Pyrimidine derivative and pharmaceutical composition comprising same

Abstract

The present invention provides: a novel pyrimidine derivative compound that inhibits the growth of cancer cells; and a pharmaceutical composition for preventing and treating cancers including lung cancer, the composition containing a pharmaceutically acceptable salt of the compound as an active ingredient. In particular, the novel compound according to the present invention has an excellent inhibitory effect on exon 20 insertion EGFR mutants and excellent selectivity to wild-type EGFR, and is useful as an agent for preventing, alleviating and treating cancers caused by these EGFR mutant species.

Description

Pyrimidine derivatives and pharmaceutical compositions containing the same

[0001] The present invention provides a pharmaceutical composition for the prevention, alleviation and treatment of cancer diseases including lung cancer, comprising as an active ingredient a novel pyrimidine derivative compound having protein kinase inhibitory activity including EGFR, a stereoisomer thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof.

[0002] Epidermal growth factor receptor (EGFR) is a membrane glycoprotein that belongs to the tyrosine kinase family of epithelial receptors in the human body, along with erb_B2 (HER2 / neu), erb_B3, and erb_B4. EGFR possesses its own tyrosine kinase activity, and when activated, it induces gene expression, cell proliferation, inhibition of apoptosis, and angiogenesis. EGFR overexpression is observed in various epithelial carcinomas, including lung cancer, and EGFR is particularly observed in precancerous bronchial epithelium, suggesting that it plays a key role in the development of lung cancer. Furthermore, in vivo and in vitro studies have shown that drug inhibition of EGFR induces apoptosis in cancer cells, slows cell growth, and inhibits angiogenesis, ultimately reducing tumor growth. EGFR gene mutations are estimated to occur in 10-15% of lung cancer patients in the United States and Europe, and in 30-35% of lung cancer patients in Asia. These mutations keep EGFR activated, leading to continued cancer cell proliferation, while also making the cancer highly sensitive to existing EGFR inhibitors such as erlotinib, gefitinib, and afatinib. Typically, patients with EGFR-mutant lung cancer begin to develop drug resistance after an average of 9-13 months of treatment with these drugs.

[0003] Lung cancer caused by the epidermal growth factor receptor (EGFR) exon 20 insertion mutation accounts for 5% of all mutations. Various EGFR inhibitors are being evaluated for the treatment of this disease, but side effects such as skin rash and diarrhea caused by simultaneous inhibition of wild-type EGFR limit the ability to increase the drug dosage. This results in a halving of the therapeutic efficacy, and therefore, there is an urgent need to develop drugs that have low growth inhibitory activity against wild-type EGFR and are selective for EGFR exon 20 insertion mutations.

[0004]

[0005] Therefore, the problem to be solved by the present invention is to provide a pharmaceutical composition for the prevention, alleviation and treatment of cancer diseases including lung cancer, comprising as an active ingredient a novel compound, a stereoisomer thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof, which has low growth inhibitory activity against wild-type EGFR and exhibits growth inhibitory activity against EGFR exon 20 insertion mutation.

[0006] In order to solve the above problem, one aspect of the present invention provides a pyrimidine derivative compound represented by the following chemical formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0007] [Chemical Formula 1]

[0008]

[0009] In the above chemical formula 1,

[0010] R 1 are each independently hydrogen, C 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or heterocycloalkyl having 3 to 10 atoms. The R1 C of 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and heterocycloalkyl of 3 to 10 atoms are each independently R 11 may be substituted with one or more substituents selected from .

[0011] R 2 are each independently hydrogen, C 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, 3 to 10 membered heterocycloalkyl, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms. The R 2 C of 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms, each independently R 11 may be substituted with one or more substituents selected from .

[0012] R 11 Silver halogen, C 1-13 Alkyl, C 1-6 Alkoxy, -OH, -OCF3, -CN, -NO2, -OR 1a , -SR 1a , -NHOR 1a , -N(OH)R 1a , -C(O)R 1a , -C(O)NR 1a R 1b , -C(O)OR 1a , -OC(O)R 1a , -OC(O)NR 1a R 1b , -NR 1a R 1b , -NR 1a C(O)R 1b , -NR 1a C(O)OR 1b , -NR 1aC(O)NR 1b R 1c , -C(=NR 1a )R 1b , -C(=NR 1a )NR 1a R 1c , -NR 1a C(=NR 1b )NR 1c R 1d , -NR 1a S(O)R 1b , -NR 1a S(O)2R 1b , -NR 1a S(O)2NR 1b R 1c , -S(O)R 1a , -S(O)NR 1a R 1b , -S(O)2R 1a , -S(O)2NR 1a R 1b , -OS(O)2R 1a , -PR 1a R 1b , -P(O)R 1a R 1b or -BR 1a R 1b am.

[0013] R 1a , R 1b , R 1c and R 1d are each independently hydrogen, C 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms.

[0014] R 3 are each independently H, halogen, -OH, C 1-10 Alkyl, C 1-10 Alkoxy, or C 3-6 It is cycloalkoxy. The above R 3 C of 1-10 Alkyl, C 1-10 Alkoxy, or C 3-6Cycloalkoxy may each be independently substituted with one or more halogens.

[0015] R 4 is hydrogen, halogen, C 1-13 Alkyl, C 1-10 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, heteroaryl of 5 to 10 atoms, -OH, -OCF3, -CN, -NO2, -OR 4a , -SR 4a , -C(O)NR 4a R 4b , -NR 4a R 4b , -NR 4a C(O)R 4b , -NR 4a S(O)2R 4b , or S(O)2NR 4a R 4b is. The above R 4 C of 1-13 Alkyl, C 1-10 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 alkenyl, and C 2-6 Alkynyl is independently R 41 may be substituted with one or more substituents selected from R. 4 C of 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, and heteroaryl of 5 to 10 atoms are each independently R 42 may be substituted with one or more substituents selected from .

[0016] R 41 are halogens, -OH, -OCF3, -CN, -NO2, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8 Aryl, heteroaryl of 5 to 10 atoms, -OR4c , -SR 4c , -NHOR 4c , -N(OH)R 4c , -C(O)R 4c , -C(O)NR 4c R 4d , -C(O)OR 4c , -OC(O)R 4c , -OC(O)NR 4c R 4d , -NR 4c R 4d , -NR 4c C(O)R 4d , -NR 4c C(O)OR 4d , -NR 4c C(O)NR 4d R 4e , -C(=NR 4c )R 4d , -C(=NR 4c )NR 4d R 4e , -NR 4c C(=NR 4d )NR 4e R 4f , -NR 4c S(O)R 4d , -NR 4c S(O)2R 4d , -NR 4c S(O)2NR 4d R 4e , -S(O)R 4c , -S(O)NR 4c R 4d , -S(O)2R 4c , -S(O)2NR 4c R 4d , -OS(O)2R 4c , -PR 4c R 4d , -P(O)R 4c R 4d or -BR 4c R 4d is. The above R 41 C of 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8Aryl, and heteroaryl of 5 to 10 atoms are each independently halogen, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 7 atoms, C 6-8 Aryl, heteroaryl of 5 to 10 atoms, -OR 4g , -SR 4g , -C(O)NR 4g R 4h , -NR 4g R 4h , -NR 4g C(O)R 4h , -NR 4g S(O)2R 4h , or S(O)2NR 4g R 4h It may be substituted with one or more substituents selected from the group consisting of .

[0017] R 42 are halogens, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8 Aryl, heteroaryl of 5 to 10 atoms, -OR 4c , -SR 4c , -NHOR 4c , -N(OH)R 4c , -C(O)R 4c , -C(O)NR 4c R 4d , -C(O)OR 4c , -OC(O)R 4c , -OC(O)NR 4c R 4d , -NR 4c R 4d , -NR4c C(O)R 4d , -NR 4c C(O)OR 4d , -NR 4c C(O)NR 4d R 4e , -C(=NR 4c )R 4d , -C(=NR 4c )NR 4d R 4e , -NR 4c C(=NR 4d )NR 4e R 4f , -NR 4c S(O)R 4d , -NR 4c S(O)2R 4d , -NR 4c S(O)2NR 4d R 4e , -S(O)R 4c , -S(O)NR 4c R 4d , -S(O)2R 4c , -S(O)2NR 4c R 4d , -OS(O)2R 4c , -PR 4c R 4d , -P(O)R 4c R 4d or -BR 4c R 4d is. The above R 42 C of 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8 Aryl, and heteroaryl of 5 to 10 atoms are each independently halogen, CF3, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 7 atoms, C6-8 Aryl, heteroaryl of 5 to 10 atoms, -OR 4g , -SR 4g , -C(O)NR 4g R 4h , -NR 4g R 4h , -NR 4g C(O)R 4h , -NR 4g S(O)2R 4h , or S(O)2NR 4g R 4h It may be substituted with one or more substituents selected from the group consisting of .

[0018] R 4a and R 4b are each independently hydrogen, C 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms. The R 4a and R 4b C of 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, and heteroaryl of 5 to 10 atoms are each independently halogen, -OH, -OCF3, -CN, -NO2, C 1-10 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, heteroaryl OR of 5 to 10 atoms 4g , -SR 4g , -C(O)NR 4g R 4h , -NR 4g R 4h , -NR 4g C(O)R4h , -NR 4g S(O)2R 4h , or S(O)2NR 4g R 4h It may be substituted with one or more substituents selected from the group consisting of .

[0019] R 4c , R 4d , R 4e , and R 4f are each independently hydrogen, C 1-10 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms. The R 4c , R 4d , R 4e and R 4f C of 1-10 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, and heteroaryl of 5 to 10 atoms are each independently -CF3, -OH, -OCF3, -CN, -NO2, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, or C 3-7 It may be substituted with one or more substituents selected from the group consisting of cycloalkyl.

[0020] R 4g and R 4h are each independently hydrogen, C 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms.

[0021] R 5 is hydrogen, halogen, C 1-6 alkyl, , or Here, R 5a , R 5b and R 5c are each independently hydrogen, halogen, C 1-6 Alkyl, C 6-10 Aryl, heteroaryl of 5 to 10 atoms, 1-piperidinomethyl, or C 1-6 Aminomethyl which may be substituted with alkyl, and R 5d are each independently hydrogen or C 1-6 It's alkyl.

[0022] In another aspect of the present invention,

[0023] R 1 are each independently hydrogen, C 1-13 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, and the above R 1 C of 1-13 Alkyl is independently R 11 may be substituted with one or more substituents selected from .

[0024] R 2 are each independently hydrogen, C 1-13 Alkyl, C 3-10 Cycloalkyl, or heterocycloalkyl of 3 to 10 atoms, wherein R 2 C of 1-13 Alkyl, C 3-10 Cycloalkyl, or heterocycloalkyl of 3 to 10 atoms, each independently R 11 may be substituted with one or more substituents selected from .

[0025] R 11 Silver halogen, C 1-13 Alkyl, C 1-6 Alkoxy, -OH, -OCF3, -CN, -NO2, -C(O)R 1a , -C(O)NR 1a R 1b , -NR 1a R1b , -NR 1a C(O)R 1b , -NR 1a S(O)2R 1b , or -S(O)2NR 1a R 1b Here, R 1a , R 1b are each independently hydrogen, C 1-13 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms.

[0026] R 3 are each independently C 1-10 Alkoxy, or C 3-6 Cycloalkoxy, and the above R 3 C of 1-10 Alkoxy, or C 3-6 Cycloalkoxy may each be independently substituted with one or more halogens.

[0027] R 4 is hydrogen, halogen, C 1-13 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, heteroaryl of 5 to 10 atoms, -OH, -OCF3, -CN, -NO2, or -NR 4a R 4b am.

[0028] The above R 4 C of 1-13 Alkyl, C 1-10 Alkoxy, and C 3-6 Cycloalkoxy is independently R 41 may be substituted with one or more substituents selected from R 4 C of 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, and heteroaryl of 5 to 10 atoms are each independently R42 may be substituted with one or more substituents selected from .

[0029] R 41 are halogens, -OH, -OCF3, -CN, -NO2, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8 Aryl, heteroaryl of 5 to 10 atoms, -OR 4c , -C(O)R 4c , -C(O)NR 4c R 4d , -NR 4c R 4d , -NR 4c C(O)R 4d , -NR 4c S(O)2R 4d , or -S(O)2NR 4c R 4d is. The above R 41 C of 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8 Aryl, and heteroaryl of 5 to 10 atoms are each independently halogen, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 7 atoms, C 6-8 Aryl, heteroaryl of 5 to 10 atoms, or -NR 4f R 4g It may be substituted with one or more substituents selected from the group consisting of .

[0030] R 42 are halogens, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8 Aryl, heteroaryl of 5 to 10 atoms, -OR 4c, -C(O)R 4c , -C(O)NR 4c R 4d , -NR 4c R 4d , -NR 4c C(O)R 4d , -NR 4c S(O)2R 4d , or -S(O)2NR 4c R 4d is. The above R 42 C of 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8 Aryl, and heteroaryl of 5 to 10 atoms are each independently halogen, CF3, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-7 Cycloalkyl, or -NR 4g R 4h It may be substituted with one or more substituents selected from the group consisting of .

[0031] R 4a and R 4b are each independently hydrogen, C 1-13 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms. The R 4a and R 4b C of 1-13 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, and heteroaryl of 5 to 10 atoms are each independently halogen, -OH, -OCF3, -CN, -NO2, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C2-6 alkynyl, C 3-7 Cycloalkyl, or -NR 4g R 4h It may be substituted with one or more substituents selected from the group consisting of .

[0032] R 4c , and R 4d are each independently hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms, and R 4g and R 4h are each independently hydrogen, C 1-13 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms.

[0033] R 5 is hydrogen, halogen, C 1-6 alkyl, , or and R 5a , R 5b and R 5c are each independently hydrogen, halogen, C 1-6 Alkyl, C 6-10 Aryl, heteroaryl of 5 to 10 atoms, or 1-piperidinomethyl, C 1-6 Aminomethyl which may be substituted with alkyl, R 5d are each independently hydrogen or C 1-6 It's alkyl.

[0034] In another aspect of the present invention,

[0035] R 1 are each independently hydrogen, or C 1-13 is alkyl, and the above R 1 C of 1-13 Alkyl is independently R 11 may be substituted with one or more substituents selected from .

[0036] R2 are each independently hydrogen, C 1-13 Alkyl, or C 3-10 Cycloalkyl, and the above R 2 C of 1-13 Alkyl, or C 3-10 Cycloalkyl is independently R 11 may be substituted with one or more substituents selected from .

[0037] R 11 Silver halogen, C 1-13 Alkyl, C 1-6 Alkoxy, -OH, -OCF3, -CN, -NO2, -C(O)R 1a , -C(O)NR 1a R 1b , -NR 1a R 1b , -NR 1a C(O)R 1b , -NR 1a S(O)2R 1b , or -S(O)2NR 1a R 1b Here, R 1a , R 1b are each independently hydrogen, C 1-13 It's alkyl.

[0038] R 3 are each independently C 1-10 Alkoxy, or C 3-6 Cycloalkoxy, and the above R 3 C of 1-10 Alkoxy, or C 3-6 Cycloalkoxy may each be independently substituted with one or more halogens.

[0039] R 4 is C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, or -NR 4a R 4b and the above R 4 C of 3-10 Cycloalkyl, and heterocycloalkyl of 3 to 10 atoms are each independently R 42 may be substituted with one or more substituents selected from .

[0040] R 42 are halogens, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, -OR 4c , -C(O)R 4c , -C(O)NR 4c R 4d , -NR 4c R 4d , -NR 4c C(O)R 4d , -NR 4c S(O)2R 4d , or -S(O)2NR 4c R 4d is. The above R 42 C of 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-7 Cycloalkyl, and heterocycloalkyl of 3 to 10 atoms are each independently halogen, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, or -NR 4g R 4h It may be substituted with one or more substituents selected from the group consisting of .

[0041] R 4a and R 4b are each independently hydrogen, C 1-13 Alkyl, C 3-10 Cycloalkyl, or heterocycloalkyl having 3 to 10 atoms. The R 4a and R 4b C of 1-13 Alkyl, C 3-10 Cycloalkyl, and heterocycloalkyl of 3 to 10 atoms are each independently halogen, -OH, -OCF3, -CN, -NO2, C 1-6 Alkoxy, C 3-6Cycloalkoxy, C 3-7 Cycloalkyl, or -NR 4g R 4h It may be substituted with one or more substituents selected from the group consisting of .

[0042] R 4c , and R 4d are each independently hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms, and R 4g and R 4h are each independently hydrogen, C 1-13 Alkyl, C 3-10 Cycloalkyl, or heterocycloalkyl of 3 to 10 atoms.

[0043] R 5 is hydrogen, halogen, C 1-6 alkyl, , or and R 5a , R 5b and R 5c are each independently hydrogen, halogen, 1-piperidinomethyl, or C 1-6 Aminomethyl which may be substituted with alkyl, R 5d are each independently hydrogen or C 1-6 It's alkyl.

[0044] In another aspect of the present invention,

[0045] R 4 Is

[0046] , , , , , , , , , , , , , , , , , , , , , , , , ,or am.

[0047] In another aspect of the present invention,

[0048] R 1 are each independently hydrogen, or C 1-13 is alkyl, and the above R 1 C of 1-13 Alkyl is independently R 11 may be substituted with one or more substituents selected from R 11 Silver halogen, C 1-13 Alkyl, C 1-6 Alkoxy, -OH, -OCF3, -CN, -NO2, -C(O)R 1a , -C(O)NR 1a R 1b , -NR 1a R 1b , -NR 1a C(O)R 1b , -NR 1a S(O)2R 1b , or -S(O)2NR 1a R 1b and R 1a , R 1b are each independently hydrogen, C 1-13 It's alkyl.

[0049] R 2 is C 3-10 Cycloalkyl, or C 3-10 Heterocycloalkyl, and the above R 2 C of 3-10 Cycloalkyl, or C 3-10 Each heterocycloalkyl may be independently substituted with a halogen.

[0050] R 3 are each independently C 1-10 Alkoxy, or C 3-6Cycloalkoxy, and the above R 3 C of 1-10 Alkoxy, or C 3-6 Cycloalkoxy may each be independently substituted with one or more halogens.

[0051] R 4 Is

[0052] , , , , , , , , , , , , , , , , , , , , , , , , ,or am.

[0053] R 5 Is , or and R 5a , R 5b and R 5c are each independently hydrogen, halogen, C 1-6 Alkyl, C 6-10 Aryl, heteroaryl of 5 to 10 atoms, or 1-piperidinomethyl, C 1-6 Aminomethyl which may be substituted with alkyl, R 5d are each independently hydrogen or C 1-6 It's alkyl.

[0054] In another aspect of the present invention,

[0055] The compound represented by the above chemical formula 1 may be any one compound selected from the following group of compounds:

[0056] (1):N-(5-((8-(2,3-dihydrobenzofuran-7-yl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0057] (2):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-(2-isopropoxyphenyl)-8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0058] (3):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0059] (4):N-(2-(4-(dimethylamino)butan-2-yl)-5-((6-isopropyl-8-(3-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0060] (5):N-(2-(4-(dimethylamino)butan-2-yl)-5-((8-(3-ethylphenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0061] (6): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-phenyl-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0062] (7):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0063] (8): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6-(1-methoxypropan-2-yl)-7-oxo-8-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0064] (9):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-isopropyl-7-oxo-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0065] (10): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-isopropyl-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0066] (11): (S)-N-(5-((8-cyclopentyl-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0067] (12): (S)-N-(5-((8-(tert-butyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0068] (13):N-(5-((8-((1s,3s)-adamantan-1-yl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0069] (14): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8-(1-methylpiperidin-4-yl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0070] (15):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-6,8-bis(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0071] (16): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0072] (17):N-(5-((8-cyclohexyl-7-oxo-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0073] (18):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(tetrahydro-2H-thiopyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0074] (19):N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0075] (20): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6-(1-methoxypropan-2-yl)-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0076] (21):N-(5-((8-(4-chlorophenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0077] (22):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-8-(3-(methylsulfonamido)phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0078] (23): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-thiopyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0079] (24): (S)-N-(5-((8-cyclohexyl-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0080] (25): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8-(4-methoxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0081] (26): (R)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0082] (27): (R)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0083] (28): (S)-N-(4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(4-methoxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0084] (29): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0085] (30):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-6-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0086] (31): (S)-N-(5-((8-(4-chlorophenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0087] (32): (S)-N-(5-((8-(4-bromophenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0088] (33): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(4-fluorophenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0089] (34): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(4-hydroxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0090] (35): (S)-N-(5-((8-(3-chloro-4-fluorophenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0091] (36): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(3-fluoro-4-methoxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0092] (37): (S)-N-(5-((8-(4-chloro-3-fluorophenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0093] (38): (S)-N-(5-((8-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0094] (39): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8-(4-methyl-3,4-dihydro-2H-benzo][1,4]oxazin-6-yl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0095] (40): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(4-ethylphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0096] (41):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-8-(4-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0097] (42):N-(5-((8-(4-bromophenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0098] (43): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0099] (44):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0100] (45): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(p-tolyl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0101] (46):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(p-tolyl)-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0102] (47):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((6-((S)-1-methoxypropan-2-yl)-7-oxo-8-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0103] (48):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0104] (49): (R)-N-(5-((8-(2-chloro-3-fluorophenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0105] (50):N-(2-(3-((dimethylamino)methyl)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0106] (51):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((8-(4-methoxyphenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0107] (52):S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)-2-fluoroacrylamide

[0108] (53):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0109] (54): (S)-N-(5-((8-(2-chloro-4-(trifluoromethyl)phenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0110] (55):N-(5-((8-(2-chloro-4-(trifluoromethyl)phenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0111] (56):N-(5-((8-(2-chloro-4-(trifluoromethyl)phenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0112] (57): (R)-N-(5-((8-(2-chloro-4-(trifluoromethyl)phenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0113] (58): (S)-N-(4-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0114] (59): (S)-N-(4-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0115] (60): (S)-N-(4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0116] (61):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((R)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0117] (62):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-((R)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0118] (63): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide

[0119] (64):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-5-((8-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0120] (65): (R)-N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0121] (66):N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide

[0122] (67): (R)-N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)acrylamide

[0123] (68):N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide

[0124] (69): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide

[0125] (70): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-ethoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide

[0126] (71):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-ethoxyphenyl)acrylamide

[0127] (72): (S)-N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0128] (73): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide

[0129] (74): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(methylsulfonyl)piperazin-1-yl)phenyl)acrylamide

[0130] (75): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)phenyl)acrylamide

[0131] (76):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide

[0132] (77): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-methylpiperazin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide

[0133] (78): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide

[0134] (79): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-isopropylpiperazin-1-yl)-4-methoxyphenyl)acrylamide

[0135] (80): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)acrylamide

[0136] (81): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methoxy-[1,4'-bipiperidin]-1'-yl)phenyl)acrylamide

[0137] (82): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-((dimethylamino)methyl)azetidin-1-yl)-4-methoxyphenyl)acrylamide

[0138] (83):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((S)-1,1,1-trifluorobutan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0139] (84): (S)-N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluorobutan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0140] (85): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluorobutan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide

[0141] (86):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((8-(4-methyltetrahydro-2H-pyran-4-yl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0142] (87):N-(3-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-6-((R)-3-(dimethylamino)pyrrolidin-1-yl)-2-fluoro-4-methoxyphenyl)acrylamide

[0143] (88): (S)-N-(3-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-fluoro-4-methoxy-6-(4-methylpiperazin-1-yl)phenyl)acrylamide

[0144] (89): (R)-N-(5-((8-(4,4-difluorocyclohexyl)-6-(2,2-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0145] (90): (R)-N-(5-((8-(4,4-difluorocyclohexyl)-6-(2,2-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0146] (91): (S)-N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0147] (92): (S)-N-(2-([1,4'-bipiperidin]-1'-yl)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0148] (93): (S)-N-(4-methoxy-2-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0149] (94): (S)-N-(2-(4-(dimethylamino)piperidin-1-yl)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0150] (95): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide

[0151] (96): (R)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0152] (97):N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0153] (98):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide

[0154] (99):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(spiro[2.5]octan-6-yl)-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0155] (100): (S)-N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((7-oxo-8-(spiro[2.5]octan-6-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0156] (101): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(3-(pyrrolidin-1-yl)azetidin-1-yl)phenyl)acrylamide

[0157] (102):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0158] (103):N-(5-((8-(4,4-difluorocyclohexyl)-6-((S)-1-fluoropropan-2-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0159] (104): (S)-N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-6-(1-fluoropropan-2-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0160] (105): (R)-N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0161] (106): (R)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide

[0162] (107): (R)-N-(2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(spiro[2.5]octan-6-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0163] (108):N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((7-oxo-8-(spiro[2.5]octan-6-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0164] (109):N-(2-([1,4'-bipiperidin]-1'-yl)-4-methoxy-5-((7-oxo-8-(spiro[2.5]octan-6-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0165] (110):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0166] (111):N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)phenyl)acrylamide

[0167] (112): (S)-N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-6-(1-fluoropropan-2-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)phenyl)acrylamide

[0168] (113):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0169] (114):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide

[0170] (115):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)but-2-ynamide

[0171] (116):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-fluoroacrylamide

[0172] (117):N-(4-methoxy-5-((8-(4-methoxyphenyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)acrylamide

[0173] (118): 2-Fluoro-N-(4-methoxy-5-((8-(4-methoxyphenyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)acrylamide

[0174] (119):N-(4-methoxy-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-5-((7-oxo-6-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0175] (120): 2-Fluoro-N-(4-methoxy-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-5-((7-oxo-6-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0176] (121):N-(5-((8-(3,3-difluorocyclobutyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0177] (122):N-(5-((8-(3,3-difluorocyclobutyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-fluoroacrylamide

[0178] (123):N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0179] (124): 2-Fluoro-N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0180] (125): (E)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(dimethylamino)but-2-enamide

[0181] (126):N-(4-methoxy-5-((8-(4-methoxyphenyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)but-2-ynamide

[0182] (127):N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)but-2-ynamide

[0183] (128):N-(5-((8-(3,3-difluorocyclobutyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)but-2-ynamide

[0184] (129):N-(4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0185] (130):N-(4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)but-2-ynamide

[0186] (131):N-(5-((8-(4-chlorophenyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0187] (132):N-(5-((8-(4-chlorophenyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide

[0188] (133):N-(2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(trifluoromethoxy)phenyl)acrylamide

[0189] (134):N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(pyridin-2-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0190] (135):N-(4-methoxy-5-((8-(1-methyl-1H-pyrazol-4-yl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0191] (136):N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((8-(1-methylpiperidin-4-yl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0192] (137):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isobutyl-7-oxo-8-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0193] (138):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0194] (139):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6-methyl-7-oxo-8-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0195] (140):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isobutyl-8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0196] (141):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-phenyl-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0197] (142):N-(5-((6,8-diisopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0198] (143):N-(5-((8-(2-chloro-3-fluorophenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0199] (144):N-(5-((6-(tert-butyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0200] (145): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6-(1-methoxypropan-2-yl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0201] (146): (S)-N-(5-((8-cyclohexyl-6-(1-methoxypropan-2-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0202] (147):N-(5-((6-(tert-butyl)-8-cyclohexyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0203] (148):N-(4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0204] (149):N-(5-((6-Isopropyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide

[0205] (150):N-(5-((6-Isopropyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide

[0206] (151):N-(4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0207] (152):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide

[0208] (153):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0209] (154):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)acrylamide

[0210] (155):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-((3aR,6aS)-5-methylhexahydropyrrolo3,4-c]pyrrol-2(1H)-yl)phenyl)acrylamide

[0211] (156):N-(2-(3-(dimethylamino)azetidin-1-yl)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0212] (157):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(2,2,2-trifluoroethoxy)phenyl)acrylamide

[0213] (158):N-(4-(2,2-difluoroethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0214] (159):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(1-methylpyrrolidin-3-yl)amino)phenyl)acrylamide

[0215] (160):N-(2-(4-(dimethylamino)piperidin-1-yl)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0216] (161):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)acrylamide

[0217] (162):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide

[0218] (163):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-((3aR,6aR)-1-methylhexahydropyrrolo3,4-b]pyrrole-5(1H)-yl)phenyl)acrylamide

[0219] (164):N-(5-((8-(4-bromophenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0220] (165): (R)-N-(5-((8-(4-bromophenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0221] (166): (R)-N-(2-(3-(dimethylamino)pyrrolidin-1-yl)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0222] (167):N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0223] (168):N-(5-((8-(4,4-difluorocyclohexyl)-6-ethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0224] (169):N-(4-(difluoromethoxy)-5-((6-isopropyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0225] (170):N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0226] (171):N-(5-((8-(4,4-difluorocyclohexyl)-6-ethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0227] (172):N-(5-((8-(4,4-difluorocyclohexyl)-6-ethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide

[0228] (173):N-(4-(difluoromethoxy)-5-((6-ethyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0229] (174):N-(5-((6-ethyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide

[0230] (175): (S)-N-(5-((8-(2-chloro-3-methoxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0231] (176): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8-(3-methoxy-4-(trifluoromethyl)phenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0232] (177):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((8-(3-methoxy-4-(trifluoromethyl)phenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide

[0233] (178):N-(5-((8-(2-chloro-3-fluorophenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0234] (179):N-(5-((8-(4-chloro-3-fluorophenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0235] (180):N-(5-((8-(2-chloro-3-(trifluoromethyl)phenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0236] (181):N-(5-((8-(3-chloro-4-(trifluoromethyl)phenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0237] (182):N-(5-((8-(3-Bromo-4-(trifluoromethyl)phenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

[0238] (183):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(2-((dimethylamino)methyl)-1H-pyrrol-1-yl)-4-methoxyphenyl)acrylamide

[0239] In another aspect of the present invention,

[0240] A pharmaceutical composition containing the above pyrimidine derivative compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient is provided.

[0241] In another aspect of the present invention,

[0242] A composition for preventing, alleviating or treating cancer is provided, comprising the above compound as an active ingredient.

[0243] In another aspect of the present invention,

[0244] The above pharmaceutical composition provides a composition for preventing, alleviating or treating cancer characterized by being caused by an EGFR mutation.

[0245] In another aspect of the present invention,

[0246] The above pharmaceutical composition provides a composition for preventing, alleviating or treating cancer, characterized in that it is administered to a patient having an EGFR mutation including an EGFR-related mutation, such as Exon 19 deletion, L858R, or Exon 20 insertion.

[0247] In this specification “ 1-13” or “C13” means that it has 1 to 13 carbon atoms. For example, C 1-13 Alkyl refers to alkyl having 1 to 13 carbon atoms.

[0248] When used herein as “heterocyclyl having 3 to 10 atoms”, it means a heterocyclyl having 3 to 10 atoms with at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.

[0249] The term "alkyl" as used herein means a saturated straight-chain or branched non-cyclic hydrocarbon. Representative saturated straight-chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl, while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-Dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-deethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and 3,3-diethylhexyl. The alkyl group may be optionally substituted.

[0250] The term “alkenyl” as used herein refers to a straight-chain or branched non-cyclic hydrocarbon having a double bond. Representative straight-chain alkenyls include 1-butene, 2-pentene, etc., while branched alkenyls include, but are not limited to, 3-methyl-1-butene, 3-methyl-1-pentene, etc. The alkenyl group may be optionally substituted.

[0251] The term “alkynyl” as used herein refers to a straight-chain or branched non-cyclic hydrocarbon group having a triple bond. Representative straight-chain alkynyl groups include ethyne, 1-propyne, 2-butyne, etc., and branched alkynyl groups include, but are not limited to, 3-methyl-1-butyne, 3-methyl-1-pentyne, etc. The alkynyl group may be optionally substituted.

[0252] As used herein, the terms “halogen” and “halo” mean fluorine, chlorine, bromine or iodine.

[0253] The term "aryl" as used herein refers to a carbon ring aromatic group containing ring atoms.

[0254] Examples of targets include, but are not limited to, phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fIuorenyl, indenyl, azulenyl, etc. Aryl groups can be optionally substituted.

[0255] As used herein, "heteroaryl" is an aromatic heterocycle ring having at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and containing at least one carbon atom, including monocyclic and bicyclic ring systems. Representative heteroaryls include, but are not limited to, triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, azepinyl, and oxazolyl. Heteroaryl groups can be optionally substituted.

[0256] The term "cycloalkyl" as used herein means a monocyclic, spirocyclic or polycyclic ring, excluding aromatic rings, having carbon and hydrogen atoms. C 3-7 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may be optionally substituted.

[0257] The term "heterocycloalkyl" as used herein means a monocyclic, spirocyclic, or polycyclic ring, excluding aromatic rings, having at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur. The heterocycloalkyl group may be optionally substituted.

[0258] In the present invention, the pyridine derivative compound represented by the above chemical formula 1 can be used in the form of a salt derived from an inorganic acid or an organic acid, and for example, can be used in the form of a salt derived from one or more acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mannmetic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.

[0259] Excipients that can be used in the pharmaceutical composition of the present invention include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, etc. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, gum tragacanth, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc.

[0260] The present invention provides a novel compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, which exhibits an excellent inhibitory effect against EGFR mutations. The pyrimidine derivative, stereoisomer thereof, hydrate thereof, or pharmaceutically acceptable salt thereof according to the present invention can effectively inhibit the growth of cancer cells expressing EGFR mutations, particularly lung cancer cells.

[0261] Figure 1 is a graph showing the tumor size measured by transplanting Ba / F3 EGFR exon 20 insertion ASV cells into BALB / c nude mice (6-8 weeks old, female) and administering drugs orally.

[0262] The compound represented by the chemical formula 1 of the present invention can be prepared by the following reaction schemes 1 to 3 or the method described in the examples. However, the preparation method of the chemical formula 1 of the present invention is not limited to these reaction schemes. In the following reaction schemes 1 to 3, R 1 , R 2 , R 3 , R 4a , R 4b , R 5a , R 5b , and R 5c may be identical to those described in this specification.

[0263] [Reaction Formula 1]

[0264]

[0265] (Step 1) A compound of chemical formula (1-2) can be prepared by adding a base such as potassium hydroxide or sodium hydroxide to a compound of chemical formula (1-1) and paraformaldehyde in a solvent such as water, acetonitrile, 1,4-dioxane, dimethylformamide, or methanol.

