CN112724145A - Pyrazine derivatives for inhibiting SHP2 activity - Google Patents

Pyrazine derivatives for inhibiting SHP2 activity Download PDF

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CN112724145A
CN112724145A CN201910975401.1A CN201910975401A CN112724145A CN 112724145 A CN112724145 A CN 112724145A CN 201910975401 A CN201910975401 A CN 201910975401A CN 112724145 A CN112724145 A CN 112724145A
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alkyl
halo
alkoxy
rex
amino
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王永辉
吴耀东
李春启
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Hangzhou Rex Pharmaceutical Co ltd
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Abstract

The invention relates to a pyrazine derivative shown as a formula (I) for preventing or treating diseases or symptoms related to abnormal activity of SHP2, and also provides a preparation method of the compound.

Description

Pyrazine derivatives for inhibiting SHP2 activity
Technical Field
The present invention relates to compounds capable of inhibiting SHP2 activity. In particular, the invention relates to a pyrazine derivative which is used for preventing or treating diseases or symptoms related to abnormal activity of SHP2, and also provides a preparation method of the compound.
Background
Sexual tumor (also called cancer) is a kind of malignant disease that seriously threatens human health, and is mainly characterized by uncontrolled growth, abnormal proliferation, apoptosis obstruction, differentiation disorder, invasion and metastasis of cells, and the like, and can cause emaciation, weakness, anemia, inappetence, fever, serious organ function damage and the like of human body, and finally cause death of patients.
According to the world cancer statistics report of the world health organization 2014, there are about 1400 ten thousand new cancer cases worldwide in 2012, and the related deaths are 820 ten thousand. And is on a rapidly increasing trend, new cases and deaths are expected to increase to 2200 and 1300 million per year within 20 years, being one of the major diseases leading to human death. The incidence of cancer in china is close to the world level, but the mortality rate is higher than the world level. In 2012, the number of cancer attacks in China is 306.5 ten thousands, which accounts for about one fifth of the worldwide attack; the number of cancer deaths is 220.5 ten thousand, accounting for about one fourth of the worldwide deaths. In 184 countries and regions worldwide, the incidence of malignant tumors in china is on the average of the upper level, accounting for about 21.8% of the incidence of malignant tumors worldwide. Wherein the cancers such as lung cancer, gastric cancer, liver cancer, esophageal cancer, colon cancer and the like are high-incidence malignant tumors. Moreover, the number of cancer patients in china is increasing at an alarming rate due to environmental pollution, lifestyle changes, and social aging, and the situation is very severe, and improvement of the therapeutic level is urgently required.
Based on modern tumor biology concepts, cancer is not a disease, but a neoplastic disease caused by at least hundreds of different molecular mechanisms; there are many signal transduction ways and pathways in human cells, which constitute a large and complex signal transduction network system to regulate physiological and canceration biological processes. The etiology of cancer is not completely elucidated, and may involve external factors such as environment and internal factors such as heredity and immunity.
The protein tyrosine phosphatase SHP2 is encoded by PTPN11 gene and is the first phosphatase containing SH2domain to be reported. The SHP2 conformation exists in two states (as shown in fig. 1), an inactive or self-inhibited state (SH2domain bound to PTP domain, closed conformation) and an activated state (SH2domain dissociated from PTP domain, exposing the active site on PTP domain, open conformation).
In recent years, the relation between the SHP2 signal pathway and tumors becomes a research hotspot, and the SHP2 signal pathway is closely related to embryonic development, regulates in vivo metabolism and is necessary for the development of a blood system and a lymphatic system; moreover, SHP2 can mediate and activate RAS-ERK signal pathway to promote survival and proliferation of cancer cells; also mediates a compensatory activation pathway after the inhibition of kinases such as MEK and the like, thereby promoting the generation of tumor drug resistance; as a downstream molecule of the PD-1 receptor, SHP2 is also involved in the transduction of T cell inhibitory signals. It has been shown that SHP2 is a downstream molecule of PD-1 signaling that not only inhibits T cell activation but also promotes T cell disability. Targeting SHP2 can restore or enhance T cell-mediated anti-tumor immune function.
Mutations in the PTPN11 gene and subsequent SHP2 have been recognized in a variety of human diseases, such as Noonan Syndrome (Noonan Syndrome), Leopard Syndrome (Leopard Syndrome), Juvenile myelomonocytic leukemia (Juvenile myelogenous leukemia), melanoma, neuroblastoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, and gastric cancer, among others. Thus, SHP2 represents a highly attractive target for the development of new therapies for the treatment of various diseases.
However, there have been many researchers to develop multiple enzyme activity inhibitors for the active site in the open conformation of SHP2 to achieve tumor inhibition, but they have not been successful. The biggest problem is that the negatively charged compounds for inhibiting the polar active site of SHP2 are difficult to effectively cross cell membrane or enter blood circulation when orally taken, so that the SHP2 inhibitors have poor curative effect and no single case can enter clinical test stage. This impasse was recently broken by researchers, who used an allosteric inhibition strategy to circumvent the traditional approach of inhibiting the enzymatic activity of SHP2 starting from the active site of PTP domain, and designed compounds that could bind to the borders of the three domains (N-SH2domain, C-SH2domain, PTP domain) of SHP2, so that SHP2 could maintain a closed conformation and maintain a self-inhibitory state, thereby inhibiting the activity of SHP2 (as shown in fig. 1), such as SHP099 of Novartis (Novartis). However, there are currently no SHP2 inhibitor drugs on the market.
In view of the above, it would be of great social benefit and value to develop and market new compounds with good SHP2 inhibitory activity and safety.
Disclosure of Invention
The invention aims to provide a pyrazine SHP2 inhibitor with a novel structure, which is synthesized and screened out a series of compounds with antitumor activity through substitution modification of groups; and the compounds are found to have the effect of preventing or treating diseases regulated and controlled by SHP 2.
In order to realize the purpose, the invention adopts the following technical scheme:
the compound of the invention has a general structure shown in a formula (I) or a pharmaceutically acceptable salt thereof:
Figure BDA0002233445500000021
wherein X is selected from absent, S or O;
the ring A is selected from 5-12 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, halogen,C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
ring B is selected from 6-12 membered substituted or unsubstituted heterocyclic ring, and the heterocyclic ring is attached to the parent nucleus through the N atom, wherein the heterocyclic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R2Selected from absent or C1-6An alkyl group;
R1、R2each of which is substituted by the parent nucleus, or, R1、R2Are connected with each other to form a 5-6 membered saturated or unsaturated carbocyclic or heterocyclic ring, and form a ring with the mother nucleus;
r3 is selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R4Selected from absent or C1-6An alkyl group;
R3、R4each of which is substituted by the parent nucleus, or, R3、R4Form of interconnectionA 5-6 membered saturated or unsaturated carbocyclic or heterocyclic ring which is fused to the parent nucleus;
R5、R6each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
The invention further provides some preferred technical schemes for the compounds represented by the formula (I).
Preferably, when R is2Is C1-6Alkyl radical, R4In the absence of R1、R2Are interconnected to form a 5-to 6-membered carbocyclic or heterocyclic ring, and form a fused ring with the parent nucleus in the structural form:
Figure BDA0002233445500000031
preferably, when R is1is-NR5R6，R2is-CH2，R4To be absent, R5、R6Each independently selected from H or C1-6When alkyl, R1、R2Are connected with each other to form a 5-6 heterocyclic ring, and form a combined ring with the mother nucleus in the following structural form:
Figure BDA0002233445500000041
more preferably, it is a compound represented by the formula (II):
Figure BDA0002233445500000042
wherein X is selected from absent, S or O;
the ring A is selected from 5-12 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
ring B is selected from 6-12 membered substituted or unsubstituted heterocyclic ring, and the heterocyclic ring is attached to the parent nucleus through the N atom, wherein the heterocyclic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R3selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
More preferably, it is a compound represented by the formula (IIa):
Figure BDA0002233445500000043
wherein X is selected from absent or S;
the ring A is selected from 6-membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R3selected from H, halogen, C1-6Alkyl, halo C1-6Alkyl, -OH, - (CH)2)nOR5；
R5Selected from H, C1-6An alkyl group;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
n is selected from 1;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
Preferably, when R is4Is C1-6Alkyl radical, R2In the absence of R3、R4Are interconnected to form a 5-to 6-membered carbocyclic or heterocyclic ring, and form a fused ring with the parent nucleus in the structural form:
Figure BDA0002233445500000051
preferably, when R is3is-NR5R6，R4is-CH2，R2Is absent，R5、R6Each independently selected from H or C1-6When alkyl, R3、R4Are connected with each other to form a 5-6 heterocyclic ring, and form a combined ring with the mother nucleus in the following structural form:
Figure BDA0002233445500000052
more preferably, it is a compound represented by the formula (III):
Figure BDA0002233445500000053
wherein X is selected from absent, S or O;
the ring A is selected from 5-12 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
ring B is selected from 6-12 membered substituted or unsubstituted heterocyclic ring, and the heterocyclic ring is attached to the parent nucleus through the N atom, wherein the heterocyclic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
More preferably, it is a compound represented by the formula (IIIa):
Figure BDA0002233445500000061
wherein X is selected from absent or S;
the ring A is selected from 6-membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl, halo C1-6Alkyl, -OH, -NH2；
R5Selected from H, C1-6An alkyl group;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
Preferably, when R is2To be absent, R4To be out of stockAt the time of R1And R3Each independently substituted with a parent nucleus, a compound of formula (IV) or a pharmaceutically acceptable salt thereof:
Figure BDA0002233445500000071
wherein X is selected from absent, S or O;
the ring A is selected from 5-12 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
ring B is selected from 6-12 membered substituted or unsubstituted heterocyclic ring, and the heterocyclic ring is attached to the parent nucleus through the N atom, wherein the heterocyclic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
the 6-12 membered substituted or unsubstituted heterocyclic ring is monocyclic, bridged, spiro or fused;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R3 is selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
More preferably, it is a compound represented by the formula (IVa):
Figure BDA0002233445500000072
wherein X is selected from absent, S or O;
the ring A is selected from 5-10 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R3Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)nNH2、-OH、-(CH2)nOH；
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
More preferably, it is a compound represented by the formula (IVa-1):
Figure BDA0002233445500000081
wherein X is selected from absent, S or O;
R1selected from H, C1-6Alkyl or-NH2；
R3Selected from H, C1-6Alkyl, -COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, -OH, -NH2A 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)nNH2；
n is selected from 1;
the heterocyclic ring contains 1-2 heteroatoms, and the heteroatoms are N, O.
More preferably, it is a compound represented by the formula (IVa-2):
Figure BDA0002233445500000082
wherein R is1Selected from H, C1-6Alkyl or-NH2；
R3Is selected from- (CH)2)nOR5or-CR5R6；
R5Selected from H, a 3-4 membered carbocyclic ring or a 3-4 membered heterocyclic ring containing 1O atom;
R6is selected from-OH or-NH2；
R8、R9Any one of them is-NH2The other is C1-6An alkyl group;
n is selected from 1.
More preferably, it is a compound represented by the formula (IVa-3):
Figure BDA0002233445500000091
wherein Y is C or O;
R1is selected from C1-6Alkyl or-NH2；
R3Is selected from H;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)nNH2；
n is selected from 1.
More preferably, it is a compound represented by the formula (IVb):
Figure BDA0002233445500000092
wherein X is selected from absent, S or O;
ring a is selected from a 5-12 membered substituted or unsubstituted aromatic ring, wherein the aromatic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R3Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)nNH2、-OH、-(CH2)nOH；
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
More preferably, it is a compound represented by the formula (IVb-1):
Figure BDA0002233445500000101
wherein X is selected from absent, S or O;
R1is selected from C1-6Alkyl or-NH2；
R3Selected from H, -COOR5Or- (CH)2)nOR5；
R5Is selected from H;
R8、R9any one of them is-NH2The other is C1-6An alkyl group;
n is selected from 1.
More preferably, it is a compound represented by the formula (IVc):
Figure BDA0002233445500000102
wherein X is selected from absent, S or O;
ring a is selected from a 5-12 membered substituted or unsubstituted aromatic ring, wherein the aromatic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R3Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, haloC1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)nNH2、-OH、-(CH2)nOH；
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
More preferably, the compound is represented by the formula (IVc-1):
Figure BDA0002233445500000111
wherein R is1Is selected from C1-6Alkyl or-NH2；
R3Is selected from H or- (CH)2)nOR5；
R5Is selected from H;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)nNH2；
n is selected from 1.
More preferably, it is a compound represented by the formula (IVd):
Figure BDA0002233445500000112
wherein X is selected from absent, S or O;
ring a is selected from a 5-12 membered substituted or unsubstituted aromatic ring, wherein the aromatic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R3Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8is selected from C1-6Alkyl, -NH2、-(CH2)nNH2、-OH、-(CH2)nOH；
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
More preferably, it is a compound represented by the formula (IVd-1):
Figure BDA0002233445500000121
wherein R is1Is selected from C1-6Alkyl or-NH2；
R3Is selected from H or- (CH)2)nOR5；
R5Is selected from H;
R8is selected from-NH2；
n is selected from 1.
More preferably, the compound is represented by formula (IVe):
Figure BDA0002233445500000122
wherein X is selected from absent, S or O;
ring a is selected from a 5-12 membered substituted or unsubstituted aromatic ring, wherein the aromatic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R3Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8is selected from C1-6Alkyl, -NH2、-(CH2)nNH2、-OH、-(CH2)nOH；
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
More preferably, it is a compound represented by the formula (IVe-1):
Figure BDA0002233445500000131
wherein R is1Is selected from C1-6Alkyl or-NH2；
R3Is selected from H or- (CH)2)nOR5；
R5Is selected from H;
R8is selected from-NH2Or- (CH)2)nOH；
n is selected from 1.
