CN112142731B - 2, 4-disubstituted pyrimidine derivative and preparation method and application thereof - Google Patents

2, 4-disubstituted pyrimidine derivative and preparation method and application thereof Download PDF

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CN112142731B
CN112142731B CN202010588937.0A CN202010588937A CN112142731B CN 112142731 B CN112142731 B CN 112142731B CN 202010588937 A CN202010588937 A CN 202010588937A CN 112142731 B CN112142731 B CN 112142731B
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陈俐娟
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Abstract

The invention belongs to the field of chemical medicine, and particularly relates to a 2, 4-disubstituted pyrimidine derivative, and a preparation method and application thereof. The invention provides a 2, 4-disubstituted pyrimidine derivative, the structure of which is shown as formula IV. The invention also provides a preparation method and application of the 2, 4-disubstituted pyrimidine derivative. The 2, 4-disubstituted pyrimidine derivative provided by the invention can be used as a kinase inhibitor with JAK2 and FLT3 dual-functional targets, can also be used as a kinase inhibitor with single JAK2 or FLT3 functional targets, and provides a new choice for preparing a multi-target inhibitor.

Description

2, 4-disubstituted pyrimidine derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to a 2, 4-disubstituted pyrimidine derivative and a preparation method and application thereof. In particular to application of a 2, 4-disubstituted pyrimidine derivative as a Janus tyrosine kinase 2 and FMS-like tyrosine kinase 3(JAK2-FLT3) inhibitor.
Background
Myeloproliferative neoplasms (MPNs) are a group of malignant myeloproliferative diseases originating from multipotent hematopoietic stem cells, and are manifested by hyperproliferation of one or more lines of myeloid cells, further increase of one or more lines of peripheral blood, and tendency to form thrombus, extramedullary hematopoiesis, myelofibrosis and transformation into acute leukemia. Such diseases include Polycythemia Vera (PV), Primary Thrombocythemia (PT) and Primary Myelofibrosis (PMF).
The current clinical treatment methods still cannot cure the diseases of the MPNs. Recent studies have found that JAK2 kinases in the janus kinase (JAK) family play an important role in MPNs. The JAK-signal converter and activator of transcription (JAK-STAT) pathway controls survival, proliferation and differentiation of a variety of cells through cytokine-mediated signaling. Whereas activation of JAK2 phosphorylation, downstream STAT phosphorylation, and gene transcription ultimately leads to increased proliferation, differentiation, and survival of erythrocytes and myeloid cells. A number of JAK2 inhibitors have been clinically tested, among which the JAK2 inhibitor Ruxolitinib has been approved by the FDA for myelofibrosis, and others such as Lestaurtinib (CEP701), CYT-387, LY2784544, BMS-911543, etc. are still under clinical study.
Furthermore, recent studies have shown that FMS-like tyrosine kinase 3(FLT3) mutations are also closely related to MPNs: ITD (internal tandem repeat) mutations, when knocked into mouse FLT3, can lead to myeloproliferative disease in mice. FLT3 is a receptor tyrosine kinase that plays a critical role in the development of hematopoietic progenitor cells. Activated FLT3 tandem repeat (ITD) mutations are found in about 30% of Acute Myeloid Leukemia (AML) patients, and are a high risk factor for disease recurrence. Small molecule FLT3 inhibitors have been in clinical trials as single or combination chemotherapies, however to date these drug candidates either failed to produce an adequate initial response or failed to maintain therapeutic benefit primarily due to secondary resistance. Clinical data also indicate that patients have a dramatic decline in peripheral blood leukemia cells after treatment, but little bone marrow response, and one of the possible mechanisms of failure is the possibility of an independent alternative survival pathway, and leukemia cells can adapt through further genetic mutation or metabolism. These pathways may include mTOR-PI3K-Akt, JAK-STAT, or Ras-MAPK. Simultaneous inhibition of these pathways would likely free leukemia cells from the limitations of FLT 3.
On this basis, targeting the JAK2 pathway simultaneously has several advantages: (a) few mutations in JAK2 were found in AML cases, (b) elevated phosphorylation-JAK 2 was found in AML, (c) down-regulation of JAK signaling, an inhibitor of cytokine 1/2/3, was significantly reduced in FLT3-TKI resistant strain FLT 3-ITD. At the same time, there is evidence that inhibition of both signaling pathways of JAK2-FLT3 can enhance the clinical efficacy of AML patients with FLT3-ITD mutations. Based on this, the JAK2/FLT3 double-target inhibitor treatment of MPNs is also becoming a research and development hotspot, so that the JAK2/FLT3 double-target inhibitor Fedratinib is approved by FDA to be preferentially used for myelofibrosis, and the macrocyclic compound Pacritinib is also being clinically researched in the third stage (used for treating myelofibrosis). However, the existing JAK2/FLT3 dual-target inhibitors have poor enzyme activity and low oral bioavailability, and still cannot meet medical requirements, so that the development of inhibitors with better selectivity, higher activity and better in-vivo pharmacokinetics is a hot spot in current research and development.
Disclosure of Invention
The invention provides a 2, 4-disubstituted pyrimidine derivative with JAK2 and FLT3 dual-function targets.
The structure of the 2, 4-disubstituted pyrimidine derivative is shown as a formula IV:
Figure BDA0002554748290000021
wherein X is N or CH; r22Is C1～C6An alkyl group;
R1、R2independently is-H, halogen, -OH, C1～C10Alkyl or C1～C10An alkoxy group;
the A ring is a 5-membered or 6-membered N-containing heterocyclic ring, and the number of N atoms is 1; r is linked to N on the ring A, R is C3～C10Cycloalkyl, substituted or unsubstituted C1～C10Alkyl radical, C2～C10Alkynyl, substituted or unsubstituted C2～C10An alkenyl group,
Figure BDA0002554748290000022
Figure BDA0002554748290000023
Said substituted C1～C10The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C10Alkoxy or C1～C10An oxycarbonyl group; said substituted C2～C10The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C1～C10Alkoxy radical, C1～C10Oxycarbonyl radical or
Figure BDA0002554748290000024
m、n＝0～2；
R5Is C1～C10Alkoxy, substituted or unsubstituted C2～C10Alkenyl, substituted or unsubstituted C1～C10An alkyl group,
Figure BDA0002554748290000025
Said substituted C1～C10The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C10Alkoxy radical, C1～C10An oxycarbonyl group,
Figure BDA0002554748290000026
Said substituted C2～C10Alkenyl is-H, -OH, halogen, -CN,
Figure BDA0002554748290000027
Phenyl or
Figure BDA0002554748290000028
R6、R7Independently is-H, C1～C10Alkyl or halogen substituted phenyl;
R8、R9independently is-H、C1～C10An alkyl group,
Figure BDA0002554748290000029
R10、R11independently-H or C1～C10An alkyl group;
R12～R16independently is-H, C1～C10Alkyl or-CF3；
R17～R21Independently is-H, C1～C10Alkyl or-CF3。
As a preferred embodiment of the present invention, the above-mentioned 2, 4-disubstituted pyrimidine derivative, R22Is C1～C4An alkyl group.
In a preferred embodiment of the present invention, the 2, 4-disubstituted pyrimidine derivative has a structure represented by formula i:
Figure BDA0002554748290000031
wherein X is N or CH;
R1、R2independently is-H, -halogen, -OH, C1～C10Alkyl or C1～C10An alkoxy group;
the A ring is a 5-membered or 6-membered N-containing heterocyclic ring, and the number of N atoms is 1; r is linked to N on the ring A, R is C3～C10Cycloalkyl, substituted or unsubstituted C1～C10Alkyl radical, C2～C10Alkynyl, substituted or unsubstituted C2～C10An alkenyl group,
Figure BDA0002554748290000032
Figure BDA0002554748290000033
Said substituted C1～C10The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C10Alkoxy or C1～C10Carbonyl oxygenA group; said substituted C2～C10The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C1～C10Alkoxy radical, C1～C10Oxycarbonyl radical or
Figure BDA0002554748290000034
m、n＝0～2；
R5Is C1～C10Alkoxy, substituted or unsubstituted C2～C10Alkenyl, substituted or unsubstituted C1～C10Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0002554748290000035
Said substituted C1～C10The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C10Alkoxy radical, C1～C10An oxycarbonyl group,
Figure BDA0002554748290000036
Said substituted C2～C10Alkenyl is-H, -OH, halogen, -CN,
Figure BDA0002554748290000037
Phenyl or
Figure BDA0002554748290000038
R6、R7Independently is-H, C1～C10Alkyl or halo-substituted phenyl;
R8、R9independently is-H, C1～C10Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0002554748290000039
R10、R11independently-H or C1～C10An alkyl group;
R12～R16independently is-H, C1～C10Alkyl or-CF3；
R17～R21Independently is-H, C1～C10Alkyl or-CF3。
As a preferred embodiment of the present invention, the above-mentioned 2, 4-disubstituted pyrimidine derivative, R1、R2Independently is-H, -halogen, -OH, C1～C8Alkyl or C1～C8An alkoxy group.
Preferably, R1、R2Independently is-H, -halogen, -OH, C1～C6Alkyl or C1～C6An alkoxy group.
Further preferably, R1、R2Independently is-H, -halogen, -OH, C1～C4Alkyl or C1～C4An alkoxy group.
More preferably, R1、R2Independently is-H, halogen or C1～C4An alkyl group.
Most preferably, R1、R2Independently is-H, -F or methyl.
Preferably, in the 2, 4-disubstituted pyrimidine derivatives, the a ring is a 5-or 6-membered N-containing heterocycle, and the number of N atoms is 1; r is connected with N on the ring A, R is C3～C8Cycloalkyl, substituted or unsubstituted C1～C8Alkyl radical, C2～C8Alkynyl, C2～C10Alkenyl, substituted C2～C8An alkenyl group,
Figure BDA0002554748290000041
Said substituted C1～C8The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C8Alkoxy or C1～C8An oxycarbonyl group; said substituted C2～C8The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C1～C8Alkoxy radical, C1～C8Oxycarbonyl radical or
Figure BDA0002554748290000042
m、n＝0～2。
Further preferably, ring a is a 5-or 6-membered N-containing heterocyclic ring, and the number of N atoms is 1; r is linked to N on the ring A, R is C3～C6Cycloalkyl, substituted or unsubstituted C1～C6Alkyl radical, C2～C6Alkynyl, C2～C10Alkenyl, substituted C2～C6An alkenyl group,
Figure BDA0002554748290000043
Said substituted C1～C6The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C6Alkoxy or C1～C6An oxycarbonyl group; said substituted C2～C6The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C1～C6Alkoxy radical, C1～C6Oxycarbonyl radical or
Figure BDA0002554748290000044
m、n＝0～2。
Still more preferably, ring A is a 5-or 6-membered N-containing heterocyclic ring, with 1N atom; r is connected with N on the ring A, R is C3～C6Cycloalkyl, substituted or unsubstituted C1～C6Alkyl radical, C2～C6Alkynyl, C2～C10Alkenyl, substituted C2～C4An alkenyl group,
Figure BDA0002554748290000045
Said substituted C1～C6The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C4Alkoxy or C1～C4An oxycarbonyl group; said substituted C2～C4The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C1～C4Alkoxy radical, C1～C4Oxycarbonyl radical or
Figure BDA0002554748290000046
m、n＝0～2。
More preferably, the A ring is 5-memberedOr a 6-membered N-containing heterocycle with 1N atom; r is connected with N on the ring A, and R is substituted or unsubstituted C1～C6Alkyl radical, C2～C6Alkynyl, C2～C10Alkenyl, substituted C2～C4An alkenyl group,
Figure BDA0002554748290000047
Figure BDA0002554748290000051
Said substituted C1～C6The substituent of the alkyl is-H, -OH, -CN, C1～C4Alkoxy or C1～C4An oxycarbonyl group; said substituted C2～C4The substituent of the alkenyl is-H, -COOH, phenyl and C1～C4Oxycarbonyl radical or
Figure BDA0002554748290000052
m and n are 0 or 1.
Most preferably, the a ring is a 5-or 6-membered N-containing heterocycle with 1N atom; r is connected with N on the ring A, and R is substituted or unsubstituted C1～C6Alkyl radical, C2～C6Alkynyl, C2～C10Alkenyl, substituted C2～C4An alkenyl group,
Figure BDA0002554748290000053
Figure BDA0002554748290000054
Said substituted C1～C6The substituents for alkyl being-H, -OH, -CN, ethoxy or
Figure BDA0002554748290000055
Said substituted C2～C4The substituent of the alkenyl is-H, -COOH, phenyl,
Figure BDA0002554748290000056
m and n are 0 or 1.
Preferably, the above 2, 4-In the disubstituted pyrimidine derivatives, R5Is C1～C8Alkoxy, substituted or unsubstituted C2～C8Alkenyl, substituted or unsubstituted C1～C8An alkyl group,
Figure BDA0002554748290000057
Said substituted C1～C8The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C8Alkoxy radical, C1～C8An oxycarbonyl group,
Figure BDA0002554748290000058
Figure BDA0002554748290000059
Said substituted C2～C8The substituent of the alkenyl is-H, -OH, halogen, -CN,
Figure BDA00025547482900000510
Phenyl or
Figure BDA00025547482900000511
R10、R11independently-H or C1～C8An alkyl group; r is12～R16Independently is-H, C1～C8Alkyl or-CF3。
Further preferably, R5Is C1～C6Alkoxy, substituted or unsubstituted C2～C6Alkenyl, substituted or unsubstituted C1～C6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA00025547482900000512
Said substituted C1～C6The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C6Alkoxy radical, C1～C6An oxycarbonyl group,
Figure BDA00025547482900000513
Said substituted C2～C6The substituent of the alkenyl is-H, -OH, halogen, -CN,
Figure BDA0002554748290000061
Phenyl or
Figure BDA0002554748290000062
R10、R11independently-H or C1～C6An alkyl group; r12～R16Independently is-H, C1～C6Alkyl or-CF3。
More preferably, R5Is C1～C6Alkoxy radical, C2～C6Alkenyl, substituted C2～C4Alkenyl radical, C1～C6Alkyl, substituted C1～C4An alkyl group,
Figure BDA0002554748290000063
Said substituted C1～C4The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C4Alkoxy radical, C1～C4An oxycarbonyl group,
Figure BDA0002554748290000064
Said substituted C2～C4The substituent of the alkenyl is-H, -OH, halogen, -CN,
Figure BDA0002554748290000065
Phenyl or
Figure BDA0002554748290000066
R10、R11independently-H or C1～C4An alkyl group; r is12～R16Independently is-H, C1～C4Alkyl or-CF3。
Most preferably, R5Is C2～C6Alkenyl, substituted C2～C4Alkenyl radical, C1～C6Alkyl, substituted C1～C4An alkyl group,
Figure BDA0002554748290000067
Said substituted C1～C4The substituent of the alkyl is-H, -OH, -CN,
Figure BDA0002554748290000068
Figure BDA0002554748290000069
Said substituted C2～C4The substituent of the alkenyl is-H,
Figure BDA00025547482900000610
Phenyl or
Figure BDA00025547482900000611
R10、R11independently-H or C1～C4An alkyl group.
Preferably, in the above 2, 4-disubstituted pyrimidine derivatives, R6、R7Independently is-H, C1～C8Alkyl or halogen substituted phenyl.
Further preferably, R6、R7Independently is-H, C1～C6Alkyl or halogen substituted phenyl.
More preferably, R6、R7Independently is-H, C1～C4Alkyl or chloro-substituted phenyl.
