WO2016029839A1

WO2016029839A1 - (substituted phenyl) (substituted pyrimidine) amino derivative, preparation method therefor, and medication use

Info

Publication number: WO2016029839A1
Application number: PCT/CN2015/088015
Authority: WO
Inventors: 魏用刚; 李瑶; 张国彪; 邱关鹏; 胡仕红; 陈雷; 李升�; 张黔
Original assignee: 四川海思科制药有限公司
Priority date: 2014-08-25
Filing date: 2015-08-25
Publication date: 2016-03-03
Also published as: CN113121575A; CN106458969A

Abstract

Provided are a (substituted phenyl) (substituted pyrimidine) amino derivative as described in formula (I), an optical isomer, pharmaceutically acceptable salt or eutectic product thereof, preparation method therefor, and use thereof in preparing tumor medications. The compound of formula is (I).

Description

(Substituted phenyl) (substituted pyrimidine) amino derivative, preparation method thereof and medicament use thereof

Technical field

The present invention relates to a (substituted phenyl) (substituted pyrimidine) amino derivative of the formula (I), and optical isomers, pharmaceutically acceptable salts or cocrystals thereof, and a process for the preparation thereof Use in the preparation of oncology drugs.

Background technique

With the advent of the industrial age, environmental pollution and lifestyle changes have led to an increase in the incidence of cancer. At present, cancer has become a major killer threatening human health. According to the International Agency for Research on Cancer (IARC), the number of new cancer cases worldwide was 12.66 million, and the number of deaths was 7.56 million, accounting for 13% of all deaths. In the next few decades, the number of cancers will continue to grow rapidly. It is estimated that there will be 21.36 million new cases of cancer in the world in 2030, and the number of deaths will reach 13.15 million. The market demand for cancer treatment will continue to grow rapidly.

The receptor tyrosine kinase superfamily in cell surface receptors plays an important role in the regulation of cellular signaling by extracellular growth factors. The receptor tyrosine kinase is capable of catalyzing the transfer of a phosphate group from ATP to the tyrosine group of the substrate. When there is no ligand-activated receptor tyrosine kinase, these kinases are in an unphosphorylated monomer state, and their kinase domain is in an inactive structure. When the ligand binds to the extracellular domain of the receptor tyrosine kinase, the receptor undergoes oligomerization, and autophosphorylation increases the catalytic activity of the kinase and forms a binding site for the signaling protein, and the signal protein binds thereto. Thereby a plurality of signal paths are activated. These signaling pathways are linked to each other to regulate cell proliferation, survival, differentiation, function, migration and apoptosis. When the receptor tyrosine kinase is deregulated and abnormally activated, the cells will transform into tumor cells, which have enhanced proliferation, growth and drug resistance, and have strong angiogenic, invasive and metastatic ability (Yarden and Sliwkowski, 2001, Nat Rev Mol Cell Biol, 2, 127-137).

The ErbB family belongs to the receptor tyrosine kinase and contains four members: epidermal growth factor receptor (EGFR/HER1/ErbB1), HER2 (neu/ErbB2), HER3 (ErbB3), and HER4 (ErbB4) (Olayioye, Neve et al. 2000, EMBO J, 19, 3159-3167; Yarden and Sliwkowski, 2001, Nat Rev Mol Cell Biol, 2, 127-137). They all contain an extracellular ligand binding domain, a single transmembrane domain, and an intracellular tyrosine kinase and regulatory domain. Its function is to catalyze the transfer of the phosphate group of ATP to the tyrosine group of the substrate protein. Ligand-dependent receptor oligomerization results in autophosphorylation of the regulatory domain of the receptor, resulting in intracellular signal transduction, which ultimately leads to cell proliferation. This signaling pathway is closely related to the occurrence and development of tumors. In a variety of tumors, hyperactivated ErbB receptors, particularly EGFR, cause loss of regulation of growth factor signaling. Activation of EGFR is usually due to continuous activation or self-division of ligands due to overexpression or mutation Secret expression. Overexpression or mutation of EGFR can be detected in various cancers such as head and neck cancer, ovarian cancer, bladder cancer, cervical cancer, esophageal cancer, gastric cancer, breast cancer, endometrial cancer, colon cancer, lung cancer and brain tumor, usually indicating This is a poor prognosis. Therefore, inhibition of EGFR is a highly anticipated anti-tumor strategy. Many small molecule inhibitors targeting EGFR have been developed, some of which have been used in clinical treatment.

The first generation of EGFR kinase inhibitors such as gefitinib and erlotinib are clinically effective in the treatment of non-small cell lung cancer, especially those with activating mutations in the EGFR kinase domain (Mok, Wu et al. 2009, N Engl J Med, 361, 947-957; Rosell, Moran et al, 2009, N Engl J Med, 361, 958-967). The most common EGFR activating mutations are L858R and delE746_A750, which increase the affinity of the receptor for gefitinib and erlotinib compared to wild-type EGFR, while reducing the affinity of the receptor for ATP (Carey, Garton et al. , 2006, Cancer Res, 66, 8163-8171; Yun, Boggon et al, 2007, Cancer Cell, 11, 217-227). However, clinically, the use of gefitinib and erlotinib was eventually limited due to the emergence of acquired resistance. More than 50% of lung cancer patients develop acquired resistance, and more than 90% of them contain T790M gatekeeper mutations in EGFR (Kobayashi, Boggon et al., 2005, N Engl J Med, 352, 786-792; Pao, Miller et al., 2005). , PLoS Med, 2, e73). The T790M mutation does not block the binding of the drug from a spatial conformation, but restores the receptor's affinity for ATP, comparable to wild type (Yun, Mengwasser et al, 2008, Proc Natl Acad Sci U S A, 105, 2070-2075).

The second generation of EGFR kinase inhibitors generally have a quinoline structure and are irreversible EGFR inhibitors. Unlike gefitinib, they contain an electrophilic ability to undergo a Michael addition reaction with a conserved cysteine group (Cys 797) in EGFR. The covalent nature of these compounds gives them a stronger ability to occupy ATP sites than reversible inhibitors, so even though the T790M mutation can increase the affinity of ATP, such inhibitors are sufficient to inhibit in preclinical models. EGFR T790M (Engelman, Zejnullahu et al, 2007, Cancer Res, 67, 11924-11932; Li, Ambrogio et al, 2008, Oncogene, 27, 4702-4711). However, existing irreversible inhibitors have a lower ability to inhibit EGFR T790M mutations in cell line models than to inhibit EGFR-only activating mutations, and at clinically available concentrations, such compounds are unable to inhibit EGFR in vitro. T790M (Yuza, Glatt et al, 2007, Cancer Biol Ther, 6, 661-667; Godin-Heymann, Ulkus et al, 2008, Mol Cancer Ther, 7, 874-879). Since the affinity of EGFR T790M for ATP is similar to that of wild-type EGFR for ATP, quinazoline EGFR inhibitors also inhibit wild-type EGFR while inhibiting EGFR T790M. Clinically, simultaneous inhibition of wild-type EGFR can lead to rash and diarrhea in patients, which limits the dose of second-generation EGFR inhibitors, so that the plasma concentration of the drug is not sufficient to inhibit T790M, making the clinical effectiveness of such drugs Subject to greater restrictions. For example, CI-1033, HKI-272, and PF00299804 are clinically very limited in the treatment of gefitinib and erlotinib-resistant non-small cell lung cancer, and dose-dependent diarrhea and rash occur. (Janne, von Pawel et al, 2007, J Clin Oncol, 25, 3936-3944; Advani, Coiffier et al, 2010, J Clin Oncol, 28, 2085-2093).

In order to be able to specifically target EGFR T790M, a third-generation EGFR mutation selective inhibitor was introduced. Such irreversible inhibitors have higher selectivity for EGFR T790M than the second-generation quinoline compounds, and may have higher activity and better tolerance in clinic. For example, the covalent pyrimidine EGFR inhibitor WZ4002, in vitro, is 30-100 fold more selective for EGFR T790M than the quinoline compound, and 100 times less resistant to wild-type EGFR. It also exhibited good pharmacodynamics in the EGFR T790M-derived animal lung cancer model (Zhou, Ercan et al, 2009, Nature, 462, 1070-1074). Another mutant selective inhibitor, co-1686, is 10-25 fold more selective for EGFR T790M than wild-type EGFR in vitro. It can selectively inhibit EGFR mutations, including the resistant mutant T790M and activating mutations (L858R, del19), but not the wild-type EGFR. In vitro, oral co-1686 can cause tumor regression in the T790M mutation and does not mediate further drug-resistant mutations in tumor cells (Walter, Sjin et al, 2013, Cancer Discov, 3, 1404-1415). In order to meet clinical needs, it is necessary to continue to develop EGFR inhibitors that do not produce significant toxic side effects at concentrations that are effective in overcoming T790M mutations.

A number of literatures have reported on protein kinase inhibitors and their use against tumors. Such as:

WO2009051822 discloses pyrimidine derivatives which are useful as EGFR inhibitors and their use in the treatment of cancer. Wherein A and B are selected from carbocyclic or heterocyclic rings, and the structure is as follows:

WO2011140338 describes heterocyclic derivatives which are useful as EGFR inhibitors, and as antitumor drugs. Wherein B is selected from 6 to 10 members of a monoaryl or diheteroaryl group containing at least one N atom, X1 is selected from O, S or N, and R ²⁹ , R ^29a and R29b are each independently selected from H, 5 to 6 A non-heteroaryl group, a 5 to 6 membered non-heteroarylmethylene group or a 5 to 6 membered non-heteroarylcarbonyl group, the structure is as follows:

WO2011090760, WO2009158571 describe pyrimidine derivatives which are useful as protein kinase inhibitors, and as a medicament for the treatment of various diseases, wherein A and B are each independently selected from a heterocyclic ring or a carbocyclic ring, and the structure is as follows:

WO2013014448 discloses pyrimidine derivatives which are useful as EGFR inhibitors and their use in the treatment of cancer. Wherein G is selected from the group consisting of 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin-3-yl, lH-indol-3-yl, 1-methyl-lH-indole-3 -yl or pyrazolo[l,5-a]pyridin-3-yl, R3 is N-dimethylaminoethyl-N-methylamino, etc., and the structure is as follows:

It is an object of the present invention to provide an EGFR inhibitor which is effective, well tolerated, highly selective or has low toxic side effects, and its use in the preparation of a medicament for treating cancer. The cancer includes head and neck cancer, ovarian cancer, bladder cancer, cervical cancer, esophageal cancer, gastric cancer, breast cancer, endometrial cancer, colon cancer, lung cancer, brain tumor, non-small cell lung cancer, pancreatic cancer, solid tumor, colorectal Tumor or malignant glioma.

Summary of the invention

The present invention relates to a compound of the formula (I) and an optical isomer, a pharmaceutically acceptable salt or a eutectic thereof, wherein:

B is selected from a 6 to 15 membered heterocyclic ring containing 1 to 4 hetero atoms selected from N, O, S or P;

R ^{1 is} independently selected from the group consisting of F, Cl, Br, I, hydroxy, cyano, C _1-10 alkyl, C _1-10 alkoxy, -NR ^1a R ^1b , -C(=O)C _{1- 10} alkyl, -S(=O) ₂ -C _1-10 alkyl, -C(=O)-3 to 15 membered heterocyclic ring, -C(=O)-C _3-15 carbocyclic ring, -(CH ₂ ) _n -3 to 15 membered heterocyclic ring, -(CH ₂ ) _n -C _3-15 carbocyclic ring, -O-(CH ₂ ) _n -C _3-15 carbocyclic ring, -O-(CH ₂ ) _n - 3- to 15-membered heterocyclic ring, -O-(CH ₂ ) _n -C(=O)C _1-6 alkyl, -O-(CH ₂ ) _n -OC(=O)C _1-6 alkyl or- O-(CH ₂ ) _n -OC _1-10 alkyl, said CH ₂ , alkyl, alkoxy, carbocyclic or heterocyclic ring optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I , =O, hydroxy, amino, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _n -OH, -(CH ₂ ) _n -F, -C( =O)C _1-6 alkyl, -OC(=O)C _1-6 alkyl, -C(=O)C _1-6 alkoxy, -C(=O)C _3-15 carbocyclic, Substituted by a substituent of -(CH ₂ ) _n -C _3-10 carbocyclic or -(CH ₂ ) _n -3 to 10 membered heterocyclic ring containing from 1 to 4 selected from N, O, S or a hetero atom of P;

R ^1a and R ^{1b are} selected from H or C _1-10 alkyl;

R ^{2 is} selected from H, F, Cl, Br, I, cyano, C _1-10 alkyl or C _1-10 alkoxy, said alkyl or alkoxy optionally further selected from 0 to 4 Substituted from a substituent of F, Cl, Br, I, C _1-6 alkyl or C _1-6 alkoxy;

R ^{3 is} selected from H, C _2-10 alkenyl, C _3-15 cycloalkyl, C _1-10 alkyl or C _1-10 alkoxy, said alkenyl, cycloalkyl, alkyl or alkoxy Further optionally, 0 to 4 are substituted with a substituent selected from F, Cl, Br, I, C _1-6 alkyl or C _1-6 alkoxy;

R ^{4 is} selected from the group consisting of H, F, Cl, Br, I, nitro, amino, C _1-10 alkyl, 5 to 15 membered spiro, 4 to 15 membered cyclo, 3 to 10 membered heterocyclic ring, -NR ^4c R ^4d , -Z-(CH ₂ ) _n R ^4a , -O-(CH ₂ ) _n R ^4b , -Z-(CH ₂ ) _n NR ^4c R ^4d or -O-(CH ₂ ) _n NR ^4c R ^4d Further, the CH ₂ , spiro, cyclo or heterocyclic ring is further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, C _1-6 alkyl, C _1-6 alkoxy , -(CH ₂ ) _n -C(=O)-R ^4e , -(CH ₂ ) _n -OC(=O)-R ^4e , -NR ^4c R ^4d , C ₃ substituted by 0 to 4 R ^4c _{a -10} carbocyclic ring or a substituent of a 3 to 10 membered heterocyclic ring substituted with 0 to 4 R ^4c , the heterocyclic ring containing 1 to 4 hetero atoms selected from N, O or S;

Z is selected from -NH- or -N(C _1-6 alkyl)-;

R ^{4a is} selected from a C _3-15 carbocyclic ring or a 3 to 15 membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O or S, optionally further to 0. To four substituents selected from the group consisting of F, Cl, Br, I, amino, hydroxy, C _1-6 alkoxy, C _1-6 alkyl or an amino group substituted by 1 to 2 C _1-6 alkyl Replace

R ^{4b is} selected from -C(=O)C _1-6 alkyl, -OC(=O)C _1-6 alkyl, C _1-10 alkoxy, C _3-15 carbocyclic or 3 to 15 membered hetero Ring, the alkyl, alkoxy, carbocyclic or heterocyclic ring optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, I, amino, -NR ^4c R ^4d , hydroxy, C _1-6 alkyl Substituted by a C _1-6 alkoxy group or a halogen-substituted C _1-6 alkyl group having 1 to 4 hetero atoms selected from N, O or S;

R ^4c and R ^{4d are} selected from H, C _1-10 alkyl, -C(=O)C _1-6 alkyl or -C(=O)C _1-6 alkoxy;

R ^{4e is} selected from amino, hydroxy, C _1-10 alkyl, C _3-15 carbocyclic or 3 to 15 membered heterocyclic ring, and the amino, alkyl, carbocyclic or heterocyclic ring is optionally further selected from 0 to 4 From F, Cl, Br, I, amino, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, -C(=O)C _1-6 alkyl, -C(=O)-NH ₂ Substituting a substituent of -OC(=O)C _1-6 alkyl or a halogen-substituted C _1-6 alkyl group containing from 1 to 4 heteroatoms selected from N, O or S;

R ^{5 is} selected from H, F, Cl, Br, I or a 5- to 15-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O or S, said heterocyclic ring optionally further 0 to 4 substituents selected from the group consisting of F, Cl, Br, I, =O, -C(=O)C _1-6 alkyl, C _1-6 alkyl or C _1-6 alkoxy;

f is selected from 0, 1, 2, 3, 4, 5 or 6;

n is selected from 0, 1, 2 or 3;

In various aspects of the invention, when -B-(R ¹ ) _{f is} selected from

And R ^{2 is} selected from H, F, Cl, methyl or cyano, R ^{3 is} selected from H, methoxy or methyl, f is 1, and when R ⁵ is H, R ^{4 is} not H,

Preferred Embodiments of the Invention, A Compound of the Formula (I), and Optical Isomers, Pharmaceutically Acceptable Salts or Eutectics thereof, wherein:

B is selected from a 6 to 15 membered heterocyclic ring containing 1 to 4 hetero atoms selected from N, O or S;

R ^{1 is} independently selected from the group consisting of F, Cl, Br, I, hydroxy, cyano, C _1-4 alkyl, C _1-4 alkoxy, -NR ^1a R ^1b , -C(=O)C _{1- 4-} alkyl, -S(=O) ₂ -C _1-4 alkyl, -C(=O)-3 to 7-membered heterocyclic ring, -C(=O)-C _3-7 carbocyclic ring, -(CH ₂ ) an _n- C _3-6 carbocyclic ring or a 3 to 7-membered heterocyclic ring, the CH ₂ , alkyl group, alkoxy group, carbocyclic ring or heterocyclic ring optionally further selected from 0 to 4 selected from F, Cl, Br, I, =O, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, -C(=O)C _1-4 alkoxy, -(CH ₂ ) _n -OH, -(CH ₂ ) _n -F, -C(=O)C _3-6 carbocyclic, -C(=O)C _1-4 alkyl, -(CH ₂ ) _n -C _3-6 carbocyclic or -(CH ₂ a _n -3 to 6-membered heterocyclic substituent containing from 1 to 4 heteroatoms selected from N, O or S;

R ^1a and R ^{1b are} selected from H or C _1-4 alkyl;

R ^{2 is} selected from H, F, Cl, Br, I, cyano, C _1-4 alkyl or C _1-4 alkoxy, said alkyl or alkoxy optionally further selected from 0 to 4 Substituted from a substituent of F, Cl, Br, I, C _1-4 alkyl or C _1-4 alkoxy;

R ^{3 is} selected from H, C _2-6 alkenyl, C _3-6 cycloalkyl, C _1-4 alkyl or C _1-4 alkoxy, said alkenyl, cycloalkyl, alkyl or alkoxy Further optionally, 0 to 4 are substituted with a substituent selected from F, Cl, Br, I, C _1-4 alkyl or C _1-4 alkoxy;

R ^{4 is} selected from the group consisting of H, F, Cl, Br, I, a 5 to 15 membered spiro ring, a 4 to 15 membered ring, a 3 to 10 membered heterocyclic ring, -Z-(CH ₂ ) _n R ^4a , and -O- ( CH ₂ ) _n R ^4b , -Z-(CH ₂ ) _n NR ^4c R ^4d or -O-(CH ₂ ) _n NR ^4c R ^4d , the heterocyclic ring containing 1 to 4 selected from N, O or S a hetero atom, the CH ₂ , spiro, cyclo or heterocyclic ring optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, I, amino, hydroxy, C _1-4 alkyl, -NR ^4c R ^4d Substituted with a substituent of -C(=O)-R ^4e or a C _1-4 alkoxy group;

Z is selected from -NH- or -N(C _1-4 alkyl)-;

R ^{4a is} selected from a C _3-6 carbocyclic ring or a 3 to 7 membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O or S, optionally further to 0. Substituted to four substituents selected from the group consisting of F, Cl, Br, I, amino, hydroxy, C _1-4 alkyl, amino substituted with 1 to 2 C _1-4 alkyl groups;

R ^{4b is} selected from a C _3-6 carbocyclic ring or a 3 to 7 membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O, S, which are optionally further to 4 substituents selected from F, Cl, Br, I, amino, hydroxy, -NR ^4c R ^4d, C _1-4 alkyl or halo substituted with 1-2 of C _1-4 alkyl substituents;

R ^4c and R ^{4d are} selected from H or C _1-4 alkyl;

R ^{4e is} selected from amino, hydroxy, C _1-4 alkyl, C _3-6 carbocyclic or 3- to 7-membered heterocyclic ring, optionally further selected from 0 to 4 Substituted from a substituent of a C _1-4 alkyl group substituted with F, Cl, Br, I, an amino group, a hydroxyl group, a C _1-4 alkyl group, a C _1-4 alkoxy group or a halogen, the heterocyclic ring containing 1 to 4 heteroatoms selected from N, O or S;

R ^{5 is} selected from H, F, Cl, Br, I or a 5- to 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O, S, said heterocyclic ring optionally further 0 to 4 substituents selected from H, F, Cl, Br, I, =O, -C(=O)C _1-4 alkyl, C _1-4 alkyl or C _1-4 alkoxy Replace

f is selected from 0, 1, 2, 3 or 4;

n are each independently selected from 0, 1, 2 or 3.

B is selected from the group consisting of 8 to 13 membered heterocyclic rings containing 1 to 4 hetero atoms selected from N, O or S;

R ^{1 is} independently selected from the group consisting of F, Cl, Br, I, hydroxy, cyano, -S(=O) ₂ -C _1-4 alkyl, -C(=O)-C _3-6 carbocyclic, C _1-4 alkyl, -(CH ₂ ) _n -C _3-6 carbocyclic or -(CH ₂ ) _n -5 to 6-membered heterocyclic ring, preferably H, F, Cl, -S(=O) ₂ -C _1-4 alkyl, C _1-4 alkyl, -C(=O)-C _3-6 carbocyclic, -(CH ₂ ) _n -C _3-6 carbocyclic or -(CH ₂ ) _n -5 to a 6-membered heterocyclic ring; the CH ₂ , alkyl, carbocyclic or heterocyclic ring optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, -CH ₂ -cyclopropyl, tert-butoxycarbonyl, -(CH ₂ ) _n -OH, -(CH ₂ ) _n -F, -C(=O)C _1-4 alkyl Substituting a substituent of -(CH ₂ ) _n -C _3-6 carbocyclic or -(CH ₂ ) _n -3 to 6-membered heterocyclic ring, preferably further from 0 to 4 selected from F, hydroxy, C _1- Substituted with a substituent of ₄ alkyl or -C(=O)C _1-4 alkyl; the heterocyclic ring containing 1 to 4 heteroatoms selected from N, O or S;

R ^{2 is} selected from H, F, Cl, C _1-4 alkyl or C _1-4 alkoxy, preferably H, F, Cl or C _1-4 alkoxy;

R ³ is H, C _2-4 alkenyl, C _3-4 cycloalkyl, C _1-4 alkyl or C _1-4 alkoxy, preferably H, C _1-4 alkyl or C _1-4 alkane An alkoxy group; optionally the alkoxy group is further substituted with 0 to 4 substituents selected from F, Cl or Br;

R ^{4 is} selected from the group consisting of H, F, Cl, a 7 to 11 membered spiro ring, a 6 to 10 membered ring, a 3 to 6 membered heterocyclic ring, -Z-(CH ₂ ) _n R ^4a , and -Z-(CH ₂ ) _n NR ^4c R ^4d , -O-(CH ₂ ) _n R ^4b or -O-(CH ₂ ) _n NR ^4c R ^4d , the heterocyclic ring containing 1 to 4 hetero atoms selected from N, O or S, Said CH ₂ , spiro, cyclo or heterocyclic ring optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, I, amino, -NH(CH ₃ ), -N(CH ₃ ) ₂ , methyl or Substituted by a substituent of an ethyl group;

Z is selected from -NH- or -N(C _1-4 alkyl)-;

R ^{4a is} selected from a C _3-4 carbocyclic ring or a 5-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O, S, optionally further from 0 to 4 a substituent selected from the group consisting of F, Cl, Br, I, amino, hydroxy, -NHCH ₃ , -N(CH ₃ ) ₂ , methyl or ethyl;

R ^{4b is} selected from a C _3-4 carbocyclic ring or a 4 to 6 membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O, S, which are optionally further Substituted to four substituents selected from the group consisting of F, Cl, Br, I, amino, hydroxy, -NH(CH ₃ ), -N(CH ₃ ) ₂ , -CH ₂ CH ₂ F, methyl or ethyl;

R ^4c and R ^{4d are} selected from H, methyl or ethyl;

R ^{5 is} selected from H, F, Cl or a 5- to 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O, S, said heterocyclic ring optionally further being from 0 to 4 Substituted with a substituent selected from F, Cl, Br, I, =O, -C(=O)C _1-4 alkyl, C _1-4 alkyl or C _1-4 alkoxy;

n is selected from 0, 1, 2 or 3.

B is selected from

Optimal

or

Further preferred

or

R ^{1 is} independently selected from the group consisting of F, Cl, Br, I, -S(=O) ₂ CH ₃ , -C(=O)-cyclopropyl, hydroxy, cyano, methyl, ethyl, isopropyl , cyclopropyl, -CH ₂ -cyclopropyl, -CH(CH ₃ )-cyclopropyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl, preferably H, F, Cl, -S (=O) ₂ CH ₃ , methyl, ethyl, isopropyl, cyclopropyl, -CH ₂ -cyclopropyl, -CH ₂ (CH ₃ )-cyclopropyl, -C(=O)-cyclo a propyl group, a morpholinyl group or a piperazinyl group; the methyl group, ethyl group, morpholinyl group, piperazinyl group, piperidinyl group or tetrahydropyrrolyl group optionally further selected from 0 to 4 selected from F, Cl, Br, I, =O, hydroxy, methyl, ethyl, methoxy, isopropyl, cyclopropyl, -CH ₂ -cyclopropyl, hydroxyethyl, 2-fluoroethyl, tert-butoxycarbonyl, Substituted with a substituent of oxetanyl, -C(=O)CH ₃ or -C(=O)CH ₂ CH ₃ , preferably further optionally from 0 to 4 selected from F, hydroxy, methyl, - Substituted with a substituent of CH ₂ -cyclopropyl, hydroxyethyl, 2-fluoroethyl, tert-butoxycarbonyl or -C(=O)CH ₃ ;

R ^{2 is} selected from H, F, Cl, methyl or methoxy, preferably H, F, Cl or methoxy;

R ^{3 is} selected from H, methyl, ethyl, vinyl, cyclopropyl, methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy, preferably H, ethyl, methoxy Or difluoromethoxy;

R ^{4 is} selected from the group consisting of H, F, Cl, 7 to 11 membered spiro ring, 3 to 6 membered heterocyclic ring, -Z-(CH ₂ ) _n R ^4a , -O-(CH ₂ ) _n R ^4b , -Z-( CH ₂ ) _n NR ^4c R ^4d or -O-(CH ₂ ) _n NR ^4c R ^4d , preferably F, 7 to 11 membered spiro ring, 3 to 6 membered heterocyclic ring, -Z-(CH ₂ ) _n R ^4a , -O-(CH ₂ ) _n R ^4b , -Z-(CH ₂ ) _n NR ^4c R ^4d or -O-(CH ₂ ) _n NR ^4c R ^4d ; the heterocyclic ring contains 1 to 4 selected from N, a hetero atom of O or S, said CH ₂ , spiro or heterocyclic ring optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, methyl, ethyl or -N(CH ₃ ) ₂ Substituted, preferably substituted further with 0 to 2 substituents selected from F or methyl;

Z is selected from -NH- or -N(CH ₃ )-;

R ^{4a is} selected from a substituted or unsubstituted cyclopropyl or tetrahydropyrrolyl group, and when substituted, optionally further 1 to 4 are selected from the group consisting of F, Cl, Br, I, amino, hydroxy, -NHCH ₃ , Substituted with a substituent of -N(CH ₃ ) ₂ , methyl or ethyl;

R ^{4b is} selected from substituted or unsubstituted cyclopropyl,

Tetrahydropyrrolyl, piperazinyl, piperidinyl or morpholinyl; when substituted, optionally further from 1 to 4 selected from the group consisting of F, Cl, Br, I, amino, hydroxy, -NHCH ₃ , -N Substituting (CH ₃ ) ₂ , -CH ₂ CH ₂ F, a methyl or ethyl substituent, preferably substituted with 1 to 4 substituents selected from amino or -CH ₂ CH ₂ F;

R ^4c and R ^{4d are} selected from H, methyl or ethyl, preferably H or methyl;

R ^{5 is} selected from H, F, Cl or morpholinyl, preferably H, F or morpholinyl;

n is selected from 0, 1, 2 or 3.

B is selected from

Optimal

or

Further preferred

or

R ^{1 is} independently selected from the group consisting of F, Cl, -S(=O) ₂ CH ₃ , hydroxy, cyano, methyl, difluoromethyl, ethyl, -CH ₂ CH ₂ OH, isopropyl, cyclopropane Base, -CH ₂ -cyclopropyl,

Morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl, preferably H, F, methyl, morpholinyl, piperazinyl,

or

Further preferred are H, F, methyl or morpholinyl;

R ^{3 is} selected from H, ethyl, methoxy or difluoromethoxy, preferably H or methoxy;

R ^{4 is} selected from the group consisting of H, F, Cl,

Preferably H,

f is selected from 0, 1, 2 or 3, preferably 0, 1 or 2.

In a preferred embodiment of the invention, -B-(R ¹ ) _{f is} selected from one of the following structures:

The present invention relates to a compound of the formula (II) and an optical isomer thereof, a pharmaceutically acceptable salt or a eutectic thereof, wherein:

B is selected from a 6-membered heterocyclic ring, a 7-membered heterocyclic ring, an 8-membered heterocyclic ring, a 9-membered heterocyclic ring or a 10-membered heterocyclic ring, which is optionally further substituted by 0, 1, 2, 3 or 4 R ¹ , The heterocyclic ring contains 1, 2, 3 or 4 hetero atoms selected from N, O, S;

R ^{1 is} independently selected from the group consisting of H, F, Cl, Br, I, S(=O) ₂ -C _1-4 alkyl, C _1-4 alkyl, NR ^1a R ^1b , -C(=O)C _1-4 alkyl, -C(=O)-3 membered heterocyclic ring, -C(=O)-4 membered heterocyclic ring, -C(=O)-5 membered heterocyclic ring, -C(=O)-6 a heterocyclic ring, a -C(=O)-7 membered heterocyclic ring, a C _1-4 alkoxy group, a C ₃ carbocyclic ring, a C ₄ carbon ring, a C ₅ carbocyclic ring, a C ₆ carbocyclic ring or a 3 membered heterocyclic ring, 4 a heterocyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring or a 7-membered heterocyclic ring, wherein the alkyl group, alkoxy group, carbocyclic ring or heterocyclic ring is further optionally selected from 0, 1, 2, 3 or 4 H, F, Cl, Br, I, (=O), C _1-4 alkyl, C _1-4 alkoxy, -C(=O)C _1-4 alkyl, C ₃ carbocyclic, C ₄ Substituted by a carbocyclic, C ₅ carbocyclic, C ₆ carbocyclic or 3 membered heterocyclic ring, 4 membered heterocyclic ring, 5 membered heterocyclic ring or 6 membered heterocyclic ring containing 1, 2, 3 or 4 a hetero atom selected from N, O, S;

R ^1a and R ^{1b are} selected from H or C _1-4 alkyl;

R ^{2 is} selected from H, F, Cl, Br, I, C _1-4 alkyl or C _1-4 alkoxy, said alkyl or alkoxy optionally further being 0, 1, 2, 3 or Substituted by four substituents selected from H, F, Cl, Br, I, C _1-4 alkyl or C _1-4 alkoxy;

R ³ is H, C _2-6 alkenyl, C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C _1-4 alkyl or C _1-4 alkoxy The alkenyl, cycloalkyl, alkyl or alkoxy group optionally further 0, 1, 2, 3 or 4 is selected from H, F, Cl, Br, I, C _1-4 alkyl or C Substituted by a substituent of _1-4 alkoxy;

R ^{4 is} selected from the group consisting of H, F, Cl, Br, I, 9-membered spiro, Z-(CH ₂ ) _n R ^4a , O-(CH ₂ ) _n R ^4b or O-(CH ₂ ) _n NR ^4c R ^4d The spiro ring contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, optionally further 0, 1, 2, 3 or 4 selected from H, F, Cl Substituted with a substituent of Br, I, C _1-4 alkyl or C _1-4 alkoxy;

Alternatively, when R ^{4 is} selected from Z-(CH ₂ ) _n -6 membered heterocyclic ring, 3-membered heterocyclic ring, 4-membered heterocyclic ring, 5-membered heterocyclic ring, 6-membered heterocyclic ring or N(CH ₃ )-(CH _{2 )} When _n NR ^4c R ^4d , the heterocyclic ring contains 1 to 4 hetero atoms selected from N, O, S, and the heterocyclic ring is optionally further further 0 to 4 H, F, Cl, Br, I, Substituted by an amino group, a C _1-4 alkyl group or a substituent of an amino group substituted by 1 to 2 C _1-4 alkyl groups, the other groups are defined by one of the following conditions:

1): R ^{3 is} selected from ethyl or C _1-4 alkyl substituted by 1, 2 or 3 F, Cl, Br or I,

^2): R 2 is selected from C _1-4 alkoxy or substituted with 1,2 or 3 F, Cl, Br or I substituted C _1-4 alkoxy,

3): B is selected from a 6-membered heterocyclic ring, a 7-membered heterocyclic ring, an 8-membered heterocyclic ring, a 9-membered heterocyclic ring or a 10-membered heterocyclic ring, and the heterocyclic ring contains 1, 2, 3 or 4 selected from N, O, a hetero atom of S, optionally further 1, 2, 3 or 4 selected from the group consisting of H, F, Cl, Br, I, S(=O) ₂ -C _1-4 alkyl, C _{1- 4-} alkyl, C _1-4 alkoxy, C ₃ carbocyclic, C ₄ carbocyclic, C ₅ carbocyclic, C ₆ carbocyclic, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic or 6-membered hetero Substituted by a substituent of the ring;

Z is selected from NH or NC _1-4 alkyl;

R ^{4a is} selected from C ₃ carbocyclic, C ₄ carbocyclic, C ₅ carbocyclic, C ₆ carbocyclic, 3 membered heterocyclic, 4 membered heterocyclic or 5-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, optionally further 0, 1, 2, 3 or 4 selected from H, F, Cl, Br, I, amino, C _{1 -4} alkyl or substituted with 1 to 2 C _1-4 alkyl substituted amino groups;

R ^{4b is} selected from a C ₃ carbocyclic ring, a C ₄ carbocyclic ring, a C ₅ carbocyclic ring, a C ₆ carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring containing 1 , 2, 3 or 4 heteroatoms selected from N, O, S, optionally further 0, 1, 2, 3 or 4 selected from H, F, Cl, Br, I Substituted with an amino group, a C _1-4 alkyl group or a substituent of an amino group substituted with 1 to 2 C _1-4 alkyl groups;

R ^4c and R ^{4d are} selected from H or C _1-4 alkyl;

R ^{5 is} selected from the group consisting of H, F, Cl, Br, I, -O-5 membered heterocyclic ring, -O-6 membered heterocyclic ring, -O-7 membered heterocyclic ring, 5-membered heterocyclic ring, 6-membered heterocyclic ring or 7-membered ring. a heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said heterocyclic ring optionally further being 0, 1, 2, 3 or 4 selected from H, Substituted with a substituent of F, Cl, Br, I, (=O), -C(=O)C _1-4 alkyl, C _1-4 alkyl or C _1-4 alkoxy;

Alternatively, when R ³ and R ⁴ are each independently H, R ^{5 is} selected from a 5-membered heterocyclic ring or a 6-membered heterocyclic ring containing 1, 2, 3 or 4 selected from N, O, S a hetero atom, optionally further 0, 1, 2, 3 or 4 selected from the group consisting of H, F, Cl, Br, I, (=O), -C(=O)C _1-4 Substituted by a substituent of an alkyl group, a C _1-4 alkyl group or a C _1-4 alkoxy group;

n is selected from 0, 1, or 2.

A preferred embodiment of the invention is a compound of the formula (II) and an optical isomer, a pharmaceutically acceptable salt or a eutectic thereof, wherein:

B is selected from an 8-membered heterocyclic ring, a 9-membered heterocyclic ring or a 10-membered heterocyclic ring, preferably a 9-membered heterocyclic ring, further preferably a pyridopyrazolyl group or a benzopyrrolyl group, which is optionally further further 0, 1, 2 , 3 or 4 R ¹ substituted, the heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O, S;

R ^{1 is} independently selected from the group consisting of H, F, Cl, Br, I, S(=O) ₂ -C _1-4 alkyl, C _1-4 alkyl, NR ^1a R ^1b , C _1-4 alkoxy , C ₃ carbocyclic ring, C ₄ carbocyclic ring, C ₅ carbocyclic ring, C ₆ carbocyclic ring, 3 membered heterocyclic ring, 4 membered heterocyclic ring, 5-membered heterocyclic ring or 6-membered heterocyclic ring, preferably H, F, Cl, Br, I, S(=O) ₂ -C _1-4 alkyl, C _1-4 alkyl, C ₅ carbocyclic, C ₆ carbocyclic, 5-membered heterocyclic or 6-membered heterocyclic ring, further preferably H, F, Cl , Br, I, S(=O) ₂ -C _1-4 alkyl, C _1-4 alkyl, 5-membered heterocyclic or 6-membered heterocyclic ring, more preferably H, F, Cl, Br, I, S ( =O) ₂ CH ₃ , methyl, isopropyl, cyclopropyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl,

R ^1a and R ^{1b are} selected from H or C _1-4 alkyl;

Said alkyl, alkoxy, carbocyclic, heterocyclic, methyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl, optionally further 0, 1, 2, 3 or 4 Selected from H, F, Cl, Br, I, (=O), C _1-4 alkyl, C _1-4 alkoxy, -C(=O)C _1-4 alkyl, C ₃ carbocyclic, Substituted by C ₄ carbocyclic, C ₅ carbocyclic, C ₆ carbocyclic or 3 membered heterocyclic ring, 4 membered heterocyclic ring, 5-membered heterocyclic ring or 6-membered heterocyclic ring substituent, preferably 0, 1, 2, 3 or 4 One selected from the group consisting of H, F, Cl, Br, I, (=O), C _1-4 alkyl, C _1-4 alkoxy, -C(=O)C _1-4 alkyl, C ₃ carbocycle Substituting a substituent of a C ₄ carbocyclic ring, a C ₅ carbocyclic ring, a C ₆ carbocyclic ring, a 3 membered heterocyclic ring, a 4 membered heterocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, further preferably 0, 1, 2 3 or 4 selected from H, F, Cl, Br, I, (=O), methyl, methoxy, isopropyl, cyclopropyl, -C(=O)CH ₃ or -C(=O Substituted by a substituent of CH ₂ CH ₃ containing 1, 2, 3 or 4 heteroatoms selected from N, O, S.

R ^{4 is} selected from the group consisting of H, F, Cl, 9-membered spiro, Z-(CH ₂ ) _n R ^4a , O-(CH ₂ ) _n R ^4b or O-(CH ₂ ) _n NR ^4c R ^4d , the snail The ring contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, optionally further 0, 1, 2, 3 or 4 selected from H, F, Cl, Br, I Substituted by a methyl or ethyl substituent;

Alternatively, when R ^{4 is} selected from Z-(CH ₂ ) _n -6 membered heterocyclic ring, 3-membered heterocyclic ring, 4-membered heterocyclic ring, 5-membered heterocyclic ring or 6-membered heterocyclic ring or N(CH ₃ )-(CH _{2 )} _n NR ^4c R ^4d , the heterocyclic ring contains 1 to 4 hetero atoms selected from N, O, S, optionally further 0 to 4 selected from H, F, Cl Substituted by a substituent of Br, I, amino, NHCH ₃ , N(CH ₃ ) ₂ , methyl or ethyl, the other groups are defined by one of the following conditions:

1): R ^{3 is} selected from ethyl or C _1-4 alkyl substituted by 1, 2 or 3 F, Cl, Br or I, preferably methyl substituted by 1, 2 or 3 F,

^2): R 2 is selected from C _1-4 alkoxy or substituted with 1,2 or 3 F, Cl, Br or I substituted C _1-4 alkoxy, preferably methoxy, fluoromethoxy, Difluoromethoxy or trifluoromethoxy,

3): B is selected from a 9-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, optionally further 1, 2, 3 or 4 Substituted by a substituent selected from H, F, Cl, Br, I, SO ₂ CH ₃ , methyl, isopropyl or cyclopropyl;

Z is selected from NH or NC _1-4 alkyl;

R ^{4a is} selected from a C ₃ carbocyclic ring, a C ₄ carbocyclic ring or a 5-membered heterocyclic ring, preferably a cyclopropyl or tetrahydropyrrolyl group, the heterocyclic ring containing 1, 2, 3 or 4 selected from N, O, S a hetero atom, optionally further 0, 1, 2, 3 or 4 selected from the group consisting of H, F, Cl, Br, I, amino, NHCH ₃ , N(CH ₃ ) ₂ , methyl Or an ethyl group substituent;

R ^{4b is} selected from a C ₃ carbocyclic ring, a C ₄ carbocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, preferably a cyclopropyl group, a tetrahydropyrrolyl group or a piperazinyl group, the heterocyclic ring containing 1, 2, 3 or 4 a hetero atom selected from N, O, S, optionally further 0, 1, 2, 3 or 4 selected from the group consisting of H, F, Cl, Br, I, amino, NHCH ₃ , Substituted by a substituent of N(CH ₃ ) ₂ , methyl or ethyl;

R ^4c and R ^{4d are} selected from H, methyl or ethyl.

B is selected from an 8-membered heterocyclic ring, a 9-membered heterocyclic ring or a 10-membered heterocyclic ring, which is optionally further substituted by 0, 1, 2, 3 or 4 R ¹ , which contains 1, 2, 3 Or 4 heteroatoms selected from N, O, S;

R ^{1 is} independently selected from the group consisting of H, F, Cl, Br, I, C _1-4 alkyl, S(=O) ₂ -C _1-4 alkyl, C _3-6 carbocyclic, 5-membered heterocyclic ring or 6-membered heterocyclic ring, NR ^1a R ^1b , -C(=O)C _1-4 alkyl, -C(=O)-3 membered heterocyclic ring, -C(=O)-4 membered heterocyclic ring, -C( =O)-5-membered heterocyclic ring, -C(=O)-6 membered heterocyclic ring or -C(=O)-7 membered heterocyclic ring, preferably H, F, Cl, Br, I, S(=O) ₂ -C _1-4 alkyl, C _1-4 alkyl or 5-membered heterocyclic or 6-membered heterocyclic ring; said alkyl or heterocyclic ring optionally further selected from 0, 1, 2, 3 or 4 selected from H , F, Cl, Br, I, (=O), C _1-4 alkyl, C _1-4 alkoxy, -C(=O)C _1-4 alkyl, C3 carbocyclic, C4 carbocyclic, Substituted by a substituent of a C5 carbocyclic ring, a C6 carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring containing 1, 2, 3 or 4 selected from N, O, S heteroatoms;

R ^1a and R ^{1b are} selected from H or C _1-4 alkyl;

R ^{2 is} selected from H, F, Cl, C _1-4 alkyl or C _1-4 alkoxy;

R ³ is H, C _2-4 alkenyl, C _3-4 cycloalkyl, C _1-4 alkyl or C _1-4 alkoxy, said alkoxy optionally further 0, 1, 2, 3 Or 4 substituted with a substituent selected from H, F, Cl or Br;

Z is selected from NH or NC _1-4 alkyl;

R ^{4a is} selected from a C ₃ carbocyclic ring, a C ₄ carbocyclic ring or a 5-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said carbocyclic or heterocyclic ring Optionally further taken by 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, amino, NHCH ₃ , N(CH ₃ ) ₂ , methyl or ethyl;

R ^{4b is} selected from a C ₃ carbocyclic ring, a C ₄ carbocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring containing 1, 2, 3 or 4 hetero atoms selected from N, O, S, The carbocyclic or heterocyclic ring is optionally further substituted by 0, 1, 2, 3 or 4 selected from H, F, Cl, Br, I, amino, NHCH ₃ , N(CH ₃ ) ₂ , methyl or ethyl. Substituted by

R ^4c and R ^{4d are} selected from H, methyl or ethyl;

R ^{5 is} selected from the group consisting of H, F, Cl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, -O-5 membered heterocyclic ring, -O-6 membered heterocyclic ring or -O-7 membered heterocyclic ring, and said heterocyclic ring contains 1 , 2, 3 or 4 heteroatoms selected from N, O, S, said heterocyclic ring optionally further being 0, 1, 2, 3 or 4 selected from the group consisting of H, F, Cl, Br, I, ( Substituted with a substituent of -O()-C(=O)C _1-4 alkyl, C _1-4 alkyl or C _1-4 alkoxy;

Alternatively, when R ³ and R ⁴ are each independently H, R ⁵ is a 5- to 6-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, The heterocyclic ring is optionally further selected from 0, 1, 2, 3 or 4 selected from the group consisting of H, F, Cl, Br, I, (=O), -C(=O)C _1-4 alkyl, C Substituted by a substituent of _1-4 alkyl or C _1-4 alkoxy.

B is selected from a 9-membered heterocyclic ring, preferably a pyridopyrazolyl or a benzopyrrolyl group, which is optionally further substituted by 0, 1, 2, 3 or 4 R ¹ , which contains 1, 2 , 3 or 4 heteroatoms selected from N, O, S;

R ^{1 is} independently selected from the group consisting of H, F, Cl, Br, I, methyl, S(=O) ₂ CH ₃ , isopropyl, cyclopropyl, NHCH ₃ , N(CH ₃ ) ₂ , N(CH) ₃ ) (C ₂ H ₅ ), -C(=O)C _1-4 alkyl, -C(=O)-cyclopropoxy, -C(=O)-cyclobutoxy, -C(= O)-tetrahydropyrrolyl, -C(=O)-morpholinyl, -C(=O)-piperazinyl, -C(=O)-piperidinyl, -C(=O)-7 Heterocyclic, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl, preferably H, F, Cl, Br, I, S(=O) ₂ CH ₃ , methyl, isopropyl, cyclopropyl , morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrole; said methyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl optionally further substituted by 0, 1, 2, 3 Or 4 selected from H, F, Cl, Br, I, (=O), methyl, methoxy, isopropyl, cyclopropyl, -C(=O)CH ₃ or -C(=O) Substituted by a substituent of CH ₂ CH ₃ ;

R ^{2 is} selected from H, F, Cl, methyl or methoxy;

R ^{3 is} selected from H, methyl, ethyl, vinyl, cyclopropyl, methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy, preferably H, methoxy, cyclopropane Or difluoromethoxy;

Alternatively, when R ^{4 is} selected from Z-(CH ₂ ) _n -6 membered heterocyclic ring, 3-membered heterocyclic ring, 4-membered heterocyclic ring, 5-membered heterocyclic ring or 6-membered heterocyclic ring or N(CH ₃ )-(CH _{2 )} _n NR ^4c R ^4d , the heterocyclic ring contains 1 to 4 hetero atoms selected from N, O, S, optionally further 0 to 4 selected from H, F, Cl The substituents of Br, I, amino, NHCH ₃ , N(CH ₃ ) ₂ , methyl or ethyl are taken, and other groups are defined by one of the following conditions:

1): R ^{3 is} selected from ethyl or methyl substituted by 1, 2 or 3 F, preferably difluoromethoxy,

2): R ² is methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy, preferably methoxy,

3): B is selected from a 9-membered heterocyclic ring, preferably a pyridopyrazolyl or a benzopyrrolyl group, the heterocyclic ring containing 1, 2, 3 or 4 hetero atoms selected from N, O, S, the hetero The ring, pyridopyrazolyl or benzopyrrolyl group is optionally further 1, 2, 3 or 4 selected from H, F, Cl, Br, I, SO ₂ CH ₃ , methyl, isopropyl or cyclopropane. Substituted by a substituent of the group;

Z is selected from NH or NCH ₃ ;

R ^{4a is} selected from substituted or unsubstituted cyclopropyl or tetrahydropyrrolyl, and when substituted, optionally further 0, 1, 2, 3 or 4 selected from H, F, Cl, Br, I, Substituted by a substituent of an amino group, NHCH ₃ , N(CH ₃ ) ₂ , methyl or ethyl;

R ^{4b is} selected from substituted or unsubstituted cyclopropyl, tetrahydropyrrolyl or piperazinyl, and when substituted, optionally further selected from 0, 1, 2, 3 or 4 selected from H, F, Cl, Br Substituted with a substituent of I, amino, NHCH ₃ , N(CH ₃ ) ₂ , methyl or ethyl;

R ^4c and R ^{4d are} selected from H, methyl or ethyl;

R ^{5 is} selected from the group consisting of H, F, Cl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl, -O-tetrahydropyrrolyl, -O-piperazinyl, -O-piperidinyl, - O-morpholinyl or -O-7 membered heterocyclic ring, preferably morpholinyl or piperazinyl, said morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl optionally further from 0 to 4 Substituents selected from the group consisting of H, F, Cl, Br, I, (=O), -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ , methyl, ethyl, methoxy Replace

Alternatively, when R ³ and R ⁴ are each independently H, R ⁵ is morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl, preferably morpholinyl or piperazinyl, said morpholine The base, piperazinyl, piperidinyl or tetrahydropyrrolyl is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, (=O), -C(=O)CH ₃ , -C (=O) Substituent of CH ₂ CH ₃ , methyl, ethyl or methoxy.

A preferred embodiment of the invention, a compound of the formula (II), and an optical isomer, a pharmaceutically acceptable salt or a eutectic thereof, wherein

B is selected from one of the following structures substituted or unsubstituted:

When substituted, optionally substituted with 1 R ¹ ;

R ^{1 is} each independently selected from the group consisting of H, F, Cl, S(=O) ₂ CH ₃ , isopropyl, cyclopropyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrole;

R ^{2 is} selected from H, F, Cl, methyl or methoxy;

R ^{3 is} selected from H, methoxy or difluoromethoxy;

R ^{4 is} selected from H, F, Cl or one of the following structures:

Alternatively, when R ^{4 is} selected from

When other groups are defined, one of the following conditions may be selected:

1): R ^{3 is} selected from ethyl or methyl substituted by 1, 2 or 3 F.

2): R ² is a methoxy group,

3): B is selected from

Or one of the following structures replaced by 1 F:

R ^{5 is} selected from the group consisting of H, F, Cl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl;

Alternatively, when R ³ and R ⁴ are each independently H, R ⁵ is morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl.

A preferred embodiment of the invention is a compound of the formula (I) or formula (II), wherein the compound is selected from one of the following structures:

The present invention relates to a compound represented by the formula (I) or the formula (II), and an optical isomer, a pharmaceutically acceptable salt or a cocrystal thereof, wherein the salt is selected from the group consisting of a hydrochloride, a sulfate, and a phosphoric acid. Salt, acetate, trifluoroacetate, fumarate, benzoate, besylate, methanesulfonate, triflate or combinations thereof.

The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the inventions described in the invention and an optical isomer, pharmaceutically acceptable salt or co-crystal thereof, and A pharmaceutically acceptable carrier or excipient.

The invention further relates to the use of a compound of the invention and an optical isomer, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment of cancer.

According to a preferred embodiment of the present invention, the cancer includes head and neck cancer, ovarian cancer, bladder cancer, cervical cancer, esophageal cancer, gastric cancer, breast cancer, endometrial cancer, colon cancer, lung cancer, brain tumor, non-small cell lung cancer, pancreatic cancer, Solid tumor, colorectal tumor or malignant glioma.

