WO2019242689A1 - Cyano-substituted pyridine and cyano-substituted pyrimidine compound, and preparation method and application thereof - Google Patents

Abstract

Provided is a compound as shown in formula (I), an isomer thereof, hydrate thereof, solvate thereof, pharmaceutically acceptable salt thereof, and prodrug thereof, and a preparation method and use of same in the preparation of a drug as a kinase inhibitor. The compound has good inhibitory activity against FGFR4, mutant FGFR4 V550L, and other kinases.

Description

Cyano-substituted pyridine and cyano-substituted pyrimidine compounds, preparation method and application thereof Technical field

The invention relates to a cyano-substituted pyridine and a cyano-substituted pyrimidine compound, a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof, and a preparation method and application thereof.

Background technique

FGFR activation mutation or expansion in cells can lead to excessive activation of the FGF-FGFR signaling pathway, allowing cells to obtain oncogenic properties such as excessive proliferation, escape from apoptosis, and easy migration, so FGFRs can be used as targets for direct or indirect tumor treatment. FGFR is mainly divided into 4 subtypes, namely FGFR1, FGFR2, FGFR3 and FGFR4. Each subtype has the general structural characteristics of receptor tyrosine kinases: extracellular domains that bind to ligands, transmembrane domains, and intracellular domains that are phosphorylated by receptors. When the ligand specifically binds to the receptor, it induces FGFR autophosphorylation and then dimerizes, causing its domain to change from an inactive state to an active state. Activated FGFR is in close proximity to intracellular kinases and phosphorylates each other, thereby activating a series of downstream related signaling pathways, and ultimately stimulating cell proliferation, differentiation, and inhibiting apoptosis. Because FGFR plays an important role in the development of tumors, targeted therapy for FGFR has become a hot area of clinical research. Existing drugs that target FGFR can be divided into two categories according to their source: the first is a small chemical inhibitor, which can competitively or noncompetitively bind to the FGFR intracellular kinase domain and inhibit FGFR itself Ability to phosphorylate, dimerize, and catalyze phosphorylation of downstream proteins, thereby inhibiting the FGFR signaling pathway. The second type is a biological monoclonal antibody or a polypeptide inhibitor, which can bind to the extracellular region of FGFR, prevent the binding of FGF and FGFR, thereby inhibiting FGFR activation and blocking the transduction of FGFR signals (Seiji Mori, Yoshikazu Takada, Med .Sci. 2013, 1, 20-36).

Small molecule tyrosine kinase inhibitors block cell proliferation signals by blocking the activity of intracellular kinase binding to ATP. Because the structures of the FGFR1, FGFR2, and FGFR3 kinase domains are similar, the inhibitors developed for these three kinases are not much different at this stage. However, there are some differences between the FGFR4 kinase domain and the FGFR1-3 kinase domain, so many can effectively inhibit FGFR1 -3 inhibitors do not work well on FGFR4. For example, AZD-4547, Infigratinib, CH-5183284, E-7090, BAY-1163877, INCB-54828, etc., which have been in clinical trials in recent years, are targeted at the FGFR1 / 2/3 target, and FGF-401, BLU-554 are targeted at Is the FGFR4 target. Small molecule FGFR inhibitors can be divided into: 1) ATP competitive reversible inhibitors, 2) covalently bound irreversible inhibitors, 3) ATP non-competitive inhibitors (Wu Daichao et al., Cancer Research 2017, 44 (1): 61-65).

AZD-4547 is a small molecule selective ATP competitive reversible inhibitor that linearly interacts with FGFR. From the protein-ligand complex co-crystal structure of FGFR1 / AZD-4547, it can be seen that the 3-aminopyrazole parent ring of AZD-4547 has 3 hydrogen bonds with Ala564 and Glu562 in the hinge region. The methoxyphenyl side chain extends into the hydrophobic pocket inward of the hinge region, and the para-chiral piperazine-substituted benzoyl group undergoes a hydrophilic or hydrophobic interaction with the near-solvent terminal domain extending outside the hinge region. Under these effects, the entire molecule is inserted into the ATP-binding region of FGFR1 in a linear form, tightly binding to the FGFR1 protein. Compounds with similar linear effects also include BGJ-398, CH-5183284 and ASP-5878.

JNJ-42756493 interacts with FGFR in a small T-type selective ATP competitive reversible inhibitor. As can be seen from the co-crystal structure of JNJ-42756493 / FGFR1, the N-position of quinoxaline parent ring of Ala564 forms a hydrogen bond, and the 3,5-dimethoxyphenyl side chain occupies the hydrophobic pocket inward of the hinge region, while the isopropylamine side chain and the pocket downward in the hinge region have a hydrophilic or hydrophobic effect. NH also has a hydrogen bond with Asp641.

Since the hinge region of the protein ATP binding site has a different cysteine residue from FGFR1, 2 and 3, FGFR1, 2 and 3 are tyrosine residues. Based on this small structural difference, a PDG inhibitor PD173074, which has nanomolar inhibitory activity, was found. Based on this, 2-aminoquinazoline derivatives that specifically inhibit FGFR4 were found. When the amino β When a substituent of acrylamide was introduced at the position, the compound BLU-9931 was obtained. It was found that the acrylamide can produce irreversible covalent binding with Cys552 of FGFR4. Its IC ₅₀ for FGFR4 inhibitory activity is 3nmol / L, and its selectivity is higher than that of FGFR1. / 2/3 are 297, 184, and 50 times higher, respectively. Through further structural optimization of BLU-9931, BLU-554 was found to be a selective FGFR4 covalent irreversible inhibitor. In September 2015, it was approved by the FDA for clinical trials for treating hepatocellular carcinoma. TAS-120 and PRN-1371 are also FGFR covalent inhibitors, and their enzyme inhibitory activity on each subtype of FGFR can reach nanomolar level.

ARQ-087 is a non-ATP-competitive inhibitor. Its selectivity to FGFR1, 2 and 3 is more than eight times greater than that of FGFR4.

Changes in FGFR have been linked to a variety of human cancers, including myeloma, breast cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, and hepatocellular carcinoma. FGFR small molecule inhibitors can be divided into pan-FGFR and FGFR4-specific small molecule inhibitors. Due to the similar structure of the FGFR1, FGFR2, and FGFR3 kinase domains, the inhibitors developed for these three kinases at the current stage have similar effects. FGFR4 has been reported to play an important role especially in liver cancer (PLoS One, 2012, Volume 7, 36713). There are some differences between FGFR4 kinase domain and FGFR1-3 kinase domain, so many inhibitors that can effectively inhibit FGFR1-3 have a poor effect on FGFR4.

In order to improve the selectivity of small molecule inhibitors to the FGFR4 kinase domain and reduce adverse reactions, H3 Biomedicine has patented WO20152015938938A120150423Pyrimidines and FGFR4inhibitors and their preparation and WO2015057963A120150423N-Aryl-heteroarylamines FGFR4-specific inhibitors were disclosed, of which H3B-6527 has entered the FDA's Phase I clinical stage and obtained orphan drug qualification. Its structure is as follows:

H3B6527 has strong antitumor activity on FGF19 gene-amplified cells, and has no bile acid-related adverse reactions in animal models of mice and monkeys. However, single administration of H3B-6527 only controls the growth of cancer cells and cannot clear cancer cells (Cancer Res; 77 (24) December 15, 2017). The resistance of H3B-6527 to V550L or V550 mutations at key sites reduces or invalidates the efficacy. How to break through the restriction of these mutations leading to drug resistance will become the focus of the next phase of FGFR4 inhibitor research.

Inhibitors targeting the FGFR4 target have many advantages, especially their excellent selectivity and resistance to mutation. There are few drugs currently on the market. Therefore, it is found that such small molecule inhibitors targeting FGFR4 will have better therapeutic effects and application prospects. The development of a new, highly selective and potent inhibitor of FGFR4 has become an urgent problem in the clinic.

Summary of the Invention

The compound represented by formula (I) provided by the present invention is a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof, which can be used to treat or prevent diseases caused by tyrosine kinase FGFR4. Including certain variants of the tyrosine kinase FGFR4 receptor.

In formula (I),

X is N or CH;

Y is N or C-M, where M is -H, -F, -Cl, methyl, methoxy;

Z is N or C-R,

Where R is -H, -F, -Cl, hydroxyl, amino, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, mono- or di-C ₁ -C ₃ Alkyl substituted amino, substituted or unsubstituted 4-6 membered heterocyclyl, or the following groups:

m is 2 or 3,

R ^a is amino, C ₁ -C ₃ alkoxy, mono- or bis C ₁ -C ₃ alkyl substituted amine,

R ^b is -H, C ₁ -C ₃ alkyl,

The substituted or unsubstituted 4-6 membered heterocyclic group described in R contains 1-2 heteroatoms selected from N, O or S. The substituted 4-6 membered heterocyclic group is independently Or different substituents selected from the group consisting of hydroxy, amino, cyano, formyl, acetyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, mono- or di-C ₁ -C ₃ Alkylamino

R ¹ is -H, a substituted or unsubstituted 4-6 membered heterocyclic group, or -LR ³ ,

Where L is L ₁ or L ₂ ,

n1为0-4的整数， L ₁ is:

n1 is an integer from 0 to 4,

L ₂ is:

n2 is an integer from 0-3, n3 is an integer from 0-2,

R ⁴ is -H or C ₁ -C ₃ alkyl,

The 4- to 6-membered heterocyclic group in R ¹ contains 1-2 heteroatoms selected from N, O or S, and the substituted 4-to-6-membered heterocyclic group is independently selected from 1-2 selected from hydroxyl, halogen , C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy,

R ³ is -H, C ₁ -C ₈ alkyl, halo C ₂ -C ₄ alkyl, hydroxy substituted C ₂ -C ₄ alkyl, cyano substituted C ₂ -C ₄ alkyl, carboxy substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy substituted C ₂ -C ₄ alkyl, bridged ring structure, substituted or unsubstituted fused ring structure, substituted or unsubstituted C ₃ -C ₈ ring Alkyl, substituted or unsubstituted 4-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted aryl,

The bridge ring structure in R ³ is a bridge ring structure of C ₅ -C ₁₁ ,

The substituted or unsubstituted fused ring structure described in R ³ is selected from the group consisting of an aromatic ring and a 5-6 membered heteroaryl group, a 5-6 membered heteroaryl ring and a 5-6 membered heteroaryl ring group, and an aromatic ring and a 5-6 membered ring. Cycloalkyl, aromatic ring and 5-6 membered heterocyclic group, 5-6 membered heteroaromatic ring and 5-6 membered heterocyclic ring or 5-6 membered heteroaryl ring and 5-6 membered heterocyclic group, substituted fused The substituent of the ring structure is selected from the group consisting of halogen, hydroxy, cyano, carbamoyl, C ₁ -C ₃ methoxy, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₃ -C ₄ cycloalkyl substituted C ₁ -C ₃ alkyl, hydroxy substituted C ₂ -C ₄ alkyl, C ₁ -C ₃ methoxy substituted C ₂ -C ₄ alkyl, cyano substituted C ₁ -C ₃ alkyl, carbamoyl substituted C ₁ -C ₃ alkyl,

The substituted C ₃ -C ₈ cycloalkyl described in R ³ is independently substituted by 1-2 identical or different substituents, the substituents being selected from halogen, hydroxyl, cyano, C ₁ -C ₃ alkoxy , C ₁ -C ₃ alkyl,

The 4- to 6-membered heteroaryl and 5- to 6-membered heteroaryl in R ³ contain 1-2 heteroatoms selected from N, O or S,

The substituted 4-6 membered heterocyclic group described in R ³ is independently substituted by 1-2 identical or different substituents, and the substituents are selected from halogen, hydroxyl, cyano, and C ₁ -C ₃ alkoxy , C ₁ -C ₃ alkyl, formyl, acetyl, carbamoyl, methylaminoformyl, dimethylaminoformyl,

The substituted aryl and 5- to 6-membered heteroaryl described in R ³ are independently substituted by 1-4 identical or different substituents, and the substituents are selected from halogen, hydroxyl, amino, cyano, carboxyl, and fluorine Methoxy, difluoromethoxy, trifluoromethoxy, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₃ alkynyl , C ₂ -C ₃ alkenyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, mono- or bis C ₁ -C ₃ alkylamino, C ₃ -C ₄ cycloalkyloxy, C ₃ -C ₄ cycloalkyl substituted C ₁ -C ₃ alkyl, cyano substituted C ₁ -C ₃ alkyl, carbamoyl substituted C ₁ -C ₃ alkyl, or the following groups:

q is an integer of 2-3,

R ^s is -H, C ₁ -C ₃ alkyl, R ^p is -H, C ₁ -C ₃ alkyl,

R ′ and R ″ are each independently -H, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl,

R ⁵ is -H, halogen, hydroxy, cyano, amino, carboxyl, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₃ alkoxy, mono- or di-C ₁ -C ₃ alkyl substituted amine groups;

R ² is -L ₃ -R ⁶ or -L ₄ -R ⁷ ,

L ₃ is:

L ₄ is:

p1 is an integer of 0-4, p2 is an integer of 2-4, p3 is an integer of 0-1,

R ^p is -H or C ₁ -C ₃ alkyl,

R ⁶ is -H, halogen, hydroxyl, amino, cyano, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, mono- or di-C ₁ -C ₃ alkylamino, substituted or unsubstituted 4-6 membered heterocyclic ring base,

The 4- to 6-membered heterocyclic group described in R ⁶ contains 1-2 heteroatoms selected from N, O or S, and the substituted 4-6-membered heterocyclic group is independently substituted with 1-2 identical or different substituents, respectively. Substituted or oxo, the substituent of the 4- to 6-membered heterocyclic group is selected from the group consisting of hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkoxy, formyl, acetyl, propionyl, Isopropyl, hydroxy-substituted C ₁ -C ₃ alkyl, carboxy-substituted C ₁ -C ₃ alkyl, or -NR ⁸ R ⁹ ,

R ⁸ and R ⁹ are each independently -H, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, hydroxyl substituted C ₂ -C ₃ alkyl, cyano substituted C ₁ -C ₂ alkyl Group, C ₁ -C ₃ alkoxy-substituted C ₂ -C ₃ alkyl group, or R ⁸ , R ⁹ and the nitrogen atom to which it is attached form a substituted or unsubstituted 4-6 membered heterocyclic group,

The 4- to 6-membered heterocyclic group described in R ⁸ and R ⁹ contains 1-2 heteroatoms selected from N, O or S, and the substituent of the substituted 4- to 6-membered heterocyclic group is selected from -H, hydroxyl, Cyano, amino, formyl, acetyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, mono- or bis C ₁ -C ₃ alkylamino, hydroxy-substituted C ₂ -C ₃ alkyl ,

R ⁷ is -H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclic group,

The 4- to 6-membered heterocyclic group in R ⁷ contains 1-2 heteroatoms selected from N, O or S, and the 4- to 6-membered heterocyclic group is unsubstituted or independently 1-2 Substituted by hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, formyl, acetyl, propionyl, isopropyl.

In a preferred embodiment, Z is N or C-R,

Where R is -H, F, Cl, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, Propoxy, isopropoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, substituted or unsubstituted 4-6 Heterocyclic group, or the following group:

m is 2 or 3,

R ^a is -H, methoxy, ethoxy, propoxy, isopropoxy, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,

R ^b is -H, methyl, ethyl,

The substituted or unsubstituted 4-6 membered heterocyclic group described in R is selected from the following groups:

R ^{10 is} selected from -H, methyl, ethyl, propyl, isopropyl,

R ¹¹ and R ¹² are each independently selected from -H, -F, hydroxyl, cyano, methyl, and ethyl.

In a preferred embodiment, R ¹ is -H, a substituted or unsubstituted 4-6 membered heterocyclic group, or -LR ³ , wherein L is L ₁ or L ₂ ,

L ₁ is:

n1 is an integer from 0 to 3;

L ₂ is:

n2 is an integer from 0-2, n3 is an integer from 0-1,

R ⁴ is -H or methyl;

The substituted or unsubstituted 4-6 membered heterocyclic group in R ¹ is selected from the following groups:

R ¹³ and R ¹⁴ are each independently selected from -H, -F, hydroxyl, cyano, methyl, ethyl, and methoxy;

R ³ is -H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, hydroxyethyl, hydroxypropyl , Cyanoethyl, cyanopropyl, carboxyethyl, carboxypropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, Isopropoxypropyl, fluoroethyl, difluoroethyl, trifluoroethyl, 2-hydroxypropyl, 2-methoxypropyl, or the following groups:

Wherein R ^{15 is} selected from -H, methyl, ethyl, propyl, isopropyl,

R ¹⁶ , R ¹⁷ , R ¹⁸ , and R ¹⁹ are each independently selected from -H, -F, -Cl, -Br, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, and tert-butyl. Methyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, methylthio, ethylthio, propylthio, isopropylthio, fluoromethyl Methyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethynyl, vinyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclo Butylmethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, or the following groups:

q is an integer of 2-3,

R ^s is -H, methyl, ethyl, R ^p is -H, methyl, ethyl,

R ′ and R ″ are independently -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl,

R ⁵ is -H, -F, hydroxyl, cyano, carboxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamine Group, ethylamino group, dimethylamino group;

R ²⁰ is -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, hydroxy Ethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, methoxybutyl, cyanomethyl, cyanoethyl, cyanopropyl, carbamoylmethyl, Carbamoylethyl, carbamoylpropyl,

R ²¹ and R ²² are each independently -H, -F, hydroxyl, cyano, methyl, ethyl, methoxy, or ethoxy.

In a preferred embodiment, R ² is -L ³ -R ⁶ or -L ⁴ -R ⁷ ,

L ³ is:

p1 is an integer of 0-3, and p2 is an integer of 2-3;

L ⁴ is:

p3 is an integer of 0-1,

R ^p is -H, methyl, ethyl;

R ⁶ is -H, F, -Cl, hydroxyl, amino, cyano, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, propyl, butyl, hexyl, iso Propyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, isopropyl Oxy, methylthio, ethylthio, propylthio, isopropylthio, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, N-methyl-N-ethyl Amine, substituted or unsubstituted 4-6 membered heterocyclyl,

The substituted or unsubstituted 4-6 membered heterocyclic group described in R ⁶ is selected from the following groups:

R ²³ is -H, -F, methyl, ethyl,

R ²⁴ is -H, -F, hydroxyl, hydroxymethyl, cyano, methyl, ethyl, methoxy, or -NR ²⁶ R ²⁷ ,

R ²⁶ and R ²⁷ are each independently -H, methyl, ethyl, propyl, isopropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, methoxyethyl, and methyl Oxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, cyclopropyl, cyclobutyl, or the nitrogen atom to which R ²⁶ or R ²⁷ is attached The substituted or unsubstituted 4-6 membered heterocyclic group is selected from the following groups:

R ²⁸ is -H, methyl, ethyl, formyl, acetyl,

R ²⁹ is -H, methyl, ethyl,

R ³⁰ is -H, hydroxyl, amino, methylamino, dimethylamino, hydroxymethyl, cyano, methyl, ethyl, methoxy,

R ²⁵ is -H, methyl, ethyl, propyl, isopropyl, formyl, acetyl, propanoyl, isopropyl, carboxymethyl, carboxyethyl, hydroxyethyl, hydroxypropyl,

R ^s1 and R ^s2 are independently H and methyl;

R ⁷ is -H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted 4-6 Membered heterocyclic group, the substituted or unsubstituted 4-6 membered heterocyclic group is selected from the following groups:

In a further preferred embodiment, R ¹ is -H, a substituted or unsubstituted 4-6 membered heterocyclic group, or -LR ³ , wherein L is L ₁ or L ₂ ,

n1为0-2的整数； L ₁ is:

n1 is an integer from 0-2;

L ₂ is:

n2 is an integer from 0-2, n3 is an integer from 0-1,

R ⁴ is -H or methyl;

R ¹ is -L ₁ -R ³ or -L ₂ -R ³ , wherein -L ₁ -R ³ is preferably from the following groups:

R ²⁰ is -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, hydroxy Ethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, methoxybutyl, cyanomethyl, cyanoethyl, cyanopropyl, carbamoylmethyl, Carbamoylethyl, carbamoylpropyl.

In a further preferred embodiment, R ¹ is -H, a substituted or unsubstituted 4-6 membered heterocyclic group, or -LR ³ , wherein L is L ₁ or L ₂ ,

n1为0-2的整数； L ₁ is:

n1 is an integer from 0-2;

L ₂ is:

n2 is an integer from 0-2, n3 is an integer from 0-1,

R ⁴ is -H or methyl;

R ¹ is -L ₁ -R ³ or -L ₂ -R ³ ,

Wherein -L ₂ -R ³ wherein R ³ is selected from: -H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl , Hexyl, hydroxyethyl, cyanoethyl, methoxyethyl, fluoroethyl, difluoroethyl, trifluoroethyl, 2-hydroxypropyl, 2-methoxypropyl, or the following groups :

Wherein R ^{15 is} selected from -H, methyl, ethyl,

R ¹⁶ , R ¹⁷ , R ¹⁸ , and R ¹⁹ are each independently selected from -H, -F, -Cl, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, tert-butyl, and methyl. Oxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, methylthio, ethylthio, propylthio, isopropylthio, fluoromethyl, di Fluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethynyl, vinyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, Amino, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, or the following groups:

q is an integer of 2-3,

R ^s is H, methyl, ethyl, R ^p is -H, methyl, ethyl,

R ′ and R ″ are each independently -H, methyl, ethyl, propyl, isopropyl, cyclopropyl,

R ⁵ is -H, -F, hydroxyl, cyano, carboxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamine Group, ethylamino group, dimethylamino group,

R ²⁰ is -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, hydroxy Ethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, methoxybutyl, cyanomethyl, cyanoethyl, cyanopropyl, carbamoylmethyl, Carbamoylethyl, carbamoylpropyl,

R ²¹ and R ²² are each independently -H, -F, hydroxyl, methyl, ethyl, or methoxy.

According to one aspect of the present invention, there is provided a compound represented by formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, and a prodrug thereof,

In formula (I),

X is N or CH;

Y is N or C-M, where M is -H, -F, -Cl, methyl or methoxy;

Z is N or C-R,

Where R is -H, -F, -Cl, hydroxyl, amino, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, mono- or di-C ₁ -C ₃ Alkyl substituted amino, substituted or unsubstituted 4-6 membered heterocyclyl, or the following groups:

m is 2 or 3,

R ^a is amino, C ₁ -C ₃ alkoxy, mono- or bis C ₁ -C ₃ alkyl substituted amine,

R ^b is -H, or C ₁ -C ₃ alkyl,

The substituted or unsubstituted 4-6 membered heterocyclic group described in R contains 1-2 heteroatoms selected from N, O or S. The substituted 4-6 membered heterocyclic group is independently Or different substituents selected from the group consisting of halogen, hydroxy, amino, cyano, formyl, acetyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, mono or bis C _1- C ₃ alkylamino;

R ¹ is -LR ³ ,

Where L is L ₁ or L ₂ ,

n1为0-4的整数， L ₁ is:

n1 is an integer from 0 to 4,

L _{2 is} selected from:

n2 is an integer from 0 to 3, n3 is an integer from 0 to 2, R ⁴ is -H or C ₁ -C ₃ alkyl,

R ^{3 is} selected from a substituted or unsubstituted fused ring structure, a substituted or unsubstituted 5-6 membered heteroaryl group, a substituted or unsubstituted aryl group,

The substituted or unsubstituted fused ring structure described in R ³ is selected from the group consisting of an aromatic ring and a 5-6 membered heteroaromatic ring, a 5-6 membered heteroaryl ring and a 5-6 membered heteroaromatic ring, and an aromatic ring and a 5-6 membered carbon. Ring, aromatic ring and 5-6 membered heterocyclic ring, 5-6 membered heteroaromatic ring and 5-6 membered carbocyclic ring or 5-6 membered heteroaromatic ring and 5-6 membered heterocyclic ring, substituted substituents of fused ring structure Selected from halogen, hydroxy, cyano, carbamoyl, C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₃ -C ₄ cycloalkyl Substituted C ₁ -C ₃ alkyl, hydroxy substituted C ₂ -C ₄ alkyl, C ₁ -C ₃ alkoxy substituted C ₂ -C ₄ alkyl, cyano substituted C ₁ -C ₃ alkyl , Carbamoyl-substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl-OCO-substituted C ₁ -C ₃ alkyl, amino, mono- or di-C ₁ -C ₃ alkyl-substituted amino , Amino substituted C ₁ -C ₃ alkyl,

The 5-6 membered heteroaryl group in R ³ contains 1-2 heteroatoms selected from N, O or S,

The substituted aryl and 5- to 6-membered heteroaryl described in R ³ are independently substituted with 1-4 identical or different substituents, which are selected from halogen, hydroxyl, amino, cyano, carboxyl, Fluoromethoxy, difluoromethoxy, trifluoromethoxy, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₃ alkyne Alkyl, C ₂ -C ₃ alkenyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, mono- or bis C ₁ -C ₃ alkylamino, C ₃ -C ₄ cycloalkyloxy , C ₃ -C ₄ cycloalkyl substituted C ₁ -C ₃ alkyl, cyano substituted C ₁ -C ₃ alkyl, carbamoyl substituted C ₁ -C ₃ alkyl, hydroxy substituted C _1- C ₃ alkyl, C ₁ -C ₃ alkoxy substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl-OCO-substituted C ₁ -C ₃ alkyl, or the following groups:

q is an integer of 2-3,

R ^{s is} selected from -H, C ₁ -C ₃ alkyl, R ^{p is} selected from -H, C ₁ -C ₃ alkyl,

R ′ and R ″ are each independently -H, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl,

R ^{5 is} selected from -H, halogen, hydroxy, cyano, amino, carboxyl, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₃ alkoxy, mono- or di-C _1- C ₃ alkyl substituted amine groups;

R ² is -L ₃ -R ⁶ ,

L ₃ is:

p1 is an integer from 0-4, p2 is an integer from 0-4,

R ^p is -H or C ₁ -C ₃ alkyl,

R ^{6 is} selected from -H, halogen, hydroxyl, amino, cyano, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl , C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, mono- or di-C ₁ -C ₃ alkylamino, substituted or unsubstituted 4-6 membered hetero Ring base,

The 4- to 6-membered heterocyclic group described in R ⁶ contains 1-2 heteroatoms selected from N, O or S. The substituted 4- to 6-membered heterocyclic group is substituted with 1-2 same or different substituents. And / or oxo, the substituent of the 4- to 6-membered heterocyclic group is selected from the group consisting of hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkoxy, formyl, acetyl, propionyl, iso Propionyl, hydroxy-substituted C ₁ -C ₃ alkyl, carboxy-substituted C ₁ -C ₃ alkyl, or -NR ⁸ R ⁹ ,

R ⁸ and R ⁹ are each independently selected from -H, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, hydroxy substituted C ₂ -C ₃ alkyl, cyano substituted C ₁ -C ₂ Alkyl, C ₁ -C ₃ alkoxy-substituted C ₂ -C ₃ alkyl, or R ⁸ , R ⁹ and the nitrogen atom to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclic group,

The 4- to 6-membered heterocyclic group described in R ⁸ and R ⁹ contains 1-2 heteroatoms selected from N, O or S, and the substituent of the substituted 4- to 6-membered heterocyclic group is selected from -H, hydroxyl, Cyano, amino, formyl, acetyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, mono- or bis C ₁ -C ₃ alkylamino, hydroxy-substituted C ₂ -C ₃ alkyl .

In some embodiments, preferably, Z is C-R,

Where R is selected from -H, F, Cl, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy , Propoxy, isopropoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, substituted or unsubstituted 4- 6-membered heterocyclic group, or the following group:

m is 2 or 3,

R ^a is -H, methoxy, ethoxy, propoxy, isopropoxy, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, Or N-methyl-N-ethylamino,

R ^b is -H, methyl, or ethyl,

The substituted or unsubstituted 4-6 membered heterocyclic group described in R is selected from the following groups:

R ^{10 is} selected from -H, methyl, ethyl, propyl, isopropyl,

R ¹¹ and R ¹² are each independently selected from -H, -F, hydroxyl, cyano, methyl, and ethyl.