[0266] (Step 2) Chemical formula (1-3) can be prepared by adding a base such as N,N-diisopropylethylamine or triethylamine to the compound of chemical formula (1-2) and phosphoryl trichloride in a solvent such as toluene, acetonitrile, tetrahydrofuran, dimethylformamide or dichloromethane.

[0267] (Step 3) Chemical formula (1-4) can be prepared by reacting the compound of chemical formula (1-3) with sodium iodide in a solvent such as acetone, acetonitrile, tetrahydrofuran, dimethylformamide, or dichloromethane.

[0268] (Step 4) Chemical formula (1-6) can be prepared by adding a base such as potassium carbonate, sodium carbonate, or cesium carbonate to the compound of chemical formula (1-4) and the compound of chemical formula (1-5) in a solvent such as acetonitrile, 1,4-dioxane, or dimethylformamide.

[0269] (Step 5) Chemical formula (1-8) can be prepared by adding a base such as triethylamine or N,N-diisopropylethylamine to the compound of chemical formula (1-6) and the compound of chemical formula (1-7) in a solvent such as acetonitrile, 1,4-dioxane, or dimethylformamide.

[0270] (Step 6) Chemical formula (1-9) can be prepared by adding a base such as triethylamine or N,N-diisopropylethylamine to the compound of chemical formula (1-8) and triphosgene in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or dichloromethane.

[0271] (Step 7) Chemical formula (1-11) can be prepared by adding an acid such as p-toluenesulfonic acid to the compound of chemical formula (1-9) and the compound of chemical formula (1-10) in a solvent such as 1,4-dioxane, acetonitrile, or dimethylformamide.

[0272] (Step 8) Chemical formula (1-13) can be prepared by adding a base such as potassium carbonate, sodium carbonate, or cesium carbonate to the compound of chemical formula (1-11) and the compound of chemical formula (1-12) in a solvent such as acetonitrile, 1,4-dioxane, or dimethylformamide.

[0273] (Step 9) Chemical formula (1-14) can be prepared by reacting the compound of chemical formula (1-13), iron, and ammonium chloride in a solvent such as ethanol, dimethylformamide, water, or a mixed solvent. Here, a reducing agent that reduces a nitro group can be used without limitation.

[0274] (Step 10) Chemical formula (1-17) can be prepared by adding an organic base such as N,N-diisopropylethylamine or triethylamine or an inorganic base such as potassium carbonate, sodium carbonate or cesium carbonate to a compound of chemical formula (1-14) and a compound of chemical formula (1-15) or (1-16) in a solvent such as acetonitrile, tetrahydrofuran or dichloromethane.

[0275] [Reaction Formula 2]

[0276]

[0277] Steps 8 to 10 of Reaction Scheme 2 can be carried out in a similar manner to Steps 8 to 10 of Reaction Scheme 1.

[0278]

[0279] [Reaction Formula 3]

[0280]

[0281] Steps 1, 2, and 5 to 10 of Reaction Scheme 3 can be carried out in a similar manner to Steps 1, 2, and 5 to 10 of Reaction Scheme 2.

[0282]

[0283] <Example>

[0284] Example 110: N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0285]

[0286] Step 1: 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione

[0287]

[0288] Pyrimidine-2,4(1H,3H)-dione (10.000 g, 89.214 mmol), paraformaldehyde (3.212 g, 107.057 mmol), and potassium hydroxide (KOH, 3.754 g, 66.911 mmol) were added to water (100 mL) at 0 °C and stirred for 30 min. The mixture was further stirred at 90 °C for 16 h, and after the temperature was lowered to 0 °C, concentrated hydrochloric acid was slowly added to the reaction mixture and stirred for 30 min to terminate the reaction. The precipitated solid was filtered, washed with hexane, and dried to obtain 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (5.770 g, 45.5%) as a white solid.

[0289] LC-MSm / zcalculated for C5H6N2O3(MH) - 141.0, found 140.9.

[0290]

[0291] Step 2: 2,4-Dichloro-5-(chloromethyl)pyrimidine

[0292]

[0293] 5-(Hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (5.770 g, 40.602 mmol), phosphoryl trichloride (18.923 mL, 203.012 mmol), and N,N-diisopropylethylamine (21.216 mL, 121.807 mmol) were dissolved in toluene (15 mL), stirred at 125 °C for 16 h, and then lowered to 0 °C. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and stirred for 30 min to terminate the reaction. Water was added to the reaction mixture, and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 50 g cartridge; ethyl acetate / hexane = from 0% to 20%) and concentrated to obtain 2,4-dichloro-5-(chloromethyl)pyrimidine (1.440 g, 18.0%) as a clear oil.

[0294] LC-MSm / zcalculated for C5H3Cl3N2(M+H) + 196.9, found 196.8.

[0295]

[0296] Step 3: 2,4-Dichloro-5-(iodomethyl)pyrimidine

[0297]

[0298] 2,4-Dichloro-5-(chloromethyl)pyrimidine (1.440 g, 7.293 mmol) and sodium iodide (1.640 g, 10.940 mmol) were added to acetone (10 mL) and stirred at 70 °C for 2 h. After cooling to room temperature, water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 25 g cartridge; ethyl acetate / hexane = from 5% to 40%) and concentrated to give 2,4-dichloro-5-(iodomethyl)pyrimidine (1.900 g, 90.2%) as a brown solid.

[0299] LC-MSm / zcalculated for C5H3Cl2IN2(M+H) + 288.9, found 288.8.

[0300]

[0301] Step 4: N-((2,4-dichloropyrimidin-5-yl)methyl)-2,2,2-trifluoroethane-1-amine

[0302]

[0303] 2,4-Dichloro-5-(iodomethyl)pyrimidine (0.250 g, 0.865 mmol), 2,2,2-trifluoroethan-1-amine (0.082 mL, 1.038 mmol), and potassium carbonate (K2CO3, 0.179 g, 1.298 mmol) were added to acetonitrile (3 mL) and stirred at 50 °C for 16 h. After cooling to room temperature, water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; ethyl acetate / hexane = from 0% to 10%) and concentrated to afford N-((2,4-dichloropyrimidin-5-yl)methyl)-2,2,2-trifluoroethan-1-amine (0.158 g, 70.3%) as a yellow oil.

[0304] LC-MSm / zcalculated for C7H6Cl2F3N3(M+H) + 260.0, found 259.9.

[0305]

[0306] Step 5: 2-Chloro-N-(4,4-difluorocyclohexyl)-5-(((2,2,2-trifluoroethyl)amino)methyl)pyrimidin-4-amine

[0307]

[0308] N-((2,4-Dichloropyrimidin-5-yl)methyl)-2,2,2-trifluoroethan-1-amine (0.158 g, 0.608 mmol), 4,4-difluorocyclohexan-1-amine hydrochloride (0.125 g, 0.730 mmol), and triethylamine (0.254 mL, 1.824 mmol) were added to acetonitrile (3 mL) and stirred at 90 °C for 1 h. After the temperature was lowered to room temperature, water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; ethyl acetate / hexane = from 6% to 50%) and concentrated to afford 2-chloro-N-(4,4-difluorocyclohexyl)-5-(((2,2,2-trifluoroethyl)amino)methyl)pyrimidin-4-amine (0.201 g, 92.2%) as a yellow oil.

[0309] LC-MSm / zcalculated for C 13 H 16 ClF5N4(M+H) + 359.1, found 359.1.

[0310]

[0311] Step 6: 7-Chloro-1-(4,4-difluorocyclohexyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0312]

[0313] 2-Chloro-N-(4,4-difluorocyclohexyl)-5-(((2,2,2-trifluoroethyl)amino)methyl)pyrimidin-4-amine (0.201 g, 0.561 mmol), triphosgene (0.250 g, 0.841 mmol), and triethylamine (0.235 mL, 1.683 mmol) were added to tetrahydrofuran (3 mL) and stirred at 70 °C for 1 h. After the temperature was lowered to room temperature, a saturated aqueous sodium bicarbonate solution was poured onto the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; ethyl acetate / hexane = from 6% to 50%) and concentrated to afford 7-chloro-1-(4,4-difluorocyclohexyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.179 g, 83.0%) as a yellow oil.

[0314] LC-MSm / zcalculated for C 14 H 14 ClF5N4O (M+H) + 385.1, found 385.0.

[0315]

[0316] Step 7: 1-(4,4-Difluorocyclohexyl)-7-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0317]

[0318] 7-Chloro-1-(4,4-difluorocyclohexyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.093 g, 0.242 mmol), 4-fluoro-2-methoxy-5-nitroaniline (0.054 g, 0.291 mmol), and p-toluenesulfonic acid monohydrate (0.069 g, 0.363 mmol) were dissolved in 1,4-dioxane (1 mL) and stirred at 120 °C for 16 h. After cooling to room temperature, saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; methanol / dichloromethane = from 1% to 10%) and concentrated to afford 1-(4,4-difluorocyclohexyl)-7-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.123 g, 94.7%) as a yellow oil.

[0319] LC-MSm / zcalculated for C 21 H 20 F6N6O4(M+H) + 533.1, found 533.1.

[0320]

[0321] Step 8: 1-(4,4-difluorocyclohexyl)-7-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0322]

[0323] 1-(4,4-Difluorocyclohexyl)-7-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.123 g, 0.229 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (0.050 g, 0.275 mmol), and potassium carbonate (K2CO3, 0.048 g, 0.344 mmol) were added to acetonitrile (3 mL) and stirred at 80 °C for 4 h. After the temperature was lowered to room temperature, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; methanol / dichloromethane = from 2% to 20%) and concentrated to afford 1-(4,4-difluorocyclohexyl)-7-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.141 g, 88.3%) as a yellow solid.

[0324] LC-MSm / zcalculated for C 31 H 40 F5N9O4(M+H) + 698.4, found 698.3.

[0325]

[0326] Step 9: (7-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-1-(4,4-difluorocyclohexyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0327]

[0328] 1-(4,4-Difluorocyclohexyl)-7-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.141 g, 0.203 mmol), iron (0.068 g, 1.215 mmol), and ammonium chloride (NH4Cl, 0.032 g, 0.608 mmol) were added to ethanol (4 mL) / water (1 mL), and stirred at 90 °C for 2 h. After the temperature was lowered to room temperature, the reaction mixture was filtered through a pad of Celite to remove solids. Water was added to the filtrate, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting product was used without further purification (7-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-1-(4,4-difluorocyclohexyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one, 0.184 g, 136.1%, brown oil).

[0329] LC-MSm / zcalculated for C 31 H 42 F5N9O2(M+H) + 668.3, found 668.3.

[0330]

[0331] Step 10: N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0332] Step 10 can be manufactured in two ways:

[0333]

[0334] Method 1: A solution of 7-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-1-(4,4-difluorocyclohexyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.184 g, 0.276 mmol), acrylyl chloride (0.022 mL, 0.276 mmol), and N,N-diisopropylethylamine (0.058 mL, 0.331 mmol) in dichloromethane (3 mL) was stirred at 0 °C for 10 min and then at room temperature for an additional 2 h. Water was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; methanol / dichloromethane = from 0% to 10%) and concentrated to afford N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (0.113 g, 56.7%) as a yellow solid.

[0335] 1H-NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1 H), 8.48 (s, 1 H), 8.14 (s, 1 H), 8.08 (s, 1 H), 6.84 (s, 1 H), 6.67 (q,J= 9.1 Hz, 1 H), 6.19 (d,J= 16.8 Hz, 1 H), 5.71 (d,J= 11.6 Hz, 1 H), 4.65 (t,J= 12.4 Hz, 1 H), 4.38 (s, 3 H), 4.21 (q,J= 9.6 Hz, 2 H), 2.99 (d,J= 13.2 Hz, 2 H), 2.66 (t,J= 11.6 Hz, 2 H), 2.20 (s, 3 H), 1.96 (s, 2 H), 1.84 - 1.64 (m, 10 H).

[0336] LC-MSm / zcalculated for C 34 H 44 F5N9O3(M+H) + 722.3, found 722.3.

[0337]

[0338] Method 2: A solution of 7-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-1-(4,4-difluorocyclohexyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (12.417 g, 18.595 mmol), 3-chloropropanoyl chloride (1.775 mL, 18.595 mmol), and potassium carbonate (K2CO3, 15.420 g, 111.571 mmol) in acetonitrile (100 mL) was stirred at 0 °C for 30 min and then at 100 °C for an additional 16 h. After lowering the temperature to room temperature, water was added to the reaction mixture, and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 50 g cartridge; methanol / dichloromethane = from 2% to 20%) and concentrated to give N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (10.604 g, 79.0%) as a pale brown solid.

[0339]

[0340] Compounds of Examples 1 to 136 were prepared in a similar manner to Example 110 above, and the compound name, chemical structural formula, of each example compound are as follows: 1 The results of H-NMR and LC-MS analysis are summarized in Table 1 below.

