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HK40013065A - Novel heterocyclic derivatives useful as shp2 inhibitors - Google Patents

Novel heterocyclic derivatives useful as shp2 inhibitors Download PDF

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Publication number
HK40013065A
HK40013065A HK42020002938.7A HK42020002938A HK40013065A HK 40013065 A HK40013065 A HK 40013065A HK 42020002938 A HK42020002938 A HK 42020002938A HK 40013065 A HK40013065 A HK 40013065A
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Hong Kong
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membered
group
alkyl
methyl
heterocyclyl
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HK42020002938.7A
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Chinese (zh)
Inventor
马存波
高攀亮
胡邵京
徐子龙
韩慧峰
吴新平
康迪
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北京加科思新药研发有限公司
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Publication of HK40013065A publication Critical patent/HK40013065A/en

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Description

Novel heterocyclic derivatives useful as SHP2 inhibitors
Technical Field
The present invention relates to certain novel pyrazine derivatives (shown in structural formula I, II, III or IV) that are inhibitors of SHP2, their synthesis and use for the treatment of SHP2 mediated disorders. More particularly, the present invention relates to fused heterocyclic derivatives useful as inhibitors of SHP2, methods of preparing such compounds, and methods of treating SHP2 mediated diseases.
Background
SHP2(Src homology region-2 protein tyrosine phosphatase, The Src homology-2 phosphotase) is a non-receptor protein tyrosine phosphatase encoded by ptpn11 gene, comprising a conserved tyrosine phosphatase domain, two N-terminal Src homology region 2(SH2) domains, and a C-terminal tail. The two SH2 domains determine the subcellular localization and functional regulation of SHP 2. In the inactive state, the N-terminal SH2 domain blocks PTP domain binding and inactivates it. When the SH2 domain binds to a specific tyrosine residue on a receptor or receptor-associated linker protein, the PTP domain is released and the autoamtic inhibition is released. Activation of SHP2, for example, by stimulation with cytokines and growth factors results in exposure of catalytic sites, resulting in enzymatic activation of SHP 2.
SHP2 is widely expressed and involved in multiple cell signaling processes, such as Ras-Erk, PI3K-Akt, Jak-Stat, Met, FGFR, EGFR, as well as the insulin receptor and NF-kB pathways, play important roles in cell proliferation, differentiation, cell cycle, and migration.
The catalytically active hyperactivation of SHP2 by germline or somatic mutations has been found in Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, myelodysplastic syndrome, B-precursor acute lymphocytic leukemia and acute myelogenous leukemia. In addition, activating mutations of PTPN11 are also found in solid tumors, such as lung cancer, colon cancer, melanoma, neuroblastoma, and liver cancer. Therefore, activated SHP2 or up-regulated SHP2 protein in human tumors or other diseases is a new therapeutic target. The compounds of the present invention satisfy the need for small molecule inhibitors of SHP 2.
Disclosure of Invention
The present invention relates to heterocyclic pyrazine compounds that are inhibitors of SHP2 for the treatment of diseases mediated by SHP 2. The invention firstly provides a compound shown as a general formula I and pharmaceutically acceptable salts thereof:
wherein:
each R1Are all independently selected from-H, halogen, -NH2-CN, substituted or unsubstituted-C1-6Alkoxy, or substituted or unsubstituted-C1-6An alkyl group;
R2selected from-H, halogen, -NH2、-CN、-OH、-NHC1-6Alkyl, -N (C)1-6Alkyl radical)2Substituted or unsubstituted-C1-6Alkoxy, substituted or unsubstituted-C1-6Alkyl or-C5-10A heterocyclic group; or
R2To adjacent R1Are linked together with the carbon atom to which they are each attached to form a 6-10 membered aromatic ring, a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring, and each ring system independently may be optionally unsubstituted or substituted with 1, 2 or 3 halogens, -NH2、-CN、-C1-6Alkyl or-CO-C1-6Alkyl substitution;
each Y1Independently selected from N or CH;
R3is selected from-H or-NH2；
Each R4aAnd R4bAre all independently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy or-C1-6An alkyl group; or
R4aAnd R4bTogether with the carbon atom to which they are both attached form CO, C ═ NH, or C ═ N-OH;
p is 0, 1, 2 or 3;
each R5aAnd R5bAre all independently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy or-C1-6An alkyl group; or
R5aAnd RsbTogether with the carbon atom to which they are both attached, form a 3-5 membered heterocyclyl or C ═ NH;
q is 0, 1, 2, 3 or 4;
w is absent, O, S or NRw(ii) a And R iswis-H, halogen, -NH2、-CN、-OH、-NO2Carboxy, -C1-6alkyl-O-C1-6Alkoxy, substituted or unsubstituted-C1-6Alkoxy, or substituted or unsubstituted-C1-6An alkyl group;
ring A is absent or is a 3-10 membered ring;
represents a single bond or a double bond;
when ring A is absent, Y2Is CR2aR2b、NR2aOr O, and Y3Is CR3aR3b、NR3aOr O;
when ring A is a 3-to 10-membered ring:
iii) whenWhen represents a single bond, Y2Is CR2aOr N, and Y3Is CH or N; or
iv) whenWhen representing a double bond, Y2Is C, and Y3Is C;
each R2a、R2b、R3aAnd R3bAre all independently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy, substituted or unsubstituted-C1-6Alkoxy, or substituted or unsubstituted-C1-6An alkyl group;
each R6Independently selected from-H, halogen, -NR6aR6b、-CN、-OH、-NO2Oxo, ═ O, carboxyl, -C1-6Alkoxy, -C1-6Alkyl, -C1-6alkenyl-NR6aR6b、-C1-6alkenyl-O-C1-6Alkyl, -C1-6Alkenyl, -CO-OR6a、-C1-6alkenyl-C3-10Heterocyclyl radical, -C1-6alkenyl-C5-10Heteroaryl, -C1-6alkenyl-CO-NR6aR6b、-C1-6alkenyl-NR6a-CO-NR6aR6b、-C1-6alkenyl-NR6a-CO-C1-6Alkyl, -CO-NR6aR6b、-CO-CO-NR6aR6b、-C3-10Carbocyclyl, -C3-10Heterocyclyl, -CO-C1-6Alkyl, -CO-C1-6alkenyl-NR6aR6b、-CO-NR6a-C3-10heterocyclyl-CO-NR6a-C3-10Heterocyclyl, -CO-C3-10Heterocyclyl, -O-C1-6alkenyl-CO-OR6a、-O-C1-6alkenyl-CO-NR6aR6b、 -O-C1-6alkenyl-NR6aR6b、-O-C3-10Carbocyclyl, -O-C3-10Heterocyclyl radical, -NR6a-CO-C1-6Alkyl, -NR6a-CO-NR6aR6b、-NR6a-CO-C5-10Heteroaryl, -NR6a-C1-6olefin-NR6aR6b、-NR6a-C1-6olefin-C3-10Heterocyclyl radical, -NR6a-C1-6olefin-C5-10Heteroaryl, -NR6a-SO2C1-6Alkyl, -S-C1-6Alkyl, -SONR6aR6b、 -SO2NR6aR6b、-5O-C1-6Alkyl, -SO2C1-6Alkyl, -PO (C)1-6Alkyl radical)2、-PO(C1-6Alkoxy group)2、-C3-10Heterocyclyl or-C5-10A heteroaryl group; each R6Each independently optionally substituted or unsubstituted with 1, 2 or 3 substituents; and n is 0, 1, 2, 3, 4, 5Or 6; or
Two adjacent R6Taken together and together with the carbon atoms to which they are respectively attached form a 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, C3-6Heterocyclyl or C3-6Carbocyclyl, and each ring system independently is optionally substituted or unsubstituted with one or more substituents;
each R6aAnd R6bAre all independently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy, substituted or unsubstituted-C1-6Alkoxy, or substituted or unsubstituted-C1-6An alkyl group.
The present invention further provides some preferred embodiments for the compounds of formula I.
A compound of the general formula (I) or a pharmaceutically acceptable salt thereof, 2. each R1Independently selected from-H; -F; -Cl; -Br; -NH2；-CN；-OH；-NO2(ii) a A carboxyl group; -C1-6An alkyl group; -C1-6An alkoxy group; by 1, 2 or 3 halogens, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkyl or-C1-3alkoxy-substituted-C1-6An alkyl group; or by 1, 2 or 3 halogens, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkyl or-C1-3alkoxy-substituted-C1-6An alkoxy group.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R1Independently selected from-H; -F; -Cl; -Br; -NH2；-CN；-OH；-NO2(ii) a A carboxyl group; a methyl group; an ethyl group; propyl; isopropyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; by 1, 2 or 3-F, -Cl, -Br, -NH2、-CN、-OH、 -NO2Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted-C1-3An alkyl group; or by 1, 2 or 3 of-F, -Cl, -Br, -NH2、-CN、-OH、-NO2C substituted by carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy1-3An alkoxy group.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R1Independently selected from-H; -F; -Cl; -Br; -NH2(ii) a -CN; -OH; a methyl group; an ethyl group; propyl; isopropyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; or methyl substituted with 1, 2 or 3 substituents, and each substituent is independently selected from-F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, R2Is selected from-H; -F; -Cl; -Br; -NH2；-CN；-OH；-NO2；-N3(ii) a A carboxyl group; -C1-3An alkyl group; -C1-3An alkoxy group; -NHC1-3An alkyl group; -N (C)1-3Alkyl radical)2；-CONH2；-CONHC1-3An alkyl group; -CON (C)1-3Alkyl radical)2；-COC1-3An alkyl group; -NHCOC1-3An alkyl group; -N (C)1-3Alkyl) -CO-C1-3An alkyl group; -C5-10A heterocyclic group; is substituted by 1, 2 or 3 substituents selected from-F, -Cl, -Br, -I, -NH2-C substituted by a substituent of-CN or-OH1-3An alkyl group; or is substituted by 1, 2 or 3 groups selected from-F, -Cl, -Br, -I, -NH2-C substituted by a substituent of-CN or-OH1-3An alkoxy group.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, R2Is selected from-H; -F; -Cl; -Br; -NH2；-CN；-OH；-NO2；-N3(ii) a A carboxyl group; a methyl group; an ethyl group; propyl; isopropyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; -NHCH3；-N(CH3)2；-CONH2；-CONHCH3；-CON(CH3)2； -COCH3；-NH-COCH3；-N(CH3)-COCH3；Or methyl or ethyl by 1, 2 or 3 substituents selected from-F, -Cl, -Br, -NH2-CN or-OH.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, R2R adjacent thereto1Are linked and taken together with the carbon atom to which they are each linked to form a 5-membered heteroaryl, 6-membered aryl, 5-membered heterocyclyl or 6-membered heterocyclyl; and each said heteroaryl or heterocyclyl group contains 1 or 2 heteroatoms selected from N or O; and each said ring system is independently optionally substituted by-F, -Cl, -Br, -I, -NH2、-CN、-OH、-NO2Carboxy, oxo, ═ O, -CONH2Substituted or unsubstituted C1-3Alkoxy, substituted or unsubstituted C1-3Alkyl, -C1-3alkenyl-O-C1-3Alkyl, -C1-3alkenyl-COOH, -C1-3alkenyl-NHCONH2、-CO-N(C1-3Alkyl radical)2、-C1-3alkenyl-NHCO-C1-3Alkyl, -CO-CO-N (C)1-3Alkyl radical)2、-CO-C1-3Alkyl, -SONH2、-SO2NH2、-SOCH3or-SO2CH3Substituted or unsubstituted.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, R2R adjacent thereto1Are linked and taken together with their respective linking carbon atoms to form a 5-membered heteroaryl, 6-membered aryl, 5-membered heterocyclyl or 6-membered heterocyclyl; and each heteroaryl or heterocyclyl group contains 1 heteroatom selected from N or O; and each ring system may be independently optionally substituted by-F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, oxo, ═ O, -CONH2Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propylOxy, isopropoxy, -CH2OCH3、-CH2COOH、-CH2NHCONH2、-CON(CH3)2、-CH2NHCOCH3、-CO-CON(CH3)2or-COCH3Substituted or unsubstituted.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, R2R adjacent thereto1Are linked and form together with the carbon atoms to which they are respectively linked
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R4aAnd R4bAre independently selected from-H, -F, -Cl, -Br, -I and-NH2、-CN、-OH、-NO2Carboxy or-C1-3An alkyl group; or
R4aAnd R4bTogether with the carbon atom to which they are both attached, form C-O, C-NH or C-N-OH.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R4aAnd R4bAre all independently selected from-H, -NH2-OH, methyl, ethyl, methoxy or ethoxy; or
R4aAnd R4bTogether with the carbon atom to which they are commonly attached, form C ═ O.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R5aAnd R5bAre each independently selected from-H; -F; -Cl; -Br; -I; -NH2；-CN；-OH；-NO2(ii) a A carboxyl group; -C1-3An alkyl group; -C1-3An alkoxy group; is substituted by-F, -Cl, -Br, -I, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkyl or-C1-3alkoxy-substituted-C1-6An alkyl group; or by-F, -Cl, -Br, -I, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkyl or-C1-3alkoxy-substituted-C1-6An alkoxy group; or
R5aAnd R5bTogether with the carbon atom to which they are both attached, form C ═ NH, 3-membered heterocyclyl, 4-membered heterocyclyl, or 5-membered heterocyclyl; and each of said heterocyclyl groups independently optionally includes 1 or 2 heteroatoms selected from N or O; and each ring system may be independently optionally substituted by-H, -F, -Cl, -Br, -I, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkoxy or-C1-3Alkyl is substituted or unsubstituted.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R5aOr R5bAre all independently selected from-H, -NH2-OH, methyl, ethyl, methoxy or ethoxy; or