The invention further relates to a method of treating cancer comprising administering a compound of the invention as indicated above, or an optical isomer, a pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition according to the invention .

resolve resolution

R ^{6 is} selected from H, F, Cl, Br, I or OH,

The definition of B, f, R ¹ , R ² , R ³ , R ⁴ or R ⁵ is identical to the definition of the compound of formula (I);

If R ⁴ is H, F, Cl, Br or I, then R ⁶ is the same as R ⁴ , the nitro group of the compound of formula (IA) is reduced to give a compound of the formula (IB), and the reducing agent is selected from H ₂ , Pt, Fe, Zn, LiAlH ₄ or NaBH ₄ ;

If R ⁴ is a nitro group, then in the compound of the formula (IA), R ⁶ is H and reacted with a nitrating reagent such as nitric acid or the like to obtain a compound of the formula (IB'), and the nitro group of the compound of the formula (IB') is Reduction to give a compound of the formula (IB);

If R ⁴ is an alkyl group, then R ⁶ is H in the compound of the formula (IA) and is reacted with a format reagent or an alkyllithium reagent or the like to give a compound of the formula (IB'), and the nitro group of the compound of the formula (IB') is Reduction to give a compound of the formula (IB);

Otherwise: a compound of the formula (IA) is reacted with HR ⁴ in the presence of a base to give a compound of the formula (IB'), and a nitro group of the compound of the formula (IB') is reduced to give a compound of the formula (IB). From diisopropylethylamine, diisopropylamine, triethylamine, potassium carbonate, sodium hydrogencarbonate, sodium carbonate, sodium t-butoxide, potassium t-butoxide, potassium acetate, sodium acetate, sodium hydride or cesium carbonate And the reducing agent is selected from the group consisting of H ₂ , Pt, Fe, Zn, LiAlH ₄ or NaBH ₄ ;

The compound of the formula (IB) is reacted with an acryloyl halide (for example acryloyl chloride) or acrylic acid in the presence of a base to give a compound of the formula (I), which is selected from the group consisting of diisopropylethylamine, diisopropylamine, Triethylamine, potassium carbonate, sodium hydrogencarbonate, sodium carbonate, sodium t-butoxide, potassium t-butoxide, potassium acetate, sodium acetate, sodium hydride or cesium carbonate;

The compound of the formula (I-A) is obtained by purchasing or referring to literature methods such as WO2013014448.

or,

R ^{6 is} selected from H, F, Cl, Br, I or OH,

B, R ¹ , R ² , R ³ , R ⁴ or R ⁵ are as defined in the definition of the compound of formula (II);

If R ⁴ is H, F, Cl, Br or I, then R ⁶ is the same as R ⁴ , and the nitro group of the compound of the formula (IA-1) is reduced to give a compound of the formula (IB-1), the reducing agent Selected from H ₂ , Pt, Fe, Zn, LiAlH ₄ or NaBH ₄ ;

If R ⁴ is a nitro group, R ^{6 in the} compound of the formula (IA-1) is H and is reacted with a nitrating reagent such as nitric acid or the like to obtain a compound of the formula (IB`-1); formula (IB`-1) The nitro group of the compound is reduced to give a compound of the formula (IB-1);

If R ⁴ is an alkyl group, then R ^{6 in the} compound of the formula (IA-1) is H and is reacted with a format reagent or an alkyllithium reagent or the like to give a compound of the formula (IB`-1), a formula (IB`-1) The nitro group of the compound is reduced to give a compound of the formula (IB-1);

Otherwise: a compound of the formula (IA-1) is reacted with HR ⁴ in the presence of a base to give a compound of the formula (IB'-1), and a nitro group of the compound of the formula (IB'-1) is reduced to give a formula (IB-1). a compound selected from the group consisting of diisopropylethylamine, diisopropylamine, triethylamine, potassium carbonate, sodium hydrogencarbonate, sodium carbonate, sodium t-butoxide, potassium t-butoxide, potassium acetate, Sodium acetate, sodium hydride or cesium carbonate, etc., the reducing agent is selected from the group consisting of H ₂ , Pt, Fe, Zn, LiAlH ₄ or NaBH ₄ ;

The compound of the formula (IB-1) is reacted with an acryloyl halide (for example, acryloyl chloride) or acrylic acid in the presence of a base to give a compound of the formula (II), which is selected from the group consisting of diisopropylethylamine and diisopropyl. Amine, triethylamine, potassium carbonate, sodium hydrogencarbonate, sodium carbonate, sodium t-butoxide, potassium t-butoxide, potassium acetate, sodium acetate, sodium hydride or cesium carbonate;

The compound of the formula (I-A-1) is obtained by purchasing or referring to the literature method such as WO2013014448.

Terms used in the specification and claims have the following meanings unless stated to the contrary.

The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention. The nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include ¹² C, ¹³ C, and ¹⁴ C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen ), 氚 (T, also known as super heavy hydrogen), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes including ¹⁴ N and ¹⁵ N, the fluorine isotope ¹⁹ F, the chlorine isotope includes ³⁵ Cl and ³⁷ Cl, and the bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"Alkyl" means a straight-chain or branched saturated aliphatic hydrocarbon group, and the main chain includes 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, further preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, still more preferably 1 to 4 C atoms of a straight chain and a branched chain, and most preferably 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl Base, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-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, 3,3-dimethyl-2-butyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl , 5-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 2-B Pentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl , 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2 -methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl and n-decyl. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, Alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged, spiro, cyclo, hydroxy Alkyl, =O, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _r -C(=O)-R ^a , -O-(CH ₂ ) _r -C(=O)-R ^a , -(CH ₂ ) _r -C(=O)-NR ^b R ^c , -(CH ₂ ) _r S(=O) _q R ^a , -(CH ₂ ) _r -alkenyl-R ^a , OR ^d or -(CH ₂ ) _r -alkynyl-R ^a (wherein r, q is 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b is independent of R ^c Selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl or trifluoromethanesulfonyl, as an option, R ^b and R ^c A five or six membered cycloalkyl or heterocycloalkyl group can be formed. R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.

"Alkylene" means a straight or branched chain alkane derived from the removal of two hydrogen atoms from the above alkyl group, including -(CH ₂ ) _v - (v is an integer from 1 to 18), and the alkylene embodiment includes but not Limited to methylene, ethylene and propylene. The alkylene group may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro Base, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, Carboxylic esters, -(CH ₂ ) _r -C(=O)-R ^a , -O-(CH ₂ ) _r -C(=O)-R ^a , -(CH ₂ ) _r -C(=O) -NR ^b R ^c , -(CH ₂ ) _r S(=O) _q R ^a , -(CH ₂ ) _r -alkenyl-R ^a , OR ^d or -(CH ₂ ) _r -alkynyl-R ^a ( Wherein r, q are 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl , alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and alternatively, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic group. . R ^a and R ^d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Alkoxy" means an -O-alkyl group wherein alkyl is as defined above. Alkoxy groups may be substituted or unsubstituted, and alkoxy embodiments include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, untertiary Butoxy, sec-butoxy, n-pentyloxy and n-hexyloxy. When substituted, the substituent is preferably from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyanide , isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester-(CH ₂ _r -C(=O)-R ^a , -O-(CH ₂ ) _r -C(=O)-R ^a , -(CH ₂ ) _r -C(=O)-NR ^b R ^c ,-( CH ₂ ) _r S(=O) _q R ^a , -(CH ₂ ) _r -alkenyl-R ^a , OR ^d or -(CH ₂ ) _r -alkynyl-R ^a (where r, q are 0, 1 Or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl And a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and R ^b and R ^c may form a five- or six-membered cycloalkyl group or a heterocyclic group, and R ^a and R ^d are each independently It is selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis-cyclyl.

"Alkenyl" means an alkyl group as defined herein above containing at least one carbon-carbon double bond, preferably having from 2 to 20 carbon atoms, further preferably from 2 to 12 carbon atoms, more preferably 2 on the backbone Up to 8 carbon atoms, the alkenyl group may be substituted or unsubstituted. Non-limiting examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentyl Alkenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1- Hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-decenyl, 3-decenyl, 1- Decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, 3-undecyl, 4 - Dodecenyl and 4,8,12-tetradecenetrienyl and the like. When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ _r -C(=O)-R ^a , -O-(CH ₂ ) _r -C(=O)-R ^a , -(CH ₂ ) _r -C(=O)-NR ^b R ^c ,-( CH ₂ ) _r S(=O) _q R ^a , -(CH ₂ ) _r -alkenyl-R ^a , OR ^d or -(CH ₂ ) _r -alkynyl-R ^a (where r, q are 0, 1 Or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl And a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and R ^b and R ^c may alternatively form a five- or six-membered cycloalkyl group or a heterocyclic group. R ^a and R ^d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Alkynyl" means an alkyl group as defined herein above containing at least one carbon-carbon triple bond, preferably containing from 2 to 20 carbon atoms, further preferably from 2 to 8 carbon atoms, more preferably 2 on the backbone Alkynyl group up to 4 carbon atoms. An alkynyl group can be substituted or unsubstituted. Non-limiting examples include ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4- Pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl , 3-octynyl, 3-decynyl, 4-decynyl, 3-undynyl and 4-dodecynyl, etc.; when substituted, the substituent is preferably one or more of the following groups , independently selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, isocyano, aryl, hetero Aryl, heterocyclic, bridged, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _r -C(=O)- R ^a , -O-(CH ₂ ) _r -C(=O)-R ^a , -(CH ₂ ) _r -C(=O)-NR ^b R ^c , -(CH ₂ ) _r S(=O) _q R ^a , -(CH ₂ ) _r -alkenyl-R ^a , OR ^d or -(CH ₂ ) _r -alkynyl-R ^a (wherein r, q are 0, 1 or 2), arylthio group, thiocarbonyl group, a silyl group, or -NR ^b R ^c, wherein R ^b and R ^c is independently selected from the group comprising H, a hydroxyl group, an amino group, a carbonyl group, an alkyl group, Group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyloxy group, alternatively, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclyl group. R ^a and R ^d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Alkylthio" means -S-alkyl or -S-(unsubstituted cycloalkyl), and non-limiting examples include methylthio, ethylthio, propylthio, butylthio and the like.

"Amino" means -NH ₂ .

"Acyl" or "carbonyl" refers to a -C(=O)-R ^a group, wherein R ^{a is} as defined above.

"Aldehyde" means -C(=O)-H.

"Sulfur" means =S.

"Halogen" means fluorine, chlorine, bromine, or iodine.

"Hydroxy" means -OH.

"Cyano" means -C≡N.

"Isocyano" means -N≡C.

"Nitro" means -NO ₂ .

"Carboxylic acid" means -C(=O)-OH.

"Carboxylic acid ester" refers to ^{-C (= O) -OR d,} R d is selected from alkyl, cycloalkyl, or heterocyclyl group.

"巯基" means -SH.

"Mercaptan" refers to a hydrocarbon in which one or more hydrogen atoms in the alkyl group are replaced by a thiol group, and non-limiting examples include methyl mercaptan, ethanethiol, 1,2-dithiol.

"Carbocycle" means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic may be a monocyclic, bicyclic, tricyclic or polycyclic ring system, non-limiting examples include rings Propyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentene, cyclohexadiene, cycloheptatriene, phenyl, naphthyl, benzocyclopentyl, two Ring [3.2.1] octyl, bicyclo [5.2.0] decyl, tricyclo [5.3.1.1] dodecyl, adamantyl or spiro[3.3] heptyl, and the like. When substituted, the substituents are independently selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, isocyanide Base, aryl, heteroaryl, heterocyclic, bridged ring, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _r - C(=O)-R ^a , -O-(CH ₂ ) _r -C(=O)-R ^a , -(CH ₂ ) _r -C(=O)-NR ^b R ^c , -(CH ₂ ) _r S(=O) _q R ^a , -(CH ₂ ) _r -alkenyl-R ^a , OR ^d or -(CH ₂ ) _r -alkynyl-R ^a (wherein r, q are 0, 1 or 2) Or arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocycle Alkyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and alternatively, R ^b and R ^c may form a five- or six-membered cycloalkyl or heterocyclic group. R ^a and R ^d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Heterocycle" means a substituted or unsubstituted saturated or unsaturated aromatic ring, a non-aromatic ring, and comprises at least one heteroatom selected from N, O, P or S, optionally substituted in a heterocyclic ring N, S, and P can be oxidized to various oxidation states. The aromatic ring, non-aromatic ring may be a monocyclic, bicyclic, tricyclic or polycyclic ring system, non-limiting examples include, ethylene oxide, azacyclopropyl, oxetanyl, azetidine Base, 1,3-dioxolan, 1,4-dioxolane, 1,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N- Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiane, dihydrofuran, Hydropyran, dithiapentane, tetrahydrofuran, tetrahydropyrrole, tetrahydroimidazole, tetrahydrothiazole, tetrahydropyran, benzimidazole, benzopyridine, pyrrolopyridine, benzodihydrofuran, azabicyclo [3.2.1] Octyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptane base,

And the like; when substituted, the substituent is preferably from 1 to 5, and the substituent is independently selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro Base, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, Carboxylate, -(CH2) _r- C(=O)-R ^a , -O-(CH2) _r -C(=O)-R ^a , -(CH2) _r -C(=O)-NR ^b R ^c , -(CH2) _r S(=O) _q R ^a , -(CH2) _r -alkenyl-R ^a , OR ^d or -(CH2) _r -alkynyl-R ^a (where r, q are 0 , 1 or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, ring Alkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and alternatively, R ^b and R ^c may form a five- or six-membered cycloalkyl or heterocyclic group. R ^a and R ^d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Cycloalkyl" means a saturated or unsaturated monocyclic cyclic hydrocarbon group which may be substituted or unsubstituted, and the ring carbon atom includes 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, further preferably 3 to 8 Carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexene A group, a cycloheptenyl group, a 1,5-cyclooctadienyl group, a 1,4-cyclohexadienyl group, a cycloheptatrienyl group, and the like. When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ _r -C(=O)-R ^a , -O-(CH ₂ ) _r -C(=O)-R ^a , -(CH ₂ ) _r -C(=O)-NR ^b R ^c ,-( CH ₂ ) _r S(=O) _q R ^a , -(CH ₂ ) _r -alkenyl-R ^a , OR ^d or -(CH ₂ ) _r -alkynyl-R ^a (where r, q are 0, 1 Or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl And a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and R ^b and R ^c may alternatively form a five- or six-membered cycloalkyl group or a heterocyclic group. R ^a and R ^d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Spiro" refers to a 5 to 20 membered polycyclic group sharing a carbon atom (referred to as a spiro atom) between substituted or unsubstituted monocyclic rings, which may contain 0 to 5 double bonds, and may contain 0 to 5 a hetero atom selected from N, O, P or S(=O) _n (n is 0, 1 or 2). It is preferably 6 to 14 members, further preferably 6 to 12 members, more preferably 6 to 10 members, non-limiting examples of which include

When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ _r -C(=O)-R ^a , -O-(CH ₂ ) _r -C(=O)-R ^a , -(CH ₂ ) _r -C(=O)-NR ^b R ^c ,-( CH ₂ ) _r S(=O) _q R ^a , -(CH ₂ ) _r -alkenyl-R ^a , OR ^d or -(CH ₂ ) _r -alkynyl-R ^a (where r, q are 0, 1 Or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl And a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and R ^b and R ^c may alternatively form a five- or six-membered cycloalkyl group or a heterocyclic group. R ^a and R ^d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Paracyclic" refers to a polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain zero or more double bonds and may be The substituted or unsubstituted, each ring in the cis ring system may contain from 0 to 5 heteroatoms selected from N, S(=O) _n or O. It is preferably 5 to 20 members, further preferably 5 to 14 members, more preferably 5 to 12 members, still more preferably 5 to 10 members. Non-limiting examples include

"Bridge ring" refers to any two polycyclic groups of carbon atoms that are not directly bonded, may contain zero or more double bonds, and may be substituted or unsubstituted, and any ring in the ring system may contain 0 to 5 are selected from N, S(=O) _n or O heteroatoms or groups (where n is 1, 1, 2). The ring atom contains 5 to 20 atoms, preferably 5 to 14 atoms, further preferably 5 to 12, and further preferably 5 to 10. Non-limiting examples include

And adamantane. When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ _r -C(=O)-R ^a , -O-(CH ₂ ) _r -C(=O)-R ^a , -(CH ₂ ) _r -C(=O)-NR ^b R ^c ,-( CH ₂ ) _r S(=O) _q R ^a , -(CH ₂ ) _r -alkenyl-R ^a , OR ^d or -(CH ₂ ) _r -alkynyl-R ^a (wherein r, q are 0, 1 Or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl And a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and R ^b and R ^c may alternatively form a five- or six-membered cycloalkyl group or a heterocyclic group. R ^a and R ^d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Benzyl" refers to -CH ₂ - phenyl, substituted or unsubstituted of substituted, non-limiting examples include -CH ₂ - phenyl, -CH ₂ - p-methylphenyl and the like.

"Aryl" means a substituted or unsubstituted 6 to 14 membered cyclic aromatic group, including monocyclic aromatic groups and fused ring aromatic groups. A 6 to 14 membered aromatic ring is preferred, a 6 to 10 membered aromatic ring is further preferred, and non-limiting examples thereof include a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group and the like. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:

When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ _r -C(=O)-R ^a , -O-(CH ₂ ) _r -C(=O)-R ^a , -(CH ₂ ) _r -C(=O)-NR ^b R ^c ,-( CH ₂ ) _r S(=O) _q R ^a , -(CH ₂ ) _r -alkenyl-R ^a , OR ^d or -(CH ₂ ) _r -alkynyl-R ^a (where r, q are 0, 1 Or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl And a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and R ^b and R ^c may alternatively form a five- or six-membered cycloalkyl group or a heterocyclic group. R ^a and R ^d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group, and a cyclo group.

"Heteroaryl" means a substituted or unsubstituted 5 to 14 membered aromatic ring and contains 1 to 5 heteroatoms or groups selected from N, O or S(=O) _n , preferably 5 to 10 membered aromatic The ring is further preferably 5 to 6 yuan. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Piperidinyl, morpholine, thiomorpholine, 1,3-dithiane, benzimidazole, piperidinyl, benzimidazole, benzopyridine, pyrrolopyridine and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include

"Arylthio" means an -S-aryl or -S-heteroaryl group as defined herein. Examples of arylthio groups include, but are not limited to, phenylthio, pyridylthio, furylthio, thienylthio, pyrimidinylthio, and the like.

"Silyl" refers to a group formed by the substitution of one or more hydrogen atoms in a silicon methane with an alkyl group, examples including, but not limited to, trimethylsilyl, triethylsilyl, tert-butyldimethyl Silyl and tert-butyldiphenylsilyl and the like.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "alkyl group optionally substituted by F" means that the alkyl group may, but need not, be substituted by F, indicating a case where the alkyl group is substituted by F and a case where the alkyl group is not substituted by F.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to maintaining the biological effectiveness and properties of the free acid or free base, and the free acid is passed through a non-toxic inorganic or organic base. Or the free acid obtained by reacting with a non-toxic inorganic or organic acid, including alkali metal salts such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, etc. Other metal salts such as iron salts, copper salts, cobalt salts, etc.; organic alkali salts such as ammonium salts, triethylamine salts, pyridinium salts, methylpyridine salts, 2,6-dimethylpyridine salts, ethanolamine salts, Diethanolamine salt, triethanolamine salt, cyclohexylamine salt, ethylenediamine salt, phosphonium salt, isopropylamine salt, trimethylamine salt, tripropylamine salt, triethanolamine salt, diethanolamine salt, ethanolamine salt, Dimethylethanolamine salt, dicyclohexylamine salt, caffeine salt, procaine salt, choline salt, betaine salt, phenicillin salt, glucosamine salt, N-methylglucamine salt, theobromine salt , tromethamine salt, sulfonium salt, piperazine salt, morpholine salt, piperidine salt, N-ethyl piperidine salt, tetramethyl Salt, dibenzylamine salt and phenylglycine alkyl ester salt; hydrogen halide such as hydrofluoride, hydrochloride, hydroiodide, hydrobromide, etc.; inorganic acid salt, such as hydrochloric acid Salts, nitrates, sulfates, perchlorates, phosphates, etc.; lower alkane sulfonates such as methanesulfonate, triflate, ethanesulfonate, etc; aryl sulfonates such as benzene Sulfonate, p-toluenesulfonate, etc.; organic acid salts such as acetate, benzoate, fumarate, formate, trifluoroacetate, citrate, gluconate, glutamine Acid Salt, glycolate, isethionate, lactate, maleate, malate, mandelate, mucate, pamoate, pantothenate, stearate, succinic acid Salt, sulfonate, tartrate, malonate, 2-hydroxypropionate, citrate, salicylate, oxalate, glycolate, glucuronate, galacturonate, Citrate, lysine, arginine, aspartate, cinnamate, and the like.

"Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt thereof, with other components, wherein the other components comprise physiologically/pharmaceutically acceptable carriers and excipients.

"Carrier" refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.

"Excipient" refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, Granules, lubricants, binders, disintegrators, and the like.

"Prodrug" means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying a phenolic group in the compound which can be removed by conventional procedures or in vivo to provide the parent compound. When a prodrug of the invention is administered to a mammalian subject, the prodrug is cleaved to form free hydroxyl groups, respectively. Examples of prodrugs include, but are not limited to, phenolic hydroxyl groups and phosphoric acid sodium salt derivatives of the compounds of the invention.

"Co-crystal" or "eutectic" refers to a crystal in which an active pharmaceutical ingredient (API) and a cocrystal former (CCF) are combined by hydrogen bonding or other non-covalent bonds. The pure state of API and CCF is solid at room temperature and there is a fixed stoichiometric ratio between the components. Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-component eutectic formed by a neutral solid with a salt or solvate. The "eutectic former" includes, but is not limited to, various pharmaceutically acceptable acids, bases, nonionic compounds, water, amino acids, alcohols, or other solvents, non-limiting examples of which include alanine (Ala), hydrazine Acid (Val), leucine (Leu), isoleucine (Ile), proline (Pro), phenylalanine (Phe), tryptophan (Trp), methionine (Met), glycine ( Gly), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), asparagine (Asn), glutamine (Gln), lysine (Lys) , arginine (Arg), histidine (His), aspartic acid (Asp), glutamic acid (Glu), pyroglutamic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid , propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinyl sulfonic acid, formic acid, fumaric acid, citric acid, gluconic acid, glucitol Acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfamic acid, tartaric acid, p-toluene Sulfonic acid, malonic acid, 2-hydroxyl Acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citrate Capric acid, lysine, arginine, aspartic acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid, ammonia, isopropylamine, trimethylamine, Diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, general Rucaine, choline, betaine, phenamine penicillin, ethylenediamine, glucosamine, methylglucamine, theobromine, tromethamine, hydrazine, piperazine, piperidine, N-ethylpiperidine, Methanol, ethanol, butynediol, 1,2-propanediol, (R) 1,2-propanediol, (S) 1,2-propanediol or 1-methyl-1,2-ethanediol.

"Effective dose" refers to an amount of a compound that causes a physiological or medical translation of a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of a compound that occurs or reduces it to some extent.

"Solvate" means a compound of the invention or a salt thereof, which also includes a stoichiometric or non-stoichiometric amount of solvent bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

"IC ₅₀ " refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

Detailed ways

The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). The NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD). ), the internal standard is tetramethylsilane (TMS).

The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).

Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.

The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere.

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature.

The room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.

Boc: tert-butoxycarbonyl;

n-Bu: n-butyl;

t-Bu: tert-butyl;

TBS: tert-butyldimethylsilyl;

TIPS: triisopropylsilyl.

Intermediate 1

5-(Difluoromethoxy)-N ¹ -(2-(dimethylamino)ethyl)-N ¹ -methyl-2-nitrobenzene-1,4-diamine (Intermediate 1)

5-(difluoromethoxy)-N ¹ -(2-(dimethylamino)ethyl)-N ¹ -methyl-2-nitrobenzene-1,4-diamine

First step: tert-butyl (4-fluoro-2-hydroxyphenyl)carbamate (1b)

Tert-butyl(4-fluoro-2-hydroxyphenyl)carbamate

2-Amino-5-fluorophenol 1a (5 g, 39.4 mmol) and tetrahydrofuran (100 mL) were added to the reaction flask, and the mixture was stirred and dissolved. Then, di-tert-butyl dicarbonate (17.2 g, 78.7 mmol) was added, and the mixture was stirred at room temperature for two days. . The organic layer was combined with EtOAc (EtOAc) (EtOAc) Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified (jjjjjjjjjjjj Tert-butyl formate (1b) (6 g, yield 67%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.55 (s, 1H), 6.95 (dd, 1H), 6.69 (dd, 1H), 6.56 (ddd, 2H), 1.52 (s, 9H).

The second step: (2-(difluoromethoxy)-4-fluorophenyl)carbamic acid tert-butyl ester (1c)

Tert-butyl(2-(difluoromethoxy)-4-fluorophenyl)carbamate

(4-Butyl-2-hydroxyphenyl)carbamic acid tert-butyl ester (1b) (4 g, 17.6 mmol) and acetonitrile (40 mL) were added to the reaction flask, and the mixture was cooled in ice-cooled, and potassium hydroxide (19.7 g, 352 mmol) was added. The solution of water (40 mL) was cooled to -78 ° C, and diethyl bromofluoromethyl phosphate (11.8 g, 44.1 mmol) was added dropwise, and the mixture was allowed to react to room temperature for 30 minutes. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjjjj The residue was purified by silica gel column chromatography (EtOAc/EtOAc (EtOAc/EtOAc) Ester (1c) (3 g, yield 61%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (t, 1H), 6.95 - 6.83 (m, 2H), 6.72 (s, 1H), 6.52 (t, 1H), 1.52 (s, 9H).

The third step: 2-(difluoromethoxy)-4-fluoro-5-nitroaniline (1d)

2-(difluoromethoxy)-4-fluoro-5-nitroaniline

Concentrated sulfuric acid (10 mL) and water (0.7 mL) were added to the reaction flask, cooled in an ice bath, and (2-(difluoromethoxy)-4-fluorophenyl)carbamic acid tert-butyl ester (1c) (2.7 g) , 9.8 mmol), stirring for 10 minutes, slowly adding potassium nitrate (0.98 g, 9.8 mmol), and adding an ice bath for 1 hour. The reaction mixture was poured into ice water (50 mL), cooled in an ice-bath, and the pH was adjusted to 9 with aqueous ammonia, and extracted with ethyl acetate (50 mL×3). The filtrate was concentrated under reduced pressure, and the residue was purified (jjjjjjjjj 4-Fluoro-5-nitroaniline (1d) (370 mg, yield 17%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.50 (d, 1H), 7.32 (s, 1H), 7.29 (t, 1H), 6.52 (t, 1H), 5.59 (s, 2H).

Fourth step: 5-(difluoromethoxy)-N ¹ -(2-(dimethylamino)ethyl)-N ¹ -methyl-2-nitrobenzene-1,4-diamine (intermediate 1)

Add 2-(difluoromethoxy)-4-fluoro-5-nitroaniline (1d) (250 mg, 1.15 mmol), N,N,N'-trimethylethylenediamine (18A) to the reaction flask. (118 mg, 1.15 mmol), diisopropylethylamine (375 mg, 2.9 mmol) and N,N'-dimethylacetamide (5 mL) were reacted in a microwave at 140 ° C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50: 1) to give a brown oil of 5- (difluoromethoxy) -N ¹ -(2-(Dimethylamino)ethyl)-N ¹ -methyl-2-nitrobenzene-1,4-diamine (Intermediate 1) (120 mg, yield 34%).

MS m/z (ESI): 305.3 [M+1] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ7.25 (t, 1H), 7.13 (d, 2H), 5.40 (s, 2H), 3.08 (t, 2H), 2.67 (t, 2H), 2.63 ( s, 3H), 2.39 (s, 6H).

Intermediate 2

3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (intermediate 2)

3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole

First step: 3-(2-chloropyrimidin-4-yl)-1H-indole (2b)

3-(2-chloropyrimidin-4-yl)-1H-indole

To the reaction flask were added hydrazine (4 g, 34.1 mmol) and 1,2-dichloroethane (114 mL), stirred and dissolved, and then cooled in an ice bath, and a solution of 3 mol/L methylmagnesium bromide tetrahydrofuran (11.4 mL, 34.1 mmol). After the completion of the incubation for 15 minutes, 2,4-dichloropyrimidine (2a) (5.6 g, 37.6 mmol) was added, and the mixture was slowly warmed to room temperature for 3 hours. The reaction mixture was cooled with ice-cooled EtOAc (EtOAc) (EtOAc) The yellow solid 3-(2-chloropyrimidin-4-yl)-1H-indole (2b) (2.9 g, yield 37%) was obtained.

MS m/z (ESI): 230.1 [M + +] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.07 (s, 1H), 8.58 - 8.47 (m, 2H), 8.47 - 8.36 (m, 1H), 7.91 (d, 1H), 7.51 (dd, 1H) ), 7.31–7.15 (m, 2H).

Second step: 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (intermediate 2)

3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole

3-(2-Chloropyrimidin-4-yl)-1H-indole (2b) (2.5 g, 10.9 mmol) and tetrahydrofuran (77 mL) were added to the reaction flask, stirred and dissolved, cooled in an ice bath, and hydrogenated in portions. Sodium (0.48 g, 12 mmol) was added to the reaction for 30 minutes, and methyl iodide (0.75 mL, 12 mmol) was added dropwise. A saturated aqueous solution of sodium hydrogencarbonate (100 mL), ethyl acetate (200 mL) was evaporated, and the mixture was evaporated, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL×1) and brine (50 mL×1). Drying over anhydrous sodium sulfate, EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ - hydrazine (intermediate 2) (2.3 g, yield 85%).

MS m / z (ESI): 244.1 [M + 1] +.

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.45 (d, 1H), 8.32 (dd, 1H), 7.98 (s, 1H), 7.51 (d, 1H), 7.45-7.30 (m, 3H), 3.90 ( s, 3H).

Intermediate 3

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 3)

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene

It is prepared by the synthesis method of intermediate 129 of WO2013014448.

Intermediate 4

5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (intermediate) 4)

5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

First step: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (4b)

3-(2,5-dichloropyrimidin-4-yl)-1H-indole

吲哚4a (12.78g, 109mmol) was dissolved in tetrahydrofuran (60mL), cooled under nitrogen, cooled to 0 ° C, methyl magnesium bromide (36.4mL, 109mmol) was added dropwise, stirring was continued for 0.5 hour, trichloropyrimidine was added (10 g, 54.5 mmol), reacted at room temperature for 1 hour, and further reacted at 60 ° C for 1.5 hours. The reaction solution was cooled to room temperature, acetic acid (6.34 mL) was added dropwise, stirred for 10 min, then (100 mL) water and tetrahydrofuran (30 mL) was added, and stirred at 60 ° C for 30 minutes, and liquid was added, and n-heptane (100 mL) was added to the organic phase. The yellow solid was precipitated, filtered, and the filter cake was washed with n-heptane (100 mL). The filter cake was dried to give 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (4b) (13 g). Rate 91%).

MS m/z: 264.0 [M + 1] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.26 (s, 1H), 8. s (s, 2H), 8.53 (s, 1H), 7.57 (s, 1H), 7.28 (s, 2H).

Step 2: 3-(2,5-Dichloropyrimidin-4-yl)-1-methyl-1H-indole (4c)

3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indole

3-(2,5-Dichloropyrimidin-4-yl)-1H-indole (4b) (6 g, 22.8 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0 ° C, and sodium hydride (1.1 g, 27.4 mmol), the reaction was continued for 30 minutes, methyl iodide (4.26 mL, 68.4 mmol) was added, and the mixture was allowed to react to room temperature for 2 hours. The reaction mixture was concentrated and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (4c), yellow solid (4.7 g, yield 75%).

MS m/z: 278.0 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (d, 2H), 8.55 (d, 1H), 7.61 (d, 1H), 7.43 - 7.22 (m, 2H), 3.96 (s, 3H).

The third step: 4-fluoro-2-methoxy-5-nitroaniline (4e)

4-fluoro-2-methoxy-5-nitroaniline

4-Fluoro-2-methoxyaniline (4d) (17.1 g, 0.1 mmol) was dissolved in concentrated sulfuric acid (100 mL), and potassium nitrate (10.1 g, 0.1 mmol) was slowly added and reacted at 10 ° C under ice bath. hour. The reaction mixture was poured into crushed ice, adjusted to pH 8 with aqueous ammonia, extracted with ethyl acetate (400 mL×2), and the organic phase was combined. Oxy-5-nitroaniline (4e), yellow solid (18.6 g, crude).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.34 (d, 1H), 7.03 (d, 1H), 5.22 (s, 2H), 3.90 (s, 3H).

The fourth step: 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2- Amine (intermediate 4)

3-(2,5-Dichloropyrimidin-4-yl)-1-methyl-1H-indole (4c) (1 g, 3.6 mmol) was dissolved in 2-pentanol (100 mL). 2-methoxy-5-nitroaniline (4e) (672 mg, 3.6 mmol) and p-toluenesulfonic acid (822 mg, 4.32 mmol) were heated to 120 ° C and refluxed for 2 days. The reaction solution was cooled to room temperature, acetonitrile (50 mL) was added, filtered, and the filter cake was washed with acetonitrile (50 mL) and water (50 mL), and the filter cake was dried to give 5-chloro-N-(4-fluoro-2-methoxy 5--5-Nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (Intermediate 4), m.p.

MS m/z: 428.0 [M+1] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ8.74 (s, 1H), 8.66 (d, 1H), 8.58 (s, 1H), 8.47 (s, 1H), 8.33 (d, 1H), 7.53 ( d, 1H), 7.38 (t, 1H), 7.27 (t, 1H), 7.06 (t, 1H), 3.97 (s, 3H), 3.92 (s, 3H).

Intermediate 5

5-((5-Chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitro Benzene (intermediate 5)

5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro- 1-nitrobenzene

First step: (E)-4-(2-butoxyvinyl)-2,5-dichloropyrimidine (5b)

(E)-4-(2-butoxyvinyl)-2,5-dichloropyrimidine

2,4,5-Trichloropyrimidine (5a) (5 g, 27.3 mmol), 1-butoxyethylene (2.85 g, 28.5 mmol), triethylamine (2.88 g, 28.5 mmol) and palladium acetate (0.21 g) , 0.95 mmol) was added to polyethylene glycol (30 mL) and reacted at 50 ° C for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, then water (50 mL) was evaporated. The title compound (E)-4-(2-butoxyvinyl)-2,5-dichloropyrimidine (5b), mp. , yield 9%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 8.07 (d, 1H), 6.09 (d, 1H), 4.03 (t, 2H), 1.76 - 1.70 (m, 2H), 1.48– 1.43 (m, 2H), 0.97 (t, 3H).

Step 2: 3-(2,5-Dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (5c)

3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine

(E)-4-(2-Butoxyvinyl)-2,5-dichloropyrimidine (5b) (0.6 g, 2.4 mmol), 1-amino-pyridine-1-indole (0.6 g, 2.4 mmol) And potassium carbonate (0.84 g, 6.0 mmol) was added to N,N-dimethylformamide (30 mL), and reacted at room temperature to 110 ° C for 5 hours. The mixture was cooled to room temperature, and water (20 mL) was evaporated. The title compound (3-(2,5-dichloropyrimidin-4-yl)pyrazole [1,5-a] was obtained from silica gel column chromatography (ethyl ether (ethyl acetate (v/v) = 10:1). Pyridine (5c), yellow solid (0.1 g, yield 16%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (s, 1H), 8.86 (d, 1H), 8.80 (s, 1H), 8.57 (d, 1H), 7.75 - 7.71 (m, 1H), 7.27 (td, 1H).

MS m/z: 265.1 [M + 1] ⁺ .

The third step: 5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro- 1-nitrobenzene (intermediate 5)

5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene

3-(2,5-Dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (5c) (1 g, 3.7 mmol), 4-fluoro-2-methoxy-5-nitro The aniline (0.84 g, 4.5 mmol) and p-toluenesulfonic acid (1.08 g, 5.6 mmol) were added to 2-pentanol (30 mL), and the mixture was warmed to 120 ° C for 12 hours. After cooling to room temperature, methanol (50 mL) was added and the mixture was filtered, and then filtered, washed with diethyl ether (30mL), and dried to give the title compound 5-((5-chloro-4-(pyrazolo[1,5- a] Pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 5), yellow solid (1 g, yield 64%).

MS m/z: 415.1 [M+1] ⁺ .

Intermediate 6

5-((4-(indol-3-yl)-5-chloropyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 6)

5-((4-(indol-3-yl)-5-chloropyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene

Prepared by the synthetic method of Intermediate 68 of WO2013014448.

Intermediate 7

5-Chloro-4-(4-fluoro-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidine-2-amine (Intermediate 7 )

5-chloro-4-(4-fluoro-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine

First step: 3-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1H-indole (7b)

3-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1H-indole

4-Fluoro-1H-indole (7a) (15 g, 0.11 mol) and tetrahydrofuran (90 mL) were added to the reaction flask, and the mixture was cooled in an ice salt bath, and a 3 mol/L solution of methylmagnesium bromide tetrahydrofuran (37 mL) was added dropwise. The internal temperature was kept below -5 ° C, the reaction was allowed to stand for 30 minutes, 2,4,5-trichloropyrimidine (10.2 g, 0.06 mol) was added, and the reaction was heated to 60 ° C for 1 hour. The reaction mixture was cooled to room temperature, and then added with EtOAc EtOAc (EtOAc) Drying, purification by silica gel column chromatography (petrole ether / ethyl acetate (v/v) = 8: 1-6:1) to give a yellow solid tert-butyl 3-(2,5-dichloropyrimidin-4-yl) 4-fluoro-1H-indole (7b) (3.7 g, yield 24%).

MS m / z (ESI): 280.1 [M-1] -.

^{1 H NMR (400MHz, DMSO-} d 6) δ12.26 (s, 1H), 8.87 (s, 1H), 8.14 (d, 1H), 7.37 (d, 1H), 7.23 (td, 1H), 6.93 ( Dd, 1H).

Second step: 5-chloro-4-(4-fluoro-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine (Intermediate 7)

To the reaction flask was added 3-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1H-indole (7b) (2.6 g, 9.1 mmol), 4-fluoro-2-methoxy- 5-Nitroaniline (4e) (1.3 g, 9.1 mmol), p-toluenesulfonic acid (1.2 g, 11.1 mmol) and 2-pentanol (55 mL) were heated to 120 ° C for 9 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with acetonitrile (5 mL×1) and dichloromethane (5 mL×1), and the filter cake was collected, and petroleum ether (30 mL) was added to the filtrate, stirred, filtered, and filtered. Acetonitrile (5 mL × 1) and methylene chloride (15 mL × 1) were collected and solids were obtained twice to give a yellow-brown solid 5-chloro-4-(4-fluoro-1H-indol-3-yl)-N- ( 4-Fluoro-2-methoxy-5-nitrophenyl)pyrimidine-2-amine (Intermediate 7) (2.2 g, yield 55%).

MS m / z (ESI): 430.1 [M-1] -.

Intermediate 8

4-(7-fluoro-1-methyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidine-2-amine (intermediate) 8)

4-(7-fluoro-1-methyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine

First step: 3-(2-chloropyrimidin-4-yl)-7-fluoro-1H-indole (8b)

3-(2-chloropyrimidin-4-yl)-7-fluoro-1H-indole

7-fluoroindole (10 g, 74 mmol) and 1,2-dichloroethane (270 mL) were added to the reaction flask, stirred and dissolved, and then cooled in an ice bath, and a solution of 3 mol/L methylmagnesium bromide tetrahydrofuran (24.7) was added dropwise. mL, 74 mmol), the reaction was allowed to stand for 15 minutes, 2,4-dichloropyrimidine (2a) (16 g, 110 mmol) was added, and the mixture was slowly warmed to 45 ° C for 24 hours. The reaction mixture was cooled with ice-cooled EtOAc (EtOAc (EtOAc) (EtOAc) Solid 3-(2-chloropyrimidin-4-yl)-7-fluoro-1H-indole (8b) (8.4 g, yield 46.6%).

MS m / z (ESI): 246.1 [M-1] -.

^{1 H NMR (400MHz, DMSO-} d 6) δ12.59 (s, 1H), 8.61-8.54 (m, 2H), 8.25 (d, 1H), 7.97 (d, 1H), 7.21 (td, 1H), 7.09 (dd, 1H).

The second step: 3-(2-chloropyrimidin-4-yl)-7-fluoro-1-methyl-1H-indole (8c)

3-(2-chloropyrimidin-4-yl)-7-fluoro-1-methyl-1H-indole

Add 3-(2-chloropyrimidin-4-yl)-7-fluoro-1H-indole (8b) (280 mg, 1.13 mmol) and tetrahydrofuran (14 mL) to the reaction flask, stir and dissolve, then cool in ice bath. Sodium hydride (58 mg, 2.4 mmol) was added in portions, and the reaction was allowed to stand for 30 minutes. Methyl iodide (0.15 mL, 2.4 mmol) was added dropwise, and the reaction was allowed to stand for 30 minutes, and heated to 40 ° C for 3 hours. The reaction mixture was cooled with ice-cooled EtOAc (EtOAc) (EtOAc) /ethyl acetate (v/v) = 3:1) to give 3-(2-chloropyrimidin-4-yl)-7-fluoro-1-methyl-1H-indole (8c) as a yellow solid. Rate 88%).

MS m/z (ESI): 262.2 [M+1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.43 (d, 1H), 8.08 (d, 1H), 7.80 (s, 1H), 7.42 (d, 1H), 7.17 (td, 1H), 6.97 (dd, 1H), 4.05 (d, 3H).

Third step: 4-(7-fluoro-1-methyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2- Amine (Intermediate 8)

To the reaction flask was added 3-(2-chloropyrimidin-4-yl)-7-fluoro-1-methyl-1H-indole (8c) (260 mg, 1 mmol), 4-fluoro-2-methoxy- 5-Nitroaniline (186 mg, 1 mmol), p-toluenesulfonic acid (132 mg, 1.2 mmol) and 2-pentanol (5 mL) were heated to 105 ° C for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with acetonitrile (10mL×1), and the filter cake was collected to give 4-(7-fluoro-1-methyl-1H-indol-3-yl)-N as a pale yellow solid. -(4-Fluoro-2-methoxy-5-nitrophenyl)pyrimidine-2-amine (Intermediate 8) (280 mg, yield 68%).

MS m / z (ESI): 410.2 [M-1] -.

Intermediate 9

N-(4-Fluoro-2-methoxy-5-nitro-phenyl)-5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidine-2- Amine (Intermediate 9)

N-(4-fluoro-2-methoxy-5-nitro-phenyl)-5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-amine

First step: (trans)-4-(2-n-butoxyvinyl)-2-chloro-5-methoxypyrimidine (9b)

(E)-4-(2-butoxyvinyl)-2-chloro-5-methoxypyrimidine

2,4-Dichloro-5-methoxypyrimidine (9a) (10.74 g, 60 mmol) was weighed and placed in a 500 mL round bottom flask, and polyethylene glycol 400 (150 mL) and triethylbenzene were sequentially added to the reaction flask. Amine (12.5 mL, 90.00 mmol), vinyl n-butyl ether (11.6 mL, 90.00 mmol) and palladium acetate (0.67 g, 3 mmol), warmed to 80 ° C and stirred for 16 hours. The reaction mixture was cooled to room temperature, water (200 mL) was added, and ethyl acetate (250 mL×2) was evaporated. The organic phase was combined, and the organic phase was washed with saturated brine (150 mL) Separation and purification (petroleum ether / ethyl acetate (v / v) = 5:1) to give (trans)-4-(2-n-butoxyvinyl)-2-chloro-5-methoxy Pyrimidine (9b) (6.64 g, yield 46%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.98-7.94 (m, 2H), 6.04-6.01 (d, 1H), 3.98-3.95 (m, 2H), 3.90 (s, 3H), 1.75-1.68 (m , 2H), 1.45-1.41 (m, 2H), 0.97-0.93 (m, 3H).

Second step: 3-(2-chloro-5-methoxy-pyrimidin-4-yl)pyrazolo[1,5-a]pyridine (9c)

3-(2-chloro-5-methoxy-pyrimidin-4-yl)pyrazolo[1,5-a]pyridine

(trans)-4-(2-n-butoxyvinyl)-2-chloro-5-methoxypyrimidine (9b) (9.0 g, 37.3 mmol) was weighed and placed in a 250 mL round bottom flask. N,N-dimethylacetamide (100 mL), 1-aminopyridine iodide (8.2 g, 37.3 mmol) and potassium carbonate (12.9 g, 92.5 mmol) were sequentially added to the reaction flask, and the mixture was heated to 110 ° C under stirring. hour. The reaction solution was cooled to room temperature, and water (100 mL) was added, and the mixture was evaporated to ethyl acetate (150 mL×2), and the organic phase was washed with brine (50 mL×2) Purification by chromatography (petroleum ether / ethyl acetate (v/v) = 3:1) to give 3-(2-chloro-5-methoxy-pyrimidin-4-yl)pyrazole as a yellow solid. , 5-a]pyridine (9c) (3.9 g, yield 40%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.81-8.78 (m, 2H), 8.57-8.56 (d, 1H), 8.15 (s, 1H), 7.46-7.44 (m, 1H), 7.02-6.99 (m) , 1H), 4.08 (s, 3H).

Third step: N-(4-fluoro-2-methoxy-5-nitro-phenyl)-5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl- Pyrimidin-2-amine (intermediate 9)

3-(2-Chloro-5-methoxy-pyrimidin-4-yl)pyrazolo[1,5-a]pyridine (9c) (1.04 g, 4 mmol) was weighed and placed in a 50 mL round bottom flask. 2-pentanol (15 mL), 4-fluoro-2-methoxy-5-nitroaniline (0.74 g, 4 mmol), p-toluenesulfonic acid (0.84 g, 4.4 mmol). The reaction system was heated to 120 ° C and stirred for 48 hours and then cooled to room temperature. Acetonitrile (20 mL) and aqueous ammonia (20 mL) were added to the reaction mixture. Filtration, the filter cake was washed with acetonitrile (10 mL×2), washed with water (10 mL×2), and the filter cake was collected and dried to give N-(4-fluoro-2-methoxy-5-nitro-benzene as a yellow solid. 5-)-5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-amine (Intermediate 9) (0.6 g, yield 37%).

Intermediate 10

N-(3,4-Difluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (Intermediate 10)

N-(3,4-difluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

First step: N-(3,4-difluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine ( Intermediate 10)

3-(2-Chloropyrimidin-4-yl)-1-methyl-1H-indole (Intermediate 2) (3 g, 12 mmol), 3,4-difluoro-2-methoxy-5-nitro The phenylaniline (10a) (3 g, 14 mmol) and p-toluenesulfonic acid (3.5 g, 18 mmol) were added to 2-pentanol (30 mL) and reacted at 120 ° C for 12 hours. The reaction solution was cooled to room temperature, MeOH (50 mL) was evaporated, filtered, and the filter cake was washed with diethyl ether (30 mL) and dried to give the title compound N-(3,4-difluoro-2-methoxy-5-nitro Benzene-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (Intermediate 10), yellow solid (3 g, yield 62.5%).

MS m/z: 494.3 [M + 1] ⁺ .

Example 1

N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1- Methyl-1,7-diazaspiro[4.4]decane-7-yl)phenyl)acrylamide (Compound 1)

N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1, 7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide

First step: 5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1 -methyl-1,7-diazaspiro[4.4]decane-7-yl)-1-nitrobenzene (1B)

5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro [4.4]nonan-7-yl)-1-nitrobenzene

5-((5-Chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitro Benzobenzene (Intermediate 5) (0.3 g, 0.72 mmol), 1-methyl-1,7-diazaspiro[4.4]decane (1A) (0.15 g, 10.8 mmol) and N,N-diiso Propylethylamine (i.e., DIPEA) (0.28 g, 2.17 mmol) was added to N,N-dimethylformamide (3 mL). After cooling to room temperature, water (20 mL) was evaporated, evaporated, evaporated, evaporated 5-((5-Chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl- 1,7-diazaspiro[4.4]decane-7-yl)-1-nitrobenzene (1B), red solid (0.3 g, yield 79%).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.94 (s, 1H), 8.84 (d, 1H), 8.68 (s, 1H), 8.41 (s, 2H), 8.06 (s, 1H), 7.32 ( m,1H),7.13(m,1H),6.56(s,1H),3.90(s,3H),3.43–3.41(m,2H), 3.26-3.24(m,1H),2.77–2.64(m, 3H), 2.31 (s, 3H), 2.12-2.09 (m, 1H), 1.79 - 1.66 (m, 5H).

MS m/z: 535.3 [M + 1] ⁺ .

Second step: 5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1) -methyl-1,7-diazaspiro[4.4]decane-7-yl)aniline (1C)

5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro [4.4]nonan-7-yl)aniline

5-((5-Chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl) -1,7-diazaspiro[4.4]decane-7-yl)-1-nitrobenzene (1B) (0.6 g, 1.12 mmol), iron powder (0.378 g, 6.7 mmol) and amine chloride added The mixture was reacted at 90 ° C for 4 hours in a mixed solution of ethanol (20 mL) and water (5 mL). After cooling to room temperature, water (20 mL) was added toEtOAc. 5-((5-Chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl- 1,7-diazaspiro[4.4]nonane-7-yl)aniline (1C), red solid (0.56 g, crude).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.94 (s, 1H), 8.82 (d, 1H), 8.44-8.36 (m, 3H), 7.32 (m, 1H), 7.12 (m, 1H), 6.94(s,1H), 6.69(s,1H), 4.26(s,2H),3.66(s,3H), 3.21(d,1H),3.13(s,1H),3.07–3.01(m,1H) , 2.70–2.64 (m, 3H), 2.34 (s, 3H), 2.10–2.03 (m, 1H), 1.93–1.83 (m, 2H), 1.80–1.61 (m, 3H).

MS m/z; 505.3 [M + 1] ⁺ .

The third step: N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2 -(1-Methyl-1,7-diazaspiro[4.4]decane-7-yl)phenyl)acrylamide (Compound 1)

5-((5-Chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl) -1,7-diazaspiro[4.4]decane-7-yl)aniline (1C) (0.6 g, 1.1 mmol), N-ethyldiisopropylamine (0.3 g, 2.2 mmol), THF (20 mL) A solution of acryloyl chloride (0.1 g, 1.1 mmol) in tetrahydrofuran (5 mL) was added dropwise at -40 ° C, and reacted at this temperature for half an hour. Water (10 mL) was added to the mixture, and the mixture was evaporated. The title compound N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl) was obtained as the title compound (m.p. Pyrimidine-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]decane-7-yl)phenyl)acrylamide (Compound 1 ), yellow solid (0.18 g, yield 27%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.10 (s, 1H), 8.93 (s, 1H), 8.54-8.51 (m, 2H), 8.41 (s, 1H), 8.18 (s, 1H), 7.40 ( s, 1H), 7.31 (m, 1H), 6.90 (t, 1H), 6.71 (s, 1H), 6.35 - 6.31 (m, 2H), 5.72 - 5.69 (m, 1H), 3.89 (s, 3H) , 3.25 (s, 2H), 3.06 (d, 1H), 2.78 (s, 3H), 2.50 (s, 3H), 2.22 (s, 1H), 2.00 (s, 2H), 1.87 (s, 3H).

MS m/z: 559.4 [M+1] ⁺ .

Example 2

(S)-N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2 -(1-methyl-1,7- Diazaspiro[4.4]decane-7-yl)phenyl)acrylamide (Compound 2)

(S)-N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1- Methyl-1,7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide

Example 3

(R)-N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2 -(1-Methyl-1,7-diazaspiro[4.4]decane-7-yl)phenyl)acrylamide (Compound 3)

(R)-N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1- Methyl-1,7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide

The resolution methods of Embodiment 2 and Embodiment 3 are as follows:

Take N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1) -Methyl-1,7-diazaspiro[4.4]decane-7-yl)phenyl)acrylamide (Compound 1) (100 mg) was used for resolution, and the preparation conditions were: instrument GX-281C0630, (0.1 % diethylamine + n-hexane) / isopropanol = 70/30, 10.0 mL / min, 254 nm, column temperature 40 ° C (AD-H20 * 250 mm 5 um H-37); two optical isomers were obtained: isomer 1 (peak 1, 50 mg, yellow solid, ee% = 100%, t = 33.97 min), isomer 2 (peak 2, 50 mg, yellow solid, ee% = 100%, t = 40.78 min).

Isomer 1

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.11 (s, 1H), 8.93 (s, 1H), 8.53 (d, 2H), 8.42 (s, 1H), 8.16 (s, 1H), 7.40 (s, 1H), 7.30 (d, 1H), 6.90 (t, 1H), 6.72 (s, 1H), 6.40 - 6.16 (m, 2H), 5.71 (d, 1H), 3.89 (s, 3H), 3.24 (d) , 2H), 3.07 (d, 1H), 2.77 (s, 3H), 2.48 (s, 3H), 2.21 (s, 1H), 2.05 - 1.78 (m, 5H).

MS m/z: 559.3 [M+1] ⁺ .

Isomer 2

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.11 (s, 1H), 8.93 (s, 1H), 8.53 (d, 2H), 8.42 (s, 1H), 8.16 (s, 1H), 7.40 (s, 1H), 7.30 (d, 1H), 6.90 (t, 1H), 6.72 (s, 1H), 6.35 - 6.25 (m, 2H), 5.71 (d, 1H), 3.89 (s, 3H), 3.34 - 3.13 (m, 2H), 3.08 - 3.06 (m, 1H), 2.95 - 2.64 (m, 3H), 2.48 (s, 3H), 2.21 (s, 1H), 2.09 - 1.78 (m, 5H).

MS m/z: 559.3 [M+1] ⁺ .

Example 4

N-(5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diaza Heterospiro[4.4]decane-7-yl)phenyl)acrylamide trifluoroacetate (compound 4)

N-(5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7- Yll)phenyl)acrylamide triflouro

First step: 5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-di Azaspiro[4.4]decane-7-yl)-1-nitrobenzene (4B)

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)- 1-nitrobenzene

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 3) (1.0 g, 2.5 mmol) and N,N-diisopropylethylamine (0.65 g, 5.0 mmol) were added to N,N-dimethylformamide (3 mL). After cooling to room temperature, water (20 ml) was added, and the mixture was combined with methylene chloride (50 mL × 3). The title compound 5-((5-chloro-4-(1-methylindol-3-yl)pyrimidine-2) was obtained as the title compound (m. -yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]decane-7-yl)-1-nitrobenzene (4B), yellow solid (0.5 g, yield 38.4%).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.54 (s, 1H), 8.36 (d, 1H), 8.34-8.25 (m, 2H), 8.04 (s, 1H), 7.51 (d, 1H), 7.24(t,1H),7.18(d,1H),7.10(t,1H),6.57(s,1H),3.96(s,3H),3.87(s,3H),3.42(d,2H),3.25 (d, 1H), 2.78 - 2.68 (m, 3H), 2.31 (s, 3H), 2.11 - 2.09 (m, 1H), 1.83 - 1.65 (m, 5H).