More preferably, the compound is represented by formula (IVf):
Figure BDA0002233445500000132
wherein X is selected from absent, S or O;
ring A is selected fromA 5-10 membered substituted or unsubstituted aromatic ring, wherein the aromatic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R3Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8is selected from C1-6Alkyl, -NH2、-(CH2)nNH2、-OH、-(CH2)nOH；
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
More preferably, it is a compound represented by the formula (IVf-1):
Figure BDA0002233445500000141
wherein Y is C or O;
R1is selected from C1-6Alkyl or-NH2；
R3Is selected from- (CH)2)nOR5；
R5Is selected from H;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)nNH2；
n is selected from 1.
More preferably, it is a compound represented by the formula (IVf-2):
Figure BDA0002233445500000142
wherein X is selected from absent, S or O;
R1is selected from C1-6Alkyl, -NH2or-NR5R6；
R3Is selected from-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5Selected from H, a 3-4 membered carbocyclic ring or a 3-4 membered heterocyclic ring containing 1O atom;
R6selected from H, C1-6Alkyl, -OH or-NH2；
n is selected from 1.
More preferably, it is a compound represented by the formula (IVf-3):
Figure BDA0002233445500000151
wherein X is selected from absent or S;
ring A is selected from 6-membered substituted or unsubstitutedWherein the aromatic ring is substituted with: halogen, C1-6An alkyl group;
R1is selected from C1-6Alkyl, -NH2；
R8、R9Each independently selected from C1-6Alkyl or-NH2；
R10Is selected from-OH or-NH2。
The invention also provides other pyrazine derivatives with similar structures as the formula (I), which are shown in the specification.
In some embodiments, the compound of formula (v) or a pharmaceutically acceptable salt thereof:
Figure BDA0002233445500000152
wherein X is selected from absent, S or O;
y, P, Q are each independently selected from C or N, and either Y or P is N and the other is C;
the ring A is selected from 5-12 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R5、R6each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)nNH2、-OH、-(CH2)nOH；
R11、R12、R13、R14Each independently selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, ═ O, -OH, -NH2One or more of the above;
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
In some embodiments, the compound is of formula (VI):
Figure BDA0002233445500000161
wherein X is selected from absent, S or O;
y ', P ', Q ' are each independently selected from C, O, N or S, and S and O are not present at the same time;
the ring A is selected from 5-12 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R5、R6each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8、R9each independently of the otherIs selected from C1-6Alkyl, -NH2、-(CH2)nNH2、-OH、-(CH2)nOH；
R15、R16、R17Each independently selected from absent, H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, ═ O, -OH, -NH2、-(CH2)nOne or more of OH;
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
In some embodiments, the compound is of formula (VII):
Figure BDA0002233445500000162
wherein X is selected from absent, S or O;
the ring A is selected from 5-12 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, ═ O, -OH, -NH2One or more of the above;
R5、R6each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)nNH2、-OH、-(CH2)nOH；
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
Furthermore, the invention also provides a particularly preferable technical scheme of the compound shown by the general formula structure or the pharmaceutically acceptable salt thereof, wherein the compound is as follows:
REX-S001:8- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-6-amine;
REX-S002 (5- (4-amino-4-methylpiperidin-1-yl) -8- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-6-yl) methanol;
REX-S003:1- (8- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-5-yl) -4-methylpiperidin-4-amine;
REX-S004:1- (5- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-8-yl) -4-methylpiperidin-4-amine;
REX-S005 2- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-5-amine;
REX-S006 5-amino-1- (4-amino-4-methylpiperidinyl) -4- (2, 3-dichlorophenyl) pyridin-2 (1H) -one;
REX-S007 6-amino-4- (4-amino-4-methylpiperidin-1-yl) -1- (2, 3-dichlorophenyl) pyridin-2 (1h) -one;
REX-S008: 3-amino-1- (4-amino-4-methylpiperidinyl) -4- (2, 3-dichlorophenyl) pyridin-2 (1h) -one;
REX-S009:4- (4-amino-4-methylpiperidin-1-yl) -1- (2, 3-dichlorophenyl) pyridin-2 (1H) -one;
REX-S010:1- (4-amino-4-methylpiperidinyl) -4- (2, 3-dichlorophenyl) pyridin-2 (1H) -one;
REX-S011 2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) thiazol-4-amine;
REX-S012 (5- (4-amino-4-methylpiperidin-1-yl) -2- (2, 3-dichlorophenyl) thiazol-4-yl) methanol;
REX-S013:1- (4-amino-5- (2, 3-dichlorophenyl) -1-methyl-1 h-imidazol-2-yl) -4-methylpiperidin-4-amine;
REX-S014 2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) oxazol-4-amine;
REX-S015 (5- (4-amino-4-methylpiperidin-1-yl) -2- (2, 3-dichlorophenyl) -1-methyl-1 h-imidazol-4-yl) methanol;
REX-S016 (3- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S017 (3- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol;
REX-S018 (5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S019 (5-amino-3- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S020 (3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol;
REX-S021 (3- (7-amino-7-methyl-4-azaspiro [2.5] octan-4-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol;
REX-S022 (3- (8-amino-5-azaspiro [2.5] octan-5-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol;
REX-S023 (3- (6- (aminomethyl) -3-azaspiro [4.1.0] heptan-3-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol;
REX-S024 (3- (6-amino-3-azaspiro [4.1.0] heptan-3-yl) -6- (2, 3-dichlorophenyl) -5-5-methylpyrazin-2-yl) methanol;
REX-S025 (5-amino-3- (3-amino-3-methyl-8-azaspiro [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S026 (5-amino-3- (7-amino-7-methyl-4-azaspiro [2.5] octan-4-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S027 (5-amino-3- (8-amino-5-azaspiro [2.5] octan-5-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S028 (5-amino-3- (6- (aminomethyl) -3-azabicyclo [4.1.0] heptan-3-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S029 (5-amino-3- (6-amino-3-azabicyclo [4.1.0] heptan-3-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S030 8- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -3-methyl-8-azabicyclo [3.2.1] octan-3-amine;
REX-S031 4- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -7-methyl-4-azaspiro [2.5] octan-7-amine;
REX-S032 5- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -5-azaspiro [2.5] octan-8-amine;
REX-S033 6- (6- (aminomethyl) -3-azaspiro [4.1.0] heptan-3-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine;
REX-S034:3- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -3-azaspiro [4.1.0] heptan-6-amine;
REX-S035:6- (4-amino-4-methylpiperidin-1-yl) -3- (3, 4-dihydroquinolin-1 (2 hydro) -yl) pyrazin-2-amine;
REX-S036- (4-amino-4-methylpiperidin-1-yl) -3- (2 hydro-benzo [ b ] [1,4] oxazin-4 (3 hydro) -yl) pyrazin-2-amine;
REX-S037 (3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (3, 4-dihydroquinolin-1 (2H) -yl) -5-methylpyrazin-2-yl) methanol;
REX-S038 (3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2-hydro-benzo [ b ] [1,4] oxazin-4 (3-hydro) -yl) -5-methylpyrazin-2-yl) methanol;
REX-S039:1- (3- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) cyclopropanol;
REX-S040:1- (3- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) cyclobutanol;
REX-S041 3- (3- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) oxetan;
REX-S042:1- (3- (3-aminocyclobutan-3-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrazin-2-yl) -4-methylpiperidin-4-amine;
REX-S043 3- (3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) oxetan-ol;
REX-S044:1- (3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) cyclopropanol;
REX-S045 (3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol;
REX-S046 (3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- ((2, 3-dichlorophenyl) thio) -5-methylpyrazin-2-yl) methanol;
REX-S047 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-hydroxycarboxylic acid;
REX-S048 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- ((2, 3-dichlorophenyl) thio) pyrazine-2-hydroxycarboxylic acid;
REX-S049 3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5- (methylamino) pyrazine-2-hydroxycarboxylic acid;
REX-S050 (3S,4S) -8- (6-amino-3- (methylamino) -5- (2, 3-dichlorophenyl) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine;
REX-S051 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-carboxamide;
REX-S052 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -N-methylpyrazine-2-carboxamide;
REX-S053 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-hydroxycarboxylic acid;
REX-S054 5-amino-3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-hydroxycarboxylic acid;
REX-S055 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- ((2, 3-dichlorophenyl) thio) pyrazine-2-carboxamide;
REX-S056 3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5- (methylamino) pyrazine-2-carboxamide;
REX-S057 3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5- (dimethylamino) pyrazine-2-carboxamide.
The structural formula of the compounds numbered REX-S001-REX-S0057 is shown as follows:
Figure BDA0002233445500000201
Figure BDA0002233445500000211
the term "compound" as used herein includes all stereoisomers, geometric isomers, tautomers and isotopes.
The "compounds" of the present invention may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the invention containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The "compound" of the present invention also includes tautomeric forms. Tautomeric forms result from the exchange of one single bond with an adjacent double bond and the concomitant migration of one proton.
The invention also includes all isotopic atoms, whether in the intermediate or final compound. Isotopic atoms include those having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.
Compounds containing the foregoing general structure, the terms used herein have the following meanings:
the term "halogen" denotes fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
The term "halo C1-6Alkyl group "," halogeno C1-6Alkoxy "means a group in which one or more (especially 1 to 3) hydrogen atoms are replaced by halogen atoms, in particular fluorine or chlorine atoms.
The term "alkyl" denotes a straight or branched chain saturated hydrocarbon group consisting of carbon and hydrogen atoms, such as C1-20Alkyl, preferably C1-6Alkyl groups such as methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylhexyl and the like. The alkyl group may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxy, aryl, heteroaryl, amino, halo, sulfonyl, sulfinyl, phosphoryl.
The terms "alkenyl" and "alkynyl" refer to straight or branched alkenes and alkynes composed of carbon and hydrogen atoms.
The term "alkoxy" refers to an oxygen ether formed from the aforementioned straight or branched chain alkyl groups.
The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, typically having 6 to 14 carbon atoms, preferably having 6 to 12 carbon atoms, and most preferably having 6 carbon atoms. Aryl groups may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxy, aryl, aralkyl, amino, halo, sulfonyl, sulfinyl, phosphoryl. Examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "heterocyclyl" refers to a monocyclic or fused ring having from 3 to 12 (an integer) ring atoms, of which 1,2 or 3 ring atoms are selected from one or more of N, O, the remaining ring atoms being C, and having a fully conjugated pi-electron system. The heterocyclyl group may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxy, aryl, aralkyl, amino, halo, sulfonyl, sulfinyl, phosphoryl. Examples of unsubstituted heterocyclyl groups include, but are not limited to, pyrrolyl, indolyl, pyrrolidinyl, imidazolyl, pyrazolyl, tetrazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, pyrimidinyl, pyrazinyl, piperazinyl, furyl, pyranyl, morpholinyl.
The term "heteroaryl" refers to an aromatic ring system containing carbon and at least one heteroatom. Heteroaryl groups may be monocyclic or polycyclic, substituted or unsubstituted. The monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, and the polycyclic heteroaryl group may have 1 to 10 heteroatoms in the ring.
The term "cycloalkyl" refers to a substituted or unsubstituted monocyclic, bicyclic, or polycyclic non-aromatic saturated ring.
The invention also provides a pharmaceutical composition, which comprises the compound or the pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.
"pharmaceutical composition" as used herein, refers to a formulation of one or more compounds of the present invention or salts thereof with a carrier generally accepted in the art for delivery of biologically active compounds to an organism (e.g., a human). The purpose of the pharmaceutical composition is to facilitate delivery of the drug to an organism.
The term "pharmaceutically acceptable carrier" refers to a substance that is co-administered with, and facilitates the administration of, an active ingredient, including, but not limited to, any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is acceptable for use in humans or animals (e.g., livestock) as permitted by the national food and drug administration. Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
The pharmaceutical composition can be prepared into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powder, granules, paste, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.
The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
The route of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof includes, but is not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. The preferred route of administration is oral.
For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient. For example, for pharmaceutical compositions intended for oral administration, tablets may be obtained in the following manner: the active ingredient is combined with one or more solid carriers, the resulting mixture is granulated if necessary, and processed into a mixture or granules, if necessary with the addition of small amounts of excipients, to form tablets or tablet cores. The core may be combined with an optional enteric coating material and processed into a coated dosage form more readily absorbed by an organism (e.g., a human).
The invention also provides application of the compounds shown in all the general structures or pharmaceutically acceptable salts thereof in preparing medicaments.
Preferably, the aforementioned medicaments are used as SHP2 inhibitors.
Preferably, the aforementioned medicament is used for treating or preventing diseases associated with abnormal activity of SHP 2.
Preferably, the aforementioned disease is specifically a tumor.
Preferably, the aforementioned disease is selected from noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large-cell lymphoma or glioblastoma.
The invention also provides a treatment method, which comprises the step of administering a therapeutically effective amount of the compound shown in the general formula structure or the pharmaceutically acceptable salt thereof to an individual needing to treat the SHP2 activity-mediated diseases, in particular to a cancer patient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Compared with the prior art, the pyrazine compound provided by the invention is based on reasonable drug design of targets, and a series of compounds with novel structures are obtained through group substitution modification; and a series of compounds with the activity of inhibiting the SHP2 are optimally screened out by combining in-vitro or in-vivo evaluation experiments such as an enzymology activity experiment, a cell proliferation experiment and the like. Therefore, the method can be used for developing a novel SHP2 inhibitor, has great clinical application value for targeted treatment or prevention of diseases related to abnormal SHP2 activity, and has considerable market potential.