[0341] Example Compound Compound Name Structure 1H-NMRLC-MS1N-(5-((8-(2,3-dihydrobenzofuran-7-yl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (400 MHz, DMSO-d6)δ 9.95 (bs, 1 H), 8.27 (bs, 1 H), 8.14 (s, 1 H), 7.14 (d,J= 4.0 Hz, 1 H), 6.96 (d,J= 8.0 Hz, 1 H), 6.86 (s, 1 H), 6.76 (t,J= 6.0 Hz, 1 H), 6.43 (bs, 1 H), 6.24 (d,J= 16.0 Hz, 1 H), 5.77 (bs, 1 H), 4.55 - 4.30 (m, 5 H), 3.74 (s, 3 H), 3.17 (bs, 2 H), 2.86 (bs, 2 H), 2.64 (s, 3 H), 2.26 (bs, 6 H), 1.18 (d,J= 4.0 Hz, 6 H)m / zcalculated C 32 H 40 N8O4for(M+H) + 601.3,found601.42N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-(2-isopropoxyphenyl)-8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4)δ 8.63 (s, 1H), 8.04 (s, 1H), 6.97 (s, 1H), 6.54 (dd,J= 17.0, 10.2 Hz, 1H), 6.37 (d,J= 16.9 Hz, 1H), 5.80 (d,J= 10.4 Hz, 1H), 4.63 (q,J= 6.9 Hz, 1H), 4.55 (t,J= 12.1 Hz, 1H), 4.17 (s, 2H), 3.93 (s, 3H), 3.11 (s, 2H), 2.70 (s, 3H), 2.64 - 2.51 (m, 2H), 2.44 - 2.33 (m, 8H), 1.70 (t,J= 18.2 Hz, 4H), 1.39 - 1.29 (m, 4H), 1.22 (d,J= 6.8 Hz, 6H)m / zcalculated for C 30 H 44 N8O3(M+H) + 565.4,found565.43N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4)δ 8.75 (s, 1H), 8.07 (s, 1H), 6.98 (s, 1H), 6.56 (dd,J= 16.9, 10.2 Hz, 1H), 6.36 (dd,J= 17.0, 1.7 Hz, 1H), 5.81 (dd,J= 10.3, 1.6 Hz, 1H), 4.85 (dt,J= 8.0, 4.0 Hz, 1H), 4.63 (p,J= 6.8 Hz, 1H), 4.19 (s, 2H), 3.94 - 3.91 (m, 5H), 3.45 (d,J= 12.2 Hz, 2H), 3.08 (s, 2H), 2.76 (dd,J= 12.6, 4.5 Hz, 2H), 2.70 (s, 3H), 2.49 (s, 2H), 2.34 (s, 6H), 1.64 - 1.59 (m, 2H), 1.23 (d,J= 6.8 Hz, 6H)m / zcalculated for C 29 H 42 N8O4(M+H) + 567.3,found567.44N-(2-(4-(dimethylamino)butan-2-yl)-5-((6-isopropyl-8-(3-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, DMSO-d6)δ 9.97 (bs, 1 H), 8.30 (s, 1 H), 8.15 (s, 1 H), 7.66 (s, 1 H), 7.24 (t,J= 6.0 Hz, 1 H), 6.86 - 6.85 (m, 2 H), 6.81 - 6.77 (m, 2 H), 6.42 (bs, 1 H), 6.24 (d,J= 16.0 Hz, 1 H), 5.76 (d,J= 8.0 Hz, 1 H), 4.56 - 4.50 (m, 1 H), 4.34 (s, 2 H), 3.73 (s, 3 H), 3.71 (s, 3 H), 2.86 (bs, 2 H), 2.64 (s, 3 H), 2.26 (bs, 6 H), 1.19 (d,J= 4.0 Hz, 6 H)m / zcalculated C 32 H41 N8O4for(M+H) + 588.3,found588.35N-(2-(4-(dimethylamino)butan-2-yl)-5-((8-(3-ethylphenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, DMSO-d6)δ 10.00 (bs, 1 H), 8.37 (bs, 1 H), 8.15 (s, 1 H), 7.64 (s, 1 H), 7.25 (t,J= 6.0 Hz, 1 H), 7.13 (d,J= 4.0 Hz, 1 H), 7.04 (d,J= 4.0 Hz, 2 H), 6.57 (s, 1 H), 6.43 - 6.37 (m, 1 H), 6.24 (d,J= 12.0 Hz, 1 H), 5.76 (d,J= 8.0 Hz, 1 H), 4.55 - 4.50 (m, 1 H), 4.34 (s, 2 H), 3.73 (s, 3 H), 2.82 (bs, 2 H), 2.64 (s, 3 H), 2.59 (q,J= 6.7 Hz, 2 H), 2.22 (bs, 6 H), 1.19 - 1.14 (m, 9 H)m / zcalculated C 33 H 43 N8O3for(M+H) + 587.3,found587.46(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-phenyl-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (500 MHz, Methanol-d4) δ 8.10 (s, 1H), 7.46 - 7.33 (m, 3H), 7.29 (t,J= 7.4 Hz, 1H), 7.20 (d,J= 7.7 Hz, 2H), 6.74 (s, 1H), 6.53 (dd,J= 17.0, 10.1 Hz, 1H), 6.42 (d,J= 16.9 Hz, 1H), 5.87 (d,J= 10.1 Hz, 1H), 5.18 (dt,J= 15.3, 7.7 Hz, 1H), 4.55 (d,J= 14.0 Hz, 1H), 4.38 (d,J=14.0 Hz, 1H), 3.82 (s, 3H), 3.30 (t,J= 5.3 Hz, 2H), 3.07 (t,J= 5.2 Hz, 2H), 2.70 (s, 6H), 2.52 (s, 3H), 1.44 (d,J= 7.2 Hz, 3H)m / zcalculated for C 30 H 35 F3N8O3(M+H) + 613.3,found613.37N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4)δ 8.46 (s, 1H), 8.18 (s, 1H), 7.71 (d,J= 8.2 Hz, 2H), 7.49 (d,J= 8.1 Hz, 2H), 6.85 (s, 1H), 6.57 (dd,J= 17.0, 10.2 Hz, 1H), 6.40 (dd,J= 17.0, 1.7 Hz, 1H), 5.84 (dd,J= 10.2, 1.8 Hz, 1H), 4.67 (h,J= 6.8 Hz, 1H), 4.47 (s, 2H), 3.82 (s, 3H), 3.01 (s, 2H), 2.62 (s, 3H), 2.44 (s, 2H), 2.31 (s, 6H), 1.31 (t,J= 5.6 Hz, 6H)m / zcalculated for C 31 H37 F3N8O3(M+H) + 627.3,found627.38(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6-(1-methoxypropan-2-yl)-7-oxo-8-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (500 MHz, Methanol-d4) δ 8.14 (s, 2H), 7.42 (t,J= 7.5 Hz, 2H), 7.35 (t,J= 7.3 Hz, 1H), 7.26 (d,J= 7.7 Hz, 2H), 6.84 (s, 1H), 6.58 (dd,J= 17.0, 10.2 Hz, 1H), 6.41 (d,J= 16.9 Hz, 1H), 5.87 (d,J= 10.3 Hz, 1H), 4.76 - 4.67 (m, 1H), 4.48 (q,J= 14.2 Hz, 2H), 3.85 (s, 3H), 3.70 - 3.63 (m, 1H), 3.48 (dd,J= 10.4, 4.8 Hz, 1H), 3.39 (s, 3H), 3.02 (s, 2H), 2.63 (s, 3H), 2.45 (s, 2H), 2.34 (s, 6H), 1.27 (d,J= 7.0 Hz, 3H)m / zcalculated for C 31 H 40 N8O4(M+H) + 589.3,found589.39N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-isopropyl-7-oxo-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, DMSO-d6)δ 10.10 (s, 1 H), 8.77 (s, 1 H), 8.07 (s, 1 H), 7.93 (s, 1 H), 6.97 (s, 1 H), 6.38 (q,J= 8.0 Hz, 1 H), 6.22 (d,J= 16.0 Hz, 1 H), 5.75 (t,J= 10.0 Hz, 1 H), 5.05 - 4.99 (m, 1 H), 4.38 - 4.33 (m, 1 H), 4.17 (s, 2 H), 3.93 (d,J= 8.0 Hz, 2 H), 3.83 (s, 3 H), 3.38 (t,J=8.0 Hz, 2 H), 2.87 (bs, 2 H), 2.69 (s, 3 H), 2.19 (bs, 6 H), 1.84 - 1.76 (m, 2 H), 1.51 (d,J= 12.0 Hz, 2 H), 1.34 (d,J= 8.0 Hz, 6 H)m / z calculated C 29 H 42 N8O4for(M+H) + 567.3,found567.310(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-isopropyl-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, DMSO-d6)δ 10.09 (bs, 1 H), 8.74 (s, 1 H), 8.14 (s, 1 H), 8.05 (s, 1 H), 6.98 (s, 1 H), 6.40 (q,J= 6.7 Hz, 1 H), 6.23 (d,J= 12.0 Hz, 1 H), 5.74 (d,J= 8.0 Hz, 1 H), 5.20 - 5.17 (m, 1 H), 5.04 - 5.00 (m, 1 H), 4.38 (d,J= 4.0 Hz, 1 H), 4.14 (d,J= 8.0 Hz, 1 H), 3.83 (s, 3 H), 2.88 (bs, 2 H), 2.69 (s, 3 H), 2.31 (bs, 2 H), 1.41 (d,J= 4.0 Hz, 3 H), 1.35 (d,J= 4.0 Hz, 6 H)m / zcalculated C 27 H 37 F3N8O3for(M+H) + 579.3,found579.311(S)-N-(5-((8-cyclopentyl-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4)δ 8.91 (s, 1H), 8.10 (s, 1H), 6.96 (s, 1H), 6.54 (dd,J= 17.0, 10.1 Hz, 1H), 6.37 (d,J= 16.9 Hz, 1H), 5.80 (d,J= 10.4 Hz, 1H), 5.29 (q,J= 8.9 Hz, 1H), 5.25 - 5.18 (m, 1H), 4.39 (d,J= 13.9 Hz, 1H), 4.24 (d,J= 14.0 Hz, 1H), 3.93 (s, 3H), 3.07 (t,J=6.1 Hz, 2H), 2.70 (s, 3H), 2.48 (s, 2H), 2.33 (s, 6H), 2.13 - 2.03 (m, 3H), 1.97 - 1.89 (m, 2H), 1.83 (s, 3H), 1.48 (d,J= 7.2 Hz, 3H)m / zcalculated for C 29 H 39 F3N8O3(M+H) + 605.3,found605.312(S)-N-(5-((8-(tert-butyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4)δ 8.69 (s, 1H), 8.11 (s, 1H), 6.95 (s, 1H), 6.52 (dd,J= 17.0, 10.2 Hz, 1H), 6.35 (d,J= 16.6 Hz, 1H), 5.80 (d,J= 10.1 Hz, 1H), 5.08 (q,J= 7.7 Hz, 1H), 4.22 (d,J= 14.3 Hz, 1H), 4.09 (d,J= 14.2 Hz, 1H), 3.91 (s, 3H), 3.08 (s, 2H), 2.70 (s, 3H), 2.47 (s, 2H), 2.32 (s, 6H), 1.64 (s, 9H), 1.45 (d,J= 7.2 Hz, 3H)m / zcalculated for C 28 H39 F3N8O3(M+H) + 593.3,found593.313N-(5-((8-((1s,3s)-adamantan-1-yl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4)δ 8.68 (s, 1H), 8.06 (s, 1H), 6.96 (s, 1H), 6.53 (dd,J= 17.0, 10.2 Hz, 1H), 6.34 (d,J= 16.8 Hz, 1H), 5.78 (d,J= 10.3 Hz, 1H), 4.51 (p,J= 6.8 Hz, 1H), 4.00 (s, 2H), 3.90 (s, 3H), 3.06 (t,J= 6.0 Hz, 2H), 2.68 (s, 3H), 2.46 (d,J= 2.8 Hz, 8H), 2.32 (d,J= 4.4 Hz, 6H), 2.06 - 1.99 (m, 3H), 1.64 (q,J= 12.3 Hz, 6H), 1.18 (d,J= 6.8 Hz, 6H)m / zcalculated for C 34 H 48 N8O3(M+H) + 617.4,found617.414(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8-(1-methylpiperidin-4-yl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (500 MHz, Methanol-d4)δ8.48(s,1H),8.03(s,1H),6.87(s,1H),6.47(dd,J= 16.8, 10.3 Hz, 1H), 6.36 - 6.24 (m, 1H), 5.76 (d,J= 10.3 Hz, 1H), 5.28 - 5.22 (m, 1H), 5.17 - 5.08 (m, 1H), 4.28 (d,J= 13.9 Hz, 1H), 4.13 (d,J= 13.9 Hz, 1H), 3.85 (s, 3H), 3.47 - 3.33 (m, 2H), 3.11 (s, 6H), 2.94 - 2.69 (m, 4H), 2.59 (s, 3H), 2.47 (s, 3H), 2.17 - 2.02 (m, 2H), 1.97 - 1.89 (m, 4H), 1.37 (d,J= 7.2 Hz, 6H)m / zcalculated for C 30 H 42 F3N9O3(M+H) + 634.3,found634.315N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-6,8-bis(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (500 MHz, Methanol-d4) δ 8.32 (s, 1H), 7.97 (s, 1H), 6.85 (s, 1H), 6.42 (dd,J= 16.9, 10.1 Hz, 1H), 6.30 (d,J= 16.9 Hz, 1H), 5.73 (d,J= 10.2 Hz, 1H), 4.77 - 4.71 (m, 1H), 4.36 (ddd,J= 12.1, 8.3, 3.9 Hz, 1H), 4.13 (s, 2H), 3.93 (dd,J= 11.4, 4.2 Hz, 2H), 3.90 - 3.80 (m, 5H), 3.46 - 3.33 (m, 4H), 3.19 - 3.13 (m, 2H), 2.85 - 2.65 (m, 4H), 2.59 (s, 3H), 2.50 (s, 6H), 1.83 (qd,J= 12.3, 4.5 Hz, 2H), 1.51 (d,J= 12.2 Hz, 4H)m / zcalculated for C 31 H 44 N8O5(M+H) + 609.3,found609.316(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.72 (s, 1H), 8.11 - 8.04 (m, 1H), 6.94 (s, 1H), 6.52 (dd,J= 17.0, 10.2 Hz, 1H), 6.32 (dd,J= 17.0, 1.7 Hz, 1H), 5.77 (dd,J= 10.2, 1.7 Hz, 1H), 5.24 - 5.16 (m, 1H), 4.34 (d,J= 14.0 Hz, 1H), 4.19 (d,J= 13.9 Hz, 1H), 3.90 - 3.84 (m, 5H), 3.45 - 3.36 (m, 2H), 3.02 (d,J= 6.1 Hz, 2H), 2.70 (d,J= 4.6 Hz, 2H), 2.66 (s, 3H), 2.44 (s, 2H), 2.29 (s, 6H), 1.62 - 1.54 (m, 2H)m / zcalculated for C 29 H 39 F3N8O4(M+H) + 621.3,found621.317N-(5-((8-cyclohexyl-7-oxo-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4) δ 8.24 (s, 1H), 8.09 (s, 1H), 6.98 (s, 1H), 6.53 (dd,J= 17.0, 9.6 Hz, 1H), 6.46 (d,J= 16.3 Hz, 1H), 5.88 (d,J= 9.9 Hz, 1H), 4.66 - 4.57 (m, 1H), 4.51 - 4.41 (m, 1H), 4.24 (s, 2H), 4.05 (dd,J= 11.5, 4.2 Hz, 2H), 4.01 (s, 3H), 3.53 (t,J= 11.6 Hz, 2H), 3.46 (s, 2H), 3.22 (s, 2H), 2.83 (s, 6H), 2.72 (s, 3H), 2.49 - 2.38 (m, 2H), 2.00 - 1.89 (m, 2H), 1.84 - 1.34 (m, 12H)m / zcalculated for C 32 H 46 N8O4(M+H) + 607.4,found607.418N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(tetrahydro-2H-thiopyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4)δ 8.58 (s, 1H), 7.95 (s, 1H), 6.86 (s, 1H), 6.44 (dd,J= 17.0, 10.2 Hz, 1H), 6.27 (dd,J= 17.1, 1.6 Hz, 1H), 5.68 (dd,J= 10.2, 1.6 Hz, 1H), 4.51 (q,J= 6.9 Hz, 1H), 4.45 (dd,J= 13.0, 9.9 Hz, 1H), 4.06 (s, 2H), 3.81 (s, 3H), 2.99 (s, 2H), 2.70 - 2.61 (m, 4H), 2.59 (s, 3H), 2.43 (d,J= 12.2 Hz, 2H), 2.28 (s, 6H), 1.97 - 1.82 (m, 4H), 1.10 (d,J= 6.9 Hz, 6H)m / zcalculated for C 29 H 42 N8O3S(M+H) + 583.3,found583.319N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4)δ 8.84 (s, 1H), 8.08 (s, 1H), 6.99 (s, 1H), 6.54 (dd,J= 17.0, 10.2 Hz, 1H), 6.34 (dd,J= 17.0, 1.6 Hz, 1H), 5.80 (dd,J= 10.3, 1.6 Hz, 1H), 4.76 (t,J= 12.0 Hz, 1H), 4.60 (h,J= 6.8 Hz, 1H), 4.22 - 4.17 (m, 2H), 3.93 (s, 3H), 3.06 (t,J= 5.8 Hz, 2H), 2.70 (s, 3H), 2.48 (s, 2H), 2.33 (s, 6H), 2.08 - 1.71 (m, 8H), 1.22 (d,J= 6.8 Hz, 6H)m / zcalculated for C 30 H 42F2N8O3(M+H) + 601.3,found601.320(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6-(1-methoxypropan-2-yl)-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (500 MHz, Methanol-d4)δ 8.36 (s, 1H), 8.17 (d,J= 1.1 Hz, 1H), 7.73 (d,J= 8.1 Hz, 2H), 7.50 (d,J= 8.1 Hz, 2H), 6.85 (s, 1H), 6.56 (dd,J= 17.0, 10.2 Hz, 1H), 6.42 (dd,J= 17.0, 1.7 Hz, 1H), 5.85 (dd,J= 10.2, 1.7 Hz, 1H), 4.72 (ddd,J= 8.4, 6.9, 4.7 Hz, 1H), 4.50 (q,J= 14.0 Hz, 2H), 3.84 (s, 3H), 3.67 (dd,J= 10.5, 8.5 Hz, 1H), 3.51 - 3.46 (m, 1H), 3.39 (s, 3H), 3.09 (s, 2H), 2.63 (s, 3H), 2.61 (s, 2H), 2.41 (s, 6H), 1.28 (d,J= 7.0 Hz, 3H)m / zcalculated for C 32 H 39 F3N8O4(M+H) + 657.3,found657.321N-(5-((8-(4-chlorophenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (400 MHz, DMSO-d6)δ 10.00 (bs, 1 H), 8.29 (bs, 1 H), 8.15 (s, 1 H), 7.78 (s, 1 H), 7.35 (d,J= 8.0 Hz, 2 H), 7.24 (d,J= 8.0 Hz, 2 H), 6.86 (s, 1 H), 6.46 (bs, 1 H), 6.25 (d,J= 16.0 Hz, 1 H), 5.77 (d,J= 12.0 Hz, 1 H), 4.54 - 4.47 (m, 1 H), 4.33 (s, 2 H), 3.72 (s, 3 H), 2.61 (s, 2 H), 2.27 (s, 2 H), 1.17 (d,J=8.0 Hz, 6 H)m / zcalculated C 30 H 37 ClN8O3for(M+H) + 593.3,found593.422N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-8-(3-(methylsulfonamido)phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, DMSO-d6)δ 9.94 (s, 1 H), 8.31 (s, 1 H), 8.11 (s, 1 H), 7.66 (s, 1 H), 7.25 (t,J= 8.0 Hz, 1 H), 7.09 (d,J= 8.0 Hz, 1 H), 6.95 - 6.93 (m, 2 H), 6.81 (s, 1 H), 6.35 (q,J= 9.3 Hz, 1 H), 6.19 (d,J= 16.0 Hz, 1 H), 5.71 (d,J= 8.0 Hz, 1 H), 4.52 - 4.45 (m, 1 H), 4.31 (s, 3 H), 3.68 (s, 3 H), 2.87 (s, 3 H), 2.76 (t,J= 4.0 Hz, 2 H), 2.61 (s, 3 H), 2.23 (t,J= 4.0 Hz, 2 H), 2.16 (s, 6 H), 1.15 (d,J= 4.0 Hz, 6 H)m / zcalculated C 31 H 41N9O5Sfor(M+H) + 652.3,found652.323(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-thiopyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.74 (s, 1H), 8.06 (d,J= 0.9 Hz, 1H), 6.94 (d,J= 2.3 Hz, 1H), 6.52 (dd,J= 17.0, 10.2 Hz, 1H), 6.33 (dd,J= 17.0, 1.6 Hz, 1H), 5.75 (dd,J= 10.2, 1.6 Hz, 1H), 5.17 (p,J= 7.5 Hz, 1H), 4.59 - 4.49 (m, 1H), 4.35 - 4.15 (m, 2H), 3.88 (s, 3H), 3.01 (t,J=6.0 Hz, 2H), 2.81 - 2.69 (m, 2H), 2.66 (s, 3H), 2.49 (dt,J= 11.9, 3.3 Hz, 2H), 2.45 - 2.39 (m, 2H), 2.28 (s, 6H), 1.99 - 1.91 (m, 4H), 1.43 (d,J= 7.2 Hz, 3H)m / zcalculated for C 29 H 39 F3N8O3S(M+H) + 637.3,found637.324(S)-N-(5-((8-cyclohexyl-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.65 (s, 1H), 8.04 (s, 1H), 6.93 (s, 1H), 6.50 (dd,J= 17.0, 10.2 Hz, 1H), 6.31 (dd,J= 17.0, 1.8 Hz, 1H), 5.75 (dd,J= 10.2, 1.7 Hz, 1H), 5.23 - 5.11 (m, 1H), 4.57 - 4.43 (m, 1H), 4.32 (d,J= 14.1 Hz, 1), 4.20 - 4.12 (m, 1H), 3.87 (s, 3H), 3.05 - 2.98 (m, 2H), 2.65 (s, 3H), 2.47 - 2.39 (m, 2H), 2.28 (s, 6H), 1.72 - 1.48 (m, 8H), 1.43 (d,J= 5.8 Hz, 5H)m / zcalculated for C 30 H 41 F3N8O3(M+H) + 619.3,found619.425(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8-(4-methoxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.44 (s, 1H), 8.17 - 8.10 (m, 1H), 7.16 - 7.12 (m, 2H), 6.94 - 6.86 (m, 2H), 6.81 (s, 1H), 6.58 - 6.45 (m, 1H), 6.35 (dd,J= 17.0, 1.8 Hz, 1H), 5.79 (dd,J= 10.1, 1.8 Hz, 1H), 5.29 - 5.20 (m, 1H), 4.62 - 4.52 (m, 1H), 4.43 (s, 1H), 3.80 (d,J= 1.6 Hz, 6H), 3.02 - 2.93 (m, 2H), 2.59 (s, 3H), 2.44 - 2.35 (m, 2H), 2.30 - 2.24 (m, 6H), 1.50 (d,J= 7.2 Hz, 3H)m / zcalculated for C 31 H 37 F3N8O4(M+H) + 643.3,found643.326(R)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.72 (s, 1H), 8.11 - 8.04 (m, 1H), 6.94 (s, 1H), 6.52 (dd,J= 17.0, 10.2 Hz, 1H), 6.32 (dd,J= 17.0, 1.7 Hz, 1H), 5.77 (dd,J= 10.2, 1.7 Hz, 1H), 5.24 - 5.16 (m, 1H), 4.34 (d,J= 14.0 Hz, 1H), 4.19 (d,J= 13.9 Hz, 1H), 3.90 - 3.84 (m, 5H), 3.45 - 3.36 (m, 2H), 3.02 (d,J= 6.1 Hz, 2H), 2.70 (d,J= 4.6 Hz, 2H), 2.66 (s, 3H), 2.44 (s, 2H), 2.29 (s, 6H), 1.62 - 1.54 (m, 2H)m / zcalculated for C 29 H 39 F3N8O4(M+H) + 621.3,found621.427(R)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.40 (s, 1H), 8.17 (d,J= 0.9 Hz, 1H), 7.67 (d,J= 8.3 Hz, 2H), 7.51 - 7.44 (m, 2H), 6.81 (s, 1H), 6.60 - 6.47 (m, 1H), 6.36 (dd,J= 17.0, 1.8 Hz, 1H), 5.79 (dd,J= 10.2, 1.8 Hz, 1H), 5.24 (p,J= 7.7 Hz, 1H), 4.62 (d,J= 14.6 Hz, 1H), 4.45 (d,J= 14.0 Hz, 1H), 3.77 (s, 3H), 2.97 (t,J= 6.0 Hz, 2H), 2.58 (s, 3H), 2.41 (s, 2H), 2.27 (s, 6H), 1.52 (d,J= 7.3 Hz, 3H)m / zcalculated for C 31 H 34 F6N8O3(M+H) + 681.3,found681.328(S)-N-(4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(4-methoxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, DMSO-d6)δ 10.16 (s, 1 H), 8.43 (s, 1 H), 8.33 (s, 1 H), 8.16 (s, 1 H), 7.12 (d,J= 8.0 Hz, 2 H), 6.98 (s, 1 H), 6.87 (d,J= 8.0 Hz, 2 H), 6.41 (q,J= 9.3 Hz, 1 H), 6.26 (d,J= 16.0 Hz, 1 H), 6.69 (d,J= 84.0 Hz, 1 H), 5.22 - 5.15 (m, 1 H), 4.57 (d,J= 12.0 Hz, 1 H), 4.34 (d,J=12.0 Hz, 1 H), 3.75 (s, 3 H), 2.77 (t,J= 6.0 Hz, 2 H), 2.64 (s, 3 H), 2.31 (t,J= 6.0 Hz, 2 H), 2.21 (s, 6 H), 1.46 (d,J= 8.0 Hz, 3 H)m / zcalculated for C 31 H 35 F5N8O4(M+H) + 679.3,found679.329(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.41 (s, 1H), 8.17 (s, 1H), 7.70 - 7.66 (m, 2H), 7.50 - 7.46 (m, 2H), 6.81 (s, 1H), 6.57 - 6.50 (m, 1H), 6.41 - 6.32 (m, 1H), 5.83 - 5.77 (m, 2H), 5.29 - 5.19 (m, 1H), 4.62 (d,J= 14.8 Hz, 1H), 4.45 (d,J= 13.9 Hz, 1H), 3.77 (s, 3H), 3.00 - 2.90 (m, 2H), 2.58 (s, 3H), 2.44 - 2.35 (m, 2H), 2.31 - 2.24 (m, 6H), 1.51 (d,J= 7.2 Hz, 3H)m / zcalculated for C 31 H 34 F6N8O3(M+H) + 681.3,found681.330N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-6-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4)δ8.16(s,1H),7.99(s,1H),7.75(d,J= 8.4 Hz, 2H), 7.49 (d,J= 7.9 Hz, 2H), 6.81 (s, 1H), 6.53 (dd,J= 17.0, 10.0 Hz, 1H), 6.41 (dd,J= 17.0, 1.9 Hz, 1H), 5.84 (dd,J= 10.0, 1.9 Hz, 1H), 4.65 (s, 2H), 4.21 (q,J= 9.2 Hz, 2H), 3.84 (s, 3H), 3.39 - 3.32 (m, 2H), 3.13 - 3.02 (m, 2H), 2.74 (s, 6H), 2.62 (s, 3H)m / zcalculated for C 30 H 32 F6N8O3(M+H) +667.3,found667.331(S)-N-(5-((8-(4-chlorophenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ8.18(d,J= 0.8 Hz, 1H), 7.82 (s, 1H), 7.44 (d,J= 8.6 Hz, 2H), 7.27 (d,J= 8.6 Hz, 2H), 6.82 (s, 1H), 6.60 (dd,J= 16.9, 10.1 Hz, 1H), 6.44 (dd,J= 17.0, 1.7 Hz, 1H), 5.88 (dd,J= 10.1, 1.7 Hz, 1H), 5.23 (p,J= 7.8 Hz, 1H), 4.60 (d,J= 14.1 Hz, 1H), 4.44 (d,J= 14.0 Hz, 1H), 3.88 (s, 3H), 3.39 (t,J= 5.7 Hz, 2H), 3.21 - 3.16 (m, 2H), 2.79 (s, 6H), 2.63 (s, 3H), 1.50 (d,J= 7.2 Hz, 3H)m / zcalculated for C 30 H 34 ClF3N8O3(M+H) + 647.2,found647.332(S)-N-(5-((8-(4-bromophenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ8.18(s,1H),7.86(s,1H),7.59(d,J= 8.6 Hz, 2H), 7.21 (d,J= 8.6 Hz, 2H), 6.82 (s, 1H), 6.61 (dd,J= 16.9, 10.1 Hz, 1H), 6.45 (dd,J= 17.0, 1.7 Hz, 1H), 5.88 (dd,J= 10.1, 1.7 Hz, 1H), 5.23 (p,J= 7.7 Hz, 1H), 4.60 (d,J= 14.1 Hz, 1H), 4.43 (d,J= 14.0 Hz, 1H), 3.87 (s, 3H), 3.39 (t,J= 5.7 Hz, 2H), 3.21 - 3.15 (m, 2H), 2.79 (s, 6H), 2.63 (s, 3H), 1.50 (d,J= 7.2 Hz, 3H)m / zcalculated for C 30 H 34 BrF3N8O3(M+H) + 691.2,found691.333(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(4-fluorophenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.18 (d,J= 0.9 Hz, 1H), 7.66 (s, 1H), 7.34 - 7.26 (m, 2H), 7.15 (t,J= 8.6 Hz, 2H), 6.82 (s, 1H), 6.54 (dd,J= 17.0, 9.9 Hz, 1H), 6.43 (dd,J= 16.8, 1.9 Hz, 1H), 5.88 (dd,J= 10.0, 1.9 Hz, 1H), 5.24 (p,J= 7.8 Hz, 1H), 4.59 (d,J= 5.2 Hz, 1H), 4.44 (d,J=14.0 Hz, 1H), 3.89 (s, 3H), 3.10 - 2.98 (m, 2H), 2.78 - 2.71 (m, 2H), 2.70 (s, 6H), 2.61 (d,J= 0.7 Hz, 3H), 1.51 (d,J= 7.2 Hz, 3H)m / zcalculated for C 30 H 34 F4N8O3(M+H) + 631.3,found631.334(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(4-hydroxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, DMSO-d6)δ 10.08 (s, 1 H), 9.49 (bs, 1 H), 8.49 (s, 1 H), 8.17 (s, 1 H), 7.75 (s, 1 H), 7.00 (d,J= 8.0 Hz, 2 H), 6.87 (s, 1 H), 6.71 (d,J= 8.0 Hz, 2 H), 6.38 (q,J= 8.0 Hz, 1 H), 6.23 (d,J= 16.0 Hz, 1 H), 5.74 (d,J= 8.0 Hz, 1 H), 5.22 - 5.16 (m, 1 H), 4.56 (d,J= 12.0 Hz, 1 H), 4.33 (d,J= 12.0 Hz, 1 H), 3.72 (s, 3 H), 2.81 (bs, 2 H), 2.65 (s, 3 H), 2.26 (bs, 2 H), 2.22 (s, 6 H), 1.46 (d,J= 4.0 Hz, 3 H)m / zcalculated C 30 H 35 F3N8O4for(M+H) + 629.3,found629.335(S)-N-(5-((8-(3-chloro-4-fluorophenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.16 (d,J= 6.2 Hz, 2H), 7.39 (s, 1H), 7.22 (d,J= 5.9 Hz, 2H), 6.83 (d,J= 5.9 Hz, 1H), 6.56 - 6.44 (m, 1H), 6.41 - 6.27 (m, 1H), 5.79 (d,J= 9.8 Hz, 1H), 5.23 (s, 1H), 4.60 (dd,J= 14.1, 5.5 Hz, 1H), 4.43 (d,J= 10.7 Hz, 1H), 3.82 (d,J= 5.7 Hz, 3H), 3.06 - 2.91 (m, 2H), 2.59 (s, 3H), 2.49 - 2.41 (m, 2H), 2.33 (s, 6H), 1.51 (t,J= 6.8 Hz, 3H)m / zcalculated for C 30 H 33 ClF4N8O3(M+H) + 665.2,found665.236(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(3-fluoro-4-methoxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.47 (s, 1H), 8.14 (s, 1H), 7.09 - 6.92 (m, 3H), 6.82 (s, 1H), 6.50 (dd,J= 17.0, 10.2 Hz, 1H), 6.32 (dd,J= 17.0, 1.8 Hz, 1H), 5.76 (dd,J= 10.2, 1.8 Hz, 1H), 5.23 (p,J= 7.7 Hz, 1H), 4.57 (d,J= 14.0 Hz, 1H), 4.40 (d,J= 14.0 Hz, 1H), 3.87 (s, 3H), 3.79 (s, 3H), 2.96 (t,J= 6.0 Hz, 2H), 2.59 (s, 3H), 2.38 (t,J= 6.0 Hz, 2H), 2.26 (s, 6H), 1.49 (d,J= 7.3 Hz, 3H)m / zcalculated for C 31 H 36 F4N8O4(M+H) + 661.3,found661.237(S)-N-(5-((8-(4-chloro-3-fluorophenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ8.26(s,1H),8.16(s,1H),7.44(t,J= 8.3 Hz, 1H), 7.25 - 7.17 (m, 1H), 7.10 (ddd,J= 8.5, 2.3, 1.2 Hz, 1H), 6.82 (s, 1H), 6.52 (dd,J= 17.0, 10.2 Hz, 1H), 6.34 (dd,J= 17.0, 1.7 Hz, 1H), 5.79 (dd,J= 10.2, 1.7 Hz, 1H), 5.23 (p,J= 7.7 Hz, 1H), 4.59 (d,J= 13.9 Hz, 1H), 4.43 (d,J= 14.0 Hz, 1H), 3.80 (s, 3H), 3.02 (d,J= 6.7 Hz, 2H), 2.60 (s, 3H), 2.45 (d,J= 9.6 Hz, 2H), 2.33 (d,J= 6.1 Hz, 6H), 1.51 (d,J= 7.2 Hz, 3H)m / zcalculated for C 30 H 33 ClF4N8O3(M+H) + 665.2,found665.238(S)-N-(5-((8-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (400 MHz, DMSO-d6)δ 10.05 (bs, 1 H), 8.43 (bs, 1 H), 8.17 (s, 1 H), 7.80 (s, 1 H), 7.06 (s, 1 H), 6.93 (d,J= 8.0 Hz, 1 H), 6.88 (s, 1 H), 6.68 (d,J= 8.0 Hz, 1 H), 6.39 (q,J= 9.3 Hz, 1 H), 6.22 (d,J= 16.0 Hz, 1 H), 5.75 (d,J= 8.0 Hz, 1 H), 5.22 - 5.14 (m, 1 H), 4.58 - 4.52 (m, 3 H), 4.33 (d,J= 16.0 Hz, 1 H), 3.73 (s, 3 H), 3.15 (t,J=8.0 Hz, 2 H), 2.81 (bs, 2 H), 2.65 (s, 3 H), 2.22 (s, 6 H), 1.46 (d,J=8.0 Hz, 3 H)m / z 32 H 37 F3N8O4for(M+H) + 655.3,found655.339(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8-(4-methyl-3,4-dihydro-2H-benzo][1,4]oxazin-6-yl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, DMSO-d6)δ 8.16 (s, 1 H), 7.76 (s, 1 H), 7.46 (d,J= 8.0 Hz, 1 H), 7.11 (d,J= 4.0 Hz, 1 H), 6.88 (s, 1 H), 6.78 (s, 1 H), 6.66 (q,J= 9.3 Hz, 1 H), 6.45 (d,J= 8.0 Hz, 1 H), 6.24 (d,J= 16.0 Hz, 1 H), 5.21 - 5.17 (m, 1 H), 4.55 (d,J= 12.0 Hz, 1 H), 4.32 (d,J= 16.0 Hz, 1 H), 4.22 (bs, 2 H), 3.75 - 3.74 (m, 5 H), 3.23 (bs, 2 H), 2.76 (s, 3 H), 2.62 (s, 3 H), 2.55 (bs, 2 H), 2.28 (s, 6 H), 1.46 (d,J= 4.0 Hz, 3 H)m / z 33 H 40 F3N9O4for(M+H) + 684.3,found684.340(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(4-ethylphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4) δ 8.43 (s, 1H), 8.14 (s, 1H), 7.25 (d,J= 8.2 Hz, 2H), 7.14 (d,J= 8.3 Hz, 2H), 6.81 (s, 1H), 6.54 (dd,J= 17.0, 10.1 Hz, 1H), 6.37 (dd,J= 17.0, 1.6 Hz, 1H), 5.81 (dd,J= 10.2, 1.6 Hz, 1H), 5.29 - 5.17 (m, 1H), 4.58 (d,J= 14.0 Hz, 1H), 4.41 (d,J=14.0 Hz, 1H), 3.79 (s, 3H), 3.02 (t,J= 5.8 Hz, 2H), 2.68 (q,J= 7.6 Hz, 2H), 2.58 (s, 3H), 2.49 (t,J= 5.3 Hz, 2H), 2.32 (s, 6H), 1.49 (d,J= 7.2 Hz, 3H), 1.24 (t,J= 7.6 Hz, 3H)m / zcalculated for C 32 H 39 F3N8O3(M+H) + 641.3,found641.341N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-8-(4-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, DMSO-d6)δ 10.00 (s, 1H), 8.43 (s, 1H), 8.10 (d,J= 0.9 Hz, 1H), 7.59 (s, 1H), 7.11 - 7.03 (m, 2H), 6.83 (dd,J= 6.5, 2.3 Hz, 2H), 6.41 - 6.32 (m, 1H), 6.20 (dd,J= 16.9, 2.2 Hz, 1H), 5.76 - 5.67 (m, 1H), 4.47 (h,J= 6.8 Hz, 1H), 4.29 (d,J= 0.9 Hz, 2H), 3.71 (s, 3H), 3.70 (s, 3H), 2.85 - 2.72 (m, 2H), 2.60 (s, 3H), 2.30 - 2.10 (m, 8H), 1.14 (d,J= 6.8 Hz, 6H)m / zcalculated for C 31 H 40 N8O4(M+H) + 589.3,found589.442N-(5-((8-(4-bromophenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.11 (d,J= 0.9 Hz, 1H), 7.85 (s, 1H), 7.55 - 7.50 (m, 2H), 7.17 - 7.13 (m, 2H), 6.64 - 6.56 (m, 2H), 6.35 (dd,J= 17.0, 1.7 Hz, 1H), 5.80 (dd,J= 10.3, 1.7 Hz, 1H), 5.28 - 5.17 (m, 1H), 4.57 (dd,J= 13.9, 1.0 Hz, 1H), 4.41 (d,J= 14.0 Hz, 1H), 3.79 (s, 3H), 3.24 - 3.07 (m, 4H), 2.92 (p,J= 7.0 Hz, 1H), 2.33 (s, 6H), 2.22 - 2.12 (m, 1H), 1.93 - 1.82 (m, 1H), 1.50 (d,J= 7.2 Hz, 3H)m / zcalculated for C 31 H 34 BrF3N8O3(M+H) + 703.2,found703.243(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (400 MHz, DMSO-d6)δ 10.24 (s, 1H), 8.74 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 6.97 (s, 1H), 6.30 (dd,J= 16.9, 10.0 Hz, 1H), 6.15 (dd,J= 16.9, 2.1 Hz, 1H), 5.70 (dd,J= 9.9, 2.1 Hz, 1H), 5.11 (dt,J= 16.3, 8.0 Hz, 1H), 4.57 (td,J= 11.9, 6.7 Hz, 1H), 4.33 (d,J= 14.0 Hz, 1H), 4.10 (d,J= 14.0 Hz, 1H), 3.77 (s, 3H), 2.79 (dd,J= 6.6, 4.6 Hz, 2H), 2.65 (s, 3H), 2.24 (t,J= 5.6 Hz, 2H), 1.99 - 1.53 (m, 8H), 1.36 (d,J= 7.2 Hz, 3H)m / zcalculated for C 30 H 39 F5N8O3(M+H) + 655.3,found655.344N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, DMSO-d6)δ 9.28 (s, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.69 (s, 1H), 6.50 (s, 1H), 6.49 - 6.43 (m, 1H), 6.12 (dd,J= 17.1, 2.1 Hz, 1H), 5.63 (dd,J= 10.1, 2.1 Hz, 1H), 5.17 - 5.05 (m, 1H), 4.50 (q,J= 11.8, 10.8 Hz, 1H), 4.30 (d,J= 14.0 Hz, 1H), 4.11 - 4.05 (m, 1H), 3.77 (s, 3H), 3.29 - 3.22 (m, 1H), 3.18 - 3.05 (m, 3H), 2.67 - 2.60 (m, 1H), 2.11 (s, 6H), 2.05 - 1.53 (m, 8H), 1.35 (d,J= 7.2 Hz, 3H)m / zcalculated for C 31 H 39 F5N8O3(M+H) + 