MS m/z: 514.3 [M + 1] ⁺ .

Second step: 5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-di Azaspiro[4.4]decane-7-yl)aniline (4C)

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)aniline

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro) [4.4] decane-7-yl)-1-nitrobenzene (4B) (0.5 g, 0.97 mmol), iron powder (0.32 g, 5.8 mmol) and amine chloride (0.52 g, 9.7 mmol) were added to ethanol In a mixed solution of (5 mL) / water (2 mL), the reaction was carried out at 90 ° C for 4 hours. After cooling to room temperature, water (20 mL) was added, and the mixture was evaporated. -((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4 ]decane-7-yl)aniline (4C), yellow solid (0.4 g, yield 85%).

MS m/z: 484.4 [M + 1] ⁺ .

The third step: N-(5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1, 7-diazaspiro[4.4]decane-7-yl)phenyl)acrylamide (4D)

N-(5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7- Yl)phenyl)acrylamide

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro) [4.4] decane-7-yl) aniline (4C) (0.5 g, 1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (ie EDCI) (0.149 g, 2.0 mmol) and acrylic acid (0.79 g, 4 mmol) were added to pyridine (5 mL) and allowed to react at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was evaporated. The title compound N-(5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino) was obtained as the title compound (m.p. 4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]decane-7-yl)phenyl)acrylamide (4D), yellow solid (0.2 g, yield 36%).

^{1 H NMR (400MHz, DMSO-} d 6) δ9.29 (s, 1H), 8.40 (s, 1H), 8.33 (d, 1H), 8.27 (d, 1H), 8.15 (s, 1H), 7.78 ( s, 1H), 7.51 (d, 1H), 7.27 - 7.11 (m, 3H), 6.59 (s, 1H), 6.56 - 6.49 (m, 1H), 6.21 (dd, 1H), 5.75 - 5.69 (m, 1H), 3.89–3.86 (m, 6H), 3.37 (d, 1H), 3.25–3.22 (m, 2H), 2.77–2.59 (m, 3H), 2.31 (s, 3H), 2.05–2.02 (m, 1H), 1.81–1.58 (m, 5H).

MS m/z: 538.1 [M+1] ⁺ .

Fourth step: N-(5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1, 7-diaza snail [4.4] decane-7-yl)phenyl)acrylamide trifluoroacetate (Compound 4)

N-(5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7- Yl)phenyl)acrylamide triflouroacetate

N-(5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-di Azaspiro[4.4]decane-7-yl)phenyl)acrylamide (4D) (50 mg, 0.09 mmol) was dissolved in dichloromethane (10 mL). Concentration to give N-(5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7 -Diazaspiro[4.4]decane-7-yl)phenyl)acrylamide trifluoroacetate (Compound 4), yellow solid (57 mg).

^{1 H NMR (400MHz, DMSO-} d 6) δ10.14 (s, 1H), 9.31 (d, 1H), 8.54 (d, 1H), 8.31-8.27 (m, 3H), 7.54 (d, 1H), 7.25–7.18(m,3H), 6.77(d,1H), 6.66–6.45(m,1H), 6.23(d,1H), 5.74(d,1H),3.91(s,3H),3.88(s, 3H), 3.75–3.51 (m, 3H), 3.18–3.13 (m, 3H), 2.88 (s, 3H), 2.38–1.90 (m, 6H).

MS m/z: 538.2 [M+1] ⁺ .

Example 5

N-(2-((1-Aminocyclopropyl)methoxy)-5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2- Amino)-4-methoxyphenyl)acrylamide trifluoroacetate (compound 5)

N-(2-((1-aminocyclopropyl)methoxy)-5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4- Methoxyphenyl)acrylamide trifluoroacetate

First step: (1-((4-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-5-methoxy -2-nitrobenzene Oxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (5B)

Tert-butyl(1-((4-((5-a)pyridin-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenoxy) Methyl)cyclopropyl)carbamate

5-Chloro-N-(4-fluoro-2-methoxy-5-nitro-phenyl)-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-amine (Intermediate 5) (0.41 g, 1.00 mmol) was placed in a round bottom flask. To the reaction flask was added tetrahydrofuran (20 mL), cooled to 0 ° C, and sodium hydride (0.08 g, 1.1 mmol, wt%) was added to the reaction flask. = 60%), stirred for 5 minutes, (1-hydroxymethylcyclopropyl)-tert-butoxycarbonylamino (5A) (0.21 g, 1.1 mmol). The reaction was allowed to rise to room temperature and the reaction was terminated for 4 hours. Water (20 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (50 mL×2), and the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate (Petroleum Ether/Ethyl acetate (v/v) = 1:1) gave (1-((4-((5-chloro-4-)pyrazolo[1,5-a]pyridine) as a yellow solid. 3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (5B) (0.56 g, yield 97 %).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.60 (s, 1H), 8.58 (s, 1H), 8.46-8.42 (m, 1H), 8.40-8.35 (m, 1H), 8.32 (s, 1H), 8.25(br,1H),7.43-7.39(m,1H),7.05-7.02(m,1H),5.25(br,1H), 4.19(s,2H),4.01(s,3H),1.42(s, 9H), 097 (s, 4H).

The second step: (1-((2-amino-4-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-5 -Methoxyphenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (5C)

Tert-butyl(1-((2-amino-4-((5-a)pyridin-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenoxy) Methyl)cyclopropyl)carbamate

Weighing (1-((4-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2 -Nitrophenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (5B) (0.58 g, 1.0 mmol), placed in a 100 mL round bottom flask, and then ethanol (21 mL) was added to the reaction flask. Water (7 mL), reduced iron powder (0.34 g, 6.0 mmol) and ammonium chloride (0.037 g, 0.7 mmol) were reacted under reflux, and after 6 hours, they were then worked up. The reaction solution was filtered, and the filter cake was washed with dichloromethane (10 mL×2) and methanol (10 mL×2), and the filtrate was concentrated, and the residue was purified by column chromatography ( petroleum ether/ethyl acetate (v/v) ) = 1:1) (1-((2-amino-4-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2) -Amino)amino)-5-methoxyphenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (5C) (0.37 g, yield 67%).

The third step: (1-((2-acrylamido-4-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino) -5-Methoxyphenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (5D)

Tert-butyl(1-((2-acrylamido-4-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenoxy) Methyl)cyclopropyl)carbamate

Weighing (1-((2-amino-4-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-5-A Oxyphenoxy Tert-butyl)methyl)cyclopropyl)carbamic acid tert-butyl ester (5C) (0.37 g, 0.67 mmol) was placed in a 100 mL round bottom flask, and tetrahydrofuran (15 mL) and diisopropyl B were sequentially added to the reaction flask. The amine (0.12 mL, 0.74 mmol) was cooled to 0 ° C, and acryloyl chloride (0.055 mL, 0.70 mmol) was added dropwise. After the dropwise addition was completed, the reaction was warmed for 1 hour. The reaction mixture was concentrated under reduced pressure. dichloromethane (50 mL) andEtOAc. The mixture was washed with brine (30 mL), dried over anhydrous sodium sulfate sulfatessssssssssssssssss (2-Acrylamide-4-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenoxyl (Methyl)cyclopropyl)carbamic acid tert-butyl ester (5D) (0.20 g, yield 49%).

Fourth step: N-(2-((1-aminocyclopropyl)methoxy)-5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)) Pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide trifluoroacetate (compound 5)

N-(2-((1-aminocyclopropyl)methoxy)-5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4- Methoxyphenyl)acrylamide 2,2,2-trifluoroacetate

Weighing (1-((2-acrylamido-4-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-5 -Methoxyphenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (5D) (0.2 g, 0.33 mmol) was placed in a 100 mL round bottom flask and dichloromethane was added to the reaction flask sequentially. 15 mL) and trifluoroacetic acid (5 mL) were reacted at room temperature for 1 hour. Concentration under reduced pressure gave N-(2-((1-aminocyclopropyl)methoxy)-5-((5-chloro-4-(pyrazolo[1,5-a]pyridine) as a yellow solid. 3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide trifluoroacetate (Compound 5) (0.03 g, yield 15%).

MS m/z (ESI): 506.3 [(MM _TFA ) +1] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ9.23 (s, 1H), 8.84 (s, 1H), 8.78-8.76 (d, 1H), 8.69 (s, 1H), 8.48 (br, 3H), 8.38(m,2H), 8.22(s,1H),7.33-7.31(m,1H),7.11-7.08(m,1H),6.88(s,1H),6.57-6.55(m,1H),6.23- 6.20 (d, 1H), 5.78-5.75 (d, 1H), 4.24 (s, 2H), 3.77 (s, 3H), 1.12-1.09 (m, 2H), 1.03-1.00 (m, 2H).

Example 6

N-(2-(((1-aminocyclopropyl)methyl)(methyl)amino)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)-4-methoxyphenyl)acrylamide trifluoroacetate (compound 6)

N-(2-(((1-aminocyclopropyl)methyl)(methyl)amino)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4- Methoxyphenyl)acrylamide trifluoroacetate

First step: (1-((4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-nitrobenzene) (m)(methyl)amino)methyl)cyclopropyl)carbamic acid tert-butyl ester (6B)

Tert-butyl-(1-((4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)(methyl)amino )methyl)cyclopropyl)carbamate

5-((4-(Indol-3-yl)-5-chloropyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 6) (1.0 g, 2.4 mmol), tert-butyl (1-((methylamino)methyl)cyclopropyl)carbamate (6A) (0.96 g, 4.8 mmol) and N,N-diisopropylethylamine (0.62) g, 4.8 mmol) was added to trifluoroethanol (3 mL) and subjected to microwave reaction at 140 ° C for 1.5 hours. The reaction mixture was cooled to room temperature, water (20 mL), EtOAc (EtOAc) Purification by chromatography (dichloromethane:methanol (v/v) = 50:1) -2-yl)amino)-5-methoxy-2-nitrophenyl)(methyl)amino)methyl)cyclopropyl)carbamic acid tert-butyl ester (6B), red solid (0.5 g, yield The rate is 34.97%).

MS m/z: 594.3 [M + 1] ⁺ .

Second step: (1-((4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-aminophenyl) )(methyl)amino)methyl)cyclopropyl)carbamic acid tert-butyl ester (6C)

Tert-butyl-(1-(((4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-aminophenyl)(methyl)amino )methyl)cyclopropyl)carbamate

(1-((4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)) Tert-butyl)amino)methyl)cyclopropyl)carbamic acid tert-butyl ester (6B) (0.27 g, 0.45 mmol), iron powder (0.15 g, 2.7 mmol) and ammonium chloride (0.24 g, 4.5 mmol) were added to ethanol (5 mL) and water (2 mL) were reacted at 90 ° C for 4 hours. After cooling to room temperature, water (20 mL) was added toEtOAc. (1-((4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-aminophenyl) (methyl) Amino)methyl)cyclopropyl)carbamic acid tert-butyl ester (6C), yellow Color solid (0.18 g, yield 70.3%).

MS m/z: 564.2 [M + 1] ⁺ .

The third step: N-(2-((1-(tert-butoxycarbonyl)aminocyclopropyl)methyl)(methyl)amino)-5-((5-chloro-4-(1H-吲) Ind-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (6D)

N-(2-((1-(tert-butoxycarbonyl)aminocyclopropyl)methyl)(methyl)amino)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)-4-methoxyphenyl)acrylamide

(1-(((4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-aminophenyl)) Amino)methyl)methyl)cyclopropyl)carbamic acid tert-butyl ester (6C) (0.16 g, 0.28 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.21 g, 1.1 mmol) and acrylic acid (40.9 mg, 0.56 mmol) were added to pyridine (5 mL) and allowed to react at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was combined with methylene chloride (50 mL × 3). The title compound N-(2-((1-(tert-butoxycarbonyl)aminocyclopropyl)methyl)(methyl) was obtained as the title compound (m.p. Amino)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (6D), yellow solid (0.15 g, yield 88%).

MS m/z: 618.2 [M + 1] ⁺ .

Fourth step: N-(2-(((1-aminocyclopropyl)methyl)(methyl)amino)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidine) -2-yl)amino)-4-methoxyphenyl)acrylamide trifluoroacetate (compound 6)

N-(2-((1-(tert-Butoxycarbonyl)aminocyclopropyl)methyl)(methyl)amino)-5-((5-chloro-4-(1H-indole-3) -yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (6D). (0.15 g, 0.24 mmol) was added to dichloromethane (2 mL) and trifluoroacetic acid (1 mL) The reaction was carried out for 2 hours at room temperature. The reaction mixture was concentrated to give the title compound N-(2-((l-aminocyclopropyl)methyl)(methyl)amino)-5-((5-chloro-4-(1H-indole-3-) Pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide trifluoroacetate (compound 6), yellow solid (0.1 g, yield 88%).

^{1 H NMR (400MHz, DMSO-} d 6) δ11.85 (s, 1H), 9.21 (s, 1H), 8.50-8.49 (m, 2H), 8.43 (s, 1H), 8.36 (s, 1H), 8.35–8.22 (m, 4H), 7.45 (m, 1H), 7.15 (m, 1H), 7.00 (m, 1H), 6.95 (s, 1H), 6.71–6.64 (m, 1H), 6.23 (d, 1H), 5.76 (d, 1H), 3.77 (s, 3H), 3.16 (s, 1H), 2.65 (s, 3H), 1.04 (s, 2H), 0.85 (s, 2H).

MS m/z: 518.1 [M+1] ⁺ .

Example 7

N-(2-((1-Aminocyclopropyl)methoxy)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4- Methoxybenzene Acrylamide (compound 7)

N-(2-((1-aminocyclopropyl)methoxy)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

First step: (1-((2-nitro-4-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5- Methoxyphenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (7B)

Tert-butyl(1-((4-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenoxy)methyl) Cyclopropyl)carbamate

5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (middle) 4) (650 mg, 1.52 mmol) was dissolved in tetrahydrofuran (50 mL), sodium hydride (121.6 mg, 3.04 mmol, wt% = 60%) was added under ice-cooling, stirred for 30 minutes, and added (1-(hydroxymethyl) tert-Butyl propyl)carbamate (313.1 mg, 1.67 mmol) was reacted overnight at room temperature. Water (100 mL) and ethyl acetate (150 mL) were added to the mixture, and the mixture was evaporated. ((2-Nitro-4-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenoxy) Methyl)cyclopropyl)carbamic acid tert-butyl ester (7B), yellow solid (903 mg).

MS m/z: 595.1 [M + 1] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ8.58 (d, 2H), 8.40 (s, 1H), 8.39-8.22 (m, 2H), 7.51 (d, 1H), 7.25 (dd, 9.8Hz, 2H), 7.01 (s, 2H), 4.29 (s, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 1.99 (s, 1H), 1.37 (s, 9H), 0.87 (s, 2H) ), 0.77 (s, 2H).

The second step: (1-((2-amino-4-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-- Oxyphenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (7C)

Tert-butyl(1-((2-amino-4-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenoxy)methyl) Cyclopropyl)carbamate

(1-((2-Nitro-4-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy tert-Butyl benzyloxy)methyl)cyclopropyl)carbamate (7B) (900mg, 1.52mmol) was dissolved in ethanol (30mL), water (10mL), iron powder (509mg, 9.12mmol) and chlorine Ammonium (57 mg, 10.6 mmol) was heated to 90 ° C and refluxed for 4 hours. The reaction solution was cooled to room temperature, filtered and concentrated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 20:1) to give compound (1-((2-amino-4-((5-chloro-4-)) 1-Methyl-1H-indol-3-ylpyrimidin-2-yl)amino)-5-methoxyphenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (7C), yellow-green Solid (800 mg, yield 93%).

MS m/z: 565.2 [M + 1] ⁺ .

Third step: N-(2-((1-(tert-butoxycarbonyl)aminocyclopropyl)methoxy)-5-((5-chloro-4-(1H-indol-3-yl)) Pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (7D)

N-(2-((1-(tert-butoxycarbonyl)aminocyclopropyl)methoxy)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl Acrylamide

(1-((2-Amino-4-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxybenzene Oxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (7C) (800 mg, 1.4 mmol) was dissolved in tetrahydrofuran (30 mL). N,N-diisopropylethylamine (0.278 mg, 1.68 mmol) The reaction solution was cooled to 0 ° C, and a solution of acryloyl chloride (0.17 mL, 2.1 mmol) in tetrahydrofuran (5 mL) was added dropwise. To the reaction mixture, aq. :1), the compound N-(2-((1-(tert-butoxycarbonyl))aminocyclopropyl)methoxy)-5-((5-chloro-4-(1H-indole-3-) Pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (7D), red solid (450 mg, yield 52%).

MS m/z: 619.2 [M+1] ⁺ .

Fourth step: N-(2-((1-aminocyclopropyl)methoxy)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino )-4-methoxyphenyl)acrylamide (compound 7)

N-(2-((1-(tert-Butoxycarbonyl)aminocyclopropyl)methoxy)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidine-2) -Amino)-4-methoxyphenyl)acrylamide (7D) (450 mg, 0.73 mmol) was dissolved in dichloromethane (12 mL). Water (50 mL) was added to the reaction mixture, and the mixture was adjusted to pH 8 with a saturated aqueous sodium hydrogen carbonate solution, ethyl acetate (100 mL) was added, and the organic phase was concentrated, and the residue was obtained to give N-(2-((1- Aminocyclopropyl)methoxy)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide Compound 7), pale yellow solid (70 mg, yield 19%).

MS m/z: 519.1 [M+1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.32 (s, 1H), 8.41 (d, 2H), 8.33 (d, 2H), 7.41 (s, 1H), 7.36 (d, 1H), 7.29 (d, 1H), 7.21(t,1H), 6.57(s,1H), 6.38(dd,1H), 6.34–6.25(m,1H), 5.70(d,1H),3.90(s,5H),3.87(s , 3H), 1.25 (s, 1H), 0.75 (t, 2H), 0.67 (t, 2H).

Example 8

N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(tetrahydropyrrole) -1-yl)ethyl)amino)phenyl)acrylamide (compound 8)

N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl) )amino)phenyl)acrylamide

First step: 5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(tetrahydro) Pyrrol-1-yl)ethyl)amino)-1-nitrobenzene (8B)

5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino) -nitrobenzene

5-((4-(Indol-3-yl)-5-chloropyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 6) (1.0 g, 2.4 mmol), N-methyl-2-(tetrahydropyrrol-1-yl)ethylamine (8A) (0.60 g, 4.8 mmol) and N,N-diisopropylethylamine (0.6 g, 4.8 mmol) was added to N,N-dimethylacetamide (3 mL), and subjected to microwave reaction at 140 ° C for 1.5 hours. The reaction mixture was cooled to room temperature, water (20 mL), EtOAc (EtOAc) Chromatographic separation and purification (dichloro Methane:methanol (v/v) = 50:1) gave the title compound 5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy 2-(Methyl(2-(tetrahydropyrrol-1-yl)ethyl)amino)-1-nitrobenzene (8B), red solid (0.5 g, yield 40%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.17 (s, 1H), 9.04 (s, 1H), 8.45 (m, 1H), 8.39 (s, 1H), 8.29 (s, 1H), 7.51 (s, 1H), 7.41 (m, 1H), 7.34 - 7.19 (m, 2H), 6.65 (s, 1H), 3.93 (s, 3H), 3.36 - 3.25 (m, 2H), 2.86 (s, 3H), 2.81 – 2.72 (m, 2H), 2.58 (s, 4H), 1.77 (s, 4H).

5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino) Aniline

5-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(tetrahydropyrrole-1) -Ethyl)amino)-1-nitrobenzene (8B) (0.5 g, 0.95 mmol), iron powder (0.32 g, 5.7 mmol) and amine chloride (0.51 g, 9.5 mmol) were added to ethanol (5 mL) ) and reacted with water (2 mL) at 90 ° C for 4 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was evaporated. The title compound 5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(tetrahydropyrrole) was obtained. 1-yl)ethyl)amino)aniline (8C), red solid (0.4 g, yield 85%).

MS m/z: 492.4 [M+1] ⁺ .

The third step: N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-) (tetrahydropyrrol-1-yl)ethyl)amino)phenyl)acrylamide (Compound 8)

5-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(tetrahydropyrrole-1) -Ethyl)amino)aniline (8C) (0.4 g, 0.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.31 g, 1.6 mmol) Acrylic acid (0.12 g, 1.6 mmol) was added to pyridine (5 mL) and allowed to react at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was evaporated. The title compound N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) was obtained as the title compound (m.p. Amino)-4-methoxy-2-(methyl(2-(tetrahydropyrrol-1-yl)ethyl)amino)phenyl)acrylamide (compound 8), yellow solid (0.12 g, yield 27 %).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.85 (s, 1H), 9.44 (s, 1H), 9.32 (s, 1H), 8.51 - 8.48 (m, 1H), 8.28 - 8.25 (m, 2H), 7.55 (s, 1H), 7.35 - 7.32 (m, 1H), 7.22 - 7.17 (m, 2H), 6.79 (s, 1H), 6.42 - 6.39 (m, 2H), 5.72 - 5.69 (m, 1H), 3.88 (s, 3H), 2.99 (s, 2H), 2.71 (s, 3H), 257 - 2.40 (m, 6H), 1.85 (s, 4H).

MS m/z: 546.3 [M + 1] ⁺ .

Example 9

N-(4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)-5-((4-(1-methyl-1H-indole-3-) Pyridin-2-yl)amino)phenyl)acrylamide (compound 9)

N-(4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl) )amino)phenyl)acrylamide

First step: 2-methoxy-N ⁴ -methyl-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-nitro-N ^4- (2-(pyrrolidin-1-yl)ethyl)phenyl-1,4-diamine (9B)

2-methoxy-N ⁴ -methyl-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-nitro-N ⁴ -(2-(pyrrolidin-1- Yl)ethyl)benzene-1,4-diamine

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 3) (1.0 g, 2.5 mmol), N-methyl-2-(pyrrolidin-1-yl)ethylamine (9A) (650 mg, 5.1 mmol), N,N-diisopropylethylamine (660 mg, 5.1 mmol) N,N-dimethylaniline (5 mL) was placed in a 25 mL microwave reaction tube and microwaved at 140 ° C for 1.5 hours. The reaction mixture was poured into water (50 mL) and dichloromethane (50 mL), and the organic layer was washed with water (50 mL×2) and brine (50 mL×1) Chromatographic separation and purification (eluent with petroleum ether: ethyl acetate (v/v) = 1:1 to 0:1, then dichloromethane: methanol (v/v) = 32:1 to 9:1 The title compound 2-methoxy-N ⁴ -methyl-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-nitro-N was obtained. ^4- (2-(Pyrrolidin-1-yl)ethyl)phenyl-1,4-diamine (9B), yellow solid ( 820 mg, yield 66%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.56 (s, 1H), 8.39 (d, 1H), 8.26 (s, 1H), 8.17 (m, 1H), 7.54 (s, 1H), 7.43 - 7.37 ( m,1H), 7.35–7.27 (m, 2H), 7.19 (d, 1H), 6.70 (s, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.41–3.34 (m, 2H) , 2.91 (s, 3H), 2.88 - 2.78 (m, 2H), 2.64 (br, 4H), 1.81 (br, 4H).

MS m/z: 502.2 [M + 1] ⁺ .

Second step: 5-methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2- (pyrrolidin-1-yl)ethyl)benzene-1,2,4-triamine (9C)

5-methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(pyrrolidin-1-yl)ethyl) Benzene-1,2,4-triamine

2-methoxy-N ⁴ -methyl-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-nitro-N ⁴ - ( 2-(Pyrrolidin-1-yl)ethyl)phenyl-1,4-diamine (9B) (820 mg, 1.63 mmol) was dissolved in ethanol (30 mL) and water (10 mL). 9.78 mmol) and ammonium chloride (872 mg, 16.3 mmol) were refluxed at 95 ° C for 3 hours. The reaction mixture was poured into water (50 mL) and dichloromethane (50 mL), and the organic layer was washed with water (30mL×2) and brine (30mL×1), dried over anhydrous sodium sulfate Separation and purification (eluent using petroleum ether: ethyl acetate (v/v) = 1:1 to 0:1, and then dichloromethane: methanol (v/v) = 32:1 to 9:1) , the title compound 5-methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2- (Pyrrolidin-1-yl)ethyl)benzene-1,2,4-triamine (9C), brown solid (410 mg, yield 53%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.48 (dd, 1H), 8.33 (d, 1H), 8.16 (s, 1H), 7.80 (s, 1H), 7.60 (s, 1H), 7.41-7.35 ( m,1H), 7.35–7.27 (m, 2H), 7.03 (d, 1H), 6.69 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.23 (t, 2H), 2.95 (m, 6H), 2.70 (s, 3H), 1.98 (br, 4H).

MS m/z: 472.3 [M + 1] ⁺ .

The third step: N-(4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)-5-((4-(1-methyl-1H-吲) Ind-3-yl)pyridin-2-yl)amino)phenyl)acrylamide (Compound 9)

5-methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(pyrrolidine) 1-yl)ethyl)benzene-1,2,4-triamine (9C) (410 mg, 0.87 mmol) was dissolved in 15 mL of pyridine, and acrylic acid (313 mg, 4.35 mmol) and 1-(3-dimethylamino) were added. Propyl)-3-ethylcarbodiimide hydrochloride (834 mg, 4.35 mmol) was reacted at room temperature for 4 hours. Water (50 mL) and dichloromethane (50 mL) were added to the reaction mixture, and the mixture was separated, and the organic phase was sequentially applied with 10% sodium hydroxide solution (50mL×2), water (50mL×2) and saturated brine (50mL×1). Washed, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate (v/v) = 1:1 to 0:1, and then dichloromethane: methanol (v/v) = 32:1 to 19:1), the title compound N-(4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)-5 -((4-(1-Methyl-1H-indol-3-yl)pyridin-2-yl)amino)phenyl)acrylamide (Compound 9) as a yellow solid (190 mg, yield 42%).

^{1 H NMR (400MHz, DMSO-} d 6) δ9.84 (s, 1H), 9.08 (s, 1H), 8.65 (s, 1H), 8.33 (d, 1H), 8.25 (d, 1H), 7.89 ( s, 1H), 7.52 (d, 1H), 7.24 (t, 2H), 7.15 (t, 1H), 7.03 (s, 1H), 6.50 (s, 1H), 6.26 (dd, 1H), 5.77 (d) , 1H), 3.91 (s, 3H), 3.87 (s, 3H), 2.98 (s, 2H), 2.71 (s, 3H), 2.55 - 2.45 (m, 6H), 1.75 (br, 4H).

MS m/z: 526.2 [M + 1] ⁺ .

Example 10

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(4) -methylpiperazin-1-yl)ethoxy)phenyl)acrylamide (Compound 10)

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(4-methylpiperazin-1) -yl)ethoxy)phenyl)acrylamide

First step: 5-chloro-N-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)-5-nitrophenyl)-4-( 1-methyl-1H-indol-3-ylpyrimidin-2-amine (10B)

5-chloro-N-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin- 2-amine

5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (middle) 4) (854.1 mg, 2 mmol) was dissolved in tetrahydrofuran (50 mL), sodium hydride (80 mg, 2.2 mmol, wt% = 60%) was added under ice bath, stirred for 30 min, and 2-(4-methyl- Pyrazin-1-yl)ethanol (576.5 mg, 4 mmol) was reacted overnight at room temperature. After completion of the reaction, 100 mL of water and 100 mL of ethyl acetate were added, and the organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 5-chloro-N-(2-methoxy-4-(2-(4-methyl) Piperazin-1-yl)ethoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (10B), yellow solid (800mg , yield 80%).

MS m/z: 552.2 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.20 (s, 1H), 8.46 (d, 1H), 8.38 (s, 1H), 8.21 (s, 1H), 7.50 (s, 1H), 7.38 (d, 1H), 7.36–7.30 (m, 1H), 7.29–7.23 (m, 1H), 6.61 (s, 1H), 4.24 (t, 2H), 3.99 (s, 3H), 3.90 (d, 3H), 2.89 (t, 2H), 2.77 - 2.64 (m, 4H), 2.50 (s, 4H), 2.31 (s, 3H).

Second step: N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-(4- Methyl piperazin-1-yl)ethoxy)phenyl-1,3-diamine (10C)

N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(dimethylamino)ethoxy)-6-methoxybenzene-1,3-diamine

5-Chloro-N-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)-5-nitrophenyl)-4-(1-A Base-1H-indol-3-ylpyrimidin-2-amine (10B) (800 mg, 1.45 mmol) was dissolved in ethanol (15 mL), water (5mL), iron powder (486.3mg, 8.7mmol) and Ammonium (54 mg, 1 mmol) was heated to 90 ° C and refluxed for 4 hours. The reaction solution was cooled to room temperature, filtered and concentrated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound N ¹ -(5-chloro-4-(1-methyl-1H-indole) 3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl-1,3-diamine (10C ), yellow solid (200 mg, yield 26.5%).

MS m/z: 522.2 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.63 (d, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 8.06 (s, 1H), 7.51 (s, 1H), 7.40 (d, 1H), 7.34 (dd, 1H), 7.28 (dd, 4.0 Hz, 1H), 6.57 (s, 1H), 4.11 (t, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 2.79 ( t, 2H), 2.66 (s, 4H), 2.60 - 2.44 (m, 4H), 2.32 (d, 3H).

The third step: N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-( 2-(4-Methylpiperazin-1-yl)ethoxy)phenyl)acrylamide (Compound 10)

N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-(4-methylpiperidine) Pyrazin-1-yl)ethoxy)phenyl-1,3-diamine (10C) (150 mg, 0.288 mmol) was dissolved in tetrahydrofuran (10 mL) and N,N-diisopropylethylamine (0.057 mL) After cooling to 0 ° C, a solution of acryloyl chloride (0.028 mL, 0.345 mmol) in tetrahydrofuran (5 mL) was added dropwise, and the mixture was allowed to react at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate (50 mL) and ethyl acetate (50 mL) were added to the mixture, and the mixture was concentrated to give the compound N-(5-((5-chloro-4-(1-methyl-1H-indole) Indole-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)acrylamide (Compound 10) ), pale yellow solid (40 mg, yield 24.1%).

MS m/z: 576.2 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.32 (s, 1H), 8.41 (s, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 7.41 (s, 1H), 7.36 (d, 1H), 7.29 (d, 1H), 7.21 (t, 1H), 6.61 (s, 1H), 6.41 - 6.35 (m, 2H), 5.71 (dd, 1H), 4.18 (t, 2H), 3.90 (s , 3H), 3.87 (s, 3H), 2.72 (t, 2H), 2.62 (s, 4H), 2.53 (s, 4H), 2.33 (s, 3H).

Example 11

N-(4-methoxy-2-(methyl(1-methyltetrahydropyrrol-3-yl)amino)-5-((5-chloro-4-(1H-indol-3-yl)) Pyrimidin-2-yl)amino)phenyl)acrylamide (compound 11)

N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(1-methylpyrrolidin-3-yl)amino) Phenyl)acrylamide

First step: N ¹ -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-2-methoxy-N ⁴ -methyl-N ⁴ -(1-A Tetrahydropyrrol-3-yl)-5-nitrobenzene-1,4-diamine (11B)

N1-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-2-methoxy-N4-methyl-N4-(1-methylpyrrolidin-3-yl)-5-nitrobenzene-1 ,4-diamine

5-((4-(Indol-3-yl)-5-chloropyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 6) (1.0 g, 2.4 mmol), N,1-dimethyltetrahydropyrrole-3-amine (11A) (0.55 g, 4.8 mmol) and N,N-diisopropylethylamine (DIPEA) (0.6 g, 4.8 mmol ) was added to N,N-dimethylacetamide (3 mL) and subjected to microwave reaction at 140 ° for 1.5 hours. The mixture was cooled to room temperature, and water (20 mL) was evaporated. The title compound N ¹ -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2- was obtained as the title compound (m.p. 2-methoxy-N ⁴ -methyl-N ⁴ -(1-methyltetrahydropyrrol-3-yl)-5-nitrobenzene-1,4-diamine (11B), red solid (0.5 g, yield 42%).

MS m/z: 508.3 [M+1] ⁺ .

Second step: N ⁴ -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N ¹ -methyl-N ¹ -(1-A Tetrahydropyrrol-3-yl)benzene-1,2,4-triamine (11C)

N4-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methyl-N1-(1-methylpyrrolidin-3-yl)benzene-1,2, 4-triamine

N ¹ -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-2-methoxy-N ⁴ -methyl-N ⁴ -(1-methyltetrahydro Pyrrol-3-yl)-5-nitrobenzene-1,4-diamine (11B) (0.5 g, 0.98 mmol), iron powder (0.33 g, 5.9 mmol) and amine chloride (0.52 g, 9.8 mmol) It was added to ethanol (5 mL) and water (2 mL), and reacted at 90 ° C for 4 hours. The reaction mixture was cooled to room temperature, EtOAc EtOAc (EtOAc m. ^4- (5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N ¹ -methyl-N ¹ -(1-methyltetrahydropyrrole- 3-yl)benzene-1,2,4-triamine (11C), red solid (0.3 g, yield 64%).

MS m/z: 478.3 [M+1] ⁺ .

The third step: N-(4-methoxy-2-(methyl(1-methyltetrahydropyrrol-3-yl)amino)-5-((5-chloro-4-(1-methyl-) 1H-indol-3-ylpyrimidin-2-yl)amino)phenyl)acrylamide (Compound 11)

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(1-methylpyrrolidin-3-) Yl)amino)phenyl)acrylamide

N ⁴ -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N ¹ -methyl-N ¹ -(1-methyltetrahydro Pyrrol-3-yl)benzene-1,2,4-triamine (11C) (0.3 g, 0.62 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (i.e., EDCI) (0.48 g, 2.5 mmol) and acrylic acid (0.09 g, 1.2 mmol) were added to pyridine (5 mL) and allowed to react at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was evaporated. The title compound N-(4-methoxy-2-(methyl(1-methyltetrahydropyrrol-3-yl)amino) was obtained as the title compound (methanol (m/v) = 50:1) -5-((5-Chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 11), yellow solid (0.07 g, Yield 21%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.50 (s, 1H), 9.22 (d, 2H), 8.49-8.47 (m, 1H), 8.29-8.28 (m, 2H), 7.56 (s, 1H), 7.35–7.33 (m, 1H), 7.21–7.18 (m, 2H), 6.74 (s, 1H), 6.40-6.38 (m, 2H), 5.73 (d, 1H), 3.88 (s, 3H), 3.59 ( s, 1H), 2.79 (s, 1H), 2.60 (br, 6H), 2.32 (s, 3H), 2.07 - 1.98 (m, 1H), 1.82 (s, 1H).

MS m/z: 546.2 [M + 1] ⁺ .

Example 12

N-(4-Methoxy-2-(methyl(1-methyltetrahydropyrrol-3-yl)amino)-5-((4-(1-methyl-1H-indol-3-yl) Pyrimidine-2-yl)amino)phenyl)acrylamide (compound 12)

N-(4-methoxy-2-(methyl(1-methylpyrrolidin-3-yl)amino)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino) Phenyl)acrylamide

First step: N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-methoxy-N ⁴ -methyl-N ⁴ -(1- Methyltetrahydropyrrol-3-yl)-5-nitrobenzene-1,4-diamine (12B)

N1-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-methoxy-N4-methyl-N4-(1-methylpyrrolidin-3-yl)-5-nitrobenzene-1 ,4-diamine

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 3) (1.0 g, 2.5 mmol), N,1-dimethylpyrrolidin-3-amine (11A) (580 mg, 5.1 mmol), N,N-diisopropylethylamine (660 mg, 5.1 mmol), trifluoroethanol ( 5 mL) was placed in a 25 mL microwave reaction tube and microwaved at 140 ° C for 1.5 hours. Water (50 mL) and dichloromethane (50 mL) were added to the mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Purification by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 1:1 to 0:1; methylene chloride:methanol (v/v) = 32:1 to 9:1) ^1- (4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-methoxy-N ⁴ -methyl-N ⁴ -(1-methyltetrahydropyrrole 3-yl)-5-nitrobenzene-1,4-diamine (12B), yellow solid (370 mg, yield 31%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.52 (s, 1H), 8.39 (d, 1H), 8.22 (s, 1H), 8.18 (dd, 1H), 7.57 (s, 1H), 7.44 - 7.36 ( m,1H), 7.35–7.28 (m, 2H), 7.19 (d, 1H), 6.66 (s, 1H), 4.03 (dd, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 2.95 - 2.85 (m, 1H), 2.84 (d, 3H), 2.79 - 2.62 (m, 3H), 2.45 (s, 3H), 2.18 (m, 1H), 2.07 - 1.93 (m, 1H).

MS m/z: 488.4 [M + 1] ⁺ .

Second step: N ⁴ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N ¹ -methyl-N ¹ -(1- Methyltetrahydropyrrol-3-yl)benzene-1,2,4-triamine (12C)

N4-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methyl-N1-(1-methylpyrrolidin-3-yl)benzene- 1,2,4-triamine

N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-methoxy-N ⁴ -methyl-N ⁴ -(1-methyltetra Hydropyrrol-3-yl)-5-nitrobenzene-1,4-diamine (12B) (0.37 g, 0.75 mmol), iron powder (0.25 g, 4.5 mmol) and amine chloride (0.4 g, 7.59 mmol) It was added to a mixed solution of ethanol (5 mL) and (2 mL) of water, and reacted at 90 ° C for 4 hours. The reaction mixture was cooled to room temperature, EtOAc (EtOAc m. ⁴ - (4- (1-methyl -1H- indol-3-yl) pyrimidin-2-yl) -5-methoxy -N ¹ - methyl -N ¹ - (1-methyl-pyrrolidine 3-yl)benzene-1,2,4-triamine (12C), black solid (0.3 g, yield 88%).

MS m/z: 458.4 [M+1] ⁺ .

The third step: N-(4-methoxy-2-(methyl(1-methyltetrahydropyrrol-3-yl)amino)-5-((4-(1-methyl-1H-oxime) -3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (compound 12)

N ⁴ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N ¹ -methyl-N ¹ -(1-methyltetra Hydropyrrol-3-yl)benzene-1,2,4-triamine (12C) (0.4g, 88mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (0.67, 3.5 mmol) and acrylic acid (0.127 g, 1.7 mmol) were added to pyridine (5 mL) and allowed to react at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was evaporated. The title compound N-(4-methoxy-2-(methyl(1-methyltetrahydropyrrol-3-yl)amino) was obtained as the title compound (methanol (m/v) = 50:1) -5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 12), yellow solid (0.012 g, yield 83% ).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 9.07 (s, 1H), 8.65 (s, 1H), 8.33 (d, 1H), 8.24 (d, 1H), 7.89 ( s, 1H), 7.52 (d, 1H), 7.26 - 7.22 (m, 2H), 7.15 (t, 1H), 7.00 (s, 1H), 6.65-5.59 (m, 1H), 6.26 (d, 1H) , 5.76 (d, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.60 (s, 1H), 2.59 (s, 5H), 2.42 (s, 2H), 2.23 (s, 3H), 1.92 (s, 1H), 1.74 (s, 1H).

MS m/z: 512.2 [M + 1] ⁺ .

Example 13

(R)-N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2 -((1-methyltetrahydropyrrol-3-yl)oxy)phenyl)acrylamide (Compound 13)

(R)-N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-((1 -methylpyrrolidin-3-yl)oxy)phenyl)acrylamide

First step: (R)-5-chloro-N-(2-methoxy-4-((1-methyltetrahydropyrrol-3-yl)oxy)-5-nitrophenyl)-4 -(pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2-diamine (13B)

(R)-5-chloro-N-(2-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)-5-nitrophenyl)-4-(pyrazolo[1,5-a]pyridin-3- Yl)pyrimidin-2-amine

Sodium hydride (0.09 g, 2.25 mmol) was added to the reaction flask, cooled to 0 ° C, tetrahydrofuran (5 mL) and 5-((5-chloro-4-(pyrazolo[1,5-a]pyridine-3-) Pyrimido-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 5) (0.413 g, 2.25 mmol), (R)-(-)-1 A solution of methyl-3-hydroxypyrrolidine (0.118 g, 1.17 mmol) in tetrahydrofuran (5 mL). The reaction mixture was cooled to 0 ° C, and a saturated aqueous solution of ammonium chloride (10 mL) was added, and the mixture was stirred, and the mixture was evaporated to give water (10 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×3). The sodium was dried, and the residue was purified (jjjjjjjjj R)-5-Chloro-N-(2-methoxy-4-((1-methyltetrahydropyrrol-3-yl)oxy)-5-nitrophenyl)-4-(pyrazole [1,5-a]pyridin-3-yl)pyrimidine-2-diamine (13B), yellow solid (0.22 g, yield 44%).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.95 (s, 1H), 8.86-8.84 (d, 1H), 8.81 (s, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 7.38-7.34 (dt, 1H), 7.17-7.13 (dt, 1H), 6.87 (s, 1H), 5.25 (s, 1H), 3.95 (s, 3H).

MS m/z: 496.2 [M + 1] ⁺ .

The second step: (R)-N ¹ -(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)-6-methoxy-4- ((1-Methyltetrahydropyrrol-3-yl)oxy)phenyl-1,3-diamine (13C)

(R)-N1-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)-6-methoxy-4-((1-methylpyrrolidin-3-yl) Oxy)benzene-1,3-diamine

(R)-5-Chloro-N-(2-methoxy-4-((1-methyltetrahydropyrrol-3-yl)oxy)-5-nitrophenyl)-4-(pyridyl) Zoxao[1,5-a]pyridin-3-yl)pyrimidine-2-diamine (13B) (0.20 g, 0.40 mmol), iron powder (0.145 g, 2.60 mmol) and ammonium chloride (0.04 g, 0.75) Methyl) was dissolved in a mixed solvent of absolute ethanol (9 mL) and water (3 mL), and the mixture was warmed to 90 ° C for 4.5 hours. The reaction was cooled to room temperature, filtered and concentrated, the residue was purified by silica gel column chromatography (methanol: dichloromethane (v / v) = 1: 2), to give the title compound (R) -N ¹ - ( 5-Chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)-6-methoxy-4-((1-methyltetrahydropyrrole-3- Alkyloxy)phenyl-1,3-diamine (13C), yellow-green solid (0.07 g, yield 38%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.93 (s, 1H), 8.62-8.55 (m, 2H), 8.35 (s, 1H), 7.90 (s, 1H), 7.44 (s, 1H), 7.38- 7.36 (dt, 1H), 6.98-6.94 (dt, 1H), 6.49 (s, 1H), 4.93 (s, 1H), 3.84 (s, 3H), 3.49 (s, 1H), 3.20-3.06 (m, 4H), 2.66 (s, 3H), 2.43 - 2.35 (m, 2H).

MS m/z: 466.3 [M + 1] ⁺ .

The third step: (R)-N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methyl Oxy-2-((1- Methyltetrahydropyrrol-3-yl)oxy)phenyl)acrylamide (Compound 13)

(R)-N ¹ -(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)-6-methoxy-4-((1) -Methyltetrahydropyrrol-3-yl)oxy)phenyl-1,3-diamine (13C) (0.07 g, 0.15 mmol) was dissolved in freshly distilled tetrahydrofuran (3 mL). A solution of diisopropylethylamine (0.3 mL) in freshly distilled tetrahydrofuran (9.7 mL) and a solution of acryloyl chloride (0.13 mL) in THF (0.87 mL) was evaporated. A saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added to the mixture, and the mixture was evaporated. Separation and purification (methanol: dichloromethane (v/v) = 1:2 to 1:1), title compound (R)-N-(5-((5-chloro-4-(pyrazolo[1,5] -a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methyltetrahydropyrrol-3-yl)oxy)phenyl)acrylamide (compound) 13), yellow solid (0.03 g, yield 41%).

^{1 H NMR (400MHz, DMSO-} d 6) δ9.27 (s, 1H), 8.93 (s, 1H), 8.82-8.81 (d, 1H), 8.65 (s, 1H), 8.37 (s, 1H), 8.14(s,1H), 7.30-7.28(dt,1H),7.11-7.08(dt,1H),6.79(s,1H),6.61-6.50(m,1H), 6.19-6.14(dd,1H), 5.70-5.67 (dd, 1H), 4.98 (s, 1H), 3.82 (s, 1H), 3.76 (s, 3H), 2.84-2.66 (m, 4H), 2.39-2.36 (m, 2H), 2.30 ( s, 3H).

MS m/z: 520.3 [M + 1] ⁺ .

Example 14

N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)) Ethoxy)-4-methoxyphenyl)acrylamide (Compound 14)

N-(5-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)ethoxy)-4- Methoxyphenyl)acrylamide

First step: 5-chloro-N-(4-(2-dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5- a] pyridin-3-yl)pyrimidin-2-amine (14B)

5-chloro-N-(4-(2-(dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-(pyrazolo[1,5-a]p Yridin-3-yl)pyrimidin-2-amine

5-((5-Chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitro The benzene (intermediate 5) (0.41 g, 1.00 mmol) was dissolved in tetrahydrofuran (20 mL), the reaction mixture was cooled to 0 ° C, sodium hydride (0.08 g, 1.1 mmol, wt% = 60%) was added and stirred for 5 minutes. N,N-Dimethylethanolamine (14A) (0.11 mL, 1.1 mmol) was added, and the reaction was allowed to proceed to room temperature for 4 hours. Water (20 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (50 mL×2), and the organic phase was combined. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate Purification (dichloromethane/methanol (v/v) = 15:1) afforded 5-chloro-N-(4-(2-dimethylamino)ethoxy)-2-methoxy- 5-Nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (14B) (0.36 g, yield 75%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.06 (s, 1H), 8.93 (s, 1H), 8.55-8.47 (m, 2H), 8.41 (s, 1H), 7.48 (s, 1H), 7.37- 7.35 (m, 1H), 6.96-6.94 (m, 1H), 6.67 (s, 1H), 4.27-4.24 (m, 2H), 4.01 (s, 3H), 2.91-2.88 (m, 2H), 2.42 ( s, 6H).

Second step: N ¹ -(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-4-(2-dimethylaminoethoxy) -6-methoxy-phenyl-1,3-diamine (14C)

N1-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-4-(2-dimethylaminoethyloxy)-6-methoxy-benzene-1,3-diamine

Weigh 5-chloro-N-(4-(2-dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a] Pyridin-3-yl)pyrimidin-2-amine (14B) (0.36 g, 0.74 mmol) was placed in a 100 mL round bottom flask, and ethanol (21 mL), water (7 mL), and reduced iron powder were sequentially added to the reaction flask. 0.25 g, 4.44 mmol) and ammonium chloride (0.028 g, 0.52 mmol) were reacted under reflux for 6 hours. The reaction solution was filtered, and the filter cake was washed with dichloromethane (10 mL×2) and methanol (10 mL×2), and the filtrate was concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) =15:1) N ¹ -(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-4-(2-dimethyl) as a gray solid Aminoethoxy)-6-methoxy-phenyl-1,3-diamine (14C) (0.30 g, yield 88%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.94 (s, 1H), 8.60-8.55 (m, 2H), 8.35 (s, 1H), 7.87 (s, 1H), 7.42-7.37 (m, 2H), 6.96-6.93 (m, 1H), 6.59 (s, 1H), 4.19-4.17 (m, 2H), 3.85 (s, 3H), 2.91-2.88 (m, 2H), 2.42 (s, 6H).

The third step: N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(2-(2) Methylamino)ethoxy)-4-methoxyphenyl)acrylamide (Compound 14)

N-[5-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-2-(2-dimethylaminoethyloxy)-4-methoxy-phenyl] Prop-2-enamide

Weigh N ¹ -(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-4-(2-dimethylaminoethoxy)-6 -Methoxy-phenyl-1,3-diamine (14C) (0.2 g, 0.43 mmol), placed in a 100 mL round bottom flask, and then, to the reaction flask was added tetrahydrofuran (15 mL) and diisopropylethyl. The amine (0.09 mL, 0.56 mmol) was cooled to 0 ° C, and acryloyl chloride (0.04 mL, 0.52 mmol) was added dropwise. The reaction mixture was concentrated under reduced vacuo. dichloromethane (EtOAc m. Washed with water (30 mL), dried over anhydrous NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 5-Chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)ethoxy)-4- Methoxyphenyl)acrylamide (Compound 14) (0.08 g, yield 48%).

MS m/z (ESI): 517.2 [M+1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ10.02 (s, 1H), 9.53 (s, 1H), 8.82 (s, 1H), 8.76-8.74 (d, 1H), 8.53-8.51 (d, 1H), 8.25(s,1H), 7.36(s,1H), 7.28-7.26(m,1H),6.91-6.89(m,1H),6.77(s,1H),6.38-6.36(m,2H),5.68- 5.65 (m, 1H), 3.98 (s, 3H), 3.87 (s, 3H), 2.82-2.80 (m, 2H), 2.72 (s, 3H), 2.34-2.30 (m, 8H).

Example 15

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((dimethylamino)ethoxy) -4-methoxyphenyl)acrylamide (compound 15)

N-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)ethoxy)-4-methoxyphenyl) Acrylamide

First step: 5-chloro-N-(4-(2-(dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H -Indol-3-yl)pyrimidin-2-amine (15B)

5-chloro-N-(4-(2-(dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (middle) 4) (500 mg, 1.17 mmol) was dissolved in tetrahydrofuran (50 mL). EtOAc (EtOAc:EtOAc. ), reacted at room temperature for 4 hours. Reaction solution Water (100 mL) and ethyl acetate (150 mL) were added, and the organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 5-chloro-N-(4-(2-dimethylamino)ethoxy. 2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (15B), yellow solid (500 mg, yield 86.2 %).

MS m/z: 497.1 [M + 1] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ8.58 (d, 2H), 8.40 (s, 1H), 8.33 (s, 1H), 8.27 (d, 1H), 7.51 (d, 1H), 7.25 ( t, 1H), 7.09 - 6.97 (m, 2H), 4.34 (t, 2H), 3.96 (d, 3H), 3.91 (d, 3H), 2.72 (t, 2H), 2.25 (d, 6H).

Second step: N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(dimethylamino)ethoxy )-6-methoxyphenyl-1,3-diamine (15C)

N1-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(dimethylamino)ethoxy)-6-methoxybenzene-1,3-diamine

5-Chloro-N-(4-(2-(dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indole -3-yl)pyrimidin-2-amine (15B) (500 mg, 1 mmol) was dissolved in a mixed solution of ethanol (15 mL) and water (5 mL), and iron powder (335 mg, 6 mmol) and ammonium chloride (37.4 mg, 0.7 mmol), the temperature was raised to 90 ° C, and the reaction was refluxed for 4 hours. The reaction was cooled to room temperature, filtered, concentrated and the residue was purified by silica gel column chromatography (methylene chloride: methanol (v / v) = 1: 0 ~ 50: 1), to give compound N ¹ - (5- chloro 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(dimethylamino)ethoxy)-6-methoxyphenyl-1 , 3-Diamine (15C), yellow solid (350 mg, yield 75.1%).

MS m/z: 467.2 [M + 1] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ8.53 (s, 1H), 8.36 (d, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 7.50 (d, 1H), 7.24 ( t,1H),7.07(t,1H),6.98(s,1H),6.74(s,1H), 5.75(s,1H), 4.23(s,2H),3.90(s,3H),3.68(s , 3H), 3.05 (d, 3H), 2.67 (s, 6H).

The third step: N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((dimethylamino) Ethoxy)-4-methoxyphenyl)acrylamide (Compound 15)

N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(dimethylamino)ethoxy)-6 -Methoxyphenyl-1,3-diamine (15C) (350 mg, 0.75 mmol) was dissolved in tetrahydrofuran (28 mL). N,N-diisopropylethylamine (ie DIPEA) (0.15 mL, 0.9 The mixture was cooled to 0 ° C, and a solution of acryloyl chloride (0.073 mL, 0.9 mmol) in THF (5 mL) was evaporated. A saturated aqueous solution of sodium hydrogencarbonate (100 mL) and dichloromethane (100 mL) were added to the mixture, and the organic phase was concentrated to give N-(5-(4-chloro-4-(1-methyl-1H) -Indol-3-yl)pyrimidin-2-yl)amino)-2-((dimethylamino)ethoxy)-4-methoxyphenyl)acrylamide (Compound 15), white solid (40 mg , 10.3%).

MS m/z: 521.2 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.65 (s, 1H), 9.38 (s, 1H), 8.39 (d, 2H), 8.33 (s, 1H), 7.45 (s, 1H), 7.35 (d, 1H), 7.29 (d, 1H), 7.22 (dd, 1H), 6.63 (s, 1H), 6.44 - 6.26 (m, 2H), 5.68 (d, 1H), 4.17 - 4.10 (m, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 2.63 (s, 2H), 2.39 (s, 6H).

Example 16

N-(5-((5-chloro-4-(1-methyl-6-morpholinyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methyl Oxyphenyl)acrylamide (compound 16)

N-(5-(5-chloro-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide

First step: 1-(6-nitro-1H-indol-1-yl)ethanone (16B)

1-(6-nitro-1H-indol-1-yl)ethanone

6-Nitroindole (16A) (16.2 g, 0.1 mol) was dissolved in pyridine (40 mL), and acetic anhydride (40.8 g, 0.4 mol) was added and allowed to react at room temperature overnight. The reaction mixture was concentrated. EtOAc (EtOAc) (EtOAc)吲哚-1-base) Ethyl ketone (16B), yellow solid (6 g, yield 30%).