R5aAnd R5bTogether with the carbon atom to which they are commonly attached, form C ═ NH, 3-membered heterocyclyl, 4-membered heterocyclyl, or 5-membered heterocyclyl; and each of said heterocyclyl groups contains 1 heteroatom selected from N or O.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, W is NRwAnd R iswSelected from-H, -F, -Cl, -Br, -I, -NH2、-CN、-OH、-NO2Carboxy, -C1-3alkyl-O-C1-3Alkyl, -C1-3Alkoxy or-C1-3An alkyl group.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, W is NRwAnd R iswSelected from-H, -F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methyl-CO-methyl or methyl-CO-methoxy.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, ring a is selected from 6-membered aryl, 10-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 9-membered heterocyclyl, 10-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, 8-membered carbocyclyl, 9-membered carbocyclyl, or 10-membered carbocyclyl; and each heteroaryl or each heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, ring a is selected from 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl; a 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, or 8-membered carbocyclyl; and each heteroaryl and each heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is selected from
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R2a、 R2b、R3aAnd R3bAre all independently selected from-H, -F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkyl or-C1-3An alkoxy group.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R2a、 R2b、R3aAnd R3bAre all independently selected from-H, -F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, R2aAnd R2bEach independently is-H or methyl, and R3aAnd R3bEach independently is-H.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R6Are all independently selected from-H, -F, -Cl, -Br, -NR6aR6b-CN, -OH, oxo, - (O), carboxy, -C1-3Alkoxy, -C1-4Alkyl, -C1-3alkenyl-NR6aR6b、-C1-3alkenyl-O-C1-3Alkyl, -C1-3alkenyl-CO-OR6a、-C1-3alkenyl-C5-6Heterocyclyl radical, -C1-3alkenyl-C5-6Heteroaryl, -C1-3alkenyl-CO-NR6aR6b、-C1-3Alkenyl, -NR6a-CO-NR6aR6b、 -CO-NR6aR6b、-CO-CO-NR6aR6b、-CO-C1-3Alkyl, -CO-NR6a-C5-6Heterocyclyl, -CO-C5-6Heterocyclyl, -O-C5-6Carbocyclyl, -O-C5-6Heterocyclyl radical, -NR6a-CO-C1-3Alkyl, -NR6a-CO-NR6aR6b、-NR6a-C1-3alkenyl-NR6aR6b、-NR6a-C1-6alkenyl-C3-6Heterocyclyl radical, -NR6a-SO2C1-3Alkyl, -S-C1-3Alkyl, -SO-C1-3Alkyl, -SO2NR6aR6b、-SO2C1-3Alkyl, -PO (C)1-3Alkyl radical)2、-PO(C1-3Alkoxy group)25-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl or 6-membered heteroaryl, and each R6Independently optionally substituted or unsubstituted with 1, 2 or 3 substituents selected from-F, -Cl, Br, -NH2-OH, carboxy, oxo, ═ O, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; each R is6aAnd R6bAre each independently selected from-H; -F; -Cl; br; i; -NH2；-CN；-OH；-NO2(ii) a A carboxyl group; -C1-3An alkoxy group; -C1-3Alkyl or substituted by 1, 2 or 3-H, halogen, -NH2-CN or-OH substituted-C1-3An alkyl group; or
Two adjacent R6 are linked together and form, together with the carbon atom to which they are each attached, a 6-membered aryl, 5-membered carbocyclyl, 5-membered heteroaryl, or 5-membered heterocyclyl; and each heteroaryl or heterocyclyl group contains 1 or 2 heteroatoms selected from N, O or S; and each said ring system is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents, each said substituent being independently selected from-F, -Cl, -Br, -NH2、-CN、-OH、-NO2- (O), oxo, carboxy, -CONH2、 -PO(CH3)2Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R6Are each independently selected from-H; -F; -Cl; -Br; -NR6aR6b(ii) a -CN; -OH; an oxo group; o; a carboxyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; a methyl group; an ethyl group; propyl; isopropyl group; a tertiary butyl group; -C1-3alkenyl-NR6aR6b； -NR6a-CO-NR6aR6b；-CO-NR6aR6b；-CO-CO-NR6aR6b(ii) a -CO-methyl; -CO-ethyl; -CO-NR6a-C5-6A heterocyclic group; -CO-C5-6A heterocyclic group; -O-C5-6A carbocyclic group; -O-C5-6A heterocyclic group; -NR6a-CO-methyl; -NR6a-CO-NR6aR6b； -NR6a-C1-3alkenyl-NR6aR6b；-NR6a-C1-6alkenyl-C3-6A heterocyclic group; -NR6a-SO2-a methyl group; -NR6a-SO2-an ethyl group; -S-methyl; -S-ethyl; -SO-methyl; -SO-ethyl; -SO2NR6aR6b；-SO2A methyl group; -SO2An ethyl group; -PO (methyl)2(ii) a -PO (ethyl)2(ii) a -PO (methoxy)2(ii) a -PO (ethoxy)2(ii) a A 5-membered heterocyclyl containing 1, 2 or 3 heteroatoms; a6 membered heterocyclyl containing 1, 2 or 3 heteroatoms; a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms; or a6 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein each R6Each independently optionally substituted or unsubstituted with 1, 2 or 3 substituents selected from-F, -Cl, Br, -NH2-OH, carboxy, oxo, ═ O, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; each R6aAnd R6bAre each independently selected from-H; -F; -Cl; br; i; -NH2；-CN；-OH；-NO2(ii) a A carboxyl group; a methyl group; an ethyl group; a methoxy group; an ethoxy group; by 1, 2 or 3 of-H, F, Cl, Br, -NH2-CN or-OH substituted methyl; or by 1, 2 or 3 of-H, F, Cl, Br, -NH2Ethyl substituted by-CN or-OH; or
Two adjacent R6Taken together and together with the carbon atoms to which they are each attached form a phenyl group, a 5-membered carbocyclyl group, a 5-membered heteroaryl group containing 1 or 2N or O, or a 5-membered heterocyclyl group containing 1 or 2N or O; and each said ring system is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents, each said substituent being independently selected from-F, -C1, -Br, -NH2、-CN、-OH、-NO2- (O), oxo, carboxy, -CONH2、-PO(CH3)2Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
In some embodiments, a compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, each R6Are independently selected from-F, -Cl, -Br, -O, -OH, -CN, -NH2,-SCH3、-SOCH3、 -SO2CH3、-PO(CH3)2、-PO(OC2H5)2、-NHSO2CH3、-C(O)NH2Methyl, ethyl, isopropyl, methoxy, ethoxy, ═ O, oxo, -OH, -CN, -NH2、-Cl、-Br、-CF3、-OCF3、-SO2NH2、-SO2CH3、 -CH2NH2、-SCH3、-NHCOCH3、-NHCONHCH3、Or
Two adjacent R6Are linked together and form together with the carbon atoms to which they are respectively attached
In some embodiments, the compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, is a compound shown in structural formula II:
wherein:
R3is selected from-H or-NH2；
Each R4aOr R4bAre all independently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy or substituted or unsubstituted-C1-3An alkyl group; or
R4aAnd R4bTogether with the carbon atom to which they are both attached form C ═ O, C ═ NH, or C ═ N-OH;
p is 0, 1, 2 or 3;
each R5aOr R5bAre all independently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy or substituted or unsubstituted-C1-3An alkyl group; or
R5aAnd R5bTogether with the carbon atom to which they are both attached form a 3-5 membered heterocyclyl; and each of said heterocyclyl groups is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents selected from-H, halogen, -NH2-CN or-OH;
q is 0, 1, 2, 3 or 4;
ring A is a 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
represents a single bond or a double bond; wherein the content of the first and second substances,
iii) whenWhen represents a single bond, Y2Is CR2aOr N, and Y3Is CH or N; or
iv) whenWhen representing a double bond, Y2Is C, and Y3Is C;
R2aselected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy or substituted or unsubstituted-C1-3An alkyl group;
each R6Independently selected from-H, halogen, -NR6aR6b、-CN、-OH、-NO2Oxo, ═ O, carboxyl, -C1-3Alkoxy, -C1-4Alkyl, -CO-NR6aR6b、-CO-CO-NR6aR6b、-CO-C1-3Alkyl, -CO-NR6a-C3-10heterocyclyl-CO-NR6a-C3-10Heterocyclyl, -CO-C4-6Heterocyclyl, -O-C3-6Carbocyclyl, -O-C3-6Heterocyclyl radical, -NR6a-CO-C1-3Alkyl, -NR6a-CO-NR6aR6b、-NR6a-CO-C5-6Heteroaryl, -NR6a-SO2C1-3Alkyl, -S-C1-3Alkyl, aryl, heteroaryl, and heteroaryl,
-SONR6aR6b、-SO2NR6aR6b、-SO-C1-3Alkyl, -SO2-C1-3Alkyl, -PO (C)1-3Alkyl radical)2、-PO(C1-3Alkoxy group)2、-C3-6Heterocyclyl or-C5-6Heteroaryl, wherein each R6Are all independentlyOptionally substituted or unsubstituted with 1, 2 or 3 substituents; and n is 0, 1, 2 or 3; or
Two adjacent R6Taken together with the carbon atoms to which they are respectively attached to form a 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, C3-6Heterocyclyl or C3-6Carbocyclyl, each said ring system being independently optionally substituted or unsubstituted with 1, 2 or 3 substituents;
each R6aAnd R6bIndependently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxyl, or substituted or unsubstituted-An alkyl group.
In some embodiments, a compound of the general formula shown in structural formula (II), or a pharmaceutically acceptable salt thereof, each R5aOr R5bIndependently selected from-H, -Cl, -Br, -NH2-OH, carboxyl, methyl, ethyl, methoxy or ethoxy; or
R5aAnd R5bTogether with the carbon atom to which they are jointly attached formAnd C represents said carbon atom and R5aAnd R5bAnd (4) connecting.
In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, ring a is 6-membered phenyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, 9-membered heteroaryl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each heteroaryl group independently comprises 1 or 2 heteroatoms selected from N, O or S; each of said heterocyclyl groups independently contains 1 or 2 heteroatoms selected from N or O.
In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, ring A is selected fromFrom
In some embodiments, a compound of the general formula shown in structural formula (II) or a pharmaceutically acceptable salt thereof, R2aIs selected from-H; -F; -Cl; -Br; -NH2；-CN；-OH；-NO2(ii) a A carboxyl group; a methyl group; an ethyl group; propyl; isopropyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; is-F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted-C1-3An alkyl group; or by-F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted-C1-3An alkoxy group.
In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt thereof, Y2Is CH or N, and Y3Is CH or N.
In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt thereof, Y2Is C, and Y3Is C.
In some embodiments, a compound of the general formula shown in structural formula (II), or a pharmaceutically acceptable salt thereof, each R6Are all independently selected from-H, -F, -Cl, -Br, -NH2、-N(CH3)2-CN, -OH, oxo, - (O), carboxy, methoxy, ethoxy, methyl, ethyl, isopropyl, tert-butyl, -CH2NH2、-CH2CH2OCH3、-CH2-COOH、 -CH2NH-CONHCH3、-CONH2、-CON(CH3)2、-CONHOH、-CONHCH2CH2OH、 -CO-CON(CH3)2、-COCH3、-SO2NH2、-SO2CH3、-SCH3、-SOCH3、-PO(CH3)2-PO(OC2H5)2-NHSO2CH3、-NH-COCH3、-NH-CONHCH3、Wherein each R6Independently optionally substituted by 1, 2 or 3-F, -Cl, -NH2-OH, oxo, ═ O, methyl, ethyl or propyl substituted or unsubstituted.
In some embodiments, a compound of the general formula shown in structural formula (II), or a pharmaceutically acceptable salt thereof, each R6aAnd R6bAre all independently selected from-H, -Cl, -Br and-NH2-OH, carboxyl, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, methyl substituted with-OH or ethyl substituted with-OH.
In some embodiments, the compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereof, is a compound shown in structural formula (III):
wherein:
each R1And R2Are all independently selected from-H, -F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkoxy or-C1-3An alkyl group; or
R1R adjacent thereto2Are linked and together with the carbon atom to which they are each linked form a 5-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N or O, and said 5-membered heterocyclic ring is optionally substituted by 1, 2 or 3 halogens, -NH2、-CN、-OH、-NO2Carboxy, oxo, ═ O, -CONH2or-CO-C1-3Alkyl substituted or unsubstituted;
Y1is selected from N or CH;
R3is selected from-H or-NH2；
Ring B is selected from a benzene ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, and each of said heteroaromatic ring groups or heterocyclic rings independently optionally comprises 1 or 2 heteroatoms selected from N or O;
iii) whenWhen represents a single bond, Y3Is CH or N; or
iv) whenWhen representing a double bond, Y3Is C;
r7 is selected from halogen, -NH2、-CN、-OH、-NO2Carboxy, oxo, ═ O, -CONH2、-NH-COCH3Substituted or unsubstituted-C1-6Alkoxy, or substituted or unsubstituted-C1-6An alkyl group; and m is 0, 1 or 2.
In some embodiments, a compound of the general formula shown in structural formula (I) or a pharmaceutically acceptable salt thereofSalt of R1R adjacent thereto2Are linked and form together with the carbon atoms to which they are respectively linkedAnd said ring system is independently optionally substituted by 1 or 2-F or-COCH3Substituted or unsubstituted.
In some embodiments, the compound of formula (III) or a pharmaceutically acceptable salt thereof, and ring B is selected from
In some embodiments, a compound of the general formula shown in structural formula (III), or a pharmaceutically acceptable salt thereof, R7Is selected from-NH2-CN, oxo, - (O) -CONH2、-NH-COCH3Methyl or methoxy.
