CN113121575A

CN113121575A - (substituted phenyl) (substituted pyrimidine) amino derivative and preparation method and pharmaceutical application thereof

Info

Publication number: CN113121575A
Application number: CN202110329149.4A
Authority: CN
Inventors: 魏用刚; 李瑶; 张国彪; 邱关鹏; 胡仕红; 陈雷; 李升�; 张黔
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2014-08-25
Filing date: 2015-08-25
Publication date: 2021-07-16
Also published as: CN106458969A; WO2016029839A1

Abstract

Provides a (substituted phenyl) (substituted pyrimidine) amino derivative as shown in a general formula (I), an optical isomer, pharmaceutically acceptable salt or eutectic crystal thereof, a preparation method and application in preparing tumor drugs.Wherein the general formula is compound (I).

Description

(substituted phenyl) (substituted pyrimidine) amino derivative and preparation method and pharmaceutical application thereof

The application is a divisional application with application number 201580023470.2, application date 2015 08-25, entitled (substituted phenyl) (substituted pyrimidine) amino derivative, and a preparation method and pharmaceutical use thereof.

Technical Field

The invention relates to a (substituted phenyl) (substituted pyrimidine) amino derivative as shown in a general formula (I), an optical isomer, pharmaceutically acceptable salt or eutectic thereof, a preparation method and application in preparing tumor drugs.

Background

With the advent of the industrialized age, environmental pollution and lifestyle changes have led to a continuous rise in the incidence of cancer. Currently, cancer has become a major killer threatening human life and health. According to international research center for cancer (IARC) reports: in 2008, the number of new cancer cases is 1,266 ten thousand and the number of death cases is 756 ten thousand, accounting for 13 percent of all deaths. In the next decades, the number of cancer patients will still increase rapidly, 2136 new cancer cases and 1315 ten thousands death cases are expected to occur in 2030 years all over the world, and the market demand for cancer treatment will continue to increase rapidly.

The receptor tyrosine kinase superfamily of cell surface receptors plays an important role in the regulation of cell signaling by extracellular growth factors. Receptor tyrosine kinases are capable of catalyzing the transfer of phosphate groups from ATP to tyrosine groups on substrates. When no ligand activates receptor tyrosine kinases, these kinases are in an unphosphorylated monomeric state with the kinase domain in an inactive configuration. When ligand is combined with extracellular segment of receptor tyrosine kinase, receptor is oligomerized and autophosphorylated, which increases the catalytic activity of kinase and forms binding site of signal protein, which is combined with it to activate multiple signal paths. These signaling pathways are interconnected to regulate cell proliferation, survival, differentiation, function, migration and apoptosis. When the receptor tyrosine kinase is out of regulation and abnormally activated, the cells are transformed into tumor cells, and the proliferation, growth and drug resistance of the cells are improved, and the cells have stronger hemangiogenic ability, invasiveness and transfer ability (Yarden and Sliwkowski,2001, Nat Rev Mol Cell Biol,2, 127-.

The ErbB family belongs to receptor tyrosine kinases and comprises 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-. 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 leads to autophosphorylation of the receptor regulatory domain, resulting in intracellular signal transduction, ultimately leading to cell proliferation. This signaling pathway is closely related to the development and progression of tumors. In many tumors, hyperactivated ErbB receptors, particularly EGFR, can lead to deregulation of growth factor signaling. Activation of EGFR is usually either sustained activation due to overexpression or mutation or autocrine expression of the ligand. Overexpression or mutation of EGFR is detected in various cancers such as head and neck cancer, ovarian cancer, bladder cancer, cervical cancer, esophageal cancer, gastric cancer, breast cancer, intimal cancer, colon cancer, lung cancer, and brain tumor, and is generally indicative of poor prognosis. Thus, inhibition of EGFR is a highly interesting anti-tumor strategy. Many small molecule inhibitors targeting EGFR have been developed in succession, some of which have been used in clinical therapy.

The first generation of EGFR kinase inhibitors such as gefitinib and erlotinib were clinically effective in the treatment of non-small cell lung cancer, especially those containing activating mutations in the EGFR kinase domain (Mok, Wu et al, 2009, N Engl J Med,361, 947-containing 957; Rosell, Moran et al, 2009, N Engl J Med,361, 958-containing 967). The most common EGFR activating mutations are L858R and delE746_ A750, which are capable of increasing the receptor affinity for gefitinib and erlotinib, but decreasing the receptor affinity for ATP, relative to wild-type EGFR (Carey, Garton et al, 2006, Cancer Res,66, 8163-. However, clinically, the use of gefitinib and erlotinib is eventually limited due to the emergence of acquired resistance. Acquired resistance occurs in more than 50% of lung cancer patients, with more than 90% containing the T790M gatekeeper residue mutation of EGFR (Kobayashi, Boggon et al, 2005, N Engl J Med,352,786 792; Pao, Miller et al, 2005, PLoS Med,2, e 73). The T790M mutation does not sterically hinder drug binding, but restores the receptor affinity for ATP, comparable to wild-type (Yun, Mengwasser et al, 2008, Proc Natl Acad Sci U S A,105, 2070-.

Second generation EGFR kinase inhibitors generally have a quinoline structure and are irreversible EGFR inhibitors. Unlike gefitinib, they contain electrophilic ability and are capable of michael addition reactions with the conserved cysteine group (Cys 797) in EGFR. The covalent nature of these compounds makes them more capable of occupying the ATP site than reversible inhibitors, and thus, although the T790M mutation can increase the affinity for ATP, such inhibitors are sufficient to inhibit EGFR T790M in preclinical models (Engelman, Zejnullahu et al, 2007, Cancer Res,67, 11924. sup. 11932; Li, Ambrogio et al, 2008, Oncogene,27, 4702. sup. 4711). However, the ability of existing irreversible inhibitors to inhibit EGFR T790M mutation was still lower than the ability to inhibit EGFR activating mutation alone in cell line models, and at clinically useful concentrations, such compounds failed to inhibit EGFR T790M in vitro (Yuza, Glatt et al, 2007, Cancer Biol Ther,6,661-667; Godin-Heymann, Ulnus et al, 2008, Mol Cancer Ther her,7,874-879). Since the affinity of EGFR T790M to ATP is similar to that of wild-type EGFR, quinazoline EGFR inhibitors inhibit wild-type EGFR while inhibiting EGFR T790M. Clinically, simultaneous inhibition of wild-type EGFR results in patients with rash and diarrhea, which limits the dosage of second generation EGFR inhibitors, such that the plasma concentration of the drug is insufficient to inhibit T790M, resulting in a greater limitation in the clinical effectiveness of such drugs. For example, CI-1033, HKI-272 and PF00299804, have very limited clinical treatment for Gefitinib and erlotinib resistant non-small cell lung cancer and can develop dose-dependent diarrhea and skin rash (Janne, von Pawel et al, 2007, J Clin Oncol,25, 3936-.

In order to be able to specifically inhibit EGFR T790M, third generation EGFR mutation selective inhibitors were developed. Compared with the second generation quinoline compounds, the irreversible inhibitor has higher selectivity on EGFR T790M, and may have higher activity and better tolerance clinically. For example, the covalent pyrimidine EGFR inhibitor WZ4002 has 30-100 times higher selectivity for EGFR T790M and 100 times lower inhibition for wild type EGFR in vitro than quinoline compounds. Better efficacy was also demonstrated in the EGFR T790M-derived animal lung cancer model (Zhou, Ercan et al, 2009, Nature,462, 1070-. Another mutation selective inhibitor, co-1686, is 10-25 fold more selective for EGFR T790M in vitro than for wild-type EGFR. Mutations that selectively inhibit EGFR, including the drug resistance mutation T790M and the activating mutation (L858R, del19), were not inhibitory to wild-type EGFR. In vitro, oral co-1686 was able to cause tumor regression of the T790M mutation without mediating further drug resistance mutations in tumor cells (Walter, Sjin et al, 2013, Cancer Discov,3, 1404-. To meet clinical needs, there is a continuing need to develop EGFR inhibitors that do not produce significant toxic side effects at concentrations effective to overcome the T790M mutation.

At present, various documents report protein kinase inhibitors and anti-tumor application thereof. Such as:

WO2009051822 discloses pyrimidine derivatives useful as EGFR inhibitors, and their use in the treatment of cancer. Wherein A, B is selected from carbocycle or heterocycle, etc., and the structure is shown as follows:

WO2011140338 describes heterocyclic derivatives that are useful as EGFR inhibitors, and their use as antitumor agents. Wherein B is selected from 6 to 10 membered mono-or bis-heteroaryl containing at least one N atom, X1 is selected from O, S or N, R²⁹、R^29aAnd R29b are each independently selected from H, 5-to 6-membered non-heteroaryl, 5-to 6-membered non-heteroarylmethylene, or 5-to 6-membered non-heteroarylcarbonyl, as shown in the following structure:

WO2011090760, WO2009158571 describe pyrimidine derivatives useful as protein kinase inhibitors and as medicaments for the treatment of various diseases, wherein A, B is independently selected from heterocyclic or carbocyclic rings, and the structures are as follows:

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

The invention aims to provide an EGFR inhibitor with good effect, good tolerance, high selectivity or low toxic and side effects, and application thereof in preparing medicaments related to cancer treatment. The cancer comprises head and neck cancer, ovarian cancer, bladder cancer, cervical cancer, esophageal cancer, gastric cancer, breast cancer, intimal cancer, colon cancer, lung cancer, brain tumor, non-small cell lung cancer, pancreatic cancer, solid tumor, colorectal tumor or malignant glioma and the like.

Disclosure of Invention

The invention relates to a compound shown in a general formula (I) and an optical isomer, pharmaceutically acceptable salt or eutectic thereof, wherein:

b is selected from 6 to 15 membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, S or P;

R¹each independently selected from F, Cl, Br, I, hydroxy, cyano, C_1-10Alkyl radical, C_1-10Alkoxy, -NR^1aR^1b、 -C(＝O)C_1-10Alkyl, -S (═ O)₂-C_1-10Alkyl, -C (═ O) -3 to 15 membered heterocycle, -C (═ O) -C_3-15Carbocyclic ring, - (CH)₂)_n-3 to 15 membered heterocycle, - (CH)₂)_n-C_3-15Carbocyclic ring, -O- (CH)₂)_n-C_3-15Carbocyclic ring, -O- (CH)₂)_n-3 to 15 membered heterocycle, -O- (CH)₂)_n-C(＝O)C_1-6Alkyl, -O- (CH)₂)_n-O-C(＝O)C_1-6Alkyl or-O- (CH)₂)_n-O-C_1-10Alkyl, said CH₂Alkyl, alkoxy, carbocyclic or heterocyclic ring optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I,Is O, hydroxy, amino, cyano, nitro, C _1-6Alkyl radical, C_1-6Alkoxy, - (CH)₂)_n-OH、-(CH₂)_n-F、 -C(＝O)C_1-6Alkyl, -O-C (═ O) C_1-6Alkyl, -C (═ O) C_1-6Alkoxy, -C (═ O) C_3-15Carbocyclic ring, - (CH)₂)_n-C_3-10Carbocyclic ring or- (CH)₂)_n-3 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from N, O, S or P;

R^1aand R^1bSelected from H or C_1-10An alkyl group;

R²selected from H, F, Cl, Br, I, cyano, C_1-10Alkyl or C_1-10Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, C_1-6Alkyl or C_1-6Substituted by a substituent of alkoxy;

R³selected from H, C_2-10Alkenyl radical, C_3-15Cycloalkyl radical, C_1-10Alkyl or C_1-10Alkoxy, said alkenyl, cycloalkyl, alkyl or alkoxy being optionally further 0 to 4 selected from F, Cl, Br, I, C_1-6Alkyl or C_1-6Substituted by a substituent of alkoxy;

R⁴selected from H, F, Cl, Br, I, nitro, amino, C_1-10Alkyl, 5-to 15-membered spirocyclic, 4-to 15-membered fused cyclic, 3-to 10-membered heterocyclic, -NR^4cR^4d、-Z-(CH₂)_nR^4a、-O-(CH₂)_nR^4b、-Z-(CH₂)_nNR^4cR^4dor-O- (CH)₂)_nNR^4cR^4dSaid CH₂Spiro, fused or heterocyclic ring optionally further substituted by 0 to 4 groups selected from F, Cl, Br, I, hydroxy, amino, C_1-6Alkyl radical, C_1-6Alkoxy, - (CH)₂)_n-C(＝O)-R^4e、-(CH₂)_n-O-C(＝O)-R^4e、 -NR^4cR^4dFrom 0 to 4R^4cSubstituted C_3-10Carbocyclic or substituted by 0 to 4R^4cSubstituted by3 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from N, O or S;

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

R^4ais selected from C_3-15A carbocycle or 3-to 15-membered heterocycle containing 1 to 4 heteroatoms selected from N, O or S, said carbocycle or heterocycle optionally further substituted with 0 to 4 heteroatoms selected from F, Cl, Br, I, amino, hydroxy, C_1-6Alkoxy radical, C_1-6Alkyl or by 1 to 2C_1-6Substituted with a substituent of an alkyl-substituted amino group;

R^4bis selected from-C (═ O) C_1-6Alkyl, -O-C (═ O) C_1-6Alkyl radical, C_1-10Alkoxy radical, C_3-15A carbocycle or a 3-to 15-membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being further substituted with 0 to 4 substituents selected from F, Cl, Br, I, amino, -NR^4cR^4dHydroxy, C_1-6Alkyl radical, C_1-6Alkoxy or halogen substituted C_1-6Alkyl, said heterocycle containing 1 to 4 heteroatoms selected from N, O or S;

R^4cand R^4dSelected from H, C_1-10Alkyl, -C (═ O) C_1-6Alkyl or-C (═ O) C_1-6An alkoxy group;

R^4eselected from amino, hydroxy, C_1-10Alkyl radical, C_3-15A carbocycle or a 3-to 15-membered heterocycle, said amino, alkyl, carbocycle or heterocycle being optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, amino, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy, -C (═ O) C_1-6Alkyl, -C (═ O) -NH₂、-O-C(＝O)C_1-6Alkyl or halogen substituted C_1-6Alkyl, said heterocycle containing 1 to 4 heteroatoms selected from N, O or S;

R⁵Selected from H, F, Cl, Br, I or a 5 to 15 membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O or S, said heterocyclic ring optionally further substituted by 0 to 4 heteroatoms selected from F, Cl, Br, I, ═ O, -C (═ O) C_1-6Alkyl radical, C_1-6Alkyl or C_1-6Substituent of alkoxyGeneration;

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

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

in each scheme of the invention, when-B- (R)¹)_fIs selected from

And R is²Selected from H, F, Cl, methyl or cyano, R³Selected from H, methoxy or methyl, f is 1, R⁵When is H, R⁴Is not H,

In a preferred embodiment of the present invention, the compound represented by the general formula (I) and an optical isomer, a pharmaceutically acceptable salt or a co-crystal thereof, wherein:

b is selected from 6 to 15 membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O or S;

R¹each independently selected from F, Cl, Br, I, hydroxy, cyano, C_1-4Alkyl radical, C_1-4Alkoxy, -NR^1aR^1b、 -C(＝O)C_1-4Alkyl, -S (═ O)₂-C_1-4Alkyl, -C (═ O) -3 to 7 membered heterocycle, -C (═ O) -C_3-7Carbocyclic ring, - (CH)₂)_n-C_3-6Carbocyclic ring or 3 to 7 membered heterocyclic ring, said CH₂Alkyl, alkoxy, carbocycle or heterocycle is optionally further substituted by 0 to 4 groups selected from F, Cl, Br, I, ═ O, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy, -C (═ O) C_1-4Alkoxy, - (CH) ₂)_n-OH、 -(CH₂)_n-F、-C(＝O)C_3-6Carbocyclic ring, -C (═ O) C_1-4Alkyl, - (CH)₂)_n-C_3-6Carbocyclic ring or- (CH)₂)_n-3 to 6 membered heteroA ring substituent, said heterocycle containing 1 to 4 heteroatoms selected from N, O or S;

R^1aand R^1bSelected from H or C_1-4An alkyl group;

R²selected from H, F, Cl, Br, I, cyano, C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R³selected from H, C_2-6Alkenyl radical, C_3-6Cycloalkyl radical, C_1-4Alkyl or C_1-4Alkoxy, said alkenyl, cycloalkyl, alkyl or alkoxy being optionally further selected from 0 to 4 from F, Cl, Br, I, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R⁴selected from H, F, Cl, Br, I, 5-to 15-membered spirocyclic ring, 4-to 15-membered fused ring, 3-to 10-membered heterocyclic ring, -Z- (CH)₂)_nR^4a、 -O-(CH₂)_nR^4b、-Z-(CH₂)_nNR^4cR^4dor-O- (CH)₂)_nNR^4cR^4dSaid heterocycle containing 1 to 4 heteroatoms selected from N, O or S, said CH₂Spiro, fused or heterocyclic ring optionally further substituted by 0 to 4 groups selected from F, Cl, Br, I, amino, hydroxy, C_1-4Alkyl, -NR^4cR^4d、-C(＝O)-R^4eOr C_1-4Substituted by a substituent of alkoxy;

z is selected from-NH-or-N (C)_1-4Alkyl) -;

R^4ais selected from C_3-6A carbocyclic ring or a 3 to 7 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from N, O or S, said carbocyclic or heterocyclic ring optionally further substituted by 0 to 4 heteroatoms selected from F, Cl, Br, I, amino, hydroxy, C _1-4Alkyl radical, by 1 to 2C_1-4Substituted with a substituent of an alkyl-substituted amino group;

R^4bis selected from C_3-6A carbocyclic ring or a 3 to 7 membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, S, the carbocyclic or heterocyclic ringThe ring is optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, amino, hydroxy, -NR^4cR^4d、 C_1-4Alkyl or C substituted by 1 to 2 halogens_1-4Alkyl is substituted by a substituent;

R^4cand R^4dIs selected from H or C_1-4An alkyl group;

R^4eselected from amino, hydroxy, C_1-4Alkyl radical, C_3-6A carbocycle or a 3-to 7-membered heterocycle, said amino, alkyl, carbocycle or heterocycle being optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, amino, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy or halogen substituted C_1-4Alkyl, said heterocycle containing 1 to 4 heteroatoms selected from N, O or S;

R⁵selected from H, F, Cl, Br, I or a 5 to 6 membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, S, said heterocyclic ring optionally further substituted with 0 to 4 heteroatoms selected from H, F, Cl, Br, I, ═ O, -C (═ O) C_1-4Alkyl radical, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

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

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

B is selected from an 8 to 13 membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O or S;

R¹each independently selected from F, Cl, Br, I, hydroxy, cyano, -S (═ O)₂-C_1-4Alkyl, -C (═ O) -C_3-6Carbon ring, C_1-4Alkyl, - (CH)₂)_n-C_3-6Carbocyclic ring or- (CH)₂)_n-5 to 6 membered heterocycle, preferably H, F, Cl, -S (═ O)₂-C_1-4Alkyl radical, C_1-4Alkyl, -C (═ O) -C_3-6Carbocyclic ring, - (CH)₂)_n-C_3-6Carbocyclic ring or- (CH)₂)_n-a 5 to 6 membered heterocyclic ring; the CH₂Alkyl, carbocyclic or heterocyclic ringIs further substituted by 0 to 4 substituents selected from F, Cl, Br, I, ═ O, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy, -CH₂-cyclopropyl, -tert-butoxycarbonyl, - (CH)₂)_n-OH、-(CH₂)_n-F、-C(＝O)C_1-4Alkyl, - (CH)₂)_n-C_3-6Carbocyclic ring or- (CH)₂)_n-3 to 6 membered heterocycle, preferably further substituted with 0 to 4 substituents selected from F, hydroxy, C_1-4Alkyl or-C (═ O) C_1-4Alkyl is substituted by a substituent; said heterocycle containing from 1 to 4 heteroatoms selected from N, O or S;

R²selected from H, F, Cl, C_1-4Alkyl or C_1-4Alkoxy, preferably H, F, Cl or C_1-4An alkoxy group;

R³is H, C_2-4Alkenyl radical, C_3-4Cycloalkyl radical, C_1-4Alkyl or C_1-4Alkoxy, preferably H, C_1-4Alkyl or C_1-4An alkoxy group; said alkoxy is optionally further substituted by 0 to 4 substituents selected from F, Cl or Br;

R⁴selected from H, F, Cl, 7-to 11-membered spirocyclic ring, 6-to 10-membered fused ring, 3-to 6-membered heterocyclic ring, -Z- (CH) ₂)_nR^4a、 -Z-(CH₂)_nNR^4cR^4d、-O-(CH₂)_nR^4bor-O- (CH)₂)_nNR^4cR^4dSaid heterocycle containing 1 to 4 heteroatoms selected from N, O or S, said CH₂Spiro, fused or heterocyclic ring optionally further substituted by 0 to 4 groups selected from F, Cl, Br, I, amino, -NH (CH)₃)、-N(CH₃)₂Methyl or ethyl;

z is selected from-NH-or-N (C)_1-4Alkyl) -;

R^4ais selected from C_3-4A carbocycle or 5-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, S, said carbocycle or heterocycle optionally further substituted with 0 to 4 heteroatoms selected from F, Cl, Br, I, amino, hydroxy, -NHCH₃、 -N(CH₃)₂Methyl or ethyl;

R^4bis selected from C_3-4A carbocycle or a 4-to 6-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, S, said carbocycle or heterocycle optionally further substituted with 0 to 4 heteroatoms selected from F, Cl, Br, I, amino, hydroxy, -NH (CH)₃)、 -N(CH₃)₂、-CH₂CH₂F. Methyl or ethyl;

R^4cand R^4dSelected from H, methyl or ethyl;

R⁵selected from H, F, Cl or a 5 to 6 membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, S, said heterocyclic ring optionally further substituted by 0 to 4 heteroatoms selected from F, Cl, Br, I, ═ O, -C (═ O) C_1-4Alkyl radical, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

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

B is selected from

Preference is given to

Or

Further preferred is

Or

R¹Each independently selected from F, Cl, Br, I, -S (═ O)₂CH₃-C (═ O) -cyclopropyl, hydroxy, cyano, methyl, ethyl, isopropyl, cyclopropyl, -CH₂-cyclopropyl, -CH (CH)₃) -cyclopropyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl, preferably H, F, Cl, -S (═ O)₂CH₃Methyl, ethyl, isopropyl, cyclopropyl, -CH₂-cyclopropyl, -CH₂(CH₃) -cyclopropyl, -C (═ O) -cyclopropyl, morpholinyl, or piperazinyl; said methyl, ethyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl group being optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, ═ O, hydroxy, methyl, ethyl, methoxy, isopropyl, cyclopropyl, -CH₂-cyclopropyl, hydroxyethyl, 2-fluoroethyl, tert-butoxycarbonyl, oxetanyl, -C (═ O) CH₃or-C (═ O) CH₂CH₃Is preferably optionally further substituted with 0 to 4 substituents selected from F, hydroxy, methyl, -CH₂-cyclopropyl, hydroxyethyl, 2-fluoroethyl, tert-butoxycarbonyl or-C (═ O) CH₃Substituted with the substituent(s);

R²selected from H, F, Cl, methyl or methoxy, preferably H, F, Cl or methoxy;

R³selected from H, methyl, ethyl, vinyl, cyclopropyl, methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy, preferably H, ethyl, methoxy or difluoromethoxy;

R⁴Selected from H, F, Cl, 7-to 11-membered spirocyclic ring, 3-to 6-membered heterocyclic ring, -Z- (CH)₂)_nR^4a、-O-(CH₂)_nR^4b、 -Z-(CH₂)_nNR^4cR^4dor-O- (CH)₂)_nNR^4cR^4dPreferably F, 7-to 11-membered spirocyclic ring, 3-to 6-membered heterocyclic ring, -Z- (CH)₂)_nR^4a、-O-(CH₂)_nR^4b、-Z-(CH₂)_nNR^4cR^4dor-O- (CH)₂)_nNR^4cR^4d(ii) a Said heterocycle containing 1 to 4 hetero atoms selected from N, O or SA, the CH₂Spiro or heterocycle optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, methyl, ethyl or-N (CH)₃)₂Is preferably optionally further substituted with 0 to 2 substituents selected from F or methyl;

z is selected from-NH-or-N (CH)₃)-；

R^4aSelected from substituted or unsubstituted cyclopropyl or tetrahydropyrrolyl, when substituted, optionally further substituted by 1 to 4 substituents selected from F, Cl, Br, I, amino, hydroxy, -NHCH₃、-N(CH₃)₂Methyl or ethyl;

R^4bselected from substituted or unsubstituted cyclopropyl,

Tetrahydropyrrolyl, piperazinyl, piperidinyl or morpholinyl; when substituted, is optionally further substituted with 1 to 4 substituents selected from F, Cl, Br, I, amino, hydroxy, -NHCH₃、 -N(CH₃)₂、-CH₂CH₂F. Methyl or ethyl, preferably by 1 to 4 substituents selected from amino or-CH₂CH₂Substituted with a substituent of F;

R^4cand R^4dSelected from H, methyl or ethyl, preferably H or methyl;

R⁵selected from H, F, Cl or morpholinyl, preferably H, F or morpholinyl;

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

b is selected from

Preference is given to

Or

Further preferred is

Or

R¹Each independently selected from F, Cl, -S (═ O)₂CH₃Hydroxy, cyano, methyl, difluoromethyl, ethyl, -CH₂CH₂OH, isopropyl, cyclopropyl, -CH₂-cyclopropyl group,

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

Or

Further preferably H, F, methyl or morpholinyl;

R²selected from H, F, Cl, methyl or methoxy, preferably H, F, Cl or methoxy;

R³selected from H, ethyl, methoxy or difluoromethoxy, preferably H or methoxy;

R⁴selected from H, F, Cl,

Preferably H、 F、

R⁵Selected from H, F, Cl or morpholinyl, preferably H, F or morpholinyl;

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

Preferred embodiment of the present invention, -B- (R)¹)_fSelected from, but not limited to, one of the following structures:

the invention relates to a compound shown in a general formula (II) and an optical isomer, pharmaceutically acceptable salt or eutectic thereof, wherein:

b is selected from 6-membered heterocycle, 7-membered heterocycle, 8-membered heterocycle, 9-membered heterocycle or 10-membered heterocycle, optionally further substituted with 0, 1, 2, 3 or 4R ¹(ii) substituted, said heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O, S;

R¹each independently selected from H, F, Cl, Br, I, S (═ O)₂-C_1-4Alkyl radical, C_1-4Alkyl, NR^1aR^1b、-C(＝O)C_1-4Alkyl, -C (═ O) -3 membered heterocycle, -C (═ O) -4 membered heterocycle, -C (═ O) -5 membered heterocycle, -C (═ O) -6 membered heterocycle, -C (═ O) -7 membered heterocycle, C_1-4Alkoxy radical, C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆Carbocycle or 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle or 7-membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle being optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, (═ O), C_1-4Alkyl radical, C_1-4Alkoxy, -C (═ O) C_1-4Alkyl radical, C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆Carbocyclic or 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, or 6-membered heterocyclic substituent, said heterocyclic containing 1, 2, 3, or 4 heteroatoms selected from N, O, S;

R^1aand R^1bSelected from H or C_1-4An alkyl group;

R²selected from H, F, Cl, Br, I, C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R³is H, C_2-6Alkenyl radical, C₃Cycloalkyl radical, C₄Cycloalkyl radical, C₅Cycloalkyl radical, C ₆Cycloalkyl radical, C_1-4Alkyl or C_1-4Alkoxy, said alkenyl, cycloalkyl, alkyl or alkoxy being optionally further 0, 1, 2, 3 or 4 selected from H, F, Cl, Br, I, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R⁴selected from H, F, Cl, Br, I, 9-membered spiro ring, Z- (CH)₂)_nR^4a、O-(CH₂)_nR^4bOr O- (CH)₂)_nNR^4cR^4dSaid spiro ring containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said spiro ring optionally further substituted with 0, 1, 2, 3 or 4 heteroatoms selected from H, F, Cl, Br, I, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

alternatively, when R⁴Is selected from Z- (CH)₂)_n-6-membered heterocycle, 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle or N (CH)₃)-(CH₂)_nNR^4cR^4dWhen said heterocycle contains from 1 to 4 heteroatoms selected from N, O, S, said heterocycle is optionally further substituted with from 0 to 4H, F, Cl, Br, I, amino, C_1-4Alkyl or by 1 to 2C_1-4Substituted by substituents of alkyl-substituted amino groups, other radicals being defined optionally byOne of the following conditions:

1)：R³selected from ethyl or C substituted by 1, 2 or 3F, Cl, Br or I_1-4An alkyl group, a carboxyl group,

2)：R²is selected from C_1-4Alkoxy or C substituted by 1, 2 or 3F, Cl, Br or I_1-4An alkoxy group,

3): b is selected from 6-membered heterocycle, 7-membered heterocycle, 8-membered heterocycle, 9-membered heterocycle, or 10-membered heterocycle, said heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, said heterocycle optionally further substituted with 1, 2, 3, or 4 heteroatoms selected from H, F, Cl, Br, I, S (═ O) ₂-C_1-4Alkyl radical, C_1-4Alkyl radical, C_1-4Alkoxy radical, C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆Carbocyclic, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, or 6-membered heterocyclic;

z is selected from NH or N-C_1-4An alkyl group;

R^4ais selected from C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆A carbocycle, a 3-membered heterocycle, a 4-membered heterocycle or a 5-membered heterocycle, said heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said carbocycle or heterocycle optionally further substituted with 0, 1, 2, 3 or 4 heteroatoms selected from H, F, Cl, Br, I, amino, C_1-4Alkyl or by 1 to 2C_1-4Substituted with a substituent of an alkyl-substituted amino group;

R^4bis selected from C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆A carbocycle, a 3-membered heterocycle, a 4-membered heterocycle, a 5-membered heterocycle or a 6-membered heterocycle, said heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said carbocycle or heterocycle optionally further substituted with 0, 1, 2, 3 or 4 heteroatoms selected from H, F, Cl, Br, I, amino, C_1-4Alkyl or by 1 to 2C_1-4Substituted with a substituent of an alkyl-substituted amino group;

R^4cand R^4dIs selected from H or C_1-4An alkyl group;

R⁵selected from H, F, Cl, Br, I, -O-5 membered heterocycle, -O-6 membered heterocycle, -O-7 membered heterocycle, 5 membered heterocycle, 6 membered heterocycle or 7 membered heterocycle,said heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said heterocycle being optionally further substituted with 0, 1, 2, 3 or 4 heteroatoms selected from H, F, Cl, Br, I, (═ O), -C (═ O) C _1-4Alkyl radical, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

alternatively, when R³And R⁴Each independently is H, R⁵Selected from a 5-membered heterocycle or a 6-membered heterocycle, said heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said heterocycle optionally further substituted with 0, 1, 2, 3 or 4 heteroatoms selected from H, F, Cl, Br, I, (═ O), -C (═ O) C_1-4Alkyl radical, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

n is selected from 0, 1 or 2.

In a preferred embodiment of the present invention, a compound represented by general formula (II) and an optical isomer, a pharmaceutically acceptable salt or a co-crystal thereof, wherein:

b is selected from 8-, 9-or 10-membered heterocycle, preferably 9-membered heterocycle, further preferably pyridopyrazinyl or benzopyrolyl, said heterocycle optionally further substituted with 0, 1, 2, 3 or 4R¹(ii) substituted, said heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O, S;

R¹each independently selected from H, F, Cl, Br, I, S (═ O)₂-C_1-4Alkyl radical, C_1-4Alkyl, NR^1aR^1b、 C_1-4Alkoxy radical, C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆Carbocycle, 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle or 6-membered heterocycle, preferably H, F, Cl, Br, I, S (═ O)₂-C_1-4Alkyl radical, C_1-4Alkyl radical, C₅Carbocyclic ring, C₆Carbocycle, 5-membered heterocycle or 6-membered heterocycle, and further preferably H, F, Cl, Br, I, S (═ O) ₂-C_1-4Alkyl radical, C_1-4Alkyl, 5-or 6-membered heterocycle, more preferably H, F, Cl, Br, I, S (═ O)₂CH₃Methyl, isopropyl, cyclopropyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl,

R^1aand R^1bSelected from H or C_1-4An alkyl group;

said alkyl, alkoxy, carbocycle, heterocycle, methyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl, optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, (═ O), C_1-4Alkyl radical, C_1-4Alkoxy, -C (═ O) C_1-4Alkyl radical, C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆Carbocyclic or 3-, 4-, 5-or 6-membered heterocyclic substituents, preferably 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, (═ O), C_1-4Alkyl radical, C_1-4Alkoxy, -C (═ O) C_1-4Alkyl radical, C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆Carbocycle, 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle or 6-membered heterocycle, and further preferably substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, (═ O), methyl, methoxy, isopropyl, cyclopropyl, -C (═ O) CH₃or-C (═ O) CH₂CH₃Said heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O, S.

R⁴Selected from H, F, Cl, 9-membered spiro ring, Z- (CH)₂)_nR^4a、O-(CH₂)_nR^4bOr O- (CH)₂)_nNR^4cR^4d(ii) said spirocyclic ring containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, said spirocyclic ring optionally further substituted with 0, 1, 2, 3, or 4 substituents selected from H, F, Cl, Br, I, methyl, or ethyl;

alternatively, when R⁴Is selected from Z- (CH)₂)_n-6-membered, 3-membered, 4-membered, 5-membered or 6-membered heterocycle or N (CH)₃)-(CH₂)_nNR^4cR^4dWhen said heterocycle contains from 1 to 4 heteroatoms selected from N, O, S, said carbocycle or heterocycle is optionally further substituted with from 0 to 4 heteroatomsFrom H, F, Cl, Br, I, amino, NHCH₃、N(CH₃)₂Methyl or ethyl, the other groups defining optionally one of the following conditions:

1)：R³selected from ethyl or C substituted by 1, 2 or 3F, Cl, Br or I_1-4Alkyl, preferably methyl substituted by 1, 2 or 3F,

2)：R²is selected from C_1-4Alkoxy or C substituted by 1, 2 or 3F, Cl, Br or I_1-4Alkoxy, 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, said heterocyclic ring optionally further substituted with 1, 2, 3 or 4 heteroatoms selected from H, F, Cl, Br, I, SO₂CH₃Methyl, isopropyl or cyclopropyl;

Z is selected from NH or NC_1-4An alkyl group;

R^4ais selected from C₃Carbocyclic ring, C₄A carbocyclic ring or a 5 membered heterocyclic ring, preferably cyclopropyl or tetrahydropyrrolyl, said heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said carbocyclic or heterocyclic ring optionally further substituted with 0, 1, 2, 3 or 4 heteroatoms selected from H, F, Cl, Br, I, amino, NHCH₃、N(CH₃)₂Methyl or ethyl;

R^4bis selected from C₃Carbocyclic ring, C₄A carbocycle, a 5-membered heterocycle or a 6-membered heterocycle, preferably cyclopropyl, tetrahydropyrrolyl or piperazinyl, said heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said carbocycle or heterocycle optionally further substituted with 0, 1, 2, 3 or 4 heteroatoms selected from H, F, Cl, Br, I, amino, NHCH₃、N(CH₃)₂Methyl or ethyl;

R^4cand R^4dSelected from H, methyl or ethyl.

b is selected from 8-membered heterocycle, 9-membered heterocycle or 10-membered heterocycle, said heterocycle optionally further substituted with 0, 1, 2, 3 or 4R¹(ii) substituted, said heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O, S;

R¹each independently selected from H, F, Cl, Br, I, C_1-4Alkyl, S (═ O)₂-C_1-4Alkyl radical, C _3-6Carbocyclic, 5-or 6-membered heterocyclic ring, NR^1aR^1b、-C(＝O)C_1-4Alkyl, -C (═ O) -3 membered heterocycle, -C (═ O) -4 membered heterocycle, -C (═ O) -5 membered heterocycle, -C (═ O) -6 membered heterocycle or-C (═ O) -7 membered heterocycle, preferably H, F, Cl, Br, I, S (═ O)₂-C_1-4Alkyl radical, C_1-4Alkyl or a 5-or 6-membered heterocycle; said alkyl or heterocycle is optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, (═ O), C_1-4Alkyl radical, C_1-4Alkoxy, -C (═ O) C_1-4Alkyl, C3 carbocycle, C4 carbocycle, C5 carbocycle, C6 carbocycle, 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, or 6-membered heterocycle, said heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O, S;

R^1aand R^1bSelected from H or C_1-4An alkyl group;

R²selected from H, F, Cl, C_1-4Alkyl or C_1-4An alkoxy group;

R³is H, C_2-4Alkenyl radical, C_3-4Cycloalkyl radical, C_1-4Alkyl or C_1-4Alkoxy, optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl or Br;

Alternatively, when R⁴Is selected from Z- (CH)₂)_n-6-membered, 3-membered, 4-membered, 5-membered or 6-membered heterocycle or N (CH)₃)-(CH₂)_nNR^4cR^4dWhen said heterocycle contains 1 to 4 heteroatoms selected from N, O, S, said carbocycle or heterocycle is optionally further substituted with 0 to 4 heteroatoms selected from H, F, Cl, Br, I, amino, NHCH₃、N(CH₃)₂Methyl or ethyl, the other groups defining optionally one of the following conditions:

z is selected from NH or NC_1-4An alkyl group;

R^4ais selected from C₃Carbocyclic ring, C₄A carbocycle or 5-membered heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said carbocycle or heterocycle optionally further substituted with 0, 1, 2, 3 or 4 heteroatoms selected from H, F, Cl, Br, I, amino, NHCH₃、N(CH₃)₂Methyl or ethyl;

R^4bis selected from C₃Carbocyclic ring, C₄A carbocycle, a 5-membered heterocycle or a 6-membered heterocycle, said heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said carbocycle or heterocycle optionally further substituted with 0, 1, 2, 3 or 4 heteroatoms selected from H, F, Cl, Br, I, amino, NHCH ₃、N(CH₃)₂Methyl or ethyl;

R^4cand R^4dSelected from H, methyl or ethyl;

R⁵selected from H, F, Cl, a 5-membered heterocycle, a 6-membered heterocycle, an-O-5-membered heterocycle, an-O-6-membered heterocycle or-O-7 membered heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said heterocycle being optionally further substituted with 0, 1, 2, 3 or 4 heteroatoms selected from H, F, Cl, Br, I, (═ O), -C (═ O) C_1-4Alkyl radical, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

alternatively, when R³And R⁴Each independently is H, R⁵Is a 5 to 6 membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said heterocyclic ring optionally further substituted with 0, 1, 2, 3 or 4 heteroatoms selected from H, F, Cl, Br, I, (═ O), -C (═ O) C_1-4Alkyl radical, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy.

b is selected from a 9-membered heterocyclic ring, preferably pyridopyrazolyl or benzopyrolyl, said heterocyclic ring optionally further substituted with 0, 1, 2, 3 or 4R¹(ii) substituted, said heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O, S;

R¹each independently selected from H, F, Cl, Br, I, methyl, S (═ O) ₂CH₃Isopropyl, cyclopropyl, NHCH₃、 N(CH₃)₂、N(CH₃)(C₂H₅)、-C(＝O)C_1-4Alkyl, -C (═ O) -cyclopropoxy, -C (═ O) -cyclobutoxy, -C (═ O) -tetrahydropyrrolyl, -C (═ O) -morpholinyl, -C (═ O) -piperazinyl, -C (═ O) -piperidinyl, -C (═ O) -7 membered heterocycle, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl, preferably H, F, Cl, Br, I, S (═ O)₂CH₃Methyl, isopropyl, cyclopropyl, morpholinyl, piperazinyl, piperidinyl, or tetrahydropyrrole; said methyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl group being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, (═ O), methyl, methoxy, isopropyl, cyclopropyl, -C (═ O) CH₃or-C (═ O) CH₂CH₃Substituted with the substituent(s);

R²selected from H, F, Cl, methyl or methoxy;

R³selected from H, methyl, ethyl, vinyl, cyclopropyl, methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy, preferably H, methoxy, cyclopropyl or difluoromethoxy;

1)：R³selected from ethyl or methyl substituted by 1, 2 or 3F, preferably difluoromethoxy,

2)：R²is methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy, preferably methoxy,

3): b is selected from a 9-membered heterocyclic ring, preferably pyridopyrazolyl or benzopyrolyl, said heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said heterocyclic ring, pyridopyrazolyl or benzopyrolyl being optionally further substituted by 1, 2, 3 or 4 heteroatoms selected from H, F, Cl, Br, I, SO₂CH₃Methyl, isopropyl or cyclopropyl;

z is selected from NH or NCH₃；

R^4aSelected from substituted or unsubstituted cyclopropyl or tetrahydropyrrolyl, when takenOptionally substituted by 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, amino, NHCH₃、N(CH₃)₂Methyl or ethyl;

R^4bSelected from substituted or unsubstituted cyclopropyl, tetrahydropyrrolyl or piperazinyl, when substituted, optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, amino, NHCH₃、N(CH₃)₂Methyl or ethyl;

R^4cand R^4dSelected from H, methyl or ethyl;

R⁵selected from H, F, Cl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl, -O-piperazinyl, -O-piperidinyl, -O-morpholinyl or-O-7 membered heterocyclic ring, preferably morpholinyl or piperazinyl, said morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl group being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, (═ O), -C (═ O) CH₃、-C(＝O)CH₂CH₃Methyl, ethyl, methoxy;

alternatively, when R³And R⁴Each independently is H, R⁵Is morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl, preferably morpholinyl or piperazinyl, said morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, (═ O), -C (═ O) CH₃、-C(＝O)CH₂CH₃Methyl, ethyl, methoxy.