MS m/z: 205.1 [M + 1] ⁺ .

The second step: 1-(6-amino-1H-indol-1-yl)ethanone (16C)

1-(6-amino-1H-indol-1-yl)ethanone

1-(6-Nitro-1H-indol-1-yl)ethanone (16B) (20 g, 0.1 mol) was dissolved in methanol (50 mL) and tetrahydrofuran (50 mL), palladium carbon (2 g, 10%) And amine formate (40.3 g, 6.4 mol), reacted at 60 ° C for 2 hours. After the reaction was completed, the mixture was filtered, washed with ethyl acetate (100 mL), and the filtrate was evaporated and evaporated, ethyl acetate (150 mL) and brine (150 mL) The organic phase was dried over anhydrous sodium sulfate and concentrated to give 1-(6-amino-1H-indol-1-yl)ethanone (16C) as a yellow solid (9.3 g, yield 53.4%) ).

The third step: 4-(1H-吲哚-6-yl)morpholine (16D)

4-(1H-indol-6-yl)morpholine

1-(6-Amino-1H-indol-1-yl)ethanone (16C) (8g, 60.1mmol) and 2,2'-dibromodiethyl ether (9mL, 72mmol) were dissolved in N,N- N,N-Diisopropylethylamine (i.e., ethyl DIP) (29.7 mL, 180 mmol) was added to methylformamide (100 mL). The reaction mixture was cooled to room temperature, ethyl acetate (200 mL) and brine (200 mL) was evaporated. 4-(1H-Indol-6-yl)morpholine (16D) was obtained as a yellow solid (9.2 g, yield 76%).

MS m/z: 203.1 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.04 (s, 1H), 7.53 (d, 1H), 7.09 (dd, 1H), 6.98-6.80 (m, 2H), 6.46 (ddd, 1H), 4.00- 3.83 (m, 4H), 3.25–3.08 (m, 4H).

Step 4: 4-(3-(2,5-Dichloropyrimidin-4-yl)-1H-indol-6-yl)morpholine (16E)

4-(3-(2,5-dichloropyrimidin-4-yl)-1H-indol-6-yl)morpholine

4-(1H-Indol-6-yl)morpholine (16D) (4.5 g, 22.3 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0 ° C under nitrogen, and methyl magnesium bromide was added dropwise. 7.5 mL, 22.3 mmol), stirring was continued for 0.5 hours, trichloropyrimidine (2.05 g, 22.3 mmol) was added, and the mixture was reacted at room temperature for 1 hour, and the mixture was heated to 60 ° C for 1 hour. The reaction solution was cooled to room temperature, and acetic acid (6.34 mL) was added dropwise, and the mixture was stirred for 10 minutes, water (100 mL) was added, and the mixture was stirred at 60 ° C for 30 minutes, and the organic phase was added with n-heptane (100 mL). Purification by column chromatography (dichloromethane:methanol (v/v) = 1:0 to 50:1) to give the compound 4-(3-(2,5-dichloropyrimidin-4-yl)-1H-indole Indole-6-yl)morpholine (16E), yellow-green solid (3 g, yield 39%).

MS m/z: 349.0 [M+1] ⁺ .

Step 5: 4-(3-(2,5-Dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)morpholine (16F)

4-(3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)morpholine

4-(3-(2,5-Dichloropyrimidin-4-yl)-1H-indol-6-yl)morpholine (16E) (3 g, 8.6 mmol) was dissolved in tetrahydrofuran (50 mL) Sodium hydride (460 mg, 11.5 mmol) was added at 0 ° C, and the mixture was reacted for 30 minutes, and then iodomethane (1.6 mL, 25.8 mmol) was added, and the mixture was allowed to react at room temperature for 3 hours. The reaction mixture was concentrated and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Indole-6-yl)morpholine (16F), light yellow solid (1.9 g, yield 61.3%).

MS m/z: 363.0 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.59 (d, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 7.07 (d, 1H), 6.82 (s, 1H), 3.99-3.89 ( m, 4H), 3.85 (s, 3H), 3.30 - 3.20 (m, 4H).

Step 6: 5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-6-morpholine-1H-indol-3-yl Pyrimidine-2-amine (16G)

5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-amine

4-(3-(2,5-Dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)morpholine (16F) (724 g, 2 mmol) was dissolved in 2-pentanol (20 mL), 4-fluoro-2-methoxy-5-nitroaniline (372 mg, 2 mmol) and p-toluenesulfonic acid (456.5 mg, 2.4 mmol) were added, and the mixture was heated to 120 ° C, and refluxed for 2 days. The reaction solution was cooled to room temperature, acetonitrile (50 mL) was added and filtered, and the filter cake was washed with water (50mL) and dried to give -chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)- 4-(1-Methyl-6-morpholine-1H-indol-3-yl)pyrimidin-2-amine (16G), m.p.

MS m/z: 513.1 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.35 (d, 1H), 8.39 (s, 1H), 8.34 (d, 1H), 8.14 (s, 1H), 7.56 (s, 1H), 6.97 (d, 1H), 6.80 (s, 1H), 6.75 (d, 1H), 4.02 (s, 3H), 3.93 (s, 4H), 3.84 (s, 3H), 3.23 (s, 4H).

Step 7: N ¹ -(5-chloro-4-(1-methyl-6-morpholine-1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxy Benzene-1,3-diamine (16H)

N1-(5-chloro-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene-1,3-diamine

-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-6-morpholine-1H-indol-3-yl)pyrimidine-2 -amine (16G) (600 mg, 1.17 mmol) was dissolved in ethanol (30 mL) and water (10 mL), and then iron powder (392 mg, 7.03 mmol) and ammonium chloride (43.8 mg, 0.82 mmol). The reaction was refluxed for 4 hours. The reaction solution was cooled to room temperature, filtered, and the filtered cake was washed with methanol (50 mL), and the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 50: 1) N ¹ -(5-chloro-4-(1-methyl-6-morpholin-1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene - 1,3-Diamine (16H), brown solid (150 mg, yield 26.6%).

MS m/z: 483.1 [M + 1] ⁺ .

Step 8: N-(5-((5-chloro-4-(1-methyl-6-morpholin-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro- 4-methoxyphenyl)acrylamide (Compound 16)

N ¹ -(5-chloro-4-(1-methyl-6-morpholine-1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene-1 , 3-diamine (16H) (150 mg, 0.31 mmol) was dissolved in THF (10 mL), N,N-diisopropylethylamine (0.06 mL, 0.37 mmol), and then cooled to 0 ° C. A solution of (0.03 mL, 0.37 mmol) in tetrahydrofuran (5 mL). A saturated aqueous solution of sodium hydrogencarbonate (100 mL) and dichloromethane (100 mL) were added to the mixture, and the mixture was concentrated to give N-(5-chloro-4-(1-methyl-6-morpholine). -1H-Indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide (Compound 16), pale yellow solid (20 mg, yield 12%).

MS m/z: 537.1 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.14 (s, 1H), 8.37 (s, 1H), 8.35 (s, 1H), 8.22 (s, 1H), 7.50 (d, 1H), 7.19 (s, 1H), 6.99 (s, 1H), 6.73 (d, 1H), 6.40 (dd, 1H), 6.26 (dd, 1H), 5.75 (d, 1H), 3.96 (s, 4H), 3.90 (s, 3H) ), 3.86 (s, 3H), 3.26 (s, 4H).

Example 17

(R)-N-(5-((5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(3-(dimethylamino) Tetrahydropyrrol-1-yl)-4-methoxyphenyl)acrylamide (Compound 17)

(R)-N-(5-((5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1 -yl)-4-methoxyphenyl)acrylamide

First step: (R)-5-chloro-N-(4-(3-(dimethylamino)tetrahydropyrrol-1-yl)-2-methoxy-5-nitrophenyl)-4- (4-fluoro-1H-indol-3-yl)pyrimidin-2-amine (17B)

(R)-5-chloro-N-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy-5-nitrophenyl)-4-(4-fluoro-1H-indol-3-yl) Pyrimidin-2-amine

To the reaction flask was added 5-chloro-4-(4-fluoro-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2- Amine (Intermediate 7) (1.1 g, 2.5 mmol), (R)-N,N-dimethylpyrrole-3-amine (17A) (0.5 g, 2.8 mmol), diisopropylethylamine (1.5 g , 11.5 mmol) and N,N'-dimethylacetamide (10 mL) were reacted in a microwave at 140 ° C for 1 hour. The reaction mixture was concentrated to dryness EtOAc mjjjjjjjjjjjjjjj -(3-(Dimethylamino)tetrahydropyrrol-1-yl)-2-methoxy-5-nitrophenyl)-4-(4-fluoro-1H-indol-3-yl)pyrimidine- 2-Amine (17B) (0.5 g, yield 38%).

MS m/z (ESI): 526.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.00 (s, 1H), 8.48 (d, 2H), 8.26 (s, 1H), 7.85 (d, 1H), 7.32 (d, 1H), 7.17 ( m,1H), 6.84 (dd, 1H), 6.51 (s, 1H), 3.94 (s, 3H), 3.40 (dd, 1H), 3.27–3.19 (m, 1H), 3.17 (d, 1H), 3.11 (d, 2H), 2.23 (s, 6H), 2.16 - 2.12 (m, 1H), 1.80 (m, 1H).

The second step: (R)-N ¹ -(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)-4-(3-(dimethylamino)tetra Hydropyrrole-1-yl)-6-methoxybenzene-1,3-diamine (17C)

(R)-N1-(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-6- Methoxybenzene-1,3-diamine

(R)-5-Chloro-N-(4-(3-(dimethylamino)tetrahydropyrrol-1-yl)-2-methoxy-5-nitrophenyl)-4 was added to the reaction flask. -(4-Fluoro-1H-indol-3-yl)pyrimidin-2-amine (17B) (0.5 g, 0.95 mmol), iron powder (0.32 g, 5.7 mmol), ammonium chloride (51 mg, 0.95 mmol) Ethanol/water (27 mL / 9.5 mL) was heated to reflux for 2 hours. The reaction solution was filtered, and the filter cake was washed with ethanol (10 mL×3), and the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 80:1-30:1 Obtained a yellow-brown solid (R)-N ¹ -(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)-4-(3-(dimethylamino) Tetrahydropyrrol-1-yl)-6-methoxybenzene-1,3-diamine (17C) (0.2 g, yield 42.6%).

MS m/z (ESI): 496.4 [M+1] ⁺ .

The third step: (R)-N-(5-((5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino)tetrahydropyrrol-1-yl)-4-methoxyphenyl)acrylamide (Compound 17)

To the reaction flask was added (R)-N ¹ -(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)-4-(3-(dimethylamino) Tetrahydropyrrol-1-yl)-6-methoxybenzene-1,3-diamine (17C) (0.18 g, 0.36 mmol), diisopropylethylamine (52 mg, 0.4 mmol) and dichloromethane (4.6 mL), chilled with ice-cooled, EtOAc (EtOAc (EtOAc) To the reaction mixture, a saturated aqueous solution of brine (10 mL) was evaporated, evaporated, evaporated, evaporated, evaporated. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v/v) = 50:1 - 25:1) to give a pale yellow solid (R)-N-(5-((5-chloro-4-) (4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)tetrahydropyrrol-1-yl)-4-methoxyphenyl) Acrylamide (Compound 17) (50 mg, yield 25.5%).

MS m/z (ESI): 550.3 [M+1] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ11.95 (s, 1H), 9.28 (s, 1H), 8.42 (s, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.84 ( s, 1H), 7.31 (d, 1H), 7.15 (m, 1H), 6.83 (dd, 1H), 6.53 (s, 2H), 6.19 (d, 1H), 5.68 (d, 1H), 3.83 (s) , 3H), 3.23 (m, 5H), 2.32 (s, 6H), 2.11 (s, 1H), 1.82 (s, 1H).

Example 18

N-(5-((5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl) (methyl)amino)-4-methoxyphenyl)acrylamide (compound 18)

N-(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino )-4-methoxyphenyl)acrylamide

First step: N ¹ -(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)- 2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (18B)

N1-(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)-N4-(2-(dimethylamino)ethyl)-2-methoxy-N4-methyl-5- Nitrobenzene-1,4-diamine

To the reaction flask was added 5-chloro-4-(4-fluoro-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2- Amine (Intermediate 7) (1 g, 2.5 mmol), N,N,N'-trimethylethylenediamine (18A) (0.28 g, 2.8 mmol), diisopropylethylamine (1.3 g, 10.4 mmol) And N,N'-dimethylacetamide (10 mL), and reacted in a microwave at 140 ° C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50: 1) to give a brown oil N ¹ - (5- chloro-4- (4 -fluoro-1H-indol-3-ylpyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5-nitro Benzene-1,4-diamine (18B) (0.55 g, yield 45.8%).

MS m/z (ESI): 514.3 [M+1] ⁺ .

Second step: N ⁴ -(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)- 5-methoxy-N ¹ -methylphenyl-1,2,4-triamine (18C)

N ⁴ -(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methylbenzene -1,2,4-triamine

To the reaction flask was added N ¹ -(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl) 2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (18B) (0.52 g, 1 mmol), iron powder (0.34 g, 6.1 mmol), ammonium chloride (54 mg) 1 mmol) and ethanol/water (28 mL/10 mL) were heated to reflux for 2 hours. The reaction solution was filtered, and the filter cake was washed with ethanol (10 mL×3), and the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100:1-50:1 Obtained a yellow solid N ⁴ -(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)- 5-methoxy-N ¹ -methylphenyl-1,2,4-triamine (18C) (350 mg, yield 71.5%).

MS m/z (ESI): 484.3 [M + +] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ11.96 (s, 1H), 8.45 (s, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.42 (s, 1H), 7.33 ( d, 1H), 7.17 (m, 1H), 6.87 (dd, 1H), 6.72 (s, 1H), 4.50 (s, 2H), 3.73 (s, 3H), 2.84 (t, 2H), 2.59 (s) , 3H), 2.32 (t, 2H), 2.15 (s, 6H).

The third step: N-(5-((5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino) Ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Compound 18)

Add N ⁴ -(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl) to the reaction flask 5-5-methoxy-N ¹ -methylphenyl-1,2,4-triamine (18C) (0.32 g, 0.66 mmol), diisopropylethylamine (94 mg, 0.73 mmol) and dichloro Methane (8.6 mL) was cooled in ice-cooled, and a solution of acryloyl chloride (60 mg, 0.66 mmol) in dichloromethane (2 mL) was added dropwise. An aqueous solution of sodium hydrogencarbonate (10 mL) was added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjjj Drying, filtration, concentrating, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 50:1 - 30:1) to give a pale yellow solid N-(5-((5-chloro-) 4-(4-Fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy Phenyl phenyl) acrylamide (compound 18) (140 m g, yield 39.4%).

MS m/z (ESI): 538.3 [M+1] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ11.98 (s, 1H), 10.03 (s, 1H), 8.81 (s, 1H), 8.46 (s, 1H), 8.22 (s, 1H), 7.93 ( d, 1H), 7.31 (d, 1H), 7.15 (m, 1H), 6.98 (s, 1H), 6.83 (dd, 1H), 6.38 (dd, 1H), 6.26 (dd, 1H), 5.74 (d) , 1H), 3.82 (s, 3H), 2.96 - 2.78 (m, 2H), 2.68 (s, 3H), 2.31 (m, 2H), 2.20 (s, 6H).

Example 19

N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-5-((4-(7-fluoro-1-methyl-1H-indol-3-yl)pyrimidine) -2-yl) ammonia Base)-4-methoxyphenyl)acrylamide (compound 19)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(7-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino )-4-methoxyphenyl)acrylamide

First step: N ¹ -(2-(dimethylamino)ethyl)-N ⁴ -(4-(7-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl) -5-methoxy-N ¹ -methyl-2-nitrobenzene-1,4-diamine (19B)

N1-(2-(dimethylamino)ethyl)-N4-(4-(7-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methyl-2- Nitrobenzene-1,4-diamine

To the reaction flask was added 4-(7-fluoro-1-methyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidine-2 -Amine (Intermediate 8) (280 mg, 0.68 mmol), N,N,N'-trimethylethylenediamine (18A) (69 mg, 0.68 mmol), diisopropylethylamine (219 mg, 1.7 mmol) N,N'-dimethylacetamide (4.5 mL) was reacted in a microwave at 140 ° C for 1.5 hours. The reaction mixture was cooled to room temperature, EtOAc (EtOAc)EtOAc. Dichloromethane/methanol (v/v) = 100:1-20:1) gave a brown solid N ¹ -(2-(dimethylamino)ethyl)-N ⁴ -(4-(7-fluoro-1-) Methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N ¹ -methyl-2-nitrobenzene-1,4-diamine (19B) (120 mg, produced The rate is 36%).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.58 (s, 1H), 8.33 (d, 1H), 8.30 (s, 1H), 8.18 (t, 1H) 8.13 (s, 1H), 7.20 (d , 1H), 7.03 (m, 2H), 6.84 (s, 1H), 4.03 (d, 3H), 3.95 (s, 3H), 3.27 (t, 2H), 2.86 (s, 3H), 2.49 (t, 2H), 2.16 (s, 6H).

Second step: N ¹ -(2-(dimethylamino)ethyl)-N ⁴ -(4-(7-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl) -5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (19C)

N1-(2-(dimethylamino)ethyl)-N4-(4-(7-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methylbenzene-1, 2,4-triamine

MS m/z (ESI): 464.6 [M+1] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ8.29 (m, 2H), 8.25 (d, 1H), 7.83 (s, 1H), 7.41 (s, 1H), 7.13 (d, 1H), 7.09- 6.99 (m, 2H), 6.76 (s, 1H), 4.04 (d, 2H), 3.73 (s, 3H), 2.89 (t, 3H), 2.63 (s, 3H), 2.37 (t, 2H), 2.18 (s, 6H).

The third step: N-(2-((2-(dimethylamino)ethyl)))(methyl)amino)-5-((4-(7-fluoro-1-methyl-1H-indole-3) -yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 19)

To the reaction flask was added N ¹ -(2-(dimethylamino)ethyl)-N ⁴ -(4-(7-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl -5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (19C) (0.36 g, 0.78 mmol), diisopropylethylamine (111 mg, 0.86 mmol) and dichloro Methane (10 mL) was cooled in ice-cooled, and EtOAc (EtOAc (EtOAc) An aqueous solution of sodium hydrogencarbonate (10 mL) was added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjj Purification by silica gel column chromatography (dichloromethane/methanol (v/v) = 30:1 - 20:1) to give N-(2-((2-(dimethylamino)ethyl)) Amino)-5-((4-(7-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide ( Compound 19) (360 mg, yield 90%).

MS m/z (ESI): 518.3 [M+1] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ10.13 (s, 1H), 9.07 (s, 1H), 8.63 (s, 1H), 8.35 (d, 1H), 8.07 (d, 1H), 7.96 ( s, 1H), 7.22 (d, 1H), 7.14 - 6.96 (m, 3H), 6.49 (dd, 1H), 6.27 (dd, 1H), 5.77 (d, 1H), 4.08 (m, 3H), 3.86 (s, 3H), 2.94 (br, 2H), 2.71 (s, 3H), 2.40 (br, 2H), 2.27 (s, 6H).

Example 20

N-(2-((2-Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((5-methoxy-4-(pyrazolo[1,5] -a]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 20)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((5-methoxy-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin -2-yl)amino)phenyl)acrylamide

First step: N ⁴ -(2-dimethylaminoethyl)-2-methoxy-N ¹ -(5-methoxy-4-pyrazolo[1,5-a]pyridine-3- -Pyrimidin-2-yl)-N ⁴ -methyl-5-nitro-phenyl-1,4-diamine (20B)

N4-(2-dimethylaminoethyl)-2-methoxy-N1-(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-N4-methyl-5-nitro- Benzene-1,4-diamine

Weigh N-(4-fluoro-2-methoxy-5-nitro-phenyl)-5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidine- 2-Amine (Intermediate 9) (0.41 g, 1 mmol) was placed in a 10 mL microwave reaction tube, and N,N-dimethylacetamide (2 mL), N, N, N'- Methyl ethylenediamine (18A) (0.16 mL, 1.2 mmol) and diisopropylethylamine (0.2 mL, 1.2 mmol) were warmed to 140 ° C for 1 hour under microwave. The reaction solution was concentrated under reduced pressure and to the residue was separated and purified by column chromatography (dichloromethane / methanol (v / v) = 15: 1) to give a red solid N ⁴ - (2- dimethylaminoethyl) - 2-methoxy-N ¹ -(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-N ⁴ -methyl-5-nitro Base-phenyl-1,4-diamine (20B) (0.22 g, yield 45%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.00 (s, 1H), 8.82 (s, 1H), 8.68-8.66 (d, 1H), 8.54-8.53 (d, 1H), 8.17 (s, 1H), 7.41-7.34 (m, 2H), 6.94-6.91 (m, 1H), 6.75 (s, 1H), 4.01 (s, 3H), 4.00 (s, 3H), 3.33-3.30 (m, 2H), 2.88 ( s, 3H), 2.66-2.63 (m, 2H), 2.37 (s, 6H).

Second step: N ¹ -(2-dimethylaminoethyl)-5-methoxy-N ⁴ -(5-methoxy-4-pyrazolo[1,5-a]pyridine-3- -Pyrimidin-2-yl)-N ¹ -methyl-phenyl-1,2,4-triamine (20C)

N ¹ -(2-dimethylaminoethyl)-5-methoxy-N ⁴ -(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-N ¹ -methyl-benzene -1,2,4-triamine

Weighing N ⁴ -(2-dimethylaminoethyl)-2-methoxy-N ¹ -(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl- Pyrimidin-2-yl)-N ⁴ -methyl-5-nitro-phenyl-1,4-diamine (20B) (0.22 g, 0.45 mmol), placed in a 100 mL round bottom flask and placed in a reaction flask Ethanol (21 mL), water (7 mL), reduced iron powder (0.15 g, 2.70 mmol) and ammonium chloride (0.017 g, 0.32 mmol) were sequentially added, and the mixture was refluxed for 6 hours. The reaction solution was filtered, and the filter cake was washed with dichloromethane (10 mL×2) and methanol (10 mL×2), and the filtrate was concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) = 15:1) N ¹ -(2-dimethylaminoethyl)-5-methoxy-N ⁴ -(5-methoxy-4-pyrazolo[1,5- a] Pyridin-3-yl-pyrimidin-2-yl)-N ¹ -methyl-phenyl-1,2,4-triamine (20C) (0.20 g, yield 98%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.82-8.80 (m, 2H), 8.55-8.53 (d, 2H), 8.11 (s, 1H), 7.94 (s, 1H), 7.37-7.36 (m, 2H ), 6.92-6.90 (m, 2H), 6.71 (s, 1H), 4.96 (br, 1H), 3.95 (s, 3H), 3.85 (s, 3H), 3.02-3.00 (m, 2H), 2.67 ( s, 3H), 2.50-2.46 (m, 2H), 2.42 (s, 6H).

The third step: N-(2-((2-dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((5-methoxy-4-(pyrazole) [1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 20)

Weigh N ¹ -(2-dimethylaminoethyl)-5-methoxy-N ⁴ -(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl- Pyrimidin-2-yl)-N ¹ -methyl-phenyl-1,2,4-triamine (20C) (0.2 g, 0.43 mmol) was placed in a 100 mL round bottom flask, then THF (15 mL) Diisopropylethylamine (0.09 mL, 0.56 mmol) was cooled to 0 ° C, EtOAc (EtOAc (EtOAc) The reaction mixture was concentrated under reduced vacuo. dichloromethane (EtOAc m. Washed with water (30 mL), dried over anhydrous sodium sulfate, EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((5-methoxy-4-(pyrazolo[1,5-a]pyridin-3-yl) Pyrimidine-2-yl)amino)phenyl)acrylamide (Compound 20) (0.08 g, yield 48%).

MS m/z (ESI): 517.2 [M+1] ⁺ .

Example 21

N-(2-((2-Dimethylamino)ethyl)(methyl)amino)-5-((5-methoxy-4-(pyrazolo[1,5-a]pyridine-3) -yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 21)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((5-methoxy-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl) )amino)phenyl)acrylamide

First step: N-(4-fluoro-3-nitro-phenyl)-5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-amine ( 21B)

N-(4-fluoro-3-nitro-phenyl)-5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-amine

3-(2-Chloro-5-methoxy-pyrimidin-4-yl)pyrazolo[1,5-a]pyridine (9c) (0.52 g, 2 mmol) was weighed and placed in a 50 mL round bottom flask. 2-pentanol (15 mL), 4-fluoro-3-nitroaniline (0.31 g, 2 mmol) and p-toluenesulfonic acid (0.46 g, 2.4 mmol) were successively added to the reaction flask, and the mixture was heated to 120 ° C for 48 hours. The reaction solution was cooled to room temperature, acetonitrile (20 mL) and aqueous ammonia (20 mL) were added and filtered. The filter cake was washed with acetonitrile (10 mL×2) and water (10 mL×2), and the filter cake was collected and dried to give N- (4-fluoro-3-nitro-phenyl)-5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-amine (21B) (0.68 g, Yield 89%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.82 (s, 1H), 8.88-8.75 (m, 4H), 8.37 (s, 1H), 8.03-8.01 (m, 1H), 7.51-7.47 (m) , 2H), 7.18-7.16 (m, 1H), 4.02 (s, 3H).

Second step: N ¹ -(2-dimethylaminoethyl)-N ⁴ -(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidine-2- -N ¹ -Methyl-2-nitro-phenyl-1,4-diamine (21C)

N1-(2-dimethylaminoethyl)-N4-(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-N1-methyl-2-nitro-benzene-1, 4-diamine

Weigh N-(4-fluoro-3-nitro-phenyl)-5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-amine (21B) (0.38 g, 1 mmol), placed in a 10 mL microwave reaction tube, and sequentially added N,N-dimethylacetamide (2 mL), N,N,N'-trimethylethylenediamine (18A) to the reaction tube. (0.16 mL, 1.2 mmol) and diisopropylethylamine (0.2 mL, 1.2 mmol) were heated to 140 ° C under microwave for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was separated and purified by column chromatography (dichloromethane / methanol (v / v) = 15: 1) to give a red solid of N ¹ - (2- dimethylaminoethyl) - N ⁴ -(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-N ¹ -methyl-2-nitro-phenyl-1 4-Diamine (21C) (0.46 g).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.82 (s, 1H), 8.64 - 8.62 (m, 1H), 8.57-8.53 (m, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 7.51-7.49 (m, 1H), 7.40-7.38 (m, 1H), 7.24-7.22 (d, 1H), 7.04 (s, 1H), 6.97-6.93 (m, 1H), 4.01 (s, 3H), 3.33-3.30 (m, 2H), 2.84-2.79 (m, 5H), 2.55 (s, 6H).

Third step: N ¹ -(2-dimethylaminoethyl)-N ⁴ -(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidine-2- -N ¹ -methyl-phenyl-1,2,4-triamine (21D)

N1-(2-dimethylaminoethyl)-N4-(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-N1-methyl-benzene-1,2,4- Triamine

Weigh N ¹ -(2-dimethylaminoethyl)-N ⁴ -(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl) -N ¹ -Methyl-2-nitro-phenyl-1,4-diamine (21C) (0.8 g, 1.73 mmol) was placed in a 100 mL round bottom flask, and ethanol (30 mL) was sequentially added to the reaction flask. Water (10 mL), reduced iron powder (0.58 g, 10.4 mmol) and ammonium chloride (0.065 g, 1.21 mmol) were reacted under reflux for 6 hours. The reaction solution was filtered, and the filter cake was washed with dichloromethane (10 mL×2), washed with methanol (10mL×2), and the filtrate was concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) = 15:1) N ¹ -(2-dimethylaminoethyl)-N ⁴ -(5-methoxy-4-pyrazolo[1,5-a]pyridine-3- Base-pyrimidin-2-yl)-N ¹ -methyl-phenyl-1,2,4-triamine (21D) (0.63 g, yield 84%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.81 (s, 1H), 8.78-8.75 (d, 1H), 8.55-8.53 (d, 1H), 8.11 (s, 1H), 7.79-7.77 (d, 2H) ), 7.28 (s, 1H), 7.20-7.17 (m, 3H), 3.98 (s, 3H), 3.18-3.15 (m, 2H), 2.90-2.87 (m, 2H), 2.64 (s, 6H).

Fourth step: N-(2-((2-dimethylamino)ethyl)(methyl)amino)-5-((5-methoxy-4-(pyrazolo[1,5-a Pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 21)

Weigh N ¹ -(2-dimethylaminoethyl)-N ⁴ -(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl) -N ¹ -Methyl-phenyl-1,2,4-triamine (21D) (0.63 g, 1.46 mmol), placed in a 100 mL round bottom flask, and then, in the reaction flask, tetrahydrofuran (15 mL) and two different Propylethylamine (0.29 mL, 1.75 mmol), the reaction mixture was cooled to 0 ° C, and acryloyl chloride (0.14 mL, 1.75 mmol) was added dropwise. After the dropwise addition was completed, the reaction was warmed for 1 hour. The reaction mixture was concentrated under reduced vacuo. dichloromethane (EtOAc m. Washed with water (30 mL), dried over anhydrous NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ((2-Dimethylamino)ethyl)(methyl)amino)-5-((5-methoxy-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidine- 2-Based)amino)phenyl)acrylamide (Compound 21) (0.15 g, yield 48%).

MS m/z (ESI): 487.3 [M+1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.82 (s, 1H), 8.77-8.73 (m, 1H), 8.56-8.53 (m, 2H), 8.21 (s, 1H), 8.02 (s, 1H), 7.78-7.76(d,1H), 7.72-7.70(m,1H), 7.30-7.28(m,1H),7.23-7.21(m,2H),7.01(s,1H),6.45-6.41(m,1H) ), 5.73-5.70 (m, 1H), 3.99 (s, 3H), 2.82-2.80 (m, 2H), 2.72 (s, 3H), 2.34-2.30 (m, 8H).

Example 22

N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-3-fluoro-4-methoxy-5-((4-(1-methyl-1H-indole) Ind-3-yl)pyrimidin-2-yl)phenyl)acrylamide (Compound 22)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-3-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2 -yl)amino)phenyl)acrylamide

First step: N ⁴ -(2-(dimethylamino)ethyl)-3-fluoro-2-methoxy-N ⁴ -methyl-N ¹ -(4-(1-methyl-1H- Ind-3-yl)pyrimidin-2-yl)-5-nitrobenzene-1,4-diamine (22B)

N ⁴ -(2-(dimethylamino)ethyl)-3-fluoro-2-methoxy-N ⁴ -methyl-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl) -5-nitrobenzene-1,4-diamine

N-(3,4-Difluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (Intermediate 10 (1.4 g, 3.4 mmol), N,N,N'-trimethylethylenediamine (18A) (0.69 g, 6.8 mmol) and N,N-diisopropylethylamine (0.87 g, 6.8 mmol) It was added to N,N-dimethylformamide (3 mL), and subjected to microwave reaction at 140 ° C for 1.5 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was evaporated. The residue was purified by silica gel column chromatography (methylene chloride: methanol (v / v) = 50: 1) to give the title compound N ⁴ - (2- (dimethylamino) ethyl) -3-fluoro-2- Methoxy-N ⁴ -methyl-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-nitrobenzene-1,4-diamine (22B), red solid (0.25 g, yield 15%).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.62 (s, 1H), 8.56 (s, 1H), 8.42-8.38 (m, 2H), 8.35 (s, 1H), 7.54 (d, 1H), 7.32(d,1H), 7.30–7.22(m,2H),7.16(t,1H),4.02(s,3H),3.88(s,3H),3.20(t,2H),2.82(s,3H) , 2.65 (s, 2H), 2.35 (s, 6H).

MS m/z: 494.3 [M + 1] ⁺ .

Second step: N ¹ -(2-(dimethylamino)ethyl)-6-fluoro-5-methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H- Ind-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine (22C)

N ¹ -(2-(dimethylamino)ethyl)-6-fluoro-5-methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl) Benzene-1,2,4-triamine

N ⁴ -(2-(Dimethylamino)ethyl)-3-fluoro-2-methoxy-N ⁴ -methyl-N ¹ -(4-(1-methyl-1H-indole- 3-yl)pyrimidin-2-yl)-5-nitrobenzene-1,4-diamine (22B) (0.25 g, 5 mmol), iron powder (0.17 g, 30 mmol) and amine chloride (0.27 g, 50 mmol) It was added to a mixed solution of ethanol (5 mL) and water (2 mL), and the mixture was heated to 90 ° C for 4 hours. The reaction mixture was cooled to room temperature, EtOAc (EtOAc m. ^1- (2-(Dimethylamino)ethyl)-6-fluoro-5-methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-indole-3- Pyrimidin-2-yl)benzene-1,2,4-triamine (22C), red solid (0.22 g, yield 96%).

MS m/z: 464.4 [M + 1] ⁺ .

Third step: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-3-fluoro-4-methoxy-5-((4-(1-methyl) -1H-indol-3-ylpyrimidin-2-yl)phenyl)acrylamide (Compound 22)

N ¹ -(2-(Dimethylamino)ethyl)-6-fluoro-5-methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-indole- 3-yl)pyrimidin-2-yl)phenyl-1,2,4-triamine (22C) (0.27 g, 0.55 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbamate Imino hydrochloride (EDCI) (0.42 g, 2.19 mmol) and acrylic acid (0.078 g, 1.09 mmol) were added to pyridine (5 mL) and allowed to react at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was evaporated. The title compound N-(2-(2-(dimethylamino)ethyl)(methyl)amino)-3-fluoro- 4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)phenyl)acrylamide (Compound 22), yellow solid (40 mg, yield 14%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H), 9.04 (s, 1H), 8.68 (s, 1H), 8.37 (d, 1H), 8.24 (d, 1H), 8.20 ( s, 1H), 7.53 (d, 1H), 7.29 (d, 1H), 7.25 (m, 1H), 7.14 (m, 1H), 6.41 - 6.25 (m, 2H), 5.83 (m, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.06 (s, 2H), 2.81 (s, 3H), 2.28 (s, 2H), 2.22 (s, 6H).

MS m/z: 518.4 [M+1] ⁺ .

Example 23

N-(4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(1-methyl-1H-indole) Ind-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 23)

N-(4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl) )amino)phenyl)acrylamide

First step: 2-(difluoromethoxy)-N ⁴ -(2-(dimethylamino)ethyl)-N ⁴ -methyl-N ¹ -(4-(1-methyl-1H-indole) Ind-3-yl)pyrimidin-2-yl)-5-nitrobenzene-1,4-diamine (23B)

2-(difluoromethoxy)-N ⁴ -(2-(dimethylamino)ethyl)-N ⁴ -methyl-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5 -nitrobenzene-1,4-diamine

Add 5-(difluoromethoxy)-N-(2-(dimethylamino)ethyl)-N-methyl-2-nitrobenzene-1,4-diamine (intermediate 1) to the reaction flask. (120 mg, 0.39 mmol), 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (intermediate 2) (115 mg, 0.47 mmol), p-toluenesulfonic acid (94 mg, 0.86) Methyl) and 2-pentanol (2 mL) were heated to 110 ° C for 3 hours. The reaction mixture was concentrated to dryness EtOAc (EtOAc m. ^4- (2-(Dimethylamino)ethyl)-N ⁴ -methyl-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5- Nitrobenzene-1,4-diamine (23B) (150 mg, yield 75%).

MS m / z (ESI): 512.3 [M + 1] +.

^{1 H NMR (400MHz, DMSO-} d 6) δ8.56 (d, 2H), 8.37-8.29 (m, 3H), 7.50 (dd, 1H), 7.39 (t, 1H), 7.30-7.22 (m, 2H ), 7.20 (s, 1H), 7.17 - 7.07 (m, 1H), 3.88 (s, 3H), 3.41 (t, 2H), 2.98 (s, 2H), 2.83 (s, 3H), 2.56 (s, 6H).

Second step: 5-(difluoromethoxy)-N ¹ -(2-(dimethylamino)ethyl)-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H- Ind-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine (23C)

5-(difluoromethoxy)-N ¹ -(2-(dimethylamino)ethyl)-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene- 1,2,4-triamine

To the reaction flask was added 2-(difluoromethoxy)-N ⁴ -(2-(dimethylamino)ethyl)-N ⁴ -methyl-N ¹ -(4-(1-methyl-1H-) Ind-3-yl)pyrimidin-2-yl)-5-nitrobenzene-1,4-diamine (23B) (150 mg, 0.29 mmol), iron powder (99 mg, 1.76 mmol), ammonium chloride (11 mg) 0.2 mmol) and ethanol/water (5 mL / 1.5 mL) were heated to reflux for 2 hours. The reaction mixture was concentrated to dryness EtOAcjjjjjjjjjjjjjjjj N ¹ -(2-(Dimethylamino)ethyl)-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene -1,2,4-triamine (23C) (100 mg, yield 72%).

MS m/z (ESI): 482.4 [M+1] ⁺ .

Third step: N-(4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(1-methyl) -1H-indol-3-ylpyrimidin-2-yl)amino)phenyl)acrylamide (Compound 23)

To the reaction flask was added 5-(difluoromethoxy)-N ¹ -(2-(dimethylamino)ethyl)-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H) -Indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine (23C) (110 mg, 0.23 mmol), diisopropylethylamine (39 mg, 0.3 mmol) and dichloro Methane (3 mL) was cooled in an ice bath, and acryloyl chloride (23 mg, 0.25 mmol) was added dropwise. Dichloromethane (20 mL) and a saturated aqueous solution (20 mL) were added to the mixture, and the mixture was evaporated. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethanol (methanol) (v/v) = 30:1) toield of N-(4-(difluoromethoxy)-2-(( 2-(Dimethylamino)ethyl)(methyl)amino)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl) Acrylamide (Compound 23) (45 g, yield 37%).

MS m/z (ESI): 536.3 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.21. (s, 1H), 8.94 (s, 1H), 8.50 (s, 1H), 8.35 - 8.28 (m, 2H), 8.24 (d, 1H), 7.51(d,1H), 7.28–7.15(m,3H), 7.10(d,1H),7.07(t,1H),6.55–6.38(m,1H), 6.27(d,1H), 5.80(d, 1H), 3.89 (s, 3H), 2.90 (s, 2H), 2.71 (s, 3H), 2.40 (m, 2H), 2.26 (s, 6H).

Example 24

N-(3-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-morpholinyl)acrylamide (Compound 24)

N-(3-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-morpholinophenyl)acrylamide

First step: 4-(3-iodo-5-nitrophenyl)morpholine (24B)

4-(3-iodo-5-nitrophenyl)morpholine

1-Fluoro-3-iodo-5-nitrobenzene (24A) (5.0 g, 18.7 mmol) and morpholine (3.4 g, 39.3 mmol) were dissolved in dimethyl sulfoxide (15 mL) and reacted at 90 ° C The reaction was completed in 17 hours, 30 mL of water was added, and the mixture was washed with methylene chloride (30 mL × 2), washed with 30 mL of water, washed with 30 mL of brine, dried over anhydrous sodium sulfate -Nitrophenyl)morpholine (24B) (6.0 g, yield 96.8%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 - 7.95 (m, 1H), 7.64 (t, 1H), 7.45 (dd, 1H), 3.86 (dd, 4H), 3.24 (dd, 4H).

LC-MS (m / z) : 335.1 [M + 1] +.

Step 2: 3-morpholinyl-5-nitroaniline (24C)

3-morpholino-5-nitroaniline

4-(3-Iodo-5-nitrophenyl)morpholine (24B) (1.0 g, 3.0 mmol) was dissolved in N,N-dimethylformamide (2 mL). Copper powder (190 mg, 3.0 mmol) was reacted overnight at 100 ° C in a closed system. After the reaction was completed, 60 mL of water was added, and dichloromethane (60 mL × 2) was evaporated. / petroleum ether = 1:10 to 1:1) gave the red solid 3-morpholinyl-5-nitroaniline (24C) (0.35 g, yield 52.23%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.14 (t, 1H), 7.01 (t, 1H), 6.42 (t, 1H), 3.87 - 3.83 (m, 4H), 3.22 - 3.16 (m, 4H).

The third step: 4-(1-methyl-1H-indol-3-yl)-N-(3-morpholinyl-5-nitrophenyl)pyrimidin-2-amine (24D)

4-(1-methyl-1H-indol-3-yl)-N-(3-morpholino-5-nitrophenyl)pyrimidin-2-amine

3-(2-Chloropyrimidin-4-yl)-1-methyl-1H-indole (Intermediate 2) (0.4 g, 1.6 mmol), 3-morpholino-5-nitroaniline (0.37 g) , 1.6 mmol), p-toluenesulfonic acid (0.31 g, 1.6 mmol) was added to 40 mL of 2-pentanol, and reacted at 120 ° C overnight. After completion of the reaction, the reaction solution was cooled, a solid was precipitated, and the filter cake was dried to give 4-(1-methyl-1H-indol-3-yl)-N-(3-morpholinyl-5-nitrate as a yellow solid. Phenylphenyl)pyrimidine-2-amine (24D) (0.3 g, yield 53.5%).

LC-MS (m / z) : 431.1 [M + 1] +.

Fourth step: N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-morpholinbenzene-1,3-diamine (24E)

N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-morpholinobenzene-1,3-diamine

Dissolving 4-(1-methyl-1H-indol-3-yl)-N-(3-morpholin-5-nitrophenyl)pyrimidin-2-amine (24D) (0.4 g, 0.93 mmol) Iron carbonate (311 mg, 5.6 mmol) and ammonium chloride (497.5 mg, 9.3 mmol) were added to a mixed solvent of ethanol (20 ml) and water (10 ml). The reaction was carried out at 90 ° C for 2 hours. Water (30 ml) was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated The title compound N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-morpholin benzene-1,3-diamine (24E) 250 mg, yield 68%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.45 (dd, 1H), 8.28 (d, 1H), 7.82 (s, 1H), 7.44-7.35 (m, 2H), 7.35-7.27 (m, 2H), 7.02(d,1H), 6.77(m,1H), 6.71(m,1H),5.99(m,1H),3.87(s,3H),3.83–3.79(m,4H),3.17–3.12(m, 4H).

MS m/z (ESI): 401.1 [M+1] ⁺ .

Step 5: N-(3-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-morpholinyl)acrylamide (Compound 24)

N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-morpholinium-1,3-diamine (24E) (250 mg, 0.625 mmol) Dissolved in 5 mL of pyridine, added with acrylic acid (90 mg, 1.25 mmol), and added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.5 mmol, 478 mg). . After adding 60 ml of dichloromethane, the mixture was washed with water (60 mL × 2), EtOAc (EtOAc) Purification (dichloromethane/methanol (v/v) = 100/1-100/3) afforded N-(3-(1-(1-methyl-1H-indole-3-) Pyrimido-2-yl)amino)-5-morpholinbenzene)acrylamide (Compound 24) (150 mg, yield 52.8%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.36 (d, 1H), 8.27 (d, 1H), 7.96 (s, 1H), 7.62 (s, 1H), 7.50 (d, 2H), 7.37 (d, 1H), 7.31 (m, 1H), 7.23 (d, 1H), 7.17 (s, 1H), 7.03 (d, 1H), 6.87 (s, 1H), 6.41 (d, 1H), 6.23 (dd, 1H) ), 5.73 (d, 1H), 3.85 (s, 3H), 3.83 - 3.76 (m, 4H), 3.20 - 3.12 (m, 4H).

MS m/z (ESI): 455.2 [M+1] ⁺ .

Example 25

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)) (M)amino)-4-ethylphenyl)acrylamide (Compound 25)

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino )-4-ethylphenyl)acrylamide

First step: 2-ethyl-4-fluoro-5-nitroaniline (25B)

2-ethyl-4-fluoro-5-nitroaniline

25 mL of concentrated sulfuric acid was added to the reaction flask, 2-ethyl-4-fluoroaniline (25A) (3.88 g, 27.9 mmol) was added dropwise at 0 ° C, potassium nitrate ((2.82 g, 27.9 mmol) was added, and the reaction was carried out at 0 ° C for 1 hour. Ice cubes (100 mL) were added to a saturated sodium bicarbonate solution (300 ml), and the reaction system was slowly poured into the above solution, and sodium bicarbonate solid was added until no more bubbles were formed. The liquid phase was separated with ethyl acetate ( 150 mL × 4), the organic phase was combined, dried over anhydrous sodium sulfate, and evaporated and evaporated. Compound orange solid 2-ethyl-4-fluoro-5-nitroaniline (25B) (3.33 g, yield 55%).

MS m/z: 185.1 [M + 1] ⁺ .

The second step: 5-chloro-N-(2-ethyl-4-fluoro-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (25C)

5-chloro-N-(2-ethyl-4-fluoro-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

2-Ethyl-4-fluoro-5-nitroaniline (25B) (1.31 g, 7.1 mmol) and 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indole哚(4c) (1.97 g, 7.1 mmol) was dissolved in 1,4-dioxane (70 mL), and 4.5-bisdiphenylphosphine-9.9-dimethyloxanium (0.46 g, 0.79 mmol) was added. Cesium carbonate (4.85 g, 14.9 mmol) and palladium acetate (0.10 g, 0.47 mmol) were cooled with liquid nitrogen, replaced with nitrogen for 0.5 hour, and allowed to react at room temperature and then at 120 ° C overnight. The mixture was cooled to room temperature, and the title compound was obtained mjjjjjjjjjjjjjjjj Chloro-N-(2-ethyl-4-fluoro-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (25C) (0.59g , yield 20%).

MS m/z: 426.1 [M + 1] ⁺ .

Third step: N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl )-2-ethyl-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (25D)

N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2-ethyl-N ⁴ -methyl -5-nitrobenzene-1,4-diamine

Add 5-chloro-N-(2-ethyl-4-fluoro-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2- to the microwave reaction tube Amine (25C) (0.56 g, 1.32 mmol) was dissolved in N,N-dimethylacetamide (8 mL), and diisopropylethylamine (0.26mL, 1.59mmol), N, N, N'- Trimethylethylenediamine (18A) (0.21 mL, 1.59 mmol) was subjected to microwave reaction at 140 ° C for 1 hour. The reaction system was cooled to room temperature and then concentrated, and the residue was purified by silica gel column chromatography ( petroleum ether: ethyl acetate (v/v) = 4:1 - 2:1 - dichloromethane: methanol (v/v) = 15:1 to 5:1), the title compound was obtained as an orange solid N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ - ( 2-(Dimethylamino)ethyl)-2-ethyl-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (25D) (0.49 g, yield 73%).

MS m/z = 509.2 [M + 1] ⁺ .

Fourth step: N ⁴ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl )-5-ethyl-N ¹ -methylphenyl-1,2,4-triamine (25E)

N ⁴ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5-ethyl-N ¹ -methylbenzene -1,2,4-triamine

N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2 -ethyl-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (25D) (0.46 g, 0.91 mmol), iron powder (0.30 g, 5.43 mmol) and ammonium chloride (0.04 g, 0.75 mmol) was added to a mixed solvent of anhydrous ethanol (12 mL) and water (4 mL), and the mixture was heated to 90 ° C overnight, and iron powder (0.15 g, 2.72 mmol) and ammonium chloride (0.02 g, 0.37 mmol) were added. The reaction was continued at 90 ° C for 2 hours. The mixture was cooled to room temperature, the solid was filtered, dried and evaporated. mjjjjjjjjjjjj ) = 10:1 to 3:1), the title compound was obtained as an orange solid N ⁴ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ - (2- (dimethylamino) ethyl) -5-ethyl -N ¹ - methyl-phenyl-1,2,4-triamine (25E) (0.43g, 92% yield).

MS m/z: 479.2 [M+1] ⁺ .

Step 5: N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethyl) Base amino)ethyl)(methyl)amino)-4-ethylphenyl)acrylamide (compound 25)

Diisopropylethylamine (1.7 mL) was added to freshly distilled tetrahydrofuran (8.3 mL) to give solution 1; acryloyl chloride (0.75 mL) was added to freshly distilled tetrahydrofuran (9.25 mL) to give solution 2. N ⁴ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5 -ethyl-N ¹ -methylphenyl-1,2,4-triamine (25E) (0.40 g, 0.84 mmol) was dissolved in freshly distilled tetrahydrofuran (10 mL), and solution 1 (1 mL) was added dropwise at 0 °C. And solution 2 (1 mL), and reacted at room temperature for 1.5 hours. Water (80 mL) was added to the reaction mixture, and the mixture was evaporated. Ethyl acetate (v/v) = 1:1 - ethyl acetate:methanol (v/v) = 10:1 to 1:1) to give the title compound as white solid N-(5-((5-chloro-) 4-(1-Methyl-1H-indol-3-yl)pyridin-2-yl)N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl) Pyrimidine-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-ethylphenyl)acrylamide (compound 25) (0.07 g, produced Rate 16%).

^{1 H NMR (400MHz, DMSO-} d 6) δ10.12 (s, 1H), 8.88 (s, 1H), 8.53 (s, 2H), 7.46-7.44 (m, 1H), 7.23 (s, 1H), 7.18-7.15(m,1H), 6.89-6.86(m,1H),6.43-6.36(m,1H),6.21-6.16(m,1H),5.74-5.72(m,1H),5.33-5.31(m , 1H), 3.87 (s, 3H), 3.17-3.16 (m, 2H), 2.75 (s, 3H), 2.58-2.52 (m, 2H), 2.37-2.34 (m, 2H), 2.21 (s, 6H) ), 1.09-1.05 (t, 3H).

MS m/z: 533.2 [M + 1] ⁺ .

Example 26

4-(3-(2-((5-acrylamido-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl) Piperazine 1-carboxylic acid tert-butyl ester (compound 26)

Tert-butyl 4-(3-(2-(5-acrylamido-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)piperazine-1-carboxylate

First step: 6-bromo-1-(triisopropylsilyl)-1hydro-indole (26B)

6-bromo-1-(triisopropylsilyl)-1H-indole

Tetrahydrofuran (250 mL) was added to a 2 L round bottom flask. At 0 ° C, sodium hydride (24.5 g, 0.612 mol, w/w = 60%) was added to the reaction flask, and 6-bromoindole (100.0 g, A solution of 0.510 mol) in tetrahydrofuran (500 mL). After completion of the dropwise addition, the mixture was stirred at 0 ° C for 30 minutes, and a solution of triisopropylchlorosilane (100 g, 0.518 mol) in tetrahydrofuran (250 mL) was added dropwise. After the dropwise addition was completed, the reaction was further stirred at 0 ° C for 30 minutes. The reaction solvent was evaporated under reduced pressure. The residue was evaporated.jjjjjjjjjjjjjjjjj Ether/ethyl acetate (v/v) = 15:1) gave 6-bromo-1-(triisopropylsilyl)-1hydro-indole (26B) as a white solid (160 g, yield 93%) ).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.63 (s, 1H), 7.49-7.47 (d, 1H), 7.20-7.18 (m, 2H), 6.59-6.58 (d, 1H), 1.71-1.64 (m , 3H), 1.16.14.14 (m, 18H).

Step 2: 4-(1H-Hydrazine-6-yl)piperidine-1-carboxylic acid tert-butyl ester (26C)

Tert-butyl 4-(1H-indol-6-yl)piperazine-1-carboxylate

6-Bromo-1-(triisopropylsilyl)-1hydro-indole (26B) (1.2 g, 3.6 mmol) was added to a 100 mL round bottom flask. O-xylene (40 mL), 1-tert-butoxycarbonylpiperazine (1.0 g, 5.4 mmol), sodium t-butoxide (0.51 g, 5.4 mmol), and tri-tert-butylphosphine (0.11 g) were sequentially added to the reaction flask. 0.54 mmol) and palladium acetate (0.04 g, 0.18 mmol) were replaced with nitrogen balls several times, stirred at room temperature for 30 minutes, and heated to 120 ° C for 2 hours. The reaction mixture was filtered, and the filtrate was washed with ethyl acetate (50 mL). This crude product was dissolved in 100 mL of tetrahydrofuran, and tetrabutylammonium fluoride (1.9 g, 7.2 mmol) was added thereto, and the mixture was reacted at room temperature for 1 hour. The reaction solvent was removed under reduced pressure and purified (EtOAc mjjjjjjjjj Tert-butyl formate (26C) (0.65 g, yield: 60%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.09 (br, 1H), 7.55-7.53 (d, 1H), 6.96 (s, 1H), 6.95-6.89 (m, 2H), 6.47 (s, 1H), 3.65 (s, 4H), 3.13 (s, 4H), 1.50 (s, 9H).

The third step: 4-(3-(2,5-dichloropyrimidin-4-yl)-1hydro-indol-6-yl)piperidine-1-carboxylic acid tert-butyl ester (26D) tert-butyl 4 -(3-(2,5-dichloropyrimidin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate

4-(1H-Hydrazine-6-yl)piperidine-1-carboxylic acid tert-butyl ester (26C) (0.3 g, 1 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (5 mL) was added to the reaction flask. A solution of methyl magnesium bromide in diethyl ether (0.5 mL, 1.5 mmol, 3 mol/L) was added dropwise at 0 ° C. After the dropwise addition was completed, the mixture was stirred at room temperature for 1 hour. 2,4,5-trichloropyrimidine (0.2 g, 1.1 mmol) was added to the reaction flask at 0 °C. The temperature was raised to reflux for 2 hours. The reaction mixture was cooled to room temperature, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated After column chromatography (petroleum ether/ethyl acetate (v/v) = 2:1), 4-(3-(2,5-dichloropyrimidin-4-yl)-1 hydrogen-indole as a yellow solid. tert-Butyl benzyl-6-yl)piperidine-1-carboxylate (26D) (0.1 g, yield 20%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.15 (s, 1H), 8.58-8.57 (d, 1H), 8.56-8.41 (m, 2H), 7.08-7.06 (d, 1H), 6.96 (s, 1H ), 3.67-3.65 (m, 4H), 3.17 (s, 4H), 1.51 (s, 9H).