667.3,found667.345(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(p-tolyl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, DMSO-d6)δ 10.00 (s, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 7.75 (s, 1H), 7.09 (q,J= 8.4 Hz, 4H), 6.84 (s, 1H), 6.36 (dd,J= 16.9, 10.0 Hz, 1H), 6.20 (dd,J= 16.9, 2.2 Hz, 1H), 5.72 (td,J= 5.7, 2.2 Hz, 1H), 5.22 - 5.08 (m, 1H), 4.54 (d,J= 14.0 Hz, 1H), 4.31 (d,J=13.9 Hz, 1H), 3.68 (s, 3H), 2.76 (t,J= 5.8 Hz, 2H), 2.61 (s, 3H), 2.27 (s, 3H), 2.24 - 2.20 (m, 2H), 2.16 (s, 6H), 1.43 (d,J= 7.2 Hz, 3H)m / zcalculated for C 31 H 37 F3N8O3(M+H) + 627.3,found627.346N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(p-tolyl)-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, DMSO-d6)δ 9.18 (t,J= 1.4 Hz, 1H), 8.11 (s, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 7.16 (d,J= 8.2 Hz, 2H), 7.06 (d,J= 8.2 Hz, 2H), 6.55 - 6.44 (m, 1H), 6.37 (s, 1H), 6.15 (dd,J= 17.0, 2.1 Hz, 1H), 5.66 (dd,J= 10.2, 2.1 Hz, 1H), 5.21 - 5.08 (m, 1H), 4.51 (d,J=14.2 Hz, 1H), 4.28 (d,J= 13.9 Hz, 1H), 3.70 (s, 3H), 3.28 - 3.21 (m, 1H), 3.13 - 3.01 (m, 3H), 2.65 - 2.57 (m, 1H), 2.31 (s, 3H), 2.10 (s, 6H), 2.06 - 1.93 (m, 2H), 1.42 (d,J= 7.2 Hz, 3H)m / zcalculated for C 32 H 37 F3N8O3(M+H) + 639.3,found639.347N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((6-((S)-1-methoxypropan-2-yl)-7-oxo-8-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, DMSO-d6)d9.08(s,1H),8.06(s,1H),7.45(s,1H),7.33-7.27(m,4H),7.14(d,J= 8.0 Hz, 2 H), 6.50 (q,J= 10.7 Hz, 1 H), 6.35 (s, 1 H), 6.16 (d,J= 20.0 Hz, 1 H), 5.68 (d,J= 8.0 Hz, 1 H), 4.54 - 4.49 (m, 1 H), 4.36 (d,J= 12.0 Hz, 1 H), 4.27 (d,J= 12.0 Hz, 1 H), 3.72 (s, 3 H), 3.49 (t,J= 9.2 Hz, 1 H), 3.35 - 3.30 (m, 1 H), 3.25 - 3.22 (m, 5 H), 3.09 (d,J= 7.6 Hz, 2 H), 2.60 (bs, 1 H), 2.10 (s, 6 H), 1.99 (bs, 1 H), 1.66 - 1.64 (m, 1 H), 1.10 (d,J=6.8 Hz, 3 H)m / zcalculated C 32 H 40 N8O4for(M+H) + 601.3,found601.448N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.13 (s, 1H), 7.92 (s, 1H), 7.69 (d,J= 8.3 Hz, 2H), 7.46 (d,J= 8.3 Hz, 2H), 6.59 - 6.49 (m, 2H), 6.35 (d,J= 16.9 Hz, 1H), 5.78 (d,J= 10.2 Hz, 1H), 5.29 - 5.17 (m, 1H), 4.60 (d,J= 14.0 Hz, 1H), 4.43 (d,J= 14.1 Hz,1H), 3.76 (s, 3H), 3.23 - 2.76 (m, 5H), 2.20 - 2.08 (m, 1H), 1.90 - 1.78 (m, 1H), 1.51 (d,J= 7.2 Hz, 3H)m / zcalculated for C 32 H 34 F6N8O3(M+H) + 693.3,found693.249(R)-N-(5-((8-(2-chloro-3-fluorophenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, DMSO-d6)δ 9.15 (s, 1 H), 8.15 (s, 1 H), 7.68 (d,J= 6.0 Hz, 1 H), 7.40 - 7.38 (m, 2 H), 7.29 - 7.26 (m, 1 H), 6.60 (bs, 1 H), 6.45 (s, 1 H), 6.23 - 6.17 (m, 1 H), 5.73 - 5.70 (m, 1 H), 4.55 - 4.48 (m, 1 H), 4.38 (s, 2 H), 3.75 (s, 3 H), 3.61 (bs, 1 H), 3.15 (bs, 2 H), 2.52 - 2.48 (m, 6 H), 1.26 - 1.24 (m, 4 H), 1.19 (d,J= 5.6 Hz, 6 H)m / zcalculated C 31 H 36 ClFN8O3for(M+H) +623.3,found623.350N-(2-(3-((dimethylamino)methyl)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.10 (s, 1H), 7.82 (s, 1H), 7.70 (d,J= 8.4 Hz, 2H), 7.45 (d,J= 8.2 Hz, 2H), 6.51 (s, 1H), 6.46 (dd,J= 17.0, 10.1 Hz, 1H), 6.32 (dd,J= 17.0, 1.7 Hz, 1H), 5.76 (dd,J= 10.1, 1.7 Hz, 1H), 5.29 - 5.16 (m, 1H), 4.57 (d,J= 14.2 Hz, 1H), 4.41 (d,J=14.0 Hz, 1H), 3.74 (s, 3H), 3.27 - 3.15 (m, 2H), 3.09 - 3.01 (m, 1H), 2.94 - 2.85 (m, 1H), 2.51 - 2.36 (m, 3H), 2.13 - 2.02 (m, 1H), 1.59 (m, 1H), 1.49 (d,J= 7.2 Hz, 3H)m / zcalculated for C 33 H 36 F6N8O3(M+H) + 707.3,found707.351N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((8-(4-methoxyphenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.10 (s, 1H), 7.89 (s, 1H), 7.13 (d,J= 8.8 Hz, 2H), 6.95 (d,J= 8.8 Hz, 2H), 6.61 - 6.49 (m, 2H), 6.33 (dd,J= 17.0, 1.5 Hz, 1H), 5.78 (dd,J= 10.2, 1.5 Hz, 1H), 5.29 - 5.17 (m, 1H), 4.56 (d,J= 14.1 Hz, 1H), 4.39 (d,J= 14.1 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.23 - 3.02 (m, 4H), 2.86 - 2.73 (m, 1H), 2.27 (s, 6H), 2.17 - 2.08 (m, 1H), 1.88 - 1.74 (m, 1H), 1.49 (d,J= 7.3 Hz, 3H)m / zcalculated for C 32 H 37 F3N8O4(M+H) + 655.3,found655.352(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)-2-fluoroacrylamide (400 MHz, Methanol-d4)δ 8.40 (s, 1H), 8.19 (d,J= 0.8 Hz, 1H), 7.70 - 7.64 (m, 2H), 7.48 - 7.44 (m, 2H), 6.89 (s, 1H), 5.73 (dd,J= 47.3, 3.4 Hz, 1H), 5.32 (dd,J= 15.4, 3.4 Hz, 1H), 5.29 - 5.18 (m, 1H), 4.62 (dd,J= 14.1, 0.9 Hz, 1H), 4.45 (d,J= 14.0 Hz, 1H), 3.79 (s, 3H), 2.97 (t,J= 6.7 Hz, 2H), 2.60 (s, 3H), 2.26 (d,J= 6.8 Hz, 2H), 2.19 (s, 6H), 1.51 (d,J= 7.2 Hz, 3H)m / zcalculated for C 31 H 33 F7N8O3(M+H) + 699.3,found699.353N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.16 (s, 1H), 8.03 (s, 1H), 6.65 (s, 1H), 6.53 (dd,J= 17.0, 10.2 Hz, 1H), 6.32 (dd,J= 17.0, 1.7 Hz, 1H), 5.76 (dd,J= 10.2, 1.7 Hz, 1H), 5.26 - 5.10 (m, 1H), 4.84 - 4.73 (m, 1H), 4.32 (d,J= 14.0 Hz, 1H), 4.16 (d,J= 13.9 Hz, 1H), 3.96 - 3.89 (m, 2H), 3.88 (s, 3H), 3.48 - 3.35 (m, 2H), 3.26 - 3.13 (m, 4H), 2.86 - 2.78 (m, 1H), 2.78 - 2.63 (m, 2H), 2.28 (s, 6H), 2.22 - 2.11 (m,1H), 1.92 - 1.77 (m, 1H), 1.62 - 1.52 (m, 2H), 1.42 (d,J= 7.2 Hz, 3H)m / zcalculated for C 30 H 39 F3N8O4(M+H) + 633.3,found633.354(S)-N-(5-((8-(2-chloro-4-(trifluoromethyl)phenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide -m / zcalculated C 31 H 33 ClF6N8O3for(M+H) + 715.2,found715.255N-(5-((8-(2-chloro-4-(trifluoromethyl)phenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide -m / zcalculated C32 H 33 ClF6N8O3for(M+H) + 727.2,found727.256N-(5-((8-(2-chloro-4-(trifluoromethyl)phenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide -m / zcalculated C 31 H 36 ClF3N8O3for(M+H) + 661.3,found661.357(R)-N-(5-((8-(2-chloro-4-(trifluoromethyl)phenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide -m / zcalculated C 32 H 36 ClF3N8O3for(M+H) + 673.3,found673.258(S)-N-(4-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.64 (s, 1H), 8.07 (s, 1H), 7.09 (s, 1H), 6.78 (t,J= 74.0 Hz, 1H), 6.52 (dd,J= 17.0, 10.3 Hz, 1H), 6.33 (dd,J= 17.0, 1.5 Hz, 1H), 5.80 (dd,J= 10.3, 1.4 Hz, 1H), 5.27 - 5.09 (m, 1H), 4.80 - 4.70 (m, 1H), 4.27 (dd,J= 62.3, 14.0 Hz, 2H), 3.86 (d,J=11.4 Hz, 2H), 3.40 - 3.31 (m, 2H), 2.91 (t,J= 4.8 Hz, 4H), 2.77 - 2.56 (m, 6H), 2.36 (s, 3H), 1.55 (dd,J= 12.4, 1.9 Hz, 2H), 1.43 (d,J= 7.2 Hz, 3H)m / zcalculated for C 29 H 35 F5N8O4(M+H) + 655.3,found655.359(S)-N-(4-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4)δ8.33(s,1H),8.16(s,1H),7.64(d,J= 8.2 Hz, 2H), 7.43 (d,J= 8.2 Hz, 2H), 6.96 (s, 1H), 6.57 (t,J= 74.0 Hz, 1H), 6.51 (dd,J= 16.9, 10.1 Hz, 1H), 6.39 - 6.33 (m, 1H), 5.83 (dd,J= 10.1, 1.6 Hz, 1H), 5.24 (p,J= 7.6 Hz, 1H), 4.62 (d,J= 14.1 Hz, 1H), 4.45 (d,J= 14.1 Hz, 1H), 2.88 (t,J= 4.6 Hz, 4H), 2.84 - 2.78 (m, 4H), 2.49 (s, 3H), 1.51 (d,J= 7.3 Hz, 3H)m / zcalculated for C 31 H 30 F8N8O3(M+H) + 715.2,found715.260(S)-N-(4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.63 (s, 1H), 8.07 (s, 1H), 7.05 (s, 1H), 6.78 (t,J= 69.1 Hz, 1H), 6.60 - 6.53 (m, 1H), 6.34 (dd,J= 16.9, 1.4 Hz, 1H), 5.80 (dd,J= 10.3, 1.3 Hz, 1H), 5.25 - 5.12 (m, J1H), 4.80 - 4.67 (m, 1H), 4.35 (d,J= 14.1 Hz, 1H), 4.19 (d,J= 14.0 Hz, 1H), 3.91 - 3.80 (m, 2H), 3.40 - 3.30 (m, 2H), 3.23 - 3.02 (m, 3H), 2.84 - 2.34 (m, 11H), 2.33 (s, 3H), 2.11 - 1.94 (m, 3H), 1.81 - 1.65 (m, 2H), 1.58 - 1.48 (m, 2H), 1.43 (d,J= 7.2 Hz, 3H)m / zcalculated for C 34 H 44 F5N9O4(M+H) + 738.3,found738.461N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((R)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.26 (s, 1H), 8.04 (d,J= 0.7 Hz, 1H), 6.71 (s, 1H), 6.54 (dd,J= 17.0, 10.3 Hz, 1H), 6.36 - 6.26 (m, 1H), 5.75 (ddd,J= 10.3, 1.7, 0.6 Hz, 1H), 5.16 (dt,J= 15.3, 7.6 Hz, 1H), 4.72 - 4.60 (m, 1H), 4.32 (d,J= 14.0 Hz, 1H), 4.17 (d,J= 13.8 Hz, 1H), 3.87 (d,J= 0.6 Hz, 3H), 3.21 (ddd,J= 13.8, 8.9, 5.7 Hz, 3H), 3.14 - 3.06 (m, 1H), 2.89 - 2.79 (m, 1H), 2.71 - 2.57 (m, 2H), 2.29 (d,J= 0.6 Hz, 6H), 2.23 - 2.14 (m, 1H), 2.04 - 1.94 (m, 2H), 1.92 - 1.82 (m, 2H), 1.77 - 1.67 (m, 3H), 1.43 (d,J= 7.3 Hz, 3H)m / zcalculated for C 31 H 39 F5N8O3(M+H) + 667.3,found667.362N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-((R)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.14 (q,J= 0.7 Hz, 1H), 7.93 (q,J= 2.5 Hz, 1H), 7.70 (d,J= 8.2 Hz, 2H), 7.47 (dt,J= 7.8, 1.3 Hz, 2H), 6.58 (s, 1H), 6.53 (dd,J= 17.0, 10.2 Hz, 1H), 6.35 (dd,J= 16.9, 1.8 Hz, 1H), 5.79 (dd,J= 10.1, 1.7 Hz, 1H), 5.27 - 5.19 (m, 1H), 4.66 - 4.58 (m, 1H), 4.43 (d,J= 14.0 Hz, 1H), 3.77 (s, 3H), 3.25 - 3.09 (m, 4H), 3.08 - 2.99 (m, 1H), 2.41 (s, 6H), 2.27 - 2.17 (m, 1H), 1.94 - 1.85 (m, 1H), 1.51 (d,J= 7.3 Hz, 3H)m / zcalculated for C 32 H 34 F6N8O3(M+H) + 693.3,found693.363(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.71 (s, 1H), 8.08 (s, 1H), 7.10 (s, 1H), 6.79 (t,J= 73.9 Hz, 4H), 6.53 (dd,J= 16.9, 10.2 Hz, 1H), 6.32 (dd,J= 17.0, 1.5 Hz, 1H), 5.80 (dd,J= 10.3, 1.5 Hz, 1H), 5.25 - 5.11 (m, 1H), 4.69 - 4.60 (m, 1H), 4.38 - 4.27 (m, 1H), 4.22 - 4.12 (m, 1H), 2.90 (t,J= 4.8 Hz, 4H), 2.72 - 2.57 (m, 6H), 2.37 (s, 3H), 1.97 - 1.91 (m, 2H), 1.87 - 1.80 (m, 2H), 1.74 - 1.66 (m, 2H), 1.43 (d,J= 7.3 Hz, 3H)m / zcalculated for C 30 H 35 F7N8O3(M+H) + 689.3,found689.364N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-5-((8-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.26 (s, 1H), 8.06 (d,J= 1.1 Hz, 1H), 6.72 (s, 1H), 6.57 (dd,J= 17.0, 10.3 Hz, 1H), 6.40 - 6.31 (m, 1H), 5.80 - 5.73 (m, 1H), 5.24 - 5.14 (m, 1H), 4.33 (d,J= 14.0 Hz, 1H), 4.24 - 4.16 (m, 1H), 3.86 (s, 3H), 3.26 - 3.08 (m, 6H), 2.99 - 2.91 (m, 2H), 2.89 - 2.82 (m, 2H), 2.30 (s, 6H), 2.19 (ddd,J= 12.3, 6.0, 3.4 Hz, 1H), 2.07 - 1.97 (m, 3H), 1.89 (ddd,J= 12.2, 8.5, 6.1 Hz, 1H), 1.43 (d,J= 7.2 Hz, 3H)m / zcalculated for C 30 H 39 F3N8O5S(M+H) + 681.3,found681.365(R)-N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, DMSO-d6)δ 9.30 (s, 1 H), 8.06 (s, 1 H), 7.87 (s, 1 H), 7.80 (s, 1 H), 6.54 - 6.51 (m, 2 H), 6.17 (q,J= 6.4 Hz, 1 H), 5.67 (dd,J= 10.2, 2.2 Hz, 1 H), 4.58 - 4.45 (m, 2 H), 4.09 (s, 2 H), 3.82 (s, 3 H), 3.16 - 3.08 (m, 3 H), 2.69 - 2.65 (m, 1 H), 2.58 - 2.55 (m, 1) H), 2.17 - 2.15 (m, 7 H), 2.07 - 1.98 (m, 3 H), 1.89 - 1.68 (m, 3 H), 1.62 - 1.60 (m, 2 H), 1.11 (d,J= 6.8 Hz, 6 H)m / zcalculated C 31 H 42 F2N8O3for(M+H) + 613.3,found613.466N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (400 MHz, DMSO-d6)δ 8.98 (s, 1 H), 8.48 (s, 1 H), 8.10 (s, 1 H), 7.95 (s, 1 H), 6.86 (s, 1 H), 6.60 (q,J= 9.1 Hz, 1 H), 6.18 (dd,J= 16.8, 2.0 Hz, 1 H), 5.71 (dd,J= 10.2, 1.4 Hz, 1 H), 4.62 - 4.56 (m, 1 H), 4.52 - 4.45 (m, 1 H), 4.11 (s, 2 H), 3.83 (s, 3 H), 2.82 (t,J= 4.0 Hz, 4 H), 2.61 - 2.50 (m, 4 H), 2.24 (s, 3 H), 1.95 - 1.76 (m, 4 H), 1.62 (d,J= 14.8 Hz, 2 H), 1.11 (d,J= 6.8 Hz, 6 H)m / zcalculated C 30 H 40 F2N8O3for(M+H) + 599.3,found599.367(R)-N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)acrylamide (400 MHz, DMSO-d6)δ 9.44 (s, 1 H), 8.32 (s, 1 H), 8.05 (s, 1 H), 7.65 (s, 1 H), 7.08 (t,J= 74.6 Hz, 1 H), 6.69 (s, 1 H), 6.53 (q,J= 9.1 Hz, 1 H), 6.19 (dd,J= 17.0, 2.2 Hz, 1 H), 5.71 (dd,J= 9.6, 1.6 Hz, 1 H), 4.50 - 4.46 (m, 2 H), 4.10 (s, 2 H), 3.15 (d,J= 8.0 Hz, 2 H), 3.10 (t,J= 8.4 Hz, 1 H), 2.67 (t,J= 9.8 Hz, 1 H), 2.15 (s, 6 H), 1.97 (bs, 2 H), 1.72 (bs, 2 H), 1.59 (bs, 2 H), 1.25 (bs, 4 H), 1.11 (d,J= 6.8 Hz, 6 H)m / zcalculated C 31 H 40 F4N8O3for(M+H) + 649.3,found649.368N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (400 MHz, DMSO-d6)δ 9.08 (s, 1 H), 8.42 (s, 1 H), 8.41 (bs, 1 H), 8.10 (s, 1 H), 7.09 - 6.90 (m, 2 H), 6.65 (q,J= 9.6 Hz, 1 H), 6.21 (dd,J= 17.0, 1.8 Hz, 1 H), 5.76 (dd,J= 10.4, 1.6 Hz, 1 H), 4.52 - 4.46 (m, 2 H), 4.12 (s, 2 H), 2.80 (t,J= 4.0 Hz, 4 H), 2.54 - 2.50 (m, 4 H), 2.25 (s, 3 H), 1.95 (bs, 2 H), 1.61 (bs, 2 H), 1.24 (bs, 4 H), 1.11 (d,J= 6.8 Hz, 6 H)m / zcalculated C 30 H 38 F4N8O3for(M+H) + 635.3,found635.369(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.71 (s, 1H), 8.07 (s, 1H), 6.91 (s, 1H), 6.49 (dd,J= 16.9, 10.2 Hz, 1H), 6.29 (dd,J= 17.0, 1.6 Hz, 1H), 5.77 (dd,J= 10.3, 1.6 Hz, 1H), 5.16 (p,J= 7.7 Hz, 1H), 4.78 - 4.68 (m, 1H), 4.33 (d,J= 14.0 Hz, 1H), 4.21 - 4.15 (m, 1H), 3.89 (s, 3H), 2.91 (t,J= 4.9 Hz, 4H), 2.68 - 2.60 (m, 4H), 2.37 (s, 3H), 2.02 - 1.61 (m, 8H), 1.43 (d,J= 7.2 Hz, 3H)m / zcalculated for C 30 H37 F5N8O3(M+H) + 653.3,found653.470(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-ethoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.73 (s, 1H), 8.08 (s, 1H), 6.90 (s, 1H), 6.55 - 6.45 (m, 1H), 6.36 - 6.28 (m, 1H), 5.80 - 5.74 (m, 1H), 5.21 - 5.11 (m, 1H), 4.79 - 4.71 (m, 1H), 4.38 - 4.19 (m, 2H), 4.16 - 4.07 (m, 2H), 2.89 (q,J= 5.2 Hz, 4H), 2.75 - 2.60 (m, 4H), 2.36 (s, 3H), 2.03 - 1.63 (m, 8H), 1.43 (ddt,J= 10.5, 7.0, 3.5 Hz, 6H)m / zcalculated for C 31 H 39 F5N8O3(M+H) + 667.3,found667.371N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-ethoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.35 (s, 1H), 8.04 (s, 1H), 6.69 (s, 1H), 6.54 (dd,J= 17.0, 10.3 Hz, 1H), 6.31 (dd,J= 17.0, 1.7 Hz, 1H), 5.73 (dd,J= 10.3, 1.7 Hz, 1H), 5.15 (p,J= 7.8 Hz, 1H), 4.82 (s, 2H), 4.73 - 4.62 (m, 1H), 4.09 (q,J= 7.0 Hz, 2H), 3.23 - 3.06 (m, 4H), 2.90 - 2.79 (m, 1H), 2.74 - 2.58 (m, 2H), 2.29 (s, 6H), 2.19 - 2.09 (m, 1H), 2.02 - 1.93 (m, 2H), 1.90 - 1.80 (m, 2H), 1.75 - 1.66 (m, 3H), 1.40 (d,J=14.0 Hz, 6H)m / zcalculated for C 32 H 41 F5N8O3(M+H) + 681.3,found681.372(S)-N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.70 (s, 1H), 8.07 (s, 1H), 6.88 (s, 1H), 6.58 - 6.49 (m, 1H), 6.34 - 6.25 (m, 1H), 5.80 - 5.73 (m, 1H), 5.21 - 5.12 (m, 1H), 4.78 - 4.68 (m, 1H), 4.37 - 4.29 (m, 1H), 4.23 - 4.14 (m, 1H), 3.87 (s, 3H), 3.11 - 2.99 (m, 2H), 2.77 - 2.57 (m, 9H), 2.05 - 1.51 (m, 16H), 1.43 (dd,J= 7.2, 2.8 Hz, 3H)m / zcalculated for C 35 H 45 F5N8O3(M+H) + 721.4,found721.373(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.68 (s, 1H), 8.08 (s, 1H), 6.94 (s, 1H), 6.56 - 6.45 (m, 1H), 6.36 - 6.24 (m, 1H), 5.82 - 5.71 (m, 1H), 5.22 - 5.12 (m, 1H), 4.73 (ddt,J= 15.7, 11.6, 3.8 Hz, 1H), 4.34 (d,J= 14.0 Hz, 1H), 4.23 - 4.15 (m, 1H), 3.89 (s, 3H), 3.15 - 3.09 (m, 2H), 2.75 - 2.69 (m, 6H), 2.66 (s, 3H), 2.04 - 1.82 (m, 8H), 1.78 - 1.70 (m, 4H), 1.43 (d,J= 7.2 Hz, 3H)m / zcalculated for C 32 H 41 F5N8O3(M+H) +681.3,found681.374(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(methylsulfonyl)piperazin-1-yl)phenyl)acrylamide (400 MHz, DMSO-d6)δ 9.04 (s, 1 H), 8.58 (s, 1 H), 8.18 (s, 1 H), 8.10 (s, 1 H), 6.95 (s, 1 H), 6.68 (q,J= 7.6 Hz, 1 H), 6.21 (d,J= 20.0 Hz, 1 H), 5.74 (d,J= 14.4 Hz, 1 H), 5.16 - 5.12 (m, 1 H), 4.62 (t,J= 12.0 Hz, 1 H), 4.37 (d,J= 13.6 Hz, 1 H), 3.84 - 3.82 (m, 7 H), 3.38 - 3.32 (m, 4 H), 2.96 - 2.93 (m, 7 H), 1.99 (bs, 2 H), 1.68 (bs, 2 H), 1.40 (d, J= 7.2 Hz, 3 H)m / zcalculated C 30 H 37 F5N8O5Sfor(M+H) + 717.3,found717.275(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)phenyl)acrylamide (400 MHz, DMSO-d6)δ 9.00 (s, 1 H), 8.46 (s, 1 H), 8.17 (s, 1 H), 8.10 (s, 1 H), 6.87 (s, 1 H), 6.63 (q,J= 8.9 Hz, 1 H), 6.19 (d,J= 13.2 Hz, 1 H), 5.72 (d,J= 10.4 Hz, 1 H), 5.18 - 5.11 (m, 1 H), 4.60 (t,J= 10.0 Hz, 1 H), 4.36 (d,J= 16.0 Hz, 1 H), 4.14 (d,J= 13.2 Hz, 1 H), 3.83 - 3.80 (m, 7 H), 3.34 - 3.33 (m, 4 H), 3.06 - 3.03 (m, 5 H), 2.84 - 2.79 (m, 6 H), 2.66 (bs, 2 H), 1.66 (bs, 2 H), 1.40 (d,J=6.8 Hz, 3 H)m / zcalculated 32 H 41 F5N8O5Sfor(M+H) + 745.3,found745.376N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.18 (s, 1H), 8.05 (s, 1H), 6.99 (s, 1H), 6.62 - 6.52 (dd,J= 16.1, 10.0 Hz, 1H), 6.35 (dd,J= 17.0, 6.1 Hz, 1H), 5.79 (dd,J= 10.3, 6.1 Hz, 1H), 5.22 - 5.11 (m, 1H),4.64 - 4.51 (m, 1H), 4.33 (d,J= 13.9 Hz, 1H), 4.22 - 4.14 (m, 1H), 3.23 - 3.07 (m, 5H), 2.94 - 2.78 (m, 1H), 2.67 - 2.49 (m, 2H), 2.30 (s, 6H), 2.25 - 2.12 (m, 2H), 2.06 - 1.84 (m, 3H), 1.72 - 1.56 (m, 2H), 1.42 (d,J= 7.1 Hz)m / zcalculated for C 31 H 36 F8N8O3(M+H) + 721.3,found721.277(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-methylpiperazin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.70 (s, 1H), 8.08 (s, 1H), 7.20 (s, 1H), 6.54 (dd,J= 16.9, 10.2 Hz, 1H), 6.34 (dd,J= 17.0, 1.4 Hz, 1H), 5.81 (dd,J= 10.2, 1.4 Hz, 1H), 5.22 - 5.11 (m, 1H), 4.67 - 4.53 (m, 1H), 4.35 (d,J= 14.0 Hz, 1H), 4.19 (d,J= 13.8 Hz, 1H), 2.99 - 2.52 (m, 10H), 2.45 (s, 3H), 2.04 - 1.54 (m, 5H), 1.43 (d,J= 7.2 Hz, 3H)m / zcalculated for C 30 H 34 F8N8O3(M+H) + 707.3,found707.278(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4) δ 8.71 (s, 1H), 8.07 (s, 1H), 6.91 (s, 1H), 6.62 - 6.45 (m, 1H), 6.29 (d,J= 17.0 Hz, 1H), 5.76 (d,J= 10.3 Hz, 1H), 5.22 - 5.07 (m, 1H), 4.72 (t,J= 12.1 Hz, 1H), 4.33 (d,J= 14.1 Hz, 1H), 4.18 (d,J= 13.5 Hz, 1H), 3.89 (s, 3H), 2.92 (t,J= 4.6 Hz, 4H), 2.79 - 2.58 (m, 5H), 2.54 (q,J= 7.3 Hz, 2H), 2.01 - 1.62 (m, 7H), 1.42 (d,J= 7.2 Hz, 3H), 1.14 (t,J= 7.2 Hz, 3H)m / zcalculated for C 31 H 39F5N8O3(M+H) + 667.3,found667.379(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-isopropylpiperazin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4) δ 8.71 (s, 1H), 8.07 (s, 1H), 6.91 (s, 1H), 6.49 (dd,J= 17.0, 10.3 Hz, 1H), 6.29 (dd,J= 17.0, 1.5 Hz, 1H), 5.77 (dd,J= 10.2, 1.4 Hz, 1H), 5.27 - 5.03 (m, 1H), 4.77 - 4.63 (m, 1H), 4.33 (d,J= 14.1 Hz, 1H), 4.18 (d,J= 12.8 Hz, 1H), 3.89 (s, 3H), 2.99 - 2.86 (m, 4H), 2.83 - 2.56 (m, 5H), 2.04 - 1.61 (m, 7H), 1.42 (d,J= 7.2 Hz, 3H), 1.13 (d,J= 6.5 Hz, 6H)m / zcalculated for C 32 H 41 F5N8O3(M+H) + 681.3,found681.380(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.70 (s, 1H), 8.07 (d,J= 0.8 Hz, 1H), 6.91 (s, 1H), 6.48 (dd,J= 16.9, 10.3 Hz, 1H), 6.29 (dd,J= 17.0, 1.5 Hz, 1H), 5.76 (dd,J= 10.2, 1.5 Hz, 1H), 5.16 (qd,J= 7.8, 4.6 Hz, 1H), 4.78 - 4.69 (m, 1H), 4.33 (d,J= 14.3 Hz, 1H), 4.18 (d,J= 14.0 Hz, 1H), 3.89 (s, 3H), 3.02 (t,J= 6.0 Hz, 2H), 2.91 (t,J= 4.8 Hz, 4H), 2.79 (d,J= 5.0 Hz, 4H), 2.70 - 2.59 (m, 2H), 2.34 (s, 3H), 2.22 - 2.13 (m, 2H), 2.00 - 1.91 (m, 5H), 1.77 - 1.68 (m, 3H), 1.69 - 1.56 (m, 3H), 1.43 (d,J= 7.2 Hz, 3H)m / zcalculated for C 35 H 46 F5N9O3(M+H) + 736.4,found736.381(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methoxy-[1,4'-bipiperidin]-1'-yl)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.69 (s, 1H), 8.07 (d,J= 0.7 Hz, 1H), 6.88 (s, 1H), 6.53 (dd,J= 17.0, 10.3 Hz, 1H), 6.37 - 6.25 (m, 1H), 5.76 (dd,J= 10.3, 1.5 Hz, 1H), 5.21 - 5.11 (m, 1H), 4.77 - 4.67 (m, 1H), 4.33 (d,J= 14.0 Hz, 1H), 4.22 - 4.16 (m, 1H), 3.88 (s, 3H), 3.33 (d,J= 0.7 Hz, 3H), 3.09 - 2.99 (m, 2H), 2.99 - 2.88 (m, 2H), 2.78 - 2.70 (m, 2H), 2.70 - 2.58 (m, 2H), 2.53 - 2.40 (m, 3H), 2.04 - 1.90 (m, 7H), 1.85 - 1.69 (m, 6H), 1.67 - 1.56 (m, 2H), 1.43 (d,J= 7.2 Hz, 3H)m / zcalculated for C 36 H 47 F5N8O4(M+H) + 751.4,found751.482(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-((dimethylamino)methyl)azetidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.00 (s, 1H), 7.79 (s, 1H), 6.42 (dd,J= 17.0, 10.1 Hz, 1H), 6.30 (ddd,J= 17.1, 1.9, 0.5 Hz, 1H), 6.22 (s, 1H), 5.74 (ddd,J= 10.0, 1.9, 0.7 Hz, 1H), 5.16 (p,J= 7.7 Hz, 1H), 4.65 (td,J= 12.0, 5.6 Hz, 1H), 4.30 (d,J= 13.9 Hz, 1H), 4.18 - 4.12 (m, 1H), 4.01 (t,J= 6.6 Hz, 2H), 3.85 (d,J= 0.8 Hz, 3H), 3.51 (t,J= 6.6 Hz, 2H), 2.92 - 2.83 (m, 1H), 2.71 (d,J= 7.2 Hz, 2H), 2.32 (s, 6H), 2.08 - 1.65 (m, 8H), 1.42 (d,J= 7.2 Hz, 3H)m / zcalculated for C 31 H 39 F5N8O3(M+H) + 667.3,found667.383N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((S)-1,1,1-trifluorobutan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.30 (s, 1H), 8.04 (s, 1H), 6.71 (s, 1H), 6.54 (dd,J= 16.9, 10.2 Hz, 1H), 6.31 (dd,J= 17.0, 1.7 Hz, 1H), 5.74 (dd,J= 10.2, 1.7 Hz, 1H), 4.98 - 4.88 (m, 1H), 4.71 - 4.63 (m, 1H), 4.25 (d,J= 14.1 Hz, 1H), 4.14 (d,J= 14.1 Hz, 1H), 3.87 (s, 3H), 3.20 (td,J= 9.1, 8.6, 4.1 Hz, 4H), 3.15 - 3.07 (m, 1H), 2.85 (p,J= 7.0 Hz, 1H), 2.74 - 2.55 (m, 2H), 2.28 (s, 6H), 2.22 - 2.12 (m, 1H), 2.05 - 1.96 (m, 2H), 1.93 - 1.82 (m, 4H), 1.77 - 1.69 (m, 2H), 0.89 (t,J= 7.4 Hz, 3H)m / zcalculated for C 32 H 41 F5N8O3(M+H) + 681.3,found681.384(S)-N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluorobutan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.72 (s, 1H), 8.07 (s, 1H), 6.87 (s, 1H), 6.53 (dd,J= 17.0, 10.3 Hz, 1H), 6.30 (dd,J= 17.0, 0.9 Hz, 1H), 5.76 (dd,J= 10.3, 0.9 Hz, 1H), 4.98 - 4.89 (m, 1H), 4.77 - 4.67 (m, 1H), 4.27 (d,J= 14.1 Hz, 1H), 4.15 (d,J= 14.1 Hz, 1H), 3.88 (s, 3H), 3.04 (d,J= 11.7 Hz, 2H), 2.78 - 2.70 (m, 6H), 2.67 - 2.52 (m, 1H), 2.04 - 1.92 (m, 4H), 1.89 - 1.76 (m, 4H), 1.67 (q,J= 5.4 Hz, 8H), 1.52 (q,J= 6.0 Hz, 2H), 0.90 (t,J= 7.3 Hz, 3H)m / zcalculated for C 36 H 47 F5N8O3(M+H) + 735.4,found735.485(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluorobutan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.73 (s, 1H), 8.07 (s, 1H), 6.91 (s, 1H), 6.48 (dd,J= 17.0, 10.2 Hz, 1H), 6.29 (dd,J= 17.0, 1.5 Hz, 1H), 5.77 (dd,J= 10.2, 1.5 Hz, 1H), 4.98 - 4.89 (m, 1H), 4.72 (ddt,J= 15.9, 12.1, 3.9 Hz, 1H), 4.27 (d,J= 14.1 Hz, 1H), 4.15 (d,J= 14.1 Hz, 1H), 3.89 (s, 3H), 2.91 (t,J= 4.8 Hz, 4H), 2.70 - 2.59 (m, 6H), 2.37 (s, 3H), 2.01 - 1.81 (m, 6H), 1.79 - 1.71 (m, 2H), 0.90 (t,J= 7.4 Hz, 3H)m / zcalculated for C 31 H 39 F5N8O3(M+H) + 667.3,found667.386N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((8-(4-methyltetrahydro-2H-pyran-4-yl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.14 (s, 1H), 8.10 (s, 1H), 6.62 (s, 1H), 6.50 (dd,J= 17.0, 10.2 Hz, 1H), 6.33 (dd,J= 17.0, 1.8 Hz, 1H), 5.77 (dd,J= 10.2, 1.8 Hz, 1H), 5.07 - 4.99 (m, 1H), 4.25 (d,J= 14.3 Hz, 1H), 4.11 (d,J= 14.3 Hz, 1H), 3.88 (s, 3H), 3.63 - 3.55 (m, 2H), 3.48 - 3.40 (m, 2H), 3.26 - 3.21 (m, 1H), 3.17 - 3.10 (m, 2H), 2.77 - 2.63 (m, 2H), 2.45 (s, 6H), 2.24 (dtd,J= 12.4, 6.8, 3.5 Hz, 1H), 2.02 - 1.90 (m, 5H), 1.70 (s, 3H), 1.41 (d,J= 7.2 Hz, 3H)m / zcalculated for C 31 H 41 F3N8O4(M+H) + 647.3,found647.387N-(3-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-6-((R)-3-(dimethylamino)pyrrolidin-1-yl)-2-fluoro-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4) δ 7.93 (s, 1H), 6.46 (dd,J= 17.1, 10.2 Hz, 1H), 6.30 (dd,J= 17.0, 1.7 Hz, 1H), 6.21 (s, 1H), 5.75 (dd,J= 10.2, 1.7 Hz, 1H), 5.21 - 5.08 (m, 1H), 4.55 - 4.37 (m, 1H), 4.28 (d,J= 13.9 Hz, 1H), 4.15 (d,J= 13.9 Hz, 1H), 3.77 (s, 3H), 3.48 - 3.31 (m, 4H), 2.89 - 2.75 (m, 1H), 2.63 - 2.44 (m, 2H), 2.28 (s, 6H), 2.23 - 2.11 (m, 2H), 2.04 - 1.54 (m, 1H), 1.42 (d,J= 7.2 Hz)m / zcalculated for C 31 H 38 F6N8O3(M+H) + 685.3,found685.388(S)-N-(3-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-fluoro-4-methoxy-6-(4-methylpiperazin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4) δ 7.95 (s, 1H), 6.56 (s, 1H), 6.49 (dd,J= 16.8, 10.3 Hz, 1H), 6.31 (dd,J= 17.0, 1.7 Hz, 1H), 5.76 (d,J= 9.4 Hz, 1H), 5.15 (dt,J= 15.3, 7.6 Hz, 1H), 4.56 - 4.41 (m, 1H), 4.30 (d,J= 14.1 Hz, 1H), 4.15 (d,J= 13.7 Hz, 1H), 3.80 (s, 3H), 3.05 - 2.94 (m, 4H), 2.69 - 2.45 (m, 6H), 2.34 (s, 3H), 2.05 - 1.84 (m, 2H), 1.81 - 1.55 (m, 4H), 1.42 (d,J= 7.3 Hz, 3H)m / zcalculated for C 30 H 36 F6N8O3(M+H) + 671.3,found671.389(R)-N-(5-((8-(4,4-difluorocyclohexyl)-6-(2,2-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4) δ 8.28 (s, 1H), 7.95 (s, 1H), 6.69 (s, 1H), 6.53 (dd,J= 17.0, 10.2 Hz,1H), 6.31 (dd,J= 17.0, 1.6 Hz, 1H), 6.00 (tt,J= 56.1, 4.1 Hz, 1H), 5.74 (dd,J= 10.3, 1.6 Hz, 1H), 4.76 - 4.63 (m, 1H), 4.33 (s, 2H), 3.86 (s, 3H), 3.69 (td,J= 14.6, 4.1 Hz, 2H), 3.24 - 3.05 (m, 4H), 2.90 - 2.76 (m, 1H), 2.69 - 2.56 (m, 2H), 2.28 (s, 6H), 2.22 - 2.09 (m, 1H), 2.04 - 1.64 (m, 6H)m / zcalculated for C 30 H 38 F4N8O3(M+H) + 635.3,found635.390(R)-N-(5-((8-(4,4-difluorocyclohexyl)-6-(2,2-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4) δ 8.69 (s, 1H), 7.99 (s, 1H), 6.90 (s, 1H), 6.48 (dd,J= 17.0, 10.2 Hz, 1H), 6.29 (dd,J= 17.0, 1.5 Hz, 1H), 6.01 (tt,J= 56.0, 4.2 Hz, 1H), 5.76 (dd,J= 10.3, 1.4 Hz, 1H), 4.80 - 4.69 (m, 1H), 4.35 (s, 2H), 3.88 (s, 3H), 2.90 (t,J= 4.7 Hz, 4H), 2.74 - 2.56 (m, 6H), 2.36 (s, 3H), 2.05 - 1.62 (m, 6H)m / zcalculated for C 29 H 36 F4N8O3(M+H)+ 621.3,found621.391(S)-N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, DMSO-d6)δ 8.98 (s, 1 H), 8.32 (s, 1 H), 8.14 - 8.13 (m, 2 H), 6.84 (s, 1 H), 6.63 (q,J= 13.1 Hz, 1 H), 6.18 (dd,J= 17.0, 1.8 Hz, 1 H), 5.71 (dd,J= 10.4, 1.6 Hz, 1 H), 4.68 - 4.62 (m, 1 H), 4.36 (d,J= 14.4 Hz, 1 H), 4.13 (d,J= 14.0 Hz, 1 H), 3.82 - 3.80 (m, 7 H), 2.84 (t,J= 4.6 Hz, 7 H), 2.53 (bs, 2 H), 2.25 (s, 4 H), 1.47 (t,J= 9.6 Hz, 2 H), 1.40 (d,J= 7.2 Hz, 3 H)m / zcalculated C 29 H 37 F3N8O4for(M+H) + 619.3,found619.292(S)-N-(2-([1,4'-bipiperidin]-1'-yl)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, DMSO-d6)δ 8.98 (s, 1 H), 8.35 (s, 1 H), 8.14 - 8.12 (m, 2 H), 6.81 (s, 1 H), 6.19 (d,J= 18.4 Hz, 1 H), 5.72 (d,J= 11.2 Hz, 1 H), 5.20 - 5.13 (m, 1 H), 4.68 - 4.62 (m, 1 H), 4.36 (d,J= 14.0 Hz, 1 H), 4.13 (d,J= 14.0 Hz, 1 H), 3.81 - 3.79 (m, 7 H), 3.23 (t,J= 11.6 Hz, 2 H), 3.04 (d,J= 8.4 Hz, 2 H), 2.67 (t,J= 7.2 Hz, 2 H), 2.57 - 2.50 (m, 2 H), 1.82 - 1.46 (m, 14 H), 1.40 (d,J= 7.2 Hz, 3 H)m / zcalculated C 34 H 45 F3N8O4for(M+H) + 687.3,found687.393(S)-N-(4-methoxy-2-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, DMSO-d6)δ 9.00 (s, 1 H), 8.32 (s, 1 H), 8.15 - 8.14 (m, 2 H), 6.84 (s, 1 H), 6.63 (q,J= 9.1 Hz, 1 H), 6.19 (dd,J= 17.0, 1.8 Hz, 1 H), 5.72 (dd,J= 9.8, 1.0 Hz, 1 H), 5.20 - 5.13 (m, 1 H), 4.68 - 4.62 (m, 1 H), 4.36 (d,J= 14.4 Hz, 1 H), 4.13 (d,J= 13.6 Hz, 1 H), 3.82 - 3.79 (m, 5 H), 3.34 - 3.32 (m, 4 H), 3.23 (t,J= 11.4 Hz, 2 H), 3.06 (s, 3 H), 2.85 (t,J= 4.4 Hz, 4 H), 2.79 (t,J= 6.8 Hz, 2 H), 2.65 (bs, 4 H), 1.48 (bs, 2 H), 1.40 (d,J= 7.2 Hz, 3 H)m / zcalculated C 31 H 41 F3N8O6Sfor(M+H) + 711.3,found711.394(S)-N-(2-(4-(dimethylamino)piperidin-1-yl)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, DMSO-d6)δ 9.00 (s, 1 H), 8.35 (s, 1 H), 8.14 (s, 2 H), 6.82 (s, 1 H), 6.67 (q,J= 9.2 Hz, 1 H), 6.20 (d,J= 16.4 Hz, 1 H), 5.72 (d,J= 10.8 Hz, 1 H), 5.18 - 5.14 (m, 1 H), 4.65 (t,J= 11.6 Hz, 1 H), 4.36 (d,J= 14.0 Hz, 1 H), 4.13 (d,J= 14.0 Hz, 1 H), 3.81 - 3.79 (m, 7 H), 3.04 (d,J= 11.6 Hz, 2 H), 2.67 (t,J= 10.6 Hz, 2 H), 2.39 (bs, 4 H), 1.89 (d,J= 12.4 Hz, 2 H), 1.79 - 1.72 (m, 2 H), 1.47 (t,J= 9.2 Hz, 2 H), 1.39 (d,J=15.2 Hz, 3 H)m / zcalculated C 31 H 41 F3N8O4for(M+H) + 647.3,found647.395(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.70 (s, 1H), 8.06 (s, 1H), 6.88 (s, 1H), 6.54 (dd,J= 17.0, 10.3 Hz, 1H), 6.30 (dd,J= 17.0, 1.6 Hz, 1H), 5.76 (dd,J= 10.3, 1.6 Hz, 1H), 5.17 (q,J= 7.7 Hz, 1H), 4.75 - 4.67 (m, 1H), 4.33 (d,J= 14.1 Hz, 1H), 4.17 (d,J= 14.1 Hz, 1H), 3.88 (s, 3H), 3.05 (d,J= 11.5 Hz, 4H), 2.76 (dd,J= 12.0, 2.2 Hz, 2H), 2.67 - 2.60 (m, 1H), 2.45 (s, 6H), 2.05 - 1.94 (m, 4H), 1.82 - 1.69 (m, 6H), 1.42 (d,J= 7.3 Hz, 3H)m / zcalculated for C 32 H 41 F5N8O3(M+H) + 681.3,found681.496(R)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.28 (s, 1H), 7.99 (s, 1H), 6.70 (s, 1H), 6.53 (dd,J= 17.0, 10.3 Hz, 1H), 6.31 (dd,J= 17.0, 1.7 Hz, 1H), 5.74 (dd,J= 10.3, 1.7 Hz, 1H), 4.73 (q,J= 12.0, 10.5 Hz, 1H), 4.36 (s, 2H), 4.09 (q,J= 9.2 Hz, 2H), 3.87 (s, 3H), 3.25 - 3.16 (m, 4H), 3.15 - 3.05 (m, 1H), 2.90 - 2.79 (m, 1H), 2.63 (q,J= 13.0 Hz, 2H), 2.28 (s, 6H), 2.20 - 2.12 (m, 1H), 2.02 - 1.94 (m, 2H), 1.91 - 1.81 (m, 2H), 1.70 (d,J=13.7 Hz, 2H)m / zcalculated for C 30 H 37 F5N8O3(M+H) + 653.3,found653.397N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.70 (d,J= 3.4 Hz, 1H), 8.02 (d,J= 0.9 Hz, 1H), 6.86 (s, 1H), 6.53 (dd,J= 17.0, 10.3 Hz, 1H), 6.30 (dd,J= 17.0, 1.5 Hz, 1H), 5.76 (dd,J= 10.3, 1.5 Hz, 1H), 4.76 (s, 1H), 4.37 (s, 2H), 4.10 (q,J= 9.2 Hz, 2H), 3.87 (d,J= 2.9 Hz, 3H), 3.03 (d,J=11.3 Hz, 2H), 2.73 (d,J= 7.6 Hz, 6H), 2.68 - 2.51 (m, 1H), 2.04 - 1.93 (m, 4H), 1.89 - 1.76 (m, 4H), 1.75 - 1.63 (m, 8H), 1.52 (s, 2H)m / zcalculated for C 34 H 43 F5N8O3(M+H) + 707.3,found707.498N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide 400 MHz, Methanol-d4)δ 8.71 (s, 1H), 8.01 (s, 1H), 6.90 (s, 1H), 6.48 (dd,J= 17.0, 10.2 Hz, 1H), 6.29 (dd,J= 17.0, 1.5 Hz, 1H), 5.76 (dd,J= 10.2, 1.5 Hz, 1H), 4.78 - 4.69 (m, 1H), 4.36 (s, 2H), 4.09 (q,J= 9.2 Hz, 2H), 3.88 (s, 3H), 2.89 (t,J= 4.8 Hz, 4H), 2.70 - 2.57 (m, 6H), 2.36 (s, 3H), 2.00 - 1.91 (m, 2H), 1.89 - 1.77 (m, 2H), 1.71 (d,J= 12.9 Hz, 2H)m / zcalculated for C 29 H 35 F5N8O3(M+H) + 639.3,found639.399N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(spiro[2.5]octan-6-yl)-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.26 (s, 1H), 8.02 (s, 1H), 6.67 (s, 1H), 6.53 (dd,J= 17.0, 10.2 Hz, 1H), 6.31 (dd,J= 17.0, 1.6 Hz, 1H), 5.74 (dd,J= 10.2, 1.7 Hz, 1H), 5.24 - 5.08 (m, 1H), 4.65 - 4.56 (m, 1H), 4.31 (d,J= 13.9 Hz, 1H), 4.15 (d,J= 13.9 Hz, 1H), 3.89 (s, 3H), 3.25 - 3.12 (m, 4H), 2.96 - 2.85 (m, 1H), 2.60 - 2.44 (m, 2H), 2.32 (s, 6H), 2.23 - 2.13 (m, 1H), 1.94 - 1.80 (m, 4H), 1.68 - 1.57 (m, 3H), 1.42 (d,J= 7.2 Hz, 3H), 0.32 - 0.06 (m, 4H)m / zcalculated for C 33 H 43 F3N8O3(M+H) + 657.3,found657.3100(S)-N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((7-oxo-8-(spiro[2.5]octan-6-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.65 (s, 1H), 8.04 (s, 1H), 6.88 (s, 1H), 6.50 (dd,J= 17.0, 10.3 Hz, 1H), 6.30 (dd,J= 17.0, 1.5 Hz, 1H), 5.75 (dd,J= 10.2, 1.5 Hz, 1H), 5.25 - 5.11 (m, 1H), 4.67 - 4.55 (m, 1H), 4.24 (dd,J= 61.8, 14.0 Hz, 1H), 3.88 (s, 3H), 2.97 - 2.86 (m, 4H), 2.67 (s, 4H), 2.57 - 2.45 (m, 2H), 2.41 - 2.32 (m, 5H), 1.96 - 1.79 (m, 2H), 1.71 - 1.60 (m, 2H), 1.42 (d,J= 7.2 Hz, 3H), 0.27 - 0.11 (m, 4H)m / zcalculated for C 32 H 41 F3N8O3(M+H) + 643.3,found643.3101(S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(3-(pyrrolidin-1-yl)azetidin-1-yl)phenyl)acrylamide (400 MHz, DMSO-d6)δ 9.26 (s, 1 H), 8.11 (s, 1 H), 7.97 (s, 1 H), 7.62 (s, 1 H), 6.47 (q,J= 9.1 Hz, 1 H), 6.21 (s, 1 H), 6.16 (dd,J= 16.8, 2.0 Hz, 1 H), 5.66 (dd,J= 10.4, 2.0 Hz, 1 H), 5.19 - 5.11 (m, 1 H), 4.56 (t,J= 12.0 Hz, 1 H), 4.34 (d,J= 14.0 Hz, 1 H), 4.11 (d,J= 14.0 Hz, 1 H), 3.91 (t,J= 7.0 Hz, 2 H), 3.81 (s, 3 H), 3.63 (t,J= 6.4 Hz, 2 H), 2.41 (s, 5 H), 2.00 (bs, 3 H), 1.87 - 1.78 (m, 1 H), 1.69 (bs, 8 H), 1.39 (d,J= 7.2 Hz, 3 H)m / zcalculated C 32 H 39 F5N8O3for(M+H) + 679.3,found679.3102N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.77 (s, 1H), 8.03 (s, 1H), 6.94 (s, 1H), 6.49 (dd,J= 17.0, 10.2 Hz, 1H), 6.31 (dd,J= 17.0, 1.7 Hz, 1H), 5.75 (dd,J= 10.2, 1.7 Hz, 1H), 4.80 - 4.72 (m, 1H), 4.38 (s, 2H), 4.11 (q,J= 9.2 Hz, 2H), 3.88 (s, 3H), 3.03 (t,J= 5.9 Hz, 2H), 2.65 (s, 3H), 2.70 - 2.58 (m, 2H), 2.48 (t,J= 5.9 Hz, 2H), 2.38 - 2.35 (m, 1H), 2.31 (s, 6H), 1.96 (s, 2H), 1.89 - 1.78 (m, 2H), 1.72 (d,J= 13.7 Hz, 2H)m / zcalculated for C 29 H 37 F5N8O3(M+H) + 641.3,found641.3103N-(5-((8-(4,4-difluorocyclohexyl)-6-((S)-1-fluoropropan-2-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.29 (s, 1H), 7.99 (s, 1H), 6.53 (dd,J= 17.0, 10.3 Hz, 1H), 6.31 (dd,J= 17.0, 1.7 Hz, 1H), 5.74 (dd,J= 10.3, 1.7 Hz, 1H), 4.71 - 4.63 (m, 1H), 4.57 - 4.36 (m, 2H), 4.21 (d,J= 12.0 Hz, 2H), 3.87 (s, 3H), 3.25 - 3.18 (m, 2H), 3.15 - 3.08 (m, 1H), 2.90 - 2.84 (m, 1H), 2.71 - 2.59 (m, 1H), 2.30 (s, 6H), 2.22 - 2.13 (m, 1H), 2.02 - 1.80 (m, 6H), 1.71 (d,J= 13.0 Hz, 2H), 1.22 (dd,J= 7.1, 1.3 Hz, 3H)m / zcalculated for C 31 H 41 F3N8O3(M+H) + 631.3,found631.4104(S)-N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-6-(1-fluoropropan-2-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.70 (s, 1H), 8.02 (s, 1H), 6.87 (s, 1H), 6.53 (dd,J= 17.0, 10.3 Hz, 1H), 6.30 (dd,J= 17.0, 1.5 Hz, 1H), 5.76 (dd,J= 10.3, 1.5 Hz, 1H), 4.76 - 4.66 (m, 1H), 4.60 - 4.37 (m, 2H), 4.22 (d,J= 13.3 Hz, 2H), 3.88 (s, 3H), 3.06 (d,J= 11.6 Hz, 2H), 2.89 - 2.81 (m, 4H), 2.76 (t,J= 11.7 Hz, 2H), 2.70 - 2.60 (m, 1H), 2.04 (d,J= 12.2 Hz, 2H), 2.01 - 1.92 (m, 2H), 1.89 - 1.79 (m, 4H), 1.77 - 1.67 (m, 8H), 1.56 (d,J= 5.8 Hz, 2H), 1.22 (dd,J= 7.1, 1.3 Hz, 3H)m / zcalculated for C 35 H 47 F3N8O3(M+H) + 685.4,found685.5105(R)-N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.70 (s, 1H), 8.07 (s, 1H), 6.88 (s, 1H), 6.53 (dd,J= 17.0, 10.3 Hz, 1H), 6.30 (dd,J= 17.0, 1.5 Hz, 1H), 5.76 (dd,J= 10.3, 1.5 Hz, 1H), 5.16 (dt,J= 15.2, 7.8 Hz, 1H), 4.77 - 4.66 (m, 1H), 4.33 (d,J= 14.0 Hz, 1H), 4.18 (d,J= 14.0 Hz, 1H), 3.88 (s, 3H), 3.07 (d,J= 11.9 Hz, 2H), 2.89 - 2.81 (m, 4H), 2.76 (t,J= 11.5 Hz, 2H), 2.68 - 2.60 (m, 1H), 2.05 (d,J= 11.8 Hz, 2H), 2.01 - 1.91 (m, 2H), 1.90 - 1.80 (m, 4H), 1.74 (t,J= 5.8 Hz, 8H), 1.57 (d,J= 6.3 Hz, 2H), 1.43 (d,J= 7.2 Hz, 3H)m / zcalculated for C 35 H 45 F5N8O3(M+H) + 721.4,found721.3106(R)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.72 (s, 1H), 8.06 (s, 1H), 6.90 (s, 1H), 6.48 (dd,J= 17.0, 10.2 Hz, 1H), 6.29 (dd,J= 17.0, 1.6 Hz, 1H), 5.76 (dd,J= 10.2, 1.6 Hz, 1H), 5.16 (p,J= 7.7 Hz, 1H), 4.72 (td,J= 10.2, 8.3, 4.8 Hz, 1H), 4.32 (d,J= 14.0 Hz, 1H), 4.16 (d,J= 14.0 Hz, 1H), 3.88 (s, 3H), 2.90 (t,J= 4.8 Hz, 4H), 2.71 - 2.56 (m, 6H), 2.37 (s, 3H), 2.02 - 1.82 (m, 4H), 1.73 (d,J= 14.8 Hz, 2H), 1.42 (d,J= 7.3 Hz, 3H)m / zcalculated for C 30 H 37 F5N8O3(M+H) + 653.3,found653.3107(R)-N-(2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(spiro[2.5]octan-6-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.19 (s, 1H), 7.98 (s, 1H), 6.68 (s, 1H), 6.58 - 6.45 (m, 1H), 6.35 - 6.27 (m, 1H), 5.75 (dd,J= 10.3, 1.5 Hz), 4.80 - 4.76 (m, 1H), 4.37 (s, 2H), 4.11 (q,J= 9.2 Hz, 2H), 3.86 (s, 3H), 3.25 - 3.13 (m, 4H), 2.99 - 2.82 (m, 1H), 2.71 - 2.51 (m, 2H), 2.48 (s, 6H), 2.33 - 1.43 (m, 8H), 0.91 - 0.2 (m, 3H)m / zcalculated for C32 H 41 F3N8O3(M+H) + 643.3,found643.3108N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((7-oxo-8-(spiro[2.5]octan-6-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.60 (s, 1H), 7.99 (s, 1H), 6.87 (s, 1H), 6.53 - 6.41 (m, 1H), 6.35 - 6.23 (m, 1H), 5.76 (d,J= 10.2 Hz, 1H), 4.79 - 4.65 (m, 1H), 4.37 (s, 2H), 4.10 (q,J= 9.1 Hz, 2H), 3.86 (s, 3H), 2.96 - 2.83 (m, 4H), 2.77 - 2.45 (m, 6H), 2.37 (s, 3H), 2.21 - 2.05 (m, 2H), 2.03 - 1.85 (m, 2H), 1.81 - 1.58 (m, 2H), 0.83 - 0.2 (m, 4H)m / zcalculated for C 31 H 39 F3N8O3(M+H) + 629.3,found629.3109N-(2-([1,4'-bipiperidin]-1'-yl)-4-methoxy-5-((7-oxo-8-(spiro[2.5]octan-6-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.59 (s, 1H), 8.00 (s, 1H), 6.84 (s, 1H), 6.59 - 6.45 (m, 1H), 6.37 - 6.24 (m), 5.76 (d,J= 10.4 Hz, 1H), 4.78 - 4.65 (m, 1H), 4.37 (s, 2H), 4.11 (q,J= 9.2 Hz, 2H), 3.85 (s, 3H), 3.08 (dd,J= 18.1, 6.7 Hz, 2H), 2.90 (s, 4H), 2.75 (t,J= 11.4 Hz, 3H), 2.67 - 2.47 (m, 1H), 2.16 - 1.99 (m, 4H), 1.99 - 1.80 (m, 4H), 1.80 - 1.48 (m, 9H), 0.83 - 0.2 (m, 4H)m / zcalculated for C 36 H 47 F3N8O3(M+H) + 697.4,found697.4111N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.68 (s, 1H), 8.04 (s, 1H), 7.06 (s, 1H), 6.75 (t,J= 74.0 Hz, 1H), 6.55 (dd,J= 16.9, 10.3 Hz, 1H), 6.32 (dd,J= 17.0, 1.4 Hz, 1H), 4.75 - 4.64 (m, 1H), 4.39 (s, 2H), 4.12 (q,J= 9.2 Hz, 2H), 3.10 - 3.04 (m,J= 12.1 Hz, 2H), 2.76 - 2.45 (m, 8H), 2.08 - 1.56 (m, 17H)m / zcalculated for C 34 H 41 F7N8O3(M+H) +743.3,found743.4112(S)-N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-6-(1-fluoropropan-2-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.71 (s, 1H), 8.04 (s, 1H), 7.08 (s, 1H), 6.85 (t,J= 73.9 Hz, 1H), 6.62 - 6.50 (m, 1H), 6.33 (dd,J= 17.0, 1.5 Hz, 1H), 5.80 (dd,J= 10.2, 1.5 Hz, 1H), 4.69 - 4.61 (m, 1H), 4.58 - 4.36 (m, 2H), 4.24 (d,J= 13.0 Hz, 2H), 3.12 (d,J= 12.0 Hz, 2H), 3.07 - 2.92 (m, 4H), 2.80 - 2.71 (m, 2H), 2.67 - 2.56 (m, 2H), 2.10 (d,J= 12.0 Hz, 2H), 2.00 - 1.88 (m, 4H), 1.69 (d,J= 13.4 Hz, 2H), 1.23 (dd,J= 7.1, 1.3 Hz, 3H), 1.83 - 1.76 (m, 8H), 1.63 - 1.58 (m, 1H)m / zcalculated for C 35 H 45 F5N8O3(M+H) + 721.4,found721.3113N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.68 (s, 1H), 8.04 (s, 1H), 7.07 (s, 1H), 6.75 (t,J= 74.0 Hz, 1H), 6.55 (dd,J= 17.0, 10.5 Hz, 1H), 6.32 (dd,J= 17.1, 1.5 Hz, 1H), 5.79 (dd,J= 10.4, 1.4 Hz, 1H), 4.74 - 4.64 (m, 1H), 4.39 (s, 2H), 4.12 (q,J= 9.3 Hz, 2H), 3.05 (d,J= 11.6 Hz, 2H), 2.77 - 2.46 (m, 12H), 2.41 - 2.32 (m, 1H), 2.28 (s, 3H), 2.04 - 1.88 (m, 4H), 1.86 - 1.64 (m, 6H)m / zcalculated for C 34 H 42 F7N9O3(M+H) + 758.3,found758.3114N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.66 (s, 1H), 8.04 (s, 1H), 7.15 (s, 1H), 6.56 (dd,J= 17.0, 10.3 Hz, 1H), 6.33 (dd,J= 16.9, 1.4 Hz, 1H), 5.81 (dd,J= 10.3, 1.5 Hz, 1H), 4.72 - 4.58 (m, 1H), 4.39 (s, 2H), 4.12 (q,J= 9.2 Hz, 2H), 3.14 - 3.03 (m, 2H), 2.90 - 2.52 (m, 12H), 2.50 - 2.43 (m, 1H), 2.40 (s, 3H), 2.08 - 1.87 (m, 4H), 1.84 - 1.60 (m, 6H)m / zcalculated for C 34 H 41F8N9O3(M+H) + 776.3,found776.4115N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)but-2-ynamide (400 MHz, Methanol-d4)δ8.55(s,1H),8.02(s,1H),6.87(s,1H),4.76-4.68(m,1H),4.38(s,2H),4.12(q,J= 9.1 Hz, 2H), 3.87 (s, 3H), 3.05 (d,J= 12.1 Hz, 2H), 2.81 - 2.49 (m, 12H), 2.43 - 2.34 (m, 1H), 2.31 (s, 3H), 2.08 - 2.04 (m, 3H), 2.01 (s, 3H), 1.97 - 1.80 (m, 3H), 1.77 - 1.68 (m, 4H)m / zcalculated C 35 H 44 F5N9O3for(M+H) + 734.4,found734.4116N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-fluoroacrylamide (400 MHz, Methanol-d4)δ8.84(s,1H),8.05(s,1H),6.96(s,1H),5.69(dd,J= 48.3, 3.5 Hz, 1H), 5.31 (dd,J= 15.7, 3.5 Hz, 1H), 4.79 - 4.72 (m, 1H), 4.39 (s, 2H), 4.12 (q,J= 9.2 Hz, 2H), 3.88 (s, 3H), 3.11 - 2.91 (m, 13H), 2.87 - 2.71 (m, 2H), 2.12 - 1.90 (m, 6H), 1.85 (s, 3H), 1.81 - 1.65 (m, 4H)m / zcalculated C 34 H 43 F6N9O3for(M+H) + 740.3,found740.4117N-(4-methoxy-5-((8-(4-methoxyphenyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)acrylamide (400 MHz, DMSO-d6) δ 8.80 (s,J= 30.6 Hz, 1H), 8.12 (s, 2H), 7.69 (s,J= 11.6 Hz, 1H), 7.09 (d,J= 8.7 Hz, 2H), 6.86 (d,J= 8.4 Hz, 2H), 6.67 (s, 1H), 6.18 (d,J= 17.0 Hz, 1H), 5.69 (d,J= 10.3 Hz), 4.53 (s, 2H), 4.23 (q,J= 9.5 Hz, 2H), 3.73 (s, 3H), 3.69 (s, 3H), 2.91 (d,J= 10.6 Hz, 2H), 2.55 (dd,J= 21.4, 9.8 Hz, 4H), 2.39 - 2.15 (m, 9H), 2.11 (s, 3H), 1.77 (d,J= 10.9 Hz, 2H), 1.69 - 1.59 (m, 2H)m / zcalculated for C 35 H 42 F3N9O4(M+H) +710.3,found710.31182-Fluoro-N-(4-methoxy-5-((8-(4-methoxyphenyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)acrylamide (400 MHz, DMSO-d6) δ 9.21 - 9.15 (s, 1H), 8.27 (s, 1H), 8.13 (s, 1H), 7.77 (s, 1H), 7.07 (d,J= 8.9 Hz, 2H, 6.84 (d,J= 8.8 Hz, 2H), 6.80 (s, 1H), 5.69 (dd, 1H), 5.41 (dd,J= 15.5, 7.8 Hz, 1H), 4.54 (s, 2H), 4.23 (q,J= 9.5 Hz, 2H), 3.72 (s, 3H), 3.70 (s, 3H), 2.87 (d,J=11.5 Hz, 2H), 2.66 (t,J= 11.2 Hz, 2H), 2.26 (m, 9H), 2.12 (s, 3H), 1.87 - 1.81 (m, 2H), 1.48 (dt,J= 20.2, 10.0 Hz, 2H)m / zcalculated for C 35 H 41 F4N9O4(M+H) + 728.3,found728.3119N-(4-methoxy-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-5-((7-oxo-6-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.66 (d,J= 8.4 Hz, 2H), 7.45 (d,J= 7.9 Hz, 2H), 6.65 (s, 1H), 6.18 (d,J= 16.8 Hz, 1H), 5.66 (D,J= 18.5 Hz, 1H), 4.56 (s, 2H), 4.24 (t,J= 9.2 Hz, 2H), 3.63 (s, 3H), 2.99 - 2.83 (m, 4H), 2.39 - 2.18 (m, 7H), 2.11 (s, 3H), 1.99 - 1.85 (m, 2H), 1.78 (d,J= 10.9 Hz, 2H), 1.70 - 1.57 (m, 2H)m / zcalculated for C 35 H 39 F6N9O3(M+H) + 748.3,found748.41202-Fluoro-N-(4-methoxy-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-5-((7-oxo-6-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.66 (d,J= 8.4 Hz, 2H), 7.45 (d,J= 7.9 Hz, 2H), 6.65 (s, 1H), 6.18 (d,J= 16.8 Hz, 1H), 5.66 (D,J= 18.5 Hz, 1H), 4.56 (s, 2H), 4.24 (t,J= 9.2 Hz, 2H), 3.63 (s, 3H), 2.99 - 2.83 (m, 4H), 2.58 (d,J=10.0 Hz, 4H), 2.39 - 2.18 (m, 3H), 2.11 (s, 3H), 1.99 - 1.85 (m, 2H), 1.78 (d,J= 10.9 Hz, 2H), 1.70 - 1.57 (m, 2H)m / zcalculated for C 35 H 38 F7N9O3(M+H) + 766.3,found766.4121N-(5-((8-(3,3-difluorocyclobutyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4)δ8.89(s,1H),8.04(s,1H),6.85(s,1H),6.51(dd,J= 16.9, 10.3 Hz, 1H), 6.32 (dd,J= 17.0, 1.5 Hz, 1H), 5.75 (dd,J= 10.3, 1.3 Hz, 1H), 4.80 - 4.78 (m, 1H), 4.39 (s, 2H), 4.13 (q,J= 9.2 Hz, 2H), 3.87 (s, 3H), 3.13 - 2.31 (m, 17H), 2.28 (s, 3H), 2.05 - 1.93 (m, 2H), 1.79 - 1.60 (m, 2H)m / zcalculated for C 32 H 40 F5N9O3(M+H) +694.3, found 694.3122N-(5-((8-(3,3-difluorocyclobutyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-fluoroacrylamide (400 MHz, Methanol-d4)δ 9.13 (s, 1H), 8.06 (s, 1H), 6.93 (s, 1H), 5.72 (dd,J= 48.3, 3.4 Hz, 1H), 5.29 (dd,J= 15.7, 3.4 Hz, 1H), 4.93 - 4.88 (m, 1H), 4.41 (s, 2H), 4.14 (q,J= 9.2 Hz, 2H), 3.88 (s, 3H), 3.08 - 2.33 (m, 17H), 2.30 (s, 3H), 2.13 - 1.96 (m, 2H), 1.66 (qd,J=12.1, 3.8 Hz, 2H)m / zcalculated for C 32 H 39 F6N9O3(M+H) + 712.3, found 712.3123N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.63 (s, 1H), 7.99 (s, 1H), 6.83 (s, 1H), 6.54 (dd,J= 17.0, 10.3 Hz, 1H), 6.31 (dd,J= 17.0, 1.6 Hz, 1H), 5.76 (dd,J= 10.2, 1.6 Hz, 1H), 4.89 - 4.84 (m, 1H), 4.35 (s, 2H), 4.09 (q,J= 9.2 Hz, 2H), 3.94 - 3.81 (m, 5H), 3.39 (t,J= 11.3 Hz, 2H), 3.02 (d,J= 11.6 Hz, 2H), 2.76 - 2.29 (m, 15H), 2.27 (s, 3H), 1.97 (d,J= 11.2 Hz, 2H), 1.74 - 1.62 (m, 2H), 1.61 - 1.50 (m, 2H)m / zcalculated for C 33 H 44 F3N9O4(M+H) + 688.4, found 688.41242-Fluoro-N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.78 (s, 1H), 8.02 (s, 1H), 6.93 (s, 1H), 5.69 (dd,J= 48.1, 3.4 Hz, 1H), 5.32 (dd,J= 15.6, 3.4 Hz, 1H), 4.93 - 4.89 (m, 1H), 4.38 (s, 2H), 4.12 (q,J= 9.3 Hz, 2H), 3.87 (s, 5H), 3.39 (t,J= 11.5 Hz, 2H), 3.28 (s, 3H), 3.02 (d,J= 11.3 Hz, 2H), 2.84 - 2.32 (m, 13H), 2.29 (s, 3H), 2.04 (d,J= 11.4 Hz, 2H), 1.73 - 1.48 (m, 4H)m / zcalculated for C 33 H 43 F4N9O4(M+H) + 706.3, found 706.4125(E)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(dimethylamino)but-2-enamide (400 MHz, Methanol-d4)δ8.71(s,1H),8.03(s,1H),6.88(s,1H),6.90-6.78(m,1H),6.45-6.34(m,1H),4.78(m,1H),4.38(s,2H),4.11(q,J= 9.2 Hz, 2H), 3.88 (s, 3H), 3.19 (dd,J= 6.7, 1.5 Hz, 2H), 3.08 - 2.99 (m, 2H), 2.78 - 2.49 (m, 12H), 2.42 - 2.35 (m, 1H), 2.30 (s, 3H), 2.29 (s, 6H), 2.04 - 1.88 (m, 6H), 1.86 - 1.66 (m, 4H)m / zcalculated C 37 H 51 F5N 10 O3for(M+H) +779.4,found779.5126N-(4-methoxy-5-((8-(4-methoxyphenyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)but-2-ynamide (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.69 (s, 1H), 7.06 (s, 2H), 6.89 (s, 2H), 6.70 (s, 1H), 4.53 (s, 2H), 4.22 (dd,J= 18.8, 9.3 Hz, 2H), 3.75 (s, 3H), 3.65 (s, 3H), 3.51 - 3.25 (m, 4H), 2.21 (s, 3H), 2.10 - 1.98 (m, 7H), 1.78 (s, 3H), 1.64 - 1.43 (m, 2H), 1.24 - 1.13 (m, 2H), 0.98 - 0.79 (m, 2H)m / zcalculated for C 36 H 42 F3N9O4(M+H) + 722.3,found722.3127N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)but-2-ynamide (400 MHz, Methanol-d4)δ8.44(s,1H),8.02(s,1H),6.85(s,1H),4.92-4.86(m,1H),4.38(s,2H),4.13(q,J= 9.2 Hz, 2H), 3.96 (dd,J= 11.3, 4.6 Hz, 2H), 3.87 (s, 3H), 3.60 - 3.39 (m, 5H), 3.21 - 2.60 (m, 18H), 2.08 - 1.93 (m, 8H)m / zcalculated for C 34 H 44 F3N9O4(M+H)+ 700.4, found 700.3128N-(5-((8-(3,3-difluorocyclobutyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)but-2-ynamide (400 MHz, Methanol-d4)δ8.75(s,1H),8.05(s,1H),6.87(s,1H),4.79-4.70(m,1H),4.40(s,2H),4.14(q,J= 9.1 Hz, 2H), 3.87 (s, 3H), 3.12 - 2.88 (m, 5H), 2.80 - 2.33 (m, 11H), 2.30 (s, 3H), 2.10 - 1.97 (m, 6H), 1.79 - 1.64 (m, 2H)m / zcalculated for C 33 H 40 F5N9O3(M+H) + 706.3, found 706.3129N-(4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4)δ8.61(s,1H),8.03(s,15H),7.06(s,1H),6.96-6.50(m,2H),6.33(dd,J= 17.0, 1.5 Hz, 1H), 5.80 (dd,J= 10.2, 1.4 Hz, 1H), 4.79 - 4.76 (m, 1H), 4.39 (s, 2H), 4.13 (q,J= 9.2 Hz, 2H), 3.86 (dd,J= 11.1, 4.3 Hz, 2H), 3.38 - 3.32 (m, 2H), 3.08 (d,J= 11.8 Hz, 2H), 2.77 - 2.30 (m, 13H), 2.28 (s, 3H), 2.08 - 1.94 (m, 2H), 1.79 - 1.62 (m, 2H), 1.61 - 1.45 (m, 2H)m / zcalculated for C 33 H 42 F5N9O4(M+H) + 724.3, found 724.4130N-(4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)but-2-yneamide (400 MHz, Methanol-d4)δ 8.47 (s, 1H), 8.02 (s, 1H), 7.05 (s, 1H), 6.76 (t,J= 73.9 Hz, 1H), 4.81 - 4.73 (m, 1H), 4.39 (s, 2H), 4.13 (q,J= 9.2 Hz, 2H), 3.92 (dd,J= 11.3, 4.5 Hz, 2H), 3.38 (t,J= 11.3 Hz, 2H), 3.08 (d,J= 11.8 Hz, 2H), 2.84 - 2.34 (m, 13H), 2.32 (s, 5H), 2.03 (s, 3H), 1.71 (qd,J= 12.0, 4.0 Hz, 2H), 1.54 (d,J= 12.8 Hz, 2H)m / zcalculated for C 34 H 42F5N9O4(M+H) + 736.3, found 736.6131N-(5-((8-(4-chlorophenyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (400 MHz, DMSO-d6)δ 8.83 (s, 1 H), 8.17 (s, 1 H), 8.04 (s, 1 H), 7.91 (s, 1 H), 7.39 (d,J= 8.4 Hz, 2 H), 7.25 (d,J= 8.8 Hz, 2 H), 6.68 (s, 2 H), 6.22 (dd,J= 16.8, 1.6 Hz, 1 H), 5.73 (d,J= 10.4 Hz, 1 H), 4.59 (d,J= 8.4 Hz, 2 H), 4.27 (q,J= 9.5 Hz, 2 H), 3.70 (s, 3 H), 2.96 (d,J=10.8 Hz, 2 H), 2.62 (t,J= 11.0 Hz, 2 H), 2.40 ~ 2.20 (m, 5 H), 2.14 (s, 4 H), 1.82 (d,J= 11.2 Hz, 2 H), 1.70 (t,J= 11.2 Hz, 2 H), 1.24 (s, 2 H), 0.86 (t,J= 7.0 Hz, 2 H)m / zcalculated for C 34 H 39 ClF3N9O3(M+H) + 714.2,found714.3132N-(5-((8-(4-chlorophenyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide (400 MHz, DMSO-d6)δ 8.99 (s, 1 H), 8.85 (s, 1 H), 8.15 (s, 1 H), 8.00 (s, 1 H), 7.37 (d,J= 8.4 Hz, 2 H), 7.21 (d,J= 8.4 Hz, 2 H), 6.93 (s, 1 H), 6.75 to 6.68 (m, 1 H), 6.25 (dd,J= 16.8, 1.6 Hz, 1 H), 5.79 (dd,J= 10.4, 1.2 Hz, 1 H), 4.58 (s, 2 H), 4.27 (q,J= 8.1 Hz, 2 H), 2.97 (d,J= 14.8 Hz, 2 H), 2.59 (t,J= 13.0 Hz, 2 H), 2.40 ~ 2.22 (m, 5 H), 2.15 (s, 4 H), 1.83 (d,J= 9.2 Hz, 2 H), 1.74 (t,J= 10.6 Hz, 2 H), 1.23 (s, 4 H)m / zcalculated for C 34 H 36 ClF6N9O3(M+H) + 768.2,found768.3133N-(2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(trifluoromethoxy)phenyl)acrylamide (400 MHz, DMSO-d6)δ 9.12 (s, 1 H), 9.04 (s, 1 H), 8.34 (s, 1 H), 8.12 (s, 1 H), 7.08 (s, 1 H), 6.74 (dd,J= 16.8, 10.4 Hz, 1 H), 6.23 (dd,J= 17.0, 1.8 Hz, 1 H), 5.77 (dd,J= 10.2, 1.8 Hz, 1 H), 4.60 (t,J= 12.0 Hz, 1 H), 4.37 (s, 3 H), 4.21 (q,J= 9.6 Hz, 2 H), 3.76 (q,J= 5.3 Hz, 2 H), 3.13 (t,J= 11.4 Hz, 2 H), 3.02 (d,J= 10.8 Hz, 2 H), 2.61 (t,J= 12.2 Hz, 2 H), 2.40 ~ 2.20 (m, 4 H), 2.15 (s, 4 H), 1.85 ~ 1.73 (m, 4 H), 1.39 (d,J= 13.2 Hz, 2 H), 1.30 ~ 1.20 (m, 2 H), 0.86 (t,J= 8.2 Hz, 2 H)m / zcalculated for C 33 H 41 F6N9O4(M+H) + 742.3,found742.3134N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(pyridin-2-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, DMSO-d6)δ 8.82 (s, 1 H), 8.46 (d,J= 5.2 Hz, 1 H), 8.20 (s, 1 H), 7.85 ~ 7.83 (m, 2 H), 7.38 ~ 7.37 (m, 2 H), 6.73 ~ 6.67 (m, 2 H), 6.24 (d,J= 16.8 Hz, 1 H), 5.76 (d,J= 11.6 Hz, 1 H), 4.62 (s, 2 H), 4.28 (q,J= 9.6 Hz, 2 H), 3.73 (s, 3 H), 2.95 (d,J= 12.0 Hz, 2 H), 2.57 (t,J= 12.0 Hz, 2 H), 2.40 ~ 2.20 (m, 4 H), 2.15 (s, 3 H), 1.80 (d,J= 11.2 Hz, 2 H), 1.65 (q,J= 12.1 Hz, 2 H), 1.25 (s, 2 H), 0.85 (t,J= 8.4 Hz, 2 H)m / zcalculated for C 33 H 39 F3N 10 O3(M+H) + 681.3,found681.4135N-(4-methoxy-5-((8-(1-methyl-1H-pyrazol-4-yl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.15 (s, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.72 (s, 1H), 7.32 (s, 1H), 6.72 (s, 1H), 6.63 (dd,J= 16.7, 10.2 Hz, 1H), 6.17 (d,J= 16.8 Hz, 1H), 5.72 (s, 1H), 5.68 (d,J= 10.0 Hz, 1H), 4.49 (s, 2H), 4.24 (q,J= 9.6 Hz, 2H), 3.76 (s, 3H), 3.71 (s, 3H), 2.96 (d,J= 11.0 Hz, 2H), 2.59 (dd,J= 20.4, 9.4 Hz, 5H), 2.21 (s, 3H), 1.95 - 1.85 (m 1H), 1.79 (d,J= 10.2 Hz, 2H), 1.66 (d,J= 9.5 Hz, 2H), 1.18 (s, 2H)m / zcalculated for C 32 H 40 F3N 11 O3(M+H) + 684.3,found684.4136N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((8-(1-methylpiperidin-4-yl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.29 (s, 1H), 8.07 (d,J= 9.5 Hz, 2H), 6.78 (s, 1H), 6.64 (dd,J= 16.7, 10.6 Hz, 1H), 6.15 (d,J= 16.9 Hz, 1H), 5.67 (d,J= 10.4 Hz, 1H), 4.41 - 4.25 (m,J= 20.6 Hz, 3H), 4.16 (q,J= 9.1 Hz, 2H), 3.76 (s, 3H), 2.97 (d,J= 10.7 Hz, 2H), 2.63 (dd,J= 23.3, 10.9 Hz, 4H), 2.25 (d,J= 19.1 Hz, 6H), 2.09 (d,J= 15.5 Hz, 6H), 1.77 (t,J= 11.2 Hz, 5H), 1.67 (d,J= 10.8 Hz, 3H), 1.39 (t,J= 12.5 Hz, 2H), 1.19 (s, 2H), 0.80 (s, 1H)m / zcalculated for C 34 H 47 F3N 10 O3(M+H) + 701.4,found701.4