In some embodiments, the compound of the general formula shown in structural formula (I), or a pharmaceutically acceptable salt thereof, is a compound of structural formula (IV):
wherein:
each R1And R2Are each independently selected from-H; -F; -Cl; -Br; -NH2；-CN；-OH；-NO2(ii) a A carboxyl group; -NHC1-3An alkyl group; -N (C)1-3Alkyl radical)2；-C1-3An alkoxy group; -C1-3Alkyl or 1, 2 or 3 halogen substituted-C1-3An alkyl group; or
R1R adjacent thereto2Are linked and taken together with the carbon atom to which they are each attached form a 6-membered carbocyclic ring, a 6-membered aryl ring, a 5-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, or a 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, and each of said ring systems is independently optionally substitutedBy 1, 2 or 3 halogens, -NH2、-CN、-OH、-NO2Carboxy, oxo, ═ O, -CONH2、-C1-3Alkoxy, -C1-3Alkyl or-CO-C1-3Alkyl substituted or unsubstituted;
Y1is N or CH;
R3is-H or-NH2；
Ring D is selected from 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, each of which independently optionally contains 1 or 2 heteroatoms selected from N, O or S;
represents a single bond or a double bond; and is
iii) whenWhen represents a single bond, Y2Is CR2aOr N, and Y3Is CR3aOr N; or
iv) whenWhen representing a double bond, Y2And Y3Are all C;
each R2aAnd R3aAre all independently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkoxy or-C1-3An alkyl group;
R8selected from halogen, -NH2、-CN、-OH、-NO2Carboxy, oxo, ═ O, C1-4Alkyl radical, C1-3Alkoxy, -SO2NR8aR8b、-S-C1-3Alkyl, -SO-C1-3Alkyl, aryl, heteroaryl, and heteroaryl,-SO2-C1-3Alkyl, -CO-NR8aR8b、-PO(C1-3Alkyl radical)2、-PO(C1-3Alkoxy group)2、-NR8a-CO-C1-3Alkyl, -NR8a-CO-NR8aR8b-O-5 membered carbocyclyl, -O-5 membered heterocyclyl, -O-6 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 5 membered heteroaryl or 6 membered heteroaryl; and each R8Each independently optionally substituted by 1, 2 or 3 substituents selected from halogen, methyl, ethyl, methoxy, oxo, -NH2A substituent of-CN or-OH; and t is 0, 1, 2 or 3; or
Two adjacent R8Taken together with the carbon atoms to which they are respectively attached to form a 6-membered aryl or 5-membered heteroaryl, and each said ring system independently is optionally substituted or unsubstituted;
each R8aAnd R8bAre all independently selected from H, halogen, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkoxy or-C1-3An alkyl group.
In some embodiments, a compound of the general formula shown in structural formula (IV), or a pharmaceutically acceptable salt thereof, each R1And R2Are all independently selected from-H, -F, -Cl, -Br, -NH2、-CN、-OH、-NO2、-CF3Carboxy, -NHCH3、 -N(CH3)2Methoxy, ethoxy, methyl or ethyl; or
R1R adjacent thereto2Are linked and taken together with the carbon atom to which they are each attached form a 6-membered carbocyclic ring, a 6-membered aryl group, a 5-membered heterocyclic group containing 1 heteroatom selected from N or O, or a 5-membered heteroaromatic ring including 1 heteroatom selected from N or O; and each said ring system is independently optionally substituted with 1, 2 or 3 substituents selected from-F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, oxo, ═ O, -CONH2Methoxy, ethoxy, methyl, ethyl, -CO-methyl or-CO-ethyl.
In some embodiments, a compound of the general formula shown in structural formula (IV), or a pharmaceutically acceptable salt thereof, each R1And R2Are all independently selected from-H, -F, -Cl, -Br, -NH2、-CN、-OH、-NO2、-CF3Carboxy, -NHCH3、 -N(CH3)2Methoxy, ethoxy, methyl or ethyl; or
R1R adjacent thereto2Are linked and form together with the carbon atoms to which they are respectively linkedAnd each of said ring systems is independently optionally substituted with 1, 2 or 3 substituents selected from-F or-COCH3Substituted or unsubstituted.
In some embodiments, the compound of formula (IV) or a pharmaceutically acceptable salt thereof, and ring D is selected from
In some embodiments, a compound of the general formula shown in structural formula (IV), or a pharmaceutically acceptable salt thereof, each R2aAnd R3aAre each independently selected from-H, methyl or methoxy.
In some embodiments, a compound of the general formula shown in structural formula (IV) or a pharmaceutically acceptable salt thereof, R8Selected from-F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxyl group, oxygenAlkyl, ═ O, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, -CO-methyl, -SO2NR8aR8b-S-methyl, -S-ethyl, -SO-methyl, -SO-ethyl, -SO2-methyl, -SO2-ethyl, -CO-C3-6heterocyclyl-CO-NR8aR8b-PO (methyl)2-PO (ethyl)2-PO (methoxy)2-PO (ethoxy)2、-NR8a-CO-methyl, -NR8a-CO-ethyl, -NR8a-CO-NR8aR8b、-NR8a-SO2Methyl, -O-5 membered carbocyclyl, -O-5 membered heterocyclyl, -O-6 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 5 membered heteroaryl or 6 membered heteroaryl, each of said heterocyclyl or heteroaryl containing 1 or 2 heteroatoms selected from O, N or S; each R8Independently optionally substituted by 1, 2 or 3 substituents selected from-F, -Cl, -Br, -NH2-CN, -OH, oxo, -O, methoxy, ethoxy, methyl or ethyl.
In some embodiments, a compound of the general formula shown in structural formula (IV) or a pharmaceutically acceptable salt thereof, R8Selected from-F, -Cl, -Br, -NH2-CN, -OH, carboxyl, oxo, - (O), methyl, ethyl, isopropyl, tert-butyl, CF3Methoxy, -SOCH3、-5O2CH3、-SCH3、P(O)(CH3)2P(O)(OC2H5)2NHS(O)2CH3、-CONH2、 -NH-COCH3、-NH-CONHCH3、-NH-COCH3、
In some embodiments, a compound of the general formula shown by structural formulae (I), (II), (III) (IV), or a pharmaceutically acceptable salt thereof, is:
in another aspect, the present invention further provides a pharmaceutical composition, comprising at least one compound represented by formula (I), (II), (III) or (IV) of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
Further, in the pharmaceutical composition, the weight ratio of the compound shown in structural formula (I), (II), (III) or (IV) or the pharmaceutically acceptable salt thereof to the auxiliary material is 0.0001-10.
In another aspect, the invention also provides the use of the pharmaceutical composition for the preparation of a medicament.
In some embodiments, the medicament is for treating, preventing, or preventing a disease or disorder mediated by SHP2 activity.
In some embodiments, the disease or disorder mediated by SHP2 activity is cancer, cancer metastasis, cardiovascular disease, immune disorders, fibrosis, or vision disorders.
In some embodiments, the disease or disorder mediated by SHP2 activity is selected from one or more of the following conditions: noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, stomach cancer, pancreatic cancer, and combinations thereof.
The term "halogen" as used herein means, unless otherwise specified, fluorine, chlorine, bromine or iodine. Preferably, halogens include fluorine, chlorine and bromine. The term "halo C1-6Alkyl group "," halogeno C2-6Alkenyl group "," halogeno C2-6Alkynyl "and" halo C1-6Alkoxy "means an alkoxy group in which one or more (especially 1, 2 or 3) hydrogen atoms are replaced by a halogen atom, in particular a fluorine or chlorine atom. In some embodiments, fluoro C is preferred1-6Alkyl, fluoro C2-6Alkenyl, fluoro C2-6Alkynyl and fluoro C1-6Alkoxy, especially fluoro C1-3Alkyl radicals, e.g. CF3、CHF2、CH2F、CH2CH2F、CH2CHF2、 CH2CF3(ii) a Fluoro C1-3Alkoxy radicals, e.g. OCF3、OCHF2、OCH2F、OCH2CH2F、OCH2CHF2Or OCH2CF3(ii) a In particular CF3、OCF3And OCHF2。
Unless otherwise specified, alkyl groups in the present invention include saturated monovalent hydrocarbon groups having straight, branched, or cyclic moieties.
For example, alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-methylpentyl and cyclohexyl. Similarly, in the present invention C1-8Alkyl is defined as a group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched arrangement.
Alkylene means a bifunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. For example, methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH 2-or-CH (CH)3) -) and propylene (i.e., -CH2-CH2-CH2-, -CH (-CH 2-CH)3)-or-CH2-CH(CH3)-)。
Alkoxy is an oxygen ether formed from a straight, branched or cyclic alkyl group as described above.
The term "aryl" as used herein by itself or as part of another substituent means, unless otherwise stated, a monocyclic or polycyclic aromatic hydrocarbon. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.
As used herein, unless otherwise specified, the term "heterocycle" by itself or as part of another substituent refers to an unsubstituted and substituted mono-or polycyclic non-aromatic, partially unsaturated or fully saturated ring system containing one or more heteroatoms. Preferred heteroatoms include N, O and S, including N-oxides, sulfur oxides and dioxides. Preferably the ring is three to eight membered and is fully saturated or has one or more unsaturations. Included in this definition are a plurality of degrees of substitution, preferably one, two or three degrees of substitution.
Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, azepanyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, oxadiazole, or oxaza.
As used herein, unless otherwise specified, the term "heteroaryl" by itself or as part of another substituent refers to an aromatic ring system containing carbon and at least one heteroatom. Heteroaryl groups can be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl groups may have 1 to 4 heteroatoms in the ring, while polycyclic heteroaryl groups may contain 1 to 10 heteroatoms. The polycyclic heteroaryl ring may contain a fused spiro or bridged ring, for example, the cyclic heteroaryl is a polycyclic heteroaryl. A bicyclic heteroaryl ring may contain 8 to 12 member atoms. Monocyclic heteroaryl rings may contain 5 to 8 member atoms (carbon number and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenosine, quinolinyl, or isoquinolinyl.
As used herein, unless otherwise specified, the term "cycloalkyl" by itself or as part of another substituent means a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated or partially unsubstituted hydrocarbon group, which optionally includes an alkylene linker through which the cycloalkyl group may be attached. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The terms "carbonyl", "-C ═ O", "-CO", "-C (O)" and "CO" refer to the groups
The term "oxo" refers to the group ═ O.
The term "oxo" or "═ O" means that it forms, together with the carbon atom to which it is attached, C ═ O.
Whenever the term "alkyl" or "aryl" or any of its prefix roots appears in the name of a substituent (e.g., aralkyl or dialkylamino), by itself or as part of another substituent, unless otherwise stated, it should be construed as including the limitations given above for "alkyl" and "aryl". The specified number of carbon atoms (e.g., Cl-6) shall independently refer to the number of carbon atoms in the alkyl moiety or the number of carbon atoms in the alkyl moiety of the larger substituent in which the alkyl group is the prefix.
Two "R" in the general formula I, II, III or IV1The substituents of "may be the same or different. Similar to "R1", and two" Y's of the formulae I, II, III or IV1The "may be the same or different.
The compounds described herein, e.g., certain compounds of formula I, II, III or IV, may contain asymmetrically substituted carbon atoms (or chiral centers) in either the R or S configuration. The present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.
The compounds described herein, when specifically designated by chemical name as the R-or S-isomer, should be understood as having the R-or S-isomer, respectively, as the predominant configuration. For example, in any of the embodiments described herein, such R-or S-designated isomer may be substantially free (e.g., less than 5%, less than 1%, or undetectable by chiral HPLC) of another isomer at each chiral center. The R-or S-isomer can be prepared by the methods exemplified herein, for example, by using a chiral auxiliary such as R-or S-tert-butylsulfinamide during the synthesis. Other methods of preparing the dominant R-or S-isomer herein include, but are not limited to, chiral HPLC purification of a mixture of stereoisomers (e.g., a racemic mixture). General methods for separating stereoisomers (e.g., enantiomers and/or diastereomers) using HPLC are known in the art.
The compounds described herein may exist in isotopically labeled or enriched forms, containing one or more atoms with an atomic mass or mass number different from the atomic mass or mass number most abundant in nature. The isotope may be a radioactive or non-radioactive isotope. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36C1, and 125I. Compounds containing other isotopes of these and/or other atoms are within the scope of the present invention. In some embodiments, one or more hydrogen atoms of any of the compounds described herein can be substituted with deuterium to provide a corresponding labeled or enriched compound.
As used herein, the term "subject" (alternatively referred to as "patient" in the present invention) refers to an animal, preferably a mammal, most preferably a human, who has been the subject of treatment, observation or experiment.
As used herein, unless otherwise indicated, the term "ring system" (which may also be referred to as "ring system") includes, but is not limited to, carbocyclic rings, heterocyclic rings, heteroaromatic rings, and the like, and may also include only heterocyclic rings and/or heteroaromatic rings, and specifically includes which rings are determined as the context requires, but in any case "ring system" does not include C-based1-6Alkyl or C1-3Cycloalkyl radicals of alkyl radicals and not including radicals based on C1-6Alkoxy or C1-3An alkoxy group.
The compounds of the formulae I, II, III or IV can have different isomeric forms. For example, any asymmetric carbon atom may be present in the (R) -, (S) -or (R, S) -configuration, preferably in the (R) -or (S) -configuration. The double bonds or especially the substituents on the ring may be present in cis (═ Z-) or trans (═ E-) form. These compounds may thus be present as mixtures of isomers or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers.
When used in the plural (e.g., compound, salt), it includes the singular (e.g., single compound, single salt). "Compound" does not exclude the presence (e.g. in a pharmaceutical formulation) of more than one compound of formula I, II, III or IV (or a salt thereof), "a" merely represents an indefinite article. Thus "a" may preferably be understood as "one or more", and should not be understood as "a"
"SHP 2" refers to "Src homology-2-containing protein tyrosine phosphatase", also known as SH-PTP2, SH-PTP3, Syp, PTP1D, PTP2C, SAP-2 or PTPN 11.
Cancers that carry "PTPNll mutations" include, but are not limited to: N58Y; D61Y, V; E69K; a72V, T, D; E76G, Q, K (ALL); G60A; D61Y; E69V; F71K; a 72V; T73I; E76G, K; R289G; G503V (AML); G60R; D61Y, V, N; Y62D; E69K; a72T, V; T73I; E76K, V, G, A, Q; E139D; G503A, R; Q506P (JMML); G60V; D61V; E69K; F71L; a 72V; E76A (MDS); Y63C (CMML); Y62C; E69K; T507K (neuroblastoma); V46L; N58S; E76V (lung cancer); R138Q (melanoma); E76G (colon cancer).
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the invention as active ingredients and processes for preparing the compounds of the invention are also part of the invention. In addition, some of the crystalline forms of the compounds of the present invention may exist as polymorphs and as such are included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of the present invention.
The compounds of the invention may also be present in the form of pharmaceutically acceptable salts. For use in medicine, salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salts include pharmaceutically acceptable acidic/anionic or basic/cationic salts. Pharmaceutically acceptable acidic/anionic salts generally take the form in which a basic nitrogen is protonated by an inorganic or organic acid, representative organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, isethionic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclamic, salicylic, saccharin or trifluoroacetic acid. Pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc.