MS m/z: 448.0 [M+1] ⁺ .

Step 4: 4-(3-(2,5-Dichloropyrimidin-4-yl)-1-methyl-1hydro-indol-6-yl)piperidine-1-carboxylic acid tert-butyl ester (26E )

Tert-butyl 4-(3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)piperazine-1-carboxylate

4-(3-(2,5-Dichloropyrimidin-4-yl)-1hydro-indol-6-yl)piperidine-1-carboxylic acid tert-butyl ester (26D) (1.1 g, 2.4 mmol) It was placed in a 100 mL round bottom flask, and N,N-dimethylformamide (20 mL) was added to the reaction flask. Sodium hydride (0.14 g, 5.9 mol, 60%) was added to the reaction flask at 0 ° C, and the reaction was continued at 0 ° C for 30 minutes. Methyl iodide (1.0 g, 7.1 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction solution was poured into water (100 mL), and a large amount of solid was precipitated, and the precipitate was filtered, washed with petroleum ether (20 mL × 2), water (20 mL × 2), and dried in vacuo to give 4-(3-( 2,5-Dichloropyrimidin-4-yl)-1-methyl-1hydro-indol-6-yl)piperidine-1-carboxylic acid tert-butyl ester (26E) (1.1 g, yield 99%) .

Step 5: 4-(3-(5-Chloro-2-((2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1hydro-indole哚-6-base) Piperidine-1-carboxylic acid tert-butyl ester (26F)

Tert-butyl 4-(3-(5-chloro-2-((2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indol-6-yl)piperazine-1- Carboxylate

4-(3-(2,5-Dichloropyrimidin-4-yl)-1-methyl-1hydro-indol-6-yl)piperidine-1-carboxylic acid tert-butyl ester (26E) (0.46 g, 1.0 mmol) was added to a 100 mL round bottom flask, and 1,4-dioxane (20 mL), 2-amino-4-nitroanisole (0.2 g, 1.2 mmol) and Sodium butoxide (0.24 g, 2.5 mmol). The reaction system was replaced with nitrogen for 10 minutes, and 4,5-bisdiphenylphosphino-9,9-dimethyloxaxime (0.063 g, 0.11 mmol) and palladium acetate (0.022 g, 0.1 mmol) were added, and the reaction system was again Nitrogen replacement. The temperature was raised to reflux and stirred for 6 hours. After the reaction mixture was cooled to room temperature, water (20 mL) was added to the reaction mixture, and the mixture was evaporated to ethyl ether (50 mL × 2). Drying, concentration under reduced pressure, EtOAc (EtOAc/EtOAc (EtOAc) 5--5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1hydro-indol-6-yl)piperidine-1-carboxylic acid tert-butyl ester (26F) (0.25 g , yield 42%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.49 (s, 1H), 8.43-8.39 (m, 2H), 8.17 (s, 1H), 7.92-7.90 (d, 1H), 7.77 (s, 1H), 7.02-6.94 (m, 3H), 4.05 (s, 3H), 3.86 (s, 3H), 3.68 (s, 4H), 3.21 (s, 4H), 1.50 (s, 9H).

Step 6: 4-(3-(2-(5-Amino-2-methoxyphenyl)amino)-5-chloro-pyrimidin-4-yl)-1-methyl-1 hydrogen-吲哚-6-yl)piperidine-1-carboxylic acid tert-butyl ester (26G)

Tert-butyl 4-(3-(2-(2-amino-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)piperazine-1-carboxylate

4-(3-(5-Chloro-2-((2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1hydro-indole-6 Tert-butyl piperidine-1-carbonate (26F) (0.12 g, 0.2 mmol) was added to a 100 mL round bottom flask, followed by ethanol (15 mL), water (5 mL), reduced iron powder (0.067 g, 1.2 Methyl) and ammonium chloride (0.007 g, 0.14 mmol) were warmed to reflux for 4 h. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane (10mL×2) and methanol (10mL×2). The filtrate was concentrated and purified by column chromatography (EtOAc/EtOAc (v/v) = 1:1) to afford 4-(3-((5-amino)-2-methoxy Phenyl)amino)-5-chloro-pyrimidin-4-yl)-1-methyl-1hydro-indol-6-yl)piperidine-1-carboxylic acid tert-butyl ester (26G) (0.06g , yield 55%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.56-8.54 (d, 1H), 8.31 (s, 1H), 8.14-8.11 (m, 1H), 7.74 (s, 1H), 7.04-7.02 (d, 1H ), 6.79 (s, 1H), 6.75-6.72 (d, 1H), 6.32-6.29 (m, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.65-3.63 (m, 4H), 3.19-3.16 (m, 4H), 1.50 (s, 9H).

Step 7: 4-(3-(2-(5-Acrylamide-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)-1-methyl-1H-indole- 6-yl)piperazine-1-carboxylic acid tert-butyl ester (compound 26)

4-(3-(2-((5-Amino-2-methoxyphenyl)amino)-5-chloro-pyrimidin-4-yl)-1-methyl-1hydro-indole- 6-Methylpiperidine-1-carboxylic acid tert-butyl ester (26G) (0.65 g, 1.2 mmol) was placed in a 50 mL round bottom flask. Pyridine (10 mL), acrylic acid (0.17 g, 2.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.88 g, 4.8 mmol) were sequentially added to the reaction flask. . The reaction was stirred at room temperature for 6 hours. The reaction solvent was evaporated under reduced pressure. EtOAc EtOAc m. After column chromatography (ethyl acetate), 4-(3-(2-((5-acrylamide-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl) tert-Butyl 1-methyl-1H-indol-6-yl)piperazine-1-carboxylate (Compound 26) (0.50 g, yield 70%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.51-8.49 (m, 2H), 8.31 (s, 1H), 8.35 (s, 1H), 8.17 (s, 1H), 7.79-7.77 (m, 2H), 7.15 (s, 1H), 7.02-7.00 (m, 1H), 6.90-6.88 (d, 1H), 6.39-6.35 (d, 1H), 6.08-6.06 (m, 1H), 5.69-5.66 (m, 1H) ), 3.93 (s, 3H), 3.86 (s, 3H), 3.69 (s, 4H), 3.22 (s, 4H), 1.50 (s, 9H).

MS m/z: 618.1 [M + 1] ⁺ .

Example 27

N-(3-((5-chloro-4-(1-methyl-6-(4-methylpiperazin-1-yl)indol-3-yl)pyrimidin-2-yl)amino)-4 -methoxyphenyl)acrylamide (Compound 27)

N-(3-((5-chloro-4-(1-methyl-6-(4-methylpiperazin-1-yl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl Acrylamide

First step: N-(3-((5-chloro-4-(1-methyl-6-(4-methylpiperazin-1-yl)indol-3-yl)pyrimidin-2-yl) Amino)-4-methoxyphenyl)acrylamide (Compound 27)

4-[3-[5-Chloro-2-[2-methoxy-5-(acrylamido)anilino]pyrimidin-4-yl]-1-methyl-indol-6-yl]piperidin The pyridine-1-carboxylic acid tert-butyl ester (Compound 26) (0.40 g, 0.65 mmol) was placed in a 50 mL round bottom flask. Dichloromethane (10 mL) and trifluoroacetic acid (5 mL) were added sequentially at 0 ° C, and the mixture was stirred at room temperature for 2 hr. Dichloromethane (50 mL), and aq. EtOAc (EtOAc) The crude product obtained. Dichloromethane (10 mL), acetic acid (2 mL), and aqueous formaldehyde (1 mL) were sequentially added to the crude product at 0 ° C and stirred for 30 minutes. Sodium triacetoxyborohydride (0.29 g, 1.3 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with aq. EtOAc (EtOAc (EtOAc) Concentration, column chromatography (dichloromethane / methanol (v / v) = 15:1) afforded N-(3-((5-chloro-4-(1-methyl-6-) -Methylpiperazin-1-yl)indol-3-ylpyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 27) (0.20 g, 56%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.54 - 8.53 (m, 1H), 8.49-8.47 (d, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 7.83-7.82 (m, 1H) ), 7.77 (s, 1H), 7.12 (s, 1H), 6.97-6.83 (m, 3H), 6.38-6.34 (d, 1H), 6.06-6.03 (m, 1H), 5.71-5.68 (d, 1H) ), 3.93 (s, 3H), 3.86 (s, 3H), 3.37 (s, 4H), 2.79 (s, 4H), 2.50 (s, 3H).

MS m/z: 532.1 [M].

Example 28

N-(2-((1-Aminocyclopropyl)methoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-) Amino)phenyl)acrylamide (compound 28)

N-(2-((1-aminocyclopropyl)methoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

First step: (1-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-nitrobenzene Oxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (28A)

Tert-butyl(1-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-nitrophenoxy)methyl)cyclopropyl)carbamate

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 3) (1 g , 2.54 mmol), dissolved in tetrahydrofuran (20 mL), sodium hydride (203 mg, 5.08 mmol), and the mixture was stirred for 30 minutes, and (1-hydroxymethylcyclopropyl)-tert-butoxycarbonylamino (951 mg, 5.08 mmol), reacted at room temperature for 8 hours. After completion of the reaction, 150 mL of water and 150 mL of ethyl acetate were added and the mixture was separated. The aqueous phase was extracted with ethyl acetate (100 mL). EtOAcjjjjjjjjjj Ind-3-yl)pyrimidin-2-yl)amino)-2-nitrophenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (28A) (1 g, yield 71.4%).

MS m/z: 561.1 [M + 1] ⁺ .

The second step: (1-((2-amino-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenoxy) Methyl)cyclopropyl)carbamic acid tert-butyl ester (28B)

Tert-butyl(1-((2-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenoxy)methyl)cyclopropyl)carbamate

(1-((5-Methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-nitrophenoxy) Methyl)cyclopropyl)carbamic acid tert-butyl ester (28A) (1.1 g, 2.1 mmol) was dissolved in 20 mL of ethanol, followed by 7 mL water, iron powder (356 mg, 6.4 mmol) and ammonium chloride (78.6 mg, 1.5 mmol), the temperature was raised to 90 ° C and refluxed for 6 hours. The reaction solution was cooled to room temperature, filtered and concentrated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a brown solid compound (1-((2-amino-5-methoxy-4-(( 4-(1-Methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (28B) (750 mg, yield 68.2%).

MS m/z: 531.1 [M + 1] ⁺ .

The third step: (1-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino) Phenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (28C)

Tert-butyl(1-((2-((())))))))))

(1-((2-Amino-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenoxy) Tert-butyl)-tert-butyl carbamate (28B) (750 mg, 1.4 mmol) dissolved in 20 mL of pyridine, followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt The acid salt (1.2 g, 6.3 mmol) and acrylic acid (0.15 mL, 2.1 mmol) were reacted at room temperature for 4 hours. The pyridine was removed by spin-drying, and 100 mL of water and 100 mL of dichloromethane were added and the mixture was separated. The organic phase was washed with a 4 mol/L aqueous sodium hydroxide solution (100 mL). The organic phase was dried over anhydrous sodium sulfate. Purify by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give white solid (1-((2-acrylamido-5-methoxy-4-) (4-(1-Methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (28C) (730mg, produced The rate is 89.4%).

MS m/z: 585.2 [M + 1] ⁺ .

Fourth step: N-(2-((1-aminocyclopropyl)methoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)) Pyrimidin-2-yl)amino)phenyl)acrylamide (compound 28)

(1-((2-Acrylamide-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenoxy) (Methyl)cyclopropyl)carbamic acid tert-butyl ester (28C) (730 mg, 1.25 mmol) was dissolved in 20 mL of dichloromethane. At the end of the reaction, the solvent was evaporated to dryness, and the mixture was adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. 100 mL of dichloromethane was added, and the organic phase was dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) afforded white compound N-(2-((1-aminocyclopropyl)methoxy) 4-Methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 28) (130 mg, 21.5%) .

MS m/z: 485.1 [M + 1] ⁺ .

Example 29

N-(4-Methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-morpholineethoxy) Phenyl)acrylamide (compound 29)

N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-morpholinoethoxy)phenyl)acrylamide

First step: N-(2-methoxy-4-(2-morpholinoethoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl) Pyrimidin-2-amine (29A)

N-(2-methoxy-4-(2-morpholinoethoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 3) (1.2 g, 3.05 mmol) was dissolved in 30 mL of tetrahydrofuran, sodium hydride (244.2 mg, 6.1 mmol) was added and the mixture was stirred for 30 minutes, and 2-morpholineethanol (800.8 mg, 6.1 mmol) was added dropwise, and the mixture was reacted at room temperature for 6 hours. After completion of the reaction, 150 mL of water and 150 mL of ethyl acetate were added and the mixture was separated. The aqueous phase was extracted with ethyl acetate (100 mL)EtOAc. 4-(1-Methyl-1H-indol-3-yl)pyrimidine-2-amine (29A) (1 g, yield 66.7%).

Second step: 6-methoxy-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-morpholinoethoxy)benzene -1,3-diamine (29B)

6-methoxy-N1-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-morpholinoethoxy)benzene-1,3-diamine

N-(2-Methoxy-4-(2-morpholinoethoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidine-2 The amine (29A) (1 g, 2 mmol) was dissolved in 30 mL of ethanol, and then 10 mL of water, iron powder (672 mg, 12 mmol) and ammonium chloride (74.2 mg, 1.4 mmol) were sequentially added, and the mixture was heated to 90 ° C for reflux for 8 hours. The reaction solution was cooled to room temperature, filtered and concentrated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to afford compound 6-methoxy-N ¹ -(4-(1-methyl-) 1H-Indol-3-yl)pyrimidin-2-yl)-4-(2-morpholinoethoxy)benzene-1,3-diamine (29B) (600 mg, yield 63.3%).

The third step: N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-morpholine) Ethoxy)phenyl)acrylamide (compound 29)

6-Methoxy-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-morpholinoethoxy)benzene-1, 3-Diamine (29B) (600 mg, 1.26 mmol) was dissolved in 10 mL of pyridine, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (722 mg, 3.78 mmol) Acrylic acid (0.13 mL, 1.89 mmol) was reacted at room temperature for 4 hours. The pyridine was removed by spin-drying, and 100 mL of water and 100 mL of dichloromethane were added and the mixture was separated. The organic phase was washed with a 4 mol/L aqueous sodium hydroxide solution (100 mL). The organic phase was dried over anhydrous sodium sulfate. Purify by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give white compound N-(4-methoxy-5-((4-(1-) -1-1H-Indol-3-yl)pyrimidin-2-yl)amino)-2-(2-morpholinoethoxy)phenyl)acrylamide (Compound 29) (65 mg, yield 7.8%).

MS m/z: 529.1 [M + 1] ⁺ .

Example 30

N-(5-((4-(1-(Difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)) (M)amino)-4-methoxyphenyl)acrylamide (Compound 30)

N-(5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide

First step: 3-(2-chloropyrimidin-4-yl)-1-(difluoromethyl)-1H-indole (30A)

3-(2-chloropyrimidin-4-yl)-1-(difluoromethyl)-1H-indole

3-(2-Chloropyrimidin-4-yl)-1H-indole (2b) (1 g, 4.35 mmol) was dissolved in 15 mL of acetonitrile, potassium hydroxide (4.88 g, 87 mmol) and 10 mL of water were added and cooled to 0. At ° C, diethyl bromofluoromethylphosphonate (2.32 g, 8.7 mmol) was added dropwise, and the mixture was warmed to room temperature and the reaction was continued for 2 hr. The reaction mixture was poured into 50 mL of EtOAc (EtOAc (EtOAc) Base)-1-(difluoromethyl)-1H-indole (30A) (1.2 g, crude).

MS m/z = 280.0 [M + 1] ⁺ .

Second step: 4-(1-(Difluoromethyl)-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2- Amine (30B)

4-(1-(difluoromethyl)-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine

3-(2-Chloropyrimidin-4-yl)-1-(difluoromethyl)-1H-indole (30A) (0.1 g, 0.36 mmol) was dissolved in 2-pentanol (10 mL). -Fluoro-2-methoxy-5-nitroaniline (4e) (67 mg, 0.36 mmol) and p-toluenesulfonic acid (83 mg, 0.43 mmol) were heated to 120 ° C to reflux for 1 day. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with water (50mL) and dried to give 4-(1-(difluoromethyl)-1H-indol-3-yl)-N-(4-fluoro 2-Methoxy-5-nitrophenyl)pyrimidine-2-amine (30B) (0.1 g, yield 66.7%).

MS m/z = 430.0 [M + 1] ⁺ .

Third step: N ¹ -(4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl )-2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (30C)

N ¹ -(4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5 -nitrobenzene-1,4-diamine

4-(1-(Difluoromethyl)-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine (30B (0.6 g, 1.4 mmol) dissolved in N,N-dimethylacetamide (5 mL), N,N-diisopropylethylamine (220 mg, 1.7 mmol) and N,N,N'- Methyl ethylenediamine (18A) (172 mg, 1.7 mmol) was reacted in a microwave at 140 ° C for 1 hour. After completion of the reaction, 150 mL of water and 150 mL of ethyl acetate were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, and concentrated to give a brown oily compound N ¹ - (4- (1- (difluoromethyl) lH-indol-3-yl) pyrimidin-2-yl) -N ⁴ - ( 2-(Dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (30C) (0.7 g, yield 97.9%).

MS m/z = 512.1 [M + 1] ⁺ .

Fourth step: N ⁴ -(4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl )-5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (30D)

N ⁴ -(4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methylbenzene-1 ,2,4-triamine

N ¹ -(4-(1-(Difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2 -Methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (30C) (0.9 g, 1.76 mmol) was dissolved in 30 mL of ethanol, followed by 10 mL of water, iron powder (295 mg, 5.28) Methyl acetate (66 mg, 1.23 mmol) was heated to 90 ° C for 4 hours and concentrated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give the brown solid compound N ⁴ -(4-(1-(difluoromethyl)-1H- Indole-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methylbenzene-1,2,4-tri Amine (30D) (350 mg, yield 41.3%).

MS m/z = 482.1 [M + 1] ⁺ .

Step 5: N-(5-((4-(1-(Difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethyl) Base amino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (compound 30)

N ⁴ -(4-(1-(Difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5 -Methoxy-N ¹ -methylbenzene-1,2,4-triamine (30D) (350 mg, 0.73 mmol) was dissolved in 10 mL of pyridine, followed by 1-(3-dimethylaminopropyl)-3 Ethylcarbodiimide hydrochloride (416 mg, 2.18 mmol) and acrylic acid (0.075 mL, 1.09 mmol) were reacted at room temperature for 4 hours. The pyridine was spun dry, and 150 mL of water and 150 mL of dichloromethane were added and the mixture was separated. The organic phase was washed with 100 mL of a 4 mol/L aqueous sodium hydroxide solution. The organic phase was dried over anhydrous sodium sulfate. Purify by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give white solid N-(5-((4-(1-(difluoromethyl))-1H) -Indol-3-ylpyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide ( Compound 30) (170 mg, yield 43.6%).

MS m/z: 536.1 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.76 (s, 1H), 9.43 (s, 1H), 8.46 (d, 1H), 8.04 (dd, 1H), 7.79 (dd, 2H), 7.38-7.32 ( m, 2H), 6.75 (s, 1H), 6.40 (d, 1H), 5.77 (d, 1H), 3.90 (s, 3H), 2.74 (s, 3H), 1.55 (s, 6H).

Example 31

N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-5-((4-(1-isopropyl-1H-indol-3-yl)pyrimidine-2 -yl)amino)-4-methoxyphenyl)acrylamide (compound 31)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4- Methoxyphenyl)acrylamide

First step: 3-(2-chloropyrimidin-4-yl)-1-isopropyl-1H-indole (31A)

3-(2-chloropyrimidin-4-yl)-1-isopropyl-1H-indole

3-(2-Chloropyrimidin-4-yl)-1H-indole (2b) (2 g, 8.7 mmol) was dissolved in 30 mL of tetrahydrofuran, and sodium hydride (836 mg, 10.4 mmol) was added at 0 ° C for 30 min. Iodoisopropane (5.24 mL, 26.3 mmol) was allowed to react to room temperature for 32 hours. At the end of the reaction, 150 mL of dichloromethane and 100 mL of water were added and the layers were separated. The aqueous phase was extracted with 100 mL of dichloromethane. Purification by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 1:0 to 2:1) to give the compound as a brown solid 3-(2-chloropyrimidin-4-yl)-1-isopropyl -1H-indole (31A) (0.75 g, yield 32.6%).

MS m/z = 272.1 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.44-8.39 (m, 1H), 8.36 (d, 1H), 8.02 (s, 1H), 7.38 (dd, 1H), 7.27 (dt, 2H), 7.22 ( d, 1H), 4.64 (dt, 1H), 1.59 - 1.45 (m, 6H).

Second step: N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-amine (31B )

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-amine

3-(2-Chloropyrimidin-4-yl)-1-isopropyl-1H-indole (31A) (0.75 g, 2.77 mmol) was dissolved in 2-pentanol (40 mL). 2-Methoxy-5-nitroaniline (4e) (515 mg, 2.77 mmol) and p-toluenesulfonic acid (632 mg, 3.33 mmol) were heated to 120 ° C to reflux for 3 days. The reaction solution was cooled to room temperature, and a solid was precipitated, which was washed sequentially with 20 mL of acetonitrile and 100 mL of water. The filter cake was dried to give a yellow solid N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-isopropyl-1H-indol-3-yl)pyrimidine-2 -Amine (31B) (0.6 g, yield 51.3%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.15 (d, 1H), 8.51 (s, 1H), 8.46-8.26 (m, 3H), 7.63 (d, 1H), 7.39 (dd, 2H), 7.25 ( t, 1H), 7.14 (t, 1H), 4.98 - 4.78 (m, 1H), 4.02 (s, 3H), 1.54 (d, 6H).

Third step: N ¹ -(2-(dimethylamino)ethyl)-N ⁴ -(4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-yl)-5 -methoxy-N ¹ -methyl-2-nitrobenzene-1,4-diamine (31C)

N ¹ -(2-(dimethylamino)ethyl)-N ⁴ -(4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N ¹ -methyl-2-nitrobenzene -1,4-diamine

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-amine (31B) (0.6 g, 1.4 mmol) was dissolved in N,N-dimethylacetamide (10 mL), followed by N,N-diisopropylethylamine (221 mg, 1.71 mmol) and N,N,N'-trimethyl Ethylenediamine (18A) (175 mg, 1.71 mmol) was reacted in a microwave at 140 ° C for 1 hour. The reaction was completed and concentrated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 30:1) to give the compound as a red solid N ¹ -(2-(dimethylamino)ethyl)-N ⁴ - (4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N ¹ -methyl-2-nitrobenzene-1,4-diamine (31C) (0.6 g, yield 85.2%).

MS m/z: 504.3 [M + 1] ⁺ .

Fourth step: N ¹ -(2-(dimethylamino)ethyl)-N ⁴ -(4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-yl)-5 -methoxy-N ¹ -methylbenzene-1,2,4-triamine (31D)

N1-(2-(dimethylamino)ethyl)-N4-(4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methylbenzene-1,2,4- Triamine

N ¹ -(2-(Dimethylamino)ethyl)-N ⁴ -(4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy Base-N ¹ -methyl-2-nitrobenzene-1,4-diamine (31C) (0.6 g, 1.2 mmol) was dissolved in 15 mL of ethanol, followed by 5 mL of water, iron powder (201 mg, 3.6 mmol) and Ammonium chloride (45 mg, 0.84 mmol) was heated to 90 ° C for reflux for 4 hours. The reaction solution was cooled to room temperature, filtered and concentrated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 30:1) to give the compound as a brown solid N ¹ -(2-(dimethylamino)ethyl)-N ⁴ -(4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (31D (550 mg, yield 96.8%).

MS m/z: 474.3 [M + 1] ⁺ .

Step 5: N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-5-((4-(1-isopropyl-1H-indol-3-yl) Pyrimidine-2-yl)amino)-4-methoxyphenyl)acrylamide (compound 31)

N ¹ -(2-(Dimethylamino)ethyl)-N ⁴ -(4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy Base-N ¹ -methylbenzene-1,2,4-triamine (31D) (550 mg, 1.16 mmol) was dissolved in 10 mL of pyridine, and 1-(3-dimethylaminopropyl)-3-ethyl carbon was added. Diimine hydrochloride (997 mg, 5.22 mmol), acrylic acid (0.12 mL, 1.74 mmol) was reacted for 4 hours at room temperature. The pyridine was sparged, and aqueous sodium hydroxide (100 mL, 4 mol/L) and 100 mL of ethyl acetate were added and the mixture was separated. The organic phase was washed with 100 mL of brine and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) afforded white compound N-(2-((2-(dimethylamino)ethyl)) Methyl)amino)-5-((4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 31 (400 mg, yield 65.5%).

MS m/z: 528.2 [M+1] ⁺ .

Example 32

N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-5-((4-(1-ethyl-1H-indol-3-yl)pyrimidin-2-) Amino)-4-methoxyphenyl)acrylamide (compound 32)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(1-ethyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4- Methoxyphenyl)acrylamide

First step: 3-(2-chloropyrimidin-4-yl)-1-ethyl-1H-indole (32A)

3-(2-chloropyrimidin-4-yl)-1-ethyl-1H-indole

3-(2-Chloropyrimidin-4-yl)-1H-indole (2b) (2 g, 8.7 mmol) was dissolved in 30 mL of tetrahydrofurane, cooled to 0 ° C, sodium hydride (0.836 g, 10.4 mmol), 0 The reaction was carried out at ° C for 30 minutes. Iodoethane (4.1 g, 26.3 mmol) was added, and the reaction was continued to room temperature for 4 hours. The reaction was completed and the solvent was evaporated. The solid was washed with 100 mL of water and 20 mL of THF. The solid was dried to give 3-(2-chloropyrimidin-4-yl)-1-ethyl-1H-indole (32A) (2.1 g, yield: 95.5%).

MS m/z: 258.0 [M + 1] ⁺ .

Second step: 4-(1-ethyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine (32B)

4-(1-ethyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine

3-(2-Chloropyrimidin-4-yl)-1-ethyl-1H-indole (32A) (0.257 g, 1 mmol) was dissolved in 2-pentanol (10 mL). Methoxy-5-nitroaniline (4e) (186 mg, 1 mmol) and p-toluenesulfonic acid (228 mg, 1.2 mmol) were heated to 120 ° C to reflux for 1 day. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with 50 mL of water and dried to give 4-(1-ethyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy 5--5-nitrophenyl)pyrimidine-2-amine (32B) (0.3 g, yield 73.7%).

MS m/z: 408.0 [M+1] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ9.15 (d, 1H), 8.48-8.35 (m, 3H), 8.27 (s, 1H), 7.59 (d, 1H), 7.39-7.33 (m, 2H ), 7.26 (t, 1H), 7.15 (t, 1H), 4.30 (q, 2H), 4.03 (s, 3H), 1.46 (t, 3H).

The third step: N ¹ -(2-(dimethylamino)ethyl)-N ⁴ -(4-(1-ethyl-1H-indol-3-yl)pyrimidin-2-yl)-5- methoxy-N ¹ -methyl-2-nitrobenzene-1,4-diamine (32C)

N1-(2-(dimethylamino)ethyl)-N4-(4-(1-ethyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy- N1-methyl-2-nitrobenzene-1,4-diamine

4-(1-Ethyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine (32B) (1 g, 2.46 mmol) was dissolved in 12 mL of N,N-dimethylacetamide, N,N-diisopropylethylamine (387.8 mg, 3 mmol), and N,N,N'-trimethylethylenediamine ( 18A) (300 mg, 3 mmol), and reacted in a microwave at 140 ° C for 1 hour. At the end of the reaction, 150 mL of water and 150 mL of dichloromethane were added and the mixture was separated. The organic phase is dried over anhydrous sodium sulfate and concentrated to give a red solid compound N ¹ -(2-(dimethylamino)ethyl)-N ⁴ -(4-(1-ethyl-1H-indol-3-yl) Pyrimidine-2-yl)-5-methoxy-N ¹ -methyl-2-nitrobenzene-1,4-diamine (32C) (1 g, yield 83.3%).

MS m/z: 490.1 [M + 1] ⁺ .

Fourth step: N ¹ -(2-(dimethylamino)ethyl)-N ⁴ -(4-(1-ethyl-1H-indol-3-yl)pyrimidin-2-yl)-5- methoxy-N ¹ -methylbenzene-1,2,4-triamine (32D)

N1-(2-(dimethylamino)ethyl)-N4-(4-(1-ethyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methylbenzene-1,2,4- Triamine

N ¹ -(2-(Dimethylamino)ethyl)-N ⁴ -(4-(1-ethyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy -N ¹ -Methyl-2-nitrobenzene-1,4-diamine (32C) (1 g, 2 mmol) was dissolved in 15 mL of ethanol, followed by 5 mL of water, iron powder (335 mg, 6 mmol) and ammonium chloride ( 75 mg, 1.4 mmol), and the mixture was heated to 90 ° C for reflux for 6 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a brown solid compound N ¹ -(2-(dimethylamino) -N ⁴ -(4-(1-ethyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N ¹ -methylbenzene-1,2,4- Triamine (32D) (800 mg, yield 87.1%).

MS m/z: 460.1 [M + 1] ⁺ .

Step 5: N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-5-((4-(1-ethyl-1H-indol-3-yl)) Pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (compound 32)

N ¹ -(2-(Dimethylamino)ethyl)-N ⁴ -(4-(1-ethyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy -N ¹ -methylbenzene-1,2,4-triamine (32D) (800 mg, 1.74 mmol) was dissolved in 15 mL of pyridine, followed by 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride (999 mg, 5.2 mmol) and acrylic acid (0.18 mL, 2.61 mmol) were reacted at room temperature for 4 hours. The pyridine was spun dry, and 100 mL of water and 100 mL of dichloromethane were added and the mixture was separated. The organic phase was washed with aqueous sodium hydroxide (100 mL, 4 mol/L). The organic phase was dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) afforded white compound N-(2-((2-(dimethylamino)ethyl)) Methyl)amino)-5-((4-(1-ethyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 32) (110 mg, yield 12.3%).

MS m/z: 514.2 [M + 1] ⁺ .

Example 33

N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-5-((4-(1-(2-hydroxyethyl))-1H-indol-3-yl) Pyrimidine-2-yl)amino)-4-methoxyphenyl)acrylamide (compound 33)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(1-(2-hydroxyethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino )-4-methoxyphenyl)acrylamide

Second step: 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(2-chloropyrimidin-4-yl)-1H-indole (33A)

1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(2-chloropyrimidin-4-yl)-1H-indole

3-(2-Chloropyrimidin-4-yl)-1H-indole (2b) (1 g, 4.35 mmol) was dissolved in 25 mL of THF, cooled to 0 ° C, sodium hydride (125.3 mg, 5.22 mmol) The reaction was carried out at ° C for 30 minutes. (2-Bromoethoxy)-tert-butyldimethylsilane (2.5 g, 8.7 mmol) was added, and the reaction was continued to room temperature for 1 day. After completion of the reaction, the solvent was evaporated to dryness, and the solid was washed with 100 mL of water, and the solid was dried to give a yellow solid compound 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(2-chloro Pyrimidin-4-yl)-1H-indole (33A) (1.3 g, yield 77.4%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.79 (d, 1H), 8.76-8.72 (m, 1H), 8.38 (s, 1H), 7.81 (d, 1H), 7.79-7.74 (m, 1H), 7.70–7.65 (m, 2H), 4.65 (t, 2H), 4.32 (t, 2H), 1.20–1.17 (m, 9H), 0.23–0.21 (m, 6H).

Second step: 2-(3-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-indol-1-yl)ethanol (33B)

2-(3-(2-(4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-indol-1-yl)ethanol

1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-3-(2-chloropyrimidin-4-yl)-1H-indole (33A) (1.3 g, 3.36 mmol) Dissolved in 2-pentanol (50 mL), followed by 4-fluoro-2-methoxy-5-nitroaniline (4e) (625 mg, 3.36 mmol) and p-toluenesulfonic acid (774 mg, 4.03 mmol). The reaction was refluxed at 120 ° C for 2 days. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with 100 mL of water and dried to give a yellow solid 2-(3-((4-fluoro-2-methoxy-5-nitrophenyl)amino) Pyrimidin-4-yl)-1H-indol-1-yl)ethanol (33B) (1.1 g, yield 78.6%).

MS m/z: 424.0 [M+1] ⁺ .

The third step: 2-(3-(2-((4-(2-methylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino) Pyrimidine-4-yl)-1H-indol-1-yl)ethanol (33C)

2-(3-(2-((4-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-indol-1- Yl)ethanol

2-(3-(2-((4-)fluoro))))) (1 g, 2.4 mmol) was dissolved in 10 mL of N,N-dimethylacetamide, followed by N,N-diisopropylethylamine (366 mg, 2.8 mmol) and N,N,N'-trimethylethylene The amine (18A) (290 mg, 2.8 mmol) was reacted in a microwave at 140 ° C for 1 hour. After completion of the reaction, 150 mL of water and 150 mL of ethyl acetate were added and the mixture was separated. The organic phase was washed with water (100 mL), dried over anhydrous sodium sulfate 2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-indol-1-yl)ethanol (33C) (1 g, yield 83.3%).

Fourth step: N ¹ -(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)pyrimidin-2-yl)- N ⁴ -(2-(Dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (33D)

N ¹ -(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)- 2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine

2-(3-(2-(4-(2-(Dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine- 4-yl)-1H-indol-1-yl)ethanol (33C) (1 g, 1.98 mmol) was dissolved in dichloromethane (20 mL), triethylamine (600 mg, 5. The chlorosilane (448 mg, 2.97 mmol) was reacted at room temperature for 4 hours. After the reaction was completed, 10 mL of water was added and the mixture was stirred for 30 minutes. 100 mL of water and 100 mL of dichloromethane were added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with 100 mL of dichloromethane and washed with 150 mL of saturated sodium chloride. Concentration of N ¹ -(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)pyrimidin-2-yl)- N ⁴ -(2-(Dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (33D) (1 g, yield 83.3%) ).

MS m/z: 620.0 [M+1] ⁺ .

Step 5: N ⁴ -(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)pyrimidin-2-yl)- N ¹ -(2-(Dimethylamino)ethyl)-5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (33E)

N ¹ -(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ - (2-(Dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (33D) (1 g, 1.6 mmol) dissolved in 30 mL of ethanol In the above, 10 mL of water, iron powder (270 mg, 4.8 mmol) and ammonium chloride (60 mg, 1.1 mmol) were successively added, and the mixture was heated to 90 ° C and refluxed for 6 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a brown solid compound N ⁴ -(4-(1-(2-) (tert-Butyldimethylsilyl)oxy)ethyl)-1H-indol-3-ylpyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5 -Methoxy-N ¹ -methylbenzene-1,2,4-triamine (33E) (1.1 g, crude).

Step 6: N-(5-((4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)pyrimidin-2- Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (33F)

N-(5-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

N ⁴ -(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ - (2-(Dimethylamino)ethyl)-5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (33E) (943 mg, 1.6 mmol) dissolved in 15 mL of pyridine 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (917 mg, 4.8 mmol), acrylic acid (0.17 mL, 2.4 mmol). The reaction solution was spin-dried to remove pyridine, and 150 mL of water and 150 mL of ethyl acetate were added and the mixture was separated. The organic phase was washed with aqueous sodium hydroxide (100 mL, 4 mol/L). The residue was purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a brown solid compound N-(5-((4-(1-(2-) (tert-Butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl) (Methyl)amino)-4-methoxyphenyl)acrylamide (33F) (360 mg, yield 35%).

MS m/z: 644.2 [M+1] ⁺ .

Step 7: N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-5-((4-(1-(2-hydroxyethyl))-1H-indole -3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (compound 33)

N-(5-((4-(1-(2-(2-tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino 2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (33F) (0.36 g, 0.52 mmol) dissolved in 10 mL dichloromethane Tetrabutylammonium fluoride (293 mg, 1.12 mmol) was added, and the mixture was reacted at room temperature for 6 hours. At the end of the reaction, 100 mL of water and 100 mL of dichloromethane were added and the layers were separated. The aqueous phase was extracted with 100 mL of dichloromethane. The organic phase was washed with 150 mL of saturated sodium chloride. The organic phase is concentrated and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a brown solid compound N-(2-((2-(dimethylamino)) Ethyl)(methyl)amino)-5-((4-(1-(2-hydroxyethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy Phenyl phenyl) acrylamide (compound 33) (0.25 g, yield 84.6%).

MS m/z: 530.1 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.69 (s, 1H), 9.08 (s, 1H), 8.38 (d, 1H), 8.08-8.00 (m, 1H), 7.72 (s, 1H), 7.46- 7.40 (m, 1H), 7.27 (d, 1H), 7.23 (t, 1H), 6.75 (s, 1H), 6.38 (d, 1H), 5.76 (d, 1H), 4.45 (t, 2H), 4.06 (t, 2H), 3.89 (s, 3H), 3.06 (d, 2H), 2.70 (s, 3H), 2.43 (s, 2H), 1.60 (s, 6H).

Example 34

N-(5-((4-(1-(cyclopropylmethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)) Ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Compound 34)

N-(5-((4-(1-(cyclopropylmethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide

First step: N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (34A)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine

3-(2-Chloropyrimidin-4-yl)-1H-indole (2b) (3 g, 13.1 mmol) was dissolved in 2-pentanol (10 mL) and 4-fluoro-2-methoxy-5 was added. -Nitroaniline (4e) (2.44 g, 13.1 mmol) and p-toluenesulfonic acid (3.02 g, 15.7 mmol) were heated to 120 ° C for reflux for 3 days. The reaction solution was cooled to room temperature, 200 mL of aqueous ammonia was added to precipitate a solid, which was filtered, and the filter cake was washed with 250 mL of water and 100 mL of petroleum ether, and dried to give a gray-green solid N-(4-fluoro-2-methoxy-5-nitro Benzene 4-(1H-indol-3-yl)pyrimidine-2-amine (34A) (4 g, yield 80.5%).

MS m/z = 380.1 [M + 1] ⁺ .

Second step: N ¹ -(4-(1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (34B)

N ¹ -(4-(1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4 -diamine

Dissolving N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (34A) (2 g, 5.3 mmol) To 15 mL of N,N-dimethylacetamide, N,N-diisopropylethylamine (1.02 g, 7.9 mmol) and N,N,N'-trimethylethylenediamine (18A) (809 mg, 7.9 mmol), microwaved at 120 ° C for 1.5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and water (200 mL) and ethyl acetate Washed with 100mL saturated brine The organic phase was dried over anhydrous sodium sulfate, and concentrated to give a red-brown solid Compound N ¹ - (4- (1H- indol-3-yl) pyrimidin-2-yl) -N ⁴ - (2- (Dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (34B) (1.8 g, yield 75%).

Third step: N ¹ -(4-(1-(cyclopropylmethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)B 2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (34C)

N ¹ -(4-(1-(cyclopropylmethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5 -nitrobenzene-1,4-diamine

N ¹ -(4-(1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2-methoxy-N ⁴ - 5--5-nitrobenzene-1,4-diamine (34B) (2g, 4.3mmol) was dissolved in 20mL dimethylformamide, cooled to 0 ° C, sodium hydride (0.26g, 6.5mmol), 0 The reaction was carried out at ° C for 30 minutes. Bromomethylcyclopropane (0.585 g, 4.3 mmol) was added, and the reaction was continued to room temperature for 6 hours. At the end of the reaction, 100 mL of water and 100 mL of ethyl acetate were added and the mixture was separated. The aqueous phase was extracted with 100 mL of ethyl acetate. The combined organic phases, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give a brown solid Compound N ¹ - (4- (1- (cyclopropylmethyl) lH-indol-3-yl) pyrimidin-2-yl) -N ⁴ -(2-(dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (34C) (2 g, yield 90.9 %).

MS m/z: 516.1 [M + 1] ⁺ .

Fourth step: N ⁴ -(4-(1-(cyclopropylmethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)B 5-)-methoxy-N ¹ -methylbenzene-1,2,4-triamine (34D)

N ⁴ -(4-(1-(cyclopropylmethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methylbenzene-1 ,2,4-triamine

N ¹ -(4-(1-(cyclopropylmethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)- 2-Methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (34C) (2 g, 3.88 mmol) was dissolved in 24 mL of ethanol, followed by 8 mL of water and iron powder (1.3 g, 23.3 mmol) and ammonium chloride (145 mg, 2.7 mmol) were heated to 92 ° C for reflux for 5 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a brown solid compound N ⁴ -(4-(1-(cyclopropyl) Methyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methylbenzene-1 2,4-Triamine (34D) (1.1 g, yield 58.5%).

MS m/z: 486.1 [M + 1] ⁺ .

Step 5: N-(5-((4-(1-(cyclopropylmethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(2) Methylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (compound 34)

N ⁴ -(4-(1-(cyclopropylmethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)- 5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (34D) (1 g, 2.06 mmol) was dissolved in 25 mL of pyridine, followed by 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (1.18 g, 6.2 mmol) and acrylic acid (0.213 mL, 3.1 mmol) were reacted at room temperature for 4 hours. The reaction solution was sparged to remove pyridine, 150 mL of ethyl acetate and aqueous sodium hydroxide (100 mL, 4 mol/L) was added, and the mixture was separated, and the aqueous phase was extracted with 100 mL of ethyl acetate. The organic phase was combined and washed with 150 mL of saturated sodium chloride. The mixture was dried over sodium sulfate, filtered, and evaporated to dryness eluting with silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a white solid compound N-(5-((4) -(1-(cyclopropylmethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino 4-methoxyphenyl)acrylamide (Compound 34) (250 mg, yield 22.7%).

MS m/z = 540.4 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ10.09 (s, 1H), 9.83 (s, 1H), 9.07 (s, 1H), 8.38 (d, 1H), 8.08 (dd, 1H), 7.71 (s, 1H), 7.51–7.42 (m, 1H), 7.28–7.24 (m, 3H), 7.22 (d, 1H), 6.79 (s, 1H), 6.40 (s, 2H), 5.74–5.67 (m, 1H) , 4.21 (d, 2H), 3.88 (s, 3H), 3.48 (s, 1H), 2.89 (dd, 2H), 2.70 (s, 3H), 2.28 (s, 8H), 1.44 (dtd, 1H), 0.61–0.52 (m, 2H), 0.50–0.42 (m, 2H).

Example 35

N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((5-methoxy-4-(1-methyl-1H) -Indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 35)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((5-methoxy-4-(1-methyl-1H-indol-3-yl)pyrimidin-2 -yl)amino)phenyl)acrylamide

First step: 3-(2-chloro-5-methoxypyrimidin-4-yl)-1H-indole (35A)

3-(2-chloro-5-methoxypyrimidin-4-yl)-1H-indole

The hydrazine (4a) (2.34 g, 20 mmol) was dissolved in 40 mL of tetrahydrofuran, cooled to 0 ° C under nitrogen, and methyl magnesium bromide (6.7 mL, 20 mmol) was added dropwise and stirring was continued for 0.5 hour. 2,4-Dichloro-5-methoxypyrimidine (3.58 g, 20 mmol) was added, and the mixture was reacted at room temperature for 1 hour, and the mixture was heated to 65 ° C for 4 hours. 150 mL of water and 150 mL of dichloromethane were added to the reaction mixture, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, dried and evaporated to silicagel Chloro-5-methoxypyrimidin-4-yl)-1H-indole (35A) (2.81 g, yield 55.1%).

MS m/z = 260.0 [M + 1] ⁺ .

Step 2: 3-(2-Chloro-5-methoxypyrimidin-4-yl)-1-methyl-1H-indole (35B)

3-(2-chloro-5-methoxypyrimidin-4-yl)-1-methyl-1H-indole

3-(2-Chloro-5-methoxypyrimidin-4-yl)-1H-indole (35A) (1.4 g, 5.4 mmol) was dissolved in 25 mL of tetrahydrofuran, cooled to 0 ° C, sodium hydride (0.261) g, 10.9 mmol), reacted at 0 ° C for 30 minutes. Methyl iodide (2.3 g, 16.2 mmol) was added, and the reaction was continued to room temperature for 4 hours. The reaction was completed. The reaction was quenched by adding 10 mL of water and the solvent was evaporated. Purification by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 1:0 to 2:1) to afford compound 3-(2-chloro-5-methoxypyrimidin-4-yl) )-1-methyl-1H-indole (35B) (0.3 g, yield 20.4%).

MS m/z = 274.0 [M + 1] ⁺ .

The third step: N-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methoxy-4-(1-methyl-1H-indol-3-yl)pyrimidine- 2-amine (35C)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methoxy-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

3-(2-Chloro-5-methoxypyrimidin-4-yl)-1-methyl-1H-indole (35B) (0.3 g, 1.1 mmol) was dissolved in 2-pentanol (20 mL). 4-Fluoro-2-methoxy-5-nitroaniline (4e) (204 mg, 1.1 mmol) and p-toluenesulfonic acid (253 mg, 1.32 mmol) were added, and the mixture was refluxed at 120 ° C for 18 hours. The reaction liquid was cooled to room temperature, and 150 mL of water and 150 mL of ethyl acetate were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography. Methanol (v/v) = 1:0 to 10:1) gave the red solid N-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methoxy-4-(1) -Methyl-1H-indol-3-ylpyrimidin-2-amine (35C) (0.55 g, yield 45.8%).

Fourth step: N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ⁴ -(5-methoxy-4-(1-methyl-1H-indole-3) -yl)pyrimidin-2-yl)-N ¹ -methyl-2-nitrobenzene-1,4-diamine (35D)

N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ⁴ -(5-methoxy-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -methyl -2-nitrobenzene-1,4-diamine

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-5-methoxy-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (35C) (1g, 2.36mmol) was dissolved in 10 mL of N,N-dimethylacetamide, and N,N-diisopropylethylamine (367 mg, 2.84 mmol), and N,N,N'- Methylethylenediamine (18A) (290 mg, 2.84 mmol) was reacted in a microwave at 125 ° C for 1 hour. At the end of the reaction, N,N-dimethylacetamide was spun off, and 150 mL of water and 150 mL of dichloromethane were added and the mixture was separated. The aqueous phase was extracted with 100 mL of dichloromethane and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a red solid Compound N ¹ - (2- (dimethylamino) ethyl) -5-methoxy -N ⁴ - (5- methoxy-4- (1-Methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -methyl-2-nitrobenzene-1,4-diamine (35D) (1 g, yield 83.3%) ).

MS m/z: 490.1 [M + 1] ⁺ .

Fifth step: N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ⁴ -(5-methoxy-4-(1-methyl-1H-indole-3) -yl)pyrimidin-2-yl)-N ¹ -methylbenzene-1,2,4-triamine (35E)

N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ⁴ -(5-methoxy-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -methylbenzene -1,2,4-triamine

N ¹ -(2-(Dimethylamino)ethyl)-5-methoxy-N ⁴ -(5-methoxy-4-(1-methyl-1H-indol-3-yl) Pyrimidin-2-yl)-N ¹ -methyl-2-nitrobenzene-1,4-diamine (35D) (3.5 g, 6.93 mmol) was dissolved in 30 mL of ethanol, followed by 10 mL of water and iron powder (2.32) g, 41.6 mmol) and ammonium chloride (260 mg, 4.85 mmol) were heated to 90 ° C for reflux for 6 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a brown solid compound N ¹ -(2-(dimethylamino)ethyl -5-methoxy-N ⁴ -(5-methoxy-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -methylbenzene-1 2,4-Triamine (35E) (2 g, yield 60.6%).

MS m/z: 476.1 [M + 1] ⁺ .

Step 6: N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((5-methoxy-4-(1-) Methyl-1H-indol-3-ylpyrimidin-2-yl)amino)phenyl)acrylamide (Compound 35)

N ¹ -(2-(Dimethylamino)ethyl)-5-methoxy-N ⁴ -(5-methoxy-4-(1-methyl-1H-indol-3-yl) Pyrimidin-2-yl)-N ¹ -methylbenzene-1,2,4-triamine (35E) (350 mg, 1.05 mmol) was dissolved in 10 mL pyridine, EDCI (600 mg, 3.14 mmol) and acrylic acid (0.11) mL, 1.57 mmol), reacted at room temperature for 4 hours. The reaction solution was spin-dried to remove pyridine, and 100 mL of water and 100 mL of dichloromethane were added and the mixture was separated. The organic phase was washed with aqueous sodium hydroxide (100 mL, 4 mol/L) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give the compound N-(2-((2-(dimethylamino)ethyl)) Methyl)amino)-4-methoxy-5-((5-methoxy-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl) Acrylamide (Compound 35) (210 mg, yield 37.8%).

MS m/z: 530.1 [M + 1] ⁺ .

Example 36

N-(4-Methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(3-morpholinepropoxy) Phenyl)acrylamide (compound 36)

N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(3-morpholinopropoxy)phenyl)acrylamide

First step: N-(2-methoxy-4-(3-morpholinopropoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidine -2-amine (36A)

N-(2-methoxy-4-(3-morpholinopropoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 3) (1 g 2.54 mmol) was dissolved in 50 mL of tetrahydrofuran, and sodium hydride (122 mg, &lt 3-morpholinyl-1-ol (552 mg, 3.8 mmol) was added dropwise and allowed to react at room temperature overnight. After completion of the reaction, 100 mL of water and 150 mL of ethyl acetate were added and the mixture was evaporated. -5-Nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amine (36A) (1 g, yield 71.4%).

MS m/z: 519.2 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.66 (d, 1H), 8.39 (dd, 1H), 8.24 (d, 1H), 8.15 (dd, 1H), 7.51 (s, 1H), 7.43 - 7.37 ( m,1H), 7.35–7.28 (m, 2H), 7.19 (d, 1H), 6.56 (s, 1H), 4.18 (t, 2H), 4.01 (s, 1H), 4.00 (s, 3H), 3.93 (d, 3H), 3.83–3.78 (m, 1H), 3.75–3.68 (m, 4H), 3.48 (s, 1H), 2.67–2.59 (m, 3H), 2.56–2.45 (m, 4H), 2.11 –1.98 (m, 2H), 1.73 (dt, 1H).

Second step: 6-methoxy-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(3-morpholinepropoxy)benzene -1,3-diamine (36B)

6-methoxy-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(3-morpholinopropoxy)benzene-1,3-diamine

N-(2-Methoxy-4-(3-morpholinepropoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2- The amine (36A) (1 g, 1.93 mmol) was dissolved in 30 mL of ethanol, followed by 10 L of water, iron powder (646.5 g, 11.58 mol) and ammonium chloride (72.3 g, 1.35 mol), and the mixture was heated to 90 ° C and refluxed for 4 hours. The reaction solution was cooled to room temperature, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a brown solid compound 6-methoxy-N ^1- (4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(3-morpholinepropoxy)benzene-1,3-diamine (36B) ( 600 mg, yield 63.7%).

MS m/z: 489.2 [M+1] ⁺ .

The third step: N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(3-morpholine) Propoxy)phenyl)acrylamide (compound 36)

6-Methoxy-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(3-morpholinepropoxy)benzene-1, 3-Diamine (36B) (600 mg, 1.23 mmol) was dissolved in 10 mL of pyridine, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (703 mg, 3.68 mmol) Acrylic acid (0.127 mL, 1.84 mmol) was reacted at room temperature for 3 hours. The reaction solution was spin-dried to remove pyridine, and 150 mL of a 4 mol/L aqueous sodium hydroxide solution and 150 mL of dichloromethane were added, and the mixture was separated. The organic phase was washed with 100 mL of brine and dried over anhydrous sodium sulfate. Purify by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a pale yellow solid compound N-(4-methoxy-5-((4-(1-) Methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(3-morpholinepropoxy)phenyl)acrylamide (Compound 36) (120 mg, yield 18%).

MS m/z = 543.2 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.68 (s, 1H), 8.87 (s, 1H), 8.34 (d, 1H), 8.09 (d, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.39 (d, 1H), 7.32 - 7.22 (m, 1H), 7.17 (d, 1H), 6.55 (s, 1H), 6.44 (d, 1H), 5.76 (d, 1H), 4.13 (t , 2H), 3.96 (s, 3H), 3.90 (s, 5H), 2.75 (s, 4H), 2.20 (s, 2H), 1.62 (s, 4H).

Example 37

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(3-morpholine) Propoxy)phenyl)acrylamide (compound 37)

N-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(3-morpholinopropoxy)phenyl)acrylamide

First step: 5-chloro-N-(2-methoxy-4-(3-morpholinopropoxy)-5-nitrophenyl)-4-(1-methyl-1H-indole-3 -yl)pyrimidin-2-amine (37A)

5-chloro-N-(2-methoxy-4-(3-morpholinopropoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (middle) (4 g, 2.34 mmol) was dissolved in 50 mL of THF. 3-morpholinopropyl-1-ol (680 mg, 4.68 mmol) was added dropwise and allowed to react at room temperature overnight. After completion of the reaction, 100 mL of water and 100 mL of ethyl acetate were added, and the organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give a yellow oil compound 5-chloro-N-(2-methoxy-4-(3- Morpholine propoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (37A) (1.2 g, yield 85.7%).