Drawings
FIG. 1 is a schematic diagram of the structure of SHP2 inhibitor.
Detailed Description
The following are specific examples of the present invention and further describe the technical solutions of the present invention, but the scope of the present invention is not limited to these examples. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.
In the preparation method of the target compound, the liquid chromatography adopts a Waters symmetry C18 chromatographic column. Thin layer chromatography was performed using GF254(0.25 mm). Nuclear Magnetic Resonance (NMR) was measured using a Bruker-400 NMR spectrometer; liquid chromatography/Mass Spectrometry (LC/MS) Using a Waters ZQ mass spectrometer (column: Waters symmetry C18, mm, 5 μm, 35 ℃ C.), the ESI (+) ion mode was used.
In addition, all operations involving easily oxidizable or hydrolyzable raw materials were carried out under nitrogen protection. Unless otherwise indicated, the starting materials used in the present invention are all commercially available starting materials and can be used without further purification.
Example 1 preparation of [ No. REX-S001 ] 8- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-6-amine
Figure BDA0002233445500000241
Step 1: preparation of 6- (2, 3-dichlorophenyl) pyrazin-2-amine (i.e. compound REX-S001-2)
Dissolving raw material 6-bromopyrazine-2-amine (namely compound REX-S001-1,8g,46.5mmol) and 2, 3-dichlorophenylboronic acid (8.8g, 46.5mmol) in dioxane (100mL), slowly adding cesium carbonate (30.2g,93mmol) and tetratriphenylphosphine palladium (0.5g) into a reaction system, replacing nitrogen after adding, and reacting at 95 ℃ for 18 hours; after completion of the reaction, the reaction mixture was poured into 500mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain REX-S001-2(5.0g) as a compound, yield: 35 percent.
MSm/z[ESI]：241.0[M+1]。
Step 2: preparation of 3, 5-dibromo-6- (2, 3-dichlorophenyl) pyrazin-2-amine (i.e., compound REX-S001-3)
Dissolving a compound REX-S001-2(5.0g,20.8mmol) in N, N-dimethylformamide (50mL), slowly adding N-bromosuccinimide (3.7g,20.8mmol) at 0-5 ℃, and reacting for 60 minutes at 0-5 ℃; after the reaction is finished, the temperature is returned to the room temperature, the mixture is poured into 50mL of water after being cooled, the mixture is extracted by ethyl acetate, and the REX-S001-3(3g) is obtained by drying, concentration and silica gel column chromatography separation, and the yield is as follows: 36 percent.
MSm/z[ESI]：398.88[M+1]。
And step 3: preparation of 6, 8-dibromo-5- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazine (i.e., compound REX-S001-4)
Compound REX-S001-3(3.0g,7.5mmol), bromoacetaldehyde diethyl acetal (2.9g,15mmol) were dissolved in tetrahydrofuran (50mL), replaced with nitrogen, and reacted at 120 ℃ for 12 hours. After the reaction, the reaction mixture was warmed to room temperature, cooled, poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain REX-S001-4(1.1g) in yield: 35 percent.
MSm/z[ESI]：422.9[M+1]。
And 4, step 4: preparation of 6, 8-dibromo-5- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazine (i.e., compound REX-S001-4)
Compound REX-S001-4(1.1g,2.6mmol), benzophenone imine (2.9g,15mmol) was dissolved in tetrahydrofuran (50mL), and the mixture was reacted at 80 ℃ for 12 hours with nitrogen substitution. After the reaction, the reaction mixture was warmed to room temperature, cooled, poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain REX-S001-5(0.3g), yield: 22 percent.
MSm/z[ESI]：523.2[M+1]。
1H-NMR(400MHz，CDCl3)：δ＝7.472-7.491(m,2H)，7.385-7.401(m,1H)，7.310-7.345(m,2H)，7.174-7.249(m,7H)，6.929-6.947(m,2H)，3.865(s,1H)，4.527-4.584(m,2H)，4.383(m,1H)，3.520-3.580(m,2H)，1.940-1.974(m,2H)，1.545-1.605(m,2H)，1.385(s,9H)，1.941(s,3H)，1.325(s,3H)。
And 5: preparation of 8- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-6-amine (i.e. compound REX-S001)
While stirring, compound REX-S001-4(0.3g, 0.57mmol) was added to dichloromethane (5mL), methanol hydrochloride (2mL) was added dropwise, and the mixture was stirred at room temperature overnight. Adjusting pH to above 10 with 5% sodium bicarbonate water solution, extracting with ethyl acetate, drying, spin drying, and separating with silica gel column chromatography to obtain REX-S001(0.1 g).
MSm/z[ESI]：392.2[M+1]。
1H-NMR(400MHz，CDCl3)：δ＝7.774-7.798(m,2H)，7.479-7.549(m,3H)，7.093(s,1H)，4.774-4.780(m,2H)，3.679-3.704(m,1H)，1.955-1.992(m,2H)，1.557(s,3H)。
Example 2 preparation of [ No. REX-S003 ] 1- (5- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-8-yl) -4-methylpiperidin-4-amine
Figure BDA0002233445500000261
Step 1: preparation of 5, 8-dibromoimidazo [1,2-a ] pyrazine (i.e. compound REX-S003-2)
The starting bromoacetaldehyde diethyl acetal (9.34g,47.4mmol) was dissolved in 48% HBr (1.2mL) and reacted at 135 deg.C for 2.h. After the reaction was complete, the mixture was added to isopropanol (48mL) and NaHCO3(9.6g,114mmol), whereupon a solid precipitated and filtered. The solid was reacted with 3, 6-dibromopyrazine-2-amine (i.e., compound REX-S003-1,4.0g,15.8mmol) as a starting material at 100 ℃ for 16 hours under nitrogen substitution. After the reaction, the reaction mixture was warmed to room temperature, cooled, poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain REX-S003-2(2.1g) in yield: 50 percent.
MSm/z[ESI]：277.9[M+1]。
Step 2: preparation of 5-bromo-8- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazine (i.e. compound REX-S003-2)
Compounds REX-S003-2(2.02g,7.32mmo), 2, 3-dichlorophenylboronic acid (1.40g,7.32mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (267mg,0.366mmol) and potassium carbonate (1.51g,10.98mmol) were dissolved in dioxane (55mL) and H2O (7.0mL) was added to the flask, and the mixture was purged with nitrogen and reacted at 95 ℃ for 18 hours. Inverse directionAfter completion of the reaction, the solvent was dried by suction, ethyl acetate and water were added, and extraction, organic phase drying and purification by silica gel column chromatography gave compound 3-1(0.12g), yield: 18 percent.
MSm/z[ESI]：344.0[M+1]。
1H NMR(400MHz,DMSO-d6)：δ＝7.95(dd,J＝8.0,2.0Hz,1H),7.91(d,J＝0.8Hz,1H),7.88(d,J＝0.8Hz,1H),7.83(s,1H),7.70(dd,J＝7.6,1.6Hz,1H),7.62(t,J＝8.0Hz,1H)。
And step 3: preparation of tert-butyl (1- (8- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-5-yl) -4-methylpiperidin-4-yl) carbamate (i.e. compound REX-S003-3)
Compound REX-S003-3(0.12g,0.349mmol), (4-methylpiperidin-4-yl) carbamic acid tert-butyl ester (74.8mg,0.349mmol) and N, N-diisopropylethylamine (90mg,0.698mmol) were dissolved in tetrahydrofuran (50mL), purged with nitrogen, and reacted at 80 ℃ for 12 hours. After the reaction, the reaction mixture was warmed to room temperature, cooled, poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain REX-S003- (0.1g) in yield: 60 percent.
MSm/z[ESI]：476.4[M+1]。
And 4, step 4: preparation of 1- (8- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-5-yl) -4-methylpiperidin-4-amine (i.e. compound REX-S003)
While stirring, compound REX-S003-3(0.1g, 0.21mmol) was added to methylene chloride (5mL), methanol hydrochloride (2mL) was added dropwise, and the mixture was stirred at room temperature overnight. Adjusting pH to above 10 with 5% sodium bicarbonate water solution, extracting with ethyl acetate, drying, spin drying, and separating with silica gel column chromatography to obtain REX-S003(50 mg).
MSm/z[ESI]：377.2[M+1]。
1H-NMR(400MHz，DMSO-d6)：δ＝8.46-8.48(m,3H)，7.78(s,1H)，7.54-7.59(m,3H)，7.39(s,1H)，4.88-4.89(m,2H)，4.05-4.07(m,2H)，1.88-1.90(m,4H)，1.43(s,3H)。
Example 3 preparation of [ No. REX-S004 ] 1- (5- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-8-yl) -4-methylpiperidin-4-amine
Figure BDA0002233445500000271
As described in the synthetic route provided in this example, with reference to the procedure of example 2, the isomer REX-S004-3 of the compound REX-S003-3 is obtained after the reaction in step 2, and the remaining steps are the same as in example 2, and the compound REX-S004 is finally obtained by the reaction in yield: 18.0 percent.
MSm/z[ESI]：377.2[M+1]。
1H-NMR(400MHz，CDCl3)：δ＝7.60-7.63(m,1H)，7.52(s,1H)，7.29-7.37(m,3H)，7.09(s,1H)，4.56-4.57(m,2H)，4.36-4.37(m,2H)，1.98-2.12(m,4H)，1.26(s,3H)。
Example 4 preparation of [ No. REX-S009 ] 4- (4-amino-4-methylpiperidin-1-yl) -1- (2, 3-dichlorophenyl) pyridin-2 (1H) -one
Figure BDA0002233445500000281
Step 1: preparation of 4- (benzyloxy) -1- (2, 3-dichlorophenyl) pyridin-2 (1h) -one (i.e. compound REX-S009-2)
The compound 4-benzyloxy-2 (1H) -pyridone (50g,0.249mol), 2, 3-dichloroiodobenzene (102g,0.374mol), cuprous iodide (9.5g,0.05mol), 3,4,7, 8-tetramethyl-1, 10-phenanthroline (11.8g,0.05mol) and potassium carbonate (51.6g,0.374mol) were dissolved in N, N-dimethylformamide (500mL), and reacted at 130 ℃ for 36 hours under nitrogen substitution. After the reaction, the reaction mixture was warmed to room temperature, cooled, poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain REX-S003-2(930g) in yield: 1 percent.
MSm/z[ESI]：346.0[M+1]。
Step 2: preparation of 4-bromo-1- (2, 3-dichlorophenyl) pyridin-2 (1h) -one (i.e. compound REX-S009-3)
Compound REX-S009-2(930mg,2.69mmol) and tribromooxyphosphorus (53.10g,10.8mmol) were dissolved in 1, 2-dichloroethane (12mL), purged with nitrogen, and reacted at 150 ℃ for 6 hours. After the reaction, the reaction mixture was warmed to room temperature, cooled, poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain REX-S009-3(250mg) in a yield: 29 percent.
MSm/z[ESI]：319.9[M+1]。
1H NMR(400MHz,CDCl3)：δ＝7.95(d,J＝5.2Hz,1H),7.37(dd,J＝8.0,1.6Hz,1H),7.26(d,J＝8.0Hz,1H),7.21((d,J＝1.6Hz,1H),7.18(dd,J＝5.2,1.6Hz,1H),7.13(dd,J＝8.0,1.6Hz,1H)。
And step 3: preparation of tert-butyl (1- (1- (2, 3-dichlorophenyl) -2-oxo-1, 2-dihydropyridin-4-yl) -4-methylpiperidin-4-yl) carbamate (i.e. compound REX-S009-4)
As described in the synthetic route provided in this example, compound REX-S009-3 and compound tert-butyl (4-methylpiperidin-4-yl) carbamate obtained in step 2 of this example were prepared according to step 3 of example 2 to obtain the target compound REX-S009-4 in yield: 28 percent.
MSm/z[ESI]：453.3[M+1]。
And 4, step 4: preparation of 4- (4-amino-4-methylpiperidin-1-yl) -1- (2, 3-dichlorophenyl) pyridin-2 (1h) -one (i.e. compound REX-S009)
As described in the synthetic route provided in this example, the compound REX-S009-4 obtained in step 3 of this example and the compound methanol hydrochloride were prepared in step 4 of example 2 to obtain the target compound REX-S009 with the following yields: 88 percent.
MSm/z[ESI]：353.3[M+1]。
1H-NMR(400MHz，DMSO-d6)：δ＝7.64-7.69(m,1H)，7.46-7.50(m,1H)，7.34-7.39(m,3H)，7.17-7.21(m,1H)，7.63-7.361(m,1H)，6.47(m,1H)，1.47-1.48(m,4H)，1.28-1.33(m,4H)，1.11(s,3H)。
Example 5 preparation of [ No. REX-S017 ] (3- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol
Figure BDA0002233445500000291
Step 1: preparation of ethyl 3-hydroxy-5-methylpyrazine-2-carboxylate (i.e. compound REX-S0017-2)
The compound 1, 2-propanediamine (5.00g,67.45mmol) and diethyl ketomalonate (11.75g,67.45mmol) were dissolved in ethanol (50mL), bubbled with oxygen, and reacted at 80 ℃ for 12 hours. After the reaction is finished, the temperature is returned to the room temperature, the mixture is poured into 50mL of water after being cooled, the ethyl acetate is used for extraction, drying, concentration and silica gel column chromatography separation are carried out, and REX-S017-2(3.3g of crude product) is obtained.
Step 2: preparation of 6-bromo-hydroxy-5-methylpyrazine-2-carboxycarboxylic acid ethyl ester (i.e. compound REX-S0017-3)
Dissolving a compound REX-S017-2(3.3g of crude product) in tetrahydrofuran (100mL), slowly adding N-bromosuccinimide (1.95g,10.98mmol) at 0 ℃, and reacting for 2 hours at the temperature of 20-25 ℃. After the reaction, the reaction mixture was poured into 250mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain REX-S017-3(1.6 g).