The invention preferably relates to a compound shown in a general formula (II) and an optical isomer, pharmaceutically acceptable salt or eutectic crystal thereof, wherein

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

when substituted, is optionally substituted with 1R¹Substitution;

R¹each independently selected from H, F, Cl, S (═ O)₂CH₃Isopropyl, cyclopropyl, morpholinyl, piperazinyl, piperidinyl, or tetrahydropyrrole;

R²selected from H, F, Cl, methyl or methoxy;

R³selected from H, methoxy or difluoromethoxy;

R⁴selected from H, F, Cl or one of the following structures:

alternatively, when R⁴Is selected from

Optionally, the other groups define one of the following conditions:

1)：R³selected from ethyl or methyl substituted by 1, 2 or 3F,

2)：R²is a methoxyl group, and the compound is a methoxyl group,

3): b is selected from

Or one of the following structures substituted with 1F:

R⁵selected from H, F, Cl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl;

alternatively, when R³And R⁴Each independently is H, R⁵Is morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl.

In a preferred embodiment of the present invention, the compound of formula (I) or formula (II) is selected from, but not limited to, one of the following structures:

the invention relates to a compound shown in a general formula (I) or a general formula (II) and an optical isomer, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein the salt is selected from hydrochloride, sulfate, phosphate, acetate, trifluoroacetate, fumarate, benzoate, benzenesulfonate, methanesulfonate, trifluoromethanesulfonate or a combination thereof.

The invention relates to a pharmaceutical composition, which contains a therapeutically effective dose of a compound shown in any one of the compounds, an optical isomer, a pharmaceutically acceptable salt or a eutectic crystal thereof, and a pharmaceutically acceptable carrier or excipient.

The invention further relates to an application of the compound, an optical isomer, pharmaceutically acceptable salt or eutectic crystal thereof, or the pharmaceutical composition in preparation of drugs for treating cancers.

In a preferred embodiment of the present invention, the cancer comprises head and neck cancer, ovarian cancer, bladder cancer, cervical cancer, esophageal cancer, gastric cancer, breast cancer, intimal cancer, colon cancer, lung cancer, brain tumor, non-small cell lung cancer, pancreatic cancer, solid tumor, colorectal tumor or glioblastoma.

The present invention further relates to a method of treating cancer, which comprises administering a compound of the invention as set forth above or an optical isomer, a pharmaceutically acceptable salt or a co-crystal thereof, or a pharmaceutical composition of the invention.

Synthesis method

R⁶Selected from H, F, Cl, Br, I or OH,

B、f、R¹、R²、R³、R⁴or R⁵Is in accordance with the definition given for the compounds of the general formula (I);

if R is⁴Is H, F, Cl, Br or I, then R⁶And R⁴In the same way, the nitro group of the compound of the general formula (I-A) is reduced to obtain the compound of the general formula (I-B), and the reducing agent is selected from H₂、Pt、Fe、Zn、LiAlH₄Or NaBH₄；

If R is⁴Is nitro, then: in the compound of the general formula (I-A)⁶Is H and reacts with a nitrating reagent (such as nitric acid and the like) to obtain a compound with a general formula (I-B '), and the nitro group of the compound with the general formula (I-B') is reduced to obtain a compound with a general formula (I-B);

if R is⁴Is alkyl, then R in the compound of the formula (I-A)⁶H, reacting with a format reagent or an alkyl lithium reagent and the like to obtain a compound with a general formula (I-B '), and reducing the nitro of the compound with the general formula (I-B') to obtain a compound with the general formula (I-B);

otherwise: compounds of the general formula (I-A) and H-R⁴Reacting in the presence of a base to obtain a compound with a general formula (I-B '), wherein the nitro group of the compound with the general formula (I-B') is reduced to obtain the compound with the general formula (I-B), the base is selected from diisopropylethylamine, diisopropylamine, triethylamine, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium tert-butoxide, potassium acetate, sodium hydride or cesium carbonate, and the reducing agent is selected from H ₂、Pt、Fe、Zn、LiAlH₄Or NaBH₄；

Reacting the compound of the general formula (I-B) with an acryloyl halide (e.g., acryloyl chloride) or acrylic acid in the presence of a base selected from diisopropylethylamine, diisopropylamine, triethylamine, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium tert-butoxide, potassium acetate, sodium hydride, cesium carbonate, or the like to obtain a compound of the general formula (I);

the compound of the general formula (I-A) is prepared by purchasing or referring to literature methods such as WO 2013014448.

Alternatively, the first and second electrodes may be,

R⁶selected from H, F, Cl, Br, I or OH,

B、R¹、R²、R³、R⁴or R⁵Is in accordance with the definition given for the compound of the general formula (II);

if R is⁴Is H, F, Cl, Br or I, then R⁶And R⁴In the same way, the nitro group of the compound of the general formula (I-A-1) is reduced to obtain the compound of the general formula (I-B-1), and the reducing agent is selected from H₂、Pt、Fe、Zn、LiAlH₄Or NaBH₄；

If R is⁴Is nitro, then R in the compound of the general formula (I-A-1)⁶Is H and reacts with a nitrating reagent (such as nitric acid and the like) to obtain a compound with a general formula (I-B' -1); the nitro group of the compound of the general formula (I-B' -1) is reduced to obtain a compound of the general formula (I-B-1);

if R is⁴Is alkyl, then R in the compound of the formula (I-A-1)⁶H, reacting with a format reagent or an alkyl lithium reagent and the like to obtain a compound of a general formula (I-B '-1), and reducing the nitro of the compound of the general formula (I-B' -1) to obtain a compound of the general formula (I-B-1);

Otherwise: compounds of the general formula (I-A-1) and H-R⁴Reacting in the presence of a base to obtain a compound with a general formula (I-B '-1), wherein the nitro group of the compound with the general formula (I-B' -1) is reduced to obtain the compound with the general formula (I-B-1), the base is selected from diisopropylethylamine, diisopropylamine, triethylamine, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium tert-butoxide, potassium acetate, sodium hydride or cesium carbonate, and the reducing agent is selected from H₂、Pt、Fe、Zn、LiAlH₄Or NaBH₄；

Reacting the compound of the general formula (I-B-1) with an acryloyl halide (e.g., acryloyl chloride) or acrylic acid in the presence of a base selected from diisopropylethylamine, diisopropylamine, triethylamine, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium tert-butoxide, potassium acetate, sodium hydride, cesium carbonate, or the like, to obtain a compound of the general formula (II);

the compound of the general formula (I-A-1) is obtained by purchasing or referring to a literature method such as WO 2013014448.

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include carbon isotopes ¹²C、¹³C and¹⁴c, isotopes of hydrogen including protium (H), deuterium (D, also known as deuterium), tritium (T, also known as deuterium), and isotopes of oxygen including¹⁶O、¹⁷O and¹⁸isotopes of O, sulfur including³²S、³³S、³⁴S and³⁶isotopes of S, nitrogen include¹⁴N and¹⁵isotopes of N, F¹⁹Isotopes of F, chlorine including³⁵Cl and³⁷cl, isotopes of bromine including⁷⁹Br and⁸¹Br。

"alkyl" means a straight and branched chain saturated aliphatic hydrocarbon group having a main chain comprising 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, still more preferably 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms, 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, 2-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, 3-dimethyl-2-butyl3, 3-dimethyl-2-butyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2-dimethylpentyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2-dimethylhexyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylhexyl, 2-ethylhexyl-pentyl, 2-ethylhexyl, 5-pentyl, 2-pentyl, 3-ethylhexyl, N-nonyl, 2-methyl-2-ethylhexyl, n-decyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, and are preferably selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid ester, - (CH) O, carbonyl, aldehyde, carboxylic acid ester, and the like ₂)_r-C(＝O)-R^a、 -O-(CH₂)_r-C(＝O)-R^a、-(CH₂)_r-C(＝O)-NR^bR^c、-(CH₂)_rS(＝O)_qR^a、-(CH₂)_r-alkenyl-R^a、OR^dOr- (CH)₂)_r-alkynyl-R^a(wherein r, q are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cWherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, and trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocycloalkyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged, spiro, or fused ring.

"alkylene" refers to straight or branched chain alkanes derived from the above alkyl group by removal of two hydrogen atoms, and includes- (CH)₂)_v- (v being an integer from 1 to 18), alkylene radicalsExamples include, but are not limited to, methylene, ethylene, and propylene, among others. The alkylene group may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid ester, - (CH) ₂)_r-C(＝O)-R^a、-O-(CH₂)_r-C(＝O)-R^a、-(CH₂)_r-C(＝O)-NR^bR^c、-(CH₂)_rS(＝O)_qR^a、 -(CH₂)_r-alkenyl-R^a、OR^dOr- (CH)₂)_r-alkynyl-R^a(wherein r, q are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cWherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or fused ring.

"alkoxy" means an-O-alkyl group, wherein alkyl is as defined herein above. Alkoxy groups may be substituted or unsubstituted, and examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and the like. When substituted, the substituents are preferably 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, carboxylic ester- (CH), aryl ester, heteroaryl ₂)_r-C(＝O)-R^a、-O-(CH₂)_r-C(＝O)-R^a、 -(CH₂)_r-C(＝O)-NR^bR^c、-(CH₂)_rS(＝O)_qR^a、-(CH₂)_r-alkenyl-R^a、OR^dOr- (CH)₂)_r-alkynyl-R^a(wherein r, q are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cWherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, and trifluoromethanesulfonyl, and optionally, R^bAnd R^cMay form a five-or six-membered cycloalkyl or heterocyclyl radical, R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring.

"alkenyl" means an alkyl group as defined herein above consisting of at least one carbon-carbon double bond, preferably containing 2 to 20 carbon atoms, more preferably 2 to 12 carbon atoms, and more preferably 2 to 8 carbon atoms in the main chain, and 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-pentenyl, 3-pentenyl, 4-pentenyl, 1-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, 2-pentenyl, and the like, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadiene, 3-undecenyl, 4-dodecenyl, and 4,8, 12-tetradecatrienyl, and the like. When substituted, the substituents are 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, fused, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, carboxylate ester, - (CH, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, fused, hydroxyalkyl, (-) O, carbonyl, aldehyde, carboxylic acid, carboxylate ₂)_r-C(＝O)-R^a、-O-(CH₂)_r-C(＝O)-R^a、-(CH₂)_r-C(＝O)-NR^bR^c、-(CH₂)_rS(＝O)_qR^a、 -(CH₂)_r-alkenyl-R^a、OR^dOr- (CH)₂)_r-alkynyl-R^a(wherein r, q are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cWherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or fused ring.

"alkynyl" means an alkyl group as defined herein above consisting of 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 from 2 to 4 carbon atoms in the backbone. Alkynyl groups may 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-nonynyl, 4-decynyl, 3-undecylynyl, 4-dodecaynyl and the like; when substituted, the substituents are preferably one or more groups independently selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid ester, - (CH) ₂)_r-C(＝O)-R^a、-O-(CH₂)_r-C(＝O)-R^a、 -(CH₂)_r-C(＝O)-NR^bR^c、-(CH₂)_rS(＝O)_qR^a、-(CH₂)_r-alkenyl-R^a、OR^dOr- (CH)₂)_r-alkynyl-R^a(wherein r, q are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cWherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, and trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring.

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

"amino" means-NH₂。

"acyl" or "carbonyl" refers to-C (═ O) -R^aGroup, wherein R^aAs defined above.

"aldehyde" refers to-C (═ O) -H.

"thio" means ═ S.

"halogen" means fluorine, chlorine, bromine, iodine.

"hydroxy" means-OH.

"cyano" means-C.ident.N.

"isocyano" means-N.ident.C.

"nitro" means-NO₂。

"carboxylic acid" refers to-C (═ O) -OH.

"Carboxylic acid ester" means-C (═ O) -O-R^d，R^dSelected from alkyl, cycloalkyl or heterocyclyl.

"mercapto" means-SH.

"mercaptan" refers to a hydrocarbon in which one or more hydrogen atoms in the alkyl group are replaced with a mercapto group, non-limiting examples include methyl mercaptan, ethyl mercaptan, 1, 2-dithiol.

"carbocyclic" means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a monocyclic, bicyclic, tricyclic or polycyclic ring system, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentene, cyclohexadiene, cycloheptatriene, phenyl, naphthyl, benzocyclopentyl, bicyclo [3.2.1 ] bicyclo]Octyl, bicyclo [5.2.0 ]]Nonanyl, tricyclo [5.3.1.1]Dodecyl, adamantyl or spiro [3.3 ]]Heptalkyl, and the like. When substituted, the substituents are independently selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid ester, - (CH), aryl, heteroaryl, heterocyclic, and heterocyclic₂)_r-C(＝O)-R^a、-O-(CH₂)_r-C(＝O)-R^a、-(CH₂)_r-C(＝O)-NR^bR^c、-(CH₂)_rS(＝O)_qR^a、-(CH₂)_r-alkenyl-R^a、OR^dOr- (CH)₂)_r-alkynyl-R^a(wherein r, q are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR ^bR^cWherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring.

"heterocycle" means a substituted or unsubstituted saturated or unsaturated aromatic, non-aromatic ring and contains at least one heteroatom selected from N, O, P or S, and optionally substituted N, S, P in the heterocyclic ring can be oxidized to various oxidation states. The aromatic and non-aromatic rings may be monocyclic, bicyclic, tricyclic or polycyclic ring systems, without limitationIllustrative examples include ethylene oxide, aziridine, oxetane, azetidine, 1, 3-dioxolane, 1, 4-dioxolane, 1, 3-dioxane, azepinyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, perinyl, morpholinyl, thiomorpholinyl, 1, 3-dithiane, dihydrofuran, dihydropyran, dithiane, tetrahydrofuran, tetrahydropyrrole, tetrahydroimidazol, thiazolidine, pyrrolopyridine, chroman, azabicyclo [ 3.2.1.1 ] azabicyclo [3.2.1 ]Octyl, azabicyclo [5.2.0 ] groups]Nonoalkyl oxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl, oxaspiro [3.3 ]]A heptylalkyl group,

Etc.; when substituted, the substituents are preferably 1 to 5, independently selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged, spiro, fused, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid ester, - (CH2)_r-C(＝O)-R^a、-O-(CH2)_r-C(＝O)-R^a、-(CH2)_r-C(＝O)-NR^bR^c、-(CH2)_rS(＝O)_qR^a、 -(CH2)_r-alkenyl-R^a、OR^dOr- (CH2)_r-alkynyl-R^a(wherein r, q are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cWherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or fused ring.

"cycloalkyl" means a saturated or unsaturated monocyclic cycloalkyl group, which may be substituted or unsubstituted, and the ring carbon atoms include 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, further preferably 3 to 8 carbon atoms, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1, 5-cyclooctadienyl, 1, 4-cyclohexadienyl, cycloheptatrienyl, and the like. When substituted, the substituents are 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, fused, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid ester, - (CH, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, fused, hydroxyalkyl, (-) O, carbonyl, aldehyde, carboxylic acid ₂)_r-C(＝O)-R^a、 -O-(CH₂)_r-C(＝O)-R^a、-(CH₂)_r-C(＝O)-NR^bR^c、-(CH₂)_rS(＝O)_qR^a、-(CH₂)_r-alkenyl-R^a、OR^dOr- (CH)₂)_r-alkynyl-R^a(wherein r, q are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cWherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring.

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

When substituted, the substituents are 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid ester, - (CH, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, (-) O, carbonyl, aldehyde ₂)_r-C(＝O)-R^a、 -O-(CH₂)_r-C(＝O)-R^a、-(CH₂)_r-C(＝O)-NR^bR^c、-(CH₂)_rS(＝O)_qR^a、-(CH₂)_r-alkenyl-R^a、OR^dOr- (CH)₂)_r-alkynyl-R^a(wherein r, q are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cWherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring.

"fused ring" means 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 0 or more double bonds, and may be substituted or unsubstituted, and each ring in the fused ring system may contain 0 to 5 rings selected from N, S (═ O)_nOr a heteroatom of O. Preferably 5 to 20, more preferably 5 to 14, more preferably 5 to 12, and even more preferably 5 to 10 yuan. Non-limiting examples include

When substituted, the substituents are 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid ester, - (CH, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, fused ring, hydroxyalkyl, (-) O, carbonyl, aldehyde, carboxylic ₂)_r-C(＝O)-R^a、-O-(CH₂)_r-C(＝O)-R^a、-(CH₂)_r-C(＝O)-NR^bR^c、-(CH₂)_rS(＝O)_qR^a、-(CH₂)_r-alkenyl-R^a、OR^dOr- (CH)₂)_r-alkynyl-R^a(wherein r, q are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cWherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring.

"bridged ring" means any two polycyclic group of carbon atoms not directly attached, which may contain 0 or more double bonds, and which may be substituted or unsubstituted, and any ring in the fused ring system may contain 0 to 5 rings selected from N, S (═ O)_nOr an O heteroatom or group (where n is 1, 2). The ring atoms contain 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 substituents are 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto Group, amino group, cyano group, isocyano group, aryl group, heteroaryl group, heterocyclic group, bridged ring group, spiro ring group, fused ring group, hydroxyalkyl group, (═ O, carbonyl group, aldehyde, carboxylic acid ester, - (CH)₂)_r-C(＝O)-R^a、-O-(CH₂)_r-C(＝O)-R^a、-(CH₂)_r-C(＝O)-NR^bR^c、-(CH₂)_rS(＝O)_qR^a、-(CH₂)_r-alkenyl-R^a、OR^dOr- (CH)₂)_r-alkynyl-R^a(wherein r, q are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cWherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring.

"benzyl" means-CH₂-phenyl, said phenyl being substituted or unsubstituted, non-limiting examples of which include-CH₂-phenyl, -CH₂P-methylphenyl, and the like.

"aryl" refers to substituted or unsubstituted 6 to 14 membered cyclic aromatic groups, including monocyclic aromatic groups and fused ring aromatic groups. Preferably 6 to 14-membered aromatic ring, further preferably 6 to 10-membered aromatic ring, non-limiting examples of which include phenyl, naphthyl, anthryl, phenanthryl and the like. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

When substituted, the substituents are 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy,Haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged cyclic, spiro cyclic, fused cyclic, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid ester, - (CH)₂)_r-C(＝O)-R^a、 -O-(CH₂)_r-C(＝O)-R^a、-(CH₂)_r-C(＝O)-NR^bR^c、-(CH₂)_rS(＝O)_qR^a、-(CH₂)_r-alkenyl-R^a、OR^dOr- (CH)₂)_r-alkynyl-R^a(wherein r, q are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cWherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from the group consisting of aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, and fused ring.

"heteroaryl" refers to a substituted or unsubstituted 5 to 14 membered aromatic ring and contains 1 to 5 substituents selected from N, O or S (═ O)_nA hetero atom or group, preferably a 5-to 10-membered heteroaromatic ring, further preferably 5-to 6-membered. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholine, thiomorpholine, 1, 3-dithiane, benzimidazole, perindopyl, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include

When substituted, 1 to 5 substituents are selected from F, Cl, Br, I, alkylA group, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, fused ring, hydroxyalkyl, (-) O, carbonyl, aldehyde, carboxylic acid ester, - (CH)₂)_r-C(＝O)-R^a、 -O-(CH₂)_r-C(＝O)-R^a、-(CH₂)_r-C(＝O)-NR^bR^c、-(CH₂)_rS(＝O)_qR^a、-(CH₂)_r-alkenyl-R^a、OR^dOr- (CH)₂)_r-alkynyl-R^a(wherein r, q are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cWherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring.

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

"silyl" refers to a group formed by substituting one or more hydrogen atoms in silane with an alkyl group, and examples include, but are not limited to, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and the like.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

"pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the biological effectiveness and properties of the free acid or free base are maintained and the free acid is obtained by reaction with a non-toxic inorganic or organic base or salts of the free acid obtained by reaction with a non-toxic inorganic or organic acid, including alkali metal salts such as sodium, potassium, lithium, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; other metal salts such as iron salts, copper salts, cobalt salts, etc.; organic base salts such as ammonium salts, triethylamine salts, pyridine salts, picoline salts, 2, 6-lutidine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, cyclohexylamine salts, ethylenediamine salts, guanidine salts, isopropylamine salts, trimethylamine salts, tripropylamine salts, triethanolamine salts, diethanolamine salts, ethanolamine salts, dimethylethanolamine salts, dicyclohexylamine salts, caffeine salts, procaine salts, choline salts, betaine salts, benzamidine penicillin salts, glucamine salts, N-methylglucamine salts, theobromine salts, tromethamine salts, purine salts, piperazine salts, morpholine salts, piperidine salts, N-ethylpiperidine salts, tetramethylamine salts, dibenzylamine salts, phenylglycine alkyl ester salts and the like; hydrohalic acid salts such as hydrofluoride, hydrochloride, hydroiodide, hydrobromide and the like; inorganic acid salts such as hydrochloride, nitrate, sulfate, perchlorate, phosphate and the like; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate and the like; arylsulfonates such as benzenesulfonate, p-toluenesulfonate and the like; organic acid salts such as acetate, benzoate, fumarate, formate, trifluoroacetate, furoate, gluconate, glutamate, glycolate, isethionate, lactate, maleate, malate, mandelate, mucate, pamoate, pantothenate, stearate, succinate, sulfa, 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 compounds described herein or a physiologically/pharmaceutically acceptable salt thereof with other ingredients, wherein the other ingredients comprise physiologically/pharmaceutically acceptable carriers and excipients.

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

"excipient" refers to an inert substance 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 types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.

"prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis to a compound of the invention that is biologically active. Prodrugs of the invention are prepared by modifying the phenolic groups in the compounds, which modifications may be removed in vivo or by conventional procedures, to provide the parent compounds. When a prodrug of the present 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 hydroxy and phosphoric acid sodium salt derivatives of the compounds of the present invention.

"cocrystal" or "cocrystal" refers to a crystal of an Active Pharmaceutical Ingredient (API) and a cocrystal former (CCF) combined by hydrogen bonding or other non-covalent bonds, wherein the API and CCF are both solid in pure form at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal formed between a neutral solid and a salt or solvate. The "co-crystal former" includes, but is not limited to, various pharmaceutically acceptable acids, bases, non-ionic compounds, water, amino acids, alcohols or other solvents, non-limiting examples of which include alanine (Ala), valine (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 (gin), 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, vinylsulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic 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, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid, ammonia, isopropylamine, trimethylamine, diethylamine, triethylammonium, tripropylammonium, diethanolamine, ethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, and mixtures thereof, Procaine, choline, betaine, phentermine, ethylenediamine, glucosamine, methylglucamine, theobromine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, methanol, ethanol, butynediol, 1, 2-propanediol, (R)1, 2-propanediol, (S)1, 2-propanediol or 1-methyl-1, 2-ethanediol.

An "effective dose" refers to an amount of a compound that causes physiological or medical translation in a tissue, system, or subject that is sought, including an amount of the compound that is sufficient to prevent, or alleviate to some extent, one or more symptoms of the condition or disorder being treated when administered to a subject.

"solvates" refers to compounds of the invention or salts thereof, which also include stoichiometric or non-stoichiometric amounts of solvents bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

The technical solutions of the present invention are described in detail below with reference to examples, but the scope of the present invention includes, but is not limited to, these examples.

Detailed Description

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

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) by 10^-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).

HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6 mm).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Anniji chemistry, Shanghai Demer, Chengdong chemical, Shaoshanghi chemical technology, and Bailingwei technology.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is room temperature, unless otherwise specified.

The room temperature is the most suitable reaction temperature and is 20-30 ℃.

Boc is tert-butyloxycarbonyl;

n-Bu is n-butyl;

t-Bu is tert-butyl;

TBS is tert-butyl dimethyl silicon base;

TIPS is triisopropylsilyl.

Intermediate 1

5- (difluoromethoxy) -N¹- (2- (dimethylamino) ethyl) -N¹-methyl-2-nitrophenyl-1, 4-diamine (intermediate 1)

5-(difluoromethoxy)-N¹-(2-(dimethylamino)ethyl)-N¹-methyl-2-nitrobenzene-1,4-dia mine

The first step is as follows: (4-fluoro-2-hydroxyphenyl) carbamic acid tert-butyl ester (1b)

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

2-amino-5-fluorophenol 1a (5g, 39.4mmol) and tetrahydrofuran (100mL) were added to a reaction flask, and after dissolving with stirring, di-tert-butyl dicarbonate (17.2g, 78.7mmol) was added, and the reaction was stirred at room temperature for two days. Concentrated to dryness under reduced pressure, water (150mL), ethyl acetate (200mL) were added to the residue, liquid separation was performed with stirring, the aqueous layer was extracted with ethyl acetate (150mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20:1) to give tert-butyl (4-fluoro-2-hydroxyphenyl) carbamate (1b) as an off-white solid (6g, yield 67%).

¹H NMR(400MHz,CDCl₃)δ8.55(s,1H),6.95(dd,1H),6.69(dd,1H),6.56(ddd, 2H),1.52(s,9H)。

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

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

Tert-butyl (4-fluoro-2-hydroxyphenyl) carbamate (1b) (4g, 17.6mmol) and acetonitrile (40mL) were added to a reaction flask, cooled in an ice bath, added with a solution of potassium hydroxide (19.7g, 352mmol) in water (40mL), cooled to-78 deg.C, and added dropwise with diethyl bromofluoromethylphosphate (11.8g, 44.1mmol) and allowed to warm to room temperature for 30 minutes. To the reaction solution was added ethyl acetate (100mL), followed by liquid separation with stirring, extraction of the aqueous layer with ethyl acetate (50mL × 2), combination of organic phases, drying of the organic phase with anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20:1) to give tert-butyl (2- (difluoromethoxy) -4-fluorophenyl) carbamate (1c) as a yellow liquid (3g, 61% yield).

¹H NMR(400MHz,CDCl₃)δ8.09(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 (10mL) and water (0.7mL) were added to the reaction flask, cooled in an ice bath, tert-butyl (2- (difluoromethoxy) -4-fluorophenyl) carbamate (1c) (2.7g, 9.8mmol) was added, stirring was completed for 10 minutes, potassium nitrate (0.98g, 9.8mmol) was slowly added, and the reaction was completed in an ice bath for 1 hour. The reaction solution was poured into ice water (50mL), cooled in an ice bath, the pH of the system was adjusted to 9 with aqueous ammonia, extracted with ethyl acetate (50mL × 3), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20:1-10:1) to give 2- (difluoromethoxy) -4-fluoro-5-nitroaniline (1d) as a brown solid (370mg, yield 17%).

¹H NMR(400MHz,DMSO-d₆)δ7.50(d,1H),7.32(s,1H),7.29(t,1H),6.52(t,1H), 5.59(s,2H)。

The fourth step: 5- (difluoromethoxy) -N¹- (2- (dimethylamino) ethyl) -N¹-methyl-2-nitrophenyl-1, 4-diamine (intermediate 1)

To a reaction flask were added 2- (difluoromethoxy) -4-fluoro-5-nitroaniline (1d) (250mg, 1.15mmol), N, N, N '-trimethylethylenediamine (18A) (118mg, 1.15mmol), diisopropylethylamine (375mg, 2.9mmol) and N, N' -dimethylacetamide (5mL), and reacted at 140 ℃ for 1 hour under microwave. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50:1) to give 5- (difluoromethoxy) -N as a brown oil ¹- (2- (dimethylamino) ethyl) -N¹Methyl-2-nitrophenyl-1, 4-diamine (intermediate 1) (120mg, 34% yield).

MS m/z(ESI):305.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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

The first step is as follows: 3- (2-Chloropyrimidin-4-yl) -1H-indole (2b)

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

Indole (4g, 34.1mmol) and 1, 2-dichloroethane (114mL) were added to the reaction flask, and after stirring and dissolution, the mixture was cooled in an ice bath, and a 3mol/L methylmagnesium bromide tetrahydrofuran solution (11.4mL, 34.1mmol) was added dropwise. After the incubation was completed for 15 minutes, 2, 4-dichloropyrimidine (2a) (5.6g, 37.6mmol) was added, and the mixture was allowed to slowly warm to room temperature for reaction for 3 hours. The reaction solution was cooled in an ice bath, methanol (10mL) was added dropwise, the mixture was stirred for 15 minutes, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4:1-2:1) to give 3- (2-chloropyrimidin-4-yl) -1H-indole (2b) as a yellow solid (2.9g, yield 37%).

MS m/z(ESI):230.1[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ12.07(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)。

The second step is that: 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) (2.5g, 10.9mmol) and tetrahydrofuran (77mL) were added to a reaction flask, and after stirring and dissolving, the mixture was cooled in an ice bath, sodium hydride (0.48g, 12mmol) was added in portions, the reaction was allowed to proceed for 30 minutes after completion of the incubation, methyl iodide (0.75mL, 12mmol) was added dropwise, and the reaction was allowed to proceed for 2 hours after completion of the incubation. To the reaction solution were added saturated aqueous sodium bicarbonate (100mL), ethyl acetate (200mL), and the mixture was stirred, separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (50mL × 1) and saturated brine (50mL × 1) in this order, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was slurried with dichloromethane (10mL × 1) to give 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (intermediate 2) (2.3g, yield 85%) as a pale yellow solid.

MS m/z(ESI):244.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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

Reference is made to the synthesis of intermediate 129 of WO 2013014448.

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

The first step is as follows: 3- (2, 5-dichloropyrimidin-4-yl) -1H-indole (4b)

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

Indole 4a (12.78g, 109mmol) was dissolved in tetrahydrofuran (60mL), cooled to 0 ℃ under nitrogen, methyl magnesium bromide (36.4mL, 109mmol) was added dropwise, stirring was continued for 0.5 h, trichloropyrimidine (10g, 54.5 mmol) was added, the reaction was carried out at room temperature for 1h, and the reaction was carried out at 60 ℃ for 1.5 h. The reaction mixture was cooled to room temperature, acetic acid (6.34 mL) was added dropwise, the mixture was stirred for 10 minutes, water (100mL) and tetrahydrofuran (30mL) were added, the mixture was stirred at 60 ℃ for 30 minutes, the mixture was separated, n-heptane (100mL) was added to the organic phase to precipitate a yellow solid, the yellow solid was filtered, the filter cake was washed with n-heptane (100mL), and the filter cake was dried to give 3- (2, 5-dichloropyrimidin-4-yl) -1H-indole (4b) (13g, yield 91%).

MS m/z:264.0[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ12.26(s,1H),8.73(s,2H),8.53(s,1H),7.57(s, 1H),7.28(s,2H)。

The second step is that: 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) (6g, 22.8mmol) was dissolved in tetrahydrofuran (100mL), cooled to 0 deg.C, sodium hydride (1.1g, 27.4mmol) was added, the reaction was continued for 30 minutes, methyl iodide (4.26 mL, 68.4mmol) was added, and the mixture was allowed to warm to room temperature for 2 hours. The reaction was concentrated and the residue was washed with water (50mL) and tetrahydrofuran (50mL), filtered, and the filter cake was dried to give the compound 3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1H-indole (4c) as a yellow solid (4.7g, 75% yield).

MS m/z:278.0[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ8.75(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) (17.1g, 0.1mmol) was dissolved in concentrated sulfuric acid (100mL) under ice bath, and potassium nitrate (10.1g, 0.1mmol) was slowly added thereto to react at 10 ℃ for 2 hours. The reaction solution was poured into crushed ice, aqueous ammonia was added to adjust the pH to 8, ethyl acetate (400 mL. times.2) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 4-fluoro-2-methoxy-5-nitroaniline (4e) as a yellow solid (18.6g, crude product).

¹H NMR(400MHz,DMSO-d₆)δ7.34(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) (1g, 3.6mmol) was dissolved in 2-pentanol (100mL), and 4-fluoro-2-methoxy-5-nitroaniline (4e) (672mg, 3.6mmol) and p-toluenesulfonic acid (822mg, 4.32mmol) were added, and the reaction was heated to 120 ℃ and refluxed for 2 days. The reaction was cooled to room temperature, acetonitrile (50mL) was added, filtered, the filter cake was washed with acetonitrile (50mL) and water (50mL) in sequence, and the filter cake was dried to give 5-chloro-N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (intermediate 4) as a pale green solid (1.48g, 97%).

MS m/z:428.0[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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-nitrobenzene (intermediate 5)

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

The first step is as follows: (E) -4- (2-butoxyvinyl) -2, 5-dichloropyrimidine (5b)

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

2,4, 5-trichloropyrimidine (5a) (5g,27.3mmol), 1-butoxyethylene (2.85g,28.5mmol), triethylamine (2.88g,28.5mmol) and palladium acetate (0.21g,0.95mmol) were added to polyethylene glycol (30mL) and reacted at 50 ℃ for 5 hours under nitrogen. The reaction solution was cooled to room temperature, water (50mL) was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 50:1) to give the title compound (E) -4- (2-butoxyvinyl) -2, 5-dichloropyrimidine (5b) as a yellow solid (0.6g, yield 9%).

¹H NMR(400MHz,CDCl₃)δ8.32(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)。

The second step is that: 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) (0.6g,2.4mmol), 1-amino-pyridin-1-ium (0.6g,2.4mmol) and potassium carbonate (0.84g,6.0mmol) were added to N, N-dimethylformamide (30mL) and reacted at room temperature to 110 ℃ for 5 hours. After cooling to room temperature, water (20mL) was added to the reaction solution, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10:1) to give the title compound 3- (2, 5-dichloropyrimidin-4-yl) pyrazolo [1,5-a ] pyridine (5c) as a yellow solid (0.1g, yield 16%).

¹H NMR(400MHz,DMSO-d₆)δ9.08(s,1H),8.96(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-nitrophenyl (intermediate 5)

3- (2, 5-dichloropyrimidin-4-yl) pyrazolo [1,5-a ] pyridine (5c) (1g,3.7mmol), 4-fluoro-2-methoxy-5-nitroaniline (0.84g,4.5mmol) and p-toluenesulfonic acid (1.08g,5.6mmol) were added to 2-pentanol (30mL), and the mixture was heated to 120 ℃ for 12 hours. Cooled to room temperature, methanol (50mL) was added to the reaction solution, filtered, the filter cake was washed with diethyl ether (30mL), and the filter cake was 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) as a yellow solid (1g, 64% yield).

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

Reference is made to the synthesis of intermediate 68 of WO 2013014448.

Intermediate 7

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

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

The first step is as follows: 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) (15g, 0.11mol) and tetrahydrofuran (90mL) are added into a reaction bottle, the mixture is cooled by an ice salt bath, 3mol/L methyl magnesium bromide tetrahydrofuran solution (37mL) is dripped, the internal temperature is kept lower than-5 ℃, the reaction is kept for 30 minutes after the dripping, 2,4, 5-trichloropyrimidine (10.2g,0.06mol) is added, and the temperature is raised to 60 ℃ after the addition for 1 hour. The reaction solution was cooled to room temperature, acetic acid (10mL), water (90mL), tetrahydrofuran (50mL) were added, the reaction was warmed to 60 ℃ for 1 hour, cooled to room temperature, the organic layer was separated, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 8:1-6:1) to give tert-butyl 3- (2, 5-dichloropyrimidin-4-yl) -4-fluoro-1H-indole (7b) as a yellow solid (3.7g, 24% yield).

MS m/z(ESI):280.1[M-1]^-。

¹H NMR(400MHz,DMSO-d₆)δ12.26(s,1H),8.87(s,1H),8.14(d,1H),7.37(d, 1H),7.23(td,1H),6.93(dd,1H)。

The second step is that: 5-chloro-4- (4-fluoro-1H-indol-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidin-2-amine (intermediate 7)

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

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) pyrimidin-2-amine (intermediate 8)

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

The first step is as follows: 3- (2-Chloropyrimidin-4-yl) -7-fluoro-1H-indole (8b)

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

7-fluoroindole (10g, 74mmol) and 1, 2-dichloroethane (270mL) are added into a reaction flask, after stirring and dissolution, the mixture is cooled in an ice bath, 3mol/L methyl magnesium bromide tetrahydrofuran solution (24.7mL, 74mmol) is added dropwise, the reaction is kept for 15 minutes after the dropwise addition, 2, 4-dichloropyrimidine (2a) (16g, 110mmol) is added, and the temperature is slowly raised to 45 ℃ for reaction for 24 hours. The reaction solution was cooled in an ice bath, methanol (100mL) was added dropwise, and the mixture was stirred for 15 minutes, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5:1-1:1) to give 3- (2-chloropyrimidin-4-yl) -7-fluoro-1H-indole (8b) (8.4g, yield 46.6%) as a yellow solid.

MS m/z(ESI):246.1[M-1]^-。

¹H NMR(400MHz,DMSO-d₆)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 is that: 3- (2-Chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (8c)

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

3- (2-Chloropyrimidin-4-yl) -7-fluoro-1H-indole (8b) (280mg, 1.13mmol) and tetrahydrofuran (14mL) were added to a reaction flask, stirred to dissolve, cooled in an ice bath, added sodium hydride (58mg, 2.4mmol) in portions, incubated for 30 minutes after completion of the incubation, added iodomethane (0.15mL, 2.4mmol) dropwise, incubated for 30 minutes after completion of the incubation, and heated to 40 ℃ for 3 hours. The reaction mixture was cooled in an ice bath, water (10mL) was added, extraction was performed with ethyl acetate (20mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3:1) to give 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (8c) as a yellow solid (260mg, 88% yield).