^{1 H NMR (400MHz, DMSO-} d 6) δ8.60 (s, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 8.32 (s, 1H), 8.25 (d, 1H), 7.51 ( d, 1H), 7.28–7.21 (m, 1H), 7.01 (t, 1H), 6.97 (s, 1H), 4.46 (s, 1H), 4.30 (t, 2H), 3.94 (s, 3H), 3.89 (d, 3H), 3.43 (t, 4H), 2.39 (d, 4H), 2.29 (s, 1H), 2.00 - 1.91 (m, 2H), 1.61 - 1.51 (m, 4H).

Second step: N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(3-morpholine propyl Oxy)benzene-1,3-diamine (37B)

N1-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(3-morpholinopro Poxy)benzene-1,3-diamine

5-Chloro-N-(2-methoxy-4-(3-morpholinopropoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl) Pyrimidin-2-amine (37A) (1 g, 1.8 mmol) was dissolved in 30 mL of ethanol, and then 10 mL of water, iron powder (606.7 mg, 10.06 mmol) and ammonium chloride (67.8 mg, 1.27 mmol) were added, and the temperature was raised to 90 ° C. The reaction was refluxed for 4 hours. The reaction solution was cooled to room temperature, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a solid compound N ¹ -(5-chloro- 4-(1-Methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(3-morpholinepropoxy)benzene-1,3-diamine ( 37B) (900 mg, yield 95.3%).

MS m/z: 523.2 [M + 1] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ8.52 (s, 1H), 8.34 (d, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 7.49 (d, 1H), 7.23 ( t, 1H), 7.05 (t, 1H), 6.96 (s, 1H), 6.68 (s, 1H), 4.05 (t, 2H), 3.90 (s, 3H), 3.66 (s, 4H), 3.65 (s) , 4H), 3.44 (t, 2H), 2.65 (d, 6H), 2.04 - 1.92 (m, 2H).

The third step: N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-( 3-morpholinepropoxy)phenyl)acrylamide (Compound 37)

N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(3-morpholinepropoxy) Benzene-1,3-diamine (37B) (900 mg, 1.72 mmol) was dissolved in 30 mL of tetrahydrofuran, N,N-diisopropylethylamine (0.34 mL, 2.06 mmol) was added, and acryloyl chloride was added dropwise at 0 °C. 5 mL of a solution of 0.17 mL, 2.06 mmol) in tetrahydrofuran was allowed to react to room temperature for 4 hours. 100 mL of a saturated aqueous sodium hydrogencarbonate solution and 100 mL of ethyl acetate were added and the mixture was separated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to afford compound N-(5-((5-chloro-4-(1-methyl-) 1H-Indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(3-morpholinepropoxy)phenyl)acrylamide (Compound 37) (330 mg, yield 41.4 %).

MS m/z: 577.2 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.27 (s, 1H), 8.41 (d, 1H), 8.38 (s, 1H), 8.29 (s, 1H), 7.65 (s, 1H), 7.35 (d, 2H), 7.29 (d, 1H), 7.20 (t, 1H), 6.57 (s, 1H), 6.36 (dd, 1H), 6.26 (dd, 1H), 5.71 (d, 1H), 4.11 (t, 2H) ), 3.89 (s, 3H), 3.88 (s, 3H), 3.77 - 3.71 (m, 4H), 2.56 (d, 2H), 2.49 (s, 4H), 2.04 (dd, 2H).

Example 38

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(3-morpholine) Propoxy)phenyl)acrylamide methanesulfonate (compound 38)

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(3-morp Holinopropoxy)phenyl)acrylamide methanesulfonate

First step: N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-( 3-morpholinepropoxy)phenyl)acrylamide methanesulfonate (compound 38)

N-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(3-morpholinopropoxy)phenyl)acrylamide methanesulfonate

Will N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(3-? Phenylpropoxy)phenyl)acrylamide (Compound 37) (120 mg, 0.208 mmol) was dissolved in 20 mL of ethanol, 10 mL of ethyl acetate was added, and methanesulfonic acid (0.0135 mL, 0.208 mmol) of acetic acid B was added dropwise at 70 °C. The ester (5 mL) solution was reacted for 2 hours. The reaction solution was spun to give a yellow solid compound N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy Base-2-(3-morpholinepropoxy)phenyl)acrylamide methanesulfonate (Compound 38) (140 mg).

MS m/z: 577.2 [M + 1] ⁺ .

Example 39

N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-pyrrolo[2, 3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 39)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl) )pyrimidin-2-yl)amino)phenyl)acrylamide

First step: 3-(2-chloropyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine (39B)

3-(2-chloropyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine

1H-pyrrolo[2,3-b]pyridine (39A) (10 g, 85.2 mmol) was dissolved in 1,2-dichloroethane (50 mL), cooled to 0 ° C under nitrogen Magnesium bromide (28.6 mL, 85.2 mmol) was stirred for 0.5 h. 2,4-Dichloropyrimidine (15.26 g, 102.4 mmol) was added and reacted at room temperature for 4 hours. 50 mL of methanol was added to the reaction mixture, and the solvent was evaporated to dryness (m.p. 4-yl)-1H-pyrrolo[2,3-b]pyridine (39B), yellow solid (10 g, yield 51.3%).

MS m/z = 230.1 [M + 1] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ12.07 (s, 1H), 8.52 (dd, 2H), 8.47-8.37 (m, 1H), 7.91 (d, 1H), 7.51 (dd, 1H), 7.29–7.19 (m, 2H).

Second step: 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (39C)

3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole

3-(2-Chloropyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine (39B) (2 g, 8.7 mmol) was dissolved in 10 mL of tetrahydrofuran, and sodium hydride (418 mg, 10.4) Methyl), the reaction was continued for 30 minutes, methyl iodide (1.63 mL, 26.2 mmol) was added, and the mixture was allowed to react to room temperature for 4 hours. The solvent was evaporated to give a solid. EtOAc m. (39C), yellow solid (2.1 g).

MS m/z: 244.1 [M + 1] ⁺ .

Third step: N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl) Pyrimidin-2-amine (39D)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

3-(2-Chloropyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (39C) (1 g, 4.1 mmol) was dissolved in 2-pentanol (20 mL) 4-Fluoro-2-methoxy-5-nitroaniline (4e) (765 mg, 4.1 mmol) and p-toluenesulfonic acid (939 mg, 4.9 mmol) were added, and the mixture was heated to reflux at 120 ° C for 2 days. The reaction solution was cooled to room temperature, 30 mL of acetonitrile was added, filtered, and the filter cake was washed once with 50 mL of water and dried to give N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1- Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine (39D), yellow solid (1.2 g, yield 75%).

Fourth step: N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-pyrrolo[2 ,3-b]pyridin-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine (39E)

N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin- 2-yl)-2-nitrobenzene-1,4-diamine

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-2 -Amine (39D) (1 g, 2.54 mmol) was dissolved in 20 mL of THF. EtOAc (EtOAc, EtOAc. 18A) (733 mg, 5.08 mmol), and allowed to react at room temperature for 8 hours. After completion of the reaction, 150 mL of water and 150 mL of ethyl acetate were added and the mixture was separated. The aqueous phase was extracted once with 100 mL of ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated to give compound N- ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(1) -methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine (39E), yellow solid (1.1 g, The yield was 84.6%).

MS m/z: 518.1 [M+1] ⁺ .

The fifth step: N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-pyrrolo[2 ,3-b]pyridin-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine (39F)

N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin- 2-yl)benzene-1,2,4-triamine

N ¹ -(2-(Dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-pyrrolo[2,3- b] Pyridin-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine (39E) (1.1 g, 2.18 mmol) was dissolved in 15 mL of ethanol, followed by 5 mL of water and iron powder. (356 mg, 6.4 mmol) and ammonium chloride (78.7 mg, 1.55 mmol) were heated to 90 ° C to reflux for 4 hours. The reaction solution was cooled to room temperature, filtered and concentrated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound N ¹ -(2-(dimethylamino)ethyl)-5-methoxy -N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)benzene-1,2,4- Triamine (39F), brown solid (550 mg, yield 51.9%).

Step 6: N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-pyrrole) And [2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 39)

N ¹ -(2-(Dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine (39F), brown solid (550 mg, 1 mmol) dissolved in 15 mL of pyridine, followed by 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (573 mg, 3 mmol) and acrylic acid (0.103 mL, 1.5 mmol) were reacted for 4 hours at room temperature. The reaction solution was spin-dried to remove pyridine, and 100 mL of water and 100 mL of dichloromethane were added and the mixture was separated. The organic phase was washed once with aqueous sodium hydroxide (100 mL, 4 mol/L). The organic phase was dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give N-(2-((2-dimethylamino)ethyl) (methyl) Amino)-4-methoxy-5-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)propene Amide (Compound 39), white solid (65 mg, yield 12%).

MS m/z: 542.1 [M + 1] ⁺ .

Example 40

N-(5-((5-chloro-4-(1-methyl-6-morpholinyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methyl Oxyphenyl)acrylamide (compound 40)

First step: 1-(6-nitro-1H-indol-1-yl)ethanone (40B)

1-(6-nitro-1H-indol-1-yl)ethanone

6-Nitro-1H-indole (40A) (16.2 g, 0.1 mol) was dissolved in 40 mL of pyridine, and acetic anhydride (40.8 g, 0.4 mol) was added and allowed to react at room temperature overnight. The reaction was completed, and the mixture was evaporated to dryness. EtOAc EtOAc (EtOAc) Ethyl ketone (40B), yellow solid (6 g, yield 30%).

MS m/z: 205.1 [M + 1] ⁺ .

Step 2: 1-(6-Amino-1H-indol-1-yl)ethanone (40C)

1-(6-amino-1H-indol-1-yl)ethanone

1-(6-Nitro-1H-indol-1-yl)ethanone (40B) (20 g, 0.1 mol) was dissolved in 50 mL of methanol and 50 mL of tetrahydrofuran, and palladium carbon (2 g, 10%) (40.3 g, 6.4 mol), reacted at 60 ° C for 2 hours. After completion of the reaction, the mixture was filtered, washed with ethyl acetate (100 mL), and the filtrate was evaporated. The aqueous phase was washed once with 150 mL of ethyl acetate. The combined organic phases were dried with anhydrous sodium sulfate (MgSO4)

The third step: 4-(1H-indol-6-yl)morpholine (40D)

4-(1H-indol-6-yl)morpholine

1-(6-Amino-1H-indol-1-yl)ethanone (40C) (8g, 60.1mmol) and 2,2'-dibromodiethyl ether (9mL, 72mmol) were dissolved in 100mLN,N-II To the methylformamide, N,N-diisopropylethylamine (DIPEA) (29.7 mL, 180 mmol) was added and the mixture was reacted at 90 ° C overnight. After the reaction was completed, it was cooled to room temperature, and 200 mL of ethyl acetate and 200 mL of saturated brine were added, and the mixture was separated. The aqueous phase was washed once with 200 mL of ethyl acetate. The combined organic phases were dried with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

MS m/z: 203.1 [M + 1] ⁺ .

Step 4: 4-(3-(2,5-Dichloropyrimidin-4-yl)-1H-indol-6-yl)morpholine (40E)

4-(3-(2,5-dichloropyrimidin-4-yl)-1H-indol-6-yl)morpholine

4-(1H-Indol-6-yl)morpholine (40D) (4.5 g, 22.3 mmol) was dissolved in 100 mL of tetrahydrofuran, cooled to 0 ° C under nitrogen, and methyl magnesium bromide (7.5 mL) was added dropwise. , 22.3 mmol), stirring was continued for 0.5 hours. Trichloropyrimidine (2.05 g, 22.3 mmol) was added, and the mixture was reacted at room temperature for 1 hour, and the temperature was raised to 60 ° C to continue the reaction for 1 hour. The reaction solution was cooled to room temperature, and 6.34 mL of acetic acid was added dropwise and stirred for 10 minutes. Add 100 mL of water, stir at 60 ° C for 30 minutes, separate the liquid, and add 100 mL of n-heptane to the organic phase, spin dry, and purify by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 50: 1) 4-(3-(2,5-Dichloropyrimidin-4-yl)-1H-indol-6-yl)morpholine (40E) was obtained as a yellow solid (3 g, yield 39%).

MS m/z: 349.0 [M+1] ⁺ .

Step 5: 4-(3-(2,5-Dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)morpholine (40F)

4-(3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)morpholine

4-(3-(2,5-Dichloropyrimidin-4-yl)-1H-indol-6-yl)morpholine (40E) (3 g, 8.6 mmol) was dissolved in 50 mL of THF. Sodium (460 mg, 11.5 mmol) was reacted for 30 minutes. Methyl iodide (1.6 mL, 25.8 mmol) was added and the mixture was warmed to room temperature for 3 hours. Spin dry, wash with 50 mL water and 20 mL tetrahydrofuran, filter, dry and concentrate to give 4-(3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl) Bromine (40F), pale yellow solid (1.9 g, yield 61.3%).

MS m/z: 363.0 [M + 1] ⁺ .

Step 6: 5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-6-morpholine-1H-indol-3-yl Pyrimidine-2-amine (40G)

4-(3-(2,5-Dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)morpholine (40F) (724 g, 2 mmol) was dissolved in 2-pentanol (20 mL), 4-fluoro-2-methoxy-5-nitroaniline (372 mg, 2 mmol) and p-toluenesulfonic acid (456.5 mg, 2.4 mmol) were added, and the mixture was heated to reflux at 120 ° C for 2 days. The reaction solution was cooled to room temperature, 50 mL of acetonitrile was added, filtered, and the filter cake was washed with 50 mL of water and dried to give 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4- (1-Methyl-6-morpholine-1H-indol-3-yl)pyrimidin-2-amine (40G), m.p.

MS m/z: 513.1 [M + 1] ⁺ .

Step 7: N ¹ -(5-chloro-4-(1-methyl-6-morpholine-1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxy Phenyl-1,3-diamine (40H)

N ¹ -(5-chloro-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene-1,3-diamine

5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-6-morpholine-1H-indol-3-yl)pyrimidine- 2-Amine (40G) (600mg, 1.17mmol) was dissolved in 30mL of ethanol, 10mL of water was added, iron powder (392mg, 7.03mmol) and ammonium chloride (43.8mg, 0.82mmol) were added in sequence, and the temperature was raised to 90 ° C, reflux reaction 4 hours. The reaction solution was cooled to room temperature, filtered, washed with 50 mL of MeOH and concentrated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 50:1) to give N ¹ -(5-chloro-4-(1-methyl-6-morpholine) 1H-Indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxyphenyl-1,3-diamine (40H), brown solid (150 mg, yield: 26.6%).

MS m/z: 483.1 [M + 1] ⁺ .

Step 8: N-(5-((5-chloro-4-(1-methyl-6-morpholinyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro -4-methoxyphenyl)acrylamide (compound 40)

N ¹ -(5-chloro-4-(1-methyl-6-morpholine-1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxyphenyl- 1,3-Diamine (40H) (150mg, 0.31mmol) was dissolved in 10mL of tetrahydrofuran, N,N-diisopropylethylamine (0.06mL, 0.37mmol) was added, and acryloyl chloride (0.03mL) was added dropwise at 0 °C. A solution of 0.37 mmol) in tetrahydrofuran (5 mL) was allowed to warm to room temperature for 1.5 hours. 100 mL of a saturated aqueous sodium hydrogencarbonate solution and 100 mL of dichloromethane were added to the reaction mixture, and the mixture was separated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give N-(5-(4-chloro-4-(1-methyl-6-)? Phytyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide (Compound 40), pale yellow solid (20 mg, yield 12%) ).

MS m/z = 537.1 [M + 1] ⁺ .

Example 41

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(4) -methylpiperazin-1-yl)ethoxy)phenyl)acrylamide (Compound 41)

First step: 5-chloro-N-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)-5-nitrophenyl)-4-( 1-methyl-1H-indol-3-ylpyrimidin-2-amine (41A)

5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (middle) 4) (854.1 mg, 2 mmol) was dissolved in 50 mL of tetrahydrofuran, and sodium hydride (80 mg, 2.2 mmol) was added and stirred. After stirring for 30 minutes, 2-(4-methylpiperazin-1-yl)ethanol (576.5 mg, 4 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. After the reaction was completed, 100 mL of water and 100 mL of ethyl acetate were added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and evaporated to give compound 5-chloro-N-(2-methoxy-4-(2-(4-) Methylpiperazin-1-yl)ethoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (41A), yellow solid (800 mg, yield 80%).

MS m/z: 552.2 [M + 1] ⁺ .

Second step: N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-(4- Methyl piperazin-1-yl)ethoxy)benzene-1,3-diamine (41B)

5-Chloro-N-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)-5-nitrophenyl)-4-(1-A Base-1H-indol-3-ylpyrimidin-2-amine (41A) (800 mg, 1.45 mmol) was dissolved in 15 mL of ethanol, followed by 5 mL of water, iron powder (486.3 mg, 8.7 mmol) and ammonium chloride ( 54 mg, 1 mmol), the temperature was raised to 90 ° C, and the reaction was refluxed for 4 hours. The reaction solution was cooled to room temperature, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound N ¹ -(5-chloro-4- (1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzene - 1,3-Diamine (41B), yellow solid (200 mg, yield 26.5%).

MS m/z: 522.2 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.63 (d, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 8.06 (s, 1H), 7.51 (s, 1H), 7.40 (d, 1H), 7.34 (dd, 1H), 7.28 (dd, 1H), 6.57 (s, 1H), 4.11 (t, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 2.79 (t, 2H) ), 2.66 (s, 4H), 2.60 - 2.44 (m, 4H), 2.32 (d, 3H).

The third step: N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-( 2-(4-Methylpiperazin-1-yl)ethoxy)phenyl)propenylamide (Compound 41)

N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-(4-methylpiperidine) Pyrazin-1-yl)ethoxy)benzene-1,3-diamine (41B) (150mg, 0.288mmol) was dissolved in 10mL of tetrahydrofuran, DIPEA (0.057mL, 0.345mmol) was added, and acryloyl chloride was added dropwise at 0 °C. 5 mL of a solution of (0.028 mL, 0.345 mmol) in tetrahydrofuran was allowed to react to room temperature for 1 hour. 50 mL of a saturated aqueous sodium hydrogencarbonate solution and 50 mL of ethyl acetate were added and the mixture was separated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound N-(5-((5-chloro-4-(1-methyl-1H-) Ind-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)propenylamide ( Compound 41), pale yellow solid (40 mg, yield 24.1%).

MS m/z = 576.2 [M + 1] ⁺ .

Example 42

N-(3-((5-chloro-4-(1-methyl-6-morpholin-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl) Acrylamide (Compound 42)

N-(3-((5-chloro-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

First step: 5-chloro-N-(2-methoxy-5-nitrophenyl)-4-(1-methyl-6-morpholine-1H-indol-3-yl)pyrimidine-2 -amine (42A)

5-chloro-N-(2-methoxy-5-nitrophenyl)-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-amine

4-(3-(2,5-Dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)morpholine (40F) (724 g, 2 mmol) was dissolved in 2-pentanol (20 mL), 2-methoxy-5-nitroaniline (336.3 mg, 2 mmol) and p-toluenesulfonic acid (456.5 mg, 2.4 mmol) were added, and the mixture was heated to reflux at 120 ° C for 3 days. The reaction solution was cooled to room temperature, 50 mL of acetonitrile was added, filtered, and the filter cake was washed with 50 mL of water and dried to give 5-chloro-N-(2-methoxy-5-nitrophenyl)-4-(1-A Benzyl-6-morpholine-1H-indol-3-ylpyrimidin-2-amine (42A), mp.

MS m/z: 495.1 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.87 (s, 1H), 8.70 (s, 1H), 8.56 (s, 1H), 8.51 (s, 1H), 8.33 (d, 1H), 8.07 ( d,1H), 7.48(d,2H), 7.36(s,1H), 7.32(d,1H),7.11(d,2H),7.02(d,1H), 3.99(s,3H),3.90(s , 8H), 3.73 (s, 19H), 2.29 (s, 3H).

Second step: N ¹ -(5-chloro-4-(1-methyl-6-morpholin-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxybenzene-1, 3-diamine (42B)

N ¹ -(5-chloro-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxybenzene-1,3-diamine

5-Chloro-N-(2-methoxy-5-nitrophenyl)-4-(1-methyl-6-morpholine-1H-indol-3-yl)pyrimidin-2-amine ( 42A) (990 mg, 2 mmol) was dissolved in 30 mL of ethanol, and then 10 mL of water, iron powder (670 mg, 12 mmol) and ammonium chloride (75 mg, 1.4 mmol) were added, and the mixture was heated to 90 ° C and refluxed overnight. The reaction solution was cooled to room temperature, filtered, washed once with 50 mL of methanol, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound N ¹ -( 5-Chloro-4-(1-methyl-6-morpholine-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxybenzene-1,3-diamine (42B), Brown solid (340 mg, yield 36.6%).

MS m/z: 465.1 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.56 (d, 1H), 8.33 (s, 1H), 8.16 (d, 1H), 8.13 (s, 1H), 7.75 (s, 1H), 7.03 (dd, 1H), 6.82 (d, 1H), 6.74 (d, 1H), 6.31 (dd, 1H), 3.97 - 3.91 (m, 4H), 3.85 (s, 3H), 3.85 (s, 3H), 3.26 - 3.19 (m, 4H).

The third step: N-(3-((5-chloro-4-(1-methyl-6-morpholin-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy Phenyl phenyl acrylamide (compound 42)

N ¹ -(5-chloro-4-(1-methyl-6-morpholine-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxybenzene-1,3-di The amine (42B) (280 mg, 0.6 mmol) was dissolved in 30 mL of THF. N. N-diisopropylethylamine (DIPEA) (0.12 mL, 0.72 mmol) was added and acryloyl chloride (0.059 mL, 0.72) was added dropwise at 0 °C. 5 mL of a tetrahydrofuran solution of mmol) was allowed to react to room temperature for 4 hours. 100 mL of a saturated aqueous sodium hydrogencarbonate solution and 100 mL of ethyl acetate were added and the mixture was separated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound N-(3-((5-chloro-4-(1-methyl-6-) Morpholine-1H-indol-3-ylpyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 42), pale yellow solid (120 mg, yield 38.7%).

MS m/z: 519.1 [M+1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.52 (dd, 2H), 8.35 (s, 1H), 8.15 (s, 1H), 7.83 (d, 1H), 7.78 (s, 1H), 7.12 (s, 1H), 6.98 (d, 1H), 6.89 (d, 1H), 6.37 (d, 1H), 6.09 (dd, 10.2 Hz, 1H), 5.69 (d, 1H), 3.93 (s, 7H), 3.87 ( s, 3H), 3.25 (s, 4H).

Example 43

N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)ethoxy)-4- Methoxyphenyl)acrylamide (compound 43)

N-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)acrylamide

First step: 5-chloro-N-(4-(2-(dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-(1H-indole-3 -yl)pyrimidin-2-amine (43A)

5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (middle) 4) (620 mg, 1.5 mmol) was dissolved in 30 mL of THF. EtOAc (EtOAc, EtOAc. After completion of the reaction, 100 mL of water and 100 mL of ethyl acetate were added, and the organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 5-chloro-N-(4-(2-(dimethylamino)ethoxy)- 2-Methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (43A), brown solid (660 mg, yield 91.3%).

Second step: N ¹ -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(dimethylamino)ethoxy)-6- Oxy-1,3-diamine (43B)

N ¹ -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(dimethylamino)ethoxy)-6-methoxybenzene-1,3-diamine

5-Chloro-N-(4-(2-(dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl) Pyrimidin-2-amine (43A) (650 mg, 1.35 mmol) was dissolved in 30 mL of ethanol, and then 10 mL of water, iron powder (452 mg, 8.1 mmol) and ammonium chloride (50.5 mg, 0.95 mmol) were added, and the temperature was raised to 90 °C. The reaction was refluxed overnight. The reaction solution is cooled to room temperature, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 20:1) to give compound N ¹ -(5-chloro-4- (1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(dimethylamino)ethoxy)-6-methoxy-1,3-diamine (43B), yellow Solid (200 mg, yield 32.8%).

MS m/z = 453.1 [M + 1] ⁺ .

The third step: N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)ethoxy) )-4-methoxyphenyl)acrylamide (compound 43)

N ¹ -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(dimethylamino)ethoxy)-6-methoxy- 1,3-Diamine (43B) (200mg, 0.44mmol) was dissolved in 15mL of tetrahydrofuran, N,N-diisopropylethylamine (DIPEA) (0.088mL, 0.53mmol) was added, and acryloyl chloride was added dropwise at 0 °C. A solution of (0.043 mL, 0.53 mmol) in tetrahydrofuran (5 mL) was warmed to room temperature for 4 hours. 100 mL of a saturated aqueous sodium hydrogencarbonate solution and 100 mL of ethyl acetate were added to the reaction mixture, and the mixture was separated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give the compound N-(5-(5-chloro-4-(1H-indole-3-) Pyrimidine-2-yl)amino)-2-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)acrylamide (Compound 43), beige solid (20 mg, yield 9.0%).

MS m/z = 507.1 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.83 (s, 1H), 9.33 (s, 1H), 9.18 (s, 1H), 8.48 (d, 1H), 8.29 (d, 1H), 8.26 (s, 1H), 7.41 (s, 1H), 7.33 (d, 1H), 7.24 - 7.14 (m, 2H), 6.65 (s, 1H), 6.41 (d, 1H), 6.27 (dd, 1H), 5.71 (d , 1H), 4.20–4.09 (m, 2H), 3.88 (s, 3H), 2.62–2.52 (m, 2H), 2.37 (s, 6H).

Example 44

(S)-N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-( (1-methylpyrrol-3-yl)oxy)phenyl)acrylamide (Compound 44)

(S)-N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin) -3-yl)oxy)phenyl)acrylamide

First step: (S)-5-chloro-N-(2-methoxy-4-((1-methylpyrrol-3-yl)oxy)-5-nitrophenyl)-4-( 1-methyl-1H-indol-3-ylpyrimidin-2-amine (44A)

(S)-5-chloro-N-(2-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl) Pyrimidin-2-amine

5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (middle) 4) (854.1 mg, 2 mmol) was dissolved in 30 mL of tetrahydrofuran, sodium hydride (160 mg, 4 mmol) was added and the mixture was stirred for 30 min, and (S)-(+)-1-methyl-3-hydroxypyrrole was added dropwise. Alkane (242.76 mg, 2.4 mmol) was reacted overnight at room temperature. After completion of the reaction, 150 mL of water and 150 mL of ethyl acetate were added, and the organic layer was dried over anhydrous sodium sulfate and concentrated to give compound (S)-5-chloro-N-(2-methoxy-4-((1- Methylpyrrol-3-yl)oxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (44A), yellow solid (1 g , yield 99%).

MS m/z: 509.1 [M+1] ⁺ .

The second step: (S)-N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(( 1-methylpyrrol-3-yl)oxy)benzene-1,3-diamine (44B)

(S)-N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-((1-methylpyrrolidin-3-yl) Oxy)benzene-1,3-diamine

(S)-5-Chloro-N-(2-methoxy-4-((1-methylpyrrol-3-yl)oxy)-5-nitrophenyl)-4-(1-A Base-1H-indol-3-ylpyrimidin-2-amine (44A) (1 g, 2 mmol) was dissolved in 30 mL of ethanol, followed by 10 mL of water, iron powder (659.3 mg, 11.8 mmol) and ammonium chloride (73.7) Mg, 1.38 mmol), warmed to 90 ° C and refluxed overnight. The reaction solution was cooled to room temperature, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound (S)-N ¹ -(5- Chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-((1-methylpyrrol-3-yl)oxy)benzene - 1,3-Diamine (44B), brown solid (410 mg, yield 42.9%).

The third step: (S)-N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy -2-((1-methylpyrrol-3-yl)oxy)phenyl)acrylamide (Compound 44)

(S)-N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-((1- Methylpyrrolidin-3-yl)oxy)phenyl)acrylamide

(S)-N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-((1-A) Pyridyl-3-yl)oxy)benzene-1,3-diamine (44B) (400 mg, 0.84 mmol) was dissolved in 30 mL of tetrahydrofuran, and N,N-diisopropylethylamine (DIPEA) (0.165 mL) , 1 mmol), a solution of acryloyl chloride (0.08 mL, 1 mmol) in tetrahydrofuran (5 mL) was added dropwise at 0 ° C, and the mixture was allowed to react at room temperature for 4 hours. 100 mL of a saturated aqueous sodium hydrogencarbonate solution and 100 mL of ethyl acetate were added to the reaction mixture, and the mixture was separated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound (S)-N-(5-((5-chloro-4-(1-) -1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrol-3-yl)oxy)phenyl)acrylamide (compound) 44), yellow-green solid (80 mg, yield 17.9%).

MS m/z: 533.1 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.33 (s, 1H), 8.39 (d, 2H), 8.32 (s, 1H), 7.42 (s, 1H), 7.36 (d, 1H), 7.29 (d, 1H), 7.21 (t, 1H), 6.53 (s, 1H), 6.37 (s, 2H), 5.74 - 5.65 (m, 1H), 4.81 (s, 1H), 3.90 (s, 3H), 3.86 (s) , 3H), 3.18 (d, 2H), 2.51 (s, 3H), 2.39 - 2.26 (m, 2H), 2.20 (d, 2H).

Example 45

(R)-N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-( (1-methylpyrrol-3-yl)oxy)phenyl)acrylamide (Compound 45)

(R)-N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin) -3-yl)oxy)phenyl)acrylamide

First step: (R)-5-chloro-N-(2-methoxy-4-((1-methylpyrrol-3-yl)oxy)-5-nitrophenyl)-4-( 1-methyl-1H-indol-3-ylpyrimidin-2-amine (45A)

(R)-5-chloro-N-(2-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)-5-nitrophenyl)-4-(1-methyl -1H-indol-3-yl)pyrimidin-2-amine

5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (middle) 4) (1 mg, 2.3 mmol) was dissolved in 30 mL of tetrahydrofuran, sodium hydride (184 mg, 4.6 mmol) was added, and the mixture was stirred for 30 minutes, and (R)-(-)-1-methyl-3-hydroxyl was added dropwise. Pyrrolidine (284 mg, 2.8 mmol) was reacted overnight at room temperature. After completion of the reaction, 150 mL of water and 150 mL of ethyl acetate were added and the mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound (R)-5-chloro-N-(2-methoxy-4-( (1-methylpyrrol-3-yl)oxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (45A), yellow Solid (1.1 g).

MS m/z: 509.0 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.19 (s, 1H), 8.46 (d, 1H), 8.39 (s, 1H), 8.23 (d, 1H), 7.49 (s, 1H), 7.38 (d, 1H), 7.34 (dd, 1H), 7.30 (dd, 1H), 6.52 (s, 1H), 4.92 (ddd, 1H), 3.99 (s, 3H), 3.91 (s, 1H), 3.90 (s, 3H) ), 3.10 (dd, 1H), 2.83 - 2.74 (m, 2H), 2.72 - 2.64 (m, 1H), 2.44 (s, 3H), 2.32 (dt, 2H), 2.19 - 2.10 (m, 1H).

The second step: (R)-N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(( 1-methylpyrrol-3-yl)oxy)benzene-1,3-diamine (45B)

(R)-N1-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-((1-methylpyrrolidin-3-yl)oxy Benzene-1,3-diamine

(R)-5-Chloro-N-(2-methoxy-4-((1-methylpyrrol-3-yl)oxy)-5-nitrophenyl)-4-(1-A Base-1H-indol-3-ylpyrimidin-2-amine (45A) (1.1 g, 2.16 mmol) was dissolved in 30 mL of ethanol, followed by 10 mL of water, iron powder (725 mg, 13 mmol) and ammonium chloride (81 mg) 1.5 mmol), the temperature was raised to 90 ° C, and the reaction was refluxed for 4 hours. The reaction solution was cooled to room temperature, filtered and concentrated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound (R)-N ¹ -(5-chloro-4-(1-methyl-1H) -Indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-((1-methylpyrrol-3-yl)oxy)benzene-1,3-diamine (45B), Green solid (900 mg, yield 90%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.63 (d, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 7.52 (s, 1H), 7.39 (d, 1H), 7.33(t,1H), 7.27(dd,1H), 6.48(s,1H),4.88(t,1H),3.90(s,3H),3.85(d,3H),3.16–2.98(m , 6H), 2.84 (s, 1H), 2.58 (s, 3H), 2.35 (dt, 1H), 2.20 (dd, 1H).

The third step: (R)-N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy -2-((1-methylpyrrol-3-yl)oxy)phenyl)acrylamide (Compound 45)

(R)-N ¹ -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-((1-A) Pyridyl-3-yl)oxy)benzene-1,3-diamine (45B) (900 mg, 1.88 mmol) was dissolved in 20 mL of tetrahydrofuran, DIPEA (0.23 mL, 2.26 mmol) was added, and acryloyl chloride was added dropwise at 0 °C. 5 mL of a solution of (0.183 mL, 2.26 mmol) in tetrahydrofuran was allowed to react to room temperature for 4 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was stirred, and ethyl acetate (150 mL) The organic phase was dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound (R)-N-(5-((5-chloro-4-(1-) -1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrol-3-yl)oxy)phenyl)acrylamide (compound) 45), pale yellow solid (180 mg, yield 16%).

MS m/z = 533.2 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.38 (s, 1H), 8.90 (s, 1H), 8.39 (d, 2H), 8.32 (s, 1H), 7.42 (s, 1H), 7.35 (d, 1H), 7.31–7.26 (m, 1H), 7.23–7.18 (m, 1H), 6.55 (s, 1H), 6.35 (qd, 2H), 5.68 (dd, 1H), 4.76 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.16 (t, 1H), 3.00 (d, 1H), 2.43 (s, 3H), 2.34 (dd, 2H), 2.31 - 2.25 (m, 1H), 2.13 (dd, 1H), 1.25 (s, 1H).

Example 46

N-(3-((5-chloro-4-(1-methyl-6-morpholin-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl) Acrylamide hydrochloride (Compound 46)

N-(3-((5-chloro-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide hydrochloride

N-(3-((5-chloro-4-(1-methyl-6-morpholin-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl) Acrylamide (Compound 42) (86 mg, 0.166 mmol) was dissolved in 1,4-dioxane (30 mL). HCl (0.083 mL, 0.332 mmol) of 1,4-dioxane was added dropwise at 0 °C. The solution was allowed to warm to room temperature for 2 hours. The reaction solution was sparged to give N-(3-((5-chloro-4-(1-methyl-6-morpholin-1H-indol-3-yl)pyrimidin-2-yl)amino)-4- Methoxyphenyl) acrylamide hydrochloride (Compound 46), yellow solid (90 mg, yield 97.8%).

MS m/z: 519.1 [M+1] ⁺ .

Example 47

(S)-N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-( (1-methylpyrrol-3-yl)oxy)phenyl)acrylamide methanesulfonate (Compound 47)

(S)-N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin) -3-yl)oxy)phenyl)acrylamide methanesulfonate

(S)-N-(5-((5-Chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2- ((1-Methylpyrrol-3-yl)oxy)phenyl)acrylamide (Compound 44) (40 mg, 0.075 mmol) was dissolved in 10 mL of ethanol, 5 mL ethyl acetate was added, and methanesulfonic acid was added dropwise at 70 ° C. (0.048 mL, 0.075 mmol) in EtOAc (3 mL) The reaction solution was spoked to give (S)-N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methyl Oxy-2-((1-methylpyrrol-3-yl)oxy)phenyl)acrylamide methanesulfonate (Compound 47), brown solid (47 mg, yield 99.8%).

MS m/z: 533.1 [M + 1] ⁺ .

Example 48

N-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-) Amino)phenyl)acrylamide (compound 48)

N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

First step: N-(4-(2-(dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indole- 3-yl)pyrimidin-2-amine (48A)

N-(4-(2-(dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 3) (1 g , 2.54 mmol) was dissolved in 50 mL of tetrahydrofuran, sodium hydride (103 mg, 2.57 mmol) was added, and the mixture was stirred for 30 minutes, and 2-(dimethylamino)ethanol (417.2 mg, 4.68 mmol) was added dropwise, and reacted at room temperature for 4 hours. . After completion of the reaction, 200 mL of water and 200 mL of ethyl acetate were added and the mixture was separated. The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated to afford compound N-(4-(2-(dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-( 1-Methyl-1H-indol-3-ylpyrimidin-2-amine (48A), yellow solid (1.05 g, yield 91.3%).

MS m/z: 463.2 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.67 (s, 1H), 8.38 (d, 1H), 8.26 (s, 1H), 8.15 (dd, 1H), 7.52 (s, 1H), 7.40 (dd, 1H), 7.34–7.27 (m, 2H), 7.19 (d, 1H), 6.63 (s, 1H), 4.23 (t, 2H), 3.99 (d, 3H), 3.93 (s, 3H), 3.48 (s) , 3H), 2.85 (t, 2H), 2.40 (s, 6H).

Second step: 4-(2-(Dimethylamino)ethoxy)-6-methoxy-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidine-2 -yl)benzene-1,3-diamine (48B)

4-(2-(dimethylamino)ethoxy)-6-methoxy-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,3-diamine

N-(4-(2-(Dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl) Pyrimidine-2-amine (48A) (1 g, 2.16 mmol) was dissolved in 30 mL of ethanol, and then 10 mL of water, iron powder (725 mg, 13 mmol) and ammonium chloride (81 mg, 1.5 mmol) were added, and the mixture was heated to reflux at 90 ° C. overnight. The reaction solution was cooled to room temperature, filtered and concentrated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound 4-(2-(dimethylamino)ethoxy)-6-methoxy -N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,3-diamine (48B), brown solid (930 mg, yield 99.7%) .

MS m/z: 433.2 [M + 1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.52 - 8.47 (m, 1H), 8.31 (d, 1H), 8.13 (s, 1H), 7.77 (s, 1H), 7.47 (s, 1H), 7.37 ( Dd, 1H), 7.30 (ddd, 2H), 6.99 (d, 1H), 6.58 (s, 1H), 4.09 (t, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.72 (t , 2H), 2.35 (s, 6H).

Third step: N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)) Pyrimidin-2-yl)amino)phenyl)acrylamide (compound 48)

4-(2-(Dimethylamino)ethoxy)-6-methoxy-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl) Benzene-1,3-diamine (48B) (600 mg, 1.38 mmol) was dissolved in 10 mL of pyridine, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (794 mg) , 4.16 mmol) and acrylic acid (0.143 mL, 2.08 mmol) were reacted at room temperature for 3 hours. The reaction solution was sparged, and aqueous sodium hydroxide (150 mL, 4 mol/L) and 150 mL The organic phase was washed once with 100 mL of water. The organic phase was dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give N-(2-(2-dimethylamino)ethoxy)-4-methyl Oxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 48), yellow solid (330 mg, yield 49.1 %).

MS m/z: 487.2 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.80 (d, 2H), 8.99 (s, 1H), 8.37 (d, 1H), 8.10-8.03 (m, 1H), 7.63 (s, 1H), 7.39 ( Dd,1H),7.19(d,1H), 6.64(s,1H),6.49(d,0H),6.44(d,1H),6.38(d,1H),5.72(dd,1H),4.17–4.09 (m, 2H), 3.98 (d, 3H), 3.88 (s, 3H), 2.59 (d, 2H), 2.37 (s, 6H).

Example 49

(S)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((1-A) Pyryrrol-3-yl)oxy)phenyl)acrylamide (Compound 49)

(S)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((1-methylpyrrolidin-3-yl) Oxy)phenyl)acrylamide

First step: (S)-N-(2methoxy-4-((1-methylpyrrol-3-yl)oxy)-5-nitrophenyl)-4-(1-methyl- 1H-indol-3-ylpyrimidin-2-amine (49A)

(S)-N-(2-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2- Amine

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 3) (1 g , 2.54 mmol) was dissolved in 30 mL of tetrahydrofuran, sodium hydride (203 mg, 5.08 mmol) was added, and the mixture was stirred for 30 minutes, and (S)-1-methylpyrrole-3-ol (308 mg, 3.05 mmol) of tetrahydrofuran was added dropwise. The solution (5 mL) was reacted at room temperature for 4 hours. After completion of the reaction, 100 mL of water and 150 mL of ethyl acetate were added to the reaction mixture, and the mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to give (S)-N-(2 methoxy-4-((1- Methylpyrrol-3-yl)oxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (49A), yellow solid (1 g , yield 83.3%).

MS m/z: 475.2 [M + 1] ⁺ .

The second step: (S)-6-methoxy-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-((1-methyl) Pyrrol-3-yl)oxy)benzene-1,3-diamine (49B)

(S)-6-methoxy-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-((1-methylpyrrolidin-3-yl)oxy)benzene- 1,3-diamine

(S)-N-(2methoxy-4-((1-methylpyrrol-3-yl)oxy)-5-nitrophenyl)-4-(1-methyl-1H-indole Indole-3-ylpyrimidin-2-amine (49A) (1 g, 2.11 mmol) was dissolved in 30 mL of ethanol, and then 10 mL of water, iron powder (707 mg, 12.65 mmol) and ammonium chloride (78.6 mg, 1.47 mmol) were added. The temperature was raised to 90 ° C and refluxed for 4 hours. The reaction solution was cooled to room temperature, filtered and concentrated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound (S)-6-methoxy-N ¹ -(4-(1-A) -1H-indol-3-yl)pyrimidin-2-yl)-4-((1-methylpyrrol-3-yl)oxy)benzene-1,3-diamine (49B), brown solid ( 500 mg, yield 53.6%).

MS m/z: 445.2 [M + 1] ⁺ .

The third step: (S)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-( (1-methylpyrrol-3-yl)oxy)phenyl)acrylamide (Compound 49)

(S)-6-Methoxy-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-((1-methylpyrrole-3) -yl)oxy)benzene-1,3-diamine (49B) (500 mg, 1.13 mmol) was dissolved in 15 mL of pyridine, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide The amine hydrochloride (646 mg, 3.38 mmol) and acrylic acid (0.116 mL, 1.69 mmol) were reacted at room temperature for 4 hours. The reaction solution was spun dry, and 150 mL of water and 200 mL of dichloromethane were added and the mixture was separated. The organic phase was washed once with 150 mL of a 4 mol/L aqueous sodium hydroxide solution. The organic phase is dried over anhydrous sodium sulfate, concentrated by filtration and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give (S)-N-(4-A) Oxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((1-methylpyrrol-3-yl)oxy) Phenyl)acrylamide (Compound 49), pale yellow solid (210 mg, yield 37.3%).

MS m/z: 499.2 [M+1] ⁺ .

Example 50

N-(4-Methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(piperidin-1-) Ethyl)phenyl)acrylamide (compound 50)

N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(piperidin-1-yl)ethoxy)phenyl Acrylamide

First step: N-(2-methoxy-5-nitro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-4-(1-methyl-1H-indole Indole-3-yl)pyrimidine-2-amine (50A)

N-(2-methoxy-5-nitro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 3) (1 g , 2.54 mmol) was dissolved in 50 mL of tetrahydrofuran, sodium hydride (122 mg, 3.1 mmol) was added under ice-cooling, and stirred for 30 min, then 2-(piperidin-1-yl)ethanol (656 mg, 5.08 mmol) was added dropwise. . After completion of the reaction, 150 mL of water and 100 mL of ethyl acetate were added and the mixture was separated. The aqueous phase was extracted with 100 mL of ethyl acetate. EtOAcjjjjjjjjjjjjj Ethoxy)phenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (50A) as a yellow solid (1.2 g, yield 94.5%).

MS m/z: 503.1 [M + 1] ⁺ .

Second step: 6-methoxy-N ¹ -(4-(1-methyll-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(piperidin-1- Ethyloxy)benzene-1,3-diamine (50B)

6-methoxy-N1-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(piperidin-1-yl)ethoxy)benzene-1,3-diamine

N-(2-Methoxy-5-nitro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-4-(1-methyl-1H-indole-3 -yl)pyrimidin-2-amine (50A) (1.2 g, 2.39 mmol) was dissolved in 15 mL of ethanol, followed by 5 mL of water, iron powder (400 mg, 7.17 mmol) and ammonium chloride (89.5 mg, 1.67 mmol). The reaction was refluxed for 6 hours at 90 °C. The reaction solution was cooled to room temperature, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound 6-methoxy-N ¹ - ( 4-(1-methyll-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(piperidin-1-yl)ethoxy)benzene-1,3-diamine (50B), brown solid (750 mg, yield 68.2%).

MS m/z: 473.3 [M + 1] ⁺ .

The third step: N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(piperider) Pyridin-1-yl)ethoxy)phenyl)acrylamide (compound 50)

6-Methoxy-N ¹ -(4-(1-methyll-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(piperidin-1-yl)B Oxy)benzene-1,3-diamine (50B) (750 mg, 1.59 mmol) was dissolved in 10 mL of pyridine, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added. (911 mg, 4.71 mmol) and acrylic acid (0.164 mL, 2.38 mmol) were reacted at room temperature for 4 hours. The reaction solution was sparged, and 100 mL of a 4 mol/L sodium hydroxide aqueous solution and 100 mL of ethyl acetate were added, and the mixture was separated. The organic phase was washed once with 100 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give N-(4-methoxy-5-((4-(1-methyl-1H) -Indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(piperidin-1-yl)ethoxy)phenyl)acrylamide (Compound 50), white solid (300 mg, yield The rate is 35.8%).

MS m/z: 527.2 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.60 (s, 1H), 9.40 (s, 1H), 8.83 (s, 1H), 8.33 (d, 1H), 8.07 (d, 1H), 7.39 (d, 1H), 7.33–7.23 (m, 1H), 7.17 (d, 1H), 6.51 (s, 1H), 6.45 (dd, 1H), 5.72 (d, 1H), 4.33 (s, 2H), 3.94 (s) , 2H), 3.87 (d, 2H), 3.62 (s, 2H), 3.33 (d, 2H), 2.68 (s, 2H), 2.33 (s, 2H), 1.84 (s, 3H), 1.55 (s, 3H).

Example 51

N-(4-Methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(4-methylpiperidine) Pyrazin-1-yl)ethoxy)phenyl)acrylamide (Compound 51)

N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(4-methylpiperazin-1-yl)ethoxy Phenyl)acrylamide

First step: N-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)-5-nitrophenyl)-4-(1-methyl -1H-indol-3-ylpyrimidin-2-amine (51A)

N-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 3) (1 g , 2.54 mmol) was dissolved in 20 mL of tetrahydrofuran, sodium hydride (203 mg, 5.08 mmol) was added under ice-cooling, stirred for 30 min, and 1-(2-hydroxyethyl)-4-methylpiperazine (733 mg, 5.08 mmol) was added dropwise. ), react at room temperature for 8 hours. After completion of the reaction, 150 mL of water and 150 mL of ethyl acetate were added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with EtOAc (EtOAc) (EtOAc) Oxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (51A) as a yellow solid (1.1 g, yield 84.6%).

MS m/z: 518.1 [M+1] ⁺ .

Second step: 6-methoxy-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(4-methylpiperazine) -1-yl)ethoxy)benzene-1,3-diamine (51B)

6-methoxy-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzene-1, 3-diamine

N-(2-Methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)-5-nitrophenyl)-4-(1-methyl-1H- Indole-3-ylpyrimidin-2-amine (51A) (1.1 g, 2.18 mmol) was dissolved in 15 mL of ethanol, followed by 5 mL of water, followed by iron powder (356 mg, 6.4 mmol) and ammonium chloride (78.7 mg). 1.55 mmol), the temperature was raised to 90 ° C, and the reaction was refluxed for 4 hours. The reaction solution was cooled to room temperature, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give 6-methoxy-N ¹ - (4) -(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzene-1,3- Diamine (51B), brown solid (550 mg, yield 51.9%).

The third step: N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(4) -methylpiperazin-1-yl)ethoxy)phenyl)acrylamide (Compound 51)

6-Methoxy-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(4-methylpiperazin-1- Ethyl) benzene-1,3-diamine (51B) (550 mg, 1 mmol) was dissolved in 15 mL of pyridine, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt was added. The acid salt (573 mg, 3 mmol) and acrylic acid (0.103 mL, 1.5 mmol) were reacted at room temperature for 4 hours. The reaction solution was sparged, and 100 mL of water and 100 mL of dichloromethane were added and the mixture was separated. The organic phase was washed once with 100 mL of a 4 mol/L aqueous sodium hydroxide solution. The organic phase was dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give N-(4-methoxy-5-((4-(1-methyl-1H) -Indol-3-ylpyrimidin-2-yl)amino)-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)acrylamide (Compound 51), white solid (65 mg, 12%).

MS m/z: 542.1 [M + 1] ⁺ .

Example 52

(R)-N-(4methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((1-methyl) Pyrrol-3-yl)amino)phenyl)acrylamide (compound 52)

(R)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((1-methylpyrrolidin-3-yl) )amino)phenyl)acrylamide

First step: (R)-tert-butyl 3-((tert-butoxycarbonyl)amino)pyrrole-1-carboxylate (52B)

(R)-tert-butyl 3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carboxylate

(R)-tert-Butyl 3-aminopyrrole-1-carboxylate (52A) (2 g, 10.74 mmol) was dissolved in 25 mL dichloromethane, triethylamine (2.17 g, 21.5 mmol) and dicarbonic acid tert-Butyl ester (2.46 g, 11.28 mmol) was reacted at room temperature for 3 hours. 100 mL of water and 100 mL of dichloromethane were added to the reaction mixture, and the mixture was separated. The organic phase is dried over anhydrous sodium sulfate and filtered Concentration gave (R)-tert-butyl 3-((tert-butoxycarbonyl)amino)pyrrole-1-carboxylate (52B) as a colorless oil (3 g).

Second step: (R)-N,1-dimethylpyrrol-3-amine (52C)

(R)-N,1-dimethylpyrrolidin-3-amine

(R)-tert-Butyl 3-((tert-butoxycarbonyl)amino)pyrrole-1-carboxylate (52B) (3 g, 10.74 mmol) was dissolved in 50 mL of tetrahydrofuran, and lithium tetrahydroaluminum was slowly added in an ice bath. (4 g, 107.4 mmol), reacted at room temperature for 1 hour, and increased to 60 ° C to continue the reaction for 3 hours. After the reaction was completed, 50 mL of acetone was added, and water was added dropwise until the reaction liquid appeared without bubbles. Filtration, washing with 50 mL of THF, EtOAc (EtOAc)

MS m/z: 115.2 [M + 1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.65 (t, 1H), 3.23 - 3.15 (m, 1H), 2.68 - 2.60 (m, 1H), 2.48 - 2.39 (m, 1H), 2.37 (s, 3H) ), 2.33 (s, 3H), 2.14 (dd, 1H), 1.70 - 1.64 (m, 1H), 1.57 (d, 1H).

Third step: (R)-2-methoxy-N ⁴ -methyl-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(1-methylpyrrol-3-yl)-5-nitrobenzene-1,4-diamine (52D)

(R)-2-methoxy-N4-methyl-N1-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N4-(1-methylpyrrolidin-3-yl)-5 -nitrobenzene-1,4-diamine

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 3) (1 g , 2.54 mmol) dissolved in 10 mL of N,N-dimethylacetamide, followed by N,N-diisopropylethylamine (DIPEA) (0.51 mL, 3.05 mmol) and (R)-N, 1- Methylpyrrol-3-amine (52C) (348 mg, 3.05 mmol) was reacted in a microwave at 140 ° C for 1 hour. After the reaction is completed, the reaction mixture is concentrated and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound (R)-2-methoxy-N ⁴ - methyl-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(1-methylpyrrol-3-yl)-5-nitro Benzene-1,4-diamine (52D), red solid (0.5 g, yield 40.3%).

MS m/z: 488.1 [M + 1] ⁺ .

Fourth step: (R)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(1-methylpyrrol-3-yl)benzene-1,2,4-triamine (52E)

(R)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N1-(1-methylpyrrolidin-3-yl)benzene- 1,2,4-triamine

(R)-2-Methoxy-N ⁴ -methyl-N ¹ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(1 -Methylpyrrol-3-yl)-5-nitrobenzene-1,4-diamine (52D) (1.24 g, 2.5 mmol) was dissolved in 20 mL of ethanol, and 7 mL of water and iron powder (419 mg, 7.5 mmol) was added. Ammonium chloride (94 mg, 1.75 mmol) was heated to 90 ° C and refluxed for 6 hours. The reaction solution is cooled to room temperature, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound (R)-5-methoxy- N ¹ -Methyl-N ⁴ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(1-methylpyrrol-3-yl)benzene- 1,2,4-Triamine (52E), brown solid (350 mg, yield 30.7%).

MS m/z: 458.1 [M + 1] ⁺ .