In some embodiments, preferably, R ¹ is -LR ³ , wherein L is L ₁ or L ₂ ,

n1为0-3的整数； L ₁ is:

n1 is an integer from 0 to 3;

L _{2 is} selected from:

n2 is an integer of 0-2, n3 is an integer of 0-1, R ⁴ is -H or methyl;

R ^{3 is} selected from the following groups:

Among them, R ¹⁶ , R ¹⁷ , R ¹⁸ , and R ¹⁹ are each independently selected from -H, -F, -Cl, -Br, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, Tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, methylthio, ethylthio, propylthio, isopropylthio, Fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethynyl, vinyl, cyclopropyl, cyclobutyl, cyclopropylmethyl , Cyclobutylmethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, hydroxymethyl, hydroxyethyl, hydroxypropyl, methyl Oxyethyl, methoxypropyl, CH ₃ OCOCH ₂ CH _2- , CH ₃ CH ₂ OCOCH ₂ CH ₂ -or the following groups:

q is an integer of 2-3,

R ^{s is} selected from -H, methyl, ethyl, and R ^{p is} selected from -H, methyl, ethyl,

R ′ and R ″ are each independently selected from -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl,

R ^{5 is} selected from -H, -F, hydroxyl, cyano, carboxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methyl Amine, ethylamino, dimethylamine;

R ^{20 is} selected from -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, Hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, methoxybutyl, cyanomethyl, cyanoethyl, cyanopropyl, carbamoylmethyl , Carbamoylethyl, carbamoylpropyl, CH ₃ OCOCH ₂ CH _2- , CH ₃ CH ₂ OCOCH ₂ CH _2- .

In some embodiments, preferably, R ² is -L ³ -R ⁶

L ^{3 is} selected from:

p1 is an integer from 0-3, and p2 is an integer from 0-3;

R ^{p is} selected from -H, methyl, ethyl;

R ^{6 is} selected from -H, F, -Cl, hydroxyl, amino, cyano, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, propyl, butyl, hexyl, Isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, iso Propoxy, methylthio, ethylthio, propylthio, isopropylthio, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, N-methyl-N-ethyl Amino, substituted or unsubstituted 4-6 membered heterocyclyl,

The substituted or unsubstituted 4-6 membered heterocyclic group described in R ⁶ is selected from the following groups:

R ²³ is -H, -F, methyl, ethyl,

R ²⁴ is -H, -F, hydroxyl, hydroxymethyl, cyano, methyl, ethyl, methoxy, or -NR ²⁶ R ²⁷ ,

R ²⁶ and R ²⁷ are each independently -H, methyl, ethyl, propyl, isopropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, methoxyethyl, and methyl Oxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, cyclopropyl, cyclobutyl, or the nitrogen atom to which R ²⁶ or R ²⁷ is attached The substituted or unsubstituted 4-6 membered heterocyclic group is selected from the following groups:

R ^{28 is} selected from -H, methyl, ethyl, formyl, acetyl,

R ^{29 is} selected from -H, methyl, ethyl,

R ^{30 is} selected from -H, hydroxyl, amino, methylamino, dimethylamino, hydroxymethyl, cyano, methyl, ethyl, methoxy,

R ^{25 is} selected from -H, methyl, ethyl, propyl, isopropyl, formyl, acetyl, propanoyl, isopropyl, carboxymethyl, carboxyethyl, hydroxyethyl, hydroxypropyl,

R ^s1 and R ^s2 are each independently selected from H and methyl.

Detailed description of the invention

The term "substituted" as referred to herein includes complex substituents (for example, phenyl, aryl, heteroalkyl, heteroaryl), more suitably 1 to 5 substituents, more preferably 1 to 3 One, preferably one or two, can be freely selected from the list of substituents.

Unless otherwise specified, alkyl groups include saturated straight-chain and branched hydrocarbon groups. C ₁ -C ₈ represents an alkyl group having 1 to 8 carbon atoms. Similarly, C ₁ -C ₃ represents an alkyl group. Carbon atoms having 1-3 carbon atoms, for example, C ₁ -C ₆ alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- Butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy is an alkyl ether composed of the linear, branched chains previously described. Similarly, alkenyl and alkynyl include straight-chain, branched-chain alkenyl or alkynyl.

Cycloalkyl refers to a cyclic group formed by carbon atoms, for example, C ₃ -C ₇ represents a carbon atom having 3 to 7 carbon atoms in an alkyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Cycloheptyl, and similarly, also include cyclic alkenyl.

The term "aryl" as used herein, unless otherwise specified, refers to an unsubstituted or substituted aromatic group, such as phenyl, naphthyl, anthracenyl. The term "aroyl" refers to -C (O) -aryl.

"Oxidized by one or two oxygen atoms" means that a sulfur atom is oxidized by one oxygen atom to form a double bond between sulfur and oxygen, or is oxidized by two oxygen atoms to form a double bond between sulfur and two oxygen.

The term "heterocyclyl" as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 3 to 8 membered monocyclic saturated ring system, which is selected from carbon atoms and selected from N, O, and S It consists of 1 to 3 heteroatoms, of which N, S heteroatoms can be oxidized at will, and N heteroatoms can also be quaternized at will. Heterocyclic rings can be combined with any heteroatom or carbon atom to form a stable structure. Examples of such heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidine Pyridyl, piperazinyl, piperazinyl oxide, piperidinyl oxide, dioxocyclopentyl, dioxocyclohexane tetrahydroimidazolyl, tetrahydrooxazolyl, thiomorpholine sulfoxide, thio Morpholine sulfone and oxadiazolyl.

The term "heteroaryl" as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system, and may also represent an unsubstituted or substituted 9 or A 10-ring benzene fused heteroaromatic ring system or a bicyclic heteroaromatic ring system, which consists of carbon atoms and 1 to 3 heteroatoms selected from N, O, and S, among which the N and S heteroatoms can be Oxidation, N heteroatoms can also be quaternized. Heteroaryl groups can be linked to any heteroatom or carbon atom to form a stable structure. Heteroaryl includes but is not limited to thienyl, furyl, imidazolyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, pyranyl, pyridyl, piperazinyl, pyrimidinyl, pyrazine, Pyridazinyl, pyrazolyl, thiadiazolyl, triazolyl, indolyl, azaindolyl, indazolyl, azaindazolyl, benzimidazolyl, benzofuranyl, benzothiophene Benzoxazolyl, benzoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenine, quinolinyl, or isoquinoline base.

The term "carbonyl" refers to a C (O) group.

Whenever the term "alkyl" or "aryl" or any of their prefixes appears in the name of a substituent (eg, aralkyl, dialkylamine), it will be considered to include the above "alkane And "aryl". The specified number of carbon atoms (e.g., C ₁ -C ₆ ) will independently represent the number of carbon atoms in an alkyl moiety or an alkyl moiety in a larger substituent (where alkyl is used as its prefix stem) Quantity.

The present invention also provides a method for preparing the corresponding compound. A variety of synthetic methods can be used to prepare the compounds described herein, including the following methods. The compound of the present invention or a pharmaceutically acceptable salt, isomer or hydrate thereof may be The following methods are used to synthesize synthetic methods known in the field of organic chemical synthesis, or by those skilled in the art to understand variations of these methods. Preferred methods include, but are not limited to, the following methods.

The final product of the present invention can be prepared by the following scheme, wherein R1, R2, X, Y, Z are as defined above,

In the first step, M in the intermediate A1 is nitro or BocNH-, and Q in the intermediate B1 is chlorine or methylsulfone (sulfoxide). The reaction can be carried out by heating under acid catalysis, neutral conditions or basic conditions. The substitution reaction synthesizes compound (C1). When Q in the intermediate B1 is chlorine, the compound (C1) can also be synthesized through a Buchwald coupling reaction;

Second step: If M is BocNH- in intermediate C1, the tert-butyloxycarbonyl protecting group can be removed under acidic conditions to obtain intermediate D1. If M is nitro in intermediate C1, compounds can be generated by reducing nitro D1.

Step 3: Synthesis of the final product (I) from intermediate D1 and acryloyl chloride.

The method for preparing the compound of the present invention includes the preparation of each of the above intermediates,

The intermediate (A1) is prepared as follows,

Step 1: Compound (A2) is reacted with (Boc) ₂ O to obtain compound (A3). X may be Cl, F, Br or I;

Step 2: Compound (A3) is reacted with R ² -H (amine or alcohol) under basic or neutral conditions to obtain compound (A4). When X is Cl, Br or I, the compound (A4) can also be obtained by Buchwald coupling reaction;

Step 3: The compound (A4) is reacted with a reducing agent to form an intermediate (A1), where M is BocNH-.

The base described in step 2 is selected from one or a combination of two or more inorganic bases such as cesium carbonate, triethylamine, sodium hydride, sodium bis (trimethylsilyl) amino, or organic bases. Puch ₂ is preferred for Buchwald conditions. (dba) ₃ , a combination of XantPhos and cesium carbonate;

The reducing agent in step 3 is selected from the group of reducing agents such as stannous chloride, hydrogen and palladium-carbon, hydrogen and Raney nickel, zinc powder and acid, iron powder and acid.

The intermediate (B1) is prepared as follows.

Step 1: Compound (B2) is subjected to substitution reaction with R ¹ -H (amine or alcohol) in the presence of a base to obtain (B3);

Step 2: Compound (B3) is dehydrated to compound (B1) under the condition of a dehydrating agent.

Or (B1) can be prepared by (B4) performing a substitution reaction with R ¹ -H (amine or alcohol) in the presence of a base. Here, Q in B1 is chlorine.

The present invention provides a preferred embodiment of the above reaction, preferably,

In step 1, the base is selected from organic or inorganic bases, such as triethylamine, N'N-diisopropylethylamine, sodium hydride, sodium bis (trimethylsilyl) amino, n-butyllithium One or a combination of two or more of them;

Preferably, the dehydrating agent is selected from the group consisting of phosphorus oxychloride, aluminum trichloride, phosphorus pentoxide, phosphorus chloride (phosphorus pentachloride or phosphorus trichloride), and the like;

In addition, in one aspect of the present invention, the preparation of another type of intermediate (B1) is provided. The process is as follows:

Step 1: Compound (B5) reacts with 1- (4-methoxyphenyl) ethyl-1-amine to form compound (B6) under the action of a base;

Step 2: Compound (B6) is heated to react to form compound (B7) under acidic conditions;

Step 3: Compound (B7) reacts with acid chloride under the action of base to form compound (B1). Here Q is chlorine.

In a preferred embodiment of the present invention, preferably, the first step base is selected from DIEA, triethylamine, or a combination of two or more;

The second step acid is selected from one or a combination of two or more of trifluoroacetic acid, phosphorus oxychloride, hydrochloric acid, and acetic acid;

The base described in step 3 is selected from one or two of triethylamine, N'N-diisopropylethylamine, sodium hydride, sodium bis (trimethylsilyl) amino, and n-butyllithium. A combination of the above;

In addition, the scheme provides the preparation of another type of intermediate (B1), the process is as follows,

Step 1: Compound (B8) undergoes substitution reaction with R1-H (amine or alcohol) under the action of acid or base, or reacts with R1 substituted boric acid or boric acid ester through Suzuki coupling reaction, or with indole heterocyclic ring Synthesis of intermediates (B9) containing different R1 substituents under Lewis acid conditions;

Step 2: Compound (B9) is reacted with an oxidant to form compound (B1). Here Q is methylsulfoxide.

The acid described in step 1 is selected from trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid, etc., and the coupling condition catalyst is selected from Pd (PPh ₃ ) ₄ , Pd (dppf) Cl ₂ , Pd (PPh ₃ ) ₂ Cl ₂ Etc., the base is selected from potassium acetate, potassium carbonate, cesium carbonate, potassium phosphate, etc., and the Lewis acid is selected from aluminum trichloride, titanium tetrachloride, tin tetrachloride, etc .;

The oxidant described in step 2 is selected from one or a combination of two or more of m-chloroperoxybenzoic acid and potassium persulfate complex salt.

In a scheme for synthesizing intermediate C1 of the present invention, intermediates containing specific functional groups in R2 or Z can be further derivatized to obtain different intermediate C1 compounds. Such compounds can also be passed through the aforementioned methods through intermediates A1 and B1. The reaction is obtained. The derivatization method is as follows.

In the first type of reaction, when the intermediate C1 'containing a phenolic hydroxyl group is obtained by the foregoing method, a substitution reaction with a halide or a sulfonic acid ester compound under basic conditions can be used to obtain a first type of intermediate (C1)

In the second type of reaction, when the intermediate C1 with a C-F bond at the Z position is obtained by the foregoing method, a substitution reaction with an amine or an alcohol compound can be performed under basic conditions to form a type of intermediate (C1).

The base mentioned in the first reaction is selected from cesium carbonate, potassium carbonate, triethylamine, sodium hydride, etc .;

The base in the second type of reaction is selected from one or a combination of two or more of cesium carbonate, potassium carbonate, triethylamine, and sodium hydride.

It is clear that compounds, isomers, crystalline forms or prodrugs of formula (I) and their pharmaceutically acceptable salts can exist in solvated and unsolvated forms. For example, the solvated form may be a water-soluble form. The invention includes all of these solvated and unsolvated forms.

The compounds of the present invention may have asymmetric carbon atoms. Based on their physical and chemical differences, such diastereomeric mixtures can be separated by known methods, such as chromatography or fractional crystallization. Into a single diastereomer. Enantiomers can be separated by first reacting with an appropriate optically active compound to convert the enantiomeric mixture into a diastereomeric mixture, separating the diastereomers, and then converting the single diastereomer Enantiomers are converted (hydrolyzed) to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers, are considered to be part of the invention.

The compound of the present invention as an active ingredient, and a method for preparing the same are the contents of the present invention. Moreover, the crystalline forms of some compounds can exist as polycrystals, and this form can also be included in the current invention. In addition, some compounds can form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also included in the scope of this invention.

The compounds of the present invention can be used for treatment in free form or, where appropriate, in the form of a pharmaceutically acceptable salt or other derivative. As used herein, the term "pharmaceutically acceptable salt" refers to the organic and inorganic salts of the compounds of the present invention. This salt is suitable for humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and is reasonable. Benefit / risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. The salt can be formed by reacting a compound of the present invention with a suitable free base or acid. Including but not limited to salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, Alternatively, these salts can be obtained by using methods well known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, and camphoric acid Salt, camphor sulfonate, citrate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glyceryl phosphate, gluconic acid Salt, hemisulfate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactate, lactate, laurate, lauryl sulfate, malate, maleate, methane Sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, per-3-phenylpropionate, Phosphate, picrate, propionate, stearate, sulfate, thiocyanate, p-toluenesulfonate, undecanoate, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include appropriate non-toxic ammonium, quaternary ammonium, and use such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate Ammonium cations formed by acid salts.

In addition, the term "prodrug" as used herein means that a compound can be converted into a compound represented by formula (I) of the present invention in vivo. This conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion into the parent compound in the blood or tissue.

The pharmaceutical composition of the present invention comprises a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressive agent, an anticancer drug, an antiviral agent, an Inflammatory agents, antifungal agents, antibiotics or additional active agents of anti-hyperplasia compounds; and any pharmaceutically acceptable carrier, adjuvant or excipient.

The compounds of the invention can be used alone or in combination with one or more other compounds of the invention or with one or more other agents. When administered in combination, the therapeutic agents can be formulated to be administered simultaneously or sequentially at different times, or the therapeutic agents can be administered as a single composition. The so-called "combination therapy" refers to the use of the compound of the present invention together with another agent. The mode of administration is simultaneous administration of each agent or sequential administration of each agent. To achieve the best results of the drug. Co-administration includes simultaneous delivery of the dosage forms, as well as separate dosage forms for each compound. Therefore, the administration of the compound of the present invention can be used concurrently with other known therapies in the art, for example, the use of radiation therapy or additional therapies such as cytostatic agents, cytotoxic agents, other anticancer agents in cancer treatment to improve Symptoms of cancer. The invention is not limited to the order of administration; the compounds of the invention may be administered previously, concomitantly, or after other anticancer or cytotoxic agents.

In order to prepare the pharmaceutical ingredient of this invention, one or more compounds or salts of formula (I) as its active ingredient can be intimately mixed with the pharmaceutical carrier, which is performed according to the traditional pharmaceutical ingredient technology, The carrier can adopt various forms according to the preparation form designed according to different administration modes (for example, oral or parenteral administration). Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical Excipients, a book jointly published by the American Pharmaceutical Association and the British Pharmaceutical Society.

The pharmaceutical composition of the present invention may have the following forms, for example, suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injections such as clear liquids, suspensions, Emulsions; or for topical application such as creams, creams; or as suppositories for rectal administration. Pharmaceutical ingredients may also be suitable for precise single-dose administration in unit dosage form. The pharmaceutical ingredient will include a traditional pharmaceutical carrier or excipient and a compound made as an active ingredient according to the current invention, and may also include other medical or pharmaceutical preparations, carriers, adjuvants, and the like.

Therapeutic compounds can also be administered to mammals rather than humans. The dosage of a drug administered to a mammal will depend on the species of the animal and its disease status or its disorder. The therapeutic compound can be administered to animals in the form of capsules, boluses, or tablet potions. Therapeutic compounds can also be introduced into animals by injection or infusion. We prepare these medicinal forms in a traditional way that meets the standards of veterinary practice. As an alternative, pharmaceutical synthetic drugs can be mixed with animal feed and fed to animals. Therefore, concentrated feed additives or premixes can be prepared to mix ordinary animal feed.

Yet another object of the present invention is to provide a method for treating cancer in a subject in need, comprising administering to the subject a method of treating a therapeutically effective amount of a composition containing a compound of the present invention.

The compounds of the present invention have selectivity over FGFR4 over other receptors, especially over other FGF receptors, such as FGFR1, FGFR2, and FGFR3. Accordingly, the present invention relates to compounds that are selective FGFR4 inhibitors.

Considering their activity as FGFR4 inhibitors, compounds of formula (I) in the form of free or pharmaceutically acceptable salts are suitable for treating conditions (such as cancer) mediated by the activity of the FGFR4 protein and / or being reactive to the inhibition of FGFR4 ( In particular, refers to a condition in a therapeutically beneficial manner), most particularly a disease or condition as mentioned herein below.

The compounds of the invention are useful in the treatment of cancer. Specifically, the compound of the present invention is useful for treating an indication selected from the group consisting of liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer, and colon cancer.

The compounds of the invention can also be used to treat solid malignancies characterized by positive FGFR4 expression.

The compounds of the invention can also be used to treat solid malignancies characterized by positive KLB (β-klotho) expression.

The compounds of the invention can also be used to treat solid malignancies characterized by positive FGF19 expression.

The compounds of the invention can also be used to treat solid malignancies characterized by positive FGFR4 and positive KLB expression.

The compounds of the invention can also be used to treat solid malignancies characterized by positive FGFR4 and positive FGF19 expression.

The compounds of the invention can also be used to treat solid malignancies characterized by positive FGFR4, positive KLB and positive FGF19 expression.

Any positive expression in FGFR4, KLB and / or FGF19 as described above can be evaluated by methods known to the skilled person, such as RT-qPCR, Western blotting, ELISA, immunohistochemistry.

Thus, as a further embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy. In other embodiments, the treatment is selected from a disease that can be treated by inhibiting FGFR4. In another embodiment, the disease is selected from the list mentioned above, suitably liver cancer.

In another embodiment, the invention provides a method of treating a disease treated by inhibiting FGFR4, comprising administering a therapeutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In other embodiments, the disease is selected from the list mentioned above, suitably liver cancer.

Therefore, as another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament. In other embodiments, the medicament is used to treat a disease that can be treated by inhibiting FGFR4. In another embodiment, the disease is selected from the list mentioned above, suitably liver cancer.

detailed description

I. Chemical reagent source

The reaction solvent was provided by Sinopharm Reagent

Common reaction chemical raw materials are provided by companies such as Inoke, Energie, Macleans, Braunwell, Medicine Stone, etc.

Thin layer chromatography silica gel plate (thickness 0.5mm, 1mm, 200X200mm) provided by Yantai Xinnuo Chemical Co., Ltd.

Silica gel (200-300 mesh) provided by China National Pharmaceutical Reagent Company

Chemical abbreviations

DMF: N’N-dimethylformamide

DIEA: N’N-diisopropylethylamine

NMP: N-methylpyrrolidone

Pd (OAc) ₂ : Palladium acetate

Pd ₂ (dba) ₃ : Tris (dibenzylideneindeneacetone) dipalladium

Xantphos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene

Binap: 1,1′-binapthyl-2,2′-bisdiphenylphosphine

(Boc) ₂ O: di-tert-butyl dicarbonate

3. Preparation of intermediates

Intermediate 1. Preparation of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

Step 1) Preparation of N, N-di-tert-butoxycarbonyl-2-nitro-5-fluoroaniline

Add 5-fluoro-2-nitroaniline (1.6 g, 10 mmol), (Boc) ₂ O (4.7 g, 22 mmol) and DMAP (0.37 g, 3 mmol) to the dichloromethane solution, stir overnight at room temperature, and concentrate. Purification by column chromatography (silica gel, mobile phase: petroleum ether / ethyl acetate = 10/1) gave 3.3 g of a bright yellow solid product, MS: 357 [M + H] ⁺ ;

Step 2) Preparation of (5- (4-ethylpiperazin-1-yl) -2-nitrophenyl) aminocarboxylic acid tert-butyl ester

N, N-di-tert-butoxycarbonyl-2-nitro-5-fluoroaniline (3.3g, 9.2mmol) and ethylpiperazine (3mL) were added to DMF, heated to 120 ° C for 8 hours, and cooled, Concentrated and purified by column chromatography to obtain 3.1 g of yellow solid, MS: 351 [M + H] ⁺ ;

Step 3) Preparation of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

(5- (4-ethylpiperazin-1-yl) -2-nitrophenyl) aminocarboxylic acid tert-butyl ester (3.1 g, 8.9 mmol) was added to a methanol solution of Pd / C, and hydrogen was replaced twice. The reaction was stirred at room temperature for 3 hours, filtered, concentrated, slurried with dichloromethane, and filtered to give 2.5 g of a white solid, MS: 321 [M + H] ⁺ ;

Intermediate 2. Preparation of (2-amino-5- (4-methylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

The experimental operation is the same as that of intermediate 1, and methylpiperazine is used instead of ethylpiperazine in step 2) of intermediate 1 to obtain a pale purple solid product, MS: 307 [M + H] ⁺ ;

Intermediate 3. Preparation of (2-amino-5-morpholinylphenyl) amino carboxylic acid tert-butyl ester

The experimental operation was the same as that of Intermediate 1. The morpholine was used to replace the ethylpiperazine in step 2) of Intermediate 1. The light purple solid product was obtained. MS: 294 [M + H] ⁺ ;

Intermediate 4. Preparation of (5- (4-acetylpiperazin-1-yl) -2-aminophenyl) aminocarboxylic acid tert-butyl ester

The experimental operation is the same as that of Intermediate 1, and 4-acetylpiperazine is used instead of ethylpiperazine in Step 2) of Intermediate 1 to obtain a light purple solid product. MS: 335 [M + H] ⁺ ;

Intermediate 5. Preparation of (2-amino-5- (tetrahydropyrrol-1-yl) phenyl) aminocarbamic acid tert-butyl ester

The experimental operation was the same as that of Intermediate 1. Tetrahydropyrrole was used to replace the ethylpiperazine in step 2) of Intermediate 1. The light purple solid product was obtained. MS: 278 [M + H] ⁺ ;

Intermediate 6. Preparation of (2-amino-5- (piperidin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

The experimental operation was the same as that of Intermediate 1. The piperidine was used to replace the ethylpiperazine in step 2) of Intermediate 1. The light purple solid product was obtained. MS: 292 [M + H] ⁺ ;

Intermediate 7. Preparation of (2-amino-5- (4- (dimethylamino) piperidin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

The experimental operation was the same as that of Intermediate 1. 4-dimethylaminopiperidine was used to replace the ethylpiperazine in step 2) of Intermediate 1. The light purple solid product was obtained. MS: 335 [M + H] ⁺ ;

Intermediate 8. Preparation of (S)-(2-amino-5- (3- (dimethylamino) tetrahydropyrrole-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

The experimental operation was the same as that of Intermediate 1. Substituting (S) -3-dimethylaminopyrrolidine for ethyl piperazine in Step 2) of Intermediate 1 gave a light purple solid product, MS: 321 [M + H] ⁺ ;

Intermediate 9. Preparation of (R)-(2-amino-5- (3- (dimethylamino) tetrahydropyrrole-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

The experimental operation is the same as that of intermediate 1. Substituting (R) -3-dimethylaminopyrrolidine for ethyl piperazine in step 2) of intermediate 1 to obtain a light purple solid product, MS: 321 [M + H] ⁺ ;

Preparation of intermediate 10.2- (4- (4-amino-3-((tert-butoxycarbonyl) amino) phenyl) piperazin-1-yl) acetic acid tert-butyl acetate

Step 1) Preparation of 4- (2- (tert-butoxy) -2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester:

Piperazine-1-carboxylic acid tert-butyl ester (2 g, 10.74 mmol) and tert-butyl 2-bromoacetate (2.1 g, 10.76 mmol) were dissolved in acetonitrile (30 mL), and triethylamine (2.17 g, 21.49 mmol) was added. , 3 hours at 25 ° C. The reaction solution was concentrated, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 2 g of a white solid. MS: 301 [M + H] ⁺ ;

Step 2) Preparation of tert-butyl 2- (piperazin-1-yl) acetate

Dissolve 4- (2- (tert-butoxy) -2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester (2 g, 6.66 mmol) in a solution of saturated hydrogen chloride in dioxane (40 mL), The reaction was carried out at 25 ° C for 4 hours. The reaction solution was evaporated to dryness, adjusted to pH 10 with a saturated sodium carbonate solution, and extracted with ethyl acetate to obtain 1.3 g of a yellow oil. MS: 201 [M + H] ⁺ ;

Step 3) Preparation of tert-butyl 2- (4- (4-amino-3-((tert-butoxycarbonyl) amino) phenyl) piperazin-1-yl) acetate

The experimental operation was the same as that of Intermediate 1, and tert-butyl 2- (piperazin-1-yl) acetate was used to replace the ethylpiperazine in Step 2) of Intermediate 1. A white solid product was obtained. MS: 407 [M + H] ⁺ ;

Intermediate 11. Preparation of (2-amino-4-chloro-5- (4- (dimethylamino) piperidin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

The experimental operation is the same as that of Intermediate 1. 4-chloro-5-fluoro-2-nitroaniline is used instead of 5-fluoro-2-nitroaniline in step 1), and 4- (dimethylamino) piperidine is used instead. Step 2) Ethylpiperazine gives the product as a light purple solid, MS: 369 [M + H] ⁺ ;

Preparation of intermediate 12 (2-amino-5- (4-ethylpiperazin-1-yl) -3-methylphenyl) amino formate

The experimental operation is the same as that of Intermediate 1. 5-fluoro-3-methyl-2-nitroaniline is used in place of 5-fluoro-2-nitroaniline in step 1). MS: 335 [M + H] ⁺ ;

Preparation of intermediate 13 4- (morpholinemethyl) -2-nitroaniline:

Step 1) Preparation of 4-amino-3-nitrobenzaldehyde

4-Fluoro-3-nitrobenzaldehyde (1.7 g, 10 mmol) was slowly added to concentrated ammonia water (30%, 30 mL), stirred at room temperature overnight, diluted with water, slurried, filtered, and dried to give 1.1 g of a yellow solid product, MS: 167 [M + H] ⁺ ;

Step 2) Preparation of 4- (morpholinemethyl) -2-nitroaniline

To a methanol solution containing morpholine (20 mmol), tetraisopropyl titanate (5.8 g, 20 mmol) and 4-amino-3-nitrobenzaldehyde (850 mg, 5 mmol) were sequentially added, and the mixture was stirred at room temperature overnight. Sodium (390 mg, 10 mmol), stirred at room temperature for 2 hours, quenched by adding water, extracted with dichloromethane, dried and concentrated to obtain 780 mg of the crude product, which was directly used in the next step. MS: 238 [M + H] ⁺ ;

Preparation of intermediate 14 (5-amino-2- (4-ethylpiperazin-1-yl) pyridin-4-yl) aminocarboxylic acid tert-butyl ester

The experimental operation is the same as that of Intermediate 1. 2-chloro-5-nitro-4-aminopyridine was used instead of 5-fluoro-2-nitroaniline in step 1) to obtain a light purple solid product. MS: 321 [M + H] ⁺ ;

Intermediate 15. Preparation of (2-amino-5-((2- (dimethylamino) ethyl) (methyl) amino) phenyl) amino formate