MS m/z(ESI):262.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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)。

The third step: 4- (7-fluoro-1-methyl-1H-indol-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidin-2-amine (intermediate 8)

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

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-pyrimidin-2-amine (intermediate 9)

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

The first step is as follows: (trans) -4- (2-n-butoxyvinyl) -2-chloro-5-methoxypyrimidine (9b)

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

2, 4-dichloro-5-methoxypyrimidine (9a) (10.74g,60mmol) was weighed out and placed in a 500mL round-bottomed flask, and polyethylene glycol 400(150mL), triethylamine (12.5mL,90.00mmol), vinyl-n-butyl ether (11.6mL,90.00mmol) and palladium acetate (0.67g,3mmol) were added to the flask in this order, and the mixture was heated to 80 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, water (200mL) was added, extraction was performed with ethyl acetate (250mL × 2), the organic phases were combined, the organic phase was washed with saturated brine (150mL), dried over anhydrous sodium sulfate, and concentrated and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5:1) to give (trans) -4- (2-n-butoxyvinyl) -2-chloro-5-methoxypyrimidine (9b) as a yellow liquid (6.64g, yield 46%).

¹H NMR(400MHz,CDCl₃)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)。

The second step is that: 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) (9.0g,37.3mmol) was weighed out and placed in a 250mL round-bottomed flask, N-dimethylacetamide (100mL), 1-aminopyridine iodide (8.2g,37.3mmol) and potassium carbonate (12.9g,92.5mmol) were added in this order to a reaction flask, and the mixture was stirred at 110 ℃ for 24 hours. The reaction solution was cooled to room temperature, water (100mL) was added, extraction was performed with ethyl acetate (150mL × 2), the organic phases were combined, the organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, and concentrated and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3:1) to give 3- (2-chloro-5-methoxy-pyrimidin-4-yl) pyrazolo [1,5-a ] pyridine (9c) as a yellow solid (3.9g, yield 40%).

¹H NMR(400MHz,CDCl₃)δ8.81-8.78(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)。

The 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)

N-(4-fluoro-2-methoxy-5-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) (1.04g,4mmol) was weighed into a 50mL round-bottomed flask and 2-pentanol (15mL), 4-fluoro-2-methoxy-5-nitroaniline (0.74 g,4mmol), p-toluenesulfonic acid (0.84g,4.4mmol) were added to the reaction flask in that order. The reaction system was warmed to 120 ℃ and stirred for 48 hours and then cooled to room temperature. Acetonitrile (20mL), aqueous ammonia (20mL) was added to the reaction flask. Filtration, washing of the filter cake with acetonitrile (10mL × 2), washing with water (10mL × 2), collecting the filter cake, and drying to give N- (4-fluoro-2-methoxy-5-nitro-phenyl) -5-methoxy-4-pyrazolo [1,5-a ] pyridin-3-yl-pyrimidin-2-amine (intermediate 9) (0.6g, 37% yield) as a yellow solid.

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-a mine

The first step is as follows: 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) (3g,12mmol), 3, 4-difluoro-2-methoxy-5-nitroaniline (10a) (3g,14mmol) and p-toluenesulfonic acid (3.5g,18mmol) were added to 2-pentanol (30mL) and reacted at 120 ℃ for 12 hours. The reaction was cooled to room temperature, methanol (50mL) was added, filtered, the filter cake was washed with ethyl ether (30mL), and the filter cake was dried to give the title compound N- (3, 4-difluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (intermediate 10) as a yellow solid (3g, 62.5% yield).

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] nonan-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

The first step is as follows: 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 (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-nitrobenzene (intermediate 5) (0.3g,0.72mmol), 1-methyl-1, 7-diazaspiro [4.4] nonane (1A) (0.15g,10.8mmol) and N, N-diisopropylethylamine (i.e., DIPEA) (0.28g,2.17mmol) were added to N, N-dimethylformamide (3 mL) and reacted with microwaves at 140 ℃ for 1.5 hours. Cooled to room temperature, water (20mL) was added to the reaction solution, extracted with ethyl acetate (50mL × 3), the organic phases were combined, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the title compound 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 (1B) as a red solid (0.3g, yield 79%).

¹H NMR(400MHz,DMSO-d₆)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]⁺。

The second step is that: 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 (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] nonan-7-yl) -1-nitrobenzene (1B) (0.6g,1.12mmol), iron powder (0.378g,6.7mmol) and ammonium chloride were added to a mixed solution of ethanol (20mL) and water (5mL) and reacted at 90 ℃ for 4 hours. Cooled to room temperature, water (20mL) was added to the reaction solution, extracted with dichloromethane (50mL × 3), the organic phases were combined, washed with water (50mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the title compound 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 (1C), a red solid (0.56g, crude product).

¹H NMR(400MHz,DMSO-d₆)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] nonan-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] nonan-7-yl) aniline (1C) (0.6g,1.1mmol), N-ethyldiisopropylamine (0.3g,2.2mmol) were added to tetrahydrofuran (20mL) and a solution of acryloyl chloride (0.1g,1.1mmol) in tetrahydrofuran (5mL) was added dropwise at-40 ℃ and allowed to react at this temperature for half an hour. Water (10mL) was added to the reaction solution, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 50:1) to give the title compound 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 (compound 1) as a yellow solid (0.18g, yield 27%).

¹H NMR(400MHz,CDCl₃)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] nonan-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] nonan-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 method of example 2 and example 3 is as follows:

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 (compound 1) (100mg) was taken for resolution under the conditions: instrument GX-281C0630, (0.1% diethylamine + n-hexane)/isopropanol 70/30, 10.0mL/min, 254nm, column temperature 40 ℃ (AD-H20 × 250mm 5um H-37); two optical isomers were obtained: isomer 1 (peak 1, 50mg, yellow solid, ee% ═ 100%, t ═ 33.97min), isomer 2 (peak 2, 50mg, yellow solid, ee% ═ 100%, t ═ 40.78 min).

Isomer 1

¹H NMR(400MHz,CDCl₃)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

¹H NMR(400MHz,CDCl₃)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-diazaspiro [4.4] nonan-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 triflouro

The first step is as follows: 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 (4B)

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazasp iro[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) (1.0g,2.5mmol) and N, N-diisopropylethylamine (0.65g,5.0mmol) were added to N, N-dimethylformamide (3mL) and reacted with microwaves at 140 ℃ for 1.5 hours. After cooling to room temperature, water (20mL) was added to the reaction solution, extraction was performed with dichloromethane (50mL × 3), the organic phases were combined, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 50:1) to give the title compound 5- ((5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2- (1-methyl-1, 7-diazaspiro [4.4] nonan-7-yl) -1-nitrobenzene (4B) as a yellow solid (0.5g, yield 38.4%).

¹H NMR(400MHz,DMSO-d₆)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]⁺。

The second step is that: 5- ((4- (1-methylindol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2- (1-methyl-1, 7-diazaspiro [4.4] nonan-7-yl) aniline (4C)

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazasp iro[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] nonan-7-yl) -1-nitrobenzene (4B) (0.5g,0.97mmol), iron powder (0.32g,5.8mmol) and ammonium chloride (0.52g,9.7 mmol) were added to a mixed solution of ethanol (5 mL)/water (2mL) and reacted at 90 ℃ for 4 hours. Cooled to room temperature, water (20mL) was added to the reaction solution, extracted with dichloromethane (50mL × 3), the organic phases were combined, washed with water (50mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the title compound 5- ((4- (1-methylindol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2- (1-methyl-1, 7-diazaspiro [4.4] nonan-7-yl) aniline (4C) as a yellow solid (0.4g, 85% yield).

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] nonan-7-yl) phenyl) acrylamide (4D)

N-(5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diaz aspiro[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] nonan-7-yl) aniline (4C) (0.5g,1mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (0.149g,2.0mmol) and acrylic acid (0.79g,4mmol) were added to pyridine (5mL) and reacted at room temperature for 2 hours. Water (10mL) was added to the reaction solution, extraction was performed with dichloromethane (50mL × 3), the organic phases were combined, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 50:1) to give the title compound 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 (4D) as a yellow solid (0.2g, yield 36%).

¹H NMR(400MHz,DMSO-d₆)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]⁺。

The fourth step: 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 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-diazaspiro [4.4] nonan-7-yl) phenyl) acrylamide (4D) (50mg,0.09mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (15mg) was added, and stirring was carried out at room temperature for 30 minutes, followed by concentration to give 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 trifluoroacetate (Compound 4), yellow solid (57 mg).

¹H NMR(400MHz,DMSO-d₆)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-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 trifluoroacetate

The first step is as follows: (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)

tert-butyl(1-((4-((5-chloro-4-(pyrazolo[1,5-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) (0.41g,1.00mmol) was placed in a round-bottom flask, tetrahydrofuran (20mL) was added to the reaction flask, cooled to 0 ℃, sodium hydride (0.08g,1.1mmol, wt% ═ 60%) was added to the reaction flask, stirred for 5 minutes, and (1-hydroxymethylcyclopropyl) -tert-butoxycarbonylamino (5A) (0.21g,1.1mmol) was added. The reaction was terminated after 4 hours when the temperature was raised to room temperature. Water (20mL) was added to the reaction flask, the aqueous phase was extracted with ethyl acetate (50mL × 2), the combined organic phases were washed with saturated brine (30mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1:1) to give tert-butyl (1- ((4- ((5-chloro-4- (pyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) -5-methoxy-2-nitrophenoxy) methyl) cyclopropyl) carbamate (5B) (0.56g, 97% yield) as a yellow solid.

¹H NMR(400MHz,CDCl₃)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 is that: (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-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)a mino)-5-methoxyphenoxy)methyl)cyclopropyl)carbamate

Tert-butyl (1- ((4- ((5-chloro-4- (pyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) -5-methoxy-2-nitrophenyloxy) methyl) cyclopropyl) carbamate (5B) (0.58g,1.0mmol) was weighed out and placed in a 100mL round-bottomed flask, ethanol (21mL), water (7mL), reduced iron powder (0.34g,6.0mmol) and ammonium chloride (0.037g,0.7mmol) were added in this order to a reaction flask, and the reaction was refluxed at elevated temperature and worked up after 6 hours. The reaction was filtered, the filter cake was washed with dichloromethane (10mL × 2) and methanol (10mL × 2) in that order, the filtrates were combined, concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1:1) to give tert-butyl (1- ((2-amino-4- ((5-chloro-4- (pyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) -5-methoxyphenoxy) methyl) cyclopropyl) carbamate (5C) (0.37g, 67% yield) as a gray solid.

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

Tert-butyl (1- ((2-amino-4- ((5-chloro-4- (pyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) -5-methoxyphenoxy) methyl) cyclopropyl) carbamate (5C) (0.37g,0.67mmol) was weighed, placed in a 100mL round-bottom flask, tetrahydrofuran (15mL) and diisopropylethylamine (0.12mL,0.74 mmol) were sequentially added to the reaction flask, cooled to 0 ℃, acryloyl chloride (0.055mL,0.70mmol) was added dropwise, and after the addition was completed, the temperature was raised for reaction for 1 hour. The reaction solution was concentrated under reduced pressure, methylene chloride (50mL) and a saturated aqueous solution of sodium hydrogencarbonate (30mL) were added to the residue, the aqueous phase was separated, the aqueous phase was extracted with methylene chloride (50mL), the organic phases were combined, the organic phase was washed with saturated brine (30mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (methylene chloride/methanol (v/v) ═ 10:1) to give 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 (5D) as a yellow solid (0.20g, yield 49%).

The 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

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 (5D) (0.2g,0.33mmol) was weighed and placed in a 100mL round-bottomed flask, and dichloromethane (15mL) and trifluoroacetic acid (5mL) were sequentially added to the reaction flask and 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 ] pyridin-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide trifluoroacetate (compound 5) as a yellow solid (0.03g, 15% yield).

MS m/z(ESI):506.3[(M-M_TFA)+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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

The first step is as follows: (1- (((4- ((5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxy-2-nitrophenyl) (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,2.4mmol), (1- ((methylamino) methyl) cyclopropyl) carbamic acid tert-butyl ester (6A) (0.96g,4.8mmol) and N, N-diisopropylethylamine (0.62g,4.8mmol) were added to trifluoroethanol (3mL) and reacted with microwaves at 140 ℃ for 1.5 hours. The reaction solution was cooled to room temperature, water (20mL) was added, extraction was performed with dichloromethane (50mL × 3), the organic phases were combined, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was chromatographed on a silica gel column (dichloromethane: methanol (v/v) ═ 50:1) to give the title compound (tert-butyl 1- (((4- ((5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxy-2-nitrophenyl) (methyl) amino) methyl) cyclopropyl) carbamate (6B), red solid (0.5g, yield 34.97%).

MS m/z:594.3[M+1]⁺。

The second step is that: (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

Tert-butyl (1- (((4- ((5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxy-2-nitrophenyl) (methyl) amino) methyl) cyclopropyl) carbamate (6B) (0.27g,0.45mmol), iron powder (0.15g,2.7mmol) and amine chloride (0.24g,4.5mmol) were added to ethanol (5mL) and water (2mL) and reacted at 90 ℃ for 4 hours. After cooling to room temperature, water (20mL) was added to the reaction solution, extraction was performed with dichloromethane (50 mL. times.3), the organic phases were combined, washed with water (50 mL. times.2), dried over anhydrous sodium sulfate, and concentrated to give the title compound (tert-butyl 1- (((4- ((5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxy-2-aminophenyl) (methyl) amino) methyl) cyclopropyl) carbamate (6C) as a yellow solid (0.18g, 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-indol-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

Tert-butyl (1- (((4- ((5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxy-2-aminophenyl) (methyl) amino) methyl) cyclopropyl) carbamate (6C) (0.16g,0.28mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.21g,1.1mmol) and acrylic acid (40.9mg,0.56mmol) were added to pyridine (5mL) and reacted at room temperature for 2 hours. Water (10mL) was added to the reaction solution, and extracted with dichloromethane (50mL × 3), the organic phases were combined, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 50:1) to give the title compound N- (2- (((1- (tert-butoxycarbonyl) aminocyclopropyl) methyl) (methyl) amino) -5- ((5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (6D) as a yellow solid (0.15g, yield 88%).

MS m/z:618.2[M+1]⁺。

The fourth step: 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- (tert-butoxycarbonyl) aminocyclopropyl) methyl) (methyl) amino) -5- ((5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (6D) (0.15g,0.24mmol) was added to dichloromethane (2mL) and trifluoroacetic acid (1mL) and reacted at room temperature for 2 hours. The reaction was concentrated to give the title compound 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) as a yellow solid (0.1g, 88% yield).

¹H NMR(400MHz,DMSO-d₆)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-methoxyphenyl) acrylamide (compound 7)

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

The first step is as follows: (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-metho xy-2-nitrophenoxy)methyl)cyclopropyl)carbamate

5-chloro-N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (intermediate 4) (650mg, 1.52mmol) was dissolved in tetrahydrofuran (50mL), and sodium hydride (121.6mg, 3.04 mmol, wt% ═ 60%) was added under ice-cooling, followed by stirring for 30 minutes, dropwise addition of tert-butyl (1- (hydroxymethyl) cyclopropyl) carbamate (313.1mg, 1.67mmol), and reaction at room temperature overnight. To the reaction mixture were added water (100mL) and ethyl acetate (150mL), the mixture was partitioned, the aqueous phase was extracted with ethyl acetate (100mL), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give compound (tert-butyl 1- ((2-nitro-4- ((5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxyphenoxy) methyl) cyclopropyl) carbamate (7B) as a yellow solid (903 mg).

MS m/z:595.1[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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 is that: (1- ((2-amino-4- ((5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxyphenoxy) 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

Tert-butyl (1- ((2-nitro-4- ((5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxyphenoxy) methyl) cyclopropyl) carbamate (7B) (900mg, 1.52mmol) was dissolved in ethanol (30mL), water (10mL), iron powder (509mg, 9.12mmol) and ammonium chloride (57mg, 10.6mmol) were added, the temperature was raised to 90 ℃ and the reaction was refluxed for 4 hours. The reaction was cooled to room temperature, filtered and concentrated. Separation and purification by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 20:1) gave compound (tert-butyl 1- ((2-amino-4- ((5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxyphenoxy) methyl) cyclopropyl) carbamate (7C) as a yellow-green solid (800mg, yield 93%).

MS m/z:565.2[M+1]⁺。

The 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

Tert-butyl (1- ((2-amino-4- ((5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxyphenoxy) methyl) cyclopropyl) carbamate (7C) (800mg, 1.4mmol) was dissolved in tetrahydrofuran (30mL), N-diisopropylethylamine (0.278mg, 1.68mmol) was added, the reaction was cooled to 0 ℃, a solution of acryloyl chloride (0.17mL, 2.1mmol) in tetrahydrofuran (5mL) was added dropwise, and the mixture was warmed to room temperature for 4 hours. To the reaction solution were added a saturated aqueous sodium bicarbonate solution (100mL) and dichloromethane (100mL), and the organic phase was separated, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 25:1) to give the compound N- (2- ((1- (tert-butoxycarbonyl) aminocyclopropyl) methoxy) -5- ((5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (7D) as a red solid (450mg, yield 52%).

MS m/z:619.2[M+1]⁺。

The 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) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (7D) (450mg, 0.73mmol) was dissolved in dichloromethane (12mL), and trifluoroacetic acid (3mL) was added to react at room temperature for 2 hours. To the reaction solution was added water (50mL), the pH was adjusted to 8 with a saturated aqueous solution of sodium hydrogen carbonate, ethyl acetate (100mL) was added, the layers were separated, the organic phase was concentrated, and the residue was purified to give N- (2- ((1-aminocyclopropyl) methoxy) -5- ((5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 7) as a pale yellow solid (70mg, yield 19%).

MS m/z:519.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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-(pyr rolidin-1-yl)ethyl)amino)phenyl)acrylamide

The first step is as follows: 5- ((5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2- (methyl (2- (tetrahydropyrrole-1-yl) ethyl) amino) -1-nitrobenzene (8B)

5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(pyrroli din-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,2.4mmol), N-methyl-2- (tetrahydropyrrol-1-yl) ethylamine (8A) (0.60g,4.8mmol) and N, N-diisopropylethylamine (0.6g,4.8mmol) were added to N, N-dimethylacetamide (3mL) and microwaved at 140 ℃ for 1.5 hours. The reaction solution was cooled to room temperature, water (20mL) was added, extraction was performed with dichloromethane (50mL × 3), the organic phases were combined, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 50:1) to give the title compound 5- ((5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2- (methyl (2- (tetrahydropyrrole-1-yl) ethyl) amino) -1-nitrobenzene (8B) as a red solid (0.5g, yield 40%).

¹H NMR(400MHz,CDCl₃)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-(pyrroli din-1-yl)ethyl)amino)aniline

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) (0.5g,0.95mmol), iron powder (0.32g,5.7mmol) and amine chloride (0.51 g,9.5mmol) were added to ethanol (5mL) and water (2mL) and reacted at 90 ℃ for 4 hours. The reaction was cooled to room temperature, water (20mL) was added to the reaction, extraction was performed with dichloromethane (50mL × 3), the organic phases were combined, washed with water (50mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the title compound 5- ((5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2- (methyl (2- (tetrahydropyrrolyl-1-yl) ethyl) amino) aniline (8C) as a red solid (0.4g, 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- (tetrahydropyrrole-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- (tetrahydropyrrol-1-yl) ethyl) amino) aniline (8C) (0.4g,0.8mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.31g,1.6mmol) and acrylic acid (0.12g,1.6mmol) were added to pyridine (5mL) and reacted at room temperature for 2 hours. Water (10mL) was added to the reaction solution, and extraction was performed with dichloromethane (50mL × 3), the organic phases were combined, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, and concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 50:1) to give the title compound 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) as a yellow solid (0.12g, yield 27%).

¹H NMR(400MHz,CDCl₃)δ9.85(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-indol-3-yl) 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

The first step is as follows: 2-methoxy-N⁴-methyl-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-nitro-N⁴- (2- (pyrrolidin-1-yl) ethyl) phenyl-1, 4-diamine (9B)

2-methoxy-N⁴-methyl-N¹-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-nitro-N⁴-(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) (1.0g,2.5mmol), N-methyl-2- (pyrrolidin-1-yl) ethylamine (9A) (650mg,5.1mmol), N-diisopropylethylamine (660mg,5.1mmol) and N, N-dimethylaniline (5mL) were placed in a 25mL microwave reaction tube and microwave reacted at 140 ℃ for 1.5 hours. The reaction mixture was added with water (50mL) and dichloromethane (50mL), separated, the organic phase was washed with water (50mL × 2) and saturated brine (50mL × 1) in turn, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent was petroleum ether: ethyl acetate (v/v) ═ 1:1 to 0:1, and dichloromethane: methanol (v/v) ═ 32:1 to 9:1) to give the title compound 2-methoxy-N⁴-methyl-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-nitro-N⁴- (2- (pyrrolidin-1-yl) ethyl) phenyl-1, 4-diamine (9B) as a yellow solid (820mg, 66% yield).

¹H NMR(400MHz,CDCl₃)δ9.56(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]⁺。

The second step is that: 5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (pyrrolidin-1-yl) ethyl) benzene-1, 2, 4-triamine (9C)

5-methoxy-N¹-methyl-N⁴-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N¹-(2-(pyrrolid in-1-yl)ethyl)benzene-1,2,4-triamine

2-methoxy-N⁴-methyl-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-nitro-N⁴- (2- (pyrrolidin-1-yl) ethyl) phenyl-1, 4-diamine (9B) (820mg,1.63mmol) was dissolved in ethanol (30mL) and water (10mL), and iron powder (546mg,9.78mmol) and ammonium chloride (872mg,16.3mmol) were added to conduct a reaction at 95 ℃ under reflux for 3 hours. The reaction mixture was added with water (50mL) and dichloromethane (50mL), separated, the organic phase was washed with water (30mL × 2) and saturated brine (30mL × 1) in turn, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent was petroleum ether: ethyl acetate (v/v) ═ 1:1 to 0:1, and then dichloromethane: methanol (v/v) ═ 32:1 to 9:1, respectively) to obtain the title compound 5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (pyrrolidin-1-yl) ethyl) benzene-1, 2, 4-triamine (9C), brown solid (410mg, 53% yield).

¹H NMR(400MHz,CDCl₃)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-indol-3-yl) pyridin-2-yl) amino) phenyl) acrylamide (Compound 9)

Reacting 5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (pyrrolidin-1-yl) ethyl) benzene-1, 2, 4-triamine (9C) (410mg,0.87mmol) was dissolved in 15mL of pyridine, and acrylic acid (313mg, 4.35mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (834mg,4.35mmol) were added and reacted at room temperature for 4 hours. Water (50mL) and dichloromethane (50mL) were added to the reaction mixture, followed by liquid separation, and the organic phase was washed with a 10% sodium hydroxide solution (50mL × 2), water (50mL × 2) and a saturated saline solution (50mL × 1) in this order, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent was petroleum ether: ethyl acetate (v/v) ═ 1:1 to 0:1, and dichloromethane: methanol (v/v) ═ 32:1 to 19:1) to give 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), yellow solid (190mg, 42% yield).

¹H NMR(400MHz,DMSO-d₆)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

The first step is as follows: 5-chloro-N- (2-methoxy-4- (2- (4-methylpiperazin-1-yl) ethoxy) -5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-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 (intermediate 4) (854.1mg, 2mmol) was dissolved in tetrahydrofuran (50mL), sodium hydride (80mg, 2.2mmol, wt% ═ 60%) was added under ice-cooling, stirred for 30 minutes, and 2- (4-methylpiperazin-1-yl) ethanol (576.5mg, 4mmol) was added dropwise and reacted at room temperature overnight. After the reaction was completed, 100mL of water and 100mL of ethyl acetate were added, the mixture was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give the 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 (10B) as a yellow solid (800mg, yield 80%).

MS m/z:552.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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)。

The second step is that: n is a radical of¹- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl-1, 3-diamine (10C)

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

Mixing 5-chloro-N- (2-methoxy-4- (2- (4-methylpiperazin-1-yl) ethoxy) -5-nitrophenyl) -4- (1-methyl-1H-indolidin-3-yl) pyrimidin-2-amine (10B) (800mg, 1.4)5mmol) was dissolved in ethanol (15mL), water (5mL), iron powder (486.3mg, 8.7mmol) and ammonium chloride (54mg, 1mmol) were added, the temperature was raised to 90 ℃ and the reaction was refluxed for 4 hours. The reaction was cooled to room temperature, filtered and concentrated. Separating and purifying the extract by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain a compound N ¹- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl-1, 3-diamine (10C), yellow solid (200mg, 26.5% yield).

MS m/z:522.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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,4.0Hz,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)

Will N¹- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl-1, 3-diamine (10C) (150mg, 0.288mmol) was dissolved in tetrahydrofuran (10mL), N-diisopropylethylamine (0.057mL, 0.345mmol) was added, cooled to 0 ℃ and a solution of acryloyl chloride (0.028mL, 0.345mmol) in tetrahydrofuran (5mL) was added dropwise and allowed to warm to room temperature for reaction for 1 hour. To the reaction solution were added a saturated aqueous sodium bicarbonate solution (50mL) and ethyl acetate (50mL), followed by liquid separation and concentration to give compound 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) as a pale yellow solid (40mg, yield 24.1%).

MS m/z:576.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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

The first step is as follows: n is a radical of¹- (5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) -2-methoxy-N⁴-methyl-N⁴- (1-Methyltetrahydropyrrole-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) (1.0g,2.4mmol), N, 1-dimethyltetrahydropyrrole-3-amine (11A) (0.55g,4.8mmol) and N, N-Diisopropylethylamine (DIPEA) (0.6g,4.8mmol) were added to N, N-dimethylacetamide (3mL) and microwaved at 140 ℃ for 1.5 hours. After cooling to room temperature, water (20mL) was added to the reaction mixture, extraction was performed with dichloromethane (50mL × 3), the organic phases were combined, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 50:1) to give the title compound N¹- (5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) -2-methoxy-N⁴-methyl-N⁴- (1-methyltetrahydropyrrole-3-yl) -5-nitrobenzene-1, 4-diamine (11B), red solid (0.5g, 42% yield).

MS m/z:508.3[M+1]⁺。

The second step is that: n is a radical of⁴- (5-chloro-4- (1H-indole-3-)Yl) pyrimidin-2-yl) -5-methoxy-N¹-methyl-N¹- (1-Methyltetrahydropyrrole-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

Will N¹- (5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) -2-methoxy-N ⁴-methyl-N⁴- (1-Methyltetrahydropyrroln-3-yl) -5-nitrobenzene-1, 4-diamine (11B) (0.5g,0.98mmol), iron powder (0.33g,5.9mmol) and ammonium chloride (0.52g,9.8mmol) were added to ethanol (5mL) and water (2mL) and reacted at 90 ℃ for 4 hours. The reaction solution was cooled to room temperature, water (20mL) was added, extraction was performed with methylene chloride (50 mL. times.3), the organic phases were combined, the organic phase was washed with water (50 mL. times.2), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound N⁴- (5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methyl-N¹- (1-Methyltetrahydropyrrole-3-yl) benzene-1, 2, 4-triamine (11C), red solid (0.3g, 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-yl) pyrimidin-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

Will N⁴- (5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methyl-N¹- (1-Methyltetrahydropyrroln-3-yl) benzene-1, 2, 4-triamine (11C) (0.3g,0.62mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (0.48g,2.5mmol) and acrylic acid (0.09g,1.2mmol) were added to pyridine (5mL) and reacted at room temperature for 2 hours. Water (10mL) was added to the reaction mixture, and extraction was performed with dichloromethane (50mL × 3), the organic phases were combined, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 50:1) to give the title compound N- (4-methoxy-2- (methyl: (1): N-methyl ether) 1-Methyltetrahydropyrroln-3-yl) amino) -5- ((5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (Compound 11) as a yellow solid (0.07g, 21% yield).

¹H NMR(400MHz,CDCl₃)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) pyrimidin-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

The first step is as follows: n is a radical of¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2-methoxy-N⁴-methyl-N⁴- (1-methyltetrahydropyrrole-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-methyl pyrrolidin-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) (1.0g,2.5mmol), N, 1-dimethylpyrrolidin-3-amine (11A) (580mg,5.1mmol), N-diisopropylethylamine (660mg,5.1mmol), and trifluoroethanol (5mL) were placed in a 25mL microwave reaction tube and reacted with microwaves at 140 ℃ for 1.5 hours. To the reaction mixture were added water (50mL) and dichloromethane (50mL), and the mixture was separated, and the organic phase was washed with water (50mL × 2), washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, concentrated, and separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 1:1-0: 1; dichloromethane: methanol (v/v) ═ 32:1 to 9:1) to give the title compound N ¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2-methoxy-N⁴-methyl-N⁴- (1-Methyltetrahydropyrrole-3-yl) -5-nitrobenzene-1, 4-diamine (12B) as a yellow solid (370mg, 31% yield).

¹H NMR(400MHz,CDCl₃)δ9.52(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]⁺。

The second step is that: n is a radical of⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methyl-N¹- (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

Will N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2-methoxy-N⁴-methyl-N⁴- (1-Methyltetrahydropyrroln-3-yl) -5-nitrobenzene-1, 4-diamine (12B) (0.37g,0.75mmol), iron powder (0.25g,4.5mmol) and ammonium chloride (0.4g,7.59mmol) were added to a mixed solution of ethanol (5mL) and water (2mL) and reacted at 90 ℃ for 4 hours. The reaction was cooled to room temperature, water (20mL) was added, extraction was performed with dichloromethane (50 mL. times.3), the organic phases were combined, washed with water (50 mL. times.2), dried over anhydrous sodium sulfate, and concentrated to give the title compound N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methyl-N¹- (1-Methyltetrahydropyrrole-3-yl) benzene-1, 2, 4-triamine (12C), black solid (0.3g, 88% yield).

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-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 12)

Will N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methyl-N¹- (1-Methyltetrahydropyrroln-3-yl) benzene-1, 2, 4-triamine (12C) (0.4g,88mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (0.67,3.5mmol) and acrylic acid (0.127g,1.7mmol) were added to pyridine (5mL) and reacted at room temperature for 2 hours. Water (10mL) was added to the reaction solution, and extraction was performed with dichloromethane (50mL × 3), the organic phases were combined, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 50:1) to give the title compound N- (4-methoxy-2- (methyl (1-methyltetrahydropyrrol-3-yl) amino) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 12) as a yellow solid (0.012g, 83% yield).

¹H NMR(400MHz,DMSO-d₆)δ9.39(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-methyltetrahydropyrrole-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

The first step is as follows: (R) -5-chloro-N- (2-methoxy-4- ((1-methyltetrahydropyrrole-3-yl) oxy) -5-nitrophenyl) -4- (pyrido [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-(pyraz olo[1,5-a]pyridin-3-yl)pyrimidin-2-amine

Sodium hydride (0.09g, 2.25mmol) was added to the reaction flask, cooled to 0 deg.C, tetrahydrofuran (5mL) and 5- ((5-chloro-4- (pyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2-fluoro-1-nitrobenzene (intermediate 5) (0.413g, 2.25mmol) were added, and a solution of (R) - (-) -1-methyl-3-hydroxypyrrolidine (0.118g, 1.17mmol) in tetrahydrofuran (5mL) was added dropwise and allowed to react overnight at room temperature. The reaction solution was cooled to 0 ℃, a saturated ammonium chloride solution (10mL) was added, the reaction was quenched, water (10mL) was added, the reaction solution was separated, the aqueous phase was extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 2:1, methanol: dichloromethane (v/v) ═ 1:2) to give the title compound (R) -5-chloro-N- (2-methoxy-4- ((1-methyltetrahydropyrrole-3-yl) oxy) -5-nitrophenyl) -4- (pyrazolo [1,5-a ] pyridin-3-yl) pyrimidine-2-diamine (13B), a yellow solid (0.22g, yield 44%).

¹H NMR(400MHz,DMSO-d₆)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 is that: (R) -N¹- (5-chloro-4- (pyrazolo [1, 5-a)]Pyridin-3-yl) pyrimidin-2-yl) -6-methoxy-4- ((1-methyltetrahydropyrrole-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-me thylpyrrolidin-3-yl)oxy)benzene-1,3-diamine

Mixing (R) -5-chloro-N- (2-methoxy-4- ((1-methyltetrahydropyrrole-3-yl) oxy) -5-nitrophenyl) -4- (pyrazolo [1, 5-a) ]Pyridin-3-yl) pyrimidine-2-diamine (13B) (0.20g,0.40mmol), iron powder (0.145g,2.60mmol) and ammonium chloride (0.04g,0.75mmol) were dissolved in a mixed solvent of absolute ethanol (9mL) and water (3mL), and the temperature was raised to 90 ℃ to react for 4.5 hours.The reaction mixture was cooled to room temperature, filtered with suction, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methanol: dichloromethane (v/v) ═ 1:2) to give the title compound (R) -N¹- (5-chloro-4- (pyrazolo [1, 5-a)]Pyridin-3-yl) pyrimidin-2-yl) -6-methoxy-4- ((1-methylpyrrolidin-3-yl) oxy) phenyl-1, 3-diamine (13C), yellow-green solid (0.07g, 38% yield).

¹H NMR(400MHz,CDCl₃)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-methoxy-2- ((1-methyltetrahydropyrrole-3-yl) oxy) phenyl) acrylamide (Compound 13)

Reacting (R) -N¹- (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) (0.07g,0.15mmol) was dissolved in freshly distilled tetrahydrofuran (3mL), the reaction solution was cooled to 0 ℃ and a solution of diisopropylethylamine (0.3mL) in freshly distilled tetrahydrofuran (9.7mL) and acryloyl chloride (0.13mL) in freshly distilled tetrahydrofuran (0.87mL) was added dropwise and reacted at room temperature for 1.5 hours. To the reaction solution was added a saturated sodium bicarbonate solution (50mL), the reaction was quenched, the aqueous phase was extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (methanol: dichloromethane (v/v) ═ 1:2 to 1:1), and the title compound (R) -N- (5- ((5-chloro-4- (pyrazolo [1, 5-a): the title compound ]Pyridin-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2- ((1-methylpyrrolidin-3-yl) oxy) phenyl) acrylamide (compound 13) as a yellow solid (0.03g, 41% yield).

¹H NMR(400MHz,DMSO-d₆)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

The first step is as follows: 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]pyridin-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-nitrobenzene (intermediate 5) (0.41g,1.00mmol) was dissolved in tetrahydrofuran (20mL), the reaction solution was cooled to 0 ℃, sodium hydride (0.08g,1.1mmol,% by weight ═ 60%) was added, and after stirring for 5 minutes, N-dimethylethanolamine (14A) (0.11 mL,1.1mmol) was added, and the reaction was warmed to room temperature and reacted for 4 hours. Water (20mL) was added to the reaction flask, the aqueous phase was extracted with ethyl acetate (50mL × 2), the organic phases were combined, the organic phase was washed with saturated brine (30mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give 5-chloro-N- (4- (2-dimethylamino) ethoxy) -2-methoxy-5-nitrophenyl) -4-pyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-amine (14B) as a yellow solid (0.36g, 75% yield).

¹H NMR(400MHz,CDCl₃)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)。

The second step is that: n is a radical of¹- (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-dimethylaminoethyl oxy)-6-methoxy-benzene-1,3-diamine

Weighing 5-chloro-N- (4- (2-dimethylamino) ethoxy) -2-methoxy-5-nitrophenyl) -4-pyrazolo [1,5-a]Pyridin-3-yl) pyrimidin-2-amine (14B) (0.36g,0.74mmol) was placed in a 100mL round-bottomed flask, ethanol (21mL), water (7mL), reduced iron powder (0.25g,4.44mmol), and ammonium chloride (0.028g,0.52 mmol) were added in this order to a reaction flask, and the reaction was refluxed at elevated temperature for 6 hours. The reaction mixture was filtered, the filter cake was washed with dichloromethane (10mL × 2) and methanol (10mL × 2) in this order, the filtrates were combined, concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give N as a gray solid¹- (5-chloro-4-pyrazolo [1, 5-a)]Pyridin-3-yl-pyrimidin-2-yl) -4- (2-dimethylaminoethoxy) -6-methoxy-phenyl-1, 3-diamine (14C) (0.30g, 88% yield).

¹H NMR(400MHz,CDCl₃)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- (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-dimethyla minoethyloxy)-4-methoxy-phenyl]prop-2-enamide

Weighing N¹- (5-chloro-4-pyrazolo [1, 5-a)]Pyridin-3-yl-pyrimidin-2-yl) -4- (2-dimethylaminoethoxy) -6-methoxy-phenyl-1, 3-diamine (14C) (0.2g,0.43mmol) was placed in a 100mL round bottom flask, and tetrahydrofuran (15mL) and diisopropylethylamine (0.09mL, 0.56mmol), cooled to 0 ℃, acryloyl chloride (0.04mL,0.52mmol) was added dropwise, and after the addition was complete, the reaction was allowed to warm for 1 hour. The reaction mixture was concentrated under reduced pressure, methylene chloride (50mL), a saturated aqueous sodium bicarbonate solution (30mL) were added to the residue, the mixture was separated, the aqueous phase was extracted with dichloromethane (50mL), the organic phases were combined, the organic phase was washed with a saturated saline solution (30mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (methylene chloride/methanol (v/v) ═ 15:1) to give N- (5- ((5-chloro-4- (pyrazolo [1, 5-a) as a yellow solid]Pyridin-3-yl) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (compound 14) (0.08g, 48% yield).

MS m/z(ESI):517.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(dimethylamino) ethoxy)-4-methoxyphenyl)acrylamide

The first step is as follows: 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 (intermediate 4) (500mg, 1.17mmol) was dissolved in tetrahydrofuran (50mL), sodium hydride (51.5mg, 1.28mmol) was added under ice-bath, stirred for 30 min, dimethylethanolamine (14A) (0.24mL, 2.34mmol) was added dropwise, and reacted at room temperature for 4 hours. To the reaction mixture were added water (100mL) and ethyl acetate (150mL), the layers were separated, the organic layer was dried over anhydrous sodium sulfate, and the concentrate was concentrated to give the compound 5-chloro-N- (4- (2- (dimethylamino) ethoxy) -2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (15B) as a yellow solid (500mg, 86.2% yield).

MS m/z:497.1[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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)。

The second step is that: n is a radical of¹- (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-indol-3-yl) pyrimidin-2-amine (15B) (500mg, 1mmol) was dissolved in a mixed solution of ethanol (15mL) and water (5mL), iron powder (335mg, 6mmol) and ammonium chloride (37.4mg, 0.7mmol) were added, the temperature was raised to 90 ℃ and the reaction was refluxed for 4 hours. Cooling the reaction solution to room temperature, filtering, concentrating, and separating and purifying the residue by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-50: 1) to obtain compound N¹- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -4- (2- (dimethylamino) ethoxy) -6-methoxyphenyl-1, 3-diamine (15C) as a yellow solid (350mg, 75.1% yield).

MS m/z:467.2[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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)

Will N¹- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -4- (2- (dimethylamino) ethoxy) -6-methoxyphenyl-1, 3-diamine (15C) (350mg, 0.75mmol) was dissolved in tetrahydrofuran (28mL), N-diisopropylethylamine (i.e., DIPEA) (0.15mL, 0.9mmol) was added, cooled to 0 deg.C, a solution of acryloyl chloride (0.073mL, 0.9mmol) in tetrahydrofuran (5mL) was added dropwise, and the mixture was allowed to warm to room temperature for reaction for 3 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate (100mL) and dichloromethane (100mL), and the organic phase was separated and concentrated to give N- (5- ((5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (compound 15) as a white solid (40mg, 10.3%).

MS m/z:521.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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-methoxyphenyl) acrylamide (compound 16)

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

The first step is as follows: 1- (6-Nitro-1H-indol-1-yl) ethanone (16B)

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

6-Nitroindole (16A) (16.2g, 0.1mol) was dissolved in pyridine (40mL), acetic anhydride (40.8g, 0.4mol) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction mixture was concentrated, and to the residue were added saturated brine (200mL) and ethyl acetate (200mL), followed by separation, drying of the organic phase over anhydrous sodium sulfate, and concentration to give the objective compound 1- (6-nitro-1H-indol-1-yl) ethanone (16B) as a yellow solid (6g, yield 30%).