Most preferably, R6、R7Independently is-H, C1～C4Alkyl or
Figure BDA00025547482900000612
Preferably, in the above 2, 4-disubstituted pyrimidine derivatives, R8、R9Independently is-H, C1～C8Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA00025547482900000613
Figure BDA00025547482900000614
R17～R21Independently is-H, C1～C8Alkyl or-CF3。
Further preferably, R8、R9Independently is-H, C1～C6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0002554748290000071
R17～R21Independently is-H, C1～C6Alkyl or-CF3。
More preferably, R8、R9Independently is-H, C1～C4An alkyl group,
Figure BDA0002554748290000072
R17～R21Independently is-H, C1～C4Alkyl or-CF3。
Most preferably, R8、R9Independently is-H, C1～C4Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0002554748290000073
As a preferred technical scheme of the invention, the 2, 4-disubstituted pyrimidine derivative has a structure shown in a formula II:
Figure BDA0002554748290000074
wherein R is4Is C3～C10Cycloalkyl, substituted or unsubstituted C1～C10Alkyl radical, C2～C10Alkynyl, substituted or unsubstituted C2～C10An alkenyl group,
Figure BDA0002554748290000075
Said substituted C1～C10The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C10Alkoxy or C1～C10An oxycarbonyl group; said substituted C2～C10The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C1～C10Alkoxy radical, C1～C10Oxycarbonyl radical or
Figure BDA0002554748290000076
m、n＝0～2；
R5Is C1～C10Alkoxy, substituted or unsubstituted C2～C10Alkenyl, substituted or unsubstituted C1～C10Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0002554748290000077
Said substituted C1～C10The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C10Alkoxy radical, C1～C10An oxycarbonyl group,
Figure BDA0002554748290000078
Said substituted C2～C10Alkenyl is-H, -OH, halogen, -CN,
Figure BDA0002554748290000079
Phenyl or
Figure BDA00025547482900000710
R6、R7Independently is-H, C1～C10Alkyl or halo-substituted phenyl;
R8、R9independently is-H, C1～C10An alkyl group,
Figure BDA0002554748290000081
R10、R11independently-H or C1～C10An alkyl group;
R12～R16independently is-H, C1～C10Alkyl or-CF3；
R17～R21Independently is-H, C1～C10Alkyl or-CF3。
Preferably, in the above 2, 4-disubstituted pyrimidine derivatives, R4Is C3～C8Cycloalkyl, substituted or unsubstituted C1～C8Alkyl radical, C2～C8Alkynyl, C2～C10Alkenyl, substituted C2～C8An alkenyl group,
Figure BDA0002554748290000082
Said substituted C1～C8The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C8Alkoxy or C1～C8An oxycarbonyl group; said substituted C2～C8The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C1～C8Alkoxy radical, C1～C8Oxycarbonyl radical or
Figure BDA0002554748290000083
m、n＝0～2。
Further preferably, R4Is C3～C6Cycloalkyl, substituted or unsubstituted C1～C6Alkyl radical, C2～C6Alkynyl, C2～C10Alkenyl, substituted C2～C6An alkenyl group,
Figure BDA0002554748290000084
Said substituted C1～C6The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C6Alkoxy or C1～C6An oxycarbonyl group; said substituted C2～C6The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C1～C6Alkoxy radical, C1～C6Oxycarbonyl radical or
Figure BDA0002554748290000085
m、n＝0～2。
Even more preferably, R4Is C3～C6Cycloalkyl, substituted or unsubstituted C1～C6Alkyl radical, C2～C6Alkynyl, C2～C10Alkenyl, substituted C2～C4An alkenyl group,
Figure BDA0002554748290000086
Said substituted C1～C6The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C4Alkoxy or C1～C4An oxycarbonyl group; said substituted C2～C4The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C1～C4Alkoxy radical, C1～C4Oxycarbonyl radical or
Figure BDA0002554748290000087
m、n＝0～2。
More preferably, R4Is substituted or unsubstituted C1～C6Alkyl radical, C2～C6Alkynyl, C2～C10Alkenyl, substituted C2～C4An alkenyl group,
Figure BDA0002554748290000088
Said substituted C1～C6The substituent of the alkyl is-H, -OH, -CN, C1～C4Alkoxy or C1～C4An oxycarbonyl group; said substituted C2～C4The substituent of the alkenyl is-H, -COOH, phenyl and C1～C4Oxycarbonyl radical or
Figure BDA0002554748290000091
m and n are 0 or 1.
Most preferably, R4Is substituted or unsubstituted C1～C6Alkyl radical, C2～C6Alkynyl, C2～C10Alkenyl, substituted C2～C4An alkenyl group,
Figure BDA0002554748290000092
Said substituted C1～C6The substituents of the alkyl groups being-H, -OH, -CN, ethoxy or
Figure BDA0002554748290000093
Said substituted C2～C4The substituent of the alkenyl is-H, -COOH, phenyl,
Figure BDA0002554748290000094
m and n are 0 or 1.
Preferably, in the above 2, 4-disubstituted pyrimidine derivatives, R5Is C1～C8Alkoxy, substituted or unsubstituted C2～C8Alkenyl, substituted or unsubstituted C1～C8An alkyl group,
Figure BDA0002554748290000095
Said substituted C1～C8The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C8Alkoxy radical, C1～C8An oxycarbonyl group,
Figure BDA0002554748290000096
Figure BDA0002554748290000097
Said substituted C2～C8The substituent of the alkenyl is-H, -OH, halogen, -CN,
Figure BDA0002554748290000098
Phenyl or
Figure BDA0002554748290000099
R10、R11independently-H or C1～C8An alkyl group; r is12～R16Independently is-H, C1～C8Alkyl or-CF3。
Further preferably, R5Is C1～C6Alkoxy, substituted or unsubstituted C2～C6Alkenyl, substituted or unsubstituted C1～C6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA00025547482900000910
Said substituted C1～C6The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C6Alkoxy radical, C1～C6An oxycarbonyl group,
Figure BDA00025547482900000911
Said substituted C2～C6The substituent of the alkenyl is-H, -OH, halogen, -CN,
Figure BDA00025547482900000912
Phenyl or
Figure BDA00025547482900000913
R10、R11independently-H or C1～C6An alkyl group; r is12～R16Independently is-H, C1～C6Alkyl or-CF3。
More preferably, R5Is C1～C6Alkoxy radical, C2～C6Alkenyl, substituted C2～C4Alkenyl radical, C1～C6Alkyl, substituted C1～C4An alkyl group,
Figure BDA0002554748290000101
Said substituted C1～C4The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C4Alkoxy radical, C1～C4An oxycarbonyl group,
Figure BDA0002554748290000102
Said substituted C2～C4The substituent of the alkenyl is-H, -OH, halogen, -CN,
Figure BDA0002554748290000103
Phenyl or
Figure BDA0002554748290000104
R10、R11independently-H or C1～C4An alkyl group; r12～R16Independently is-H, C1～C4Alkyl or-CF3。
Most preferably, R5Is C2～C6Alkenyl, substituted C2～C4Alkenyl radical, C1～C6Alkyl, substituted C1～C4Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0002554748290000105
Said substituted C1～C4The substituent of the alkyl is-H, -OH, -CN,
Figure BDA0002554748290000106
Figure BDA0002554748290000107
Said substituted C2～C4The substituent of the alkenyl is-H,
Figure BDA0002554748290000108
Phenyl or
Figure BDA0002554748290000109
R10、R11independently-H or C1～C4An alkyl group.
Preferably, in the above 2, 4-disubstituted pyrimidine derivatives, R6、R7Independently is-H, C1～C8Alkyl or halogen substituted phenyl.
Further preferably, R6、R7Independently is-H, C1～C6Alkyl or halogen substituted phenyl.
More preferably, R6、R7Independently is-H, C1～C4Alkyl or chloro-substituted phenyl.
Most preferably, R6、R7Independently is-H, C1～C4Alkyl or
Figure BDA00025547482900001010
Preferably, in the above 2, 4-disubstituted pyrimidine derivatives, R8、R9Independently is-H, C1～C8An alkyl group,
Figure BDA00025547482900001011
Figure BDA00025547482900001012
R17～R21Independently is-H, C1～C8Alkyl or-CF3。
Further preferably, R8、R9Independently is-H, C1～C6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA00025547482900001013
R17～R21Independently is-H, C1～C6Alkyl or-CF3。
More preferably, R8、R9Independently is-H, C1～C4An alkyl group,
Figure BDA0002554748290000111
R17～R21Independently is-H, C1～C4Alkyl or-CF3。
Most preferably, R8、R9Independently is-H, C1～C4Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0002554748290000112
As a preferred technical scheme of the invention, the 2, 4-disubstituted pyrimidine derivative has a structure shown in a formula III:
Figure BDA0002554748290000113
wherein R is1Is methyl or-F; r3Is C3～C10Cycloalkyl, substituted or unsubstituted C1～C10Alkyl radical, C2～C10Alkynyl, substituted or unsubstituted C2～C10An alkenyl group,
Figure BDA0002554748290000114
Said substituted C1～C10The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C10Alkoxy or C1～C10An oxycarbonyl group; said substituted C2～C10The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C1～C10Alkoxy radical, C1～C10Oxycarbonyl radical or
Figure BDA0002554748290000115
m、n＝0～2；
R5Is C1～C10Alkoxy, substituted or unsubstituted C2～C10Alkenyl, substituted or unsubstituted C1～C10An alkyl group,
Figure BDA0002554748290000116
Said substituted C1～C10The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C10Alkoxy radical, C1～C10An oxycarbonyl group,
Figure BDA0002554748290000117
Said substituted C2～C10Alkenyl is-H, -OH, halogen, -CN,
Figure BDA0002554748290000118
Phenyl or
Figure BDA0002554748290000119
R6、R7Independently is-H, C1～C10Alkyl or halo-substituted phenyl;
R8、R9independently is-H, C1～C10An alkyl group,
Figure BDA00025547482900001110
R10、R11independently-H or C1～C10An alkyl group;
R12～R16independently is-H, C1～C10Alkyl or-CF3；
R17～R21Independently is-H, C1～C10Alkyl or-CF3。
Preferably, in the above 2, 4-disubstituted pyrimidine derivatives, R3Is C3～C8Cycloalkyl, substituted or unsubstituted C1～C8Alkyl radical, C2～C8Alkynyl, C2～C10Alkenyl, substituted C2～C8An alkenyl group,
Figure BDA0002554748290000121
Said substituted C1～C8The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C8Alkoxy or C1～C8An oxycarbonyl group; said substituted C2～C8The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C1～C8Alkoxy radical, C1～C8Oxycarbonyl radical or
Figure BDA0002554748290000122
m、n＝0～2。
Further preferably, R3Is C3～C6Cycloalkyl, substituted or unsubstituted C1～C6Alkyl radical, C2～C6Alkynyl, C2～C10Alkenyl radicalSubstituted C2～C6An alkenyl group,
Figure BDA0002554748290000123
Said substituted C1～C6The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C6Alkoxy or C1～C6An oxycarbonyl group; said substituted C2～C6The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C1～C6Alkoxy radical, C1～C6Oxycarbonyl radical or
Figure BDA0002554748290000124
m、n＝0～2。
More preferably, R3Is C3～C6Cycloalkyl, substituted or unsubstituted C1～C6Alkyl radical, C2～C6Alkynyl, C2～C10Alkenyl, substituted C2～C4An alkenyl group,
Figure BDA0002554748290000125
Said substituted C1～C6The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C4Alkoxy or C1～C4An oxycarbonyl group; said substituted C2～C4The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C1～C4Alkoxy radical, C1～C4Oxycarbonyl radical or
Figure BDA0002554748290000126
m、n＝0～2。
More preferably, R3Is substituted or unsubstituted C1～C6Alkyl radical, C2～C6Alkynyl, C2～C10Alkenyl, substituted C2～C4An alkenyl group,
Figure BDA0002554748290000127
Said substituted C1～C6The substituent of the alkyl is-H, -OH, -CN, C1～C4Alkoxy or C1～C4An oxycarbonyl group; said substituted C2～C4The substituent of the alkenyl is-H, -COOH, phenyl and C1～C4Oxycarbonyl radical or
Figure BDA0002554748290000128
m and n are 0 or 1.
Most preferably, R3Is substituted or unsubstituted C1～C6Alkyl radical, C2～C6Alkynyl, C2～C10Alkenyl, substituted C2～C4An alkenyl group,
Figure BDA0002554748290000129
Said substituted C1～C6The substituents of the alkyl groups being-H, -OH, -CN, ethoxy or
Figure BDA0002554748290000131
Said substituted C2～C4The substituent of the alkenyl is-H, -COOH, phenyl,
Figure BDA0002554748290000132
m and n are 0 or 1.
Preferably, in the above 2, 4-disubstituted pyrimidine derivatives, R5Is C1～C8Alkoxy, substituted or unsubstituted C2～C8Alkenyl, substituted or unsubstituted C1～C8Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0002554748290000133
Said substituted C1～C8The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C8Alkoxy radical, C1～C8An oxycarbonyl group,
Figure BDA0002554748290000134
Figure BDA0002554748290000135
Said substituted C2～C8The substituent of the alkenyl is-H, -OH, halogen, -CN,
Figure BDA0002554748290000136
Phenyl or
Figure BDA0002554748290000137
R10、R11independently-H or C1～C8An alkyl group; r12～R16Independently is-H, C1～C8Alkyl or-CF3。
Further preferably, R5Is C1～C6Alkoxy, substituted or unsubstituted C2～C6Alkenyl, substituted or unsubstituted C1～C6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0002554748290000138
Said substituted C1～C6The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C6Alkoxy radical, C1～C6An oxycarbonyl group,
Figure BDA0002554748290000139
Said substituted C2～C6The substituent of the alkenyl is-H, -OH, halogen, -CN,
Figure BDA00025547482900001310
Phenyl or
Figure BDA00025547482900001311
R10、R11independently-H or C1～C6An alkyl group; r is12～R16Independently is-H, C1～C6Alkyl or-CF3。
More preferably, R5Is C1～C6Alkoxy radical, C2～C6Alkenyl, substituted C2～C4Alkenyl radical, C1～C6Alkyl radicalSubstituted C1～C4Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA00025547482900001312
Said substituted C1～C4The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C4Alkoxy radical, C1～C4An oxycarbonyl group,
Figure BDA00025547482900001313
Said substituted C2～C4The substituent of the alkenyl is-H, -OH, halogen, -CN,
Figure BDA0002554748290000141
Phenyl or
Figure BDA0002554748290000142
R10、R11independently-H or C1～C4An alkyl group; r is12～R16Independently is-H, C1～C4Alkyl or-CF3。
Most preferably, R5Is C2～C6Alkenyl, substituted C2～C4Alkenyl radical, C1～C6Alkyl, substituted C1～C4Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0002554748290000143
Said substituted C1～C4The substituent of the alkyl is-H, -OH, -CN,
Figure BDA0002554748290000144
Figure BDA0002554748290000145
Said substituted C2～C4The substituent of the alkenyl is-H,
Figure BDA0002554748290000146
Phenyl or
Figure BDA0002554748290000147
R10、R11independently-H or C1～C4An alkyl group.
Preferably, in the above 2, 4-disubstituted pyrimidine derivatives, R6、R7Independently is-H, C1～C8Alkyl or halogen substituted phenyl.
Further preferably, R6、R7Independently is-H, C1～C6Alkyl or halogen substituted phenyl.
More preferably, R6、R7Independently is-H, C1～C4Alkyl or chloro substituted phenyl.