The experimental operation is the same as that of intermediate 1. Substituting N ¹ , N ¹ , N ² -trimethylethyl-1,2-diamine for the ethyl piperazine in step 2) of intermediate 1 to obtain a pale purple solid product, MS : 309 [M + H] ⁺ ;

Intermediate 16. Preparation of (2-amino-5-((2- (dimethylamino) ethyl) amino) phenyl) aminocarboxylic acid tert-butyl ester

The experimental operation was the same as that of Intermediate 1. Substituting N ¹ , N ¹ -dimethylethyl-1,2-diamine for the ethyl piperazine in step 2) of Intermediate 1 gave a light purple solid product, MS: 295 [ M + H] ⁺ ;

Intermediate 17. Preparation of (2-amino-4-chloro-5- (4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

The experimental operation was the same as that of Intermediate 1. 4-chloro-5-fluoro-2-nitroaniline was used instead of 5-fluoro-2-nitroaniline in step 1) to obtain a light purple solid product. MS: 355 [M + H] ⁺ ;

Preparation of intermediate 18 (2-amino-5- (4-methyl-2-oxoprazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

Step 1) Same as step 1) in Intermediate 1

Step 2) Preparation of (2-((3-((tert-butoxycarbonyl) amino) -4-nitrophenyl) amino) ethyl) (methyl) amino formate

Tert-Butyl N, N-di-tert-butoxycarbonyl-2-nitro-5-fluoroaniline (1 g, 2.8 mmol) and (2-aminoethyl) (methyl) aminoformate (980 mg, 5.6 mmol ) Was dissolved in DMF (10 mL) and reacted at 110 ° C for 4 hours. The reaction solution was evaporated to dryness by column chromatography to obtain 850 mg of a yellow solid. MS: 411 [M + H] ⁺ ;

Step 3) (2- (N- (3-((tert-butoxycarbonyl) amino) -4-nitrophenyl) -2-chloroacetylamino) ethyl (methyl) amino formate Preparation of esters

Tert-butyl (2-((3-((tert-butoxycarbonyl) amino) -4-nitrophenyl) amino) ethyl) (methyl) aminoformate (850 mg, 2.1 mmol) and three Ethylamine (251 mg, 2.5 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and under the protection of argon, chloroacetyl chloride (281 mg, 2.5 mmol) was added at 0 ° C, and reacted at 25 ° C for 16 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered and evaporated to dry out column chromatography to obtain 850 mg of a yellow oil, MS: 487 [M + H] ⁺ ;

Step 4) Preparation of N- (3-amino-4-nitrophenyl) -2-chloro-N- (2- (methylamino) ethyl) acetamide

Tert-butyl (2- (N- (3-((tert-butoxycarbonyl) amino) -4-nitrophenyl) -2-chloroacetylamino) ethyl (methyl) aminoformate ( 850mg, 1.4mmol) was dissolved in dichloromethane (5mL), and trifluoroacetic acid (5mL) was added dropwise, and reacted for 3 hours at 25 ° C. The reaction solution was diluted with dichloromethane, washed with saturated sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and filtered Evaporation to dryness gave 400 mg of yellow oil, MS: 287 [M + H] ⁺ ;

Step 5) Preparation of 1- (3-amino-4-nitrophenyl) -4-methylpiperazin-2-one

N- (3-amino-4-nitrophenyl) -2-chloro-N- (2- (methylamino) ethyl) acetamide (400 mg, 1.4 mmol), cesium carbonate (1.36 g, 4.2 mmol) and potassium iodide (24 mg, 0.14 mmol) were dissolved in DMF (8 mL) and reacted at 25 ° C for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to dryness to obtain 320 mg of a yellow oil, MS: 251 [M + H] ⁺ ;

Step 6) Preparation of (5- (4-methyl-2-oxopiperazin-1-yl) -2-nitrophenyl) aminocarboxylic acid tert-butyl ester

1- (3-amino-4-nitrophenyl) -4-methylpiperazin-2-one (320 mg, 1.3 mmol), Boc ₂ O (280 mg, 1.3 mmol) and DMAP (32 mg, 0.3 mmol) It was dissolved in DCM and reacted at 25 ° C for 16 hours. The reaction solution was evaporated to dryness and column chromatography to obtain 400 mg of a yellow oil, MS: 351 [M + H] ⁺ ;

Step 7) Preparation of (2-amino-5- (4-methyl-2-oxopiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

(5- (4-methyl-2-oxopiperazin-1-yl) -2-nitrophenyl) aminocarboxylic acid tert-butyl ester (400 mg, 1.1 mmol) was dissolved in a mixture of ethyl acetate and ethanol Raney nickel was added to the solution (10 mL + 10 mL), and the reaction was performed under a hydrogen condition for 2 hours. The reaction solution was filtered through celite, and the filtrate was evaporated to dryness to obtain 220 mg of a brown oil. MS: 321 [M + H] ⁺ .

Preparation of intermediate 19 (2-amino-5-((4-methyl-2-oxopiperazin-1-yl) methyl) phenyl) aminodicarboxylic acid di-tert-butyl ester 1) (5- Preparation of methyl-2-nitrophenyl) aminodicarboxylic acid di-tert-butyl ester

The experimental operation is the same as step 1) in Intermediate 1, using 5-methyl-2-nitroaniline instead of 5-fluoro-2-nitroaniline. MS: 353 [M + H] ⁺ . Step 2) (5- ( Preparation of bromomethyl) -2-nitrophenyl) aminodicarboxylic acid di-tert-butyl ester

Di-tert-butyl (5-methyl-2-nitrophenyl) aminodicarboxylate (1.5 g, 4.3 mmol), azobisisobutyronitrile (280 mg, 1.7 mmol), and bromosuccinimide ( 830 mg, 4.7 mmol) was dissolved in carbon tetrachloride (3 mL) and reacted at 55 ° C for 3 hours. The reaction solution was evaporated to dryness and preparative thin layer chromatography yielded 400 mg of a yellow oil. MS: 431 [M + H] ⁺ .

Step 3) Preparation of (5-((4-methyl-2-oxopiperazin-1-yl) methyl) -2-nitrophenyl) aminodicarboxylic acid di-tert-butyl ester

Dissolve 4-methylpiperazin-2-one (110 mg, 1 mmol) in DMF (2 mL), add sodium hydride (38 mg, 1 mmol) at 0 ° C, and after 15 minutes, add (5- (bromomethyl) -2- A solution of di-tert-butyl nitrophenyl) aminodicarboxylate (400 mg, 0.9 mmol) in DMF (2 mL) was reacted at 25 ° C for 3 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 400 mg of a crude yellow oil, MS: 465 [M + H] ⁺ .

Step 4) Preparation of (2-amino-5-((4-methyl-2-oxopiperazin-1-yl) methyl) phenyl) aminodicarboxylic acid di-tert-butyl ester

(5-((4-methyl-2-oxopiperazin-1-yl) methyl) -2-nitrophenyl) aminodi-tert-butyl dicarboxylate (400 mg, 0.86 mmol) was dissolved in methanol (10 mL), Raney nickel was added, and the reaction was performed under hydrogen for 1 hour. Filtered and evaporated to dryness to give 400 mg of a yellow oil, MS: 435 [M + H] ⁺ .

Intermediate 20. (2-amino-4-chloro-5- (4-((2-methoxyethyl) (methyl) amino) piperidin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

The experimental operation is the same as that of intermediate 1. Instead of 5-fluoro-2-nitroaniline in step 1), 4-chloro-5-fluoro-2-nitroaniline is used, and N- (2-methoxyethyl) is used. -N-methylpiperidine-4-amine instead of step 2) ethylpiperazine to give the product as a light purple solid, MS: 413 [M + H] ⁺ ;

Intermediate 21. (2-amino-4-chloro-5- (4-((3-methoxypropyl) (methyl) amino) piperidin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

The experimental operation is the same as that of intermediate 1. Instead of 5-fluoro-2-nitroaniline in step 1), 4-chloro-5-fluoro-2-nitroaniline is used, and N- (3-methoxypropyl) is used. -N-methylpiperidine-4-amine instead of step 2) ethylpiperazine to give the product as a light purple solid, MS: 427 [M + H] ⁺ ;

Intermediate 22. (2-amino-4-chloro-5- (4- (ethyl (methyl) amino) piperidin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

The experimental operation is the same as that of intermediate 1. Instead of 5-fluoro-2-nitroaniline in step 1), 4-chloro-5-fluoro-2-nitroaniline is used, and N-ethyl-N-methylpiperidine is used. -4-amine replaced step 2) ethylpiperazine to give a light purple solid product, MS: 383 [M + H] ⁺ ;

The following table shows the structure, name, and characterization of Intermediate 23-37. Intermediate 23-37 is obtained by selecting a suitable reactant using a similar method to the preparation of Intermediate 1-22 above.

Four. Preparation of specific examples

Example 1.N- (2-((5-cyano-4- (isopropylamino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) benzene Acrylamide

Step 1) Preparation of 2-chloro-4- (isopropylamino) pyrimidine-5-carboxamide

To a solution of 2,4-dichloropyrimidine-5-carboxamide (200 mg, 1.05 mmol) and diisopropylethylamine (0.5 ml, 3 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise isopropylamine (60 mg, 1 mmol). , Reaction at room temperature for 10 hours, adding water (20 mL) to beat and stir for 0.5 hours, filtering and drying to obtain 180 mg of white solid product, MS: 215 [M + H] ⁺ ;

Step 2) Preparation of 2-chloro-4- (isopropylamino) pyrimidine-5-carbonitrile

The intermediate 2-chloro-4- (isopropylamino) pyrimidine-5-carboxamide (110 mg, 0.5 mmol) was dissolved in phosphorus oxychloride (3 mL), heated under reflux for 2 hours, cooled, concentrated, and dichloro Methane was dissolved, saturated sodium bicarbonate was washed, and the organic phase was dried and concentrated to obtain a black oil. The product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3/1) to obtain 80 mg of a pale yellow solid product. MS: 197 [M + H ] ⁺ ;

Step 3) (2-((5-cyano-4- (isopropylamino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) amine Of tert-butyl carbamate

2-chloro-4- (isopropylamino) pyrimidin-5-carbonitrile (50 mg, 0.25 mmol), (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) Tert-butyl aminoformate (80 mg, 0.25 mmol) and trifluoroacetic acid (10 μl) were added to a sealed tube of sec-butanol (5 mL), heated at 120 ° C for 8 hours, cooled, concentrated, and prepared from silica gel Purification on a thin plate (0.5 mm) (developing phase dichloromethane / methanol = 20/1) gave 65 mg of light yellow solid product, MS: 481 [M + H] ⁺ .

Step 4) N- (2-((5-cyano-4- (isopropylamino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl ) Preparation of acrylamide

To intermediates containing (2-((5-cyano-4- (isopropylamino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl aminoformate (50 mg, 0.1 mmol) in dichloromethane (3 mL), and the mixture was reacted at room temperature for 1 hour. The obtained light purple oil was concentrated and dissolved in anhydrous tetrahydrofuran ( 1 mL), and acryloyl chloride (20 μL) was added dropwise thereto at 0 ° C. and reacted for 0.5 hours, quenched by addition of water, extracted with dichloromethane, washed with saturated sodium bicarbonate, the organic phase was separated, dried, concentrated, and prepared using a thin plate ( 0.5 mm, silica gel) (developing system: dichloromethane / methanol volume ratio 100: 9) to give 25 mg of a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 8.60 (s, 1H), 8.21 (s, 1H), 7.43 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 6.79 (d, J = 9.1 Hz, 1H), 6.50 (dd, J = 17.0, 10.1 Hz, 1H), 6.25 (d, J = 17.0 Hz, 1H), 5.83 5.71 (m, 1H), 4.20 (br, 1H), 3.11 (br, 4H), 2.52 (br, 4H), 2.40 (br, 2H), 1.13 (d, J = 6.5Hz, 6H), 1.04 (t , J = 7.1Hz, 3H). MS: 435 [M + H] ⁺ ;

Example 2.N- (2-((5-cyano-4- (2-chloroaniline) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) benzene Preparation of acrylamide

Step 1) Preparation of 2-chloro-4-((2-chlorophenyl) amino) pyrimidine-5-carboxamide:

To an NMP solution (5 mL) of 2,4-dichloropyrimidine-5-carboxamide (200 mg, 1.05 mmol) and diisopropylethylamine (0.5 mL, 3 mmol) was added o-chloroaniline (130 mg, 1 mmol), and heated Reaction to 100 ° C for 3 hours, cooling, adding water (20 mL) to beat for 0.5 hours, filtering and drying to obtain 240 mg of white solid product, MS: 283 [M + H] ⁺ ;

Steps 2) to 4) The experimental operation is the same as that of steps 2) to 4) in Example 1, and 2-chloro-4-((2-chlorophenyl) amino) pyrimidine-5-carboxamide is used instead of step 2) in Example 1. Of 2-chloro-4- (isopropylamino) pyrimidine-5-carboxamide to give the product as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.66 (s, 1H), 9.23 (s, 1H), 8.77 (s, 1H), 8.42 (s, 1H), 7.60-7.50 (m, 2H), 7.38-7.20 (m, 3H), 7.05 (br, 1H), 6.60 (s, 1H), 6.49-6.42 (m, 1H), 6.25-6.20 (m, 1H), 5.76-5.72 (m, 1H), 3.07 (br, 4H), 2.52 (br, 4H), 2.38 (br, 2H), 1.04 (t, J = 8.0Hz, 3H). MS: 503 [M + H] ⁺ ;

Example 3.N- (2-((4-((1-acetylpiperidin-4-yl) amino) -5-cyanopyrimidin-2-yl) amino) -5- (4-ethyl Piperazin-1-yl) phenyl) acrylamide

Step 1) Preparation of 4-((1-acetylpiperidin-4-yl) amino) -2-chloropyrimidine-5-carbonitrile

1-Acetyl-4-aminopiperidine was slowly added dropwise to a tetrahydrofuran solution (5 mL) of 2,4-dichloro-5-cyanopyrimidine (180 mg, 1 mmol) containing DIEA (0.5 mL) under ice salt bath conditions. A solution of pyridine (150 mg, 1 mmol) in tetrahydrofuran (1 mL) was stirred at room temperature overnight, quenched with water, filtered, and dried to obtain a white solid, which was purified from a preparation plate (0.5 mm, silica gel) to obtain 120 mg of the target product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.86-8.84 (m, 1H), 8.79-8.72 (m, 1H), 4.27 (br, 1H), 4.11-3.89 (m, 1H), 3.80 (br , 1H), 3.23-3.07 (m, 1H), 2.80-2.61 (m, 1H), 2.00 (s, 3H), 1.93-1.70 (m, 2H), 1.54-1.22 (m, 2H). MS: 280 [M + H] ⁺ ;

Step 2) (2-((4-((1-acetylpiperidin-4-yl) amino) -5-cyanopyrimidin-2-yl) amino) -5- (4-ethylpiperazine -1-yl) phenyl) amino tert-butyl carbamate

The same procedure as in step 3) of Example 1 was performed to obtain a pale yellow product. MS: 564 [M + H] ⁺ .

Step 3) N- (2-((4-((1-acetylpiperidin-4-yl) amino) -5-cyanopyrimidin-2-yl) amino) -5- (4-ethyl Preparation of piperazin-1-yl) phenyl) acrylamide

The same operation as in step 4) of Example 1 was performed to obtain a white solid product. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.75 (br, 1H), 8.47 (s, 1H), 8.33-8.09 (m, 1H), 7.64 (d, J = 7.3Hz, 1H), 7.41- 7.01 (m, 2H), 6.82-6.65 (m, 1H), 6.54-6.32 (m, 1H), 6.20 (dd, J = 16.9, 6.9Hz, 1H), 5.70 (d, J = 10.1Hz, 1H) , 4.19 (br, 1H), 3.91 (br, 1H), 3.67 (br, 1H), 3.08-3.04 (m, 4H), 2.97 (br, 1H), 2.84 (br, 1H), 2.52 (br, 4H) ), 2.30 (q, J = 7.4Hz, 2H), 1.90 (s, 3H), 1.67 (br, 2H), 1.30-1.01 (m, 2H), 0.96 (t, J = 7.2Hz, 3H) .MS : 518 [M + H] ⁺ .

Example 4.N- (2-((4- (tert-butylamino) -5-cyanopyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) propene Preparation of amide:

Same operation as in Example 3, substituting t-butylamine for Example 3, step 1) 1-acetyl-4-aminopiperidine, and reacting with the same operation, 1H NMR (400MHz, DMSO-d6) δ 9.74 (s, 1H), 8.58 (s, 1H), 8.23 (s, 1H), 7.32 (d, J = 8.9Hz, 1H), 7.28-7.16 (m, 1H), 6.79 (dd, J = 9.0, 2.8Hz, 1H), 6.51 ( dd, J = 17.0, 10.1 Hz, 1H), 6.29-6.14 (m, 2H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 3.16-3.04 (m, 4H), 2.53-2.50 (m, 4H), 2.37 (q, J = 7.2Hz, 2H), 1.36-1.20 (m, 9H), 1.03 (t, J = 7.1Hz, 3H). MS: 449 [M + H] ⁺ .

Example 5.N- (2-((5-cyano-4-phenoxypyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide

Step 1) Preparation of 2-chloro-4-phenyloxypyrimidine-5-carboxamide

In an ice-water bath, phenol (240 mg, 2.5 mmol) was slowly added dropwise to a tetrahydrofuran solution containing sodium hydride (100 mg, 2, 5 mmol), and the reaction was stirred for half an hour. Then, 2,4-dichloro-5amide pyrimidine (190 mg , 1 mmol) of tetrahydrofuran (1 mL) solution was slowly added dropwise to the above solution, and the reaction was stirred at room temperature overnight, quenched with water, extracted with ethyl acetate, and purified by silica gel column chromatography to obtain 160 mg of white solid, MS: 250 [M + H] ⁺ .

Step 2) Preparation of 2-chloro-4-phenyloxypyrimidine-5-carbonitrile

Pyridine (2mL) and phosphorus oxychloride (0.5mL) were added to the acetonitrile (20mL) solution, and then the intermediate 2-chloro-4-phenyloxypyrimidine-5-carboxamide (130mg, 0.5 mmol), the reaction was heated to reflux for 1 hour, cooled, quenched by adding water, washed with saturated sodium bicarbonate, extracted with dichloromethane, dried from the organic phase, and concentrated to give 110 mg of a yellow solid, MS: 232 [M + H] ⁺ .

Step 3) (2-((5-cyano-4-phenoxypyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl Preparation of esters

2-chloro-4-phenyloxypyrimidine-5-carbonitrile (90mg, 0.25mmol), (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid Tert-butyl ester (80 mg, 0.25 mmol) and trifluoroacetic acid (10 μl) were added to a sealed tube of n-butanol (5 mL), heated at 120 ° C for 8 hours, cooled, concentrated, and a thin plate prepared from silica gel (0.5 mm) purified 95 mg as a white solid, MS: 516 [M + H] ⁺ .

Step 4) N- (2-((5-cyano-4-phenoxypyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide preparation

Tert-containing intermediate (2-((5-cyano-4-phenoxypyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid Trifluoroacetic acid (1 mL) was added to a solution of butyl ester (50 mg, 0.1 mmol) in dichloromethane (3 mL), and the mixture was reacted at room temperature for 1 hour. The light purple oil obtained after concentration was dissolved in anhydrous tetrahydrofuran (1 mL) at 0 ° C Acryloyl chloride was added dropwise thereto and reacted for 0.5 hours, quenched with water, extracted with dichloromethane, washed with saturated sodium bicarbonate water, the organic phase was separated, dried, concentrated, and purified using a preparation sheet (0.5 mm, silica gel) to obtain 25 mg of a white solid. ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.74 (s, 1H), 9.36 (s, 1H), 8.70 (s, 1H), 7.29 (br, 6H), 7.00 (s, 1H), 6.45 (d, J = 14.2 Hz, 1H), 6.75-6.70 (m, 1H), 6.24 (d, J = 17.7 Hz, 1H), 5.75 (s, 1H), 3.06 (br, 4H), 2.52 (br, 4H), 2.36 (q, J = 7.2Hz, 2H), 1.03 (t, J = 7.1Hz, 3H). MS: 470 [M + H] ⁺ .

Example 6.N- (2-((5-cyano-4-((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -5- (4- Preparation of ethylpiperazin-1-yl) phenyl) acrylamide

Step 1) Preparation of 4-((2- (dimethylphosphoryl) phenyl) amino) -2- (methylthio) pyrimidine-5-carbonitrile

4-Chloro-2- (methylthio) pyrimidine-5-carbonitrile (400 mg, 2.16 mmol) and (2-aminophenyl) dimethylphosphine oxide (400 mg, 2.36 mmol) were dissolved in isopropanol (5 mL ), Concentrated hydrochloric acid (0.05 mL) was added, and the mixture was reacted at 80 ° C for 16 hours. Cooling and filtering gave 400 mg of a white solid. MS: 319 [M + H] ⁺ .

Step 2) Preparation of 4-((2- (dimethylphosphoryl) phenyl) amino) -2- (methylsulfone) pyrimidine-5-carbonitrile

4-((2- (Dimethylphosphoryl) phenyl) amino) -2- (methylthio) pyrimidine-5-carbonitrile (200 mg, 0.63 mmol) was dissolved in chloroform (4 mL) at 0 ° C. Add m-chloroperoxybenzoic acid (163 mg, 0.94 mmol), and react at 25 ° C for 3 hours. The reaction solution was diluted with dichloromethane, washed with saturated sodium carbonate and brine, dried over anhydrous sodium sulfate, and evaporated to give 160 mg of a yellow solid. MS: 335 [M + H] ⁺ .

Step 3) (2-((5-cyano-4-((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine Preparation of tert-butyl azin-1-yl) phenyl) carbamate:

Add 4-((2- (dimethylphosphoryl) phenyl) amino) -2- (methylsulfone) pyrimidine-5-carbonitrile (160 mg, 0.49 mmol), (2-amino-5- (4 -Ethylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester (154 mg, 0.48 mmol) and trifluoroacetic acid (0.5 mL) were dissolved in sec-butanol (4 mL) and reacted at 80 ° C for 16 hours. The reaction solution was evaporated to dryness, a mixed solution (1: 2) of petroleum ether and ethyl acetate was added, and 110 mg of a brown solid was obtained by filtration. MS: 591 [M + H] ⁺ .

Step 4) N- (2-((5-cyano-4-((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -5- (4-ethyl Of Benzylpiperazin-1-yl) phenyl) acrylamide

The operation is the same as that in step 4 of Example 1, using (2-((5-cyano-4-((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -5 -(4-ethylpiperazin-1-yl) phenyl) carbamic acid tert-butyl ester instead of (2-((5-cyano-4- (isopropylamino) pyrimidin-2-yl) amino ) Tert-Butyl-5- (4-ethylpiperazin-1-yl) phenyl) carbamate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.59 (s, 1H), 9.64 (s, 1H), 8.93 (s, 1H), 8.45 (s, 1H), 8.21 (brs, 1H), 7.53 ( brs, 1H), 7.42-7.02 (m, 4H), 6.86 (brs, 1H), 6.51 (dd, J = 17.0, 10.2 Hz, 1H), 6.23 (d, J = 17.0 Hz, 1H), 5.73 (d , J = 10.1Hz, 1H), 3.14 (t, J = 4.8Hz, 4H), 2.55-2.51 (m, 4H), 2.38 (q, J = 7.2Hz, 2H), 1.78 (s, 3H), 1.75 (s, 3H), 1.05 (t, J = 7.1Hz, 3H). MS: 545.2 [M + H] ⁺ .

Example 130. N- (2-((5-cyano-4-((2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine-1 -Yl) phenyl) acrylamide

Step 1) Preparation of 2-chloro-4-((2-hydroxyethyl) amino) pyrimidine-5-carboxamide

The operation is the same as step 1) of Example 1, and ethanolamine is used instead of isopropylamine.

Step 2) Preparation of 2-((5-carbamoyl-2-chloropyrimidin-4-yl) amino) acetate

Dissolve 2-chloro-4-((2-hydroxyethyl) amino) pyrimidine-5-carboxamide (440 mg, 2.03 mmol) and pyridine (322 mg, 4.08 mmol) in dichloromethane, and add ethyl dropwise at 0 ° C. Acid chloride (320 mg, 4.08 mmol) was reacted at 25 ° C for 2 hours. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 240 mg of a yellow solid. MS: 259.1 [M + H] ⁺ .

Step 3) Preparation of 2-((2-chloro-5-cyanopyrimidin-4-yl) aminoacetate

2-((5-carbamoyl-2-chloropyrimidin-4-yl) amino) acetate (165 mg, 0.60 mmol) was dissolved in phosphorus oxychloride (2 mL) and reacted at 120 ° C for 3 hours. The reaction solution was evaporated to dryness, a small amount of ice was added, the saturated sodium carbonate was adjusted to pH = 10, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 180 mg of a yellow oil. MS: 241.0 [M + H] ⁺ .

Step 4) 2-((2-((2-((tert-butoxycarbonyl) amino) -4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidine Preparation of 4--4-yl) amino) ethyl acetate

Add 2-((2-chloro-5-cyanopyrimidin-4-yl) aminoacetate (180 mg, 0.75 mmol) and tert-butyl (2-amino-5- (4-ethylpiperazine-1) -Yl) phenyl) carbamate (240 mg, 0.75 mmol) was added to sec-butanol (2 mL), and reacted at 110 ° C for 3 hours. The reaction solution was evaporated to dryness and column chromatography was performed to obtain 140 mg of a brown solid. MS: 525.3 [M + H] ⁺ .

Step 5) 2-((5-cyano-4-((2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) benzene Preparation of t-butylaminocarbamate

2-((2-((2-((tert-butoxycarbonyl) amino) -4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidine-4 -Yl) amino) ethyl acetate (140 mg, 0.27 mmol) was dissolved in methanol (4 mL), potassium carbonate (111 mg, 0.80 mmol) was added, and the mixture was reacted at 25 ° C for 2 hours. The reaction solution was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 120 mg of a white solid. MS: 483.3 [M + H] ⁺ .

Step 6) N- (2-((5-cyano-4-((2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine-1- Of phenyl) phenyl) acrylamide

2-((5-cyano-4-((2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) Tert-butyl aminoformate (120 mg, 0.25 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at 25 ° C for 2 hours. The reaction solution was evaporated to dryness, and the oil was dissolved in tetrahydrofuran (3 mL). Allyl chloride (24 mg, 0.27 mmol) was added dropwise at 0 ° C, and the mixture was reacted at 25 ° C for 30 minutes. The reaction solution was quenched with saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered and evaporated to dryness to obtain 50 mg of a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.71 (s, 1H), 8.65 (s, 1H), 8.23 (s, 1H), 7.52-7.32 (m, 2H), 7.15 (s, 1H), 6.80 (d, J = 8.9 Hz, 1H), 6.49 (dd, J = 17.0, 10.1 Hz, 1H), 6.25 (d, J = 17.0 Hz, 1H), 5.76 (d, J = 10.0 Hz, 1H), 4.71 (brs, 1H), 3.59-3.46 (m, 2H), 3.46-3.37 (m, 2H), 3.16-2.99 (m, 4H), 2.58-2.50 (m, 4H), 2.38 (q, J = 7.2 Hz, 2H), 1.04 (t, J = 7.2Hz, 3H). MS: 437.2 [M + H] ⁺ .

Example 131. 4-((2-((2-Allylacylamino-4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidin-4-yl Preparation of) amino) benzoic acid

Step 1) Preparation of 4-((5-carbamoyl-2-chloropyrimidin-4-yl) amino) benzoate

2,4-Dichloropyrimidine-5-carboxamide (300 mg, 1.56 mmol), ethyl 4-aminobenzoate (258 mg, 1.56 mmol) and diisopropylethylamine (605 mg, 4.69 mmol) were dissolved in tetrahydrofuran (5 mL) at 50 ° C for 48 hours. Water was added to the reaction solution, and 200 mg of a white solid was obtained by filtration. MS: 321.1 [M + H] ⁺ .