[0342] Example 168: N-(5-((8-(4,4-difluorocyclohexyl)-6-ethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0343]

[0344] Step 1: Ethyl 4-((4,4-difluorocyclohexyl)amino)-2-(methylthio)pyrimidine-5-carboxylate

[0345]

[0346] Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (0.300 g, 1.289 mmol), 4,4-difluorocyclohexylamine hydrochloride (0.266 g, 1.547 mmol), and N,N-diisopropylethylamine (0.337 mL, 1.934 mmol) were dissolved in 1,4-dioxane (3 mL) / methanol (1 mL), and the mixture was stirred at 90 °C for 16 h. After cooling to room temperature, water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; ethyl acetate / hexane = 30%) and concentrated to give ethyl 4-((4,4-difluorocyclohexyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (0.225 g, 52.7%) as a white solid.

[0347] LC-MSm / zcalculated for C 14 H 19 F2N3O2S (M+H) + 332.1, found 332.1.

[0348]

[0349] Step 2: (4-((4,4-difluorocyclohexyl)amino)-2-(methylthio)pyrimidin-5-yl)methanol

[0350]

[0351] Ethyl 4-((4,4-difluorocyclohexyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (0.256 g, 0.773 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride solution (1 M solution THF, 1.31 mL, 1.313 mmol) was slowly added dropwise at 0 °C. The mixture was stirred for 30 min and further stirred at room temperature for 18 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; ethyl acetate / hexane = from 0% to 50%) and concentrated to afford (4-((4,4-difluorocyclohexyl)amino)-2-(methylthio)pyrimidin-5-yl)methanol (0.151 g, 67.6%) as a white solid.

[0352] LC-MSm / zcalculated for C 12 H 17 F2N3OS (M+H) + 290.1, found 290.1.

[0353]

[0354] Step 3: 4-((4,4-difluorocyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde

[0355]

[0356] (4-((4,4-Difluorocyclohexyl)amino)-2-(methylthio)pyrimidin-5-yl)methanol (0.151 g, 0.522 mmol) and manganese dioxide (0.136 g, 1.566 mmol) were dissolved in dichloromethane (3 mL) at room temperature and stirred at the same temperature for 16 h. The reaction mixture was filtered through a pad of Celite to remove the solid, and the filtrate was concentrated under reduced pressure. The obtained product was used without further purification. (4-((4,4-Difluorocyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde, 0.125 g, 83.4%, white solid).

[0357] LC-MSm / zcalculated for C12H 15 F2N3OS (M+H) + 288.1, found 288.1.

[0358]

[0359] Step 4: N-(4,4-difluorocyclohexyl)-5-((ethylamino)methyl)-2-(methylthio)pyrimidin-4-amine

[0360]

[0361] 4-((4,4-Difluorocyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (0.125 g, 0.435 mmol), ethylamine hydrochloride (0.046 g, 0.566 mmol), N,N-diisopropylethylamine (0.099 mL, 0.566 mmol), and acetic acid (0.032 mL, 0.566 mmol) were dissolved in ethanol (10 mL) and stirred at 120 °C for 1 h. After the temperature was lowered to 0 °C, sodium borohydride (0.049 g, 1.305 mmol) was added and stirred at room temperature for an additional 18 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; ethyl acetate / hexane = 0% to 30%) and concentrated to afford N-(4,4-difluorocyclohexyl)-5-((ethylamino)methyl)-2-(methylthio)pyrimidin-4-amine (0.163 g, 118.4%) as a yellow oil.

[0362] LC-MSm / zcalculated for C 14 H 22 F2N4S (M+H) + 317.2, found 317.1.

[0363]

[0364] Step 5: 1-(4,4-difluorocyclohexyl)-3-ethyl-7-(methylthio)-3,4-dihydropyrimi[4,5-d]pyrimidin-2(1H)-one

[0365]

[0366] N-(4,4-Difluorocyclohexyl)-5-((ethylamino)methyl)-2-(methylthio)pyrimidin-4-amine (0.136 g, 0.430 mmol), triphosgene (0.128 g, 0.430 mmol), and triethylamine (0.180 mL, 1.289 mmol) were dissolved in tetrahydrofuran (3 mL) and stirred at 80 °C for 16 h. After the temperature was lowered to room temperature, water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; ethyl acetate / hexane = from 0% to 40%) and concentrated to afford 1-(4,4-difluorocyclohexyl)-3-ethyl-7-(methylthio)-3,4-dihydropyrimi[4,5-d]pyrimidin-2(1H)-one (0.111 g, 75.4%) as a white solid.

[0367] LC-MSm / zcalculated for C 15 H 20 F2N4OS (M+H) + 343.1, found 343.1.

[0368]

[0369] Step 6: 1-(4,4-difluorocyclohexyl)-3-ethyl-7-(methylsulfonyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0370]

[0371] 1-(4,4-Difluorocyclohexyl)-3-ethyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.111 g, 0.324 mmol) and meta-chloroperoxybenzoic acid, 77% (0.168 g, 0.973 mmol) were dissolved in dichloromethane (3 mL) at room temperature and stirred at the same temperature for 16 h. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification. 1-(4,4-Difluorocyclohexyl)-3-ethyl-7-(methylsulfonyl)-3,4-dihydropyrimi[4,5-d]pyrimidin-2(1H)-one, 0.272 g, 224.1%, white solid).

[0372] LC-MSm / zcalculated for C 15 H 20 F2N4O3S (M+H) + 375.1, found 375.1.

[0373]

[0374] Step 7: 1-(4,4-difluorocyclohexyl)-3-ethyl-7-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0375]

[0376] 1-(4,4-Difluorocyclohexyl)-3-ethyl-7-(methylsulfonyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.122 g, 0.326 mmol), 4-fluoro-2-methoxy-5-nitroaniline (0.073 g, 0.391 mmol), and potassium t-butoxide solution (1.0 M solution THF, 0.652 mL, 0.652 mmol) were dissolved in N,N-dimethylformamide (2 mL), stirred at 0 °C for 1 h, and then stirred at room temperature for an additional 1 h. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; methanol / dichloromethane = from 0% to 5%) and concentrated to afford 1-(4,4-difluorocyclohexyl)-3-ethyl-7-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-3,4-dihydropyrimi[4,5-d]pyrimidin-2(1H)-one (0.151 g, 96.5%) as a brown solid.

[0377] LC-MSm / zcalculated for C 21 H 23 F3N6O4(M+H) + 481.2, found 481.2.

[0378]

[0379] Step 8: 1-(4,4-difluorocyclohexyl)-3-ethyl-7-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0380]

[0381] 1-(4,4-Difluorocyclohexyl)-3-ethyl-7-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.151 g, 0.314 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (0.075 g, 0.409 mmol), and potassium carbonate (K2CO3, 0.065 g, 0.471 mmol) were dissolved in acetonitrile (3 mL), and the mixture was stirred at 100 °C for 1 h. After cooling to room temperature, water was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; methanol / dichloromethane = from 0 % to 10 %) and concentrated to afford 1-(4,4-difluorocyclohexyl)-3-ethyl-7-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.078 g, 38.6 %) as an orange solid.

[0382] LC-MSm / zcalculated for C 31 H 43 F2N9O4(M+H) + 644.3, found 644.3.

[0383]

[0384] Step 9: 7-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-1-(4,4-difluorocyclohexyl)-3-ethyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0385]

[0386] 1-(4,4-Difluorocyclohexyl)-3-ethyl-7-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.078 g, 0.121 mmol), iron (0.047 g, 0.848 mmol), and ammonium chloride (0.032 g, 0.606 mmol) were added to ethanol (2 mL) / water (0.5 mL) and stirred at 90 °C for 1 h. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite to remove the solid. The filtrate was concentrated under reduced pressure and the obtained product was used without further purification (7-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-1-(4,4-difluorocyclohexyl)-3-ethyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one, 0.059 g, 79.3%, green solid).

[0387] LC-MSm / zcalculated for C 31 H 45 F2N9O2(M+H) + 614.4, found 614.3.

[0388]

[0389] Step 10: N-(5-((8-(4,4-difluorocyclohexyl)-6-ethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0390] Step 10 can be manufactured in two ways:

[0391]

[0392] Method 1: 7-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-1-(4,4-difluorocyclohexyl)-3-ethyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.059 g, 0.096 mmol), acryl chloride (0.010 g, 0.115 mmol), and N,N-diisopropylethylamine (0.020 mL, 0.115 mmol) were dissolved in dichloromethane (10 mL), stirred at 0 °C for 30 min, and then stirred at room temperature for an additional 30 min. Aqueous N-sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 5 g cartridge; methanol / dichloromethane = from 0% to 10%) and concentrated to afford N-(5-((8-(4,4-difluorocyclohexyl)-6-ethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (0.017 g, 25.7%) as a light yellow solid.

[0393] 1H NMR (400 MHz, Methanol-d4) δ 8.70 (s, 1H), 7.98 (s, 1H), 6.87 (s, 1H), 6.52 (dd,J= 17.0, 10.3 Hz, 1H), 6.29 (dd,J= 17.0, 1.5 Hz, 1H), 5.76 (dd,J= 10.3, 1.5 Hz, 1H), 4.74 (dd,J= 13.2, 9.2 Hz, 1H), 4.25 (s, 2H), 3.87 (s, 3H), 3.40 (q,J= 7.2 Hz, 2H), 3.03 (d,J= 11.5 Hz, 2H), 2.76 - 2.63 (m, 8H), 2.59 - 2.44 (m, 4H), 2.35 (ddt,J= 11.4, 7.6, 3.7 Hz, 1H), 2.28 (s, 3H), 2.00 - 1.90 (m, 4H), 1.89 - 1.76 (m, 2H), 1.70 (dd,J= 12.0, 3.8 Hz, 4H), 1.14 (t,J= 7.1 Hz, 3H).

[0394] LC-MSm / zcalculated for C 34 H 47 F2N9O3(M+H) + 668.4, found 668.4.

[0395]

[0396] Method 2: 7-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-1-(4,4-difluorocyclohexyl)-3-ethyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.059 g, 0.096 mmol), 3-chloropropionyl chloride (0.013 g, 0.102 mmol), and potassium carbonate (K2CO3, 0.079 g, 0.574 mmol) were dissolved in dichloromethane (10 mL), stirred at 0 °C for 30 min, and then stirred at 110 °C for an additional 16 h. After the temperature was lowered to room temperature, water was added to the reaction mixture, and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 5 g cartridge; methanol / dichloromethane = from 0% to 10%) and concentrated to afford N-(5-((8-(4,4-difluorocyclohexyl)-6-ethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (0.017 g, 25.8%) as a light yellow solid.

[0397]

[0398] Compounds of Examples 137 to 174 were prepared in a similar manner to Example 168 above, and the compound name, chemical structural formula, of each example compound are as follows: 1 The results of H-NMR and LC-MS analysis are summarized in Table 2 below.

[0399] Example Compound Compound Name Structure 1 H-NMRLC-MS137N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isobutyl-7-oxo-8-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4) δ 8.03 (s, 1H), 7.42 - 7.39 (m, 1H), 7.35 (t,J= 7.5 Hz, 2H), 7.27 (t,J= 7.3 Hz, 1H), 7.16 (d,J= 7.4 Hz, 2H), 6.73 (s, 1H), 6.55 (dd,J= 16.9, 10.1 Hz, 1H), 6.41 (d,J= 16.9 Hz, 1H), 5.87 (d,J= 10.1 Hz, 1H), 4.43 (s, 2H), 3.82 (s, 2H), 3.32 - 3.27 (m, 2H), 3.10 - 3.05 (m, 2H), 2.70 (s, 6H), 2.52 (s, 3H), 2.01 (dt,J= 13.5, 6.8 Hz, 1H), 1.19 (s, 2H), 0.86 (d,J= 6.7 Hz, 6H)m / zcalculated for C 31 H 40 N8O3(M+H) + 573.3,found573.3138N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4) δ 8.06 (s, 1H), 7.41 - 7.33 (m,J= 3H), 7.27 (t,J= 7.4 Hz, 1H), 7.17 (d,J= 7.9 Hz, 2H), 6.73 (s, 1H), 6.52 (dd,J= 16.9, 10.0 Hz, 1H), 6.42 (d,J= 16.8 Hz, 1H), 5.88 (d,J= 10.0 Hz, 1H), 4.56 (dt,J= 13.7, 6.8 Hz, 1H), 4.35 (s, 2H), 3.83 (s, 3H), 3.32 - 3.27 (m, 2H), 3.09 - 3.05 (m, 2H), 2.71 (s, 6H), 2.52 (s, 3H), 1.18 (d,J= 6.8 Hz, 6H)m / zcalculated for C 30 H38 N8O3(M+H) + 559.3,found559.3139N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6-methyl-7-oxo-8-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (500 MHz, Methanol-d4) δ 8.15 (s, 1H), 7.47 (t,J= 7.6 Hz, 3H), 7.39 (t,J= 7.2 Hz, 1H), 7.28 (d,J= 8.0 Hz, 2H), 6.85 (s, 1H), 6.60 (d,J= 9.9 Hz, 1H), 6.54 (d,J= 16.4 Hz, 1H), 6.00 (d,J= 10.2 Hz, 1H), 4.56 (s, 2H), 3.94 (s, 3H), 3.43 - 3.39 (m, 2H), 3.21 - 3.15 (m, 2H), 3.09 (s, 3H), 2.82 (s, 6H), 2.64 (s, 3H)m / zcalculated for C 28 H 34 N8O3(M+H) + 531.3,found531.3140N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isobutyl-8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4)δ8.29(s,1H),7.93(s,1H),6.82(s,1H),6.49(dd,J= 16.9, 10.1 Hz, 1H), 6.34 (d,J= 16.9 Hz, 1H), 5.76 (d,J= 10.2 Hz, 1H), 4.94 (dt,J= 13.8, 6.8 Hz, 1H), 4.18 (s, 2H), 3.88 (s, 3H), 3.38 - 3.32 (m, 2H), 3.18 - 3.15 (m, 2H), 2.74 (s, 6H), 2.62 (s, 3H), 1.94 - 1.91 (m, 1H), 1.38 (d,J= 6.9 Hz, 6H), 0.83 (d,J= 6.5 Hz, 6H)m / zcalculated for C 28 H 42 N8O3(M+H) + 539.3,found539.4141N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-phenyl-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (500 MHz, Methanol-d4) δ 8.18 (s, 1H), 7.52 - 7.45 (m, 3H), 7.39 (t,J= 7.3 Hz, 1H), 7.30 (d,J= 7.7 Hz, 2H), 6.85 (s, 1H), 6.63 (dd,J= 17.0, 10.0 Hz, 1H), 6.54 (d,J= 16.7 Hz, 1H), 6.00 (d,J= 9.9 Hz, 1H), 4.57 - 4.46 (m, 3H), 4.07 (dd,J= 11.4, 4.2 Hz, 2H), 3.94 (s, 3H), 3.53 (t,J= 11.6 Hz, 2H), 3.42 (t,J= 5.4 Hz, 2H), 3.19 (t,J= 5.2 Hz, 2H), 2.83 (s, 6H), 2.64 (s, 3H), 2.10 - 2.00 (m, 4H)m / zcalculated for C 32 H 40 N8O4(M+H)+ 601.3,found601.4142N-(5-((6,8-diisopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4) δ 8.41 (s, 1H), 8.08 (s, 1H), 6.95 (s, 1H), 6.58 (dd,J= 16.9, 10.1 Hz, 1H), 6.46 (dd,J= 16.9, 1.3 Hz, 1H), 5.88 (dd,J= 10.2, 1.1 Hz, 1H), 5.09 - 4.98 (m, 1H), 4.68 - 4.56 (m, 1H), 4.19 (s, 2H), 4.00 (s, 3H), 3.46 (t,J= 5.5 Hz, 2H), 3.24 (t,J= 5.5 Hz, 2H), 2.84 (s, 6H), 2.74 (s, 3H), 1.50 (t,J= 6.3 Hz, 6H), 1.23 (d,J= 6.8 Hz, 6H)m / zcalculated for C 27 H 40 N8O3(M+H) + 525.3,found525.3143N-(5-((8-(2-chloro-3-fluorophenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4)δ 8.20 (s, 1H), 8.10 (s, 1H), 7.36 (q,J= 7.3, 6.8 Hz, 1H), 7.27 (t,J= 8.6 Hz, 2H), 6.85 (s, 1H), 6.57 (dd,J= 17.0, 10.2 Hz, 1H), 6.41 (d,J= 17.0 Hz, 1H), 5.87 (d,J= 10.2 Hz, 1H), 4.67 (h,J= 6.9 Hz, 1H), 4.49 (s, 2H), 3.86 (s, 3H), 3.03 (s, 2H), 2.63 (s, 3H), 2.45 (s, 2H), 2.34 (s, 6H), 1.31 (d,J= 6.6 Hz, 6H)m / zcalculated for C 30 H 36 ClFN8O3(M+H) + 611.3,found611.3144N-(5-((6-(tert-butyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4) δ 8.30 (s, 1H), 7.93 (s, 1H), 6.84 (s, 1H), 6.42 (dd,J= 16.9, 10.0 Hz, 1H), 6.30 (d,J= 16.9 Hz, 1H), 5.73 (d,J= 10.1 Hz, 1H), 4.74 - 4.62 (m, 1H), 4.15 (s, 2H), 3.93 - 3.83 (m, 5H), 3.38 (t,J= 11.9 Hz, 2H), 2.89 - 2.71 (m, 4H), 2.59 (s, 3H), 2.53 (s, 6H), 1.98 - 1.47 (m, 4H), 1.38 (s, 9H)m / zcalculated for C 30 H 44 N8O4(M+H) +581.4,found581.4145(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6-(1-methoxypropan-2-yl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (500 MHz, Methanol-d4) δ 8.26 (s, 1H), 7.95 (s, 1H), 6.85 (s, 1H), 6.42 (dd,J= 17.0, 10.1 Hz, 1H), 6.31 (d,J= 16.5 Hz, 1H), 5.73 (d,J= 10.9 Hz, 1H), 4.76 - 4.70 (m, 1H), 4.60 - 4.53 (m, 1H), 4.11 (q,J= 14.1 Hz, 2H), 3.92 - 3.81 (m, 5H), 3.49 - 3.44 (m, 1H), 3.38 (t,J= 11.6 Hz, 2H), 3.32 (dd,J= 10.5, 4.8 Hz, 1H), 3.24 (s, 3H), 2.92 - 2.82 (m, 2H), 2.80 - 2.69 (m,J= 12.6, 8.1 Hz, 2H), 2.60 (s,J= 21.8 Hz, 3H), 2.55 (s, 6H), 1.98 - 1.45 (m, 4H), 1.09 (d,J= 7.0 Hz, 3H)m / zcalculated for C 30 H 44 N8O5(M+H) + 597.3,found597.3146(S)-N-(5-((8-cyclohexyl-6-(1-methoxypropan-2-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4) δ 8.24 (s, 1H), 8.06 (s, 1H), 6.97 (s, 1H), 6.53 (dd,J= 17.0, 9.6 Hz, 1H), 6.46 (d,J= 16.0 Hz, 1H), 5.87 (d,J= 9.7 Hz, 1H), 4.71 - 4.65 (m, 1H), 4.62 - 4.56 (m, 1H), 4.22 (q,J= 14.2 Hz, 2H), 4.00 (s, 3H), 3.60 - 3.53 (m, 1H), 3.50 - 3.39 (m, 3H), 3.36 (s, 3H), 3.24 - 3.21 (m, 2H), 2.83 (s, 6H), 2.72 (s, 3H), 2.50 - 2.38 (m, 2H), 2.10 - 1.49 (m, 8H), 1.20 (d,J= 6.9 Hz, 3H)m / zcalculated for C 31 H 46 N8O4(M+H) + 595.4,found595.3147N-(5-((6-(tert-butyl)-8-cyclohexyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (500 MHz, Methanol-d4) δ 8.17 (s, 1H), 7.92 (s, 1H), 6.85 (s, 1H), 6.42 (dd,J= 17.0, 9.9 Hz, 1H), 6.33 (dd,J= 16.9, 1.7 Hz, 1H), 5.75 (dd,J= 9.9, 1.7 Hz, 1H), 4.42 (t,J= 12.0 Hz, 1H), 4.14 (s, 2H), 3.88 (s, 3H), 3.31 (s, 2H), 3.05 (s, 2H), 2.67 (s, 6H), 2.60 (s, 3H), 2.39 - 2.28 (m, 2H), 1.74 - 1.45 (m, 8H), 1.39 (s, 9H)m / zcalculated for C 31 H 46 N8O3(M+H)+ 579.4,found579.3148N-(4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.23 ​​(s, 1H), 8.06 (s, 1H), 7.14 (s, 1H), 6.90 (t,J= 73.6 Hz, 1H), 6.62 (dd,J= 17.0, 10.1 Hz, 1H), 6.42 (dd,J= 17.0, 1.6 Hz, 1H), 5.84 (dd,J= 10.2, 1.4 Hz, 1H), 4.78 - 4.73 (m, 1H), 4.66 - 4.53 (m, 1H), 4.16 (s, 2H), 3.96 (dd,J= 11.1, 4.3 Hz, 2H), 3.44 - 3.36 (m, 4H), 3.27 - 3.24 (m, 2H), 2.89 - 2.81 (m, 8H), 2.68 (s, 3H), 1.61 - 1.49 (m, 2H), 1.19 (d,J= 6.8 Hz, 6H).m / zcalculated for C 29 H 40 F2N8O4(M+H) + 603.3,found603.3149N-(5-((6-Isopropyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.59 (s, 1H), 8.04 (s, 1H), 6.91 (s, 1H), 6.65 - 6.55 (m, 1H), 6.34 (dd,J= 17.0, 1.2 Hz, 1H), 5.79 (d,J= 10.2 Hz, 1H), 4.79 - 4.72 (m, 1H), 4.63 - 4.53 (m, 1H), 4.15 (s, 2H), 3.94 - 3.87 (m, 6H), 3.47 - 3.36 (m, 2H), 2.96 (s, 3H), 2.78 - 2.66 (m, 2H), 1.60 - 1.48 (m, 2H), 1.18 (d,J= 6.8 Hz, 6H)m / zcalculated for C 29 H 40 N8O4(M+H) + 565.3,found565.3150N-(5-((6-Isopropyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide (400 MHz, Methanol-d4) δ 8.59 (s, 1H), 8.02 (s, 1H), 6.88 (s, 1H), 6.54 (dd,J= 17.0, 10.3 Hz, 1H), 6.31 (dd,J= 17.0, 1.5 Hz, 1H), 5.77 (dd,J= 10.3, 1.4 Hz, 1H), 4.83 - 4.75 (m, 1H), 4.64 - 4.50 (m, 1H), 4.14 (s, 2H), 3.92 - 3.86 (m, 5H), 3.86 - 3.81 (m, 4H), 3.41 (t,J= 11.2 Hz, 2H), 2.94 - 2.84 (m, 4H), 2.72 (qd,J= 12.5, 4.7 Hz, 2H), 1.62 - 1.50 (m, 2H), 1.18 (d,J= 6.8 Hz, 6H)m / zcalculated for C 28 H 37 N7O5(M+H) +552.3,found552.3151N-(4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.45 (s, 1H), 8.12 (s, 1H), 7.63 (d,J= 8.0 Hz, 2H), 7.43 (d,J= 8.1 Hz, 2H), 6.96 (s, 1H), 6.75 - 6.33 (m, 3H), 5.81 (d,J= 10.1 Hz, 1H), 4.62 (dt,J= 13.4, 6.5 Hz, 1H), 4.41 (s, 2H), 2.91 (t,J= 5.5 Hz, 2H), 2.42 (t,J= 5.3 Hz, 2H), 2.26 (s, 6H), 1.25 (d,J= 6.9 Hz, 6H)m / zcalculated for C 31 H 35 F5N8O3(M+H) + 663.3,found663.3152N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.32 (s, 1H), 8.12 (s, 1H), 7.64 (d,J= 8.5 Hz, 2H), 7.42 (d,J= 8.2 Hz, 2H), 6.78 (s, 1H), 6.48 (dd,J= 16.9, 10.2 Hz, 1H), 6.34 (dd,J= 17.0, 1.6 Hz, 1H), 5.81 (dd,J= 10.2, 1.5 Hz, 1H), 4.67 - 4.57 (m, 1H), 4.41 (s, 2H), 3.78 (s, 3H), 2.84 (t,J= 4.7 Hz, 4H), 2.66 (s, 4H), 2.38 (s, 3H), 1.25 (d,J= 6.8 Hz, 6H)m / zcalculated for C 31 H 35 F3N8O3(M+H) + 625.3,found625.3153N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.31 (s, 1H), 8.11 (s, 1H), 7.63 (d,J= 8.3 Hz, 2H), 7.41 (d,J= 8.2 Hz, 2H), 6.74 (s, 1H), 6.51 (dd,J= 17.0, 10.2 Hz, 1H), 6.34 (dd,J= 17.0, 1.3 Hz, 1H), 5.80 (dd,J= 10.2, 1.3 Hz, 1H), 4.66 - 4.57 (m, 1H), 4.40 (s, 2H), 3.75 (s, 3H), 3.00 - 2.90 (m, 2H), 2.79 - 2.26 (m, 13H), 2.04 - 1.92 (m, 2H), 1.76 - 1.58 (m, 2H), 1.25 (d,J= 6.8 Hz, 6H)m / zcalculated for C 36 H 44 F3N9O3(M+H) +708.4,found708.3154N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.04 (s, 1H), 7.70 (d,J= 8.4 Hz, 2H), 7.56 (s, 1H), 7.42 (d,J= 8.2 Hz, 2H), 6.44 (dd,J= 17.0, 10.0 Hz, 1H), 6.34 (dd,J= 17.0, 2.0 Hz, 1H), 6.11 (s, 1H), 5.79 (dd,J= 10.0, 2.0 Hz, 1H), 4.75 (s, 4H), 4.36 (s, 2H), 3.92 (s, 4H), 3.74 (s, 3H), 1.23 (d,J= 6.8 Hz, 6H)m / zcalculated for C 31 H 32 F3N7O4(M+H) + 624.3,found624.3155N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-((3aR,6aS)-5-methylhexahydropyrrolo3,4-c]pyrrol-2(1H)-yl)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.11 (s, 1H), 8.08 (s, 1H), 7.67 (dd,J= 8.2, 5.6 Hz, 2H), 7.42 (dd,J= 8.1, 5.7 Hz, 2H), 6.70 (s, 1H), 6.55 - 6.42 (m, 1H), 6.41 - 6.29 (m, 1H), 5.85 - 5.75 (m, 1H), 4.67 - 4.54 (m, 1H), 4.40 (s, 2H), 3.76 (s, 3H), 2.96 - 2.82 (m, 6H), 2.76 (s, 2H), 2.56 (s, 2H), 2.38 (s, 3H), 1.24 (d,J= 5.7 Hz, 6H)m / zcalculated for C 33 H 37 F3N8O3(M+H) + 651.3,found651.3156N-(2-(3-(dimethylamino)azetidin-1-yl)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4) δ 8.06 (s, 1H), 7.71 (d,J= 8.4 Hz, 2H), 7.62 (s, 1H), 7.44 (d,J= 8.2 Hz, 2H), 6.44 (dd,J= 17.0, 10.0 Hz, 1H), 6.33 (dd,J= 17.0, 1.9 Hz, 1H), 6.17 (s, 1H), 5.77 (dd,J= 10.0, 1.9 Hz, 1H), 4.66 - 4.55 (m, 1H), 4.38 (s, 2H), 3.90 (t,J= 7.2 Hz, 2H), 3.76 (s, 3H), 3.59 - 3.53 (m, 2H), 3.17 - 3.09 (m, 1H), 2.16 (s, 6H), 1.24 (d,J= 6.8 Hz, 6H)m / zcalculated for C 31 H 35 F3N8O3(M+H) +625.3,found625.3157N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(2,2,2-trifluoroethoxy)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.15 (s, 1H), 7.89 (s, 1H), 7.71 (d,J= 8.6 Hz, 2H), 7.46 (d,J= 8.5 Hz, 2H), 6.91 (s, 1H), 6.56 (dd,J= 17.0, 10.1 Hz, 1H), 6.43 (dd,J= 17.0, 1.7 Hz, 1H), 5.85 (dd,J= 10.1, 1.6 Hz, 1H), 4.68 - 4.51 (m, 3H), 4.43 (s, 2H), 3.37 (t,J= 5.7 Hz, 2H), 3.20 - 3.12 (m, 2H), 2.79 (s, 6H), 2.63 (s, 3H), 1.26 (d,J= 6.8 Hz, 6H)m / zcalculated for C 32 H 36 F6N8O3(M+H) + 695.3,found695.3158N-(4-(2,2-difluoroethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.15 (s, 1H), 7.93 (s, 1H), 7.71 (d,J= 8.4 Hz, 2H), 7.46 (d,J= 8.2 Hz, 2H), 6.87 (s, 1H), 6.54 (dd,J= 16.9, 10.0 Hz, 1H), 6.42 (dd,J= 16.9, 1.8 Hz, 1H), 6.12 (tt,J= 55.0, 3.9 Hz, 1H), 5.85 (dd,J= 10.0, 1.8 Hz, 1H), 4.67 - 4.58 (m, 1H), 4.43 (s, 2H), 4.27 (td,J= 13.8, 3.8 Hz, 2H), 3.33 (dd,J= 6.4, 4.7 Hz, 2H), 3.09 (s, 2H), 2.73 (s, 6H), 2.61 (s, 3H), 1.26 (d,J= 6.8 Hz, 6H)m / zcalculated for C 32 H 37 F5N8O3(M+H) + 677.3,found677.3159N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(1-methylpyrrolidin-3-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.14 (s, 1H), 7.65 (d,J= 8.3 Hz, 2H), 7.44 (d,J= 8.1 Hz, 2H), 6.79 (s, 1H), 6.58 (dd,J= 17.0, 10.2 Hz, 1H), 6.36 (dd,J= 17.0, 1.6 Hz, 1H), 5.79 (dd,J= 10.3, 1.6 Hz, 1H), 4.63 (dt,J= 13.7, 6.9 Hz, 1H), 4.42 (s, 2H), 3.77 (s, 3H), 3.68 - 3.62 (m, 1H), 2.83 - 2.74 (m, 1H), 2.68 (dd,J= 10.3, 3.8 Hz, 1H), 2.52 - 2.40 (m, 5H), 2.36 (s, 3H), 2.06 - 1.92 (m, 1H), 1.65 - 1.55 (m, 1H), 1.26 (d,J= 6.8 Hz, 6H)m / zcalculated for C 32 H 37 F3N8O3(M+H) + 639.3,found639.2160N-(2-(4-(dimethylamino)piperidin-1-yl)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4) δ 8.31 (s, 1H), 8.13 (s, 1H), 7.66 (d,J= 8.3 Hz, 2H), 7.43 (d,J= 8.2 Hz, 2H), 6.76 (s, 1H), 6.56 (dd,J= 17.0, 10.2 Hz, 1H), 6.37 (d,J= 16.0 Hz, 1H), 5.81 (d,J= 11.3 Hz, 1H), 4.69 - 4.57 (m, 1H), 4.42 (s, 2H), 3.78 (s, 3H), 3.07 (d,J= 11.9 Hz, 2H), 2.89 (s, 6H)2.77 (t,J= 11.2 Hz, 2H), 2.15 - 2.08 (m, 2H), 2.02 - 1.90 (m, 3H), 1.25 (d,J= 6.8 Hz, 6H)m / zcalculated for C 33 H 39 F3N8O3(M+H) + 653.3,found653.4161N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.23 ​​(s, 1H), 8.15 (s, 1H), 7.70 (d,J= 8.4 Hz, 2H), 7.45 (d,J= 8.2 Hz, 2H), 6.85 (s, 1H), 6.60 (dd,J= 17.0, 10.2 Hz, 1H), 6.40 (dd,J= 17.0, 1.6 Hz, 1H), 5.84 (dd,J= 10.2, 1.6 Hz, 1H), 4.67 - 4.56 (m, 1H), 4.42 (s, 2H), 3.82 (s, 3H), 3.57 - 3.47 (m, 1H), 3.39 (s, 1H), 3.15 - 2.93 (m, 2H), 2.66 (s, 3H), 2.62 (s, 3H), 2.27 - 2.09 (m, 1H), 2.09 - 1.90 (m, 2H), 1.81 - 1.65 (m, 1H), 1.25 (d,J= 6.8 Hz, 6H)m / zcalculated for C 33 H 39 F3N8O3(M+H) + 653.3,found653.3162N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.15 (s, 1H), 7.96 (s, 1H), 7.74 (d,J= 8.3 Hz, 2H), 7.47 (d,J= 8.2 Hz, 2H), 6.80 (s, 1H), 6.57 (dd,J= 16.9, 10.2 Hz, 1H), 6.35 (dd,J= 16.9, 1.7 Hz, 1H), 5.83 (dd,J= 10.2, 1.7 Hz, 1H), 4.66 - 4.57 (m, 1H), 4.42 (s, 2H), 3.84 (s, 3H), 3.49 (s, 2H), 3.40 - 3.36 (m, 2H), 3.27 - 3.23 (m, 2H), 3.01 (s, 2H), 2.63 (s, 3H), 2.17 - 2.07 (m, 4H), 1.25 (d,J= 6.9 Hz, 6H)m / zcalculated for C 33 H 39 F3N8O3(M+H) + 653.3,found653.3163N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-((3aR,6aR)-1-methylhexahydropyrrolo3,4-b]pyrrol-5(1H)-yl)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.16 (s, 1H), 8.11 (s, 1H), 7.66 (d,J= 8.4 Hz, 2H), 7.43 (d,J= 8.2 Hz, 2H), 6.70 (s, 1H), 6.59 (dd,J= 17.0, 10.2 Hz, 1H), 6.39 (dd,J= 17.0, 1.7 Hz, 1H), 5.80 (dd,J= 10.2, 1.7 Hz, 1H), 4.67 - 4.53 (m, 1H), 4.40 (s, 2H), 3.77 (s, 3H), 3.16 - 3.05 (m, 2H), 3.00 - 2.93 (m, 1H), 2.90 - 2.73 (m, 3H), 2.70 - 2.62 (m, 1H), 2.46 (s, 3H), 2.39 - 2.28 (m, 1H), 2.23 - 2.12 (m, 1H), 1.69 - 1.55 (m, 1H), 1.25 (d,J= 6.8 Hz, 6H)m / zcalculated for C 33 H 37 F3N8O3(M+H) + 651.3,found651.3164N-(5-((8-(4-bromophenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4) δ 8.14 (s, 1H), 7.86 (s, 1H), 7.58 (d,J= 8.5 Hz, 2H), 7.19 (d,J= 8.6 Hz, 2H), 6.82 (s, 1H), 6.60 (dd,J= 16.9, 10.2 Hz, 1H), 6.45 (d,J= 16.9 Hz, 1H), 5.88 (d,J= 10.2 Hz, 1H), 4.71 - 4.57 (m, 1H), 4.40 (s, 2H), 3.87 (s, 3H), 3.41 - 3.36 (m, 2H), 3.18 - 3.14 (m, 2H), 2.78 (s, 6H), 2.63 (s, 3H), 1.24 (d,J= 6.8 Hz, 6H)m / zcalculated for C 30 H 37 BrN8O(M+H) + 637.2,found637.2165(R)-N-(5-((8-(4-bromophenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4) δ 8.08 (s, 1H), 7.85 (s, 1H), 7.52 (d,J= 8.3 Hz, 2H), 7.14 (d,J= 8.1 Hz, 2H), 6.63 (dd,J= 16.9, 6.0 Hz, 1H), 6.58 (s, 1H), 6.36 (d,J= 17.3 Hz, 2H), 5.81 (d,J= 10.4 Hz, 1H), 4.68 - 4.57 (m, 1H), 4.38 (s, 2H), 3.79 (s, 3H), 3.24 - 2.89 (m, 5H), 2.34 (s, 6H), 2.25 - 2.10 (m, 1H), 1.94 - 1.80 (m, 1H), 1.24 (d,J= 6.8 Hz, 6H)m / zcalculated for C 31 H 37 BrN8O3(M+H) +649.2,found649.2166(R)-N-(2-(3-(dimethylamino)pyrrolidin-1-yl)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4) δ 8.09 (s, 1H), 7.94 (s, 1H), 7.67 (d,J= 8.4 Hz, 2H), 7.43 (d,J= 8.3 Hz, 2H), 6.60 - 6.48 (m, 2H), 6.34 (dd,J= 17.0, 1.5 Hz, 1H), 5.77 (dd,J= 10.3, 1.6 Hz, 1H), 4.68 - 4.55 (m, 1H), 4.40 (s, 2H), 3.76 (s, 3H), 3.23 - 3.08 (m, 3H), 3.08 - 3.00 (m, 1H), 2.88 - 2.76 (m, 1H), 2.27 (s, 6H), 2.19 - 2.09 (m, 1H), 1.90 - 1.77 (m, 1H), 1.25 (d,J= 6.8 Hz, 6H)m / zcalculated for C 32 H 37 F3N8O3(M+H) + 639.3,found639.3167N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.73 (s, 1H), 8.01 (s, 1H), 6.86 (s, 1H), 6.52 (dd,J= 16.9, 10.3 Hz, 1H), 6.29 (dd,J= 17.0, 1.5 Hz, 1H), 5.75 (dd,J= 10.3, 1.5 Hz, 1H), 4.75 - 4.66 (m, 1H), 4.55 (p,J= 6.8 Hz, 1H), 4.12 (s, 2H), 3.87 (s, 3H), 3.05 - 2.97 (m, 2H), 2.77 - 2.61 (m, 8H), 2.59 - 2.43 (m, 4H), 2.39 - 2.32 (m, 1H), 2.29 (s, 3H), 2.02 - 1.94 (m, 4H), 1.91 - 1.78 (m, 2H), 1.75 - 1.65 (m, 4H), 1.16 (d,J= 6.8 Hz, 6H)m / zcalculated for C 35 H 49 F2N9O3(M+H) + 682.4,found682.4169N-(4-(difluoromethoxy)-5-((6-isopropyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.61 (s, 1H), 8.02 (s, 1H), 7.05 (s, 1H), 6.97 - 6.52 (m, 2H), 6.38 - 6.29 (m, 1H), 5.87 - 5.75 (m, 1H), 4.84 - 4.74 (m, 1H), 4.64 - 4.55 (m, 1H), 4.15 (s, 2H), 3.90 - 3.83 (m, 2H), 3.13 - 3.04 (m, 2H), 2.88 - 2.32 (m, 15H), 2.28 (s, 3H), 2.05 - 1.95 (m, 2H), 1.78 - 1.64 (m, 2H), 1.56 - 1.48 (m, 2H), 1.18 (d,J= 6.8 Hz, 6H)m / zcalculated for C 34 H 47 F2N9O4(M+H) + 684.4, found 684.4170N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4)δ 8.70 (s, 1H), 8.03 (s, 1H), 7.06 (s, 1H), 6.97 - 6.50 (m, 2H), 6.32 (d,J= 17.0 Hz, 1H), 5.79 (d,J= 10.3 Hz, 1H), 5.03 - 4.93 (m, 1H), 4.61 - 4.52 (m, 1H), 4.15 (s, 2H), 3.10 - 2.99 (m, 2H), 2.77 - 2.31 (m, 17H), 2.28 (s, 3H), 2.07 - 1.84 (m, 4H), 1.80 - 1.61 (m, 2H), 1.18 (d,J= 6.8 Hz, 6H)m / zcalculated for C 35 H 47 F4N9O3(M+H) +718.4, found 718.4171N-(5-((8-(4,4-difluorocyclohexyl)-6-ethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (400 MHz, Chloroform-d) δ 9.17 (s, 1H), 8.55 (s, 1H), 7.98 (s, 1H), 6.46 (t,J= 73.7 Hz, 1H), 6.36 (dd,J= 16.9, 1.4 Hz, 1H), 6.28 (d,J= 1.9 Hz, 1H), 5.77 (dd,J= 10.0, 1.4 Hz, 1H), 4.79 - 4.67 (m, 1H), 4.19 (s, 2H), 3.44 (q,J= 7.1 Hz, 2H), 3.05 - 2.98 (m, 2H), 2.91 - 2.60 (m, 13H), 2.46 (s, 3H), 2.10 - 1.99 (m, 6H), 1.88 - 1.65 (m, 4H), 1.17 (t,J= 7.1 Hz, 3H)m / zcalculated C 34 H 45 F4N9O3for(M+H) + 704.4,found704.4172N-(5-((8-(4,4-difluorocyclohexyl)-6-ethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide (400 MHz, Methanol-d4)δ8.66(s,1H),8.00(s,1H),7.15(d,J= 1.4 Hz, 1H), 6.57 (dd,J= 17.0, 10.3 Hz, 1H), 6.33 (dd,J= 17.0, 1.5 Hz, 1H), 5.81 (dd,J= 10.3, 1.5 Hz, 1H), 4.68 - 4.57 (m, 1H), 4.27 (s, 2H), 3.42 (q,J= 7.1 Hz, 2H), 3.06 (d,J= 11.6 Hz, 2H), 2.83 - 2.41 (m, 12H), 2.43 - 2.35 (m, 1H), 2.29 (s, 3H), 2.06 - 1.87 (m, 4H), 1.81 - 1.59 (m, 6H), 1.15 (t,J= 7.1 Hz, 3H)m / zcalculated C 34 H 44 F5N9O3for(M+H) + 722.4,found722.4173N-(4-(difluoromethoxy)-5-((6-ethyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (400 MHz, Methanol-d4)δ8.60(s,1H),7.99(s,1H),7.05(s,1H),6.76(t,J= 74.1 Hz, 1H), 6.58 (d,J= 17.0, Hz, 1H), 6.33 (dd,J= 17.0, 1.5 Hz, 1H), 5.80 (dd,J= 10.2, 1.5 Hz, 1H), 4.84 - 4.72 (m, 1H), 4.27 (s, 2H), 3.86 (dd,J= 11.1, 4.5 Hz, 1H), 3.43 (q,J= 7.3 Hz, 2H), 3.12 - 3.04 (m, 2H), 2.78 - 2.33 (m, 13H), 2.28 (s, 3H), 1.79 - 1.64 (m, 3H), 1.60 - 1.46 (m, 4H), 1.16 (t,J= 7.1 Hz, 3H), 0.85 (dt,J= 16.7, 6.7 Hz, 2H)m / zcalculated C 33 H 45 F2N9O4for(M+H) + 670.4,found670.4174N-(5-((6-Ethyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide (400 MHz, Methanol-d4)δ8.60(s,1H),7.99(s,1H),7.14(s,1H),6.57(dd,J= 17.0, 10.3 Hz, 1H), 6.34 (dd,J= 17.0, 1.5 Hz, 1H), 5.81 (dd,J= 10.3, 1.5 Hz, 1H), 4.80 - 4.68 (m, 1H), 4.27 (s, 2H), 3.83 (dd,J= 11.2, 4.5 Hz, 1H), 3.43 (q,J= 7.3 Hz, 2H), 3.08 (d,J= 12.1 Hz, 2H), 2.83 - 2.41 (m, 12H), 2.43 - 2.31 (m, 1H), 2.28 (s, 3H), 1.81 - 1.63 (m, 3H), 1.61 - 1.45 (m, 4H), 1.16 (t,J= 7.1 Hz, 3H), 0.92 - 0.78 (m, 2H)m / zcalculated C 33 H 44 F3N9O4for(M+H) + 688.4,found688.3

