butoxycarbonyl)amino)propanoate

[0396] ##STR00389##

[0397] A mixture of the product of Step 3 (0.28 g, 0.69 mmol) and 10% Pd/C (0.164 g, 0.155 mmol) in 25 mL EtOAc was stirred for 1 h at rt with a balloon of H.sub.2. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated. To the residue was dissolved in 20 mL Methanol and treated with Raney Ni (3.1 g). The reaction mixture was stirred for 2 h at 30° C. with a balloon of H.sub.2. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to give the title compound (0.2514 g) as a colorless oil. MS (ESI+): 379.2 [M+1].sup.+.

Step 5 tert-butyl 3-((tert-butoxycarbonyl)(2-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-3-isopropylphenyl)amino)propanoate

[0398] ##STR00390##

[0399] Starting with 2,6-dichloro-5-fluoronicotinamide (3.67 g) and the product of Step 4 (3.58 g), the title product was obtained as a white solid (3.8 g) by following the procedure described in Step 3 of Example 1. MS (ESI+): 611.2 [M−1].sup.+.

Step 6 tert-butyl 3-((tert-butoxycarbonyl)(2-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)amino)propanoate

[0400] ##STR00391##

[0401] Starting with 2,6-dichloro-5-fluoronicotinamide (3.67 g) and the product of Step 5 (3.35 g), the title product was obtained as a white solid (1.94 g) by following the procedure described in Step 3 of Example 8. MS (ESI+): 575.1 [M−1].sup.+.

Step 7 3-((2-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)amino)propanoic acid

[0402] ##STR00392##

[0403] A solution of the product of Step 6 (0.8295 g, 1.437 mmol) in TFA (10.0 mL) and dichloromethane (10 mL) was stirred for 5 h at rt. Toluene (10 mL) was added and the mixture was concentrated to give the title compound as a grey solid (0.80 g). MS (ESI+): 421.1 [M+1].sup.+.

Step 8 3-((2-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)amino)propanoic acid

[0404] ##STR00393##

[0405] Starting with the product of Step 7 (0.6 g) and 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.50 g), the title product was obtained as a white solid (0.66 g) by following the procedure described in Step 8 of Example 17. MS (ESI+): 496.2 [M+1].sup.+.

Step 9 2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.,2.SUP.3.,2.SUP.4.-tetrahydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphane-2.SUP.2.,2.SUP.4.,5-trione

[0406] ##STR00394##

[0407] Starting with the product of Step 8 (0.24 g), the title product was obtained as a grey solid (0.11 g) by following the procedure described in Step 7 of Example 1. MS (ESI+): 632.0 [M+1].sup.+.

Step 10 (S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphane-2.SUP.2.,5-dione

[0408] ##STR00395##

[0409] Starting with the product of Step 9 (44 mg) and Intermediate 1 (69 mg), the title product was obtained as a white solid (12 mg) by following the procedure described in Step 13 of Example 17, except the crude product was purified by reverse phase column chromatography (C-18, grain size: 40 m, pore size distribution: 120 A) eluted with CH.sub.3CN/H.sub.2O (10-80%). MS (ESI+): 614.3 [M+1].sup.+.

EXAMPLE 22

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphan-2.SUP.2.-one

[0410] ##STR00396##

Step 1 2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.,2.SUP.3.,2.SUP.4.-tetrahydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphane-2.SUP.2.,2.SUP.4.-dione

[0411] ##STR00397##

[0412] Starting with the product of Step 9 of Example 21 (190 mg), the title product was obtained as a yellow solid (70 mg) by following the procedure described in Step 7 of Example 1. MS (ESI+): 464.2 [M+1].sup.+.

Step 2 (S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphan-2.SUP.2.-one

[0413] ##STR00398##

[0414] Starting with the product of Step 1 (50 mg) and Intermediate 1 (101 mg), the title product was obtained as a white solid (2.3 mg) by following the procedure described in Step 13 of Example 17, except the crude product was purified by reverse phase column chromatography (C-18, grain size: 40 m, pore size distribution: 120 A) eluted with CH.sub.3CN/H.sub.2O (10-80%). MS (ESI+): 600.3 [M+1].sup.+.