Prodrugs of the compounds of the invention are also included within the scope of the invention. Typically, such prodrugs are functional derivatives of the compounds of the present invention which are readily convertible in vivo into the desired compound. Thus, in the methods of treatment of the present invention, the term "administering" shall include the use of the compounds of the present invention specifically disclosed, as well as the use of compounds that may not be specifically disclosed, but which may be converted in vivo to the specified compound after administration to a patient for the treatment of various conditions or disorders. Conventional methods for selecting and preparing suitable prodrugs are described, for example, prodrug design, published in 1985 by h.
In the present invention, the definition of any substituent or variable at a particular position is independent of the definition of that substituent or variable at other positions in the molecule. It is to be understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be readily synthesized by techniques known in the art and those methods set forth herein.
The compounds encompassed by the present invention may contain one or more asymmetric centers and thus may give rise to diastereomers and optical isomers. The present invention includes all those possible diastereoisomers and their racemic mixtures, their substantially pure, resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.
The above formulae I, II, III or IV do not show the stereochemistry determined at a specific position. The present invention includes all stereoisomers of formula I, II, III or IV and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers as well as isolated, defined stereoisomers are also included. The products of these processes may be mixtures of stereoisomers during the synthetic procedures used to prepare these compounds, or during the use of racemization or epimerization procedures known to those skilled in the art.
When tautomers exist for compounds of formula I, II, III or IV, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise specified.
When the compounds of formula I, II, III or IV and pharmaceutically acceptable salts thereof exist in solvate form or in polymorphic form, the present invention includes any possible solvate and polymorphic form. The kind of the solvent forming the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, or the like can be used.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds of the present invention are acidic, their corresponding salts may be conveniently prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases. When the compounds of the present invention are basic, their corresponding salts may be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds of formula I, II, III or IV are for pharmaceutical use, they are preferably provided in substantially pure form, e.g. at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% on a weight basis).
The pharmaceutical composition of the present invention comprises a compound represented by formula I, II, III or IV (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any given case will depend on the particular subject and the nature and severity of the condition to which the active ingredient is being administered. The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
In practice, the compounds represented by formula I, II, III or IV or prodrugs or metabolites thereof or pharmaceutically acceptable salts thereof as active ingredients of the present invention may be combined with a pharmaceutical carrier in intimate admixture according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention may be presented as discrete units suitable for oral administration, for example, as capsules, cachets (cachets) or tablets each containing a predetermined amount of the active ingredient. Furthermore, the composition may be in the form of a powder, granules, a solution, a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. In addition to the above-mentioned conventional dosage forms, the compound represented by formula I, II, III or IV or a pharmaceutically acceptable salt thereof may be administered through a controlled release device and/or a delivery device. The composition may be prepared by any pharmaceutical method. Generally, these methods include the step of bringing into association the active ingredient with the carrier which contains one or more of the necessary ingredients.
Typically, the compositions are prepared by uniformly and intimately admixing (unifonm and inteimately admixing) the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired form.
Accordingly, the pharmaceutical compositions of the present invention may include a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt of formula I, II, III or IV. The compounds of formula I, II, III or IV or pharmaceutically acceptable salts thereof may also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier used may be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gas carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical medium may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations (e.g., suspensions, elixirs (elixirs), and solutions); and carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used to form oral solid preparations (e.g., powders, capsules and tablets). Because of their ease of administration, tablets and capsules are the preferred oral dosage units, whereby solid pharmaceutical carriers are employed. Optionally, the tablets may be coated by standard aqueous or non-aqueous techniques.
Tablets containing the composition of the invention may be prepared by compression or molding, optionally together with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient, and each cachet or capsule preferably contains from about 0.05mg to about 5g of the active ingredient. For example, a formulation intended for oral administration to humans may contain from about 0.5mg to about 5g of the active agent, in admixture with a suitable and convenient amount of carrier material which may vary from about 5 to about 95% of the total composition. Unit dosage forms generally contain between about 1mg to about 2g of active ingredient, typically 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or 1000 mg.
Pharmaceutical compositions of the invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compound in water. Suitable surfactants may comprise, for example, hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. In addition, preservatives may be included to prevent the unwanted growth of microorganisms.
Pharmaceutical compositions of the invention suitable for injectable use include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injection must be sterile and must be an effective liquid to facilitate injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage; it is therefore preferred that the contaminating action of microorganisms such as bacteria and fungi should be prevented. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as aerosols, creams, ointments, lotions, dusting powders (dustings) and the like. Further, the composition may be in a form suitable for use in a transdermal device. These formulations can be prepared by conventional processing methods using the compounds represented by formula I, II, III or IV of the present invention or pharmaceutically acceptable salts thereof. For example, a cream or ointment is prepared by mixing a hydrophilic material and water with about 5% to about 10% by weight of the compound to produce a cream or ointment having a desired consistency.
The pharmaceutical compositions of the invention may be in a form suitable for rectal administration and the carrier is a solid. Preferably, the mixture forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with the softened or molten carrier, followed by cooling and shaping in a mould.
In addition to the above-described carrier ingredients, the above-described pharmaceutical formulations may optionally include one or more additional carrier ingredients, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like. In addition, other adjuvants may be included to make the formulation isotonic with the blood of the target recipient. Compositions containing a compound described by formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, may also be prepared in the form of a powder or liquid concentrate.
In general, the above conditions may be treated with a daily dosage level of from about 0.01mg/kg body weight to about 150mg/kg body weight per day, or alternatively from about 0.5mg to about 7g per patient. For example, inflammation, cancer, psoriasis, allergy/asthma, diseases and disorders of the immune system, diseases and disorders of the Central Nervous System (CNS) can be effectively treated by administering about 0.01 to 50mg of the compound per kilogram of body weight per day, or about 0.5mg to about 3.5g of the compound per patient per day.
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.
These and other aspects will become apparent from the following written description of the invention.
Examples
The following intermediates and examples are provided to illustrate the present invention. Unless otherwise expressly indicated, all parts and percentages are by weight and all temperatures are in degrees Celsius. The following abbreviations are used in the examples:
intermediate A1
To a solution of 6-methoxy-2, 3-dihydro-1H-inden-1-one (1.50g, 9.25mmol) in DMF (10mL) under nitrogen was added sodium hydride (60% dispersion in mineral oil, 1.11g, 27.75mmol) portionwise. The mixture was heated to 60 ℃ and stirred at this temperature for 20 minutes. Tert-butyl bis (2-chloroethyl) carbamate (2.46g, 10.17mmol) was added dropwise and the mixture was concentratedThe mixture was stirred for 85 min. After cooling to RT, the reaction was diluted with EA (200mL), washed with brine (3X 200mL) and the organic phase was washed with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 12, v/v) to give 6-methoxy-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine) as a yellow solid]-1' -Carboxylic acid tert-butyl ester (557 mg). MS: m/z 332(M + H)+.
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 1
Intermediate A2
Step a: diethanolamine (198.15g, 1.88mol), K2CO3A mixture of (520.95g, 3.77mol), benzyl bromide (386.79g, 2.26mol) and acetonitrile (2000mL) was stirred at 90 ℃ for 2.5 h. After cooling to RT, filtration and rinsing of the filter cake with EA (2X 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM ═ 1: 10, v/v) to give N-benzyldiethanolamine (89.44g) as a colourless oil. MS: m/z 196(M + H)+.
Step b: to a 0 deg.C solution of N-benzyldiethanolamine (30.66g, 0.16mol) in toluene (300mL) was added phosphorus tribromide (69.13g, 0.26mol) dropwise. The system was warmed to 105 ℃ and stirred for 16 h. After cooling to RT, the volatiles were removed by concentration under reduced pressure. The residue was diluted with water (300mL) and the pH adjusted to 9 with NaOH. The system was extracted with EA (3X 150mL) and combined withOrganic phase, over anhydrous Na2SO4Dried and filtered. The filtrate was concentrated under reduced pressure to give N-benzyl-2-bromo-N- (2-bromoethyl) ethan-1-amine (41.58g), which was used in the next step without any further purification. MS: m/z 320(M + H)+.
Step c: under nitrogen atmosphere, to 0 ℃ 6, 7-dihydro-5H-cyclopenta [ b ]]To a solution of pyridin-5-one (1.70g, 12.77 mmol) in DMF (20mL) was added sodium hydride (60% dispersion in mineral oil, 982mg, 24.55mmol) in three portions, and the mixture was heated to 60 ℃ and stirred at this temperature for 1 h. N-benzyl-2-bromo-N- (2-bromoethyl) ethan-1-amine (4.54g, 14.14mmol) was then added and stirred at 60 ℃ for an additional 1 h. After cooling to RT, the reaction was quenched with water (80mL) and extracted with EA (3X 80 mL). The combined organic phases were washed with water (3X 80mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA) to give 1' -benzylspiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5(7H) -one (1.14 g). MS: m/z 293(M + H)+.
Step d: to 0 ℃ of 1' -benzylspiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]To a solution of-5 (7H) -one (1.05g, 3.59mmol) in DCE (10mL) was added dropwise chloro-1-chloroethyl chloroformate (903mg, 6.32 mmol). The system was stirred at RT for 1.5 h. The volatiles were removed by concentration under reduced pressure and the residue was dissolved in MeOH (20mL) and stirred at 80 ℃ for 4 h. The volatiles were removed by concentration under reduced pressure and the residue was dissolved in DCM (20 mL). DIEA (1.33g, 10.32mmol) and (Boc) were added2O (1.38g, 6.32 mmol). The resulting solution was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 1, v/v) to give 5-oxo-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (438 mg). MS: m/z303(M + H)+.
Intermediate A3
Step a: LDA (2M THF/Hex solution, 24mL, 48.00mmol) was added dropwise to a-70 deg.C solution of 1-tert-butyl 4-ethyl piperidine-1, 4-dicarboxylate (8.14g, 31.64mmol) in THF (80mL) under a nitrogen atmosphere. After the resulting solution was stirred at this temperature for 70min, 1-bromo-4- (bromomethyl) benzene (7.91g, 31.64mmol) was added portionwise. The resulting solution was stirred at-70 ℃ for 3h, then carefully quenched with saturated ammonium chloride solution (50 mL). The separated aqueous phase was extracted with EA (1X 80mL), and the organic phases were combined and washed with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure to give 4- (4-bromobenzyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (14.55g) as a brown oil, which was used in the next step without any further purification. MS: m/z426(M + H)+.
Step b: a mixture of 4- (4-bromobenzyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (14.55g, 34.13mmol), NaOH (8.12g, 203.00mmol), MeOH (80mL) and water (80mL) was stirred at 75 ℃ for 16.5 h. After cooling to RT, the volatiles were removed by concentration under reduced pressure. The system was extracted with EA (3X 80 mL). The combined organic phases were washed with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure to give 4- (4-bromobenzyl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (16.87g) which was used in the next step without any further purification. MS: m/z 398(M + H)+.
Step c: a mixture of 4- (4-bromobenzyl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (16.87g, 42.36mmol) and PPA (60mL) was stirred at 120 ℃ for 30 min. The reaction was poured into an ice-water mixture (300mL) and the pH was adjusted to 10 with NaOH. Then add (Boc)2O (13.86g, 63.53mmol) and stirred at RT for 18 h. The reaction was extracted with EA (3X 150 mL). The combined organic phases were freed from Na2SO4Drying, filtering and concentrating under reduced pressure to obtain 6-bromo-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]Tert-butyl (16.87g) -1' -carboxylate, which was used in the next step without any further purification. MS: m/z 380(M + H)+.
The following compounds were synthesized using the above procedure or modified procedure and the corresponding starting materials.
TABLE 2
Intermediate A4
Under nitrogen atmosphere, 6-bromo-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (2.06g, 5.42 mm0l), Pd (PPh)3)4A mixture of (626mg, 0.54mmol), DBU (252mg, 1.66mmol), t-BuOH (15mL), water (15mL) and potassium ferrocyanide trihydrate (1.16g, 2.75mmol) was stirred at 90 ℃ for 22.5 h. After cooling to RT, the mixture was diluted with EA (30mL), filtered and the filter cake rinsed with EA (15 mL). The filtrate was washed with brine (1X 30mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 10, v/v) to give 6-cyano-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (1.86 g). MS: m/z 327(M + H)+.
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 3
Intermediate A5
Mixing 4-cyano-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (0.93g, 2.85mmol), KOH (1.60g, 28.50mmol), MeOH (15mL) and water (15mL)Stirring was carried out at 100 ℃ for 2 h. After cooling to RT, the reaction was diluted with water (30mL) and extracted with EA (60mL, 30 mL). The combined organic phases were washed with brine (1X 80mL) and anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain 4-carbamoyl-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]Tert-butyl (1.04g) -1' -carboxylate, was used in the next step without any further purification. MS: m/z345(M + H)+.
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 4
Intermediate A6
To 6-carbamoyl-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]To a solution of tert-butyl (1.57g, 4.56mmol) of (E) -1' -carboxylate in DMF (15mL) was added sodium hydride (60% dispersion in mineral oil, 0.91g, 22.79mmol) followed by CH3I (1mL, 16.06 mmol). The system was stirred at RT for 17 h. The reaction was quenched with brine (50mL) and extracted with EA (2X 50 mL). The combined organic phases were washed with brine (1X 100mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 3, v/v) to give 6- (dimethylcarbamoyl) -1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (0.82 g). MS: m/z373 (M + H)+.
Intermediate A7
Step a-c: step (a-c) using intermediate A3 gave 1 '- (tert-butyloxycarbonyl) -1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-6-carboxylic acid. MS: m/z346(M + H)+.
Intermediate A8
To a 50mL sealed tube was added 6-bromo-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (998mg, 2.62 mmol), DMSO (8mL), water (4mL), CuI (217mg, 1.14mmol) and ammonium hydroxide (25%, 4 mL). The system was stirred at 100 ℃ for 5 days. After cooling to RT, the reaction was diluted with brine (20mL) and EA (30 mL). Separating the organic phase with anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain 6-amino-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (750 mg). MS: m/z317(M + H)+.