[0400] Example 175: (S)-N-(5-((8-(2-chloro-3-methoxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0401]

[0402] Step 1: Ethyl 4-((2-chloro-3-methoxyphenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate

[0403]

[0404] Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (0.500 g, 2.149 mmol), 2-chloro-3-methoxyaniline (0.508 g, 3.223 mmol), palladium(II) acetate (0.048 g, 0.215 mmol), 4,5-bis(diphenylphosphino)-9,9-diphenylxanthenate (Xantphos, 0.249 g, 0.430 mmol), and cesium carbonate (Cs2CO3, 1.400 g, 4.298 mmol) were added to 1,4-dioxane (3 mL) and stirred at 110 °C for 16 h. After the temperature was lowered to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; ethyl acetate / hexane = from 0% to 25%) and concentrated to afford ethyl 4-((2-chloro-3-methoxyphenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (0.837 g, 119.6%) as a light yellow solid.

[0405]

[0406] Step 2: (4-((2-chloro-3-methoxyphenyl)amino)-2-(methylthio)pyrimidin-5-yl)methanol

[0407]

[0408] Ethyl 4-((2-chloro-3-methoxyphenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (0.837 g, 2.36 mmol) was dissolved in tetrahydrofuran (8 mL), and lithium aluminum hydride solution (1.00 M solution in tetrahydrofuran, 2.84 mL, 2.84 mmol) was slowly added at 0 °C, stirred for 10 min, and then stirred for an additional 13 h at room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; methanol / dichloromethane = from 0% to 2%) and concentrated to afford (4-((2-chloro-3-methoxyphenyl)amino)-2-(methylthio)pyrimidin-5-yl)methanol (0.195 g, 29.1%) as a yellow solid.

[0409]

[0410] Step 3: N-(2-chloro-3-methoxyphenyl)-5-(chloromethyl)-2-(methylthio)pyrimidin-4-amine

[0411]

[0412] (4-((2-chloro-3-methoxyphenyl)amino)-2-(methylthio)pyrimidin-5-yl)methanol (0.195 g, 0.626 mmol) was dissolved in tetrahydrofuran (10 mL), thionyl chloride (0.114 mL, 1.565 mmol) was added, and the mixture was stirred at 0 °C for 10 min and then at 75 °C for an additional 1.5 h. After the temperature was lowered to room temperature, water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification. N-(2-chloro-3-methoxyphenyl)-5-(chloromethyl)-2-(methylthio)pyrimidin-4-amine (0.125 g, black solid)

[0413]

[0414] Step 4: (S)-N-(2-chloro-3-methoxyphenyl)-2-(methylthio)-5-(((1,1,1-trifluoropropan-2-yl)amino)methyl)pyrimidin-4-amine

[0415]

[0416] N-(2-Chloro-3-methoxyphenyl)-5-(chloromethyl)-2-(methylthio)pyrimidin-4-amine (0.125 g, 0.379 mmol), (S)-2-amino-1,1,1-trifluoropropane hydrochloride (0.085 g, 0.568 mmol), sodium iodide (NaI, 0.085 g, 0.568 mmol), and N,N-diisopropylethylamine (0.132 mL, 0.757 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the mixture was stirred at 50 °C for 2 h. After cooling to room temperature, water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; ethyl acetate / hexane = from 0% to 25%) and concentrated to afford (S)-N-(2-chloro-3-methoxyphenyl)-2-(methylthio)-5-(((1,1,1-trifluoropropan-2-yl)amino)methyl)pyrimidin-4-amine (0.099 g, 64.3%) as a light yellow solid.

[0417]

[0418] Step 5: (S)-1-(2-chloro-3-methoxyphenyl)-7-(methylthio)-3-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0419]

[0420] (S)-N-(2-Chloro-3-methoxyphenyl)-2-(methylthio)-5-(((1,1,1-trifluoropropan-2-yl)amino)methyl)pyrimidin-4-amine (0.099 g, 0.243 mmol) and triethylamine (0.137 mL, 0.973 mmol) were dissolved in tetrahydrofuran (2 mL), triphosgene (0.072 g, 0.243 mmol) was added at 0 °C, stirred for 5 min, and then stirred for an additional 16 h at 70 °C. After the temperature was lowered to room temperature, water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; ethyl acetate / hexane = 35%) and concentrated to afford (S)-3-(2-chloro-3-methoxyphenyl)-7-(methylthio)-1-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.088 g, 83.9%) as a light yellow solid.

[0421]

[0422] Step 6: (S)-1-(2-chloro-3-methoxyphenyl)-7-(methylsulfonyl)-3-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0423]

[0424] (S)-3-(2-chloro-3-methoxyphenyl)-7-(methylthio)-1-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.088 g, 0.203 mmol) was dissolved in dichloromethane (2 mL), 3-chloroperbenzoic acid (77.00%, 0.105 g, 0.608 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 18 hours. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, stirred for 20 minutes, and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification. (S)-1-(2-chloro-3-methoxyphenyl)-7-(methylsulfonyl)-3-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one, 0.071 g, white solid)

[0425]

[0426] Step 7: (S)-1-(2-chloro-3-methoxyphenyl)-7-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-3-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0427]

[0428] (S)-1-(2-Chloro-3-methoxyphenyl)-7-(methylsulfonyl)-3-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.071 g, 0.154 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (0.034 g, 0.184 mmol) were dissolved in N,N-dimethylformamide (4 mL), potassium tert-butoxide (1.00 M solution THF, 0.308 mL, 0.308 mmol) was added at 0 °C, and the mixture was stirred for 5 min and then further stirred at room temperature for 2 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; methanol / dichloromethane = from 0% to 5%) and concentrated to afford (S)-1-(2-chloro-3-methoxyphenyl)-7-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-3-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.062 g, 70.5%) as a brown solid.

[0429]

[0430] Step 8: (S)-1-(2-chloro-3-methoxyphenyl)-7-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-3-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0431]

[0432] (S)-1-(2-chloro-3-methoxyphenyl)-7-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-3-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.034 g, 0.060 mmol), N1 ,N 1 ,N 2 -Trimethylethane-1,2-diamine (0.010 mL, 0.078 mmol) and potassium carbonate (K2CO3, 0.011 g, 0.078 mmol) were dissolved in acetonitrile (1 mL) and stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the concentrate was purified by column chromatography (SiO2, 5 g cartridge; methanol / dichloromethane = from 2% to 3%) to afford (S)-1-(2-chloro-3-methoxyphenyl)-7-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-3-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.023 g, 58.7%) as an orange solid.

[0433]

[0434] Step 9: (S)-7-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-1-(2-chloro-3-methoxyphenyl)-3-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0435]

[0436] (S)-1-(2-Chloro-3-methoxyphenyl)-7-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-3-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.023 g, 0.035 mmol), iron (0.014 g, 0.248 mmol), and ammonium chloride (NH4Cl, 0.010 g, 0.175 mmol) were added to ethanol (2.0 mL) / water (0.5 mL), and stirred at 90 °C for 1 h. The reaction mixture was filtered through a pad of Celite, and water was added to the filtrate to remove the solid, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification. (S)-7-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-1-(2-chloro-3-methoxyphenyl)-3-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one, 0.022 g, light yellow solid)

[0437]

[0438] Step 10: (S)-N-(5-((8-(2-chloro-3-methoxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0439]

[0440] (S)-7-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-1-(2-chloro-3-methoxyphenyl)-3-(1,1,1-trifluoropropan-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.022 g, 0.035 mmol), acryloyl chloride (0.003 g, 0.038 mmol), and N,N-diisopropylethylamine (0.007 mL, 0.038 mmol) were dissolved in dichloromethane (1 mL), stirred at 0 °C for 30 min, and then at room temperature for an additional 2 h. Water was added to the reaction mixture, and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 5 g cartridge; methanol / dichloromethane = from 0% to 10%) and concentrated to afford (S)-N-(5-((8-(2-chloro-3-methoxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (0.014 g, 59.5%) as a light yellow solid.

[0441] 1H NMR (400 MHz, Methanol-d4) δ 8.18 (dt,J= 3.5, 0.7 Hz, 1H), 7.32 (td,J= 8.2, 5.4 Hz, 1H), 7.07 (dd,J= 8.6, 1.5 Hz, 1H), 7.02 (ddd,J= 7.9, 3.3, 1.3 Hz, 1H), 6.81 (s, 1H), 6.59 - 6.52 (m, 1H), 6.44 - 6.37 (m, 1H), 5.88 - 5.83 (m, 1H), 5.29 - 5.22 (m, 1H), 4.63 (dd,J= 14.1, 6.3 Hz, 1H), 4.46 (d,J= 14.1 Hz, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 3.14 - 3.02 (m, 2H), 2.59 (s, 5H), 2.46 - 2.34 (m, 6H), 1.52 (dd,J= 7.3, 1.5 Hz, 3H).

[0442] LC-MSm / zcalculated for C 31 H 36 ClF3N8O4(M+H) + 677.3, found 677.2.

[0443]

[0444] Compounds of Examples 176 to 182 were prepared in a similar manner to Example 175, and the compound name, chemical structural formula, of each example compound are as follows: 1 The results of H-NMR and LC-MS analysis are summarized in Table 3 below.

[0445] Example Compound Compound Name Structure 1 H-NMRLC-MS176(S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8-(3-methoxy-4-(trifluoromethyl)phenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 8.16 (s, 1H), 7.57 (d,J= 8.2 Hz, 1H), 7.09 (s, 1H), 6.99 (dd,J= 8.1, 1.2 Hz, 1H), 6.81 (s1 H), 6.50 (dd,J= 17.0, 10.2 Hz, 1H), 6.31 (dd,J= 17.0, 1.7 Hz, 1H), 5.76 (dd,J= 10.1, 1.7 Hz, 1H), 5.33 - 5.18 (m, 1H), 4.61 (d,J= 14.2 Hz, 1H), 4.44 (d,J= 14.1 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 2.96 (t,J= 5.9 Hz, 2H), 2.59 (s, 3H), 2.38 (t,J= 5.9 Hz, 2H), 2.25 (s, 6H), 1.51 (d,J= 7.2 Hz, 3H)m / zcalculated for C 32 H 36 F6N8O4(M+H) + 711.3,found711.2177N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((8-(3-methoxy-4-(trifluoromethyl)phenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (400 MHz, Methanol-d4) δ 8.12 (s, 1H), 7.90 (s, 1H), 7.59 (d,J= 8.3 Hz, 1H), 7.09 (s, 1H), 6.97 (dd,J= 8.0, 1.3 Hz, 1H), 6.56 (s, 1H), 6.50 (dd,J= 17.0, 10.3 Hz, 1H), 6.32 (dd,J= 16.9, 1.7 Hz, 1H), 5.76 (dd,J= 10.2, 1.7 Hz, 1H), 5.29 - 5.18 (m, 1H), 4.60 (d,J= 14.2 Hz, 1H), 4.43 (d,J= 14.0 Hz, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 3.23 - 3.08 (m, 4H), 3.02 - 2.89 (m, 1H), 2.35 (s, 6H), 2.21 - 2.11 (m, 1H), 1.93 - 1.82 (m, 1H), 1.51 (d,J= 7.3 Hz, 3H)m / zcalculated for C 33 H 36 F6N8O4(M+H) + 723.3,found723.3178N-(5-((8-(2-chloro-3-fluorophenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.16 (dd,J= 3.5, 0.8 Hz, 1H), 7.59 - 7.44 (m, 1H), 7.39 - 7.19 (m, 3H), 6.59 - 6.49 (m, 2H), 6.36 (ddd,J= 17.1, 4.9, 1.7 Hz, 1H), 5.83 (ddd,J= 10.2, 4.4, 1.8 Hz, 1H), 5.30 - 5.20 (m, 1H), 4.67 - 4.59 (m, 1H), 4.50 - 4.44 (m, 1H), 3.83 (s, 3H), 3.26 - 3.11 (m, 4H), 3.02 - 2.90 (m, 1H), 2.36 (d,J= 4.6 Hz, 6H), 2.24 - 2.12 (m, 1H), 1.91 - 1.80 (m, 1H), 1.52 (d,J= 7.2 Hz, 3H)m / zcalculated for C 31 H 33 ClF4N8O3(M+H) + 677.2,found677.3179N-(5-((8-(4-chloro-3-fluorophenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.12 (d,J= 0.9 Hz, 1H), 7.85 - 7.78 (m, 1H), 7.46 (t,J= 8.3 Hz, 1H), 7.21 (dd,J= 9.8, 2.3 Hz, 1H), 7.09 (ddd,J= 8.5, 2.3, 1.2 Hz, 1H), 6.58 (d,J= 2.0 Hz, 1H), 6.57 - 6.49 (m, 1H), 6.33 (dd,J= 17.0, 1.7 Hz, 1H), 5.78 (dd,J= 10.3, 1.7 Hz, 1H), 5.28 - 5.19 (m, 1H), 4.58 (d,J= 13.2 Hz, 1H), 4.41 (d,J= 14.0 Hz, 1H), 3.79 (s, 3H), 3.26 - 3.11 (m, 4H), 2.98 (p,J= 7.0 Hz, 1H), 2.37 (s, 6H), 2.24 - 2.16 (m, 1H), 1.95 - 1.84 (m, 1H), 1.50 (d,J= 7.3 Hz, 3H)m / zcalculated for C 31 H 33 ClF4N8O3(M+H) + 677.2,found677.2180N-(5-((8-(2-chloro-3-(trifluoromethyl)phenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ8.17(d,J= 2.9 Hz, 1H), 7.78 (dd,J= 8.2, 1.6 Hz, 1H), 7.67 (td,J= 7.9, 1.6 Hz, 1H), 7.62 - 7.48 (m, 2H), 6.60 - 6.48 (m, 2H), 6.36 (ddd,J= 17.0, 7.7, 1.8 Hz, 1H), 5.82 (ddd,J= 10.2, 5.8, 1.8 Hz, 1H), 5.24 (ddt,J= 12.6, 7.9, 4.6 Hz, 1H), 4.64 (dd,J= 14.1, 4.5 Hz, 1H), 4.47 (dd,J= 14.0, 5.5 Hz, 1H), 3.80 (d,J= 2.5 Hz, 3H), 3.25 - 2.90 (m, 5H), 2.36 (d,J= 8.0 Hz, 6H), 2.23 - 2.12 (m, 1H), 1.93 - 1.81 (m, 1H), 1.52 (dd,J= 7.3, 3.4 Hz, 3H)m / zcalculated for C 32 H 33 ClF6N8O3(M+H) + 727.2,found727.2181N-(5-((8-(3-chloro-4-(trifluoromethyl)phenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.13 (t,J= 0.9 Hz, 1H), 7.92 - 7.90 (m, 1H), 7.79 - 7.76 (m, 1H), 7.59 - 7.55 (m, 1H), 7.45 - 7.40 (m, 1H), 6.58 (s, 1H), 6.55 - 6.46 (m, 1H), 6.32 (dd,J= 17.0, 1.7 Hz, 1H), 5.75 (dd,J= 10.2, 1.7 Hz, 1H), 5.28 - 5.19 (m, 1H), 4.64 - 4.55 (m, 1H), 4.43 (d,J= 9.6 Hz, 1H), 3.76 (s, 3H), 3.23 - 3.12 (m, 3H), 3.12 - 3.05 (m, 1H), 2.94 - 2.86 (m, 1H), 2.32 (s, 6H), 2.22 - 2.13 (m, 1H), 1.91 - 1.82 (m, 1H), 1.50 (t,J= 5.6 Hz, 3H)m / zcalculated for C 32 H 33 ClF6N8O3(M+H) + 727.2,found727.2182N-(5-((8-(3-Bromo-4-(trifluoromethyl)phenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (400 MHz, Methanol-d4)δ 8.14 - 8.12 (m, 1H), 7.92 - 7.89 (m, 1H), 7.79 - 7.72 (m, 2H), 7.50 - 7.44 (m, 1H), 6.59 - 6.56 (m, 1H), 6.51 (dd,J= 17.0, 10.2 Hz, 1H), 6.36 - 6.29 (m, 1H), 5.75 (dd,J= 10.2, 1.7 Hz, 1H), 5.23 (qd,J= 7.8, 3.8 Hz, 1H), 4.61 - 4.56 (m, 1H), 4.45 - 4.37 (m, 1H), 3.75 (s, 3H), 3.21 - 3.11 (m, 3H), 3.09 - 3.02 (m, 1H), 2.89 - 2.78 (m, 1H), 2.29 (s, 6H), 2.19 - 2.09 (m, 1H), 1.87 - 1.78 (m, 1H), 1.50 (t,J= 6.5 Hz, 3H)m / zcalculated for C 32 H 33 BrF6N8O3(M+H) + 771.2,found771.2

[0446] Example 183: N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(2-((dimethylamino)methyl)-1H-pyrrol-1-yl)-4-methoxyphenyl)acrylamide

[0447]

[0448] Step 1: tert-Butyl (4-fluoro-2-methoxy-5-nitrophenyl)carbamate

[0449]

[0450] 4-Fluoro-2-methoxy-5-nitroaniline (10.000 mmol, 10.000 mmol) and N,N-dimethylpyridin-4-amine (DMAP, 0.122 g, 1.000 mmol) were dissolved in dichloromethane (10 mL), di-tert-butyl dicarbonate (2.297 mL, 10.000 mmol) was added at 0 °C, stirred for 10 minutes, and then stirred for an additional 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by column chromatography (SiO2, 10 g cartridge; ethyl acetate / hexane = from 0% to 20%) and concentrated to obtain tert-butyl (4-fluoro-2-methoxy-5-nitrophenyl)carbamate (2.280 g, 79.6%) as a yellow solid.

[0451]

[0452] Step 2: tert-Butyl (2-methoxy-5-nitro-4-(1H-pyrrol-1-yl)phenyl)carbamate

[0453]

[0454] Tert-Butyl (4-fluoro-2-methoxy-5-nitrophenyl)carbamate (0.286 g, 0.999 mmol), cesium carbonate (Cs2CO3, 0.391 g, 1.199 mmol), and pyrrole (0.104 mL, 1.499 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 60 °C for 18 h. After cooling to room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; ethyl acetate / hexane = from 10% to 25%) and concentrated to afford tert-butyl (2-methoxy-5-nitro-4-(1H-pyrrol-1-yl)phenyl)carbamate (0.099 g, 29.7%) as a yellow solid.

[0455]

[0456] Step 3: tert-Butyl (5-amino-2-methoxy-4-(1H-pyrrol-1-yl)phenyl)carbamate

[0457]

[0458] tert-Butyl (2-methoxy-5-nitro-4-(1H-pyrrol-1-yl)phenyl)carbamate (0.099 g, 0.297 mmol) was dissolved in methanol (5 mL), Pd / C (10 mg) was slowly added, a hydrogen balloon was attached, and the mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through a pad of Celite to remove solids, and the filtrate was concentrated under reduced pressure. The obtained product was used without further purification. (tert-Butyl (5-amino-2-methoxy-4-(1H-pyrrol-1-yl)phenyl)carbamate, 0.088 g, brown solid)

[0459]

[0460] Step 4: tert-Butyl (5-acrylamido-2-methoxy-4-(1H-pyrrol-1-yl)phenyl)carbamate

[0461]

[0462] tert-Butyl (5-amino-2-methoxy-4-(1H-pyrrol-1-yl)phenyl)carbamate (0.088 g, 0.290 mmol) and potassium carbonate (K2CO3, 0.241 g, 1.741 mmol) were added to acetonitrile (4 mL), 3-chloropropanoyl chloride (0.039 g, 0.305 mmol) was added at 0 °C, stirred for 15 min, and then stirred for an additional 15 h at 100 °C. After cooling to room temperature, the reaction mixture was stirred under reduced pressure to remove the solvent, and the concentrate was purified by column chromatography (SiO2, 10 g cartridge; ethyl acetate / hexane = from 10% to 20%) and concentrated to obtain tert-butyl (5-acrylamido-2-methoxy-4-(1H-pyrrol-1-yl)phenyl)carbamate (0.067 g, 64.6%) as a white solid.

[0463]

[0464] Step 5: tert-Butyl (5-acrylamido-4-(2-((dimethylamino)methyl)-1H-pyrrol-1-yl)-2-methoxyphenyl)carbamate

[0465]

[0466] Tert-Butyl (5-acrylamido-2-methoxy-4-(1H-pyrrol-1-yl)phenyl)carbamate (0.067 g, 0.187 mmol), dimethylamine (2.00 M solution EtOH, 0.187 mL, 0.375 mmol), and formaldehyde (35.00 % solution DW, 0.022 mL, 0.206 mmol) were dissolved in acetic acid (1 mL), and the mixture was stirred at room temperature for 3 h. The reaction mixture was adjusted to pH 8 by adding saturated aqueous sodium bicarbonate solution, and then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; methanol / dichloromethane = from 0% to 2%) and concentrated to afford tert-butyl (5-acrylamido-4-(2-((dimethylamino)methyl)-1H-pyrrol-1-yl)-2-methoxyphenyl)carbamate (0.030 g, 38.6%) as a white solid.

[0467]

[0468] Step 6: N-(5-amino-2-(2-((dimethylamino)methyl)-1H-pyrrol-1-yl)-4-methoxyphenyl)acrylamide

[0469]

[0470] tert-Butyl (5-acrylamido-4-(2-((dimethylamino)methyl)-1H-pyrrol-1-yl)-2-methoxyphenyl)carbamate (0.030 g, 0.072 mmol) was dissolved in dichloromethane (2 mL) / trifluoroacetic acid (0.5 mL) and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting concentrate was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting product was used without further purification. (N-(5-amino-2-(2-((dimethylamino)methyl)-1H-pyrrol-1-yl)-4-methoxyphenyl)acrylamide, 0.028 g, yellow solid)

[0471] LC-MSm / zcalculated for C 17 H 22 N4O2(M+H) + 315.2, found 315.2.

[0472]

[0473] Step 7: N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(2-((dimethylamino)methyl)-1H-pyrrol-1-yl)-4-methoxyphenyl)acrylamide

[0474]

[0475] 7-Chloro-1-(4,4-difluorocyclohexyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.031 g, 0.081 mmol), N-(5-amino-2-(2-((dimethylamino)methyl)-1H-pyrrol-1-yl)-4-methoxyphenyl)acrylamide (0.025 g, 0.081 mmol) and cesium carbonate (Cs2CO3, 0.039 g, 0.121 mmol) were dissolved in 1,4-dioxane (1.5 mL) and stirred at 100 °C for 15 h. After the temperature was lowered to room temperature, water was added to the reaction mixture and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 10 g cartridge; methanol / dichloromethane = from 0% to 5%) and concentrated to afford N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(2-((dimethylamino)methyl)-1H-pyrrol-1-yl)-4-methoxyphenyl)acrylamide (0.004 g, 7.7%) as a yellow solid.

[0476] 1 H NMR (400 MHz, Methanol-d4) δ 8.58 (s, 1H), 8.12 (s, 1H), 6.92 (s, 1H), 6.73 (dd,J= 2.4, 1.8 Hz, 1H), 6.27 (s, 1H), 6.21 - 6.15 (m, 2H), 6.10 (dd,J= 17.1, 9.7 Hz, 1H), 5.68 (dd,J= 9.8, 2.0 Hz, 1H), 4.78 - 4.73 (m, 1H), 4.42 (s, 2H), 4.13 (q,J= 9.1 Hz, 2H), 3.93 (s, 3H), 2.72 (s, 2H), 2.36 (s, 6H), 2.11 - 1.63 (m, 8H).

[0477] LC-MSm / zcalculated for C 31 H 35 F5N8O3(M+H) + 663.3, found 663.3.

[0478]

[0479] <Experimental Example>

[0480] Experimental Example 1: Evaluation of Growth Inhibition Against Cancer Cells

[0481] In this experiment, we aimed to determine the effects of the compounds of Examples 1 to 183 on the activity of cancer cells expressing EGFR wild-type and mutant forms. To this end, a BaF3 cell line harboring an EGFR mutation was generated using a mouse pro-B cell (Ba / F3) cell line. In addition, A431, an EGFR wild-type cell line, was used.

[0482] Specifically, Ba / F3 cells were infected with retroviruses containing EGFR wild-type (WT), Exon 19 deletion, L858R, and Exon 20 insertion mutant genes to stably express each gene. Five types of Ba / F3 EGFR wild-type (EGFR-WT), Exon 19 deletion, L858R, and Exon 20 insertion mutants; ASV (V769_D770insASV, EGFR-ASV), SVD (D770_N771insSVD, EGFR-SVD), FQEA (A763_Y764insFQEA, EGFR-FQEA), NPH (H773_V774insNPH, EGFR-NPH), H (H773_V774insH, EGFR-H)) cell line was prepared.