EXAMPLE 23A and 23B

2.SUP.4.-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphan-2.SUP.2.-one

[0415] ##STR00399##

[0416] To a solution of the product of Step 1 of Example 22 (0.0598 g, 0.125 mmol) and DIPEA (0.22 mL, 1.26 mmol) in 5 mL dry MeCN was added POCl.sub.3 (0.0800 mL, 0.858 mmol). The reaction mixture was stirred for 1 hour under reflux. MeCN was evaporated off and the residue was treated with a solution of Intermediate 3 (0.0738 g, 0.262 mmol), DIPEA (0.24 mL, 1.38 mmol) in 5 mL dry MeCN. The reaction mixture was stirred for 1 hour and then concentrated. The residue was first purified by gel silica column chromatography eluted with DCM/MeOH (100:0 to 90:10), then by reverse phase column chromatography (C-18, grain size: 40 m, pore size distribution: 120 Å) eluted with CH.sub.3CN/H.sub.2O (10-80%) to give Example 23A (0.0070 g, fast eluted) and Example 23B (0.0074 g, slow eluted) as yellow solids. MS (ESI+): 614.3 [M+1].sup.+.

EXAMPLE 24A and 24B

2.SUP.4.-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphane-2.SUP.2.,5-dione

[0417] ##STR00400##

[0418] To a solution of the product of Step 9 of Example 21 (0.0470 g, 0.0984 mmol) and DIPEA (0.18 mL, 1.03 mmol) in 5 mL dry MeCN was added POCl.sub.3 (0.0600 mL, 0.644 mmol). The reaction mixture was stirred for 1 hour under reflux. MeCN was evaporated off and the residue was treated with a solution of Intermediate 3 (0.0744 g, 0.264 mmol), DIPEA (0.22 mL, 1.26 mmol) in 5 mL dry MeCN. The reaction mixture was stirred for 1 hour and then was concentrated. The residue was first purified by gel silica column chromatography eluted with DCM/MeOH (100:0 to 90:10), then by reverse phase column chromatography (C-18, grain size: 40 μm, pore size distribution: 120 Å) eluted with CH.sub.3CN/H.sub.2O (10-80%) to give Example 24A (0.0012 g, fast eluted) and Example 24B (0.0018 g, slow eluted) as yellow solids. MS (ESI+): 628.3 [M+1].sup.+.

EXAMPLE 25

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphane-2.SUP.2.,5-dione

[0419] ##STR00401##

Step 1 tert-butyl N-(3-bromo-2-nitrophenyl)-N-(tert-butoxycarbonyl)glycinate

[0420] ##STR00402##

[0421] To a pre-cooled solution of 3-bromo-2-nitroaniline (5 g, 23.0 mmol) in dry THF (100 mL) was added NaH (2.03 g, 50.7 mmol) in portions in an ice bath under nitrogen atmosphere. After stirring at 0° C. for 0.5 h, Boc.sub.2O (6.42 mL, 27.7 mmol) was added, stirred for another 2 h. BrCH.sub.2CO.sub.2.sup.tBu (4.07 mL, 27.7 mmol) was added, and the reaction mixture was stirred at rt overnight. The reaction mixture was poured into a mixture of water and sat. NH.sub.4Cl (100/100 mL), extracted with ethyl acetate (80 mL×3). The combined extracts were concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate: 100/0 to 95/5) to give the title compound (6.664 g) as a yellow oil. MS (ESI): 275.0/277.0 [M+H-isobutylene-Boc].sup.+.

[0422] .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.74-7.66 (m, 1H), 7.62 (dd, J=8.2, 1.2 Hz, 1H), 7.42-7.32 (m, 1H), 4.52 (d, J=17.2 Hz, 1H), 3.60 (d, J=17.2 Hz, 1H), 1.51-1.43 (m, 13H), 1.34 (s, 6H).

Step 2 tert-butyl N-(tert-butoxycarbonyl)-N-(2-nitro-3-(prop-1-en-2-yl)phenyl)glycinate

[0423] ##STR00403##

[0424] Starting with the product of Step 1 (6.66 g), the title product was obtained as a light-yellow oil (4.26 g) by following the procedure described in Step 3 of Example 21. MS (ESI): 237.1 [M+H-isobutylene-Boc].sup.+.

