Indoline compounds and derivatives as EGFR inhibitors

Abstract

Novel pharmaceutically active compounds and methods for their preparation are provided, which inhibit mutant EGFR and are useful in the treatment of oncological diseases.

Description

[Technical Field]

[0001] Disclosed herein are novel pharmaceutically active compounds and methods for their preparation, which inhibit mutant EGFR and are useful in the treatment of oncological diseases. [Background technology]

[0002] The epidermal growth factor receptor (EGFR), a member of the ErbB family, is a transmembrane receptor tyrosine kinase (RTK) that plays a fundamental role in cell proliferation, differentiation, and motility (Y. Yarden, et al., Nat. Rev. Mol. Cell Biol. 2001;2:127-137). Homodimerization or heterodimerization of EGFR with other ErbB family members activates the cytoplasmic tyrosine kinase domain, initiating intracellular signaling. Overexpression or activating mutations of EGFR are associated with the development of many types of cancer, including pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, and non-small cell lung cancer (Yewale C., et al., Biomaterials. 2013,34(34):8690-8707). Activating mutations in the EGFR tyrosine kinase domain (L858R mutation and exon 19 deletion) have been identified as oncogenic drivers of NSCLC (Konduri, K., et al. Cancer Discovery 2016, 6(6), 601-611). The first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, have been approved for patients with NSCLC harboring EGFR-activating mutations (M. Maemondo, N. Engl. J. Med. 362(2010)2380-2388). While most patients with EGFR-mutated NSCLC respond to these therapies, patients typically develop resistance after an average of one year of treatment. There are several mechanisms underlying acquired resistance to gefitinib and erlotinib, including a secondary threonine 790 to methionine 790 mutation (T790M), also known as the "gatekeeper" T790M mutation (Xu Y., et al. Cancer Biol Ther. 2010, 9(8):572-582). Therefore, the second-generation EGFR-TKI afatinib and the third-generation EGFR-TKI osimertinib (AZD9291) were developed as irreversible EGFR inhibitors binding to Cys797 for the treatment of patients with the T790M mutation. In particular, osimertinib, which largely preserves WT EGFR, has achieved higher clinical responses in NSCLC patients with EGFR T790M mutation.However, several recent studies have reported a tertiary Cys797 to Ser797 (C797S) point mutation in osimertinib clinical therapy (Thress KS, et al. Nat. Med. 2015, 21(6):560-562.). Drugs that can overcome EGFR (C797S) resistance in non-small cell lung cancer (NSCLC) are needed.

[0003] The present application provides novel EGFR-TKIs for inhibiting oncogenic EGFR harboring all current resistance mutations: L858R, T790M, and C797S. Summary of the Invention [Means for solving the problem]

[0004] One object of the present invention is to provide compounds and derivatives that are selective tyrosine kinase inhibitors of mutant EGFR, their use as therapeutically active substances, in particular as agents for the treatment of neoplastic diseases, and methods for their preparation.

[0005] Aspect 1. A compound of formula (I): [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug thereof, wherein: X 1 is a single bond, NR 4 , O, S, S(O), S(O)2, or CH2; Z 1 But N or CR 9 and Z 2 But N or CR 10 and Z 3 But N or CR 11 and Z 4 But N or CR 12 and R 1 But -S(O)R 1a , -S(O)2R 1a , -C(O)R 1a, -P(O)R 1a R 1b ,or [ka] and R 1a and R 1b are each independently H, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR 1d , -CH2CONR 1d R 1e , -CH2CH2CONR 1d R 1e , -CH2CH2CH2CONR 1d R 1e , -NR 1d R 1e , -CH2NR 1d R 1e , -CH2CH2NR 1d R 1e , -CH2CH2CH2NR 1d R 1e , or -NR 1d COR 1e and the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains at least one substituent R 1f is replaced by R 1d and R 1e are each independently hydrogen, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 1d and R 1etogether with the atom(s) to which they are attached form a 3- to 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one substituent R 1f is replaced by R 1f Each occurrence of each independently represents a hydrogen, halogen, or -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -OR 1g , -COR 1g , -CO2R 1g , -CONR 1g R 1h , -NR 1g R 1h , -NR 1g COR 1h , or -NR 1g CO2R 1h or 2 R's 1f together with the atom(s) to which they are attached form a 3- to 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one substituent hydrogen, halogen, hydroxyl, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, or -CN; R 1g and R 1h each independently represents hydrogen, halogen, hydroxyl, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 2 , R 3a , R 3b , and R 3c are hydrogen, halogen, and -C, respectively. 1-8 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, oxo (=O), -OR 2a , -COR 2a , -CO2R 2a , -CONR 2a R 2b , -NR 2a R 2b , -NR 2a COR 2b , or -NR 2a CO2R 2b and -C 1-8 Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains at least one substituent R 2c is replaced by, or (R 2 and R 3a ), together with the atoms to which they are attached, form a 3- to 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one substituent R 2c is replaced by, or If m ≥ 2, two geminal R 2 together with the atom to which they are attached form a 3- to 12-membered spiro ring, or two R 2 together with the atoms to which they are attached form a 3- to 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one substituent R 2c or (R 3a and R 3b ) or (R 3b and R3c ), together with the atoms to which they are attached, form a 3- to 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one substituent R 2c is replaced by R 2a and R 2b are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 alkyl-, cycloalkyl, heterocyclyl, aryl or heteroaryl, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Each of the alkyl-, cycloalkyl, heterocyclyl, aryl, or heteroaryl may optionally contain at least one substituent R 2c is replaced by R 2c Each occurrence of each independently represents a halogen, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -OR 2d , -COR 2d , -CO2R 2d , -CONR 2d R 2e , -NR 2d R 2e , -NR 2d COR 2e , or -NR 2d CO2R 2e and R 2d and R 2e are each independently hydrogen, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 4 and R 7 are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, or cycloalkyl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, or cycloalkyl optionally contains at least one substituent R 4a is replaced by R 4a are independently hydrogen, halogen, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, -CN, or -OR 4b and R 4b But hydrogen, -C 1-8 Alkyl, -haloC 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 alkyl-, or -C3-6cycloalkyl; R 5 and R 6 are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR 5a , -COR 5a , -CO2R 5a , -CONR 5a R 5b , -NR 5a R 5b , or -NR 5a COR 5b and the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains at least one substituent R 5c is replaced by R 5a and R 5b are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 alkyl-, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Each of the alkyl-, cycloalkyl, heterocyclyl, aryl, or heteroaryl may optionally contain at least one substituent R 5c is replaced by R 5c Each occurrence independently represents a halogen, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or R 5 and R 6 together with the atoms to which they are attached form a 3- to 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, sulfur, or optionally oxidized sulfur, and which ring optionally contains at least one substituent R 56 is replaced by R 56 But hydrogen, halogen, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-6 cycloalkyl, 3-8 membered heterocyclyl, -C6- 12 Aryl, 3-8 membered heteroaryl, C 1-8Alkoxy-C 1-8 Alkyl-, oxo(=O), -CN, -OR 56a , -COR 56a , -CO2R 56a , -CONR 56a R 56b , -NR 56a R 56b , or -NR 56a COR 56b and R 56a and R 56b are each independently hydrogen, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 alkyl-, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 8 But halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8a , or -NR 8a R 8b and the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains at least one substituent R 8c is replaced by R 8a and R 8b are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 alkyl-, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C1-8 Each of the alkyl-, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains at least one substituent R 8d is replaced by, or R 8a and R 8b together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one substituent R 8d is replaced by R 8c are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -OR 8f , -COR 8f , -CO2R 8f , -CONR 8f R 8g , -NR 8f R 8g , or -NR 8f COR 8g and the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally comprises at least one R 8e is replaced by, or 2 R's 8c together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and the ring optionally contains at least one R 8e is replaced by R 8d and R 8e are each independently hydrogen, halogen, -C1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -OR 8h , -COR 8h , -CO2R 8h , -CONR 8h R 8i , -NR 8h R 8i , or -NR 8h COR 8i and the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains at least one halogen, —C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, -C 1-8 Alkoxy or C 1-8 Alkoxy-C 1-8 alkyl-substituted or 2 R's 8e together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, -C 1-8 Alkoxy or C 1-8 Alkoxy-C 1-8 alkyl-substituted, R 8f , R 8g , R 8h , and R 8i are each independently hydrogen, -C 1-8Alkyl, -haloC 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 9 , R 10 , R 11 , and R 12 are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, -C 6-12 Aryl, heteroaryl, -CN, -OR 9d , -CH2CONR 9d R 9e , -CH2CH2CONR 9d R 9e , -CH2CH2CH2CONR 9d R 9e , -NR 9d R 9e , -CH2NR 9d R 9e , -CH2CH2NR 9d R 9e , -CH2CH2CH2NR 9d R 9e , or -NR 9d COR 9e and the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains at least one substituent R 9f is replaced by, or (R 9 and R 11 ) or (R 10 and R 12), together with the atom(s) to which they are attached, form a 3- to 12-membered ring, the ring containing, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and the ring optionally containing at least one substituent R 9f is replaced by R 9d and R 9e are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains at least one halogen, —C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, -C 1-8 Alkoxy or C 1-8 Alkoxy-C 1-8 alkyl-substituted or R 9d and R 9e together with the atom(s) to which they are attached form a 3- to 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one substituent R 9f is replaced by R 9f Each occurrence is independently hydrogen, halogen, or -haloC 1-8 Alkyl, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, aryl, heteroaryl, oxo (=O), -CN, -OR 9g, -COR 9g , -CO2R 9g , -CONR 9g R 9h , -NR 9g R 9h , -NR 9g COR 9h , or -NR 9g CO2R 9h or 2 R's 9f together with the atom(s) to which they are attached form a 3- to 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one halogen, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, -C 1-8 Alkoxy or C 1-8 Alkoxy-C 1-8 alkyl-substituted, R 9g and R 9h each independently represents hydrogen, halogen, hydroxyl, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; n is 0, 1, 2, or 3; A compound, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug thereof, wherein m is 0, 1, 2, 3, or 4.

[0006] In some embodiments, Z 1 But, CR 9 and Z 2 But, CR 10 and Z 3 But, CR 11 and Z4 But, CR 12 In some embodiments, Z 1 , Z 2 , Z 3 , and Z 4 and each is CH. In some embodiments, Z 1 is N and Z 2 But, CR 10 and Z 3 But, CR 11 and Z 4 But, CR 12 In some embodiments, Z 1 is N and Z 2 , Z 3 , and Z 4 are CH, respectively.

[0007] Aspect 2.R 1 But -S(O)2R 1a , -C(O)R 1a ,or [ka] and R 1a and R 1b are respectively H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, azacyclopropanyl, azacyclobutanyl, tetrahydropyrrole, piperidinyl, piperazinyl, morphinyl, epoxyethyl, epoxybutanyl, oxacyclopentanyl, tetrahydropyran, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thienyl, oxazolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzopyrazolyl, -CH2CONR 1d R 1e , -CH2CH2CONR 1d R 1e , -CH2CH2CH2CONR 1d R 1e , -NR 1d R 1e , -CH2NR1d R 1e , -CH2CH2NR 1d R 1e , or -CH2CH2CH2NR 1d R 1e wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, azacyclopropanyl, azacyclobutanyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morphinyl, epoxyethyl, epoxybutanyl, oxacyclopentanyl, tetrahydropyran, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thienyl, oxazolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, or benzopyrazolyl optionally contains at least one substituent R 1f is replaced by R 1d and R 1e are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, azacyclopropanyl, azacyclobutanyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morphinyl, epoxyethyl, epoxybutanyl, oxacyclopentanyl, tetrahydropyran, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thienyl, oxazolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, or benzopyrazolyl; R 1fis independently at each occurrence hydrogen, -F, -Cl, -Br, -I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, azacyclopropanyl, azacyclobutanyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morphinyl, epoxyethyl, epoxybutanyl, oxacyclopentanyl, tetrahydropyran, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thienyl, oxazolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzopyrazolyl, or -CN; 2 R's 1f together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one substituent hydrogen, F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl ... substituted by cyclohexyl, cycloheptyl, cyclooctyl, azacyclopropanyl, azacyclobutanyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morphinyl, epoxyethyl, epoxybutanyl, oxacyclopentanyl, tetrahydropyran, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thienyl, oxazolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzopyrazolyl, oxo, or -CN; R 1g and R 1hare each independently hydrogen, F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, azacyclopropanyl, azacyclobutanyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morphinyl, epoxyethyl, epoxybutane, oxacyclopentanyl, tetrahydropyran, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thienyl, oxazolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, or benzopyrazolyl.

[0008] Aspect 3.R 1 But -S(O)2R 1a , -C(O)R 1a ,or [ka] and R 1a -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -cyclopropyl, -tert-butyl, [ka] The compound of embodiment 1, wherein the compound is -CH2F, -CHF2, -CF3, -N(CH3)2, -NHCH3, -CH2N(CH3)2, -CH2CH2N(CH3)2, or -CH2CH2CH2N(CH3)2.

[0009] Aspect 4.R 2 and R 3a , R 3b and R 3c However, for each occurrence, hydrogen, -F, -Cl, -Br, -I, -C 1-8 Alkyl, C3-8 cycloalkyl, -CN, oxo (=O), -OR 2a , or -COR 2a and -C 1-8Alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, or 5- to 12-membered heteroaryl optionally contains at least one substituent R 2c is replaced by (R 2 and R 3a ), two R 2 , or (R 3a and R 3b ), or (R 3b and R 3c ), together with the atom(s) to which they are attached, form a 3- to 8-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one substituent R 2c is replaced by R 2a are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Alkyl-, C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C6- 12 aryl, or 5- to 12-membered heteroaryl; 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Each of the alkyl-, or C3-8 cycloalkyl optionally contains at least one substituent R 2c is replaced by R 2c each occurrence independently represents -F, -Cl, -Br, -I, hydroxyl, -NH2, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CH 13 , -CH 15 , -CH 17 , phenyl, oxo(=O), -CN, -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 , -OC6H 13, -OC7H 15 , -OC8H 17 , -COCH3, -COC2H5, -COC3H7, -COC4H9, -COC5H 11 , -COCH 13 , -COC7H 15 , -COC8H 17 , -CO2CH3, -CO2C2H5, -CO2C3H7, -CO2C4H9, -CO2C5H 11 , -CO2C6H 13 , -CO2C7H 15 , or -CO2C8H 17 2. The compound of embodiment 1, wherein

[0010] Aspect 5.R 2 are hydrogen, -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CH 13 , -CH 15 , -CH 17 , -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, or oxo; If m ≥ 2, two geminal R 2 together with the atom to which they are attached form a 3-, 4-, 5-, or 6-membered spiro ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur.

[0011] Aspect 6.R 2 are hydrogen, F, Cl, Br, I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, or oxo; If m ≥ 2, two geminal R 2 together with the atom to which they are attached form a spirocyclopropyl or spirocyclobutyl.

[0012] Aspect 7.R 3a , R3b , and R 3c are respectively hydrogen, F, Cl, Br, I, -methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -OR 2a , -COR 2a , or -CO2R 2a wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl optionally contains at least one substituent R 2c is replaced by R 2a are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 alkyl-, or C3-8 cycloalkyl, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Each of the alkyl-, or C3-8 cycloalkyl optionally contains at least one substituent R 2c is replaced by R 2c Each occurrence of each independently represents a hydroxyl, a halogen, or -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 The compound according to embodiment 1, wherein the aryl is alkynyl, or -C3-8 cycloalkyl.

[0013] Aspect 8.R 3a , R 3b , and R 3c are -H, -F, -Cl, -Br, -I, hydroxyl, amino, -CH3, -C2H5, -C3H7, -C4H9, and -C5H, respectively. 11 , -CH 13 , -CH 15 , -CH 17, phenyl, oxo(=O), -CN, -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 , -OC6H 13 , -OC7H 15 , -OC8H 17 , -COCH3, -COC2H5, -COC3H7, -COC4H9, -COC5H 11 , -COCH 13 , -COC7H 15 , -COC8H 17 , -CO2CH3, -CO2C2H5, -CO2C3H7, -CO2C4H9, -CO2C5H 11 , -CO2C6H 13 , -CO2C7H 15 , or -CO2C8H 17 2. The compound of embodiment 1, wherein

[0014] Aspect 9. [ka] 2. The compound of embodiment 1, wherein

[0015] Aspect 10.R 4 and R 7 are each independently -H, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CH 13 , -CH 15 , or -CH 17 2. The compound of embodiment 1, wherein

[0016] Aspect 11.R 5 and R 6 are independently hydrogen, -F, -Cl, -Br, -I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -OR 5a , or -NR 5a R 5bwherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl optionally contains at least one substituent R 5c is replaced by R 5a and R 5b are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 alkyl-, or -Ccycloalkyl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 Each alkyl-, or -C3-6cycloalkyl may optionally contain at least one substituent R 5c is replaced by R 5c is independently at each occurrence -F, -Cl, -Br, -I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl.

[0017] Aspect 12.R 5 and R 6 are independently -H, -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , [ka] -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 , —CH 2 F, —CHF 2 , —CF 3 , —CN, —NH 2 , —NHCH 3 , —NHC 2 H 5 , or —N(CH 3 ) 2 .

[0018] Aspect 13.R 5 and R 6together with the atom(s) to which they are attached form a 4-, 5-, 6-, or 7-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one substituent R 56 is replaced by R 56 is -H, -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CH 13 , -CH 15 , -CH 17 , -C 2-8 Alkenyl, -C 2-8 Alkynyl, -CN, -OR 56a , -COR 56a , or -CO2R 56a and -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CH 13 , -CH 15 , -CH 17 , -C 2-8 Alkenyl, or -C 2-8 The compound according to embodiment 1, wherein each alkynyl is optionally substituted with at least one halogen.

[0019] Aspect 14. [ka] 2. The compound of embodiment 1, wherein

[0020] Aspect 15. [ka] wherein * is -N(R 7 )-moiety, and ** indicates the position where the R 8 and wherein the compound of any one of claims 1 to 3 is linked to

[0021] Aspect 16.R 9 , R 10 , R 11, and R 12 are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, 3- to 8-membered heterocyclyl, -CN, or -OR 9d and the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, -C 6-12 Each aryl or 5- to 8-membered heteroaryl may optionally contain at least one substituent R 9f is replaced by, or (R 9 and R 11 ), or (R 10 and R 12 ), or (R 14 and R 15 ), together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one substituent R 9f is replaced by R 9d and R 9e are each independently -H, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CH 13 , -CH 15 , or -C8H 17 or R 9d and R 9e together with the atom(s) to which they are attached form a 3- to 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one substituent R 9f is replaced by R 9f Each occurrence of each independently represents hydrogen, halogen, hydroxyl, -C1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, -C 6-12 Aryl, 5-8 membered heteroaryl, oxo (=O), -CN, -OR 9g , -COR 9g , -CO2R 9g , -CONR 9g R 9h , -NR 9g R 9h , -NR 9g COR 9h , or -NR 9g CO2R 9h and R 9g and R 9h are each independently -H, -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CH 13 , -CH 15 , -CH 17 or —OH.

[0022] Aspect 17.R 9 , R 10 , R 11 , and R 12 are each independently -H, -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CH 13 , -CH 15 , -CH 17 , -CN, -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 , -OC6H 13 , -OC7H 15 , or -OC8H 17 or (R 9 and R 11 ), or (R 10 and R 12), together with the atom(s) to which they are attached, form a 5-, 6-, or 7-membered ring, which ring contains 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen or oxygen, and which ring optionally contains at least one substituent R 9f is replaced by R 9f each occurrence independently represents -H, -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CH 13 , -CH 15 , -CH 17 , -CN, -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 , -OC6H 13 , -OC7H 15 , or -OC8H 17 or 2 R's 9f together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one of -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -CH 11 , -CH 13 , -CH 15 , -CH 17 , -CN, -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 , -OC6H 13 , -OC7H 15 , or -OC8H 17 20. The compound of any one of embodiments 1 to 15, wherein

[0023] Aspect 18. [ka] and In the formula, * represents -N(R 7 )-moiety, and ** indicates the position where the R8 20. The compound of any one of embodiments 1 to 15, wherein the compound is linked to

[0024] Aspect 19.R 8 is -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 4- to 8-membered monocyclic heterocyclyl containing 1 or 2 nitrogen atoms as ring member(s), azaspiro[5.5]undecanyl, diazaspiro[5.5]undecanyl, azaspiro[4.5]decanyl, diaza spiro[4.5]decanyl, azaspiro[3.5]nonanyl, diazaspiro[3.5]nonanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl, azaspiro[3.3]heptanyl, or diazaspiro[3.3]heptanyl (preferably 3,9-diazaspiro[5.5]undecan-9-yl, 2,7-diazaspiro[3.5]nonanyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl, diazabicyclo[3.1.1]heptanyl, azabicyclo[2.2.2]octanyl, diazabicyclo[2.2.2]octanyl, diazabicyclo[2.2.2]hexanyl, 2,6-diazaspiro[3.3]heptan-6-yl, 2,8-diazaspiro[4.5]decane-8-yl, or 2,6-diazaspiro[3.3]heptan-6-yl; ]octanyl, azabicyclo[3.2.1]octanyl, or diazabicyclo[3.2.1]octanyl (preferably 2-azabicyclo[2.2.1]heptan-2-yl, 6-azabicyclo[3.1.1]heptan-3-yl, 2-azabicyclo[2.2.2]octan-5-yl, or 3-azabicyclo[3.2.1]octan-8-yl), a bridged heterocyclyl selected from the group consisting of: -OR 8a , or -NR 8a R 8bwherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 4- to 8-membered monocyclic heterocyclyl, spiroheterocyclyl, or heteroaryl optionally contains at least one substituent R 8c is replaced by R 8a and R 8b each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclobutyl, cyclopentyl, cyclohexyl, 4- to 8-membered heterocyclyl, 5- to 8-membered heteroaryl, C 1-8 Alkoxy-C 1-8 alkyl-, phenyl, or 5- to 8-membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclobutyl, cyclopentyl, cyclohexyl, 4- to 8-membered heterocyclyl, 5- to 8-membered heteroaryl, C 1-8 Alkoxy-C 1-8 Each of the alkyl-, phenyl, or 5- to 8-membered heteroaryl optionally contains at least one substituent R 8d is replaced by, or R 8a and R 8b together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen or oxygen, and which ring optionally contains at least one substituent R 8d is replaced by R 8c are independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl-C 2-8 Alkenyl, -C 2-8 Alkynyl, 3-12 membered heterocyclyl, 5-8 membered heteroaryl, oxo (=O), -CN, -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 , -OC6H13 , -OC7H 15 , -OC8H 17 , -COCH3, -COC2H5, -COC3H7, -COC4H9, -COC5H 11 , -COCH 13 , -COC7H 15 , -COC8H 17 , -CONR 8f R 8g , -NR 8f R 8g , or -NR 8f COR 8g and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl-C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, 3- to 12-membered heterocyclyl, and 5- to 8-membered heteroaryl may optionally be selected from the group consisting of at least one R 8e is replaced by, or 2 R's 8c together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one R 8e is replaced by R 8d and R 8e each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 8-membered heteroaryl, oxo (=O), -CN, -OH, -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 , -OC6H 13 , -OC7H 15 , -OC8H 17 , -COCH3, -COC2H5, -COC3H7, -COC4H9, -COC5H 11, -COCH 13 , -COC7H 15 , -COC8H 17 , -CO2CH3, -CO2C2H5, -CO2C3H7, -CO2C4H9, -CO2C5H 11 , -CO2C6H 13 , -CO2C7H 15 , -CO2C8H 17 , -CONR 8h R 8i , -NR 8h R 8i , or -NR 8h COR 8i and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 8-membered heteroaryl may optionally be selected from the group consisting of at least one of -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclobutyl, cyclopentyl, cyclohexyl, and -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 8-membered heteroaryl, phenyl, hydroxyl, -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 , -OC6H 13 , -OC7H 15 , -OC8H 17 , or C 1-8 Alkoxy-C 1-8 alkyl-substituted, R 8f , R 8g , R 8h , and R 8i are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8The compound according to embodiment 1, which is alkynyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 8-membered heteroaryl.

[0025] Aspect 20.R 8 is F, Cl, Br, methyl, ethyl, propyl, butyl, pentyl, azacyclopropyl, azacyclobutyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrazolyl, -OR 8a , or -NR 8a R 8b wherein each of the methyl, ethyl, propyl, butyl, pentyl, azacyclopropyl, azacyclobutyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, and pyrazolyl optionally contains at least one substituent R 8c is replaced by R 8a and R 8b are each independently methyl, ethyl, propyl, butyl, pentyl, azacyclopropyl, azacyclobutyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, or pyrazolyl, and each of said methyl, ethyl, propyl, butyl, pentyl, azacyclopropyl, azacyclobutyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, or pyrazolyl optionally contains at least one substituent R 8d is replaced by, or R 8a and R 8btogether with the atom(s) to which they are attached form a 4-, 5-, 6-, 7-, or 8-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen or oxygen, and which ring optionally contains at least one substituent R 8d is replaced by R 8c are independently hydrogen, F, Cl, Br, methyl, ethyl, propyl, butyl, pentyl, oxo(=O), azacyclopropyl, azacyclobutyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrazolyl, -CN, -OR 8f , or -NR 8f R 8g wherein each of the methyl, ethyl, propyl, butyl, pentyl, azacyclopropyl, azacyclobutyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, and pyrazolyl optionally comprises at least one R 8e is replaced by, or 2 R's 8c together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which ring contains, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring optionally contains at least one R 8e is replaced by R 8d and R 8e each independently represents hydrogen, F, Cl, Br, methyl, ethyl, propyl, butyl, pentyl, oxo (=O), azacyclopropyl, azacyclobutyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrazolyl, -CN, -OR 8h, or -NR 8h R 8i wherein each of the methyl, ethyl, propyl, butyl, pentyl, azacyclopropyl, azacyclobutyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrazolyl is optionally substituted with at least one F, Cl, Br, methyl, ethyl, propyl, butyl, pentyl, azacyclopropyl, azacyclobutyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, or pyrazolyl; 2 R's 8e together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which ring contains as ring member(s) 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and which ring is optionally substituted with at least one F, Cl, Br, methyl, ethyl, propyl, butyl, pentyl, azacyclopropyl, azacyclobutyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrazolyl, or -CN; R 8f , R 8g , R 8h , and R 8i is each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, azacyclopropyl, azacyclobutyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, or pyrazolyl.

[0026] Aspect 21.R 8 but, [ka] 2. The compound of embodiment 1, wherein

[0027] Aspect 22. The compound of aspect 1, wherein the compound is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0028] Embodiment 23. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 22, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, together with a pharmaceutically acceptable excipient.

[0029] Embodiment 24. A method of treating a disease in which EGFR modulation is implicated, comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1 to 22, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug thereof.

[0030] Embodiment 25. The method of embodiment 24, wherein the disease is cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

[0031] Embodiment 26. Use of a compound according to any one of embodiments 1 to 22, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, in the preparation of a medicament for treating a disease that can be affected by EGFR modulation.

[0032] Embodiment 27. The use according to embodiment 26, wherein the disease is cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

[0033] Embodiment 28. Use of a compound according to any one of embodiments 1 to 22 in the preparation of a PROTAC medicament for the treatment of a disease that can be affected by EGFR modulation. In an embodiment of the present invention, for example, the following items are provided: (Item 1) A compound of formula (I), [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug thereof, wherein: X 1 is a single bond, NR 4 , O, S, S(O), S(O) 2 , or CH 2 and Z 1 But N or CR 9 and Z 2 But N or CR 10 and Z3 But N or CR 11 and Z 4 But N or CR 12 and R 1 But -S(O)R 1a , -S(O) 2 R 1a , -C(O)R 1a , -P(O)R 1a R 1b ,or

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

[0034] The following terms have the indicated meanings throughout this specification.