Most preferably, R6、R7Independently is-H, C1～C4Alkyl or
Figure BDA0002554748290000148
Preferably, in the above 2, 4-disubstituted pyrimidine derivatives, R8、R9Independently is-H, C1～C8Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0002554748290000149
Figure BDA00025547482900001410
R17～R21Independently is-H, C1～C8Alkyl or-CF3。
Further preferably, R8、R9Independently is-H, C1～C6An alkyl group,
Figure BDA00025547482900001411
R17～R21Independently is-H, C1～C6Alkyl or-CF3。
More preferably, R8、R9Independently is-H, C1～C4An alkyl group,
Figure BDA00025547482900001412
R17～R21Independently is-H, C1～C4Alkyl or-CF3。
Most preferably, R8、R9Independently is-H, C1～C4Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA00025547482900001413
The 2, 4-disubstituted pyrimidine derivative has the following structural formula:
Figure BDA0002554748290000151
Figure BDA0002554748290000161
the invention also provides a preparation method of the 2, 4-disubstituted pyrimidine derivative, and the synthetic route is as follows:
Figure BDA0002554748290000171
the preparation method of the 2, 4-disubstituted pyrimidine derivative comprises the following steps:
1) heating and reacting the raw material 1 with a halide for 4-8 hours under an alkaline condition to obtain an intermediate 1; the alkali is cesium carbonate or potassium carbonate; the solvent for reaction is any one of acetonitrile, N-dimethylformamide or dioxane; the reaction temperature of the raw material 1 and the halide is 60-80 ℃;
2) under the protection of nitrogen and alkaline conditions, the intermediate 1 and a 2, 4-disubstituted pyrimidine compound are subjected to a Suzuki reaction under the conditions of dioxane, water and ethanol to obtain an intermediate 2; the alkali is sodium carbonate or potassium carbonate; the solvent for the reaction is any one of a dioxane/water/ethanol mixed system, a toluene/water mixed system and a 1, 2-dichloroethane/water mixed system; the reaction temperature is 80-95 ℃; the reaction time is 2-5 hours; wherein the using amount of the borate is 1.3 equivalent;
3) under the protection of nitrogen and alkaline conditions, carrying out Buchwald-Hartwig coupling reaction on the raw material 2 and the intermediate 2 to obtain a formula intermediate 3; the alkali is cesium carbonate or potassium tert-butoxide; the solvent for the reaction is any one of dioxane and toluene; the reaction temperature is 100-110 ℃; the reaction time is 4-6 hours; wherein the dosage of the intermediate 2 is 1.2 equivalents;
4) removing the protection of Boc anhydride from the intermediate 3 under an acidic condition to obtain an intermediate 4; the acid is trifluoroacetic acid or hydrochloric acid; the solvent for reaction is any one of dichloromethane, ethyl acetate and tetrahydrofuran; the reaction temperature is 20-30 ℃; the reaction time is 2-5 hours;
5) reacting the intermediate 4 with a halide under an alkaline condition to obtain a compound shown in a formula I or IV, and reacting the intermediate 4 with an acid under an alkaline condition to obtain a compound shown in a formula I or IV of an amide; the alkali is any one of DIEA, potassium carbonate or cesium carbonate; the solvent for the reaction is any one of dichloromethane, N-dimethylformamide or tetrahydrofuran; the reaction temperature is 20-30 ℃; the reaction time is 1-2 hours;
wherein X is N or CH; r is22Is C1～C6An alkyl group;
R1、R2independently is-H, -halogen, -OH, C1～C10Alkyl or C1～C10An alkoxy group;
the A ring is a 5-membered or 6-membered N-containing heterocyclic ring, and the number of N atoms is 1; r is connected with N on the ring A, R is C3～C10Cycloalkyl, substituted or unsubstituted C1～C10Alkyl radical, C2～C10Alkynyl, substituted or unsubstituted C2～C10An alkenyl group,
Figure BDA0002554748290000181
Figure BDA0002554748290000182
Said substituted C1～C10Substitution of alkyl groupsThe radicals being-H, -OH, halogen, -CN, C1～C10Alkoxy or C1～C10An oxycarbonyl group; said substituted C2～C10The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C1～C10Alkoxy radical, C1～C10Oxycarbonyl radical or
Figure BDA0002554748290000183
m、n＝0～2；
R5Is C1～C10Alkoxy, substituted or unsubstituted C2～C10Alkenyl, substituted or unsubstituted C1～C10Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0002554748290000184
Said substituted C1～C10The substituent of the alkyl is-H, -OH, halogen, -CN, C1～C10Alkoxy radical, C1～C10An oxycarbonyl group,
Figure BDA0002554748290000185
Said substituted C2～C10Alkenyl is-H, -OH, halogen, -CN,
Figure BDA0002554748290000186
Phenyl or
Figure BDA0002554748290000187
R6、R7Independently is-H, C1～C10Alkyl or halo-substituted phenyl;
R8、R9independently is-H, C1～C10Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0002554748290000188
R10、R11independently-H or C1～C10An alkyl group;
R12～R16independently is-H, C1～C10Alkyl or-CF3；
R17～R21Independently is-H, C1～C10Alkyl or-CF3。
The invention also provides the 2, 4-disubstituted pyrimidine derivatives, including tautomers, stereoisomers and mixtures thereof in all proportions, and also includes isotopically substituted compounds thereof.
The invention also provides pharmaceutically acceptable salts of the 2, 4-disubstituted pyrimidine derivatives. Wherein the salt with an acid is obtained by reacting the free base of the parent compound with an inorganic or organic acid. The inorganic acid includes hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, or the like. The organic acid includes acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid, malonic acid, or the like.
The term "pharmaceutically acceptable" as used herein, means that they are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and other mammals without undue toxicity, irritation, allergic response and the like, and which, upon administration to a recipient, provide, directly or indirectly, a compound of the invention or a prodrug of a compound.
The invention also provides a pharmaceutically acceptable hydrate of the 2, 4-disubstituted pyrimidine derivative. The term "hydrate" refers to a compound that further binds stoichiometric or non-stoichiometric water by non-covalent intermolecular forces.
The invention also provides a pharmaceutically acceptable polymorphic substance of the 2, 4-disubstituted pyrimidine derivative. The term "polymorph" denotes a solid crystalline form of a compound or complex thereof, which may be characterized by physical means, such as x-ray powder diffraction patterns or infrared spectroscopy.
The invention also provides the 2, 4-two-takingThe pharmaceutical composition is a preparation prepared by adding pharmaceutically acceptable auxiliary components into 2, 4-disubstituted pyrimidine derivatives shown in formulas I-III and IV, salts or hydrates thereof. The auxiliary component is cyclodextrin, arginine or meglumine. The cyclodextrin is selected from alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin and (C)1-4Alkyl) -alpha-cyclodextrin, (C)1-4Alkyl) -beta-cyclodextrin, (C)1-4Alkyl) -gamma-cyclodextrin, (hydroxy-C)1-4Alkyl) -alpha-cyclodextrin, (hydroxy-C)1-4Alkyl) -beta-cyclodextrin, (hydroxy-C)1-4Alkyl) -gamma-cyclodextrin, (carboxy-C)1-4Alkyl) -alpha-cyclodextrin, (carboxy-C)1-4Alkyl) -beta-cyclodextrin, (carboxy-C)1-4Alkyl) -gamma-cyclodextrin, saccharide ethers of alpha-cyclodextrin, saccharide ethers of beta-cyclodextrin, saccharide ethers of gamma-cyclodextrin, sulfobutyl ethers of alpha-cyclodextrin, sulfobutyl ethers of beta-cyclodextrin and sulfobutyl ethers of gamma-cyclodextrin. The auxiliary components also comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. Can be used in pharmaceutically acceptable pharmaceutical composition, and also comprises ion exchanger, aluminum oxide, aluminum stearate, and lecithin; buffer substances include phosphate, glycine, arginine, sorbic acid, and the like.
The pharmaceutical composition may be in liquid form or solid form. Wherein the liquid form may be an aqueous solution. The solid form can be in the form of powder, granules, tablets or freeze-dried powder. The pharmaceutical composition further comprises water for injection, saline solution, aqueous glucose solution, saline for injection/infusion, glucose for injection/infusion, Grignard solution or Grignard solution containing lactate. Further, the preparation is a tablet, a capsule, a powder, a granule, an ointment, a solution, a suspension, an injection, an inhalant, a gel, a microsphere or an aerosol.
The 2, 4-disubstituted pyrimidine derivatives shown in formulas I to III and IV, and the application of the salts, hydrates or pharmaceutical compositions thereof in preparing JAK2 inhibitors.
Use of 2, 4-disubstituted pyrimidine derivatives shown in formulas I-III and IV, salts, hydrates or pharmaceutical compositions thereof in preparation of FLT3 inhibitors.
The 2, 4-disubstituted pyrimidine derivatives shown in formulas I-III and IV, salts, hydrates or pharmaceutical compositions thereof are used for preparing JAK2-FLT3 inhibitors.
Use of 2, 4-disubstituted pyrimidine derivatives shown in formulas I-III and IV, salts, hydrates or pharmaceutical compositions thereof in preparing medicaments for treating and/or preventing tumors.
In the above uses, the tumor comprises a solid tumor and/or a hematological tumor.
In the above use, the solid tumor comprises: lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic lymphoma, lymphoplasmacytic lymphoma, ovarian cancer, breast cancer, prostate cancer, bladder cancer, kidney cancer, esophageal cancer, neck cancer, pancreatic cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, thyroid cancer, brain cancer, lymphatic cancer, epidermal hyperproliferation, psoriasis, prostate cancer, and combinations thereof.
The use as described above, the hematological neoplasm comprising: acute myelogenous leukemia, chronic myelogenous leukemia, myeloma, acute lymphocytic leukemia, acute myelogenous leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated leukemia, myelodysplastic syndromes, myelodysplasia, myelofibrosis, multiple myeloma, myxosarcoma, and combinations thereof.
The 2, 4-disubstituted pyrimidine derivatives shown in formulas I-III and IV, and the application of the salts, hydrates or pharmaceutical compositions thereof in preparing medicines for treating and/or preventing immune diseases.
In the above uses, the immune diseases include: psoriasis, rheumatoid arthritis, inflammatory bowel disease (e.g., crohn's disease, ulcerative colitis, etc.), sjogren's syndrome, behcet's disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, polymyositis, Dermatomyositis (DM), Periartherococcosis Nodosa (PN), Mixed Connective Tissue Disease (MCTD), scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves ' disease, autoimmune gastritis, type I and type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, addison's disease, abnormal immune response, arthritis, dermatitis, radiodermatitis, etc.) (particularly psoriasis, rheumatoid arthritis, inflammatory bowel disease, sjogren's syndrome, dermatitis, etc.) (particularly, psoriasis, rheumatoid arthritis, inflammatory bowel disease, sjogren's syndrome, morbus, and so forth), Behcet's disease, multiple sclerosis, and systemic lupus erythematosus).
Use of 2, 4-disubstituted pyrimidine derivatives represented by formulas I-III, IV, salts, hydrates or pharmaceutical compositions thereof in the preparation of medicaments for treating and/or preventing inflammatory-related diseases.
In the above uses, the inflammatory-related diseases include: inflammatory bowel disease, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, Chronic Obstructive Pulmonary Disease (COPD), inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, Systemic Inflammatory Response Syndrome (SIRS), post-surgical or post-traumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury, meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, and the like.
The 2, 4-disubstituted pyrimidine derivatives shown in formulas I-III and IV, and the application of the salts, hydrates or pharmaceutical compositions thereof in preparing oral or intravenous injection preparations.
For administration purposes, the compounds of the present invention may be administered as the starting chemical, or they may be formulated for administration as a pharmaceutical composition. The pharmaceutical compositions of the present invention comprise a compound of structure I, II, III or iv and a pharmaceutically acceptable carrier, diluent or excipient. The compounds of structure I, II, III or IV are present in the composition in an amount effective to treat the particular disease or condition of interest-i.e., an amount sufficient to treat a different cancer and preferably with acceptable toxicity to the patient. JAK2 and/or FLT3 kinase activity of compounds of structure I, II, III or iv can be determined by one of skill in the art, for example, as described in the examples below. Suitable concentrations and dosages can be readily determined by those skilled in the art.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be administered in pure form or in the form of suitable pharmaceutical compositions by an acceptable mode of administration of the active agent for similar uses. The pharmaceutical compositions of the present invention may be prepared by combining a compound of the present invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and they may be formulated into solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suspensions, injections, inhalants, gels, microspheres and aerosols. Typical routes of administration for such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. The pharmaceutical compositions of the present invention may be formulated so as to allow the active ingredients contained therein to be bioavailable when the composition is adapted to a patient. The composition for administration to a subject or patient may take the form of one or more dosage units, for example, wherein a tablet may be a single dosage unit and a container of a compound of the invention in aerosol form may carry a plurality of dosage units. The exact method of making such dosage forms is known or will be apparent to those skilled in the art; see, for example, Remington, The Science and Practice of Pharmacy, 20 th edition (Philadelphia College of Pharmacy and Science, 2000). In any event, the administered composition comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for treating a disease or condition of interest in accordance with the teachings of the present invention.
The pharmaceutical compositions of the present invention may be in solid or liquid form. In one aspect, the carrier is a particle, such that the composition is in the form of a tablet or powder, for example. The carrier may be a liquid, wherein the composition is, for example, an oral syrup, an injectable liquid, or an aerosol, e.g., for administration by inhalation.
When intended for oral administration, the pharmaceutical compositions are preferably in solid or liquid form, including semi-solid, semi-liquid, suspension, and gel forms, where solid or liquid forms are recognized herein.
As solid compositions for oral administration, the pharmaceutical compositions may be formulated as powders, granules, compressed tablets, pills, capsules, chewing gums, wafers, and the like. Such solid compositions typically comprise one or more inert diluents or edible carriers. In addition, one or more of the following ingredients may be present: a binder such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as starch, lactose or dextrin; disintegrating agents, such as alginic acid, sodium alginate, Primogel, corn starch, and the like; lubricants, such as magnesium stearate or hydrogenated vegetable oil; glidants, such as colloidal silicon dioxide; sweetening agents, such as sucrose or saccharin: flavoring agents, such as peppermint, methyl salicylate, or orange flavor; and a colorant.
When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or an oil.
The pharmaceutical composition may be in liquid form, e.g. an acid, syrup, solution, emulsion or suspension. As two examples, the liquid may be for oral administration or delivered by injection. When intended for oral administration, preferred compositions contain, in addition to a compound of the invention, one or more of sweetening agents, preserving agents, dyes/colorants and taste enhancers. In compositions intended for administration by injection, one or more of surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffering agents, stabilizing agents and isotonic agents may be included.
The liquid compositions of the invention, whether they be in solution, suspension or other similar form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solutions, preferably physiological saline, ringer's solution and isotonic sodium chloride, fixed oils, such as synthetic mono-or diglycerides that may serve as a solvent or suspending medium, polyethylene glycols, glycerol, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetate, citrate or phosphate: and agents for adjusting tonicity, such as sodium chloride or glucose. Parenteral formulations may be enclosed in ampoules, disposable syringes or multiple dose glass or rate vials. Physiological saline is a preferred excipient. The injectable pharmaceutical composition is preferably sterile.
Liquid pharmaceutical compositions of the invention intended for parenteral or oral administration should contain an amount of a compound of the invention such that a suitable dosage can be obtained.
The pharmaceutical compositions of the invention are intended for topical administration in advance, in which case the carrier may suitably comprise a solution, emulsion, emollient or gel base. For example, the matrix may comprise one or more of the following components: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickeners may be present in the pharmaceutical composition for topical application. If transdermal administration is contemplated, the composition may include a transdermal patch or iontophoretic device.
The pharmaceutical composition of the invention is intended for rectal administration, for example in the form of suppositories, where it melts and releases the drug. Compositions for rectal administration may comprise an oily base as a suitable non-irritating excipient. Such bases include, but are not limited to, lanolin, cocoa butter, and polyethylene glycols.
The pharmaceutical compositions of the present invention may include a variety of materials that alter the physical form of the solid or liquid dosage form. For example, the composition may include a material that forms a shell around the active ingredient. The material forming the coating is typically inert and may be selected from, for example, sugars, shellac, and other enteric coatings. Alternatively, the active ingredient may be packaged in gelatin capsules.
Pharmaceutical compositions of the invention in solid or liquid form may include agents that bind to the compounds of the invention and thereby facilitate delivery of the compounds. Suitable agents that can function in this capacity include monoclonal or polyclonal antibodies, proteins, or liposomes.
The pharmaceutical compositions of the present invention may be comprised of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to those consisting of pressurized packaging. Delivery may be by liquefied or pressurised gas or by a suitable pump system which dispenses the active ingredient. Aerosols of the compounds of the invention may be delivered in the form of single, biphasic or triphasic systems for delivery of the active ingredient. The aerosol delivered includes the necessary containers, actuators, valves, sub-containers (subcontainers), etc., which together may form a cartridge. One skilled in the art can determine preferred aerosols without undue experimentation.
The invention also provides application of the 2, 4-disubstituted pyrimidine derivatives shown in the formulas I-III and IV, salts, hydrates or pharmaceutical compositions thereof in preparing oral or intravenous injection preparations. The oral or intravenous injection preparation at least comprises one 2, 4-disubstituted pyrimidine derivative shown in formulas I-III and IV, and salt, hydrate or pharmaceutical composition thereof, and any excipient and/or adjuvant.
The 2, 4-disubstituted pyrimidine derivative provided by the invention can be used as a kinase inhibitor with JAK2 and FLT3 dual-functional targets, can also be used as a kinase inhibitor with single JAK2 or FLT3 functional targets, and provides a new choice for preparing medicines for treating and/or preventing tumors, inflammatory diseases and immune diseases.
Detailed Description
EXAMPLE 16 preparation of hydroxypropyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -5,6,7, 8-tetrahydronaphthyridin-2-amine (CLJ-100)
Figure BDA0002554748290000231
Step 1: synthesis of 1-propylpyrazole-4-boronic acid pinacol ester (compound of formula 2)
4-boronic acid pinacol ester (1.9g, 10mmol), 2-iodopropane (3.4g, 20mmol), cesium carbonate (6.5g, 20mmol) were added to acetonitrile (50ml) and reacted in an oil bath at 80 ℃ for 2 hours. After the reaction is finished, filtering while the solution is hot and concentrating the filtrate to obtain the compound of formula 2.
And 2, step: synthesis of 2-chloro-5-methyl-4- (1-isopropyl-1H-pyrazol-4-yl) pyrimidine (compound of formula 3) A compound of formula 2 (1.9g, 10mmol), 2, 4-dichloro-5-fluoropyrimidine (1.7g, 10mmol), potassium carbonate (3.4g, 25mmol) and dppf (Pd2Cl2) (0.75g, 1mmol) were charged into a 250mL three-necked flask, dioxane/ethanol/water ═ 7:3:4 (70 mL in total) was added as a solvent, and the mixture was allowed to react in an oil bath at 85 ℃ for 2 hours after replacing nitrogen three times. After the reaction is finished, concentrating the reaction solution to be dry, mixing the sample, and separating by a silica gel column to obtain the compound shown in the formula 3 which is a white-like solid. 1H NMR (500MHz, Chloroform-d) δ:8.43(d, J ═ 8.1Hz,1H),8.14(t, J ═ 1.7Hz,1H),7.46(t, J ═ 1.7Hz,1H),4.78(m,1H),0.99(d, J ═ 8.0Hz,6H).