[0425] .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.65-7.56 (m, 1H), 7.48-7.39 (m, 1H), 7.29-7.24 (m, 1H), 5.22-5.16 (m, 1H), 4.99 (s, 1H), 4.55 (d, J=17.7 Hz, 1H), 3.65 (d, J=17.7 Hz, 1H), 2.08 (s, 3H), 1.52-1.44 (m, 13H), 1.33 (s, 6H).

Step 3 tert-butyl N-(2-amino-3-isopropylphenyl)-N-(tert-butoxycarbonyl)glycinate

[0426] ##STR00404##

[0427] To the solution of the product of Step 2 (4.45 g, 11.3 mmol) in MeOH (50 mL) were added 7M NH.sub.3 in MeOH (0.5 mL) and 10% Pd/C (1.2 g, 1.13 mmol) under nitrogen atmosphere. The mixture was stirred under H.sub.2 atmosphere at room temperature for 11.5 h. The solution was filtered through Celite, and the Celite pad was washed with EtOAc. The filtrate was concentrated to give the title compound (4.27 g) as a pale-yellow oil. MS (ESI): 265.2 [M+H].sup.+.

Step 4 tert-butyl N-(tert-butoxycarbonyl)-N-(2-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-3-isopropylphenyl)glycinate

[0428] ##STR00405##

[0429] Starting with 2,6-dichloro-5-fluoronicotinamide (2.34 g) and the product of Step 3 (3.31 g), the title product was obtained as a white solid (4.71 g) by following the procedure described in Step 3 of Example 1. MS (ESI): 597.0 [M−H].sup.−.

Step 5 tert-butyl N-(tert-butoxycarbonyl)-N-(2-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)glycinate

[0430] ##STR00406##

[0431] Starting with the product of Step 4 (4.21 g), the title product was obtained as a white solid (2.73 g) by following the procedure described in Step 3 of Example 8. MS (ESI): 564.2 [M+H].sup.+.

Step 6 (2-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)glycine

[0432] ##STR00407##

[0433] To the solution of the product of Step 5 (600 mg, 1.07 mmol) in DCM (6 mL) was added TFA (4 mL). After stirring at rt for 16 h, 4 mL 1,4-dioxane was added and the solution was concentrated to give a brown oil, which was used for the next step without further purification. MS (ESI): 407.1 [M+H].sup.+.

Step 7 (2-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)glycine

[0434] ##STR00408##

[0435] Starting with the product of Step 6 (505.5 mg) and 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (736.5 mg), the title product was obtained as a white solid (637 mg) by following the procedure described in Step 8 of Example 17. MS (ESI): 482.1 [M+H].sup.+.

Step 8 2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.,2.SUP.3.,2.SUP.4.-tetrahydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphane-2.SUP.2.,2.SUP.4.,5-trione

[0436] ##STR00409##

[0437] To the turbid solution of the product of Step 7 (637 mg, 1.32 mmol) in dry MeCN (10 mL) was added pyridine (320 μL, 3.97 mmol). N-methylimidazole (320 μL, 3.97 mmol) was added, followed by dry DMF (10 mL) and TCFH (562.5 mg, 1.98 mmol). After stirring for 11 h, the reaction mixture was poured into 0.5N HCl solution (12 mL), and extracted with EtOAc (15 mL×4). The organic phase was washed with brine (5 mL×2), and the water phase was extracted with EtOAc (5 mL×2). The combined organic phase was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 100/0 to 50/50) to give the title product as a yellow solid (200 mg). MS (ESI): 464.1 [M+H].sup.+.

Step 9 (S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphane-2.SUP.2.,5-dione

[0438] ##STR00410##

[0439] Starting with the product of Step 8 (60 mg) and Intermediate 2 (69 mg), the title product was obtained as a white solid (2.14 mg) by following the procedure described in Step 13 of Example 17. MS (ESI): 600.3 [M+H].sup.+.

EXAMPLE 26

2.SUP.4.-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphane-2.SUP.2.,5-dione

[0440] ##STR00411##

[0441] Starting with the product of Step 8 (55 mg) and Intermediate 3 (133 mg), the title product was obtained as a yellow solid (7.8 mg) by following the procedure described in Step 13 of Example 17. MS (ESI): 614.3[M+H].sup.+.