[0035] Unless specifically defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0036] The following terms have the indicated meanings throughout this specification.

[0037] As used in this specification, including the appended claims, singular words such as "a," "an," and "the" include their corresponding plural references unless the context clearly dictates otherwise.

[0038] The term "or" is used to mean, and is used interchangeably with, the term "and / or," unless context clearly dictates otherwise.

[0039] The term "alkyl" includes hydrocarbon groups selected from linear and branched saturated hydrocarbon groups containing 1 to 18, for example, 1 to 12, further 1 to 10, further 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1-6 Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0040] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0041] The term "butyl" includes 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), and 1,1-dimethylethyl or t-butyl ("t-Bu").

[0042] The term "pentyl" includes 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl.

[0043] The term "hexyl" includes 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0044] The term "halogen" includes fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0045] The term "alkenyl" includes hydrocarbon groups selected from straight-chain and branched-chain hydrocarbon groups containing at least one C=C double bond and 2 to 18, for example, 2 to 8, further for example, 2 to 6, carbon atoms. Examples of alkenyl groups, for example, C2-6 alkenyl, include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

[0046] The term "alkynyl" includes hydrocarbon groups selected from straight-chain and branched-chain hydrocarbon groups containing at least one C≡C triple bond and 2 to 18, such as 2 to 8, further such as 2 to 6, carbon atoms. Examples of alkynyl groups, e.g., C2-6 alkynyl, include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0047] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyls.

[0048] For example, the cycloalkyl group can contain 3 to 12, such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Still further, for example, the cycloalkyl group can be selected from monocyclic groups containing 3 to 12, such as 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. Specifically, saturated monocyclic cycloalkyl groups, such as C 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, cycloalkyl is a monocyclic ring (C) containing 3 to 6 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3-6 Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0049] The term "spirocycloalkyl" includes cycloalkyl, as defined herein, formed by at least two rings that share one atom. The term "spirobicycloalkyl" refers to a bicyclic saturated carbocyclic ring system in which the two rings are connected through one atom. Spirobicycloalkyl rings are derived from, but are not limited to, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, spiro[2.6]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.7]decanyl, spiro[3.6]decanyl, spiro[4.5]decanyl, spiro[3.7]undecanyl, spiro[4.6]undecanyl, spiro[5.5]undecanyl, spiro[4.7]dodecanyl, and spiro[5.6]dodecanyl.

[0050] The term "fused cycloalkyl" includes bicyclic cycloalkyl groups, as defined herein, that are saturated and formed by two or more rings that share two adjacent atoms.

[0051] The term "bridged cycloalkyl" includes cycloalkyls, as defined herein, that contain carbon atoms and are formed by two rings that share two non-adjacent atoms. The term "7-10 membered bridged cycloalkyl" includes cyclic structures that contain 7-12 carbon atoms and are formed by two rings that share two non-adjacent atoms.

[0052] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo 3- to 8-membered cycloalkyl, benzo C 4-6These include, but are not limited to, cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8-9 membered fused rings, referring to ring structures containing 8-9 ring atoms in the above examples.

[0053] The term "aryl", used alone or in combination with other terms, includes groups selected from: - 5- and 6-membered carbocyclic aromatic rings, for example phenyl groups, bicyclic ring systems, such as 7-12 membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, e.g. naphthyl, and - Tricyclic ring systems, such as 10-15 membered tricyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example fluorenyl, anthracenyl, or phenanthrenyl.

[0054] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 (aryl). Examples of monocyclic, bicyclic, or tricyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0055] Specifically, the term "bicyclic fused aryl" includes bicyclic aryl rings as defined herein. An exemplary bicyclic fused aryl is naphthalene.

[0056] The term "heteroaryl" includes groups selected from: a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), for example, 1 to 4, or in some embodiments 1 to 3, and in some embodiments 1 to 2 heteroatoms, with the remaining ring atoms being carbon; - 7-12 membered bicyclic rings containing at least one heteroatom selected from N, O, and S, for example, 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being in the aromatic ring; and - an 11-14 membered tricyclic ring containing at least one heteroatom selected from N, O, and S, for example, 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being in the aromatic ring.

[0057] When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group can be oxidized to form an N-oxide.

[0058] Specifically, the term "bicyclic fused heteroaryl" includes 7- to 12-membered, preferably 7- to 10-membered, and more preferably 9- or 10-membered fused bicyclic heteroaryl rings as defined herein. Typically, bicyclic fused heteroaryls are 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclics. Groups can be attached to the remainder of the molecule via either ring.

[0059] "Heterocyclyl," "heterocycle," or "heterocyclic ring" are interchangeable and include non-aromatic heterocyclyl groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro rings, i.e., monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclic groups.

[0060] "Spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl having rings connected through one common carbon atom (called a spiroatom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, S, SO, or SO heteroatoms as ring atoms, and the remaining ring atoms are C. One or more rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. Preferably, the spiroheterocyclyl has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of common spiro atoms, spiroheterocyclyl is divided into monospiroheterocyclyl, dispiroheterocyclyl, or polyspiroheterocyclyl, preferably monospiroheterocyclyl or dispiroheterocyclyl, and more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl. Representative examples of spiroheterocyclyl include the following groups: azaspiro[5.5]undecanyl, diazaspiro[5.5]undecanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, azaspiro[3.5]nonanyl, diazaspiro[3.5]nonanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, azaspiro[3.4]octanyl, diazaspiro[3.5]octanyl, diazaspiro[4.5 ...4.5]octanyl, diazaspiro[3.5]octanyl, diazaspiro[4.5]octanyl, diazaspiro[4.5]octanyl, diazaspiro[3.5 and 2,6-diazaspiro[3.3]heptan-6-yl, preferably 3,9-diazaspiro[5.5]undecan-9-yl, 2,7-diazaspiro[3.5]nonan-7-yl, 2,8-diazaspiro[4.5]decan-8-yl, or 2,6-diazaspiro[3.3]heptan-6-yl.

[0061] "Fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl group, in which each ring in the system shares adjacent carbon atom pairs with another ring, and one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system, and the ring has one or more heteroatoms selected from the group consisting of N, O, S, SO, or SO as ring atoms, with the remaining ring atoms being C. Preferably, the fused heterocyclyl has 6 to 14 ring members, more preferably 7 to 10 ring members. According to the number of ring members, the fused heterocyclyl is divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, and preferably refers to a bicyclic or tricyclic fused heterocyclyl, more preferably refers to a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl.

[0062] "Bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group, in which every two rings in the system share two non-consecutive atoms, the rings may have one or more double bonds, but none of the rings has a fully conjugated pi-electron system, and the rings have one or more heteroatoms selected from the group consisting of N, O, S, SO, or SO heteroatoms as ring atoms, with the remaining ring atoms being C. Preferably, the bridged heterocyclyl has 6 to 14 ring members, more preferably 7 to 10 ring members. According to the number of ring members, the bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, and preferably refers to bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, more preferably refers to bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyls include, but are not limited to, the following groups: azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl, diazabicyclo[3.1.1]heptanyl, azabicyclo[2.2.2]octanyl, diazabicyclo[2.2.2]octanyl, azabicyclo[3.2.1]octanyl, or diazabicyclo[3.2.1]octanyl, preferably 2-azabicyclo[2.2.1]heptan-2-yl, 6-azabicyclo[3.1.1]heptan-3-yl, 2-azabicyclo[2.2.2]octan-5-yl, 3-azabicyclo[3.2.1]octan-8-yl.

[0063] The heterocyclyl ring can be fused to an aryl, heteroaryl, or cycloalkyl ring, and the ring structures together link the parent heterocyclic group. The heterocyclyl can be optionally substituted or unsubstituted.

[0064] In some embodiments, groups such as alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally deuterated. The term "deuterated" is used herein to modify a chemical structure or organic group or radical in which one or more carbon-bonded hydrogen(s) are replaced with one or more deuterium(s), such as, for example, "deuterated alkyl," "deuterated cycloalkyl," "deuterated heterocyclyl," "deuterated aryl," and "deuterated heteroaryl." For example, the term "deuterated alkyl," as defined above, refers to an alkyl group, as defined herein, in which at least one carbon-bonded hydrogen atom is replaced with deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to deuterium, and it is possible for a carbon atom to be bonded to more than one deuterium, and it is also possible for more than one carbon atom in an alkyl group to be bonded to deuterium.

[0065] The term "at least one substituent" disclosed herein includes 1 to 4 substituents, such as 1 to 3, or even 1 or 2, as long as valence theory is satisfied. For example, "at least one substituent F" disclosed herein includes 1 to 4, such as 1 to 3, or even 1 or 2, substituents F.

[0066] The compounds disclosed herein may have asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. When the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All possible stereoisomers are intended to be included, including substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specifically stated, a reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is not specified, all possible isomers are included.

[0067] When the compounds disclosed herein contain olefinic double bonds, unless specified otherwise, it is intended that such double bonds include both E and Z geometric isomers.

[0068] When the compounds disclosed herein comprise a disubstituted cyclic ring system, the substituents found in such ring system can adopt cis and trans configuration.Cis configuration means that both substituents are found above the two substituent positions on carbon, while trans means that they are on opposite sides.For example, the disubstituted cyclic ring system can be a cyclohexyl or cyclobutyl ring.

[0069] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter "separated") to the desired degree of homogeneity by techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include any number of methods, including, for example, reverse-phase and normal-phase, size exclusion, ion exchange, high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatus, small-scale analytical, simulated moving bed ("SMB"), and preparative thin- or thick-layer chromatography, as well as small-scale thin-layer and flash chromatography techniques. Those skilled in the art can select and apply the techniques most likely to achieve the desired separation.

[0070] "Diastereomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereoisomers to the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0071] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolution of racemic mixtures using methods such as the formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H., et al. "Chromatographic resolution of enantiomers: Selective review," J. Chromatogr., 113(3)(1975): pp. 283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) the formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) the formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers, and (3) the direct separation of substantially pure or enriched stereoisomers under chiral conditions. See Reference: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0072] Some of the compounds disclosed herein may exist at different points of hydrogen attachment, called tautomers. For example, compounds containing a carbonyl -CHC(O)- group (keto form) may undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Where applicable, both the keto and enol forms, as well as mixtures thereof, are intended to be included.

[0073] "Prodrug" refers to a derivative of an active agent that requires a transformation within the body to release the active agent. In some embodiments, the transformation is enzymatic. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the active agent.

[0074] "Pharmaceutically acceptable salt" refers to salts that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or can be prepared separately by reacting a free base function with a suitable organic acid, or an acidic group with a suitable base. The term also includes salts of stereoisomers (e.g., enantiomers and / or diastereomers), tautomers, and prodrugs of the compounds of the invention.

[0075] In addition, if the compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, for example, a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0076] As used herein, the terms "administration," "administering," "treating," and "treatment," when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to the contact of an exogenous pharmaceutical, therapeutic, diagnostic, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent with a cell as well as contact of a reagent with a biological fluid, where the biological fluid is in contact with the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment, e.g., of a cell, with a reagent, diagnostic, binding compound, or another cell. As used herein, the term "subject" includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0077] The term "effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient, such as a compound, that, when administered to a subject to treat a disease or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or condition. The term "therapeutically effective amount" may vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given case will be apparent to one of ordinary skill in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer, tautomer, or prodrug thereof, and / or at least one pharmaceutically acceptable salt thereof, that is effective in "treating" a disease or disorder, as defined herein, in a subject. In the case of a combination therapy, the term "therapeutically effective amount" refers to the total amount of the combined entities for effective treatment of the disease, disorder, or condition.

[0078] The term "disease" refers to any disease, ailment, illness, symptom, or indication, and may be used interchangeably with the terms "disorder" or "condition."

[0079] Throughout this specification and the claims that follow, unless the context otherwise requires, the word "comprise," as well as variations such as "comprises" and "comprising," are intended to specify the presence of the subsequent feature but do not exclude the presence or addition of one or more other features. As used herein, the word "comprising" can be replaced with the words "containing," "including," or, in some cases, "having."

[0080] Throughout this specification and the claims that follow, "C n-mThe term "" denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 , C 1-6 These include:

[0081] Unless specifically defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0082] General reaction scheme for compound preparation The compounds of the present invention and their pharmaceutically acceptable salts can be prepared from (a) commercially available starting materials, (b) known starting materials that can be prepared as described in literature procedures, or (c) new intermediates described in the schemes and experimental procedures herein. In making the compounds of the present invention, the order of the synthetic steps can be altered to increase the yield of the desired product. Some of the compounds of the present invention can be produced by the methods shown in the following reaction schemes and accompanying descriptions. Scheme A [ka] Scheme B [ka] [Example]

[0083] The following examples are intended to be purely illustrative and should not be construed as limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Temperatures are in degrees Celsius unless otherwise specified. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI and used without further purification unless otherwise indicated. Unless otherwise indicated, reactions described below were carried out in anhydrous solvents under a positive pressure of nitrogen or argon or using dry tubes; reaction flasks were fitted with rubber septa for introducing substrates and reagents via syringe; and glassware was oven-dried and / or heat-dried.

[0084] 1 1 H NMR spectra were recorded on an Agilent instrument operating at 400 MHz. 1 H NMR spectra were obtained in CDCl, CDCl, CDOD, DO, d-DMSO, d-acetone, or (CD)CO as solvents, using tetramethylsilane (0.00 ppm) or residual solvent (CDCl: 7.25 ppm, CDOD: 3.31 ppm, DO: 4.79 ppm, d-DMSO: 2.50 ppm, d-acetone: 2.05 ppm, (CD)CO: 2.05 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broadened), dd (double doublet), and dt (double triplet). Coupling constants, when given, are reported in Hertz (Hz).

[0085] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity) Detector: MWD (190-400 nm), Mass Detector: 6120 SQ Mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid Column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 pm Gradient method: Flow rate: 1.8 mL / min Time (min) A (%) B (%) [Table 1]

[0086] LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II) Detector: MWD (190-400 nm), Mass Detector: G6125C SQ Mobile phase: A: Water containing 0.1% formic acid, B: Acetonitrile containing 0.1% formic acid Column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 pm Gradient method: Flow rate: 1.8 mL / min Time (min) A (%) B (%) [Table 2]

[0087] LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II) Detector: MWD (190-400 nm), Mass Detector: G6125C SQ Mobile phase: A: Water containing 0.1% formic acid, B: Acetonitrile containing 0.1% formic acid Column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 pm Gradient method: Flow rate: 1.2 mL / min Time (min) A (%) B (%) [Table 3]

[0088] Preparative HPLC was performed on a column (150 x 21.2 mm ID, 5 μm, Gemini NXC 18) at a flow rate of 20 ml / min, injection volume of 2 ml, room temperature, and UV detection at 214 nm and 254 nm.

[0089] In the examples below, the following abbreviations are used: [Table 4-1] [Table 4-2] [Table 4-3]

[0090] Example 30: 5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: 1-(methylsulfonyl)-7-nitroindoline [ka] To a stirred solution of 7-nitroindoline (300 mg, 1.8 mmol) and NaH (146 mg, 3.6 mmol, 60% dispersion in mineral oil) in DMF (5 mL) was added methanesulfonyl chloride (315 mg, 2.7 mmol) dropwise. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated NH4Cl (aqueous) solution and extracted with EtOAc (2 x 50.0 mL). The combined organic layers were washed with brine (2 x 50.0 mL), dried over Na2SO4, and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (390 mg, 88%). [M+H] + = 243.1.

[0091] Step 2: 1-(methylsulfonyl)indoline-7-amine [ka] To a solution of 1-(methylsulfonyl)-7-nitroindoline (390 mg, 1.6 mmol) in MeOH (20 mL) was added 10% Pd / C (50 mg) at room temperature under N2. The mixture was then exchanged with H2 twice and stirred under H2 atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS. The mixture was filtered through a pad of Celite and washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the title product (340 mg, 99%). [M+H] + = 213.1.

[0092] Step 3: N-(2,5-dichloropyrimidin-4-yl)-1-(methylsulfonyl)indolin-7-amine [ka] A mixture of 1-(methylsulfonyl)indoline-7-amine (340 mg, 1.6 mmol), 2,4,5-trichloropyrimidine (584 mg, 3.2 mmol), and DIEA (412 mg, 3.2 mmol) in i-PrOH (20 mL) was stirred in a round-bottom flask at 100 °C for 16 h. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (540 mg, 94%). [M+H] + = 359.2.

[0093] Step 4: 5-Chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] A mixture of N-(2,5-dichloropyrimidin-4-yl)-1-(methylsulfonyl)indoline-7-amine (50 mg, 0.14 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (50 mg, 0.17 mmol), Pd(dba) (13 mg, 0.014 mmol), BINAP (18 mg, 0.028 mmol), and KPO (88 mg, 0.42 mmol) in toluene (8 mL) was stirred in a round-bottom flask at 100 °C under N overnight. The mixture was evaporated in vacuo to give the crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (32 mg, 37%). 1 H NMR (400 MHz, DMSO) δ H8.93 (s, 1H), 8.08 (s, 1H), 7.89 (s, 2H), 7.44 (d, J = 8.3 Hz, 1H), 7.15 (s, 2H), 6.60 (s, 1H), 6.40 (d, J = 8.7 Hz, 1H), 4.05 (s, 2H), 3.76 (s, 3H), 3.69 (d, J = 11.7 Hz, 2H), 3.10 (s, 2H), 3.04 (s, 3H), 2.64 (t, J = 11.9 Hz, 2H), 2.51 (s, 4H), 2.45 - 2.25 (m, 5H), 2.16 (s, 3H), 1.84 (d, J = 10.6 Hz, 2H), 1.51 (d, J = 10.9 Hz, 2H);[M+H] + = 627.3.

[0094] Example 1: 5-chloro-N 4 -(4-fluoro-1-(methylsulfonyl)indolin-7-yl)-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine Step 1: N-(2,5-dichloropyrimidin-4-yl)-4-fluoroindoline-7-amine [ka] A mixture of 4-fluoroindoline-7-amine (200 mg, 1.3 mmol), 2,4,5-trichloropyrimidine (360 mg, 2.0 mmol), and DIEA (340 mg, 2.6 mmol) in i-PrOH (20 mL) was stirred in a round-bottom flask at 100 °C for 16 h. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (170 mg, 43%). [M+H] + = 299.1.

[0095] Step 2: N-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(methylsulfonyl)indoline-7-amine [ka] To a stirred solution of N-(2,5-dichloropyrimidin-4-yl)-4-fluoroindoline-7-amine (70 mg, 0.23 mmol), DMAP (34 mg, 0.28 mmol), and TEA (47 mg, 0.47 mmol) in DCM (5 mL) was added dropwise methanesulfonyl chloride (40 mg, 0.35 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was extracted with EtOAc, and the organic layer was washed with brine (2 × 50.0 mL), dried over NaSO, and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (50 mg, 58%). [M+H] + = 377.1.

[0096] Step 3: 5-Chloro-N 4 -(4-fluoro-1-(methylsulfonyl)indolin-7-yl)-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a manner similar to Example 30. 1 H NMR (400 MHz, DMSO) δ H8.84 (s, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.83 (s, 1H), 7.39 (d, J = 7.4 Hz, 1H), 7.04 (s, 1H), 6.59 (s, 1H), 6.40 (d, J = 8.2 Hz, 1H), 4.10 (t, J = 6.5 Hz, 2H), 3.76 (s, 3H), 3.69 (d, J = 11.5 Hz, 2H), 3.36 (s, 3H), 3.11 (s, 5H), 2.64 (t, J = 11.4 Hz, 2H), 2.52 (s, 2H), 2.38 - 2.23 (m, 4H), 2.14 (s, 3H), 1.84 (d, J = 10.4 Hz, 2H), 1.50 (dd, J = 21.4, 10.5 Hz, 2H);[M+H] + = 645.3.

[0097] Example 2: N 4 -(4-Bromo-1-(methylsulfonyl)indolin-7-yl)-5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine Step 1: 4-Bromo-N-(2,5-dichloropyrimidin-4-yl)indolin-7-amine [ka] The title compound (76 mg, 56%) was prepared from 4-bromoindolin-7-amine and 2,4,5-trichloropyrimidine in a manner similar to Step 1 of Example 1. [M+H] + = 359.1 / 361.1.

[0098] Step 2: 4-Bromo-N-(2,5-dichloropyrimidin-4-yl)-1-(methylsulfonyl)indoline-7-amine [ka] The title compound (85 mg, 90%) was prepared from 4-bromo-N-(2,5-dichloropyrimidin-4-yl)indolin-7-amine in a manner similar to Step 2 of Example 1. [M+H] + = 436.1 / 438.1.

[0099] Step 3:N 4 -(4-Bromo-1-(methylsulfonyl)indolin-7-yl)-5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine [ka] A mixture of 4-bromo-N-(2,5-dichloropyrimidin-4-yl)-1-(methylsulfonyl)indolin-7-amine (50 mg, 0.11 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (42 mg, 0.14 mmol), and MsOH (6 mg, 0.06 mmol) in t-BuOH (5 mL) was stirred in a round-bottom flask at 100° C. for 16 hours. The mixture was evaporated in vacuo to give the crude product, which was purified by preparative HPLC (0.1% FA in water:acetonitrile = 90:1 to 50:50 gradient elution) to give the title product (9 mg, 11%). 1 H NMR (400 MHz, CD3OD) δ H8.51 (s, 1H), 7.99 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 6.64 (s, 1H), 6.41 (d, J = 8.5 Hz, 1H), 4.13 (t, J = 7.5 Hz, 2H), 3.83 (s, 3H), 3.71 (d, J = 12.4 Hz, 2H), 3.16 (t, J = 7.7 Hz, 2H), 2.99 (s, 3H), 2.90 - 2.48 (m, 10H), 2.43 (t, J = 9.7 Hz, 1H), 2.36 (s, 3H), 2.04 (d, J = 11.7 Hz, 2H), 1.68 (q, J = 13.9 Hz, 2H);[M+H] + = 705.2 / 707.2.

[0100] Example 4: 5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(4-methyl-1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: N-(2,5-dichloropyrimidin-4-yl)-4-methylindoline-7-amine [ka] The title compound (170 mg, 52%) was prepared from 4-methylindolin-7-amine and 2,4,5-trichloropyrimidine in a manner similar to Step 1 of Example 1. [M+H] + = 295.2.

[0101] Step 2: N-(2,5-dichloropyrimidin-4-yl)-4-methyl-1-(methylsulfonyl)indoline-7-amine [ka] The title compound (50 mg, 76%) was prepared from N-(2,5-dichloropyrimidin-4-yl)-4-methylindolin-7-amine in a manner similar to Step 2 of Example 1. [M+H] + = 373.2.

[0102] Step 3: 5-Chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(4-methyl-1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a manner similar to Example 30. 1 H NMR (400 MHz, DMSO) δ H 8.83 (s, 1H), 8.05 (s, 1H), 7.83 (s, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 6.59 (s, 1H), 6.39 (d, J = 8.6 Hz, 1H), 4.04 (t, J = 6.9 Hz, 2H), 3.76 (s, 3H), 3.69 (d, J = 11.4 Hz, 2H), 3.02 (s, 5H), 2.65 (t, J = 11.5 Hz, 2H), 2.51 (s, 5H), 2.34 (dt, J = [M+H] + = 641.3.

[0103] Example 5: 5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4-(5-methyl-1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: N-(2,5-dichloropyrimidin-4-yl)-5-methylindoline-7-amine [ka] The title compound (170 mg, 52%) was prepared from 5-methylindolin-7-amine and 2,4,5-trichloropyrimidine in a manner similar to Step 1 of Example 1. [M+H] + = 295.2.

[0104] Step 2: N-(2,5-dichloropyrimidin-4-yl)-5-methyl-1-(methylsulfonyl)indoline-7-amine [ka] The title compound (35 mg, 56%) was prepared from N-(2,5-dichloropyrimidin-4-yl)-5-methylindolin-7-amine in a manner similar to Step 2 of Example 1. [M+H] + = 373.2.

[0105] Step 3: 5-Chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(5-methyl-1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a manner similar to Example 30. 1 H NMR (400 MHz, DMSO) δ H8.92 (s, 1H), 8.21 (s, 1H), 7.78 - 7.65 (m, 2H), 7.32 (d, J = 32.7 Hz, 1H), 7.11 (s, 1H), 6.60 (s, 1H), 6.47 (d, J = 9.0 Hz, 1H), 4.25 (t, J = 8.0 Hz, 2H), 3.80 (s, 3H), 3.67 (d, J = 11.6 Hz, 2H), 3.07 (s, 2H), 2.94 (s, 3H), 2.62 (t, J = 11.4 Hz, 2H), 2.57 - 2.51 (m, 5H), 2.38 - 2.22 (m, 7H), 2.16 (s, 3H), 1.83 (d, J = 11.1 Hz, 2H), 1.50 (dd, J = 22.1, 10.4 Hz, 2H);[M+H] + = 641.3.

[0106] Example 6: 5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(propylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound (8.25 mg, 22%) was synthesized by 5-chloro-N 4 -(indolin-7-yl)-N 2 Prepared in a similar manner to Step 7 of Example 7 from -(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine and propane-1-sulfonyl chloride. 1H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.82 (s, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.14 (s, 2H), 6.59 (s, 1H), 6.38 (d, J = 8.6 Hz, 1H), 4.02 (s, 2H), 3.76 (s, 3H), 3.69 (d, J = 11.6 Hz, 2H), 3.25 - 3.16 (m, 2H), 3.09 (s, 2H), 2.62 (d, J = 14.0 Hz, 7H), 2.36 (s, 4H), 2.24 (s, 3H), 1.85 (d, J = 11.6 Hz, 2H), 1.67 (dd, J = 14.7, 7.6 Hz, 2H), 1.51 (d, J = 10.9 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H);[M+H] + = 655.29.

[0107] Example 7: 5-chloro-N 4 -(1-(cyclopropylsulfonyl)indolin-7-yl)-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine Step 1: 1H-indole-7-amine [ka] To a solution of 7-nitro-1H-indole (10 g, 61.7 mmol) in MeOH (20 mL) under N2, 10% Pd / C (2 g) was added at room temperature. The mixture was then exchanged with H2 twice and stirred under H2 atmosphere at room temperature for 4 hours. The reaction was monitored by LC-MS. The mixture was filtered through a pad of Celite and washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the title product (7.5 g, 92%). [M+H] + = 133.1.

[0108] Step 2: N-(2,5-dichloropyrimidin-4-yl)-1H-indol-7-amine [ka] A mixture of 1H-indole-7-amine (2 g, 15.2 mmol), 2,4,5-trichloropyrimidine (4.1 g, 22.7 mmol), and DIEA (3.9 g, 30.4 mmol) in i-PrOH (100 mL) was stirred in a round-bottom flask at room temperature for 16 h. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (4 g, 94%). [M+H] + = 279.1.

[0109] Step 3: N-(2,5-dichloropyrimidin-4-yl)indolin-7-amine [ka] To a solution of N-(2,5-dichloropyrimidin-4-yl)-1H-indol-7-amine (2 g, 7.2 mmol) in AcOH (60 mL) was added NaBHCN (540 mg, 8.6 mmol) at 0 °C. The mixture was then heated to room temperature for 4 h. The reaction was monitored by LC-MS. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine (2 x 150 mL) and saturated NaHCO3 (aqueous) solution (2 x 150 mL), dried over Na2SO4, and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (1.8 g, 91%). [M+H] + = 281.1.