And step 3: synthesis of 6-Boc-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -5,6,7, 8-tetrahydronaphthyridin-2-amine (Compound of formula 5)
2-amino-N-Boc-5, 6,7, 8-tetrahydronaphthyridine (2.5g, 10mmol), 2-chloro-5-methyl-4- (1-isopropyl-1H-pyrazol-4-yl) pyrimidine (2.7g, 10mmol), cesium carbonate (6.5g, 20mmol), Pd2DBA3(260mg, 1mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (520mg, 2mmol) were added to dioxane (50ml), and the mixture was reacted in an oil bath at 103 ℃ for 2 hours with nitrogen exchange. After the reaction is finished, filtering while the reaction is hot, concentrating the filtrate, mixing the crude silica gel with a sample, and separating (EA) by using a flash column to obtain the compound shown in the formula 5.
And 4, step 4: synthesis of N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -5,6,7, 8-tetrahydronaphthyridin-2-amine (compound of formula 6)
6-Boc-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -5,6,7, 8-tetrahydronaphthyridin-2-amine (2.3g, 5mmol) was added to dichloromethane (50ml), trifluoroacetic acid (1.2g, 10mmol) was added thereto, and the mixture was reacted at room temperature for 1 hour, after the reaction was completed, the solvent was distilled off under reduced pressure to obtain a compound of formula 6.
And 5: synthesis of 6-hydroxypropyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -5,6,7, 8-tetrahydronaphthyridin-2-amine (CLJ-100)
Adding N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -5,6,7, 8-tetrahydronaphthyridine-2-amine (350mg, 1mmol) into acetonitrile (20ml), adding 3-bromopropanol (180mg, 1.3mmol) and cesium carbonate (650mg, 2mmol), reacting at room temperature for 1H, after the reaction is finished, adding 40ml of water, extracting with dichloromethane, distilling the organic phase under reduced pressure, and pulping the crude product with diethyl ether to obtain the final product CLJ-100.1H NMR(400MHz,DMSO-d6)δ:9.19(s,1H),8.38–8.30(m,2H),8.11(t,J＝4.2Hz,2H),7.47(d,J＝8.5Hz,1H),4.63(h,J＝6.6Hz,1H),4.44(d,J＝38.4Hz,1H),3.55–3.44(m,4H),2.80(t,J＝5.9Hz,2H),2.73(t,J＝6.1Hz,2H),2.54(d,J＝7.1Hz,2H),2.33(s,3H),1.72–1.64(m,2H),1.48(d,J＝6.7Hz,6H).13C NMR(101MHz,DMSO)δ:159.93,158.01,157.82,152.89,151.72,139.55,136.47,129.69,123.47,120.45,117.59,110.21,59.81,55.19,54.71,53.83,50.98,32.20,30.45,23.03,17.19.m/z:408.5230[M+H]+.
Example 22 preparation of hydroxyethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine alcohol (CLJ-101)
Figure BDA0002554748290000241
CLJ-101 was synthesized in the same manner as in example 1 except that 6-amino-N-Boc-1, 2,3, 4-tetrahydroisoquinoline was used in place of 2-amino-N-Boc-5, 6,7, 8-tetrahydronaphthyridine and 2-iodoethanol was used in place of 3-bromo-1-propanol to obtain CLJ-101 as a final product.1H NMR(400MHz,DMSO-d6)δ:9.20(s,1H),8.29(d,J＝22.7Hz,2H),8.08(s,1H),7.65(d,J＝2.3Hz,1H),7.46(dd,J＝8.3,2.3Hz,1H),6.94(d,J＝8.4Hz,1H),4.62(h,J＝6.6Hz,1H),4.46(s,1H),3.67–3.46(m,4H),2.80(d,J＝5.8Hz,2H),2.71(t,J＝5.8Hz,2H),2.57(t,J＝6.2Hz,2H),2.31(s,3H),1.48(d,J＝6.7Hz,6H).13C NMR(101MHz,DMSO)δ:159.88,159.00,157.63,139.42,139.31,134.44,129.38,127.92,126.71,120.74,118.31,116.72,116.35,60.74,59.30,56.07,53.83,51.64,29.63,23.03,17.15.m/z:393.5070[M+H]+.
Example preparation of 32-hydroxyethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-fluoro-6-amine (CLJ-102)
Figure BDA0002554748290000242
The pyrimidine moiety synthesis of CLJ-102 was the same as in example 2;
the aromatic amine moiety was synthesized as follows:
step 1: synthesis of 4-fluorophenylethylamine trifluoroacetamide (compound of formula 2)
4-fluorophenylethylamine (7g,50mmol), triethylamine (13g,125mmol) were dissolved in dichloromethane (100mL), trifluoroacetic anhydride (12.6g,60mmol) was added dropwise, reacted at room temperature for 30min, a large amount of water (about 200mL) was added, vigorously stirred, subjected to liquid separation, the organic phase was concentrated by reduced pressure distillation, and slurried with diethyl ether to give the compound of formula 2.
Step 2: synthesis of 7-fluoro-1, 2,3, 4-tetrahydroisoquinoline trifluoroacetamide (compound of formula 3)
Dissolving 4-fluorophenethylamine trifluoroacetamide (4.7g,20mmol) in concentrated sulfuric acid (20ml), adding glacial acetic acid (5ml) and paraformaldehyde (1.8g,20mmol), reacting at room temperature for 4h, after the reaction is finished, adding concentrated sulfuric acid into a large amount of ice water, extracting with dichloromethane, concentrating, and pulping with n-hexane/diethyl ether (1:1) to obtain the compound of formula 3.
And step 3: synthesis of 7-fluoro-6-nitro-1, 2,3, 4-tetrahydroisoquinoline trifluoroacetamide (compound of formula 4) 4-fluoro-1, 2,3, 4-tetrahydroisoquinoline trifluoroacetamide (4.9g,20mmol) is dissolved in concentrated sulfuric acid (20ml), a solution of potassium nitrate (3g,30mmol) in concentrated sulfuric acid (20ml) is slowly dripped in at 0 ℃, reaction is continued for 2 hours after the dripping is finished, the concentrated sulfuric acid is added into a large amount of ice water after the reaction is finished, and the mixture is filtered, dried and pulped with n-hexane/diethyl ether (1:1) to obtain the compound of formula 4.
And 4, step 4: synthesis of 7-fluoro-6-nitro-1, 2,3, 4-tetrahydroisoquinoline (compound of formula 5)
Dissolving 4-fluoro-5-nitro-1, 2,3, 4-tetrahydroisoquinoline trifluoroacetamide (4.4g,15mmol) in methanol (40mL), adding 5mL of concentrated hydrochloric acid, reacting at 60 ℃ for 1h, adjusting to neutrality after the reaction is finished, performing suction filtration, and drying to obtain the compound shown in the formula 5.
And 5: synthesis of N-Boc-7-fluoro-6-nitro-1, 2,3, 4-tetrahydroisoquinoline (Compound of formula 6)
Adding 4-fluoro-5-nitro-1, 2,3, 4-tetrahydroisoquinoline (2g,10mmol) into acetonitrile (50ml), then adding potassium carbonate (2.8g,20mmol) and Boc anhydride (5ml), reacting at 60 ℃ for 1h, after the reaction is finished, adding a large amount of water and extracting with dichloromethane, concentrating the organic phase by vacuum distillation, and then pulping with diethyl ether to obtain the compound of formula 6.
And 6: synthesis of 2-N-Boc-7-fluoro-6-amino-1, 2,3, 4-tetrahydroisoquinoline A compound of formula 8 and CLJ-102 were synthesized in the same manner as in example 2 except that 7-fluoro-6-amino-N-Boc-1, 2,3, 4-tetrahydroisoquinoline was used in place of 6-amino-N-Boc-1, 2,3, 4-tetrahydroisoquinoline.1H NMR(400MHz,DMSO-d6)δ:8.56(s,1H),8.26(d,J＝25.6Hz,2H),8.01(s,1H),7.67(d,J＝8.0Hz,1H),6.92(d,J＝11.5Hz,1H),4.61(p,J＝6.7Hz,1H),4.54(s,1H),3.82–3.42(m,4H),2.96–2.63(m,4H),2.55(t,J＝6.5Hz,2H),2.30(s,3H),1.46(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO)δ:159.91,159.09,157.81,154.07,151.66,139.34,130.75,129.94,129.42,123.69,120.56,116.87,113.15,60.46,59.27,55.69,53.82,51.37,28.78,23.02,17.08.m/z:411.4974[M+H]+.
EXAMPLE 42 preparation of hydroxypropyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-103)
Figure BDA0002554748290000251
CLJ-103 Synthesis As in example 2, CLJ-103 was obtained as the final product by substituting 3-iodopropanol for 2-iodoethanol.1H NMR(400MHz,DMSO-d6)δ:8.56(s,1H),8.27(d,J＝25.6Hz,2H),8.00(s,1H),7.66(d,J＝8.0Hz,1H),6.94(d,J＝11.5Hz,1H),4.62(p,J＝6.7Hz,1H),4.54(s,1H),3.81–3.43(m,4H),2.95–2.64(m,4H),2.53(t,J＝6.5Hz,2H),2.30(s,3H),1.57(m,2H),1.46(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO)δ:159.89,159.00,157.64,139.46,139.31,134.46,129.39,127.83,126.75,120.74,118.30,116.75,116.36,59.96,55.86,55.56,53.83,51.25,30.34,29.66,23.04,17.15。m/z:407.5340[M+H]+.
Example 52 preparation of hydroxybutyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-104)
Figure BDA0002554748290000261
CLJ-104 Synthesis As in example 2, the final product CLJ-104 was obtained by substituting 4-bromo-1-butanol for 2-iodoethanol.1H NMR(400MHz,DMSO-d6)δ:9.19(s,1H),8.29(d,J＝23.0Hz,2H),8.08(s,1H),7.64(d,J＝2.3Hz,1H),7.46(dd,J＝8.3,2.3Hz,1H),6.95(d,J＝8.4Hz,1H),4.63(q,J＝6.6Hz,1H),4.56(d,J＝26.0Hz,1H),3.56–3.35(m,4H),2.80(t,J＝5.9Hz,2H),2.63(t,J＝5.8Hz,2H),2.43(t,J＝7.0Hz,2H),2.31(s,3H),1.55(q,J＝7.2Hz,2H),1.48(d,J＝6.7Hz,6H).13C NMR(101MHz,DMSO)δ:159.03,158.27,158.19,140.86,139.50,131.80,129.78,127.32,121.05,120.48,118.02,117.76,116.99,60.49,60.22,55.58,53.89,52.27,49.47,29.86,29.68,25.74,23.02,22.91,21.01,17.16.m/z:421.2638[M+H]+.
Example 62 preparation of hydroxypentyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-105)
Figure BDA0002554748290000262
CLJ-105 was synthesized as in example 2, substituting 5-bromo-1-pentanol for 2-iodoethanol to obtain CLJ-105 as the final product.1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.32(s,1H),8.27(s,1H),8.08(s,1H),7.65(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.3Hz,1H),6.95(d,J＝8.3Hz,1H),4.63(p,J＝6.7Hz,1H),4.34(s,1H),3.40(t,J＝5.7Hz,2H),2.80(t,J＝5.9Hz,2H),2.63(t,J＝5.9Hz,2H),2.43(t,J＝7.3Hz,2H),2.31(s,3H),1.58–1.41(m,10H),1.35(qd,J＝9.8,8.4,4.5Hz,2H).m/z:435.2794[M+H]+.
EXAMPLE 72 preparation of hydroxyethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-fluoropyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-106)
Figure BDA0002554748290000263
CLJ-106 Synthesis As in example 2, the final product CLJ-106 was obtained by substituting 2, 4-dichloro-5-fluoropyrimidine for 2, 4-dichloro-5-methylpyrimidine.1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.49(d,J＝2.9Hz,1H),8.38(s,1H),8.08(s,1H),7.62(s,1H),7.48(d,J＝8.3Hz,1H),6.99(d,J＝8.4Hz,1H),4.66(td,J＝14.4,13.9,7.2Hz,2H),3.83–3.50(m,4H),2.78(d,J＝66.0Hz,6H),1.48(d,J＝6.7Hz,6H).m/z:397.2074[M+H]+.
EXAMPLE 82 preparation of hydroxypropyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-fluoropyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-107)
Figure BDA0002554748290000264
CLJ-107 was synthesized as in example 7, substituting 3-iodo-1-propanol for 2-iodoethanol to give the final product CLJ-107.1H NMR(400MHz,DMSO-d6)δ:10.24(s,1H),9.68(s,1H),8.53(d,J＝3.0Hz,1H),8.40(d,J＝2.0Hz,1H),8.10(d,J＝1.1Hz,1H),7.76(d,J＝2.2Hz,1H),7.60(dd,J＝8.4,2.2Hz,1H),7.14(d,J＝8.5Hz,1H),4.67(p,J＝6.6Hz,1H),4.25(d,J＝36.4Hz,2H),3.37(s,4H),3.24(t,J＝8.1Hz,2H),3.12(s,2H),1.94(dq,J＝11.9,6.0Hz,2H),1.48(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO)δ:156.98,149.96,147.48,146.97,146.18,139.09,138.86,134.51,128.24,126.82,118.38,116.85,115.73,59.94,55.80,55.52,54.00,51.18,30.28,29.56,22.94.m/z:411.2230[M+H]+.
Example preparation of 92-hydroxybutyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-fluoropyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-108)
Figure BDA0002554748290000271
Synthesis of CLJ-108 As in example 8, the final product CLJ-108 was obtained by substituting 4-bromo-1-butanol for 3-iodo-1-propanol.1H NMR(400MHz,DMSO-d6)δ:9.48(s,1H),8.49(d,J＝3.0Hz,1H),8.38(d,J＝1.9Hz,1H),8.08(d,J＝1.3Hz,1H),7.60(d,J＝2.2Hz,1H),7.46(dd,J＝8.3,2.2Hz,1H),6.98(d,J＝8.4Hz,1H),4.68(h,J＝6.6Hz,1H),4.56(s,1H),3.42(t,J＝6.3Hz,2H),2.81(t,J＝5.9Hz,2H),2.64(t,J＝5.8Hz,2H),2.44(t,J＝7.1Hz,2H),1.60–1.40(m,10H).13C NMR(101MHz,DMSO)δ:157.01,149.95,147.47,146.97,145.96,139.05,138.85,134.58,129.78,128.38,126.82,118.39,116.83,115.73,61.22,58.22,55.74,54.00,51.11,31.13,29.61,23.80,22.95.m/z:425.2387[M+H]+.
EXAMPLE 102 preparation of hydroxypentyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-fluoropyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-109)
Figure BDA0002554748290000272
CLJ-109 was synthesized as in example 9, substituting 5-bromo-1-pentanol for 4-bromo-1-butanol to give CLJ-109 as the final product.1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.49(d,J＝3.0Hz,1H),8.38(d,J＝1.6Hz,1H),8.08(s,1H),7.59(s,1H),7.46(dd,J＝8.4,1.9Hz,2H),6.98(d,J＝8.3Hz,1H),4.67(dt,J＝13.3,6.6Hz,2H),4.35(t,J＝4.9Hz,2H),3.50(s,1H),3.44–3.37(m,5H),2.86–2.75(m,4H),2.66(s,0H),2.44(d,J＝5.0Hz,1H),1.58–1.40(m,8H),1.33(dt,J＝15.3,7.1Hz,3H).m/z:439.2543[M+H]+.
EXAMPLE 112 preparation of hydroxyacetyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-fluoropyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-110)
Figure BDA0002554748290000273
CLJ-110 was synthesized as in example 10, substituting 2-hydroxyacetyl chloride for 5-bromo-1-pentanol to give CLJ-120.1H NMR(400MHz,DMSO-d6)δ:9.55(d,J＝4.7Hz,1H),8.44(d,J＝45.8Hz,2H),8.09(s,1H),7.68(s,1H),7.55(t,J＝6.6Hz,1H),7.11(dd,J＝13.3,8.1Hz,1H),4.76–4.42(m,4H),4.19(d,J＝5.2Hz,2H),3.64(dt,J＝51.4,5.8Hz,2H),2.83(dt,J＝28.2,5.8Hz,2H),1.48(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO)δ:170.87,156.92,150.02,147.54,146.90,146.25,139.54,138.88,134.92,129.87,126.97,126.44,118.39,117.31,115.71,60.74,54.01,43.89,41.70,29.42,22.96.m/z:411.1867[M+H]+.