EXAMPLE 27A and 27B

2.SUP.4.-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphan-2.SUP.2.-one

[0442] ##STR00412##

Step 1 2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-2.SUP.1.,2.SUP.2.,2.SUP.3.,2.SUP.4.-tetrahydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphane-2.SUP.2.,2.SUP.4.-dione

[0443] ##STR00413##

[0444] Starting with the product of Step 8 of Example 25 (100 mg), the title product was obtained as a yellow solid (16 mg) by following the procedure described in Step 7 of Example 1. MS (ESI): 450.1 [M+H].sup.+.

Step 2 2.SUP.4.-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-16-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphan-2.SUP.2.-one

[0445] ##STR00414##

[0446] To a solution of the product of Step 1 (20 mg, 0.04 mmol) in dry MeCN (2 mL) were added DIPEA (74 μL, 0.44 mmol) and POCl.sub.3 (25 μL, 0.27 mmol) under argon atmosphere. After stirring at 80° C. for 1 h the reaction mixture was concentrated. To the residue were added DIEA (74 μL, 0.44 mmol) and a solution of 1-((2R,5S)-2,5-dimethylpiperazin-1-yl)prop-2-en-1-one (Intermediate 3, 75 mg, purity 30%, 0.13 mmol) in dry DMF (1.0 mL). After stirring at rt for 1.5 h, the reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL×4). The combined extracts were washed with sat. NH.sub.4Cl (3 mL), concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 80/20 to 0/100 then DCM/EtOAc: 90/10 to 20/80 then DCM/MeOH: 100/0 to 92/8) to provide Example 27A (fast eluted) as a yellow solid (5.4 mg) and a mixture of Example 27A and Example 27B (slow eluted). The mixture was further purified by prep-TLC (petroleum ether:ethyl acetate=1:5, eluted twice) to give another 1.0 mg of Example 27A and Example 27B as a yellow solid (5.6 mg). MS (ESI): 600.3[M+H].sup.+.

[0447] Example 27A: .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.83-7.73 (m, 1H), 7.31-7.26 (m, 1H), 7.26-7.19 (m, 1H), 6.81 (dd, J=17.4, 7.9 Hz, 2H), 6.66-6.54 (m, 1H), 6.54-6.45 (m, 2H), 6.44-6.34 (m, 1H), 5.84-5.75 (m, 1H), 5.38-5.27 (m, 1H), 5.14 (brs, 1H), 5.04-4.94 (m, 1H), 4.40-4.27 (m, 1H), 4.14-4.06 (m, 1H), 4.04-3.97 (m, 1H), 3.97-3.89 (m, 1H), 3.84 (d, J=12.6 Hz, 1H), 3.71-3.61 (m, 1H), 3.33-3.18 (m, 2H), 3.18-3.08 (m, 1H), 2.70-2.58 (m, 1H), 1.39 (d, J=6.8 Hz, 2H), 1.37-1.24 (m, 4H), 1.21 (d, J=6.8 Hz, 2H), 1.16 (d, J=6.8 Hz, 2H), 0.84 (d, J=6.8 Hz, 2H).

[0448] Example 27B: .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.82 (dd, J=19.6, 9.2 Hz, 1H), 7.30-7.27 (m, 1H), 7.25-7.19 (m, 1H), 6.88-6.74 (m, 2H), 6.67 (dd, J=16.9, 10.9 Hz, 1H), 6.59-6.34 (m, 3H), 5.87-5.75 (m, 1H), 5.21-5.12 (m, 1H), 4.98 (d, J=14.5 Hz, 1H), 4.90-4.71 (m, 1H), 4.61-4.48 (m, 1H), 4.45-4.36 (m, 1H), 3.92-3.81 (m, 1H), 3.79-3.53 (m, 3H), 3.33-3.06 (m, 3H), 2.67-2.56 (m, 1H), 1.64 (d, J=6.8 Hz, 1H), 1.56-1.41 (m, 7H), 1.20 (d, J=6.8 Hz, 2H), 0.99-0.89 (m, 2H).