Intermediate A9
Under nitrogen atmosphere, 6-bromo-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (531mg, 1.40mmol), Methanesulfonamide (371mg, 3.90mmol), K2CO3A mixture of (1.10g, 7.95mmol), N, N' -dimethyl-1, 2-ethylenediamine (85mg, 0.96mmol), CuI (72mg, 0.38mmol) and 1, 4-dioxane (20mL) was stirred at 110 ℃ for 23 h. Further, methanesulfonamide (370mg, 3.89mmol), N, N' -dimethyl-1, 2-ethylenediamine (85mg, 0.96mmol) and CuI (75mg, 0.39mmol) were added, and stirring was continued at the same temperature for 7 hours. After cooling to RT, the reaction was quenched with water (30mL) and extracted with EA (3X 50 mL). The combined organic phases were passed over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 2: 3, v/v) to give 6- (methylsulfonylamino) -1-oxoSubstituted-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (562 mg). MS: m/z 395 (M + H)+.
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 5
Intermediate A10
To 6-amino-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]To a solution of tert-butyl (1' -carboxylate) (0.66g, 2.09mmol) in AcOH (5mL) and water (10mL) was added dropwise a solution of sodium cyanate (0.28g, 4.31mmol) in water (2 mL). The system was stirred at 50 ℃ for 4 h. After cooling to RT, the pH of the reaction was adjusted to 12 with aqueous ammonia (25%) and extracted with DCM (60mL, 30 mL). The combined organic phases were washed with brine (1X 60mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 2: 1, v/v) to give 1-oxo-6-ureido-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (0.39 g). MS: m/z360 (M + H)+.
Intermediate A11
To 0 ℃ 6- (methylthio) -1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]To a solution of tert-butyl (336mg, 0.97 mmol) 1' -carboxylate in MeOH (20mL) and water (20mL) was added potassium peroxymonosulfate (296mg, 1.76 mmol). The system was stirred at 0 ℃ for 1 h. Saturated Na for reaction solution2S2O3(10mL) quench and concentrate under reduced pressure to removeAnd removing volatile matters. The system was extracted with EA (3X 40mL) and the combined organic phases were passed over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (elution with EA: Hex. RTM.4: 1, v/v) to give 6- (methylsulfinyl) -1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (285 mg). MS: m/z 364(M + H)+.
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 6
Intermediate A12
Under nitrogen atmosphere, 6-bromo-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (1.51g, 3.97 mmol), dimethyl-phosphorus oxide (503mg, 6.44mmol), Pd (OAc)2(92mg，0.41mmol)，Xantphos (457mg，0.79mmol)，K3PO4A mixture of (1.57g, 7.40mmol) and DMF (30mL) was stirred at 130 ℃ for 16.5 h. After cooling to RT, the reaction was quenched with water (120mL) and extracted with EA (3X 80 mL). The combined organic phases were washed with brine (1X 120mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM ═ 1: 30, v/v) to give 6- (dimethylphosphoryl) -1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine as a white solid]-1' -carboxylic acid tert-butyl ester (0.81 g). MS: m/z 378(M + H)+.
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 7
Intermediate A13
Under nitrogen atmosphere, 6-bromo-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (1.09g, 2.87 mmol), 1H-imidazole (180mg, 2.64mmol), CuBr (34mg, 0.24mmol), Cs2CO3A mixture of (851mg, 2.61mmol), 1, 2, 3, 4-tetrahydro-8-hydroxyquinoline (74mg, 0.49mmol) and DMSO (10mL) was stirred at 110 ℃ for 23 h. After cooling to RT, the reaction was quenched with water (30mL) and extracted with EA (1X 40 mL). The organic phase is passed through anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA) to give 6- (1H-imidazol-1-yl) -1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine as a yellow solid]-1' -Carboxylic acid tert-butyl ester (142 mg). MS: m/z368(M + H)+.
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 8
Intermediate A14
1 '- (tert-butyloxycarbonyl) -1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]6-carboxylic acid (345mg, 1.00mmol), piperidine (129mg, 1.51mmol) and HATU (422mg, 1.11mmol) were stirred in DMF for 1 h. The reaction was diluted with water (30mL) and EA (30 mL). The organic phase was separated, washed with brine (1X 30mL), dried over anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain 1-oxo-6- (piperidine-1-carbonyl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (380 mg). MS: m/z413(M + H)+.
Intermediate A15
Under nitrogen atmosphere, 6-bromo-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (1.02g, 2.68 mmol), morpholine (0.67g, 7.69mmol), Cu (OAc)2A mixture of (0.51g, 2.81mmol), DBU (1.03g, 6.77mmol) and DMSO (10mL) was stirred at 130 ℃ for 23 h. After cooling to RT, the reaction was diluted with water (70mL) and extracted with EA (3X 50 mL). The combined organic phases were passed over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 1, v/v) to give 6-morpholino-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (467 mg). MS: m/z387(M + H)+.
Intermediate A16
Under nitrogen atmosphere, 6-bromo-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (500mg, 1.31 mmol), 1-methylpiperazine (270mg, 2.70mmol), Cs2CO3(1306mg，4.01mmol)，Pd2(dba)3A mixture of (66mg, 0.07mmol), XantPhos (75mg, 0.13mmol) and 1, 4-dioxane (18mL) was stirred at 100 ℃ for 0.5 h. After cooling to RT, the reaction was quenched with water and extracted with EA (2X 100 mL). The combined organic phases were washed with brine (1X 100mL) and anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain 6- (4-methylpiperazin-1-yl) -1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (0.87g, crude) And used in the next step without any further purification. MS: m/z400(M + H)+.
Intermediate A17
Step a: LDA (2M solution in THF/Hex, 45.00mL, 90.00 mmol) was added dropwise to a-60 deg.C solution of 1-tert-butyl 4-ethyl piperidine-1, 4-dicarboxylate (15.52g, 60.31 mmol) in THF (100mL) under nitrogen. The system is naturally heated to-20 ℃ and stirred for 50min, then cooled to-50 ℃, and CH is dripped3I (8.56g, 60.31 mmol) in THF (20 mL). Then stirred at this temperature for 50 min. The reaction was carefully quenched with saturated ammonium chloride (80mL) and extracted with EA (100mL, 50 mL). The combined organic phases were washed with anhydrous Na2SO4Drying, filtration and concentration under reduced pressure gave 4-methylpiperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (17.70g) which was used in the next step without any further purification. MS: m/z216(M + H-56)+.
Step b: to a 0 deg.C solution of 4-methylpiperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (17.70g, 65.23mmol) in THF (150mL) was added LiBH4(2M in THF, 98.00mL, 196.00 mmol). The system was stirred at 70 ℃ for 18 h. After cooling to RT, quench dropwise with water (100 mL). The system was extracted with EA (200mL, 100mL), the combined organic phases were washed with brine (1X 200mL), anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure to give tert-butyl 4- (hydroxymethyl) -4-methylpiperidine-1-carboxylate (12.90g), which was used in the next step without any further purification. MS: m/z 174(M + H-56)+.
Step c: to a solution of oxalyl chloride (10.71g, 84.38mmol) in DCM (150mL) at-78 deg.C was added dropwise a solution of DMSO (10.99g, 140.63mmol) in DCM (30mL) and stirred at that temperature for 30 min. A solution of tert-butyl 4- (hydroxymethyl) -4-methylpiperidine-1-carboxylate (12.90g, 56.25mmol) in DCM (30mL) was added dropwise and stirred at-78 deg.C for 30 min. Triethylamine (22.77g, 225.02 g) was added dropwisemmol), then naturally heating to-20 deg.C, and stirring for 40 min. The reaction was quenched with water (80 mL). The organic phase was collected and the aqueous phase was extracted with DCM (1X 80 mL). The combined organic phases were washed with brine (1X 200mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 20, v/v) to give 4-formyl-4-methylpiperidine-1-carboxylic acid tert-butyl ester (11.82 g). M/z172(M + H-56)+.
Step d: LDA (2M solution in THF/Hex, 11.00mL, 22.00mmol) was added dropwise to a-70 deg.C solution of 3-chloropyridine (2.25g, 17.64mmol) in THF (50 mL). The system was warmed to-60 ℃ and stirred for 1.5 h. A solution of tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (3.95g, 17.37mmol) in THF (10mL) is added dropwise at-70 ℃. After stirring for 1h, the mixture was quenched with water (50 mL). The organic phase was collected and the aqueous phase was separated and extracted with EA (60mL, 30 mL). The combined organic phases were washed with brine (1X 80mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure to give tert-butyl 4- ((3-chloropyridin-4-yl) (hydroxy) methyl) -4-methylpiperidine-1-carboxylate (8.10g) which was used in the next step without any purification. MS: m/z341(M + H)+.
Step e: to a solution of tert-butyl 4- ((3-chloropyridin-4-yl) (hydroxy) methyl) -4-methylpiperidine-1-carboxylate (8.10g, 23.76 mmol) in DCM (50ml) was added dess-martin oxidant (20.12g, 47.44 mmol). The system was stirred at RT for 16 h. The reaction was diluted with DCM (100mL) and saturated Na2S2O3(25%, 1X 80mL), saturated NaHCO3(1X 80mL) and brine (1X 100 mL). The organic phase is passed through anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 3, v/v) to give 4- (3-chloroisonicotinyl) -4-methylpiperidine-1-carboxylic acid tert-butyl ester (4.81 g). MS: m/z339(M + H)+.
Step f: under a nitrogen atmosphere, tert-butyl 4- (3-chloroisonicotinoyl) -4-methylpiperidine-1-carboxylate (6.31g, 18.62 mmol), Cs2CO3(6.72g, 21.90mmol), pivalic acid (571mg, 5.60mmol), Pd (OAc)2(0.22g，0.98mmol), a mixture of Cy3PH BF4(0.70g, 1.90mmol) and 1, 3, 5-trimethylbenzene (40mL) was stirred at 140 ℃ for 72 h. After cooling to RT, filtration was followed by EA (3X 40mL) rinsing. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 1, v/v) to give 5-oxo-5, 7-dihydrospiro [ cyclopenta [ c ] a]Pyridine-6, 4' -piperidines]-1' -carboxylic acid tert-butyl ester (2.82 g). MS: m/z303(M + H)+.
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 9
Intermediate A18
Step a: to a solution of 3-bromo-6-chloropyridine-2-carboxylic acid (9.98g, 42.21mmol) in MeOH (100mL) was added H dropwise2SO4(98%, 10.00 mL). Stirring was carried out at 70 ℃ for 3 h. After cooling to RT, the pH of the reaction solution was adjusted to 9 by adding ammonia (25%). The volatiles were removed by concentration under reduced pressure. The mixture was diluted with water (60mL) and extracted with EA (1X 100 mL). The organic phase was washed with brine (1X 60mL) and anhydrous Na2SO4Drying, filtration and concentration under reduced pressure gave methyl 3-bromo-6-chloropyridine-2-carboxylate (10.14g) as an off-white solid. MS: m/z250(M + H)+.
Step b: to a solution of methyl 3-bromo-6-chloropyridine-2-carboxylate (10.14g, 40.48mmol) in MeOH (150mL) at 0 deg.C was added NaBH in portions4(4.62g, 122.13 mmol). The mixture was warmed to RT and stirred for 16 h. The reaction was diluted with brine (110mL) and concentrated under reduced pressure to remove MeOH. Extracted with EA (100mL, 80mL) and the organic phase with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure to give (3-bromo-6-chloropyridin-2-yl) methanol (8.31 g).MS：m/z222 (M+H)+.
Step c: to a solution of (3-bromo-6-chloropyridin-2-yl) methanol (8.31g, 37.35mmol) and triethylamine (7.63g, 75.40mmol) in DCM (100mL) at-15 deg.C was added MsC1(4.71g, 41.12mmol) dropwise. The mixture was warmed to RT and stirred for 2 h. The reaction was quenched with water (50mL) and the aqueous phase was separated. The organic phase was washed with brine (1X 50mL) and anhydrous Na2SO4Drying, filtration and concentration under reduced pressure gave methanesulfonic acid (3-bromo-6-chloropyridin-2-yl) methyl ester (8.54 g). MS: m/z300(M + H)+.
Step d: LDA (2M solution of THF/Hex, 23.00mL, 46.00mmol) was added dropwise to a-50 deg.C solution of 1-tert-butyl 4-ethyl piperidine-1, 4-dicarboxylate (9.66g, 37.54mmol) in THF (30mL) under nitrogen. Stirring was carried out at this temperature for 1 h. A solution of methanesulfonic acid (3-bromo-6-chloropyridin-2-yl) methyl ester (8.54g, 28.41mmol) in THF (15mL) was added dropwise, warmed to RT naturally and stirred for 1 h. The reaction was quenched with brine (60mL) and extracted with EA (1X 30 mL). The organic phase is passed through anhydrous Na2SO4Drying, filtration and concentration under reduced pressure gave 4- ((3-bromo-6-chloropyridin-2-yl) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (17.73g) which was used in the next step without further purification. MS: m/z461(M + H)+.
Step e: a mixture of 4- ((3-bromo-6-chloropyridin-2-yl) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (17.73g, 38.39 mmol), NaOH (8.03g, 200.75mmol), MeOH (100mL) and water (20mL) was stirred at 65 ℃ for 16 h. After cooling to RT, the volatiles were removed by concentration under reduced pressure and the system was diluted with water (150 mL). The pH was adjusted to 6 with a saturated citric acid solution. Extraction with EA (2X 100mL), combined organic phases were washed with brine (1X 100mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 10, v/v) to give a mixture of 4- ((3-bromo-6-chloropyridin-2-yl) methyl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid and 4- ((3-bromo-6-methoxypyridin-2-yl) methyl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (18.24 g). MS: m/z 433 (M + H)+，MS：m/z 429(M+H)+.
Step f: to a solution of a mixture of 4- ((3-bromo-6-chloropyridin-2-yl) methyl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid and 4- ((3-bromo-6-methoxypyridin-2-yl) methyl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (3.80g, 8.76mmol) in THF (20mL) at-15 ℃ was added sodium hydride (60% dispersion in mineral oil, 0.42g, 10.50 mmol) portionwise under nitrogen. After stirring at this temperature for 1h, the mixture was cooled to-60 ℃. To the mixture was added n-BuLi (2.5M Hex solution, 5mL, 12.50mmol) dropwise, followed by stirring for 1 h. The reaction was quenched with water (20mL) and extracted with EA (1X 40 mL). The organic phase was washed with brine (1X 30mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA: Hex ═ 1: 10, v/v) to give 2-chloro-5-oxo-5, 7-dihydrospiro [ cyclopenta [ b ] penta-eno [ b ]]Pyridine-6, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester and 2-methoxy-5-oxo-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester mixture (1.48 g). MS: m/z 337(M + H)+.MS：m/z 333(M+H)+.