MS m/z:205.1[M+1]⁺。

The second step is that: 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) (20g, 0.1mol) was dissolved in methanol (50mL) and tetrahydrofuran (50mL), palladium on carbon (2g, 10%) and ammonium formate (40.3g, 6.4mol) were added, and the mixture was reacted at 60 ℃ for 2 hours. After the reaction, filtration was performed, the filter cake was washed with ethyl acetate (100mL), the filtrates were combined, concentrated, ethyl acetate (150mL) and saturated brine (150mL) were added to the residue, followed by liquid separation, the aqueous phase was washed with ethyl acetate (150mL), the organic phases were combined, 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 (9.3g, 53.4% yield).

The third step: 4- (1H-indol-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-dimethylformamide (100mL), and N, N-diisopropylethylamine (i.e., ethyl DIP acetate) (29.7mL, 180mmol) was added and reacted at 90 ℃ overnight. The reaction was cooled to room temperature, ethyl acetate (200mL) and saturated brine (200mL) were added, the layers were separated, the aqueous layer was washed with ethyl acetate (200mL), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give 4- (1H-indol-6-yl) morpholine (16D) as a yellow solid (9.2g, 76% yield).

MS m/z:203.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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)。

The fourth step: 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) (4.5g, 22.3mmol) was dissolved in tetrahydrofuran (100mL), cooled to 0 ℃ under nitrogen, methyl magnesium bromide (7.5mL, 22.3mmol) was added dropwise, stirring was continued for 0.5H, trichloropyrimidine (2.05g, 22.3mmol) was added, the reaction was allowed to react at room temperature for 1H, and the temperature was raised to 60 ℃ for 1H. The reaction mixture was cooled to room temperature, acetic acid (6.34mL) was added dropwise, the mixture was stirred for 10 minutes, water (100mL) was added, the mixture was stirred at 60 ℃ for 30 minutes, the mixture was separated, the organic phase was added with n-heptane (100mL), the mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 50:1) to give compound 4- (3- (2, 5-dichloropyrimidin-4-yl) -1H-indol-6-yl) morpholine (16E) as a yellowish green solid (3g, yield 39%).

MS m/z:349.0[M+1]⁺。

The fifth step: 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) (3g, 8.6mmol) was dissolved in tetrahydrofuran (50mL), cooled to 0 ℃, sodium hydride (460mg, 11.5mmol) was added, the reaction was carried out for 30 minutes, methyl iodide (1.6mL, 25.8mmol) was added, and the mixture was warmed to room temperature and reacted for 3 hours. The reaction was concentrated and the residue was washed with water (50mL) and tetrahydrofuran (20mL), filtered, and the filter cake was dried to give 4- (3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1H-indol-6-yl) morpholine (16F) as a pale yellow solid (1.9g, 61.3% yield).

MS m/z:363.0[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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)。

And a sixth step: 5-chloro-N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-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) (724g, 2mmol) was dissolved in 2-pentanol (20mL), 4-fluoro-2-methoxy-5-nitroaniline (372mg, 2mmol) and p-toluenesulfonic acid (456.5mg, 2.4mmol) were added, and the reaction was heated to 120 ℃ and refluxed for 2 days. The reaction was cooled to room temperature, acetonitrile (50mL) was added, filtered, the filter cake was washed with water (50mL), and dried to give-chloro-N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-amine (16G) as a grey solid (800mg, 80% yield).

MS m/z:513.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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)。

The seventh step: n is a radical of¹- (5-chloro-4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-yl) -4-fluoro-6-methoxybenzene-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-morpholin-1H-indol-3-yl) pyrimidin-2-amine (16G) (600mg, 1.17mmol) was dissolved in ethanol (30mL) and water (10mL), iron powder (392mg, 7.03mmol) and ammonium chloride (43.8mg, 0.82mmol) were added, the temperature was raised to 90 ℃ and the reaction was refluxed for 4 hours. Cooling the reaction solution to room temperature, filtering, washing a filter cake with methanol (50mL), combining filtrates, concentrating, and purifying the residue by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-50: 1) to obtain N¹- (5-chloro-4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-yl) -4-fluoro-6-methoxybenzene-1, 3-diamine (16H), brown solid (150mg, 26.6% yield).

MS m/z:483.1[M+1]⁺。

Eighth step: n- (5- ((5-chloro-4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-fluoro-4-methoxyphenyl) acrylamide (compound 16)

Will N¹- (5-chloro-4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-yl) -4-fluoro-6-methoxybenzene-1, 3-diamine (16H) (150mg, 0.31mmol) was dissolved in tetrahydrofuran (10mL), N-diisopropylethylamine (0.06mL, 0.37mmol) was added, cooled to 0 deg.C, a solution of acryloyl chloride (0.03mL, 0.37mmol) in tetrahydrofuran (5mL) was added dropwise, and the mixture was allowed to warm to room temperature for reaction for 1.5 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate (100mL) and dichloromethane (100mL), which were separated and concentrated to give N- (5- ((5-chloro-4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-fluoro-4-methoxyphenyl) acrylamide (compound 16) as a pale yellow solid (20mg, yield 12%).

MS m/z:537.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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) pyrrolidin-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-(dimethyl amino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

The first step is as follows: (R) -5-chloro-N- (4- (3- (dimethylamino) pyrrolidin-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

5-chloro-4- (4-fluoro-1H-indol-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidin-2-amine (intermediate 7) (1.1g, 2.5mmol), (R) -N, N-dimethylpyrrol-3-amine (17A) (0.5g, 2.8mmol), diisopropylethylamine (1.5g, 11.5mmol) and N, N' -dimethylacetamide (10mL) were added to a reaction flask and reacted at 140 ℃ for 1 hour under microwave. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100:1) to give (R) -5-chloro-N- (4- (3- (dimethylamino) pyrrolidin-1-yl) -2-methoxy-5-nitrophenyl) -4- (4-fluoro-1H-indol-3-yl) pyrimidin-2-amine (17B) as a brown oil (0.5g, 38% yield).

MS m/z(ESI):526.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ12.00(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 is that: (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 (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

To a reaction flask were added (R) -5-chloro-N- (4- (3- (dimethylamino) pyrrolidin-1-yl) -2-methoxy-5-nitrophenyl) -4- (4-fluoro-1H-indol-3-yl) pyrimidin-2-amine (17B) (0.5g, 0.95mmol), iron powder (0.32g, 5.7mmol), ammonium chloride (51mg, 0.95mmol) and ethanol/water (27mL/9.5mL), and the mixture was heated to reflux for 2 hours. The reaction solution was filtered, the filter cake was washed with ethanol (10mL × 3), the filtrates were combined, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanolic ammonia (v/v) ═ 80:1-30:1) to give (R) -N as a yellowish brown solid ¹- (5-chloro-4- (4-fluoro-1H-indole-3-yl) pyrimidin-2-yl) -4- (3- (dimethylamino) pyrrolidin-1-yl) -6-methoxybenzene-1, 3-diamine (17C) (0.2g, 42.6% yield).

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) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide (Compound 17)

Adding (R) -N into a reaction bottle¹- (5-chloro-4- (4-fluoro-1H-indol-3-yl) pyrimidin-2-yl) -4- (3- (dimethylamino) tetrahydropyrrole-1-yl) -6-methoxybenzene-1, 3-diamine (17C) (0.18g, 0.36mmol), diisopropylethylamine (52 mg, 0.4mmol) and dichloromethane (4.6mL) were cooled in an ice bath, acryloyl chloride (33mg,0.36mmol) in dichloromethane (1mL) was added dropwise and reacted in an ice bath for 2 hours. To the reaction mixture was added a saturated aqueous sodium chloride solution (10mL), the mixture was stirred, the aqueous layer was extracted with dichloromethane (30mL × 3), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50:1-25:1) to give (R) -N- (5- ((5-chloro-4- (4-fluoro-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (3- (dimethylamino) tetrahydropyrrole-1-yl) -4-methoxyphenyl) acrylamide (compound 17) (50mg, yield 25.5%) as a pale yellow solid.

MS m/z(ESI):550.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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-((5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylami no)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The first step is as follows: n is a radical of¹- (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 (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

5-chloro-4- (4-fluoro-1H-indol-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidin-2-amine (intermediate 7) (1g, 2.5mmol), N, N, N '-trimethylethylenediamine (18A) (0.28g, 2.8mmol), diisopropylethylamine (1.3g, 10.4mmol) and N, N' -dimethylacetamide (10mL) were added to a reaction flask and reacted at 140 ℃ for 1 hour under microwave. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50:1) to give a brown oil N¹- (5-chloro-4- (4-fluoro-1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴Methyl-5-nitrophenyl-1, 4-diamine (18B) (0.55g, 45.8% yield).

MS m/z(ESI):514.3[M+1]⁺。

The second step is that: n is a radical of⁴- (5-chloro-4- (4-fluoro-1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylphenyl-1, 2, 4-triamine (18C)

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

Adding N into a reaction bottle¹- (5-chloro-4- (4-fluoro-1H-indol-3-yl) pyrimidin-2-yl) -N ⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴Methyl-5-nitrophenyl-1, 4-diamine (18B) (0.52g, 1mmol), iron powder (0.34g, 6.1 mmol), ammonium chloride (54mg, 1mmol) and ethanol/water (28mL/10mL) heated to reflux for 2 hours. The reaction was filtered, the filter cake was washed with ethanol (10 mL. times.3), the filtrates were combined, concentrated, and the residue was washed with silicaSeparating and purifying by gel column chromatography (dichloromethane/ammonia methanol (v/v) ═ 100:1-50:1) to obtain yellow solid N⁴- (5-chloro-4- (4-fluoro-1H-indole-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylphenyl-1, 2, 4-triamine (18C) (350mg, 71.5% yield).

MS m/z(ESI):484.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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)

Adding N into a reaction bottle⁴- (5-chloro-4- (4-fluoro-1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylphenyl-1, 2, 4-triamine (18C) (0.32g, 0.66mmol), diisopropylethylamine (94 mg, 0.73mmol) and dichloromethane (8.6mL), cooled in an ice bath, a solution of acryloyl chloride (60mg,0.66mmol) in dichloromethane (2mL) was added dropwise, and the reaction was carried out for 2 hours in an ice bath. To the reaction solution was added an aqueous sodium bicarbonate solution (10mL), followed by stirring, liquid separation, extraction of the aqueous layer with dichloromethane (30mL × 3), combination of organic phases, washing of the organic phase with saturated brine (20mL), drying over anhydrous sodium sulfate, filtration, concentration, and column chromatography of the residue on silica gel (dichloromethane/methanol (v/v) ═ 50:1-30:1) to give 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) (140m g, yield 39.4%) as a pale yellow solid.

MS m/z(ESI):538.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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) pyrimidin-2-yl) amino) -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

The first step is as follows: n is a radical of¹- (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 (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 a reaction flask were added 4- (7-fluoro-1-methyl-1H-indol-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidin-2-amine (intermediate 8) (280mg, 0.68mmol), N, N, N '-trimethylethylenediamine (18A) (69mg, 0.68mmol), diisopropylethylamine (219mg, 1.7mmol) and N, N' -dimethylacetamide (4.5mL) and reacted at 140 ℃ for 1.5 hours under microwave. Cooling the reaction solution to room temperature, adding water (10mL), extracting with ethyl acetate (20mL × 2), combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating, and purifying the residue by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100:1-20:1) to obtain a brown solid N¹- (2- (dimethylamino) ethyl) -N⁴- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹Methyl-2-nitrophenyl-1, 4-diamine (19B) (120mg, 36% yield).

¹H NMR(400MHz,DMSO-d₆)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)。

The second step is that: n is a radical of¹- (2- (dimethylamino) ethyl) -N ⁴- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-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]⁺。

¹H NMR(400MHz,DMSO-d₆)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-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (Compound 19)

Adding N into a reaction bottle¹- (2- (dimethylamino) ethyl) -N⁴- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (19C) (0.36g, 0.78mmol), diisopropylethylamine (111 mg, 0.86mmol) and dichloromethane (10mL), cooled in an ice bath, and a solution of acryloyl chloride (70mg,0.78mmol) in dichloromethane (2mL) was added dropwise over 2 hours of the ice bath reaction. To the reaction solution was added an aqueous sodium bicarbonate solution (10mL), followed by partition with stirring, extraction of the aqueous layer with dichloromethane (20mL × 2), combination of the organic phases, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30:1-20:1) to give N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 19) as a brown oil (360mg, 90% yield).

MS m/z(ESI):518.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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-(pyrazol o[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step is as follows: n is a radical of⁴- (2-dimethylaminoethyl) -2-methoxy-N¹- (5-methoxy-4-pyrazolo [1, 5-a)]Pyridin-3-yl-pyrimidin-2-yl) -N⁴-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

Weighing N- (4-fluoro-2-methoxy-5-nitro-phenyl) -5-methoxy-4-pyrazolo [1,5-a]Pyridin-3-yl-pyrimidin-2-amine (intermediate 9) (0.41g,1mmol) was placed in a 10mL microwave reaction tube, N, N-dimethylacetamide (2mL), N, N, N' -trimethylethylenediamine (18A) (0.16mL,1.2mmol) and diisopropylethylamine (0.2mL,1.2mmol) were added sequentially to the reaction tube, and the reaction was heated to 140 ℃ for 1 hour under microwave. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give N as a red solid⁴- (2-dimethylaminoethyl) -2-methoxy-N¹- (5-methoxy-4-pyrazolo [1, 5-a)]Pyridin-3-yl-pyrimidin-2-yl) -N⁴-methyl-5-nitro-phenyl-1, 4-diamine (20B) (0.22g, 45% yield).

¹H NMR(400MHz,CDCl₃)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)。

The second step is that: n is a radical of¹- (2-dimethylaminoethyl) -5-methoxy-N⁴- (5-methoxy-4-pyrazolo [1, 5-a) ]Pyridin-3-yl-pyrimidin-2-yl) -N¹-methyl-phenyl-1, 2, 4-triamine (20C)

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

Weighing N⁴- (2-dimethylaminoethyl) -2-methoxy-N¹- (5-methoxy-4-pyrazolo [1, 5-a)]Pyridin-3-yl-pyrimidin-2-yl) -N⁴Methyl-5-nitro-phenyl-1, 4-diamine (20B) (0.22g,0.45mmol) was placed in a 100mL round-bottomed flask, ethanol (21mL), water (7mL), reduced iron powder (0.15g,2.70mmol) and ammonium chloride (0.017g,0.32mmol) were added to the flask in this order, and the reaction was refluxed at elevated temperature for 6 hours. The reaction mixture was filtered, the filter cake was washed with dichloromethane (10mL × 2) and methanol (10mL × 2) in this order, the filtrates were combined, concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give N as a gray solid¹- (2-dimethylaminoethyl) -5-methoxy-N⁴- (5-methoxy-4-pyrazolo [1, 5-a)]Pyridin-3-yl-pyrimidin-2-yl) -N¹Methyl-phenyl-1, 2, 4-triamine (20C) (0.20g, 98% yield).

¹H NMR(400MHz,CDCl₃)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- (pyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 20)

Weighing N¹- (2-dimethylaminoethyl) -5-methoxy-N⁴- (5-methoxy-4-pyrazolo [1, 5-a)]Pyridin-3-yl-pyrimidin-2-yl) -N ¹-methyl-phenyl-1, 2, 4-triamine (20C) (0.2g,0.43mmol), placed in a 100mL round bottom flask, tetrahydrofuran (15mL) and diisopropylethylamine (0.09mL,0.56mmol) were added sequentially, cooled to 0 deg.C, acryloyl chloride (0.04mL,0.52mmol) was added dropwise, and allowed to warm to room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and methylene chloride (50mL), a saturated aqueous sodium bicarbonate solution (30mL) and added to the residue, followed by liquid separation, extraction of the aqueous phase with methylene chloride (50mL), combination of the organic phases, washing of the organic phase with a saturated saline solution (30mL), drying over anhydrous sodium sulfate, concentration under reduced pressure, and column chromatography purification (methylene chloride/methanol (v/v) ═ 15:1) gave N- (2- ((2-dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((5-methoxy-4- (pyrazolo [1, 5-a): 5) as a yellow solid]Pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 20) (0.08g, 48% yield).

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 ] pyridin-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]pyri din-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step is as follows: 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-a mine

3- (2-chloro-5-methoxy-pyrimidin-4-yl) pyrazolo [1,5-a ] pyridine (9c) (0.52g,2mmol) was weighed and placed in a 50mL round-bottomed flask, 2-pentanol (15mL), 4-fluoro-3-nitroaniline (0.31g,2mmol) and p-toluenesulfonic acid (0.46g,2.4mmol) were added sequentially to a reaction flask, and the mixture was heated to 120 ℃ for 48 hours. The reaction solution was cooled to room temperature, acetonitrile (20mL) and aqueous ammonia (20mL) were added, filtered, the filter cake was washed with acetonitrile (10mL × 2) and water (10mL × 2), 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) as a yellow solid (0.68g, 89% yield).

¹H NMR(400MHz,DMSO-d₆)δ9.82(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)。

The second step is that: n is a radical of¹- (2-dimethylaminoethyl) -N⁴- (5-methoxy-4-pyrazolo [1, 5-a)]Pyridin-3-yl-pyrimidin-2-yl) -N¹-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

Weighing N- (4-fluoro-3-nitro-phenyl) -5-methoxy-4-pyrazolo [1,5-a]Pyridin-3-yl-pyrimidin-2-amine (21B) (0.38g,1mmol) was placed in a 10mL microwave reaction tube and N, N-dimethylacetamide (2mL), N, N, N' -trimethylethylenediamine (18A) (0.16mL,1.2mmol) and diisopropylethylamine (0.2mL, 1.2mmol) were added to the reaction tube in that order,the temperature is raised to 140 ℃ and the reaction is carried out for 1 hour under microwave. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give N as a red solid¹- (2-dimethylaminoethyl) -N⁴- (5-methoxy-4-pyrazolo [1, 5-a)]Pyridin-3-yl-pyrimidin-2-yl) -N¹-methyl-2-nitro-phenyl-1, 4-diamine (21C) (0.46 g).

¹H NMR(400MHz,CDCl₃)δ8.82(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)。

The third step: n is a radical of¹- (2-dimethylaminoethyl) -N⁴- (5-methoxy-4-pyrazolo [1, 5-a)]Pyridin-3-yl-pyrimidin-2-yl) -N¹-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

Weighing N¹- (2-dimethylaminoethyl) -N⁴- (5-methoxy-4-pyrazolo [1, 5-a)]Pyridin-3-yl-pyrimidin-2-yl) -N¹Methyl-2-nitro-phenyl-1, 4-diamine (21C) (0.8g,1.73mmol) was placed in a 100mL round-bottomed flask, ethanol (30mL), water (10mL), reduced iron powder (0.58g,10.4mmol) and ammonium chloride (0.065g,1.21mmol) were added to the reaction flask in this order, and the reaction was refluxed at elevated temperature for 6 hours. The reaction mixture was filtered, the filter cake was washed with dichloromethane (10mL × 2) and methanol (10mL × 2), the filtrates were combined, concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give N as a gray solid ¹- (2-dimethylaminoethyl) -N⁴- (5-methoxy-4-pyrazolo [1, 5-a)]Pyridin-3-yl-pyrimidin-2-yl) -N¹-methyl-phenyl-1, 2, 4-triamine (21D) (0.63g, 84% yield).

¹H NMR(400MHz,CDCl₃)δ8.81(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)。

The 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)

Weighing N¹- (2-dimethylaminoethyl) -N⁴- (5-methoxy-4-pyrazolo [1, 5-a)]Pyridin-3-yl-pyrimidin-2-yl) -N¹Methyl-phenyl-1, 2, 4-triamine (21D) (0.63g,1.46mmol) was placed in a 100mL round bottom flask, tetrahydrofuran (15mL) and diisopropylethylamine (0.29mL,1.75mmol) were sequentially added to the reaction flask, the reaction solution was cooled to 0 ℃, acryloyl chloride (0.14mL,1.75mmol) was added dropwise, and after completion of the addition, the temperature was raised for reaction for 1 hour. The reaction mixture was concentrated under reduced pressure, methylene chloride (50mL), a saturated aqueous sodium bicarbonate solution (30mL) were added to the residue, the mixture was separated, the aqueous phase was extracted with methylene chloride (50mL), the organic phases were combined, the organic phase was washed with a saturated saline solution (30mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (methylene chloride/methanol (v/v) ═ 15:1) to give N- (2- ((2-dimethylamino) ethyl) (methyl) amino) -5- ((5-methoxy-4- (pyrazolo [1, 5-a) as a yellow solid ]Pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 21) (0.15g, 48% yield).

MS m/z(ESI):487.3[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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-indol-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

The first step is as follows: n is a radical of⁴- (2- (dimethylamino) ethyl) -3-fluoro-2-methoxy-N⁴-methyl-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-nitrophenyl-1, 4-diamine (22B)

N⁴-(2-(dimethylamino)ethyl)-3-fluoro-2-methoxy-N⁴-methyl-N¹-(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) (1.4g,3.4mmol), N, N, N' -trimethylethylenediamine (18A) (0.69g,6.8mmol) and N, N-diisopropylethylamine (0.87g,6.8mmol) were added to N, N-dimethylformamide (3mL) and reacted with microwave at 140 ℃ for 1.5 hours. The reaction solution was cooled to room temperature, water (20mL) was added to the reaction solution, extraction was performed with dichloromethane (50mL × 3), the organic phases were combined, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 50:1) to give the title compound N⁴- (2- (dimethylamino) ethyl) -3-fluoro-2-methoxy-N⁴-methyl-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-nitrobenzene-1, 4-diamine (22B) as a red solid (0.25g, 15% yield).

¹H NMR(400MHz,DMSO-d₆)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]⁺。

The second step is that: n is a radical of¹- (2- (dimethylamino) ethyl) -6-fluoro-5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (22C)

N¹-(2-(dimethylamino)ethyl)-6-fluoro-5-methoxy-N¹-methyl-N⁴-(4-(1-methyl-1H- indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine

Will N⁴- (2- (dimethylamino) ethyl) -3-fluoro-2-methoxy-N⁴-methyl-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-nitrobenzene-1, 4-diamine (22B) (0.25g,5mmol), iron powder (0.17g,30mmol) and ammonium chloride (0.27g,50mmol) were added to a mixed solution of ethanol (5mL) and water (2mL), and the temperature was raised to 90 ℃ for 4 hours. The reaction mixture was cooled to room temperature, water (20mL) was added, extraction was performed with dichloromethane (50 mL. times.3), the organic phases were combined, the organic phase was washed with water (50 mL. times.2), dried over anhydrous sodium sulfate, and concentrated to give the title compound N¹- (2- (dimethylamino) ethyl) -6-fluoro-5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (22C), red solid (0.22g, 96% yield).

MS m/z:464.4[M+1]⁺。

The third step: 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)

Will N¹- (2- (dimethylamino) ethyl) -6-fluoro-5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) phenyl-1, 2, 4-triamine (22C) (0.27g,0.55mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (0.42g,2.19mmol) and acrylic acid (0.078g,1.09mmol) were added to pyridine (5mL) and reacted at room temperature for 2 hours. Water (10mL) was added to the reaction solution, and extraction was performed with dichloromethane (50mL × 3), the organic phases were combined, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 50:1) to give 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) as a yellow solid (40mg, yield 14%).

¹H NMR(400MHz,DMSO-d₆)δ10.58(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-indol-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

The first step is as follows: 2- (difluoromethoxy) -N⁴- (2- (dimethylamino) ethyl) -N⁴-methyl-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-nitrophenyl-1, 4-diamine (23B)

2-(difluoromethoxy)-N⁴-(2-(dimethylamino)ethyl)-N⁴-methyl-N¹-(4-(1-methyl-1H-i ndol-3-yl)pyrimidin-2-yl)-5-nitrobenzene-1,4-diamine

To a reaction flask was added 5- (difluoromethoxy) -N- (2- (dimethylamino) ethyl) -N-methyl-2-nitrobenzene-1, 4-diamine (intermediate 1) (120mg, 0.39mmol), 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (intermediate 2) (115 mg, 0.47mmol), p-toluenesulfonic acid (94mg, 0.86mmol) and 2-pentanol (2mL), and heated to 110 ℃ for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/aminomethanol (v/v) ═ 50:1) to give 2- (difluoromethoxy) -N as a brown oil⁴- (2- (dimethylamino) ethyl) -N⁴-methyl-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-nitrophenyl-1, 4-diamine (23B) (150mg, 75% yield).

MS m/z(ESI):512.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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)。

The second step is that: 5- (difluoromethoxy) -N¹- (2- (dimethylamino) ethyl) -N¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (23C)

5-(difluoromethoxy)-N¹-(2-(dimethylamino)ethyl)-N¹-methyl-N⁴-(4-(1-methyl-1H-in dol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine

Adding 2- (difluoromethoxy) -N into a reaction bottle⁴- (2- (dimethylamino) ethyl) -N⁴-methyl-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-nitrobenzene-1, 4-diamine (23B) (150mg, 0.29mmol), iron powder (99 mg, 1.76mmol), ammonium chloride (11mg, 0.2mmol) and ethanol/water (5mL/1.5mL) were heated to reflux for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/aminomethanol (v/v) ═ 50:1) to give 5- (difluoromethoxy) -N as a brown solid¹- (2- (dimethylamino) ethyl) -N¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (23C) (100mg, 72% yield).

MS m/z(ESI):482.4[M+1]⁺。

The third step: 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)

Adding 5- (difluoromethoxy) -N into a reaction bottle¹- (2- (dimethylamino) ethyl) -N¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (23C) (110mg, 0)23mmol), diisopropylethylamine (39mg, 0.3mmol) and dichloromethane (3mL) were cooled in an ice bath, acryloyl chloride (23mg,0.25mmol) was added dropwise, and the reaction was carried out in an ice bath for 1 hour after the addition. Dichloromethane (20mL) and saturated brine (20mL) were added to the reaction solution, and the mixture was separated, and the aqueous layer was extracted with dichloromethane (10mL × 4), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30:1) to give 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) (45m g, yield 37%) as a pale yellow oil.

MS m/z(ESI):536.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ10.21(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-morpholinylbenzene) acrylamide (compound 24)

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

The first step is as follows: 4- (3-iodo-5-nitrophenyl) morpholine (24B)

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

1-fluoro-3-iodo-5-nitrobenzene (24A) (5.0g, 18.7mmol) and morpholine (3.4g,39.3mmol) were dissolved in dimethyl sulfoxide (15mL) and reacted at 90 ℃ for 17 hours to complete the reaction, 30mL of water was added, extraction was performed with dichloromethane (30 mL. times.2), 30mL of water was washed, 30mL of saturated brine was washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4- (3-iodo-5-nitrophenyl) morpholine (24B) as a yellow solid (6.0g, 96.8% yield).

¹H NMR(400MHz,CDCl₃)δ7.99–7.95(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]⁺。

The second step is that: 3-morpholinyl-5-nitroaniline (24C)

3-morpholino-5-nitroaniline

4- (3-iodo-5-nitrophenyl) morpholine (24B) (1.0g, 3.0mmol) was dissolved in N, N-dimethylformamide (2mL), and ammonia (51mg, 30mmol) and copper powder (190mg, 3.0mmol) were added to react overnight in a closed system at 100 ℃. After completion of the reaction, 60mL of water was added, followed by extraction with dichloromethane (60mL × 2), washing with water (60mL), washing with saturated brine (60mL), drying over anhydrous sodium sulfate, concentration under reduced pressure, and silica gel column chromatography (ethyl acetate/petroleum ether: 1:10 to 1:1) to give 3-morpholinyl-5-nitroaniline (24C) (0.35g, yield 52.23%) as a red solid.

¹H NMR(400MHz,CDCl₃)δ7.14(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) (0.4g, 1.6mmol), 3-morpholino-5-nitroaniline (0.37g, 1.6mmol), p-toluenesulfonic acid (0.31g, 1.6mmol) was added to 40mL of 2-pentanol and reacted at 120 ℃ overnight. After the reaction, the reaction mixture was cooled to precipitate a solid, which was then filtered and the cake was dried to give 4- (1-methyl-1H-indol-3-yl) -N- (3-morpholinyl-5-nitrophenyl) pyrimidin-2-amine (24D) as a yellow solid (0.3g, 53.5% yield).

LC-MS(m/z):431.1[M+1]⁺。

The fourth step: n is a radical of¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-morpholinylbenzene-1, 3-diamine (24E)

N¹-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-morpholinobenzene-1,3-diamine

4- (1-methyl-1H-indol-3-yl) -N- (3-morpholin-5-nitrophenyl) pyrimidin-2-amine (24D) (0.4g, 0.93mmol) was dissolved in a mixed solvent of ethanol (20ml) and water (10ml), and iron powder (311mg, 5.6mmol) and ammonium chloride (497.5mg, 9.3mmol) were added. The reaction was carried out at 90 ℃ for 2 hours. Water (30mL) was added to the reaction mixture, followed by extraction with methylene chloride (30 mL. times.2), and the organic phases were combined, washed successively with water (30mL) and saturated brine (30mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-morpholinylbenzene-1, 3-diamine (24E) as a brown solid (250mg, 68% yield).

¹H NMR(400MHz,CDCl₃)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]⁺。

The fifth step: n- (3- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -5-morpholinylbenzene) acrylamide (compound 24)

Will N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -5-morpholinylbenzene-1, 3-diamine (24E) (250mg, 0.625mmol) was dissolved in 5mL of pyridine, acrylic acid (90mg, 1.25mmol) was added, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.5mmol, 478mg) was added, and the reaction was carried out at room temperature for 2 hours. 60mL of methylene chloride was added, and the mixture was washed with water (60 mL. times.2), saturated sodium bicarbonate (60 mL. times.2), and saturated brine (30mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol (v/v) ═ 100/1-100/3) to give N- (3- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -5-morpholinylbenzene) acrylamide (compound 24) (150mg, yield 52.8%) as a pale red solid.

¹H NMR(400MHz,CDCl₃)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) ethyl) (methyl) amino) -4-ethylphenyl) acrylamide (compound 25)

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

The first step is as follows: 2-Ethyl-4-fluoro-5-nitroaniline (25B)

2-ethyl-4-fluoro-5-nitroaniline

To a reaction flask was added 25mL of concentrated sulfuric acid, 2-ethyl-4-fluoroaniline (25A) (3.88g, 27.9mmol) was added dropwise at 0 ℃, potassium nitrate ((2.82g, 27.9mmol) was added, and the reaction was carried out at 0 ℃ for 1 hour, ice cubes (100mL) were added to a saturated sodium bicarbonate solution (300mL), the reaction system was slowly poured into the above solution, sodium bicarbonate solid was added until no more bubbles were generated, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (150mL × 4), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10:1 to 2:1) to give the title compound 2-ethyl-4-fluoro-5-nitroaniline (25B) (3.33g, yield 55%) as an orange solid.

MS m/z:185.1[M+1]⁺。

The second step is that: 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-a mine

2-Ethyl-4-fluoro-5-nitroaniline (25B) (1.31g,7.1mmol) and 3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1H-indole (4c) (1.97g,7.1mmol) were dissolved in 1, 4-dioxane (70mL), 4.5-bis-diphenylphosphine-9.9-dimethylxanthene (0.46g,0.79mmol), cesium carbonate (4.85g,14.9mmol) and palladium acetate (0.10g,0.47 mmol) were added, the mixture was cooled with liquid nitrogen, replaced with nitrogen for 0.5 hour, and the mixture was allowed to warm to room temperature and reacted at 120 ℃ overnight. Cooled to room temperature, the solid was filtered off with suction, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10:1 to 3:1) to give the title compound 5-chloro-N- (2-ethyl-4-fluoro-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (25C) as a yellow-green solid (0.59g, 20% yield).

MS m/z:426.1[M+1]⁺。

The third step: n is a radical of¹- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-ethyl-N⁴-methyl-5-nitrophenyl-1, 4-diamine (25D)

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

5-chloro-N- (2-ethyl-4-fluoro-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (25C) (0.56g,1.32mmol) was added to a microwave reaction tube, N, N-dimethylacetamide (8mL) was added thereto and dissolved, and diisopropylethylamine (0.26mL,1.59mmol), N, N, N' -trimethylethylenediamine (18A) (0.21mL,1.59mmol) and microwave-reacted at 140 ℃ for 1 hour. The reaction system was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 4:1 to 2:1 to dichloromethane: methanol (v/v) ═ 15:1 to 5:1) to give the title compound as an orange solid N ¹- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-ethyl-N⁴Methyl-5-nitrophenyl-1, 4-diamine (25D) (0.49g, 73% yield).

MS m/z＝509.2[M+1]⁺。

The fourth step: n is a radical of⁴- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-ethyl-N¹-methylphenyl-1, 2, 4-triamine (25E)

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

Will N¹- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-ethyl-N⁴-methyl-5-nitrobenzene-1, 4-diamine (25D) (0.46g,0.91mmol), iron powder (0.30g,5.43mmol) and ammonium chloride (0.04g,0.75mmol) were added to a mixed solvent of absolute ethanol (12mL) and water (4mL), heated to 90 ℃ for reaction overnight, supplemented with iron powder (0.15g,2.72mmol) and ammonium chloride (0.02g,0.37mmol), and reacted at 90 ℃ for 2 hours. Cooling to room temperature, suction-filtering to remove the solid, concentrating, and separating and purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 1: 1-ethyl acetate: methanol (v/v) ═ 10: 1-3: 1) to obtain the title compound as an orange solid N⁴- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-ethyl-N¹-methylphenyl-1, 2, 4-triamine (25E) (0.43g, 92% yield).

MS m/z:479.2[M+1]⁺。

The fifth step: n- (5- ((5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-ethylphenyl) acrylamide (compound 25)

Diisopropylethylamine (1.7mL) was added to freshly distilled tetrahydrofuran (8.3mL) to give solution 1; acryloyl chloride (0.75mL) was added to freshly distilled tetrahydrofuran (9.25mL) to give solution 2. Will N⁴- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-ethyl-N¹-methylphenyl-1, 2, 4-triamine (25E) (0.40g,0.84mmol) was dissolved in freshly distilled tetrahydrofuran (10mL), and solution 1(1mL) and solution 2(1 mL) were added dropwise at 0 ℃ and reacted at room temperature for 1.5 hours. The reaction mixture was quenched by adding water (80mL), the aqueous phase was extracted with ethyl acetate (70mL × 5), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 1: 1-acetic acid)Ethyl ester methanol (v/v) ═ 10:1 to 1:1) to give the title compound 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) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-ethylphenyl) acrylamide (compound 25) (0.07g, 16% yield) as a white solid.

¹H NMR(400MHz,DMSO-d₆)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

The first step is as follows: 6-bromo-1- (triisopropylsilyl) -1-hydro-indole (26B)

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

Tetrahydrofuran (250mL) was added to a 2L round bottom flask, and sodium hydride (24.5 g,0.612mol, 60% w/w) was added to the flask at 0 deg.C, and a solution of 6-bromoindole (100.0g,0.510mol) in tetrahydrofuran (500mL) was added dropwise. After completion of the addition, the mixture was stirred at 0 ℃ for 30 minutes, and a solution of triisopropylchlorosilane (100g,0.518mol) in tetrahydrofuran (250mL) was added dropwise. After the addition was complete, the reaction was stirred for a further 30 minutes at 0 ℃. The reaction solvent was removed under reduced pressure, the residue was poured into ethyl acetate (3000mL), the organic phase was washed successively with water (1000mL), saturated brine (500mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography (petroleum ether/ethyl acetate (v/v) ═ 15:1) to give 6-bromo-1- (triisopropylsilyl) -1-hydro-indole (26B) as a white solid (160g, 93% yield).

¹H NMR(400MHz,CDCl₃)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),1.16-1.14(m,18H)。

The second step is that: 4- (1H-indol-6-yl) piperidine-1-carboxylic acid tert-butyl ester (26C)

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

6-bromo-1- (triisopropylsilyl) -1-hydro-indole (26B) (1.2g, 3.6mmol) was charged in a 100mL round-bottom flask, and o-xylene (40mL), 1-tert-butoxycarbonylpiperazine (1.0g, 5.4mmol), sodium tert-butoxide (0.51g, 5.4mmol), tri-tert-butylphosphine (0.11g, 0.54mmol), and palladium acetate (0.04g, 0.18mmol) were added sequentially to the reaction flask, and replaced with a nitrogen balloon several times, stirred at room temperature for 30 minutes, and the reaction was continued for 2 hours while the temperature was raised to 120 ℃. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (50 mL. times.2), the filtrate was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was dissolved in 100mL of tetrahydrofuran, and tetrabutylammonium fluoride (1.9g,7.2mmol) was added thereto and reacted at room temperature for 1 hour. The reaction solvent was removed under reduced pressure, and column chromatography separation (petroleum ether/ethyl acetate (v/v) ═ 2:1) gave tert-butyl 4- (1 h-indol-6-yl) piperidine-1-carboxylate (26C) as a white solid (0.65g, yield: 60%).

¹H NMR(400MHz,CDCl₃)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) -1H-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

Tert-butyl 4- (1-hydro-indol-6-yl) piperidine-1-carboxylate (26C) (0.3g, 1mmol) was added to a 50mL round-bottom flask, and tetrahydrofuran (5mL) was added to the reaction flask. An ether solution of methyl magnesium bromide (0.5mL, 1.5mmol,3mol/L) was added dropwise at 0 deg.C, after which the reaction was allowed to warm to room temperature and stirred for 1 hour. 2,4, 5-trichloropyrimidine (0.2g,1.1mmol) was added to the reaction flask at 0 ℃. The reaction was heated to reflux for 2 hours. The reaction solution was cooled to room temperature, water (20mL) was added to quench the reaction, the residue was extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2:1) to separate 4- (3- (2, 5-dichloropyrimidin-4-yl) -1 h-indol-6-yl) piperidine-1-carboxylic acid tert-butyl ester (26D) as a yellow solid (0.1g, 20% yield).

¹H NMR(400MHz,CDCl₃)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]⁺。

The fourth step: 4- (3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1H-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-car boxylate

Tert-butyl 4- (3- (2, 5-dichloropyrimidin-4-yl) -1 h-indol-6-yl) piperidine-1-carboxylate (26D) (1.1g, 2.4mmol) was added to a 100mL round-bottom flask and N, N-dimethylformamide (20mL) was added to the reaction flask. Sodium hydride (0.14g,5.9mol, 60%) was added to the reaction flask at 0 ℃ and the reaction was continued at 0 ℃ for 30 minutes. Methyl iodide (1.0g,7.1mmol) was added to the reaction solution, and the reaction was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into water (100mL), a large amount of solid precipitated, and the precipitate was filtered, washed with petroleum ether (20mL × 2) and water (20mL × 2) in this order, and naturally dried to give tert-butyl 4- (3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1 h-indol-6-yl) piperidine-1-carboxylate (26E) (1.1g, yield 99%) as a yellow solid.