The fifth step: (R)-N-(4-methoxy-2-(methyl(1-methylpyrrol-3-yl)amino)-5-((4-(1-methyl-1H-) Ind-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 52)

(R)-N-(4-methoxy-2-(methyl(1-methylpyrrolidin-3-yl)amino)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2- Yl)amino)phenyl)acrylamide

(R)-5-Methoxy-N ¹ -methyl-N ⁴ -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(1 -Methylpyrrol-3-yl)benzene-1,2,4-triamine (52E) (350 mg, 0.76 mmol) was dissolved in 10 mL of pyridine, and 1-(3-dimethylaminopropyl)-3-ethyl was added. The carbodiimide hydrochloride (EDCI) (436 mg, 2.28 mmol) and acrylic acid (0.08 mL, 1.14 mmol) were reacted at room temperature for 4 hours. The reaction solution was sparged, and 100 mL of water and 100 mL of dichloromethane were added and the mixture was separated. The organic phase was washed once with 100 mL of a 4 mol/L aqueous sodium hydroxide solution. The organic phase is dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give (R)-N-(4- Methoxy-2-(methyl(1-methylpyrrol-3-yl)amino)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl) Amino)phenyl)acrylamide (Compound 52), brown solid (80 mg, yield 20.6%).

MS m/z: 512.2 [M + 1] ⁺ .

Example 53

N-(5-((4-(1-(1-cyclopropylethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethyl) Amino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Compound 53)

N-(5-((4-(1-(1-cyclopropylethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino )-4-methoxyphenyl)acryamide

First step: N ¹ -(4-(1-(1-cyclopropylethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino) Ethyl)-2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (53A)

N1-(4-(1-(1-cyclopropylethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N4-(2-(dimethylamino)ethyl)-2-methoxy-N4-methyl-5- Nitrobenzene-1,4-diamine

N ¹ -(4-(1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2-methoxy-N ⁴ - 5--5-nitrobenzene-1,4-diamine (34B) (0.065 g, 0.14 mmol) was dissolved in 10 mL dichloromethane, triphenylphosphine (0.074 g, 0.28 mmol) and 1-cyclopropyl Ethanol (0.012 g, 0.14 mmol), cooled to 0 ° C under nitrogen atmosphere, diisopropyl azodicarboxylate (ie DIAD) (56.6 mg, 0.28 mmol) was added dropwise and allowed to react to room temperature for 4 hours. The reaction solution was dried and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 20:1) to give compound N ¹ -(4-(1-(1-cyclopropyl) -1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5-nitro Benzo-1,4-diamine (53A), brown solid (0.03 g, yield 40.5%).

MS m/z: 530.1 [M + 1] +.

Second step: N ⁴ -(4-(1-(1-cyclopropylethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino) Ethyl)-5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (53B)

N ⁴ -(4-(1-(1-cyclopropylethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N1-(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methylbenzene- 1,2,4-triamine

N ¹ -(4-(1-(1-cyclopropylethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl 2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (53A) (0.85 g, 1.6 mmol) was dissolved in 30 mL of ethanol, and 10 mL of water and iron powder were added in sequence ( 0.538 g, 9.6 mmol) and ammonium chloride (60 mg, 1.1 mmol) were heated to 90 ° C and refluxed for 6 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound N ⁴ -(4-(1-(1-cyclopropyl) -1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methylbenzene-1, 2,4-Triamine (53B), brown solid (0.3 g, yield 37.5%).

MS m/z: 500.1 [M + 1] ⁺ .

The third step: N-(5-((4-(1-(1-cyclopropylethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Compound 53)

N-(5-((4-(1-(1-cyclopropylethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino )-4-methoxyphenyl)acrylamide

N ⁴ -(4-(1-(1-cyclopropylethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl -5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (53B) (0.3 g, 0.6 mmol) was dissolved in 10 mL of pyridine, and 1-(3-dimethylaminopropyl) was added. 3-Ethylcarbodiimide hydrochloride (0.344 g, 1.8 mmol) and acrylic acid (0.062 mL, 0.9 mmol) were reacted at room temperature for 4 hours. The reaction solution was dried to dryness, and then 150 mL of ethyl acetate and ethyl alcohol (dichloroacetic acid) (100 mL) was added, and the mixture was separated, and the aqueous phase was extracted with 100 mL of ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 20:1) to give compound N-(5-((4- (1-(1-Cyclopropylethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl) Amino)-4-methoxyphenyl)acrylamide (Compound 53), yellow solid (170 mg, yield 51.2%).

MS m/z: 554.2 [M + 1] ⁺ .

Compound 53 was resolved by high performance liquid phase to give two optical isomers: compound 53-1 (peak 1, t = 4.50 min), compound 53-2 (peak 2, t = 5.07 min). Resolution conditions: detection wavelength: 254 nM, column temperature: 30 ° C, mobile phase: acetonitrile and water (0.1% ammonia), acetonitrile / water = 81%: 19% isocratic elution.

Example 54

N-(2-(((1-aminocyclopropyl)methyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indole-3-) Pyrimido-2-yl)amino)phenyl)acrylamide (Compound 54)

N-(2-(((amino)methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino) Phenyl)acrylamide

First step: (1-((tert-Butoxycarbonyl)amino)cyclopropyl)methyl methanesulfonate (54B)

(1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl methanesulfonate

tert-Butyl (1-(hydroxymethyl)cyclopropyl)carbamate (54A) (5 g, 26.7 mmol) was dissolved in dichloromethane (30 mL) and triethylamine (5.4 g, 53.4 mmol) Methanesulfonyl chloride (3.36 g, 29.4 mmol) was added dropwise, and the reaction was carried out at low temperature for 2 hours, and the reaction was continued to room temperature for 6 hours. After completion of the reaction, 150 mL of water and 150 mL of dichloromethane were added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted once with 100 mL of dichloromethane, and the organic phases were combined and washed with 150 mL of brine. The mixture was washed with EtOAc (EtOAc m.).

MS m/z: 288.1 [M+23] ⁺ .

Step 2: (1-((Methylamino)methyl)cyclopropyl)carbamic acid tert-butyl ester (54C)

Tert-butyl(1-((methylamino)methyl)cyclopropyl)carbamate

(1-((tert-Butoxycarbonyl)amino)cyclopropyl)methyl methanesulfonate (54B) (3.5 g, 13.2 mmol) was dissolved in 50 mL of tetrahydrofuran and methylamine (615 mg, 19.8 mmol) was added, 50 The reaction was carried out at ° C for 6 hours. At the end of the reaction, the solvent was dried. 150 mL of water and 200 mL of ethyl acetate were added and the layers were separated. The organic phase was dried over anhydrous sodium sulfate (MgSO4jjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH .

MS m/z: 201.2 [M + 1] ⁺ .

The third step: (1-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-nitro) Phenyl)(methyl)amino)methyl)cyclopropyl)carbamic acid tert-butyl ester (54D)

Tert-butyl(1-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-nitrophenyl)(methyl)amino) Methyl)cyclopropyl)carbamate

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene (Intermediate 3) (1 g , 2.54 mmol) dissolved in 15 mL of N,N-dimethylacetamide, N,N-diisopropylethylamine (0.63 mL, 3.82 mmol) and tert-butyl (1-((methylamino))) Base propyl)carbamate (54C) (764 mg, 3.82 mmol) was reacted in a microwave at 140 ° C for 1 hour. After the reaction was completed, 100 mL of dichloromethane and 100 mL of water were added, and the aqueous phase was separated, and the aqueous phase was extracted once with 100 mL of dichloromethane. The organic phase was combined, washed twice with 200 mL of brine, dried over anhydrous sodium sulfate -(((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-nitrophenyl) (methyl Amino)methyl)cyclopropyl)carbamic acid tert-butyl ester (54D) (1.1 g, yield 91.6%).

MS m/z: 574.2 [M+1] ⁺ .

The fourth step: (1-(((2-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)benzene (m)(methyl)amino)methyl)cyclopropyl)carbamic acid tert-butyl ester (54E)

Tert-butyl(1-(((2-amino-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino )methyl)cyclopropyl)carbamate

(1-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-nitrophenyl) (Methyl)amino)methyl)cyclopropyl)carbamic acid tert-butyl ester (54D) (1.1 g, 1.92 mmol) was dissolved in 60 mL of ethanol, followed by 20 mL of water, iron powder (643 mg, 11.5 mmol) and chlorine Ammonium (72 mg, 1.34 mmol) was heated to 90 ° C and refluxed for 4 hours. The reaction solution was cooled to room temperature, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a brown solid compound (1-(((2-) Amino-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)benzene (Methyl)amino)methyl)cyclopropyl)carbamic acid tert-butyl ester (54E) (900 mg, yield 90%).

MS m/z: 544.2 [M + 1] ⁺ .

Step 5: (1-(((2-(1-(1-methyl-1-H-H-indol-3-yl)pyrimidin-2-yl)amino) Phenyl)(methyl)amino)methyl)cyclopropyl)carbamic acid tert-butyl ester (54F)

Tert-butyl(1-(((((((((((((((((((((((((((((( )methyl)cyclopropyl)carbamate

(1-(((2-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl) Methyl)amino)methyl)cyclopropyl)carbamic acid tert-butyl ester (54E) (900 mg, 1.66 mmol) was dissolved in 15 mL of pyridine and 1-(3-dimethylaminopropyl)-3-ethyl was added. The carbodiimide hydrochloride (EDCI) (955 mg, 5 mmol) and acrylic acid (0.17 mL, 2.48 mmol) were reacted at room temperature for 2 hours. The reaction solution was sparged, and 100 mL of water and 100 mL of dichloromethane were added and the mixture was separated. The organic phase was washed once with 100 mL of a 4 mol/L aqueous sodium hydroxide solution and dried over anhydrous sodium sulfate. Concentration to a yellow oil (1-(((2-(2-(1-)-l-l-l-l-indol-3-yl)pyrimidin-2-yl) Amino)phenyl)(methyl)amino)methyl)cyclopropyl)carbamic acid tert-butyl ester (54F) (600 mg, yield 60.5%).

MS m/z: 598.2 [M + 1] ⁺ .

Step 6: N-(2-(((1-aminocyclopropyl)methyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indole) Ind-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 54)

(1-(((2-(1-methyl-1-H-indol-3-yl)pyrimidin-2-yl)amino)phenyl) (Methyl)amino)methyl)cyclopropyl)carbamic acid tert-butyl ester (54F) (600 mg, 1 mmol) was dissolved in 20 mL of dichloromethane. The reaction solution was spoked, 100 mL of water was added, and the solution was adjusted to pH 8 with saturated sodium hydrogen carbonate, and 150 mL of dichloromethane was added and the mixture was separated. The aqueous phase was extracted once with 100 mL of dichloromethane, and the organic phase was combined, washed with 150 ml of brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (m. 0～10:1), obtained as a brown solid N-(2-((1-aminocyclopropyl)methyl)(methyl)amino)-4-methoxy-5-((4-(1- Methyl-1H-indol-3-ylpyrimidin-2-yl)amino)phenyl)acrylamide (Compound 54) (450 mg, yield 90.5%).

MS m/z: 498.1 [M + 1] ⁺ .

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.88 (s, 1H), 9.65 (s, 1H), 9.07 (s, 1H), 8.38 (d, 1H), 8.07 (d, 1H), 7.68 (s, 1H), 7.39 (d, 1H), 7.20 (d, 1H), 6.72 (s, 1H), 6.48 (dd, 2H), 5.70 (d, 1H), 3.99 (s, 3H), 3.88 (s, 3H) ), 2.80 (s, 3H), 2.73 (d, 2H), 1.55 (m, 4H).

Example 55

N-(5-((4-(1-(cyclopropylcarbonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)) (M)amino)-4-methoxyphenyl)acrylamide (Compound 55)

N-(5-((4-(1-(cyclopropanecarbonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide

First step: cyclopropyl (3-(2-((4-(2-methylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl) Amino)pyrimidin-4-yl)-1H-indol-1-yl)methanone (55A)

Cyclopropyl(3-(2-((4-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-indol-1-yl Methone

N ¹ -(4-(1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2-methoxy-N ⁴ - 5--5-nitrophenyl-1,4-diamine (34B) (1 g, 2.17 mmol) was dissolved in 20 mL of THF. N,N-diisopropylethylamine (0.42 g, 3.25 mmol). After cooling to 0 ° C, cyclopropanoyl chloride (0.3 mL, 3.25 mmol) was added dropwise, and the mixture was reacted at 0 ° C for 1 hour, and the reaction was continued to room temperature for 1 hour. After completion of the reaction, the reaction was quenched by the addition of 10 mL of water, and the mixture was evaporated to dryness. The aqueous phase was extracted once with 100 mL of dichloromethane. The combined organic phases were washed once with 100 mL of brine, dried over anhydrous sodium sulfate Amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-indol-1-yl)methanone (55A), brown solid (1 g, yield 87 %).

MS m/z = 530.1 [M + 1] ⁺ .

Second step: (3-(2-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidine- 4-yl)-1H-indol-1-yl)(cyclopropyl)methanone (55B)

(3-(-(5-amino-4-((2-aminoamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)py Rimidin-4-yl)-1H-indol-1-yl)(cyclopropyl)methanone

Cyclopropyl (3-(2-((4-((2-methylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine 4-yl)-1H-indol-1-yl)methanone (55A) (1 g, 1.89 mmol) was dissolved in 30 mL of ethanol, followed by 10 mL of water, iron powder (0.633 g, 11.3 mmol) and chlorinated Ammonium (71 mg, 1.32 mmol) was heated to 90 ° C and refluxed for 6 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give compound (3-(2-(5-amino-4-(( 2-(Dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1H-indol-1-yl)(cyclopropyl)methyl Ketone (55B), brown solid (0.5 g, yield 53%).

The third step: N-(5-((4-(1-(cyclopropylcarbonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethyl) (amino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (compound 55)

(3-(2-((5-amino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl -1H-indol-1-yl)(cyclopropyl)methanone (55B) (0.5 g, 1 mmol) dissolved in 10 mL of pyridine and added 1-(3-dimethylaminopropyl)-3-ethyl The carbodiimide hydrochloride (0.573 g, 3 mmol) was added with acrylic acid (0.103 mL, 1.5 mmol) and allowed to react at room temperature for 3 hours. The reaction solution was sparged, and 150 mL of ethyl acetate and 100 mL of a 4 mol/L aqueous sodium hydroxide solution were added, and the mixture was separated, and the aqueous phase was extracted once with 100 mL of ethyl acetate. The organic phase is combined, washed with 150 mL of a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to obtain N -(5-((4-(1-(cyclopropylcarbonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl) (Methyl)amino)-4-methoxyphenyl)acrylamide (Compound 55), pale yellow solid (60 mg, yield 11.3%).

MS m/z: 554.4 [M+1] ⁺ .

Example 56

N-(3-((5-chloro-4-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-1-methyl-1H-indol-3-yl)pyrimidine- 2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 56)

N-(3-((5-chloro-4-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino )-4-methoxyphenyl)acrylamide

First step: N-(3-((5-chloro-4-(1-methyl-6-(piperazin-1-yl)-1H-indol-3-yl)pyrimidin-2-yl)amino )-4-methoxyphenyl)acrylamide (56A)

N-(3-((5-chloro-4-(1-methyl-6-(piperazin-1-yl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

4-(3-(2-((5-Acrylamide-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl) Piperazine-1-carboxylic acid tert-butyl ester (Compound 26) (0.40 g, 0.65 mmol) was placed in a 50 mL round bottom flask. Dichloromethane (10 mL) and trifluoroacetic acid (5 mL) were sequentially added to the reaction mixture at 0 °C. The reaction was stirred at room temperature for 2 hours. Dichloromethane (50 mL), EtOAc (EtOAc (EtOAc. Yellow oily N-(3-((5-chloro-4-(1-methyl-6-(piperazin-1-yl)-1H-indol-3-yl)pyrimidin-2-yl)amino)- 4-methoxyphenyl)acrylamide (56A) (0.335 g).

Second step: N-(3-((5-chloro-4-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-1-methyl-1H-indole-3- Pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 56)

N-(3-((5-Chloro-4-(1-methyl-6-(piperazin-1-yl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4 -Methoxyphenyl)acrylamide (56A) (0.16 g, 0.31 mmol) was dissolved in 40 mL of acetonitrile, potassium carbonate (86 mg, 0.62 mmol), bromoethanol (58.1 mg, 0.47 mmol), and reacted at 60 ° C for 3 hours. . After completion of the reaction, the solvent was evaporated to dryness. EtOAc (EtOAc) The residue was concentrated and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to afford yellow solid N-(3-((5-chloro-4-(6) -(4-(2-hydroxyethyl)piperazin-1-yl)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl) Acrylamide (Compound 56) (150 mg, yield 86.2%).

LC-MS m / z: 562.3 [M + 1] +.

Example 57

N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl) (Methyl)amino)-4-methoxyphenyl)acrylamide (Compound 57)

N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino )-4-methoxyphenyl)acrylamide

First step: 3-(2-chloropyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine (57B)

3-(2-chloropyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine

7-Azaindole (57A) (6 g, 50.8 mmol) was dissolved in 100 mL of THF, cooled to 0 ° C under nitrogen, and methyl magnesium bromide (17 mL, 50.8 mmol) was added dropwise and stirring was continued for 0.5 hour. 2,4-Dichloropyrimidine (7.6 g, 50.8 mmol) was added, and the mixture was reacted at room temperature for 1 hour, and the temperature was raised to 60 ° C to continue the reaction for 2 hours. 30 mL of methanol and 20 mL of acetic acid were added to the reaction solution, the solvent was evaporated, washed with water (200 mL), washed with 10 mL of THF, and dried to give a yellow solid 3-(2-chloropyrimidin-4-yl)-1H-pyrrole[2,3- b] Pyridine (57B) (10 g, yield 86.2%).

LC-MS (m / z) : 231.0 [M + 1] +.

Second step: N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine (57C)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine

3-(2-Chloropyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine (57B) (2 g, 8.7 mmol) was dissolved in 20 mL of 2-pentanol and 4-fluoro-2 was added. Methoxy-5-nitroaniline (4e) (1.62 g, 8.7 mmol) and p-toluenesulfonic acid monohydrate (2 g, 10.4 mmol) were heated to 120 ° C to reflux for 18 hours. The reaction solution was cooled to room temperature, 50 mL of aqueous ammonia was added, filtered, and the filter cake was washed with 100 mL of water. Drying to a yellow solid N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2- Amine (57C) (2.3 g, yield 69.7%).

LC-MS (m / z) : 381.0 [M + 1] +.

Third step: N ¹ -(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl) -2-methoxy-N ⁴ -methyl-5-nitrobenzo-1,4-diamine (57D)

N ¹ -(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl -5-nitrobenzene-1,4-diamine

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine (57C) (2.5 g, 6.58 mmol) was dissolved in 15 mL of N,N-dimethylacetamide, and N,N-diisopropylethylamine (1.02 g, 7.9 mmol), and N,N,N'- Ethylenediamine (18A) (807 mg, 7.89 mmol) was reacted in a microwave at 120 ° C for 1.5 hours. At the end of the reaction, the solvent was dried. Purification by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 10:1) to give a reddish brown solid N ¹ -(4-(1H-pyrrolo[2,3-b] Pyridin-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5-nitrobenzo-1 4-Diamine (57D) (1 g, yield 33.3%).

LC-MS (m / z) : 463.1 [M + 1] +.

Fourth step: N ⁴ -(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl) -5-methoxy-N ¹ -methylbenzo-1,2,4-triamine (57E)

N ⁴ -(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methylbenzene -1,2,4-triamine

N ¹ -(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2- Methoxy-N ⁴ -methyl-5-nitrobenzo-1,4-diamine (57D) (1 g, 2.11 mmol) was dissolved in 30 mL of ethanol, followed by 10 mL of water and iron powder (362 mg, 6.44 mmol). And ammonium chloride (81 mg, 1.5 mmol), and the mixture was heated to 90 ° C and refluxed for 6 hours. The reaction solution was cooled to room temperature, filtered and concentrated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a brown solid N ⁴ -(4-(1H-pyrrolo[2,3-b]pyridine 3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methylbenzo-1,2,4-triamine (57E) (933 mg).

LC-MS (m / z) : 433.1 [M + 1] +.

Step 5: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethyl) Amino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Compound 57)

N ⁴ -(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5- Methoxy-N ¹ -methylbenzo-1,2,4-triamine (57E) (500 mg, 1.16 mmol) was dissolved in 15 mL of pyridine and 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride (665 mg, 3.48 mmol), acrylic acid (0.12 mL, 1.74 mmol) was reacted at room temperature for 6 hours. The pyridine was spun dry, and 100 mL of water and 100 mL of dichloromethane were added and the mixture was separated. The organic phase was washed with a 4 mol/L aqueous sodium hydroxide solution (100 mL) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 10:1) to give white solid N-(5-((4-(1H-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide ( Compound 57) (330 mg, yield 58.5%).

LC-MS (m / z) : 487.1 [M + 1] +.

1H NMR (400MHz, DMSO-d ₆ ) δ 10.07 (s, 1H), 9.03 (s, 1H), 8.88 (s, 1H), 8.37 - 8.32 (m, 1H), 8.31 (d, 1H), 8.01 (dd, 1.7 Hz, 1H), 7.18 (dd, 4.7 Hz, 1H), 7.01 (s, 1H), 6.76 (s, 1H), 6.64 (d, 1H), 6.43 (dd, 10.1 Hz, 1H), 6.25 (dd, 1.9 Hz, 1H), 5.80–5.71 (m, 1H), 3.87 (d, 3H), 2.88 (t, 2H), 2.75–2.67 (m, 3H), 2.32 (t, 2H), 2.19 (d, 6H).

Example 58

N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 58)

N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

First step: N-(2-methoxy-5-nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine (58A)

N-(2-methoxy-5-nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine

3-(2-Chloropyrimidin-4-yl)-1H-pyrrole[2,3-b]pyridine (57B) (2 g, 8.7 mmol) was dissolved in 2-pentanol (30 mL). Oxy-5-nitroaniline (1.46 g, 8.7 mmol) and p-toluenesulfonic acid (2 g, 10.44 mmol) were heated to 120 ° C to reflux for 18 hours. The reaction solution was cooled to room temperature, 50 mL of aqueous ammonia was added, filtered, and the filter cake was washed with 100 mL of water and dried to give a yellow solid N-(2-methoxy-5-nitrophenyl)-4-(1H-pyrrole[ 2,3-b]pyridin-3-yl)pyrimidin-2-amine (58A) (2.5 g, yield 80.6%).

LC-MS (m / z) : 363.1 [M + 1] +.

Second step: N ¹ -(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-6-methoxybenzo-1,3-triamine ( 58B)

N ¹ -(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-6-methoxybenzene-1,3-diamine

N-(2-Methoxy-5-nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine (58A) (0.5 g, 1.38 mmol) was dissolved in 100 mL of methanol, and palladium on carbon (0.15 g, 30%) was added thereto, and the mixture was replaced with three times in a hydrogen atmosphere at room temperature for 8 hours. End of the reaction, the reaction mixture was filtered through celite, washed with dichloromethane (50mL) and methanol (50mL), and concentrated to give a reddish brown solid N ¹ - (4- (1H- pyrrolo [2,3-b] pyridine 3-yl)pyrimidin-2-yl)-6-methoxybenzo-1,3-triamine (58B) (0.458 g).

Third step: N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 58)

N ¹ -(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-6-methoxybenzo-1,3-triamine (58B) ( 0.458 mg, 1.38 mmol) was dissolved in 15 mL of pyridine, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (527 mg, 2.76 mmol) and acrylic acid (0.14 mL, 2.07 mmol). ), react at room temperature for 6 hours. The pyridine was spun dry, and 100 mL of water and 100 mL of dichloromethane were added and the mixture was separated. The organic phase was washed with a 4 mol/L aqueous sodium hydroxide solution (100 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 10:1) , white solid N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 58) (230 mg, yield 43.2%).

LC-MS (m / z) : 387.0 [M + 1] +.

^{1 H NMR (400MHz, DMSO-} d 6) δ9.96 (s, 1H), 9.11 (s, 1H), 8.62 (s, 1H), 8.38-8.32 (m, 1H), 8.27 (d, 1H), 8.02 (dd, 1H), 7.34 (dd, 1H), 7.19 (dd, 1H), 7.06 (d, 1H), 6.84 (d, 1H), 6.67 (d, 1H), 6.46 (dd, 1H), 6.26 (dd, 1H), 5.75 (dd, 1H), 3.85 (s, 3H).

Example 59

N-(4-Methoxy-3-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)propene Amide (compound 59)

N-(4-methoxy-3-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

First step: N-(2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2- Amine (59A)

N-(2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine

N-(2-Methoxy-5-nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine (58A) (0.4 g, 1.1 mmol) was dissolved in 20 mL of tetrahydrofuran, cooled to 0 ° C, sodium hydride (0.053 g, 2.2 mmol) was added and the mixture was reacted for 30 minutes, and iodomethane (0.2 mL, 3.3 mmol) was added and allowed to react at room temperature for 4 hours. After completion of the reaction, 60 mL of water was added to precipitate a solid, which was washed with 100 mL of water and 50 mL of petroleum ether and dried to give a yellow solid N-(2-methoxy-5-nitrophenyl)-4-(1-methyl -1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine (59A) (0.413 g).

Second step: N ¹ -(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-6-methoxybenzo-1,3-diamine ( 59B)

N-(2-Methoxy-5-nitrophenyl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine (59A (0.5 g, 1.33 mmol) was dissolved in 50 mL of methanol, palladium carbon (0.15 g, 30%) was added, and the mixture was replaced with three times in a hydrogen atmosphere, and reacted at room temperature for 1 day. The reaction was complete, the reaction mixture was filtered through celite, washed with dichloromethane (100mL) and methanol (100 mL), and concentrated to give a yellow solid N ¹ - (4- (1H- pyrrolo [2,3-b] pyridin-3 Pyrimidin-2-yl)-6-methoxybenzo-1,3-diamine (59B) (0.46 g).

LC-MS (m / z) : 347.1 [M + 1] +.

Third step: N-(4-methoxy-3-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino) Phenyl)acrylamide (compound 59)

N ¹ -(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-6-methoxybenzo-1,3-diamine (59B) ( 0.46 mg, 1.33 mmol) was dissolved in 15 mL of pyridine, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (762 mg, 4 mmol) and acrylic acid (0.14 mL, 2 mmol). The reaction was carried out for 6 days at room temperature. The pyridine was spun dry, and 100 mL of water and 100 mL of dichloromethane were added and the mixture was separated. The organic phase was washed with a 4 mol/L aqueous sodium hydroxide solution (100 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 10:1) , obtained as a brown solid N-(4-methoxy-3-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino) Phenyl) acrylamide (Compound 59) (400 mg, yield 75.2%).

LC-MS (m / z) : 401.1 [M + 1] +.

Example 60

N-(5-((4-(1-(Difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(4) -methylpiperazin-1-yl)ethoxy)phenyl)acrylamide (Compound 60)

N-(5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(4-methylpiperazin-1-yl) Ethoxy)phenyl)acrylamide

First step: 4-(1-(difluoromethyl)-1H-indol-3-yl)-N-(2-methoxy-4-(2-(4-methylpiperazin-1-) Ethyloxy)-5-nitrophenyl)pyrimidine-2-amine (60A)

4-(1-(difluoromethyl)-1H-indol-3-yl)-N-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)-5-nitrophenyl)pyrimidin-2- Amine

4-(1-(Difluoromethyl)-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine (30B (1 g, 2.33 mmol) was dissolved in 30 mL of tetrahydrofuran, sodium hydride (112 mg, 4.46 mmol) was slowly added, stirred for 30 min, and 2-(4-methylpiperazin-1-yl)ethanol (672 mg, 4.66 mmol) was added. The reaction was carried out at room temperature for 4 hours. At the end of the reaction, 150 mL of water and 150 mL of dichloromethane were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and evaporated tolulululululululululululululululu 4-Methylpiperazin-1-yl)ethoxy)-5-nitrophenyl)pyrimidine-2-amine (60A) (1.2 g, yield 93.0%).

LC-MS (m / z) = 554.3 [M + 1] +.

Second step: N ¹ -(4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-(4- Methyl piperazin-1-yl)ethoxy)benzo-1,3-diamine (60B)

N ¹ -(4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzene- 1,3-diamine

4-(1-(Difluoromethyl)-1H-indol-3-yl)-N-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)) Oxy)-5-nitrophenyl)pyrimidine-2-amine (60A) (1.2 g, 2.17 mmol) was dissolved in 30 mL of ethanol, 10 mL of water, iron powder (727 mg, 13 mmol) and ammonium chloride (81.3 mg) 1.52 mmol), the temperature was raised to 90 ° C and refluxed for 4 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a brown solid N ¹ -(4-(1-difluoromethyl) -1H-indol-3-ylpyrimidin-2-yl)-6-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzo-1,3 - Diamine (60B) (740 mg, yield 65.5%).

The third step: N-(5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-( 2-(4-Methylpiperazin-1-yl)ethoxy)phenyl)acrylamide (Compound 60)

N ¹ -(4-(1-(Difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-(4-methylpiperidine) Pyrazin-1-yl)ethoxy)benzo-1,3-diamine (60B) (740 mg, 1.4 mmol) was dissolved in 20 mL of pyridine and 1-(3-dimethylaminopropyl)-3-ethyl was added. The carbodiimide hydrochloride (802 mg, 4.2 mmol), acrylic acid (0.146 mL, 2.1 mmol) was reacted at room temperature for 4 hours. The pyridine in the reaction solution was spun dry, and 150 mL of water and 150 mL of dichloromethane were added and the mixture was separated. The organic phase was washed with a 4 mol/L aqueous sodium hydroxide solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane: methanol (v/v) = 1:0 to 10:1 , a white solid N-(5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2- (2-(4-Methylpiperazin-1-yl)ethoxy)phenyl)acrylamide (Compound 60) (200 mg, yield 24.8%).

LC-MS (m / z) = 578.3 [M + 1] +.

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.68 (s, 1H), 9.34 (s, 1H), 8.59 (s, 1H), 8.44 (d, 1H), 8.04 (dd, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 7.35 (dd, 2H), 7.22 (d, 1H), 6.62 (s, 1H), 6.43 (m, 2H), 5.79 (d, 1H), 4.19 (t, 2H) ), 3.90 (s, 3H), 2.80 - 2.74 (m, 2H), 2.69 (s, 4H), 2.62 (s, 4H), 2.38 (s, 3H).

Example 61

N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(7-methyl-1H-indole-3-) Pyrimido-2-yl)amino)phenyl)acrylamide (compound 61)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(7-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino Phenyl)acrylamide

First step: 3-(2-chloropyrimidin-4-yl)-7-methyl-1H-indole (61B)

3-(2-chloropyrimidin-4-yl)-7-methyl-1H-indole

7-Methyl hydrazine (61A) (10g, 76.2mmol) was dissolved in 100mL of 1,2-dichloroethane, protected with nitrogen, cooled to 0 ° C, added methyl magnesium bromide (25.4mL, 76.2mmol) ), stirring was continued for 0.5 hours. 2,4-Dichloropyrimidine (11.4 g, 76.2 mmol) was added, and the reaction was carried out for 40 minutes at room temperature, and the reaction was carried out at 60 ° C for 8 hours. Add 20 mL of methanol and 20 mL of acetic acid, react for 20 minutes, spin dry the solvent, precipitate a solid, wash the solid with 200 mL of water and 50 mL of petroleum ether. The filter cake is dried with an infrared lamp to obtain a yellow solid 3-(2-chloropyrimidin-4-yl) 7-Methyl-1H-indole (61B) (12 g, yield 64.9%).

LC-MS (m / z) : 244.0 [M + 1] +.

Second step: N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(7-methyl-1H-indol-3-yl)pyrimidin-2-amine (61C)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(7-methyl-1H-indol-3-yl)pyrimidin-2-amine

3-(2-Chloropyrimidin-4-yl)-7-methyl-1H-indole (61B) (4.2 g, 17.28 mmol) was dissolved in 80 mL of 2-pentanol, and 4-fluoro-2-methyl was added. Oxy-5-nitroaniline (4e) (3.2 g, 17.28 mmol) and p-toluenesulfonic acid monohydrate (3.98 g, 20.7 mmol) were heated to reflux at 120 ° C for 3 days. After cooling to room temperature, 200 mL of aqueous ammonia was added to precipitate a solid, which was filtered and washed with 200 mL of water and 100 mL of petroleum ether. Drying dark green solid N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(7-methyl-1H-indol-3-yl)pyrimidin-2-amine ( 61C) (4.5 g, yield 66.3%).

LC-MS (m / z) : 394.1 [M + 1] +.

^{1 H NMR (400MHz, DMSO-} d 6) δ11.85 (s, 1H), 9.15 (d, 1H), 8.39 (d, 1H), 8.36 (d, 1H), 8.23 (s, 1H), 8.19 ( d, 1H), 7.41 (d, 1H), 7.38 - 7.32 (m, 1H), 7.04 - 6.96 (m, 2H), 4.07 - 4.00 (m, 3H), 3.31 (s, 3H), 2.50 (d, 6H).

Third step: N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(7-methyl-1H-indole-3) -yl)pyrimidin-2-yl)-2-nitrobenzo-1,4-diamine (61D)

N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(7-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene -1,4-diamine

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(7-methyl-1H-indol-3-yl)pyrimidin-2-amine (61C) (2.5 g , 6.35 mmol) dissolved in N,N-dimethylacetamide (10 mL), N,N-diisopropylethylamine (986 mg, 7.63 mmol) and N,N,N'-trimethylethylene The amine (18A) (780 mg, 7.63 mmol) was reacted in a microwave at 120 ° C for 1.5 hours. The reaction was completed, concentrated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 10:1) to give a brown solid N ¹ -(2-(dimethylamino)ethyl) -5-methoxy-N ¹ -methyl-N ⁴ -(4-(7-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzo-1 4-Diamine (61D) (2.1 g, yield 70%).

LC-MS (m / z) : 476.3 [M + 1] +.

Fourth step: N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(7-methyl-1H-indole-3) -yl)pyrimidin-2-yl)benzo-1,2,4-triamine (61E)

N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(7-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene, 2,4-triamine

N ¹ -(2-(Dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(7-methyl-1H-indol-3-yl) Pyrimidin-2-yl)-2-nitrobenzo-1,4-diamine (61D) (1.3 g, 2.74 mmol) was dissolved in 30 mL of ethanol, 10 mL of water, iron powder (0.918 g, 16.4 mmol) and Ammonium chloride (102.7 mg, 1.92 mmol) was heated to 90 ° C for 4 hours under reflux. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane / methanol (v/v) = 1:0 to 10:1) to give a brown solid N ¹ -(2-(dimethylamino)ethyl) -5-methoxy-N ¹ -methyl-N ⁴ -(4-(7-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzo-1,2,4-tri Amine (61E) (0.8 g, yield 66.7%).

LC-MS (m / z) : 446.1 [M + 1] +.

Step 5: N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(7-methyl-1H-indole) Ind-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 61)

N ¹ -(2-(Dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(7-methyl-1H-indol-3-yl) Pyrimidin-2-yl)benzo-1,2,4-triamine (61E) (0.8 g, 1. mmol) was dissolved in 15 mL of pyridine, followed by 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride (1.03 g, 5.4 mmol) and acrylic acid (0.19 mL, 2.7 mmol) were reacted at room temperature for 4 hours. The pyridine was sparged, 150 mL of dichloromethane and 4 mol/L aqueous sodium hydroxide solution (100 mL) were added, and the mixture was separated, and the aqueous phase was extracted once with 150 mL of dichloromethane. The organic phase was combined and washed with 200 mL of saturated sodium chloride. Drying, purification by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 10:1) to give a yellow solid N-(2-((2-(dimethylamino)ethyl)) (Methyl)amino)-4-methoxy-5-((4-(7-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 61 (400 mg, yield 44.5%).

LC-MS (m / z) : 500.2 [M + 1] +.

¹ H NMR (400 MHz, CDCl 3 ) δ 10.21 (s, 1H), 9.81 (s, 1H), 9.25 (s, 1H), 8.89 (s, 1H), 8.37 (d, 1H), 7.95 (d, 1H) ), 7.69 (s, 1H), 7.16 (d, 1H), 7.14 - 7.08 (m, 1H), 6.80 (s, 1H), 6.51 (dd, 1.4 Hz, 1H), 6.37 (s, 1H), 5.69 (d, 1H), 3.88 (d, 3H), 2.91 (s, 2H), 2.84 (s, 2H), 2.71 (s, 3H), 2.49 (s, 3H), 2.26 (s, 6H), 1.73 ( s, 2H).

Example 62

N-(5-((4-(1,7-Dimethyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl) (Methyl)amino)-4-methoxyphenyl)acrylamide (Compound 62)

N-(5-((4-(1,7-dimethyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl)acrylamide

First step: 3-(2-chloropyrimidin-4-yl)-1,7-dimethyl-1H-indole (62A)

3-(2-chloropyrimidin-4-yl)-1,7-dimethyl-1H-indole

3-(2-Chloropyrimidin-4-yl)-7-methyl-1H-indole (61B) (10 g, 41.1 mmol) was dissolved in 100 mL of tetrahydrofuran, cooled to 0 ° C, sodium hydride (3.3 g, 82.2 mmol), reacted at 0 ° C for 30 minutes, added methyl iodide (17.5 g, 123.4 mmol), and allowed to react at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated, and the solid was washed with 200 mL of water and 50 mL of petroleum ether and dried to give 3-(2-chloropyrimidin-4-yl)-1,7-dimethyl-1H-indole (62A). (10 g, yield 95.2%).

Second step: 4-(1,7-dimethyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine (62B)

4-(1,7-dimethyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine

3-(2-Chloropyrimidin-4-yl)-1,7-dimethyl-1H-indole (62A) (5 g, 19.4 mmol) was dissolved in 100 mL of 2-pentanol, 4-fluoro-2- Methoxy-5-nitroaniline (4e) (3.62 g, 19.4 mmol) and p-toluenesulfonic acid monohydrate (4.47 g, 23.3 mmol) were heated to reflux at 120 ° C for 3 days. After cooling to room temperature, 200 mL of ammonia water was added to precipitate a solid, which was filtered, and the filter cake was washed successively with 200 mL of water and 100 mL of petroleum ether, and dried to give a yellow solid 4-(1,7-dimethyl-1H-indol-3-yl) -N-(4-Fluoro-2-methoxy-5-nitrophenyl)pyrimidine-2-amine (62B) (6 g, yield 75.9%).

LC-MS (m / z) : 408.0 [M + 1] +.

^{1 H NMR (400MHz, DMSO-} d 6) δ9.11 (d, 1H), 8.38 (d, 1H), 8.24 (d, 3H), 7.34 (d, 1H), 7.27 (d, 1H), 7.01- 6.92 (m, 2H), 4.14 (s, 3H), 4.02 (s, 3H), 2.76 (s, 3H).

Third step: N ¹ -(4-(1,7-dimethyl-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl) -2-methoxy-N ⁴ -methyl-5-nitrobenzo-1,4-amine (62C)

N ¹ -(4-(1,7-dimethyl-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5 -nitrobenzene-1,4-diamine

4-(1,7-Dimethyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine (62B) (3g, 7.37mmol) was dissolved in 10mL of N,N-dimethylacetamide, N,N-diisopropylethylamine (1.14g, 8.84mmol) and N,N,N'-trimethylethyl The diamine (18A) (904 mg, 8.84 mmol) was reacted in a microwave at 120 ° C for 1.5 hours. At the end of the reaction, 150 mL of water and 150 mL of dichloromethane were added and the mixture was separated. The aqueous phase was extracted with 150 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and concentrated to give a brown solid N ¹ - (4- (1,7- dimethyl--1H- indol-3-yl) pyrimidin-2-yl) -N ⁴ - (2- (Dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5-nitrobenzo-1,4-amine (62C) (3.6 g).

LC-MS (m / z) : 490.2 [M + 1] +.

Fourth step: N ⁴ -(4-(1,7-dimethyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl) -5-methoxy-N ¹ -methylbenzo-1,2,4-triamine (62D)

N ⁴ -(4-(1,7-dimethyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methylbenzene-1 ,2,4-triamine

N ¹ -(4-(1,7-Dimethyl-1H-indol-3-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)-2- Methoxy-N ⁴ -methyl-5-nitrobenzo-1,4-amine (62C) (3.6 g, 7.36 mmol) was dissolved in 30 mL of ethanol, and 10 mL of water and iron powder (2.46 g, 44.1) were added. Methyl acetate (273 mg, 5.1 mmol) was heated to 90 ° C for 4 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 10:1) to give a yellow solid N ⁴ -(4-(1,7-dimethyl-) 1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methylbenzo-1,2, 4-Triamine (62D) (2.3 mg, yield 69.7%).

LC-MS (m / z) : 460.1 [M + 1] +.

Step 5: N-(5-((4-(1,7-Dimethyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethyl) Amino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (compound 62)

N ⁴ -(4-(1,7-Dimethyl-1H-indol-3-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5- Methoxy-N ¹ -methylbenzo-1,2,4-triamine (62D) (1.66 g, 3.62 mmol) was dissolved in 30 mL of pyridine, followed by 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (2.07 g, 10.85 mmol) and acrylic acid (0.38 mL, 5.43 mmol) were reacted at room temperature for 6 hours. The pyridine was spin-dried, and 4 mol/L aqueous sodium hydroxide solution (200 mL) and 200 mL of dichloromethane were added, and the mixture was separated. The organic phase was washed once with 100 mL of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 10:1) to give a brown solid N- (5-((4-(1,7-Dimethyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)) Methyl)amino)-4-methoxyphenyl)acrylamide (Compound 62) (1 g, yield 53.8%).

LC-MS (m / z) : 514.2 [M + 1] +.

Example 63

N-(4-Methoxy-3-((4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 63 )

N-(4-methoxy-3-((4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

First step: 1-(2-chloropyrimidin-4-yl)-2-methyl-1H-benzo[d]imidazole (63B)

1-(2-chloropyrimidin-4-yl)-2-methyl-1H-benzo[d]imidazole

2-Methylbenzimidazole (63A) (6.6 g, 50 mmol) was dissolved in 100 mL of N,N-dimethylformamide, cooled to 0 ° C under nitrogen and sodium hydride (2.4 g, 60 mmol). Stirring was continued for 0.5 hours, 2,4-dichloropyrimidine (7.5 g, 50 mmol) was added, and the mixture was reacted at room temperature for 10 hours. After adding 250 mL of water, the solid was precipitated, filtered, and the filter cake was washed with 200 mL of water and 100 mL of petroleum ether to give a white solid 1-(2-chloropyrimidin-4-yl)-2-methyl-1H-benzo[d] Imidazole (63B) (23 g).

LC-MS (m / z) : 245.0 [M + 1] +.

^{1 H NMR (400MHz, CDCl3)} δ8.69 (d, 1H), 8.36-8.27 (m, 1H), 7.76-7.68 (m, 1H), 7.36-7.31 (m, 2H), 7.26 (s, 1H) , 2.99 (s, 3H).

Second step: N-(2-methoxy-5-nitrophenyl)-4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine (63C)

N-(2-methoxy-5-nitrophenyl)-4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine

1-(2-Chloropyrimidin-4-yl)-2-methyl-1H-benzo[d]imidazole (63B) (2.44 g, 10 mmol) was dissolved in 30 mL of 2-pentanol, 2-methoxy 5-Nitroaniline (1.68 g, 10 mmol) and p-toluenesulfonic acid (1.92 g, 10 mmol) were heated to 120 ° C for reflux for 3 days. After cooling to room temperature, 100 mL of ammonia water was added to precipitate a solid, which was filtered, and the filter cake was washed with 250 mL of water and 100 mL of petroleum ether to give a yellow solid N-(2-methoxy-5-nitrophenyl)-4-(2) Methyl-1H-benzo[d]imidazol-1-ylpyrimidin-2-amine (63C) (2.7 g, yield 71.8%).

LC-MS (m / z) : 377.0 [M + 1] +.

The third step: N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(2-methyl-1H-benzo[d] Imidazol-1-yl)pyrimidin-2-yl)-2-nitrobenzo-1,4-diamine (63D)

N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl) -2-nitrobenzene-1,4-diamine

N-(2-Methoxy-5-nitrophenyl)-4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine (63C) (1 g, 2.6 mmol) was dissolved in 20 mL of methanol, and palladium carbon (0.334 g, 30%) was added thereto, and the mixture was replaced with three times in a hydrogen atmosphere, and reacted at room temperature for 3 hours. The reaction was completed, the Celite was filtered and washed with 50 mL methanol. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1: 0 ~ 50: 1), to give a yellow solid N ¹ - (2- (dimethylamino) ethyl) - 5-methoxy-N ¹ -methyl-N ⁴ -(4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)-2-nitrobenzo -1,4-Diamine (63D) (0.6 g, yield 65.9%).

LC-MS (m / z) : 347.1 [M + 1] +.

Fourth step: N-(4-methoxy-3-((4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino)phenyl)propene Amide (compound 63)

N ¹ -(2-(Dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(2-methyl-1H-benzo[d]imidazole- 1-yl)pyrimidin-2-yl)-2-nitrobenzo-1,4-diamine (63D) (0.6 g, 1.73 mmol) was dissolved in 15 mL of pyridine, followed by the addition of 1-(3-dimethylamino) Propyl)-3-ethylcarbodiimide hydrochloride (0.993 g, 5.2 mmol) and acrylic acid (0.18 mL, 2.6 mmol). The pyridine was spin-dried, 100 mL of ethyl acetate and 100 mL of a 4 mol/L aqueous sodium hydroxide solution were added, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane/methanol (v/) v) = 1:0 to 50:1) to give a white solid N-(4-methoxy-3-((4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidine) 2-yl)amino)phenyl)acrylamide (Compound 63) (150 mg, yield 21.7%).

LC-MS (m / z) : 401.1 [M + 1] +.

^{1 H NMR (400MHz, CDCl3)} δ8.39 (d, 1H), 8.33 (s, 1H), 8.18-8.14 (m, 1H), 7.72 (dd, 1H), 7.66-7.59 (m, 1H), 7.51 (d, 1H), 7.40 (d, 1H), 6.94 - 6.89 (m, 1H), 6.73 - 6.66 (m, 1H), 6.40 - 6.32 (m, 1H), 6.15 (dd, 1H), 5.71 (d , 1H), 3.92 (s, 3H), 2.92 (d, 3H).

Example 64

N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-methyl-1H-benzo[d]] Imidazol-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 64)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2 -yl)amino)phenyl)acrylamide

First step: N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2- Amine (64A)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine

1-(2-Chloropyrimidin-4-yl)-2-methyl-1H-benzo[d]imidazole (63B) (0.244 g, 1 mmol) was dissolved in 30 mL of 2-pentanol and 4-fluoro- 2-Methoxy-5-nitroaniline (4e) (0.186 g, 1 mmol) and p-toluenesulfonic acid monohydrate (0.192 g, 1 mmol) were heated to reflux at 120 ° C for 1 day. The reaction solution was cooled to room temperature, 200 mL of aqueous ammonia was added, and the solid was separated, filtered, and the filter cake was washed with 250 mL of water and 100 mL of petroleum ether. Drying to a brown solid N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidine-2 -Amine (64A) (3.7 g, yield 93.9%).

LC-MS (m / z) : 395.1 [M + 1] +.

Second step: N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(2-methyl-1H-benzo[d] Imidazol-1-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine (64B)

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine (64A (2g, 5mmol) was dissolved in N,N-dimethylacetamide (12mL), N,N-diisopropylethylamine (0.775g, 6mmol) and N,N,N'-trimethyl Ethylenediamine (18A) (613 mg, 6 mmol) was reacted in a microwave at 120 ° C for 2 hours. After the reaction was completed, the reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 20:1) to give red-brown solid N1-(2-(dimethylamino) Ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)-2- Nitrobenzene-1,4-diamine (64B) (0.87 g, yield 39.5%).

The third step: N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(2-methyl-1H-benzo[d] Imidazol-1-yl)pyrimidin-2-yl)benzene-1,2,4-triamine (64C)

N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl) Benzene-1,2,4-triamine

N ¹ -(2-(Dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(2-methyl-1H-benzo[d]imidazole- 1-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine (64B) (0.87 g, 1.95 mmol) was dissolved in 30 mL of ethanol, followed by 10 mL of water and iron powder (0.653 g, 11.7 mmol) and ammonium chloride (73 mg, 1.37 mmol) were heated to 90 ° C for reflux for 4 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 20:1) to give a brown solid N ¹ -(2-(dimethylamino)ethyl) -5-methoxy-N ¹ -methyl-N ⁴ -(4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)benzene-1,2, 4-triamine (64C) (0.6 g, yield 73.6%).

Fourth step: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-methyl-1H-benzene) And [d]imidazol-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 64)

N ¹ -(2-(Dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(2-methyl-1H-benzo[d]imidazole- 1-yl)pyrimidin-2-yl)benzo-1,2,4-triamine (64C) (0.6 g, 1.34 mmol) was dissolved in 20 mL of pyridine, followed by 1-(3-dimethylaminopropyl) 3-Ethylcarbodiimide hydrochloride (0.764 g, 4 mmol) and acrylic acid (0.14 mL, 2 mmol) were reacted at room temperature for 3 hours. The pyridine was removed by spin-drying, and 150 mL of ethyl acetate and 4 mol/L aqueous sodium hydroxide solution (100 mL) were added, and the mixture was separated, and the aqueous phase was extracted with 100 mL of ethyl acetate. The organic phase was combined and washed with 150 mL of saturated sodium chloride. Drying, purification by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 20:1) to give a pale yellow solid N-(2-((2-(dimethylamino)ethyl) (methyl)amino)-4-methoxy-5-((4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino)phenyl) Acrylamide (Compound 64) (300 mg, yield 44.8%).

LC-MS (m / z) : 501.1 [M + 1] +.

^{1 H NMR (400MHz, CDCl3)} δ8.76 (s, 1H), 8.44 (d, 1H), 8.23-8.12 (m, 1H), 7.74-7.63 (m, 1H), 7.28 (d, 1H), 7.24 (d, 1H), 7.07 (s, 1H), 6.93 (d, 1H), 6.83 (s, 1H), 6.43 (d, 1H), 5.72 (d, 1H), 3.87 (s, 3H), 2.92 ( s, 5H), 2.75 (s, 3H), 2.32 (s, 8H).

Example 65

N-(3-((5-chloro-4-(6-(2,6-dimethyl-morpholine)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino )-4-methoxy-phenyl)acrylamide (Compound 65)

N-(3-((5-chloro-4-(6-(2,6-dimethylmorpholino)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

First step: 6-bromo-1-(triisopropylsilyl)-1H-indole (65B)

6-bromo-1-(triisopropylsilyl)-1H-indole

6-bromoindole (65A) (30 g, 153.02 mmol) was dissolved in 200 mL of tetrahydrofuran. Sodium hydride (4.04 g, 168.32 mmol) was slowly added to the ice bath, stirred for 30 minutes, and triisopropylchlorosilane (35.4) was added dropwise. g, 183.6 mmol), reacted at room temperature for 1 hour. The reaction solution was quenched by adding 20 mL of water, and 200 mL of water and 500 mL of ethyl acetate were added. The layers were separated and the aqueous extracted with EtOAc EtOAc. The organic phase was dried over anhydrous sodium sulfate, EtOAc (EtOAc) (Triisopropylsilyl)-1H-indole (65B) (46 g, yield 87.9%).

Step 2: 2,6-Dimethyl-4-(1-(triisopropylsilyl)-1H-indol-6-yl)morpholine (65C)

2,6-dimethyl-4-(1-(triisopropylsilyl)-1H-indol-6-yl)morpholine

6-Bromo-1-(triisopropylsilyl)-1H-indole (65B) (1 g, 3 mmol) was dissolved in 30 mL of o-xylene, followed by 2,6-dimethylmorpholine (518 mg, 4.5 mmol), sodium tert-butoxide (577 mg, 6 mmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan (173.6 mg, 0.3 mmol) and palladium acetate (67.4 mg, 0.3 mmol) ), cooled to -20 ° C, and replaced with nitrogen for 30 minutes. The reaction was raised to 120 ° C for 4 hours. After completion of the reaction, 10 mL of water was added, and the mixture was filtered through Celite, washed with 100 mL of ethyl acetate. The aqueous phase was extracted with EtOAc (EtOAc) (EtOAc)EtOAc. 6-yl)morpholine (65C) (1.1 g, yield 94.8%).

LC-MS (m / z) : 387.1 [M + 1] +.

The third step: 4-(1H-indol-6-yl)-2,6-dimethyl-morpholine (65D)

4-(1H-indol-6-yl)-2,6-dimethylmorpholine

2,6-Dimethyl-4-(1-(triisopropylsilyl)-1H-indol-6-yl)morpholine (65C) (1.1 g, 2.8 mmol) was dissolved in an ice bath To 20 mL of tetrahydrofuran, tetrabutylammonium fluoride (2.8 mL, 2.8 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the reaction was quenched by the addition of 10 mL of water, and concentrated, and purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v/v) = 1:0 to 2:1) to give a yellow solid 4-(1H-indole) -6-yl)-2,6-dimethyl-morpholine (65D) (0.6 g, yield 93.2%).

LC-MS (m / z) : 231.1 [M + 1] +.