EXAMPLE 122 preparation of hydroxyacetyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-111)
Figure BDA0002554748290000281
CLJ-111 was synthesized as in example 11, substituting 2, 4-dichloro-5-methylpyrimidine for 2, 4-dichloro-5-fluoropyrimidine to give the final product CLJ-111.1H NMR(400MHz,DMSO-d6)δ:9.30(d,J＝4.8Hz,1H),8.30(d,J＝20.6Hz,2H),8.09(s,1H),7.74(s,1H),7.55(d,J＝7.4Hz,1H),7.09(dd,J＝13.7,8.2Hz,1H),4.72–4.44(m,4H),4.18(d,J＝5.5Hz,2H),3.64(dt,J＝50.9,5.8Hz,2H),2.92–2.73(m,2H),2.31(s,3H),1.48(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO)δ:170.86,159.90,158.92,157.69,139.95,139.33,134.83,129.45,126.90,125.90,120.67,118.22,117.22,116.59,60.74,53.84,43.89,41.72,29.48,23.04,17.16.m/z:407.2117[M+H]+.
EXAMPLE 132 preparation of propionamidoformyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-112)
Figure BDA0002554748290000282
CLJ-112 was synthesized as in example 12, substituting 2-hydroxyacetyl chloride with propylisocyanate to give the final product CLJ-112.1H NMR(400MHz,DMSO-d6)δ:9.26(s,1H),8.30(d,J＝22.9Hz,2H),8.09(s,1H),7.71(d,J＝2.2Hz,1H),7.54(dd,J＝8.4,2.2Hz,1H),7.03(d,J＝8.3Hz,1H),6.50(t,J＝5.5Hz,1H),4.63(hept,J＝6.7Hz,1H),4.43(s,2H),3.55(t,J＝5.8Hz,2H),3.02(q,J＝7.8,7.0Hz,2H),2.76(t,J＝5.8Hz,2H),2.32(s,3H),1.46(dd,J＝18.8,6.9Hz,8H),0.84(t,J＝7.4Hz,3H).13C NMR(101MHz,DMSO)δ:159.90,158.95,157.88,157.67,139.70,139.32,135.21,129.43,126.99,126.60,120.70,118.43,117.08,116.51,53.83,45.50,42.47,41.44,29.22,23.56,23.04,17.15,11.87.m/z:434.2590[M+H]+.
Example 142 preparation of 3- (3-Chloroanilinoformyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-113)
Figure BDA0002554748290000283
CLJ-113 Synthesis the final product CLJ-113 was obtained in the same manner as in example 13, replacing propyl isocyanate with 3-chlorophenyl isocyanate.1H NMR(400MHz,DMSO-d6)δ:9.30(s,1H),8.73(s,1H),8.31(d,J＝21.9Hz,2H),8.09(s,1H),7.72(d,J＝26.0Hz,2H),7.57(d,J＝8.3Hz,1H),7.45(d,J＝8.3Hz,1H),7.26(t,J＝8.1Hz,1H),7.09(d,J＝8.4Hz,1H),6.98(d,J＝7.9Hz,1H),4.61(d,J＝16.3Hz,3H),3.71(t,J＝5.8Hz,2H),2.85(t,J＝5.9Hz,2H),2.32(s,3H),1.49(d,J＝6.7Hz,6H).13C NMR(101MHz,DMSO)δ:159.90,158.95,157.69,155.14,142.73,139.93,139.34,135.07,133.20,130.35,129.44,126.68,126.38,121.69,120.70,119.38,118.38,118.27,117.16,116.57,53.84,45.80,41.95,29.27,23.04,17.16.m/z:502.2044[M+H]+.
Example 152-preparation of acetamidoformyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-114)
Figure BDA0002554748290000291
Synthesis of CLJ-114 As in example 14, the final product CLJ-114 was obtained by replacing 3-chlorophenyl isocyanate with ethyl isocyanate.1H NMR(400MHz,DMSO-d6)δ:9.26(s,1H),8.30(d,J＝22.7Hz,2H),8.08(s,1H),7.70(d,J＝2.2Hz,1H),7.53(dd,J＝8.3,2.3Hz,1H),7.03(d,J＝8.3Hz,1H),6.49(t,J＝5.4Hz,1H),4.62(h,J＝6.5Hz,1H),4.41(s,2H),3.54(t,J＝5.8Hz,2H),3.08(dt,J＝12.5,6.3Hz,2H),2.75(t,J＝5.9Hz,2H),2.31(s,3H),1.48(d,J＝6.6Hz,6H),1.03(t,J＝7.1Hz,3H).13C NMR(101MHz,DMSO)δ:159.90,158.95,157.80,157.67,139.71,139.32,135.21,129.43,126.95,126.59,120.70,118.43,117.08,116.51,53.83,45.46,41.38,35.38,29.23,23.04,17.15,16.15.m/z:420.2434[M+H]+.
Example 162 preparation of Acetylmethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-115)
Figure BDA0002554748290000292
CLJ-115 was synthesized as in example 15, replacing ethyl isocyanate with 1-chloropropone to give CLJ-115 as the final product.1H NMR(400MHz,DMSO-d6)δ:9.24(s,1H),8.30(d,J＝24.3Hz,2H),8.09(s,1H),7.67(d,J＝2.2Hz,1H),7.47(dd,J＝8.4,2.3Hz,1H),6.94(d,J＝8.4Hz,1H),4.63(hept,J＝6.6Hz,1H),3.53(s,2H),2.82(t,J＝5.8Hz,2H),2.68(t,J＝5.8Hz,2H),2.31(s,3H),2.13(s,3H),1.48(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO)δ:207.56,159.90,158.99,157.64,139.55,139.32,134.09,129.40,127.42,126.69,120.72,118.38,116.80,116.40,67.91,55.46,53.83,51.13,29.50,28.01,23.04,17.15.m/z:405.2325[M+H]+.
Example 172 preparation of carbamoylmethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-116)
Figure BDA0002554748290000293
CLJ-116 Synthesis As in example 16, 1-chloropropionamide was used in place of 1-chloropropionone ester to give CLJ-116 as the final product.1H NMR(400MHz,DMSO-d6)δ:9.24(s,1H),8.30(d,J＝23.8Hz,2H),8.09(s,1H),7.68(d,J＝2.2Hz,1H),7.48(dd,J＝8.4,2.2Hz,1H),7.20(dd,J＝38.0,3.0Hz,2H),6.96(d,J＝8.4Hz,1H),4.63(hept,J＝6.7Hz,1H),3.61(s,2H),3.03(s,2H),2.86(t,J＝5.8Hz,2H),2.71(t,J＝5.8Hz,2H),2.31(s,3H),1.48(d,J＝6.7Hz,6H).13C NMR(101MHz,DMSO)δ:172.30,159.91,158.98,157.64,139.56,139.32,134.19,129.41,127.44,126.71,120.71,118.37,116.78,116.41,61.74,55.65,53.83,51.34,29.54,23.05,17.15.m/z:406.2277[M+H]+.
Example 182- (2-ethoxyethyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-117) preparation
Figure BDA0002554748290000301
CLJ-117 was synthesized as in example 17, substituting 2-ethoxychloroethane for 1-chloropropylamide to give CLJ-117 as the final product.1H NMR(400MHz,DMSO-d6)δ:9.20(s,1H),8.30(d,J＝22.7Hz,2H),8.08(s,1H),7.65(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.2Hz,1H),6.94(d,J＝8.3Hz,1H),4.63(hept,J＝6.7Hz,1H),3.61–3.51(m,4H),3.46(q,J＝7.0Hz,2H),2.79(d,J＝5.8Hz,2H),2.70(t,J＝5.8Hz,2H),2.64(t,J＝6.0Hz,2H),2.31(s,3H),1.49(d,J＝6.7Hz,6H),1.12(t,J＝7.0Hz,3H).13C NMR(101MHz,DMSO)δ:159.87,159.01,157.63,139.46,139.32,134.35,129.35,127.83,126.68,120.76,118.31,116.74,116.34,68.48,65.94,57.73,56.03,53.83,51.59,29.65,23.02,17.15,15.62.m/z:421.2638[M+H]+.
Example 192 preparation of cyanomethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-118)
Figure BDA0002554748290000302
CLJ-118 Synthesis As in example 18, the final product CLJ-118 was obtained using chloroacetonitrile instead of 2-ethoxychloroethane.1H NMR(400MHz,DMSO-d6)δ:9.24(s,1H),8.30(d,J＝21.8Hz,2H),8.09(s,1H),7.69(d,J＝2.3Hz,1H),7.51(dd,J＝8.3,2.2Hz,1H),7.00(d,J＝8.4Hz,1H),4.63(hept,J＝6.7Hz,1H),3.91(s,2H),3.62(s,2H),2.86(d,J＝6.0Hz,2H),2.77(d,J＝5.7Hz,2H),2.32(s,3H),1.49(d,J＝6.7Hz,6H).13C NMR(101MHz,DMSO)δ:159.87,158.97,157.66,139.77,139.34,133.54,129.35,126.77,126.45,120.74,118.35,116.96,116.47,116.34,53.85,53.79,49.74,45.59,29.43,23.01,17.16.m/z:388.2171[M+H]+.
Example 202 preparation of propargyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-119)
Figure BDA0002554748290000303
Synthesis of CLJ-119 As in example 19, the chloroacetonitrile was replaced by 3-chloropropyne to give CLJ-119 as the final product.1H NMR(400MHz,DMSO-d6)δ:9.22(s,1H),8.30(d,J＝22.4Hz,2H),8.09(s,1H),7.75–7.61(m,1H),7.56–7.42(m,1H),6.98(d,J＝8.4Hz,1H),4.63(p,J＝6.7Hz,1H),3.59(s,2H),3.51–3.40(m,2H),3.23–3.13(m,1H),2.84(s,2H),2.72(s,2H),2.32(s,3H),1.49(d,J＝6.7Hz,6H).m/z:387.2219[M+H]+.
EXAMPLE 212 preparation of allyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-120)
Figure BDA0002554748290000304
CLJ-120 was synthesized as in example 20, substituting allyl chloride for 3-chloropropyne to give CLJ-120 as the final product.1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.33(s,1H),8.27(d,J＝0.8Hz,1H),8.08(s,1H),7.66(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.2Hz,1H),6.95(d,J＝8.3Hz,1H),5.91(ddt,J＝16.6,10.2,6.3Hz,1H),5.26(dq,J＝17.2,1.7Hz,1H),5.18(ddt,J＝10.1,2.2,1.2Hz,1H),4.62(h,J＝6.7Hz,1H),3.48(s,2H),3.12(dt,J＝6.4,1.4Hz,2H),2.81(t,J＝5.9Hz,2H),2.65(t,J＝5.8Hz,2H),2.31(s,3H),1.49(d,J＝6.6Hz,6H).m/z:389.2375[M+H]+.
Example 222 preparation of- (3-methyl-2-butenyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-121)
Figure BDA0002554748290000311
Synthesis of CLJ-121 As in example 21, 1-chloro-3-methyl-2-butene was used instead of allyl chloride to give the final product CLJ-121.1H NMR(400MHz,DMSO-d6)δ:9.20(s,1H),8.32(s,1H),8.27(s,1H),8.08(s,1H),7.65(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.2Hz,1H),6.95(d,J＝8.4Hz,1H),5.28(td,J＝7.4,6.9,3.9Hz,1H),4.63(hept,J＝6.6Hz,1H),3.47(s,2H),3.06(d,J＝6.8Hz,2H),2.80(t,J＝5.9Hz,2H),2.64(t,J＝5.8Hz,2H),2.31(s,3H),1.74(d,J＝1.5Hz,3H),1.66(d,J＝1.4Hz,3H),1.49(d,J＝6.6Hz,6H).m/z:417.2688[M+H]+.
Example 232 preparation of- (2-pentynyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-122)
Figure BDA0002554748290000312
CLJ-122 was synthesized as in example 22, substituting 1-chloro-2-pentyne for 1-chloro-3-methyl-2-butene to give the final product CLJ-122.1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.30(d,J＝22.4Hz,2H),8.09(s,1H),7.66(s,1H),7.48(d,J＝8.4Hz,1H),6.98(d,J＝8.3Hz,1H),4.63(dt,J＝13.5,6.8Hz,1H),3.57(s,2H),3.38(d,J＝22.7Hz,2H),2.83(t,J＝5.7Hz,2H),2.70(t,J＝5.9Hz,2H),2.32(s,3H),2.22(d,J＝7.6Hz,2H),1.49(d,J＝6.7Hz,6H),1.10(q,J＝7.4,6.9Hz,3H).m/z:415.2332[M+H]+.
Example 242 preparation of- (2-butynyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-123)
Figure BDA0002554748290000313
Synthesis of CLJ-123 As in example 23, 1-chloro-2-pentene was replaced with 1-chloro-2-butyne to give the final product CLJ-123.1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.33(s,1H),8.27(s,1H),8.08(s,1H),7.66(d,J＝2.3Hz,1H),7.48(dd,J＝8.4,2.2Hz,1H),6.97(d,J＝8.4Hz,1H),4.63(hept,J＝6.7Hz,1H),3.38(q,J＝2.4Hz,2H),2.82(t,J＝5.8Hz,2H),2.70(t,J＝5.9Hz,2H),2.32(s,3H),1.83(t,J＝2.3Hz,3H),1.49(d,J＝6.6Hz,6H).m/z:401.2375[M+H]+.
Example 252 preparation of- (Phenylpropenyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-124)
Figure BDA0002554748290000314
CLJ-124 was synthesized as in example 24, substituting cinnamyl chloride for 1-chloro-2-butyne to give the final product CLJ-124.1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.30(d,J＝22.2Hz,2H),8.09(s,1H),7.68(d,J＝2.2Hz,1H),7.54–7.42(m,3H),7.34(t,J＝7.6Hz,2H),7.28–7.22(m,1H),6.96(d,J＝8.4Hz,1H),6.61(d,J＝15.9Hz,1H),6.39(dt,J＝15.9,6.4Hz,1H),4.63(hept,J＝6.7Hz,1H),3.54(s,2H),3.31–3.21(m,2H),2.84(t,J＝5.8Hz,2H),2.71(t,J＝5.8Hz,2H),2.31(s,3H),1.48(d,J＝6.7Hz,6H).m/z:467.2688[M+H]+.
Example 262- (4-Alkenylpentanoyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-125) preparation
Figure BDA0002554748290000321
Step 1: preparation of 2- (4-alkenylpentanoyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-125)
Reacting N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylPyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (348mg,1mmoL), HATU (380mg,1mmoL), N-diisopropylethylamine (320mg,2.5mmoL), 4-pentenoic acid (100mg,1mmoL) were added to dichloromethane (20mL), stirred at room temperature for 30 minutes, concentrated under reduced pressure to remove the solvent, and then the crude silica gel was added to mix with the sample, and the final product, CLJ-125, was obtained by separation with a dichloromethane/methanol system through a silica gel column.1H NMR(400MHz,DMSO-d6)δ:9.28(d,J＝4.7Hz,1H),8.30(d,J＝20.9Hz,2H),8.08(s,1H),7.76–7.69(m,1H),7.54(t,J＝8.6Hz,1H),7.09(dd,J＝8.4,4.7Hz,1H),5.93–5.80(m,1H),5.11–5.01(m,1H),4.99–4.91(m,1H),4.69–4.50(m,3H),3.67(t,J＝5.9Hz,2H),2.89–2.81(m,1H),2.75(t,J＝5.9Hz,1H),2.29(d,J＝14.7Hz,5H),1.48(d,J＝6.7Hz,6H).m/z:431.2481[M+H]+.
Example 272 preparation of- (3-cyanopropionyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-126)
Figure BDA0002554748290000322
CLJ-126 was synthesized as in example 26, substituting 3-cyanopropionic acid for 4-pentenoic acid to give CLJ-126 as a final product.1H NMR(400MHz,DMSO-d6)δ:9.30(d,J＝5.3Hz,1H),8.34(s,1H),8.28(s,1H),8.09(s,1H),7.74(dd,J＝5.7,2.3Hz,1H),7.62–7.50(m,1H),7.29(s,1H),7.10(dd,J＝11.5,8.4Hz,1H),6.72(s,1H),4.71–4.46(m,3H),3.68(q,J＝6.5Hz,2H),2.88(q,J＝6.0,5.3Hz,1H),2.75(t,J＝6.0Hz,1H),2.61(t,J＝7.0Hz,2H),2.34(d,J＝11.9Hz,5H),1.49(d,J＝6.7Hz,6H).m/z:430.2277[M+H]+.