And step 3: preparation of 6-bromo-5-methyl-3- (tosyl) pyrazine-2-carboxylic acid ethyl ester (i.e., compound REX-S0017-4)
The compound REX-S017-3(1.6g,6.1mmol) and triethylamine (2.5mL,18.3mmol) are dissolved in dichloromethane (10mL), p-toluenesulfonyl chloride (1.4g,7.3mmol) is slowly added at 0 ℃, and the temperature is kept at 20-25 ℃ for reaction for 2 hours. After the reaction, the reaction mixture was poured into 250mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain REX-S017-4(1.5g) in yield: 60 percent.
And 4, step 4: preparation of ethyl 3- (4-amino-4-methylpiperidin-1-yl) -6-bromo-5-methylpyrazine-2-carboxylate (i.e. compound REX-S0017-5)
The compound REX-S017-4(400mg,0.96mmol), 4-methylpiperidine-4-amine (242mg,1.44mmol) and potassium carbonate (400mg,2.8mmol) were dissolved in N, N-dimethylformamide (10mL), and the reaction was carried out at 50 to 55 ℃ for 12 hours. After the reaction, the reaction mixture was poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain REX-S017-4(300mg) in yield: 84 percent.
And 5: preparation of ethyl 3- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazine-2-carboxylate (i.e. compound REX-S0017-6)
Compound REX-S017-5(310mg,0.8mmol), 2, 3-dichlorobenzene boric acid (182mg,0.9mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (50mg,0.05mol) and potassium carbonate (335mg,2.4mmol) were dissolved in dioxane (55mL) and H2O (7.0mL) was added to the flask, and the mixture was purged with nitrogen and reacted at 95 ℃ for 18 hours. After the reaction is finished, the solvent is dried by spinning, ethyl acetate and water are added, extraction, organic phase drying and silica gel column chromatography purification are carried out, and the compound REX-S017-6(260mg) is obtained, and the yield is as follows: 73 percent.
Step 6: preparation of (3- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol (i.e. compound REX-S0017)
The compound REX-S017-6(260mg,0.6mmol) and diisobutylaluminum hydride (1.5M,1.9mL) were dissolved in dichloromethane (10mL) and reacted at 20-25 ℃ for 1 hour. After the reaction, the reaction mixture was poured into 10mL of water, extracted with methylene chloride, dried, concentrated, and subjected to silica gel column chromatography to obtain REX-S017(53g) in a yield of: 21 percent.
MSm/z[ESI]：382.2[M+1]。
1H-NMR(400MHz，DMSO-d6)：δ＝7.70-7.72(m,1H)，7.39-7.78(m,2H)，5.29(m,1H)，4.47(m,2H)，3.31(s,3H)，2.16-2.23(m,4H)，1.57-1.61(m,4H)，1.15(s,3H)。
Example 6 preparation of 3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol [ code REX-S020 ]
Figure BDA0002233445500000301
Figure BDA0002233445500000311
Synthesis scheme 1: preparation of 6-bromo-5-methyl-3- (tosyl) pyrazine-2-carboxylic acid ethyl ester (i.e. compound REX-S017-4)
As described in the synthetic route provided in this example, the intermediate REX-S017-4 is obtained by preparation according to step 1, step 2 and step 3 of example 5, with yield: 60 percent.
Synthesis scheme 2: preparation of 3-methyl-8-azabicyclo [3.2.1] octan-3-amine (i.e. compound REX-S020-5)
Step 1: preparation of 8-benzyl-3-methyl-8-azabicyclo [3.2.1] octan-3-one (i.e. compound REX-S020-2)
Dissolving a compound REX-S020-1(10g,46.5mmol) in tetrahydrofuran (100mL), slowly adding isopropyl magnesium chloride (77mL,232mmol) at-20 ℃, keeping the temperature between-20 ℃ and-25 ℃, reacting for 1 hour, and then heating to 20-25 ℃ for reacting for 16 hours. After completion of the reaction, the reaction mixture was poured into 250mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain REX-S020-2(5.3g) in yield: 50 percent.
Step 2: preparation of N- (8-benzyl-3-methyl-8-azabicyclo [3.2.1] octan-3-yl) carboxamide (i.e. Compound REX-S020-3)
Compound REX-S020-2(5.3g,22.9mmol) was dissolved in trimethylsilonitrile (15mL), concentrated sulfuric acid (2mL) was slowly added at 0 ℃ and the temperature was maintained at 0-5 ℃ for reaction for 6 hours. After completion of the reaction, the reaction mixture was poured into 250mL of water, the pH was adjusted to 10, and the mixture was extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain REX-S020-3(1.8g) in yield: 31 percent.
And step 3: preparation of 8-benzyl-3-methyl-8-azabicyclo [3.2.1] octan-3-amine (i.e. compound REX-S020-4)
Compound REX-S020-3(500mg,1.9mmol) and 30% potassium hydroxide (15mL) were dissolved in methanol (15mL), purged with nitrogen, and reacted at 135 ℃ for 18 hours. After the reaction was completed, the solvent was dried by evaporation, ethyl acetate and water were added, extraction, organic phase drying, and purification by silica gel column chromatography to obtain compound EX-S020-4(400mg), yield: 91 percent.
And 4, step 4: preparation of 3-methyl-8-azabicyclo [3.2.1] octan-3-amine (i.e. compound REX-S020-5)
The compound REX-S020-4(400mg,1.7mmol) and palladium on carbon (150mg) were dissolved in methanol (15mL), replaced with hydrogen, and reacted at 25 ℃ for 18 hours. After the reaction was completed, the solvent was dried by evaporation, ethyl acetate and water were added, extraction, organic phase drying, and purification by silica gel column chromatography to obtain compound EX-S020-5(150mg), yield: and 63 percent.
Synthesis scheme 3: preparation of (3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol (i.e. compound REX-S020)
As described in the synthetic route provided in this example, the compound REX-S017-4 and the compound REX-S020-5 prepared in this example were prepared according to step 4, step 5 and step 6 of example 5, and the target compound REX-S020 was obtained in yield: 12 percent.
MSm/z[ESI]：407.3[M+1]。
1H-NMR(400MHz，DMSO-d6)：δ＝8.09(s,2H),7.72(d,J＝7.9Hz,1H),7.47(t,J＝7.8Hz,1H),7.40(d,J＝7.4Hz,1H),4.61(s,2H),4.53(s,2H),2.16(s,3H),2.11-1.92(m,8H),1.26(s,3H)。
Example 7 preparation of [ No. REX-S030 ] 8- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -3-methyl-8-azabicyclo [3.2.1] octan-3-amine
Scheme one
Figure BDA0002233445500000321
Scheme two
Figure BDA0002233445500000322
Synthesis scheme 1: preparation of 3-methyl-8-azabicyclo [3.2.1] octan-3-amine (i.e. compound REX-S020-5)
As described in the synthetic route presented in this example, with reference to the method of synthetic scheme 2 of example 6, the reaction yielded compound REX-S020-5 in yield: 20 percent.
Synthesis scheme 2: preparation of 8- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -3-methyl-8-azabicyclo [3.2.1] octan-3-amine (i.e. compound REX-S030)
Step 1: preparation of 6-chloro-3- (2, 3-dichlorophenyl) pyrazin-2-amine (i.e. compound REX-S030-2)
The compounds REX-S030-1(10.0g,48.1mmol), 2, 3-dichlorophenylboronic acid (13.1g,48.1mmol) and [1,1' -bis (diphenylphosphino) are reacted) Ferrocene]Palladium dichloride (3.5g,4.8mmol) and potassium carbonate (19.9g,144.3mmol) were dissolved in dioxane (300mL) and H2O (30mL) was added to the flask, purged with nitrogen, and reacted at 95 ℃ for 18 hours. After the reaction is finished, the solvent is dried by spinning, ethyl acetate and water are added, extraction, organic phase drying and silica gel column chromatography purification are carried out, and the compound REX-S030-2(10.0g,36.4mmol) is obtained, wherein the yield is as follows: 75.7 percent.
Step 2: preparation of 8- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -3-methyl-8-azabicyclo [3.2.1] octan-3-amine (i.e. compound REX-S030)
The compounds REX-S030-2(300mg,1.1mmol), REX-S020-5(210mg,1.5mmol) and diisopropylethylamine (426mg,3.3mmol) were dissolved in N-methylpyrrolidone (5mL), and the mixture was placed in a sealed tube, purged with nitrogen, and reacted at 160 ℃ for 6 hours. After the reaction was completed, the solvent was dried by spinning, ethyl acetate and water were added, extraction, organic phase drying, and purification by silica gel column chromatography to obtain compound REX-S030(103mg), yield: 30.1 percent.
MSm/z[ESI]：378.3[M+1]。
1H-NMR(400MHz，DMSO-d6)：δ＝7.62-7.60(m,1H),7.41-7.32(m,3H),5.55(s,2H),4.46(s,2H),2.36-2.34(m,2H),1.82-1.73(m,4H),1.49-1.41(m,4H),0.94(s,3H)。
Example 8 [ No. REX-S035 ] preparation of 6- (4-amino-4-methylpiperidin-1-yl) -3- (3, 4-dihydroquinolin-1 (2H) -yl) pyrazin-2-amine
Figure BDA0002233445500000331
As described in the scheme provided in this example, referring to the method of scheme 2 of example 7, and replacing 2, 3-dichlorophenylboronic acid in scheme 2, step 1 of example 7 with 1,2,3, 4-tetrahydroquinoline of this example, the remaining steps are the same as in scheme 2, step 1 of example 7, to obtain intermediate REX-S035-2; further, ReX-S020-5, a compound obtained in step 2 of Synthesis scheme 2 of example 7, was replaced with 4-amino-1-methylpiperidine, and the remaining steps were the same as in step 2 of Synthesis scheme 2 of example 7 to obtain REX-S035(53mg), a target compound.
MSm/z[ESI]：339.4[M+1]。
Example 9 preparation of (3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2-hydro-benzo [ b ] [1,4] oxazin-4 (3-hydro) -yl) -5-methylpyrazin-2-yl) methanol [ code REX-S038 ]
Scheme one
Figure BDA0002233445500000341
Scheme two
Figure BDA0002233445500000342
Scheme three
Figure BDA0002233445500000343
Synthesis scheme 1: preparation of 6-bromo-5-methyl-3- (tosyl) pyrazine-2-carboxylic acid ethyl ester (i.e. compound REX-S017-4)
As described in the synthetic route provided in this example, the intermediate REX-S017-4 is obtained by preparation according to step 1, step 2 and step 3 of example 5, with yield: 60 percent.
Synthesis scheme 2: preparation of (3S,4S) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine (Compound REX-S038-2)
Compound REX-S038-1(2g,5.34mmol) was dissolved in hydrochloric acid/dioxane (4M,3.0mL) and added to a sealed tube, and reacted at 25 ℃ for 3 hours with nitrogen substitution. After the reaction is finished, the solvent is dried by spinning, ethyl acetate and water are added, extraction and organic phase drying are carried out, and the compound REX-S038-2(1.29g) is obtained, wherein the yield is as follows: 99 percent.
Synthesis scheme 3: preparation of (3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2-hydro-benzo [ b ] [1,4] oxazin-4 (3-hydro) -yl) -5-methylpyrazin-2-yl) methanol (i.e. Compound REX-S038)
As shown in the synthetic route provided in this example, the compounds REX-S017-4 and REX-S038-2 prepared in this example were prepared according to the methods of synthesis scheme 3, step 1, step 2 and step 3 of example 6, and only 2, 3-dichlorophenylboronic acid in synthesis scheme 3, step 2 of example 6 was replaced with 3, 4-dihydro-2 hydro-benzo [ b ] [1,4] oxazine of this example, and the remainder was unchanged, to obtain the compound REX-S038 in yield: 15 percent.
MSm/z[ESI]：426.5[M+1]。
1H-NMR(400MHz，DMSO-d6)：δ＝6.83–6.76(m,1H),6.66(dd,J＝5.7,3.8Hz,2H),6.17–6.06(m,1H),5.21(s,1H),4.45(d,J＝4.8Hz,2H),4.37–4.27(m,2H),4.15–4.05(m,1H),3.74–3.62(m,3H),3.54(d,J＝8.5Hz,1H),3.49–3.38(m,3H),3.07–2.89(m,3H),2.27(s,3H),1.82(m,2H),1.60(m,2H),1.12(d,J＝6.4Hz,3H)。
Example 10 preparation of 3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol [ code REX-S045 ]
Scheme one
Figure BDA0002233445500000351
Scheme two
Figure BDA0002233445500000352
Scheme three
Figure BDA0002233445500000353
Synthesis scheme 1: preparation of 6-bromo-5-methyl-3- (tosyl) pyrazine-2-carboxylic acid ethyl ester (i.e. compound REX-S017-4)
As described in the synthetic route provided in this example, the intermediate REX-S017-4 is obtained by preparation according to step 1, step 2 and step 3 of example 5, with yield: 60 percent.
Synthesis scheme 2: preparation of 3-methyl-8-azabicyclo [3.2.1] octan-3-amine (i.e. compound REX-S020-5)
As illustrated in the synthetic route provided in this example, prepared according to step 1, step 2, step 3 and step 4 of synthetic scheme 2 of example 6, compound REX-S020-5 was obtained in yield: 20 percent.