EXAMPLE 28

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-8-methyl-2.SUP.1.,2.SUP.2.-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphan-2.SUP.2.-one

[0449] ##STR00415##

Step 1 ethyl 3-((3-bromo-2-nitrophenyl)(methyl)amino)propanoate

[0450] ##STR00416##

[0451] Starting with ethyl 3-(methylamino)propanoate and 1-bromo-3-fluoro-2-nitrobenzene, the title product was obtained as a yellow oil by following the procedure described in Step 1 of Example 21. MS: (ESI+): 353.7 [M+23].sup.+.

Step 2 ethyl 3-(methyl(2-nitro-3-(prop-1-en-2-yl)phenyl)amino)propanoate

[0452] ##STR00417##

[0453] Starting with the product of Step 1 and isopropenylboronic acid pinacol ester, the title product was obtained as a yellow oil by following the procedure described in Step 3 of Example 21. MS: (ESI+): 293.1 [M+1].sup.+.

Step 3 ethyl 3-((2-amino-3-isopropylphenyl)(methyl)amino)propanoate

[0454] ##STR00418##

[0455] Starting with the product of Step 2, the title product was obtained as an oil by following the procedure described in Step 4 of Example 21. MS: (ESI+): 265.1 [M+1].sup.+.

Step 4 ethyl 3-((2-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-3-isopropylphenyl)(methyl)amino)propanoate

[0456] ##STR00419##

[0457] Starting with the product of Step 3, the title product was obtained as a yellow solid by following the procedure described in Step 5 of Example 21. MS: (ESI+): 499.1 [M+1].sup.+.

Step 5 ethyl 3-((2-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)(methyl)amino)propanoate

[0458] ##STR00420##

[0459] Starting with 2,6-dichloro-5-fluoronicotinamide (2.45 g), the title product was obtained as a brown solid (1.19 g) by following the procedure described in Step 3 of Example 8. MS: (ESI+): 463.2 [M+1].sup.+.

Step 6 ethyl 3-((2-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)(methyl)amino)propanoate

[0460] ##STR00421##

[0461] Starting with the product of Step 5 (0.67 g) and 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.75 g), the title product was obtained as a brown solid (0.53 g) by following the procedure described in Step 8 of Example 17. MS: (ESI+): 538.2 [M+1].sup.+.

Step 7 3-((2-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)(methyl)amino)propanoic acid

[0462] ##STR00422##

[0463] To a solution of the product of Step 6 (420 mg) in THF (2.5 mL), was added LiOH (141 mg) in H.sub.2O (2.5 mL). After stirring at rt for 2 hours, the reaction mixture was concentrated to dryness and dissolved in water (10 mL), washed with Et.sub.2O (2 mL×5). The water phase was acidified with 1N HCl to pH=7 and concentrated under reduced pressure to dryness. The residue was co-evaporated with toluene (2 mL×3) to obtain the title compound as lithium salt (400 mg, yellow solid). MS: (ESI+): 510.2 [M+1].sup.+.

Step 8 2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-8-methyl-2.SUP.1.,2.SUP.2.,2.SUP.3.,2.SUP.4.-tetrahydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphane-2.SUP.2.,2.SUP.4.,5-trione

[0464] ##STR00423##

[0465] Starting with the product of Step 7 (0.20 g), the title product was obtained as a yellow solid (0.14 g) by following the procedure described in Step 7 of Example 1. MS: (ESI+): 492.2 [M+1].sup.+.

Step 9 2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-8-methyl-2.SUP.1.,2.SUP.2.,2.SUP.3.,2.SUP.4.-tetrahydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphane-2.SUP.2.,2.SUP.4.-dione

[0466] ##STR00424##

[0467] Starting with the product of Step 8 (10 mg), the title product was obtained as a yellow solid (13 mg, crude) by following the procedure described in Step 1 of Example 2. MS: (ESI+): 478.1 [M+1].sup.+.

Step 10 (S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-8-methyl-2.SUP.1.,2.SUP.2.-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphan-2.SUP.2.-one

[0468] ##STR00425##

[0469] Starting with the product of Step 9 (10 mg) and Intermediate 2 (47 mg), the title product was obtained as a brown solid (3.23 mg) by following the procedure described in Step 13 of Example 17. MS (ESI+): 614.3 [M+1].sup.+.