EXAMPLE 28 preparation of (E) -2- (3, 7-dimethyl-2, 6-pentadienyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-127)
Figure BDA0002554748290000323
CLJ-127 Synthesis as in example 24, substituting geranyl bromide for 1-chloro-2-butyne gave the final productSubstance CLJ-127.1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.30(d,J＝22.1Hz,2H),8.08(s,1H),7.66(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.2Hz,1H),6.94(d,J＝8.3Hz,1H),5.31–5.24(m,1H),5.15–5.03(m,1H),4.63(p,J＝6.6Hz,1H),3.51(s,2H),3.11(s,2H),2.81(d,J＝5.9Hz,2H),2.68(s,2H),2.31(s,3H),2.17–1.98(m,4H),1.66(d,J＝1.4Hz,6H),1.59(d,J＝1.3Hz,3H),1.49(d,J＝6.7Hz,6H).m/z:485.3314[M+H]+.
Example 29 preparation of (E) -methyl 4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoate (CLJ-128)
Figure BDA0002554748290000331
CLJ-128 was synthesized as in example 28, substituting methyl (E) -4-bromo-2-butenoate for geranyl bromide to give CLJ-128 as the final product.1H NMR(400MHz,DMSO-d6)δ:9.22(s,1H),8.33(s,1H),8.29(s,1H),8.08(s,1H),7.67(d,J＝2.2Hz,1H),7.52–7.44(m,1H),6.96(d,J＝8.8Hz,2H),6.10(d,J＝15.7Hz,1H),4.63(hept,J＝6.7Hz,1H),3.68(s,3H),3.52(s,2H),2.83(t,J＝5.8Hz,2H),2.68(t,J＝5.8Hz,2H),2.32(s,3H),1.49(d,J＝6.6Hz,6H).m/z:447.2430[M+H]+.
Example 302 preparation of- (5-alkenylhexyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-129)
Figure BDA0002554748290000332
Synthesis of CLJ-129 As in example 29, methyl (E) -4-bromo-2-butenoate was replaced with 6-bromo-1-hexene to give CLJ-129 as a final product.1H NMR(400MHz,DMSO-d6)δ:9.19(s,1H),8.33(d,J＝0.7Hz,1H),8.27(d,J＝0.7Hz,1H),8.08(d,J＝0.7Hz,1H),7.65(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.2Hz,1H),6.95(d,J＝8.4Hz,1H),5.82(ddt,J＝16.9,10.2,6.6Hz,1H),5.03(dq,J＝17.2,1.7Hz,1H),4.96(ddt,J＝10.2,2.3,1.2Hz,1H),4.63(p,J＝6.6Hz,1H),3.47(s,2H),2.80(t,J＝5.8Hz,2H),2.63(t,J＝5.8Hz,2H),2.44(t,J＝7.2Hz,2H),2.35–2.28(m,3H),2.07(q,J＝7.1Hz,2H),1.58–1.37(m,10H).m/z:431.2845[M+H]+.
Example preparation of 312- (3-Enebutyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-130)
Figure BDA0002554748290000333
Synthesis of CLJ-130 As in example 30, the end product CLJ-130 was obtained by substituting 4-bromo-1-butene for 6-bromo-1-hexene.1H NMR(400MHz,DMSO-d6)δ:9.20(s,1H),8.33(s,1H),8.27(s,1H),8.08(s,1H),7.65(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.2Hz,1H),6.96(d,J＝8.3Hz,1H),5.86(ddt,J＝17.0,10.2,6.7Hz,1H),5.10(dq,J＝17.2,1.7Hz,1H),5.00(ddt,J＝10.3,2.4,1.3Hz,1H),4.63(hept,J＝6.6Hz,1H),3.51(s,2H),2.80(t,J＝5.9Hz,2H),2.67(t,J＝5.8Hz,2H),2.34–2.25(m,5H),1.49(d,J＝6.7Hz,6H).m/z:403.2532[M+H]+.
Example 322 preparation of- (4-Enopentyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-131)
Figure BDA0002554748290000341
CLJ-131 was synthesized as in example 31, substituting 5-bromo-1-pentene for 4-bromo-1-butene to give the final product CLJ-131.1H NMR(400MHz,DMSO-d6)δ:9.20(s,1H),8.33(d,J＝0.7Hz,1H),8.27(d,J＝0.7Hz,1H),8.11–8.06(m,1H),7.65(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.2Hz,1H),6.95(d,J＝8.4Hz,1H),5.86(ddt,J＝16.9,10.1,6.6Hz,1H),5.08–4.94(m,2H),4.63(p,J＝6.7Hz,1H),3.48(s,2H),2.80(t,J＝5.8Hz,2H),2.64(t,J＝5.8Hz,2H),2.44(t,J＝7.3Hz,2H),2.31(s,3H),2.09(tdd,J＝6.6,5.3,1.4Hz,2H),1.62(p,J＝7.4Hz,2H),1.49(d,J＝6.7Hz,6H).m/z:417.2688[M+H]
Example preparation of 332- (2-methyl-2-pentenoyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-132)
Figure BDA0002554748290000342
CLJ-132 Synthesis As in example 26, the end product CLJ-132 was obtained by substituting 2-methyl-2-pentenoic acid for 4-pentenoic acid.1H NMR(400MHz,DMSO-d6)δ:9.29(s,1H),8.30(d,J＝23.2Hz,2H),8.09(s,1H),7.75(s,1H),7.56(d,J＝8.4Hz,1H),7.07(d,J＝8.3Hz,1H),5.51(t,J＝7.4Hz,1H),4.59(d,J＝28.3Hz,3H),3.68(t,J＝6.0Hz,2H),2.69(s,5H),2.31(s,3H),2.10(p,J＝7.4Hz,2H),1.76(s,3H),1.48(d,J＝6.8Hz,6H).m/z:445.2638[M+H]
Example 342- (3-Benzoylacryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-133) preparation
Figure BDA0002554748290000343
CLJ-133 was synthesized as in example 33, replacing 2-methyl-2-pentenoic acid with 3-benzoylacrylic acid to give the final product CLJ-133.1H NMR(400MHz,DMSO-d6)δ:9.31(d,J＝2.2Hz,1H),8.33(s,1H),8.28(s,1H),8.13–8.02(m,3H),7.85–7.79(m,1H),7.76(d,J＝2.2Hz,1H),7.74–7.68(m,1H),7.64–7.50(m,4H),7.15(dd,J＝8.5,4.3Hz,1H),4.73(d,J＝36.9Hz,2H),4.63(p,J＝6.7Hz,1H),3.83(dt,J＝11.2,5.9Hz,2H),2.88(dt,J＝23.7,6.0Hz,2H),2.32(s,3H),1.49(dd,J＝6.7,1.9Hz,6H).m/z:507.2430[M+H].
Example 352 preparation of- (5-Enohexanoyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-134)
Figure BDA0002554748290000344
CLJ-134 was synthesized as in example 34, replacing 5-hexenoic acid3-Benzoylacrylic acid gives the end product CLJ-134.1H NMR(400MHz,DMSO-d6)δ:9.29(d,J＝5.0Hz,1H),8.34(s,1H),8.28(s,1H),8.09(s,1H),7.74(dd,J＝8.0,2.2Hz,1H),7.59–7.52(m,1H),7.10(dd,J＝8.5,4.8Hz,1H),5.83(ddtd,J＝16.6,9.8,6.5,3.1Hz,1H),5.06–4.95(m,2H),4.68–4.60(m,1H),4.56(d,J＝14.9Hz,2H),3.67(q,J＝5.8Hz,2H),2.80(dt,J＝39.4,6.0Hz,2H),2.41(t,J＝7.4Hz,2H),2.32(s,3H),2.07(q,J＝7.8Hz,2H),1.63(td,J＝7.7,5.1Hz,2H),1.49(d,J＝6.7Hz,6H).m/z:445.2638[M+H]+.
Example 362- (2-Methylallyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-135)
Figure BDA0002554748290000351
CLJ-135 Synthesis the final product CLJ-135 was obtained in the same manner as in example 31, except that 3-bromo-2-methylpropene was used instead of 4-bromo-1-butene.1H NMR(400MHz,DMSO-d6)δ:9.20(s,1H),8.32(s,1H),8.26(s,1H),8.09(s,1H),7.67(d,J＝2.2Hz,1H),7.48(dd,J＝8.3,2.3Hz,1H),6.94(d,J＝8.4Hz,1H),4.97–4.85(m,2H),4.62(p,J＝6.7Hz,1H),3.42(s,2H),2.98(s,2H),2.81(t,J＝5.9Hz,2H),2.58(t,J＝5.8Hz,2H),2.31(s,3H),1.73(s,3H),1.48(d,J＝6.7Hz,6H).m/z:403.2532[M+H]+.
Example 37 preparation of (E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid (CLJ-136)
Figure BDA0002554748290000352
Step 1: (E) synthesis of (E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid (CLJ-136)
(E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) methyl crotonate (446.6mg,1mmol) was added to a solution ofMethanol (5mL), sodium hydroxide aqueous solution (2mmol/L,2.5mL) is added, the mixture is heated and reacted for 2 hours at 50 ℃, diluted hydrochloric acid is used for adjusting the mixture to be neutral, and the CLJ-136 is obtained after suction filtration and drying.1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.30(d,J＝22.4Hz,2H),8.08(s,1H),7.67(d,J＝2.3Hz,1H),7.48(dd,J＝8.3,2.2Hz,1H),6.96(d,J＝8.4Hz,1H),6.79(dt,J＝15.6,5.9Hz,1H),6.02–5.94(m,1H),4.62(h,J＝6.6Hz,1H),3.51(s,2H),3.27(d,J＝5.5Hz,2H),3.18(s,1H),2.83(t,J＝5.8Hz,2H),2.67(t,J＝5.8Hz,2H),2.31(s,3H),1.49(d,J＝6.6Hz,6H).m/z:433.2274[M+H]+.
Example 38 preparation of (E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid propionamide (CLJ-137)
Figure BDA0002554748290000353
Step 1: (E) synthesis of (E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid propionamide (CLJ-137)
(E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) crotonic acid (432mg,1mmol), propylamine (120mg,2mmol), N, N-diisopropylethylamine (320mg,2.5mmol) and HATU (380mg,1mmol) were added to dichloromethane (10mL), reacted at room temperature for 1H, suction filtered and dried to obtain the final product CLJ-137.1H NMR(400MHz,DMSO-d6)δ:9.23(s,1H),8.30(d,J＝21.5Hz,2H),8.08(s,1H),8.01(s,1H),7.68(s,1H),7.48(d,J＝8.3Hz,1H),6.97(d,J＝8.4Hz,1H),6.63(dt,J＝15.3,5.9Hz,1H),6.13(d,J＝15.4Hz,1H),4.63(p,J＝6.6Hz,1H),3.57(d,J＝39.5Hz,3H),3.08(d,J＝6.3Hz,2H),2.85(s,2H),2.71(d,J＝22.4Hz,2H),2.32(s,3H),1.43(s,8H),1.27(s,2H),0.86(s,4H).m/z:474.2903[M+H]+.
Example 39 preparation of (E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid (piperidin-1-ylethylamine) amide (CLJ-138)
Figure BDA0002554748290000361
CLJ-138 was synthesized as in example 38, substituting 1- (2-aminoethyl) piperidine for propylamine to give CLJ-138 as the final product.1H NMR(400MHz,DMSO-d6)δ:9.22(s,1H),8.33(s,1H),8.27(s,1H),8.09(s,2H),7.68(d,J＝2.2Hz,1H),7.48(dd,J＝8.3,2.2Hz,1H),6.96(d,J＝8.3Hz,1H),6.67(dt,J＝15.4,5.9Hz,1H),6.14(d,J＝15.5Hz,1H),4.62(h,J＝6.6Hz,1H),3.53(s,2H),3.29–3.21(m,3H),2.87–2.81(m,2H),2.69(d,J＝8.0Hz,2H),2.32(s,3H),1.49(d,J＝6.6Hz,12H).m/z:543.3482[M+H]+.
Example 40 preparation of (E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid tert-butylamide (CLJ-139)
Figure BDA0002554748290000362
CLJ-139 Synthesis the same as in example 39, substituting tert-butylamine for 1- (2-aminoethyl) piperidine gave the final product CLJ-139.1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.30(d,J＝22.0Hz,2H),8.09(s,1H),7.71–7.56(m,2H),7.48(dd,J＝8.3,2.2Hz,1H),6.96(d,J＝8.4Hz,1H),6.58(dt,J＝15.4,5.9Hz,1H),6.15(dd,J＝15.4,1.6Hz,1H),4.63(p,J＝6.6Hz,1H),3.50(s,2H),3.26–3.15(m,2H),2.84(t,J＝5.8Hz,2H),2.66(t,J＝5.8Hz,2H),2.32(s,3H),1.49(d,J＝6.6Hz,6H),1.29(s,9H).m/z:488.3060[M+H]+.
Example 41 preparation of (E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid diethylamide (CLJ-140)
Figure BDA0002554748290000363
CLJ-140 was synthesized as in example 40, substituting diethylamine for t-butylamine to give the final product CLJ-140.1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.30(d,J＝22.5Hz,2H),8.08(s,1H),7.67(d,J＝2.2Hz,1H),7.48(dd,J＝8.4,2.2Hz,1H),6.96(d,J＝8.4Hz,1H),6.71(dt,J＝15.1,6.0Hz,1H),6.61–6.52(m,1H),4.63(hept,J＝6.7Hz,1H),3.52(s,2H),3.38(s,3H),3.30–3.25(m,2H),2.83(t,J＝5.9Hz,2H),2.68(t,J＝5.8Hz,2H),2.32(s,3H),1.49(d,J＝6.7Hz,6H),1.17–0.99(m,7H).m/z:488.3062[M+H]+.
Example 422 preparation of cyanomethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-141)
Figure BDA0002554748290000371
Synthesis of the pyrimidine moiety of CLJ-141 example 19; synthesis of aromatic amine moiety As in step 3 of example 3, 1,2,3, 4-tetrahydroisoquinoline was used in place of 7-fluoro-1, 2,3, 4-tetrahydroisoquinoline trifluoroacetamide, and the resulting product was subjected to silica gel column chromatography using petroleum ether/ethyl acetate (5: 1).1H NMR(400MHz,DMSO-d6)δ:9.25(s,1H),8.30(d,J＝21.5Hz,2H),8.09(s,1H),7.65(d,J＝2.3Hz,1H),7.50(dd,J＝8.3,2.2Hz,1H),7.04(d,J＝8.4Hz,1H),4.63(hept,J＝6.7Hz,1H),3.93(s,2H),3.68(s,2H),2.84–2.71(m,4H),2.32(s,3H),1.49(d,J＝6.6Hz,6H).m/z:388.2171[M+H]+.
Example 432 preparation of- (2-methyl-2-pentenoyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-142)
Figure BDA0002554748290000372
CLJ-142 was synthesized in the same manner as in example 33 except that 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline was used instead of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-142 as a final product.1H NMR(400MHz,DMSO-d6)δ:9.29(s,1H),8.31(d,J＝21.1Hz,2H),8.09(s,1H),7.74(s,1H),7.55–7.49(m,1H),7.08(d,J＝8.3Hz,1H),5.53(t,J＝7.3Hz,1H),4.62(d,J＝6.3Hz,3H),3.68(t,J＝5.9Hz,2H),2.76(t,J＝6.0Hz,2H),2.11(p,J＝7.5Hz,2H),1.78(s,3H),1.49(d,J＝6.7Hz,6H),0.99(t,J＝7.5Hz,3H).m/z:445.2638[M+H]+.
EXAMPLE 442 preparation of hydroxybutyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-143)
Figure BDA0002554748290000373
CLJ-143 was synthesized in the same manner as in example 5 except that 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline was used in place of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-143 as a final product.1H NMR(400MHz,DMSO-d6)δ:9.20(s,1H),8.30(d,J＝24.4Hz,2H),8.08(s,1H),7.62(d,J＝2.3Hz,1H),7.46(dd,J＝8.2,2.3Hz,1H),7.00(d,J＝8.3Hz,1H),4.62(dq,J＝13.4,6.7Hz,2H),3.43(t,J＝6.3Hz,2H),2.73(d,J＝5.7Hz,2H),2.64(t,J＝5.8Hz,2H),2.46(t,J＝7.0Hz,2H),2.32(s,3H),1.62–1.43(m,11H).m/z:421.2638[M+H]+.