[0110] Step 4: tert-Butyl 7-((2,5-dichloropyrimidin-4-yl)amino)indoline-1-carboxylate [ka] A mixture of N-(2,5-dichloropyrimidin-4-yl)indoline-7-amine (600 mg, 2.1 mmol), di-tert-butyl dicarbonate (560 mg, 2.6 mmol), and TEA (636.3 mg, 6.3 mmol) in THF (50 mL) was stirred in a round-bottom flask at room temperature for 16 hours. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (500 mg, 62%). [M+H] + = 381.2.

[0111] Step 5: tert-butyl 7-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)indoline-1-carboxylate [ka] The title compound (500 mg, 49%) was prepared from tert-butyl 7-((2,5-dichloropyrimidin-4-yl)amino)indoline-1-carboxylate and 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline in a manner similar to Step 4 of Example 30. [M+H] + = 649.3.

[0112] Step 6: 5-Chloro-N 4 -(indolin-7-yl)-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine [ka] A mixture of tert-butyl 7-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)indoline-1-carboxylate (500 mg, 0.77 mmol) and trifluoroacetic acid (10 ml) in DCM (10 mL) was stirred at room temperature for 2 h in a round-bottom flask. The mixture was extracted with DCM (2 x 50 mL). The combined organic layers were washed with saturated NaHCO3 (aq) solution (50 mL), dried over Na2SO4, and concentrated in vacuo to give the title product (350 mg, 83%). [M+H] + = 549.2.

[0113] Step 7: 5-Chloro-N 4 -(1-(cyclopropylsulfonyl)indolin-7-yl)-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine [ka] 5-Chloro-N in DCM (5 mL) 4 -(indolin-7-yl)-N 2 To a stirred solution of -(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine (30 mg, 0.055 mmol), DMAP (8 mg, 0.066 mmol), and TEA (17 mg, 0.16 mmol) was added cyclopropanesulfonyl chloride (10 mg, 0.066 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was extracted with DCM, washed with brine (2×50.0 mL), dried over NaSO, and concentrated in vacuo to give the crude residue, which was purified by preparative HPLC (0.1% FA in water:acetonitrile = 90:1 to 50:50 gradient elution) to give the title product (16 mg, 45%). 1 NMR (400 MHz, DMSO) δ H8.88 (s, 1 H), 8.08 (s, 1 H, ), 7.89 (s, 2 H), 7.44 (d, J =8.4, 1 H), 7.15 (s, 2 H), 6.60 (s, 1 H,), 6.40 (d, J =8.4, 1 H), 4.07 (m, 2 H), 3.76 (s, 3 H), 3.69 (d, J =11.2, 3 H), 3.43-3.36 (m, 2 H), 3.18-3.11 (m, 2 H), 2.76 (s, 1 H), 2.64 (t, J =11.2, 2 H), 2.5-2.52 (m, 2 H), 2.41-2.26 (m, 4 H), 2.16 (s, 3 H), 1.84 (d, J =11.6, 2 H), 1.51 (q, J =12.0, 2 H), 1.01-0.82 (m, 4 H);[M+H] + = 653.3.

[0114] Example 8: 5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(phenethylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 7. 1 H NMR (400 MHz, DMSO) δ H8.89 (s, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.33 - 7.09 (m, 7H), 6.59 (s, 1H), 6.37 (d, J = 8.4 Hz, 1H), 4.06 (s, 2H), 3.76 (s, 3H), 3.68 (d, J = 11.5 Hz, 2H), 3.55 (s, 2H), 3.09 (s, 2H), 2.95 (s, 2H), 2.63 (t, J = 11.7 Hz, 2H), 2.51 (s, 5H), 2.40 - 2.25 (m, 4H), 2.14 (s, 3H), 1.84 (d, J = 11.5 Hz, 2H), 1.50 (q, J = 11.4 Hz, 2H);[M+H] + = 717.3.

[0115] Example 9:N 4 -(1-(tert-butylsulfonyl)indolin-7-yl)-5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine Step 1:N 4 -(1-(tert-butylsulfinyl)indolin-7-yl)-5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine [ka] The title compound (80 mg, 82%) was synthesized by 5-chloro-N 4 -(indolin-7-yl)-N 2 Prepared from -(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine and 2-methylpropane-2-sulfine chloride in a manner similar to Step 7 of Example 7, [M+H] + = 653.3.

[0116] Step 2:N 4 -(1-(tert-butylsulfonyl)indolin-7-yl)-5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine [ka] N in DCE (10 mL) 4 -(1-(tert-butylsulfinyl)indolin-7-yl)-5-chloro-N 2 To a stirred solution of -(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine (80 mg, 0.12 mmol) was added m-CPBA (84 mg, 0.49 mmol) at 80 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NaSO (aqueous) solution and extracted with DCE (2 × 50 mL). The combined organic layers were washed with saturated NaHCO (aqueous) solution (2 × 50 mL), dried over NaSO, and concentrated in vacuo to give the crude residue, which was purified by preparative HPLC (0.1% FA in water:acetonitrile = 90:1 to 50:50 gradient elution) to give the title product (42 mg, 49%). 1 H NMR (400 MHz, DMSO) δ H8.49 (s, 1H), 8.08 (s, 1H), 7.73 (s, 1H), 7.54 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.17 (s, 2H), 6.56 (s, 1H), 6.30 (d, J = 8.1 Hz, 1H), 4.00 (s, 2H), 3.76 (s, 3H), 3.64 (d, J = 10.6 Hz, 2H), 3.06 (s, 2H), 2.59 (d, J = 11.6 Hz, 2H), 2.50 - 2.45 (m, 5H), 2.38 - 2.22 (m, 4H), 2.14 (s, 3H), 1.82 (d, J = 11.4 Hz, 2H), 1.56 - 1.46 (m, 2H), 1.44 (s, 9H);[M+H] + = 669.3.

[0117] Example 10: 5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-8-yl)pyrimidine-2,4-diamine Step 1: N-(2,5-dichloropyrimidin-4-yl)-1,2,3,4-tetrahydroquinolin-8-amine [ka] The title compound (280 mg, 91%) was prepared from 1,2,3,4-tetrahydroquinolin-8-amine and 2,4,5-trichloropyrimidine in a manner similar to Step 1 of Example 1. [M+H] + = 295.2.

[0118] Step 2: N-(2,5-dichloropyrimidin-4-yl)-1-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-8-amine [ka] The title compound (280 mg, 91%) was prepared from N-(2,5-dichloropyrimidin-4-yl)-1,2,3,4-tetrahydroquinolin-8-amine and methanesulfonyl chloride in a manner similar to Step 2 of Example 1. [M+H] + = 373.1.

[0119] Step 3: 5-Chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-8-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a manner similar to Example 30. 1 H NMR (400 MHz, DMSO) δ H 8.57 (s, 1H), 8.06 (s, 1H), 7.81 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.20 (s, 1H), 7.05 (d, J = 6.6 Hz, 1H), 6.58 (s, 1H), 6.35 (d, J = 7.7 Hz, 1H), 3.75 (s, 3H), 3.68 (d, J = 11.1 Hz, 2H), 3.54 - 3.40 (m, 5H), 3.09 (s, 3H), 2.76 (s, 2H), 2.69 - 2.55 (m, 5H), 2.48 - 2.43 (m, 2H), 2.43 - 2.31 (m, 2H), 2.25 (s, 3H), 2.00 (dd, J = 11.7, 4.5 Hz, 1H), 1.85 (d, J = 11.1 Hz, 2H), 1.51 (dd, J = 22.8, 11.4 Hz, 2H) ;[M+H] + = 641.3.

[0120] Example 11: 5-chloro-N 4-(1-(((3,3-difluorocyclobutyl)methyl)sulfonyl)indolin-7-yl)-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 7. 1 H NMR (400 MHz, CD3OD) δ H 8.50 (s, 1H), 7.99 (s, 1H), 7.79 - 7.65 (m, 2H), 7.23 (s, 2H), 6.63 (s, 1H), 6.35 (dd, J = 7.9, 1.2 Hz, 1H), 4.08 (t, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.65 (d, J = 10.9 Hz, 2H), 3.36 (d, J = 6.4 Hz, 2H), 3.15 (t, J = 6.5 Hz, 2H), 3.00 - 2.63 (m, 12H), 2.58 - 2.35 (m, 7H), 2.02 (d, J = 11.4 Hz, 2H), 1.76 - 1.59 (m, 2H);[M+H] + = 717.3.

[0121] Example 12: 5-chloro-N 4 -(1-((fluoromethyl)sulfonyl)indolin-7-yl)-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 7. 1H NMR (400 MHz, DMSO) δ 8.72 (s, 1H), 8.09 (s, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.43 (d, J = 8.7 Hz, 1H), 7.15 (d, J = 6.2 Hz, 2H), 6.59 (d, J = 2.2 Hz, 1H), 6.37 (d, J = 8.7 Hz, 1H), 5.81 (s, 1H), 5.70 (s, 1H), 4.08 (t, J = 7.0 Hz, 2H), 3.76 (s, 3H), 3.68 (d, J = 11.4 Hz, 2H), 3.09 (t, J = 6.9 Hz, 2H), 2.64 (t, J = 11.6 Hz, 2H), 2.50 (s, 5H), 2.34 (s, 4H), 2.17 (s, 3H), 1.84 (d, J = 11.6 Hz, 2H), 1.51 (d, J = 9.5 Hz, 2H);[M+H] + = 645.29.

[0122] Example 13: 7-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N,N-dimethylindoline-1-sulfonamide [ka] The title compound was prepared in a similar manner to Example 7. 1 H NMR (400 MHz, CD3OD) δ H7.98 (s, 1H), 7.81 - 7.71 (m, 2H), 7.27 - 7.15 (m, 2H), 6.63 (s, 1H), 6.38 (d, J = 8.5 Hz, 1H), 4.60 (s, 1H), 3.91 (t, J = 5.8 Hz, 2H), 3.84 (s, 3H), 3.65 (d, J = 11.4 Hz, 2H), 3.14 (t, J = 6.9 Hz, 2H), 2.90 (s, 6H), 2.83 - 2.49 (m, 9H), 2.46 - 2.33 (m, 4H), 2.01 (d, J = 11.7 Hz, 2H), 1.72 - 1.56 (m, 2H) ; [M+H] + = 656.3.

[0123] Example 14: 7-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylindoline-1-sulfonamide [ka] The title compound was prepared in a similar manner to Example 7. 1 H NMR (400 MHz, CD3OD) δ H 8.51 (s, 1H), 7.98 (s, 1H), 7.79 (t, J = 8.8 Hz, 2H), 7.29 - 7.10 (m, 2H), 6.64 (s, 1H), 6.40 (d, J = 8.6 Hz, 1H), 3.97 (t, J = 6.6 Hz, 2H), 3.85 (s, 3H), 3.66 (d, J = 12.2 Hz, 2H), 3.15 (t, J = 6.7 Hz, 2H), 3.07 - 2.57 (m, 14H), 2.49 (m, 4H), 2.02 (d, J = 11.3 Hz, 2H), 1.80 - 1.59 (m, 2H) ;[M+H] + = 642.3.

[0124] Example 15: 7-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N,N-dimethylindoline-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 7. 1 H NMR (400 MHz, CD3OD) δ H 8.53 (s, 1H), 7.94 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.19 - 7.03 (m, 2H), 6.62 (s, 1H), 6.34 (d, J = 8.2 Hz, 1H), 4.00 (t, J = 7.8 Hz, 2H), 3.85 (s, 3H), 3.66 (t, J = 19.7 Hz, 2H), 3.16 (t, J = 7.7 Hz, 2H), 2.97 (s, 6H), 2.88 - 2.53 (m, 9H), 2.50 - 2.43 (m, 1H), 2.41 (s, 3H), 2.01 (d, J = 10.8 Hz, 2H), 1.66 (q, J = 11.4 Hz, 2H), 1.36 (d, J = 6.5 Hz, 1H);[M+H] + = 620.3.

[0125] Example 16: 7-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylindoline-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 7. 1 H NMR (400 MHz, DMSO) δ H9.92 (s, 1H), 8.01 (s, 1H), 7.60 (s, 3H), 7.17 (s, 1H), 7.00 (s, 2H), 6.58 (s, 1H), 6.37 (s, 1H), 3.96 (t, J = 8.8 Hz, 2H), 3.77 (s, 3H), 3.69 - 3.62 (m, 2H), 3.28 - 3.20 (m, 4H), 3.07 (t, J = 5.6 Hz, 2H), 2.71 (s, 3H), 2.68 - 2.58 (m, 3H), 2.39 - 2.27 (m, 4H), 2.17 (s, 3H), 1.83 (s, 2H), 1.50 (dd, J = 21.9, 11.2 Hz, 2H);[M+H] + = 606.3.

[0126] Example 17: 1-(7-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)indolin-1-yl)ethan-1-one [ka] The title compound was prepared in a similar manner to Example 7. 1 H NMR (400 MHz, DMSO) δ H9.74 (s, 1H), 8.02 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.7 Hz, 1H), 7.16 - 7.07 (m, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.56 (d, J = 2.5 Hz, 1H), 6.34 (dd, J = 8.8, 2.5 Hz, 1H), 4.10 (t, J = 7.7 Hz, 2H), 3.75 (s, 3H), 3.64 (d, J = 12.2 Hz, 2H), 3.05 (t, J = 7.7 Hz, 2H), 2.61 (dd, J = 21.5, 10.8 Hz, 3H), 2.49 (s, 2H), 2.43 (d, J = 1.9 Hz, 2H), 2.36 - 2.22 (m, 7H), 2.13 (s, 3H), 1.81 (d, J = 11.6 Hz, 2H), 1.48 (q, J = 11.8 Hz, 2H) ;[M+H] + = 591.3.

[0127] Example 18: 5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(2-methyl-1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: N-(2,5-dichloropyrimidin-4-yl)-2-methylindoline-7-amine [ka] The title compound (200 mg, 84%) was prepared from 2-methylindoline-7-amine and 2,4,5-trichloropyrimidine in a manner similar to Step 1 of Example 1. [M+H] + = 295.2.

[0128] Step 2: N-(2,5-dichloropyrimidin-4-yl)-2-methyl-1-(methylsulfonyl)indoline-7-amine [ka] The title compound (100 mg, 79%) was prepared from N-(2,5-dichloropyrimidin-4-yl)-2-methylindolin-7-amine and methanesulfonyl chloride in a manner similar to Step 2 of Example 1. [M+H] + = 373.2.

[0129] Step 3: 5-Chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(2-methyl-1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a manner similar to Example 30. 1 H NMR (400 MHz, DMSO) δ H 8.96 (s, 1H), 8.06 (s, 1H), 7.92 (d, J = 9.4 Hz, 2H), 7.40 (d, J = 8.6 Hz, 1H), 7.12 (dd, J = 8.6, 5.3 Hz, 2H), 6.58 (d, J = 2.5 Hz, 1H), 6.40 (dd, J = 8.8, 2.5 Hz, 1H), 4.58 (p, J = 7.0 Hz, 1H), 3.73 (s, 3H), 3.68 (d, J = 10.6 Hz, 2H), 3.55 (dd, J = 16.3, 7.8 Hz, 3H), 3.00 (s, 3H), 2.62 (t, J = 11.1 Hz, 2H), 2.53 - 2.49 (m, 3H), 2.41 - 2.24 (m, 5H), 2.16 (s, 3H), 1.83 (d, J = 11.7 Hz, 2H), 1.49 (dd, J = 20.0, 11.9 Hz, 2H), 1.10 (d, J = 6.7 Hz, 3H);[M+H] + = 641.3.

[0130] Example 23: 5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(3-methyl-1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: N-(2,5-dichloropyrimidin-4-yl)-3-methylindoline-7-amine [ka] The title compound (205 mg, 85%) was prepared from 3-methylindoline-7-amine and 2,4,5-trichloropyrimidine in a manner similar to Step 1 of Example 1. [M+H] + = 295.2.

[0131] Step 2: N-(2,5-dichloropyrimidin-4-yl)-3-methyl-1-(methylsulfonyl)indoline-7-amine [ka] The title compound (98 mg, 78%) was prepared from N-(2,5-dichloropyrimidin-4-yl)-3-methylindolin-7-amine and methanesulfonyl chloride in a manner similar to Step 2 of Example 1. [M+H] + = 373.2.

[0132] Step 3: 5-Chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(3-methyl-1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a manner similar to Example 30. 1 H NMR (400 MHz, CD3OD) δ H7.98 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 7.3 Hz, 1H), 6.64 (s, 1H), 6.40 (d, J = 8.6 Hz, 1H), 4.60 (s, 1H), 4.43 - 4.31 (m, 1H), 3.84 (s, 3H), 3.66 (d, J = 12.0 Hz, 3H), 3.49 (t, J = 11.5 Hz, 1H), 2.99 (s, 3H), 2.87 - 2.45 (m, 9H), 2.38 (t, J = 9.4 Hz, 1H), 2.31 (s, 3H), 2.02 (d, J = 11.5 Hz, 2H), 1.73 - 1.57 (m, 2H), 1.33 (d, J = 6.5 Hz, 3H);[M+H] + = 641.3.

[0133] Example 28: 5-Bromo-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1'-(methylsulfonyl)spiro[cyclopropane-1,3'-indoline]-7'-yl)pyrimidine-2,4-diamine Step 1: 1'-(methylsulfonyl)-7'-nitrospiro[cyclopropane-1,3'-indoline] [ka] The title compound (370 mg, 72%) was prepared from 7'-nitrospiro[cyclopropane-1,3'-indoline] and methanesulfonyl chloride in a manner similar to Step 1 of Example 30. [M+H] + = 269.1.

[0134] Step 2: 1'-(methylsulfonyl)spiro[cyclopropane-1,3'-indoline]-7'-amine [ka] The title compound (320 mg, 91%) was prepared from 1'-(methylsulfonyl)-7'-nitrospiro[cyclopropane-1,3'-indoline] and Pd in ​​a manner similar to Step 1 of Example 30. [M+H] + = 239.1.

[0135] Step 3: N-(5-bromo-2-chloropyrimidin-4-yl)-1'-(methylsulfonyl)spiro[cyclopropane-1,3'-indoline]-7'-amine [ka] The title compound (380 mg, 84%) was prepared from 1'-(methylsulfonyl)spiro[cyclopropane-1,3'-indoline]-7'-amine and 5-bromo-2,4-dichloropyrimidine in a manner similar to Step 3 of Example 30. [M+H] + = 429.1,431.1.

[0136] Step 4: 5-Bromo-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1'-(methylsulfonyl)spiro[cyclopropane-1,3'-indoline]-7'-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H8.80 (s, 1H), 8.14 (s, 1H), 7.86 (s, 1H), 7.79 (d, J=7.6, 1H), 7.42 (d, J=8.6, 1H), 7.13 (t, J=7.7, 1H), 6.70 (d, J=6.8, 1H), 6.59 (d, J=2.3, 1H), 6.38 (dd, J=8.7, 2.5, 1H), 4.02 (s, 2H), 3.76 (s, 3H), 3.68 (d, J=11.9, 2H), 3.29 - 3.24 (m, 5H), 3.02 (s, 3H), 2.70 - 2.60 (m, 2H), 2.30 (dd, J=15.9, 10.5, 4H), 2.16 (s, 3H), 1.84 (d, J=11.6, 2H), 1.50 (dd, J=22.7, 11.2, 2H), 1.24 (s, 2H), 1.06 (s, 2H);[M+H] + = 697.2, 699.2.

[0137] Example 31:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine Step 1: 2-chloro-N-(3-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)-5-(trifluoromethyl)pyrimidin-4-amine [ka] The title compound (170 mg, 82%) was prepared from 1-(methylsulfonyl)indolin-7-amine and 2,4-dichloro-5-(trifluoromethyl)pyrimidine in a manner similar to Step 3 of Example 30. [M+H] + = 392.1.

[0138] Step 2:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4 -(1-(methylsulfonyl)indolin-7-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H 8.83 (s, 1H), 8.48 (s, 1H), 8.36 (s, 1H), 7.76 (s, 1H), 7.41 - 7.29 (m, 1H), 7.27 - 7.09 (m, 2H), 6.65 (s, 1H), 6.50 - 6.37 (m, 1H), 4.44 - 4.20 (m, 2H), 4.13 - 3.98 (m, 3H), 3.79 (m, 5H), 3.15 (s, 2H), 3.09 (s, 3H), 2.72 (t, J = 11.4 Hz, 2H), 2.61 (s, 2H), 2.44 (dd, J = 12.6, 8.8 Hz, 4H), 2.27 (s, 3H), 1.91 (d, J = 10.9 Hz, 2H), 1.57 (dd, J = 20.6, 10.1 Hz, 2H);[M+H] + = 661.3.

[0139] Example 32: 5-Fluoro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: N-(2-chloro-5-fluoropyrimidin-4-yl)-1-(methylsulfonyl)indoline-7-amine [ka] The title compound (620 mg, 74%) was prepared from 1-(methylsulfonyl)indolin-7-amine and 2,4-dichloro-5-fluoropyrimidine in a manner similar to Step 3 of Example 30. [M+H]+ = 343.1.

[0140] Step 2: 5-Fluoro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a manner similar to Example 30. 1 H NMR (400 MHz, DMSO) δ H 8.91 (s, 1H), 8.06 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.68 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.24 - 7.07 (m, 2H), 6.60 (s, 1H), 6.41 (d, J = 8.2 Hz, 1H), 4.06 (t, J = 7.7 Hz, 2H), 3.77 (s, 3H), 3.67 (d, J = 10.8 Hz, 2H), 3.31 - 3.22 (m, 4H), 3.15 - 2.99 (m, 6H), 2.63 (t, J = 12.2 Hz, 2H), 2.40 - 2.24 (m, 4H), 2.15 (s, 3H), 1.84 (d, J = 11.6 Hz, 2H), 1.61 - 1.40 (m, 2H);[M+H] + = 611.3.

[0141] Example 33: 2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-4-((1-(methylsulfonyl)indolin-7-yl)amino)pyrimidine-5-carbonitrile Step 1: 2-chloro-4-((1-(methylsulfonyl)indolin-7-yl)amino)pyrimidine-5-carbonitrile [ka] The title compound (80 mg, 64%) was prepared from 2,4-dichloropyrimidine-5-carbonitrile and 1-(methylsulfonyl)indolin-7-amine in a manner similar to Step 3 of Example 30. [M+H] + = 350.1.

[0142] Step 2: 2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-4-((1-(methylsulfonyl)indolin-7-yl)amino)pyrimidine-5-carbonitrile [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H 8.96 (s, 1H), 8.80 (s, 1H), 8.43 (s, 1H) , 7.69 (s, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.14 (s, 1H), 7.08 (s, 1H), 6.59 (s, 1H), 6.41 (d, J = 6.3 Hz, 1H), 4.03 (s, 2H), 3.74 (s, 3H), 3.74 - 3.65 (m, 2H), 3.34 - 3.22 (m, 4H), 3.16 - 3.04 (m, 3H), 3.03 (s, 3H), 2.67 (t, J = 11.4 Hz, 2H), 2.40 - 2.24 (m, 4H), 2.15 (s, 3H), 1.84 (d, J = 11.9 Hz, 2H), 1.50 (q, J = 9.8 Hz, 2H);[M+H] + = 618.3.

[0143] Example 34: 5-Bromo-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound (6.35 mg, 18%) was prepared from N-(5-bromo-2-chloropyrimidin-4-yl)-1-(methylsulfonyl)indolin-7-amine and 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline in a manner similar to Step 3 of Example 21. 1 H NMR (400 MHz, DMSO) δ 8.78 (s, 1H), 8.14 (s, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.15 (s, 2H), 6.59 (s, 1H), 6.39 (d, J = 8.9 Hz, 1H), 4.04 (s, 2H), 3.76 (s, 3H), 3.69 (d, J = 11.0 Hz, 2H), 3.10 (s, 2H), 3.04 (s, 3H), 2.64 (t, J = 11.8 Hz, 2H), 2.51 (s, 4H), 2.34 (s, 5H), 2.17 (s, 3H), 1.84 (d, J = 12.5 Hz, 2H), 1.51 (d, J = 11.2 Hz, 2H);[M+H] / [M+3] + = 671.20 / 673.2.

[0144] Example 35:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-5-methyl-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: N-(2-chloro-5-methylpyrimidin-4-yl)-1-(methylsulfonyl)indoline-7-amine [ka] The title compound (60 mg, 42%) was prepared from 1-(methylsulfonyl)indolin-7-amine and 2,4-dichloro-5-methylpyrimidine in a manner similar to Step 3 of Example 30. [M+H] + = 339.1.

[0145] Step 2:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-5-methyl-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a manner similar to Example 30. 1 H NMR (400 MHz, DMSO) δ H 8.55 (s, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.98 (s, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.49 (s, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.1 Hz, 1H), 6.72 (s, 1H), 6.50 (d, J = 8.9 Hz, 1H), 4.18 (s, 2H), 3.90 (s, 3H), 3.82 - 3.72 (m, 5H), 3.22 (s, 2H), 3.18 (s, 3H), 2.73 (t, J = 11.8 Hz, 3H), 2.55 - 2.37 (m, 5H), 2.28 (s, 3H), 2.14 (s, 3H), 1.96 (d, J = 11.3 Hz, 2H), 1.63 (dd, J = 22.4, 11.0 Hz, 2H);[M+H] + = 607.3.

[0146] Example 36: 5-chloro-N 2 -(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound (8.45 mg, 30%) was prepared from N-(2,5-dichloropyrimidin-4-yl)-1-(methylsulfonyl)indoline-7-amine and 1-(4-amino-3-methoxyphenyl)-N,N-dimethylpiperidin-4-amine in a manner similar to Step 4 of Example 30. 1 H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.08 (s, 1H), 7.89 (s, 2H), 7.45 (d, J = 8.6 Hz, 1H), 7.15 (s, 2H), 6.61 (s, 1H), 6.41 (d, J = 8.5 Hz, 1H), 4.05 (s, 2H), 3.76 (s, 3H), 3.69 (d, J = 11.5 Hz, 2H), 3.10 (s, 3H), 3.04 (s, 3H), 2.64 (t, J = 11.8 Hz, 2H), 2.26 (s, 6H), 1.86 (d, J = 11.5 Hz, 2H), 1.65 - 1.41 (m, 2H); [M+H] + = 572.2.

[0147] Example 39: 5-chloro-N 2 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 30. 1 NMR (400 MHz, DMSO) δ H8.95 (1 H, s), 8.11 (1 H, s), 7.88 (2 H, s), 7.46 (1 H, s), 7.16 (2 H, s), 6.68 (1 H, s), 4.06 (2 H, s), 3.76 (3 H, s), 3.33-3.28 (2 H, m), 3.13-3.05 (4 H, m), 3.04 (3 H, s), 2.71-2.52 (5 H, m), 2.40-2.25 (4 H, m), 2.16 (3 H, s), 2.08 (3 H, s), 1.90-1.79 (2 H, m), 1.56 (2 H, q, J= 12Hz) ;[M+H] + = 641.3.

[0148] Example 40: 5-Bromo-N 2 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: N-(5-bromo-2-chloropyrimidin-4-yl)-1-(methylsulfonyl)indoline-7-amine [ka] The title compound (520 mg, 88%) was prepared from 1-(methylsulfonyl)indolin-7-amine and 5-bromo-2,4-dichloropyrimidine in a manner similar to Step 3 of Example 30. [M+H] + = 402.8 / 404.9.