Synthesis scheme 3: preparation of (3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol (i.e. Compound REX-S045)
As shown in the synthetic route provided in this example, the compounds REX-S017-4 and REX-S020-5 prepared in this example were prepared according to the methods of step 1, step 2 and step 3 of the synthetic scheme 3 of example 6, only 2, 3-dichlorophenylboronic acid in step 2 of the synthetic scheme 3 of example 6 was replaced with 2, 3-dichlorophenol of this example, and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium was replaced with cuprous iodide, and the rest was unchanged, so as to obtain the target compound REX-S045, yield: 25 percent.
MSm/z[ESI]：424.3[M+1]。
1H-NMR(400MHz，DMSO-d6)：δ＝7.59(s,2H),7.47(d,J＝8.1Hz,1H),7.37(t,J＝8.2Hz,1H),7.16(d,J＝8.3Hz,1H),5.18(t,J＝5.4Hz,1H),4.34(d,J＝5.3Hz,3H),2.41(s,3H),2.13–2.03(m,2H),1.92(dd,J＝23.8,9.1Hz,6H),1.25(s,3H)。
Example 11 preparation of [ No. REX-S046 ] methanol (3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- ((2, 3-dichlorophenyl) thio) -5-methylpyrazin-2-yl)
Scheme one
Figure BDA0002233445500000361
Scheme two
Figure BDA0002233445500000362
Scheme three
Figure BDA0002233445500000363
Synthesis scheme 1: preparation of 6-bromo-5-methyl-3- (tosyl) pyrazine-2-carboxylic acid ethyl ester (i.e. compound REX-S017-4)
As described in the synthetic route provided in this example, the intermediate REX-S017-4 is obtained by preparation according to step 1, step 2 and step 3 of example 5, with yield: 60 percent.
Synthesis scheme 2: preparation of 3-methyl-8-azabicyclo [3.2.1] octan-3-amine (i.e. compound REX-S020-5)
As illustrated in the synthetic route provided in this example, prepared according to step 1, step 2, step 3 and step 4 of synthetic scheme 2 of example 6, compound REX-S020-5 was obtained in yield: 20 percent.
Synthesis scheme 3: preparation of (3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- ((2, 3-dichlorophenyl) thio) -5-methylpyrazin-2-yl) methanol (i.e. compound REX-S046)
As shown in the synthetic route provided in this example, the compounds REX-S017-4 and REX-S020-5 prepared in this example were prepared according to the methods of step 1, step 2 and step 3 of the synthetic scheme 3 of example 6, only 2, 3-dichlorophenylboronic acid in step 2 of the synthetic scheme 3 of example 6 was replaced with 2, 3-dichlorothiophenol of this example, and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium was replaced with cuprous iodide, and the rest was unchanged, so as to obtain the target compound REX-S046, with yield: 50 percent.
MSm/z[ESI]：440.3[M+1]。
1H-NMR(400MHz，DMSO-d6)：δ＝7.46(dd,J＝8.0,1.3Hz,1H),7.23(t,J＝8.0Hz,1H),6.72(dd,J＝8.0,1.3Hz,1H),5.36(t,J＝5.6Hz,1H),4.68(s,2H),4.48(d,J＝5.4Hz,2H),2.38(s,3H),2.13–1.79(m,9H),1.23(s,1H),1.13(s,3H)。
Example 12 preparation of [ No. REX-S018 ] 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol
Scheme one
Figure BDA0002233445500000371
Scheme two
Figure BDA0002233445500000372
Scheme three
Figure BDA0002233445500000373
Synthesis scheme 1: preparation of 5-amino-3-chloro-6- (2, 3-dichlorophenyl) pyrazine-2-carbonitrile (i.e., compound REX-S018-4)
Step 1: preparation of 6-chloro-3- (2, 3-dichlorophenyl) pyrazin-2-amine (i.e. compound REX-S018-2)
The starting material, 3-bromo-6-chloropyrazin-2-amine (i.e. compound REX-S018-1,10.0g,48.1mmol), 2, 3-dichlorophenylboronic acid (13.1g,48.1mmol) was dissolved in dioxane (100mL) while potassium carbonate (9.9g,144.3mmol) and Pd (dppf) Cl were added2(3.5g,4.8mmol) is slowly added into the reaction system, and after the addition is finished, nitrogen is replaced, and the reaction is carried out for 18 hours at 95 ℃; after the reaction, the reaction mixture was poured into 500mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S018-2(10.0g,36.4mmol), yield: 75.5 percent.
Step 2: preparation of 5-bromo-6-chloro-3- (2, 3-dichlorophenyl) pyrazin-2-amine (i.e. compound REX-S018-3)
Dissolving the raw material REX-S018-2(5.0g,18.2mmol) and bromosuccinimide (4.9g,27.3mmol) in N, N-dimethylformamide (100mL), replacing with nitrogen, and reacting at 25 ℃ for 1 hour; after the reaction, the reaction mixture was poured into 100mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S018-3(4.0g,11.3mmol), yield: 62.1 percent.
And step 3: preparation of 5-amino-3-chloro-6- (2, 3-dichlorophenyl) pyrazine-2-carbonitrile (i.e., compound REX-S018-4)
Dissolving the raw material REX-S018-3(3.0g,7.6mmol) and cuprous cyanide (3.4g,38.0mmol) in N, N-dimethylformamide (100mL), replacing with nitrogen, and reacting at 100 ℃ for 2 hours; after the reaction, the reaction mixture was poured into 200mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S018-4(1.8g,6.0mmol), yield: 78.9 percent.
Synthesis scheme 2: preparation of (3S,4S) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine (Compound REX-S038-2)
Prepared according to the procedure of scheme 2 of example 9, as provided in the synthetic scheme provided in this example, to give compound REX-S038-2 in yield: 99 percent.
Synthesis scheme 3: preparation of (5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol
Step 1: preparation of 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-carbonitrile (i.e. Compound REX-S018-5)
The starting materials REX-S018-4(300mg,1.0mmol), REX-S038-2(241mg,1.0mmol), diisopropylethylamine (645mg,5.0mmol) and dimethylaminopyridine (122mg,1.0mmol) were dissolved in dioxane (100mL) and reacted at 100 ℃ for 18 hours with nitrogen substitution; after the reaction, the reaction mixture was poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S018-5(280mg,0.65mmol), yield: and (4) 64.7%.
Step 2: preparation of 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-carbaldehyde (i.e. compound REX-S018-6)
The starting material REX-S018-5(500mg,1.15mmol), diisobutylaluminum hydride (1.5M,3.8mL,5.75mmol) was dissolved in tetrahydrofuran (50mL), replaced with nitrogen, and reacted at 25 ℃ for 4 hours; after the reaction, the reaction mixture was poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S018-6(130mg) in yield: 25.9 percent.
And step 3: preparation of (5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol (i.e. compound REX-S018)
Dissolving REX-S018-6(130mg,0.30mmol), sodium borohydride (57mg,1.5mmol) in tetrahydrofuran (10mL), replacing with nitrogen, and reacting at 25 ℃ for 4 hours; after completion of the reaction, the reaction mixture was poured into 10mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain compound REX-S018(2mg) in yield: 15 percent.
MSm/z[ESI]：439.3[M+1]。
1H-NMR(400MHz，MeOD)：δ＝7.60(dd,J＝7.8,1.8Hz,1H),7.43–7.27(m,2H),5.37–5.25(m,1H),4.57(s,2H),4.27–4.15(m,1H),3.85(d,J＝8.7Hz,1H),3.72(d,J＝8.5Hz,1H),3.57(s,2H),3.18–3.08(m,1H),3.03(d,J＝4.9Hz,1H),2.18(dd,J＝14.7,7.0Hz,1H),2.03(d,J＝5.7Hz,1H),1.97–1.82(m,2H),1.73(d,J＝13.2Hz,2H),1.60(s,1H),1.22(d,J＝6.5Hz,3H)。
Example 13 preparation of (3S,4S) -8- (6-amino-3- (methylamino) -5- (2, 3-dichlorophenyl) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine [ code REX-S050 ]
Scheme one
Figure BDA0002233445500000391
Scheme two
Figure BDA0002233445500000392
Scheme three
Figure BDA0002233445500000393
Synthesis scheme 1: preparation of 5-amino-3-chloro-6- (2, 3-dichlorophenyl) pyrazine-2-carbonitrile (i.e., compound REX-S018-4)
Prepared as described in the synthetic route presented in this example with reference to scheme 1 of example 12 to give compound REX-S018-4 in yield: 14 percent.
Synthesis scheme 2: preparation of (3S,4S) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine (Compound REX-S038-2)
Prepared according to the procedure of scheme 2 of example 9, as provided in the synthetic scheme provided in this example, to give compound REX-S038-2 in yield: 99 percent.
Synthesis scheme 3: preparation of (3S,4S) -8- (6-amino-3- (methylamino) -5- (2, 3-dichlorophenyl) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine (i.e. compound REX-S050)
Step 1: preparation of 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-carbonitrile (i.e. Compound REX-S018-5)
The starting materials REX-S018-4(300mg,1.0mmol), REX-S038-2(241mg,1.0mmol), diisopropylethylamine (645mg,5.0mmol) and dimethylaminopyridine (122mg,1.0mmol) were dissolved in dioxane (100mL) and reacted at 100 ℃ for 18 hours with nitrogen substitution; after the reaction, the reaction mixture was poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S018-5(280mg,0.65mmol), yield: and (4) 64.7%.
Step 2: preparation of (3S,4S) -8- (6-amino-3- (methylamino) -5- (2, 3-dichlorophenyl) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine (i.e. compound REX-S050)
The starting material REX-S018-5(500mg,1.15mmol), diisobutylaluminum hydride (1.5M,3.8mL,5.75mmol) was dissolved in tetrahydrofuran (50mL), replaced with nitrogen, and reacted at 25 ℃ for 4 hours; after completion of the reaction, the reaction mixture was poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain compound REX-S050(26mg) in yield: 5.2 percent.
MSm/z[ESI]：438.3[M+1]。
1H-NMR(400MHz，DMSO-d6)：δ＝7.65(dd,J＝7.9,1.7Hz,1H),7.50–7.28(m,2H),5.62(s,2H),4.07(dd,J＝11.7,6.3Hz,1H),3.71–3.54(m,3H),3.50(t,J＝9.3Hz,1H),3.02–2.93(m,1H),2.90(t,J＝7.1Hz,2H),1.93–1.64(m,3H),1.58(d,J＝15.2Hz,2H),1.23(s,1H),1.06(dd,J＝16.7,6.4Hz,3H)。
Example 14 preparation of 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-hydroxycarboxylic acid [ code REX-S053 ]
Scheme one
Figure BDA0002233445500000401
Scheme two
Figure BDA0002233445500000402
Scheme three
Figure BDA0002233445500000411
Synthesis scheme 1: preparation of 5-amino-3-chloro-6- (2, 3-dichlorophenyl) pyrazine-2-carbonitrile (i.e., compound REX-S018-4)
Prepared as described in the synthetic route presented in this example with reference to scheme 1 of example 12 to give compound REX-S018-4 in yield: 14 percent.
Synthesis scheme 2: preparation of (3S,4S) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine (Compound REX-S038-2)
Prepared according to the procedure of scheme 2 of example 9, as provided in the synthetic scheme provided in this example, to give compound REX-S038-2 in yield: 99 percent.
Synthesis scheme 3: preparation of 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-hydroxycarboxylic acid (i.e. Compound REX-S053)
Step 1: preparation of 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-carbonitrile (i.e. Compound REX-S018-5)
The starting materials REX-S018-4(300mg,1.0mmol), REX-S038-2(241mg,1.0mmol), diisopropylethylamine (645mg,5.0mmol) and dimethylaminopyridine (122mg,1.0mmol) were dissolved in dioxane (100mL) and reacted at 100 ℃ for 18 hours with nitrogen substitution; after the reaction, the reaction mixture was poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S018-5(280mg,0.65mmol), yield: and (4) 64.7%.
Step 2: preparation of 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-hydroxycarboxylic acid (i.e. Compound REX-S053)
Dissolving REX-S018-5(100mg,0.23mmol), 5N sodium hydroxide (1mL,5.75mmol) in methanol (5mL), replacing with nitrogen, and reacting at 100 deg.C for 10 hr; after completion of the reaction, the reaction mixture was poured into 50mL of water, the pH was adjusted to 4 to 5, and the mixture was extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain compound REX-S053(20mg) in yield: 17.4 percent.
MSm/z[ESI]：453.3[M+1]。
1H-NMR(400MHz，DMSO-d6)：δ＝8.18(s,2H),7.73–7.62(m,1H),7.48–7.36(m,2H),4.22–4.17(m,1H),3.92–3.61(m,4H),3.40(d,J＝5.0Hz,1H),3.10–2.92(m,2H),1.88(dd,J＝24.1,10.7Hz,2H),1.77–1.51(m,2H),1.21(t,J＝20.5Hz,3H)。
Example 15 preparation of 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-carboxamide [ code REX-S051 ]
Scheme one
Figure BDA0002233445500000421
Scheme two
Figure BDA0002233445500000422
Scheme three
Figure BDA0002233445500000423
Synthesis scheme 1: preparation of 5-amino-3-chloro-6- (2, 3-dichlorophenyl) pyrazine-2-carbonitrile (i.e., compound REX-S018-4) prepared according to the procedure provided in this example under the synthetic route outlined in scheme 1 of example 12 to afford compound REX-S018-4 in yield: 14 percent.
Synthesis scheme 2: preparation of (3S,4S) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine (Compound REX-S038-2)
Prepared according to the procedure of scheme 2 of example 9, as provided in the synthetic scheme provided in this example, to give compound REX-S038-2 in yield: 99 percent.