Example 452 preparation of butyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-144)
Figure BDA0002554748290000374
Synthesis of CLJ-144 As in example 19, 1-bromobutane was used instead of chloroacetonitrile to give the final product CLJ-144.1H NMR(400MHz,DMSO-d6)δ:9.19(s,1H),8.29(d,J＝23.5Hz,2H),8.09(s,1H),7.65(s,1H),7.47(d,J＝7.7Hz,1H),6.94(d,J＝8.2Hz,1H),4.70–4.56(m,J＝6.8Hz,1H),3.46(s,2H),2.79(s,2H),2.61(s,2H),2.41(s,2H),2.31(s,3H),1.48(d,J＝6.8Hz,8H),1.31(p,J＝7.3Hz,2H),0.90(t,J＝7.2Hz,3H).m/z:405.2688[M+H]+.
Example 462-preparation of hydroxyethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-fluoro-6-amine (CLJ-145)
Figure BDA0002554748290000381
CLJ-145 was synthesized as in example 3, substituting 4-bromon-butanol for 2-iodoethanol to give CLJ-145 as the final product.1H NMR(400MHz,DMSO-d6)δ:8.56(s,1H),8.30(s,1H),8.23(s,1H),8.02(s,1H),7.68(d,J＝8.1Hz,1H),6.93(d,J＝11.5Hz,1H),4.61(p,J＝6.7Hz,1H),4.54(s,1H),3.50(s,2H),3.42(d,J＝6.3Hz,2H),2.78(t,J＝5.9Hz,2H),2.64(t,J＝5.9Hz,2H),2.44(t,J＝7.0Hz,2H),2.30(s,3H),1.58–1.41(m,10H).m/z:439.2543[M+H]+.
Example 47 preparation of (E) -4- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid (CLJ-146)
Figure BDA0002554748290000382
CLJ-146 was synthesized in the same manner as in example 37 except that 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline was used instead of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-146 as a final product.1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.29(d,J＝20.0Hz,2H),8.07(s,1H),7.60(d,J＝2.2Hz,1H),7.48(dd,J＝8.3,2.2Hz,1H),7.02(d,J＝8.3Hz,1H),6.82(dt,J＝15.6,5.9Hz,1H),5.99(d,J＝15.6Hz,1H),4.61(h,J＝6.7Hz,1H),3.57(s,2H),3.29(s,2H),2.72(dt,J＝36.8,5.9Hz,4H),2.31(s,3H),1.49(d,J＝6.7Hz,6H).m/z:433.2274[M+H]+.
Example 48 preparation of (E) -4- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid isobutyramide (CLJ-147)
Figure BDA0002554748290000383
CLJ-147 was synthesized in the same manner as in example 41, using 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline in place of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline and isobutylamine in place of diethylamine to obtain CLJ-147.1H NMR(400MHz,DMSO-d6)δ:9.22(s,1H),8.30(d,J＝19.8Hz,1H),8.07(s,1H),7.99(t,J＝5.8Hz,1H),7.61(d,J＝1.6Hz,1H),7.48(dt,J＝13.7,6.8Hz,1H),7.02(d,J＝8.4Hz,1H),6.64(dt,J＝15.5,5.8Hz,1H),6.17(d,J＝15.5Hz,1H),4.75–4.49(m,1H),3.59(s,1H),3.28(d,J＝5.5Hz,1H),2.96(t,J＝6.3Hz,1H),2.78(d,J＝5.1Hz,1H),2.70(s,1H),2.31(s,1H),1.77–1.65(m,1H),1.48(d,J＝6.7Hz,3H),0.86(d,J＝6.7Hz,3H).m/z:488.3060[M+H]+.
Example 49 preparation of (E) -4- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid diethylamide (CLJ-148)
Figure BDA0002554748290000384
Synthesis of CLJ-148 As in example 48, the final product, CLJ-148, was obtained by substituting diethylamine for isobutylamine.1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.29(d,J＝20.9Hz,2H),8.07(s,1H),7.60(d,J＝1.7Hz,1H),7.49(dd,J＝8.3,2.1Hz,1H),7.02(d,J＝8.4Hz,1H),6.71(dt,J＝15.0,6.0Hz,1H),6.59(s,1H),4.62(s,1H),3.58(s,2H),3.42–3.27(m,8H),2.76(d,J＝5.2Hz,2H),2.69(d,J＝5.1Hz,2H),1.09(dt,J＝28.2,6.9Hz,6H).m/z:488.3062[M+H]+.
Example 50 preparation of (E) -4- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid (3-trifluoromethylphenethylamine) amide (CLJ-149)
Figure BDA0002554748290000391
CLJ-149 Synthesis As in example 49, 3-trifluoromethylphenethylamine was used instead of diethylamine to give CLJ-149 as a final product.1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.64(t,J＝6.0Hz,1H),8.29(d,J＝20.6Hz,2H),8.07(s,1H),7.69–7.52(m,5H),7.49(dd,J＝8.3,2.0Hz,1H),7.02(d,J＝8.4Hz,1H),6.72(dt,J＝15.5,5.7Hz,1H),6.21(d,J＝15.5Hz,1H),4.61(dt,J＝13.3,6.6Hz,1H),4.44(d,J＝5.9Hz,2H),3.58(s,2H),3.28(d,J＝5.4Hz,2H),2.77(d,J＝5.4Hz,2H),2.69(d,J＝5.3Hz,2H),2.31(s,3H),1.48(d,J＝6.7Hz,6H).
m/z:590.2777[M+H]+.
Example 51 preparation of (E) -4-dimethylamino-1- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) -2-butenoic acid (CLJ-150)
Figure BDA0002554748290000392
CLJ-150 Synthesis As in example 26, 4-dimethylamino-2-butenoic acid was used in place of 4-pentenoic acid to give the final product CLJ-150.1H NMR(400MHz,DMSO-d6)δ:9.30(d,J＝5.2Hz,1H),8.30(d,J＝20.8Hz,2H),8.09(s,1H),7.75(d,J＝6.4Hz,1H),7.56(t,J＝9.0Hz,1H),7.10(t,J＝8.8Hz,1H),6.85(d,J＝15.1Hz,1H),6.70–6.56(m,1H),4.71(s,1H),4.65–4.57(m,2H),3.77(dt,J＝18.4,5.8Hz,2H),3.51(d,J＝6.6Hz,2H),2.84(dt,J＝28.8,6.0Hz,2H),2.32(s,3H),1.49(d,J＝6.6Hz,6H).m/z:460.2747[M+H]+.
EXAMPLE 522 preparation of cyanoethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-151)
Figure BDA0002554748290000393
CLJ-151 Synthesis As in example 19, CLJ-151 was obtained as the final product by substituting 3-chloropropionitrile for 2-chloroacetonitrile.1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.29(d,J＝22.7Hz,2H),8.08(s,1H),7.67(d,J＝2.2Hz,1H),7.48(dd,J＝8.3,2.2Hz,1H),6.95(d,J＝8.3Hz,1H),4.63(hept,J＝6.7Hz,1H),2.76(ddt,J＝20.6,9.8,5.7Hz,8H),2.31(s,3H),1.48(d,J＝6.6Hz,6H).m/z:402.2328[M+H]+.
Example 532- (3-benzoylacryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-152) preparation
Figure BDA0002554748290000394
CLJ-152 was synthesized in the same manner as in example 34 except that 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline was used in place of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-152 as a final product.1H NMR(400MHz,DMSO-d6)δ:9.31(d,J＝3.6Hz,1H),8.34(s,1H),8.28(d,J＝7.3Hz,1H),8.12–8.01(m,3H),7.85–7.75(m,2H),7.73–7.67(m,1H),7.62–7.50(m,4H),7.10(d,J＝8.3Hz,1H),4.79(d,J＝40.6Hz,2H),4.61(dq,J＝13.3,6.7Hz,1H),3.82(dt,J＝10.9,5.9Hz,2H),2.82(dt,J＝24.6,5.9Hz,2H),2.32(d,J＝4.6Hz,3H),1.48(dd,J＝16.7,6.6Hz,6H).m/z:507.2430[M+H]+.
Example 542-preparation of cyanoethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-153)
Figure BDA0002554748290000401
CLJ-153 was synthesized in the same manner as in example 52 using 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline in place of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-153 as a final product.1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.29(d,J＝24.5Hz,2H),8.07(s,1H),7.60(d,J＝2.2Hz,1H),7.48(dd,J＝8.3,2.3Hz,1H),7.01(d,J＝8.3Hz,1H),4.63(p,J＝6.7Hz,1H),3.63(s,2H),2.76(dq,J＝15.2,4.9Hz,8H),2.31(s,3H),1.49(d,J＝6.6Hz,6H).m/z:402.2328[M+H]+.
Example 552- (3-Phenylacryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-154) preparation
Figure BDA0002554748290000402
CLJ-154 was synthesized as in example 53, substituting 3-benzoylacrylic acid for 3-phenylacrylic acid to obtain the final product CLJ-154.1H NMR(400MHz,DMSO-d6)δ:9.32(d,J＝6.4Hz,1H),8.37(d,J＝17.1Hz,1H),8.29(s,1H),8.10(s,1H),7.91–7.69(m,3H),7.55(d,J＝15.1Hz,2H),7.41(q,J＝6.6Hz,4H),7.10(d,J＝8.0Hz,1H),4.95(s,1H),4.74(s,1H),4.64(dt,J＝13.9,7.7Hz,1H),3.88(dt,J＝55.8,5.8Hz,2H),2.81(dt,J＝33.6,5.8Hz,2H),2.28(s,3H),1.55–1.42(m,6H).m/z:479.2481[M+H]+.
Example 562- (3-Phenylacryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-155)
Figure BDA0002554748290000403
CLJ-155 was synthesized in the same manner as in example 53, 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline was substituted for 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-155 as a final product.1H NMR(400MHz,DMSO-d6)δ:9.31(d,J＝3.6Hz,1H),8.31(d,J＝21.8Hz,2H),8.10(s,1H),7.82–7.70(m,3H),7.63–7.50(m,2H),7.48–7.31(m,4H),7.14(d,J＝8.4Hz,1H),4.95–4.57(m,3H),3.88(dt,J＝55.9,5.8Hz,2H),2.87(dt,J＝32.1,5.9Hz,2H),2.32(s,3H),1.49(d,J＝6.6Hz,6H).m/z:479.2483[M+H]+.
Example 572- (3- (4-Methylbenzoyl) propionyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-156)
Figure BDA0002554748290000411
CLJ-156 was synthesized as in example 56, substituting 3- (4-methylbenzoyl) propionic acid for 3-phenylacrylic acid to give the final product CLJ-156.1H NMR(400MHz,DMSO-d6)δ:9.30(d,J＝5.9Hz,1H),8.31(d,J＝20.9Hz,2H),8.09(d,J＝1.7Hz,1H),7.88(d,J＝8.0Hz,2H),7.75(dd,J＝11.7,1.8Hz,1H),7.61–7.51(m,1H),7.33(d,J＝7.8Hz,2H),7.11(dd,J＝25.0,8.4Hz,1H),4.71–4.49(m,3H),3.71(dt,J＝35.7,5.9Hz,2H),3.24(t,J＝6.2Hz,2H),2.95–2.71(m,4H),2.35(d,J＝24.3Hz,6H),1.49(d,J＝6.6Hz,6H).m/z:523.2743[M+H]+.
Example preparation of 582- (2-Methylphenylacryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-157)
Figure BDA0002554748290000412
CLJ-157 Synthesis As in example 57, the final product CLJ-157 was obtained by substituting 2-methyl-phenylacrylic acid for 3- (4-methylbenzoyl) propionic acid.1H NMR(400MHz,DMSO-d6)δ:9.30(s,1H),8.31(d,J＝21.5Hz,2H),8.09(s,1H),7.76(s,1H),7.56(d,J＝8.4Hz,1H),7.42(d,J＝4.5Hz,4H),7.32(pd,J＝5.7,3.9,3.3Hz,1H),7.11(d,J＝8.5Hz,1H),6.58(s,1H),4.63(d,J＝6.0Hz,3H),3.77(t,J＝5.8Hz,2H),2.88(t,J＝5.9Hz,2H),2.32(s,3H),2.06(s,3H),1.48(d,J＝6.6Hz,6H).m/z:493.2638[M+H]+.
Example 592- (3- (4-Methylbenzoyl) propionyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-158) preparation
Figure BDA0002554748290000413
CLJ-158 was synthesized in the same manner as in example 57 except that 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline was used in place of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-158 as a final product.1H NMR(400MHz,DMSO-d6)δ:9.30(d,J＝15.6Hz,1H),8.42–8.22(m,2H),8.08(d,J＝5.5Hz,1H),7.88(d,J＝7.8Hz,2H),7.77(dd,J＝35.8,2.1Hz,1H),7.53(td,J＝8.3,2.2Hz,1H),7.33(d,J＝7.9Hz,2H),7.09(t,J＝8.1Hz,1H),4.77–4.53(m,3H),3.71(dt,J＝33.7,5.9Hz,2H),3.24(s,2H),2.88–2.64(m,4H),2.44–2.23(m,6H),1.48(dd,J＝6.6,5.0Hz,6H).m/z:523.2743[M+H]+.
Example 602- (2-Methylphenylacryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-159)
Figure BDA0002554748290000414
CLJ-159 was synthesized in the same manner as in example 58 except that 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline was used instead of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-159 as a final product.1H NMR(400MHz,DMSO-d6)δ:9.30(s,1H),8.30(d,J＝20.3Hz,2H),8.08(s,1H),7.77(s,1H),7.53(dd,J＝8.4,2.2Hz,1H),7.45–7.37(m,4H),7.31(tq,J＝5.4,3.5,2.4Hz,1H),7.10(d,J＝8.4Hz,1H),6.58(d,J＝1.9Hz,1H),4.65(d,J＝36.4Hz,3H),3.76(t,J＝5.9Hz,2H),2.81(t,J＝6.0Hz,2H),2.31(s,3H),2.11–1.99(m,3H),1.47(dd,J＝7.1,3.6Hz,6H).m/z:493.2638[M+H]+.
Example 612- (3- (4-Methylbenzoyl) acryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-160) preparation
Figure BDA0002554748290000421
CLJ-160 Synthesis As in example 57, the 3- (4-methylbenzoyl) propionic acid was replaced by 3- (4-methylbenzoyl) acrylic acid to give CLJ-160 as a final product.1H NMR(400MHz,DMSO-d6)δ:9.31(d,J＝2.1Hz,1H),8.33(s,1H),8.28(s,1H),8.09(s,1H),7.96(dd,J＝8.3,2.8Hz,2H),7.84–7.72(m,2H),7.59–7.48(m,2H),7.39(d,J＝8.0Hz,2H),7.14(dd,J＝8.5,3.8Hz,1H),4.79–4.58(m,3H),3.82(dt,J＝10.1,5.9Hz,2H),2.88(dt,J＝23.6,6.0Hz,2H),2.40(s,3H),2.32(s,3H),1.48(dd,J＝6.7,1.7Hz,6H).m/z:521.2587[M+H]+.
Example 622- (3- (4-Methylbenzoyl) acryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-161) preparation
Figure BDA0002554748290000422
Synthesis of CLJ-161 in the same embodimentEXAMPLE 61 replacement of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline by 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline gave CLJ-161, a final product.1H NMR(400MHz,DMSO-d6)δ:9.31(d,J＝3.4Hz,1H),8.39–8.21(m,2H),8.08(d,J＝10.4Hz,1H),7.96(dd,J＝8.0,4.3Hz,2H),7.88–7.68(m,2H),7.61–7.47(m,2H),7.38(dd,J＝8.1,4.2Hz,2H),7.10(d,J＝8.3Hz,1H),4.94–4.49(m,3H),3.82(dt,J＝9.7,5.9Hz,2H),2.81(dt,J＝24.2,5.9Hz,2H),2.40(d,J＝3.7Hz,3H),2.32(d,J＝4.5Hz,3H),1.48(dd,J＝16.3,6.7Hz,6H).m/z:521.2587[M+H]+.
Example 634 preparation of methyl 6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butyrate (CLJ-162)
Figure BDA0002554748290000423
Synthesis of CLJ-162 As in example 29, the final product, CLJ-162, was obtained by substituting methyl 4-bromobutyrate for methyl (E) -4-bromo-2-butenoate.1H NMR(400MHz,DMSO-d6)δ:9.18(s,1H),8.32(s,1H),8.26(s,1H),8.07(s,1H),7.64(s,1H),7.46(d,J＝8.4Hz,1H),6.95(d,J＝8.3Hz,1H),4.62(dt,J＝13.2,6.6Hz,1H),3.57(d,J＝9.1Hz,3H),3.46(s,2H),2.78(d,J＝5.3Hz,2H),2.62(t,J＝5.6Hz,2H),2.44(t,J＝6.9Hz,2H),2.36(t,J＝7.2Hz,2H),2.31(s,3H),1.83–1.74(m,2H),1.48(d,J＝6.6Hz,6H).m/z:449.2587[M+H]+.