[0149] Step 2: 5-Bromo-N 2 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, CD3OD) δ H 8.05 (s, 1H), 7.75 (d, J = 4.0 Hz, 1H), 7.63 (s, 1H), 7.18 (s, 2H), 6.62 (s, 1H), 4.10 (t, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.35 - 3.25 (m, 2H), 3.16 - 2.94 (m, 13H), 2.70 - 2.58 (m, 6H), 2.00 (m, 5H), 1.71 (m, 2H);[M+H] + = 685.2 / 687.2.

[0150] Example 41: 5-chloro-N 2 -(5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a manner similar to Example 30. 1 H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.13 (d, J = 7.7 Hz, 1H), 7.94 (s, 1H), 7.82 (s, 1H), 7.48 (s, 1H), 7.13 (d, J = 12.2 Hz, 2H), 6.74 (s, 1H), 4.05 (t, J = 7.7 Hz, 2H), 3.76 (s, 3H), 3.34 (s, 4H), 3.10 (t, J = 6.4 Hz, 2H), 3.05 (s, 3H), 3.00 (d, J = 10.5 Hz, 3H), 2.90 - 2.80 (m, 2H), 2.68 (t, J = 11.4 Hz, 3H), 2.49 - 2.30 (m, 6H), 1.88 (s, 2H), 1.62 (s, 2H), 1.01 (t, J = 7.1 Hz, 3H);[M+H]+ = 655.3.

[0151] Example 42: 5-Bromo-N 2 -(2-Methoxy-5-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H 8.80 (s, 1H), 8.18 (s, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 7.45 (s, 1H), 7.16 (s, 2H), 6.65 (s, 1H), 4.05 (t, J=7.1, 2H), 3.77 (s, 3H), 3.11 (t, J=7.1, 2H), 3.05 (s, 3H), 2.86 (d, J=10.7, 2H), 2.45 (d, J=11.0, 2H), 2.39 - 2.27 (m, 2H), 2.23 (s, 3H), 2.08 (s, 3H), 1.05 (d, J=6.0, 6H) ;[M+H] + = 630.2 / 632.2.

[0152] Example 43: (S)-5-Bromo-N 2 -(4-(3,4-dimethylpiperazin-1-yl)-2-methoxy-5-methylphenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H8.85 - 8.74 (m, 1H), 8.18 (s, 1H), 7.88 (s, 1H), 7.81 (d, J=6.7, 1H), 7.44 (s, 1H), 7.15 (s, 2H), 6.67 (s, 1H), 4.05 (t, J=6.8, 2H), 3.77 (s, 3H), 3.10 (t, J=7.5, 2H), 3.05 (s, 3H), 2.91 - 2.74 (m, 4H), 2.44 (t, J=10.2, 1H), 2.31 (t, J=10.4, 1H), 2.23 (s, 4H), 2.08 (s, 3H), 1.03 (d, J=6.1, 3H); [M+H] + = 616.2 / 618.2.

[0153] Example 44: 5-Bromo-N 2 -(5-chloro-2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H 8.85 (s, 1H), 8.22 (d, J=1.9, 1H), 7.95 (s, 1H), 7.80 (d, J=7.7, 1H), 7.73 (s, 1H), 7.28 - 7.11 (m, 2H), 6.83 (s, 1H), 4.05 (t, J=7.3, 2H), 3.81 (s, 3H), 3.11 (t, J=7.1, 2H), 3.05 (s, 3H), 2.91 (s, 4H), 2.40 (s, 4H), 2.23 (s, 3H), 1.55 (d, J=14.6, 8H) ;[M+H] + = 690.2 / 692.2.

[0154] Example 45: 5-Bromo-N 2-(2-Methoxy-5-methyl-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H 8.80 (s, 1H), 8.17 (s, 1H), 7.85 (s, 1H), 7.81 (d, J=5.8, 1H), 7.44 (s, 1H), 7.19 - 7.08 (m, 2H), 6.65 (s, 1H), 4.05 (t, J=7.3, [M+H] + = 642.2 / 644.2.

[0155] Example 46: 5-Bromo-N 2 -(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-methylphenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H8.80 (s, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.81 (d, J=6.3, 1H), 7.44 (s, 1H), 7.20 - 7.09 (m, 2H), 6.68 (s, 1H), 4.05 (t, J=7.2, 2H), 3.76 (s, 3H), 3.14 - 3.05 (m, 4H), 3.05 (s, 3H), 2.61 (t, J=11.1, 2H), 2.33 (s, 1H), 2.29 (s, 6H), 2.08 (s, 3H), 1.88 (d, J=11.1, 2H), 1.57 (q, J=10.9, 2H) ;[M+H] + = 630.2 / 632.2.

[0156] Example 47: 5-chloro-N 2 -(4-(4-(dimethylamino)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a manner similar to Example 30. 1 H NMR (400 MHz, CD3OD) δ H 8.53 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.16 (s, 2H), 6.38 (d, J = 8.7 Hz, 1H), 4.62 - 4.50 (m, 2H), 4.12 (s, 2H), 3.45 (d, J = 12.4 Hz, 2H), 3.18 (dd, J = 15.1, 7.4 Hz, 4H), 2.95 (s, 3H), 2.79 - 2.70 (m, 3H), 2.69 (s, 6H), 2.11 (d, J = 11.7 Hz, 2H), 1.78 (dd, J = 21.5, 10.8 Hz, 2H); [M+H] + = 584.2

[0157] Example 48: 5-Bromo-N 2 -(4-(4-(dimethylamino)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H 8.75 (s, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 7.86 (s, 1H), 7.15 - 7.00 (m, 3H), 6.35 (d, J = 8.6 Hz, 1H), 4.44 (t, J = 8.4 Hz, 2H), 4.04 (t, J = 6.0 Hz, 2H), 3.15 - 3.03 (m, 8H), 2.60 (t, J = 11.4 Hz, 2H), 2.24 (s, 8H), 1.87 (d, J = 11.3 Hz, 2H), 1.52 (q, J = 12.1 Hz, 2H) ;[M+H] + = 628.2 / 630.2.

[0158] Example 49: 5-chloro-N 2 -(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a manner similar to Example 30. 1 H NMR (400 MHz, CD3OD) δ H8.49 (s, 1H), 7.96 (s, 1H), 7.86 (s, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.16 (s, 2H), 6.36 (d, J = 8.7 Hz, 1H), 4.52 (t, J = 8.5 Hz, 2H), 4.11 (t, J = 7.4 Hz, 2H), 3.43 (t, J = 17.1 Hz, 2H), 3.16 (dd, J = 19.1, 8.0 Hz, 4H), 2.95 (s, 3H), 2.94 - 2.63 (m, 10H), 2.54 (s, 4H), 2.02 (d, J = 11.1 Hz, 2H), 1.77 - 1.60 (m, 2H) ; [M+H] + = 639.2

[0159] Example 50: 5-Bromo-N 2 -(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H 8.74 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.87 (s, 1H), 7.15 - 7.00 (m, 3H), 6.35 (d, J = 8.3 Hz, 1H), 4.44 (s, 2H), 4.04 (s, 2H), 3.30 - 3.23 (m, 3H), 3.15 - 3.02 (m, 9H), 2.61 (d, J = 11.6 Hz, 3H), 2.41 - 2.27 (m, 5H), 2.17 (s, 3H), 1.86 (d, J = 10.2 Hz, 2H), 1.53 (dd, J = 21.0, 10.2 Hz, 2H) ;[M+H] + = 683.2 / 685.2.

[0160] Example 51: 5-chloro-N2-(7-(4-(dimethylamino)piperidin-1-yl)benzo[d][1,3]dioxol-4-yl)-N4-(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: 7-Bromobenzo[d][1,3]dioxol-4-amine [ka] To a stirred solution of benzo[d][1,3]dioxol-4-amine (500 mg, 3.6 mmol) in CHCN (15 mL) was added NBS (633 mg, 3.6 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with HO and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over NaSO, and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (400 mg, 52%). [M+H] + = 215.9 / 217.8.

[0161] Step 2: 4-Bromo-7-nitrobenzo[d][1,3]dioxole [ka] To a stirred solution of m-CPBA (1.3 g, 7.4 mmol) in DCE (25 mL) was added 7-bromobenzo[d][1,3]dioxol-4-amine (400 mg, 1.8 mmol) at 80 °C. The resulting mixture was stirred at 80 °C for 2 h. The reaction was quenched with HO and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over NaSO, and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (320 mg, 73%). [M+H] + = 245.9 / 247.7.

[0162] Step 3: N,N-Dimethyl-1-(7-nitrobenzo[d][1,3]dioxol-4-yl)piperidin-4-amine [ka] A mixture of 4-bromo-7-nitrobenzo[d][1,3]dioxole (320 mg, 1.3 mmol), N,N-dimethylpiperidin-4-amine (250 mg, 2.0 mmol), Pd(dba) (118 mg, 0.13 mmol), BINAP (162 mg, 0.26 mmol), and KPO (551 mg, 2.6 mmol) in toluene (20 mL) was stirred in a round-bottom flask at 120 °C under N overnight. The mixture was evaporated in vacuo to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (280 mg, 73%). [M+H] + = 294.2.

[0163] Step 4: 1-(7-aminobenzo[d][1,3]dioxol-4-yl)-N,N-dimethylpiperidin-4-amine [ka] The title compound (180 mg, 72%) was prepared from N,N-dimethyl-1-(7-nitrobenzo[d][1,3]dioxol-4-yl)piperidin-4-amine in a manner similar to step 3 of example 30, [M+H] + = 264.2.

[0164] Step 5: 5-chloro-N2-(7-(4-(dimethylamino)piperidin-1-yl)benzo[d][1,3]dioxol-4-yl)-N4-(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound (9.36 mg, 25%) was prepared from N-(2,5-dichloropyrimidin-4-yl)-1-(methylsulfonyl)indolin-7-amine and 1-(7-aminobenzo[d][1,3]dioxol-4-yl)-N,N-dimethylpiperidin-4-amine in a manner similar to Step 4 of Example 30. 1 H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 7.96 (s, 1H), 7.90 (s, 1H), 7.12 (s, 2H), 6.98 (d, J = 8.8 Hz, 1H), 6.42 (d, J = 8.8 Hz, 1H), 5.85 (s, 2H), 4.59 (s, 2H), 4.11 (s, 2H), 3.75 (d, J = 12.0 Hz, 2H), 3.14 (s, 2H), 2.94 (s, 3H), 2.70 (s, 7H), 2.10 (d, J = 11.7 Hz, 2H), 1.79 (d, J = 10.2 Hz, 2H);[M+H] + = 586.2.

[0165] Example 52: 5-Bromo-N 2 -(7-(4-(dimethylamino)piperidin-1-yl)benzo[d][1,3]dioxol-4-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound (12.35 mg, 35%) was prepared from N-(5-bromo-2-chloropyrimidin-4-yl)-1-(methylsulfonyl)indoline-7-amine and 1-(7-aminobenzo[d][1,3]dioxol-4-yl)-N,N-dimethylpiperidin-4-amine in a manner similar to Step 3 of Example 21. 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 7.85 (s, 1H), 7.12 (s, 2H), 6.97 (d, J = 8.9 Hz, 1H), 6.41 (d, J = 8.9 Hz, 1H), 5.84 (s, 2H), 4.61 (s, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.77 (d, J = 10.4 Hz, 2H), 3.15 (d, J = 7.8 Hz, 3H), 2.95 (s, 3H), 2.82 - 2.78 (m, 9H), 2.14 (d, J = 11.7 Hz, 2H), 1.84 (d, J = 11.6 Hz, 2H). [M+H] + = 630.5 / 632.6.

[0166] Example 53: 5-Bromo-N 2 -(7-(4-(dimethylamino)piperidin-1-yl)-2,3-dihydro-1H-inden-4-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: 7-Bromo-2,3-dihydro-1H-inden-4-amine [ka] The title compound (300 mg, 70%) was prepared from 2,3-dihydro-1H-inden-4-amine in a manner similar to Step 1 of Example 51. [M+H] + = 211.9 / 213.1.

[0167] Step 2: 4-Bromo-7-nitro-2,3-dihydro-1H-indene [ka] The title compound (233 mg, 68%) was prepared from 7-bromo-2,3-dihydro-1H-inden-4-amine in a manner similar to Step 2 of Example 51. [M+H] + = 241.9. Step 3: N,N-Dimethyl-1-(7-nitro-2,3-dihydro-1H-inden-4-yl)piperidin-4-amine [ka]

[0168] The title compound (182 mg, 65%) was prepared from 4-bromo-7-nitro-2,3-dihydro-1H-indene and N,N-dimethylpiperidin-4-amine in a manner similar to Step 3 of Example 51. [M+H] + = 290.2.

[0169] Step 4: 1-(7-amino-2,3-dihydro-1H-inden-4-yl)-N,N-dimethylpiperidin-4-amine [ka] The title compound (150 mg, 90%) was prepared from N,N-dimethyl-1-(7-nitro-2,3-dihydro-1H-inden-4-yl)piperidin-4-amine in a manner similar to Step 3 of Example 30. [M+H] + = 260.2.

[0170] Step 5: 5-Bromo-N 2 -(7-(4-(dimethylamino)piperidin-1-yl)-2,3-dihydro-1H-inden-4-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound (8.35 mg, 25%) was prepared from N-(5-bromo-2-chloropyrimidin-4-yl)-1-(methylsulfonyl)indoline-7-amine and 1-(7-amino-2,3-dihydro-1H-inden-4-yl)-N,N-dimethylpiperidin-4-amine in a manner similar to Step 3 of Example 21. 1H NMR (400 MHz, DMSO) δ 8.72 (s, 1H), 8.60 (s, 1H), 8.13 (s, 1H), 7.80 (s, 1H), 7.13 (s, 2H), 7.02 (s, 1H), 6.68 (d, J = 8.6 Hz, 1H), 4.03 (s, 2H), 3.06 (m, 6H), 2.75 (m, 2H), 2.67 (m, 2H), 2.58 (m, 4H), 2.29 (s, 6H), 1.87 (s, 4H), 1.55 (d, J = 11.5 Hz, 2H);[M+H] + = 626.18.

[0171] Example 54: 5-Bromo-N 2 -(8-(4-(dimethylamino)piperidin-1-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: 5-Bromo-8-nitro-2,3-dihydrobenzo[b][1,4]dioxine [ka] The title compound (1.1 g, 86%) was prepared from 8-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-amine and m-CPBA in a manner similar to Step 2 of Example 51. [M+H] + = 260.0 / 262.0.

[0172] Step 2: N,N-Dimethyl-1-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-4-amine [ka] The title compound (230 mg, 62%) was prepared from 5-bromo-8-nitro-2,3-dihydrobenzo[b][1,4]dioxine and N,N-dimethylpiperidin-4-amine in a manner similar to Step 3 of Example 51. [M+H] += 308.2.

[0173] Step 3: 1-(8-amino-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-N,N-dimethylpiperidin-4-amine [ka] The title compound (190 mg, 92%) was prepared from N,N-dimethyl-1-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-4-amine in a manner similar to Step 4 of Example 51. [M+H] + = 278.2.

[0174] Step 4: 5-Bromo-N 2 -(8-(4-(dimethylamino)piperidin-1-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H 8.80 (s, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.84 (d, J=7.1, 1H), 7.21 - 7.04 (m, 3H), 6.38 (d, J=8.7, 1H), 4.21 (s, 4H), 4.05 (t, J=7.1, 2H), 3.28 - 3.24 (m, 3H), 3.11 (t, J=6.7, 2H), 3.05 (s, 3H), 2.54 (s, 1H), 2.26 (s, 7H), 1.83 (d, J=11.5, 2H), 1.63 - 1.43 (m, 2H) ;[M+H] + = 644.2 / 646.2.

[0175] Example 55: 5-Bromo-N 2-(4-(4-(dimethylamino)piperidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: 1-(2,2-dimethyl-7-nitro-2,3-dihydrobenzofuran-4-yl)-N,N-dimethylpiperidin-4-amine [ka] The title compound (180 mg, 45%) was prepared from 4-bromo-2,2-dimethyl-7-nitro-2,3-dihydrobenzofuran (the intermediate was prepared according to the method described in WO2016169504 A1) and N,N-dimethylpiperidin-4-amine in a manner similar to Step 3 of Example 51. [M+H] + = 320.2.

[0176] Step 2: 1-(7-amino-2,2-dimethyl-2,3-dihydrobenzofuran-4-yl)-N,N-dimethylpiperidin-4-amine [ka] The title compound (160 mg, 87%) was prepared from 1-(2,2-dimethyl-7-nitro-2,3-dihydrobenzofuran-4-yl)-N,N-dimethylpiperidin-4-amine and Pd / C in a manner similar to Step 4 of Example 51. [M+H] + = 290.2.

[0177] Step 3: 5-Bromo-N 2 -(4-(4-(dimethylamino)piperidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1H NMR (400 MHz, DMSO) δ H 8.74 (s, 1H), 8.12 (s, 1H), 8.04 (s, 1H), 7.86 (d, J=7.6, 1H), 7.21 - 7.09 (m, 2H), 7.04 (t, J=5.6, 1H), 6.33 (d, J=8.6, 1H), 4.03 (t, J=7.1, 2H), 3.30 - 3.27 (m, 2H), 3.09 (t, J=6.9, 2H), 3.04 (s, 3H), 2.93 (s, 2H), 2.58 (t, J=11.6, 2H), 2.22 (s, 7H), 1.85 (d, J=11.3, 2H), 1.50 (q, J=11.6, 2H), 1.33 (s, 6H);[M+H] + = 656.2, 658.2.

[0178] Example 56: 5-Bromo-N 2 -(2,2-dimethyl-4-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: 1-(2,2-dimethyl-7-nitro-2,3-dihydrobenzofuran-4-yl)-4-methylpiperazine [ka] The title compound (170 mg, 62%) was prepared from 4-bromo-2,2-dimethyl-7-nitro-2,3-dihydrobenzofuran and 1-methylpiperazine in a manner similar to Step 3 of Example 51. [M+H] + = 292.2.

[0179] Step 2: 2,2-dimethyl-4-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-7-amine [ka] The title compound (110 mg, 84%) was prepared from 1-(2,2-dimethyl-7-nitro-2,3-dihydrobenzofuran-4-yl)-4-methylpiperazine in a manner similar to Step 4 of Example 51. [M+H] + = 262.2.

[0180] Step 3: 5-Bromo-N 2 -(2,2-dimethyl-4-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H 8.74 (s, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.86 (d, J=7.4, 1H), 7.20 - 7.10 (m, 2H), 7.04 (t, J=7.2, 1H), 6.32 (d, J=8.5, 1H), 4.03 (t, J=7.0, 2H), 3.09 (t, J=7.1, 2H), 3.03 (s, 3H), 2.93 (s, 6H), 2.46 (s, 4H), 2.23 (s, 3H), 1.33 (s, 6H);[M+H] + = 628.2.

[0181] Example 57: 5-Bromo-N 2 -(2,2-dimethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: 1-(1-(2,2-dimethyl-7-nitro-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)-4-methylpiperazine [ka] The title compound (190 mg, 51%) was prepared from 4-bromo-2,2-dimethyl-7-nitro-2,3-dihydrobenzofuran and 1-methyl-4-(piperidin-4-yl)piperazine in a manner similar to Step 3 of Example 51. [M+H] + = 375.3.

[0182] Step 2: 2,2-dimethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-amine [ka] The title compound (190 mg, 51%) was prepared from 1-(1-(2,2-dimethyl-7-nitro-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)-4-methylpiperazine in a manner similar to Step 3 of Example 51. [M+H] + = 345.3.

[0183] Step 3: 5-Bromo-N 2 -(2,2-dimethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H8.74 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.85 (d, J=7.9, 1H), 7.18 - 7.09 (m, 2H), 7.04 (t, J=7.1, 1H), 6.32 (d, J=8.5, 1H), 4.03 (t, J=7.1, 2H), 3.32 - 3.28 (m, 5H), 3.09 (t, J=6.9, 2H), 3.03 (s, 3H), 2.92 (s, 2H), 2.66 - 2.52 (m, 4H), 2.39 - 2.25 (m, 4H), 2.17 (s, 3H), 1.84 (d, J=11.5, 2H), 1.52 (dd, J=21.6, 10.8, 2H), 1.33 (s, 6H);[M+H] + = 711.2 / 713.2.

[0184] Example 58: 5-Bromo-N 2 -(5-fluoro-4-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was synthesized using a procedure similar to that of Example 59. 1 H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 8.19 (s, 2H), 7.85 (d, J = 7.5 Hz, 1H), 7.22 - 7.04 (m, 3H), 4.47 (t, J = 8.6 Hz, 2H), 4.05 (t, J = [M+H] + = 618.1 / 620.2.

[0185] Example 59: 5-Bromo-N 2-(4-(4-(dimethylamino)piperidin-1-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: 4-Bromo-5-fluoro-2,3-dihydrobenzofuran-7-amine [ka] The title compound (1.3 g, 91%) was prepared from 5-fluoro-2,3-dihydrobenzofuran-7-amine and NBS in a manner similar to Step 1 of Example 51. [M+H] + = 232.0 / 234.0.

[0186] Step 2: 4-Bromo-5-fluoro-7-nitro-2,3-dihydrobenzofuran [ka] The title compound (1.1 g, 87%) was prepared from 4-bromo-5-fluoro-2,3-dihydrobenzofuran-7-amine in a manner similar to Step 2 of Example 51. [M+H] + = 232.0 / 234.0.

[0187] Step 3: 1-(5-fluoro-7-nitro-2,3-dihydrobenzofuran-4-yl)-N,N-dimethylpiperidin-4-amine [ka] The title compound (160 mg, 62%) was prepared from 4-bromo-5-fluoro-7-nitro-2,3-dihydrobenzofuran and N,N-dimethylpiperidin-4-amine in a manner similar to Step 3 of Example 51. [M+H] + = 310.2.

[0188] Step 4: 1-(7-amino-5-fluoro-2,3-dihydrobenzofuran-4-yl)-N,N-dimethylpiperidin-4-amine [ka] The title compound (120 mg, 89%) was prepared from 1-(5-fluoro-7-nitro-2,3-dihydrobenzofuran-4-yl)-N,N-dimethylpiperidin-4-amine in a manner similar to Step 4 of Example 51. [M+H] + = 280.2.

[0189] Step 5: 5-Bromo-N 2 -(4-(4-(dimethylamino)piperidin-1-yl)-5-fluoro-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H 8.83 (s, 1H), 8.20 (t, J=6.1, 2H), 7.85 (d, J=7.7, 1H), 7.14 (dt, J=15.3, 10.6, 3H), 4.47 (t, J=8.5, 2H), 4.05 (t, J=7.0, 2H), 3.25 - 3.17 (m, 4H), 3.10 (t, J=6.8, 2H), 3.05 (s, 3H), 2.94 (t, J=11.4, 2H), 2.25 (s, 7H), 1.82 (d, J=11.6, 2H), 1.48 (dd, J=21.0, 10.7, 2H) ;[M+H] + = 646.2 / 648.2.

[0190] Example 60: 5-Bromo-N 2 -(5-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: 1-(1-(5-fluoro-7-nitro-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)-4-methylpiperazine [ka] The title compound (180 mg, 47%) was prepared from 4-bromo-5-fluoro-7-nitro-2,3-dihydrobenzofuran and 1-methyl-4-(piperidin-4-yl)piperazine in a manner similar to Step 3 of Example 51. [M+H] + = 365.2.

[0191] Step 2: 5-Fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-amine [ka] The title compound (150 mg, 91%) was prepared from 1-(1-(5-fluoro-7-nitro-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)-4-methylpiperazine and Pd in ​​a manner similar to Step 4 of Example 51. [M+H] + = 335.2.

[0192] Step 3: 5-Bromo-N 2 -(5-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H8.83 (s, 1H), 8.25 - 8.12 (m, 2H), 7.84 (d, J=7.3, 1H), 7.25 - 7.07 (m, 3H), 4.47 (t, J=8.5, 2H), 4.05 (t, J=7.2, 2H), 3.29 - 3.14 (m, 8H), 3.10 (t, J=6.9, 2H), 3.04 (s, 3H), 2.94 (t, J=11.3, 2H), 2.41 - 2.24 (m, 5H), 2.15 (s, 3H), 1.80 (d, J=11.3, 2H), 1.49 (dd, J=21.8, 10.4, 2H) ;[M+H] + = 701.2 / 703.2.

[0193] Example 61: 5-Bromo-N 2 -(2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: 1-methyl-4-(1-(2-methyl-7-nitro-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)piperazine [ka] The title compound (160 mg, 42%) was prepared from 4-bromo-2-methyl-7-nitro-2,3-dihydrobenzofuran and 1-methyl-4-(piperidin-4-yl)piperazine in a manner similar to Step 3 of Example 51. [M+H] + = 361.2.

[0194] Step 2: 2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-amine [ka] The title compound (120 mg, 87%) was prepared from 1-methyl-4-(1-(2-methyl-7-nitro-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)piperazine in a manner similar to Step 4 of Example 51. [M+H] + = 331.2

[0195] Step 3: 5-Bromo-N 2 -(2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H 8.74 (s, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 7.87 (d, J=7.8, 1H), 7.11 (d, J=5.4, 2H), 7.05 (s, 1H), 6.33 (d, J=8.6, 1H), 4.82 (dd, J=13.3, 7.0, 1H), 4.03 (t, J=6.7, 2H), 3.29 - 3.19 (m, 5H), 3.09 (t, J=6.2, 2H), 3.04 (s, 3H), 2.72 (dd, J=15.0, 7.6, 1H), 2.65 - 2.52 (m, 5H), 2.40 - 2.24 (m, 4H), 2.17 (s, 3H), 1.85 (d, J=10.6, 2H), 1.52 (dd, J=22.3, 10.1, 2H), 1.32 (d, J=5.9, 3H);[M+H] + = 697.2 / 699.2.

[0196] Example 62: 5-Bromo-N 2 -(2-methyl-4-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4-(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was synthesized in a similar manner to Example 2. 1 H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 7.80 (d, J = 7.4 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.17 (s, 2H), 6.34 (d, J = 8.3 Hz, 1H), 4.90 (d, J = 6.0 Hz, 1H), 4.11 (s, 3H), 3.14 (d, J = 7.5 Hz, 2H), 3.07 (s, 4H), 2.96 (s, 3H), 2.77 (s, 6H), 2.47 (s, 3H), 1.39 (d, J = 6.2 Hz, 3H);[M+H] + = 614.1 / 616.2.

[0197] Example 65: 5-Bromo-N 2 -(4-(4-(dimethylamino)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine Step 1: N,N-Dimethyl-1-(2-methyl-7-nitro-2,3-dihydrobenzofuran-4-yl)piperidin-4-amine [ka] The title compound (180 mg, 61%) was prepared from 4-bromo-2-methyl-7-nitro-2,3-dihydrobenzofuran and N,N-dimethylpiperidin-4-amine in a manner similar to Step 3 of Example 51. [M+H] + = 306.1.

[0198] Step 2: 1-(7-amino-2-methyl-2,3-dihydrobenzofuran-4-yl)-N,N-dimethylpiperidin-4-amine [ka] The title compound (160 mg, 91%) was prepared from N,N-dimethyl-1-(2-methyl-7-nitro-2,3-dihydrobenzofuran-4-yl)piperidin-4-amine in a manner similar to Step 4 of Example 51. [M+H] + = 276.3.