Step 2) Preparation of 4-((2-chloro-5-cyanopyrimidin-4-yl) amino) benzoate

Ethyl 4-((5-aminoformyl-2-chloropyrimidin-4-yl) amino) benzoate (100 mg, 0.31 mmol) was dissolved in phosphorus oxychloride (2 mL) and reacted at 110 ° C for 2 hours . The reaction solution was evaporated to dryness, a small amount of ice was added, the saturated sodium carbonate was adjusted to pH 11, and 80 mg of a yellow solid was obtained by filtration. MS: 303.1 [M + H] ⁺ .

Step 3) 4-((2-((2-((tert-butoxycarbonyl) amino) -4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidine Preparation of 4--4-yl) amino) benzoic acid ethyl ester

Add 4-((2-chloro-5-cyanopyrimidin-4-yl) amino) benzoate (80 mg, 0.26 mmol) and tert-butyl (2-amino-5- (4-ethylpiperazine) 1-yl) phenyl) carbamate (85 mg, 0.26 mmol) was added to sec-butanol (2 mL) and reacted at 110 ° C for 3 hours. The reaction solution was evaporated to dryness and subjected to column chromatography to obtain 120 mg of a light gray solid. MS: 587.3 [M + H] ⁺ .

Step 4) 4-((2-((2-((tert-butoxycarbonyl) amino) -4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidine Preparation of 4--4-yl) amino) benzoic acid

4-((2-((2-((tert-butoxycarbonyl) amino) -4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidine-4 -Amino) aminoethylbenzoate (120 mg, 0.20 mmol) was dissolved in methanol, and a solution of lithium hydroxide (74 mg, 3.08 mmol) in water (2 mL) was added, and the reaction solution was stirred at 25 ° C for 16 hours. Dilute with water, extract with ether, adjust the aqueous phase to pH 4 with hydrochloric acid, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and evaporate the thin layer to obtain 80 mg. MS: 559.3 [M + H] ⁺ .

Step 5) 4-((2-((2-Allylacylamino-4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidin-4-yl) Preparation of amino) benzoic acid

4-((2-((2-((tert-butoxycarbonyl) amino) -4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidine-4 -Amino) amino) benzoic acid (80 mg, 0.14 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added, and reacted at 25 ° C for 3 hours. The reaction solution was evaporated to dryness, and a brown oil was dissolved in tetrahydrofuran (2 mL). Allyl chloride (10 mg, 0.11 mmol) was added dropwise at 0 ° C, and the mixture was reacted at 25 ° C for 30 minutes. The reaction solution was quenched with saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered and evaporated to dryness to obtain 5 mg of a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.67 (s, 1H), 9.56 (s, 1H), 8.93 (s, 1H), 8.48 (s, 1H), 8.30 (s, 1H), 7.96- 7.55 (m, 4H), 7.31 (s, 1H), 7.25-7.05 (m, 1H), 6.82 (d, J = 8.9Hz, 1H), 6.52 (dd, J = 17.0, 10.2Hz, 1H), 6.24 (d, J = 17.1 Hz, 1H), 5.74 (d, J = 10.1 Hz, 1H), 3.19-3.06 (m, 4H), 2.66-2.53 (m, 4H), 2.41-2.29 (m, 2H), 1.05 (t, J = 7.1Hz, 3H). MS: 513.2 [M + H] ⁺ .

Example 132.4-((2-((2-Allylacylamino-4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidin-4-yl) amine Preparation of benzamide

Step 1) Preparation of 4-((5-carbamoyl-2-chloropyrimidin-4-yl) amino) benzoic acid tert-butyl ester

The operation was the same as in Example 131, and tert-butyl 4-aminobenzoate was used instead of ethyl 4-aminobenzoate.

Step 2) Preparation of 4-((2-chloro-5-cyanopyrimidin-4-yl) amino) benzoyl chloride:

4-((5-carbamoyl-2-chloropyrimidin-4-yl) amino) benzoic acid tert-butyl ester (450 mg, 1.29 mmol) was dissolved in phosphorus oxychloride (6 mL) and reacted at 110 ° C for 3 hours . The reaction solution was evaporated to dryness, and the reaction was quenched by adding crushed ice, and filtered to obtain 300 mg of a yellow solid. MS: 293.0 [M + H] ⁺ .

Step 3) Preparation of 4-((2-chloro-5-cyanopyrimidin-4-yl) amino) benzamide

4-((2-Chloro-5-cyanopyrimidin-4-yl) amino) benzoyl chloride (45 mg, 0.15 mmol) was dissolved in tetrahydrofuran (4 mL), and aqueous ammonia (20 mg, 30%) was added dropwise at -10 ° C. ), The reaction solution was stirred at low temperature for 10 minutes. Water was added and filtered to obtain 30 mg of a yellow solid. MS: 274.0 [M + H] ⁺ .

Step 4) (2-((4-((4-aminoformylphenyl) amino) -5-cyanopyrimidin-2-yl) amino) -5- (4-ethylpiperazine-1 -Yl) phenyl) amino t-butyl carbamate

The operation was the same as in Example 131, and 4-((2-chloro-5-cyanopyrimidin-4-yl) amino) benzamide was used instead of 4-((2-chloro-5-cyanopyrimidin-4-yl). Amino) ethyl benzoate.

Step 5) 4-((2-((2-Allylacylamino-4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidin-4-yl) Preparation of amino) benzamide

The operation was the same as in Example 131, and (2-((4-((4-aminoformylphenyl) amino) -5-cyanopyrimidin-2-yl) amino) -5- (4-ethyl Piperazin-1-yl) phenyl) carbamic acid tert-butyl ester instead of 4-((2-((2-((tert-butoxycarbonyl) amino) -4--4-ethylpiperazine-1- Group) phenyl) amino) -5-cyanopyrimidin-4-yl) amino) benzoic acid to finally obtain a white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.69 (s, 1 H), 9.49 (s, 1H), 8.88 (s, 1H), 8.45 (s, 1H), 7.93-7.66 (m, 4H), 7.66-7.52 (m, 1H), 7.44-7.28 (m, 1H), 7.28- 7.14 (m, 2H), 6.81 (d, J = 9.0 Hz, 1H), 6.49 (dd, J = 16.8, 10.1 Hz, 1H), 6.24 (dd, J = 17.0, 1.9 Hz, 1H), 5.74 (d , J = 10.2Hz, 1H), 3.19-3.06 (m, 4H), 2.72-2.51 (m, 4H), 2.38 (q, J = 7.2Hz, 2H), 1.04 (t, J = 7.1Hz, 3H) .MS: 512.2 [M + H] ⁺ .

The compounds in the following table were operated with reference to Example 132, and different R'H was used instead of the ammonia synthesis in step 3).

Example 136.N- (2-((5-cyano-4-((4-hydroxyphenyl) amino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine-1 -Yl) phenyl) acrylamide

Step 1) Preparation of 2-chloro-4-((4-methoxyphenyl) amino) pyrimidine-5-carboxamide:

The operation is the same as step 1) of Example 1, and 4-methoxyaniline is used instead of isopropylamine.

Step 2) Preparation of 2-chloro-4-((4-methoxyphenyl) amino) pyrimidine-5-carbonitrile

The operation is the same as that in Example 2 step 2), and 2-chloro-4-((4-methoxyphenyl) amino) pyrimidine-5-carboxamide is used instead of 2-chloro-4- (isopropylamino) pyrimidine -5-formamide.

Step 3) Preparation of 2-chloro-4-((4-hydroxyphenyl) amino) pyrimidine-5-carbonitrile

2-Chloro-4-((4-methoxyphenyl) amino) pyrimidine-5-carbonitrile (780 mg, 2.99 mmo) was dissolved in dichloromethane (8 mL), and boron tribromide was added dropwise at 0 ° C. A solution of dichloromethane (1M, 9 mL) was reacted at 25 ° C for 3 hours. Saturated ammonium chloride was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 130 mg of a yellow solid. MS: 247.0 [M + H] ⁺ .

Step 4): (2-((5-cyano-4-((4-hydroxyphenyl) amino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl ) Phenyl) t-butylaminocarbamate

The operation was the same as that in step 3) of Example 1, and 2-chloro-4-((4-hydroxyphenyl) amino) pyrimidine-5-carbonitrile was used instead of 2-chloro-4- (isopropylamino) pyrimidine-5 -Nitrile.

Step 5) N- (2-((5-cyano-4-((4-hydroxyphenyl) amino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine-1- Of phenyl) phenyl) acrylamide

The operation is the same as that in Example 4 step 4), using (2-((5-cyano-4-((4-hydroxyphenyl) amino) pyrimidin-2-yl) amino) -5- (4-ethyl Piperazin-1-yl) phenyl) carbamic acid tert-butyl ester instead of (2-((5-cyano-4- (isopropylamino) pyrimidin-2-yl) amino) -5- (4 -Ethylpiperazin-1-yl) phenyl) carbamic acid tert-butyl ester. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.66 (s, 1H), 9.25 (s, 1H), 9.11 (s, 1H), 8.68 (s, 1H), 8.34 (s, 1H), 7.45- 7.13 (m, 4H), 6.74 (d, J = 8.9 Hz, 1H), 6.69-6.56 (m, 2H), 6.48 (dd, J = 16.9, 10.1 Hz, 1H), 6.23 (d, J = 17.0 Hz , 1H), 5.74 (d, J = 10.1 Hz, 1H), 3.17-3.03 (m, 4H), 2.59-2.51 (m, 4H), 2.38 (q, J = 7.1 Hz, 2H), 1.04 (t, J = 7.1Hz, 3H). MS: 485.2 [M + H] ⁺ .

The compounds in the table below were synthesized with reference to Example 136.

Example 141. 3- (4-((2-((2-Allylacylamino-4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidine- Preparation of 4-yl) amino) phenoxy) propionic acid

Step 1) to Step 4) are the same as Step 1) to Step 4) of Example 136.

Step 5) 3- (4-((2-((2-((tert-butoxycarbonyl) amino-4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyano Of Pyrimidin-4-yl) amino) phenoxy) propionic acid

(2-((5-cyano-4-((4-hydroxyphenyl) amino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl ) Tert-butyl aminoformate (200 mg, 0.38 mmol) was dissolved in DMF (2 mL), sodium hydride (60%, 38 mg, 0.95 mmol) was added at 0 ° C, and after stirring at 25 ° C for 2 hours, 3-bromopropionic acid ( 116 mg, 0.76 mmol), and reacted at 25 ° C for 16 hours. It was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered to dryness to obtain 80 mg of a yellow oil, MS: 603 [M + H] ⁺ .

Step 6): 3- (4-((2-((2-Allylacylamino-4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidine- Preparation of 4-yl) amino) phenoxy) propionic acid

The operation was the same as that in step 4) of Example 1, using 3- (4-((2-((2-((tert-butoxycarbonyl) amino-4- (4-ethylpiperazin-1-yl) phenyl)) Amine) -5-cyanopyrimidin-4-yl) amino) phenoxy) propionic acid instead of (2-((5-cyano-4- (isopropylamino) pyrimidin-2-yl) amine ) -5- (4-ethylpiperazin-1-yl) phenyl) carbamic acid tert-butyl ester. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.73 (s, 1H), 9.27 (s, 1H), 8.73 (s, 1H), 8.48-8.28 (m, 2H), 7.39-7.13 (m, 4H), 6.87-6.64 (m, 3H), 6.50 (dd, J = 16.9, 10.1Hz, 1H) , 6.24 (d, J = 17.0 Hz, 1H), 5.74 (d, J = 10.3 Hz, 1H), 4.21-3.97 (m, 2H), 3.24-2.98 (m, 4H), 2.73-2.59 (m, 4H ), 2.59-2.54 (m, 2H), 2.43-2.34 (m, 2H), 1.13-0.98 (m, 3H). MS: 557.3 [M + H] ⁺ .

Example 142. N- (4-Chloro-2-((5-cyano-4- (cyclobutylamino) pyrimidin-2-yl) amino) -5- (4- (ethyl (methyl ) Amino) piperidine-1-yl) phenyl) acrylamide

The same operation as in Example 1 was carried out. Cyclobutylamine was used instead of step 1) isopropylamine. (2-Amino-4-chloro-5- (4- (ethyl (methyl) amino) piperidine) Pyridin-1-yl) phenyl) t-butylaminocarbamate was performed in place of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) carbamate in step 3). The reaction gave a white solid product;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.81 (s, 1H), 8.87 (s, 1H), 8.29 (s, 1H), 7.92 (d, J = 6.9 Hz, 1H), 7.83 (s, 1H), 7.45 (s, 1H), 6.50 (dd, J = 17.0, 10.1 Hz, 1H), 6.27 (dd, J = 16.9, 2.0 Hz, 1H), 5.78 (dd, J = 10.1, 2.0 Hz, 1H ), 4.41 (s, 1H), 3.29 (s, 2H), 2.66-2.52 (m, 5H), 2.24 (s, 3H), 2.21-2.03 (m, 4H), 1.81 (d, J = 11Hz, 2H), 1.71-1.51 (m, 4H), 1.01 (t, J = 7.1Hz, 3H). MS: 509 [M + H] ⁺ ;

Example 143. 2- (4- (3-Allylacylamino-4-((5-cyano-4- (cyclobutylamino) pyrimidin-2-yl) amino) phenyl) piperazine Preparation of 1-1-yl) acetic acid

Step 1) and step 2) were performed in the same manner as in step 1) and step 2) of Example 1, and cyclobutylamine was used instead of isopropylamine.

Step 3) 2- (4- (3-((tert-butoxycarbonyl) amino) -4-((5-cyano-4- (cyclobutylamino) pyrimidin-2-yl) amino) benzene Of phenyl) piperazin-1-yl) t-butyl acetate

The operation is the same as that in step 3) of Example 1, using 2-chloro-4- (cyclobutylamino) pyrimidine-5-carbonitrile and 2- (4- (4-amino-3-((tert-butoxycarbonyl)) Amino) phenyl) piperazin-1-yl) t-butyl acetate was synthesized.

Step 4) 2- (4- (3-Allylacylamino-4-((5-cyano-4- (cyclobutylamino) pyrimidin-2-yl) amino) phenyl) piperazine- Preparation of 1-yl) acetic acid

2- (4- (3-((tert-butoxycarbonyl) amino) -4-((5-cyano-4- (cyclobutylamino) pyrimidin-2-yl) amino) phenyl) Piperazin-1-yl) t-butyl acetate (120 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was reacted at 25 ° C for 4 hours. The reaction solution was evaporated to dryness, and the oil was dissolved in tetrahydrofuran (2.5 mL). Acryloyl chloride (22 mg, 0.24 mmol) was added dropwise at 0 ° C, and the reaction was carried out for 30 minutes. Quench with water, extract with dichloromethane, wash with saturated sodium bicarbonate, separate the organic phase, dry, concentrate, and obtain 30 mg of white solid by column chromatography. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.73 (s, 1 H ), 8.66 (s, 1H), 8.23 (s, 1H), 7.79 (d, J = 7.0Hz, 1H), 7.46 (s, 1H), 7.19 (s, 1H), 6.82 (d, J = 9.0Hz , 1H), 6.50 (dd, J = 17.0, 10.2 Hz, 1H), 6.25 (d, J = 17.0 Hz, 1H), 5.75 (d, J = 10.1 Hz, 1H), 4.73-4.42 (m, 1H) , 4.42-4.12 (m, 1H), 3.21 (s, 2H), 3.14 (t, J = 5.0Hz, 4H), 2.73 (t, J = 4.9Hz, 4H), 2.17-1.99 (m, 4H), 1.70-1.46 (m, 2H) .MS: 477.2 [M + H] ⁺ ;

The compounds in the following table were synthesized by referring to Example 143 and substituting the corresponding R'H for cyclobutylamine.

The compounds listed in the following table were synthesized from the raw materials A and B by referring to the related examples.

The compounds listed in the following table were synthesized from the corresponding starting materials A and B by referring to Example 1.

Example 167. N- (2-((5-Cyano-4- (phenylamino) pyrimidin-2-yl) amino) -5- (2- (dimethylamino) ethoxy) benzene Acrylamide

Step 1) Preparation of 2-((4-hydroxy-2-nitrophenyl) amino) -4- (phenylamino) pyrimidine-5-carbonitrile

Add 2-chloro-4- (phenylamino) pyrimidine-5-carbonitrile (2.3 g, 10 mmol), 4-hydroxy-2-nitroaniline (1.5 g, 10 mmol), and trifluoroacetic acid (10 μl) ) Was added to a sealed tube of tert-butanol (15 mL), heated to 120 ° C. and stirred for 12 hours, cooled, concentrated, purified using column chromatography to obtain 3.1 g of yellow solid, MS: 349 [M + H] ⁺ ;

Step 2) Preparation of 2-((4- (2-bromoethoxy) -hydroxy-2-nitrophenyl) amino) -4- (phenylamineamino) pyrimidine-5-carbonitrile

2-((4-hydroxy-2-nitrophenyl) amino) -4- (phenylamino) pyrimidine-5-carbonitrile (3.1 g), 1,2-dibromoethane (3 mL ) And cesium carbonate (3g) were added to DMF (20mL), heated to 120 ° C for 6 hours, cooled, quenched with water, extracted with ethyl acetate, dried in organic phase and concentrated to obtain 3.5g of dark yellow solid product, MS : 455 [M + H] ⁺ ;

Step 3) 2-((4- (2- (dimethylamino) ethoxy) -hydroxy-2-nitrophenyl) amino) -4- (phenylamino) pyrimidine-5-carbonitrile Preparation

The intermediate 2-((4- (2-bromoethoxy) -hydroxy-2-nitrophenyl) amino) -4- (phenylamino) pyrimidine-5-carbonitrile (130 mg, 0.3 mmol), dimethylamine in tetrahydrofuran (2M, 1mL) was added to NMP (5mL) containing DIEA (1mL), heated to 120 ° C and stirred for 5 hours, cooled, quenched with water, extracted with ethyl acetate, saturated chlorinated Wash with sodium, dry the organic phase, and concentrate to obtain 110 mg of yellow solid product, MS: 420 [M + H] ⁺ ;

Step 4) N- (2-((5-cyano-4- (phenylamino) pyrimidin-2-yl) amino) -5- (2- (dimethylamino) ethoxy) phenyl ) Preparation of acrylamide

The intermediate 2-((4- (2- (dimethylamino) ethoxy) -hydroxy-2-nitrophenyl) amino) -4- (phenylamino) pyrimidine-5-carbonitrile (110mg), zinc powder (650mg, 10mmol) was added to an ethanol (10mL) solution containing ammonium chloride (1g, 19mmol), stirred overnight, filtered, extracted with dichloromethane, washed with saturated sodium bicarbonate, and taken the organic phase Dry, concentrate, dissolve in anhydrous tetrahydrofuran (2mL), add acryloyl chloride (50 microliters) dropwise under ice water bath conditions, and continue the reaction for half an hour, quench with water, extract with dichloromethane, and wash with saturated sodium bicarbonate The organic phase was dried, concentrated, and purified using a preparative sheet (0.5 mm) to obtain 33 mg of a white solid product, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.62 (s, 1 H), 9.34 (s, 1 H), 8.92 ( s, 1H), 8.44 (s, 1H), 7.51 (br, 2H), 7.42-7.15 (m, 4H), 7.03 (s, 1H), 6.76 (d, J = 8.9Hz, 1H), 6.52 (dd , J = 16.9, 10.1 Hz, 1H), 6.24 (d, J = 17.1 Hz, 1H), 5.74 (d, J = 10.1 Hz, 1H), 4.04 (t, J = 5.7 Hz, 2H), 2.64 (t , J = 5.7Hz, 2H), 2.23 (s, 6H). MS: 444 [M + H] ⁺ ;

The compounds in the following table were obtained by following the procedure of Example 167 and synthesized by the corresponding R "X instead of dibromoethane.

Example 173. N- (2-((5-Cyano-4- (phenylamino) pyrimidin-2-yl) amino) -4- (4-methylpiperazin-1-yl) phenyl )Acrylamide

Step 1) Preparation of 2-((5-fluoro-2-nitrophenyl) amino) -4- (phenylamino) pyrimidine-5-carbonitrile

2-chloro-4- (aniline) pyrimidine-5-carbonitrile (700 mg, 3 mml), 5-fluoro-2-nitroaniline (500 mg, 3 mmol), Pd ₂ (dba) ₃ (30 mg), Xantphos (30 mg ), Cs ₂ CO ₃ (1 g, 3 mmol) were added to sealed tubes containing toluene (10 mL), replaced with argon, heated to 110 ° C. for 12 hours, cooled, filtered, and the filtrate was concentrated by column chromatography to obtain 330 mg of a yellow solid. MS: 351 [M + H] ⁺ ;

Step 2) Preparation of 2-((5- (4-methylpiperazin-1-yl) -2-nitrophenyl) amino) -4- (phenylamino) pyrimidine-5-carbonitrile

2-((5-fluoro-2-nitrophenyl) amino) -4- (phenylamino) pyrimidine-5-carbonitrile (110mg, 0.3mmol), methylpiperazine (1mL) was added to In NMP (5mL) solvent, the reaction was heated to 120 ° C for two hours, cooled, slurried with water, and filtered to obtain 94 mg of a yellow solid product, MS: 431 [M + H] ⁺ ;

Step 3) Preparation of 2-((5- (4-methylpiperazin-1-yl) -2-nitrophenyl) amino) -4- (aniline) pyrimidine-5-carbonitrile

2-((5- (4-methylpiperazin-1-yl) -2-nitrophenyl) amino) -4- (phenylamino) pyrimidine-5-carbonitrile (94 mg, 0.22 mmol) , Zinc powder (330g, 6mmol) was added to a solution of ammonium chloride (1.1g, 20mmol) in ethanol (10mL), stirred at room temperature for half an hour, quenched with water, extracted with dichloromethane, dried, and concentrated to give a light purple oil. Compound 80mg, MS: 401 [M + H] ⁺ ;

Step 4) N- (2-((5-cyano-4- (phenylamino) pyrimidin-2-yl) amino) -4- (4-methylpiperazin-1-yl) phenyl) Acrylamide

In an ice-water bath condition, it contains 2-((5- (4-methylpiperazin-1-yl) -2-nitrophenyl) amino) -4- (aniline) pyrimidine-5-carbonitrile. (80 mg, 0.2 mmol) of tetrahydrofuran (1 mL) was added dropwise with acryloyl chloride (2 drops, 30 mg), and the reaction was stirred for half an hour, quenched with water, extracted with dichloromethane, washed with saturated sodium bicarbonate, dried and concentrated the organic phase. Purified by preparative thin plate chromatography to obtain 33 mg of white solid product, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.66 (s, 1 H), 9.36 (s, 1 H), 8.94 (s, 1 H), 8.47 (s , 1H), 7.59-7.57 (m, 2H), 7.37 (d, J = 8.9Hz, 1H), 7.22-7.20 (m, 2H), 7.11 (d, J = 2.8Hz, 1H), 7.05-7.03 ( m, 1H), 6.80 (d, J = 8.9 Hz, 1H), 6.46 (dd, J = 17.0, 10.2 Hz, 1H), 6.23 (d, J = 17.0 Hz, 1H), 5.73 (d, J = 10.1 Hz, 1H), 3.00 (t, J = 4.9 Hz, 4H), 2.39 (t, J = 4.9 Hz, 4H), 2.21 (s, 3H). MS: 455 [M + H] ⁺ .

The compounds in the following table were synthesized by referring to Example 173 using the corresponding R ₃ H

Example 176. N- (2-((5-cyano-4- (phenylamino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) -3 -Methylphenyl) acrylamide

Step 1) (2-((5-cyano-4- (phenylamino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) -3-methyl Preparation of tert-butyl phenyl) aminoformate

The intermediate 2-chloro-4- (phenylamino) pyrimidin-5-cyano (60 mg, 0.25 mmol) and the intermediate 12 (2-amino-5- (4-ethylpiperazin-1-yl ) -3-Methylphenyl) amino carboxylic acid tert-butyl ester (82 mg, 0.25 mmol) and trifluoroacetic acid (10 μl) were added to a sealed tube of sec-butanol (5 mL), and heated at 120 ° C. for 8 hours , Cooled, concentrated, purified from a silica gel preparative thin plate (0.5 mm) (developing phase dichloromethane / methanol = 20/1) to obtain 65 mg of pale yellow solid product, MS: 529 [M + H] ⁺

Step 2) N- (2-((5-cyano-4- (phenylamino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) -3- Preparation of (methylphenyl) acrylamide

The same operation as in step 1) of Example 1 was performed from N- (2-((5-cyano-4- (phenylamino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine- 1-yl) -3-methylphenyl) acrylamide reacts to give a white solid product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 9.29 (s, 1H), 9.17 (s, 1H), 8.62 (s, 1H), 8.46 (d, J = 10.6 Hz, 1H), 7.76-7.28 (m, 3H), 7.00 (br, 1H), 6.91 (br, 1H), 6.70 (d, J = 28.4Hz, 1H), 6.55 (br, 1H), 6.19 (d, J = 16.8Hz, 1H), 5.69 (d, J = 10.2Hz, 1H), 3.30 (br, 4H), 3.15 (br, 4H), 2.40 (br, 2H), 2.06 (s, 3H), 1.13-0.96 (m, 3H) .MS: 483 [M + H] ⁺

Example 177. N- (2-((5-cyano-4- (cyclohexylamino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) -3 -Methylphenyl) acrylamide

Step 1) (2-((5-cyano-4- (cyclohexylamino) pyrimidin-2-ylamino))-5- (4-ethylpiperazin-1-yl) -3-methylbenzene Preparation of t-butylaminocarbamate

The intermediate 2-chloro-4- (cyclohexylamino) pyrimidin-5-cyano (60 mg, 0.25 mmol) and the intermediate (2-amino-5- (4-ethylpiperazin-1-yl) Tert-butyl-3-methylphenyl) carbamate (82 mg, 0.25 mmol) and trifluoroacetic acid (10 µl) were added to a sealed tube of sec-butanol (5 mL), and heated at 120 ° C for 8 hours. Cool, concentrate, and purify from a silica gel preparative sheet (0.5 mm) (developing phase: dichloromethane / methanol = 20/1) to obtain 65 mg of pale yellow solid product. MS: 535 [M + H] ⁺

Step 2) N- (2-((5-cyano-4- (cyclohexylamino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) -3- Preparation of (methylphenyl) acrylamide

Same as step 4) in Example 1, from (2-((5-cyano-4- (cyclohexylamino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine-1- The reaction of tert-butyl 3-methylphenyl) carbamate gave a white solid product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (d, J = 19.0 Hz, 1H), 8.21 (br, 2H), 7.25 (br, 2H), 6.66 (s, 1H), 6.53 (dd, J = 17.0, 10.2 Hz, 1H), 6.19 (d, J = 16.9 Hz, 1H), 5.69 (dd, J = 10.1, 2.2 Hz, 1H), 3.30 (br, 4H), 3.11 (br, 4H), 2.57-2.50 (m, 1H), 2.38 (br, 2H), 2.07 (br, 3H), 1.86-1.68 (m, 2H), 1.66-1.34 (m, 5H), 1.32-1.10 (m, 2H), 1.04 (t, J = 7.2Hz, 3H). MS: 489 [M + H] ⁺

Example 178. N- (2-((5-cyano-4- (phenylamino) pyrimidin-2-yl) amino) -5- (morpholinemethyl) phenyl) acrylamide

Step 1) Preparation of 2-((4- (morpholinemethyl) -2-nitrophenyl) amino) -4- (phenylamino) pyrimidine-5-carbonitrile

4- (morpholinemethyl) -2-nitroaniline (240mg, 1mmol), 2-chloro-4- (phenylamino) pyrimidine-5-carbonitrile (230mg, 1mmol), Pd (OAc) ₂ (10 mg), Xantphos (10 mg), Na ₂ CO ₃ (210 mg, 2 mmol), and dioxane (2 mL) were added to 15 mL sealed tubes. After replacing with argon, the reaction was heated under sealed conditions for 10 hours, cooled, and used. Preparative thin plate chromatography purification gave 180 mg of yellow solid product, MS: 432 [M + H] ⁺ ;

Step 2) Preparation of 2-((2-amino-4- (morpholinemethyl) phenyl) amino) -4- (phenylamino) pyrimidine-5-carbonitrile

Add 2-((4- (morpholinemethyl) -2-nitrophenyl) amino) -4- (phenylamino) pyrimidine-5-carbonitrile (100 mg, 0.25 mmol), zinc powder (330 g , 6 mmol) were added to a solution of ammonium chloride (1.1 g, 20 mmol) in ethanol (10 mL), stirred at room temperature for half an hour, quenched with water, extracted with dichloromethane, dried, and concentrated to obtain 80 mg of a light purple oil directly used Next step

Step 3) Preparation of N- (2-((5-cyano-4- (phenylamino) pyrimidin-2-yl) amino) -5- (morpholinemethyl) phenyl) acrylamide

Under ice-water bath conditions, tetrahydrofuran (1 mL containing 2-((2-amino-4- (morpholinemethyl) phenyl) amino) -4- (phenylamino) pyrimidine-5-carbonitrile ) Acryloyl chloride (2 drops, 30 mg) was added dropwise, and the reaction was stirred for half an hour, quenched by addition of water, extracted with dichloromethane, washed with saturated sodium bicarbonate, dried, concentrated, and purified by preparative thin plate chromatography to obtain a white solid Product; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.79 (s, 1H), 9.40 (s, 1H), 9.00 (s, 1H), 8.47 (s, 1H), 7.68-7.42 (m, 4H ), 7.22 (br, 2H), 7.15-7.00 (m, 2H), 6.50 (dd, J = 17.0, 10.1 Hz, 1H), 6.26 (d, J = 17.0 Hz, 1H), 5.76 (d, J = 10.1Hz, 1H), 3.59 (t, J = 4.5Hz, 4H), 3.45 (s, 2H), 2.36 (t, J = 4.5Hz, 4H). MS: 456 [M + H] ⁺ ;

Example 179. N- (4-Chloro-2-((5-cyano-4-((3-methoxyphenyl) amino) pyrimidin-2-yl) amino) -5- (4- Ethylpiperazin-1-yl) phenyl) acrylamide

The same operation as in Example 1 was carried out, and 3-methoxyaniline was used instead of step 1) isopropylamine. (2-amino-4-chloro-5- (4-ethylpiperazin-1-yl) described in intermediate 17 Phenyl) tert-butylaminoformate was used in place of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) tert-butylaminoformate in step 3) to obtain a white solid product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.85 (s, 1H), 9.34 (s, 1H), 9.03 (s, 1H), 8.47 (s, 1H), 7.61 (s, 1H), 7.50 ( s, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.16-7.14 (m, 2H), 6.64 (d, J = 8.1 Hz, 1H), 6.51 (dd, J = 16.8, 10.2 Hz, 1H ), 6.30-6.21 (m, 1H), 5.77 (d, J = 10.3 Hz, 1H), 3.65 (s, 3H), 3.02 (br, 4H), 2.72 (br, 4H), 2.57 (br, 2H) 1.09 (t, J = 7.1 Hz, 3H). MS: 533 [M + H] ⁺ .