The following compounds were synthesized using the above procedure and the corresponding starting materials.
Watch 10
Intermediate A19
Step a: LDA (2M solution of THF/Hex, 6.00mL, 12.00mmol) was added dropwise to a solution of piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (2.83g, 11.00mmol) in THF (50mL) at-78 deg.C under nitrogen. Stirring was carried out at this temperature for 1 h. 2-chloro-5- (chloromethyl) thiazole (dissolved in 3mL THF, 1.69g, 10.06mmol) was added dropwise and stirred for 1 h. Using the reaction solutionQuenched with brine (50mL) and extracted with EA (2X 30 mL). The combined organic phases were passed over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 20, v/v) to give 4- ((2-chlorothiazol-5-yl) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.15 g). MS: m/z389(M + H)+.
Step b: LDA (2M solution in THF/Hex, 3.00mL, 6.00mmol) was added dropwise to a-78 deg.C solution of 4- ((2-chlorothiazol-5-yl) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (900mg, 2.31mmol) in THF (50mL) under a nitrogen atmosphere. After stirring for 30min, quench with brine (30 mL). Extraction with EA (2X 30mL), combining the organic phases and adding anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain 2-chloro-4-oxo-4, 6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5, 4' -piperidines]-1' -carboxylic acid tert-butyl ester (832 mg). MS: m/z343(M + H)+.
Intermediate A20
Step a: to a solution of 2-methylnicotinic acid (4.56g, 33.25mmol) in THF (50mL) at 0 deg.C was added LAH (1.51g, 39.90 mmol). The mixture was warmed to RT and stirred for 4 h. The reaction was carefully diluted with saturated ammonium chloride (50 mL). Filtering, separating the filtrate, and using anhydrous Na as organic phase2SO4Dried, filtered again, and the filtrate was concentrated under reduced pressure to give (2-methylpyridin-3-yl) methanol (1.42g) as a yellow oil. MS: m/z 124(M + H)+.
Step b: to a solution of (2-methylpyridin-3-yl) methanol (1.41g, 11.45mmol) in DCM (20mL) at 0 deg.C was added PBr dropwise3(1.86g, 6.87 mmol). The system was warmed to RT and stirred for 1.5 h. Aqueous NaOH (5M, 10mL) was added to adjust the pH of the reaction solution to 8. The aqueous phase was separated and the organic phase was washed with brine (1X 20mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 3-bromomethyl-2-methylpyridine (3.52g) as a yellow oil which was used without further purificationIn the next step. MS: m/z 186(M + H)+.
Step c: to a solution of piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (4.63g, 18.00mmol) at-50 ℃ in THF (30mL) was added LDA (2M solution in THF/Hex, 12.00mL, 24.00mmol) dropwise and stirred at this temperature for 1 h. 3-bromomethyl-2-methylpyridine (3.25g, 18.00mmol) was added, the temperature was raised to RT naturally and stirring was carried out for 16 h. Saturated NH for reaction solution4Cl (50mL) was diluted carefully. The aqueous phase was separated and the organic phase was washed with brine (1X 50mL) and anhydrous Na2SO4Drying, filtration and concentration under reduced pressure gave 4- ((2-methylpyridin-3-yl) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (4.87g) as a red oil which was used in the next step without further purification. MS: m/z363(M + H)+.
Step d: to a solution of 4- ((2-methylpyridin-3-yl) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (4.23g, 11.67mmol) in THF (40mL) at-20 deg.C was added LDA (2M in THF/Hex, 12.00mL, 24.00mmol) dropwise, warmed to RT and stirred for 2 h. The reaction was carefully diluted with brine (50 mL). Separating the aqueous phase and the organic phase with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 1, v/v) to give 7 ' -oxo-7 ', 8 ' -dihydro-5 ' H-spiro [ piperidine-4, 6 ' -quinoline as a yellow oil]-1-carboxylic acid tert-butyl ester (1.23 g). MS: m/z317(M + H)+.
Intermediate A21
Step a: to a mixture of t-BuOK (5.92g, 52.76mmol) and 1, 2-dimethoxyethane (50mL) at-60 deg.C was added dropwise a solution of 2-tosylacetonitrile (5.08g, 26.02mmol) in 1, 2-dimethoxyethane (20 mL). To the system was added dropwise a solution of 2-bromonicotinaldehyde (4.81g, 25.86mmol) in 1, 2-dimethoxyethane (20 mL). After stirring at this temperature for 1h, MeOH (50mL) was added, the temperature was naturally raised to RT, stirred for 1h and raised to 85 ℃,stirring for another 1 h. After cooling to RT, the volatiles were removed by concentration under reduced pressure, diluted with brine (200mL) and extracted with EA (3 × 150 mL). The combined organic phases were passed over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 10, v/v) to give 2- (2-bromopyridin-3-yl) acetonitrile (2.21 g). MS: m/z 197(M + H)+.
Step b: to a solution of 2- (2-bromopyridin-3-yl) acetonitrile (2.21g, 11.21mmol) in DMF (20mL) at 0 deg.C was added sodium hydride (60% dispersion in mineral oil, 1.12g, 28.03mmol) in portions. The reaction was warmed to 60 ℃ and stirred for 1.5 h. Tert-butyl bis (2-chloroethyl) carbamate (3.26g, 13.46mmol) was added to the mixture and stirred at 60 ℃ for 2 h. After cooling to RT, the reaction was quenched with brine (50mL) and extracted with EA (3X 100 mL). The combined organic phases were washed with brine (3X 80mL) and over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 3, v/v) to give 4- (2-bromopyridin-3-yl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester (1.56 g). MS: m/z 366(M + H) +.
Step c: under nitrogen atmosphere, 4- (2-bromopyridin-3-yl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester (1.56g, 4.26 mmol), K2CO3(2.35g, 17.04mmol), trimethylcyclotriboroxane (1.07g, 8.52mmol), Pd (PPh3)4A mixture of (47mg, 0.041mmol), 1, 4-dioxane (40mL) and water (8mL) was stirred at 110 ℃ for 2 h. Supplemented with trimethylcyclotriboroxane (2.15g, 17.13mmol) and Pd (PPh3)4(45mg, 0.039mmol) and stirred for a further 3 h. After cooling to RT, the reaction was diluted with brine (100mL), extracted with EA (3X 100mL), the organic phases combined and washed with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 2: 1, v/v) to give 4-cyano-4- (2-methylpyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester (1.08 g). MS: m/z302(M + H)+.
Step d: to a solution of tert-butyl 4-cyano-4- (2-methylpyridin-3-yl) piperidine-1-carboxylate (1.08g, 3.58mmol) in MeOH (50mL) at 0 deg.CDropwise addition of H2SO4(98%, 45 mL). The system was stirred at reflux temperature for 18 h. After cooling to room temperature, the reaction was poured into an ice/water mixture (200mL) and the pH was adjusted to 9 with NaOH. To the mixture was added (Boc)2O (11.00g, 50.40mmol) and stirred at room temperature for 2 h. Extracting with EA (3X 100mL), combining the organic phases, and purifying with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA) to give 4- (2-methylpyridin-3-yl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (467 mg). MS: m/z 335(M + H)+.
Step e: to a solution of 4- (2-methylpyridin-3-yl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester-4-methyl ester (467mg, 1.40mmol) in THF (10.50mL) at 0 deg.C was added dropwise potassium bis (trimethylsilyl) amide (1M in THF, 7.00mL, 7.00mmol) under a nitrogen atmosphere. It was allowed to warm to RT and stirred for 3.5h, then quenched with saturated ammonium chloride (10mL) and extracted with EA (3X 40 mL). The combined organic phases were passed over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA) to give 6-oxo-6, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-5, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (170 mg). MS: m/z303(M + H)+.
Intermediate A22
Step a: to a solution of tert-butyl 4-formylpiperidine-1-carboxylate (15.00g, 70.33mmol) in DMF (60mL) at 0 deg.C was added lithium tert-butoxide (6.75g, 84.44mmol) in portions. The system was stirred for 30 minutes at 0 ℃. To the mixture was added 3-bromopropene (9.73g, 80.44mmol) dropwise at 0 ℃ and stirred at this temperature for 1 h. The reaction was diluted with brine (100mL) and extracted with EA (3X 200 mL). The organic phases were combined and washed with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (elution with EA: Hex. RTM.1: 20, v/v) to give 4-allyl-4-formylpiperidine-1-carboxylic acid tert-butyl ester (7.01 g). MS: m/z254(M + H)+.
Step b: to a solution of tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (7.01g, 27.63mmol) in THF (30mL) at-78 deg.C was added allyl magnesium bromide (1M in THF, 63.55mL, 63.55mmol) dropwise. Warm to RT and stir for 1.5 h. The reaction was quenched with saturated ammonium chloride. Extract with EA (3X 200 mL). The combined organic phases were washed with brine (1X 200mL) and anhydrous Na2SO4Drying, filtration and concentration under reduced pressure gave tert-butyl 4-allyl-4- (1-hydroxyallyl) piperidine-1-carboxylate (7.01 g). MS: m/z 282(M + H)+.
Step c: to a solution of tert-butyl 4-allyl-4- (1-hydroxyallyl) piperidine-1-carboxylate (7.00g, 24.88mmol) in DCM (50mL) was added dess-martin oxidant (12.66g, 29.85mmol) in portions. After stirring at RT for 1.5h, the reaction was diluted with brine (150mL) and extracted with EA (3X 200 mL). The combined organic phases were passed over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA: Hex ═ 1: 30, v/v) to give 4-acryloyl-4-allylpiperidine-1-carboxylic acid tert-butyl ester (5.63 g). MS: m/z280(M + H)+.
Step d: a mixture of tert-butyl 4-acryloyl-4-allylpiperidine-1-carboxylate (5.63g, 20.15mmol), GrubbsII (428mg, 0.50mmol) and toluene (30mL) was stirred at 85 ℃ for 3.5h under nitrogen. After cooling to RT, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 5, v/v) to give 1-oxo-8-azaspiro [ 4.5-]Tert-butyl dec-2-ene-8-carboxylate (3.61 g). MS: m/z252(M + H)+.
Step e: to a DMSO (50mL) solution of trimethyl sulfoxide iodide (3.79g, 17.22mmol) was added sodium hydride (60% dispersion in mineral oil, 730mg, 18.25mmol) in portions, and after stirring for 30min, 1-oxo-8-azaspiro [4.5 ] was added dropwise]Tert-butyl dec-2-ene-8-carboxylate (DMSO solution, 3.61g, 14.36 mmol). The system was stirred at RT for 1.5 h. The reaction was diluted with brine (200mL) and extracted with EA (3X 200 mL). The combined organic phases are usedWashed with brine (3X 200mL) and anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain 2-oxo spiro [ bicyclo [3.1.0 ]]Hexane-3, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (3.60 g). MS: m/z 266(M + H)+.
Intermediate A23
Step a: to a solution of tetrahydro-2H-pyran-4-ol (3.54g, 34.66mmol), triethylamine (4.65g, 45.95mmol) in DCM (100mL) at-10 deg.C was added MsCl (4.61g, 40.24 mmol). After stirring for 30min, the reaction was diluted with water (100mL) and extracted with DCM (100mL, 50 mL). The combined organic phases were washed with brine (1X 50mL) and anhydrous Na2SO4Drying, filtration and concentration under reduced pressure gave tetrahydro-2H-pyran-4-yl methanesulfonate (6.74 g). MS: m/z 181(M + H)+.
Step b: to 1 '-benzyl-6-methoxyspiro [ indene-2, 4' -piperidine]A solution of (1M in DCM, 15.00mL, 15.00mmol) of (4.35g, 13.53mmol) in DCM (200mL) was added and stirred at 45 ℃ for 13H. Supplement BBr3(1M in DCM, 5.00mL, 5.00mmol) and stirred at 45 ℃ for 24 h. After cooling to RT, the reaction was diluted with water (150mL) and NaHCO was added portionwise3(20.00 g). The resulting mixture was extracted with DCM (2X 100mL), the organic phases were combined and washed with anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain 1 '-benzyl-6-hydroxy spiro [ indene-2, 4' -piperidine]-1(3H) -one (2.80g), used in the next step without further purification. MS: m/z308 (M + H)+.
Step c: 1 '-benzyl-6-hydroxy spiro [ indene-2, 4' -piperidine]-1(3H) -one (2.80g, 9.11mmol), tetrahydro-2H-pyran-4-yl methanesulfonate (3.40g, 18.87mmol) and K2CO3A mixture of (8.23g, 59.55mmol) and DMF (60mL) was stirred at 110 ℃ for 5.5 h. Supplemented with tetrahydro-2H-pyran-4-yl-methanesulfonate (1.10g, 6.10mmol) and K2CO3(4.55g，32.92mmol) and stirred at 110 ℃ for 1.5 h. After cooling to RT, the mixture was diluted with water (300mL) and EA (600 mL). The aqueous phase was separated and extracted with EA (1X 200mL), and the organic phases were combined, washed with water (2X 300mL) and brine (1X 300mL), dried over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM ═ 1: 40, v/v) to give 1 '-benzyl-6- ((tetrahydro-2H-pyran-4-yl) oxy) spiro [ indene-2, 4' -piperidine]-1(3H) -one (1.70 g). MS: m/z392(M + H)+.
Step d: reacting 1 '-benzyl-6- ((tetrahydro-2H-pyran-4-yl) oxy) spiro [ indene-2, 4' -piperidine in hydrogen atmosphere]-1(3H) -one (1.70g, 4.34mmol) and Pd (OH)2A solution of (10%, 1.21g) MeOH was stirred at RT for 3 h. The reaction system was filtered. To the filtrate was added (Boc)2O (1.10g, 5.04mmol) and stirred at room temperature for 40 h. The reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 5, v/v) to give 1-oxo-6- ((tetrahydro-2H-pyran-4-yl) oxy) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (1.45 g). MS: m/z402(M + H) intermediate A24
Under nitrogen atmosphere, 6-bromo-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (1017mg, 2.67 mmol), phosphonic acid diethyl ester (564mg, 4.08mmol), potassium phosphate (1156mg, 5.45mmol), Pd (OAc)2A mixture of (63 mg, 0.28mmol), XantPhos (307mg, 0.53mmol) and DMF (10mL) was stirred at 130 ℃ for 21 h. After cooling to RT, the reaction was quenched with water (60mL), filtered, and the filter cake rinsed with EA (2X 30 mL). The filtrates were separated and the aqueous layer was extracted with EA (2X 60 mL). The combined organic phases were passed over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA) to give 6- (diethoxyphosphoryl) -1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (134mg), used without further purificationAnd (5) next step. MS: m/z438(M + H)+.