[0199] Step 3: 5-Bromo-N 2 -(4-(4-(dimethylamino)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 2. 1 H NMR (400 MHz, DMSO) δ H 8.80 - 8.68 (m, 1H), 8.20 - 8.14 (m, 1H), 8.13 (s, 1H), 7.93 - 7.80 (m, 1H), 7.17 - 7.08 (m, 2H), 7.05 (dd, J = 11.0, 3.8 Hz, 1H), 6.34 (d, J = 8.6 Hz, 1H), 4.82 (dd, J = 13.2, 6.8 Hz, 1H), 4.03 (t, J = 6.1 Hz, 2H), 3.30 - 3.22 (m, 3H), 3.09 (t, J = 6.8 Hz, 2H), 3.04 (s, 3H), 2.73 (dd, J = 15.3, 8.0 Hz, 1H), 2.59 (dd, J = 23.9, 12.1 Hz, 2H), 2.25 (s, 7H), 1.86 (d, J = 11.5 Hz, 2H), 1.51 (dd, J = 21.4, 10.0 Hz, 2H), 1.32 (d, J = 6.1 Hz, 3H);[M+H] + = 642.2 / 644.2.

[0200] Example 68:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-9-methyl-N 6 -(1-(methylsulfonyl)indolin-7-yl)-9H-purine-2,6-diamine Step 1: 2-chloro-9-methyl-N-(1-(methylsulfonyl)indolin-7-yl)-9H-purin-6-amine [ka] A mixture of 1-(methylsulfonyl)indoline-7-amine (50 mg, 0.23 mmol), 2,6-dichloro-9-methyl-9H-purine (70 mg, 0.35 mmol), and DIEA (60 mg, 0.46 mmol) in i-PrOH (8 mL) was stirred in a round-bottom flask at 100 °C for 16 h. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 1:1 gradient elution) to give the title product (45 mg, 51%). [M+H] + = 379.2.

[0201] Step 2:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-9-methyl-N 6 -(1-(methylsulfonyl)indolin-7-yl)-9H-purine-2,6-diamine [ka] A mixture of 2-chloro-9-methyl-N-(1-(methylsulfonyl)indolin-7-yl)-9H-purin-6-amine (45 mg, 0.12 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (43 mg, 0.14 mmol), Pd(dba) (11 mg, 0.012 mmol), BINAP (15 mg, 0.024 mmol), and KPO (76 mg, 0.36 mmol) in toluene (8 mL) was stirred in a round-bottom flask at 100 °C under N overnight. The mixture was evaporated in vacuo to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 5:1 gradient elution) to give the crude product, which was further purified by preparative HPLC to give the title product (7 mg, 9.1%). 1 H NMR (400 MHz, DMSO) δ H 9.15 (s, 1H), 8.17 (d, J = 7.7 Hz, 1H), 7.90 (s, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.53 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.12 (s, 1H), 6.63 (s, 1H), 6.46 (d, J = 8.8 Hz, 1H), 4.07 (s, 2H), 3.81 (s, 3H), 3.67 (d, J = 13.3 Hz, 5H), 3.11 (s, 2H), 3.05 (s, 3H), 2.63 (t, J = 11.7 Hz, 2H), 2.51 (s, 4H), 2.33 (s, 5H), 2.16 (s, 3H), 1.85 (d, J = 11.7 Hz, 2H), 1.53 (d, J = 11.8 Hz, 2H);[M+H] + = 647.5.

[0202] Example 69:N 5 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-methyl-N 7 -(1-(methylsulfonyl)indolin-7-yl)-2H-pyrazolo[4,3-d]pyrimidine-5,7-diamine Step 1: 5-chloro-2-methyl-N-(1-(methylsulfonyl)indolin-7-yl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine [ka] A mixture of 1-(methylsulfonyl)indolin-7-amine (80 mg, 0.38 mmol), 5,7-dichloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (114 mg, 0.57 mmol), and DIEA (98 mg, 0.76 mmol) in i-PrOH (10 mL) was stirred in a round-bottom flask at 100 °C for 16 h. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 1:2 gradient elution) to give the title product (90 mg, 63%). [M+H] + = 379.2.

[0203] Step 2:N 5 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-methyl-N 7 -(1-(methylsulfonyl)indolin-7-yl)-2H-pyrazolo[4,3-d]pyrimidine-5,7-diamine [ka] A mixture of 5-chloro-2-methyl-N-(1-(methylsulfonyl)indolin-7-yl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (40 mg, 0.11 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (40 mg, 0.13 mmol), Pd(dba) (11 mg, 0.011 mmol), BINAP (15 mg, 0.022 mmol), and KPO (70 mg, 0.33 mmol) in toluene (6 mL) was stirred in a round-bottom flask at 100 °C under N overnight. The mixture was evaporated in vacuo to give the crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 8:1 gradient elution) to give the title product (4 mg, 6%).1 H NMR (400 MHz, DMSO) δ H 9.32 (s, 1H), 8.27 (s, 1H), 8.07 - 8.02 (m, 1H), 8.00 (s, 1H), 7.24 (s, 2H), 7.19 (s, 1H), 6.62 (s, 1H), 6.47 (s, 1H), 4.09 (s, 4H), 3.82 (s, 3H), 3.66 (d, J = 11.0 Hz, 2H), 3.14 (s, 2H), 3.05 (s, 3H), 2.62 (s, 2H), 2.52 (s, 2H), 2.45 - 2.25 (m, 8H), 2.16 (s, 3H), 1.83 (s, 2H), 1.52 (d, J = 9.0 Hz, 2H);[M+H] + = 647.5.

[0204] Example 70:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-7-methyl-N 6 -(1-(methylsulfonyl)indolin-7-yl)-7H-purine-2,6-diamine Step 1: 2-chloro-7-methyl-N-(1-(methylsulfonyl)indolin-7-yl)-7H-purin-6-amine [ka] A mixture of 1-(methylsulfonyl)indoline-7-amine (60 mg, 0.28 mmol), 2,6-dichloro-7-methyl-7H-purine (86 mg, 0.42 mmol), and DIEA (72 mg, 0.56 mmol) in i-PrOH (8 mL) was stirred in a round-bottom flask at 100 °C for 16 h. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 1:1 gradient elution) to give the title product (55 mg, 51%). [M+H] + = 379.2.

[0205] Step 2:N 2-(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-7-methyl-N 6 -(1-(methylsulfonyl)indolin-7-yl)-7H-purine-2,6-diamine [ka] Under N2 atmosphere 、 A mixture of 2-chloro-7-methyl-N-(1-(methylsulfonyl)indolin-7-yl)-7H-purin-6-amine (55 mg, 0.15 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (52 mg, 0.17 mmol), G3 BrettPhos Pd (13 mg, 0.015 mmol), and CsCO (98 mg, 0.30 mmol) in 1,4-dioxane (8 mL) was stirred in a round-bottom flask at 100 °C for 16 h. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 5:1 gradient elution) to give the crude product, which was purified by preparative HPLC to give the title product (8 mg, 8.5%). 1 H NMR (400 MHz, DMSO) δ H 8.60 (s, 1H), 8.07 (s, 1H), 7.90 (s, 2H), 7.24 (d, J = 7.8 Hz, 1H), 7.19 (s, 2H), 6.60 (s, 1H), 6.41 (d, J = 9.1 Hz, 1H), 4.04 (d, J = 19.9 Hz, 5H), 3.80 (s, 3H), 3.65 (d, J = 11.1 Hz, 2H), 3.11 (d, J = 17.2 Hz, 5H), 2.70 - 2.52 (m, 9H), 2.40 (s, 2H), 2.32 (s, 3H), 1.87 (d, J = 10.6 Hz, 2H), 1.54 (d, J = 10.2 Hz, 2H);[M+H] + = 647.5.

[0206] Example 71:N 2-(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine Step 1: 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine [ka] To a solution of 1-(methylsulfonyl)indolin-7-amine (60 mg, 0.28 mmol) and 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (79 mg, 0.42 mmol) in i-PrOH (8 mL) was added concentrated HCl (0.2 mL). The resulting mixture was heated at 80 °C overnight. The organic solvent was removed under reduced pressure, and the residue was basified with saturated NaHCO (aqueous) solution and extracted with DCM (2 × 30 mL). The combined organic layers were dried over NaSO and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 1:1 gradient elution) to give the title product (100 mg, 97%). [M+H] + = 364.2.

[0207] Step 2:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine [ka] Under N2 atmosphere 、A mixture of 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (40 mg, 0.11 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (37 mg, 0.12 mmol), G3 BrettPhos Pd (10 mg, 0.011 mmol), and CsCO (72 mg, 0.22 mmol) in 1,4-dioxane (6 mL) was stirred in a round-bottom flask at 100 °C overnight. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 5:1 gradient elution) to give the crude product, which was further purified by preparative HPLC to give the title product (12 mg, 17%). 1 H NMR (400 MHz, DMSO) δ H 11.17 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.43 (s, 1H), 7.22 (s, 1H), 7.13 (s, 1H), 7.03 (s, 1H), 6.61 (s, 1H), 6.43 (d, J = 8.9 Hz, 1H), 6.19 (s, 1H), 4.07 (s, 2H), 3.83 (s, 3H), 3.62 (d, J = 12.0 Hz, 2H), 3.13 (s, 2H), 2.96 (s, 3H), 2.61 (d, J = 12.6 Hz, 6H), 2.33 (d, J = 32.7 Hz, 5H), 2.18 (s, 3H), 1.85 (d, J = 12.2 Hz, 2H), 1.53 (d, J = 11.3 Hz, 2H);[M+H] + = 632.5.

[0208] Example 72:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(1-(methylsulfonyl)indolin-7-yl)-9H-purine-2,6-diamine Step 1: 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-9H-purin-6-amine [ka] To a solution of 1-(methylsulfonyl)indoline-7-amine (100 mg, 0.47 mmol) and 2,6-dichloro-9H-purine (133 mg, 0.71 mmol) in i-PrOH (10 mL) was added concentrated HCl (0.4 mL). The resulting mixture was heated at 100 °C overnight. The organic solvent was removed under reduced pressure to give a crude residue, which was basified with saturated NaHCO (aqueous) solution and extracted with DCM (2 × 50 mL). The combined organic layers were dried over NaSO and concentrated in vacuo to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (120 mg, 70%). [M+H] + = 365.2.

[0209] Step 2:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 6 -(1-(methylsulfonyl)indolin-7-yl)-9H-purine-2,6-diamine [ka] A mixture of 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-9H-purin-6-amine (50 mg, 0.14 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (49 mg, 0.16 mmol), G3 BrettPhos Pd (13 mg, 0.014 mmol), and CsCO (91 mg, 0.28 mmol) in dry DMF (5 mL) was stirred in a round-bottom flask at 100 °C under N overnight. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 5:1 gradient elution) to give the crude product, which was further purified by preparative HPLC to give the title product (9 mg, 10%). 1 H NMR (400 MHz, DMSO) δ H 12.57 (s, 1H), 9.13 (s, 1H), 8.23 ​​(d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.43 (s, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 6.62 (d, J = 2.3 Hz, 1H), 6.45 (dd, J = 8.8, 2.2 Hz, 1H), 4.07 (t, J = 7.4 Hz, 2H), 3.80 (s, 3H), 3.67 (d, J = 12.3 Hz, 2H), 3.12 (t, J = 7.3 Hz, 2H), 3.05 (s, 3H), 2.63 (t, J = 11.7 Hz, 2H), 2.51 (s, 4H), 2.43 - 2.25 (m, 5H), 2.17 (s, 3H), 1.85 (d, J = 11.4 Hz, 2H), 1.59 - 1.46 (m, 2H);[M+H] + = 633.5.

[0210] Example 73: 5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: 2,4,5-trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine [ka] To a stirred solution of 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.3 mmol) and NaH (136 mg, 3.4 mmol, 60% dispersion in mineral oil) in DMF (10 mL) was added SEM-Cl (564 mg, 3.4 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated NH4Cl (aqueous) solution and extracted with EtOAc (2 × 75 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 5:1 gradient elution) to give the title product (780 mg, 98%). [M+H] + = 352.2.

[0211] Step 2: 2,5-Dichloro-N-(1-(methylsulfonyl)indolin-7-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] To a stirred solution of 1-(methylsulfonyl)indoline-7-amine (150 mg, 0.7 mmol) and 2,4,5-trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (370 mg, 1.1 mmol) in dry DMF (8 mL) was added NaH (44 mg, 1.1 mmol, 60% dispersion in mineral oil) portionwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl (aqueous) solution and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (290 mg, 78%). [M+H] + = 528.2.

[0212] Step 3: 5-Chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] A mixture of 2,5-dichloro-N-(1-(methylsulfonyl)indolin-7-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80 mg, 0.15 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (52 mg, 0.17 mmol), G3 BrettPhos Pd (13 mg, 0.015 mmol), and CsCO (98 mg, 0.30 mmol) in 1,4-dioxane (10 mL) was stirred in a round-bottom flask at 100 °C under N overnight. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (90 mg, 75%). [M+H] + = 796.5.

[0213] Step 4: 5-Chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] 5-Chloro-N in DCM (6 mL) 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 To a stirred solution of -(1-(methylsulfonyl)indolin-7-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (90 mg, 0.11 mmol) at room temperature was added TFA (3 mL). The resulting mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo to give the crude intermediate, which was dissolved in MeOH (5 mL). A solution of NH3.HO (0.5 mL) was added and the resulting mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to give the crude residue, which was purified by preparative HPLC to give the title product (48 mg, 64%). 1H NMR (400 MHz, DMSO) δ H 11.46 (s, 1H), 8.66 (s, 1H), 8.12 (s, 1H), 7.76 (s, 1H), 7.35 (s, 1H), 7.23 - 6.99 (m, 3H), 6.61 (s, 1H), 6.43 (s, 1H), 4.06 (s, 2H), 3.74 (d, J = 37.4 Hz, 5H), 3.15 - 2.85 (m, 11H), 2.64 (s, 6H), 2.37 - 2.27 (m, 2H), 1.88 (s, 2H), 1.56 (s, 2H);[M+H] + = 666.5.

[0214] Example 74:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine Step 1: 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine [ka] To a solution of 1-(methylsulfonyl)indolin-7-amine (100 mg, 0.47 mmol) and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (132 mg, 0.70 mmol) in i-PrOH (8 mL) was added concentrated HCl (0.4 mL). The resulting mixture was heated at 80 °C overnight. The organic solvent was removed under reduced pressure, and the residue was basified with saturated NaHCO (aqueous) solution and extracted with DCM (2 × 30 mL). The combined organic layers were dried over NaSO and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 1:1 gradient elution) to give the title product (50 mg, 29%). [M+H] + = 365.2.

[0215] Step 2:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine [ka] A mixture of 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (50 mg, 0.14 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (50 mg, 0.17 mmol), Pd(dba) (13 mg, 0.014 mmol), BINAP (18 mg, 0.028 mmol), and KPO (88 mg, 0.42 mmol) in toluene (8 mL) was stirred in a round-bottom flask at 100 °C under N overnight. The mixture was evaporated in vacuo to give the crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 8:1 gradient elution) to give the product (17 mg, 20%). 1 H NMR (400 MHz, DMSO) δ H 8.41 (s, 1H), 8.06 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.09 (s, 1H), 6.61 (s, 1H), 6.41 (d, J = 8.6 Hz, 1H), 4.06 (s, 2H), 3.79 (s, 3H), 3.66 (d, J = 10.8 Hz, 2H), 3.10 (s, 2H), 3.05 (s, 3H), 2.74 - 2.53 (m, 10H), 2.37 (d, J = 36.5 Hz, 5H), 2.21 (s, 3H), 2.03 (s, 2H), 1.85 (d, J = 11.0 Hz, 2H), 1.52 (d, J = 11.5 Hz, 2H);[M+H] += 633.5.

[0216] Example 75:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)thieno[3,2-d]pyrimidine-2,4-diamine Step 1: 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)thieno[3,2-d]pyrimidin-4-amine [ka] A mixture of 1-(methylsulfonyl)indolin-7-amine (50 mg, 0.23 mmol), 2,4-dichlorothieno[3,2-d]pyrimidine (70 mg, 0.35 mmol), and DIEA (60 mg, 0.46 mmol) in i-PrOH (8 mL) was stirred in a round-bottom flask at 100 °C for 16 h. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (55 mg, 61%). [M+H] + = 381.1.

[0217] Step 2:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)thieno[3,2-d]pyrimidine-2,4-diamine [ka] A mixture of 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)thieno[3,2-d]pyrimidin-4-amine (55 mg, 0.14 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (50 mg, 0.17 mmol), Pd(dba) (13 mg, 0.014 mmol), BINAP (18 mg, 0.028 mmol), and KPO (88 mg, 0.42 mmol) in toluene (8 mL) was stirred in a round-bottom flask at 100 °C under N overnight. The mixture was evaporated in vacuo to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 8:1 gradient elution) to give the impure product, which was further purified by preparative HPLC to give the title product (30 mg, 32%). 1 H NMR (400 MHz, DMSO) δ H 8.98 (s, 1H), 8.06 (s, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.55 (s, 1H), 7.20 (d, J = 12.1 Hz, 3H), 6.62 (s, 1H), 6.44 (d, J = 8.3 Hz, 1H), 4.08 (s, 2H), 3.80 (s, 3H), 3.68 (d, J = 10.5 Hz, 2H), 3.13 (s, 2H), 3.07 (s, 3H), 2.63 (t, J = 11.8 Hz, 2H), 2.51 (s, 4H), 2.34 (s, 5H), 2.17 (s, 3H), 1.85 (d, J = 10.6 Hz, 2H), 1.53 (d, J = 11.2 Hz, 2H);[M+H] + = 649.4.

[0218] Example 76:N 6 -(4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine Step 1: 4,6-Dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine [ka] To a stirred solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (800 mg, 4.2 mmol) and DIEA (1.1 g, 8.4 mmol) in DCM (20 mL) was added SEM-Cl (1.1 g, 6.6 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with DCM (2 × 75 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over NaSO, and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 10:1 gradient elution) to give the title product (1.1 g, 81%). [M+H] + = 319.2.

[0219] Step 2: 6-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka] A mixture of 1-(methylsulfonyl)indolin-7-amine (80 mg, 0.38 mmol), 4,6-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (179 mg, 0.56 mmol), and DIEA (97 mg, 0.76 mmol) in i-PrOH (10 mL) was stirred at 100 °C overnight in a round-bottom flask. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (150 mg, 81%). [M+H] + = 495.2.

[0220] Step 3:N 6-(4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine [ka] A mixture of 6-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (60 mg, 0.12 mmol), 4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-3-fluoroaniline (38 mg, 0.12 mmol) (the preparation of this intermediate is described in WO2020060268 A1), G3 BrettPhos Pd (11 mg, 0.012 mmol), and CsCO (79 mg, 0.24 mmol) in 1,4-dioxane (8 mL) was stirred overnight at 100 °C under N in a round-bottom flask. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (70 mg, 75%). [M+H] + = 765.5.

[0221] Step 4:N 6 -(4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine [ka] N in DCM (5 mL) 6 -(4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-N 4To a stirred solution of -(1-(methylsulfonyl)indolin-7-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (70 mg, 0.1 mmol) at room temperature was added TFA (2 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to give an intermediate, which was dissolved in MeOH (5 mL). A solution of NH3.HO (0.5 mL) was then added, and the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to give the crude residue, which was purified by preparative HPLC to give the title product (35 mg, 60%). 1 H NMR (400 MHz, DMSO) δ H 13.04 (s, 1H), 9.31 (s, 1H), 9.24 (s, 1H), 8.03 (s, 1H), 7.83 (d, J = 14.3 Hz, 1H), 7.69 (s, 1H), 7.27 (dd, J = 21.6, 13.8 Hz, 3H), 6.94 (d, J = 9.3 Hz, 1H), 4.09 (s, 2H), 3.30 (d, J = 9.5 Hz, 2H), 3.14 (s, 2H), 3.05 (s, 3H), 2.68 - 2.53 (m, 11H), 2.39 (s, 2H), 1.86 (d, J = 11.3 Hz, 2H), 1.58 (d, J = 11.2 Hz, 2H), 1.05 (s, 3H);[M+H] + = 635.5.

[0222] Example 77:N 2 -(4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: tert-butyl 4-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate [ka] A mixture of 1,2-difluoro-4-nitrobenzene (500 mg, 3.1 mmol), tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (915 mg, 3.4 mmol), and K2CO3 (855 mg, 6.2 mmol) in DMF (15 mL) was stirred in a round-bottom flask at 80 °C overnight. The reaction was cooled to room temperature, and the mixture was poured into water (50 mL) and stirred for 10 minutes. The solid was filtered, washed with water (30 mL × 2), and dried to give the product (750 mg, 58%). [M+H] + = 409.4.

[0223] Step 2: 1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)piperazine [ka] A solution of tert-butyl 4-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (750 mg, 1.84 mmol) in HCl / 1,4-dioxane (4 M, 15 mL) was stirred in a round-bottom flask at room temperature for 2 hours. The mixture was evaporated in vacuo to give the crude product (560 mg, 99%), which was used in the next step without further purification. [M+H] + = 309.4.

[0224] Step 3: 1-Ethyl-4-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)piperazine [ka] A mixture of 1-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)piperazine (260 mg, 0.84 mmol), acetaldehyde (111 mg, 2.52 mmol), and NaOAc (207 mg, 2.52 mmol) in DCM (20 mL) and MeOH (4 mL) was stirred at room temperature in a round-bottom flask for 1 h. NaBHCN (156 mg, 2.52 mmol) was then added, and the mixture was stirred at room temperature in a round-bottom flask for 2 h. The reaction was quenched with water (50 mL) and extracted with DCM (50 mL × 2). The combined organic layers were dried over anhydrous NaSO and evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (220 mg, 78%). [M+H] + = 337.4.

[0225] Step 4: 4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-3-fluoroaniline [ka] To a solution of 1-ethyl-4-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)piperazine (220 mg, 0.65 mmol) in MeOH (20 mL) under N was added 10% Pd / C (50 mg) at 25° C. The mixture was then exchanged with H twice and stirred under H atmosphere at 25° C. for 2 h. The reaction was monitored by LC-MS. The mixture was filtered through a pad of Celite and washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the product (190 mg, 95%). [M+H] + = 307.4.

[0226] Step 5:N 2 -(4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] A mixture of 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (40 mg, 0.11 mmol), 4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-3-fluoroaniline (37 mg, 0.12 mmol), G3 BrettPhos Pd (10 mg, 0.011 mmol), and CsCO (72 mg, 0.22 mmol) in 1,4-dioxane (6 mL) was stirred in a round-bottom flask at 100 °C under N overnight. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 5:1 gradient elution) to give the title product (10 mg, 14%). 1 H NMR (400 MHz, DMSO) δ H 11.33 (s, 1H), 9.03 (s, 1H), 8.93 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 15.4 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.25 (s, 1H), 7.13 (d, J = 6.7 Hz, 1H), 6.96 (s, 1H), 6.91 (s, 1H), 6.21 (s, 1H), 4.11 (s, 2H), 3.28 (d, J = 10.0 Hz, 2H), 3.12 (d, J = 15.6 Hz, 5H), 2.61 (d, J = 11.0 Hz, 6H), 2.46 - 2.22 (m, 7H), 1.84 (d, J = 12.1 Hz, 2H), 1.56 (d, J = 10.8 Hz, 2H), 1.00 (d, J = 7.1 Hz, 3H);[M+H] + = 634.5.

[0227] Example 78:N 2 -(4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-3,5-difluorophenyl)-N 4-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: tert-butyl 4-(1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate [ka] The title compound (1.2 g, 93%) was prepared from 1,2,3-trifluoro-5-nitrobenzene and tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate in a manner similar to Step 1 of Example 77. [M+H] + = 427.2

[0228] Step 2: 1-(1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)piperazine [ka] The title compound (920 mg, 88%) was prepared from tert-butyl 4-(1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate in a manner similar to Step 2 of Example 77. [M+H] + = 327.2.

[0229] Step 3: 1-(1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)-4-ethylpiperazine [ka] The title compound (210 mg, 72%) was prepared from 1-(1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)piperazine in a manner similar to Step 3 of Example 77. [M+H] + = 355.2.

[0230] Step 4: 4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-3,5-difluoroaniline [ka] The title compound (170 mg, 81%) was prepared from 1-(1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)-4-ethylpiperazine in a manner similar to Step 4 of Example 77. [M+H] + = 325.2.

[0231] Step 5:N 2 -(4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-3,5-difluorophenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.41 (s, 1H), 9.17 (s, 1H), 9.08 (s, 1H), 8.20 (d, J=7.7, 1H), 7.52 (d, J=12.5, 2H), 7.25 (t, J=7.8, 1H), 7.14 (d, J=7.3, 1H), 7.01 (s, 1H), 6.23 (s, 1H), 4.11 (t, J=7.2, 2H), 3.18 - 3.12 (m, 3H), 3.09 (s, 3H), 3.06 (s, 3H), 3.02 - 2.94 (m, 3H), 2.53 (s, 2H), 2.45 - 2.26 (m, 6H), 1.77 (d, J=11.3, 2H), 1.51 (dd, J=21.7, 10.8, 2H), 0.99 (t, J=7.1, 3H);[M+H] + = 652.3.

[0232] Example 79:N 2 -(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.33 (s, 1H), 9.03 (s, 1H), 8.93 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 15.3 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.12 (d, J = 7.0 Hz, 1H), 6.97 (s, 1H), 6.91 (t, J = 9.7 Hz, 1H), 6.21 (s, 1H), 4.11 (t, J = 6.7 Hz, 2H), 3.29 - 3.26 (m, 4H), 3.16 - 3.07 (m, 7H), 2.60 (t, J = 10.5 Hz, 6H), 2.34 (s, 1H), 2.27 (s, 3H), 1.85 (d, J = 10.8 Hz, 2H), 1.57 (dd, J = 21.7, 11.3 Hz, 2H);[M+H] + = 620.3.

[0233] Example 80:N 2 -(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was synthesized in a similar manner to Example 77. 1H NMR (400 MHz, CD3OD) δ 8.31 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.25 (s, 1H), 7.09 (d, J = 6.9 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 3.5 Hz, 1H), 6.35 (d, J = 3.5 Hz, 1H), 4.16 (t, J = 7.5 Hz, 2H), 3.15 (t, J = 7.3 Hz, 2H), 3.08 - 2.70 (m, 12H), 2.67 - 2.51 (m, 7H), 1.97 (d, J = 11.2 Hz, 2H), 1.75 (d, J = 11.4 Hz, 2H);[M+H] + = 636.26.

[0234] Example 81:N 2 -(3-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H11.25 (s, 1H), 8.97 (s, 1H), 8.68 (s, 1H), 8.38 (d, J=7.7, 1H), 7.45 (s, 1H), 7.33 (d, J=8.7, 1H), 7.22 (t, J=7.9, 1H), 7.10 (d, J=7.0, 1H), 6.94 (s, 1H), 6.76 (d, J=8.5, 1H), 6.19 (s, 1H), 4.10 (t, J=7.8, 2H), 3.73 (s, 3H), 3.26 - 3.22 (m, 5H), 3.13 (s, 2H), 3.09 (s, 3H), 2.60 (s, [M+H] + = 632.4. .

[0235] Example 82:N 2 -(3-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 7.44 (s, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 6.87 (d, J = 3.5 Hz, 1H), 6.32 (d, J = 3.5 Hz, 1H), 4.16 (t, J = 7.4 Hz, 2H), 3.14 -3.11 (m, 4H), 3.00 - 2.86 (m, 10H), 2.65 (t, J = 11.1 Hz, 4H), 2.57 (s, 3H), 2.25 (s, 3H), 2.00 (d, J = 11.6 Hz, 2H), 1.72 (q, J = 11.4 Hz, 2H);[M+H] + = 616.31.