The fifth step: 4- (3- (5-chloro-2- ((2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1-methyl-1 h-indol-6-yl) piperidine-1-carboxylic acid tert-butyl ester (26F)

tert-butyl 4-(3-(5-chloro-2-((2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-meth yl-1H-indol-6-yl)piperazine-1-carboxylate

Tert-butyl 4- (3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1 h-indol-6-yl) piperidine-1-carboxylate (26E) (0.46g, 1.0mmol) was charged to a 100mL round-bottomed flask, and to the reaction flask were added 1, 4-dioxane (20mL), 2-amino-4-nitrobenzyl ether (0.2g, 1.2mmol), and sodium tert-butoxide (0.24g, 2.5mmol) in that order. The reaction system was purged with nitrogen for 10 minutes, and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.063g, 0.11mmol) and palladium acetate (0.022g, 0.1mmol) were added to replace the reaction system with nitrogen again. The temperature is increased to reflux reaction and stirring is carried out for 6 hours. After the reaction was cooled to room temperature, the reaction was quenched by adding water (20mL), the residue was extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2:1) to give 4- (3- (5-chloro-2- ((2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1-methyl-1 h-indol-6-yl) piperidine-1-carboxylic acid tert-butyl ester (26F) (0.25g, 42% yield) as a yellow solid.

¹H NMR(400MHz,CDCl₃)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)。

And a sixth step: 4- (3- (2- ((5-amino-2-methoxyphenyl) amino) -5-chloro-pyrimidin-4-yl) -1-methyl-1 h-indol-6-yl) piperidine-1-carboxylic acid tert-butyl ester (26G)

tert-butyl 4-(3-(2-((5-amino-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)-1-met hyl-1H-indol-6-yl)piperazine-1-carboxylate

Tert-butyl 4- (3- (5-chloro-2- ((2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1-methyl-1 h-indol-6-yl) piperidine-1-carbonate (26F) (0.12g,0.2mmol) was charged to a 100mL round-bottomed flask, ethanol (15mL), water (5mL), reduced iron powder (0.067g,1.2mmol), and ammonium chloride (0.007g,0.14mmol) were added in that order, and the temperature was raised to reflux for 4 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane (10 mL. times.2) and methanol (10 mL. times.2). The filtrate was concentrated and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1:1) to give tert-butyl 4- (3- (2- ((5-amino-2-methoxyphenyl) amino) -5-chloro-pyrimidin-4-yl) -1-methyl-1 h-indolin-6-yl) piperidine-1-carboxylate (26G) as a yellow solid (0.06G, 55% yield).

¹H NMR(400MHz,CDCl₃)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)。

The seventh step: 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-amino-2-methoxyphenyl) amino) -5-chloro-pyrimidin-4-yl) -1-methyl-1 h-indol-6-yl) piperidine-1-carboxylate (26G) (0.65G,1.2mmol) was added to a 50mL round-bottom flask. To the reaction flask were added pyridine (10mL), acrylic acid (0.17g,2.4mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.88g,4.8mmol) in that order. The reaction was stirred at room temperature for 6 hours. The reaction solvent was removed under reduced pressure, a saturated aqueous sodium bicarbonate solution (40mL) was added, the residue was extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with saturated brine (40mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography (ethyl acetate) to isolate tert-butyl 4- (3- (2- ((5-acrylamido-2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) -1-methyl-1H-indol-6-yl) piperazine-1-carboxylate (compound 26) as a yellow solid (0.50g, yield 70%).

¹H NMR(400MHz,CDCl₃)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

The first step is as follows: n- (3- ((5-chloro-4- (1-methyl-6- (4-methylpiperazin-1-yl) indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 27)

Tert-butyl 4- [3- [ 5-chloro-2- [ 2-methoxy-5- (acrylamido) anilino ] pyrimidin-4-yl ] -1-methyl-indol-6-yl ] piperidine-1-carboxylate (compound 26) (0.40g,0.65mmol) was added to a 50mL round-bottom flask. At 0 ℃, dichloromethane (10mL) and trifluoroacetic acid (5mL) were added in this order, and the reaction was stirred at room temperature for 2 hours. Dichloromethane (50mL) and saturated aqueous sodium bicarbonate (20mL) were added to the reaction mixture, the layers were separated, the aqueous phase was extracted with dichloromethane (50mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. Methylene chloride (10mL), acetic acid (2mL) and an aqueous formaldehyde solution (1mL) were added to the crude product in this order at 0 ℃ and stirred for 30 minutes. Sodium triacetoxyborohydride (0.29g,1.3mmol) was added to the reaction solution, and the reaction was warmed to room temperature and stirred for 3 hours. The reaction was quenched by dropwise addition of saturated aqueous sodium bicarbonate (30mL), extracted with dichloromethane (50mL × 2), the organic phases were combined, washed with saturated brine (40mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatographed (dichloromethane/methanol (v/v) ═ 15:1) to give N- (3- ((5-chloro-4- (1-methyl-6- (4-methylpiperazin-1-yl) indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 27) (0.20g, 56%) as a yellow solid.

¹H NMR(400MHz,CDCl₃)δ8.54-8.53(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-yl) amino) phenyl) acrylamide (compound 28)

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

The first step is as follows: (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)

tert-butyl(1-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-nitr ophenoxy)methyl)cyclopropyl)carbamate

5- ((4- (1-Methylindol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2-fluoro-1-nitrobenzene (intermediate 3) (1g, 2.54mmol) was dissolved in tetrahydrofuran (20mL), sodium hydride (203mg, 5.08mmol) was added under ice-cooling, stirred for 30 minutes, added dropwise (1-hydroxymethylcyclopropyl) -tert-butoxycarbonylamino (951mg, 5.08mmol), and reacted at room temperature for 8 hours. After completion of the reaction, 150mL of water and 150mL of ethyl acetate were added and the mixture was separated. The aqueous phase was extracted with 100mL ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give the compound tert-butyl 1- ((5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrophenoxy) methyl) cyclopropyl) carbamate (28A) as a yellow solid (1g, 71.4% yield).

MS m/z:561.1[M+1]⁺。

The second step is that: (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-amino-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amin o)phenoxy)methyl)cyclopropyl)carbamate

Tert-butyl (1- ((5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrophenoxy) methyl) cyclopropyl) carbamate (28A) (1.1g, 2.1mmol) was dissolved in 20mL of ethanol, 7mL of water, iron powder (356mg, 6.4mmol) and ammonium chloride (78.6mg, 1.5mmol) were added in this order, and the mixture was heated to 90 ℃ for reflux reaction for 6 hours. The reaction was cooled to room temperature, filtered and concentrated. Purification by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) gave tert-butyl (1- ((2-amino-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenoxy) methyl) cyclopropyl) carbamate (28B) as a brown solid (750mg, 68.2% yield).

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-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl) amino)phenoxy)methyl)cyclopropyl)carbamate

Tert-butyl (1- ((2-amino-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenoxy) methyl) cyclopropyl) carbamate (28B) (750mg, 1.4mmol) was dissolved in 20mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.2g, 6.3mmol) and acrylic acid (0.15mL, 2.1mmol) were added in that order and reacted at room temperature for 4 hours. Pyridine was removed by spin-drying, and 100mL of water and 100mL of methylene chloride were added to separate the layers. The organic phase was washed with 4mol/L aqueous sodium hydroxide (100 mL). The organic phase was dried over anhydrous sodium sulfate. Silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) gave tert-butyl (1- ((2-acrylamido-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenoxy) methyl) cyclopropyl) carbamate (28C) as a white solid (730mg, 89.4% yield).

MS m/z:585.2[M+1]⁺。

The 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)

Tert-butyl (1- ((2-acrylamido-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenoxy) methyl) cyclopropyl) carbamate (28C) (730mg, 1.25mmol) was dissolved in 20mL of dichloromethane, 10mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 2 hours. After the reaction, the solvent was removed by spin-drying, and the pH of the solution was adjusted to 8 with a saturated aqueous solution of sodium hydrogen carbonate. 100mL of methylene chloride was added, the layers were separated, and the organic layer was dried over anhydrous sodium sulfate. The resulting product was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) to give N- (2- ((1-aminocyclopropyl) methoxy) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 28) (130mg, 21.5%) as a white solid.

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-morpholinoethoxy) phenyl) acrylamide (compound 29)

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

The first step is as follows: 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)pyr imidin-2-amine

5- ((4- (1-methylindol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2-fluoro-1-nitrobenzene (intermediate 3) (1.2 g, 3.05mmol) was dissolved in 30mL of tetrahydrofuran, and sodium hydride (244.2mg, 6.1mmol) was added under ice-cooling, followed by stirring for 30 minutes, dropwise addition of 2-morpholinoethanol (800.8mg, 6.1mmol), and reaction at room temperature for 6 hours. After completion of the reaction, 150mL of water and 150mL of ethyl acetate were added and the mixture was separated. The aqueous phase was extracted with 100mL ethyl acetate and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the compound N- (2-methoxy-4- (2-morpholinoethoxy) -5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (29A) as a yellow solid (1g, 66.7% yield).

The second step is that: 6-methoxy-N¹- (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)b enzene-1,3-diamine

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

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

Reacting 6-methoxy-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -4- (2-morpholinoethoxy) benzene-1, 3Diamine (29B) (600mg, 1.26mmol) was dissolved in 10mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (722mg, 3.78mmol) and acrylic acid (0.13mL, 1.89mmol) were added in this order to react at room temperature for 4 hours. Pyridine was removed by spin-drying, and 100mL of water and 100mL of methylene chloride were added to separate the layers. The organic phase was washed with 4mol/L aqueous sodium hydroxide (100 mL). The organic phase was dried over anhydrous sodium sulfate. The compound N- (4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (2-morpholinoethoxy) phenyl) acrylamide (compound 29) was obtained as a white solid by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) (65mg, 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) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (compound 30)

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

The first step is as follows: 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) (1g, 4.35mmol) was dissolved in 15mL acetonitrile, potassium hydroxide (4.88g, 87mmol) and 10mL water were added, the temperature was reduced to 0 deg.C, diethyl bromofluoromethylphosphonate (2.32g, 8.7mmol) was added dropwise, and the reaction was allowed to warm to room temperature for 2 hours. The reaction solution was poured into 50mL of water, extracted with ethyl acetate (50mL), and the organic phase was washed with water (50mL), dried over anhydrous sodium sulfate, and concentrated to give 3- (2-chloropyrimidin-4-yl) -1- (difluoromethyl) -1H-indole (30A) (1.2g, crude) as a brown solid.

MS m/z＝280.0[M+1]⁺。

The second step is that: 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) (0.1g, 0.36mmol) was dissolved in 2-pentanol (10mL), 4-fluoro-2-methoxy-5-nitroaniline (4e) (67mg, 0.36mmol) and p-toluenesulfonic acid (83 mg, 0.43mmol) were added, and the reaction was heated to 120 ℃ for 1 day under reflux. The reaction 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) pyrimidin-2-amine (30B) as a yellow solid (0.1g, 66.7% yield).

MS m/z＝430.0[M+1]⁺。

The third step: n is a radical of¹- (4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenzene-1, 4-diamine (30C)

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

4- (1- (difluoromethyl) -1H-indol-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidin-2-amine (30B) (0.6g, 1.4mmol) was dissolved in N, N-dimethylacetamide (5mL), N, N-diisopropylethylamine (220mg, 1.7mmol) and N, N, N' -trimethylethylenediamine (18A) (172mg, 1.7mmol) were added, and the mixture was reacted at 140 ℃ for 1 hour under microwave. After completion of the reaction, 150mL of water and 150mL 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 N¹- (4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴Methyl-5-nitrophenyl-1, 4-diamine (30C) (0.7g, 97.9% yield).

MS m/z＝512.1[M+1]⁺。

The fourth step: n is a radical of⁴- (4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (30D)

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

Will N¹- (4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenzene-1, 4-diamine (30C) (0.9g, 1.76mmol) was dissolved in 30mL ethanol, 10mL water, iron powder (295mg, 5.28mmol) and ammonium chloride (66mg, 1.23mmol) were added sequentially, the reaction was refluxed for 4 hours at 90 ℃ and concentrated. Separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain brown solid compound N ⁴- (4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (30D) (350mg, 41.3% yield).

MS m/z＝482.1[M+1]⁺。

The fifth step: n- (5- ((4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (compound 30)

Will N⁴- (4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (30D) (350mg, 0.73mmol) was dissolved in 10mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (416mg, 2.18mmol) and acrylic acid (0.075mL, 1.09mmol) were added in this order to react at room temperature for 4 hours. The pyridine was spin-dried, 150mL of water and 150mL of dichloromethane were added, and the layers were separated. The organic phase was washed with 100mL of 4mol/L aqueous sodium hydroxide solution. The organic phase was dried over anhydrous sodium sulfate. Separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain white solid N- (5- ((4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (meth) amino) -4-methoxyphenyl) acrylamide (compound 30) (170mg, yield 43.6%).

MS m/z:536.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 31)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(1-isopropyl-1H-indol-3-yl)pyri midin-2-yl)amino)-4-methoxyphenyl)acrylamide

The first step is as follows: 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) (2g, 8.7mmol) was dissolved in 30mL of tetrahydrofuran, and sodium hydride (836mg, 10.4mmol) was added at 0 ℃ to react for 30 minutes, and isopropyl iodide (5.24mL, 26.3mmol) was added and warmed to room temperature to react for 32 hours. After completion of the reaction, 150mL of methylene chloride and 100mL of water were added to separate the reaction solution. The aqueous phase was extracted with 100mL of dichloromethane and the organic phase was dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 1:0 to 2:1) gave 3- (2-chloropyrimidin-4-yl) -1-isopropyl-1H-indole (31A) as a brown solid (0.75g, 32.6% yield).

MS m/z＝272.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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)。

The second step is that: 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-ami ne

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

¹H NMR(400MHz,CDCl₃)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)。

The third step: n is a radical of¹- (2- (dimethylamino) ethyl) -N⁴- (4- (1-isopropyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methyl-2-nitrobenzene-1, 4-diamine (31C)

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

N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-isopropyl-1H-indol-3-yl) pyrimidin-2-amine (31B) (0.6g, 1.4mmol) was dissolved in N, N-dimethylacetamide (10mL), followed by the addition of N, N-diisopropylethylamine (221mg, 1.71mmol) and N, N, N' -trimethylethylenediamine (18A) (175mg, 1.71mmol), and reacted at 140 ℃ for 1 hour under microwave. After the reaction, the mixture was concentrated. Separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-30: 1) to obtain red solid compound N¹- (2- (dimethylamino) ethyl) -N⁴- (4- (1-isopropyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹Methyl-2-nitrophenyl-1, 4-diamine (31C) (0.6g, 85.2% yield).

MS m/z:504.3[M+1]⁺。

The fourth step: n is a radical of¹- (2- (dimethylamino) ethyl) -N⁴- (4- (1-isopropyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (31D)

N1-(2-(dimethylamino)ethyl)-N4-(4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-yl)-5-me thoxy-N1-methylbenzene-1,2,4-triamine

Will N¹- (2- (dimethylamino) ethyl) -N⁴- (4- (1-isopropyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methyl-2-nitrophenyl-1, 4-diamine (31C) (0.6g, 1.2mmol) was dissolved in 15mL of ethanol, and 5mL of water, iron powder (201mg, 3.6mmol) and ammonium chloride (45mg, 0.84mmol) were added in this order, and the mixture was heated to 90 ℃ for 4 hours under reflux. The reaction was cooled to room temperature, filtered and concentrated. Separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-30: 1) to obtain brown solid compound N ¹- (2- (dimethylamino) ethyl) -N⁴- (4- (1-isopropyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (31D) (550mg, 96.8% yield).

MS m/z:474.3[M+1]⁺。

The fifth step: n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1-isopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 31)

Will N¹- (2- (dimethylamino) ethyl) -N⁴- (4- (1-isopropyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (31D) (550mg, 1.16mmol) was dissolved in 10mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (997mg, 5.22mmol) and acrylic acid (0.12mL, 1.74mmol) were added to react at room temperature for 4 hours. Pyridine was dried by spinning, and an aqueous solution of sodium hydroxide (100mL, 4mol/L) and 100mL of ethyl acetate were added to separate the layers. The organic phase was washed with 100mL of saturated brine and dried over anhydrous sodium sulfate. Separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain a white solid compound N- (2- ((2- (bis)Methylamino) ethyl) (methyl) amino) -5- ((4- (1-isopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 31) (400mg, 65.5% yield).

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-yl) amino) -4-methoxyphenyl) acrylamide (compound 32)

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

The first step is as follows: 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) (2g, 8.7mmol) was dissolved in 30mL of tetrahydrofuran, cooled to 0 ℃ and reacted at 0 ℃ for 30 minutes with sodium hydride (0.836g, 10.4 mmol). Iodothane (4.1g, 26.3mmol) was added, the reaction was allowed to warm to room temperature and continued for 4 hours, after which the reaction was terminated and the solvent was spin-dried. The solid was washed with 100mL of water and 20mL of tetrahydrofuran. The solid was dried to give 3- (2-chloropyrimidin-4-yl) -1-ethyl-1H-indole (32A) (2.1g, 95.5% yield) as a yellow solid.

MS m/z:258.0[M+1]⁺。

The second step is that: 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) (0.257g, 1mmol) was dissolved in 2-pentanol (10mL), 4-fluoro-2-methoxy-5-nitroaniline (4e) (186mg, 1mmol) and p-toluenesulfonic acid (228mg, 1.2 mmol) were added, and the reaction was heated to 120 ℃ for 1 day under reflux. The reaction was cooled to room temperature, filtered, and the filter cake was washed with 50mL of water and dried to give 4- (1-ethyl-1H-indol-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidin-2-amine (32B) as a yellow solid (0.3g, 73.7% yield).

MS m/z:408.0[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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 is a radical of¹- (2- (dimethylamino) ethyl) -N⁴- (4- (1-ethyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methyl-2-nitrobenzene-1, 4-diamine (32C)

N1-(2-(dimethylamino)ethyl)-N4-(4-(1-ethyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methox y-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) (1g, 2.46mmol) was dissolved in 12mL of N, N-dimethylacetamide, and N, N-diisopropylethylamine (387.8mg, 3mmol), and N, N, N' -trimethylethylenediamine (18A) (300mg, 3mmol) were added and reacted at 140 ℃ for 1 hour under microwave. After completion of the reaction, 150mL of water and 150mL of methylene chloride were added and the mixture was separated. Drying the organic phase with anhydrous sodium sulfate, and concentrating to obtain red solid compound N¹- (2- (dimethylamino) ethyl) -N⁴- (4- (1-ethyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹Methyl-2-nitrophenyl-1, 4-diamine (32C) (1g, 83.3% yield).

MS m/z:490.1[M+1]⁺。

The fourth step: n is a radical of¹- (2- (dimethylamino) ethyl) -N⁴- (4- (1-ethyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (32D)

N1-(2-(dimethylamino)ethyl)-N4-(4-(1-ethyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methox y-N1-methylbenzene-1,2,4-triamine

Will N¹- (2- (dimethylamino) ethyl) -N⁴- (4- (1-ethyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methyl-2-nitrophenyl-1, 4-diamine (32C) (1g, 2 mmol)) Dissolved in 15mL of ethanol, 5mL of water, iron powder (335mg, 6mmol) and ammonium chloride (75mg, 1.4mmol) were added in this order, and the mixture was heated to 90 ℃ for reflux reaction for 6 hours. Concentrating the reaction solution, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain brown solid compound N ¹- (2- (dimethylamino) ethyl) -N⁴- (4- (1-ethyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (32D) (800mg, 87.1% yield).

MS m/z:460.1[M+1]⁺。

The fifth step: n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1-ethyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 32)

Will N¹- (2- (dimethylamino) ethyl) -N⁴- (4- (1-ethyl-1H-indol-3-yl) pyrimidin-2-yl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (32D) (800mg, 1.74mmol) was dissolved in 15mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (999mg, 5.2mmol) and acrylic acid (0.18mL, 2.61mmol) were added in this order to react at room temperature for 4 hours. The pyridine was spin-dried, 100mL of water and 100mL of dichloromethane were added, and the layers were separated. The organic phase was washed with aqueous sodium hydroxide (100mL, 4 mol/L). The organic phase was dried over anhydrous sodium sulfate. The resulting product was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) to give N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1-ethyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 32) as a white solid (110mg, 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) pyrimidin-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

The second step is that: 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) (1g, 4.35mmol) was dissolved in 25mL tetrahydrofuran, cooled to 0 deg.C, and reacted at 0 deg.C for 30 min with sodium hydride (125.3mg, 5.22 mmol). (2-Bromoethoxy) -tert-butyldimethylsilane (2.5g, 8.7mmol) was added, and the reaction was allowed to warm to room temperature for 1 day. At the end of the reaction, the solvent was spun off, the solid was washed with 100mL water and the solid was dried to give the compound 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (2-chloropyrimidin-4-yl) -1H-indole (33A) as a yellow solid (1.3g, 77.4% yield).

¹H NMR(400MHz,CDCl₃)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)。

The second step is that: 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)eth anol

1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (2-chloropyrimidin-4-yl) -1H-indole (33A) (1.3g, 3.36mmol) was dissolved in 2-pentanol (50mL), and 4-fluoro-2-methoxy-5-nitroaniline (4e) (625mg, 3.36mmol) and p-toluenesulfonic acid (774mg, 4.03mmol) were added in this order, and the mixture was heated to 120 ℃ for reflux for 2 days. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with 100mL of water and dried to give 2- (3- (2- ((4-fluoro-2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1H-indol-1-yl) ethanol (33B) (1.1g, 78.6% yield) as a yellow solid.

MS m/z:424.0[M+1]⁺。

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

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

2- (3- (2- ((4-fluoro-2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1H-indol-1-yl) ethanol (33B) (1g, 2.4mmol) was dissolved in 10mL of N, N-dimethylacetamide, and N, N-diisopropylethylamine (366mg, 2.8mmol) and N, N, N' -trimethylethylenediamine (18A) (290mg, 2.8mmol) were added in this order, and the reaction was carried out by microwave at 140 ℃ for 1 hour. After completion of the reaction, 150mL of water and 150mL of ethyl acetate were added and the mixture was separated. The organic phase was washed with 100mL of water, dried over anhydrous sodium sulfate, filtered and concentrated to give the compound 2- (3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1H-indol-1-yl) ethanol (33C) as a red oil (1g, 83.3% yield).

The fourth step: n is a radical of¹- (4- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenzene-1, 4-diamine (33D)

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

2- (3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1H-indol-1-yl) ethanol (33C) (1g, 1.98mmol) was dissolved in 20mL of dichloromethane, triethylamine (600mg, 5.94mmol) was added, tert-butyldimethylchlorosilane (448mg, 2.97mmol) was added dropwise, and the reaction was carried out at room temperature for 4 hours. After the reaction, 10mL of water was added and the mixture was stirred for 30 minutes. 100mL of water and 100mL of methylene chloride were added to the reaction mixture, and the mixture was separated. The aqueous phase is extracted with 100mL of dichloromethane and washed with 150mL of saturated sodium chloride. Concentrating to obtain red oily N ¹- (4- (1- (2- ((tert-butyldimethylsilyl) silicon)Yl) oxy) ethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴Methyl-5-nitrophenyl-1, 4-diamine (33D) (1g, 83.3% yield).

MS m/z:620.0[M+1]⁺。

The fifth step: n is a radical of⁴- (4- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (33E)

Will N¹- (4- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenzene-1, 4-diamine (33D) (1g, 1.6mmol) was dissolved in 30mL of ethanol, 10mL of water, iron powder (270mg, 4.8mmol) and ammonium chloride (60mg, 1.1mmol) were added in this order, and the mixture was heated to 90 ℃ for reflux reaction for 6 hours. Concentrating the reaction solution, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain brown solid compound N⁴- (4- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (33E) (1.1g, crude).

And a sixth step: 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)

N-(5-((4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)pyrimidin-2-yl)ami no)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Will N⁴- (4- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (33E) (943mg, 1.6mmol) was dissolved in 15mL pyridine, and the solution was added sequentially1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (917mg, 4.8mmol), acrylic acid (0.17mL, 2.4mmol) were added and reacted at room temperature for 4 hours. The reaction solution was spin-dried to remove pyridine, and 150mL of water and 150mL of ethyl acetate were added to separate the solution. The organic phase was washed with aqueous sodium hydroxide (100mL, 4mol/L), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) to give 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) as a brown solid (360mg, yield 35%).

MS m/z:644.2[M+1]⁺。

The seventh step: n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- (2-hydroxyethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 33)

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) (0.36g, 0.52 mmol) was dissolved in 10mL of dichloromethane, and tetrabutylammonium fluoride (293mg, 1.12mmol) was added and reacted at room temperature for 6 hours. After completion of the reaction, 100mL of water and 100mL of methylene chloride were added and the mixture was separated. The aqueous phase was extracted with 100mL of dichloromethane, the organic phases were combined and the organic phase was washed with 150mL of saturated sodium chloride. The organic phase was concentrated and purified by column chromatography on silica gel (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) to give N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- (2-hydroxyethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 33) as a brown solid (0.25g, 84.6% yield).

MS m/z:530.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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-(dimeth ylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The first step is as follows: 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) (3g, 13.1mmol) was dissolved in 2-pentanol (10mL), 4-fluoro-2-methoxy-5-nitroaniline (4e) (2.44g, 13.1mmol) and p-toluenesulfonic acid (3.02g, 15.7mmol) were added, and the reaction was heated to 120 ℃ for 3 days under reflux. The reaction solution was cooled to room temperature, 200mL of aqueous ammonia was added to precipitate a solid, which was filtered, and the filter cake was washed with 250mL of water and 100mL of petroleum ether and dried to obtain a pale green solid, N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1H-indol-3-yl) pyrimidin-2-amine (34A) (4g, yield 80.5%).

MS m/z＝380.1[M+1]⁺。

The second step is that: n is a radical of¹- (4- (1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenzene-1, 4-diamine (34B)

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

Reacting N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1H-indol-3-yl) pyrimidin-2-amine (II)34A) (2g, 5.3mmol) was dissolved in 15mL of N, N-dimethylacetamide, and N, N-diisopropylethylamine (1.02g, 7.9mmol) and N, N, N' -trimethylethylenediamine (18A) (809mg, 7.9mmol) were added and reacted at 120 ℃ for 1.5 hours under microwave. After completion of the reaction, the reaction mixture was cooled to room temperature, and 200mL of water and 200mL of ethyl acetate were added to separate the reaction mixture. The organic phase was washed with 100mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to give Compound N as a reddish brown solid ¹- (4- (1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴Methyl-5-nitrophenyl-1, 4-diamine (34B) (1.8g, 75% yield).

The third step: n is a radical of¹- (4- (1- (cyclopropylmethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenzene-1, 4-diamine (34C)

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

Will N¹- (4- (1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenzene-1, 4-diamine (34B) (2g, 4.3mmol) was dissolved in 20mL dimethylformamide, cooled to 0 deg.C, sodium hydride (0.26g, 6.5mmol) was added and reacted at 0 deg.C for 30 minutes. Bromomethylcyclopropane (0.585g, 4.3mmol) was added, and the reaction was allowed to warm to room temperature for 6 hours. After completion of the reaction, 100mL of water and 100mL of ethyl acetate were added and the mixture was separated. The aqueous phase was extracted with 100mL of ethyl acetate. Combining the organic phases, drying the organic phase with anhydrous sodium sulfate, and concentrating to obtain brown solid compound N¹- (4- (1- (cyclopropylmethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴Methyl-5-nitrophenyl-1, 4-diamine (34C) (2g, 90.9% yield).

MS m/z:516.1[M+1]⁺。

The fourth step: n is a radical of⁴- (4- (1- (cyclopropylmethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N ¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (34D)

N⁴-(4-(1-(cyclopropylmethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N¹-(2-(dimethylamino)e thyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine

Will N¹- (4- (1- (cyclopropylmethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenzene-1, 4-diamine (34C) (2g, 3.88mmol) was dissolved in 24mL ethanol, 8mL water, iron powder (1.3g, 23.3mmol) and ammonium chloride (145mg, 2.7mmol) were added in that order, and the reaction was refluxed at 92 ℃ for 5 hours. Concentrating the reaction solution, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain brown solid compound N⁴- (4- (1- (cyclopropylmethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (34D) (1.1g, 58.5% yield).

MS m/z:486.1[M+1]⁺。

The fifth step: n- (5- ((4- (1- (cyclopropylmethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (compound 34)

Will N⁴- (4- (1- (cyclopropylmethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (34D) (1g, 2.06mmol) was dissolved in 25mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.18g, 6.2mmol) and acrylic acid (0.213mL, 3.1 mmol) were added in this order to react at room temperature for 4 hours. Removing pyridine from the reaction liquid by rotary drying, adding 150mL of ethyl acetate and sodium hydroxide aqueous solution (100mL, 4mol/L), separating, extracting the aqueous phase with 100mL of ethyl acetate, combining the organic phases, washing with 150mL of saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, rotary drying, separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain a white solid compound N- (5- ((4- (1- (cyclopropylmethyl) -1H-indole) compound -3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (compound 34) (250mg, 22.7% yield).

MS m/z＝540.4[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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-indole-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (Compound 35)

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

The first step is as follows: 3- (2-chloro-5-methoxypyrimidin-4-yl) -1H-indole (35A)

3-(2-chloro-5-methoxypyrimidin-4-yl)-1H-indole

Indole (4a) (2.34g, 20mmol) was dissolved in 40mL tetrahydrofuran, cooled to 0 ℃ under nitrogen, and methyl magnesium bromide (6.7mL, 20mmol) was added dropwise with stirring for an additional 0.5 h. 2, 4-dichloro-5-methoxypyrimidine (3.58g, 20mmol) was added thereto, and the mixture was reacted at room temperature for 1 hour and at elevated temperature to 65 ℃ for 4 hours. 150mL of water and 150mL of methylene chloride were added to the reaction mixture, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10:1 to 2:1) to give 3- (2-chloro-5-methoxypyrimidin-4-yl) -1H-indole (35A) (2.81g, 55.1% yield) as a yellow solid.

MS m/z＝260.0[M+1]⁺。

The second step is that: 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) (1.4g, 5.4mmol) was dissolved in 25mL of tetrahydrofuran, and the solution was cooled to 0 ℃ and reacted with sodium hydride (0.261g, 10.9mmol) at 0 ℃ for 30 minutes. Methyl iodide (2.3g, 16.2mmol) was added, the reaction was continued at room temperature for 4 hours, and after completion of the reaction, 10mL of water was added to quench the reaction, and the solvent was dried by spinning. Separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 1:0 to 2:1) gave 3- (2-chloro-5-methoxypyrimidin-4-yl) -1-methyl-1H-indole (35B) (0.3g, yield 20.4%) as a yellow solid.

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) pyrimidin-2-amine (35C)

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

3- (2-chloro-5-methoxypyrimidin-4-yl) -1-methyl-1H-indole (35B) (0.3g, 1.1mmol) was dissolved in 2-pentanol (20mL), 4-fluoro-2-methoxy-5-nitroaniline (4e) (204mg, 1.1mmol) and p-toluenesulfonic acid (253 mg, 1.32mmol) were added, and the reaction was heated to 120 ℃ for 18 hours under reflux. The reaction mixture was cooled to room temperature, and 150mL of water and 150mL of ethyl acetate were added to separate the reaction mixture. The organic phase was dried over anhydrous sodium sulfate, and separated and purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) to give N- (4-fluoro-2-methoxy-5-nitrophenyl) -5-methoxy-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (35C) (0.55g, yield 45.8%) as a red solid.

The fourth step: n is a radical of¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (5-methoxy-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹-methyl-2-nitrobenzene-1, 4-diamine (35D)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N⁴-(5-methoxy-4-(1-methyl-1H-indol-3-yl)p yrimidin-2-yl)-N¹-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 10mL of N, N-dimethylacetamide, and N, N-diisopropylethylamine (367mg, 2.84mmol) and N, N, N' -trimethylethylenediamine (18A) (290mg, 2.84mmol) were added and reacted at 125 ℃ for 1 hour under microwave. After the reaction, N-dimethylacetamide was removed by rotation, 150mL of water and 150mL of dichloromethane were added, and the mixture was separated. The aqueous phase was extracted with 100mL of dichloromethane and the organic phases were combined. Drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain red solid compound N ¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (5-methoxy-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹Methyl-2-nitrophenyl-1, 4-diamine (35D) (1g, 83.3% yield).

MS m/z:490.1[M+1]⁺。

The fifth step: n is a radical of¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (5-methoxy-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹-methylbenzene-1, 2, 4-triamine (35E)

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

Will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (5-methoxy-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹-methyl-2-nitrobenzene-1, 4-diamine (35D) (3.5g, 6.93mmol) was dissolved in 30mL of ethanol, 10mL of water, iron powder (2.32g, 41.6mmol) and ammonium chloride (260mg, 4.85mmol) were added in this order, and the mixture was heated to 90 ℃ for reflux reaction for 6 hours. Concentrating the reaction solution, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain brown solid compound N¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (5-methoxy-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹-methylbenzene-1, 2, 4-triamine (35E) (2g, 60.6% yield).

MS m/z:476.1[M+1]⁺。

And a sixth step: 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)

Will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (5-methoxy-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹-methylbenzene-1, 2, 4-triamine (35E) (350mg, 1.05mmol) was dissolved in 10mL of pyridine, EDCI (600mg, 3.14mmol) and acrylic acid (0.11mL, 1.57mmol) were added, and the reaction was carried out at room temperature for 4 hours. The reaction mixture was spin-dried to remove pyridine, and 100mL of water and 100mL of dichloromethane were added to separate the reaction mixture. The organic phase was washed with aqueous sodium hydroxide (100mL, 4mol/L) and dried over anhydrous sodium sulfate. The brown solid 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) was obtained by separation and purification by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) (210mg, 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-morpholinopropoxy) phenyl) acrylamide (compound 36)

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

The first step is as follows: n- (2-methoxy-4- (3-morpholinopropoxy) -5-nitrobenzene) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (36A)

N-(2-methoxy-4-(3-morpholinopropoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)p yrimidin-2-amine

5- ((4- (1-methylindol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2-fluoro-1-nitrobenzene (intermediate 3) (1g, 2.54mmol) was dissolved in 50mL tetrahydrofuran, and sodium hydride (122mg, 3.1mmol) was added under ice bath and stirred for 30 min. 3-Morpholinopropyl-1-ol (552mg, 3.8mmol) was added dropwise and reacted at room temperature overnight. After the reaction was completed, 100mL of water and 150mL of ethyl acetate were added, the mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give N- (2-methoxy-4- (3-morpholinopropoxy) -5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (36A) (1g, yield 71.4%) as a yellow solid.

MS m/z:519.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.66(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)。

The second step is that: 6-methoxy-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -4- (3-morpholinepropoxy) benzene-1, 3-diamine (36B)

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

N- (2-methoxy-4- (3-morpholinopropoxy) -5-nitrobenzene) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (36A) (1g, 1.93mmol) was dissolved in 30mL of ethanol, and 10L of water, iron powder (646.5g, 11.58mol) and ammonium chloride (72.3g, 1.35mol) were sequentially added, and the mixture was heated to 90 ℃ for reflux reaction for 4 hours. Cooling the reaction solution to room temperature, filtering, concentrating, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain a brown solid compound 6-methoxy-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -4- (3-morpholinopropoxy) benzene-1, 3-diamine (36B) (600mg, 63.7% yield).

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-morpholinopropoxy) phenyl) acrylamide (compound 36)

Reacting 6-methoxy-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -4- (3-morpholinopropoxy) benzene-1, 3-diamine (36B) (600mg, 1.23mmol) was dissolved in 10mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (703mg, 3.68mmol) and acrylic acid (0.127mL, 1.84mmol) were added in this order to react at room temperature for 3 hours. The reaction mixture was spin-dried to remove pyridine, and 150mL of a 4mol/L aqueous sodium hydroxide solution and 150mL of dichloromethane were added to separate the reaction mixtures. The organic phase was washed with 100mL of saturated brine and dried over anhydrous sodium sulfate. The resulting product was purified 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- (3-morpholinopropoxy) phenyl) acrylamide (compound 36) as a pale yellow solid (120mg, yield 18%).

MS m/z＝543.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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-morpholinopropoxy) phenyl) acrylamide (compound 37)

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

The first step is as follows: 5-chloro-N- (2-methoxy-4- (3-morpholinopropoxy) -5-nitrobenzene) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (37A)

5-chloro-N-(2-methoxy-4-(3-morpholinopropoxy)-5-nitrophenyl)-4-(1-methyl-1H-ind ol-3-yl)pyrimidin-2-amine

5-chloro-N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (intermediate 4) (1g, 2.34mmol) was dissolved in 50mL of tetrahydrofuran, and sodium hydride (103mg, 2.57mmol) was added under ice-bath and stirred for 30 min. 3-Morpholpropyl-1-ol (680mg, 4.68mmol) was added dropwise and reacted at room temperature overnight. After the reaction was completed, 100mL of water and 100mL of ethyl acetate were added, the mixture was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound 5-chloro-N- (2-methoxy-4- (3-morpholinopropoxy) -5-nitrobenzene) -4- (1-methyl-1H-indolin-3-yl) pyrimidin-2-amine (37A) (1.2g, yield 85.7%) as a yellow oil.

¹H NMR(400MHz,DMSO-d₆)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)。

The second step is that: n is a radical of¹- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-4- (3-morpholinepropoxy) benzene-1, 3-diamine (37B)

N1-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(3-morpholino propoxy)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) (1g, 1.8mmol) was dissolved in 30mL of ethanol, 10mL of water, iron powder (606.7mg, 10.06 mmol) and ammonium chloride (67.8mg, 1.27mmol) were added in this order, and the mixture was heated to 90 ℃ for 4 hours under reflux. Cooling the reaction solution to room temperature, filtering, concentrating, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain black solid compound N ¹- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-4- (3-morpholinopropoxy) benzene-1, 3-diamine (37B) (900mg, 95.3% yield).

MS m/z:523.2[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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-morpholinopropoxy) phenyl) acrylamide (compound 37)

Will N¹- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-4- (3-morpholinopropoxy) benzene-1, 3-diamine (37B) (900mg, 1.72mmol) was dissolved in 30mL of tetrahydrofuran, N-diisopropylethylamine (0.34mL, 2.06mmol) was added, and a solution of acryloyl chloride (0.17mL, 2.06mmol) in tetrahydrofuran was added dropwise at 0 ℃ to 5mL, and the mixture was allowed to warm to room temperature for reaction for 4 hours. 100mL of a saturated aqueous sodium bicarbonate solution and 100mL of ethyl acetate were added to separate the layers. The resulting product was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) to give N- (5- ((5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2- (3-morpholinopropoxy) phenyl) acrylamide (compound 37) as a yellow solid (330mg, yield 41.4%).

MS m/z:577.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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-morpholinopropoxy) phenyl) acrylamide mesylate (Compound 38)

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(3-m orpholinopropoxy)phenyl)acrylamide methanesulfonate

The first step is as follows: n- (5- ((5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2- (3-morpholinopropoxy) phenyl) acrylamide mesylate (Compound 38)

N- (5- ((5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2- (3-morpholinopropoxy) phenyl) acrylamide (compound 37) (120mg, 0.208mmol) was dissolved in 20mL of ethanol, 10mL of ethyl acetate was added, and a solution of methanesulfonic acid (0.0135mL, 0.208mmol) in ethyl acetate (5mL) was added dropwise at 70 ℃ and reacted for 2 hours. The reaction mixture was spin-dried to give a yellow solid compound, N- (5- ((5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2- (3-morpholinopropoxy) 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-pyrro lo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step is as follows: 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) (10g, 85.2mmol) was dissolved in 1, 2-dichloroethane (50mL), cooled to 0 ℃ under nitrogen, methylmagnesium bromide (28.6mL, 85.2mmol) was added dropwise, and stirring was continued for 0.5H. 2, 4-dichloropyrimidine (15.26g, 102.4mmol) was added, and the mixture was reacted at room temperature for 4 hours. To the reaction solution, 50mL of methanol was added, the solvent was dried by spinning, and the mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 1:0 to 2:1) to give 3- (2-chloropyrimidin-4-yl) -1H-pyrrolo [2,3-B ] pyridine (39B) as a yellow solid (10g, yield 51.3%).