Synthesis scheme 3: preparation of 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-carboxamide (i.e. Compound REX-S051)
Step 1: preparation of 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-carbonitrile (i.e. Compound REX-S018-5)
The starting materials REX-S018-4(300mg,1.0mmol), REX-S038-2(241mg,1.0mmol), diisopropylethylamine (645mg,5.0mmol) and dimethylaminopyridine (122mg,1.0mmol) were dissolved in dioxane (100mL) and reacted at 100 ℃ for 18 hours with nitrogen substitution; after the reaction, the reaction mixture was poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S018-5(280mg,0.65mmol), yield: and (4) 64.7%.
Step 2: preparation of 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-carboxamide (i.e. Compound REX-S051)
Dissolving REX-S018-5(200mg,0.46mmol) and potassium carbonate (127mg,0.92mmol) in dimethyl sulfoxide (5mL), slowly adding 30% hydrogen peroxide (3.8mL) at 0-5 ℃, and reacting for 60 minutes at 0-5 ℃; after the reaction, the reaction mixture was warmed to room temperature, poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S051(38mg) in yield: 18.3 percent.
MSm/z[ESI]：452.3[M+1]。
1H-NMR(400MHz，DMSO-d6)：δ＝7.66(dd,J＝7.2,2.2Hz,1H),7.42(q,J＝7.5Hz,2H),7.33(s,1H),6.90(s,1H),6.24(s,2H),4.07(dt,J＝12.1,6.1Hz,1H),3.72–3.45(m,4H),3.27–3.07(m,2H),2.91(d,J＝4.9Hz,1H),1.84–1.73(m,1H),1.73–1.62(m,1H),1.53(d,J＝18.6Hz,2H),1.07(dd,J＝16.8,6.3Hz,3H)。
Example 16 preparation of 5-amino-3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-hydroxycarboxylic acid [ code No. REX-S054 ]
Scheme one
Figure BDA0002233445500000431
Scheme two
Figure BDA0002233445500000432
Scheme three
Figure BDA0002233445500000433
Synthesis scheme 1: preparation of 5-amino-3-chloro-6- (2, 3-dichlorophenyl) pyrazine-2-carbonitrile (i.e., compound REX-S018-4) prepared according to the procedure provided in this example under the synthetic route outlined in scheme 1 of example 12 to afford compound REX-S018-4 in yield: 14 percent.
Synthesis scheme 2: preparation of 3-methyl-8-azabicyclo [3.2.1] octan-3-amine (i.e. compound REX-S020-5)
As described in the synthetic route presented in this example, with reference to the method of synthetic scheme 2 of example 6, the reaction yielded compound REX-S020-5 in yield: 20 percent.
Synthesis scheme 3: preparation of 5-amino-3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-hydroxycarboxylic acid (i.e. compound REX-S054)
Step 1: preparation of 5-amino-3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-carbonitrile (i.e. Compound REX-S054-1)
The starting materials REX-S018-4(300mg,1.0mmol), REX-S020-5(140mg,1.0mmol), diisopropylethylamine (645mg,5.0mmol) and dimethylaminopyridine (122mg,1.0mmol) were dissolved in dioxane (100mL), replaced with nitrogen, and reacted at 100 ℃ for 18 hours; after the reaction, the reaction mixture was poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S054-1(260mg,0.64mmol) in yield: 64.0 percent.
Step 2: preparation of 5-amino-3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-hydroxycarboxylic acid (i.e. compound REX-S054)
Dissolving REX-S054-1(100mg,0.25mmol) and 5N sodium hydroxide (1mL,5.75mmol) in methanol (5mL), replacing with nitrogen, and reacting at 100 deg.C for 10 hr; after completion of the reaction, the reaction mixture was poured into 50mL of water, the pH was adjusted to 4 to 5, and the mixture was extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain compound REX-S054(20mg) in yield: 26.5 percent.
MSm/z[ESI]：423.3[M+1]。
1H-NMR(400MHz，DMSO-d6)：δ＝8.00(s,2H),7.68–7.66(m,1H),7.43-7.41(m,2H),4.51(s,2H),2.21-2.13(m,2H),1.94-1.91(m,6H),1.25(s,3H)。
Example 17 preparation of 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- ((2, 3-dichlorophenyl) thio) pyrazine-2-carboxamide, [ code No. REX-S055 ]
Scheme one
Figure BDA0002233445500000441
Scheme two
Figure BDA0002233445500000442
Scheme three
Figure BDA0002233445500000443
Synthesis scheme 1: preparation of 5-bromo-6-chloro-3- ((2, 3-dichlorophenyl) thio) pyrazin-2-amine (i.e. compound REX-S055-3)
Step 1: preparation of 6-chloro-3- ((2, 3-dichlorophenyl) thio) pyrazin-2-amine (i.e. compound REX-S055-2)
Dissolving raw materials of 3-bromo-6-chloropyrazine-2-amine (namely a compound REX-S055-2,2.0g,9.6mmol), 2, 3-dichlorothiophenol (2.6g,14.5mmol) in dioxane (100mL), slowly adding potassium phosphate (6.1g,28.8mmol), 1, 10-o-phenanthroline (180mg,1.0mmol) and cuprous iodide (190mg,1.0mmol l) into a reaction system, replacing with nitrogen after the addition is finished, and reacting at 80 ℃ for 18 hours; after the reaction, the reaction mixture was poured into 100mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S055-2(1.6g,5.2mmol), yield: 54 percent.
Step 2: preparation of 5-bromo-6-chloro-3- ((2, 3-dichlorophenyl) thio) pyrazin-2-amine (i.e. compound REX-S055-3)
Dissolving the raw material REX-S055-2(1.5g,4.9mmol) and bromosuccinimide (1.3g,7.3mmol) in N, N-dimethylformamide (50mL), replacing with nitrogen, and reacting at 25 ℃ for 1 hour; after the reaction, the reaction mixture was poured into 100mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S055-3(1.6g,4.2mmol), yield: 85 percent.
Synthesis scheme 2: preparation of (3S,4S) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine (Compound REX-S038-2)
Prepared according to the procedure of scheme 2 of example 9, as provided in the synthetic scheme provided in this example, to give compound REX-S038-2 in yield: 99 percent.
Synthesis scheme 3: preparation of 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- ((2, 3-dichlorophenyl) thio) pyrazine-2-carboxamide (i.e. compound REX-S055)
Step 1: preparation of (3S,4S) -8- (6-amino-3-bromo-5- ((2, 3-dichlorophenyl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine (i.e. compound REX-S055-4)
Dissolving the raw materials REX-S055-3(500mg,1.3mmol), REX-S038-2(312mg,1.3mmol), diisopropylethylamine (503mg,3.9mmol) and dimethylaminopyridine (73mg,0.6mmol l) in dioxane (100mL), replacing with nitrogen, and reacting at 100 ℃ for 18 hours; after the reaction, the reaction mixture was poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S055-4(650mg,1.25mmol), yield: 96.9 percent.
Step 2: preparation of 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- ((2, 3-dichlorophenyl) thio) pyrazine-2-carbonitrile (i.e. compound REX-S055-5)
Dissolving REX-S055-4(650mg,1.25mmol) and cuprous cyanide (225mg,2.5mmol) in N, N-dimethylformamide (50mL), replacing with nitrogen, and reacting at 100 deg.C for 2 hr; after the reaction, the reaction mixture was poured into 200mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S055-5(130mg,0.28mmol), yield: 22.4 percent.
And step 3: preparation of 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- ((2, 3-dichlorophenyl) thio) pyrazine-2-carboxamide (i.e. compound REX-S055)
Dissolving REX-S055-5(130mg,0.28mmol) and potassium carbonate (77mg,0.56mmol) in dimethyl sulfoxide (3mL), slowly adding 30% hydrogen peroxide (3mL) at 0-5 ℃, and reacting for 60 minutes at 0-5 ℃; after the reaction was completed, the reaction mixture was warmed to room temperature, poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain compound REX-S055(21mg,0.04mmol), yield: 15.2 percent.
MSm/z[ESI]：484.4[M+1]。
1H-NMR(400MHz，DMSO-d6)：δ＝7.36(dd,J＝8.0,1.4Hz,1H),7.14(t,J＝8.0Hz,1H),6.80(dd,J＝8.0,1.4Hz,1H),4.33–4.18(m,1H),3.89(dt,J＝29.5,9.1Hz,4H),3.42(d,J＝4.1Hz,1H),3.14–2.88(m,2H),2.02–1.79(m,3H),1.64(d,J＝12.5Hz,1H),1.30(s,3H)。
Example 18 preparation of 3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5- (methylamino) pyrazine-2-carboxamide, [ code REX-S056 ]
Scheme one
Figure BDA0002233445500000461
Figure BDA0002233445500000462
Synthesis scheme 1: preparation of 3-chloro-6- (2, 3-dichlorophenyl) -5- (methylamino) pyrazine-2-carbonitrile (i.e. compound REX-S056-5)
Step 1: preparation of 6-chloro-3- (2, 3-dichlorophenyl) pyrazin-2-amine (i.e. compound REX-S056-2)
The starting material, 3-bromo-6-chloropyrazin-2-amine (i.e., compound REX-S056-1,10.0g,48.1mmol), 2, 3-dichlorophenylboronic acid (13.1g,48.1mmol) was dissolved in dioxane (100mL) while potassium carbonate (9.9g,144.3mmol) and Pd (dppf) Cl were added2(3.5g,4.8mmol) is slowly added into the reaction system, and after the addition is finished, nitrogen is replaced, and the reaction is carried out for 18 hours at 95 ℃; after the reaction, the reaction mixture was poured into 500mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S056-2(10.0g,36.4mmol) in yield: 75.5 percent.
Step 2: preparation of 5-bromo-6-chloro-3- (2, 3-dichlorophenyl) pyrazin-2-amine (i.e. compound REX-S056-3)
Dissolving the raw material REX-S056-2(5.0g,18.2mmol) and bromosuccinimide (4.9g,27.3mmol) in N, N-dimethylformamide (100mL), replacing with nitrogen, and reacting at 25 ℃ for 1 hour; after the reaction, the reaction mixture was poured into 100mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S056-3(4.0g,11.3mmol) in yield: 62.1 percent.
And step 3: preparation of 5-amino-3-chloro-6- (2, 3-dichlorophenyl) pyrazine-2-carbonitrile (i.e., compound REX-S056-4)
Dissolving the raw material REX-S056-3(3.0g,7.6mmol) and cuprous cyanide (3.4g,38.0mmol) in N, N-dimethylformamide (100mL), replacing with nitrogen, and reacting at 100 deg.C for 2 hr; after the reaction, the reaction mixture was poured into 200mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S056-4(1.8g,6.0mmol) in yield: 78.9 percent.
And 4, step 4: preparation of 3-chloro-6- (2, 3-dichlorophenyl) -5- (methylamino) pyrazine-2-carbonitrile (i.e. compound REX-S056-5)
Dissolving a raw material REX-S056-4(300mg,1.0mmol) in tetrahydrofuran (200mL), slowly adding sodium hydride (48mg,1.2mmol, 60% in oil) at 0-5 ℃, and reacting for 30 minutes at 0-5 ℃; then, slowly adding iodomethane (426mg,3.0mmol), and keeping the temperature at 0-5 ℃ for reaction for 2 hours; after the reaction is finished, the temperature is returned to the room temperature, the reaction product is poured into 200mL of water after being cooled, the mixture is extracted by ethyl acetate, dried, concentrated and separated by silica gel column chromatography to obtain REX-S056-5(120mg,0.385mmol), and the yield: 38.5 percent.
Synthesis scheme 2: preparation of (3S,4S) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine (Compound REX-S038-2)
Prepared according to the procedure of scheme 2 of example 9, as provided in the synthetic scheme provided in this example, to give compound REX-S038-2 in yield: 99 percent.
Synthesis scheme 3: preparation of 3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5- (methylamino) pyrazine-2-carboxamide (i.e. Compound REX-S056)
Step 1: preparation of 3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5- (methylamino) pyrazine-2-carbonitrile (i.e. Compound REX-S056-6)
Dissolving the raw materials REX-S056-5(120mg,0.385mmol), REX-S038-2(65.5mg,0.385mmol), diisopropylethylamine (149mg,1.12mmol) and dimethylaminopyridine (24.4mg,0.2mmol) in dioxane (10mL), replacing with nitrogen, and reacting at 100 ℃ for 18 hours; after the reaction, the reaction mixture was poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S056-6(110mg,0.247mmol) in yield: 64.2 percent.
Step 2: preparation of 3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5- (methylamino) pyrazine-2-carboxamide (i.e. Compound REX-S056)
Dissolving a raw material REX-S056-6(110mg,0.247mmol) and potassium carbonate (68.2mg,0.494mmol) in dimethyl sulfoxide (5mL), slowly adding 30% hydrogen peroxide (4mL) at 0-5 ℃, and reacting for 60 minutes at 0-5 ℃; after the reaction, the reaction mixture was warmed to room temperature, poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S056(12mg) in yield: 10.5 percent.