[0236] Example 83:N 2 -(4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-N 4 -(4'-Fluoro-1'-(methylsulfonyl)spiro[cyclobutan-1,3'-indoline]-7'-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: 4'-Fluoro-7'-nitrospiro[cyclobutane-1,3'-indoline] [ka] To a stirred solution of 4'-fluorospiro[cyclobutane 1,3'-indoline] (400 mg, 2.26 mmol) in DCM (5 mL) was added concentrated HNO (0.5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was extracted with EtOAc. The organic layer was washed with saturated NaHCO (aqueous) solution (2 × 50 mL) and brine (2 × 50 mL), dried over NaSO, and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (350 mg, 70%). [M+H]+ = 223.2.

[0237] Step 2: 4'-Fluoro-1'-(methylsulfonyl)-7'-nitrospiro[cyclobutane-1,3'-indoline] [ka] The title compound (310 mg, 78%) was prepared from 4'-fluoro-7'-nitrospiro[cyclobutane-1,3'-indoline] and methanesulfonyl chloride dropwise in a manner similar to Step 1 of Example 30. [M+H] + = 301.1.

[0238] Step 3: 4'-Fluoro-1'-(methylsulfonyl)spiro[cyclobutane-1,3'-indoline]-7'-amine [ka] The title compound (270 mg, 91%) was prepared from 4'-fluoro-1'-(methylsulfonyl)-7'-nitrospiro[cyclobutane-1,3'-indoline] and Pd in ​​a manner similar to Step 2 of Example 30. [M+H] + = 271.1.

[0239] Step 4: N-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4'-fluoro-1'-(methylsulfonyl)spiro[cyclobutane-1,3'-indoline]-7'-amine [ka] The title compound (120 mg, 51%) was prepared from 4'-fluoro-1'-(methylsulfonyl)spiro[cyclobutane-1,3'-indoline]-7'-amine and 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine in a manner similar to Step 1 of Example 71. [M+H] + = 422.2.

[0240] Step 5:N 2-(4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-N 4 -(4'-Fluoro-1'-(methylsulfonyl)spiro[cyclobutan-1,3'-indoline]-7'-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.45 (s, 1H), 9.35 (s, 1H), 8.93 (s, 1H), 8.45 (d, J=8.5, 1H), 7.90 (d, J=16.1, 1H), 7.33 (d, J=7.8, 1H), 7.15 (t, J=8.2, 1H), 7.03 (s, 1H), 6.96 (t, J=9.4, 1H), 6.71 (s, 1H), 4.67 (s, 2H), 3.26 - 3.20 (m, 3H), 3.00 (s, 3H), 2.73 - 2.54 (m, 8H), 2.46 - 2.28 (m, 8H), 2.17 - 2.05 (m, 2H), 1.85 (d, J=11.3, 2H), 1.57 (dd, J=21.8, 12.1, 2H), 1.01 (t, J=7.1, 3H);[M+H] + = 692.3.

[0241] Example 84:N 2 -(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound (6.42 mg, 20%) was prepared from 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 3-fluoro-4-(4-methylpiperazin-1-yl)aniline in a manner similar to Step 3 of Example 77. 1 H NMR (400 MHz, CD3OD) δ 8.29 (d, J = 8.1 Hz, 1H), 7.83 (dd, J = 15.4, 2.3 Hz, 1H), 7.25 (s, 2H), 7.11 (s, 1H), 6.95 (s, 1H), 6.90 (d, J = [M+H] + = 537.6.

[0242] Example 85:N 2 -(2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound (4.28 mg, 22%) was obtained by the synthesis of 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 2,3-difluoro-4-(4-methylpiperazin-1-yl)aniline (this intermediate is described in WO2015 / 027222 A2) in the same manner as in Step 3 of Example 77. 1H NMR (400 MHz, CD3OD) δ 8.14 (d, J = 8.1 Hz, 1H), 7.81 (t, J = 8.6 Hz, 1H), 7.18 (s, 1H), 7.10 (s, 1H), 6.90 (d, J = 3.5 Hz, 1H), 6.77 (t, J = 8.6 Hz, 1H), 6.33 (d, J = 3.4 Hz, 1H), 4.16 (t, J = 7.4 Hz, 2H), 3.22 (s, 4H), 3.15 (t, J = 7.3 Hz, 2H), 3.03 (s, 4H), 2.98 (s, 3H), 2.65 (s, 3H);[M+H] + = 555.6.

[0243] Example 90:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] To a solution of 1-(methylsulfonyl)indolin-7-amine (150 mg, 0.70 mmol) and 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (158 mg, 0.84 mmol) in i-PrOH (8 mL) was added concentrated HCl (0.4 mL). The resulting mixture was heated at 100 °C overnight. The organic solvent was removed under reduced pressure, and the residue was basified with saturated NaHCO (aqueous) solution and extracted with DCM (2 × 30 mL). The combined organic layers were dried over NaSO and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 1:1 gradient elution) to give the title product (75 mg, 29%). [M+H] + = 364.2.

[0244] Step 2:N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] A mixture of 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (40 mg, 0.11 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (37 mg, 0.12 mmol), G3 BrettPhos Pd (10 mg, 0.011 mmol), and CsCO (72 mg, 0.22 mmol) in 1,4-dioxane (6 mL) was stirred in a round-bottom flask at 100 °C under N overnight. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 5:1 gradient elution) to give the title product (8 mg, 12%). 1 H NMR (400 MHz, DMSO) δ H 11.25 (s, 1H), 8.99 (s, 1H), 8.22 (d, J = 9.2 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.22 (s, 2H), 7.10 (s, 1H), 6.92 (s, 1H), 6.62 (s, 1H), 6.45 (d, J = 8.5 Hz, 1H), 6.19 (s, 1H), 4.09 (s, 2H), 3.82 (s, 3H), 3.66 (d, J = 11.0 Hz, 2H), 3.11 (d, J = 14.0 Hz, 5H), 2.66 - 2.52 (m, 6H), 2.34 (d, J = 27.6 Hz, 5H), 2.18 (s, 3H), 1.85 (d, J = 12.2 Hz, 2H), 1.53 (d, J = 9.6 Hz, 2H);[M+H] + = 632.4.

[0245] Example 91:N 2 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.25 (s, 1H), 9.02 (s, 1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.24 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 3.3 Hz, 1H), 6.93 (s, 1H), 6.67 (d, J = 4.1 Hz, 1H), 6.19 (s, 1H), 4.07 (s, 2H), 3.79 (d, J = 4.0 Hz, 3H), 3.14 - 2.96 (m, 10H), 2.65 - 2.52 (m, 4H), 2.32 (s, 4H), 2.14 (dd, J = 10.4, 4.0 Hz, 6H), 1.81 (s, 2H), 1.53 (d, J = 21.9 Hz, 2H);[M+H] + = 646.3.

[0246] Example 92:N 2 -(2-isopropoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: 1-Fluoro-5-isopropoxy-2-methyl-4-nitrobenzene [ka] A mixture of 5-fluoro-4-methyl-2-nitrophenol (500 mg, 2.9 mmol), 2-iodopropane (1.0 g, 5.8 mmol), and K2CO3 (807 mg, 5.8 mmol) in DMF (10 mL) was stirred overnight at room temperature in a round-bottom flask. The reaction was poured into water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 10:1 gradient elution) to give the title product (410 mg, 66%). [M+H] + = 214.2.

[0247] Step 2: 1-(1-(5-isopropoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine [ka] A mixture of 1-fluoro-5-isopropoxy-2-methyl-4-nitrobenzene (410 mg, 1.9 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (420 mg, 2.3 mmol), and K2CO3 (528 mg, 3.8 mmol) in DMF (10 mL) was stirred in a round-bottom flask at 100 °C overnight. The reaction was cooled to room temperature, and the mixture was poured into water (50 mL) and stirred for 10 minutes. The solid was filtered, washed with water (2 × 30 mL), and dried to give the product (320 mg, 44%). [M+H] + = 377.5.

[0248] Step 3: 2-Isopropoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka] To a solution of 1-(1-(5-isopropoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (320 mg, 0.85 mmol) in MeOH (20 mL) under N was added 10% Pd / C (80 mg) at 25° C. The mixture was then exchanged with H twice and stirred under H atmosphere at 25° C. for 2 h. The mixture was filtered through a pad of Celite and washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the product (260 mg, 88%). [M+H] + = 347.5.

[0249] Step 4:N 2 -(2-isopropoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was synthesized in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.27 (s, 1H), 9.08 (s, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.10 (s, 1H), 7.21 (s, 2H), 7.12 (d, J = 7.3 Hz, 1H), 6.96 (s, 1H), 6.69 (s, 1H), 6.22 (s, 1H), 4.54 (s, 1H), 4.11 (s, 2H), 3.11 (d, J = 17.6 Hz, 5H), 3.02 (d, J = 10.4 Hz, 2H), 2.59 (d, J = 11.2 Hz, 5H), 2.33 (s, 6H), 2.15 (d, J = 6.4 Hz, 6H), 1.83 (d, J = 11.7 Hz, 2H), 1.55 (d, J = 9.7 Hz, 2H), 1.29 (d, J = 5.8 Hz, 6H);[M+H] + = 674.5.

[0250] Example 93:N 2 -(2-ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: 5-Fluoro-4-methyl-2-nitrophenol [ka] To a solution of 3-fluoro-4-methylphenol (1 g, 7.9 mmol) in DCM (25 mL) was added 65% HNO (1 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (30 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were dried over NaSO and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 10:1 gradient elution) to give the title product (1.2 g, 88%). [M+H] + = 172.2.

[0251] Step 2: 1-ethoxy-5-fluoro-4-methyl-2-nitrobenzene [ka] A mixture of 5-fluoro-4-methyl-2-nitrophenol (700 mg, 4.1 mmol), iodoethane (1.3 g, 8.2 mmol), and K2CO3 (1.2 g, 8.7 mmol) in DMF (15 mL) was stirred overnight at room temperature in a round-bottom flask. The reaction was poured into water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 10:1 gradient elution) to give the title product (620 mg, 76%). [M+H] + = 200.2.

[0252] Step 3: 1-(1-(5-ethoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine [ka] A mixture of 1-ethoxy-5-fluoro-4-methyl-2-nitrobenzene (300 mg, 1.5 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (330 mg, 1.8 mmol), and K2CO3 (414 mg, 3.0 mmol) in DMF (10 mL) was stirred in a round-bottom flask at 100 °C overnight. The reaction was cooled to room temperature, and the mixture was poured into water (50 mL) and stirred for 10 minutes. The solid was filtered, washed with water (2 × 30 mL), and dried to give the product (260 mg, 48%). [M+H] + = 363.5.

[0253] Step 4: 2-Ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka] To a solution of 1-(1-(5-ethoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (260 mg, 0.72 mmol) in MeOH (20 mL) under N was added 10% Pd / C (80 mg) at 25 °C. The mixture was then exchanged with H twice and stirred under H atmosphere at 25 °C overnight. The mixture was filtered through a pad of Celite and washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the product (210 mg, 88%). [M+H] + = 333.5.

[0254] Step 5:N 2 -(2-ethoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was synthesized in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.26 (s, 1H), 9.06 (s, 1H), 8.18 (d, J = 7.0 Hz, 1H), 8.05 (s, 1H), 7.27 - 7.18 (m, 2H), 7.11 (d, J = 7.3 Hz, 1H), 6.96 (s, 1H), 6.68 (s, 1H), 6.22 (s, 1H), 4.14 - 4.03 (m, 4H), 3.16 - 3.02 (m, 8H), 2.60 (d, J = 10.7 Hz, 5H), 2.34 (s, 5H), 2.15 (d, J = 10.4 Hz, 6H), 1.84 (d, J = 11.6 Hz, 2H), 1.56 (d, J = 11.1 Hz, 2H), 1.35 (t, J = 6.9 Hz, 3H);[M+H] + = 660.5.

[0255] Example 94 N 2 -(5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H11.27 (s, 1H), 9.01 (s, 1H), 8.21 (s, 1H), , 8.06 (s, 1H), 7.29 (s, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 7.1 Hz, 1H), 6.95 (s, 1H), 6.75 (s, 1H), 6.21 (s, 1H), 4.09 (t, J = 7.0 Hz, 2H), 3.81 (s, 3H), 3.12 (dd, J = 15.7, 9.6 Hz, 7H), 2.98 (d, J = 11.3 Hz, 2H), 2.67 (t, J = 11.2 Hz, 3H), 2.56 (d, J = 7.6 Hz, 3H), 2.40 - 2.23 (m, 5H), 2.16 (s, 3H), 1.84 (d, J = 12.1 Hz, 2H), 1.61 - 1.52 (m, 2H), 1.11 (t, J = 7.4 Hz, 3H) ;[M+H] + = 660.3.

[0256] Example 95:N 2 -(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: 1-(1-(2-chloro-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine [ka] A mixture of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene (200 mg, 0.97 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (196 mg, 1.07 mmol), and K2CO3 (267 mg, 1.94 mmol) in DMF (10 mL) was stirred overnight at 100 °C in a round-bottom flask. The reaction was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (330 mg, 91%). [M+H] + = 369.2.

[0257] Step 2: 5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline [ka] To a solution of 1-(1-(2-chloro-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (330 mg, 0.9 mmol) in EtOH (10 mL) and saturated NH4Cl (aqueous) solution (5 mL) was added Zn powder (580 mg, 9.0 mmol). The reaction was stirred at room temperature for 2 hours. The mixture was filtered through a pad of Celite and washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (280 mg, 92%). [M+H] + = 339.2.

[0258] Step 3:N 2 -(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was synthesized in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.40 (s, 1H), 9.08 (s, 1H), 8.38 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.3 Hz, 1H), 6.99 (s, 1H), 6.79 (s, 1H), 6.24 (s, 1H), 4.10 (s, 2H), 3.88 (s, 3H), 3.29 - 3.23 (m, 3H), 3.11 (d, J = 16.0 Hz, 5H), 2.65 (d, J = 10.5 Hz, 8H), 2.36 (d, J = 35.2 Hz, 5H), 1.86 (s, 2H), 1.60 (d, J = 9.8 Hz, 2H);[M+H] + = 666.5.

[0259] Example 96:N 2 -(5-chloro-2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: tert-butyl 9-(2-chloro-5-methoxy-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate [ka] A mixture of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene (500 mg, 2.4 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (681 mg, 2.7 mmol), and K2CO3 (673 mg, 4.8 mmol) in DMF (15 mL) was stirred overnight at 100 °C in a round-bottom flask. The reaction was cooled to room temperature, and the mixture was poured into water (60 mL) and stirred for 10 minutes. The solid was filtered, washed with water (30 mL × 2), and dried to give the product (950 mg, 89%). [M+H] + = 440.2.

[0260] Step 2: 3-(2-chloro-5-methoxy-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane [ka] A solution of tert-butyl 9-(2-chloro-5-methoxy-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (950 mg, 2.2 mmol) in HCl / 1,4-dioxane (4 M, 15 mL) was stirred in a round-bottom flask at room temperature for 2 hours. The mixture was evaporated in vacuo to give the crude product (730 mg, 99%), which was used in the next step without further purification. [M+H] + = 340.2.

[0261] Step 3: 3-(2-chloro-5-methoxy-4-nitrophenyl)-9-methyl-3,9-diazaspiro[5.5]undecane [ka] 3-(2-chloro-5-methoxy-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane (712 mg, 2.1 mmol), (CHO) in DCM (25 mL) and MeOH (5 mL). nA mixture of (336 mg) and NaOAc (516 mg, 6.3 mmol) was stirred in a round-bottom flask at room temperature for 1 hour. Then, NaBHCN (390 mg, 6.3 mmol) was added, and the mixture was stirred in a round-bottom flask at room temperature for 2 hours. The reaction was quenched with water (50 mL) and extracted with DCM (75 mL × 2). The combined organic layers were dried over anhydrous NaSO and evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (750 mg, 98%). [M+H] + = 354.2.

[0262] Step 4: 5-chloro-2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)aniline [ka] To a solution of 3-(2-chloro-5-methoxy-4-nitrophenyl)-9-methyl-3,9-diazaspiro[5.5]undecane (680 mg, 1.9 mmol) in EtOH (20 mL) and saturated NH4Cl (aqueous) solution (8 mL) was added Zn powder (620 mg, 9.5 mmol). The reaction was stirred at room temperature for 2 hours. The mixture was filtered through a pad of Celite and washed with MeOH (30 mL). The filtrate was concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (550 mg, 88%). [M+H] + = 324.2.

[0263] Step 5:N 2 -(5-chloro-2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was synthesized in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.39 (s, 1H), 9.08 (s, 1H), 8.36 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 7.1 Hz, 1H), 6.98 (s, 1H), 6.85 (s, 1H), 6.23 (s, 1H), 4.10 (s, 2H), 3.88 (s, 3H), 3.11 (d, J = 16.7 Hz, 5H), 2.91 (s, 4H), 2.37 (s, 4H), 2.22 (s, 3H), 1.55 (d, J = 16.5 Hz, 8H);[M+H] + = 651.5.

[0264] Example 97:N 2 -(5-fluoro-2-methoxy-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: 2-(2-fluoro-5-methoxy-4-nitrophenyl)-6-methyl-2,6-diazaspiro[3.3]heptane [ka] The title compound (190 mg, 63%) was prepared from 1,2-difluoro-4-methoxy-5-nitrobenzene and 2-methyl-2,6-diazaspiro[3.3]heptane in a manner similar to Step 1 of Example 95. [M+H] + = 282.1.

[0265] Step 2: 5-Fluoro-2-methoxy-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)aniline [ka] The title compound (165 mg, 85%) was prepared from 2-(2-fluoro-5-methoxy-4-nitrophenyl)-6-methyl-2,6-diazaspiro[3.3]heptane in a manner similar to Step 2 of Example 95. [M+H] + = 252.1.

[0266] Step 3:N 2 -(5-fluoro-2-methoxy-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.31 (s, 1H), 9.05 (s, 1H), 8.14 (dd, J = 16.6, 12.8 Hz, 2H), 7.22 (d, J = 9.6 Hz, 2H), 7.13 (s, 1H), 6.96 (s, 1H), 6.22 (d, J = [M+H] + = 579.2.

[0267] Example 98:N 2 -(5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1H NMR (400 MHz, DMSO) δ H 11.38 (s, 1H), 9.07 (s, 1H), 8.25 (s, 1H), 8.20 (d, J = 10.0 Hz, 1H), 7.28 (s, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.3 Hz, 1H), 6.99 - 6.94 (m, 1H), 6.66 (d, J = 8.3 Hz, 1H), 6.22 - 6.17 (m, 1H), 4.08 (t, J = 7.4 Hz, 2H), 3.84 (s, 3H), 3.31 - 3.29 (m, 3H), 3.11 (t, J = 7.4 Hz, 3H), 3.07 (s, 3H), 2.63 (t, J = 11.1 Hz, 2H), 2.55 - 2.50 (m, 2H), 2.39 - 2.21 (m, 5H), 2.14 (s, 3H), 1.82 (d, J = 11.2 Hz, 2H), 1.55 (dd, J = 19.6, 11.3 Hz, 2H) ;[M+H] + = 650.3.

[0268] Example 99:N 2 -(2-methoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: 4-(5-methoxy-2-methyl-4-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine [ka] Under N2 atmosphere 、A mixture of 1-bromo-5-methoxy-2-methyl-4-nitrobenzene (300 mg, 1.2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (326 mg, 1.5 mmol), Pd(PPh3)4 (140 mg, 0.12 mmol), and Cs2CO3 (596 mg, 1.8 mmol) in 1,4-dioxane (20 mL) and HO (4 mL) was stirred at 80 °C for 2 h in a round-bottom flask. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (315 mg, 98%). [M+H] + = 263.2.

[0269] Step 2: 2-Methoxy-5-methyl-4-(1-methylpiperidin-4-yl)aniline [ka] To a solution of 4-(5-methoxy-2-methyl-4-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (315 mg, 1.2 mmol) in MeOH (20 mL) under N was added 10% Pd / C (80 mg) at 25 °C. The mixture was then exchanged with H twice and stirred under H atmosphere at 25 °C overnight. The mixture was filtered through a pad of Celite and washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the product (275 mg, 98%). [M+H] + = 235.2.

[0270] Step 3:N 2 -(2-methoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was synthesized in a similar manner to Example 77. 1H NMR (400 MHz, DMSO) δ H 11.29 (s, 1H), 9.06 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.30 (s, 1H), 7.22 (s, 1H), 7.11 (s, 1H), 6.97 (s, 1H), 6.80 (s, 1H), 6.22 (s, 1H), 4.10 (s, 2H), 3.83 (s, 3H), 3.16 - 3.06 (m, 5H), 2.93 (s, 2H), 2.60 (s, 1H), 2.22 (d, J = 21.2 Hz, 6H), 2.07 (s, 2H), 1.66 (s, 4H);[M+H] + = 562.5.

[0271] Example 100 N 2 -(2-Methoxy-5-methyl-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.24 (s, 1H), 9.01 (s, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.19 (dd, J = 15.3, 8.9 Hz, 2H), 7.07 (s, 1H), 6.92 (s, 1H), 6.64 (s, 1H), 6.18 (s, 1H), 4.06 (s, 2H), 3.78 (s, 3H), 3.12 - 3.03 (m, 8H), 2.68 (s, 5H), 2.42 (s, 3H), 2.11 (s, 3H), 1.80 (s, 4H) ;[M+H] + = 603.3.

[0272] Example 101:N 2-(2-Methoxy-5-methyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: 1-(5-methoxy-2-methyl-4-nitrophenyl)-4-methyl-1,4-diazepane [ka] The title compound (230 mg, 60%) was prepared from 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-1,4-diazepane in a manner similar to Step 1 of Example 77. [M+H] + = 280.2.

[0273] Step 2: 2-Methoxy-5-methyl-4-(4-methyl-1,4-diazepan-1-yl)aniline [ka] The title compound (180 mg, 88%) was prepared from 1-(5-methoxy-2-methyl-4-nitrophenyl)-4-methyl-1,4-diazepane in a manner similar to Step 4 of Example 77. [M+H] + = 250.2.

[0274] Step 3:N 2 -(2-Methoxy-5-methyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound (12.52 mg, 23%) was prepared from 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 2-methoxy-5-methyl-4-(4-methyl-1,4-diazepan-1-yl)aniline in a manner similar to Step 5 of Example 77. 1 H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 8.19 (s, 1H), 7.24 (s, 1H), 7.11 (d, J = 7.2 Hz, 1H), 6.89 (d, J = 3.5 Hz, 1H), 6.77 (s, 1H), 6.33 (d, J = 3.6 Hz, 1H), 4.18 (s, 2H), 3.89 (s, 3H), 3.60 - 3.50 (m, 2H), 3.43 (s, 2H), 3.37 (d, J = 4.9 Hz, 3H), 3.20 - 3.11 (m, 4H), 2.99 (s, 3H), 2.97 (s, 3H), 2.23 (s, 3H), 2.21 - 2.13 (m, 2H);[M+H] + = 577.7.

[0275] Example 102:N 2 -(2-Methoxy-5-methyl-4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: (3aR,6aS)-2-(5-methoxy-2-methyl-4-nitrophenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole [ka] A mixture of 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (200 mg, 1.1 mmol), (3aR,6aS)-2-methyloctahydropyrrole[3,4-c]pyrrole (150 mg, 1.2 mmol), and CsCO (704 mg, 2.2 mmol) in DMF (10 mL) was stirred overnight at 100 °C in a round-bottom flask. The reaction was cooled to room temperature, poured into water (30 mL), and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (240 mg, 76%). [M+H] + = 292.2.

[0276] Step 2: 2-Methoxy-5-methyl-4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)aniline [ka] To a solution of (3aR,6aS)-2-(5-methoxy-2-methyl-4-nitrophenyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole (240 mg, 0.82 mmol) in MeOH (20 mL) under N was added 10% Pd / C (80 mg) at 25 °C. The mixture was then exchanged with H twice and stirred under an H atmosphere at 25 °C for 2 h. The mixture was filtered through a pad of Celite and washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the product (210 mg, 97%). [M+H] + = 262.2.

[0277] Step 3:N 2 -(2-Methoxy-5-methyl-4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was synthesized in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.25 (s, 1H), 9.03 (s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.25 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 7.3 Hz, 1H), 6.94 (s, 1H), 6.65 (s, 1H), 6.21 (s, 1H), 4.10 (t, J = 7.4 Hz, 2H), 3.81 (s, 3H), 3.15 - 3.08 (m, 5H), 3.02 (s, 2H), 2.77 (dd, J = 26.1, 8.7 Hz, 6H), 2.31 (d, J = 5.5 Hz, 2H), 2.27 (s, 3H), 2.17 (s, 3H);[M+H] + = 589.5.

[0278] Example 103:N 2 -(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-methylphenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H11.26 (s, 1H), 9.02 (s, 1H), 8.26 - 8.14 (m, 1H), 7.98 (s, 1H), 7.24 (s, 1H), 7.22 - 7.16 (m, 1H), 7.12 - 7.05 (m, 1H), 6.93 (s, 1H), 6.67 (s, 1H), 6.19 (s, 1H), 4.08 (s, 2H), 3.79 (s, 3H), 3.12 - 3.02 (m, 7H), 2.59 (s, 2H), 2.25 (s, 7H), 2.13 (s, 3H), 1.83 (s, 2H), 1.55 (t, J = 17.9 Hz, 2H); [M+H] + = 591.3.

[0279] Example 104:N 2 -(4-(4-(dimethylamino)cyclohexyl)-2-methoxy-5-methylphenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound (10.32 mg, 18%) was prepared from 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 4-(4-(dimethylamino)cyclohexyl)-2-methoxy-5-methylaniline (this intermediate was prepared according to the method described in WO2008073687 A2) in a manner similar to Step 5 of Example 77. 1H NMR (400 MHz, CD3OD) δ 8.19 (d, J = 7.9 Hz, 1H), 8.15 (s, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 6.9 Hz, 1H), 6.89 (d, J = 3.5 Hz, 1H), 6.78 (s, 1H), 6.33 (d, J = 3.5 Hz, 1H), 4.18 (s, 2H), 3.88 (s, 3H), 3.17 (s, 2H), 2.99 (s, 3H), 2.80 (s, 7H), 2.22 (s, 3H), 2.17 (s, 3H), 1.99 (s, 2H), 1.66 (d, J = 7.1 Hz, 4H); [M+H] + = 590.7.

[0280] Example 105: (S)-N 2 -(4-(3,4-dimethylpiperazin-1-yl)-2-methoxy-5-methylphenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound (8.36 mg, 19%) was prepared from 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and (S)-4-(3,4-dimethylpiperazin-1-yl)-2-methoxy-5-methylaniline in a manner similar to Step 4 of Example 106. 1H NMR (400 MHz, CD3OD) δ 8.49 (s, 1H), 8.19 (d, J = 4.6 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.12 (d, J = 7.4 Hz, 1H), 6.89 (d, J = 3.6 Hz, 1H), 6.73 (s, 1H), 6.33 (d, J = 3.6 Hz, 1H), 4.18 (t, J = 7.6 Hz, 2H), 3.90 (s, 3H), 3.13 - 3.09 (m, 6H), 2.99 (s, 3H), 2.71 (d, J = 18.2 Hz, 4H), 2.20 (s, 3H), 2.03 (s, 2H), 1.32 (d, J = 6.4 Hz, 3H);[M+H] + = 577.3.