Example 64 preparation of (E) -methyl 4- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) crotonate (CLJ-163)
Figure BDA0002554748290000424
CLJ-163 was synthesized in the same manner as in example 29, using 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline in place of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline, thereby obtaining CLJ-163 as a final product.1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.32(s,1H),8.26(d,J＝5.5Hz,1H),8.07(d,J＝6.0Hz,1H),7.61(s,1H),7.50–7.45(m,1H),7.00(t,J＝9.9Hz,1H),6.93(dt,J＝15.7,5.8Hz,1H),6.10(d,J＝15.7Hz,1H),4.62(dt,J＝13.3,6.6Hz,1H),3.68(s,3H),3.58(s,2H),3.32–3.29(m,2H),2.75(d,J＝5.1Hz,2H),2.67(t,J＝5.4Hz,2H),2.30(d,J＝9.3Hz,3H),1.48(d,J＝6.7Hz,6H).m/z:447.2430[M+H]+.
Example preparation of methyl 654- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butyrate (CLJ-164)
Figure BDA0002554748290000431
CLJ-164 Synthesis As in example 64, the final product CLJ-164 was obtained by substituting methyl 4-bromobutyrate for methyl (E) -4-bromo-2-butenoate.1H NMR(400MHz,DMSO-d6)δ:9.19(s,1H),8.32(s,1H),8.26(s,1H),8.07(s,1H),7.61(s,1H),7.45(dd,J＝8.3,1.8Hz,1H),6.99(d,J＝8.3Hz,1H),4.62(dp,J＝12.9,6.4Hz,1H),3.56(s,3H),3.52(s,2H),2.71(d,J＝5.3Hz,2H),2.62(t,J＝5.6Hz,2H),2.46(t,J＝6.9Hz,2H),2.36(t,J＝7.2Hz,2H),2.30(d,J＝11.3Hz,3H),1.79(p,J＝7.1Hz,2H),1.47(dd,J＝11.7,5.9Hz,6H).m/z:449.2587[M+H]+.
Example 664-preparation of dimethylamino-1- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) -2-butanamide (CLJ-165)
Figure BDA0002554748290000432
CLJ-165 Synthesis As in example 51, the end product was obtained by substituting 4-dimethylaminobutyric acid for (E) -4-dimethylamino-2-butenoic acid
CLJ-165。1H NMR(400MHz,DMSO-d6)δ:9.30(d,J＝6.4Hz,1H),8.33(s,1H),8.28(s,1H),8.09(s,1H),7.75(dd,J＝10.1,2.2Hz,1H),7.56(ddd,J＝14.8,8.4,2.2Hz,1H),7.10(d,J＝8.4Hz,1H),4.68–4.54(m,3H),3.68(dt,J＝12.1,5.9Hz,2H),3.09–2.99(m,2H),2.88(s,8H),2.56–2.51(m,2H),2.32(s,3H),1.87(p,J＝7.0Hz,2H),1.48(d,J＝6.6Hz,6H).m/z:462.2903[M+H]+.
Example 674-preparation of dimethylamino-1- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) -2-butanamide (CLJ-166)
Figure BDA0002554748290000433
CLJ-166 can be synthesized in the same manner as in example 66 except that 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline is used in place of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-166 as a final product.1H NMR(400MHz,DMSO-d6)δ:9.31(d,J＝12.8Hz,1H),8.34(d,J＝8.0Hz,1H),8.28(s,1H),8.09(d,J＝1.9Hz,1H),7.76(d,J＝2.7Hz,1H),7.52(dd,J＝8.4,2.4Hz,1H),7.09(dd,J＝8.4,4.3Hz,1H),4.63(dd,J＝7.7,5.3Hz,3H),3.68(dt,J＝14.1,5.9Hz,2H),3.09–2.99(m,2H),2.82(t,J＝5.9Hz,1H),2.76(s,6H),2.74–2.67(m,1H),2.55(dd,J＝13.4,6.8Hz,2H),2.32(d,J＝2.5Hz,3H),1.88(p,J＝7.0Hz,2H),1.49(d,J＝6.6Hz,6H).m/z:462.2903[M+H]+.
Example 68 preparation of (E) -4-dimethylamino-1- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) -2-butenamide (CLJ-167)
Figure BDA0002554748290000441
CLJ-167 Synthesis in the same manner as in example 67, CLJ-167 was obtained as a final product by substituting (E) -4-dimethylamino-2-butenoic acid for 4-dimethylaminobutyric acid.1H NMR(400MHz,DMSO-d6)δ:9.32(d,J＝10.3Hz,1H),8.34(d,J＝5.4Hz,1H),8.28(s,1H),8.10(s,1H),7.76(d,J＝13.3Hz,1H),7.54(dd,J＝8.3,2.3Hz,1H),7.10(d,J＝8.4Hz,1H),6.95(dd,J＝23.4,15.0Hz,1H),6.65(dt,J＝14.7,6.8Hz,1H),4.79(s,1H),4.69(s,1H),4.63(q,J＝6.7Hz,1H),3.79(dt,J＝15.3,5.9Hz,2H),3.68(d,J＝6.9Hz,2H),2.79(dt,J＝30.7,5.8Hz,2H),2.63(s,6H),2.32(s,3H),1.50(d,J＝6.7Hz,6H).m/z:460.2747[M+H]+.
Example 69 preparation of (R) -5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -isoindoline-2-pyrrolidonecarboxamide (CLJ-168)
Figure BDA0002554748290000442
CLJ-168 was synthesized in the same manner as in example 26 except that 5-aminoisoindoline was used in place of 1,2,3, 4-tetrahydroisoquinoline, and (R) -2-pyrrolinocarboxylic acid was used in place of 4-pentenoic acid.1H NMR(400MHz,DMSO-d6)δ:9.42(d,J＝4.7Hz,1H),8.34(s,1H),8.29(s,1H),8.10(d,J＝2.6Hz,1H),7.93(t,J＝3.0Hz,1H),7.64(dd,J＝8.4,2.0Hz,1H),7.25(t,J＝8.5Hz,1H),4.87(ddd,J＝74.2,28.4,14.4Hz,3H),4.64(dt,J＝20.2,6.0Hz,2H),3.80(q,J＝7.5Hz,1H),3.01(dt,J＝10.9,6.0Hz,1H),2.74–2.60(m,1H),2.32(s,3H),2.15–2.01(m,1H),1.76–1.59(m,3H),1.49(d,J＝1.1Hz,3H),1.48(d,J＝1.2Hz,3H).m/z:432.2512[M+H]+.
Example 70 preparation of (R) -5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indoline-2-pyrroline carboxamide (CLJ-169)
Figure BDA0002554748290000443
CLJ-169 was synthesized as in example 69, replacing 5-aminoisoindoline with 5-aminoindoline.1H NMR(400MHz,DMSO-d6)δ:9.28(s,1H),8.32(s,1H),8.26(s,1H),8.08(s,1H),7.99(d,J＝8.7Hz,1H),7.79(s,1H),7.51(d,J＝8.8Hz,1H),4.63(p,J＝6.8Hz,1H),4.23(q,J＝9.1Hz,1H),4.06(q,J＝9.1Hz,1H),3.86(t,J＝6.9Hz,1H),3.38(q,J＝7.0Hz,1H),3.17(t,J＝8.3Hz,2H),3.10–2.97(m,1H),2.79–2.64(m,1H),2.31(s,3H),2.17–2.00(m,1H),1.84–1.60(m,3H),1.48(d,J＝6.5Hz,6H).m/z:432.2512[M+H]+.
Example 715- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indoline-3-morpholinepropanamide (CLJ-170)
Figure BDA0002554748290000444
CLJ-170 was synthesized as in example 70, replacing (R) -2-pyrroline carboxylic acid with 3-morpholinopropionic acid.1H NMR(400MHz,DMSO-d6)δ:9.26(s,1H),8.32(s,1H),8.26(s,1H),8.07(s,1H),7.98(d,J＝8.8Hz,1H),7.77(s,1H),7.50(d,J＝8.9Hz,1H),4.62(h,J＝6.6Hz,1H),4.10(t,J＝8.5Hz,2H),3.61(s,4H),3.44(s,2H),3.16(t,J＝8.3Hz,2H),2.66(s,4H),2.48(s,2H),2.31(s,3H),1.48(d,J＝6.7Hz,6H).m/z:476.2774[M+H]+.
Pharmacological Activity test the following representative test (not limited thereto) was used to analyze the biological activity of the compound of the present invention
MTT assay for inhibition of cell proliferation of MV4-11, MOLM-13 and SET-2
To test the effect of the test compounds of the present invention on the viability of cancer cells, MV4-11, MOLM-13, and SET-2 were purchased from ATCC (American type culture Collection), MV4-11 and MOLM-13 are human leukemia cell lines, express the FLT3 receptor, and contain the FLT3-ITD mutation; SET-2 is a primary thrombocythemia cell, persistently expresses the JAK2 receptor, and comprises the V617F mutation.
MV4-11, MOLM-13 and SET-2 cells were plated in 96-well dishes in 100. mu.L IMDM containing 10% fetal bovine serum (100 mL/vial, 100 mL/20 ℃ closed cryopreserved) with 10000-15000 cells per well, test compounds were prepared in 100% DMSO (dimethyl sulfoxide) and added to the cells to obtain concentrations of 100nM to 0.032nM (6 concentration points at 5-fold dilution), 100. mu.L fresh medium was added to each well of the blank control, an equal volume of fresh medium containing DMSO equivalent to the highest experimental concentration of drug was added to each well of the solvent control, 3-5 parallel wells were placed in each group, 5% CO at 37 ℃ with 5% CO2And culturing for 72 h. At the end point, 20. mu.L of MTT (5mg/mL) was added to each well and the cells were incubated for an additional 1-3 hours. After treatment with 20% SDS overnight, the absorbance OD at a wavelength of 570nM was obtained on a spectrophotometer (Molecular Devices, Sunnyvale, USA).
The inhibition ratio of each experimental group was calculated as [ (mean OD value of solvent control group-mean OD value of experimental group)/(mean OD value of solvent control group-mean OD value of blank control group) ] × 100%.
After calculating the inhibition rate of each concentration of compound on cell proliferation activity, the treatment concentration of compound and the corresponding inhibition rate were fitted to a dose-response curve using graphpad prism software, and IC was fitted50The value is obtained. The results are shown in Table 1.
In vitro kinase Activity assay
In one reaction tube, buffer (8mM MOPS, pH 7.0,0.2mM EDTA,10mM MnCl) was added in sequence2) The kinase to be tested, the substrate for the kinase to be tested, a 10mM magnesium acetate and gamma 33P-ATP solution, and compounds at different concentrations, MgATP was then added to the reaction to start the enzymatic reaction process, and incubated at room temperature for 40 minutes. Finally, stopping the reaction by using 5 microliter of 3% phosphate buffer solution, titrating 10 microliter of reaction solution onto a Filtermat A membrane, washing three times by using 75mM phosphate solution, washing for 5 minutes each time by using methanol, finally drying the Filtermat A membrane and carrying out scintillation counting on the Filtermat A membrane, wherein the scintillation counting value reflects the phosphorylation degree of a substrate, so that the kinase activity inhibition condition can be represented. The kinase activity @500nM indicates the inhibition (%) of the enzyme at the 500nM level, as determined by Eurofins. The results are shown in Table 1.
TABLE 1 IC inhibition of cell proliferation by test Compounds50Value and kinase Activity
Figure BDA0002554748290000461
Figure BDA0002554748290000471
Figure BDA0002554748290000481
The results show that most of tested compounds have good inhibitory activity on cell proliferation of MV4-11, MOLM-13 and SET-2, have good activity on JAK2 and FLT3, and are novel and potential inhibitors with the potential for treating JAK2-FLT3-ITD related diseases.
The test compound with good activity is preferably selected for FLT3 and JAK family kinase half inhibition activity IC50Value determination, in one reaction tube, buffers (8mM MOPS, pH 7.0,0.2mM EDTA,10mM MnCl) were added in sequence2) The kinase to be tested, the substrate for the kinase to be tested, a 10mM magnesium acetate and gamma 33P-ATP solution, and compounds at various concentrations, MgATP was then added to the reaction to start the enzymatic reaction process, and incubated at room temperature for 40 minutes. Finally, stopping the reaction by using 5 microliter of 3% phosphate buffer solution, titrating 10 microliter of reaction solution onto a Filtermat A membrane, washing three times by using 75mM phosphate solution, washing for 5 minutes each time by using methanol, finally drying the Filtermat A membrane and carrying out scintillation counting on the Filtermat A membrane, wherein the scintillation counting value reflects the phosphorylation degree of a substrate, so that the kinase activity inhibition condition can be represented. The results are shown in Table 2.
TABLE 2 Activity of preferred Compounds of the invention against JAK1/2/3 and FLT3 kinase inhibitors
Figure BDA0002554748290000482
The results show that the preferable compounds CLJ-118, CLJ-128 and CLJ-144 of the invention have better in-vitro enzymology inhibitory activity and good selectivity.

Claims (15)

  1. A 2, 4-disubstituted pyrimidine derivative having the formula:
    Figure FDA0003649271910000011
    Figure FDA0003649271910000021
    Figure FDA0003649271910000031
    Figure FDA0003649271910000041
  2. 2. a pharmaceutically acceptable salt of the 2, 4-disubstituted pyrimidine derivative of claim 1.
  3. 3. A pharmaceutical composition which is a preparation comprising the 2, 4-disubstituted pyrimidine derivative according to claim 1 or the salt according to claim 2 and a pharmaceutically acceptable auxiliary component.
  4. 4. The pharmaceutical composition of claim 3, wherein the formulation is a tablet, capsule, powder, granule, ointment, solution, suspension, injection, inhalation, gel, microsphere, or aerosol.
  5. 5. The pharmaceutical composition of claim 3, wherein the formulation is an oral or intravenous formulation.
  6. 6. Use of a 2, 4-disubstituted pyrimidine derivative according to claim 1, a salt according to claim 2 or a pharmaceutical composition according to any one of claims 3 to 5 in the preparation of a JAK2 inhibitor.
  7. 7. Use of a 2, 4-disubstituted pyrimidine derivative according to claim 1, a salt according to claim 2 or a pharmaceutical composition according to any one of claims 3 to 5 in the preparation of an FLT3 inhibitor.
  8. 8. Use of the 2, 4-disubstituted pyrimidine derivative according to claim 1, the salt according to claim 2 or the pharmaceutical composition according to any one of claims 3 to 5 for the preparation of a medicament for the treatment or/and prevention of tumors.
  9. 9. The use of claim 8, the tumor comprises a solid tumor and/or a hematological tumor; the solid tumor comprises: lymphoma, ovarian, breast, prostate, bladder, kidney, esophagus, neck, pancreas, colorectal, stomach, non-small cell lung, thyroid, brain, epidermal hyperproliferation, psoriasis, and/or prostate cancer; the hematological neoplasm comprises: acute myeloid leukemia, chronic myeloid leukemia, myeloma, acute lymphocytic leukemia, acute myelogenous leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated cell leukemia, myelodysplastic syndrome, myelodysplasia, myelofibrosis, multiple myeloma, and/or myelosarcoma.
  10. 10. The use of claim 9, wherein the lymphoma comprises B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic lymphoma, lymphoplasmacytic lymphoma, and/or lymphoma.
  11. 11. Use of the 2, 4-disubstituted pyrimidine derivative according to claim 1, the salt according to claim 2 or the pharmaceutical composition according to any one of claims 3 to 5 for the preparation of a medicament for the treatment or/and prevention of immune diseases.
  12. 12. The use of claim 11, the immune disease comprising: psoriasis, rheumatoid arthritis, inflammatory bowel disease, sjogren's syndrome, behcet's disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, polymyositis, dermatomyositis, periarteritis nodosa, mixed connective tissue disease, scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves 'disease, autoimmune gastritis, type I and type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, addison's disease, abnormal immune responses, arthritis and/or radiodermatitis.
  13. 13. The use of claim 12, the immune disease comprising: psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, and/or systemic lupus erythematosus.
  14. 14. Use of a 2, 4-disubstituted pyrimidine derivative according to claim 1, a salt according to claim 2 or a pharmaceutical composition according to any one of claims 3 to 5 for the manufacture of a medicament for the treatment or/and prevention of inflammatory-related diseases.
  15. 15. The use of claim 14, the inflammatory-related disease comprising: acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome, post-operative or post-traumatic inflammation, nephritis, cystitis, pharyngolaryngitis, gastric mucosal injury, meningitis, spondylitis, arthritis, dermatitis, and/or bronchitis.
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