Step 4: 4-(3-(2,5-Dichloropyrimidin-4-yl)-1H-indol-6-yl)-2,6-dimethyl-morpholine (65E)

4-(3-(2,5-dichloropyrimidin-4-yl)-1H-indol-6-yl)-2,6-dimethylmorpholine

4-(1H-Indol-6-yl)-2,6-dimethyl-morpholine (65D) (0.6 g, 2.6 mmol) was dissolved in 30 mL of tetrahydrofuran under nitrogen and cooled to 0 ° C. Methylmagnesium bromide (0.87 mL, 2.6 mmol) was added, and the mixture was reacted for 30 minutes, and 2,4,5-trichloropyrimidine (0.477 g, 2.6 mmol) was added thereto, and the mixture was reacted at 65 ° C for 6 hours. After completion of the reaction, 150 mL of water and 150 mL of ethyl acetate were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate (MgSO4) 2,5-Dichloropyrimidin-4-yl)-1H-indol-6-yl)-2,6-dimethyl-morpholine (65E) (0.64 g, yield 65.5%).

LC-MS (m / z) : 377.0 [M + 1] +.

Step 5: 4-(3-(2,5-Dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)-2,6-dimethyl-morpholine (65F )

4-(3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)-2,6-dimethylmorpholine

4-(3-(2,5-Dichloropyrimidin-4-yl)-1H-indol-6-yl)-2,6-dimethyl-morpholine (65E) (1.44 g, 3.8 mmol) Dissolved in 30 mL of tetrahydrofuran, sodium hydride (306.5 mg, 7.6 mmol) was added under ice-cooling, and stirred for 30 min. After completion of the reaction, the reaction was quenched by the addition of 20 mL of water, the solvent was evaporated, and the solid was washed with 100 mL of water and dried to give 4-(3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H as a yellow solid. -吲哚-6-yl)-2,6-dimethyl-morpholine (65F) (1.3 g, yield 87.8%).

Step 6: 5-Chloro-4-(6-(2,6-dimethyl-morpholine)-1-methyl-1H-indol-3-yl)-N-(2-methoxy- 5-nitrophenyl)pyrimidine-2-amine (65G)

5-chloro-4-(6-(2,6-dimethylmorpholino)-1-methyl-1H-indol-3-yl)-N-(2-methoxy-5-nitrophenyl)pyrimidin-2-amine

4-(3-(2,5-Dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)-2,6-dimethyl-morpholine (65F) (1.3 g, 3.33 mmol) was dissolved in 30 mL of 2-pentanol, 2-methoxy-5-nitroaniline (561 mg, 3.33 mmol) and p-toluenesulfonic acid (768 mg, 4 mmol) were added and heated to 120 ° C for reflux for 3 days. . The reaction solution was cooled to room temperature, 150 mL of aqueous ammonia was added, a solid was precipitated, and filtered, and the filter cake was washed with 200 mL of water and 100 mL of petroleum ether, and dried to give a brown solid 5-chloro-4-(6-(2,6-dimethyl-) Morpholine)-1-methyl-1H-indol-3-yl)-N-(2-methoxy-5-nitrophenyl)pyrimidine-2-amine (65G) (1 g, yield 58.8%) ).

LC-MS (m / z) : 523.0 [M + 1] +.

Step 7: N1-(5-chloro-4-(6-(2,6-dimethyl-morpholine)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)- 6-methoxybenzo-1,3-diamine (65H)

N1-(5-chloro-4-(6-(2,6-dimethylmorpholino)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxybenzene-1,3-diamine

5-Chloro-4-(6-(2,6-dimethyl-morpholine)-1-methyl-1H-indol-3-yl)-N-(2-methoxy-5-nitro Phenyl phenyl pyrimidine-2-amine (65G) (1g, 1.9mmol) was dissolved in 30mL of ethanol, and then 10mL of water, iron powder (642mg, 11.5mmol) and ammonium chloride (71mg, 1.33mmol) were added to the temperature. The mixture was refluxed at 90 ° C for 6 hours, cooled to room temperature, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 50:1) to give a yellow solid N1-( 5-Chloro-4-(6-(2,6-dimethyl-morpholine)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxybenzo - 1,3-Diamine (65H) (800 mg, yield 85.6%).

LC-MS (m / z) : 493.0 [M + 1] +.

Step 8: N-(3-((5-chloro-4-(6-(2,6-dimethyl-morpholine)-1-methyl-1H-indol-3-yl)pyrimidine-2 -yl)amino)-4-methoxy-phenyl)acrylamide (compound 65)

N1-(5-Chloro-4-(6-(2,6-dimethyl-morpholine)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-A Oxybenzo-1,3-diamine (65H) (800mg, 1.6mmol) was dissolved in 15mL of pyridine, followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Salt (917 mg, 4.8 mmol) and acrylic acid (0.17 mL, 2.44 mmol) were reacted at room temperature for 4 hours. The pyridine was sparged, and a 4 mol/L aqueous sodium hydroxide solution (150 mL) and 150 mL of ethyl acetate were added and the mixture was separated. The aqueous phase was extracted once with 1000 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate (MgSO4) -Chloro-4-(6-(2,6-dimethyl-morpholine)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy- Phenyl) acrylamide (Compound 65) (400 mg, yield 45.8%).

LC-MS (m / z) : 547.1 [M + 1] +.

Example 66

N-(5-((4-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)amino)-2-(( 2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Compound 66)

N-(5-((4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)amino)-2-((2- Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

First step: 3-(2-chloropyrimidin-4-yl)-7-methyl-1H-indole (66B)

3-(2-chloropyrimidin-4-yl)-7-methyl-1H-indole

5,6-Dihydro-4H-pyrrolo[3,2,1-IJ]quinoline (66A) (0.78 g, 5 mmol) was dissolved in 10 mL of 1,2-dichloroethane under nitrogen and cooled. To 0 ° C, 2,4-dichloropyrimidine (0.745 g, 5 mmol) was added, and aluminum trichloride (0.667 g, 5 mmol) was reacted at room temperature for 40 minutes and raised to 80 ° C for 6 hours. 10 mL of water was added to the reaction solution, and the mixture was filtered, and the filter cake was washed with methanol (3 mL×3) and dried by infrared light to give 3-(2-chloropyrimidin-4-yl)-7-methyl-1H-indole as a yellow solid.哚 (66B) (1.0 g, yield 75%).

^{1 H NMR (400MHz, CDCl3)} δ8.40 (d, 1H), 7.99 (m, 2H), 7.47 (d, 1H), 7.22 (t, 1H), 7.03 (d, 1H), 4.22 (t, 2H ), 3.02 (t, 2H), 2.27 (m, 2H).

Second step: 4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-N-(4-fluoro-2-methoxy-5- Nitrophenyl)pyrimidine-2-amine (66C)

4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine

3-(2-Chloropyrimidin-4-yl)-7-methyl-1H-indole (66B) (0.54 g, 2.0 mmol) was dissolved in 8 mL of 2-pentanol, 4-fluoro-2-methyl Oxy-5-nitroaniline (4e) (0.37 g, 2.0 mmol) and p-toluenesulfonic acid monohydrate (0.46 g, 2.4 mmol) were heated to reflux at 120 ° C for 8 hours. After cooling to room temperature, 200 mL of aqueous ammonia was added to precipitate a solid, which was filtered and washed with 200 mL of water and 100 mL of petroleum ether. Dry to pale yellow solid 4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-N-(4-fluoro-2-methoxy- 5-Nitrophenyl)pyrimidine-2-amine (66C) (0.6 g, yield 71.6%).

LC-MS (m / z) : 420.1 [M + 1] +.

¹ H NMR (400 MHz, CDCl 3 ) δ 9.85 (d, 1H), 8.40 (d, 1H), 8.29 (s, 1H), 7.88 (d, 1H), 7.66 (s, 1H), 7.18-7.26 (m) , 1H), 7.01 (d, 1H), 6.74 (d, 1H), 4.74 (br, 1H), 4.31 (t, 2H), 4.02 (s, 3H), 3.04 (t, 2H), 2.29 (t, 2H).

The third step: N ¹ -(4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)-N ⁴ -(2 -(dimethylamino)ethyl)-2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (66D)

N ¹ -(4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)- 2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine

4-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-N-(4-fluoro-2-methoxy-5-nitrobenzene The pyrimidine-2-amine (66C) (0.6 g, 1.43 mmol) was dissolved in 10 mL of N,N-dimethylacetamide, and N,N-diisopropylethylamine (278 mg, 2.15 mmol) and N N,N'-trimethylethylenediamine (18A) (219 mg, 2.15 mmol) was reacted in a microwave at 130 ° C for 1.5 hours. After the reaction was completed, the reaction solution was concentrated. 100mL of water and 100mL ethyl acetate was added, liquid separation, the aqueous phase was extracted with 100mL of ethyl acetate, the organic phases were combined, washed with 100mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give a red solid N ¹ - (4- ( 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-ylpyrimidin-2-yl)-N ⁴ -(2-(dimethylamino)ethyl)- 2-Methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (66D) (716 mg).

LC-MS (m / z) : 502.3 [M + 1] +.

Fourth step: N ⁴ -(4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)-N ¹ -(2 -(dimethylamino)ethyl)-5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (66E)

N ⁴ -(4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)- 5-methoxy-N ¹ -methylbenzene-1,2,4-triamine

N ¹ -(4-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)-N ⁴ -(2-(2) Methylamino)ethyl)-2-methoxy-N ⁴ -methyl-5-nitrobenzene-1,4-diamine (66D) (716 mg, 1.43 mmol) was dissolved in 15 mL of ethanol, then 5 mL was added sequentially Water, iron powder (0.479 g, 8.58 mmol) and ammonium chloride (53.5 mg, 1 mmol) were heated to 90 ° C for reflux for 6 hours. After the reaction was completed, the reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 10:1) to give a brown solid N ⁴ -(4-(5,6- Hydrogen-4H-pyrrolo[3,2,1-ij]quinolin-1-ylpyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)-5-methoxy -N ¹ -methylbenzene-1,2,4-triamine (66E) (0.43 g, yield 63.9%).

LC-MS (m / z) : 472.4 [M + 1] +.

^{1 H NMR (400MHz, CDCl3)} δ8.32 (d, 1H), 8.17 (s, 1H), 8.12 (d, 1H), 7.87 (s, 1H), 7.67 (s, 1H), 7.23-7.16 (m , 1H), 7.06 (d, 1H), 7.01 (d, 1H), 6.66 (s, 1H), 4.30 - 4.21 (m, 2H), 3.85 (s, 3H), 3.48 (s, 2H), 3.34 ( t, 2H), 3.11 - 2.99 (m, 4H), 2.83 (s, 6H), 2.72 (s, 3H), 2.34 - 2.23 (m, 2H).

Step 5: N-(5-((4-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)amino)- 2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-phenyl)acrylamide (Compound 66)

N ⁴ -(4-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)-N ¹ -(2-(2) Methylamino)ethyl)-5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (66E) (430 mg, 0.91 mmol) was dissolved in 15 mL of pyridine. Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.523 g, 2.74 mmol) and acrylic acid (0.094 mL, 1.37 mmol) were reacted for 4 hours at room temperature. The pyridine was spun, and 100 mL of dichloromethane and 4 mol/L aqueous sodium hydroxide (100 mL) were added, and the mixture was separated, and the aqueous phase was extracted with 100 mL of dichloromethane, and the organic phase was combined and washed with 150 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate (MgSO4) 4-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino) Ethyl)(methyl)amino)-4-methoxy-phenyl)acrylamide (Compound 66) (140 mg, yield 29.3%).

LC-MS (m / z) : 526.3 [M + 1] +.

¹ H NMR (400 MHz, CDCl 3 ) δ 10.21 (s, 1H), 9.81 (s, 1H), 9.25 (s, 1H), 8.89 (s, 1H), 8.37 (d, 1H), 7.95 (d, 1H) ), 7.69 (s, 1H), 7.16 (d, 1H), 7.14 - 7.08 (m, 1H), 6.80 (s, 1H), 6.51 (dd, 1H), 6.37 (s, 1H), 5.69 (d, 1H), 3.88 (d, 3H), 2.91 (s, 2H), 2.84 (s, 2H), 2.71 (s, 3H), 2.49 (s, 3H), 2.26 (s, 6H), 1.73 (s, 2H) ).

Example 67

N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(spiro[cyclopropyl-1,3'-oxime])哚]-1'-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 67)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(spiro[cyclopropane-1,3'-indolin]-1'-yl)pyrimidin- 2-yl)amino)phenyl)acrylamide

First step: 3-(2-hydroxyethyl)indol-2-one (67B)

3-(2-hydroxyethyl)indolin-2-one

2-nonanone (67A) (5g, 37.6mmol) was dissolved in 100mL of 1.2-ethylene glycol, and reacted in an autoclave at 200 ° C for 10 hours, the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite, 50 mL After washing with methanol, most of the solvent was removed, and 100 mL of ethyl acetate and 100 mL of water were added and the mixture was separated. The aqueous phase was extracted with EtOAc (EtOAc) (EtOAc)EtOAc. (4.5 g, yield 68.2%).

LC-MS (m / z) : 178.1 [M + 1] +.

Step 2: Spiro [cyclopropyl-1,3'-吲哚]-2'-one (67C)

Spiro[cyclopropane-1,3'-indolin]-2'-one

3-(2-Hydroxyethyl)indol-2-one (67B) (3 g, 16.9 mmol) was dissolved in dichloromethane (60 mL), triethylamine (6.5 mL, 46.8 mmol). Methanesulfonyl chloride (1.51 mL, 82.2 mmol) was added dropwise and the mixture was warmed to room temperature overnight. At the end of the reaction, 100 mL of water and 60 mL of dichloromethane were added, and the mixture was separated. The organic phase is extracted, dried over anhydrous sodium sulfate, and the solvent is evaporated, then purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 20:1) to obtain a red solid snail [cyclopropyl] Base-1,3'-oxime-2'-one (67C) (1.6 g, yield 59.7%).

LC-MS (m / z) : 160.2 [M + 1] +.

The third step: snail [cyclopropyl-1,3'-吲哚] (67D)

Spiro[cyclopropane-1,3'-indoline]

The spiro [cyclopropyl-1,3'-indole]-2'-one (67C) was dissolved in 50 mL of tetrahydrofuran, lithium aluminum hydride (1.25 g, 33 mmol) was slowly added, and reacted at room temperature for 30 minutes to 65 ° C. Reaction for 4 hours. After completion of the reaction, the mixture was poured into a 100 mL ice water bath, and the pH was adjusted to 8 with a sodium hydroxide aqueous solution. The aqueous phase was extracted with ethyl acetate (100 mL), EtOAc (EtOAc) =1:0 to 50:1), a brown oily snail [cyclopropyl-1,3'-indole] (67D) (0.8 g, yield 55.2%) was obtained.

LC-MS (m / z) : 146.2 [M + 1] +.

The fourth step: 1'-(2-chloropyrimidin-4-yl) snail [cyclopropyl-1,3'-吲哚] (67E)

1'-(2-chloropyrimidin-4-yl)spiro[cyclopropane-1,3'-indoline]

Spiro [cyclopropyl-1,3'-indole] (67D) (145.09 mg, mmol) was dissolved in 10 mL of dimethyl sulfoxide, potassium carbonate (276.4 mg, 2 mmol) and 2,4-dichloropyrimidine were added. (149 mg, 1 mmol), which was allowed to react at 80 ° C for 1.5 hours. At the end of the reaction, 100 mL of water and 100 mL of ethyl acetate were added and the mixture was separated. The aqueous phase was extracted with 100 mL of ethyl acetate. EtOAc (EtOAc m. Propyl-1,3'-oxime] (67E) (0.2 g, yield 77.8%).

LC-MS (m / z) : 258.1 [M + 1] +.

Step 5: N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(spiro[cyclopropyl-1,3'-indole]-1'-yl)pyrimidine- 2-amine (67F)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(spiro[cyclopropane-1,3'-indolin]-1'-yl)pyrimidin-2-amine

1'-(2-chloropyrimidin-4-yl)spiro[cyclopropyl-1,3'-indole] (67E) (1 g, 3.89 mmol) was dissolved in 60 mL of 2-pentanol, 4-fluoro 2-methoxy-5-nitroaniline (4e) (724 mg, 3.89 mmol) and p-toluenesulfonic acid (0.887 g, 4.67 mmol) were heated to 130 ° C to reflux for 6 hours. After the reaction was completed, the solvent was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjjj Separation and purification (petroleum ether / ethyl acetate (v / v) = 4:1 - dichloromethane / methanol = 10:1) to give a brown solid N-(4-fluoro-2-methoxy-5-nitro Phenyl)-4-(spiro[cyclopropyl-1,3'-indole]-1'-yl)pyrimidin-2-amine (67F) (1.2 g, yield 95.2%).

LC-MS (m / z) : 408.3 [M + 1] +.

Step 6: N ¹ -(2-(Dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-2-nitro-N ⁴ -(4-(spiro[cyclopropyl- 1,3'-吲哚]-1'-yl)pyrimidin-2-yl)benzene-1,4-diamine (67G)

N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-2-nitro-N4-(4-(spiro[cyclopropane-1,3'-indolin]-1'-yl)pyrimidin-2- Yl)benzene-1,4-diamine

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(spiro[cyclopropyl-1,3'-indole]-1'-yl)pyrimidin-2-amine (67F) (1.2g, 2.95mmol) was dissolved in 5 mL of N,N-dimethylacetamide, and N,N-diisopropylethylamine (0.571 g, 4.42 mmol) and N,N,N'- Trimethylethylenediamine (18A) (452 mg, 4.42 mmol) was reacted in a microwave at 130 ° C for 1.5 hours. At the end of the reaction, 150 mL of water and 150 mL of dichloromethane were added and the mixture was separated. The aqueous phase was extracted with 150mL methylene chloride, the combined organic phases with saturated brine (200mL), dried over anhydrous sodium sulfate, and concentrated to give a brown solid N ¹ - (2- (dimethylamino) ethyl) -5- oxy-N ¹ -methyl-2-nitro-N ⁴ -(4-(spiro[cyclopropyl-1,3'-indole]-1'-yl)pyrimidin-2-yl)benzene-1 4-Diamine (67G) (1.2 g, yield 85.7%).

LC-MS (m / z) : 490.3 [M + 1] +.

Step 7: N ¹ -(2-(Dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(spiro[cyclopropyl-1,3'--吲哚]-1'-yl)pyrimidin-2-yl)benzene-1,2,4-,triamine (67H)

N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(spiro[cyclopropane-1,3'-indolin]-1'-yl)pyrimidin-2-yl Benzene-1,2,4-triamine

N ¹ -(2-(Dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-2-nitro-N ⁴ -(4-(spiro[cyclopropyl-1,3] '-吲哚]-1'-yl)pyrimidin-2-yl)benzene-1,4-diamine (67G) (1.2g, 2.45mmol) was dissolved in 24mL of ethanol, followed by 8mL of water, iron powder (0.822) g, 14.7 mmol) and ammonium chloride (92 mg, 1.7 mmol) were heated to 90 ° C to reflux for 4 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane / methanol (v/v) = 1:0 to 10:1) to give a brown solid N ¹ -(2-(dimethylamino)ethyl) -5-methoxy-N ¹ -methyl-N ⁴ -(4-(spiro[cyclopropyl-1,3'-indole]-1'-yl)pyrimidin-2-yl)benzene-1, 2,4-,Triamine (67H) (440 mg, yield 40%).

LC-MS (m / z) : 460.4 [M + 1] +.

Step 8: N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(spiro[cyclopropyl-1], 3'-吲哚]-1'-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 67)

N ¹ -(2-(Dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-(spiro[cyclopropyl-1,3'-吲哚]] -1'-yl)pyrimidin-2-yl)benzene-1,2,4-,triamine (67H) (0.44 g, 0.96 mmol) was dissolved in 15 mL of pyridine, followed by 1-(3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (0.55 g, 2.88 mmol) and acrylic acid (0.1 mL, 1.44 mmol) were reacted at room temperature for 4 hours. The pyridine was sparged, and a 4 mol/L aqueous sodium hydroxide solution (100 mL) and 100 mL of dichloromethane were added, and the mixture was separated, and the aqueous phase was extracted with dichloromethane (100 mL), and the organic phase was washed with saturated aqueous sodium chloride (100 mL) Drying with sodium sulfate and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 10:1) to give a yellow solid N-(2-((2-(dimethylamino))) Ethyl)(methyl)amino)-4-methoxy-5-((4-(spiro[cyclopropyl-1,3'-indole]-1'-yl)pyrimidin-2-yl)amino) Phenyl) acrylamide (Compound 67) (100 mg, yield 20.3%).

LC-MS (m / z) : 514.3 [M + 1] +.

^{1 H NMR (400MHz, CDCl3)} δ9.97 (s, 1H), 9.45 (s, 1H), 8.16 (d, 1H), 7.80 (s, 1H), 7.45 (s, 1H), 7.16-7.07 (m , 1H), 6.89 (t, 1H), 6.77 (s, 1H), 6.70 - 6.65 (m, 1H), 6.43 (s, 1H), 6.37 (d, 2H), 5.71 - 5.62 (m, 1H), 4.33 (s, 2H), 3.87 (s, 3H), 2.91 (s, 2H), 2.70 (s, 3H), 2.29 (s, 6H), 1.58 (s, 4H).

Example 68

N-(5-((4-(6-Cyano-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)) Ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Compound 68)

N-(5-((4-(6-cyano-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino )-4-methoxyphenyl)acrylamide

First step: 1-methyl-1H-indole-6-carbonitrile (68B)

1-methyl-1H-indole-6-carbonitrile

6-Cyano-indole (68A) (5g, 35.17mmol) was dissolved in 30mL of tetrahydrofuran, sodium hydride (1.69g, 70.34mmol) was slowly added, and reacted at room temperature for 20 minutes, and iodomethane (14.97g, 105.5mmol) was added. The reaction was carried out for 3 hours at room temperature. At the end of the reaction, the reaction was quenched by the addition of 100 mL of water. Most of the solvent was removed, and 100 mL of ethyl acetate and 100 mL of water were added and the mixture was separated. The aqueous phase was extracted with 100 mL of ethyl acetate. Dry over sodium sulfate and concentrate to give a yellow solid <RTI ID=0.0></RTI> <RTIgt;

Second step: 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole-6-carbonitrile (68C)

3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole-6-carbonitrile

1-Methyl-1H-indole-6-carbonitrile (68B) (5.4 g, 34.6 mmol) was dissolved in 40 mL of ethylene glycol dimethyl ether, and 2,4-dichloropyrimidine (5.15 g, 34.6 mmol) was added. And aluminum trichloride (4.61 g, 34.6 mmol), and reacted to 80 ° C for 4 hours. After the reaction was completed, 100 mL of water was added to precipitate a solid, which was filtered, washed with 150 mL of water, and dried with an infrared lamp to give 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole-6 as a yellow solid. - carbonitrile (68C) (9 g, yield 97.8%).

LC-MS (m / z) : 269.1 [M + 1] +.

The third step: 3-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-6- Nitrile (68D)

3-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-6-carbonitrile

3-(2-Chloropyrimidin-4-yl)-1-methyl-1H-indole-6-carbonitrile (68C) (8 g, 29.8 mmol) was dissolved in 150 mL of 2-pentanol. 2-Methoxy-5-nitroaniline (4e) (5.55 g, 29.8 mmol) and p-toluenesulfonic acid monohydrate (6.82 g, 35.9 mmol) were heated to reflux at 120 ° C for 2 days. After cooling to room temperature, 200 mL of aqueous ammonia was added to precipitate a solid, which was filtered and washed with 200 mL of water and 100 mL of petroleum ether. Drying to a brown solid 3-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-6- Formonitrile (68D) (10 g, yield 80.6%).

LC-MS (m / z) : 419.0 [M + 1] +.

Step 4: 3-(2-((4-(2-(Dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-4 -yl)-1-methyl-1H-indole-6-carbonitrile (68E)

3-(2-((4-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-6 -carbonitrile

3-(2-((4-Fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-6-carbonitrile (68D) (10g, 23.9mmol) was dissolved in 60mL of N,N-dimethylacetamide, N,N-diisopropylethylamine (4.64g, 35.87mmol) and N,N,N'-trimethyl Ethylenediamine (18A) (3.67 g, 35.87 mmol) was reacted in a microwave at 130 ° C for 1.5 hours. The reaction was completed and concentrated. After adding 200 mL of water and 200 mL of ethyl acetate, the mixture was separated, and the aqueous layer was extracted with ethyl acetate (200 mL). 4-((2-(Dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H- Indole-6-carbonitrile (68E) (10 g, yield 84%).

LC-MS (m / z) : 501.1 [M + 1] +.

Step 5: 3-(2-((5-amino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidine-4 -yl)-1-methyl-1H-indole-6-carbonitrile (68F)

3-(2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-6 -carbonitrile

3-(2-((4-(2-(Dimethylamino)ethyl))(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl) 1-Methyl-1H-indole-6-carbonitrile (68E) (11 g, 22 mmol) was dissolved in 100 mL of ethanol, followed by 33 mL water, iron powder (7.37 g, 132 mmol) and ammonium chloride (824 mg, 15.4) Methyl), the temperature was raised to 90 ° C and refluxed for 6 hours. After completion of the reaction, the reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:0 to 10:1) to give a brown solid 3-(2-((5-amino-4) -((2-(Dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-6- Formonitrile (68F) (6 g, yield 58.3%).

LC-MS (m / z) : 471.1 [M + 1] +.

Step 6: N-(5-((4-(6-Cyano-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(2) Methylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Compound 68)

3-(2-((5-amino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl) 1-Methyl-1H-indole-6-carbonitrile (68F) (6 g, 12.7 mmol) was dissolved in 50 mL of pyridine and 1-(3-dimethylaminopropyl)-3-ethylcarbodiphenyl was added. The amine hydrochloride (7.3 g, 38.2 mmol) and acrylic acid (1.3 mL, 19.1 mmol) were reacted at room temperature for 4 hours. The pyridine was sparged, and 200 mL of dichloromethane and a 4 mol/L aqueous sodium hydroxide solution (200 mL) were added and the mixture was separated. The aqueous phase was extracted with 200 mL of dichloromethane, and the organic phase was combined, washed with saturated sodium chloride (400 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (v/v) = 1:0 10:1), a yellow solid N-(5-((4-(6-cyano-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(( 2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Compound 68) (1.2 g, yield 18.2%).

LC-MS (m / z) : 525.2 [M + 1] +.

Example 69

N-(5-((4-(1-(Difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-morpholine) Ethyloxy)phenyl)acrylamide (Compound 69)

N-(5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-morpholinoethoxy)phenyl)acrylamide

First step: 4-(1-(difluoromethyl)-1H-indol-3-yl)-N-(2-methoxy-4-(2-morpholinoethoxy)-5-nitrate Phenyl)pyrimidine-2-amine (69A)

4-(1-(difluoromethyl)-1H-indol-3-yl)-N-(2-methoxy-4-(2-morpholinoethoxy)-5-nitrophenyl)pyrimidin-2-amine

4-(1-(Difluoromethyl)-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine (30B (1 g, 2.33 mmol) was dissolved in 30 mL of tetrahydrofuran, sodium hydride (112 mg, 4.46 mmol) was slowly added, stirred for 30 min, and 2-morpholineethanol (611 mg, 4.66 mmol) was added and allowed to react at room temperature for 4 hours. At the end of the reaction, 150 mL of water and 150 mL of dichloromethane were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate (MgSO4) -morpholineethoxy)-5-nitrophenyl)pyrimidine-2-amine (69A) (1.1 g, yield 88%).

LC-MS (m / z) : 541.3 [M + 1] +.

Second step: N ¹ -(4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-morpholinyl) Ethoxy)benzene-1,3-diamine (69B)

N ¹ -(4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-morpholinoethoxy)benzene-1,3-diamine

4-(1-(Difluoromethyl)-1H-indol-3-yl)-N-(2-methoxy-4-(2-morpholinoethoxy)-5-nitrophenyl Pyrimidine-2-amine (69A) (1.1 g, 2.03 mmol) was dissolved in 30 mL of ethanol, 10 mL water was added, then iron powder (682 mg, 12.2 mmol) and ammonium chloride (76 mg, 1.42 mmol) were added and the temperature was raised to 90 ° C. The reaction was refluxed for 4 h and concentrated. Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a brown solid N ¹ -(4-(1-difluoromethyl)-1H-indole Ind-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-morpholinylethoxy)benzene-1,3-diamine (69B) (1 g, yield 97.1%) .

The third step: N-(5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-( 2-morpholinylethoxy)phenyl)acrylamide (Compound 69)

N ¹ -(4-(1-(Difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-morpholinylethoxy) Benzene-1,3-diamine (69B) (1 g, 1.96 mmol) was dissolved in 30 mL of pyridine, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.12) was added. g, 5.88 mmol), acrylic acid (0.202 mL, 2.94 mmol). The pyridine in the reaction mixture was sparged, and 150 mL of water and 150 mL of dichloromethane were added and the mixture was separated. The organic phase was washed with a 4 mol/L aqueous sodium hydroxide solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane: methanol (v/v) = 1:0 to 10:1 , a white solid N-(5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2- (2-morpholinylethoxy)phenyl)acrylamide (Compound 69) (400 mg, yield 36.4%).

LC-MS (m / z) : 565.3 [M + 1] +.

Example 70

N-(2-((1-Aminocyclopropyl)methoxy)-5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl) Amino)-4-methoxyphenyl)acrylamide (compound 70)

N-(2-((1-aminocyclopropyl)methoxy)-5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

First step: (1-((4-(4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2 -Nitrophenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (70A)

Tert-butyl(1-((4-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenoxy)methyl)cyclopropyl) Carbamate

4-(1-(Difluoromethyl)-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine (30B (1g, 2.33mmol) was dissolved in 30mL of tetrahydrofuran, sodium hydride (112mg, 4.66mmol) was slowly added, and stirred for 30 minutes. (1-Hydroxymethylcyclopropyl)-tert-butoxycarbonylamino (873 mg, 4.66 mmol) was added, and the mixture was reacted at room temperature for 4 hours. At the end of the reaction, 150 mL of water and 150 mL of dichloromethane were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate (MgSO4) Amino)-5-methoxy-2-nitrophenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (70A) (1 g, yield 72.5%).

LC-MS (m / z) : 597.3 [M + 1] +.

The second step: (1-((2-(4-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-A Oxyphenyl)methyl)cyclopropyl)carbamic acid tert-butyl ester (70B)

Tert-butyl(1-((2-amino-4-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenoxy)methyl)cyclopropyl) Carbamate

(1-((4-(4-(1-(Difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-nitro Benzyloxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (70A) (1 g, 1.68 mmol) was dissolved in 30 mL of ethanol, 10 mL water, iron powder (562 mg, 10 mmol) and ammonium chloride (63 mg, 1.2 mmol), the temperature was raised to 90 ° C and refluxed for 4 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 1:0 to 10:1) to give a brown solid (1-((2-amino-4-((4-) (1-(Difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenyl)methyl)cyclopropyl)carbamic acid tert-butyl ester ( 70B) (951 mg).

LC-MS (m / z) : 567.3 [M + 1] +.

The third step: (1-((2-acrylamido-4-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5 -Methoxyphenyl)methyl)cyclopropyl)carbamic acid tert-butyl ester (70C)

Tert-butyl(1-((2-(((((()))))))))) Carbamate

(1-((2-amino-4-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxybenzene Tert-butyl)methyl)cyclopropyl)carbamic acid tert-butyl ester (70B) (951 mg, 1.68 mmol) was dissolved in 30 mL of pyridine, and 1-(3-dimethylaminopropyl)-3-ethylcarbazide was added. The amine hydrochloride (963 mg, 5.04 mmol) and acrylic acid (0.173 mL, 2.52 mmol) were reacted at room temperature for 4 hours. The pyridine in the reaction mixture was sparged, and 150 mL of water and 150 mL of dichloromethane were added and the mixture was separated. The organic phase was washed with a 4 mol/L aqueous sodium hydroxide solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane: methanol (v/v) = 1:0 to 10:1 , a yellow solid (1-((2-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)- tert-Butyl 5-methoxyphenyl)methyl)cyclopropyl)carbamate (70C) (800 mg, yield 76.9%).

LC-MS (m / z) : 621.3 [M + 1] +.

Fourth step: N-(2-((1-aminocyclopropyl)methoxy)-5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidine- 2-yl)amino)-4-methoxyphenyl)acrylamide (compound 70)

(1-((2-Aminoamino)-4-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy tert-Butyl phenyl)methyl)cyclopropyl)carbamate (70C) (0.8 g, 1.29 mmol) was dissolved in 50 mL of dichloromethane. Most of the solvent was spun off, 100 mL of water was added, and the pH was adjusted to 8 with a saturated aqueous solution of sodium bicarbonate. The aqueous phase was extracted with 100 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated and evaporated to silicagel 1-aminocyclopropyl)methoxy)-5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy Phenyl phenyl) acrylamide (Compound 70) (370 mg, yield 55.1%).

LC-MS (m / z) : 521.2 [M + 1] +.

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.75 (s, 1H), 9.37 (s, 1H), 8.78 (s, 1H), 8.44 (d, 1H), 8.05 (dd, 1H), 7.82-7.75 ( m, 1H), 7.69 (s, 1H), 7.35 (dd, 2H), 7.22 (d, 1H), 6.60 (s, 1H), 6.40 (d, 2H), 5.77 (t, 1H), 1.26 (s) , 3H), 0.88 (s, 2H), 0.74 (d, 2H), 0.68 (t, 2H).

Test Example 1: Testing cancer cell growth inhibition

The serially passaged tumor cells were trypsinized, suspended in a medium, counted, and seeded into a 96-well cell culture plate. Non-small cell lung cancer cells NCI-H1975 10000 cells per well, human epithelial cancer cell A431 cell line 10000 cells per well, cultured overnight at 37 ° C, 5% CO ₂ incubator. On the next day, 6 wells of each cell were fixed by adding 30 μl of 50% trichloroacetic acid; the remaining wells were separately added to the test compound. The test compound was formulated into a solution in DMSO at a maximum concentration of 10 μM, and 10 concentrations to be tested were diluted 5 times as described below. For the NCI-H1975, A431 cell line, the test was diluted with a medium containing 0.1% FBS and made to a final concentration of 2 times. The 96-well cell culture plate medium in which NCI-H1975 and A431 cells were seeded was replaced with fresh medium containing 0.1% FBS (100 ul per well), and 100 ul of the test compound containing 2 times the final concentration was added. Each 96-well cell culture plate was incubated at 37 ° C in a 5% CO ₂ cell incubator for 72 hours. Then, 50 μl of 50% trichloroacetic acid was added to each well, and the mixture was fixed in a refrigerator at 4 ° C for 1 hour.

The trichloroacetic acid in each well was discarded and washed 5 times with 300 μl of double distilled water. After drying at room temperature, 50 μl of a 0.4% SRB (Sulforhodamine-B) dye solution (1% acetic acid / 0.4% SRB) was added to each well for 15 min. The dye solution of each well was discarded, washed 6-7 times with 1% acetic acid, and dried at room temperature. 200 μl of a 10 mM Tris solution (pH = 10.5) was added to each well and dissolved by shaking. The absorbance at 490 nm of each well was measured by a microplate reader. The reading of the wells at which the concentration of the test compound was 0 was used as a control, and the half-effect inhibitory concentration (IC ₅₀ ) of the test compound was calculated and analyzed using origin 7.5.

The anti-tumor cell proliferation activity of the compound of the present invention was measured by the above test, and the measured IC ₅₀ values are shown in Table 1.

Table 1 Anti-tumor cell proliferation activity test results

Conclusion: The compounds of the present invention have significant growth inhibitory effects on non-small cell lung cancer cells NCI-H1975, especially the growth inhibitory activities of compound 20 and compound 33 are <1 nM. The compound of the present invention has obvious selectivity to non-small cell lung cancer cells NCI-H1975, especially the growth inhibitory activities of compounds 16, 27, 30, 38, 40, 46, 47 on non-small cell lung cancer cells NCI-H1975 are human The growth inhibitory activity of epithelial cancer cell A431 is more than 100 times.

Claims

A compound of the formula (I): and an optical isomer, a pharmaceutically acceptable salt or a eutectic thereof, wherein:

B is selected from a 6 to 15 membered heterocyclic ring containing 1 to 4 hetero atoms selected from N, O, S or P;

R 1 is independently selected from the group consisting of F, Cl, Br, I, hydroxy, cyano, C 1-10 alkyl, C 1-10 alkoxy, -NR 1a R 1b , -C(=O)C 1- 10 alkyl, -S(=O) 2 -C 1-10 alkyl, -C(=O)-3 to 15 membered heterocyclic ring, -C(=O)-C 3-15 carbocyclic ring, -(CH 2 ) n -3 to 15 membered heterocyclic ring, -(CH 2 ) n -C 3-15 carbocyclic ring, -O-(CH 2 ) n -C 3-15 carbocyclic ring, -O-(CH 2 ) n - 3- to 15-membered heterocyclic ring, -O-(CH 2 ) n -C(=O)C 1-6 alkyl, -O-(CH 2 ) n -OC(=O)C 1-6 alkyl or- O-(CH 2 ) n -OC 1-10 alkyl, said CH 2 , alkyl, alkoxy, carbocyclic or heterocyclic ring optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I , =O, hydroxy, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) n -OH, -(CH 2 ) n -F, -C( =O)C 1-6 alkoxy, -C(=O)C 1-6 alkyl, -C(=O)C 3-15 carbocyclic ring, -OC(=O)C 1-6 alkyl group, Substituted by a substituent of -(CH 2 ) n -C 3-10 carbocyclic or -(CH 2 ) n -3 to 10 membered heterocyclic ring containing from 1 to 4 selected from N, O, S or a hetero atom of P;

R 1a and R 1b are selected from H or C 1-10 alkyl;

R 2 is selected from H, F, Cl, Br, I, cyano, C 1-10 alkyl or C 1-10 alkoxy, said alkyl or alkoxy optionally further selected from 0 to 4 Substituted from a substituent of F, Cl, Br, I, C 1-6 alkyl or C 1-6 alkoxy;

R 3 is selected from H, C 2-10 alkenyl, C 3-15 cycloalkyl, C 1-10 alkyl or C 1-10 alkoxy, said alkenyl, cycloalkyl, alkyl or alkoxy Further optionally, 0 to 4 are substituted with a substituent selected from F, Cl, Br, I, C 1-6 alkyl or C 1-6 alkoxy;

R 4 is selected from the group consisting of H, F, Cl, Br, I, nitro, amino, C 1-10 alkyl, 5 to 15 membered spiro, 4 to 15 membered cyclo, 3 to 10 membered heterocyclic ring, -NR 4c R 4d , -Z-(CH 2 ) n R 4a , -O-(CH 2 ) n R 4b , -Z-(CH 2 ) n NR 4c R 4d or -O-(CH 2 ) n NR 4c R 4d Further, the CH 2 , spiro, cyclo or heterocyclic ring is further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy , -(CH 2 ) n -C(=O)-R 4e , -(CH 2 ) n -OC(=O)-R 4e , -NR 4c R 4d , C 3 substituted by 0 to 4 R 4c a -10 carbocyclic ring or a substituent of a 3 to 10 membered heterocyclic ring substituted with 0 to 4 R 4c , the heterocyclic ring containing 1 to 4 hetero atoms selected from N, O or S;

Z is selected from -NH- or -N(C 1-6 alkyl)-;

R 4a is selected from a C 3-15 carbocyclic ring or a 3 to 15 membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O or S, optionally further to 0. To four substituents selected from the group consisting of F, Cl, Br, I, amino, hydroxy, C 1-6 alkoxy, C 1-6 alkyl or an amino group substituted by 1 to 2 C 1-6 alkyl Replace

R 4b is selected from -C(=O)C 1-6 alkyl, -OC(=O)C 1-6 alkyl, C 1-10 alkoxy, C 3-15 carbocyclic or 3 to 15 membered hetero Ring, the alkyl, alkoxy, carbocyclic or heterocyclic ring optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, I, amino, -NR 4c R 4d , hydroxy, C 1-6 alkyl Substituted by a C 1-6 alkoxy group or a halogen-substituted C 1-6 alkyl group having 1 to 4 hetero atoms selected from N, O or S;

R 4c and R 4d are selected from H, C 1-10 alkyl, -C(=O)C 1-6 alkyl or -C(=O)C 1-6 alkoxy;

R 4e is selected from amino, hydroxy, C 1-10 alkyl, C 3-15 carbocyclic or 3 to 15 membered heterocyclic ring, and the amino, alkyl, carbocyclic or heterocyclic ring is optionally further selected from 0 to 4 From F, Cl, Br, I, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, -C(=O)C 1-6 alkyl, -C(=O)-NH 2 Substituting a substituent of -OC(=O)C 1-6 alkyl or a halogen-substituted C 1-6 alkyl group containing from 1 to 4 heteroatoms selected from N, O or S;

R 5 is selected from H, F, Cl, Br, I or a 5- to 15-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O or S, said heterocyclic ring optionally further 0 to 4 substituents selected from the group consisting of F, Cl, Br, I, =O, -C(=O)C 1-6 alkyl, C 1-6 alkyl or C 1-6 alkoxy;

f is selected from 0, 1, 2, 3, 4, 5 or 6;

n is selected from 0, 1, 2 or 3;

The condition is that when -B-(R 1 ) f is selected from
And R 2 is selected from H, F, Cl, methyl or cyano, R 3 is selected from H, methoxy or methyl, f is 1, and when R 5 is H, R 4 is not H,
A compound according to claim 1 and an optical isomer, pharmaceutically acceptable salt or eutectic thereof, wherein:

B is selected from a 6 to 15 membered heterocyclic ring containing 1 to 4 hetero atoms selected from N, O or S;

R 1 is independently selected from the group consisting of F, Cl, Br, I, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, -NR 1a R 1b , -C(=O)C 1- 4- alkyl, -S(=O) 2 -C 1-4 alkyl, -C(=O)-3 to 7-membered heterocyclic ring, -C(=O)-C 3-7 carbocyclic ring, -(CH 2 ) n- C 3-6 carbocyclic or -(CH 2 ) n -3 to 7-membered heterocyclic ring, said CH 2 , alkyl, alkoxy, carbocyclic or heterocyclic ring optionally further being from 0 to 4 One selected from the group consisting of F, Cl, Br, I, =0, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, -(CH 2 ) n -OH, -(CH 2 ) n -F, - C(=O)C 1-4 alkoxy, -C(=O)C 3-6 carbocyclic, -C(=O)C 1-4 alkyl, -(CH 2 ) n -C 3-6 Substituted by a carbocyclic ring or a -(CH 2 ) n -3 to 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O or S;

R 1a and R 1b are selected from H or C 1-4 alkyl;

R 2 is selected from H, F, Cl, Br, I, cyano, C 1-4 alkyl or C 1-4 alkoxy, said alkyl or alkoxy optionally further selected from 0 to 4 Substituted from a substituent of F, Cl, Br, I, C 1-4 alkyl or C 1-4 alkoxy;

R 3 is selected from H, C 2-6 alkenyl, C 3-6 cycloalkyl, C 1-4 alkyl or C 1-4 alkoxy, said alkenyl, cycloalkyl, alkyl or alkoxy Further optionally, 0 to 4 are substituted with a substituent selected from F, Cl, Br, I, C 1-4 alkyl or C 1-4 alkoxy;

R 4 is selected from the group consisting of H, F, Cl, Br, I, a 5 to 15 membered spiro ring, a 4 to 15 membered ring, a 3 to 10 membered heterocyclic ring, -Z-(CH 2 ) n R 4a , and -O- ( CH 2 ) n R 4b , -Z-(CH 2 ) n NR 4c R 4d or -O-(CH 2 ) n NR 4c R 4d , the heterocyclic ring containing 1 to 4 selected from N, O or S a hetero atom, the CH 2 , spiro, cyclo or heterocyclic ring optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, I, amino, hydroxy, C 1-4 alkyl, -NR 4c R 4d Substituted with a substituent of -C(=O)-R 4e or a C 1-4 alkoxy group;

Z is selected from -NH- or -N(C 1-4 alkyl)-;

R 4a is selected from a C 3-6 carbocyclic ring or a 3 to 7 membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O or S, optionally further to 0. Substituted to four substituents selected from the group consisting of F, Cl, Br, I, amino, hydroxy, C 1-4 alkyl, amino substituted with 1 to 2 C 1-4 alkyl groups;

R 4b is selected from a C 3-6 carbocyclic ring or a 3 to 7 membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O, S, which are optionally further to 4 substituents selected from F, Cl, Br, I, amino, hydroxy, -NR 4c R 4d, C 1-4 alkyl or halo substituted with 1-2 of C 1-4 alkyl substituents;

R 4c and R 4d are selected from H or C 1-4 alkyl;

R 4e is selected from amino, hydroxy, C 1-4 alkyl, C 3-6 carbocyclic or 3- to 7-membered heterocyclic ring, optionally further selected from 0 to 4 Substituted from a substituent of a C 1-4 alkyl group substituted with F, Cl, Br, I, an amino group, a hydroxyl group, a C 1-4 alkyl group, a C 1-4 alkoxy group or a halogen, the heterocyclic ring containing 1 to 4 heteroatoms selected from N, O or S;

R 5 is selected from H, F, Cl, Br, I or a 5- to 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O, S, said heterocyclic ring optionally further 0 to 4 substituents selected from the group consisting of F, Cl, Br, I, =O, -C(=O)C 1-4 alkyl, C 1-4 alkyl or C 1-4 alkoxy;

f is selected from 0, 1, 2, 3 or 4;

n are each independently selected from 0, 1, 2 or 3.
A compound according to claim 2, and an optical isomer, pharmaceutically acceptable salt or co-crystal thereof, wherein:

B is selected from the group consisting of 8 to 13 membered heterocyclic rings containing 1 to 4 hetero atoms selected from N, O or S;

R 1 is independently selected from the group consisting of F, Cl, Br, I, hydroxy, cyano, -S(=O) 2 -C 1-4 alkyl, C 1-4 alkyl, -C(=O)-C 3-6 carbocyclic, -(CH 2 ) n -C 3-6 carbocyclic or -(CH 2 ) n -5 to 6-membered heterocyclic ring, optionally CH 2 , alkyl, carbocyclic or heterocyclic ring Further from 0 to 4 selected from the group consisting of F, Cl, Br, I, =O, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, -CH 2 -cyclopropyl, tert-butoxycarbonyl, - (CH 2 ) n -OH, -(CH 2 ) n -F, -C(=O)C 1-4 alkyl, -(CH 2 ) n -C 3-6 carbocyclic or -(CH 2 ) n Substituted by a substituent of a 3- to 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O or S;

R 2 is selected from H, F, Cl, C 1-4 alkyl or C 1-4 alkoxy;

R 3 is H, C 2-4 alkenyl, C 3-4 cycloalkyl, C 1-4 alkyl or C 1-4 alkoxy, and the alkoxy group is optionally further 0 to 4 selected from Substituted by a substituent of F, Cl or Br;

R 4 is selected from the group consisting of H, F, Cl, a 7 to 11 membered spiro ring, a 6 to 10 membered ring, a 3 to 6 membered heterocyclic ring, -Z-(CH 2 ) n R 4a , and -Z-(CH 2 ) n NR 4c R 4d , -O-(CH 2 ) n R 4b or -O-(CH 2 ) n NR 4c R 4d , the heterocyclic ring containing 1 to 4 hetero atoms selected from N, O or S, Said CH 2 , spiro, cyclo or heterocyclic ring optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, I, amino, -NH(CH 3 ), -N(CH 3 ) 2 , methyl or Substituted by a substituent of an ethyl group;

Z is selected from -NH- or -N(C 1-4 alkyl)-;

R 4a is selected from a C 3-4 carbocyclic ring or a 5-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O, S, optionally further from 0 to 4 a substituent selected from the group consisting of F, Cl, Br, I, amino, hydroxy, -NHCH 3 , -N(CH 3 ) 2 , methyl or ethyl;

R 4b is selected from a C 3-4 carbocyclic ring or a 4 to 6 membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O, S, which are optionally further Substituted to four substituents selected from the group consisting of F, Cl, Br, I, amino, hydroxy, -NH(CH 3 ), -N(CH 3 ) 2 , -CH 2 CH 2 F, methyl or ethyl;

R 4c and R 4d are selected from H, methyl or ethyl;

R 5 is selected from H, F, Cl or a 5- to 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O, S, said heterocyclic ring optionally further being from 0 to 4 Substituted with a substituent selected from F, Cl, Br, I, =O, -C(=O)C 1-4 alkyl, C 1-4 alkyl or C 1-4 alkoxy;

n is selected from 0, 1, 2 or 3.
A compound according to claim 3, and an optical isomer, pharmaceutically acceptable salt or co-crystal thereof, wherein:

B is selected from

R 1 is independently selected from the group consisting of F, Cl, Br, I, -S(=O) 2 CH 3 , -C(=O)-cyclopropyl, hydroxy, cyano, methyl, ethyl, isopropyl , cyclopropyl, -CH 2 -cyclopropyl, -CH(CH 3 )-cyclopropyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl, said methyl, ethyl, Morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrole optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, methyl, ethyl, methoxy, iso Propyl, cyclopropyl, -CH 2 -cyclopropyl, hydroxyethyl, 2-fluoroethyl, tert-butoxycarbonyl, oxetanyl, -C(=O)CH 3 or -C(=O Substituting a substituent of CH 2 CH 3 ;

R 2 is selected from H, F, Cl, methyl or methoxy;

R 3 is selected from H, methyl, ethyl, vinyl, cyclopropyl, methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy;

R 4 is selected from the group consisting of H, F, Cl, 7 to 11 membered spiro ring, 3 to 6 membered heterocyclic ring, -Z-(CH 2 ) n R 4a , -O-(CH 2 ) n R 4b , -Z-( CH 2 ) n NR 4c R 4d or -O-(CH 2 ) n NR 4c R 4d , the heterocyclic ring containing 1 to 4 hetero atoms selected from N, O or S, the CH 2 , spiro or The heterocyclic ring is optionally further substituted with from 0 to 4 substituents selected from the group consisting of F, Cl, Br, I, methyl, ethyl or -N(CH 3 ) 2 ;

Z is selected from -NH- or -N(CH 3 )-;

R 4a is selected from a substituted or unsubstituted cyclopropyl or tetrahydropyrrolyl group, and when substituted, optionally further 1 to 4 are selected from the group consisting of F, Cl, Br, I, amino, hydroxy, -NHCH 3 , Substituted with a substituent of -N(CH 3 ) 2 , methyl or ethyl;

R 4b is selected from substituted or unsubstituted cyclopropyl,
Pyrrolidine-yl, piperazinyl, piperidinyl or morpholinyl group, when substituted, optionally further substituted by 1 to 4 substituents selected from F, Cl, Br, I, amino, hydroxyl, -NHCH 3, -N Substituted by a substituent of (CH 3 ) 2 , -CH 2 CH 2 F, methyl or ethyl;

R 4c and R 4d are selected from H, methyl or ethyl;

R 5 is selected from H, F, Cl or morpholinyl;

n is selected from 0, 1, 2 or 3.
A compound according to claim 4, and an optical isomer, pharmaceutically acceptable salt or eutectic thereof, wherein:

B is selected from

R 1 is independently selected from the group consisting of F, Cl, -S(=O) 2 CH 3 , hydroxy, cyano, methyl, difluoromethyl, ethyl, -CH 2 CH 2 OH, isopropyl, cyclopropane Base, -CH 2 -cyclopropyl,

Morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl;

R 2 is selected from H, F, Cl, methyl or methoxy;

R 3 is selected from H, ethyl, methoxy or difluoromethoxy;

R 4 is selected from the group consisting of H, F, Cl,

R 5 is selected from H, F, Cl or morpholinyl;

f is selected from 0, 1, 2 or 3.
The compound according to claim 1 and an optical isomer, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from one of the following structures:
A compound according to any one of claims 1 to 6 and an optical isomer, pharmaceutically acceptable salt or co-crystal thereof, wherein said salt is selected from the group consisting of hydrochloride, sulfate, phosphate, acetate, Trifluoroacetate, fumarate, benzoate, besylate, methanesulfonate, triflate or combinations thereof.
A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6, or an optical isomer, a pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable An acceptable carrier or excipient.
Use of the compound according to any one of claims 1 to 7 and an optical isomer thereof, a pharmaceutically acceptable salt or cocrystal thereof, or the pharmaceutical composition according to claim 8, for the preparation of a medicament for treating cancer .
The use according to claim 9, wherein the cancer comprises head and neck cancer, ovarian cancer, bladder cancer, and cervix Cancer, esophageal cancer, gastric cancer, breast cancer, endometrial cancer, colon cancer, lung cancer, brain tumor, non-small cell lung cancer, pancreatic cancer, solid tumor, colorectal tumor or malignant glioma.
A method for treating cancer, which comprises administering a compound according to any one of claims 1 to 7, or an optical isomer, a pharmaceutically acceptable salt or a cocrystal thereof, or the medicament according to claim 8. combination.
The method according to claim 11, wherein the cancer comprises head and neck cancer, ovarian cancer, bladder cancer, cervical cancer, esophageal cancer, gastric cancer, breast cancer, endometrial cancer, colon cancer, lung cancer, brain tumor, non-small cell lung cancer. , pancreatic cancer, solid tumor, colorectal tumor or malignant glioma.