[0281] Example 106:N 2 -(2-Methoxy-5-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: (3S,5R)-1-(5-methoxy-2-methyl-4-nitrophenyl)-3,5-dimethylpiperazine [ka] A mixture of 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (500 mg, 2.7 mmol), (2S,6R)-2,6-dimethylpiperazine (370 mg, 3.2 mmol), and K2CO3 (746 mg, 5.4 mmol) in DMF (15 mL) was stirred overnight at 60 °C in a round-bottom flask. The reaction was cooled to room temperature, poured into water (60 mL), and extracted with EtOAc (2 × 75 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (750 mg, 99%). [M+H] + = 280.2.

[0282] Step 2: (2S,6R)-4-(5-methoxy-2-methyl-4-nitrophenyl)-1,2,6-trimethylpiperazine [ka] (3S,5R)-1-(5-methoxy-2-methyl-4-nitrophenyl)-3,5-dimethylpiperazine (680 mg, 2.4 mmol), (CHO) in DCM (20 mL) and MeOH (4 mL). n A mixture of (450 mg) and AcOH (144 mg, 2.4 mmol) was stirred in a round-bottom flask at room temperature for 1 hour. Then, NaBHCN (450 mg, 7.2 mmol) was added, and the mixture was stirred in a round-bottom flask at room temperature for 2 hours. The reaction was quenched with water (75 mL) and extracted with DCM (100 mL × 2). The combined organic layers were dried over anhydrous NaSO and evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (580 mg, 81%). [M+H] + = 294.2.

[0283] Step 3: 2-Methoxy-5-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)aniline [ka] To a solution of (2S,6R)-4-(5-methoxy-2-methyl-4-nitrophenyl)-1,2,6-trimethylpiperazine (580 mg, 2.0 mmol) in MeOH (30 mL) under N was added 10% Pd / C (100 mg) at 25 °C. The mixture was then exchanged with H twice and stirred under an H atmosphere at 25 °C overnight. The mixture was filtered through a pad of Celite and washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the product (515 mg, 99%). [M+H] + = 264.4.

[0284] Step 4:N2 -(2-Methoxy-5-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was synthesized in a similar manner to Step 5 of Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.28 (s, 1H), 9.05 (s, 1H), 8.18 (s, 1H), 8.03 (s, 1H), 7.23 (dd, J = 17.1, 9.4 Hz, 2H), 7.12 (s, 1H), 6.95 (s, 1H), 6.67 (s, 1H), 6.22 (s, 1H), 4.10 (s, 2H), 3.83 (s, 3H), 3.11 (d, J = 15.1 Hz, 5H), 2.86 (d, J = 10.5 Hz, 2H), 2.45 (d, J = 11.1 Hz, 2H), 2.33 (s, 2H), 2.23 (s, 3H), 2.16 (s, 3H), 1.05 (d, J = 5.6 Hz, 6H);[M+H] + = 591.5.

[0285] Example 107: (R)—N2-(4-(3,4-dimethylpiperazin-1-yl)-2-methoxy-5-methylphenyl)-N4-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was synthesized in a similar manner to Example 77. 1H NMR (400 MHz, CD3OD) δ 8.17 (s, 1H), 8.14 (s, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 6.9 Hz, 1H), 6.88 (d, J = 3.3 Hz, 1H), 6.69 (s, 1H), 6.32 (d, J = 3.2 Hz, 1H), 4.15 (t, J = 7.3 Hz, 2H), 3.87 (s, 3H), 3.31 (s, 2H), 3.17 - 3.01 (m, 7H), 2.97 (s, 3H), 2.77 (d, J = 12.6 Hz, 1H), 2.73 (s, 3H), 2.17 (s, 3H), 1.32 (d, J = 5.6 Hz, 3H);[M+H] + = 577.3.

[0286] Example 108: 2-(4-(5-methoxy-2-methyl-4-((4-((1-(methylsulfonyl)indolin-7-yl)amino))-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-1-yl)ethan-1-ol Step 1: tert-butyl 4-(5-methoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] A mixture of 1-bromo-5-methoxy-2-methyl-4-nitrobenzene (500 mg, 2.0 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (753 mg, 2.4 mmol), Pd(PPh) (234 mg, 0.2 mmol), and CsCO (993 mg, 3.0 mmol) in 1,4-dioxane (30 mL) and HO (6 mL) was stirred in a round-bottom flask at 80 °C under N for 2 h. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 4:1 gradient elution) to give the title product (700 mg, 98%). [M+H] + = 349.2.

[0287] Step 2: tert-butyl 4-(4-amino-5-methoxy-2-methylphenyl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(5-methoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (450 mg, 1.3 mmol) in MeOH (20 mL) under N was added 10% Pd / C (100 mg) at 25 °C. The mixture was then exchanged with H twice and stirred under H atmosphere at 25 °C overnight. The mixture was filtered through a pad of Celite and washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the product (320 mg, 77%). [M+H] + = 321.4.

[0288] Step 3: tert-butyl 4-(5-methoxy-2-methyl-4-((4-((1-(methylsulfonyl)indolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate [ka] A mixture of 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.27 mmol), tert-butyl 4-(4-amino-5-methoxy-2-methylphenyl)piperidine-1-carboxylate (97 mg, 0.30 mmol), G3 BrettPhos Pd (30 mg, 0.03 mmol), and CsCO (180 mg, 0.54 mmol) in 1,4-dioxane (10 mL) was stirred overnight at 100 °C under N in a round-bottom flask. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 1:2 gradient elution) to give the title product (80 mg, 45%). [M+H] + = 648.5.

[0289] Step 4:N 2 -(2-Methoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] A solution of tert-butyl 4-(5-methoxy-2-methyl-4-((4-((1-(methylsulfonyl)indolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (80 mg, 0.12 mmol) in HCl / 1,4-dioxane (4 M, 10 mL) was stirred at room temperature in a round-bottom flask for 2 hours. The mixture was evaporated in vacuo to give the crude product (65 mg, 96%), which was used in the next step without further purification. [M+H] + = 548.5.

[0290] Step 5: 2-(4-(5-methoxy-2-methyl-4-((4-((1-(methylsulfonyl)indolin-7-yl)amino))-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-1-yl)ethan-1-ol [ka] N in DMF (2 mL) 2 -(2-Methoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N 4 A mixture of -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (30 mg, 0.05 mmol), 2-bromoethan-1-ol (25 mg, 0.2 mmol), and KCO (14 mg, 0.1 mmol) was stirred in a round-bottom flask overnight at room temperature. The inorganic salts were removed by filtration. The filtrate was purified by preparative HPLC to give the title product (7 mg, 22%). 1 H NMR (400 MHz, DMSO) δ H 11.28 (s, 1H), 9.06 (s, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.03 (s, 1H), 7.29 (s, 1H), 7.22 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 7.1 Hz, 1H), 6.96 (s, 1H), 6.81 (s, 1H), 6.23 (s, 1H), 4.10 (s, 2H), 3.84 (s, 3H), 3.54 (s, 3H), 3.11 (d, J = 16.5 Hz, 5H), 3.03 (d, J = 10.7 Hz, 2H), 2.64 (s, 1H), 2.48 - 2.45 (m, 2H), 2.25 - 2.09 (m, 5H), 1.79 - 1.60 (m, 4H);[M+H] + = 592.5.

[0291] Example 109:N 2 -(4-(1-(2-(dimethylamino)ethyl)piperidin-4-yl)-2-methoxy-5-methylphenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] N in DCM (2 mL) / MeOH (5 mL) 2 -(2-Methoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N 4 To a solution of -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (40 mg, 0.07 mmol), 2-(dimethylamino)acetaldehyde hydrochloride (26 mg, 0.21 mmol), and AcOH (9 mg, 0.15 mmol) was added DIEA (45 mg, 0.35 mmol). After stirring at room temperature for 2 minutes, NaBHCN (22 mg, 0.35 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with DCM (2 × 30 mL). The combined organic layers were washed once with brine, dried over NaSO, filtered, and concentrated in vacuo to give the crude residue, which was further purified by preparative HPLC to give the product (5.5 mg, 12%). 1 H NMR (400 MHz, DMSO) δ H 11.28 (s, 1H), 9.06 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.29 (s, 1H), 7.22 (s, 1H), 7.11 (d, J = 7.1 Hz, 1H), 6.97 (s, 1H), 6.80 (s, 1H), 6.23 (s, 1H), 4.10 (s, 2H), 3.84 (s, 3H), 3.13 (s, 2H), 3.07 (d, J = 13.6 Hz, 5H), 2.68 (s, 2H), 2.55 (s, 3H), 2.30 (s, 6H), 2.18 (d, J = 18.7 Hz, 5H), 1.77 - 1.63 (m, 4H); [M+H] + = 619.5.

[0292] Example 110:N 2 -(2-Methoxy-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound (3.12 mg, 15%) was prepared from 2-chloro-N-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 2-methoxy-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)aniline in a manner similar to Step 3 of Example 77. 1 H NMR (400 MHz, CD3OD) δ 8.17 (d, J = 7.7 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.1 Hz, 1H), 6.86 (s, 1H), 6.35 (s, 1H), 6.29 (d, J = 3.4 Hz, 1H), 6.20 (d, J = 8.6 Hz, 1H), 4.63 (s, 2H), 4.33 (s, 1H), 4.17 (t, J = 7.4 Hz, 2H), 3.90 (s, 3H), 3.73 - 3.70 (m, 2H), 3.40 (d, J = 10.8 Hz, 1H), 3.16 (t, J = 7.1 Hz, 2H), 2.98 (s, 3H), 2.93 (s, 3H), 2.34 (s, 2H);[M+H] + = 561.23.

[0293] Example 111:N 2 -(2-Methoxy-4-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: (1R,5S)-8-(3-methoxy-4-nitrophenyl)-3-methyl-3,8-diazabicyclo[3.2.1]octane [ka] The title compound (300 mg, 86%) was prepared from 4-fluoro-2-methoxy-1-nitrobenzene and (1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octane in a manner similar to Step 1 of Example 95. [M+H] + = 278.2.

[0294] Step 2: 2-Methoxy-4-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)aniline [ka] The title compound (240 mg, 84%) was prepared from (1R,5S)-8-(3-methoxy-4-nitrophenyl)-3-methyl-3,8-diazabicyclo[3.2.1]octane in a manner similar to Step 2 of Example 95. [M+H] + = 248.2.

[0295] Step 3 N 2 -(2-Methoxy-4-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H11.21 (s, 1H), 8.97 (s, 1H), 8.25 (d, J=7.8, 1H), 7.85 (d, J=8.6, 1H), 7.24 - 7.16 (m, 2H), 7.08 (d, J=6.7, 1H), 6.91 (s, 1H), 6.48 (s, 1H), 6.34 (d, J=8.4, 1H), 6.18 (s, 1H), 4.21 (s, 2H), 4.09 (t, J=7.2, 2H), 3.79 (s, 3H), 3.13 (d, J=7.4, 2H), 3.09 (s, 3H), 2.47 (s, 2H), 2.34 (d, J=9.8, 2H), 2.09 (s, 3H), 1.85 (dd, J=19.9, 8.0, 4H);[M+H] + = 575.3.

[0296] Example 112:N 2 -(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.18 (s, 1H), 8.95 (s, 1H), 8.25 (d, J=8.4, 1H), 7.79 (d, J=8.9, 1H), 7.24 - 7.13 (m, 2H), 7.07 (d, J=7.3, 1H), 6.90 (s, 1H), 6.38 (s, 1H), 6.24 (d, J=8.5, 1H), 6.18 (s, 1H), 4.09 (t, J=7.2, 2H), 3.80 (s, 3H), 3.32 - 3.29 (m, 2H), 3.13 (d, J=7.4, 2H), 3.08 (s, 3H), 2.90 (s, 3H), 2.43 (d, J=6.8, 2H), 2.22 (s, 6H);[M+H]+ = 551.3.

[0297] Example 113:N 2 -(4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: 2-(4-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)-N,N-dimethylethan-1-amine [ka] A mixture of 4-chloro-2-methoxy-1-nitrobenzene (500 mg, 2.7 mmol), N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-amine (780 mg, 2.9 mmol), Pd(PPh) (309 mg, 0.27 mmol), and CsCO (1.3 g, 4.0 mmol) in 1,4-dioxane (30 mL) and HO (6 mL) was stirred in a round-bottom flask at 80 °C under N for 2 h. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (760 mg, 97%). [M+H] + = 291.2.

[0298] Step 2: 4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-2-methoxyaniline [ka] To a solution of 2-(4-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)-N,N-dimethylethan-1-amine (760 mg, 2.6 mmol) in MeOH (30 mL) under N was added 10% Pd / C (200 mg) at 25 °C. The mixture was then exchanged with H twice and stirred under H atmosphere at 25 °C overnight. The mixture was filtered through a pad of Celite and washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the product (680 mg, 99%). [M+H] + = 261.2.

[0299] Step 3:N 2 -(4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was synthesized in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.36 (s, 1H), 9.07 (s, 1H), 8.36 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 7.9 Hz, 1H), 8.14 (s, 1H), 7.85 (s, 1H), 7.39 (s, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.18 (s, 1H), 7.14 (d, J = 7.3 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.99 (s, 1H), 6.23 (s, 1H), 4.20 (s, 2H), 4.10 (t, J = 7.2 Hz, 2H), 3.93 (s, 3H), 3.13 (d, J = 6.7 Hz, 2H), 3.09 (s, 3H), 2.68 (s, 2H), 2.19 (s, 6H);[M+H] + = 588.5.

[0300] Example 114:N2 -(2-Methoxy-4-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: 3-((4-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)methyl)pyridine [ka] A mixture of 4-chloro-2-methoxy-1-nitrobenzene (500 mg, 2.7 mmol), 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine (838 mg, 2.9 mmol), Pd(PPh3)4 (309 mg, 0.27 mmol), and Cs2CO3 (1.3 g, 4.0 mmol) in 1,4-dioxane (30 mL) and HO (6 mL) was stirred in a round-bottom flask at 80 °C under N2 for 2 h. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 20:1 gradient elution) to give the title product (820 mg, 98%). [M+H] + = 311.2.

[0301] Step 2: 2-Methoxy-4-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)aniline [ka] To a solution of 3-((4-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)methyl)pyridine (820 mg, 2.6 mmol) in MeOH (30 mL) under N was added 10% Pd / C (200 mg) at 25 °C. The mixture was then exchanged with H twice and stirred under H atmosphere at 25 °C overnight. The mixture was filtered through a pad of Celite and washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the product (735 mg, 99%). [M+H] + = 281.2.

[0302] Step 3:N 2 -(2-Methoxy-4-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was synthesized in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.37 (s, 1H), 9.07 (s, 1H), 8.56 (s, 1H), 8.52 (d, J = 3.4 Hz, 1H), 8.37 (d, J = 8.3 Hz, 1H), 8.29 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.93 (s, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.39 (s, 2H), 7.28 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H), 7.12 (dd, J = 15.4, 7.7 Hz, 2H), 6.99 (s, 1H), 6.23 (s, 1H), 5.40 (s, 2H), 4.10 (t, J = 7.5 Hz, 2H), 3.93 (s, 3H), 3.14 (t, J = 7.0 Hz, 2H), 3.09 (s, 3H);[M+H] + = 608.5.

[0303] Example 115:N 2 -(2-Methoxy-4-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine Step 1: 1-(2-(4-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-4-methylpiperazine [ka] A mixture of 4-chloro-2-methoxy-1-nitrobenzene (200 mg, 1.1 mmol), 1-methyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)piperazine (376 mg, 1.2 mmol), Pd(PPh) (123 mg, 0.11 mmol), and CsCO (523 mg, 1.6 mmol) in 1,4-dioxane (20 mL) and HO (4 mL) was stirred in a round-bottom flask at 80 °C under N for 2 h. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the title product (255 mg, 69%). [M+H] + = 346.2.

[0304] Step 2: 2-Methoxy-4-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)aniline [ka] To a solution of 1-(2-(4-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-4-methylpiperazine (255 mg, 0.74 mmol) in MeOH (20 mL) under N was added 10% Pd / C (50 mg) at 25 °C. The mixture was then exchanged with H twice and stirred under H atmosphere at 25 °C overnight. The mixture was filtered through a pad of Celite and washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the product (210 mg, 90%). [M+H] + = 316.2.

[0305] Step 3:N 2 -(2-Methoxy-4-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)-N 4-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was synthesized in a similar manner to Step 5 of Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.36 (s, 1H), 9.07 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.85 (s, 1H), 7.39 (s, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.18 (s, 1H), 7.14 (d, J = 7.3 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.99 (s, 1H), 6.23 (s, 1H), 4.21 (s, 2H), 4.10 (s, 2H), 3.93 (s, 3H), 3.14 (s, 2H), 3.09 (s, 3H), 2.74 (d, J = 6.7 Hz, 2H), 2.44 (s, 4H), 2.32 (s, 4H), 2.15 (s, 3H);[M+H] + = 643.5.

[0306] Example 123:N 2 -(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was synthesized in a similar manner to Example 001. 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.20 (s, 1H), 7.09 (s, 1H), 6.87 (s, 2H), 6.32 (s, 1H), 4.16 (s, 2H), 3.62 (s, 3H), 3.11 - 3.08 (m, 7H), 2.98 (s, 3H), 2.72 (s, 3H);[M+H] + = 520.6.

[0307] Example 124:N 2 -(4-(4-(dimethylamino)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (400 MHz, DMSO) δ H 11.20 (s, 1H), 8.95 (s, 1H), 8.26 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.12 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.88 (d, J = 2.2 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 6.16 (s, 1H), 4.49 (t, J = 8.7 Hz, 2H), 4.05 (t, J = 7.5 Hz, 2H), 3.15 - 3.03 (m, 9H), 2.71 - 2.54 (m, 9H), 1.99 (s, 2H), 1.66 (dd, J = 24.2, 13.1 Hz, 2H);[M+H] + = 589.3.

[0308] Example 125:N 2-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N 4 -(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (400 MHz, CD3OD) δ H 8.48 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.22 - 7.16 (m, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 3.6 Hz, 1H), 6.44 (d, J = 8.7 Hz, 1H), 6.31 (d, J = 3.6 Hz, 1H), 4.78 (s, 1H), 4.64 - 4.57 (m, 7H), 4.16 (t, J = 7.6 Hz, 2H), 3.41 (d, J = 13.0 Hz, 2H), 3.21 - 3.14 (m, [M+H] + = 644.3.

[0309] Example 134: 5-Bromo-N4-(2,2-dimethyl-1-(methylsulfonyl)indolin-7-yl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (500 MHz, DMSO) δ H8.82 (s, 1H), 8.13 (s, 1H), 7.86 (d, J = 13.2 Hz, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.15 (s, 2H), 6.59 (d, J = 2.2 Hz, 1H), 6.37 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H), 3.68 (d, J = 12.4 Hz, 2H), 3.02 - 2.98 (m, 5H), 2.64 (t, J = 11.3 Hz, 2H), 2.55 - 2.52 (m, 4H), 2.44 - 2.25 (m, 5H), 2.16 (s, 3H), 1.85 (d, J = 11.9 Hz, 2H), 1.56 - 1.47 (m, 2H), 1.41 (s, 6H). [M+H] + = 699.5.

[0310] Example 136: 5-Bromo-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1'-(methylsulfonyl)spiro[cyclopropane-1,2'-indoline]-7'-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 28. 1 H NMR (500 MHz, DMSO) δ H8.74 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 6.7 Hz, 2H), 6.60 (d, J = 2.4 Hz, 1H), 6.41 (dd, J = 8.8, 2.3 Hz, 1H), 4.94 (d, J = 6.5 Hz, 1H), 4.09 (s, 1H), 3.75 (s, 3H), 3.70 (d, J = 12.0 Hz, 2H), 2.83 (s, 3H), 2.65 (t, J = 11.2 Hz, 2H), 2.49 - 2.22 (m, 11H), 2.15 (s, 3H), 1.98 - 1.89 (m, 1H), 1.84 (d, J = 12.4 Hz, 2H), 1.62 (s, 1H), 1.51 (d, J = 8.6 Hz, 2H). [M+H] + = 697.5.

[0311] Example 142: 5-chloro-N2-(3,3-dimethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)-N4-(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 30. 1H NMR (500 MHz, DMSO) δ 8.96 (s, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.85 (s, 1H), 7.68 (s, 1H), 7.15 (d, J = 6.9 Hz, 2H), 6.58 (s, 1H), 4.13 (s, 2H), 4.07 (t, J = 7.2 Hz, 2H), 3.12 (t, J = 7.2 Hz, 2H), 3.06 (s, 3H), 2.94 (d, J = 10.8 Hz, 2H), 2.66 - 2.53 (m, 5H), 2.36 - 2.29 (m, 6H), 2.17 (s, 3H), 1.81 (d, J = 11.9 Hz, 2H), 1.47 (d, J = 11.4 Hz, 2H), 1.17 (s, 6H).

[0312] Example 143: 5-chloro-N2-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzofuran-7-yl)-N4-(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 30. 1H NMR (500 MHz, DMSO) δ 8.98 (s, 1H), 8.89 (s, 1H), 8.11 (s, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.51 (s, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 7.3 Hz, 1H), 6.96 (d, J = 2.2 Hz, 1H), 6.82 (s, 1H), 6.60 (d, J = 8.3 Hz, 1H), 4.01 (t, J = 7.4 Hz, 2H), 3.58 (d, J = 11.9 Hz, 2H), 3.12 - 2.93 (m, 6H), 2.70 (s, 2H), 2.54 (s, 3H), 2.43 - 2.24 (m, 5H), 2.17 (s, 3H), 1.89 (s, 2H), 1.73 - 1.62 (m, 2H).

[0313] Example 147: N2-(3-(difluoromethoxy)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 94. 1H NMR (500 MHz, MeOD) δ 8.29 (d, J = 8.2 Hz, 1H), 7.65 (s, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 7.3 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 3.5 Hz, 1H), 6.33 (d, J = 3.4 Hz, 1H), 4.17 (t, J = 7.5 Hz, 2H), 3.38 (d, J = 11.3 Hz, 2H), 3.16 (t, J = 7.5 Hz, 3H), 2.98 (s, 3H), 2.90 - 2.82 (s, 8H), 2.65 (t, J = 11.6 Hz, 3H), 2.49 (s, 3H), 2.01 (d, J = 12.4 Hz, 2H), 1.70 (d, J = 11.1 Hz, 2H).

[0314] Example 148: N2-(3-fluoro-5-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (500 MHz, DMSO) δ H11.30 (s, 1H), 9.04 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.59 (s, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 7.3 Hz, 1H), 6.98 - 6.93 (m, 1H), 6.69 (t, J = 9.0 Hz, 1H), 6.20 (d, J = 1.9 Hz, 1H), 4.09 (t, J = 7.4 Hz, 2H), 3.83 (s, 3H), 3.12 (t, J = 7.3 Hz, 2H), 3.09 (s, 3H), 2.91 - 2.55 (m, 10H), 2.48 - 2.36 (m, 6H), 1.87 (s, 2H), 1.61 (s, 2H). [M+H] + = 650.5.

[0315] Example 149: N2-(2-fluoro-5-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (500 MHz, DMSO) δ H11.26 (s, 1H), 8.97 (s, 1H), 8.31 (d, J = 7.5 Hz, 1H), 8.05 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.05 (s, 2H), 6.93 (d, J = 2.6 Hz, 1H), 6.76 (d, J = 12.5 Hz, 1H), 6.19 (s, 1H), 4.08 (s, 2H), 3.70 (s, 3H), 3.42 - 3.36 (m, 4H), 3.12 - 3.06 (m, 5H), 2.65 - 2.52 (m, 6H), 2.40 - 2.22 (m, 6H), 1.83 (s, 2H), 1.56 (d, J = 10.2 Hz, 2H). [M+H] + = 650.5.

[0316] Example 154: N2-(5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)-N4-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1H NMR (500 MHz, DMSO) δ 11.39 (s, 1H), 9.06 (s, 1H), 8.72 (t, J = 8.1 Hz, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.94 (s, 1H), 7.34 (d, J = 9.2 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H), 6.99 (s, 1H), 6.24 (s, 1H), 4.10 (t, J = 7.0 Hz, 2H), 3.63 (d, J = 11.6 Hz, 2H), 3.13 (t, J = 7.3 Hz, 2H), 3.09 (s, 3H), 2.63 (t, J = 11.7 Hz, 2H), 2.59 - 2.51 (m, 4H), 2.34 (dd, J = 33.8, 22.9 Hz, 5H), 2.20 (s, 3H), 1.86 (d, J = 11.7 Hz, 2H), 1.59 - 1.48 (m, 2H). [M+H] + =603.3.

[0317] Example 181: 5-bromo-N2-(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1'-(methylsulfonyl)spiro[cyclopropane-1,3'-indoline]-7'-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 28. 1H NMR (500 MHz, DMSO) δ 8.82 (s, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.42 (s, 1H), 7.12 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 7.3 Hz, 1H), 6.67 (s, 1H), 4.03 (s, 2H), 3.75 (s, 3H), 3.29 - 3.23 (m, 3H), 3.04 (d, J = 16.4 Hz, 5H), 2.65 - 2.53 (m, 4H), 2.41 - 2.25 (m, 4H), 2.17 (s, 3H), 2.06 (s, 3H), 1.84 (d, J = 11.7 Hz, 2H), 1.55 (q, J = 11.4 Hz, 2H), 1.25 (s, 2H), 1.06 (s, 2H). [M+H] + =711.2.

[0318] Example 182: N2-(7-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzo[d][1,3]dioxol-4-yl)-N4-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1H NMR (500 MHz, DMSO) δ 11.22 (s, 1H), 8.95 (s, 1H), 8.35 (d, J = 5.2 Hz, 2H), 7.94 (s, 1H), 7.09 (t, J = 7.7 Hz, 1H), 7.02 (dd, J = 13.4, 8.1 Hz, 2H), 6.90 (d, J = 2.3 Hz, 1H), 6.40 (d, J = 8.9 Hz, 1H), 6.18 (s, 1H), 5.90 (s, 2H), 4.08 (t, J = 7.4 Hz, 2H), 3.58 (d, J = 11.7 Hz, 2H), 3.35 - 3.30 (m, 3H), 3.13 - 3.05 (m, 5H), 2.61 (t, J = 11.5 Hz, 2H), 2.54 (s, 2H), 2.40 - 2.25 (m, 4H), 2.15 (s, 3H), 1.84 (d, J = 11.6 Hz, 2H), 1.52 (dd, J = 20.5, 11.6 Hz, 2H). [M+H] + =646.3.

[0319] Example 184: N2-(6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)-N4-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1H NMR (500 MHz, DMSO) δ 11.24 (s, 1H), 8.98 (s, 1H), 8.60 (s, 1H), 8.42 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.91 (dd, J = 9.1, 2.5 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 7.3 Hz, 1H), 6.93 - 6.87 (m, 1H), 6.77 (d, J = 9.1 Hz, 1H), 6.18 (d, J = 1.9 Hz, 1H), 4.19 (d, J = 12.9 Hz, 2H), 4.10 (t, J = 7.5 Hz, 2H), 3.24 - 3.19 (m, 2H), 3.12 (t, J = 7.4 Hz, 2H), 3.09 (s, 3H), 2.70 (t, J = 11.6 Hz, 2H), 2.53 (d, J = 15.7 Hz, 2H), 2.39 - 2.22 (m, 5H), 2.13 (s, 3H), 1.81 (d, J = 12.2 Hz, 2H), 1.46 - 1.33 (m, 2H). [M+H] + =603.3.