MSm/z[ESI]：466.3[M+1]。
1H-NMR(400MHz，DMSO-d6)：δ＝7.96(s,3H),7.71-7.69(m,1H),7.47-7.34(m,2H),7.33(br,1H),6.88(br,1H),6.50(br,1H),4.25-4.19(m,1H),3.91-3.85(m,3H),3.71-3.69(m,1H),3.45-3.42(m,1H),3.08-2.99(m,2H),2.80(s,3H),1.91-1.81(m,2H),1.74-1.70(m,1H),1.59-1.56(m,1H),1.23-1.21(dd,J＝1.22,8.0Hz,3H)。
Example 19 preparation of 3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5- (dimethylamino) pyrazine-2-carboxamide, [ code No. REX-S057 ]
Scheme one
Figure BDA0002233445500000481
Figure BDA0002233445500000482
Synthesis scheme 1: preparation of 3-chloro-6- (2, 3-dichlorophenyl) -5- (dimethylamino) pyrazine-2-carbonitrile (i.e., compound REX-S057-5)
Step 1: preparation of 6-chloro-3- (2, 3-dichlorophenyl) pyrazin-2-amine (i.e. compound REX-S057-2)
The starting material, 3-bromo-6-chloropyrazin-2-amine (i.e., compound REX-S057-1,10.0g,48.1mmol), 2, 3-dichlorophenylboronic acid (13.1g,48.1mmol) was dissolved in dioxane (100mL) while potassium carbonate (9.9g,144.3mmol) and Pd (dppf) Cl were added2(3.5g,4.8mmol) is slowly added into the reaction system, and after the addition is finished, nitrogen is replaced, and the reaction is carried out for 18 hours at 95 ℃; after the reaction, the reaction mixture was poured into 500mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S057-2(10.0g,36.4mmol) in yield: 75.5 percent.
Step 2: preparation of 5-bromo-6-chloro-3- (2, 3-dichlorophenyl) pyrazin-2-amine (i.e. compound REX-S057-3)
Dissolving the raw material REX-S057-2(5.0g,18.2mmol) and bromosuccinimide (4.9g,27.3mmol) in N, N-dimethylformamide (100mL), replacing with nitrogen, and reacting at 25 ℃ for 1 hour; after the reaction, the reaction mixture was poured into 100mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S057-3(4.0g,11.3mmol) in yield: 62.1 percent.
And step 3: preparation of 5-amino-3-chloro-6- (2, 3-dichlorophenyl) pyrazine-2-carbonitrile (i.e., compound REX-S057-4)
Dissolving the raw material REX-S057-3(3.0g,7.6mmol) and cuprous cyanide (3.4g,38.0mmol) in N, N-dimethylformamide (100mL), replacing with nitrogen, and reacting at 100 deg.C for 2 hr; after the reaction, the reaction mixture was poured into 200mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S057-4(1.8g,6.0mmol) in yield: 78.9 percent.
And 4, step 4: preparation of 3-chloro-6- (2, 3-dichlorophenyl) -5- (dimethylamino) pyrazine-2-carbonitrile (i.e., compound REX-S057-5)
Dissolving a raw material REX-S057-4(300mg,1.0mmol) in tetrahydrofuran (200mL), slowly adding sodium hydride (48mg,1.2mmol, 60% in oil) at 0-5 ℃, and reacting for 30 minutes at 0-5 ℃; then, slowly adding iodomethane (426mg,3.0mmol), and keeping the temperature at 0-5 ℃ for reaction for 2 hours; after the reaction, the reaction mixture was warmed to room temperature, cooled and poured into 200mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain REX-S057-5(150mg,0.46mmol) in yield: 46 percent.
Synthesis scheme 2: preparation of (3S,4S) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine (Compound REX-S038-2)
Prepared according to the procedure of scheme 2 of example 9, as provided in the synthetic scheme provided in this example, to give compound REX-S038-2 in yield: 99 percent.
Synthesis scheme 3: preparation of 3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5- (dimethylamino) pyrazine-2-carboxamide (i.e. Compound REX-S057)
Step 1: preparation of 3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5- (dimethylamino) pyrazine-2-carbonitrile (i.e. Compound REX-S057-6)
Dissolving the raw materials REX-S057-5(150mg,0.46mmol), REX-S038-2(79mg,0.46mmol), diisopropylethylamine (178mg,1.38mmol) and dimethylaminopyridine (24.4mg,0.2mmol) in dioxane (10mL), replacing with nitrogen, and reacting at 100 ℃ for 18 hours; after the reaction, the reaction mixture was poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S056-6(180mg,0.39mmol) in yield: 84.5 percent.
Step 2: preparation of 3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5- (dimethylamino) pyrazine-2-carboxamide (i.e. Compound REX-S057)
Dissolving REX-S056-6(180mg,0.39mmo) and potassium carbonate (108mg,0.78mmol) in dimethyl sulfoxide (5mL), slowly adding 30% hydrogen peroxide (8mL) at 0-5 ℃, and reacting for 60 minutes at 0-5 ℃; after the reaction, the reaction mixture was warmed to room temperature, poured into 50mL of water, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to obtain a compound REX-S057(70mg) in yield: 37.5 percent.
MSm/z[ESI]：480.4[M+1]。
1H-NMR(400MHz，DMSO-d6)：δ＝7.63(dt,J＝8.2,4.1Hz,1H),7.59(dd,J＝7.8,1.6Hz,1H),7.43(t,J＝7.9Hz,2H),7.02(s,1H),4.14–3.95(m,1H),3.77–3.53(m,3H),3.55–3.42(m,1H),3.27–3.16(m,1H),2.91(t,J＝11.3Hz,1H),2.77(s,6H),1.78(dt,J＝18.7,12.6Hz,1H),1.72–1.61(m,1H),1.53(dd,J＝22.5,9.1Hz,3H),1.06(dd,J＝14.7,6.3Hz,3H)。
Example 20 phosphatase Activity assay
This experiment was conducted to test the degree of inhibition of SHP2 enzyme activity by the compound using IC50Expressed by this index, IC50I.e. the concentration of the compound at which the activity of the SHP2 enzyme is inhibited by 50%.
SHP2 enzyme solution (diluted to 0.5nM in the reaction solution) was incubated with 2-P-IRS-1 peptide (dPEG8) in a reaction solution (50mM 4-hydroxyethylpiperazineethanesulfonic acid (HEPES), pH7.4, 75mM sodium chloride (NaCl), 75mM potassium chloride (KCl), 1mM EDTA, 0.05% Tween 20, 2% DMSO, and 5mM Dithiothreitol (DTT)) using DiFMUP as a reaction substrate. After incubation at room temperature (25 ℃) for 30-60 minutes, 25. mu.L of DiFMUP (final concentration of 10. mu.M) was added to the reaction, the reaction was started, the plate was left at room temperature (25 ℃) for 30 minutes, and then the intensity of the fluorescence signal (excitation light 358nm, emission light 455nm) was measured with a plate reader.
IC for inhibiting SHP2 enzyme activity measured by compound of the invention50The results are shown in Table 1.
TABLE 1 determination of enzymatic Activity of the Compounds of the examples
SHP2IC50(uM)
SHP099 0.044
REX-S017 0.041
REX-S018 0.013
REX-S051 0.014
REX-S053 0.021
REX-S055 0.029
Example 21 cell proliferation assay
This experiment measures the inhibition of 3D proliferation by the compounds of the invention by cell growth in a globular shape in methylcellulose 3D (methylcellulose 3D) medium, mimicking the in vivo growth state of cells.
Test compounds: positive control SHP099, a compound prepared in the examples of the present invention.
Cell lines: NCI-H358, adherent, in RPMI1640+ 10% FBS.
The experimental method comprises the following steps:
1. cell culture and inoculation:
collecting cells in logarithmic growth phase, counting the cells by a platelet counter, and detecting the cell viability by a trypan blue exclusion method to ensure that the cell viability is over 90 percent. Adjusting cell concentration to make the final concentration of Methylellulose 0.65%, mixing and standing; when no visible gas is present in the cell suspension, 180. mu.L of the cell suspension was added to a 96-well plate. The cells in a 96-well plate were placed at 37 ℃,5％CO2And cultured overnight under 95% humidity conditions.
2. Drug dilution and dosing:
preparing 10 times of medicinal solution, wherein the highest concentration is 100 mu M, 9 concentrations are obtained, and the medicinal solution is diluted by 3.16 times; adding 20 mu L of medicine solution into each hole of a 96-hole plate inoculated with cells, setting three multiple holes for each medicine concentration, wherein the highest concentration of a tested compound is 10 mu M, 9 concentrations are obtained, and the final concentration range is 1 nM-10 mu M; the DMSO content was 0.1%. The cells in the dosed 96-well plate were placed at 37 ℃ in 5% CO2And further cultured under 95% humidity conditions for 120 hours, after which CTG analysis was performed.
3. Reading the plate at the end:
the CTG reagent was thawed and the cell plates were equilibrated to room temperature for 30 minutes, 100. mu.L of CTG solution was added to each well, the cells were lysed by shaking on an orbital shaker for 5 minutes, the cell plates were placed at room temperature for 20 minutes to stabilize the luminescence signal, and the luminescence values were read.
4. Data processing:
data were analyzed using GraphPad Prism 7.0 software, fitted to the data using non-linear sigmoidal regression to derive a dose-effect curve, and IC was calculated therefrom50The value is obtained.
Cell survival rate (%) ═ (Lum)Drug to be tested-LumCulture fluid control)/(LumCell controls-LumCulture fluid control)×100％。
The calculation results are shown in Table 2.
TABLE 2 inhibitory Effect of the compounds of the examples on cell line NCI-H358
SHP2 IC50(uM)
SHP099 1.729
REX-S051 0.329
REX-S053 0.461
REX-S055 0.049

Claims (37)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000011
wherein X is selected from absent, S or O;
the ring A is selected from 5-12 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
ring B is selected from 6-12 membered substituted or unsubstituted heterocyclic ring, and the heterocyclic ring is attached to the parent nucleus through the N atom, wherein the heterocyclic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R2Selected from absent or C1-6An alkyl group;
R1、R2each of which is substituted by the parent nucleus, or, R1、R2Are connected with each other to form a 5-6 membered saturated or unsaturated carbocyclic or heterocyclic ring, and form a ring with the mother nucleus;
r3 is selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R4Selected from absent or C1-6An alkyl group;
R3、R4each of which is substituted by the parent nucleus, or, R3、R4Are connected with each other to form a 5-6 membered saturated or unsaturated carbocyclic or heterocyclic ring, and form a ring with the mother nucleus;
R5、R6each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
2. The compound of claim 1, wherein: when R is2Is C1-6Alkyl radical, R4In the absence of R1、R2Are interconnected to form a 5-to 6-membered carbocyclic or heterocyclic ring, and form a fused ring with the parent nucleus in the structural form:
Figure FDA0002233445490000021
3. the compound of claim 1, wherein: when R is1is-NR5R6，R2is-CH2，R4To be absent, R5、R6Each independently selected from H or C1-6When alkyl, R1、R2Are connected with each other to form a 5-6 heterocyclic ring, and form a combined ring with the mother nucleus in the following structural form:
Figure FDA0002233445490000022
4. a compound according to claim 3, characterized in that: is a compound represented by the formula (II):
Figure FDA0002233445490000023
wherein X is selected from absent, S or O;
the ring A is selected from 5-12 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
ring B is selected from 6-12 membered substituted or unsubstituted heterocyclic ring, andthe heterocycle is linked to the parent nucleus by an N atom, wherein the heterocycle is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R3selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
5. A compound according to any one of claims 2 to 4, characterized in that: is a compound of formula (IIa) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000031
wherein X is selected from absent or S;
the ring A is selected from 6-membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R3selected from H, halogen, C1-6Alkyl, halo C1-6Alkyl, -OH, - (CH)2)nOR5；
R5Selected from H, C1-6An alkyl group;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
n is selected from 1;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
6. The compound of claim 1, wherein: when R is4Is C1-6Alkyl radical, R2In the absence of R3、R4Are interconnected to form a 5-to 6-membered carbocyclic or heterocyclic ring, and form a fused ring with the parent nucleus in the structural form:
Figure FDA0002233445490000032
7. the compound of claim 1, wherein: when R is3is-NR5R6，R4is-CH2，R2To be absent, R5、R6Each independently selected from H or C1-6When alkyl, R3、R4Are connected with each other to form a 5-6 heterocyclic ring, and form a combined ring with the mother nucleus in the following structural form:
Figure FDA0002233445490000041
8. the compound of claim 7, wherein: is a compound represented by the formula (III) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000042
wherein X is selected from absent, S or O;
the ring A is selected from 5-12 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
ring B is selected from 6-12 membered substituted or unsubstituted heterocyclic ring, and the heterocyclic ring is attached to the parent nucleus through the N atom, wherein the heterocyclic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
9. A compound according to any one of claims 6 to 8, characterized in that: is a compound of formula (IIIa) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000051
wherein X is selected from absent or S;
the ring A is selected from 6-membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl, halo C1-6Alkyl, -OH, -NH2；
R5Selected from H, C1-6An alkyl group;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
10. The compound of claim 1, wherein: when R is2To be absent, R4Is absentWhen R is1And R3Each independently substituted with a parent nucleus, a compound of formula (IV) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000052
wherein X is selected from absent, S or O;
the ring A is selected from 5-12 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
ring B is selected from 6-12 membered substituted or unsubstituted heterocyclic ring, and the heterocyclic ring is attached to the parent nucleus through the N atom, wherein the heterocyclic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
the 6-12 membered substituted or unsubstituted heterocyclic ring is monocyclic, bridged, spiro or fused;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R3 is selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
11. The compound of claim 10, wherein: is a compound represented by the formula (IVa) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000061
wherein X is selected from absent, S or O;
the ring A is selected from 5-10 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R3Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, haloGeneration C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)n NH2、-OH、-(CH2)n OH；
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
12. The compound of claim 10 or 11, wherein: is a compound represented by the formula (IVa-1) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000071
wherein X is selected from absent, S or O;
R1selected from H, C1-6Alkyl or-NH2；
R3Selected from H, C1-6Alkyl, -COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, -OH, -NH2A 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)n NH2；
n is selected from 1;
the heterocyclic ring contains 1-2 heteroatoms, and the heteroatoms are N, O.