EXAMPLE 29

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-8-methyl-2.SUP.1.,2.SUP.2.-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphane-2.SUP.2.,5-dione

[0470] ##STR00426##

[0471] Starting with the product of Step 8 (15 mg) of Example 28 and Intermediate 2 (30 mg), the title product was obtained as a yellow solid (0.85 mg) by following the procedure described in Step 13 of Example 17. MS (ESI+): 628.3 [M+1].sup.+.

EXAMPLE 30

2.SUP.4.-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.6.-isopropyl-8-methyl-2.SUP.1.,2.SUP.2.-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphane-2.SUP.2.,5-dione

[0472] ##STR00427##

[0473] Starting with the product of Step 8 (40 mg) of Example 28 and Intermediate 3 (245 mg), the title product was obtained as a white solid (12 mg) by following the procedure described in Step 13 of Example 17, except the crude was purified by C-18 reverse phase column chromatography eluted with a gradient of aqueous 0.1% formic acid solution/MeCN (100% to 0%) to obtain the title compound (2.9 mg; Yield: 5.68%) as a white solid. MS (ESI+): 642.3 [M+1].sup.+.

EXAMPLE 31

(S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-1.SUP.2.-isopropyl-4-methyl-2.SUP.1.,2.SUP.2.-dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0474] ##STR00428##

Step 1 tert-butyl 2-mercaptoacetate

[0475] ##STR00429##

[0476] The mixture of tert-butyl 2-bromoacetate (20 g, 0.10 mol) and potassium ethanethioate (18 g, 0.16 mol) in EtOH (200 ml) was stirred for 16 h at rt. The reaction mixture was treated with 2N NaOH (205 ml) and stirred for 1 h. The pH of the mixture was adjusted with 1N HCl to 7 and the reaction mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to get 8.5 g of crude product as brown oil which was used to the next step without further purification.

Step 2 tert-butyl 2-((3-amino-2-isopropylpyridin-4-yl)thio)acetate

[0477] ##STR00430##

[0478] The mixture of Intermediate 5 (6.25 g, 23.86 mmol), tert-butyl 2-mercaptoacetate (8.84 g, 59.64 mmol), DIPEA (12.31 g, 95.42 mmol), Pd.sub.2(dba).sub.3 (4.37 g, 4.77 mmol) and Xantphos (5.52 g, 9.54 mmol) in 1,4-Dioxane (30 ml) was heat to 90° C. and stirred for 2 h under Ar. After the reaction was completed, the mixture was cool to rt, quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1) to give 4.6 g of pure product as a yellow solid. MS (ES+): 283 [M+1].sup.+

Step 3 tert-butyl 2-((3-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-2-isopropylpyridin-4-yl)thio)acetate

[0479] ##STR00431##

[0480] Starting with 2,6-dichloro-5-fluoronicotinamide (6.67 g) and the product of Step 2 (4.5 g), the title product was obtained as a yellow solid (3.1 g) by following the procedure described in Step 3 of Example 1. MS (ES+): 517 [M+1].sup.+.

Step 4 tert-butyl 2-((3-(7-chloro-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)thio)acetate

[0481] ##STR00432##

[0482] Starting with the product of Step 3 (3.0 g), the title product was obtained as a white solid (2.1 g) by following the procedure described in Step 3 of Example 8. MS (ES+): 481 [M+1].sup.+.

Step 5 tert-butyl 2-((3-(7-(2-amino-6-fluorophenyl)-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)thio)acetate

[0483] ##STR00433##

[0484] Starting with the product of Step 4 (700 mg) and 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.45 g), the title product was obtained as a white solid (575 mg) by following the procedure described in Step 8 of Example 17. MS (ES+): 556 [M+1].sup.+.

Step 6 2.SUP.6.,3.SUP.6.-difluoro-2.SUP.4.-hydroxy-1.SUP.2.-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-2.SUP.2.,5-dione

[0485] ##STR00434##

[0486] To a stirred solution of the product of Step 5 (240 mg, 0.43 mmol) in DCM (3 ml) was added TFA (3 ml) at rt. The resulting mixture was stirred for 1 h at rt, and then concentrated. The residue was dissolved in DMF (60 ml). NMI (532 mg, 6.49 mmol) and TCFH (393 mg, 1.30 mmol) were added at rt under Ar. The resulting mixture was stirred for 1 h at rt and then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (PE:EA=1:1) to get 92 mg of the title product as a yellow solid. MS (ES+): 482 [M+1].sup.+.