Intermediate A25
Intermediate a25 was synthesized according to the procedure of y.utoet./bioorg.med.chem.lett.20 (2010) 746-754.
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 11
Intermediate A26
Step a: LDA (2M solution of THF/Hex, 12.00mL, 24.00mmol) was added dropwise to a solution of piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (5.23g, 20.32mmol) in THF (30mL) at-65 ℃. The resulting mixture was stirred at this temperature for 1.0 h. 2-bromobenzaldehyde (3.44g, 18.59mmol) was added dropwise at-70 ℃. After stirring for 1h, the mixture was quenched with brine (40 mL). Separating the organic phase with anhydrous Na2SO4Drying, filtration and concentration under reduced pressure gave 4- ((2-bromophenyl) (hydroxy) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (9.15g) which was used in the next step without further purification. MS: m/z442(M + H)+.
Step b: to a solution of 4- ((2-bromophenyl) (hydroxy) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (9.15g, 20.68mmol) in DCM (70ml) at-5 deg.C was added dess-martin oxidant (18.02g, 42.49 mmol). The system was stirred at RT for 2.5 h. With Na2S2O3Aqueous solution (25%, 1X 80mL), saturated NaHCO3 (g/g) (1X 80mL)1X 80mL) and brine (1X 100 mL). The organic phase is passed through anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 5, v/v) to give 4- (2-bromobenzoyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (7.16 g). MS: m/z440(M + H)+.
Step c: to a solution of 4- (2-bromobenzoyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (2.00g, 4.54mmol) in THF (20mL) at-80 deg.C was added 1.8mL of n-butyllithium (2.5M in THF/Hex) with nitrogen blanketing. The system naturally returns to the room temperature, and stirring is continued for 1 h. The system was quenched by adding 30mL of saturated brine and the organic phase was collected. The aqueous phase was extracted by adding 20mL of EA. The organic phases were combined and anhydrous Na2SO4Drying, filtering, and concentrating under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 10, v/v) to give 1, 3-dioxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (500mg), MS: m/z316(M + H) +.
Intermediate A27
Intermediate A27 was synthesized according to the procedure of J.org.chem.1999, 64, 5504-.
Intermediate A28
Step a: to a 0 deg.C solution of ethyl 2-chlorothiazole-4-carboxylate (24.95g, 130.19mmol) in MeOH (250mL) was added NaBH in portions4(17.29g, 456.97 mmol). The mixture was warmed to RT and stirred for 2 h. The reaction was diluted with water (200mL) and concentrated under reduced pressure to remove volatiles. The system was extracted with EA (2X 200mL), the combined organic phases were washed with brine (1X 400mL), anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain (2-chlorothiazole-4-Mesityl) methanol (18.88 g). MS: m/z150(M + H)+.
Step b: to a solution of (2-chlorothiazol-4-yl) methanol (18.88g, 130.19mmol) and triethylamine (25.56g, 252.57mmol) in DCM (200mL) was added MsCl (15.96g, 139.30mmol) dropwise over 15 min. The system was stirred at RT for 25 min. The reaction was quenched with brine (200mL) and the aqueous phase was separated. Anhydrous Na for organic phase2SO4Dried, filtered and concentrated under reduced pressure to give (2-chlorothiazol-4-yl) methyl methanesulfonate, which was used in the next step without further purification. MS: m/z228(M + H)+.
Step c: LDA (2M THF/Hex solution, 75.00mL, 150.00mmol) was added dropwise to a-60 ℃ solution of 1-tert-butyl 4-piperidine-1, 4-dicarboxylate (35.67g, 138.62 mmol) in THF (200mL) under nitrogen for 30 min. Then a solution of methanesulfonic acid (2-chlorothiazol-4-yl) methyl ester in THF (50mL) was added dropwise, warmed to RT naturally and stirred for 2 h. The reaction was quenched with brine (300 mL). Separating the organic phase with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 10, v/v) to give 4- ((2-chlorothiazol-4-yl) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (38.12 g). MS: m/z389(M + H)+.
Step d: LDA (2M solution in THF/Hex, 11.00mL, 22.00mmol) was added dropwise to a-60 deg.C solution of 4- ((2-chlorothiazol-4-yl) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (8.51g, 21.88mmol) in THF (80mL) under a nitrogen atmosphere. After the completion of the dropping, the reaction solution was quenched with brine (50 mL). Separating the organic phase with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 10, v/v) to give 2-chloro-6-oxo-4, 6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (1.93 g). MS: m/z343(M + H)+.
Intermediate A29
Step (a-c): synthesis of 1- (tert-butoxycarbonyl) -4- (thien-2-ylmethyl) piperidine-4-carboxylic acid with reference to step (b-c) of intermediate A28 and step (b) of intermediate A3.
Step d: a mixture of 1- (tert-butoxycarbonyl) -4- (thien-2-ylmethyl) piperidine-4-carboxylic acid (4.92g, 15.12mmol) and PPA (30.12g) was stirred at 110 ℃ for 5 h. The reaction was poured into an ice/water mixture (100mL) and the pH was adjusted to 10 with NaOH. Then add (Boc)2O (5.05g, 23.14mmol) and stirred at room temperature for 18 h. Extract with EA (2X 50 mL). The combined organic phases were washed with brine (1X 50mL) over anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain 2-tert-butyl-4-oxo-4, 6-dihydrospiro [ cyclopenta [ b ]]Thiophene-5, 4' -piperidines]-1' -carboxylic acid tert-butyl ester (1.70 g). MS: m/z 364(M + H)+.
Step e: a mixture of 1- (tert-butoxycarbonyl) -4- (thien-2-ylmethyl) piperidine-4-carboxylic acid (4.88g, 15.12mmol), HCl (4M in 1, 4-dioxane, 8mL), and DCM (50mL) was stirred at RT for 1 h. The reaction was concentrated under reduced pressure. PPA (21.15g) was added and the system was stirred at 110 ℃ for 1.5 h. The reaction was poured into an ice/water mixture (100mL) and the pH was adjusted to 10 with NaOH. Then add (Boc)2O (5.12g, 23.46mmol) and stirred at room temperature for 18 h. Extract with EA (2X 50 mL). The combined organic phases were washed with brine (1X 100mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 10, v/v) to give 4-oxo-4, 6-dihydro-4 spiro [ cyclopenta [ b ] b]Thiophene-5, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (2.71 g). MS: m/z308 (M + H)+.
Intermediate A30
Step a: to benzyl alcohol (5.1)5g, 47.62mmol) in DMF (50mL) was added portionwise sodium hydride (60% dispersion in mineral oil, 3.01g, 75.25mmol) and stirred for 20 min. 4-chloropyridine-2-carboxylic acid (2.68g, 17.01mmol) was added and stirred at 85 ℃ for 3.5 h. After cooling to RT, HCl (4M in 1, 4-dioxane, 10mL) was added. The system was used directly in the next step. MS: m/z 230(M + H)+.
Step b: c, reacting the reaction system in the step a with NaHCO3(7.51g，89.39mmol)，CH3I (1.5mL) was mixed with DMF (10 mL). After stirring for 0.5h, CH is added3I (1.5mL) and stirred for 16 h. The reaction was diluted with EA (250mL), filtered, and the filtrate was washed with brine (2X 150 mL). The organic phase is passed through anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 1, v/v) to give methyl 4- (benzyloxy) pyridine-2-carboxylate (1.50 g). MS: m/z 244(M + H)+.
Step c: methyl 4- (benzyloxy) pyridine-2-carboxylate (1.50g, 6.17mmol), LiBH4A mixture of (2M in THF, 9.00mL, 18.00mmol) and THF (40mL) was stirred at 50 ℃ for 1 h. The reaction was diluted with MeOH (15mL) and water (150mL) and extracted with EA (200mL, 50 mL). The combined organic phases were washed with brine (2X 100mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA) to give (4- (benzyloxy) pyridin-2-yl) methanol (0.50 g). MS: m/z216(M + H)+.
Step d: (4- (benzyloxy) pyridin-2-yl) methanol (0.50g, 2.32mmol), dess-Martin's oxidant (1.25 mmol)g2.95mmol) and DCM (20mL) was stirred for 1.5 h. The reaction solution is saturated NaHSO3Aqueous solution, saturated NaHCO3Aqueous and DCM (50 mL). The aqueous phase was separated and extracted with DCM (50 mL). The combined organic phases were washed with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 4- (benzyloxy) pyridine-2-carbaldehyde (0.40 g). MS: m/z 214(M + H)+.
Step e: to 0 deg.CPiperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (0.52)g2.02mmol) in THF (15mL) was added dropwise LDA (2M solution in THF/Hex, 1.30mL, 2.60 mmol). The system was cooled to-70 ℃ and a solution of 4- (benzyloxy) pyridine-2-carbaldehyde (0.40g, 1.88mmol) in THF (5mL) was added. It was warmed to-15 ℃ and stirred for 30min, then quenched with saturated ammonium chloride (10mL), diluted with water (50mL) and extracted with EA (1X 100 mL). The organic phase was washed with brine (2X 50mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 1) to give 4- ((4- (benzyloxy) pyridin-2-yl) (hydroxy) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.25 g). MS: m/z471(M + H)+.
Step f: 4- ((4- (benzyloxy) pyridin-2-yl) (hydroxy) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.25g, 0.53mmol), LiBH4(2M in THF, 1.00mL, 2.00mmol) in THF (10mL) was stirred at 55 deg.C for 40 min. The reaction was quenched with MeOH (10mL) and concentrated under reduced pressure to remove volatiles. The residue was diluted with water (150mL) and extracted with EA (1X 50 mL). The organic phase was washed with brine (1X 30mL) and anhydrous Na2SO4Drying, filtration and concentration under reduced pressure gave tert-butyl 4- ((4- (benzyloxy) pyridin-2-yl) (hydroxy) methyl) -4- (hydroxymethyl) piperidine-1-carboxylate (0.22 g). MS: m/z 429(M + H)+.
Step g: a mixture of tert-butyl 4- ((4- (benzyloxy) pyridin-2-yl) (hydroxy) methyl) -4- (hydroxymethyl) piperidine-1-carboxylate (0.22g, 0.51mmol), Pd/C (10%, 0.12g) and MeOH (20mL) was stirred under a hydrogen atmosphere for 1.5 h. The reaction mixture was filtered, the filter cake was rinsed with MeOH, and the filtrate was concentrated under reduced pressure to give tert-butyl 4- (hydroxy (4-hydroxypyridin-2-yl) methyl) -4- (hydroxymethyl) piperidine-1-carboxylate (154 mg). MS: m/z339(M + H)+.
Step h: to a solution of tert-butyl 4- (hydroxy (4-hydroxypyridin-2-yl) methyl) -4- (hydroxymethyl) piperidine-1-carboxylate (120mg, 0.36mmol) and triphenylphosphine (175mg, 0.67mmol) in THF (10mL) was added N, N, N' -tetramethylazodicarboxamide (158mg, 0.68 mmol). Mixing the raw materialsThe material was stirred at RT for 30 min. Purification by silica gel chromatography (eluting with MeOH: DCM ═ 1: 7, v/v) afforded 1-hydroxy-7-oxo-1, 7-dihydro-3H-spiro [ indolizine-2, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (100 mg). MS: m/z 321(M + H)+.
Step i: 1-hydroxy-7-oxo-1, 7-dihydro-3H-spiro [ indolizine-2, 4' -piperidine]A mixture of tert-butyl (0.35g, 1.09 mmol) -1' -carboxylate, dess-martin oxidant (0.72g, 1.70mmol) and DCM (35mL) was stirred at RT for 2 h. Saturated Na for system2SO3(1X 20mL) and saturated NaHCO3Aqueous (1X 20mL) wash. Anhydrous Na for organic phase2SO4Drying, filtering and concentrating under reduced pressure to obtain 1, 7-dioxo-1, 7-dihydro-3H-spiro [ indolizine-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (0.33 g). MS: m/z 319(M + H)+.
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 12
Intermediate B1
According to the steps of WO 2017211303A 1, 4-iodoisatin is used as a raw material to synthesize an intermediate B1 through three steps.
Intermediate B2
According to the steps of WO 2017211303A 1, 2-amino-3-bromo-6-chloropyrazine is used as a raw material to synthesize an intermediate B2 through 2 steps.
The following compounds were synthesized using the above procedure and the corresponding starting materials.
Watch 13
Intermediate B3
2-fluoro-3-chloro-4-iodopyridine (10.10g, 39.23mmol) and DMSO (50mL) were added to a sealed tube and ammonia (25%, 50mL) was added dropwise. The system was stirred at 80 ℃ for 16 h. After cooling to RT, the reaction was poured into water (250mL), filtered to give a precipitate, dissolved in DCM (280mL), washed with brine (1X 100mL), and washed with anhydrous Na2SO4Drying, filtration and concentration under reduced pressure gave 3-chloro-4-iodopyridin-2-amine (7.01 g). MS: m/z255(M + H)
The following compounds were synthesized using the above procedure and the corresponding starting materials.
TABLE 14
Intermediate B4
Under nitrogen atmosphere, 3-chloro-4-iodopyridin-2-amine (25.53g, 100.33mmol), sodium 3-amino-5-chloropyrazine-2-mercaptide (20.18g, 109.92mmol), Pd2(dba)3A mixture of (4.47g, 4.88mmol), XantPhos (5.81g, 10.04mmol) and DIEA (26.12g, 202.10mmol) in 1, 4-dioxane (100mL) was stirred at 70 ℃ for 1.5 h. Cooling to room temperature, filtering the reaction system by diatomite,then washed with 1, 4-dioxane (30mL) and the filtrate was concentrated under reduced pressure. DCM (100mL) and EA (100mL) were added to the residue and stirred for 40 min. The precipitate was collected and dried in a vacuum oven to give 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (13.86 g). MS: m/z 288(M + H)+.