13. The compound of claim 12, wherein: is a compound represented by the formula (IVa-2) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000072
wherein R is1Selected from H, C1-6Alkyl or-NH2；
R3Is selected from- (CH)2)nOR5or-CR5R6；
R5Selected from H, a 3-4 membered carbocyclic ring or a 3-4 membered heterocyclic ring containing 1O atom;
R6is selected from-OH or-NH2；
R8、R9Any one of them is-NH2The other is C1-6An alkyl group;
n is selected from 1.
14. The compound of claim 10 or 11, wherein: is a compound represented by the formula (IVa-3) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000081
wherein Y is C or O;
R1is selected from C1-6Alkyl or-NH2；
R3Is selected from H;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)n NH2；
n is selected from 1.
15. The compound of claim 10, wherein: is a compound represented by the formula (IVb) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000082
wherein X is selected from absent, S or O;
ring a is selected from a 5-12 membered substituted or unsubstituted aromatic ring, wherein the aromatic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R3Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)n NH2、-OH、-(CH2)n OH；
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
16. The compound of claim 10 or 15, wherein: is a compound represented by the formula (IVb-1) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000091
wherein X is selected from absent, S or O;
R1is selected from C1-6Alkyl or-NH2；
R3Selected from H, -COOR5Or- (CH)2)nOR5；
R5Is selected from H;
R8、R9any one of them is-NH2The other is C1-6An alkyl group;
n is selected from 1.
17. The compound of claim 10, wherein: is a compound represented by the formula (IVc):
Figure FDA0002233445490000092
wherein X is selected from absent, S or O;
ring A is selected from 5-12 membered substituted or unsubstituted aromatic rings, wherein the aromatic ring is substituted withGroup substitution: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R3Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)n NH2、-OH、-(CH2)n OH；
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
18. The compound of claim 10 or 17, wherein: is a compound represented by the formula (IVc-1) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000101
wherein R is1Is selected from C1-6Alkyl or-NH2；
R3Is selected from H or- (CH)2)nOR5；
R5Is selected from H;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)n NH2；
n is selected from 1.
19. The compound of claim 10, wherein: is a compound represented by the formula (IVd) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000111
wherein X is selected from absent, S or O;
ring a is selected from a 5-12 membered substituted or unsubstituted aromatic ring, wherein the aromatic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R3Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8is selected from C1-6Alkyl, -NH2、-(CH2)n NH2、-OH、-(CH2)n OH；
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
20. The compound of claim 10 or 19, wherein: is a compound represented by the formula (IVd-1) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000112
wherein R is1Is selected from C1-6Alkyl or-NH2；
R3Is selected from H or- (CH)2)nOR5；
R5Is selected from H;
R8is selected from-NH2；
n is selected from 1.
21. The compound of claim 10, wherein: is a compound of formula (IVe) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000121
wherein X is selected from absent, S or O;
ring a is selected from a 5-12 membered substituted or unsubstituted aromatic ring, wherein the aromatic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R3Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8is selected from C1-6Alkyl, -NH2、-(CH2)n NH2、-OH、-(CH2)n OH；
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
22. The compound of claim 10 or 21, wherein: is a compound represented by the formula (IVe-1) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000131
wherein R is1Is selected from C1-6Alkyl or-NH2；
R3Is selected from H or- (CH)2)nOR5；
R5Is selected from H;
R8is selected from-NH2Or- (CH)2)n OH；
n is selected from 1.
23. The compound of claim 10, wherein: is a compound represented by the formula (IVf):
Figure FDA0002233445490000132
wherein X is selected from absent, S or O;
ring a is selected from a 5-10 membered substituted or unsubstituted aromatic ring, wherein the aromatic ring is substituted with: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、-CR5R6or-NR5R6；
R3Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, -OH, -NH2、＝O、-COR5、-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5、R6Each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8is selected from C1-6Alkyl, -NH2、-(CH2)n NH2、-OH、-(CH2)n OH；
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
24. The compound of claim 10 or 23, wherein: is a compound represented by the formula (IVf-1) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000141
wherein Y is C or O;
R1is selected from C1-6Alkyl or-NH2；
R3Is selected from- (CH)2)nOR5；
R5Is selected from H;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)n NH2；
n is selected from 1.
25. The compound of claim 10 or 23, wherein: is a compound represented by the formula (IVf-2) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000142
wherein X is selected from absent, S or O;
R1is selected from C1-6Alkyl, -NH2or-NR5R6；
R3Is selected from-COOR5、-CONR5R6、-(CH2)nOR5、-CR5R6or-NR5R6；
R5Selected from H, a 3-4 membered carbocyclic ring or a 3-4 membered heterocyclic ring containing 1O atom;
R6selected from H, C1-6Alkyl, -OH or-NH2；
n is selected from 1.
26. The compound of claim 10 or 23, wherein: is a compound represented by the formula (IVf-3) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000151
wherein X is selected from absent or S;
ring a is selected from 6-membered substituted or unsubstituted aromatic rings, wherein the aromatic ring is substituted with: halogen, C1-6An alkyl group;
R1is selected from C1-6Alkyl, -NH2；
R8、R9Each independently selected from C1-6Alkyl or-NH2；
R10Is selected from-OH or-NH2。
27. A compound of formula (V) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000152
wherein X is selected from absent, S or O;
y, P, Q are each independently selected from C or N, and either Y or P is N and the other is C;
the ring A is selected from 5-12 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R5、R6each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)n NH2、-OH、-(CH2)n OH；
R11、R12、R13、R14Each independently selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, ═ O, -OH, -NH2One or more of the above;
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
28. A compound of formula (VI) or a pharmaceutically acceptable salt thereof:
Figure FDA0002233445490000161
wherein X is selected from absent, S or O;
y ', P ', Q ' are each independently selected from C, O, N or S, and S and O are not present at the same time;
the ring A is selected from 5-12 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R5、R6each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)n NH2、-OH、-(CH2)n OH；
R15、R16、R17Each independently selected from absent, H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, ═ O, -OH, -NH2、-(CH2)nOne of OHOr a plurality of the components;
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
29. A compound represented by the formula (VII):
Figure FDA0002233445490000171
wherein X is selected from absent, S or O;
the ring A is selected from 5-12 membered substituted or unsubstituted aromatic ring and heteroaromatic ring, wherein the aromatic ring and the heteroaromatic ring are substituted by the following groups: halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, halo C1-6Alkoxy, -NR5R6、-OR7、-COOR7、-SR7、-SOR7、-CONH2、-NH2、-NO2-CN or ═ O;
R1selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, ═ O, -OH, -NH2One or more of the above;
R5、R6each independently selected from H, C1-6Alkyl, ═ O, -OH, -NH2、-NO2-CN, 3-6 membered carbocycle or 3-6 membered heterocycle;
R7selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6An alkoxy group;
R8、R9each independently selected from C1-6Alkyl, -NH2、-(CH2)n NH2、-OH、-(CH2)n OH；
n is selected from 1,2,3,4, 5 or 6;
the heteroaromatic ring and the heterocyclic ring contain 1-2 heteroatoms, and the heteroatoms are N, O.
30. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, wherein the compound is selected from the group consisting of:
REX-S001:8- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-6-amine;
REX-S002 (5- (4-amino-4-methylpiperidin-1-yl) -8- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-6-yl) methanol;
REX-S003:1- (8- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-5-yl) -4-methylpiperidin-4-amine;
REX-S004:1- (5- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-8-yl) -4-methylpiperidin-4-amine;
REX-S005 2- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-5-amine;
REX-S006 5-amino-1- (4-amino-4-methylpiperidinyl) -4- (2, 3-dichlorophenyl) pyridin-2 (1H) -one;
REX-S007 6-amino-4- (4-amino-4-methylpiperidin-1-yl) -1- (2, 3-dichlorophenyl) pyridin-2 (1h) -one;
REX-S008: 3-amino-1- (4-amino-4-methylpiperidinyl) -4- (2, 3-dichlorophenyl) pyridin-2 (1h) -one;
REX-S009:4- (4-amino-4-methylpiperidin-1-yl) -1- (2, 3-dichlorophenyl) pyridin-2 (1H) -one;
REX-S010:1- (4-amino-4-methylpiperidinyl) -4- (2, 3-dichlorophenyl) pyridin-2 (1H) -one;
REX-S011 2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) thiazol-4-amine;
REX-S012 (5- (4-amino-4-methylpiperidin-1-yl) -2- (2, 3-dichlorophenyl) thiazol-4-yl) methanol;
REX-S013:1- (4-amino-5- (2, 3-dichlorophenyl) -1-methyl-1 h-imidazol-2-yl) -4-methylpiperidin-4-amine;
REX-S014 2- (4-amino-4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) oxazol-4-amine;
REX-S015 (5- (4-amino-4-methylpiperidin-1-yl) -2- (2, 3-dichlorophenyl) -1-methyl-1 h-imidazol-4-yl) methanol;
REX-S016 (3- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S017 (3- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol;
REX-S018 (5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S019 (5-amino-3- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S020 (3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol;
REX-S021 (3- (7-amino-7-methyl-4-azaspiro [2.5] octan-4-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol;
REX-S022 (3- (8-amino-5-azaspiro [2.5] octan-5-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol;
REX-S023 (3- (6- (aminomethyl) -3-azaspiro [4.1.0] heptan-3-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol;
REX-S024 (3- (6-amino-3-azaspiro [4.1.0] heptan-3-yl) -6- (2, 3-dichlorophenyl) -5-5-methylpyrazin-2-yl) methanol;
REX-S025 (5-amino-3- (3-amino-3-methyl-8-azaspiro [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S026 (5-amino-3- (7-amino-7-methyl-4-azaspiro [2.5] octan-4-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S027 (5-amino-3- (8-amino-5-azaspiro [2.5] octan-5-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S028 (5-amino-3- (6- (aminomethyl) -3-azabicyclo [4.1.0] heptan-3-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S029 (5-amino-3- (6-amino-3-azabicyclo [4.1.0] heptan-3-yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) methanol;
REX-S030 8- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -3-methyl-8-azabicyclo [3.2.1] octan-3-amine;
REX-S031 4- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -7-methyl-4-azaspiro [2.5] octan-7-amine;
REX-S032 5- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -5-azaspiro [2.5] octan-8-amine;
REX-S033 6- (6- (aminomethyl) -3-azaspiro [4.1.0] heptan-3-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine;
REX-S034:3- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -3-azaspiro [4.1.0] heptan-6-amine;
REX-S035:6- (4-amino-4-methylpiperidin-1-yl) -3- (3, 4-dihydroquinolin-1 (2 hydro) -yl) pyrazin-2-amine;
REX-S036- (4-amino-4-methylpiperidin-1-yl) -3- (2 hydro-benzo [ b ] [1,4] oxazin-4 (3 hydro) -yl) pyrazin-2-amine;
REX-S037 (3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (3, 4-dihydroquinolin-1 (2H) -yl) -5-methylpyrazin-2-yl) methanol;
REX-S038 (3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2-hydro-benzo [ b ] [1,4] oxazin-4 (3-hydro) -yl) -5-methylpyrazin-2-yl) methanol;
REX-S039:1- (3- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) cyclopropanol;
REX-S040:1- (3- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) cyclobutanol;
REX-S041 3- (3- (4-amino-4-methylpiperidin-1-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) oxetan;
REX-S042:1- (3- (3-aminocyclobutan-3-yl) -5- (2, 3-dichlorophenyl) -6-methylpyrazin-2-yl) -4-methylpiperidin-4-amine;
REX-S043 3- (3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) oxetan-ol;
REX-S044:1- (3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) cyclopropanol;
REX-S045 (3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) -5-methylpyrazin-2-yl) methanol;
REX-S046 (3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- ((2, 3-dichlorophenyl) thio) -5-methylpyrazin-2-yl) methanol;
REX-S047 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-hydroxycarboxylic acid;
REX-S048 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- ((2, 3-dichlorophenyl) thio) pyrazine-2-hydroxycarboxylic acid;
REX-S049 3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5- (methylamino) pyrazine-2-hydroxycarboxylic acid;
REX-S050 (3S,4S) -8- (6-amino-3- (methylamino) -5- (2, 3-dichlorophenyl) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine;
REX-S051 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-carboxamide;
REX-S052 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -N-methylpyrazine-2-carboxamide;
REX-S053 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-hydroxycarboxylic acid;
REX-S054 5-amino-3- (3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl) -6- (2, 3-dichlorophenyl) pyrazine-2-hydroxycarboxylic acid;
REX-S055 5-amino-3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- ((2, 3-dichlorophenyl) thio) pyrazine-2-carboxamide;
REX-S056 3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5- (methylamino) pyrazine-2-carboxamide;
REX-S057 3- ((3S,4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] decan-8-yl) -6- (2, 3-dichlorophenyl) -5- (dimethylamino) pyrazine-2-carboxamide.
31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, as an active ingredient, together with one or more pharmaceutically acceptable carriers.
32. Use of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament.
33. The use as an SHP2 inhibitor according to claim 32.
34. The use of claim 32, wherein the medicament is for the treatment or prevention of a disease associated with abnormal SHP2 activity.
35. The use of claim 32, wherein the disease is cancer.
36. The use according to claim 34, wherein the disease is selected from noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large-cell lymphoma or glioblastoma.
37. A method of treatment comprising administering to a subject in need of treatment for a disease mediated by SHP2 activity a therapeutically effective amount of a compound as claimed in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, in particular a cancer patient.
CN201910975401.1A 2019-10-14 2019-10-14 Pyrazine derivatives for inhibiting SHP2 activity Pending CN112724145A (en)

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