Step 7 2.SUP.6.,3.SUP.6.-difluoro-2.SUP.4.-hydroxy-12-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0487] ##STR00435##

[0488] To a stirred solution of the product of Step 6 (92 mg, 0.19 mmol) in THF (1 ml) was added borane-tetrahydrofuran complex (1 M, 0.6 ml, 0.57 mmol) at 0° C. under Ar balloon. The mixture was stirred for 1 h at rt under Ar and then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (PE:EA=2:1) to get 57 mg of the title product as a yellow solid. MS (ES+): 468 [M+1].sup.+.

Step 8 (S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-12-isopropyl-2.SUP.1.,2.SUP.2.-dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0489] ##STR00436##

[0490] Starting with the product of Step 7 (57 mg) and Intermediate 2 (79 mg), the title product was obtained as a yellow solid (37 mg) by following the procedure described in Step 8 of Example 17. MS (ES+): 604 [M+1].sup.+.

Step 9 (S)-2.SUP.4.-(4-acryloyl-2-methylpiperazin-1-yl)-2.SUP.6.,3.SUP.6.-difluoro-12-isopropyl-4-methyl-2.SUP.1.,2.SUP.2.-dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-2.SUP.2.-one

[0491] ##STR00437##

[0492] To a stirred solution of the product of Step 8 (35 mg, 0.06 mmol) in THF (1 ml) were added HCHO (30%) (5 ml) and STAB (121 mg, 0.60 mmol) at rt. After stirring for 1 h, the mixture was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-TLC (EA) to get 17 mg of the title product as a yellow solid. MS (ES+): 618 [M+1].sup.+.

Synthesis of Intermediates

Intermediate 1

(S)-1-(3-methylpiperazin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetate

[0493] ##STR00438##

Step 1 tert-butyl (S)-4-acryloyl-2-methylpiperazine-1-carboxylate

[0494] ##STR00439##

[0495] To a stirred solution of tert-butyl (S)-2-methylpiperazine-1-carboxylate (4.7971 g, 23.952 mmol) and triethylamine (8.0 mL, 57.4 mmol) in DCM (80 mL) was added acrylyl chloride (2.10 mL, 25.8 mmol) in 15 minutes at 0° C. The reaction mixture was then treated with 20 mL of water and extracted with 200 mL of EtOAc. The organic layer was washed with 60 mL of 2 N HCl (aq), and 5×50 mL water, brine and dried over Na.sub.2SO.sub.4. The solution was filtered, concentrated to give the title compound as a light yellow oil. MS (ESI+): 277.1 [M+23].sup.+.

Step 2 (S)-1-(3-methylpiperazin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetate

[0496] ##STR00440##

[0497] A solution of tert-butyl (S)-4-acryloyl-2-methylpiperazine-1-carboxylate (3.57 g, 14.0 mmol) and TFA (8.0 mL, 107.7 mmol) in DCM (20 mL) was stirred for 5 h at rt. Then 20 mL toluene was added. The resulted mixture was evaporated off to give the title compound (4.24 g) as a light oil. MS (ESI+): 155.1[M+1].sup.+.

Intermediate 2

(S)-1-(3-methylpiperazin-1-yl)prop-2-en-1-one

[0498] ##STR00441##

[0499] The crude Intermediate 1 (4.24 g) was dissolved in 25 mL NaOH (aq) (2.67 g NaOH). The reaction mixture was saturated with 10 g NaCl and extracted with 3×30 mL of DCM. The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give the Intermediate 2 (2.3 g). MS (ESI+): 155.1[M+1].sup.+.