Example 180.N- (4-Chloro-2-((5-cyano-4-((2-fluoro-6-methoxybenzyl) amino) pyrimidin-2-yl) amino) -5 -(4-ethylpiperazin-1-yl) phenyl) acrylamide

The same operation as in Example 1 was carried out, and 2-fluoro-6-methoxybenzylamine was used instead of step 1) isopropylamine. (2-amino-4-chloro-5- (4-ethylpiperazine) described in intermediate 17 1-yl) phenyl) t-butylaminoformate was used in place of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) aminoformate in step 3) The product was obtained as a white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.86 (s, 1H), 8.84 (s, 1H), 8.30 (s, 1H), 7.83 (s, 1H), 7.70 (s, 1H), 7.41 (s, 1H), 7.32 (br, 1H), 6.87 (d, J = 8.4Hz, 1H), 6.78 (t, J = 8.9Hz, 1H), 6.51 (dd, J = 17.1, 10.1 Hz, 1H), 6.29 (d, J = 17.3 Hz, 1H), 5.84-5.76 (m, 1H), 4.56 (d, J = 4.9 Hz, 2H), 3.80 (s, 3H), 2.95 (br, 4H ), 2.52 (br, 4H), 2.38 (q, J = 7.2 Hz, 2H), 1.02 (t, J = 7.1 Hz, 3H). MS: 565 [M + H] ⁺ .

Example 181. N- (4-Chloro-2-((5-cyano-4- (cyclobutylamino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine-1 -Yl) phenyl) acrylamide

The same operation as in Example 1 was carried out, in which cyclobutylamine was used instead of step 1) isopropylamine, and (2-amino-4-chloro-5- (4-ethylpiperazin-1-yl) phenyl) described in intermediate 17 Tert-butyl aminoformate was used in place of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) aminocarbamic acid tert-butyl ester of step 3), and a white solid product was obtained. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.94 (s, 1H), 8.87 (s, 1H), 8.29 (s, 1H), 7.92-7.88 (m, 2H), 7.43 (s, 1H), 6.50 (d , J = 13.1 Hz, 1H), 6.28 (d, J = 16.3 Hz, 1H), 5.79 (d, J = 9.8 Hz, 1H), 4.41 (br, 1H), 2.99 (br, 4H), 2.61 (br , 4H), 2.45 (br, 2H), 2.19-2.07 (m, 4H), 1.67-1.54 (m, 2H), 1.05 (br, 3H). MS: 481 [M + H] ⁺ .

Example 182. N- (4-Chloro-2-((5-cyano-4- (phenylamino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine-1- ) Phenyl) acrylamide

The same operation as in Example 1 was performed, in which step 1) isopropylamine was replaced by aniline, and (2-amino-4-chloro-5- (4-ethylpiperazin-1-yl) phenyl) amino group described in intermediate 17 Tert-butyl formate was used instead of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) amino formate in step 3) and the same reaction was performed to obtain a white solid product; ¹ H NMR (400 MHz DMSO-d ₆ ) δ9.76 (s, 1H), 9.38 (s, 1H), 8.99 (s, 1H), 8.47 (s, 1H), 7.63-7.48 (m, 4H), 7.27-7.23 (m , 2H), 7.06 (br, 1H), 6.50 (dd, J = 17.0, 10.2 Hz, 1H), 6.26 (d, J = 17.0 Hz, 1H), 5.80-5.72 (m, 1H), 3.00-2.93 ( m, 4H), 2.55 (br, 4H), 2.40 (q, J = 7.1 Hz, 2H), 1.04 (t, J = 7.1 Hz, 3H). MS: 503 [M + H] ⁺ .

Example 183. N- (4-Chloro-2-((5-cyano-4-((3-methoxyphenyl) amino) pyrimidin-2-yl) amino) -5- (4- (Dimethylamino) piperidin-1-yl) phenyl) acrylamide

The same operation as in Example 1 was performed, in which step 1) isopropylamine was replaced by 3-methoxyaniline, and (2-amino-4-chloro-5- (4- (dimethylamino) piperidine) described in Intermediate 11- 1-yl) phenyl) t-butylaminoformate was used in place of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) aminotformate in step 3) to obtain the same reaction. Product as a white solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.76 (s, 1H), 9.33 (s, 1H), 9.01 (s, 1H), 8.47 (s, 1H), 7.59 (s, 1H ), 7.50 (s, 1H), 7.24 (s, 1H), 7.15 (br, 2H), 6.64 (d, J = 8.2 Hz, 1H), 6.49 (dd, J = 17.0, 10.1 Hz, 1H), 6.30 -6.20 (m, 1H), 5.76 (d, J = 10.3 Hz, 1H), 3.65 (s, 3H), 3.34-3.25 (m, 2H), 2.60 (t, J = 11.4 Hz, 2H), 2.22 ( br, 7H), 1.86 (d, J = 12.2 Hz, 2H), 1.63-1.52 (m, 2H). MS: 547 [M + H] ⁺ ;

Example 184.N- (4-Chloro-2-((5-cyano-4-((2-fluoro-6-methoxyphenyl) amino) pyrimidin-2-yl) amino) -5 Preparation of-(4- (dimethylamino) piperidin-1-yl) phenyl) acrylamide

The same operation as in Example 1 was carried out, and 2-fluoro-6-methoxybenzylamine was used instead of step 1) isopropylamine. The (2-amino-4-chloro-5- (4- (dimethyl) Amino) piperidin-1-yl) phenyl) carbamic acid tert-butyl ester Instead of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) carbamic acid tert. Of step 3) Butyl ester was subjected to the same reaction to obtain a white solid product; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.82 (s, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 7.81 (s, 1H) , 7.70 (s, 1H), 7.44 (s, 1H), 7.32 (br, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.78 (br, 1H), 6.51 (dd, J = 17.0, 10.1 Hz, 1H), 6.33-6.24 (m, 1H), 5.79 (d, J = 10.2 Hz, 1H), 4.56 (d, J = 4.8 Hz, 2H), 3.80 (s, 3H), 3.27 (br, 2H ), 2.59 (t, J = 11.2 Hz, 2H), 2.20 (br, 7H), 1.84 (d, J = 11.9 Hz, 2H), 1.54 (t, J = 11.4 Hz, 2H). MS: 579 [M + H] ⁺ ;

Example 185. N- (4-Chloro-2-((5-cyano-4- (cyclopropylamino) pyrimidin-2-yl) amino) -5- (4- (dimethylamino) piperidine -1-yl) phenyl) acrylamide

The same operation as in Example 1 was carried out, in which cyclobutylamine was used instead of step 1) isopropylamine, and (2-amino-4-chloro-5- (4- (dimethylamino) piperidin-1-yl) described in intermediate 11 ) Phenyl) tert-butylaminoformate was used instead of tert-butyl (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) aminoformate in step 3) to give a white solid product. ;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.81 (s, 1H), 8.84 (s, 1H), 8.29 (s, 1H), 7.90 (d, J = 6.9 Hz, 1H), 7.84 (s, 1H), 7.44 (s, 1H), 6.50 (dd, J = 16.9, 10.2 Hz, 1H), 6.27 (dd, J = 16.9, 2.0 Hz, 1H), 5.79 (dd, J = 10.1, 2.0 Hz, 1H ), 4.41 (s, 1H), 3.28 (br, 2H), 2.60 (t, J = 11.3 Hz, 2H), 2.28-2.06 (m, 11H), 1.85 (br, 2H), 1.67-1.52 (m, 4H) .MS: 495 [M + H] ⁺ ;

Example 186. N- (4-Chloro-2-((5-cyano-4- (phenylamino) pyrimidin-2-yl) amino) -5- (4- (dimethylamino) piper Pyridin-1-yl) phenyl) acrylamide

The same operation as in Example 1 was performed, in which step 1) isopropylamine was replaced by aniline, and (2-amino-4-chloro-5- (4- (dimethylamino) piperidin-1-yl) benzene described in intermediate 11 Tert-butylaminocarbamate instead of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) aminocarbamate in step 3) and the same reaction was performed to obtain a white solid product;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.73 (s, 1H), 9.37 (s, 1H), 9.00 (s, 1H), 8.47 (s, 1H), 7.59-7.53 (m, 4H), 7.25 (br, 2H), 7.06 (br, 1H), 6.50 (dd, J = 17.0, 10.1 Hz, 1H), 6.25 (dd, J = 16.9 Hz, 1H), 5.76 (dd, J = 10.1, 2.0 Hz) , 1H), 3.30 (br, 2H), 2.60 (t, J = 11.3 Hz, 2H), 2.22 (br, 7H), 1.92-1.82 (m, 2H), 1.63-1.50 (m, 2H). MS: 517 [M + H] ⁺ ;

Example 187.N- (2-((5-cyano-4- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) -5- (4-ethyl Preparation of piperazin-1-yl) phenyl) acrylamide

Step 1) Preparation of 4- (1-methyl-1H-pyrazol-4-yl) -2- (methylthio) pyrimidine-5-carbonitrile:

4-Chloro-2- (methylthio) pyrimidine-5-carbonitrile (400 mg, 2.15 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborane-2-yl) -1H-pyrazole (780 mg, 3.74 mmol), Pd (dppf) Cl ₂ (185 mg, 0.25 mmol), potassium acetate (422 mg, 4.31 mmol) dissolved in dioxane (10 mL) and water (2 mL) in a mixed solvent at 90 ° C. for 16 hours. The reaction solution was evaporated to dryness and column chromatography to obtain 300 mg of off-white solid, MS: 232 [M + H] ⁺ .

Step 2) Preparation of 4- (1-methyl-1H-pyrazol-4-yl) -2- (methylsulfoxide) pyrimidine-5-carbonitrile:

Add 4- (1-methyl-1H-pyrazol-4-yl) -2- (methylthio) pyrimidine-5-carbonitrile (220 mg, 0.95 mmol) to ethylene glycol dimethyl ether (10 mL), Add m-chloroperoxybenzoic acid (197 mg, 1.14 mmol) slowly, and react at 25 ° C for 2 hours. Petroleum ether was added to the reaction solution, and 175 mg of an off-white solid was obtained by filtration, MS: 248 [M + H] ⁺ .

Step 3) (2-((5-cyano-4- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine- Preparation of 1-yl) phenyl) amino carboxylic acid tert-butyl ester:

The operation was the same as that in step 3 of Example 6, and 4- (1-methyl-1H-pyrazol-4-yl) -2- (methylsulfoxide) pyrimidine-5-carbonitrile was used instead of 4-((2- ( Dimethylphosphoryl) phenyl) amino) -2- (methylsulfone) pyrimidine-5-carbonitrile was reacted to obtain a white solid, MS: 504 [M + H] ⁺ .

Step 4) N- (2-((5-cyano-4- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine Preparation of azin-1-yl) phenyl) acrylamide

The operation is the same as that in step 4 of Example 1 with (2-((5-cyano-4- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) -5- ( 4-ethylpiperazin-1-yl) phenyl) carbamic acid tert-butyl ester instead of (2-((5-cyano-4- (isopropylamino) pyrimidin-2-yl) amino)- Tert-Butyl 5- (4-ethylpiperazin-1-yl) phenyl) carbamate to give a white solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.67 (s, 1H), 9.23 ( s, 1H), 8.70 (s, 1H), 8.53-8.28 (m, 1H), 8.21-7.95 (m, 1H), 7.54-7.33 (m, 1H), 7.27 (s, 1H), 6.90-6.75 ( m, 1H), 6.56-6.40 (m, 1H), 6.23 (d, J = 16.9Hz, 1H), 5.72 (d, J = 10.2Hz, 1H), 3.94 (s, 3H), 3.23-3.02 (m , 4H), 2.59-2.51 (m, 4H), 2.38 (q, J = 7.2 Hz, 2H), 1.04 (t, J = 7.1 Hz, 3H). MS: 458 [M + H] ⁺ .

Example 188. N- (2-((4- (1H-Indol-3-yl) -5-cyanopyrimidin-2-yl) amino) -5- (4-ethylpiperazine-1- Of phenyl) phenyl) acrylamide

Step 1) Preparation of 2-chloro-4- (1H-indol-3-yl) pyrimidine-5-carbonitrile

Dissolve 2,4-dichloropyrimidine-5-carbonitrile (100 mg, 0.57 mmol) and 1H-indole (68 mg, 0.58 mmol) in 1,2-dichloroethane (4 mL) under argon protection Then, aluminum trichloride (77 mg, 0.58 mmol) was slowly added, and then reacted at 80 ° C for 1 hour. After cooling, the reaction solution was filtered, and the filter cake was washed with water to obtain 120 mg of a yellow solid, MS: 255 [M + H] ⁺ .

Step 2) (2-((5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) benzene Preparation of t-butylaminocarbamate

The operation is the same as step 3) in Example 1, and 2-chloro-4- (1H-indol-3-yl) pyrimidine-5-carbonitrile is used instead of 2-chloro-4- (isopropylamino) pyrimidine-5- Nitrile to give a brown solid, MS: 539 [M + H] ⁺ .

Step 3) N- (2-((4- (1H-Indol-3-yl) -5-cyanopyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl ) Phenyl) acrylamide

The operation is the same as that in step 4 of Example 1. Using (2-((5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine) Tert-butyl azin-1-yl) phenyl) carbamate instead of (2-((5-cyano-4- (isopropylamino) pyrimidin-2-yl) amino) -5- (4- Ethylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester to give a yellow solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.99 (s, 1H), 9.69 (s, 1H), 9.31-8.99 (m, 1H), 8.67 (s, 1H), 8.52 (d, J = 3.1Hz, 1H), 7.58-7.30 (m, 3H), 7.19 (s, 1H), 7.17-7.03 (m, 1H), 7.03-6.90 (m, 1H), 6.90-6.71 (m, 1H), 6.54 (dd, J = 16.8, 10.0Hz, 1H), 6.25 (d, J = 17.5Hz, 1H), 5.73 (d , J = 10.2 Hz, 1H), 3.26-3.05 (m, 4H), 2.56-2.51 (m, 4H), 2.05-1.91 (m, 2H), 1.16-1.04 (m, 3H). MS: 493 [M + H] ⁺ .

The compounds in the table below were synthesized with reference to Examples 187 and 188.

Example 206. N- (2-((5-cyano-4- (1- (2-hydroxyethyl) -1H-indole-3-yl) pyrimidin-2-yl) amino) -5- Preparation of (4-ethylpiperazin-1-yl) phenyl) acrylamide

Step 1) Preparation of methyl 2- (3- (2-chloro-5-cyanopyrimidin-4-yl) -1H-indole-1-yl) acetate

The operation was the same as in Example 188, and 2- (1H-indol-1-yl) ethyl acetate was used instead of 1H-indole to obtain a white solid. MS: 341 [M + H] ⁺ step 2) 2- (3- ( 2-((2-((tert-butoxycarbonyl) amino) -4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidin-4-yl) -1H -Indol-1-yl) ethyl acetate

The operation was the same as that in Example 188, step 2), and 2- (3- (2-chloro-5-cyanopyrimidin-4-yl) -1H-indole-1-yl) acetate was used instead of 2-chloro-4- (1H-Indol-3-yl) pyrimidine-5-carbonitrile to give a brown solid, MS: 625 [M + H] ⁺ .

Step 3) (2-((5-cyano-4- (1- (2-hydroxyethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (4- Preparation of tert-butyl ethylpiperazin-1-yl) phenyl) carbamate

2- (3- (2-((2-((tert-butoxycarbonyl) amino) -4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidine Ethyl-4-yl) -1H-indole-1-yl) ethyl acetate (220 mg, 0.38 mmol) was dissolved in methanol (3 mL), potassium carbonate (104 mg, 0.75 mmol) was added, and the reaction was performed at room temperature for 3 hours. The reaction solution was evaporated to dryness and subjected to column chromatography to obtain a light brown solid, MS: 583 [M + H] ⁺ .

Step 4) N- (2-((5-cyano-4- (1- (2-hydroxyethyl) -1H-indol-3-yl) pyrimidin-2-yl) aminoamine) -5- Preparation of (4-ethylpiperazin-1-yl) phenyl) acrylamide

The operation was the same as in Example 188, and (2-((5-cyano-4- (1- (2-hydroxyethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -5 -(4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester instead of (2-((5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl ) Amino) -5- (4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester to give a yellow solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.71 (s, 1H), 9.37-8.94 (m, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 8.09-7.85 (m, 1H), 7.58 (s, 1H), 7.47-7.34 (m, 2H) , 7.31-7.14 (m, 1H), 7.00-6.88 (m, 1H), 6.88-6.77 (m, 1H), 6.53 (dd, J = 17.0, 10.2Hz, 1H), 6.25 (d, J = 16.7Hz , 1H), 5.73 (d, J = 10.1 Hz, 1H), 5.06-4.85 (m, 1H), 4.42-4.26 (m, 2H), 3.83-3.65 (m, 2H), 3.24-3.08 (m, 4H ), 2.62-2.52 (m, 4H), 2.40 (q, J = 7.2 Hz, 2H), 1.06 (t, J = 7.1 Hz, 3H). MS: 537 [M + H] ⁺

Example 207. N- (2-((4- (1- (3-amino-3-oxopropyl) -1H-indol-3-yl) -5-cyanopyrimidin-2-yl) amine Of phenyl) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide

Step 1) Preparation of methyl 3- (3- (2-chloro-5-cyanopyrimidin-4-yl) -1H-indole-1-yl) propanoate

The operation was the same as in Example 188, and 3- (1H-indol-1-yl) propanoic acid methyl ester was used instead of 1H-indole to obtain a white solid. MS: 341 [M + H] ⁺ step 2) 3- (3- (2-((2-((tert-butoxycarbonyl) amino) -4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidin-4-yl)- Preparation of 1H-indol-1-yl) propionic acid methyl ester

The operation is the same as that in Example 188, step 2), and 3- (3- (2-chloro-5-cyanopyrimidin-4-yl) -1H-indole-1-yl) propanoic acid methyl ester is used instead of 2-chloro-4 -(1H-indol-3-yl) pyrimidine-5-carbonitrile to give a brown solid, MS: 625 [M + H] ⁺ .

Step 3) (2-((4- (1- (3-amino-3-oxopropyl) -1H-indol-3-yl) -5-cyanopyrimidin-2-yl) amino)- Preparation of 5- (4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

3- (3- (2-((2-((tert-butoxycarbonyl) amino) -4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidine 4-methyl) -1H-indole-1-yl) propanoic acid methyl ester (100 mg, 0.16 mmol), a methanol solution of ammonia was added, and the tube was sealed at 100 ° C. for 24 hours to react. The reaction solution was evaporated to dryness and column chromatography to obtain 40 mg of a brown solid, MS: 610 [M + H] ⁺ .

Step 4) N- (2-((4- (1- (3-amino-3-oxopropyl) -1H-indol-3-yl) -5-cyanopyrimidin-2-yl) amino ) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide

The procedure was the same as in Example 188, and (2-((4- (1- (3-amino-3-oxopropyl) -1H-indole-3-yl) -5-cyanopyrimidin-2-yl) (Amino) -5- (4-ethylpiperazin-1-yl) phenyl) amino-carboxylic acid tert-butyl ester instead of (2-((5-cyano-4- (1H-indol-3-yl) Pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) carbamic acid tert-butyl ester to give a yellow solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9 .67 (s, 1H), 9.33-8.96 (m, 1H), 8.66 (s, 1H), 8.51 (s, 1H), 7.95 (br, 2H), 7.67-7.53 (m, 1H), 7.50-7.32 (m, 3H), 7.32-7.14 (m, 1H), 6.97-6.82 (m, 2H), 6.60-6.46 (m, 1H), 6.24 (d, J = 16.8 Hz, 1H), 5.73 (d, J = 10.0Hz, 1H), 4.56-4.45 (m, 2H), 3.26-3.08 (m, 4H), 2.69-2.53 (m, 6H), 2.45-2.33 (m, 2H), 1.15-1.00 (m, 3H) ) .MS: 564 [M + H] ⁺

Example 208. N- (2-((5-cyano-4- (1- (3-hydroxypropyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -5- Preparation of (4-ethylpiperazin-1-yl) phenyl) acrylamide

Step 1) Preparation of methyl 3- (4- (5-cyano-2- (methylthio) pyrimidin-4-yl) -1H-pyrazol-1-yl) propanoate

The experimental operation was the same as that in step 1) of Example 187, and 3- (4- (4,4,5,5,5, -tetramethyl-1,3,2-dioxaborane-2-yl) -1H- Pyrazol-1-yl) propanoic acid methyl ester instead of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) -1H -Pyrazole, MS: 304 [M + H] ⁺ ;

Step 2) Preparation of methyl 3- (4- (5-cyano-2- (methylsulfoxide) pyrimidin-4-yl) -1H-pyrazol-1-yl) propanoate

The experimental operation was the same as that in step 2) of Example 187, using 3- (4- (5-cyano-2- (methylthio) pyrimidin-4-yl) -1H-pyrazol-1-yl) propanoic acid methyl ester Instead of 4- (1-methyl-1H-pyrazol-4-yl) -2- (methylthio) pyrimidine-5-carbonitrile, MS: 320 [M + H] ⁺ ;

Step 3) 3- (4- (2-((2-((tert-butoxycarbonyl) amino) -4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyano Of methylpyrimidin-4-yl) -1H-pyrazol-1-yl) propanoate

The experimental operation was the same as that in step 3) of Example 187, and 3- (4- (5-cyano-2- (methylsulfoxide) pyrimidin-4-yl) -1H-pyrazol-1-yl) propanoate was used. Ester instead of 4- (1-methyl-1H-pyrazol-4-yl) -2- (methylsulfoxide) pyrimidine-5-carbonitrile, MS: 576 [M + H] ⁺ ;

Step 4) (2-((4- (1- (3-amino-3-oxopropyl) -1H-pyrazol-4-yl) -5-cyanopyrimidin-2-yl) amino)- Preparation of 5- (4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester

The experimental operation was the same as that in step 3) of Example 208, and 3- (4- (2-((2-((tert-butoxycarbonyl) amino))-4- (4-ethylpiperazin-1-yl) benzene Methyl) amino) -5-cyanopyrimidin-4-yl) -1H-pyrazol-1-yl) propanoic acid methyl ester instead of 3- (3- (2-((2-((tert-butoxycarbonyl)) Amino) -4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidin-4-yl) -1H-indole-1-yl) propanoic acid methyl ester, MS: 561 [M + H] ⁺ ;

Step 5) N- (2-((4-((1- (3-amino-3-oxopropyl) -1H-pyrazol-4-yl) -5-cyanopyrimidin-2-yl) amine Of phenyl) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide

The operation is the same as that in step 4 of Example 1. Using (2-((4- (1- (3-amino-3-oxopropyl) -1H-pyrazol-4-yl) -5-cyanopyrimidine-2 -Yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) carbamic acid tert-butyl ester instead of (2-((5-cyano-4- (isopropylamino)) Pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) carbamic acid tert-butyl ester, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.77-9.52 (m, 1H), 9.24 (s, 1H), 8.69 (s, 1H), 8.39 (s, 1H), 8.23-7.92 (m, 1H), 7.50-7.35 (m, 2H), 7.35-7.15 (m , 1H), 6.90 (s, 1H), 6.86-6.75 (m, 1H), 6.49 (dd, J = 16.7, 10.1Hz, 1H), 6.29-6.11 (m, 1H), 5.72 (d, J = 10.1 Hz, 1H), 4.41 (t, J = 6.7 Hz, 2H), 3.14 (t, J = 4.9 Hz, 4H), 2.66 (t, J = 6.8 Hz, 2H), 2.57-2.51 (m, 4H), 2.38 (q, J = 7.1Hz, 2H), 1.04 (t, J = 7.2Hz, 3H). MS: 515 [M + H] ⁺ ;

Example 209. N- (2-((5-cyano-4- (cyclobutylamino) pyrimidin-2-yl) amino) -5- (4-methyl-2-oxopiperazine-1 -Yl) phenyl) acrylamide

The operation was the same as in Example 1. Cyclobutylamine was used in place of isopropylamine in step 1), and Intermediate 18 was used in place of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl group in step 3). ) Tert-Butyl aminoformate, ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.02 (s, 1H), 7.48-7.33 (m, 1H), 7.13 (s, 1H), 6.79 (d, J = 9.1Hz, 1H), 6.46-6.14 (m, 2H), 5.68 (d, J = 9.6Hz, 1H), 4.43-4.23 (m, 1H), 3.75 (s, 2H), 3.49-3.39 (m, 4H ), 2.93 (s, 3H), 2.24-2.07 (m, 2H), 1.99-1.91 (m, 2H), 1.71-1.53 (m, 2H). MS: 447 [M + H] ⁺

Example 210. N- (2-((5-cyano-4- (cyclobutylamino) pyrimidin-2-yl) amino) -5- (4-methyl-2-oxopiperazine-1 -Yl) methyl) phenyl) acrylamide

The operation was the same as in Example 1. Cyclobutylamine was used in place of isopropylamine in step 1) and intermediate 19 was used in place of (2-amino-5- (4-ethylpiperazin-1-yl) benzene in step 3). T-butyl aminocarbamate, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.74 (s, 1H), 8.73 (s, 1H), 8.20 (s, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.40 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.43 (dd, J = 17.0, 10.0 Hz, 1H), 6.20 (dd, J = 17.1, 1.9 Hz, 1H), 5.70 (d, J = 10.2 Hz, 1H), 4.43 (s, 2H), 4.39-4.18 (m, 1H), 3.18-3.10 (m, 2H) , 2.94 (s, 2H), 2.49 (t, J = 5.5Hz, 2H), 2.14 (s, 3H), 2.10-1.96 (m, 4H), 1.63-1.43 (m, 2H). MS: 461 [M + H] ⁺

Example 211. Preparation of N- (2-((5-cyano-4- (cyclohexaneylamino) pyrimidin-2-yl) amino) -3-methylphenyl) acrylamide

The operation was the same as in Example 1. Cyclohexylamine was used in place of isopropylamine in step 1), and intermediate (2-amino-3-methylphenyl) aminocarbamate was used in place of (2-) in step 3). Amino-5- (4-ethylpiperazin-1-yl) phenyl) carbamic acid tert-butyl ester, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.58 (s, 1H), 8.26 (s, 1H), 7.71 (s, 1H), 7.24 (s, 1H), 7.22-7.13 (m, 1H), 7.05 (d, J = 7.5Hz, 1H), 6.55 (dd, J = 17.0, 10.2 Hz, 1H), 6.21 (d, J = 16.9 Hz, 1H), 5.71 (d, J = 10.1 Hz, 1H), 2.13 (s, 3H), 1.97-1.69 (m, 1H), 1.60 -1.45 (m, 12H), 1.24-1.11 (m, 6H), 0.98-0.85 (m, 5H). MS: 377 [M + H] ⁺ .