MS m/z＝230.1[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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)。

The second step is that: 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) (2g, 8.7mmol) was dissolved in 10mL of tetrahydrofuran, and sodium hydride (418mg, 10.4mmol) was added at 0 ℃ to continue the reaction for 30 minutes, and iodomethane (1.63mL, 26.2mmol) was added thereto and allowed to warm to room temperature for 4 hours. The solvent was dried by evaporation to give a solid, which was washed with 50mL of water and 50mL of tetrahydrofuran, filtered, and dried to give the compound 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-pyrrolo [2,3-b ] pyridine (39C) as a yellow solid (2.1 g).

MS m/z:244.1[M+1]⁺。

The 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) (1g, 4.1mmol) was dissolved in 2-pentanol (20mL), 4-fluoro-2-methoxy-5-nitroaniline (4e) (765mg, 4.1mmol) and p-toluenesulfonic acid (939mg, 4.9mmol) were added, and the mixture was heated to 120 ℃ for 2 days under reflux. The reaction was cooled to room temperature, 30mL acetonitrile was added, filtered, and the filter cake was washed once with 50mL 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) as a yellow solid (1.2g, 75% yield).

The fourth step: n is a radical of¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) pyrimidin-2-yl) -2-nitrophenyl-1, 4-diamine (39E)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(1-methyl-1H-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine

Reacting N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-pyrrolo [2,3-b ]]Pyridin-3-yl) pyrimidin-2-amine (39D) (1g, 2.54mmol) was dissolved in 20mL of tetrahydrofuran, sodium hydride (203mg, 5.08mmol) was added under ice-cooling, stirred for 30 minutes, N, N, N' -trimethylethylenediamine (18A) (733mg, 5.08mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 8 hours. After completion of the reaction, 150mL of water and 150mL of ethyl acetate were added and the mixture was separated. The aqueous phase was extracted once with 100mL ethyl acetate and the organic phases were combined. Drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain compound N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) pyrimidin-2-yl) -2-nitrophenyl-1, 4-diamine (39E) as a yellow solid (1.1g, 84.6% yield).

MS m/z:518.1[M+1]⁺。

The fifth step: n is a radical of¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (39F)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(1-methyl-1H-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine

Will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-pyrrolo [2, 3-b) ]Pyridin-3-yl) pyrimidin-2-yl) -2-nitrophenyl-1, 4-diamine (39E) (1.1g, 2.18mmol) in water5mL of water, iron powder (356mg, 6.4mmol) and ammonium chloride (78.7mg, 1.55mmol) were added in this order to 15mL of ethanol, and the mixture was heated to 90 ℃ and reacted under reflux for 4 hours. The reaction was cooled to room temperature, filtered and concentrated. Separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain a compound N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (39F) as a brown solid (550mg, 51.9% yield).

And a sixth step: 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)

Will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (39F) and a brown solid (550mg, 1mmol) were dissolved in 15mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (573mg, 3mmol) and acrylic acid (0.103mL, 1.5mmol) were added in that order and reacted at room temperature for 4 hours. The reaction mixture was spin-dried to remove pyridine, and 100mL of water and 100mL of dichloromethane were added to separate the reaction mixture. The organic phase was washed once with aqueous sodium hydroxide (100mL, 4 mol/L). The organic phase was dried over anhydrous sodium sulfate. Separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyl-5- ((4- (1-methyl-1H-pyrrolo [2,3-b ] pyrrole [2 ]Pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 39) as a white solid (65mg, 12% yield).

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-methoxyphenyl) acrylamide (compound 40)

The first step is as follows: 1- (6-nitro-1H-indol-1-yl) ethanone (40B)

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

6-Nitro-1H-indole (40A) (16.2g, 0.1mol) was dissolved in 40mL of pyridine, and acetic anhydride (40.8g, 0.4mol) was added to the solution to conduct reaction at room temperature overnight. After the reaction, the mixture was spin-dried, 200mL of saturated brine and 200mL of ethyl acetate were added, followed by liquid separation, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to give 1- (6-nitro-1H-indol-1-yl) ethanone (40B) as a yellow solid (6g, yield 30%).

MS m/z:205.1[M+1]⁺。

The second step is that: 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) (20g, 0.1mol) was dissolved in 50mL of methanol and 50mL of tetrahydrofuran, and palladium on carbon (2g, 10%) and ammonium formate (40.3g, 6.4mol) were added and reacted at 60 ℃ for 2 hours. After completion of the reaction, the reaction mixture was filtered, washed with 100mL of ethyl acetate, and the filtrate was spin-dried, followed by addition of 150mL of ethyl acetate and 150mL of saturated saline and separation. The aqueous phase was washed once with 150mL ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate to give 1- (6-amino-1H-indol-1-yl) ethanone (40C) as a yellow solid (9.3g, 53.4% yield).

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 100mL of N, N-dimethylformamide, and N, N-Diisopropylethylamine (DIPEA) (29.7mL, 180mmol) was added and reacted at 90 ℃ overnight. After completion of the reaction, the mixture was cooled to room temperature, and 200mL of ethyl acetate and 200mL of saturated saline were added thereto and the mixture was separated. The aqueous phase was washed once with 200mL ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give compound 4- (1H-indol-6-yl) morpholine (40D) as a yellow solid (9.2g, 76% yield).

MS m/z:203.1[M+1]⁺。

The fourth step: 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) (4.5g, 22.3mmol) was dissolved in 100mL tetrahydrofuran, cooled to 0 ℃ under nitrogen, methyl magnesium bromide (7.5mL, 22.3mmol) was added dropwise and stirring continued for 0.5H. Trichloropyrimidine (2.05g, 22.3mmol) was added and the reaction was allowed to proceed at room temperature for 1 hour, then the reaction was allowed to warm to 60 ℃ and continued for 1 hour. The reaction solution was cooled to room temperature, and 6.34mL of acetic acid was added dropwise and stirred for 10 minutes. 100mL of water was added, the mixture was stirred at 60 ℃ for 30 minutes, the organic phase was separated, 100mL of n-heptane was added, the mixture was spin-dried, and the resulting mixture was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 50:1) to give 4- (3- (2, 5-dichloropyrimidin-4-yl) -1H-indol-6-yl) morpholine (40E) as a yellow-green solid (3g, 39% yield).

MS m/z:349.0[M+1]⁺。

The fifth step: 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) (3g, 8.6mmol) was dissolved in 50mL of tetrahydrofuran, and sodium hydride (460mg, 11.5mmol) was added thereto at 0 ℃ to react for 30 minutes. Methyl iodide (1.6mL, 25.8mmol) was added and the reaction was allowed to warm to room temperature for 3 hours. Spin-dry, wash with 50mL water and 20mL tetrahydrofuran, filter, dry and concentrate to give 4- (3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1H-indol-6-yl) morpholine (40F) as a light yellow solid (1.9g, 61.3% yield).

MS m/z:363.0[M+1]⁺。

And a sixth step: 5-chloro-N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-amine (40G)

4- (3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1H-indol-6-yl) morpholine (40F) (724g, 2mmol) was dissolved in 2-pentanol (20mL), 4-fluoro-2-methoxy-5-nitroaniline (372mg, 2mmol) and p-toluenesulfonic acid (456.5mg, 2.4mmol) were added, and the reaction was heated to 120 ℃ for 2 days under reflux. The reaction was cooled to room temperature, 50mL acetonitrile was added, filtered, the filter cake washed with 50mL water and dried to give 5-chloro-N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-amine (40G) as a grey solid (800mg, 80% yield).

MS m/z:513.1[M+1]⁺。

The seventh step: n is a radical of¹- (5-chloro-4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-yl) -4-fluoro-6-methoxyphenyl-1, 3-diamine (40H)

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

5-chloro-N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-amine (40G) (600mg, 1.17mmol) was dissolved in 30mL of ethanol, 10mL of water was added, and iron powder (392mg, 7.03mmol) and ammonium chloride (43.8mg, 0.82mmol) were added in this order, and the mixture was heated to 90 ℃ and refluxed for 4 hours. The reaction was cooled to room temperature, filtered, washed once with 50mL of methanol, and concentrated. Separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v): 1: 0-50: 1) to obtain N¹- (5-chloro-4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-yl) -4-fluoro-6-methoxyphenyl-1, 3-diamine (40H), brown solid (150mg, 26.6% yield).

MS m/z:483.1[M+1]⁺。

Eighth step: n- (5- ((5-chloro-4- (1-methyl-6-morpholinyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-fluoro-4-methoxyphenyl) acrylamide (compound 40)

Will N¹- (5-chloro-4- (1-methyl-6-morpholin-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-diisopropylethylamine (0.06mL, 0.37mmol) was added, and a solution of acryloyl chloride (0.03mL, 0.37mmol) in tetrahydrofuran (5mL) was added dropwise at 0 ℃ and the mixture was allowed to warm to room temperature for reaction for 1.5 hours. To the reaction mixture were added 100mL of a saturated aqueous sodium bicarbonate solution and 100mL of dichloromethane, and the mixture was separated. Purification by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) gave N- (5- ((5-chloro-4- (1-methyl-6-morpholinyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-fluoro-4-methoxyphenyl) acrylamide (compound 40) as a pale yellow solid (20mg, 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)

The first step is as follows: 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)

5-chloro-N-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)-5-nitrophenyl)-4-(1-me thyl-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 (intermediate 4) (854.1mg, 2mmol) was dissolved in 50mL of tetrahydrofuran, sodium hydride (80mg, 2.2mmol) was added under ice-bath, stirred for 30 minutes, 2- (4-methylpiperazin-1-yl) ethanol (576.5mg, 4mmol) was added dropwise, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, 100mL of water and 100mL of ethyl acetate were added, the mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, and then concentrated 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) as a yellow solid (800mg, yield 80%).

MS m/z:552.2[M+1]⁺。

The second step is that: n is a radical of¹- (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)

Reacting 5-chloro-N- (2-methoxy-4- (2- (4-methylpiperazin-1-yl) ethoxy) -5-nitrophenyl) -4- (1-methyl-1H-indolidin-3-yl) ) Pyrimidin-2-amine (41A) (800mg, 1.45mmol) was dissolved in 15mL of ethanol, and 5mL of water, iron powder (486.3mg, 8.7mmol) and ammonium chloride (54mg, 1mmol) were added in this order, and the reaction was refluxed at 90 ℃ for 4 hours. Cooling the reaction solution to room temperature, filtering, concentrating, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain compound N¹- (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 (200mg, 26.5% yield).

MS m/z:522.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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) acrylamide (Compound 41)

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(dimethylami no)ethoxy)-4-methoxyphenyl)acrylamide

Will N¹- (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) (150mg, 0.288mmol) was dissolved in 10mL of tetrahydrofuran, DIPEA (0.057mL, 0.345mmol) was added, a solution of acryloyl chloride (0.028mL, 0.345mmol) in tetrahydrofuran was added dropwise at 0 ℃ to 5mL, and the mixture was warmed to room temperature to react for 1 hour. 50mL of a saturated aqueous sodium bicarbonate solution and 50mL of ethyl acetate were added to separate the layers. The compound 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) was obtained by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1), and was a pale yellow solid (40mg, 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-m ethoxyphenyl)acrylamide

The first step is as follows: 5-chloro-N- (2-methoxy-5-nitrophenyl) -4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-amine (42A)

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

4- (3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1H-indol-6-yl) morpholine (40F) (724g, 2mmol) was dissolved in 2-pentanol (20mL), 2-methoxy-5-nitroaniline (336.3mg, 2mmol) and p-toluenesulfonic acid (456.5mg, 2.4mmol) were added, and the reaction was heated to 120 ℃ for 3 days under reflux. The reaction was cooled to room temperature, 50mL acetonitrile was added, filtered, the filter cake washed with 50mL water and dried to give 5-chloro-N- (2-methoxy-5-nitrophenyl) -4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-amine (42A) as a pale green solid (990 mg).

MS m/z:495.1[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ8.87(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)。

The second step is that: n is a radical of¹- (5-chloro-4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxybenzene-1, 3-diamine (42B)

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

5-chloro-N- (2-methoxy-5-nitrophenyl) -4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-amine (42A) (990mg, 2mmol) was dissolved in 30mL of ethanol, 10mL of water, iron powder (670mg, 12mmol) and ammonium chloride (75mg, 1.4mmol) were added in this order, and the mixture was heated to 90 ℃ for reflux reaction overnight. Cooling the reaction solution to room temperature, filtering, washing with 50mL of methanol once, concentrating, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain compound N ¹- (5-chloro-4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxybenzene-1, 3-diamine (42B), brown solid (340mg, 36.6% yield).

MS m/z:465.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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-methoxyphenyl) acrylamide (compound 42)

Will N¹- (5-chloro-4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxybenzene-1, 3-diamine (42B) (280mg, 0.6mmol) was dissolved in 30mL of tetrahydrofuran, N-Diisopropylethylamine (DIPEA) (0.12mL, 0.72mmol) was added, 5mL of a solution of acryloyl chloride (0.059mL, 0.72mmol) in tetrahydrofuran was added dropwise at 0 ℃, and the mixture was allowed to warm to room temperature for reaction for 4 hours. 100mL of a saturated aqueous sodium bicarbonate solution and 100mL of ethyl acetate were added to separate the layers. Purification by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) gave compound N- (3- ((5-chloro-4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 42) as a pale yellow solid (120mg, yield 38.7%).

MS m/z:519.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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,10.2Hz,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-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)ethoxy )-4-methoxyphenyl)acrylamide

The first step is as follows: 5-chloro-N- (4- (2- (dimethylamino) ethoxy) -2-methoxy-5-nitrophenyl) -4- (1H-indol-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 (intermediate 4) (620mg, 1.5mmol) was dissolved in 30mL of tetrahydrofuran, and sodium hydride (66mg, 1.65mmol) was added under ice-cooling, followed by stirring for 30 minutes, dimethyl ethanolamine (0.3mL, 3mmol) was added dropwise, and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, 100mL of water and 100mL of ethyl acetate were added, the mixture was separated, the organic phase 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) as a brown solid (660mg, yield 91.3%).

The second step is that: n is a radical of¹- (5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) -4- (2- (dimethylamino) ethoxy) -6-methoxy-1, 3-diamine (43B)

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

5-chloro-N- (4- (2- (dimethylamino) ethoxy) -2-methoxy-5-nitrophenyl) -4- (1H-indol-3-yl) pyrimidin-2-amine (43A) (650mg, 1.35mmol) was dissolved in 30mL of ethanol, 10mL of water, iron powder (452mg, 8.1mmol) and ammonium chloride (50.5mg, 0.95mmol) were added in this order, the temperature was raised to 90 ℃ and the reaction was refluxed overnight. Cooling the reaction solution to room temperature, filtering, concentrating, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-20: 1) to obtain compound N ¹- (5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) -4- (2- (dimethylamino) ethoxy) -6-methoxy-1, 3-diamine (43B) as a yellow solid (200mg, 32.8% yield).

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)

Will N¹- (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-Diisopropylethylamine (DIPEA) (0.088mL, 0.53mmol) was added, and a solution of acryloyl chloride (0.043mL, 0.53mmol) in tetrahydrofuran (5mL) was added dropwise at 0 ℃ and allowed to warm to room temperature for 4 hours. To the reaction mixture were added 100mL of a saturated aqueous sodium bicarbonate solution and 100mL of ethyl acetate, and the mixture was separated. The compound N- (5- ((5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide (compound 43) was obtained by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1), and was a beige solid (20mg, yield 9.0%).

MS m/z＝507.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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

The first step is as follows: (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)

(S)-5-chloro-N-(2-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)-5-nitrophenyl)-4-(1-met hyl-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 (intermediate 4) (854.1mg, 2mmol) was dissolved in 30mL of tetrahydrofuran, sodium hydride (160mg, 4mmol) was added under ice-cooling, stirred for 30 minutes, and (S) - (+) -1-methyl-3-hydroxypyrrolidine (242.76mg, 2.4mmol) was added dropwise and reacted at room temperature overnight. After the reaction was completed, 150mL of water and 150mL of ethyl acetate were added, the mixture was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give compound (S) -5-chloro-N- (2-methoxy-4- ((1-methylpyrrolidin-3-yl) oxy) -5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (44A) as a yellow solid (1g, yield 99%).

MS m/z:509.1[M+1]⁺。

The second step is that: (S) -N¹- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-4- ((1-methylpyroll-3-yl) oxy) benzene-1, 3-diamine (44B)

(S)-N¹-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-((1-methyl pyrrolidin-3-yl)oxy)benzene-1,3-diamine

Reacting (S) -5-chloro-N- (2-methoxy-4- ((1-methylpyrrol-3-yl) oxy) -5-nitrophenyl) -4- (1-methyl-1H-indole-3-yl) pyrimidin-2-amine (44A) (1g, 2mmol) was dissolved in 30mL of ethanol, 10mL of water, iron powder (659.3mg, 11.8mmol) and ammonium chloride (73.7mg, 1.38mmol) were added in that order, the temperature was raised to 90 ℃ and the reaction was refluxed overnight. Cooling the reaction solution to room temperature, filtering, concentrating, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain the 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 (410mg, 42.9% yield).

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)

Reacting (S) -N¹- (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) (400mg, 0.84mmol) was dissolved in 30mL of tetrahydrofuran, N-Diisopropylethylamine (DIPEA) (0.165mL, 1mmol) was added, and a tetrahydrofuran solution (5mL) of acryloyl chloride (0.08mL, 1mmol) was added dropwise at 0 ℃ and allowed to warm to room temperature for 4 hours. To the reaction mixture were added 100mL of a saturated aqueous sodium bicarbonate solution and 100mL of ethyl acetate, and the mixture was separated. The compound (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) was obtained by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1), and a yellow-green solid (80mg, yield 17.9%).

MS m/z:533.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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

The first step is as follows: (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)

(R)-5-chloro-N-(2-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)-5-nitrophenyl)-4-(1-met hyl-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 (intermediate 4) (1mg, 2.3mmol) was dissolved in 30mL of tetrahydrofuran, and sodium hydride (184mg, 4.6mmol) was added under ice-cooling, stirred for 30 minutes, and (R) - (-) -1-methyl-3-hydroxypyrrolidine (284mg, 2.8mmol) was added dropwise and reacted at room temperature overnight. After the reaction was completed, 150mL of water and 150mL of ethyl acetate were added, 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-methylpyrrolidin-3-yl) oxy) -5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (45A) as a yellow solid (1.1 g).

MS m/z:509.0[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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 is that: (R) -N¹- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-4- ((1-methylpyroll-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-methyl pyrrolidin-3-yl)oxy)benzene-1,3-diamine

(R) -5-chloro-N- (2-methoxy-4- ((1-methylpyrrol-3-yl) oxy) -5-nitrophenyl) -4- (1-methyl-1H-indole-3-yl) pyrimidin-2-amine (45A) (1.1g, 2.16mmol) was dissolved in 30mL of ethanol, 10mL of water, iron powder (725mg, 13mmol) and ammonium chloride (81mg, 1.5mmol) were added in this order, the temperature was raised to 90 ℃ and the reaction was refluxed for 4 hours. The reaction was cooled to room temperature, filtered and concentrated. Separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain the 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 (900mg, 90% yield).

¹H NMR(400MHz,CDCl₃)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)

Reacting (R) -N¹- (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) (900mg, 1.88mmol) was dissolved in 20mL of tetrahydrofuran, DIPEA (0.23mL, 2.26mmol) was added, a solution of acryloyl chloride (0.183mL, 2.26mmol) in tetrahydrofuran was added dropwise at 0 ℃ to 5mL, and the mixture was allowed to warm to room temperature for reaction for 4 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture to adjust the mixture to alkaline, and 100 mL of ethyl acetate and 150mL of saturated brine were added to separate the mixture. The organic phase was dried over anhydrous sodium sulfate. Separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain the compound (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) as a pale yellow solid (180mg, 16% yield).

MS m/z＝533.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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-m ethoxyphenyl)acrylamide hydrochloride

N- (3- ((5-chloro-4- (1-methyl-6-morpholin-1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 42) (86mg, 0.166mmol) was dissolved in 1, 4-dioxane (30mL), a solution of hydrochloric acid (0.083mL, 0.332mmol) in 1, 4-dioxane was added dropwise at 0 ℃ and allowed to warm to room temperature for 2 hours. The reaction was spin dried 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) as a yellow solid (90mg, 97.8% yield).

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) (40mg, 0.075mmol) was dissolved in 10mL of ethanol, 5mL of ethyl acetate was added, and a solution of methanesulfonic acid (0.048mL, 0.075mmol) in ethyl acetate (3mL) was added dropwise at 70 ℃ and reacted for 2 hours. The reaction was spin-dried to give (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) as a brown solid (47mg, 99.8% yield).

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-yl) 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

The first step is as follows: n- (4- (2- (dimethylamino) ethoxy) -2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indol-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) (1g, 2.54mmol) was dissolved in 50mL of tetrahydrofuran, and sodium hydride (103mg, 2.57mmol) was added under ice-cooling, followed by stirring for 30 minutes, dropwise addition of 2- (dimethylamino) ethanol (417.2mg, 4.68mmol), and reaction at room temperature for 4 hours. After completion of the reaction, 200mL of water and 200mL of ethyl acetate were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the compound N- (4- (2- (dimethylamino) ethoxy) -2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indolin-3-yl) pyrimidin-2-amine (48A) as a yellow solid (1.05g, 91.3% yield).

MS m/z:463.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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)。

The second step is that: 4- (2- (dimethylamino) ethoxy) -6-methoxy-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 3-diamine (48B)

4-(2-(dimethylamino)ethoxy)-6-methoxy-N¹-(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) pyrimidin-2-amine (48A) (1g, 2.16mmol) was dissolved in 30mL of ethanol, 10mL of water, iron powder (725mg, 13mmol) and ammonium chloride (81mg, 1.5mmol) were added in this order, and the mixture was heated to 90 ℃ and refluxed overnight. The reaction solution was cooled to room temperature, filtered and concentrated. Separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain the compound 4- (2- (dimethylamino) ethoxy) -6-methoxyl-N ¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 3-diamine (48B), brown solid (930mg, 99.7% yield).

MS m/z:433.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.52–8.47(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)。

The 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)

Reacting 4- (2- (dimethylamino) ethoxy) -6-methoxy-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 3-diamine (48B) (600mg, 1.38mmol) was dissolved in 10mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (794mg, 4.16mmol) and acrylic acid (0.143mL, 2.08mmol) were added in this order to react at room temperature for 3 hours. The reaction mixture was spin-dried, and an aqueous solution of sodium hydroxide (150mL, 4mol/L) and 150mL of methylene chloride were added to separate the reaction mixture. The organic phase was washed once with 100mL of water. The organic phase was dried over anhydrous sodium sulfate. The resulting product was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) to give N- (2- (2- (dimethylamino) ethoxy) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 48) as a yellow solid (330mg, yield 49.1%).

MS m/z:487.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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-methylpyrrol-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-methyl pyrrolidin-3-yl)oxy)phenyl)acrylamide

The first step is as follows: (S) -N- (2 methoxy-4- ((1-methylpyrrol-3-yl) oxy) -5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (49A)

(S)-N-(2-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)-5-nitrophenyl)-4-(1-methyl-1H-i ndol-3-yl)pyrimidin-2-amine

5- ((4- (1-methylindol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2-fluoro-1-nitrobenzene (intermediate 3) (1g, 2.54mmol) was dissolved in 30mL of tetrahydrofuran, and sodium hydride (203mg, 5.08mmol) was added under ice-bath, followed by stirring for 30 minutes, dropwise addition of a solution of (S) -1-methylpyrrol-3-ol (308mg, 3.05mmol) in tetrahydrofuran (5mL), and reaction at room temperature for 4 hours. After the reaction was completed, 100mL of water and 150mL of ethyl acetate were added to the reaction solution, followed by liquid separation, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give (S) -N- (2 methoxy-4- ((1-methylpyrrolidin-3-yl) oxy) -5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (49A) as a yellow solid (1g, yield 83.3%).

MS m/z:475.2[M+1]⁺。

The second step is that: (S) -6-methoxy-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -4- ((1-methylpyrrol-3-yl) oxy) benzene-1, 3-diamine (49B)

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

(S) -N- (2-methoxy-4- ((1-methylpyrrol-3-yl) oxy) -5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (49A) (1g, 2.11mmol) was dissolved in 30mL of ethanol, 10mL of water, iron powder (707mg, 12.65mmol) and ammonium chloride (78.6mg, 1.47mmol) were added in this order, the mixture was heated to 90 ℃ and refluxed for 4 hours. The reaction was cooled to room temperature, filtered and concentrated. Separating and purifying the extract by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) to obtain the compound (S) -6-methoxy-N ¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -4- ((1-methylpyrrol-3-yl) oxy) benzene-1, 3-diamine (49B), brown solid (500mg, 53.6% yield).

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)

Reacting (S) -6-methoxy-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -4- ((1-methylpyrrol-3-yl) oxy) benzene-1, 3-diamine (49B) (500mg, 1.13mmol) was dissolved in 15mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (646mg, 3.38mmol) and acrylic acid (0.116mL, 1.69mmol) were added in this order and reacted at room temperature for 4 hours. The reaction solution was spin-dried, 150mL of water and 200mL of methylene chloride were added, and the mixture was separated. The organic phase is washed once with 150mL of 4 mol/L aqueous sodium hydroxide solution. 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 10:1) to give (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) as a pale yellow solid (210mg, 37.3% yield).

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-yl) ethoxy) phenyl) acrylamide (compound 50)

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

The first step is as follows: n- (2-methoxy-5-nitro-4- (2- (piperidin-1-yl) ethoxy) phenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-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) (1g, 2.54mmol) was dissolved in 50mL of tetrahydrofuran, and sodium hydride (122mg, 3.1mmol) was added under ice-cooling, followed by stirring for 30min, dropwise addition of 2- (piperidin-1-yl) ethanol (656mg, 5.08mmol), and reaction at room temperature overnight. After completion of the reaction, 150mL of water and 100mL of ethyl acetate were added and the mixture was separated. The aqueous phase was extracted with 100mL ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound N- (2-methoxy-5-nitro-4- (2- (piperidin-1-yl) ethoxy) phenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (50A) as a yellow solid (1.2g, 94.5% yield).

MS m/z:503.1[M+1]⁺。

The second step is that: 6-methoxy-N¹- (4- (1-methyl-l-1H-indol-3-yl) pyrimidin-2-yl) -4- (2- (piperidin-1-yl) ethoxy) benzene-1, 3-diamine (50B)

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

N- (2-methoxy-5-nitro-4- (2- (piperidin-1-yl) ethoxy) phenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (50A) (1.2g, 2.39mmol) was dissolved in 15mL of ethanol, and 5mL of water, iron powder (400mg, 7.17mmol) and ammonium chloride (89.5mg, 1.67mmol) were sequentially added, and the mixture was heated to 90 ℃ and refluxed for 6 hours. Cooling the reaction solution to room temperature, filtering, concentrating, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain the compound 6-methoxy-N ¹- (4- (1-methyl l-1H-indol-3-yl) pyrimidin-2-yl) -4- (2- (piperidin-1-yl) ethoxy) benzene-1, 3-diamine (50B), brown solid (750mg, 68.2% yield).

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- (piperidin-1-yl) ethoxy) phenyl) acrylamide (compound 50)

Reacting 6-methoxy-N¹- (4- (1-methyl l-1H-indol-3-yl) pyrimidin-2-yl) -4- (2- (piperidin-1-yl) ethoxy) benzene-1, 3-diamine (50B) (750mg, 1.59mmol) was dissolved in 10mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (911mg, 4.71mmol) and acrylic acid (0.164mL, 2.38mmol) were added and reacted at room temperature for 4 hours. The reaction mixture was spin-dried, and 100mL of a 4mol/L aqueous sodium hydroxide solution and 100mL of ethyl acetate were added to separate the reaction mixture. The organic phase was washed once with 100mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate. Column chromatography on silica gel (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) gave 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) as a white solid (300mg, 35.8% yield).

MS m/z：527.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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-methylpiperazin-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-methylp iperazin-1-yl)ethoxy)phenyl)acrylamide

The first step is as follows: n- (2-methoxy-4- (2- (4-methylpiperazin-1-yl) ethoxy) -5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (51A)

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

5- ((4- (1-methylindol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2-fluoro-1-nitrobenzene (intermediate 3) (1g, 2.54mmol) was dissolved in 20mL of tetrahydrofuran, and sodium hydride (203mg, 5.08mmol) was added under ice-bath, followed by stirring for 30 minutes, dropwise addition of 1- (2-hydroxyethyl) -4-methylpiperazine (733mg, 5.08mmol), and reaction at room temperature for 8 hours. After completion of the reaction, 150mL of water and 150mL of ethyl acetate were added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with 100mL ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give N- (2-methoxy-4- (2- (4-methylpiperazin-1-yl) ethoxy) -5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (51A) as a yellow solid (1.1g, 84.6% yield).

MS m/z:518.1[M+1]⁺。

The second step is that: 6-methoxy-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -4- (2- (4-methylpiperazin-1-yl) ethoxy) benzene-1, 3-diamine (51B)

6-methoxy-N¹-(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-indol-3-yl) pyrimidin-2-amine (51A) (1.1g, 2.18mmol) was dissolved in 15mL of ethanol, 5mL of water was added in this order, and then iron powder (356mg, 6.4mmol) and ammonium chloride (78.7mg, 1.55mmol) were added, and the mixture was heated to 90 ℃ and refluxed for 4 hours. Cooling the reaction solution to room temperature, filtering, concentrating, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain 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 (550mg, 51.9% yield).

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)

Reacting 6-methoxy-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -4- (2- (4-methylpiperazin-1-yl) ethoxy) benzene-1, 3-diamine (51B) (550mg, 1mmol) was dissolved in 15mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (573mg, 3mmol) and acrylic acid (0.103mL, 1.5mmol) were added and reacted at room temperature for 4 hours. The reaction solution was spin-dried, and 100mL of water and 100mL of methylene chloride were added to separate the solution. The organic phase is washed once with 100mL of 4mol/L aqueous sodium hydroxide solution. The organic phase was dried over anhydrous sodium sulfate. The resulting product was purified 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- (4-methylpiperazin-1-yl) ethoxy) phenyl) acrylamide (compound 51) as a white solid (65mg, 12%).

MS m/z:542.1[M+1]⁺。

Example 52

(R) -N- (4 methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((1-methylpyrrol-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-methy lpyrrolidin-3-yl)amino)phenyl)acrylamide

The first step is as follows: (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) (2g, 10.74mmol) was dissolved in 25mL of dichloromethane, and triethylamine (2.17g, 21.5mmol) and di-tert-butyl dicarbonate (2.46g, 11.28mmol) were added to react at room temperature for 3 hours. 100mL of water and 100mL of methylene chloride were added to the reaction mixture, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give (R) -tert-butyl 3- ((tert-butoxycarbonyl) amino) pyrrole-1-carboxylate (52B) as a colorless oil (3 g).

The second step is that: (R) -N, 1-dimethylpyrrol-3-amine (52C)

(R)-N,1-dimethylpyrrolidin-3-amine

(R) -tert-butyl 3- ((tert-butoxycarbonyl) amino) pyrrole-1-carboxylate (52B) (3g, 10.74mmol) was dissolved in 50mL of tetrahydrofuran, and lithium aluminum hydride (4g, 107.4mmol) was slowly added under ice-bath to react at room temperature for 1 hour, and the reaction was continued for 3 hours by raising the temperature to 60 ℃. After the reaction, 50mL of acetone was added, and water was added dropwise until no bubbles were formed in the reaction solution. Filtration, washing with 50mL tetrahydrofuran, and concentration gave (R) -N, 1-dimethylpyrrol-3-amine (52C) as a yellow liquid (1.65 g).

MS m/z:115.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ3.65(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)。

The third step: (R) -2-methoxy-N⁴-methyl-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (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-me thylpyrrolidin-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) (1g, 2.54mmol) was dissolved in 10mL of N, N-dimethylacetamide, and N, N-Diisopropylethylamine (DIPEA) (0.51mL, 3.05mmol) and (R) -N, 1-dimethylpyrrol-3-amine (52C) (348mg, 3.05mmol) were added in that order and reacted at 140 ℃ for 1 hour under microwave. After the reaction is finished, concentrating the reaction solution, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain the compound (R) -2-methoxyl-N⁴-methyl-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (1-methylpyrrol-3-yl) -5-nitrobenzene-1, 4-diamine (52D), red solid (0.5g, 40.3% yield).

MS m/z:488.1[M+1]⁺。

The fourth step: (R) -5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹- (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-me thylpyrrolidin-3-yl)benzene-1,2,4-triamine

Reacting (R) -2-methoxy-N⁴-methyl-N¹- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (1-Methylpyrrol-3-yl) -5-nitrobenzene-1, 4-diamine (52D) (1.24g, 2.5mmol) was dissolved in 20mL of ethanol, 7mL of water, iron powder (419mg, 7.5mmol) and ammonium chloride (94mg, 1.75mmol) were added, the temperature was raised to 90 ℃ and the reaction was refluxed for 6 hours. Cooling the reaction solution to room temperature, filtering, concentrating, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain the compound (R) -5-methoxy-N ¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹- (1-methylpyrrol-3-yl) benzene-1, 2, 4-triamine (52E), brown solid (350mg, 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-indol-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-ind ol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

Reacting (R) -5-methoxy-N¹-methyl-N⁴- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹- (1-Methylpyrrol-3-yl) benzene-1, 2, 4-triamine (52E) (350mg, 0.76mmol) was dissolved in 10mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (436mg, 2.28mmol) and acrylic acid (0.08mL, 1.14mmol) were added and reacted at room temperature for 4 hours. The reaction solution was spin-dried, and 100mL of water and 100mL of methylene chloride were added to separate the solution. The organic phase is washed once with 100mL of 4mol/L aqueous sodium hydroxide solution. Drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, separating and purifying by silica gel column chromatography (dichloro-chlorine)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) as a brown solid (80mg, 20.6% yield).

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- (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-(dimeth ylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acryamide

The first step is as follows: n is a radical of¹- (4- (1- (1-cyclopropylethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrophenyl-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

Will N¹- (4- (1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴Dissolving (0.065g, 0.14mmol) of (-methyl) -5-nitrobenzene-1, 4-diamine (34B) in 10mL of dichloromethane, adding triphenylphosphine (0.074g, 0.28mmol) and 1-cyclopropylethanol (0.012g, 0.14mmol), cooling to 0 ℃ under the protection of nitrogen, dropwise adding diisopropyl azodicarboxylate (DIAD) (56.6mg, 0.28mmol), heating to room temperature for 4 hours, reacting, spin-drying the reaction solution, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-20: 1) to obtain a compound N¹- (4- (1- (1-cyclopropylethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴Methyl-5-nitrobenzene-1, 4-diamine (53A), brown solid (0.03g,yield 40.5%).

MS m/z:530.1[M+1]+。

The second step is that: n is a radical of⁴- (4- (1- (1-cyclopropylethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N ¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (53B)

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

Will N¹- (4- (1- (1-cyclopropylethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrophenyl-1, 4-diamine (53A) (0.85g, 1.6mmol) was dissolved in 30mL of ethanol, 10mL of water, iron powder (0.538g, 9.6mmol) and ammonium chloride (60mg, 1.1mmol) were added in this order, the temperature was raised to 90 ℃ and the reaction was refluxed for 6 hours. Concentrating the reaction solution, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain a compound N⁴- (4- (1- (1-cyclopropylethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (53B), brown solid (0.3g, 37.5% yield).

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-(dimeth ylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Will N⁴- (4- (1- (1-cyclopropylethyl) -1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (53B) (0.3g, 0.6mmol) was dissolved in 10mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.344g, 1.8mmol) and acrylic acid (0.062mL, 0.9mmol) were added and reacted at room temperature for 4 hours. The reaction solution was spin-dried, and 150mL of ethyl acetate and 4mol/L of hydrogen were added to oxidize Aqueous sodium solution 100mL, liquid separation, aqueous phase with water 100mL ethyl acetate extraction, combined organic phase, 150mL saturated sodium chloride washing once. 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 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) as a yellow solid (170mg, yield 51.2%).

MS m/z:554.2[M+1]⁺。

Compound 53 is resolved by high performance liquid chromatography to give two optical isomers: compound 53-1 (peak 1, t ═ 4.50min), compound 53-2 (peak 2, t ═ 5.07 min). Splitting conditions are as follows: detection wavelength: 254nM, column temperature: 30 ℃, mobile phase: acetonitrile and water (0.1% ammonia), and acetonitrile/water 81% and 19% in water.

Example 54

N- (2- (((1-aminocyclopropyl) methyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 54)

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

The first step is as follows: (1- ((tert-Butoxycarbonyl) amino) cyclopropyl) methyl methanesulfonate (54B)

(1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl methanesulfonate

Tert-butyl (1- (hydroxymethyl) cyclopropyl) carbamate (54A) (5g, 26.7mmol) was dissolved in 30mL of dichloromethane, triethylamine (5.4g, 53.4mmol) was added under ice bath, methanesulfonyl chloride (3.36g, 29.4mmol) was added dropwise, the reaction was allowed to proceed at room temperature for 2 hours, and the reaction was continued for 6 hours while warming to room temperature. After completion of the reaction, 150mL of water and 150mL of methylene chloride were added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted once with 100mL of dichloromethane, the organic phases were combined, washed once with 150mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give (1- ((tert-butoxycarbonyl) amino) cyclopropyl) methyl methanesulfonate (54B) as a white solid (4g, 89.3% yield).

MS m/z:288.1[M+23]⁺。

The second step is that: (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) (3.5g, 13.2mmol) was dissolved in 50mL of tetrahydrofuran, methylamine (615mg, 19.8mmol) was added, and the reaction was carried out at 50 ℃ for 6 hours. After the reaction is finished, the solvent is dried by spinning. 150mL of water and 200mL of ethyl acetate were added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound (tert-butyl 1- ((methylamino) methyl) cyclopropyl) carbamate (54C) as a white solid (1.1g, 42.3% yield).

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-nitrophenyl) (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-nit rophenyl)(methyl)amino)methyl)cyclopropyl)carbamate

5- ((4- (1-methylindol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2-fluoro-1-nitrobenzene (intermediate 3) (1g, 2.54mmol) was dissolved in 15mL of N, N-dimethylacetamide, N-diisopropylethylamine (0.63mL, 3.82mmol) and tert-butyl (1- ((methylamino) methyl) cyclopropyl) carbamate (54C) (764mg, 3.82mmol) were added and reacted at 140 ℃ for 1 hour under microwave. After the reaction was completed, 100mL of methylene chloride and 100mL of water were added, the layers were separated, the aqueous phase was extracted once with 100mL of methylene chloride, the organic phases were combined, washed once with 200mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a brown solid compound, tert-butyl 1- (((5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrophenyl) (methyl) amino) methyl) cyclopropyl) carbamate (54D) (1.1g, yield 91.6%).

MS m/z:574.2[M+1]⁺。

The fourth step: (1- (((2-amino-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) (methyl) amino) methyl) cyclopropyl) carbamic acid tert-butyl ester (54E)

tert-butyl(1-(((2-amino-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)ami no)phenyl)(methyl)amino)methyl)cyclopropyl)carbamate

Tert-butyl (1- (((5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrophenyl) (methyl) amino) methyl) cyclopropyl) carbamate (54D) (1.1g, 1.92mmol) was dissolved in 60mL of ethanol, 20mL of water, iron powder (643mg, 11.5mmol) and ammonium chloride (72mg, 1.34mmol) were added in this order, the temperature was raised to 90 ℃ and the reaction was refluxed for 4 hours. The reaction mixture was cooled to room temperature, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) to obtain tert-butyl 1- (((2-amino-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) (methyl) amino) methyl) cyclopropyl) carbamate (54E) (900mg, yield 90%) as a brown solid.