[0483] Each cell was cultured in RPMI Medium 1640 containing 10% FBS and 1% penicillin / streptomycin. 2,500 cells were seeded in a well plate (white 96-well plate, Corning) before compound treatment. The compounds were diluted in dimethyl sulfoxide (5-fold dilution, total of 10 concentrations) and injected 20 μl each at a final concentration of 0.005 nM - 10 μM (at this time, the final DMSO concentration was 0.1%). After incubating the compound-treated cells at 37°C and 5% carbon dioxide for 72 hours, cell lysis was induced for 2 minutes at room temperature using CellTiter-Glo Reagent (CTG, Promega). After stabilizing the luminescence signal for 5 minutes, the luminescence intensity was measured using an EnVision™LUX multimode microplate reader. Each test was repeated three times. The results were calculated as the cell growth rate (%) compared to the control group. The concentration that inhibited cell growth by 50% of each compound (GI 50 ) values ​​were calculated using the log(inhibitor) vs. response - Variable slope (four parameters) analysis of the GraphPad Prism program, and the results are summarized and presented in Tables 4 and 5. Referring to Table 4, it can be seen that the example compounds according to the present invention have low growth inhibitory activity on EGFR wild type (EGFR-WT) and are selective for EGFR exon 20 insertion mutation. In particular, example compounds 17, 18, 24, 44, 48, 61, 66, 97, 102, 103, 104, and 129 are highly selective compounds for EGFR exon 20 insertion mutation, and example compounds 44, 97, 102, 103, 104, and 129 show remarkable selectivity in A431 (EGFR wild-type cell).

[0484] Example compound Ba / F3, GI 50 (nM)A431,GI50(nM)EGFR-WTEGFR-ASVEGFR-SVDEGFR-FQEAEGFR-NPHEGFR-H1DBBAndndnd2CABAndndnd3BAAAAAnd4CBBAndndnd5BABAndndnd6CAAAndndnd7DABAndndnd8DBBBndndnd9CBCBndndnd10DBCBndndnd11DCDBndndnd12EDDCndndnd13ndDDCndndnd14ndBDCndndnd15BAAABBnd16CAAABAnd17DBDBndndnd18103.77.813.66.016.48.5nd19111.36.120.46.458.516.0nd20DBCBndndnd21CAAABAnd22FndndDF nd23CABABAnd24146.59.266.63.065.252.9nd25CAAAAAnd26BAAndAndnd27DBBndBndnd28CAAndAndnd29DBBndBndnd30DBBndBndnd31CABndAndnd32CAAndBndnd33CABndBndnd34DBBndBndnd35BABndBndnd36BAAndAndnd37CAAndAndnd38CBBndCndnd39DDDndDndnd40CAAndAndnd41CBBndBndnd42CABndBndnd43CABABAnd44494.421.947.63.556.121.6514.045BAAACAnd46BAAABBnd47EDDCDEnd48157.19.714.32.816.618.6nd49ECDDBDnd50DBndndndBnd51DBndndndBnd52ECndndndCnd53BAAABAnd54EDndndndDnd55EDndndndDnd56FDndndndDnd57DDndndndDnd58CBndndndBnd59DCndndndCnd60CBndndndBnd61182.916.824.82.725.120.7nd62CBndndndBnd63CBndndndBnd64DCndndndCnd65DBBABBnd66242.617.422.43.324.214.0nd67CAndndndBnd68DBndndndBnd69DBCBCBnd70DDDndndDnd71DCDndndCnd72DBCBDCnd73DCDBDCnd74FDEndndDnd75FDDndndDn d76DBCndndCnd77DCDndndCnd78DCCBDCnd79ECDBDCnd80DBCBDCnd81DBCndndBnd82EDDndndDnd83EDDndndDnd84EDDndndDnd85F DDndndDnd86FFFndndFnd87DDDndndDnd88FFFndndFnd89CABABBnd90CBBAAnd91DCDndndCnd92DCDndndBnd93FEEndndEnd94ECD ndndDnd95ECCndndCnd96EBCBCBnd97182.814.731.34.154.120.9418.798DBCBCBnd99DBCndndBnd100FCDndndDnd101FCDndndD nd102166.38.817.46.633.721.2273.0103308.323.844.715.1nd52.11000.0104200.126.332.27.161.336.91500.0105DBBnd ndCnd106DBCndndCnd107DABndndBnd108CABndndBnd109DCDndndCnd110DBBABBnd111DAAndndBnd112DABndndBnd113DBBABBnd1 14DBBABBnd115CABndndBnd116EDDndndDnd117FDEDEEnd118FFFndndFnd119FDDDEDnd120FFFndndFnd121EDDCDDnd122FFFndndE nd123DBDBDCnd124FDEndndDnd125DCCBCCnd126EDDndndDnd127DBBndndBnd128DBCndndBnd129109.013.611.35.124.116.3408.7130DBBndndBnd131FDEndndEnd132EDEndndDnd133DBBndndBnd134FFFndndFnd135FDFndndFnd136FFFndndFnd137DABAndndnd138CAAABand139EDDDndndnd140DBCBndndnd141BBCBndndnd142CBBAndndnd143BBAAndnd dnd144DABABBnd145CBBABBnd146DCDBndndnd147EDEDndndnd148BAAAndAnd149DBCBCBnd150DCCndDndnd15 1DABndBndnd152DCCBDCnd153ECDndDndnd154FDDndDndnd155DABndBndnd156DABndBndnd157DABndBndnd15 8DBBndBndnd159EBDndDndnd160EBDndDndnd161DBBndBndnd162DABndBndnd163DABndBndnd164AAAAAAnd165CAAAABnd166CAndndndndBnd167DBBABBnd168195.916.528.98.139.316.3599.2169CABndndndBnd170BAAndndBnd171CABndndAnd172DBBndndndBnd173DBBndndBnd174DBCndndBnd175DBndndndBnd176DBndndndBnd177DBndndndBnd178ECndndndCnd179CAndndndndBnd180DCndndndCnd181DBndndndBnd182DBndndndndBnd183FDDDEDnd< GI. 50 의 하다 >A < 10 nM; 10 nM ≤ B < 50 nM; 50 nM ≤ C < 100 nM 100 nM ≤ D < 500 nM; 500 nM ≤ E < 1000 nM; F ≥ 1000 nMnd: not determined

[0485] example compoundBa / F3, GI 50 (nM)EGFR-Exon 19 deletionEGFR-L858R169BA< GI 50Classification >A < 10 nM; 10 nM ≤ B < 50 nM; 50 nM ≤ C < 100 nM 100 nM ≤ D < 500 nM; 500 nM ≤ E < 1000 nM; F ≥ 1000 nMnd: not determined

[0486] Experimental Example 2: Pharmacokinetic Evaluation in Normal Rats

[0487] The pharmacokinetic profile of Example Compound 97 was investigated by single intravenous and oral administration using male Sprague-Dawley rats. Blood was collected over a certain period of time after administration, and the plasma obtained by centrifugation was used to analyze the blood concentration of Example Compound 97 by LC-MS / MS, and the pharmacokinetic parameters were calculated. The analysis results are summarized in Table 6. Referring to Table 6, Example Compound 97 showed very high absorption when administered orally and was confirmed to remain in the blood for a long time. This is an advantageous aspect in terms of antitumor activity in a mouse model.

[0488] Example Compound 97 Parameter IVPODose (mg / kg) 210 Tmax (h) - 2.0 Cmax (ng / ml) - 343.7 T1 / 2 (h) 8.8 8.2 AUClast (ng*h / ml) 2030.15 363.7 AUCinf (ng*h / ml) 2358.16 390.4 CL (L / h / kg) 0.9 - Vd (L / kg) 11.2 - F (%) - 54.2

[0489] Experimental Example 3: Evaluation of antitumor activity in a mouse model

[0490] The tumor suppression efficacy of Example Compound 97 according to the present invention was evaluated in a mouse xenograft tumor model. BALB / c nude mice (6-8 weeks old, female) were used, and after an acclimatization period, Ba / F3 EGFR exon 20 insertion ASV cells were subcutaneously transplanted into the right flank of the mice. After confirming tumor formation, the average tumor size per group was approximately 100 mm. 3After randomly dividing the groups into groups, drug administration was performed. During administration, tumor size and body weight were measured three times a week.

[0491] In the experimental group that was administered the compound 97 (30 mg / kg) orally once a day, the tumor growth inhibition rate due to drug administration was confirmed to be 104%, and no change in body weight was observed. The results are summarized and shown in Fig. 1. Referring to Fig. 1, it can be seen that the compound 97 has excellent efficacy against EGFR exon 20 insertion mutation and is non-toxic.

Claims

A compound selected from the group consisting of a compound represented by the following chemical formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] [Chemical Formula 1] In the above chemical formula 1, R 1 are each independently hydrogen, C 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, or heterocycloalkyl of 3 to 10 atoms, The above R 1 C of 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and heterocycloalkyl of 3 to 10 atoms are each independently R 11 may be substituted with one or more substituents selected from; R 2 are each independently hydrogen, C 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms, The above R 2 C of 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms, each independently R 11 may be substituted with one or more substituents selected from; R 11 Silver halogen, C 1-13 Alkyl, C 1-6 Alkoxy, -OH, -OCF3, -CN, -NO2, -OR 1a , -SR 1a , -NHOR 1a , -N(OH)R 1a , -C(O)R 1a , -C(O)NR 1a R 1b , -C(O)OR 1a , -OC(O)R 1a , -OC(O)NR 1a R 1b , -NR 1a R 1b , -NR 1a C(O)R 1b , -NR 1a C(O)OR 1b , -NR 1a C(O)NR 1b R 1c , -C(=NR 1a )R 1b , -C(=NR 1a )NR 1a R 1c , -NR 1a C(=NR 1b )NR 1c R 1d , -NR 1a S(O)R 1b , -NR 1a S(O)2R 1b , -NR 1a S(O)2NR 1b R 1c , -S(O)R 1a , -S(O)NR 1a R 1b , -S(O)2R 1a , -S(O)2NR 1a R 1b , -OS(O)2R 1a , -PR 1a R 1b , -P(O)R 1a R 1b or -BR 1a R 1b and; R 1a , R 1b , R 1c and R 1d are each independently hydrogen, C 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms; R 3 are each independently H, halogen, -OH, C 1-10 Alkyl, C 1-10 Alkoxy, or C 3-6 It is cycloalkoxy, The above R 3 C of 1-10 Alkyl, C 1-10 Alkoxy, or C 3-6 Cycloalkoxy may each be independently substituted with one or more halogens; R 4 is hydrogen, halogen, C 1-13 Alkyl, C 1-10 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, heteroaryl of 5 to 10 atoms, -OH, -OCF3, -CN, -NO2, -OR 4a , -SR 4a , -C(O)NR 4a R 4b , -NR 4a R 4b , -NR 4a C(O)R 4b , -NR 4a S(O)2R 4b , or S(O)2NR 4a R 4b And, The above R 4 C of 1-13 Alkyl, C 1-10 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 alkenyl, and C 2-6 Alkynyl is independently R 41 may be substituted with one or more substituents selected from The above R 4 C of 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, and heteroaryl of 5 to 10 atoms are each independently R 42 may be substituted with one or more substituents selected from; R 41 are halogens, -OH, -OCF3, -CN, -NO2, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8 Aryl, heteroaryl of 5 to 10 atoms, -OR 4c , -SR 4c , -NHOR 4c , -N(OH)R 4c , -C(O)R 4c , -C(O)NR 4c R 4d , -C(O)OR 4c , -OC(O)R 4c , -OC(O)NR 4c R 4d , -NR 4c R 4d , -NR 4c C(O)R 4d , -NR 4c C(O)OR 4d , -NR 4c C(O)NR 4d R 4e , -C(=NR 4c )R 4d , -C(=NR 4c )NR 4d R 4e , -NR 4c C(=NR 4d )NR 4e R 4f , -NR 4c S(O)R 4d , -NR 4c S(O)2R 4d , -NR 4c S(O)2NR 4d R 4e , -S(O)R 4c , -S(O)NR 4c R 4d , -S(O)2R 4c , -S(O)2NR 4c R 4d , -OS(O)2R 4c , -PR 4c R 4d , -P(O)R 4c R 4d or -BR 4c R 4d And, The above R 41 C of 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8 Aryl, and heteroaryl of 5 to 10 atoms are each independently halogen, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 7 atoms, C 6-8 Aryl, heteroaryl of 5 to 10 atoms, -OR 4g , -SR 4g , -C(O)NR 4g R 4h , -NR 4g R 4h , -NR 4g C(O)R 4h , -NR 4g S(O)2R 4h , or S(O)2NR 4g R 4h may be substituted with one or more substituents selected from the group consisting of; R 42 are halogens, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8 Aryl, heteroaryl of 5 to 10 atoms, -OR 4c , -SR 4c , -NHOR 4c , -N(OH)R 4c , -C(O)R 4c , -C(O)NR 4c R 4d , -C(O)OR 4c , -OC(O)R 4c , -OC(O)NR 4c R 4d , -NR 4c R 4d , -NR 4c C(O)R 4d , -NR 4c C(O)OR 4d , -NR 4c C(O)NR 4d R 4e , -C(=NR 4c )R 4d , -C(=NR 4c )NR 4d R 4e , -NR 4c C(=NR 4d )NR 4e R 4f , -NR 4c S(O)R 4d , -NR 4c S(O)2R 4d , -NR 4c S(O)2NR 4d R 4e , -S(O)R 4c , -S(O)NR 4c R 4d , -S(O)2R 4c , -S(O)2NR 4c R 4d , -OS(O)2R 4c , -PR 4c R 4d , -P(O)R 4c R 4d or -BR 4c R 4d And, The above R 42 C of 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8 Aryl, and heteroaryl of 5 to 10 atoms are each independently halogen, CF3, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 7 atoms, C 6-8 Aryl, heteroaryl of 5 to 10 atoms, -OR 4g , -SR 4g , -C(O)NR 4g R 4h , -NR 4g R 4h , -NR 4g C(O)R 4h , -NR 4g S(O)2R 4h , or S(O)2NR 4g R 4h may be substituted with one or more substituents selected from the group consisting of; R 4a and R 4b are each independently hydrogen, C 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms, The above R 4a and R 4b C of 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, and heteroaryl of 5 to 10 atoms are each independently halogen, -OH, -OCF3, -CN, -NO2, C 1-10 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, heteroaryl of 5 to 10 atoms, -OR 4g , -SR 4g , -C(O)NR 4g R 4h , -NR 4g R 4h , -NR 4g C(O)R 4h , -NR 4g S(O)2R 4h , or S(O)2NR 4g R 4h may be substituted with one or more substituents selected from the group consisting of; R 4c , R 4d , R 4e , and R 4f are each independently hydrogen, C 1-10 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms, The above R 4c , R 4d , R 4e and R 4f C of 1-10 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, and heteroaryl of 5 to 10 atoms are each independently -CF3, -OH, -OCF3, -CN, -NO2, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, or C 3-7 which may be substituted with one or more substituents selected from the group consisting of cycloalkyl; R 4g and R 4h are each independently hydrogen, C 1-13 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms; R 5 is hydrogen, halogen, C 1-6 alkyl, , or and; R 5a , R 5b and R 5c are each independently hydrogen, halogen, C 1-6 Alkyl, C 6-10 Aryl, heteroaryl of 5 to 10 atoms, 1-piperidinomethyl, or C 1-6 Aminomethyl which may be substituted with alkyl; R 5d are each independently hydrogen or C 1-6 It's alkyl. In the first paragraph, R 1 are each independently hydrogen, C 1-13 Alkyl, C 2-6 Alkenyl, or C 2-6 It is alkynyl, The above R 1 C of 1-13 Alkyl is independently R 11 may be substituted with one or more substituents selected from; R 2 are each independently hydrogen, C 1-13 Alkyl, C 3-10 Cycloalkyl, or heterocycloalkyl of 3 to 10 atoms, The above R 2 C of 1-13 Alkyl, C 3-10 Cycloalkyl, or heterocycloalkyl of 3 to 10 atoms, each independently R 11 may be substituted with one or more substituents selected from; R 11 Silver halogen, C 1-13 Alkyl, C 1-6 Alkoxy, -OH, -OCF3, -CN, -NO2, -C(O)R 1a , -C(O)NR 1a R 1b , -NR 1a R 1b , -NR 1a C(O)R 1b , -NR 1a S(O)2R 1b , or -S(O)2NR 1a R 1b and; R 1a , R 1b are each independently hydrogen, C 1-13 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms; R 3 are each independently C 1-10 Alkoxy, or C 3-6 It is cycloalkoxy, The above R 3 C of 1-10 Alkoxy, or C 3-6 Cycloalkoxy may each be independently substituted with one or more halogens; R 4 is hydrogen, halogen, C 1-13 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, heteroaryl of 5 to 10 atoms, -OH, -OCF3, -CN, -NO2, or -NR 4a R 4b And, The above R 4 C of 1-13 Alkyl, C 1-10 Alkoxy, and C 3-6 Cycloalkoxy is independently R 41 may be substituted with one or more substituents selected from The above R 4 C of 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, and heteroaryl of 5 to 10 atoms are each independently R 42 may be substituted with one or more substituents selected from; R 41 are halogens, -OH, -OCF3, -CN, -NO2, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8 Aryl, heteroaryl of 5 to 10 atoms, -OR 4c , -C(O)R 4c , -C(O)NR 4c R 4d , -NR 4c R 4d , -NR 4c C(O)R 4d , -NR 4c S(O)2R 4d , or -S(O)2NR 4c R 4d And, The above R 41 C of 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8 Aryl, and heteroaryl of 5 to 10 atoms are each independently halogen, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 7 atoms, C 6-8 Aryl, heteroaryl of 5 to 10 atoms, or -NR 4f R 4g may be substituted with one or more substituents selected from the group consisting of; R 42 are halogens, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8 Aryl, heteroaryl of 5 to 10 atoms, -OR 4c , -C(O)R 4c , -C(O)NR 4c R 4d , -NR 4c R 4d , -NR 4c C(O)R 4d , -NR 4c S(O)2R 4d , or -S(O)2NR 4c R 4d And, The above R 42 C of 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-8 Aryl, and heteroaryl of 5 to 10 atoms are each independently halogen, CF3, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-7 Cycloalkyl, or -NR 4g R 4h may be substituted with one or more substituents selected from the group consisting of; R 4a and R 4b are each independently hydrogen, C 1-13 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms, The above R 4a and R 4b C of 1-13 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, and heteroaryl of 5 to 10 atoms are each independently halogen, -OH, -OCF3, -CN, -NO2, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-7 Cycloalkyl, or -NR 4g R 4h may be substituted with one or more substituents selected from the group consisting of; R 4c , and R 4d are each independently hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms; R 4g and R 4h are each independently hydrogen, C 1-13 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms; R 5 is hydrogen, halogen, C 1-6 alkyl, or and; R 5a , R 5b and R 5c are each independently hydrogen, halogen, C 1-6 Alkyl, C 6-10 Aryl, heteroaryl of 5 to 10 atoms, or 1-piperidinomethyl, C 1-6 Aminomethyl which may be substituted with alkyl; R 5d are each independently hydrogen or C 1-6 It is an alkyl, A compound selected from the group consisting of a compound represented by the formula (I), a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. In the first paragraph, R 1 are each independently hydrogen, or C 1-13 It is alkyl, The above R 1 C of 1-13 Alkyl is independently R 11 may be substituted with one or more substituents selected from; R 2 are each independently hydrogen, C 1-13 Alkyl, or C 3-10 is cycloalkyl; The above R 2 C of 1-13 Alkyl, or C 3-10 Cycloalkyl is independently R 11 may be substituted with one or more substituents selected from; R 11 Silver halogen, C 1-13 Alkyl, C 1-6 Alkoxy, -OH, -OCF3, -CN, -NO2, -C(O)R 1a , -C(O)NR 1a R 1b , -NR 1a R 1b , -NR 1a C(O)R 1b , -NR 1a S(O)2R 1b , or -S(O)2NR 1a R 1b and; R 1a , R 1b are each independently hydrogen, C 1-13 It is alkyl; R 3 are each independently C 1-10 Alkoxy, or C 3-6 It is cycloalkoxy, The above R 3 C of 1-10 Alkoxy, or C 3-6 Cycloalkoxy may each be independently substituted with one or more halogens; R 4 is C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, or -NR 4a R 4b And, The above R 4 C of 3-10 Cycloalkyl, and heterocycloalkyl of 3 to 10 atoms are each independently R 42 may be substituted with one or more substituents selected from; R 42 are halogens, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-7 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, -OR 4c , -C(O)R 4c , -C(O)NR 4c R 4d , -NR 4c R 4d , -NR 4c C(O)R 4d , -NR 4c S(O)2R 4d , or -S(O)2NR 4c R 4d And, The above R 42 C of 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-7 Cycloalkyl, and heterocycloalkyl of 3 to 10 atoms are each independently halogen, -OH, -OCF3, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, or -NR 4g R 4h may be substituted with one or more substituents selected from the group consisting of; R 4a and R 4b are each independently hydrogen, C 1-13 Alkyl, C 3-10 Cycloalkyl, or heterocycloalkyl of 3 to 10 atoms, The above R 4a and R 4b C of 1-13 Alkyl, C 3-10 Cycloalkyl, and heterocycloalkyl of 3 to 10 atoms are each independently halogen, -OH, -OCF3, -CN, -NO2, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-7 Cycloalkyl, or -NR 4g R 4h may be substituted with one or more substituents selected from the group consisting of; R 4c , and R 4d are each independently hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl of 3 to 10 atoms, C 6-10 Aryl, or heteroaryl of 5 to 10 atoms; R 4g and R 4h are each independently hydrogen, C 1-13 Alkyl, C 3-10 Cycloalkyl, or heterocycloalkyl of 3 to 10 atoms; R 5 is hydrogen, halogen, C 1-6 alkyl, or and; R 5a , R 5b and R 5c are each independently hydrogen, halogen, 1-piperidinomethyl, or C 1-6 Aminomethyl which may be substituted with alkyl; R 5d are each independently hydrogen or C 1-6 It is an alkyl, A compound selected from the group consisting of a compound represented by the formula (I), a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. In the first paragraph, R 4 Is , , , , , , , , , , , , , , , , , , , , , , , , , or It is, A compound selected from the group consisting of a compound represented by the formula (I), a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. In the first paragraph, R 1 are each independently hydrogen, or C 1-13 It is alkyl, The above R 1 C of 1-13 Alkyl is independently R 11 may be substituted with one or more substituents selected from; R 11 Silver halogen, C 1-13 Alkyl, C 1-6 Alkoxy, -OH, -OCF3, -CN, -NO2, -C(O)R 1a , -C(O)NR 1a R 1b , -NR 1a R 1b , -NR 1a C(O)R 1b , -NR 1a S(O)2R 1b , or -S(O)2NR 1a R 1b and; R 1a , R 1b are each independently hydrogen, C 1-13 It is alkyl; R 2 is C 3-10 Cycloalkyl, or C 3-10 It is heterocycloalkyl, The above R 2 C of 3-10 Cycloalkyl, or C 3-10 Each heterocycloalkyl may be independently substituted with halogen; R 3 are each independently C 1-10 Alkoxy, or C 3-6 It is cycloalkoxy, The above R 3 C of 1-10 Alkoxy, or C 3-6 Cycloalkoxy may each be independently substituted with one or more halogens; R 4 Is , , , , , , , , , , , , , , , , , , , , , , , , , or And, R 5 Is or and; R 5a , R 5b and R 5c are each independently hydrogen, halogen, C 1-6 Alkyl, C 6-10 Aryl, heteroaryl of 5 to 10 atoms, or 1-piperidinomethyl, C 1-6 Aminomethyl which may be substituted with alkyl; R 5d are each independently hydrogen or C 1-6 It is an alkyl, A compound selected from the group consisting of a compound represented by the formula (I), a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. In the first paragraph, The compound is a compound selected from the group of compounds below, a stereoisomer thereof, a hydrate thereof and a pharmaceutically acceptable salt thereof. (1):N-(5-((8-(2,3-dihydrobenzofuran-7-yl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (2):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-(2-isopropoxyphenyl)-8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (3):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (4):N-(2-(4-(dimethylamino)butan-2-yl)-5-((6-isopropyl-8-(3-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (5):N-(2-(4-(dimethylamino)butan-2-yl)-5-((8-(3-ethylphenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (6): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-phenyl-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (7):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (8): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6-(1-methoxypropan-2-yl)-7-oxo-8-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (9):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-isopropyl-7-oxo-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (10): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-isopropyl-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (11): (S)-N-(5-((8-cyclopentyl-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (12): (S)-N-(5-((8-(tert-butyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (13):N-(5-((8-((1s,3s)-adamantan-1-yl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (14): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8-(1-methylpiperidin-4-yl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (15):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-6,8-bis(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (16): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (17):N-(5-((8-cyclohexyl-7-oxo-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (18):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(tetrahydro-2H-thiopyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (19):N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (20): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6-(1-methoxypropan-2-yl)-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (21):N-(5-((8-(4-chlorophenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (22):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-8-(3-(methylsulfonamido)phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (23): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-thiopyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (24): (S)-N-(5-((8-cyclohexyl-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (25): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8-(4-methoxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (26): (R)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (27): (R)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (28): (S)-N-(4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(4-methoxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (29): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (30):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-6-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (31): (S)-N-(5-((8-(4-chlorophenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (32): (S)-N-(5-((8-(4-bromophenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (33): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(4-fluorophenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (34): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(4-hydroxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (35): (S)-N-(5-((8-(3-chloro-4-fluorophenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (36): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(3-fluoro-4-methoxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (37): (S)-N-(5-((8-(4-chloro-3-fluorophenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (38): (S)-N-(5-((8-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (39): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8-(4-methyl-3,4-dihydro-2H-benzo][1,4]oxazin-6-yl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (40): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((8-(4-ethylphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (41):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-8-(4-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (42):N-(5-((8-(4-bromophenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (43): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (44):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (45): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(p-tolyl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (46):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(p-tolyl)-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (47):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((6-((S)-1-methoxypropan-2-yl)-7-oxo-8-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (48):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (49): (R)-N-(5-((8-(2-chloro-3-fluorophenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (50):N-(2-(3-((dimethylamino)methyl)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (51):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((8-(4-methoxyphenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (52):S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)-2-fluoroacrylamide (53):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (54): (S)-N-(5-((8-(2-chloro-4-(trifluoromethyl)phenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (55):N-(5-((8-(2-chloro-4-(trifluoromethyl)phenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (56):N-(5-((8-(2-chloro-4-(trifluoromethyl)phenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (57): (R)-N-(5-((8-(2-chloro-4-(trifluoromethyl)phenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (58): (S)-N-(4-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (59): (S)-N-(4-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (60): (S)-N-(4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (61):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((R)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (62):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(4-(trifluoromethyl)phenyl)-6-((R)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (63): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (64):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-5-((8-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (65): (R)-N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (66):N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (67): (R)-N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)acrylamide (68):N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (69): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (70): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-ethoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (71):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-ethoxyphenyl)acrylamide (72): (S)-N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (73): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide (74): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(methylsulfonyl)piperazin-1-yl)phenyl)acrylamide (75): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)phenyl)acrylamide (76):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide (77): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-methylpiperazin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide (78): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)acrylamide (79): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-isopropylpiperazin-1-yl)-4-methoxyphenyl)acrylamide (80): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)acrylamide (81): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methoxy-[1,4'-bipiperidin]-1'-yl)phenyl)acrylamide (82): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-((dimethylamino)methyl)azetidin-1-yl)-4-methoxyphenyl)acrylamide (83):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((S)-1,1,1-trifluorobutan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (84): (S)-N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluorobutan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (85): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluorobutan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (86):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((8-(4-methyltetrahydro-2H-pyran-4-yl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (87):N-(3-((8-(4,4-difluorocyclohexyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-6-((R)-3-(dimethylamino)pyrrolidin-1-yl)-2-fluoro-4-methoxyphenyl)acrylamide (88): (S)-N-(3-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-fluoro-4-methoxy-6-(4-methylpiperazin-1-yl)phenyl)acrylamide (89): (R)-N-(5-((8-(4,4-difluorocyclohexyl)-6-(2,2-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (90): (R)-N-(5-((8-(4,4-difluorocyclohexyl)-6-(2,2-difluoroethyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (91): (S)-N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (92): (S)-N-(2-([1,4'-bipiperidin]-1'-yl)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (93): (S)-N-(4-methoxy-2-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (94): (S)-N-(2-(4-(dimethylamino)piperidin-1-yl)-4-methoxy-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (95): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide (96): (R)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (97):N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (98):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (99):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(spiro[2.5]octan-6-yl)-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (100): (S)-N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((7-oxo-8-(spiro[2.5]octan-6-yl)-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (101): (S)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(3-(pyrrolidin-1-yl)azetidin-1-yl)phenyl)acrylamide (102):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (103):N-(5-((8-(4,4-difluorocyclohexyl)-6-((S)-1-fluoropropan-2-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (104): (S)-N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-6-(1-fluoropropan-2-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (105): (R)-N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (106): (R)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (107): (R)-N-(2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((7-oxo-8-(spiro[2.5]octan-6-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (108):N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((7-oxo-8-(spiro[2.5]octan-6-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (109):N-(2-([1,4'-bipiperidin]-1'-yl)-4-methoxy-5-((7-oxo-8-(spiro[2.5]octan-6-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (110):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (111):N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)phenyl)acrylamide (112): (S)-N-(2-([1,4'-bipiperidin]-1'-yl)-5-((8-(4,4-difluorocyclohexyl)-6-(1-fluoropropan-2-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)phenyl)acrylamide (113):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (114):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide (115):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)but-2-ynamide (116):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-fluoroacrylamide (117):N-(4-methoxy-5-((8-(4-methoxyphenyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)acrylamide (118): 2-Fluoro-N-(4-methoxy-5-((8-(4-methoxyphenyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)acrylamide (119):N-(4-methoxy-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-5-((7-oxo-6-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (120): 2-Fluoro-N-(4-methoxy-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-5-((7-oxo-6-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (121):N-(5-((8-(3,3-difluorocyclobutyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (122):N-(5-((8-(3,3-difluorocyclobutyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-fluoroacrylamide (123):N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (124): 2-Fluoro-N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (125): (E)-N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(dimethylamino)but-2-enamide (126):N-(4-methoxy-5-((8-(4-methoxyphenyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)but-2-ynamide (127):N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)but-2-ynamide (128):N-(5-((8-(3,3-difluorocyclobutyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)but-2-ynamide (129):N-(4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (130):N-(4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)but-2-ynamide (131):N-(5-((8-(4-chlorophenyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (132):N-(5-((8-(4-chlorophenyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide (133):N-(2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(trifluoromethoxy)phenyl)acrylamide (134):N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((7-oxo-8-(pyridin-2-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (135):N-(4-methoxy-5-((8-(1-methyl-1H-pyrazol-4-yl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (136):N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((8-(1-methylpiperidin-4-yl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (137):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isobutyl-7-oxo-8-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (138):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (139):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6-methyl-7-oxo-8-phenyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (140):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isobutyl-8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (141):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((7-oxo-8-phenyl-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (142):N-(5-((6,8-diisopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (143):N-(5-((8-(2-chloro-3-fluorophenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (144):N-(5-((6-(tert-butyl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (145): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6-(1-methoxypropan-2-yl)-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (146): (S)-N-(5-((8-cyclohexyl-6-(1-methoxypropan-2-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (147):N-(5-((6-(tert-butyl)-8-cyclohexyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (148):N-(4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (149):N-(5-((6-Isopropyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (150):N-(5-((6-Isopropyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide (151):N-(4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (152):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide (153):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (154):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)acrylamide (155):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-((3aR,6aS)-5-methylhexahydropyrrolo3,4-c]pyrrol-2(1H)-yl)phenyl)acrylamide (156):N-(2-(3-(dimethylamino)azetidin-1-yl)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (157):N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(2,2,2-trifluoroethoxy)phenyl)acrylamide (158):N-(4-(2,2-difluoroethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (159):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(1-methylpyrrolidin-3-yl)amino)phenyl)acrylamide (160):N-(2-(4-(dimethylamino)piperidin-1-yl)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (161):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)acrylamide (162):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide (163):N-(5-((6-Isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-((3aR,6aR)-1-methylhexahydropyrrolo3,4-b]pyrrole-5(1H)-yl)phenyl)acrylamide (164):N-(5-((8-(4-bromophenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (165): (R)-N-(5-((8-(4-bromophenyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (166): (R)-N-(2-(3-(dimethylamino)pyrrolidin-1-yl)-5-((6-isopropyl-7-oxo-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (167):N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (168):N-(5-((8-(4,4-difluorocyclohexyl)-6-ethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (169):N-(4-(difluoromethoxy)-5-((6-isopropyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (170):N-(5-((8-(4,4-difluorocyclohexyl)-6-isopropyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (171):N-(5-((8-(4,4-difluorocyclohexyl)-6-ethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-4-(difluoromethoxy)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (172):N-(5-((8-(4,4-difluorocyclohexyl)-6-ethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide (173):N-(4-(difluoromethoxy)-5-((6-ethyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (174):N-(5-((6-ethyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(trifluoromethoxy)phenyl)acrylamide (175): (S)-N-(5-((8-(2-chloro-3-methoxyphenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (176): (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((8-(3-methoxy-4-(trifluoromethyl)phenyl)-7-oxo-6-(1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (177):N-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxy-5-((8-(3-methoxy-4-(trifluoromethyl)phenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)phenyl)acrylamide (178):N-(5-((8-(2-chloro-3-fluorophenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (179):N-(5-((8-(4-chloro-3-fluorophenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (180):N-(5-((8-(2-chloro-3-(trifluoromethyl)phenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (181):N-(5-((8-(3-chloro-4-(trifluoromethyl)phenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (182):N-(5-((8-(3-Bromo-4-(trifluoromethyl)phenyl)-7-oxo-6-((S)-1,1,1-trifluoropropan-2-yl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (183):N-(5-((8-(4,4-difluorocyclohexyl)-7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(2-((dimethylamino)methyl)-1H-pyrrol-1-yl)-4-methoxyphenyl)acrylamide A pharmaceutical composition containing as an active ingredient a compound selected from the compounds described in any one of claims 1 to 6, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for preventing, alleviating or treating cancer, comprising as an active ingredient a compound selected from the compounds described in any one of claims 1 to 6, a stereoisomer thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof. In paragraph 8, The above pharmaceutical composition is a composition for preventing, alleviating or treating cancer characterized by being caused by an EGFR mutation. In paragraph 8, A composition for preventing, alleviating or treating cancer, characterized in that the pharmaceutical composition is administered to a patient having an EGFR mutation including an EGFR-related mutation, such as Exon 19 deletion, L858R, or Exon 20 insertion.

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