Example 212. Preparation of N- (2-((5-cyano-4- (cyclohexaneylamino) pyrimidin-2-yl) amino) -3-methoxyphenyl) acrylamide

The operation was the same as in Example 1. Cyclohexylamine was used in place of isopropylamine in step 1), and intermediate (2-amino-3-methoxyphenyl) aminoformate was used in place of (2-) in step 3). Tert-butyl amino-5- (4-ethylpiperazin-1-yl) phenyl) carbamate, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 (s, 1H), 8.34 (s, 1H), 8.25-8.00 (m, 1H), 7.56 (d, J = 8.4Hz, 1H), 7.41-7.06 (m, 2H), 6.84 (d, J = 8.3Hz, 1H), 6.59 (dd, J = 16.9, 10.2 Hz, 1H), 6.22 (d, J = 17.0 Hz, 1H), 5.71 (dd, J = 10.0 Hz, 1H), 4.37-3.97 (m, 1H), 3.70 (s, 3H), 2.05 -1.37 (m, 7H), 1.35-1.06 (m, 1H), 1.03-0.70 (m, 2H). MS: 393 [M + H] ⁺ .

Example 213. N- (2-((4- (1-Acetylazetidin-3-yl) amino) -5-cyanopyrimidin-2-yl) amino) -5- (4 -Ethylpiperazin-1-yl) phenyl) acrylamide

The operation was the same as in Example 3, and 1- (3-aminoazetidin-1-yl) ethyl-1-one was used in place of step 1) 1-acetyl-4-aminopiperidine in Example 3, and the same reaction was performed. A white solid product was obtained; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.81 (s, 1H), 8.63 (s, 1H), 8.38-8.18 (m, 1H), 7.47-7.11 (m, 2H), 6.92-6.77 (m, 1H), 6.60-6.41 (m, 1H), 6.27 (d, J = 16.9Hz, 1H), 5.76 (d, J = 10.1Hz, 1H), 4.22-3.98 (m, 2H) , 3.95-3.79 (m, 2H), 3.77-3.58 (m, 1H), 3.14 (t, J = 5.0Hz, 4H), 2.59-2.50 (m, 4H), 2.37 (q, J = 7.2Hz, 2H ), 1.70 (s, 3H), 1.04 (t, J = 7.1 Hz, 3H). MS: 490 [M + H] ⁺ .

Example 214. N- (4-Chloro-2-((5-cyano-4- (cyclobutylamino) pyrimidin-2-yl) amino) -5- (4-((2-methoxy Ethyl) (meth) aminoamino) piperidin-1-yl) phenyl) acrylamide

The same operation as in Example 1 was carried out, in which cyclobutylamine was used instead of step 1) isopropylamine, and (2-amino-4-chloro-5- (4-((2-methoxyethyl) (methyl) (Amino) amino) piperidine-1-yl) phenyl) carbamic acid tert-butyl ester Instead of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) amino group of step 3) Tert-butyl formate was subjected to the same reaction to obtain a white solid product; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.82 (s, 1H), 8.87 (s, 1H), 8.29 (s, 1H), 7.92 (d, J = 6.9 Hz, 1H), 7.84 (s, 1H), 7.44 (s, 1H), 6.50 (dd, J = 17.0, 10.2 Hz, 1H), 6.27 (dd, J = 17.0, 2.0 Hz, 1H), 5.78 (dd, J = 10.1, 2.0 Hz, 1H), 4.40 (s, 1H), 3.40 (t, J = 6.1 Hz, 2H), 3.30 (d, J = 11.1 Hz, 2H), 3.24 (s, 3H ), 2.64-2.54 (m, 4H), 2.48-2.40 (m, 1H), 2.24 (s, 3H), 2.20-2.05 (m, 4H), 1.78 (d, J = 12.1 Hz, 2H), 1.69- 1.51 (m, 4H) .MS: 539 [M + H] ⁺

Example 215. N- (4-Chloro-2-((5-cyano-4- (cyclobutylamino) pyrimidin-2-yl) amino) -5- (4-((3-methoxy Propyl) (meth) amino) piperidin-1-yl) phenyl) acrylamide

The same operation as in Example 1 was carried out, in which cyclobutylamine was used instead of step 1) isopropylamine, and (2-amino-4-chloro-5- (4-((3-methoxypropyl)) ( Methyl) amino) piperidine-1-yl) phenyl) carbamic acid tert-butyl ester instead of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) amine of step 3) Tert-butyl carbamate was subjected to the same reaction to obtain a white solid product;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.76 (s, 1H), 8.80 (s, 1H), 8.22 (s, 1H), 7.86 (d, J = 6.9 Hz, 1H), 7.77 (s, 1H), 7.37 (s, 1H), 6.44 (dd, J = 17.0, 10.1 Hz, 1H), 6.20 (dd, J = 16.9, 2.0 Hz, 1H), 5.72 (dd, J = 10.1, 2.0 Hz, 1H ), 4.34 (s, 1H), 3.29 (d, J = 6.3Hz, 2H), 3.22 (s, 2H), 3.15 (s, 3H), 2.58-2.48 (m, 4H), 2.40 (s, 1H) , 2.16-1.99 (m, 7H), 1.71 (d, J = 11.8 Hz, 2H), 1.65-1.45 (m, 6H). MS: 553 [M + H] ⁺

Example 216. N- (2-((5-cyano-4- (phenylamino) pyridin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl ) Preparation of acrylamide

Step 1) Preparation of 6-chloro-4- (phenylamino) nicotinic acid

To a solution of aniline (190 mg, 2 mmol) in tetrahydrofuran (5 mL) was slowly added HMDSNa (2M, 1 mL) dropwise at -70 ° C, followed by stirring at this temperature for 1 hour, and then adding 2,4-dichloro-5- Niacin (190mg, 1mmol), the temperature was naturally raised to room temperature and stirred overnight. After the reaction was completed, the pH was adjusted to 2 with 1N dilute hydrochloric acid, extracted with ethyl acetate, dried, and concentrated to obtain 220 mg of a white solid product, yield 88%. MS: 249 [M + H] ⁺ ;

Step 2) Preparation of 6-chloro-4- (phenylamino) nicotinamide

The intermediate 6-chloro-4- (phenylamino) nicotinic acid (120 mg, 0.5 mmol) was added to dichlorosulfoxide (5 mL) and reacted at reflux for 1 hour, cooled, concentrated and dissolved in 1 mL of anhydrous dichloromethane. . The resulting solution was slowly dropped into a crushed ice solution of concentrated ammonia (30%, 2 mL), stirred for 1 hour, filtered, and dried to give 190 mg of a white solid, yield 86%, MS: 248 [M + H] ⁺ ;

Step 3) Preparation of 6-chloro-4- (phenylamino) nicotinonitrile

The intermediate 6-chloro-4- (phenylamino) nicotinamide (190 mg, 0.83 mmol) was dissolved in phosphorus oxychloride (3 mL) and heated to 110 ° C for two hours, concentrated, dissolved in dichloromethane, and saturated carbonic acid. Wash with sodium hydrogen solution, dry the organic phase, and concentrate to give 150 mg of a yellow solid, MS: 230 [M + H] ⁺ ;

Step 4) (2-((5-cyano-4- (phenylamino) pyridin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) amino Preparation of tert-butyl formate

The intermediate 6-chloro-4- (phenylamino) nicotinonitrile (100 mg, 0.4 mmol), tert- (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid Butyl ester (120 mg, 0.4 mmol), Pd ₂ (dba) ₃ (10 mg), Xantphos (10 mg) and sodium carbonate (110 mg, 1 mmol) were each dissolved in a sealed tube containing dioxane (5 mL). The reaction system After being replaced by argon, the reaction was heated at 120 ° C for 10 hours, cooled, filtered, and the filtrate was concentrated. The filtrate was directly purified from a preparation thin-layer plate (1 mm, silica gel) to obtain 130 mg of a pale yellow solid product, yield 63%. MS: 514 [M + H] ⁺ ;

Step 5) N- (2-((5-cyano-4- (phenylamino) pyridin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) Preparation of acrylamide

Tert- (2-((5-cyano-4- (phenylamino) pyridin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid Trifluoroacetic acid (1 mL) was added to a dichloride solution (3 mL) of butyl ester (100 mg, 0.2 mmol), and the reaction was stirred at room temperature for 1 hour. The resulting yellow oil was dissolved in anhydrous tetrahydrofuran (2 mL) under ice-water bath conditions. Acryloyl chloride (50 microliters) was added dropwise thereto, and the reaction was continued for half an hour, quenched by addition of water, extracted with dichloromethane, washed with saturated sodium bicarbonate solution, dried the organic phase, concentrated, and prepared from a thin plate (0.5 mm, silica gel) ) Purification (developing agent volume ratio dichloromethane / methanol = 110/9) gave 33 mg of a white solid with a yield of 35%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.55 (s, 1H), 8.64 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 7.39-7.16 (m, 6H), 7.10-7.08 (m, 1H), 6.78-6.68 (m, 1H), 6.49 (dd, J = 17.0, 10.1Hz, 1H), 6.21 (dd, J = 17.1, 2.2Hz, 1H), 6.11 (s, 1H), 5.74-5.66 (m, 1H), 3.17-2.97 (m, 4H), 2.52 (br, 4H), 2.40-2.30 (m, 2H), 1.04 (t, J = 7.2Hz, 3H) .MS : 468 [M + H] ⁺ ;

Example 217. N- (2-((5-cyano-4- (cyclohexylamino) pyridin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl )Acrylamide

Step 1) Preparation of 6-chloro-4- (cyclohexylamino) nicotinamide

To a solution of 2,4-dichloro-5-nicotinamide (192 mg, 1 mmol) in NMP (5 mL), cyclohexylamine (100 mg, 1 mmol) and DIEA (0.5 mL, 3 mmol) were sequentially added dropwise, and the reaction was heated to 100 ° C with stirring. 6 hours, quenched by adding water (20 mL), continued stirring for half an hour to beat, filtered, and dried to obtain 230 mg of a white solid, yield 91%, MS: 254 [M + H] ⁺

Step 2) Preparation of 6-chloro-4- (cyclohexylamino) nicotinonitrile

The intermediate 6-chloro-4- (cyclohexylamino) nicotinamide (230 mg, 0.9 mmol) was dissolved in phosphorus oxychloride (2 mL) and heated to 110 ° C for two hours, concentrated, dissolved in dichloromethane, and saturated carbonic acid. The sodium hydrogen solution was washed, and the organic phase was dried and concentrated to obtain 170 mg of a yellow solid with a yield of 80%. MS: 236 [M + H] ⁺ ;

Step 3) tert- (2-((5-cyano-4- (cyclohexylamino) pyridin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) carboxylic acid Preparation of butyl ester

6-Chloro-4- (cyclohexylamino) nicotinonitrile (100 mg, 0.4 mmol), (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester (120mg, 0.4mmol), Pd ₂ (dba) ₃ (10mg), Xantphos (10mg) and sodium carbonate (110mg, 1mmol) were dissolved in sealed tubes containing dioxane (5mL) and water (0.5mL), respectively. In the reaction system, the reaction system was replaced by argon and heated at 120 ° C for 10 hours, cooled, filtered, and the filtrate was concentrated. The filtrate was directly purified from the preparation of a thin-layer plate (thickness 1 mm, loaded with silica gel) (the volume ratio of the developed system was V _{dichloromethane / methanol} = 200/9) yielded 117 mg of pale yellow solid product in 56% yield. MS: 520 [M + H] ⁺

Step 4) N- (2-((5-cyano-4- (cyclohexylamino) pyridin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) Preparation of acrylamide

(2-((5-Cyano-4- (cyclohexylamino) pyridin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) carboxylic acid tert-butyl ester (100 mg, 0.2 mmol) in dichloro solution (3 mL) was added with trifluoroacetic acid (1 mL), and the reaction was stirred at room temperature for 1 hour, and concentrated to obtain a yellow oily substance dissolved in anhydrous tetrahydrofuran (2 mL). Acryloyl chloride (50 μl) was added dropwise, and the reaction was continued for half an hour, quenched by adding water, extracted with dichloromethane, washed with saturated sodium bicarbonate solution, dried the organic phase, concentrated, and purified by a preparation sheet (0.5 mm, silica gel) (Developing agent volume ratio methylene chloride / methanol = 110/9) 36 mg of a white solid was obtained with a yield of 38%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.60 (s, 1H), 8.18 (s, 1H), 8.03 (d, J = 2.8 Hz, 1H), 7.32 (s, 1H), 7.20 (d, J = 8.9Hz, 1H), 6.90-6.64 (m, 1H), 6.62-6.39 (m, 1H), 6.32-6.12 (m, 1H), 6.05 (d, J = 7.8Hz, 1H), 5.80-5.56 (m, 2H), 3.10 (br, 4H), 2.52 (br, 5H), 2.45-2.35 (m, 2H), 1.88-1.62 (m, 4H), 1.39-1.10 (m, 6H), 1.02 (t , J = 7.4Hz, 3H). MS: 474 [M + H] ⁺

Example 218. N- (2-((5-cyano-4-((3-methoxypyridin-2-yl) amino) pyridin-2-yl) aminoamine) -5- (4- Ethylpiperazin-1-yl) phenyl) acrylamide

Step 1) Preparation of 6-chloro-4-((3-methoxypyridin-2-yl) amino) nicotinamide

To a solution of 2-amino-3-methoxypyridine (250 mg, 2 mmol) in tetrahydrofuran (5 mL) under ice salt bath conditions, HMDSNa (2N, 1 mL) was slowly added dropwise, and the reaction was continued for half an hour, followed by the dropwise addition of 2, A solution of 4-dichloro-5-nicotinamide (190 mg, 1 mmol) in tetrahydrofuran (1 mL) was stirred under an ice-water bath overnight, quenched by adding water, and filtered to obtain 220 mg of a pale yellow solid, yield 79%, MS: 279 [M + H] ⁺ ;

Step 2) Preparation of 6-chloro-4-((3-methoxypyridin-2-yl) amino) nicotinonitrile

Add pyridine (2mL) and phosphorus oxychloride (0.5mL) to the acetonitrile (20mL) solution, and then add the intermediate 6-chloro-4-((3-methoxypyridin-2-yl) to the solution. Amine) nicotinamide (220 mg, 0.8 mmol), the reaction was heated to reflux for 1 hour, cooled, quenched by adding water, washed with saturated sodium bicarbonate, extracted with dichloromethane, dried and concentrated to give 233 mg of a yellow solid, yield 80%, MS: 261 [M + H] ⁺ ;

Step 3) (2-((5-cyano-4-((3-methoxypyridin-2-yl) amino) pyridin-2-yl) amino) -5- (4-ethylpiperazine Preparation of tert-butyl-1-yl) phenyl) carbamate

6-chloro-4-((3-methoxypyridin-2-yl) amino) nicotinonitrile (120 mg, 0.4 mmol), (2-amino-5- (4-ethylpiperazin-1-yl ) Phenyl) tert-butyl aminocarbamate (120mg, 0.4mmol), Pd ₂ (dba) ₃ (10mg), Xantphos (10mg) and sodium carbonate (110mg, 1mmol) were dissolved in dioxane (5mL) ) And water (0.5mL), the reaction system was replaced by argon and heated at 120 ° C for 10 hours, cooled, filtered, and the filtrate was concentrated to directly purify from a preparation thin-layer plate (1mm, silica gel) to obtain a pale yellow solid. Product 88 mg, yield 40%, MS: 545 [M + H] ⁺ ;

Step 4) N- (2-((5-cyano-4-((3-methoxypyridin-2-yl) amino) pyridin-2-yl) amino) -5- (4-ethyl Preparation of piperazin-1-yl) phenyl) acrylamide

(2-((5-cyano-4-((3-methoxypyridin-2-yl) amino) pyridin-2-yl) amino) -5- (4-ethylpiperazine-1 -Phenyl) phenyl) -tert-butyl carbamate (88 mg, 0.16 mmol) was added to a dichloromethane (3 mL) solution containing trifluoroacetic acid (1 mL), stirred at room temperature for 1 hour, concentrated, and anhydrous tetrahydrofuran (2 mL) was added. Then, add acryloyl chloride (40 microliters) dropwise under ice-water bath conditions and continue stirring for half an hour, quench with water, extract with dichloromethane, wash with saturated sodium bicarbonate, dry the organic phase, concentrate and prepare a preparative sheet (0.5mm , Loaded silica gel) purification (developing system V _{dichloromethane / methanol} = 10/1) to obtain 25 mg of white solid product, yield 31%, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.57 (s, 1 H), 8.54 (s, 1H), 8.28 (s, 1H), 7.91 (s, 1H), 7.79 (br, 2H), 7.44-7.34 (m, 2H), 7.26 (d, J = 8.9Hz, 1H), 7.02 -6.99 (m, 1H), 6.81 (d, J = 8.9 Hz, 1H), 6.49 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (d, J = 17.0 Hz, 1H), 5.71 (d, J = 10.1Hz, 1H), 3.92 (s, 3H), 3.16-3.09 (m, 4H), 2.52 (br, 4H), 2.38 (q, J = 7.1Hz, 2H), 1.04 (t, J = 7.1 Hz, 3H) .MS: 499 [M + H] ⁺

Example 219. N- (2-((5-cyano-4-((4-hydroxy-3-methoxybenzyl) amino) pyridin-2-yl) amino) -5- (4- Ethylpiperazin-1-yl) phenyl) acrylamide

Step 1) Preparation of 6-chloro-4-((4-hydroxy-3-methoxybenzyl) amino) nicotinamide

To a solution of 2,4-dichloro-5-nicotinic acid (192 mg, 1 mmol) in NMP (5 mL), 4-hydroxy-3-methoxybenzylamine (150 mg, 1 mmol) and DIEA (0.5 mL, 3 mmol), heated to 100 ° C. and stirred for 6 hours, quenched by adding water (20 mL), continued stirring for half an hour, filtered, and dried to give 246 mg of a white solid, yield 80%, MS: 308 [M + H] ⁺

Step 2) Preparation of 6-chloro-4-((4-hydroxy-3-methoxybenzyl) amino) nicotinonitrile

Add pyridine (2mL) and phosphorus oxychloride (0.5mL) to the acetonitrile (20mL) solution, and then add the intermediate 6-chloro-4-((4-hydroxy-3-methoxybenzyl) to the above solution. ) Amine) Nicotinamide (246 mg, 0.8 mmol), the reaction was heated to reflux for 1 hour, cooled, quenched with water, washed with saturated sodium bicarbonate, extracted with dichloromethane, dried and concentrated to give 180 mg of a yellow solid. The rate is 77%. MS: 290 [M + H] ⁺

Step 3) (2-((5-cyano-4-((4-hydroxy-3-methoxybenzyl) amino) pyridin-2-yl) amino) -5- (4-ethylpiperazine Preparation of tert-butyl azin-1-yl) phenyl) carbamate

The intermediate 6-chloro-4-((4-hydroxy-3-methoxybenzyl) amino) nicotinonitrile (115 mg, 0.4 mmol), (2-amino-5- (4-ethylpiperazine- Tert-butyl 1-yl) phenyl) carbamate (120 mg, 0.4 mmol), Pd ₂ (dba) ₃ (10 mg), Xantphos (10 mg) and sodium carbonate (110 mg, 1 mmol) were each dissolved in dioxane. In a sealed tube with a ring (5 mL) and water (0.5 mL), the reaction system was replaced with argon and heated at 120 ° C for 10 hours, cooled, filtered, and the filtrate was concentrated to prepare a thin layer plate (thickness 1 mm, loaded with silica gel). Purification (developing system volume ratio V dichloromethane / methanol = 200/9) gave 126 mg of a pale yellow solid product with a yield of 55%. MS: 574 [M + H] ⁺

Step 4) N- (2-((5-cyano-4-((4-hydroxy-3-methoxybenzyl) amino) pyridin-2-yl) amino) -5- (4-ethyl Of Benzylpiperazin-1-yl) phenyl) acrylamide

The same operation as in step 5) of Example 1 was carried out to obtain a white solid product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.63 (s, 1H), 8.86 (s, 1H), 8.13-8.01 (m, 2H), 7.27-7.19 (m, 1H), 7.16 (br, 1H ), 6.91 (d, J = 8.8Hz, 1H), 6.81 (d, J = 1.9Hz, 1H), 6.73-6.62 (m, 2H), 6.60 (d, J = 8.1Hz, 1H), 6.45 (dd , J = 17.0, 10.3Hz, 1H), 6.23 (d, J = 17.0Hz, 1H), 5.74 (br, 1H), 5.58 (s, 1H), 4.14 (d, J = 5.8Hz, 2H), 3.68 (s, 3H), 3.12 (br, 4H), 2.53 (br, 4H), 2.40 (br, 2H), 1.06 (t, J = 7.2Hz, 3H). MS: 528 [M + H] ⁺ ;

Example 220. N- (2-((5-cyano-4-((2-hydroxypropyl) amino) pyridin-2-yl) amino) -5- (4-ethylpiperazine-1 -Yl) phenyl) acrylamide

Step 1) Preparation of 6-chloro-4-((2-hydroxypropyl) amino) nicotinamide

To a solution of 2,4-dichloro-5-nicotinamide (192 mg, 1 mmol) in NMP (5 mL), 2-hydroxypropylamine (80 mg, 1.06 mmol) and DIEA (0.5 mL, 3 mmol) were sequentially added dropwise, and heated to 100 ° C. Stir the reaction for 6 hours, quench by adding water (20 mL), continue stirring for half an hour to beat, filter, and dry to obtain 210 mg of a white solid, yield 91%, MS: 230 [M + H] ⁺ ;

Step 2) Preparation of 1-((5-carbamoyl-2-chloropyridin-4-yl) amino) propane-2-yl acetate

To 6-chloro-4-((2-hydroxypropyl) amino) nicotinamide (210 mg, 0.9 mmol) in methylene chloride (5 mL) were added acetyl chloride (120 mg, 1.5 mmol) and DIEA (0.5 mL, 3 mmol), stirred overnight at room temperature, washed with saturated sodium bicarbonate water, dried the organic phase, and concentrated to obtain a yellow oil which was used directly in the next step;

Step 3) Preparation of 1-((5-cyano-2-chloropyridin-4-yl) amino) propane-2-yl acetate

1-((5-carbamoyl-2-chloropyridin-4-yl) amino) propane-2-yl acetate was dissolved in pyridine (2 mL), phosphorus oxychloride (0.5 mL) and acetonitrile (20 mL) The solution was heated under reflux for 2 hours, cooled, quenched by adding water, washed with saturated sodium bicarbonate, extracted with dichloromethane, dried and concentrated to give 150 mg of a yellow solid, yield 67%, MS: 254 [M + H] ⁺ ;

Step 4) Acetic acid 1-((2-((2-((tert-butyloxycarbonyl) amino) -4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyano Of pyridyl-4-yl) amino) propyl-2-yl ester:

The same operation as in step 3) of Example 218 was performed to obtain a pale yellow solid product, MS: 538 [M + H] ⁺ ;

Step 5) 1-((2-((2-acrylamido-4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyridine-4-yl) amine Of propyl) propyl-2-yl ester

The same operation as in step 4) of Example 218 was performed to obtain an off-white solid product, MS: 492 [M + H] ⁺ ;

Step 6) N- (2-((5-cyano-4-((2-hydroxypropyl) amino) pyridin-2-yl) amino) -5- (4-ethylpiperazine-1- ) Phenyl) acrylamide:

Step 5) The product acetic acid 1-((2-((2-acrylamido-4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyridine-4-yl ) Amino) propyl-2-yl ester was dissolved in a mixed solution of THF (3 mL), methanol (3 mL), water (0.5 mL), and then lithium hydroxide (50 mg) was added, and the mixture was stirred at room temperature for 2 hours. Ester extraction, the aqueous phase was adjusted to pH 6, extracted with dichloromethane, dried, and 30 mg of white solid product was obtained by preparative thin plate chromatography (0.5 mm); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.64 (s , 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.29-7.19 (m, 2H), 6.79 (d, J = 8.9Hz, 1H), 6.47 (dd, J = 17.0, 10.2Hz, 1H), 6.27-6.14 (m, 2H), 5.73 (d, J = 10.1Hz, 1H), 5.69 (s, 1H), 4.91 (d, J = 4.8Hz, 1H), 3.80-3.79 (m, 1H ), 3.11 (t, J = 5.0 Hz, 4H), 3.05-2.86 (m, 2H), 2.49 (br, 4H), 2.36 (q, J = 7.2 Hz, 2H), 1.09-1.00 (m, 6H) .MS: 450 [M + H] ⁺

Example 317. N- (2-((5-cyano-4- (cyclohexyloxy) pyridin-2-yl) amineamino) -5- (4-ethylpiperazin-1-yl) benzene Acrylamide

Step 1) Preparation of 6-chloro-4- (cyclohexyloxy) nicotinamide

In an ice water bath, cyclohexanol (250 mg, 2.5 mmol) was slowly added dropwise to a tetrahydrofuran solution containing sodium hydride (100 mg, 2.5 mmol), and the reaction was stirred for half an hour. Then, 2,4-dichloro-5-amidepyridine was added. (190mg, 1mmol) of tetrahydrofuran (1mL) was slowly added dropwise to the above solution, and the reaction was stirred overnight at room temperature, quenched with water, extracted with ethyl acetate, and purified by silica gel column chromatography to obtain 160mg of a white solid, yield 63%, MS: 255 [ M + H] ⁺ ;

Step 2) Preparation of 6-chloro-4- (cyclohexyloxy) nicotinonitrile

Pyridine (2 mL) and phosphorus oxychloride (0.5 mL) were added to the acetonitrile (20 mL) solution, and then 6-chloro-4- (cyclohexyloxy) nicotinamide (130 mg, 0.5 mmol) was added to the solution, The reaction was heated to reflux for 1 hour, cooled, quenched by adding water, washed with saturated sodium bicarbonate, extracted with dichloromethane, dried and concentrated to obtain 110 mg of a yellow solid, yield 96%, MS: 237 [M + H] ⁺ ;

Step 3) (2-((5-cyano-4- (cyclohexyloxy) pyridin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) amino Preparation of tert-butyl formate

The procedure was carried out in the same manner as in step 4) of Example 218 to obtain a pale yellow solid product. MS: 521 [M + H] ⁺

Step 4) N- (2-((5-cyano-4- (cyclohexyloxy) pyridin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) Preparation of acrylamide

The same operation as in step 5) of Example 218 was performed to obtain a white solid product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.57 (s, 1H), 8.64 (s, 1H), 8.25 (s, 1H), 7.37-7.17 (m, 2H), 6.79 (dd, J = 8.9 , 2.8Hz, 1H), 6.49 (dd, J = 17.0, 10.2Hz, 1H), 6.26-6.08 (m, 2H), 5.72 (dd, J = 10.1, 2.1Hz, 1H), 4.45-4.34 (m, 1H), 3.11 (br, 4H), 2.52 (br, 4H), 2.37 (q, J = 7.2Hz, 2H), 1.86 (br, 2H), 1.68 (br, 2H), 1.60-1.44 (m, 3H ), 1.42-1.26 (m, 3H), 1.04 (t, J = 7.1Hz, 3H). MS: 475 [M + H] ⁺

Example 328. N- (2-((5-cyano-4-((2-hydroxyphenyl) amino) pyridin-2-yl) amino) -5- (4-ethylpiperazine-1 -Yl) phenyl) acrylamide