MS m/z:544.2[M+1]⁺。

The fifth step: (1- (((2-acrylamido-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) (methyl) amino) methyl) cyclopropyl) carbamic acid tert-butyl ester (54F)

tert-butyl(1-(((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl )amino)phenyl)(methyl)amino)methyl)cyclopropyl)carbamate

Tert-butyl (1- (((2-amino-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) (methyl) amino) methyl) cyclopropyl) carbamate (54E) (900mg, 1.66mmol) was dissolved in 15mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (955mg, 5mmol) and acrylic acid (0.17mL, 2.48mmol) were added and reacted at room temperature for 2 hours. The reaction mixture was spin-dried, and 100mL of water and 100mL of dichloromethane were added to separate the reaction mixture. The organic phase was washed once with 100mL of a 4mol/L aqueous solution of sodium hydroxide and dried over anhydrous sodium sulfate. Concentration gave tert-butyl (1- (((2-acrylamido-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) (methyl) amino) methyl) cyclopropyl) carbamate (54F) as a yellow oil (600mg, 60.5% yield).

MS m/z:598.2[M+1]⁺。

And a sixth step: n- (2- (((1-aminocyclopropyl) methyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 54)

Tert-butyl (1- (((2-acrylamido-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) (methyl) amino) methyl) cyclopropyl) carbamate (54F) (600mg, 1mmol) was dissolved in 20mL of dichloromethane and 10mL of trifluoroacetic acid was added to react at room temperature for 3 hours. The reaction mixture was spin-dried, 100mL of water was added, the pH of the solution was adjusted to 8 with saturated sodium bicarbonate, 150mL of dichloromethane was added, and the layers were separated. The aqueous phase was extracted once with 100mL of dichloromethane, the organic phases were combined, washed once with 150mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and subjected to silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) to give N- (2- (((1-aminocyclopropyl) methyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 54) as a brown solid (450mg, yield 90.5%).

MS m/z:498.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (compound 55)

N-(5-((4-(1-(cyclopropanecarbonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dim ethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The first step is as follows: cyclopropyl (3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1H-indol-1-yl) methanone (55A)

cyclopropyl(3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophe nyl)amino)pyrimidin-4-yl)-1H-indol-1-yl)methanone

Will N¹- (4- (1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenzene-1, 4-diamine (34B) (1g, 2.17mmol) was dissolved in 20mL tetrahydrofuran, N-diisopropylethylamine (0.42g, 3.25mmol) was added, cooled to 0 ℃ under nitrogen, cyclopropanecarbonyl chloride (0.3mL, 3.25mmol) was added dropwise, the reaction was allowed to proceed at 0 ℃ for 1 hour, and the reaction was allowed to warm to room temperature for 1 hour. After completion of the reaction, 10mL of water was added to quench the reaction, the reaction mixture was spin-dried, 100mL of water and 100mL of dichloromethane were added, and the mixture was separated. The aqueous phase was extracted once with 100mL of dichloromethane. The organic phases were combined, washed once with 100mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the compound cyclopropyl (3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1H-indol-1-yl) methanone (55A) as a brown solid (1g, 87% yield).

MS m/z＝530.1[M+1]⁺。

The second step is that: (3- (2- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) pyrimidin-4-yl) -1H-indol-1-yl) (cyclopropyl) methanone (55B)

(3-(2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino )pyrimidin-4-yl)-1H-indol-1-yl)(cyclopropyl)methanone

Cyclopropyl (3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1H-indol-1-yl) methanone (55A) (1g, 1.89mmol) was dissolved in 30mL of ethanol, 10mL of water was added, followed by iron powder (0.633g, 11.3mmol) and ammonium chloride (71mg, 1.32mmol), the mixture was heated to 90 ℃ and refluxed for 6 hours. The reaction solution was concentrated, and separated and purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) to obtain a compound (3- (2- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) pyrimidin-4-yl) -1H-indol-1-yl) (cyclopropyl) methanone (55B) as a brown solid (0.5g, yield 53%).

The third step: n- (5- ((4- (1- (cyclopropylcarbonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (compound 55)

(3- (2- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) pyrimidin-4-yl) -1H-indol-1-yl) (cyclopropyl) methanone (55B) (0.5g, 1mmol) was dissolved in 10mL of pyridine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.573g, 3mmol) was added, acrylic acid (0.103mL, 1.5mmol) was added, and the reaction was allowed to proceed at room temperature for 3 hours. The reaction mixture was spin-dried, 150mL of ethyl acetate and 100mL of 4mol/L aqueous sodium hydroxide solution were added, the mixture was separated, and the aqueous phase was extracted once with 100mL of ethyl acetate. The organic phases were combined, washed once with 150mL of a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography on silica gel (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) to give N- (5- ((4- (1- (cyclopropylcarbonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (compound 55) as a pale yellow solid (60mg, 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) pyrimidin-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)pyri midin-2-yl)amino)-4-methoxyphenyl)acrylamide

The first step is as follows: 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

Tert-butyl 4- (3- (2- ((5-acrylamido-2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) -1-methyl-1H-indol-6-yl) piperazine-1-carboxylate (compound 26) (0.40g,0.65mmol) was placed in a 50mL round-bottom flask. To the reaction flask were added dichloromethane (10mL) and trifluoroacetic acid (5mL) in this order at 0 ℃. The reaction was warmed to room temperature and stirred for 2 hours. To the residue was added dichloromethane (50mL), saturated aqueous sodium bicarbonate (20mL), the layers were separated, the aqueous phase was extracted with dichloromethane (50mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give N- (3- ((5-chloro-4- (1-methyl-6- (piperazin-1-yl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (56A) as a yellow oil (0.335 g).

The second step is that: 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)

N- (3- ((5-chloro-4- (1-methyl-6- (piperazin-1-yl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (56A) (0.16g, 0.31mmol) was dissolved in 40mL of acetonitrile, and potassium carbonate (86mg,0.62 mmol) and bromoethanol (58.1mg, 0.47mmol) were added, followed by reaction at 60 ℃ for 3 hours. After the reaction, the solvent was dried by spinning, 100mL of water and 100mL of dichloromethane were added, the mixture was separated, the aqueous phase was extracted with 100mL of dichloromethane, and the organic phases were combined, washed with 150mL of saturated brine, and dried over anhydrous sodium sulfate. Concentration and purification of the residue by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) gave 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) as a yellow solid (150mg, 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

The first step is as follows: 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) (6g,50.8mmol) was dissolved in 100mL tetrahydrofuran, cooled to 0 ℃ under nitrogen, methylmagnesium bromide (17mL,50.8mmol) was added dropwise, and stirring was continued for 0.5 h. 2, 4-dichloropyrimidine (7.6g, 50.8mmol) was added, the reaction was carried out at room temperature for 1 hour, and the reaction was continued for 2 hours while the temperature was raised to 60 ℃. To the reaction mixture were added 30mL of methanol and 20mL of acetic acid, the solvent was evaporated, the reaction mixture was washed with 200mL of water and 10mL of tetrahydrofuran, and the mixture was dried to give 3- (2-chloropyrimidin-4-yl) -1H-pyrrolo [2,3-B ] pyridine (57B) as a yellow solid (10g, 86.2% yield).

LC-MS(m/z):231.0[M+1]⁺。

The second step is that: 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) (2g, 8.7mmol) was dissolved in 20mL of 2-pentanol, 4-fluoro-2-methoxy-5-nitroaniline (4e) (1.62g, 8.7mmol) and p-toluenesulfonic acid monohydrate (2g, 10.4mmol) were added, and the reaction was heated to 120 ℃ for 18 hours under reflux. The reaction was cooled to room temperature, 50mL of aqueous ammonia was added, the mixture was filtered, and the filter cake was washed with 100mL of water. Oven dried to give N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-2-amine (57C) as a yellow solid (2.3g, 69.7% yield).

LC-MS(m/z):381.0[M+1]⁺。

The third step: n is a radical of¹- (4- (1H-pyrrolo [2,3-b ]]Pyridin-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenzo-1, 4-diamine (57D)

N¹-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-N⁴-(2-(dimethylamino)ethyl)-2 -methoxy-N⁴-methyl-5-nitrobenzene-1,4-diamine

Reacting N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1H-pyrrolo [2, 3-b)]Pyridin-3-yl) pyrimidin-2-amine (57C) (2.5g, 6.58mmol) was dissolved in 15mL of N, N-dimethylacetamide, and N, N-diisopropylethylamine (1.02g, 7.9mmol) and N, N, N' -trimethylethylenediamine (18A) (807mg, 7.89mmol) were added and reacted at 120 ℃ for 1.5 hours under microwave. After the reaction is finished, the solvent is dried by spinning. Separating and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-10: 1), Obtaining a reddish brown solid N¹- (4- (1H-pyrrolo [2,3-b ]]Pyridin-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenzo-1, 4-diamine (57D) (1g, 33.3% yield).

LC-MS(m/z):463.1[M+1]⁺。

The fourth step: n is a radical of⁴- (4- (1H-pyrrolo [2,3-b ]]Pyridin-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzo-1, 2, 4-triamine (57E)

N⁴-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-N¹-(2-(dimethylamino)ethyl)-5 -methoxy-N¹-methylbenzene-1,2,4-triamine

Will N¹- (4- (1H-pyrrolo [2,3-b ]]Pyridin-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenzo-1, 4-diamine (57D) (1g, 2.11mmol) was dissolved in 30mL of ethanol, 10mL of water, iron powder (362mg, 6.44mmol) and ammonium chloride (81mg, 1.5mmol) were added in this order, and the mixture was heated to 90 ℃ and reacted under reflux for 6 hours. The reaction was cooled to room temperature, filtered and concentrated. Separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain brown solid N⁴- (4- (1H-pyrrolo [2,3-b ]]Pyridin-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzo-1, 2, 4-triamine (57E) (933 mg).

LC-MS(m/z):433.1[M+1]⁺。

The fifth step: 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)

Will N⁴- (4- (1H-pyrrolo [2,3-b ]]Pyridin-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzo-1, 2, 4-triamine (57E) (500mg, 1.16mmol) was dissolved in 15mL pyridine, and 1 was added- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (665mg, 3.48mmol) and acrylic acid (0.12mL, 1.74 mmol) were reacted at room temperature for 6 hours. The pyridine was spin-dried, 100mL of water and 100mL of dichloromethane were added, and the layers were separated. The organic phase was washed with a 4mol/L aqueous solution of sodium hydroxide (100mL) and dried over anhydrous sodium sulfate. Separating and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-10: 1) to obtain 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) (330mg, 58.5% yield).

LC-MS(m/z):487.1[M+1]⁺。

1H NMR(400MHz,DMSO-d₆)δ10.07(s,1H),9.03(s,1H),8.88(s,1H),8.37– 8.32(m,1H),8.31(d,1H),8.01(dd,1.7Hz,1H),7.18(dd,4.7Hz,1H),7.01(s,1H),6.76 (s,1H),6.64(d,1H),6.43(dd,10.1Hz,1H),6.25(dd,1.9Hz,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)acr ylamide

The first step is as follows: 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-pyrrolo [2,3-B ] pyridine (57B) (2g, 8.7mmol) was dissolved in 2-pentanol (30mL), the compound 2-methoxy-5-nitroaniline (1.46g, 8.7mmol) and p-toluenesulfonic acid (2g, 10.44 mmol) were added, and the reaction was heated to 120 ℃ for 18 hours under reflux. The reaction was cooled to room temperature, 50mL of aqueous ammonia was added, filtered, and the filter cake was washed with 100mL of water and dried to give N- (2-methoxy-5-nitrophenyl) -4- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-2-amine (58A) (2.5g, 80.6% yield) as a yellow solid.

LC-MS(m/z):363.1[M+1]⁺。

The second step is that: n is a radical of¹- (4- (1H-pyrrolo [2,3-b ]]Pyridin-3-yl) pyrimidin-2-yl) -6-methoxybenzo-1, 3-triamine (58B)

N¹-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-6-methoxybenzene-1,3-diamine

Reacting N- (2-methoxy-5-nitrophenyl) -4- (1H-pyrrolo [2, 3-b)]Pyridin-3-yl) pyrimidin-2-amine (58A) (0.5g, 1.38mmol) was dissolved in 100mL of methanol, palladium on carbon (0.15g, 30%) was added, and the mixture was replaced with hydrogen atmosphere three times and reacted at room temperature for 8 hours. After completion of the reaction, the reaction mixture was filtered through celite, washed with dichloromethane (50mL) and methanol (50mL), and concentrated to give N as a red-brown solid¹- (4- (1H-pyrrolo [2,3-b ]]Pyridin-3-yl) pyrimidin-2-yl) -6-methoxybenzo-1, 3-triamine (58B) (0.458 g).

The third step: n- (3- ((4- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyridin-2-yl) amino) -4-methoxyphenyl) propenamide (Compound 58)

Will N¹- (4- (1H-pyrrolo [2,3-b ]]Pyridin-3-yl) pyrimidin-2-yl) -6-methoxybenzo-1, 3-triamine (58B) (0.458mg, 1.38mmol) was dissolved in 15mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (527mg, 2.76mmol) and acrylic acid (0.14mL, 2.07mmol) were added to react at room temperature for 6 hours. The pyridine was spin-dried, 100mL of water and 100mL of dichloromethane were added, and the layers were separated. Washing the organic phase with 4mol/L sodium hydroxide aqueous solution (100mL), drying with anhydrous sodium sulfate, filtering, concentrating, separating and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-10: 1) to obtain white solid N- (3- ((4- (1H-pyrrolo [2,3-b ] of N- (3-methyl) pyrrole) ]Pyridin-3-yl) pyridin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 58) (230mg, 43.2% yield).

LC-MS(m/z):387.0[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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) acrylamide (compound 59)

N-(4-methoxy-3-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino) phenyl)acrylamide

The first step is as follows: 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) (0.4g, 1.1mmol) was dissolved in 20mL of tetrahydrofuran, cooled to 0 deg.C, sodium hydride (0.053g, 2.2mmol) was added, reacted for 30 minutes, iodomethane (0.2mL, 3.3mmol) was added, and reacted at room temperature for 4 hours. After the reaction, 60mL of water was added to precipitate a solid, which was washed with 100mL of water and 50mL of petroleum ether and dried to give N- (2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-2-amine (59A) (0.413g) as a yellow solid.

The second step is that: n is a radical of¹- (4- (1H-pyrrolo [2,3-b ]]Pyridin-3-yl) pyrimidin-2-yl) -6-methoxybenzo-1, 3-diamine (59B)

Reacting N- (2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) pyrimidin-2-amine (59A) (0.5g,1.33mmol) was dissolved in 50mL of methanol, palladium on carbon (0.15g, 30%) was added, and the mixture was replaced with hydrogen atmosphere three times and reacted at room temperature for 1 day. After the reaction, the reaction mixture was washed with celite Filtration, washing with dichloromethane (100mL) and methanol (100mL), and concentration afforded N as a yellow solid¹- (4- (1H-pyrrolo [2,3-b ]]Pyridin-3-yl) pyrimidin-2-yl) -6-methoxybenzo-1, 3-diamine (59B) (0.46 g).

LC-MS(m/z):347.1[M+1]⁺。

The 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)

Will N¹- (4- (1H-pyrrolo [2,3-b ]]Pyridin-3-yl) pyrimidin-2-yl) -6-methoxybenzo-1, 3-diamine (59B) (0.46mg, 1.33mmol) was dissolved in 15mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (762mg, 4mmol) and acrylic acid (0.14mL, 2mmol) were added to react at room temperature for 6 days. The pyridine was spin-dried, 100mL of water and 100mL of dichloromethane were added, and the layers were separated. Washing the organic phase with 4mol/L sodium hydroxide aqueous solution (100mL), drying with anhydrous sodium sulfate, filtering, concentrating, separating and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-10: 1) to obtain brown solid N- (4-methoxy-3- ((4- (1-methyl-1H-pyrrolo [2, 3-b): brown solid]Pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 59) (400mg, 75.2% yield).

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

The first step is as follows: 4- (1- (difluoromethyl) -1H-indol-3-yl) -N- (2-methoxy-4- (2- (4-methylpiperazin-1-yl) ethoxy) -5-nitrophenyl) pyrimidin-2-amine (60A)

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

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, stirred for 30 minutes, 2- (4-methylpiperazin-1-yl) ethanol (672mg, 4.66mmol) was added, and the reaction was carried out at room temperature for 4 hours. After completion of the reaction, 150mL of water and 150mL of methylene chloride were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to give 4- (1- (difluoromethyl) -1H-indol-3-yl) -N- (2-methoxy-4- (2- (4-methylpiperazin-1-yl) ethoxy) -5-nitrophenyl) pyrimidin-2-amine (60A) (1.2g, 93.0% yield) as a yellow solid.

LC-MS(m/z)＝554.3[M+1]⁺。

The second step is that: n is a radical of¹- (4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-4- (2- (4-methylpiperazin-1-yl) ethoxy) benzo-1, 3-diamine (60B)

N¹-(4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-(4-methylpi perazin-1-yl)ethoxy)benzene-1,3-diamine

4- (1- (difluoromethyl) -1H-indol-3-yl) -N- (2-methoxy-4- (2- (4-methylpiperazin-1-yl) ethoxy) -5-nitrophenyl) pyrimidin-2-amine (60A) (1.2g, 2.17mmol) was dissolved in 30mL of ethanol, 10mL of water, iron powder (727mg, 13mmol) and ammonium chloride (81.3mg, 1.52mmol) were added, and the mixture was heated to 90 ℃ for 4 hours under reflux. Concentrating the reaction solution, and separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain brown solid N ¹- (4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-4- (2- (4-methylpiperazin-1-yl) ethoxy) benzo-1, 3-diamine (60B) (740mg, 65.5% yield).

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)

Will N¹- (4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-4- (2- (4-methylpiperazin-1-yl) ethoxy) benzo-1, 3-diamine (60B) (740mg, 1.4mmol) was dissolved in 20mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (802mg, 4.2mmol) and acrylic acid (0.146mL, 2.1mmol) were added and reacted at room temperature for 4 hours. The reaction mixture was spin-dried with 150mL of water and 150mL of dichloromethane, and the mixture was separated. The organic phase was washed with 4mol/L aqueous sodium hydroxide (100mL), 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 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) (200mg, yield 24.8%) as a white solid.

LC-MS(m/z)＝578.3[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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-indol-3-yl) pyrimidin-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

The first step is as follows: 3- (2-Chloropyrimidin-4-yl) -7-methyl-1H-indole (61B)

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

7-methylindole (61A) (10g, 76.2mmol) was dissolved in 100mL 1, 2-dichloroethane, cooled to 0 ℃ under nitrogen, methylmagnesium bromide (25.4mL, 76.2mmol) was added dropwise, and stirring was continued for 0.5 h. 2, 4-dichloropyrimidine (11.4g, 76.2mmol) was added, the reaction was carried out at room temperature for 40 minutes, and the reaction was carried out at 60 ℃ for 8 hours. 20mL of methanol and 20mL of acetic acid were added and the reaction was carried out for 20 minutes, the solvent was evaporated, a solid was precipitated, the solid was washed with 200mL of water and 50mL of petroleum ether, and the cake was dried with an infrared lamp to give 3- (2-chloropyrimidin-4-yl) -7-methyl-1H-indole (61B) (12g, yield 64.9%) as a yellow solid.

LC-MS(m/z):244.0[M+1]⁺。

The second step is that: 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) (4.2g, 17.28mmol) was dissolved in 80mL 2-pentanol, 4-fluoro-2-methoxy-5-nitroaniline (4e) (3.2g, 17.28mmol) and p-toluenesulfonic acid monohydrate (3.98g, 20.7mmol) were added, and the reaction was heated to 120 ℃ for 3 days under reflux. Cooled to room temperature, 200mL of ammonia was added, the solid precipitated, filtered, and the filter cake washed with 200mL of water and 100mL of petroleum ether. Oven dried to give N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (7-methyl-1H-indol-3-yl) pyrimidin-2-amine (61C) as a dark green solid (4.5g, 66.3% yield).

LC-MS(m/z):394.1[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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)。

The third step: n is a radical of¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (7-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2-nitrobenzo-1, 4-diamine (61D)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(7-methyl-1H-indol-3-yl)p yrimidin-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) (2.5g, 6.35mmol) was dissolved in N, N-dimethylacetamide (10mL), N, N-diisopropylethylamine (986mg, 7.63mmol) and N, N, N' -trimethylethylenediamine (18A) (780mg, 7.63mmol) were added, and the mixture was reacted at 120 ℃ for 1.5 hours under microwave. After the reaction is finished, concentrating, separating and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-10: 1) to obtain brown solid N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (7-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2-nitrobenz-1, 4-diamine (61D) (2.1g, 70% yield).

LC-MS(m/z):476.3[M+1]⁺。

The fourth step: n is a radical of¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (7-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzo-1, 2, 4-triamine (61E)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(7-methyl-1H-indol-3-yl)p yrimidin-2-yl)benzene-1,2,4-triamine

Will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (7-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2-nitrobenz-1, 4-diamine (61D) (1.3g, 2.74mmol) was dissolved in 30mL of ethanol, 10mL of water, iron powder (0.918g, 16.4mmol) and ammonium chloride (102.7mg, 1.92mmol) were added, and the mixture was heated to 90 ℃ and reacted under reflux for 4 hours. Concentrating the reaction solution, and separating and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-10: 1) to obtain brown solid N ¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (7-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzo-1, 2, 4-triamine (61E) (0.8g, 66.7% yield).

LC-MS(m/z):446.1[M+1]⁺。

The fifth step: 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)

Will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (7-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzo-1, 2, 4-triamine (61E) (0.8g, 1.mmol) was dissolved in 15mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.03g, 5.4mmol) and acrylic acid (0.19mL, 2.7mmol) were added in this order to react at room temperature for 4 hours. Pyridine was dried by spinning, 150mL of dichloromethane and 4mol/L aqueous sodium hydroxide solution (100mL) were added, the solution was separated, the aqueous phase was extracted once with 150mL of dichloromethane, the organic phases were combined, washed once with 200mL of saturated 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 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) (400mg, yield 44.5%) as a yellow solid.

LC-MS(m/z):500.2[M+1]⁺。

¹H NMR(400MHz,CDCl3)δ10.21(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,1.4Hz,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)et hyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The first step is as follows: 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) (10g, 41.1mmol) was dissolved in 100mL of tetrahydrofuran, cooled to 0 deg.C, sodium hydride (3.3g, 82.2mmol) was added, the reaction was carried out at 0 deg.C for 30 minutes, methyl iodide (17.5g, 123.4mmol) was added, and the reaction was allowed to warm to room temperature for 1 hour. At the end of the reaction, the solvent was spun off, the solid was washed with 200mL of water and 50mL of petroleum ether and dried to give 3- (2-chloropyrimidin-4-yl) -1, 7-dimethyl-1H-indole (62A) (10g, 95.2% yield) as a reddish brown solid.

The second step is that: 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-a mine

3- (2-Chloropyrimidin-4-yl) -1, 7-dimethyl-1H-indole (62A) (5g, 19.4mmol) was dissolved in 100mL 2-pentanol, 4-fluoro-2-methoxy-5-nitroaniline (4e) (3.62g, 19.4mmol) and p-toluenesulfonic acid monohydrate (4.47g, 23.3mmol) were added, and the reaction was heated to 120 ℃ for 3 days under reflux. Cooled to room temperature, added with 200mL of ammonia, precipitated a solid, filtered, and the filter cake was washed with 200mL of water and 100mL of petroleum ether in that order and dried to give 4- (1, 7-dimethyl-1H-indol-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidin-2-amine (62B) (6g, 75.9% yield) as a yellow solid.

LC-MS(m/z):408.0[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)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)。

The third step: n is a radical of¹- (4- (1, 7-dimethyl-1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenz-1, 4-amine (62C)

N¹-(4-(1,7-dimethyl-1H-indol-3-yl)pyrimidin-2-yl)-N⁴-(2-(dimethylamino)ethyl)-2-m ethoxy-N⁴-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, and N, N-diisopropylethylamine (1.14g, 8.84mmol) and N, N, N' -trimethylethylenediamine (18A) (904mg, 8.84mmol) were added and reacted at 120 ℃ for 1.5 hours under microwave. After completion of the reaction, 150mL of water and 150mL of methylene chloride were added and the mixture was separated. The aqueous phase was extracted with 150mL of dichloromethane, and the organic phases were combined and washed with 200mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to give brown solid N¹- (4- (1, 7-dimethyl-1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenz-1, 4-amine (62C) (3.6 g).

LC-MS(m/z):490.2[M+1]⁺。

The fourth step: n is a radical of⁴- (4- (1, 7-dimethyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzo-1, 2, 4-triamine (62D)

N⁴-(4-(1,7-dimethyl-1H-indol-3-yl)pyrimidin-2-yl)-N¹-(2-(dimethylamino)ethyl)-5-m ethoxy-N¹-methylbenzene-1,2,4-triamine

Will N¹- (4- (1, 7-dimethyl-1H-indol-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenz-1, 4-amine (62C) (3.6g, 7.36mmol) was dissolved in 30mL ethanol, 10mL water, iron powder (2.46 g, 44.1mmol) and ammonium chloride (273mg, 5.1mmol) were added, and the reaction was refluxed at 90 ℃ for 4 hours. Concentrating the reaction solution, and separating and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-10: 1) to obtain yellow solid N ⁴- (4- (1, 7-dimethyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzo-1, 2, 4-triamine (62D) (2.3mg, 69.7% yield).

LC-MS(m/z):460.1[M+1]⁺。

The fifth step: 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)

Will N⁴- (4- (1, 7-dimethyl-1H-indol-3-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzo-1, 2, 4-triamine (62D) (1.66g, 3.62mmol) was dissolved in 30mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.07g, 10.85mmol) and acrylic acid (0.38mL, 5.43mmol) were added in this order to react at room temperature for 6 hours. After the pyridine was dried by spinning, a 4mol/L aqueous solution of sodium hydroxide (200mL) and 200mL of methylene chloride were added to separate the layers. The organic phase was washed once with 100mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and purified by column chromatography on silica gel (dichloromethane/methanol (v/v) ═ 1:0 to 10:1) to give 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) (1g, yield 53.8%) as a brown solid.

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)phen yl)acrylamide

The first step is as follows: 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) (6.6g, 50mmol) was dissolved in 100mL of N, N-dimethylformamide, cooled to 0 ℃ under nitrogen, sodium hydride (2.4g, 60mmol) was added, stirring was continued for 0.5 h, 2, 4-dichloropyrimidine (7.5g, 50mmol) was added, and the reaction was allowed to proceed at room temperature for 10 h. 250mL of water was added to precipitate a solid, which was filtered, and the filter cake was washed with 200mL of water and 100mL of petroleum ether and dried to give 1- (2-chloropyrimidin-4-yl) -2-methyl-1H-benzo [ d ] imidazole (63B) (23g) as a white solid.

LC-MS(m/z):245.0[M+1]⁺。

¹H 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)。

The second step is that: 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-am ine

1- (2-Chloropyrimidin-4-yl) -2-methyl-1H-benzo [ d ] imidazole (63B) (2.44g, 10mmol) was dissolved in 30mL 2-pentanol, 2-methoxy-5-nitroaniline (1.68g, 10mmol) and p-toluenesulfonic acid (1.92g, 10mmol) were added, and the reaction was heated to 120 ℃ for 3 days under reflux. Cooled to room temperature, 100mL of aqueous ammonia was added, the solid precipitated, filtered, and the filter cake washed with 250mL of water and 100mL of petroleum ether and dried to give N- (2-methoxy-5-nitrophenyl) -4- (2-methyl-1H-benzo [ d ] imidazol-1-yl) pyrimidin-2-amine (63C) as a yellow solid (2.7g, 71.8% yield).

LC-MS(m/z):377.0[M+1]⁺。

The third step: n is a radical of¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (2-methyl-1H-benzo [ d ]]Imidazol-1-yl) pyrimidin-2-yl) -2-nitrobenzo-1, 4-diamine (63D)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(2-methyl-1H-benzo[d]imi dazol-1-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine

Reacting N- (2-methoxy-5-nitrophenyl) -4- (2-methyl-1H-benzo [ d]Imidazol-1-yl) pyrimidin-2-amine (63C) (1g, 2.6mmol) was dissolved in 20mL of methanol, and palladium on carbon (0.334g, 30%) was added and the mixture was replaced with hydrogen atmosphere three times to conduct a reaction at room temperature for 3 hours. After the reaction was complete, the mixture was filtered through Celite and washed with 50mL of methanol. Concentrating the filtrateConcentrating, separating and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-50: 1), and obtaining yellow solid N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (2-methyl-1H-benzo [ d ]]Imidazol-1-yl) pyrimidin-2-yl) -2-nitrobenzo-1, 4-diamine (63D) (0.6g, 65.9% yield).

LC-MS(m/z):347.1[M+1]⁺。

The fourth step: n- (4-methoxy-3- ((4- (2-methyl-1H-benzo [ d ] imidazol-1-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 63)

Will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (2-methyl-1H-benzo [ d ]]Imidazol-1-yl) pyrimidin-2-yl) -2-nitrobenz-1, 4-diamine (63D) (0.6g, 1.73mmol) was dissolved in 15mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.993g, 5.2mmol) and acrylic acid (0.18mL, 2.6mmol) were added in that order and reacted at room temperature for 4 hours. Drying pyridine, adding 100mL ethyl acetate and 100mL 4mol/L sodium hydroxide aqueous solution, separating, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-50: 1) to obtain white solid N- (4-methoxy-3- ((4- (2-methyl-1H-benzo [ d ] b) ]Imidazol-1-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 63) (150mg, 21.7% yield).

LC-MS(m/z):401.1[M+1]⁺。

¹H 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

The first step is as follows: 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)pyrimi din-2-amine

1- (2-Chloropyrimidin-4-yl) -2-methyl-1H-benzo [ d ] imidazole (63B) (0.244g, 1mmol) was dissolved in 30mL 2-pentanol, 4-fluoro-2-methoxy-5-nitroaniline (4e) (0.186g, 1mmol) and p-toluenesulfonic acid monohydrate (0.192g, 1mmol) were added, and the reaction was heated to 120 ℃ for 1 day under reflux. The reaction mixture was cooled to room temperature, 200mL of aqueous ammonia was added to precipitate a solid, which was filtered, and the filter cake was washed with 250mL of water and 100mL of petroleum ether. Oven dried to give N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (2-methyl-1H-benzo [ d ] imidazol-1-yl) pyrimidin-2-amine (64A) (3.7g, 93.9% yield) as a brown solid.

LC-MS(m/z):395.1[M+1]⁺。

The second step is that: n is a radical of¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (2-methyl-1H-benzo [ d ]]Imidazol-1-yl) pyrimidin-2-yl) -2-nitrophenyl-1, 4-diamine (64B)

Reacting 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' -trimethylethylenediamine (18A) (613mg, 6mmol) were added, and the mixture was reacted at 120 ℃ for 2 hours under microwave. After the reaction is finished, the reaction solution is concentrated, and is separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-20: 1), so that red brown solid N1- (2- (dimethylamino) ethyl ester is obtainedYl) -5-methoxy-N¹-methyl-N⁴- (4- (2-methyl-1H-benzo [ d ]]Imidazol-1-yl) pyrimidin-2-yl) -2-nitrophenyl-1, 4-diamine (64B) (0.87g, 39.5% yield).

The third step: n is a radical of¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (2-methyl-1H-benzo [ d ]]Imidazol-1-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (64C)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(2-methyl-1H-benzo[d]imi dazol-1-yl)pyrimidin-2-yl)benzene-1,2,4-triamine

Will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (2-methyl-1H-benzo [ d ]]Imidazol-1-yl) pyrimidin-2-yl) -2-nitrobenzene-1, 4-diamine (64B) (0.87g, 1.95mmol) was dissolved in 30mL of ethanol, 10mL of water, iron powder (0.653g, 11.7mmol) and ammonium chloride (73mg, 1.37mmol) were added in this order, and the mixture was heated to 90 ℃ for reflux reaction for 4 hours. Concentrating the reaction solution, and separating and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-20: 1) to obtain brown solid N ¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (2-methyl-1H-benzo [ d ]]Imidazol-1-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (64C) (0.6g, 73.6% yield).

The fourth step: 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)

Will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (2-methyl-1H-benzo [ d ]]Imidazol-1-yl) pyrimidin-2-yl) benzo-1, 2, 4-triamine (64C) (0.6g, 1.34mmol) was dissolved in 20mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.764g, 4mmol) and acrylic acid (0.14mL, 2mmol) were added in that order to react at room temperature for 3 hours. Removing pyridine by rotary drying, adding 150mL ethyl acetate and 4mol/L sodium hydroxide water solutionSeparating the solution (100mL), extracting the aqueous phase with 100mL ethyl acetate, combining the organic phases, washing with 150mL saturated sodium chloride, drying over anhydrous sodium sulfate, separating and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-20: 1) to obtain a light yellow solid N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (2-methyl-1H-benzo [ d ] d)]Imidazol-1-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 64) (300mg, 44.8% yield).

LC-MS(m/z):501.1[M+1]⁺。

¹H 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

The first step is as follows: 6-bromo-1- (triisopropylsilyl) -1H-indole (65B)

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

6-bromoindole (65A) (30g, 153.02mmol) was dissolved in 200mL of tetrahydrofuran, and sodium hydride (4.04g, 168.32mmol) was slowly added under ice-bath, followed by stirring for 30 minutes, and triisopropylchlorosilane (35.4g, 183.6mmol) was added dropwise, followed by reaction at room temperature for 1 hour. To the reaction solution was added 20mL of water to quench the reaction, 200mL of water and 500mL of ethyl acetate were added, the mixture was separated, and the aqueous phase was extracted with 500mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, the solvent was dried by spinning, and the product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 50:1 to 20:1) to give 6-bromo-1- (triisopropylsilyl) -1H-indole (65B) as a white solid (46g, 87.9% yield).

The second step is that: 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) (1g, 3mmol) was dissolved in 30mL of o-xylene, and 2, 6-dimethylmorpholine (518mg, 4.5mmol), sodium tert-butoxide (577mg, 6mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (173.6mg, 0.3mmol) and palladium acetate (67.4mg, 0.3mmol) were added in this order, cooled to-20 ℃ and replaced with nitrogen for 30 minutes. The reaction was allowed to warm to 120 ℃ for 4 hours. After completion of the reaction, 10mL of water was added, the mixture was filtered through Celite, and the filtrate was washed with 100mL of ethyl acetate, and 100mL of water was added to the filtrate to separate the layers. The aqueous phase was extracted with 100mL ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 2, 6-dimethyl-4- (1- (triisopropylsilyl) -1H-indol-6-yl) morpholine (65C) (1.1g, 94.8% yield) as a brown solid.

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) (1.1g, 2.8mmol) was dissolved in 20mL of tetrahydrofuran under ice-bath, tetrabutylammonium fluoride (2.8mL, 2.8mmol) was added, and the reaction was carried out at room temperature for 2 hours. After the reaction, 10mL of water was added to quench the reaction, and the reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1:0 to 2:1) to give 4- (1H-indol-6-yl) -2, 6-dimethyl-morpholine (65D) (0.6g, 93.2% yield) as a yellow solid.

LC-MS(m/z):231.1[M+1]⁺。

The fourth step: 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) (0.6g, 2.6mmol) was dissolved in 30mL of tetrahydrofuran, cooled to 0 ℃ under nitrogen, methylmagnesium bromide (0.87mL, 2.6mmol) was added dropwise and reacted for 30 minutes, 2,4, 5-trichloropyrimidine (0.477g, 2.6mmol) was added and reacted for 6 hours at 65 ℃. After completion of the reaction, 150mL of water and 150mL of ethyl acetate were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1:0 to 2:1) to give 4- (3- (2, 5-dichloropyrimidin-4-yl) -1H-indol-6-yl) -2, 6-dimethyl-morpholine (65E) (0.64g, 65.5% yield) as a yellow solid.

LC-MS(m/z):377.0[M+1]⁺。

The fifth step: 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) (1.44g, 3.8mmol) was dissolved in 30mL of tetrahydrofuran, and sodium hydride (306.5mg, 7.6mmol) was added thereto under ice-cooling, followed by stirring for 30 minutes, dropwise addition of methyl iodide (0.72mL, 11.5mmol), and reaction at room temperature for 1 hour. After the reaction was complete, the reaction was quenched by the addition of 20mL of water, the solvent was dried, the solid washed with 100mL of water and dried to give 4- (3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1H-indol-6-yl) -2, 6-dimethyl-morpholine (65F) as a yellow solid (1.3g, 87.8% yield).

And a sixth step: 5-chloro-4- (6- (2, 6-dimethyl-morpholine) -1-methyl-1H-indol-3-yl) -N- (2-methoxy-5-nitrophenyl) pyrimidin-2-amine (65G)

5-chloro-4-(6-(2,6-dimethylmorpholino)-1-methyl-1H-indol-3-yl)-N-(2-methoxy-5-ni trophenyl)pyrimidin-2-amine

4- (3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1H-indol-6-yl) -2, 6-dimethyl-morpholine (65F) (1.3g, 3.33mmol) was dissolved in 30mL 2-pentanol, 2-methoxy-5-nitroaniline (561mg, 3.33mmol) and p-toluenesulfonic acid (768mg, 4mmol) were added, and the reaction was heated to 120 ℃ for 3 days under reflux. The reaction solution was cooled to room temperature, 150mL of aqueous ammonia was added, a solid precipitated, filtered, and the filter cake was washed with 200mL of water and 100mL of petroleum ether and dried to give 5-chloro-4- (6- (2, 6-dimethyl-morpholine) -1-methyl-1H-indol-3-yl) -N- (2-methoxy-5-nitrophenyl) pyrimidin-2-amine (65G) (1G, 58.8% yield) as a brown solid.

LC-MS(m/z):523.0[M+1]⁺。

The seventh step: 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

Dissolving 5-chloro-4- (6- (2, 6-dimethyl-morpholine) -1-methyl-1H-indol-3-yl) -N- (2-methoxy-5-nitrophenyl) pyrimidin-2-amine (65G) (1G, 1.9mmol) in 30mL of ethanol, sequentially adding 10mL of water, iron powder (642mg, 11.5mmol) and ammonium chloride (71mg, 1.33mmol), heating to 90 ℃ for reflux reaction for 6 hours, cooling to room temperature, filtering, concentrating the filtrate, and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-50: 1) to obtain N1- (5-chloro-4- (6- (2, 6-dimethyl-morpholine) -1-methyl-1H-indol-3-yl) pyrimidine as a yellow solid -2-yl) -6-methoxybenzo-1, 3-diamine (65H) (800mg, 85.6% yield).

LC-MS(m/z):493.0[M+1]⁺。

Eighth step: 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)

N1- (5-chloro-4- (6- (2, 6-dimethyl-morpholine) -1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxybenzo-1, 3-diamine (65H) (800mg, 1.6mmol) was dissolved in 15mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (917mg, 4.8mmol) and acrylic acid (0.17mL, 2.44mmol) were added in this order and reacted at room temperature for 4 hours. After the pyridine was dried by spinning, a 4mol/L aqueous solution of sodium hydroxide (150mL) and 150mL of ethyl acetate were added to separate the layers. The aqueous phase is extracted once with 1000mL of ethyl acetate, the organic phases are combined and washed once with 150mL of water. 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 20:1) to give 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) (400mg, yield 45.8%) as a white solid.