Intermediate 3

1-((2R,5S)-2,5-dimethylpiperazin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetate

[0500] ##STR00442##

Step 1 tert-butyl (2S,5R)-4-acryloyl-2,5-dimethylpiperazine-1-carboxylate

[0501] ##STR00443##

[0502] To a stirred solution of tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate (3.83 g, 17.9 mmol) and triethylamine (5.2 mL, 37.3 mmol) in DCM (30 mL) was added acrylylchloride (1.70 mL, 20.9 mmol) at 0° C. After stirring for 15 min at 0° C., water (10 mL) was added and the reaction mixture was stirred for additional 1 h at rt. The mixture was extracted with 50 mL EtOAc and the organic layer was washed with 20 mL 2 N HCl (aq), 2×20 mL 0.2 M HCl (aq), 2×20 mL water, brine and dried over Na.sub.2SO.sub.4. The solution was filtered and concentrated to give the title compound as a light oil. MS (ESI+): 291.1 [M+23].sup.+.

Step 2 1-((2R,5S)-2,5-dimethylpiperazin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetate

[0503] ##STR00444##

[0504] A solution of the product of Step 1 (3.85 g, 14.3 mmol) and TFA (10.0 mL, 134.6 mmol) in DCM (40 mL) was stirred for 1 h at rt. Toluene (40 mL) was added and the reaction mixture was evaporated off to give the title compound (4.0 g) as a light yellow oil. MS (ESI+): 169.2 [M+1].sup.+.

Intermediate 4

3-chloro-1-((2R,5S)-2,5-dimethylpiperazin-1-yl)propan-1-one hydrochloride

[0505] ##STR00445##

[0506] The product of Step 1 of Intermediate 3 (200.0 mg, 0.746 mmol) was added to 4N HCl/dioxane solution (1.0 mL). After stirring at rt for 1 h, the reaction mixture was concentrated to dryness to afford the title compound (150 mg). MS (ESI+): 205.1 [M+1].sup.+.

[0507] 1HNMR (400 MHz, DMSO-d.sub.6): δ 3.82-3.79 (m, 2H), 0.60-3.57 (m, 4H), 3.45-3.35 (m, 2H), 2.99-2.95 (m, 1H), 2.82-2.75 (m, 1H), 1.29-1.21 (m, 6H).

Intermediate 5

2-iodo-4-isopropylpyridin-3-amine

[0508] ##STR00446##

Step 1 2,4-dichloropyridin-3-amine

[0509] ##STR00447##

[0510] To a stirred solution of 2,4-dichloro-3-nitropyridine (150 g, 0.78 mol) in CH.sub.3COOH (750 ml) was added Fe (140 g, 2.49 mol) at rt. After stirring for 3 h at 40° C., the pH of the reaction mixture was adjusted to 8˜9 by Na.sub.2CO.sub.3 (aq.) and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give 120 g of the crude title product as a brown solid. MS (ES+): 162.9 [M+1].sup.+.

Step 2 4-chloro-2-(prop-1-en-2-yl)pyridin-3-amine

[0511] ##STR00448##

[0512] To a stirred solution of 2,4-dichloropyridin-3-amine (85 g, 0.52 mol), 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethan-1-one (115 g, 0.68 mol), K.sub.3PO.sub.4 (287 g, 1.36 mol) in THF (1.7 L)/H.sub.2O (340 ml) was added Pd(dppf)Cl.sub.2.DCM (32 g, 0.039 mol) at rt under Ar. The mixture was stirred for 7 h at 75° C. and then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=2:1) to give 84 g of the title product as a white solid. MS (ES+): 168.9 [M+1].sup.+.

Step 3 4-iodo-2-isopropylpyridin-3-amine

[0513] ##STR00449##

[0514] The mixture of 4-chloro-2-(prop-1-en-2-yl)pyridin-3-amine (84 g, 0.5 mol) in HI (aq. 55-58%, 1.26 L) was stirred overnight at 120° C. under Ar. The pH of the reaction mixture was then adjusted to 9-10 with Na.sub.2CO.sub.3 (aq.) and extracted with EA. The organic layer was washed with NaHSO.sub.3 (aq.) and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give 90 g of crude product as brown oil which was used to the next step without further purification. MS (ES+): 262.8 [M+1].sup.+.

[0515] All literatures mentioned in the present application are incorporated herein by reference, as though each one is individually incorporated by reference. Additionally, it should be understood that after reading the above teachings, those skilled in the art can make various changes and modifications to the present invention. These equivalents also fall within the scope defined by the appended claims.