Step 1) Preparation of 6-chloro-4-((2-methoxyphenyl) amino) nicotinamide

Same as in Example 218, Step 1) Reaction of 2-methoxybenzylamine instead of cyclohexylamine to obtain a white solid product. MS: 292 [M + H] ⁺ ;

Step 2) Preparation of 6-chloro-4-((2-methoxybenzyl) amino) nicotinonitrile

The reaction was carried out in the same manner as in step 2) of Example 218 to obtain a pale yellow solid product. MS: 274 [M + H] ⁺ ;

Step 3) Preparation of 6-chloro-4-((2-hydroxybenzyl) amino) nicotinonitrile

To a solution of boron tribromide (1M, 3mL) in dichloromethane was added the intermediate 6-chloro-4-((2-methoxybenzyl) amino) nicotinonitrile (140mg, 0.5mmol), and the reaction was stirred at room temperature. Overnight, 5 ml of methanol was added and stirred at reflux for 2 hours, concentrated, dissolved in dichloromethane, washed with saturated sodium bicarbonate water, the organic phase was concentrated, and purified by silica gel column chromatography to obtain 110 mg of white solid, yield 85%, MS : 260 [M + H] ⁺ ;

Step 4) (2-((5-cyano-4-((2-hydroxybenzyl) amino) pyridin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) Tert-butyl phenyl) carbamate

The product was obtained as a pale yellow solid in the same manner as in step 4) of Example 218. MS: 544 [M + H] ⁺ ;

Step 5) N- (2-((5-cyano-4-((2-hydroxybenzyl) amino) pyridin-2-yl) aminoamino) -5- (4-ethylpiperazine-1 -Yl) phenyl) acrylamide

The product was obtained as a white solid by the same procedure as in step 5) of Example 218. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.63-9.61 (m, 2H), 8.12 (s, 1H), 8.06 (s, 1H), 7.21 (s, 1H), 7.09 (t, J = 7.7 Hz, 1H), 7.02-6.89 (m, 3H), 6.83 (d, J = 8.0Hz, 1H), 6.75 (t, J = 7.4Hz, 1H), 6.61 (d, J = 9.2Hz, 1H), 6.45 (dd, J = 17.0, 10.1 Hz, 1H), 6.21 (d, J = 16.8 Hz, 1H), 5.72 (d, J = 10.1 Hz, 1H), 5.59 (s, 1H), 4.23 (d, J = 5.7Hz, 2H), 3.10 (br, 4H), 2.52 (br, 4H), 2.41 (br, 2H), 1.05 (t, J = 7.2Hz, 3H). MS: 498 [M + H] ⁺ ;

Example 329. (R) -N- (2-((5-cyano-4-((1- (4-fluorophenethyl)) amino) pyridin-2-yl) aminoamine) -5 -(4-ethylpiperazin-1-yl) phenyl) acrylamide:

The preparation method is the same as that in Example 218, and the reaction is performed by replacing the cyclohexylamine of step 1) with (S) -1- (4-fluorophenethyl) -1-amino; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.61 (s, 1H), 8.05 (d, J = 8.5Hz, 2H), 7.38-7.18 (m, 3H), 7.18-7.01 (m, 2H), 6.84-6.82 (m, 2H), 6.68 ( d, J = 8.9 Hz, 1H), 6.44 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (d, J = 17.0 Hz, 1H), 5.72 (d, J = 10.0 Hz, 1H), 5.42 ( s, 1H), 4.51-4.35 (m, 1H), 3.14 (t, J = 5.0Hz, 4H), 2.54 (br, 4H), 2.39 (q, J = 7.2Hz, 2H), 1.44 (d, J = 6.8Hz, 3H), 1.05 (t, J = 7.2Hz, 3H). MS: 514 [M + H] ⁺

Example 330. N- (2-((5-cyano-4-((4-aminobenzyl) amino) pyridin-2-yl) amino) -5- (4-ethylpiperazine- 1-yl) phenyl) acrylamide

Step 1) Preparation of 6-chloro-4-((4-nitrobenzyl) amineamino) nicotinamide

To a solution of 2,4-dichloro-5-nicotinamide (192 mg, 1 mmol) in NMP (5 mL) was sequentially added dropwise 4-nitrobenzylamine (150 mg, 1 mmol) and DIEA (0.5 mL, 3 mmol), and heated to The reaction was stirred at 100 ° C for 3 hours, quenched by adding water (20 mL), continued stirring for half an hour to beat, filtered, and dried to give 255 mg of a white solid, yield 83%, MS: 307 [M + H] ⁺

Step 2) Preparation of 6-chloro-4-((4-nitrophenyl) amino) nicotinonitrile

The intermediate 6-chloro-4-((4-nitrobenzyl) amino) nicotinamide (255 mg, 0.8 mmol) was dissolved in phosphorus oxychloride (2 mL) and heated to 110 ° C for two hours and concentrated. Methylene chloride was dissolved, the saturated sodium bicarbonate solution was washed, the organic phase was dried, and concentrated to give 190 mg of a yellow solid with a yield of 82%. MS: 289 [M + H] ⁺

Step 3) (2-((5-cyano-4-((4-nitrobenzyl) amino) pyridin-2-yl) amino) -5- (4-ethylpiperazin-1-yl ) Phenyl) t-butylaminocarbamate

The intermediate 6-chloro-4-((4-nitrobenzyl) amino) nicotinonitrile (120 mg, 0.4 mmol), (2-amino-5- (4-ethylpiperazin-1-yl) benzene Tert-butyl aminocarbamate (120 mg, 0.4 mmol), Pd ₂ (dba) ₃ (10 mg), Xantphos (10 mg) and sodium carbonate (110 mg, 1 mmol) were dissolved in dioxane (5 mL) and In a sealed tube of water (0.5mL), the reaction system was replaced with argon and heated at 120 ° C for 10 hours, cooled, filtered, and the filtrate was concentrated. The purified thin-layer plate (1mm, silica gel) was directly purified to obtain 105 mg of a pale yellow solid product. , Yield 46%, MS: 573 [M + H] ⁺ ;

Step 4) N- (2-((5-cyano-4-((4-nitrobenzyl) amino) pyridin-2-yl) amino) -5- (4-ethylpiperazine-1 -Yl) phenyl) acrylamide

(2-((5-cyano-4-((4-nitrobenzyl) amino) pyridin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) benzene Tert-butyl aminocarbamate (100 mg, 0.17 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and acryloyl chloride (50 microliters) was added dropwise under ice-water bath conditions and reacted for 30 minutes, quenched by adding water, using Extraction with methyl chloride, washing with saturated sodium bicarbonate solution, drying the organic phase, concentrating, and purifying from a preparation plate (0.5 mm, silica gel) (developing agent volume ratio methylene chloride / methanol = 110/9) to obtain 75 mg of a white solid, yield 84%, MS: 527 [M + H] ⁺ ;

Step 5) N- (2-((5-cyano-4-((4-aminobenzyl) amino) pyridin-2-yl) amineamino) -5- (4-ethylpiperazine- Preparation of 1-yl) phenyl) acrylamide

N- (2-((5-cyano-4-((4-nitrobenzyl) amino) pyridin-2-yl) aminoamine) -5- (4-ethylpiperazine-1- (Phenyl) phenyl) acrylamide (70 mg, 0.13 mmol) in ethanol (10 mL), followed by successive addition of anhydrous ammonium chloride (530 mg, 10 mmol), zinc powder (330 mg, 5 mmol), stirring at room temperature for 48 hours, filtration, concentration, Prepare a thin plate (0.5mm, silica gel) and purify (developing agent volume ratio dichloromethane / methanol = 10/1) to obtain 23 mg of a white solid with a yield of 36%;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.61 (s, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.24 (s, 1H), 7.04 (br, 1H), 6.94 (d, J = 8.8Hz, 1H), 6.86 (d, J = 8.1Hz, 2H), 6.70 (d, J = 8.9Hz, 1H), 6.52-6.39 (m, 3H), 6.22 (d, J = 17.1Hz, 1H), 5.78-5.69 (m, 1H), 5.59 (s, 1H), 4.98 (s, 2H), 4.05 (d, J = 5.8Hz, 2H), 3.12 (t, J = 5.0Hz, 4H), 2.72-2.63 (m, 4H), 2.41-2.30 (m, 2H), 1.04 (t, J = 7.2Hz, 3H). MS: 497 [M + H] ⁺ ;

Example 331. N- (2-((2-acrylamido-4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyridine-4-yl) -2 -Fluoro-6-methoxybenzamide

Step 1) Preparation of 6-chloro-4-((1- (4-methoxyphenyl) ethyl) amino) nicotinamide

2,4-Dichloro-5-nicotinic acid (1.92 g, 10 mmol), (4-methoxyphenyl) ethyl-1-amine (1.51 g, 10 mmol) and DIEA (3.9 g, 30 mmol) were added to NMP, respectively (10 mL), heated to 120 ° C. and reacted for 3 hours, cooled, slurried with water, filtered, and dried to give a white solid 2.8 g, yield 92%, MS: 306 [M + H] ⁺

Step 2) Preparation of 4-amino-6-chloronicotonitrile

Add intermediate 6-chloro-4-((1- (4-methoxyphenyl) ethyl) amino) nicotinamide (2.8 g, 9.2 mmol) to phosphorus oxychloride (10 mL) and heat at reflux The reaction was carried out for two hours, cooled, concentrated, and added with dichloromethane (3 mL), washed with saturated sodium bicarbonate solution (30 mL), a large amount of white solid precipitated in the aqueous phase, and filtered to dry to obtain a white solid product; the organic phase was concentrated, and a small amount of ethyl acetate White solid was washed; 1.35 g of white solids were combined twice, yield 96%, MS: 154 [M + H] ⁺ ;

Step 3) Preparation of N- (2-chloro-5-cyanopyridine-4-yl) -2-fluoro-6-methoxybenzamide

Add 2-fluoro-6-methoxybenzoic acid (0.17 g, 1 mmol) to dichlorosulfoxide (3 mL) and heat under reflux for one hour, cool, and concentrate to obtain a yellow oil in anhydrous tetrahydrofuran (1 mL) for later use; The intermediate 4-amino-6-chloronicotinonitrile (0.15 g, 1 mmol) was added to tetrahydrofuran (2 mL) containing NaH (80 mg, 2 mmol) under ice-water bath conditions, and then the 2-fluoro- A solution of 6-methoxybenzoyl chloride in tetrahydrofuran, stirred at 0 ° C overnight, quenched with water, beaten, filtered and dried to give a white solid product 260 mg, yield 85%, MS: 306 [M + H] ⁺ ;

Step 4) (2-((5-cyano-4- (2-fluoro-6-methoxybenzoylamino) pyridin-2-yl) amino) -5- (4-ethylpiperazine Preparation of tert-butyl-1-yl) phenyl) carbamate

Add N- (2-chloro-5-cyanopyridine-4-yl) -2-fluoro-6-methoxybenzamide (120 mg, 0.4 mmol), (2-amino-5- (4-ethyl Piperazin-1-yl) phenyl) carbamic acid tert-butyl ester (120 mg, 0.4 mmol), Pd ₂ (dba) ₃ (10 mg), Xantphos (10 mg) and sodium carbonate (110 mg, 1 mmol) were separately dissolved in In a sealed tube of dioxane (5mL) and water (0.5mL), the reaction system was replaced with argon and heated at 120 ° C for 10 hours, cooled, filtered, and the filtrate was concentrated. The thin layer plate (1mm, silica gel) was prepared directly. ) Purification yielded 85 mg of light yellow solid product, yield 36%, MS: 590 [M + H] ⁺ ;

Step 5) N- (2-((2-acryloylamino-4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyridine-4-yl) -2 Of 2-fluoro-6-methoxybenzamide

(2-((5-cyano-4- (2-fluoro-6-methoxybenzamide) pyridin-2-yl) amino) -5- (4-ethylpiperazine-1- (Phenyl) phenyl) amino tert-butyl carbamate (85 mg, 0.14 mmol) was added to a dichloromethane (3 mL) solution containing trifluoroacetic acid (1 mL), stirred at room temperature for 1 hour, concentrated, and anhydrous tetrahydrofuran (2 mL) was added. Acryloyl chloride (40 microliters) was then added dropwise under ice-water bath conditions and stirring was continued for half an hour, quenched by addition of water, extracted with dichloromethane, washed with saturated sodium bicarbonate, dried the organic phase, concentrated, and subjected to a preparative sheet (0.5 mm, Purification on silica gel (developing system V _{dichloromethane / methanol} = 12/1) to obtain 33 mg of white solid product, yield 42%, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.69 (s, 1 H), 9.57 (s, 1H), 8.88 (s, 1H), 8.37 (s, 1H), 7.52-7.46 (m, 2H), 7.40-7.25 (m, 2H), 7.00 (d, J = 8.5Hz, 1H), 6.95-6.79 (m, 2H), 6.54 (dd, J = 17.0, 10.1 Hz, 1H), 6.23 (d, J = 17.0 Hz, 1H), 5.74 (d, J = 10.0 Hz, 1H), 3.84 (s , 3H), 3.11 (br, 4H), 2.55 (br, 4H), 2.40 (br, 2H), 1.23 (t, J = 7.2Hz, 3H). MS: 544 [M + H] ⁺

Example 347. N- (2-((5-cyano-4- (cyclohexylamino) pyridin-2-yl) amino) -5- (4-methylpiperazin-1-yl) phenyl )Acrylamide

Step 1) Preparation of 6-chloro-4- (cyclohexylamino) nicotinamide

To a solution of 2,4-dichloro-5-nicotinamide (192 mg, 1 mmol) in NMP (5 mL), cyclohexylamine (100 mg, 1 mmol) and DIEA (0.5 mL, 3 mmol) were sequentially added dropwise, and the reaction was heated to 100 ° C with stirring. 6 hours, quenched by adding water (20 mL), continued stirring for half an hour to beat, filtered, and dried to obtain 230 mg of a white solid, yield 91%, MS: 254 [M + H] ⁺

Step 2) Preparation of 6-chloro-4- (cyclohexylamino) nicotinonitrile

Add pyridine (2mL) and phosphorus oxychloride (0.5mL) to the acetonitrile (20mL) solution, and then add the intermediate 6-chloro-4- (cyclohexylamino) nicotinamide (230mg, 0.9mmol) to the solution. ), The reaction was heated to reflux for 1 hour, cooled, quenched by adding water, washed with saturated sodium bicarbonate, extracted with dichloromethane, dried from the organic phase, and concentrated to give 170 mg of a yellow solid with a yield of 80%. MS: 236 [M + H] ⁺ ;

Step 3) tert- (2-((5-cyano-4- (cyclohexylamino) pyridin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) carboxylic acid Preparation of butyl ester

6-chloro-4- (cyclohexylamino) nicotinonitrile (100 mg, 0.4 mmol), (2-amino-5- (4-methylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester (120mg, 0.4mmol), Pd ₂ (dba) ₃ (10mg), Xantphos (10mg) and sodium carbonate (110mg, 1mmol) were dissolved in sealed tubes containing dioxane (5mL) and water (0.5mL), respectively. In the reaction system, the reaction system was replaced by argon and heated at 120 ° C for 10 hours, cooled, filtered, and the filtrate was concentrated. The filtrate was directly purified from the preparation of a thin-layer plate (thickness 1 mm, loaded with silica gel) (the volume ratio of the developed system was V dichloromethane / methanol = 200/9) gave 130 mg of light yellow solid product with a yield of 64%. MS: 506 [M + H] ⁺

Step 4) N- (2-((5-cyano-4- (cyclohexylamino) pyridin-2-yl) amino) -5- (4-methylpiperazin-1-yl) phenyl) Preparation of acrylamide

(2-((5-cyano-4- (cyclohexylamino) pyridin-2-yl) amino) -5- (4-methylpiperazin-1-yl) phenyl) carboxylic acid tert-butyl ester (100 mg, 0.2 mmol) in dichloro solution (3 mL) was added with trifluoroacetic acid (1 mL), and the reaction was stirred at room temperature for 1 hour, and concentrated to obtain a yellow oily substance dissolved in anhydrous tetrahydrofuran (2 mL). Acryloyl chloride (50 μl) was added dropwise, and the reaction was continued for half an hour, quenched by adding water, extracted with dichloromethane, washed with saturated sodium bicarbonate solution, dried the organic phase, concentrated, and purified by a preparation sheet (0.5 mm, silica gel) (Developing agent volume ratio methylene chloride / methanol = 110/9) 31 mg of a white solid was obtained with a yield of 34%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.56 (s, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.33 (s, 1H), 7.20 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 6.54-6.41 (m, 1H), 6.21 (d, J = 17.0 Hz, 1H), 6.01 (d, J = 7.9 Hz, 1H), 5.78- 5.64 (m, 2H), 3.15 (br, 1H), 3.10 (br, 4H), 2.50 (br, 4H), 2.24 (s, 3H), 1.82-1.68 (m, 4H), 1.58 (br, 1H) , 1.35-1.06 (m, 5H) .MS: 460 [M + H] ⁺ ;

Example 379. N- (2-((5-cyano-4- (cyclobutylamino) pyridin-2-yl) amino) pyridin-3-yl) acrylamide

Step 1) Preparation of 4- (cyclobutylamino) -6-((diphenylenyl) amino) nicotinonitrile

6-chloro-4- (cyclobutylamino) nicotinonitrile (200 mg, 1 mmol), benzophenone imine (180 mg, 1 mmol), Pd (OAc) 2 (30 mg), Binap (30 mg), tert-butyl Sodium alkoxide (190mg, 2mmol) was added to toluene. After argon replacement, it was heated to 90 degrees Celsius in a sealed tube and reacted for 12 hours, cooled, filtered, and concentrated. 250 mg of pale yellow solid product was obtained by silica gel column chromatography with a yield of 71. %, MS: 353 [M + H] ⁺ ;

Step 2) Preparation of 6-amino-4- (cyclobutylamino) nicotinonitrile

4- (Cyclobutylamino) -6-((diphenylenyl) amino) nicotinonitrile (250 mg, 0.7 mmol), sodium acetate (0.13 g, 1.6 mmol), hydroxylamine hydrochloride (82 mg, 1.2 mmol) was added to methanol (10 mL), and the reaction was stirred at room temperature for 1 hour, concentrated, dissolved in dichloromethane, filtered, and the filtrate was concentrated to obtain 105 mg of a white solid product by silica gel column chromatography. Yield 80%. + H] ⁺ ;

Step 3) Preparation of 4- (cyclobutylamino) -6-((3-nitropyridin-2-yl) amino) nicotinonitrile

6-Amino-4- (cyclobutylamino) nicotinonitrile (90mg, 0.5mmol), palladium acetate (20mg), xanphos (20mg), potassium carbonate (270mg, 2mmol) were added to the dry 1,4- In dioxane (5mL), after argon replacement, heat to 100 ° C in a sealed tube for 10 hours, cool, filter, and concentrate to obtain 130 mg of a yellow solid product by silica gel column chromatography. Yield: 84%. MS: 311 [M + H] ⁺ ;

Step 4) 6-((3-aminopyridin-2-yl) amino) -4- (cyclobutylamino) nicotinonitrile

Add 4- (cyclobutylamino) -6-((3-nitropyridin-2-yl) amino) nicotinonitrile (100 mg, 0.33 mmol) to a solution containing stannous dichlorotin (450 mg, 2 mmol) In ethanol (5mL) solution, continue heating under reflux for two hours, cool, concentrate, add dichloromethane to dissolve, adjust the pH to 8 with saturated sodium bicarbonate solution, filter, dry the organic phase, and concentrate to obtain 91 mg of off-white solid product. Yield: 90%, MS: 281 [M + H] ⁺ ;

Step 5) Preparation of N- (2-((5-cyano-4- (cyclobutylamino) pyridin-2-yl) amino) pyridin-3-yl) acrylamide

6-((3-aminopyridin-2-yl) amino) -4- (cyclobutylamino) nicotinonitrile (14 mg, 0.05 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), and the solution was transferred to an ice-water bath. Acryloyl chloride (10 microliters) was added thereto, and the reaction was stirred for 10 minutes, quenched with water, washed with saturated sodium bicarbonate, extracted with dichloromethane, concentrated, and purified from a preparation plate to obtain 6 mg of a white solid product. MS: 335 [M + H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.00 (s, 1H), 8.81 (s, 1H), 8.25-8.14 (m, 2H), 7.93 (d, J = 8.0Hz, 1H ), 7.29 (s, 1H), 7.08 (dd, J = 7.9, 4.8 Hz, 1H), 6.96 (d, J = 5.6 Hz, 1H), 6.51 (dd, J = 17.2, 10.0 Hz, 1H), 6.29 (dd, J = 17.1, 1.9 Hz, 1H), 5.82 (dd, J = 10.1, 1.9 Hz, 1H), 3.93 (q, J = 7.4 Hz, 1H), 2.33 (br, 2H), 2.16-2.03 ( m, 2H), 1.82-1.69 (m, 2H).

Example 380.N- (5-((5-cyano-4- (cyclobutylamino) pyridin-2-yl) amino) -2- (4-ethylpiperazin-1-yl) pyridine-4 -Yl) acrylamide

The same operation as in Example 217 was performed, and cyclohexylamine was replaced by cyclobutylamine in step 1), and tert-butyl (5-amino-2- (4-ethylpiperazin-1-yl) pyridin-4-yl) carbamate was replaced. Step 3) tert-butyl (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) carbamate is reacted to obtain a white solid product; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9 .53 (s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.58 (s, 1H), 6.71-6.53 (m, 2H ), 6.24 (dd, J = 16.9, 2.0 Hz, 1H), 5.76 (dd, J = 10.1, 2.0 Hz, 1H), 5.55 (s, 1H), 3.80 (br, 1H), 3.42 (t, J = 4.9Hz, 4H), 2.47 (br, 4H), 2.38 (q, J = 7.1Hz, 2H), 2.21 (br, 2H), 2.06-1.94 (m, 2H), 1.68 (br, 2H), 1.04 ( t, J = 7.1Hz, 3H). MS: 447 [M + H] ⁺ ;

Example 381. N- (2-((5-cyano-4- (cyclobutylamino) pyrimidin-2-yl) amino) -5- (4- (dimethylamino) piperidin-1-yl ) Phenyl) acrylamide

Step 1): 2-chloro-4- (cyclobutylamino) pyrimidine-5-carbonitrile (50mg, 0.25mmol), (2-amino-5- (4- (dimethylamino) piperidine) Tert-butyl-1-yl) phenyl) carbamate (85 mg, 0.25 mmol) and trifluoroacetic acid (10 μl) were added to a sealed tube of sec-butanol (5 mL), heated at 120 ° C for 8 hours, and cooled , Concentrated, purified from a silica gel preparative thin plate (0.5 mm) (developing phase dichloromethane / methanol = 95/5) to give 65 mg of light yellow solid product, MS: 507 [M + H] ⁺ .

Step 2): To (2-((5-cyano-4- (cyclobutylamino) pyrimidin-2-yl) amino) -5- (4- (dimethylamino) piperidin-1-yl ) Phenyl) carbamic acid tert-butyl ester (50 mg, 0.1 mmol) in dichloromethane (3 mL) was added with trifluoroacetic acid (1 mL), reacted at room temperature for 1 hour, and the resulting light purple oil was concentrated and dissolved in Water tetrahydrofuran (1 mL), acryloyl chloride (20 μL) was added dropwise thereto at 0 ° C. and reacted for 0.5 hours, quenched by addition of water, extracted with dichloromethane, washed with saturated sodium bicarbonate, the organic phase was separated, dried, concentrated, used A thin plate (0.5 mm, silica gel) was prepared and purified (developing system: dichloromethane / methanol volume ratio 100: 9) to obtain 25 mg of a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.65 (s, 1H), 8.62 (s, 1H), 8.22 (s, 1H), 7.75 (d, J = 7.0 Hz, 1H), 7.40 (s, 1H), 7.19 (s, 1H), 6.80 (dd, J = 9.1, 2.8 Hz, 1H), 6.49 (dd, J = 17.0, 10.2 Hz, 1H), 6.24 (dd, J = 17.0, 2.0 Hz, 1H ), 5.75 (dd, J = 10.1, 2.0 Hz, 1H), 4.36 (br, 1H), 3.66 (d, J = 12.6 Hz, 2H), 2.67 (td, J = 12.3, 2.4 Hz, 2H), 2.20 (br, 7H), 2.11 (br, 4H), 1.83 (d, J = 11.5 Hz, 2H), 1.67-1.40 (m, 4H). MS: 461 [M + H] ⁺ ;

The compounds in the following table were prepared by referring to the preparation method of Example 381 using the corresponding substituent reaction. The following table lists the structures, names, and their NMR and MS data of the compounds prepared in Examples 382-394.

Example 395: N- (2-((5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (4- (dimethylamino) piperidine -1-yl) phenyl) acrylamide

Step 1): 2-chloro-4- (cyclobutylamino) pyrimidine-5-carbonitrile (65mg, 0.25mmol), (2-amino-5- (4- (dimethylamino) piperidine) Tert-butyl-1-yl) phenyl) carbamate (85 mg, 0.25 mmol) and trifluoroacetic acid (10 μl) were added to a sealed tube of sec-butanol (5 mL), heated at 120 ° C for 8 hours, and cooled , Concentrated, purified from a silica gel preparative thin plate (0.5 mm) (developing phase dichloromethane / methanol = 95/5) to give 65 mg of light yellow solid product, MS: 553 [M + H] ⁺ .

Step 2): To (2-((5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (4- (dimethylamino) piperidine Trifluoroacetic acid (1 mL) was added to a solution of t-butyl-1-yl) phenyl) carbamic acid tert-butyl ester (55 mg, 0.1 mmol) in dichloromethane (3 mL), and the mixture was reacted at room temperature for 1 hour. The obtained light purple oil was concentrated. It was dissolved in anhydrous tetrahydrofuran (1 mL), and acryloyl chloride (20 μL) was added dropwise thereto at 0 ° C. and reacted for 0.5 hours, quenched by adding water, extracted with dichloromethane, washed with saturated sodium bicarbonate, and separated into organic phases and dried. , Concentrated, purified using a preparative sheet (0.5 mm, silica gel) (developing system dichloromethane / methanol volume ratio 100: 9) to obtain 25 mg of a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.00 (s, 1H), 9.69 (s, 1H), 9.04 (br, 2H), 8.67 (s, 1H), 8.52 (d, J = 3.2 Hz, 1H), 7.99 (s, 1H), 7.44 (d, J = 29.3Hz, 3H), 7.19 (s, 1H), 6.89 (s, 1H), 6.58-6.47 (m, 1H), 6.25 (d, J = 17.2 Hz, 1H), 5.74 (d, J = 10.3 Hz, 1H), 3.74 (s, 2H), 2.75 (s, 2H), 2.24 (br, 7H), 1.88 (d, J = 12.4 Hz, 2H ), 1.53 (d, J = 11.5 Hz, 2H). MS: 507 [M + H] ⁺ ;

The compounds in the following table are prepared by referring to the preparation method of Example 395 and using the corresponding substituent reactions.

The structures and names of the compounds prepared in Examples 396-422, as well as their NMR and MS data.