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

The first step is as follows: 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) (0.78g, 5mmol) is dissolved in 10mL of 1, 2-dichloroethane, cooled to 0 ℃ under the protection of nitrogen, 2, 4-dichloropyrimidine (0.745g, 5mmol) is added, aluminum trichloride (0.667g, 5mmol) is added, the reaction is carried out at room temperature for 40 minutes, and the reaction is carried out at 80 ℃ for 6 hours. To the reaction solution was added 10mL of water, filtered, and the filter cake was washed with methanol (3 mL. times.3) and dried with an infrared lamp to give 3- (2-chloropyrimidin-4-yl) -7-methyl-1H-indole (66B) (1.0g, yield 75%) as a yellow solid.

¹H 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)。

The second step is that: 4- (5, 6-dihydro-4H-pyrrolo [3,2,1-ij ] quinolin-1-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidin-2-amine (66C)

4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-N-(4-fluoro-2-methoxy-5-nitrophen yl)pyrimidin-2-amine

3- (2-Chloropyrimidin-4-yl) -7-methyl-1H-indole (66B) (0.54g, 2.0mmol) was dissolved in 8mL 2-pentanol, 4-fluoro-2-methoxy-5-nitroaniline (4e) (0.37g, 2.0mmol) and p-toluenesulfonic acid monohydrate (0.46g, 2.4mmol) were added, and the reaction was heated to 120 ℃ for 8 hours under reflux. After cooling to room temperature, 200mL of ammonia was added, the solid was precipitated, filtered, and the filter cake was washed with 200mL of water and 100mL of petroleum ether. Drying afforded 4- (5, 6-dihydro-4H-pyrrolo [3,2,1-ij ] quinolin-1-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidin-2-amine (66C) as a pale yellow solid (0.6g, 71.6% yield).

LC-MS(m/z):420.1[M+1]⁺。

¹H NMR(400MHz,CDCl3)δ9.85(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 is a radical of¹- (4- (5, 6-dihydro-4H-pyrrolo [3,2, 1-ij)]Quinolin-1-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrobenzene-1, 4-diamine (66D)

N¹-(4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)-N⁴-(2-(dimethyl amino)ethyl)-2-methoxy-N⁴-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-nitrophenyl) pyrimidin-2-amine (66C) (0.6g, 1.43mmol) was dissolved in 10mL of N, N-dimethylacetamide, N, N-diisopropylethylamine (278mg, 2.15mmol) and N, N, N' -trimethylethylenediamine (18A) (219mg, 2.15mmol) were added, and the mixture was reacted at 130 ℃ for 1.5 hours by microwave. After the reaction, the reaction mixture was concentrated. Adding 100mL of water and 100mL of ethyl acetate, separating, extracting the aqueous phase with 100mL of ethyl acetate, combining the organic phases, washing with 100mL of saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a red solid N¹- (4- (5, 6-dihydro-4H-pyrrolo [3,2, 1-ij)]Quinolin-1-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrophenyl-1, 4-diamine (66D) (716 mg).

LC-MS(m/z):502.3[M+1]⁺。

The fourth step: n is a radical of⁴- (4- (5, 6-dihydro)-4H-pyrrolo [3,2,1-ij]Quinolin-1-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (66E)

N⁴-(4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)-N¹-(2-(dimethyl amino)ethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine

Will N¹- (4- (5, 6-dihydro-4H-pyrrolo [3,2, 1-ij) ]Quinolin-1-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy-N⁴-methyl-5-nitrophenyl-1, 4-diamine (66D) (716mg, 1.43mmol) was dissolved in 15mL of ethanol, 5mL of water, iron powder (0.479g, 8.58mmol) and ammonium chloride (53.5mg, 1mmol) were added in this order, and the reaction was refluxed at 90 ℃ for 6 hours. After the reaction is finished, concentrating the reaction solution, and separating and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-10: 1) to obtain brown solid N⁴- (4- (5, 6-dihydro-4H-pyrrolo [3,2, 1-ij)]Quinolin-1-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (66E) (0.43g, 63.9% yield).

LC-MS(m/z):472.4[M+1]⁺。

¹H 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)。

The fifth step: 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)

Will N⁴- (4- (5, 6-dihydro-4H-pyrrolo [3,2, 1-ij)]Quinolin-1-yl) pyrimidin-2-yl) -N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methylbenzene-1, 2, 4-triamine (66E) (430mg, 0.91)mmol) was dissolved in 15mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.523g, 2.74mmol) and acrylic acid (0.094mL, 1.37mmol) were added to react at room temperature for 4 hours. The pyridine was dried by spinning, 100mL of dichloromethane and 4mol/L aqueous sodium hydroxide (100mL) were added, the layers were separated, the aqueous layer was extracted with 100mL of dichloromethane, and the organic layers were combined and washed with 150mL of saturated sodium chloride. Drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-10: 1) to obtain yellow solid 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) (140mg, 29.3% yield).

LC-MS(m/z):526.3[M+1]⁺。

¹H NMR(400MHz,CDCl3)δ10.21(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 '-indol ] -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

The first step is as follows: 3- (2-hydroxyethyl) indol-2-one (67B)

3-(2-hydroxyethyl)indolin-2-one

2-Indolinone (67A) (5g, 37.6mmol) was dissolved in 100mL of 1.2-ethanediol, reacted at 200 ℃ in an autoclave for 10 hours, the reaction was completed, the reaction mixture was cooled to room temperature, filtered through celite, washed with 50mL of methanol, most of the solvent was removed by evaporation, 100mL of ethyl acetate and 100mL of water were added, and the mixture was separated. The aqueous phase was extracted with 100mL of ethyl acetate, and the combined organic phases were washed with 150mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3- (2-hydroxyethyl) indol-2-one (67B) as a yellow oil (4.5g, 68.2% yield).

LC-MS(m/z):178.1[M+1]⁺。

The second step is that: spiro [ cyclopropyl-1, 3 '-indol ] -2' -one (67C)

spiro[cyclopropane-1,3'-indolin]-2'-one

3- (2-hydroxyethyl) indol-2-one (67B) (3g, 16.9mmol) was dissolved in 60mL of dichloromethane, triethylamine (6.5mL, 46.8mmol) was added, the temperature was reduced to 0 deg.C, methanesulfonyl chloride (1.51mL, 82.2mmol) was added dropwise, and the reaction was continued overnight with warming to room temperature. After the reaction, 100mL of water and 60mL of dichloromethane were added, the mixture was separated, the aqueous phase was extracted with 100mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was dried by spin-drying, and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1:0 to 20:1) to obtain spiro [ cyclopropyl-1, 3 '-indol ] -2' -one (67C) (1.6g, yield 59.7%) as a red solid.

LC-MS(m/z):160.2[M+1]⁺。

The third step: spiro [ cyclopropyl-1, 3' -indole ] (67D)

spiro[cyclopropane-1,3'-indoline]

Spiro [ cyclopropyl-1, 3 '-indol ] -2' -one (67C) was dissolved in 50mL of tetrahydrofuran, and lithium aluminum hydride (1.25g, 33mmol) was slowly added thereto, reacted at room temperature for 30 minutes, and then heated to 65 ℃ for 4 hours. After the reaction, the mixture was poured into 100mL of an ice-water bath, the pH was adjusted to 8 with an aqueous solution of sodium hydroxide, and 100mL of ethyl acetate was added for liquid separation. The aqueous phase was extracted with 100mL of ethyl acetate, the organic phases were combined, washed with 200mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was dried and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1:0 to 50:1) to give spiro [ cyclopropyl-1, 3' -indole ] (67D) (0.8g, yield 55.2%) as a brown oil.

LC-MS(m/z):146.2[M+1]⁺。

The fourth step: 1'- (2-Chloropyrimidin-4-yl) spiro [ cyclopropyl-1, 3' -indole ] (67E)

1'-(2-chloropyrimidin-4-yl)spiro[cyclopropane-1,3'-indoline]

Spiro [ cyclopropyl-1, 3' -indole ] (67D) (145.09mg, mmol) was dissolved in 10mL of dimethyl sulfoxide, potassium carbonate (276.4mg, 2mmol) and 2, 4-dichloropyrimidine (149mg, 1mmol) were added, and the mixture was raised to 80 ℃ and reacted for 1.5 hours. After completion of the reaction, 100mL of water and 100mL of ethyl acetate were added and the mixture was separated. The aqueous phase was extracted with 100mL of ethyl acetate, the organic phases were combined, washed with saturated brine (150mL), dried over anhydrous sodium sulfate, and the solvent was dried by rotary drying to give 1'- (2-chloropyrimidin-4-yl) spiro [ cyclopropyl-1, 3' -indole ] (67E) as a yellow solid (0.2g, 77.8% yield).

LC-MS(m/z):258.1[M+1]⁺。

The fifth step: n- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (spiro [ cyclopropyl-1, 3 '-indol ] -1' -yl) pyrimidin-2-amine (67F)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(spiro[cyclopropane-1,3'-indolin]-1'-yl)pyri midin-2-amine

1'- (2-Chloropyrimidin-4-yl) spiro [ cyclopropyl-1, 3' -indole ] (67E) (1g, 3.89mmol) was dissolved in 60mL 2-pentanol, 4-fluoro-2-methoxy-5-nitroaniline (4E) (724mg, 3.89mmol) and p-toluenesulfonic acid (0.887g, 4.67 mmol) were added, and the mixture was heated to 130 ℃ for reflux reaction for 6 hours. After the reaction, the solvent was dried by rotation, 150mL of water and 150mL of ethyl acetate were added, the mixture was separated, the aqueous phase was extracted with 150mL of ethyl acetate, the organic phases were combined, washed with saturated brine (200mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4:1 to dichloromethane/methanol ═ 10:1) to give N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (spiro [ cyclopropyl-1, 3 '-indol ] -1' -yl) pyrimidin-2-amine (67F) (1.2g, yield 95.2%) as a brown solid.

LC-MS(m/z):408.3[M+1]⁺。

And a sixth step: n is a radical of¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-2-nitro-N⁴- (4- (spiro [ cyclopropyl-1, 3' -indole)]-1' -yl) pyrimidin-2-yl) benzene-1, 4-diamine (67G)

N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-2-nitro-N4-(4-(spiro[cyclopropa ne-1,3'-indolin]-1'-yl)pyrimidin-2-yl)benzene-1,4-diamine

Reacting 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 5mL of N, N-dimethylacetamide, N, N-diisopropylethylamine (0.571g, 4.42mmol) and N, N, N' -trimethylethylenediamine (18A) (452mg, 4.42mmol) were added, and the reaction was carried out by microwave at 130 ℃ for 1.5 hours. After completion of the reaction, 150mL of water and 150mL of methylene chloride were added and the mixture was separated. The aqueous phase was extracted with 150mL of dichloromethane, the combined organic phases were washed with saturated brine (200mL), dried over anhydrous sodium sulfate, and concentrated to give N as a brown solid ¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-2-nitro-N⁴- (4- (spiro [ cyclopropyl-1, 3' -indole)]-1' -yl) pyrimidin-2-yl) benzene-1, 4-diamine (67G) (1.2G, 85.7% yield).

LC-MS(m/z):490.3[M+1]⁺。

The seventh step: n is a radical of¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (spiro [ cyclopropyl-1, 3' -indole)]-1' -yl) pyrimidin-2-yl) benzene-1, 2,4-, triamine (67H)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(spiro[cyclopropane-1,3'-in dolin]-1'-yl)pyrimidin-2-yl)benzene-1,2,4-triamine

Will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-2-nitro-N⁴- (4- (spiro [ cyclopropyl-1, 3' -indole)]-1' -yl) pyrimidin-2-yl) benzene-1, 4-diamine (67G) (1.2G, 2.45mmol) was dissolved in 24mL of ethanol, and 8mL of water, iron powder (0.822G, 14.7mmol) and ammonium chloride (92mg, 1.7mmol) were added in this order, and the mixture was heated to 90 ℃ and reacted for 4 hours under reflux. Concentrating the reaction solution, and separating and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-10: 1) to obtain brown solid N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (spiro [ cyclopropyl-1, 3' -indole)]-1' -yl) pyrimidin-2-yl) benzene-1, 2,4-, triamine (67H) (440mg, 40% yield).

LC-MS(m/z):460.4[M+1]⁺。

Eighth step: n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (spiro [ cyclopropyl-1, 3 '-indol ] -1' -yl) pyrimidin-2-yl) amino) phenyl) acrylamide (compound 67)

Will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (spiro [ cyclopropyl-1, 3' -indole)]-1' -yl) pyrimidin-2-yl) benzene-1, 2,4-, triamine (67H) (0.44g, 0.96mmol) was dissolved in 15mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.55g, 2.88mmol) and acrylic acid (0.1mL, 1.44mmol) were added in that order to react at room temperature for 4 hours. Drying pyridine, adding 4mol/L aqueous solution of sodium hydroxide (100mL) and 100mL of dichloromethane, separating liquid, extracting aqueous phase with dichloromethane (100mL), combining organic phase, washing with saturated aqueous solution of sodium chloride (100mL), drying with anhydrous sodium sulfate, separating and purifying by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0-10: 1) to obtain 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) (100mg, 20.3% yield).

LC-MS(m/z):514.3[M+1]⁺。

¹H 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-(dimethylami no)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The first step is as follows: 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 the mixture was reacted at room temperature for 20 minutes, and iodomethane (14.97g, 105.5mmol) was added and the reaction was allowed to react at room temperature for 3 hours. After the reaction, 100mL of water was added to quench the reaction. Most of the solvent was removed, and 100mL of ethyl acetate and 100mL of water were added to separate the layers. The aqueous phase was extracted with 100mL of ethyl acetate, and the organic phases were combined, washed with saturated brine (150mL), dried over anhydrous sodium sulfate, and concentrated to give 1-methyl-1H-indole-6-carbonitrile (68B) (5.4g) as a yellow solid.

The second step is that: 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) (5.4g, 34.6mmol) was dissolved in 40mL ethylene glycol dimethyl ether, 2, 4-dichloropyrimidine (5.15g, 34.6mmol) and aluminum trichloride (4.61g, 34.6mmol) were added, and the mixture was raised to 80 ℃ and reacted for 4 hours. After the reaction was complete, 100mL of water was added to precipitate a solid, which was filtered, the filter cake was washed with 150mL of water and dried by infrared lamp to give 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole-6-carbonitrile (68C) as a yellow solid (9g, 97.8% yield).

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-carbonitrile (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) (8g, 29.8mmol) was dissolved in 150mL 2-pentanol, 4-fluoro-2-methoxy-5-nitroaniline (4e) (5.55g, 29.8mmol) and p-toluenesulfonic acid monohydrate (6.82g, 35.9mmol) were added, and the reaction was heated to 120 ℃ for 2 days under reflux. Cooled to room temperature, 200mL of ammonia was added, the solid precipitated, filtered, and the filter cake washed with 200mL of water and 100mL of petroleum ether. Drying gave 3- (2- ((4-fluoro-2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1-methyl-1H-indole-6-carbonitrile (68D) as a brown solid (10g, 80.6% yield).

LC-MS(m/z):419.0[M+1]⁺。

The fourth step: 3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1-methyl-1H-indole-6-carbonitrile (68E)

3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)p yrimidin-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, and N, N-diisopropylethylamine (4.64g, 35.87mmol) and N, N, N' -trimethylethylenediamine (18A) (3.67g, 35.87mmol) were added and reacted at 130 ℃ for 1.5 hours under microwave. After the reaction, the mixture was concentrated. 200mL of water and 200mL of ethyl acetate were added, the layers were separated, the aqueous phase was extracted with 200mL of ethyl acetate, the organic phases were combined, washed with saturated brine (400mL), dried over anhydrous sodium sulfate, and concentrated to give 3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1-methyl-1H-indole-6-carbonitrile (68E) (10g, 84% yield) as a yellow solid.

LC-MS(m/z):501.1[M+1]⁺。

The fifth step: 3- (2- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) pyrimidin-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) (11g, 22mmol) was dissolved in 100mL of ethanol, 33mL of water, iron powder (7.37g, 132mmol) and ammonium chloride (824mg, 15.4mmol) were added in this order, and the mixture was heated to 90 ℃ for 6 hours under reflux. After the reaction, the reaction mixture was concentrated, and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1:0 to 10:1) to obtain 3- (2- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) pyrimidin-4-yl) -1-methyl-1H-indole-6-carbonitrile (68F) (6g, 58.3% yield) as a brown solid.

LC-MS(m/z):471.1[M+1]⁺。

And a sixth step: 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)

3- (2- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) pyrimidin-4-yl) -1-methyl-1H-indole-6-carbonitrile (68F) (6g, 12.7mmol) was dissolved in 50mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (7.3g, 38.2mmol) and acrylic acid (1.3mL, 19.1mmol) were added and reacted at room temperature for 4 hours. After the pyridine was dried by spinning, 200mL of methylene chloride and 4mol/L aqueous sodium hydroxide solution (200mL) were added to separate the solution. The aqueous phase was extracted with 200mL of dichloromethane, the organic phases were combined, washed with saturated sodium chloride (400mL), dried over anhydrous sodium sulfate, and purified by column chromatography on silica gel (dichloromethane/methanol (v/v) ═ 1:0 to 10:1) to give 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) (1.2g, 18.2% yield) as a yellow solid.

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-morpholinoethoxy) phenyl) acrylamide (compound 69)

N-(5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-m orpholinoethoxy)phenyl)acrylamide

The first step is as follows: 4- (1- (difluoromethyl) -1H-indol-3-yl) -N- (2-methoxy-4- (2-morpholinoethoxy) -5-nitrophenyl) pyrimidin-2-amine (69A)

4-(1-(difluoromethyl)-1H-indol-3-yl)-N-(2-methoxy-4-(2-morpholinoethoxy)-5-nitrop henyl)pyrimidin-2-amine

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 added slowly, the mixture was stirred for 30 minutes, 2-morpholinoethanol (611mg, 4.66mmol) was added, and the reaction was carried out at room temperature for 4 hours. After completion of the reaction, 150mL of water and 150mL of methylene chloride were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 4- (1- (difluoromethyl) -1H-indol-3-yl) -N- (2-methoxy-4- (2-morpholinoethoxy) -5-nitrophenyl) pyrimidin-2-amine (69A) (1.1g, 88% yield) as a yellow solid.

LC-MS(m/z):541.3[M+1]⁺。

The second step is that: n is a radical of¹- (4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-4- (2-morpholinoethoxy) benzene-1, 3-diamine (69B)

N¹-(4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-morpholino ethoxy)benzene-1,3-diamine

4- (1- (difluoromethyl) -1H-indol-3-yl) -N- (2-methoxy-4- (2-morpholinoethoxy) -5-nitrophenyl) pyrimidin-2-amine (69A) (1.1g, 2.03mmol) was dissolved in 30mL of ethanol, 10mL of water was added, iron powder (682mg, 12.2mmol) and ammonium chloride (76mg, 1.42mmol) were added, the temperature was raised to 90 ℃, the reaction was refluxed for 4H, and concentrated. Separating and purifying by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1: 0-10: 1) to obtain brown solid N ¹- (4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-4- (2-morpholinoethoxy) benzene-1, 3-diamine (69B) (1g, 97.1% yield)。

The third step: n- (5- ((4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2- (2-morpholinoethoxy) phenyl) acrylamide (compound 69)

Will N¹- (4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-4- (2-morpholinoethoxy) benzene-1, 3-diamine (69B) (1g, 1.96mmol) was dissolved in 30mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.12g, 5.88mmol) and acrylic acid (0.202mL, 2.94mmol) were added and the reaction was carried out at room temperature for 4 hours. The pyridine in the reaction solution was spin-dried, 150mL of water and 150mL of methylene chloride were added, and the mixture was separated. The organic phase was washed with 4mol/L aqueous sodium hydroxide (100mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) to give N- (5- ((4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2- (2-morpholinoethoxy) phenyl) acrylamide (compound 69) (400mg, yield 36.4%) as a white solid.

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)pyrimi din-2-yl)amino)-4-methoxyphenyl)acrylamide

The first step is as follows: (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-meth oxy-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, stirred for 30 minutes, and (1-hydroxymethylcyclopropyl) -tert-butoxycarbonylamino (873mg, 4.66mmol) was added and reacted at room temperature for 4 hours. After completion of the reaction, 150mL of water and 150mL of methylene chloride were added and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (1- ((4- ((4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxy-2-nitrophenoxy) methyl) cyclopropyl) carbamate (70A) (1g, 72.5% yield) as a yellow solid.

LC-MS(m/z):597.3[M+1]⁺。

The second step is that: (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)

tert-butyl(1-((2-amino-4-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino )-5-methoxyphenoxy)methyl)cyclopropyl)carbamate

Tert-butyl (1- ((4- ((4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxy-2-nitrophenoxy) methyl) cyclopropyl) carbamate (70A) (1g, 1.68mmol) was dissolved in 30mL of ethanol, 10 mL of water, iron powder (562mg, 10mmol) and ammonium chloride (63mg, 1.2mmol) were added, and the mixture was heated to 90 ℃ for 4 hours under reflux. The reaction solution was concentrated, and separated and purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 10:1) to give tert-butyl (1- ((2-amino-4- ((4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxybenzyl) methyl) cyclopropyl) carbamate (70B) (951mg) as a brown solid.

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-acrylamido-4-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)a mino)-5-methoxyphenoxy)methyl)cyclopropyl)carbamate

Tert-butyl (1- ((2-amino-4- ((4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxyphenyl) methyl) cyclopropyl) carbamate (70B) (951mg, 1.68mmol) was dissolved in 30mL of pyridine, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (963mg, 5.04mmol) and acrylic acid (0.173mL, 2.52mmol) were added and reacted at room temperature for 4 hours. The pyridine in the reaction solution was spin-dried, 150mL of water and 150mL of dichloromethane were added, and the mixture was separated. The organic phase was washed with 4mol/L aqueous sodium hydroxide (100mL), 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 tert-butyl 1- ((2-acrylamido-4- ((4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxyphenyl) methyl) cyclopropyl) carbamate (70C) as a yellow solid (800mg, 76.9% yield).

LC-MS(m/z):621.3[M+1]⁺。

The fourth step: n- (2- ((1-Aminocyclopropyl) methoxy) -5- ((4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 70)

Tert-butyl (1- ((2-acrylamido-4- ((4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -5-methoxyphenyl) methyl) cyclopropyl) carbamate (70C) (0.8g, 1.29mmol) was dissolved in 50mL of dichloromethane, and 20mL of trifluoroacetic acid was added and reacted at room temperature for 4 hours. Most of the solvent was removed by rotation, 100mL of water was added, the pH was adjusted to 8 with a saturated aqueous sodium bicarbonate solution, 150mL of dichloromethane was added, and the layers were separated. The aqueous phase was extracted with 100mL of dichloromethane, and the organic phases were combined and washed with 150mL of saturated aqueous sodium chloride solution. 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 10:1) to give N- (2- ((1-aminocyclopropyl) methoxy) -5- ((4- (1- (difluoromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (compound 70) as a white solid (370mg, 55.1% yield).

LC-MS(m/z):521.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)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

Serial passage tumor cells were trypsinized, suspended in culture medium, counted and plated into 96-well cell culture plates. Non-small cell lung cancer cell NCI-H1975 10000 cells per well, human epithelial cancer cell A431 cell line 10000 cells per well, 5% CO at 37 deg.C ₂Incubate overnight. On the next day, 6 wells of each cell were fixed by adding 30. mu.l of 50% trichloroacetic acid; the test compound was added to each of the remaining wells. Test compounds were prepared as solutions in DMSO at a maximum concentration of 10 μ M, and diluted 5-fold for 10 test concentrations as described below. For the NCI-H1975, A431 cell line, the assay was diluted with a gradient of medium containing 0.1% FBS and brought to a final concentration of 2-fold. The culture medium of a 96-well cell culture plate seeded with NCI-H1975, A431 cells was changed to fresh medium containing 0.1% FBS (100 ul per well), and 100ul of the test compound at 2-fold final concentration was added. Each 96-well cell culture plate was incubated at 37 ℃ with 5% CO₂The cell incubator was incubated for 72 hours. Then 50. mu.l of 50% trichloroacetic acid was added to each well and fixed in a refrigerator at 4 ℃ for 1 hour.

The trichloroacetic acid in each well was discarded and washed 5 times with 300. mu.l of double distilled water. After drying at room temperature, 50. mu.l of a 0.4% SRB (Sulforhodamine-B) dye solution (1% acetic acid/0.4% SRB) was added to each well and reacted for 15 min. The dye solution in each well was discarded, washed with 1% acetic acid 6-7 times, and dried at room temperature. To each well was added 200. mu.l of a 10mM Tris solution (pH 10.5), and the solution was dissolved with shaking. The absorbance at 490nm of each well was measured using a microplate reader. Calculation and analysis of the semi-effective Inhibitory Concentration (IC) of test compound using origin7.5, using readings from wells with test compound concentration of 0 as control ₅₀)。

Anti-tumor cell proliferation of the Compounds of the inventionReproductive Activity measured by the above assay, IC₅₀The values are shown in Table 1.

TABLE 1 test results of antitumor cell proliferation Activity

And (4) conclusion: the compound has obvious growth inhibition effect on non-small cell lung cancer cells NCI-H1975, and particularly the growth inhibition activity of the compound 20, the compound 33 and the like is less than 1 nM. The compound of the invention has obvious selectivity on the NCI-H1975 of the non-small cell lung cancer cells, and particularly, the growth inhibition activity of the compounds 16, 27, 30, 38, 40, 46, 47 and the like on the NCI-H1975 of the non-small cell lung cancer cells is more than 100 times of the growth inhibition activity on the A431 of the human epithelial cell cancer cells.

Claims

1. A compound of formula (I) and optical isomers, pharmaceutically acceptable salts or co-crystals thereof, wherein:

R¹each independently selected from F, Cl, Br, I, hydroxy, cyano, C_1-10Alkyl radical, C_1-10Alkoxy, -NR^1aR^1b、-C(＝O)C_1-10Alkyl, -S (═ O)₂-C_1-10Alkyl, -C (═ O) -3 to 15 membered heterocycle, -C (═ O) -C_3-15Carbocyclic ring, - (CH)₂)_n-3 to 15 membered heterocycle, - (CH)₂)_n-C_3-15Carbocyclic ring, -O- (CH)₂)_n-C_3-15Carbocyclic ring, -O- (CH)₂)_n-3 to 15 membered heterocycle, -O- (CH)₂)_n-C(＝O)C_1-6Alkyl, -O- (CH) ₂)_n-O-C(＝O)C_1-6Alkyl or-O- (CH)₂)_n-O-C_1-10Alkyl, said CH₂Alkyl, alkoxy, carbocycle or heterocycle is optionally further substituted by 0 to 5 groups selected from F, Cl, Br, I, ═ O, hydroxy, amino, cyano, nitro, C_1-6Alkyl radical, C_1-6Alkoxy, - (CH)₂)_n-OH、-(CH₂)_n-F、-C(＝O)C_1-6Alkoxy, -C (═ O) C_1-6Alkyl, -C (═ O) C_3-15Carbocyclic ring, -O-C (═ O) C_1-6Alkyl, - (CH)₂)_n-C_3-10Carbocyclic ring or- (CH)₂)_n-3 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from N, O, S or P;

R^1aand R^1bSelected from H or C_1-10An alkyl group;

R³selected from H, C_2-10Alkenyl radical, C_3-15Cycloalkyl radical, C_1-10Alkyl or C_1-10Alkoxy, said alkenyl, cycloalkyl, alkyl or alkoxy being optionally further selected from 0 to 4 groups selected from F, Cl, Br, I, C_1-6Alkyl or C_1-6Substituted by a substituent of alkoxy;

R⁴selected from H, F, Cl, Br, I, nitro, amino, C_1-10Alkyl, 5-to 15-membered spirocyclic, 4-to 15-membered fused cyclic, 3-to 10-membered heterocyclic, -NR^4cR^4d、-Z-(CH₂)_nR^4a、-O-(CH₂)_nR^4b、-Z-(CH₂)_nNR^4cR^4dor-O- (CH)₂)_nNR^4cR^4dSaid CH₂Spiro, fused or heterocyclic ring optionally further substituted by 0 to 4 substituents selected from F, Cl, Br,I. Hydroxy, amino, C _1-6Alkyl radical, C_1-6Alkoxy, - (CH)₂)_n-C(＝O)-R^4e、-(CH₂)_n-O-C(＝O)-R^4e、-NR^4cR^4dFrom 0 to 4R^4cSubstituted C_3-10Carbocyclic or substituted by 0 to 4R^4cSubstituted with a substituent of a substituted 3-to 10-membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O or S;

z is selected from-NH-or-N (C)_1-6Alkyl) -;

R^4eselected from amino, hydroxy, C_1-10Alkyl radical, C_3-15A carbocycle or a 3-to 15-membered heterocycle, said amino, alkyl, carbocycle or heterocycle being optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, amino, hydroxy, C _1-6Alkyl radical, C_1-6Alkoxy, -C (═ O) C_1-6Alkyl, -C (═ O) -NH₂、-O-C(＝O)C_1-6Alkyl or halogen substituted C_1-6Alkyl, said heterocycle containing 1 to 4 heteroatoms selected from N, O or S;

R⁵selected from H, F, Cl, Br, I or a 5 to 15 membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O or S, said heterocyclic ring optionally further substituted by 0 to 4 heteroatoms selected from F, Cl, Br, I, ═ O, -C (═ O) C_1-6Alkyl radical, C_1-6Alkyl or C_1-6Substituted by a substituent of alkoxy;

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

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

with the proviso that when-B- (R)¹)_fIs selected from

And R is²Selected from H, F, Cl, methyl or cyano, R³Selected from H, methoxy or methyl, f is 0 or 1, R⁵When is H, R⁴Is not H,

2. A compound according to claim 1, wherein:

R¹each independently selected from F, Cl, Br, I, hydroxy, cyano, C_1-4Alkyl radical, C_1-4Alkoxy, -NR^1aR^1b、-C(＝O)C_1-4Alkyl, -S (═ O)₂-C_1-4Alkyl, -C (═ O) -3 to 7 membered heterocycle, -C (═ O) -C_3-7Carbocyclic ring, - (CH)₂)_n-C_3-6Carbocyclic ring or- (CH)₂)_n-3 to 7 membered heterocycle, said CH₂Alkyl, alkoxy, carbocyclic or The heterocycle is optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, ═ O, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy, - (CH)₂)_n-OH、-(CH₂)_n-F、-C(＝O)C_1-4Alkoxy, -C (═ O) C_3-6Carbocyclic ring, -C (═ O) C_1-4Alkyl, - (CH)₂)_n-C_3-6Carbocyclic ring or- (CH)₂)_n-a 3 to 6 membered heterocyclic substituent, said heterocyclic ring containing 1 to 4 heteroatoms selected from N, O or S;

R^1aand R^1bSelected from H or C_1-4An alkyl group;

R³selected from H, C_2-6Alkenyl radical, C_3-6Cycloalkyl radical, C_1-4Alkyl or C_1-4Alkoxy, said alkenyl, cycloalkyl, alkyl or alkoxy being optionally further selected from 0 to 4 groups selected from F, Cl, Br, I, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R⁴selected from H, F, Cl, Br, I, 5-to 15-membered spirocyclic ring, 4-to 15-membered fused ring, 3-to 10-membered heterocyclic ring, -Z- (CH)₂)_nR^4a、-O-(CH₂)_nR^4b、-Z-(CH₂)_nNR^4cR^4dor-O- (CH)₂)_nNR^4cR^4dSaid heterocycle containing 1 to 4 heteroatoms selected from N, O or S, said CH₂Spiro, fused or heterocyclic ring optionally further substituted by 0 to 4 groups selected from F, Cl, Br, I, amino, hydroxy, C_1-4Alkyl, -NR^4cR^4d、-C(＝O)-R^4eOr C_1-4Substituted by a substituent of alkoxy;

z is selected from-NH-or-N (C)_1-4Alkyl) -;

R^4aIs selected from C_3-6A carbocyclic ring or a 3 to 7 membered heterocyclic ring containing 1 to 4 hetero atoms selected from N, O or SThe carbocycle or heterocycle is optionally further substituted by 0 to 4 atoms selected from F, Cl, Br, I, amino, hydroxy, C_1-4Alkyl radical, by 1 to 2C_1-4Substituted with a substituent of an alkyl-substituted amino group;

R^4bis selected from C_3-6A carbocycle or 3-to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, S, said carbocycle or heterocycle optionally further substituted with 0 to 4 heteroatoms selected from F, Cl, Br, I, amino, hydroxy, -NR^4cR^4d、C_1-4Alkyl or C substituted by 1 to 2 halogens_1-4Alkyl is substituted by a substituent;

R^4cand R^4dIs selected from H or C_1-4An alkyl group;

R⁵selected from H, F, Cl, Br, I or a 5 to 6 membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, S, said heterocyclic ring optionally further substituted with 0 to 4 heteroatoms selected from F, Cl, Br, I, ═ O, -C (═ O) C_1-4Alkyl radical, C_1-4Alkyl or C _1-4Substituted by a substituent of alkoxy;

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

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

3. A compound according to claim 2, wherein:

R¹each independently selected from F, Cl, Br, I, hydroxy, cyano, -S (═ O)₂-C_1-4Alkyl radical, C_1-4Alkyl, -C (═ O) -C_3-6Carbocyclic ring, - (CH)₂)_n-C_3-6Carbocyclic ring or- (CH)₂)_n-5 to 6 membered heterocycle, said CH₂Alkyl, carbocycle or heterocycle is optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, ═ O, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy, -CH₂-cyclopropyl, -tert-butoxycarbonyl, - (CH)₂)_n-OH、-(CH₂)_n-F、-C(＝O)C_1-4Alkyl, - (CH)₂)_n-C_3-6Carbocyclic ring or- (CH)₂)_n-a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from N, O or S;

R²selected from H, F, Cl, C_1-4Alkyl or C_1-4An alkoxy group;

R³is H, C_2-4Alkenyl radical, C_3-4Cycloalkyl radical, C_1-4Alkyl or C_1-4Alkoxy, optionally further substituted with 0 to 4 substituents selected from F, Cl or Br;

R⁴selected from H, F, Cl, 7-to 11-membered spirocyclic ring, 6-to 10-membered fused ring, 3-to 6-membered heterocyclic ring, -Z- (CH)₂)_nR^4a、-Z-(CH₂)_nNR^4cR^4d、-O-(CH₂)_nR^4bor-O- (CH)₂)_nNR^4cR^4dSaid heterocycle containing 1 to 4 heteroatoms selected from N, O or S, said CH ₂Spiro, fused or heterocyclic ring optionally further substituted by 0 to 4 groups selected from F, Cl, Br, I, amino, -NH (CH)₃)、-N(CH₃)₂Methyl or ethyl;

z is selected from-NH-or-N (C)_1-4Alkyl) -;

R^4ais selected from C_3-4A carbocycle or 5-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, S, said carbocycle or heterocycle optionally further substituted with 0 to 4 heteroatoms selected from F, Cl, Br, I, amino, hydroxy, -NHCH₃、-N(CH₃)₂Methyl or ethyl;

R^4bis selected from C_3-4Carbocyclic ring or 4 to 6 membered heterocyclic ring, said heterocyclic ringContaining 1 to 4 heteroatoms selected from N, O, S, said carbocyclic or heterocyclic ring being optionally further substituted by 0 to 4 heteroatoms selected from F, Cl, Br, I, amino, hydroxy, -NH (CH)₃)、-N(CH₃)₂、-CH₂CH₂F. Methyl or ethyl;

R^4cand R^4dSelected from H, methyl or ethyl;

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

4. A compound according to claim 3, wherein:

b is selected from

R¹Each independently selected from F, Cl, Br, I, -S (═ O) ₂CH₃-C (═ O) -cyclopropyl, hydroxy, cyano, methyl, ethyl, isopropyl, cyclopropyl, -CH₂-cyclopropyl, -CH (CH)₃) -cyclopropyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl, said methyl, ethyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl being optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, ═ O, hydroxy, methyl, ethyl, methoxy, isopropyl, cyclopropyl, -CH₂-cyclopropyl, hydroxyethyl, 2-fluoroethyl, tert-butoxycarbonyl, oxetanyl, -C (═ O) CH₃or-C (═ O) CH₂CH₃Substituted with the substituent(s);

R²selected from H, F, Cl, methyl or methoxy;

R³selected from H, methyl, ethyl, vinyl, cyclopropyl, methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy;

R⁴selected from H, F, Cl, 7-to 11-membered spirocyclic ring, 3-to 6-membered heterocyclic ring, -Z- (CH)₂)_nR^4a、-O-(CH₂)_nR^4b、-Z-(CH₂)_nNR^4cR^4dor-O- (CH)₂)_nNR^4cR^4dSaid heterocycle containing 1 to 4 heteroatoms selected from N, O or S, said CH₂Spiro or heterocycle optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, methyl, ethyl or-N (CH)₃)₂Substituted with the substituent(s);

z is selected from-NH-or-N (CH)₃)-；

R^4aSelected from substituted or unsubstituted cyclopropyl or tetrahydropyrrolyl, when substituted, optionally further substituted by 1 to 4 substituents selected from F, Cl, Br, I, amino, hydroxy, -NHCH ₃、-N(CH₃)₂Methyl or ethyl;

R^4bselected from substituted or unsubstituted cyclopropyl,

Tetrahydropyrrolyl, piperazinyl, piperidinyl or morpholinyl, when substituted, optionally further substituted by 1 to 4 substituents selected from F, Cl, Br, I, amino, hydroxy, -NHCH₃、-N(CH₃)₂、-CH₂CH₂F. Methyl or ethyl;

R^4cand R^4dSelected from H, methyl or ethyl;

R⁵selected from H, F, Cl or morpholinyl;

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

5. A compound according to claim 4, wherein:

b is selected from

Morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl;

R²selected from H, F, Cl, methyl or methoxy;

R³selected from H, ethyl, methoxy or difluoromethoxy;

R⁴selected from H, F, Cl,

R⁵Selected from H, F, Cl or morpholinyl;

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

6. A compound according to claim 1, wherein the compound is selected from one of the following structures:

7. the compound of any one of claims 1 to 6, and optical isomers, pharmaceutically acceptable salts or co-crystals thereof, wherein the salts are selected from hydrochloride, sulfate, phosphate, acetate, trifluoroacetate, fumarate, benzoate, benzenesulfonate, methanesulfonate, trifluoromethanesulfonate or combinations thereof.

8. 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 a co-crystal thereof, and a pharmaceutically acceptable carrier or excipient.

9. Use of a compound as claimed in any one of claims 1 to 7, and an optical isomer, a pharmaceutically acceptable salt or a co-crystal thereof, or a pharmaceutical composition as claimed in claim 8, in the preparation of a medicament for the treatment of cancer.

10. The use of claim 9, wherein the cancer comprises head and neck cancer, ovarian cancer, bladder cancer, cervical cancer, esophageal cancer, gastric cancer, breast cancer, intimal cancer, colon cancer, lung cancer, brain tumor, non-small cell lung cancer, pancreatic cancer, solid tumor, colorectal tumor, or glioblastoma.

11. A method of 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 co-crystal thereof, or a pharmaceutical composition according to claim 8.

12. The method of claim 11, wherein the cancer comprises head and neck cancer, ovarian cancer, bladder cancer, cervical cancer, esophageal cancer, gastric cancer, breast cancer, intimal cancer, colon cancer, lung cancer, brain tumor, non-small cell lung cancer, pancreatic cancer, solid tumor, colorectal tumor, or glioblastoma.