[0320] Example 185: 5-Bromo-N2-(4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-2,5-difluorophenyl)-N4-(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1H NMR (500 MHz, DMSO) δ 8.86 (s, 2H), 8.21 (s, 1H), 7.81 (d, J = 7.0 Hz, 1H), 7.39 (dd, J = 13.8, 7.6 Hz, 1H), 7.18 - 7.07 (m, 2H), 6.91 (dd, J = 12.3, 8.3 Hz, 1H), 4.04 (t, J = 7.3 Hz, 2H), 3.25 - 3.17 (m, 3H), 3.09 (t, J = 7.3 Hz, 2H), 3.05 (s, 3H), 2.62 (t, J = 11.3 Hz, 2H), 2.51 (s, 4H), 2.37 (d, J = 5.2 Hz, 2H), 2.29 (dd, J = 14.3, 7.1 Hz, 4H), 1.85 (d, J = 11.9 Hz, 2H), 1.54 (dd, J = 20.9, 11.5 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H). [M+H] + =691.3.

[0321] Example 186: 4-(1-(3-methoxy-4-((4-((1-(methylsulfonyl)indolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)-1-methylpiperazin-2-one [ka] The title compound was prepared in a similar manner to Example 77. 1H NMR (500 MHz, DMSO) δ 11.26 (s, 1H), 9.00 (s, 1H), 8.22 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.29 - 7.17 (m, 2H), 7.10 (d, J = 7.4 Hz, 1H), 6.94 - 6.88 (m, 1H), 6.63 (d, J = 2.3 Hz, 1H), 6.45 (dd, J = 8.8, 2.3 Hz, 1H), 6.19 (dd, J = 3.3, 1.9 Hz, 1H), 4.09 (t, J = 7.5 Hz, 2H), 3.82 (s, 3H), 3.65 (d, J = 12.1 Hz, 2H), 3.26 - 3.23 (m, 2H), 3.14 - 3.08 (m, 7H), 2.82 (s, 3H), 2.75 (t, J = 5.3 Hz, 2H), 2.63 (t, J = 11.1 Hz, 2H), 2.37 (t, J = 11.1 Hz, 1H), 1.88 (d, J = 11.1 Hz, 2H), 1.53 (dd, J = 20.3, 11.5 Hz, 2H). + =646.3.

[0322] Example 187: 5-chloro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1'-(methylsulfonyl)spiro[cyclopropane-1,3'-indoline]-7'-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 28. 1H NMR (500 MHz, DMSO) δ 8.95 (s, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 6.59 (d, J = 2.3 Hz, 1H), 6.39 (dd, J = 8.8, 2.2 Hz, 1H), 4.03 (s, 2H), 3.76 (s, 3H), 3.69 (d, J = 12.3 Hz, 2H), 3.32 - 3.25 (m, 3H), 3.03 (s, 3H), 2.64 (t, J = 11.4 Hz, 2H), 2.29 (dd, J = 14.9, 7.2 Hz, 6H), 2.14 (s, 3H), 1.84 (d, J = 11.6 Hz, 2H), 1.50 (td, J = 11.7, 8.7 Hz, 2H), 1.24 (t, J = 5.5 Hz, 2H), 1.06 (q, J = 4.5 Hz, 2H). + =653.3.

[0323] Example 188: 5-chloro-N2-(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1'-(methylsulfonyl)spiro[cyclopropane-1,3'-indoline]-7'-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 28. 1H NMR (500 MHz, DMSO) δ 8.97 (s, 1H), 8.12 (s, 1H), 7.88 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.46 (s, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.72 (d, J = 7.4 Hz, 1H), 6.67 (s, 1H), 4.03 (s, 2H), 3.76 (s, 3H), 3.38 - 3.30 (m, 2H), 3.04 (d, J = 15.6 Hz, 5H), 2.59 (dd, J = 23.3, 12.2 Hz, 5H), 2.34 (dd, J = 32.1, 20.8 Hz, 4H), 2.20 (s, 3H), 2.07 (s, 3H), 1.84 (d, J = 11.4 Hz, 2H), 1.56 (td, J = 11.5, 8.7 Hz, 2H), 1.25 (t, J = 5.4 Hz, 2H), 1.06 (q, J = 4.5 Hz, 2H). [M+H] + =667.3.

[0324] Example 189: N2-(2-methoxy-4-(4-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1H NMR (500 MHz, DMSO) δ 11.24 (s, 1H), 8.99 (s, 1H), 8.22 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.29 - 7.17 (m, 2H), 7.09 (d, J = 6.7 Hz, 1H), 6.92 (dd, J = 3.4, 2.3 Hz, 1H), 6.61 (d, J = 2.5 Hz, 1H), 6.44 (dd, J = 8.8, 2.5 Hz, 1H), 6.19 (dd, J = 3.4, 1.9 Hz, 1H), 4.09 (t, J = 7.5 Hz, 2H), 3.82 (s, 3H), 3.64 (d, J = 11.8 Hz, 2H), 3.12 (t, J = 7.4 Hz, 2H), 3.09 (s, 3H), 2.76 - 2.72 (m, 2H), 2.63 (t, J = 11.0 Hz, 2H), 2.56 - 2.52 (m, 2H), 2.30 (dt, J = 18.0, 11.7 Hz, 3H), 2.18 (s, 3H), 1.86 (d, J = 11.3 Hz, 2H), 1.58 - 1.46 (m, 2H), 0.57 (t, J = 5.2 Hz, 2H), 0.32 (q, J = 4.6 Hz, 2H). [M+H] + =658.3.

[0325] Example 190: N2-(4-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)-N4-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1H NMR (500 MHz, DMSO) δ 11.18 (s, 1H), 8.93 (s, 1H), 8.26 (d, J = 9.2 Hz, 2H), 7.39 (s, 1H), 7.11 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.91 - 6.77 (m, 1H), 6.44 (s, 1H), 6.23 - 6.08 (m, 1H), 4.31 (d, J = 13.0 Hz, 2H), 4.09 (d, J = 7.4 Hz, 2H), 3.80 (s, 3H), 3.17 (d, J = 4.0 Hz, 1H), 3.12 - 3.07 (m, 5H), 2.76 (t, J = 11.7 Hz, 2H), 2.37 (dd, J = 25.4, 14.1 Hz, 8H), 2.15 (s, 3H), 1.82 (d, J = 11.7 Hz, 2H), 1.39 (dd, J = 20.5, 11.9 Hz, 2H). [M+H] + =633.3.

[0326] Example 191: 1-(1-(3-methoxy-4-((4-((1-(methylsulfonyl)indolin-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)-4-methylpiperazin-2-one [ka] The title compound was prepared in a similar manner to Example 77. 1H NMR (500 MHz, DMSO) δ 11.26 (s, 1H), 9.00 (s, 1H), 8.22 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.10 (d, J = 7.3 Hz, 1H), 6.92 (dd, J = 3.4, 2.3 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 6.47 (dd, J = 8.8, 2.4 Hz, 1H), 6.19 (dd, J = 3.4, 1.9 Hz, 1H), 4.37 (t, J = 12.1 Hz, 1H), 4.09 (t, J = 7.5 Hz, 2H), 3.83 (s, 3H), 3.71 (d, J = 12.2 Hz, 2H), 3.24 (d, J = 5.3 Hz, 2H), 3.12 (t, J = 7.4 Hz, 2H), 3.09 (s, 3H), 2.95 (s, 2H), 2.70 (t, J = 11.3 Hz, 2H), 2.59 - 2.55 (m, 2H), 2.20 (s, 3H), 1.85 (dt, J = 12.1, 8.5 Hz, 2H), 1.59 (d, J = 11.3 Hz, 2H). [M+H] + =646.3.

[0327] Example 192: 5-bromo-N2-(2-methoxy-4-(4-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a manner similar to Example 30. 1H NMR (500 MHz, DMSO) δ 8.77 (s, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.83 (s, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.17 - 7.12 (m, 2H), 6.58 (d, J = 2.3 Hz, 1H), 6.39 (dd, J = 8.7, 2.2 Hz, 1H), 4.04 (t, J = 7.4 Hz, 2H), 3.75 (s, 3H), 3.68 (d, J = 12.3 Hz, 2H), 3.09 (t, J = 7.3 Hz, 2H), 3.05 (d, J = 7.8 Hz, 3H), 2.79 - 2.72 (m, 2H), 2.66 (t, J = 11.3 Hz, 2H), 2.57 - 2.53 (m, 2H), 2.41 - 2.27 (m, 3H), 2.19 (s, 3H), 1.86 (d, J = 11.7 Hz, 2H), 1.56 - 1.44 (m, 2H), 0.58 (t, J = 5.1 Hz, 2H), 0.32 (t, J = 5.2 Hz, 2H). [M+H] + =697.2

[0328] Example 193: 5-Bromo-N2-(8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-N4-(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 51. 1H NMR (500 MHz, MeOD) δ 8.30 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.37 - 7.26 (m, 2H), 7.08 (d, J = 9.0 Hz, 1H), 4.46 (s, 2H), 4.41 (s, 2H), 4.09 (t, J = 7.5 Hz, 2H), 4.01 - 3.44 (m, 13H), 3.21 (t, J = 7.5 Hz, 2H), 3.05 (s, 3H), 2.97 (s, 3H), 2.54 (d, J = 9.5 Hz, 2H), 2.43 (d, J = 11.4 Hz, 2H). [M+H] + =699.2.

[0329] Example 194: N2-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl)indolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 77. 1 H NMR (500 MHz, DMSO) δ H11.22 (s, 1H), 8.97 (s, 1H), 8.60 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 9.0 Hz, 2H), 7.26 - 7.20 (m, 1H), 7.10 (d, J = 7.3 Hz, 1H), 6.91 (dd, J = 3.4, 2.3 Hz, 1H), 6.83 (d, J = 9.1 Hz, 2H), 6.18 (dd, J = 3.4, 1.9 Hz, 1H), 4.10 (t, J = 7.4 Hz, 2H), 3.58 (d, J = 12.3 Hz, 2H), 3.13 (t, J = 7.4 Hz, 2H), 3.09 (s, 3H), 2.64 - 2.51 (m, 6H), 2.41 - 2.23 (m, 5H), 2.16 (s, 3H), 1.84 (d, J = 11.6 Hz, 2H), 1.52 (dd, J = 11.9, 3.4Hz, 2H). [M+H] + = 602.5.

[0330] Example 195: N2-(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl)indolin-7-yl)-5-(prop-1-yn-1-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 28. 1 H NMR (500 MHz, DMSO) δ H9.02 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 7.91 (s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.12 (dd, J = 14.2, 7.4 Hz, 2H), 6.60 (s, 1H), 6.42 (d, J = 6.8 Hz, 1H), 4.05 (t, J = 7.3 Hz, 2H), 3.76 (s, 3H), 3.69 (d, J = 12.2 Hz, 2H), 3.09 (t, J = 7.2 Hz, 2H), 3.05 (s, 3H), 2.64 (t, J = 11.3 Hz, 2H), 2.49 - 2.42 (m, 4H), 2.38 - 2.24 (m, 5H), 2.14 (s, 3H), 2.08 (s, 3H), 1.84 (d, J = 11.3 Hz, 2H), 1.51 (d, J = 8.8 Hz, 2H). [M+H] + = 631.5.

[0331] Example 196: 5-ethynyl-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine [ka] The title compound was prepared in a similar manner to Example 28. 1 H NMR (500 MHz, DMSO) δ H8.88 (s, 1H), 8.16 (s, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.12 (s, 2H), 6.60 (s, 1H), 6.41 (d, J = 8.6 Hz, 1H), 4.51 (s, 1H), 4.04 (s, 2H), 3.76 (s, 3H), 3.70 (d, J = 11.2 Hz, 2H), 3.44 (d, J = 6.0 Hz, 1H), 3.09 (s, 2H), 3.03 (s, 3H), 2.70 - 2.55 (m, 5H), 2.45 - 2.28 (m, 5H), 2.18 (s, 3H), 1.85 (d, J = 10.7 Hz, 2H), 1.51 (d, J = 10.8 Hz, 2H). [M+H] + = 617.5.

[0332] Example 194: 5-Bromo-N2-(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4,6-triamine [ka] The title compound was prepared in a similar manner to Example 28. 1 H NMR (500 MHz, DMSO) δ H8.54 (s, 1H), 8.18 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.71 (s, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 7.5 Hz, 2H), 6.65 (s, 1H), 6.47 (s, 2H), 4.05 (t, J = 7.3 Hz, 2H), 3.78 (s, 3H), 3.11 (d, J = 6.9 Hz, 2H), 3.06 - 3.00 (m, 6H), 2.62 - 2.55 (m, 3H), 2.40 - 2.26 (m, 7H), 2.16 (s, 3H), 2.06 (d, J = 6.7 Hz, 3H), 1.83 (d, J = 11.5 Hz, 2H), 1.54 (d, J = 8.8 Hz, 2H). [M+H] + = 700.5.

[0333] Biochemical EGFR inhibition assay Compounds were tested for inhibition of kinase activity against EGFR (aa 668-1210, Invitrogen), EGFR (L858R_T790M_C797S) (aa 695-end, Invitrogen), and EGFR (Del19_T790M_C797S) (aa 669-1210, in-house) in an assay based on time-resolved fluorescence resonance energy transfer (TR-FRET) methodology. Recombinant EGFR, EGFR (L858R_T790M_C797S), or EGFR (Del19_T790M_C797S) were preincubated with compounds for 15 min at room temperature in assay buffer containing 50 mM HEPES pH 7.5, 10 mM MgCl, 2 mM DTT, 1 mM EGTA, 0.1% BSA, and 0.01% Tween-20. The reaction was initiated by adding ATP (at a concentration of ATP Km) and the substrate biotin-polyGT. After 60 minutes at room temperature, the stop / detection solution was added. The stop / detection solution contained Eu in a buffer containing 50 mM HEPES pH 7.0, 800 mM KF, 20 mM EDTA, and 0.1% BSA. 3+The plates contained a cryptate-conjugated mouse monoclonal antibody (PT66) anti-phosphotyrosine and XL665-conjugated streptavidin. The plates were sealed and incubated at room temperature for 1 hour, and the TR-FRET signal (the ratio of fluorescence emission at 665 nm to emission at 620 nm upon excitation at 337 nm wavelength) was recorded using a PHERAstar FS plate reader (BMG Labtech). Residual enzyme activity in the presence of increasing concentrations of compound was calculated based on the ratio of fluorescence at 665 nm to 620 nm. The IC50 for each compound was derived by fitting the data to a four-parameter logistic equation using Dotmatics or Graphpad Prism software.

[0334] These biochemical EGFR enzyme-form compound dose-response assays quantitate kinase activity via phosphorylation of a tagged poly-GT substrate. Assay results are presented as IC50 values. The lower the IC50 value reported for a particular compound, the more potently that compound inhibits the kinase activity of the EGFR enzyme toward the poly-GT substrate. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0335] cell therapy BaF3 cells were seeded at 5,000 cells / well in 90 μl / well of cell culture medium (BaF3-WT cells require one wash with PBS to rinse off IL-3) [RPMI 1640 (Gibco, Catalog No. 2240089), 10% heat-inactivated FBS (Gibco, Catalog No. 10099-141), 1% PS (Gibco, Catalog No. 10378)] in Corning 96-well plates (Cat. No. 3903). BaF3 cells were treated with compounds diluted in 0.2% DMSO according to the following protocol: (1) 5x dilutions were made from 5 mM to create a 500x stock solution in DMSO, resulting in a total of 8 doses; (2) 2 μl of the 500x stock solution was transferred to 98 μl of medium to create a 10x solution in cell culture medium; (3) 10 μl of the 10x solution was added to the cells and incubated for 48 hours.

[0336] Cell antiproliferation assay After 48 hours of treatment, 30 μl of CellTiter-Glo reagent (CellTiter-Glo® 2.0, (Promega, Cat. No. G9242)) was added to each well, the plate was sealed, and incubated on a plate shaker at room temperature for 2 minutes. The plate was then incubated at room temperature for 10 minutes to stabilize the luminescence signal. Luminescence was recorded on a BMG PheraStar using the luminescence protocol.

[0337] The percentage of inhibition of the compound was calculated by the following formula: Percentage of inhibition of compound = 100 - 100 x (signal - low control) / (high control - low control), where signal = each test compound group. Low control = medium group only (no cells), showing complete inhibition of cell proliferation; High control = cell group with DMSO but no compound, showing uninhibited cell growth; Imax is the maximum percentage of inhibition.

[0338] Compound IC 50 The value can be obtained by fitting the following formula Y = bottom + (top - bottom) / (1 + ((IC 50 / X)^slope)) where X and Y are known values ​​and IC 50 , slope, top, and bottom are parameters obtained by fitting with the software. Y is the inhibition rate (calculated from the formula), X is the compound concentration, and IC 50 is the concentration of the compound at which 50% inhibition is reached. 50 The smaller the value, the stronger the inhibitory ability of the compound. 50 The higher the value, the weaker the inhibitory ability of the compound. The slope represents the gradient of the fitted curve, which is generally about 1*. The bottom represents the minimum value of the curve obtained by data fitting, which is generally 0% ± 20%. The top represents the maximum value of the curve obtained by data fitting, which is generally 100% ± 20%. The experimental data were fitted by calculation and analysis using Dotmatics data analysis software. [Table 6-1] [Table 6-2]

[0339] The foregoing examples and descriptions of specific embodiments should be construed as illustrative rather than limiting of the invention as defined by the claims. As will be readily appreciated, numerous variations and combinations of the features described above can be utilized without departing from the invention as set forth in the claims. All such variations are intended to be within the scope of the present invention. All cited references are incorporated herein by reference in their entirety.

[0340] Where any prior art publication is referred to herein, it is to be understood that such reference does not constitute an admission that the publication forms part of the common general knowledge in the art in any country.

Claims

1. A compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: X １ But NR ４ or O, 【Chemistry 9】 wherein * indicates the position of attachment to the —N(R 7 )— moiety and ** indicates the position of attachment to R 8 ; R １ But -S(O) ２ R １ａ or —C(O)R1a , R1a is -C １－８ Alkyl, cycloalkyl or -NR １ｄ R1e, and the -C １－８ Each of the alkyl or said cycloalkyl may optionally contain at least one substituent R １ｆ is replaced by R １ｄ and R １ｅ are each independently hydrogen, —C １－８ Alkyl, -haloC １－８ alkyl or cycloalkyl; R １ｆ each occurrence independently represents a halogen, -C １－８ Alkyl, -haloC １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl; R 3a , R 3b and R 3c are each —H, —F, —Cl, —Br, —I, hydroxyl, amino, —CH 3 , —C 2 H 5 , —C 3 H 7 , —C 4 H 9 , —C 5 H 11 , —C 6 H 13 , —C 7 H 15 , —C 8 H 17 , phenyl, —CN, —OCH 3 , —OC 2 H 5 , —OC 3 H 7 , —OC 4 H 9 , —OC 5 H 11 , —OC 6 H 13 , —OC 7 H 15 , —OC 8 H 17 , —COCH 3 , —COC 2 H 5 , —COC 3 H 7 , -COC4H9, -COC5H11, -COC6H13, -COC7H15, -COC8H17, -CO2CH3, -CO2C2H5, -CO2C3H7, -CO2C4 H 9 , -CO 2 C 5 H 11 , -CO 2 C 6 H 13 , -CO 2 C 7 H 15 or -CO 2 C 8 H 17 , R2 is hydrogen, halogen or -C １－８ alkyl, and —C １－８ Each alkyl may optionally contain at least one substituent R ２ｃ is replaced by, or If m≧2, two geminal R ２ together with the atoms to which they are attached form a 3- to 12-membered spiro ring, or two R ２ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing at least one substituent R ２ｃ is replaced by R ２ｃ each occurrence independently represents a halogen, an amino, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -OR ２ｄ , -COR ２ｄ , -CO ２ R ２ｄ , -CONR ２ｄ R ２ｅ , -NR ２ｄ R ２ｅ , -NR ２ｄ COR ２ｅ , or -NR ２ｄ CO ２ R ２ｅ and R ２ｄ and R ２ｅ are each independently hydrogen, —C １－８ Alkyl, -haloC １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ４ and R ７ are each independently hydrogen; R 5 and R 6 are independently hydrogen, —F, —Cl, —Br, —I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, —CN, —OR 5a , or —NR 5a R 5b , wherein each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, or said cyclooctyl is optionally substituted with at least one substituent R 5c ; R 5a and R 5b are each independently hydrogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, C 1-8 alkoxy-C 1-8 alkyl-, or —C 3-6 cycloalkyl, each of said —C 1-8 alkyl, said —C 2-8 alkenyl, said —C 2-8 alkynyl, said C 1-8 alkoxy-C 1-8 alkyl-, or said —C 3-6 cycloalkyl optionally substituted with at least one substituent R 5c ; R 5c at each occurrence is independently -F, -Cl, -Br, -I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; or R 5 and R 6 together with the atom(s) to which they are attached form a 4-, 5-, 6-, or 7-membered ring, said ring containing, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, said ring being optionally substituted with at least one substituent R 56 ; R 56 is -F, -Cl, -Br, -I, -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C 5 H 11 , -C 6 H 13 , -C 7 H 15 , -C 8 H 17 , -C 2-8 alkenyl, -C 2-8 alkynyl, -CN, -OR 56a , -COR 56a , or -CO 2 R 56a , and -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C 5 H 11 , -C 6 H 13 , -C 7 H 15 , the above-C 8 H 17 , each of said —C 2-8 alkenyl, or said —C 2-8 alkynyl is optionally substituted with at least one halogen; R56a is hydrogen, —C １－８ Alkyl, -haloC １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, C １－８ Alkoxy-C １－８ alkyl-, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ８ but, 【Chemistry 2】 and R 9 , R 10 , R 11 , and R 12 are each independently hydrogen, halogen, —C 1-8 alkyl, —C 2-8 alkenyl, 3- to 8-membered heterocyclyl, —CN, or —OR 9d , wherein each of said —C 1-8 alkyl, said —C 2-8 alkenyl, or said 3- to 8-membered heterocyclyl is optionally substituted with at least one substituent R 9f ; or (R 9 and R 11 ) or (R 10 and R 12 ) together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, said ring being optionally substituted with at least one substituent R 9f ; R 9d and R 9e are each independently —H, —CH 3 , —C 2 H 5 , —C 3 H 7 , —C 4 H 9 , —C 5 H 11 , —C 6 H 13 , —C 7 H 15 , or —C 8 H 17 ; or R 9d and R 9e together with the atom(s) to which they are attached form a 3- to 12-membered ring, said ring containing, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, said ring being optionally substituted with at least one substituent R 9f ; R 9f at each occurrence is independently halogen, hydroxyl, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, —C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, —C 6-12 aryl, 5- to 8-membered heteroaryl, oxo (═O), —CN, —OR 9g , —COR 9g , —CO 2 R 9g , —CONR 9g R 9h , —NR 9g R 9h , —NR 9g COR 9h , or —NR 9g CO 2 R 9h ; R 9g and R 9h are each independently —H, —F, —Cl, —Br, —I, —CH 3 , —C 2 H 5 , —C 3 H 7 , —C 4 H 9 , —C 5 H 11 , —C 6 H 13 , —C 7 H 15 , —C 8 H 17 , or —OH; n is 0, 1, 2, or 3; The compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein m is 0, 1, 2, 3, or 4.

2. R １ But -S(O) ２ R １ａ or —C(O)R1a , R1a is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -NR １ｄ R1e, wherein each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl or said cyclooctyl optionally contains at least one substituent R １ｆ is replaced by R １ｄ and R １ｅ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; R １ｆ is independently at each occurrence -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, azacyclopropanyl, azacyclobutanyl, or phenyl; The compound of claim 1.

3. R １ But -S(O) ２ R １ａ or —C(O)R1a , R １ａ But -CH ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -cyclopropyl, 【Transformation 5】 -CH ２ F, -CHF ２ , -CF ３ , -N(CH ３ ) ２ , -NHCH ３ , -CH ２ N (CH ３ ) ２ , -CH ２ CH ２ N (CH ３ ) ２ , or -CH ２ CH ２ CH ２ N (CH ３ ) ２ 2. The compound of claim 1, wherein:

4. R ２ is hydrogen, —F, —Cl, —Br, —I, —CH ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -C ６ H １３ , -C ７ H １５ , -C ８ H １７ , -CH ２ OH, -CH ２ CH ２ OH or -CH ２ CH ２ CH ２ OH, or If m≧2, two geminal R ２ together with the atoms to which they are attached form a 3-, 4-, 5-, or 6-membered spiro ring, said ring containing, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur.

5. R ２ is hydrogen, F, Cl, Br, I, -CH ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -CH ２ OH, -CH ２ CH ２ OH or -CH ２ CH ２ CH ２ OH, or If m≧2, two geminal R ２ 10. The compound of claim 1, wherein together with the atom to which they are attached form a spirocyclopropyl or spirocyclobutyl. 【Request Item 6】 【Transformation 6】 2. The compound of claim 1, wherein:

7. R ５ and R ６ are independently —H, —F, —Cl, —Br, —I, or —CH ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , 【Transformation 7】 -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , -OC ４ H ９ , -OC ５ H １１ , -CH ２ F, -CHF ２ , -CF ３ , -CN, -NH ２ , -NHCH ３ , -NHC ２ H ５ , or -N(CH ３ ) ２ 2. The compound of claim 1, wherein: 【Request Item 8】 【Transformation 8】 2. The compound of claim 1, wherein:

9. R ９ , R １０ , R １１ , and R １２ are each independently —H, —F, —Cl, —Br, —I, or —CH ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -C ６ H １３ , -C ７ H １５ , -C ８ H １７ , -CN, -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , -OC ４ H ９ , -OC ５ H １１ , -OC ６ H １３ , -OC ７ H １５ , or -OC ８ H １７ or (R ９ and R １１ ), or (R １０ and R １２ ), together with the atom(s) to which they are attached, form a 5-, 6-, or 7-membered ring, said ring containing 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen or oxygen, and said ring optionally containing at least one substituent R ９ｆ is replaced by R ９ｆ each occurrence independently represents —F, —Cl, —Br, —I, —CH ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -C ６ H １３ , -C ７ H １５ , -C ８ H １７ , -CN, -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , -OC ４ H ９ , -OC ５ H １１ , -OC ６ H １３ , -OC ７ H １５ , or -OC ８ H １７ or Two R's ９ｆ together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing, as ring member(s), 0, 1, or 2 additional heteroatom(s) independently selected from the group consisting of nitrogen, oxygen, or optionally oxidized sulfur, and said ring optionally containing at least one of -F, -Cl, -Br, -I, -CH ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -C ６ H １３ , -C ７ H １５ , -C ８ H １７ , -CN, -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , -OC ４ H ９ , -OC ５ H １１ , -OC ６ H １３ , -OC ７ H １５ , or -OC ８ H １７ 2. The compound of claim 1 , substituted with: 【Request Item 10】 【Chemistry 10】 and In the formula, * is -N(R ７ )-moiety, and ** indicates the position where the R ８ The compound of claim 1, wherein the compound is linked to

11. A compound, wherein the compound is: 【Chemistry 12-1】 【Chemistry 12-2】 【Chemistry 12-3】 【Chemistry 12-4】 【Chemistry 12-5】 【Chemistry 12-6】 【Chemistry 12-7】 【Chemistry 12-8】 【Chemistry 12-9】 【Chemistry 12-10】 【Chemistry 12-11】

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, together with a pharmaceutically acceptable excipient.

13. A composition for use in a method for treating cancer, comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

14. The composition of claim 13 for use in a method for treating pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

15. 12. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in the preparation of a medicament for treating a disease that can be affected by EGFR modulation, wherein the disease is cancer.

16. Use of claim 15 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof in the preparation of a medicament for treating a disease that can be affected by EGFR modulation, wherein the disease is pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

Images