Example 423. N- (2-((5-Cyano-4-phenylpyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide

The same method as in Example 187 was used, and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane) in step 1) of Example 187 was replaced by phenylboronic acid -2-yl) -1H-pyrazole; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 9.44 (s, 1H), 8.83 (s, 1H), 7.88 ( s, 2H), 7.59 (s, 3H), 7.32 (s, 2H), 6.83 (dd, J = 8.9, 2.8 Hz, 1H), 6.52 (dd, J = 17.0, 10.2 Hz, 1H), 6.26 (dd , J = 17.0, 2.1Hz, 1H), 5.74 (dd, J = 10.1, 2.1Hz, 1H), 3.14 (t, J = 4.9Hz, 4H), 2.54-2.48 (m, 4H), 2.39 (q, J = 7.2Hz, 2H), 1.04 (t, J = 7.2Hz, 3H). MS: 454 [M + H] ⁺ ;

Example 424.N- (2-((5-cyano-4- (1H-indazol-4-yl) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl ) Phenyl) acrylamide

By the same method as in Example 187, (1H-indazol-4-yl) boronic acid was used to replace 1-methyl-4- (4,4,5,5-tetramethyl-1,3 in step 1) of Example 187. , 2-Dioxaborane-2-yl) -1H-pyrazole; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.35 (s, 1H), 9.82 (s, 1H), 9.60 (d, J = 12.2 Hz, 1H), 8.94 (s, 1H), 8.42-8.11 (m, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.71 (s, 1H), 7.53 (t, J = 7.8Hz, 2H), 7.36 (s, 1H), 6.52 (dd, J = 17.0, 10.1Hz, 1H), 6.27 (dd, J = 17.0, 2.0Hz, 1H), 5.77 (dd, J = 9.9 , 2.1Hz, 1H), 3.02 (t, J = 4.7Hz, 4H), 2.54 (d, J = 5.2Hz, 4H), 2.39 (d, J = 7.2Hz, 2H), 1.03 (t, J = 7.2 Hz, 3H) .MS: 494 [M + H] ⁺ ;

Example 425. N- (2-((5-Cyano-4- (2-ethoxypyridin-3-yl) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine-1 -Yl) phenyl) acrylamide

By the same method as in Example 187, (2-ethoxypyridin-3-yl) boronic acid was used to replace 1-methyl-4- (4,4,5,5-tetramethyl-1) in step 1) of Example 187. , 3,2-dioxaborane-2-yl) -1H-pyrazole; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.80 (s, 1 H), 9.61 (s, 1 H) , 8.87 (s, 1H), 8.36 (dd, J = 5.0, 2.0 Hz, 1H), 7.87 (d, J = 7.1 Hz, 1H), 7.64-7.08 (m, 4H), 6.49 (dd, J = 17.0 , 10.2Hz, 1H), 6.26 (dd, J = 17.0, 2.0Hz, 1H), 5.77 (dd, J = 10.1, 2.0Hz, 1H), 4.40 (q, J = 7.0Hz, 2H), 3.01 (t , J = 4.7Hz, 4H), 2.54 (s, 4H), 2.40 (q, J = 7.2Hz, 2H), 1.33 (t, J = 7.0Hz, 3H), 1.04 (t, J = 7.2Hz, 3H ) .MS: 499 [M + H] ⁺ ;

Experimental example 1.

The test of small molecule compounds inhibiting FGFR4 kinase activity is as follows:

1) Compound dilution:

In a 96-well plate a, dilute the compound with DMSO solution three times to form 11 gradients. The 12th gradient is a pure DMSO solution (as a positive control); take a new 96-well plate b and use the above solution with 25 times dilution with ultrapure water (4% DMSO concentration)

2) Turn the compound to a 384-well plate:

Turn the compound solution diluted with ultrapure water in the 96-well plate b into a corresponding well of a 384-well plate.

3) Add 4 × kinase solution: use a row gun to take 2.5 μl of the above 4 × kinase solution and add it to the corresponding reaction wells of a 384-well plate, mix well and pre-react for 5 minutes at room temperature.

4) Add 2 × substrate / ATP mixed solution: Use a row gun to take 5 μl of the above 2 × substrate / ATP mixed solution into the corresponding reaction wells of a 384-well plate.

5) Negative control: set a negative control well in a 384-well plate, and add 2.5 μl 4 × substrate, 2.5 μl 4 × enzyme solution, 2.5 μl 1 × Kinase Assay Buffer and 2.5 μl ultrapure water containing 4% DMSO .

6) Mix by centrifugation and react at room temperature in the dark for 2 hours.

7) Stop the enzymatic reaction:

Pipette 5 μl of the above 4 × stop solution into the corresponding well of a 384-well plate, mix by centrifugation, and react at room temperature for 5 minutes.

8) Color reaction:

Pipette 5 μl of the above 4 × test solution into the corresponding wells of a 384-well plate, mix by centrifugation, and react at room temperature for 1 hour.

9) Put the 384-well plate into the plate reader and get the corresponding program detection signal.

10) IC ₅₀ analysis:

Well reading = 10000 * EU665 value / EU615 value

Inhibition rate = (read value of positive control well-read value of experimental well) / (read value of positive control well-read value of negative control well) * 100%

The corresponding drug concentration and the inhibition rate calculated process input GraphPad Prism 5 the corresponding IC _50.

FGFR4 kinase activity inhibition molecular screening experimental conditions:

The final concentration of FGFR4 kinase in the reaction system was 3.85 nM, the final concentration of ATP was 100 μM, the final concentration of the substrate ULight ^™ -labeled JAK-1 (Tyr1023) Peptide was 100 nM, and the enzymatic reaction time was 2 hours.

The maximum final concentration of the compound in the reaction system was 2.5 μM. After a 3-fold gradient dilution, the total final concentration was 11 and the lowest final concentration was 0.042 nM. The final DMSO concentration was 1%.

Table (1) lists the results of determination of the tyrosine kinase FGFR4 inhibitory activity of some of the compounds in this patent, where A means IC _{50 is} less than or equal to 10 nM, B means IC _{50 is} greater than 10 nM but less than or equal to 100 nM, and C means IC ₅₀ More than 100 nM but less than or equal to 1000 nM.

Table (1): Results of determination of FGFR4 kinase inhibitory activity of the compounds of the present invention

Experimental example 2.

The test for inhibiting the activity of FGFR4 and V550L mutant kinase by small molecule compounds is the same as that of Experimental Example 1. The experimental conditions are as follows:

FGFR4 V550L kinase activity inhibition molecular screening experimental conditions:

The final concentration of FGFR4 V550L kinase in the reaction system was 1 nM, the final concentration of ATP was 10 μM, the final concentration of the substrate ULight ^™ -labeled PolyGT was 100 nM, and the enzymatic reaction time was 2 hours.

The maximum final concentration of the compound in the reaction system was 2.5 μM. After a 3-fold gradient dilution, the total final concentration was 11 and the lowest final concentration was 0.042 nM. The final DMSO concentration was 1%.

Table (b) lists the results of the determination of the inhibitory activity of some compounds in this patent on the tyrosine kinase FGFR4 of the mutant V550L, where A represents an IC _{50 of} less than or equal to 10 nM, and B represents an IC _{50 of} greater than 10 nM but less than or equal to 100 nM, C Indicates that the IC _{50 is} greater than 100 nM but less than or equal to 1000 nM.

Table (II): Results of determination of FGFR4 kinase inhibitory activity of the compound of the present invention on V550L mutation

The biological data provided by the present invention indicate that the compounds of the present invention are beneficial for the treatment or prevention of diseases caused by abnormal FGFR4 kinases, including diseases caused by mutations in the FGFR4 gene (V550L, V550M, etc.), including primary and metastatic cancers. Including solid tumors. Such cancers include, but are not limited to, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, intrauterine Membrane cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelogenous leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, nasopharyngeal cancer, esophageal cancer, brain Tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary sarcoma, and bile duct cancer. The compounds of the invention also include treating cancers that are resistant to one or more other treatments. The compounds of the present invention can also be used in diseases other than cancer related to FGFR4 kinase, including but not limited to fundus diseases, psoriasis, rheumatoid arthritis, atherosclerosis, pulmonary fibrosis, liver fibrosis. The compound of the present invention can be used as a monotherapy or a combination therapy, and can be used in combination with a plurality of compounds of the present invention or in combination with drugs other than the present invention.

The above is the preferred embodiment of the present invention. It should be noted that, for those of ordinary skill in the art, without departing from the principles described in the present invention, the embodiments of the present invention can also make several improvements and modifications. These improvements and modifications should also be regarded as the protection scope of the present invention.

Claims (13)

A compound represented by formula (I), an isomer, a hydrate, a solvate thereof, a pharmaceutically acceptable salt thereof, and a prodrug thereof,

In formula (I), X is N or CH; Y is N or C-M, where M is -H, -F, -Cl, methyl or methoxy; Z is N or C-R, Where R is -H, -F, -Cl, hydroxyl, amino, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, mono- or di-C ₁ -C ₃ Alkyl substituted amino, substituted or unsubstituted 4-6 membered heterocyclyl, or the following groups:

m is 2 or 3, R ^a is amino, C ₁ -C ₃ alkoxy, mono- or bis C ₁ -C ₃ alkyl substituted amine, R ^b is -H, or C ₁ -C ₃ alkyl, The substituted or unsubstituted 4-6 membered heterocyclic group described in R contains 1-2 heteroatoms selected from N, O or S. The substituted 4-6 membered heterocyclic group is independently Or different substituents selected from the group consisting of hydroxy, amino, cyano, formyl, acetyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, mono- or di-C ₁ -C ₃ Alkylamino R ¹ is -H, a substituted or unsubstituted 4-6 membered heterocyclic group, or -LR ³ , Where L is L ₁ or L ₂ , L ₁ is:

n1 is an integer from 0 to 4, L _{2 is} selected from:

n2 is an integer from 0-3, n3 is an integer from 0-2, R ⁴ is -H or C ₁ -C ₃ alkyl, The 4- to 6-membered heterocyclic group in R ¹ contains 1-2 heteroatoms selected from N, O or S, and the substituted 4-to-6-membered heterocyclic group is independently selected from 1-2 selected from hydroxyl, halogen , C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, R ^{3 is} selected from -H, C ₁ -C ₈ alkyl, halo C ₂ -C ₄ alkyl, hydroxy substituted C ₂ -C ₄ alkyl, cyano substituted C ₂ -C ₄ alkyl, carboxy substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy substituted C ₂ -C ₄ alkyl, bridged ring structure, substituted or unsubstituted fused ring structure, substituted or unsubstituted C ₃ -C ₈ Cycloalkyl, substituted or unsubstituted 4-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted aryl, The bridge ring structure in R ³ is a bridge ring structure of C ₅ -C ₁₁ , The substituted or unsubstituted fused ring structure described in R ³ is selected from the group consisting of an aromatic ring and a 5-6 membered heteroaryl group, a 5-6 membered heteroaryl ring and a 5-6 membered heteroaryl ring group, and an aromatic ring and a 5-6 membered ring. Cycloalkyl, aromatic ring and 5-6 membered heterocyclic group, 5-6 membered heteroaromatic ring and 5-6 membered heterocyclic ring or 5-6 membered heteroaryl ring and 5-6 membered heterocyclic group, substituted fused The substituent of the ring structure is selected from the group consisting of halogen, hydroxy, cyano, carbamoyl, C ₁ -C ₃ methoxy, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₃ -C ₄ cycloalkyl substituted C ₁ -C ₃ alkyl, hydroxy substituted C ₂ -C ₄ alkyl, C ₁ -C ₃ methoxy substituted C ₂ -C ₄ alkyl, cyano substituted C ₁ -C ₃ alkyl, carbamoyl substituted C ₁ -C ₃ alkyl, The substituted C ₃ -C ₈ cycloalkyl described in R ³ is independently substituted by 1-2 identical or different substituents, the substituents being selected from halogen, hydroxy, cyano, C ₁ -C ₃ alkyl Oxygen, C ₁ -C ₃ alkyl, The 4- to 6-membered heteroaryl and 5- to 6-membered heteroaryl in R ³ contain 1-2 heteroatoms selected from N, O or S, The substituted 4-6 membered heterocyclic group described in R ³ is independently substituted with 1-2 identical or different substituents, the substituents being selected from halogen, hydroxyl, cyano, C ₁ -C ₃ alkoxy , C ₁ -C ₃ alkyl, formyl, acetyl, carbamoyl, methylaminoformyl, dimethylaminoformyl, The substituted aryl and 5- to 6-membered heteroaryl described in R ³ are independently substituted with 1-4 identical or different substituents, which are selected from halogen, hydroxyl, amino, cyano, carboxyl, Fluoromethoxy, difluoromethoxy, trifluoromethoxy, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₃ alkyne Alkyl, C ₂ -C ₃ alkenyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, mono- or bis C ₁ -C ₃ alkylamino, C ₃ -C ₄ cycloalkyloxy , C ₃ -C ₄ cycloalkyl substituted C ₁ -C ₃ alkyl, cyano substituted C ₁ -C ₃ alkyl, carbamoyl substituted C ₁ -C ₃ alkyl, or the following groups:

q is an integer of 2-3, R ^{s is} selected from -H, C ₁ -C ₃ alkyl, R ^{p is} selected from -H, C ₁ -C ₃ alkyl, R ′ and R ″ are each independently -H, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, R ^{5 is} selected from -H, halogen, hydroxy, cyano, amino, carboxyl, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₃ alkoxy, mono- or di-C _1- C ₃ alkyl substituted amine groups; R ² is -L ₃ -R ⁶ or -L ₄ -R ⁷ , L ₃ is:

L ₄ is:

p1 is an integer of 0-4, p2 is an integer of 2-4, p3 is an integer of 0-1, R ^p is -H or C _1- C ₃ alkyl, R ^{6 is} selected from -H, halogen, hydroxyl, amino, cyano, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl , C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, mono- or di-C ₁ -C ₃ alkylamino, substituted or unsubstituted 4-6 membered hetero Ring base, The 4- to 6-membered heterocyclic group described in R ⁶ contains 1-2 heteroatoms selected from N, O or S, and the substituted 4-6-membered heterocyclic group is independently substituted with 1-2 identical or different substituents, respectively. Substituted or oxo, the substituent of the 4- to 6-membered heterocyclic group is selected from the group consisting of hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkoxy, formyl, acetyl, propionyl, Isopropyl, hydroxy-substituted C ₁ -C ₃ alkyl, carboxy-substituted C ₁ -C ₃ alkyl, or -NR ⁸ R ⁹ , R ⁸ and R ⁹ are each independently selected from -H, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, hydroxy substituted C ₂ -C ₃ alkyl, cyano substituted C ₁ -C ₂ Alkyl, C ₁ -C ₃ alkoxy-substituted C ₂ -C ₃ alkyl, or R ⁸ , R ⁹ and the nitrogen atom to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclic group, The 4- to 6-membered heterocyclic group described in R ⁸ and R ⁹ contains 1-2 heteroatoms selected from N, O or S, and the substituent of the substituted 4- to 6-membered heterocyclic group is selected from -H, hydroxyl, Cyano, amino, formyl, acetyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, mono- or bis C ₁ -C ₃ alkylamino, hydroxy-substituted C ₂ -C ₃ alkyl , R ^{7 is} selected from -H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclic group, The 4- to 6-membered heterocyclic group in R ⁷ contains 1-2 heteroatoms selected from N, O or S, and the 4- to 6-membered heterocyclic group is unsubstituted or independently 1-2 Substituted by a substituent selected from the group consisting of hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, formyl, acetyl, propionyl, isopropyl. The compound of formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, and a prodrug thereof according to claim 1, wherein: Z is C-R, Where R is selected from -H, F, Cl, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy , Propoxy, isopropoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, substituted or unsubstituted 4- 6-membered heterocyclic group, or the following group:

m is 2 or 3, R ^a is -H, methoxy, ethoxy, propoxy, isopropoxy, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, Or N-methyl-N-ethylamino, R ^b is -H, methyl, or ethyl, The substituted or unsubstituted 4-6 membered heterocyclic group described in R is selected from the following groups:

R ^{10 is} selected from -H, methyl, ethyl, propyl, isopropyl, R ¹¹ and R ¹² are each independently selected from -H, -F, hydroxyl, cyano, methyl, and ethyl. The compound of formula (I), isomers, hydrates, solvates, pharmaceutically acceptable salts thereof, and prodrugs thereof according to claim 1, wherein: R ¹ is -H, substituted or unsubstituted 4-6 membered heterocyclic group or -LR ³ , wherein L is L ₁ or L ₂ , L ₁ is:

n1 is an integer from 0 to 3; L _{2 is} selected from:

n2 is an integer of 0-2, n3 is an integer of 0-1, R ⁴ is -H or methyl; The substituted or unsubstituted 4-6 membered heterocyclic group in R ¹ is selected from the following groups:

R ¹³ and R ¹⁴ are each independently selected from -H, -F, hydroxyl, cyano, methyl, ethyl, and methoxy; R ^{3 is} selected from -H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, hydroxyethyl, hydroxypropyl Methyl, cyanoethyl, cyanopropyl, carboxyethyl, carboxypropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl , Isopropyloxypropyl, fluoroethyl, difluoroethyl, trifluoroethyl, 2-hydroxypropyl, 2-methoxypropyl, or the following groups:

Wherein R ^{15 is} selected from -H, methyl, ethyl, propyl, isopropyl, R ¹⁶ , R ¹⁷ , R ¹⁸ , and R ¹⁹ are each independently selected from -H, -F, -Cl, -Br, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, and tert-butyl. Methyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, methylthio, ethylthio, propylthio, isopropylthio, fluoromethyl Methyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethynyl, vinyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclo Butylmethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, or the following groups:

q is an integer of 2-3, R ^{s is} selected from -H, methyl, ethyl, and R ^{p is} selected from -H, methyl, ethyl, R ′ and R ″ are each independently selected from -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, R ^{5 is} selected from -H, -F, hydroxyl, cyano, carboxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methyl Amine, ethylamino, dimethylamine; R ^{20 is} selected from -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, Hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, methoxybutyl, cyanomethyl, cyanoethyl, cyanopropyl, carbamoylmethyl , Carbamoylethyl, carbamoylpropyl, R ²¹ and R ²² are each independently selected from -H, -F, hydroxyl, cyano, methyl, ethyl, methoxy, and ethoxy. The compound of formula (I), isomers, hydrates, solvates, pharmaceutically acceptable salts thereof, and prodrugs thereof according to claim 1, wherein: R ² is -L ³ -R ⁶ or -L ⁴ -R ⁷ , L ^{3 is} selected from:

p1 is an integer of 0-3, and p2 is an integer of 2-3; L ⁴ is:

p3 is an integer of 0-1, R ^{p is} selected from -H, methyl, ethyl; R ^{6 is} selected from -H, F, -Cl, hydroxyl, amino, cyano, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, propyl, butyl, hexyl, Isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, iso Propoxy, methylthio, ethylthio, propylthio, isopropylthio, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, N-methyl-N-ethyl Amino, substituted or unsubstituted 4-6 membered heterocyclyl, The substituted or unsubstituted 4-6 membered heterocyclic group described in R ⁶ is selected from the following groups:

R ²³ is -H, -F, methyl, ethyl, R ²⁴ is -H, -F, hydroxyl, hydroxymethyl, cyano, methyl, ethyl, methoxy, or -NR ²⁶ R ²⁷ , R ²⁶ and R ²⁷ are each independently -H, methyl, ethyl, propyl, isopropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, methoxyethyl, and methyl Oxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, cyclopropyl, cyclobutyl, or the nitrogen atom to which R ²⁶ or R ²⁷ is attached The substituted or unsubstituted 4-6 membered heterocyclic group is selected from the following groups:

R ^{28 is} selected from -H, methyl, ethyl, formyl, acetyl, R ^{29 is} selected from -H, methyl, ethyl, R ^{30 is} selected from -H, hydroxyl, amino, methylamino, dimethylamino, hydroxymethyl, cyano, methyl, ethyl, methoxy, R ^{25 is} selected from -H, methyl, ethyl, propyl, isopropyl, formyl, acetyl, propanoyl, isopropyl, carboxymethyl, carboxyethyl, hydroxyethyl, hydroxypropyl, R ^s1 and R ^s2 are each independently selected from H and methyl; R ^{7 is} selected from -H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted 4- 6-membered heterocyclic group, the substituted or unsubstituted 4-6 membered heterocyclic group is selected from the following groups:

The compound of formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, and a prodrug thereof according to claim 3, wherein: R ¹ is -H, a substituted or unsubstituted 4-6 membered heterocyclic group, or -LR ³ , wherein L is L ₁ or L ₂ , L ₁ is:

n1 is an integer from 0-2; L _{2 is} selected from:

n2 is an integer from 0-2, n3 is an integer from 0-1, R ⁴ is -H or methyl; R ¹ is -L ₁ -R ³ or -L ₂ -R ³ , wherein -L ₁ -R ^{3 is} selected from the following groups:

R ^{20 is} selected from -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, Hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, methoxybutyl, cyanomethyl, cyanoethyl, cyanopropyl, carbamoylmethyl , Carbamoylethyl, carbamoylpropyl. The compound of formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, and a prodrug thereof according to claim 3, wherein: R ¹ is -H, a substituted or unsubstituted 4-6 membered heterocyclic group, or -LR ³ , wherein L is L ₁ or L ₂ , L ₁ is:

n1 is an integer from 0-2; L _{2 is} selected from:

n2 is an integer from 0-2, n3 is an integer from 0-1, R ⁴ is -H or methyl; R ¹ is -L ₁ -R ³ or -L ₂ -R ³ , Wherein -L ₂ -R ³ wherein R ³ is selected from: -H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl , Hexyl, hydroxyethyl, cyanoethyl, methoxyethyl, fluoroethyl, difluoroethyl, trifluoroethyl, 2-hydroxypropyl, 2-methoxypropyl, or the following groups :

Wherein R ^{15 is} selected from -H, methyl, ethyl, R ¹⁶ , R ¹⁷ , R ¹⁸ , and R ¹⁹ are each independently selected from -H, -F, -Cl, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, tert-butyl, and methyl. Oxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, methylthio, ethylthio, propylthio, isopropylthio, fluoromethyl, di Fluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethynyl, vinyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, Amino, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, or the following groups:

q is an integer of 2-3, R ^{s is} selected from H, methyl, ethyl, and R ^{p is} selected from -H, methyl, ethyl, R ′ and R ″ are independently selected from -H, methyl, ethyl, propyl, isopropyl, and cyclopropyl, R ^{5 is} selected from -H, -F, hydroxyl, cyano, carboxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methyl Amino, ethylamino, dimethylamino, R ^{20 is} selected from -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, Hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, methoxybutyl, cyanomethyl, cyanoethyl, cyanopropyl, carbamoylmethyl , Carbamoylethyl, carbamoylpropyl, R ²¹ and R ²² are each independently selected from -H, -F, hydroxy, methyl, ethyl, and methoxy. A compound represented by formula (I), an isomer, a hydrate, a solvate thereof, a pharmaceutically acceptable salt thereof, and a prodrug thereof,

In formula (I), X is N or CH; Y is N or C-M, where M is -H, -F, -Cl, methyl or methoxy; Z is N or C-R, Where R is -H, -F, -Cl, hydroxyl, amino, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, mono- or di-C ₁ -C ₃ Alkyl substituted amino, substituted or unsubstituted 4-6 membered heterocyclyl, or the following groups:

m is 2 or 3, R ^a is amino, C ₁ -C ₃ alkoxy, mono- or bis C ₁ -C ₃ alkyl substituted amine, R ^b is -H, or C ₁ -C ₃ alkyl, The substituted or unsubstituted 4-6 membered heterocyclic group described in R contains 1-2 heteroatoms selected from N, O or S. The substituted 4-6 membered heterocyclic group is independently Or different substituents selected from the group consisting of halogen, hydroxy, amino, cyano, formyl, acetyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, mono or bis C _1- C ₃ alkylamino; R ¹ is -LR ³ , where L is L ₁ or L ₂ , L ₁ is:

n1 is an integer from 0 to 4, L _{2 is} selected from:

n2 is an integer from 0 to 3, n3 is an integer from 0 to 2, R ⁴ is -H or C ₁ -C ₃ alkyl, R ^{3 is} selected from a substituted or unsubstituted fused ring structure, a substituted or unsubstituted 5-6 membered heteroaryl group, a substituted or unsubstituted aryl group, The substituted or unsubstituted fused ring structure described in R ³ is selected from the group consisting of an aromatic ring and a 5-6 membered heteroaromatic ring, a 5-6 membered heteroaryl ring and a 5-6 membered heteroaromatic ring, and an aromatic ring and a 5-6 membered carbon. Ring, aromatic ring and 5-6 membered heterocyclic ring, 5-6 membered heteroaromatic ring and 5-6 membered carbocyclic ring or 5-6 membered heteroaromatic ring and 5-6 membered heterocyclic ring, substituted substituents of fused ring structure Selected from halogen, hydroxy, cyano, carbamoyl, C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₃ -C ₄ cycloalkyl Substituted C ₁ -C ₃ alkyl, hydroxy substituted C ₂ -C ₄ alkyl, C ₁ -C ₃ alkoxy substituted C ₂ -C ₄ alkyl, cyano substituted C ₁ -C ₃ alkyl , Carbamoyl-substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl-OCO-substituted C ₁ -C ₃ alkyl, amino, mono- or di-C ₁ -C ₃ alkyl-substituted amino , Amino substituted C ₁ -C ₃ alkyl, The 5-6 membered heteroaryl group in R ³ contains 1-2 heteroatoms selected from N, O or S, The substituted aryl and 5- to 6-membered heteroaryl described in R ³ are independently substituted with 1-4 identical or different substituents, which are selected from halogen, hydroxyl, amino, cyano, carboxyl, Fluoromethoxy, difluoromethoxy, trifluoromethoxy, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₃ alkyne Alkyl, C ₂ -C ₃ alkenyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, mono- or bis C ₁ -C ₃ alkylamino, C ₃ -C ₄ cycloalkyloxy , C ₃ -C ₄ cycloalkyl substituted C ₁ -C ₃ alkyl, cyano substituted C ₁ -C ₃ alkyl, carbamoyl substituted C ₁ -C ₃ alkyl, hydroxy substituted C _1- C ₃ alkyl, C ₁ -C ₃ alkoxy substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl-OCO-substituted C ₁ -C ₃ alkyl, or the following groups:

q is an integer of 2-3, R ^{s is} selected from -H, C ₁ -C ₃ alkyl, R ^{p is} selected from -H, C ₁ -C ₃ alkyl, R ′ and R ″ are each independently -H, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, R ^{5 is} selected from -H, halogen, hydroxy, cyano, amino, carboxyl, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₃ alkoxy, mono- or di-C _1- C ₃ alkyl substituted amine groups; R ² is -L ₃ -R ⁶ , L ₃ is:

p1 is an integer from 0-4, p2 is an integer from 0-4, R ^p is -H or C ₁ -C ₃ alkyl, R ^{6 is} selected from -H, halogen, hydroxyl, amino, cyano, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl , C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, mono- or di-C ₁ -C ₃ alkylamino, substituted or unsubstituted 4-6 membered hetero Ring base, The 4- to 6-membered heterocyclic group described in R ⁶ contains 1-2 heteroatoms selected from N, O or S. The substituted 4- to 6-membered heterocyclic group is substituted with 1-2 same or different substituents. And / or oxo, the substituent of the 4- to 6-membered heterocyclic group is selected from the group consisting of hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkoxy, formyl, acetyl, propionyl, iso Propionyl, hydroxy-substituted C ₁ -C ₃ alkyl, carboxy-substituted C ₁ -C ₃ alkyl, or -NR ⁸ R ⁹ , R ⁸ and R ⁹ are each independently selected from -H, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, hydroxy substituted C ₂ -C ₃ alkyl, cyano substituted C ₁ -C ₂ Alkyl, C ₁ -C ₃ alkoxy-substituted C ₂ -C ₃ alkyl, or R ⁸ , R ⁹ and the nitrogen atom to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclic group, The 4- to 6-membered heterocyclic group described in R ⁸ and R ⁹ contains 1-2 heteroatoms selected from N, O or S, and the substituent of the substituted 4- to 6-membered heterocyclic group is selected from -H, hydroxyl, Cyano, amino, formyl, acetyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, mono- or bis C ₁ -C ₃ alkylamino, hydroxy-substituted C ₂ -C ₃ alkyl . The compound according to claim 1 or 7, an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, and a prodrug thereof, the compound is selected from:

A method for preparing a compound according to claim 1 or 7, comprising the following steps,

In the first step, M in the intermediate A1 is nitro or BocNH-, and Q in the intermediate B1 is chlorine or methylsulfone or methylsulfoxide. The reaction is carried out under acid-catalyzed, neutral or basic conditions. Substitution reaction or synthesis of compound (C1) by Buchwald coupling reaction; Second step: if M is BocNH- in intermediate C1, remove the tert-butyloxycarbonyl protecting group under acidic conditions to obtain intermediate D1; if M in intermediate C1 is nitro, reduce compound nitro to generate compound D1; Step 3: Synthesis of the final product (I) from intermediate D1 and acryloyl chloride. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or a hydrate thereof or a solvate thereof or a prodrug thereof, and a pharmaceutically acceptable carrier Or excipient composition. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition further comprises one or more other therapeutic agents. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof for preparing a medicament for treating a disease related to tyrosine kinase FGFR4 and an autoimmune disease Application. The use according to claim 12, wherein the diseases related to tyrosine kinase FGFR4 and autoimmune diseases include fundus disease, dry eye disease, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colon Inflammation, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosclerosis, pulmonary fibrosis, liver fibrosis, bone marrow fibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glial Tumor, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic granuloma Cell leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary sarcoma, and bile duct cancer.