The following compounds were synthesized using the above procedure and the corresponding starting materials.
Watch 15
Example 1
(R) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2, 3-dihydrospiro [ indene-1, 4' -piperidine ] -2-amine
Step a: a mixture of compound 1H-indene (11.62g, 0.10mol) and LiHMDS (220mL, 1mol/L solution in THF) in THF (120mL) was stirred at-50 ℃ for 1H. Tert-butyl bis (2-chloroethyl) carbamate (24.21g, 0.10mol) was added to the reaction solution and stirred at-50 ℃ for 1 h. Quench with brine (300 mL). The organic phase was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the compound spiro [ indene-1, 4' -piperidine as a yellow solid]-1' -Carboxylic acid tert-butyl ester (10.36g, 36%). MS: 286(M + H)+.
Step b: the compound spiro [ indene-1, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (117.02g, 0.41mol) and borane dimethylsulfide complexA solution of (10mol/L, 220mL) in THF (800mL) was stirred at 0 deg.C for 3 h. NaOH (2mol/L, 1.2L) and H were added2O2(300mL) and stirred at 0 ℃ for 1 h. Collecting organic phase, and adding anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain 2-hydroxy-2, 3-dihydrospiro [ indene-1, 4' -piperidine]-1 '-Carboxylic acid tert-butyl ester and 3-hydroxy-2, 3-dihydrospiro [ indene-1, 4' -piperidine]Tert-butyl-1' -carboxylate, yellow oil (130.33g, crude). MS: 304(M + H)+.
Step c: 2-hydroxy-2, 3-dihydrospiro [ indene-1, 4' -piperidine]-1 '-Carboxylic acid tert-butyl ester and 3-hydroxy-2, 3-dihydrospiro [ indene-1, 4' -piperidine]A mixture of tert-butyl (130.02g, 0.43mol) -1' -carboxylate, dess-martin oxidant (364.76g, 0.86mol) and DCM (2L) was stirred at 25 ℃ for 12 h. The reaction solution was filtered, and the filtrate was washed with saturated sodium bicarbonate solution (1L) and brine (1L), followed by anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. Purifying the residue by column chromatography to obtain 3-oxo-2, 3-dihydrospiro [ indene-1, 4' -piperidine as a white solid]Tert-butyl (41.75g, 34%, two-step yield) 1' -carboxylate. MS: 302(M + H)+.
Step d: to the compound 3-oxo-2, 3-dihydrospiro [ indene-1, 4' -piperidine]To a solution of tert-butyl (41.01g, 0.14mol) of (E) -1' -carboxylate in ethyl titanate (80mL) was added R- (+) -tert-butylsulfinamide (49.46g, 0.41 mol). The system was stirred at 85 ℃ for 2 h. EA (0.5L) and water (0.5L) were added to the reaction system. The reaction was filtered and the organic phase was collected. The aqueous phase was extracted with EA (200 mL. times.2). The combined organic phases were washed with brine (500mL) and anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain compound (R, E) -2- ((tert-butylsulfinyl) imino) -2, 3-dihydrospiro [ indene-1, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (132.05g, crude). MS: 405(M + H)+The impure sample was used directly in the next step. .
Step e: the compound (R, E) -2- ((tert-butylsulfinyl) imino) -2, 3-dihydrospiro [ indene-1, 4' -piperidine]A solution of tert-butyl (132.02g, 0.33mol) of (E) -1' -carboxylate in THF (200mL) was cooled to-50 ℃ and stirred. Adding intoNaBH4(7.71g, 0.51mol), the temperature was raised naturally to RT. Quench with saturated ammonium chloride solution (100 mL). Collecting organic phase, and adding anhydrous Na2S04Dried, filtered and concentrated under reduced pressure. Purifying the residue by column chromatography to obtain (R) -2- (((R) -tert-butylsulfinyl) amino) -2, 3-dihydrospiro [ indene-1, 4' -piperidine]Tert-butyl (E) -1' -carboxylate was a white solid (27.25g, 49%, two-step yield). MS: 407(M + H)+.
Step f: (R) -2- (((R) -tert-butylsulfinyl) amino) -2, 3-dihydrospiro [ indene-1, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (1.16g, 3.98mmol), CF3A solution of COOH (3.6mL) in DCM (20mL) was stirred at 25 ℃ for 1.5 h. The reaction solution was concentrated under reduced pressure, the residue was dissolved in NMP (15mL), and 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (1.03g, 3.59mmol) and K were added2CO3(6.60g, 47.76mmol), and stirred at 90 ℃ for 16 h. Adding H to the reaction solution2O (30mL) and filtered. The filter cake was dissolved in DCM (40mL) and washed with brine (40 mL). Anhydrous Na for organic phase2SO4Drying, filtering and concentrating under reduced pressure to obtain compound (R) -N- ((R) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-3-yl) pyrimidin-4-yl) thio) pyrazin-2-yl) -2, 3-dihydrospiro [ indene-1, 4' -piperidine]-2-yl) -2-methylpropane-2-sulfinamide (1.55g, 70%) as a yellow solid.
Step g: to the compound (R) -N- ((R) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2, 3-dihydrospiro [ indene-1, 4' -piperidine]To a solution of (2-yl) -2-methylpropane-2-sulfinamide (1.52g, 2.72mmol) in DCM (20mL) was added HCl/1, 4-dioxane (2mL, 4 mol/L). The system was stirred at 25 ℃ for 1h and the precipitate was collected by filtration. The filter cake was dispersed in DCM (30mL) and ammonium hydroxide (5mL) was added to adjust the pH to > 10. The mixture was washed with brine (40mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure. Purifying the residue by column chromatography to obtain the compound (R) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2, 3-dihydrospiro [ indene-1, 4' -piperidine]2-amine as a yellow solid (530mg, 42%). MS: 454(M + H)+.1HNMR(400MHz，DMSO-d6)δ7.64-7.66(m，2H)，7.30(d，1H)，7.20(d，1H)，7.13-7.15(m，2H)，6.78(d，1H)，4.05-4.09(m，1H)，3.91-3.95(m，1H)，3.54-3.60(m，3H)，3.12-3.18(m，1H)，2.57-2.63(m，1H)，1.91-2.09(m，2H)，1.66-1.76(m，1H)，1.49-1.58(m，1H).
Example 2
(S) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ] -1-amine
Step a: sodium hydride (60%) (3.63g, 90.80mmol) was added to a solution of compound 2, 3-dihydro-1H-inden-1-one (4.00 g, 30.27mmol) in DMF (80 mL). The mixture was stirred at 16 ℃ for 30 min. Tert-butyl bis (2-chloroethyl) carbamate (8.06g, 33.29mmol) was added dropwise. The mixture was then stirred at 60 ℃ for 16 h. The mixture was quenched with brine (200mL) and extracted with EA (100 mL. times.2). The organic phases were combined and washed with brine (100 mL. times.2) and anhydrous Na2SO4And (5) drying. After concentration, the residue was purified by column chromatography to give the compound 1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (1.21g, 13%) dark red oil. MS: 302(M + H)+.
Step b: after heating ethyl titanate (12.00g) to 90 deg.C, the compound 1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (1.21g, 4.01mmol) and (R) -2-methylpropane-2-sulfinamide (1.22g, 12.04mmol) were added. After stirring at 90 ℃ for 19 h. The mixture was poured into EA (200mL) and brine (200mL) was added. After stirring for 15 minutes, filtration was carried out. The filtrate was partitioned. The organic phase was washed with brine (200 mL. times.2) over anhydrous Na2SO4And (5) drying. The solid was filtered off and the filtrate was concentrated under reduced pressure. Purifying the residue by column chromatography to obtain (R, Z) -1- ((tert-butylsulfinyl) imino1, 3-dihydrospiro [ indene-2, 4' -piperidine)]Tert-butyl-1' -carboxylate (1.01g, 62%) as a black solid. MS: 405(M + H)+.
Step c: reacting (R, Z) -1- ((tert-butylsulfinyl) imino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]A solution of tert-butyl (1.01g, 2.50mmol) of the (E) -1' -carboxylate in THF (10mL) was cooled to-50 ℃. Adding NaBH in portions4(142mg, 3.74 mmol). The mixture was allowed to warm to room temperature, stirred for 15.5h, and then poured into EA (100 mL). The mixture was washed with brine (100 mL. times.3). The organic phase was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. Purifying the residue by column chromatography to obtain the compound (S) -1- (((R) -tert-butylsulfinyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]Tert-butyl 1-carboxylate (580mg, 57%) as a yellow oil. MS: 407(M + H)+.
Step d: the compound (S) -1- (((R) -tert-butylsulfinyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]A solution of tert-butyl (580mg, 1.43mmol) -1' -carboxylate (580mg, 1.43mmol) and TFA (1mL) in DCM (5mL) was stirred at 20 ℃ for 40 min. Concentrating the solution to obtain compound (R) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropane-2-sulfinamide (520mg, 90%) as a yellow oil. MS: 307(M + H)+.
Step e: mixing the compound (R) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropane-2-sulfinamide (260mg, 0.62mmol), 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (196mg, 0.68mmol), K2CO3(427mg, 3.09mmol) and NMP (8mL) were stirred at 100 ℃ for 16 h. The mixture was poured into EA (200mL) and washed with brine (200mL × 3). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purifying the residue by column chromatography to obtain the compound (R) -N- ((S) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) inden-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropane-2-sulfinamide (260mg, 65%) as a yellow solid. MS: 558(M + H)+.
Step f: the compound (R) -N- ((S) -1' - (6-amino-5- ((2-amino-3-chloropyridine)-4-yl) thio) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropane-2-sulfinamide (260mg, 0.47mmol) was dissolved in DCM (5mL) and HCl/1, 4-dioxane (4mol/L, 5mL) was added dropwise. The mixture was stirred at 20 ℃ for 30 minutes. The mixture was concentrated and the residue was dissolved in methanol (2 mL). And EA (5mL) was added. The solid was collected by filtration to give the compound (S) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-amine (123mg, 54%) as an off-white solid. MS: 454(M + H)+.1HNMR(400MHz，DMSO-d6)δ7.81 (d，1H)，7.72(s，1H)，7.62(d，1H)，7.27-7.36(m，3H)，6.12(d，1H)，4.21-4.35(m，3H)，2.97- 3.24(m，4H)，1.77-1.91(m，2H)，1.49-1.59(m，2H).
Example 3
(R) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine ] -2-amine
Step a: a solution of the compound tert-butyl bis (2-chloroethyl) carbamate (11.00g, 45.43mmol) in HCl/1, 4-dioxane (4mol/L, 200mL) was stirred at 20 ℃ for 1 h. The solution was concentrated and the residue was dissolved in DCE (200 mL). Triethylamine (22.95g, 227.14mmol) and benzaldehyde (7.23g, 68.14mmol) were added. Then add NaBH (OAc) in portions3(24.07g, 113.57 mmol). The mixture was stirred at 20 ℃ for 54h, then EA (300mL) and brine (200mL) were added. The organic phase was separated and concentrated under reduced pressure. The residue was dissolved in HCl solution (2mol/L, 200mL) and washed with EA (100 mL). With saturated Na2CO3The solution adjusted the pH of the aqueous phase to 9. The mixture was extracted with EA (200 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the compound N-benzyl-2-chloro-N- (2-chloroethyl) ethane-1-amine (8.52g, 81%) as a colorless oil.
Step b: to a mixed solution of the compound N-benzyl-2-chloro-N- (2-chloroethyl) ethan-1-amine (8.52g, 36.70mmol) and 3, 4-dihydronaphthalen-2 (1H) -one (4.88g, 33.36mmol) in THF (80mL) and DMSO (50mL) was added potassium tert-butoxide (9.36g, 83.14 mmol). Stirring was carried out at 20 ℃ for 20 h. The mixture was concentrated and diluted with EA (200 mL). Then washed with brine (200 mL. times.3). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 1 '-benzyl-3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine as a black oil]2-ketone (2.32g, 21%). MS: 306(M + H)+.
Step c: adding the compound 1 '-benzyl-3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine to ethyl titanate]-2-ketone (2.32g, 7.60mmol) and (R) -2-methylpropane-2-sulfinamide (2.76g, 22.79 mmol). Stirring was carried out at 100 ℃ for 19 h. EA (200mL) and water (200mL) were added. After filtration, the filtrate was separated into layers and the organic phase was collected. The organic phase was washed with brine (100mL × 5), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purifying the residue by column chromatography to obtain the compound (R, E) -N- (1 '-benzyl-3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine)]-2-ylidene) -2-methylpropane-2-sulfinamide (660mg, 21%) as a yellow oil. MS: 409(M + H)+.
Step d: the compound (R, E) -N- (1 '-benzyl-3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine)]A solution of (E) -2-ylidene) -2-methylpropane-2-sulfinamide (660mg, 1.62mmol) in THF (10mL) was cooled to-50 ℃. Then add NaBH in portions4(122mg, 3.23 mmol). The mixture was stirred for 18h and allowed to warm to RT. Quenched with water (50mL) and extracted with EA (50 mL. times.2). The organic phases were combined and washed with brine (50mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purifying the residue by column chromatography to obtain the compound (R) -N- ((R) -1 '-benzyl-3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine)]-2-yl) -2-methylpropane-2-sulfinamide (195mg, 29%) as a yellow oil. MS: 411(M + H)+.
Step e: to the compound (R) -N- ((R) -1 '-benzyl-3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperazinePyridine (I)]To a solution of (2-yl) -2-methylpropane-2-sulfinamide (195mg, 0.47mmol) in methanol (5mL) was added palladium hydroxide (20%, 120 mg). Stirring for 18h at 40 ℃ under hydrogen atmosphere. Filtering and concentrating under reduced pressure to obtain compound (R) -N- ((R) -3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine)]-2-yl) -2-methylpropane-2-sulfinamide (92mg, 60%). MS: 321(M + H)+.
Step f: the compound (R) -N- ((R) -3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine)]-2-yl) -2-methylpropane-2-sulfinamide (92mg, 0.29mmol) was dissolved in NMP (3 mL). 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (91mg, 0.32mmol) and K were added2CO3(198mg, 1.44 mmol). After stirring at 100 ℃ for 3h, it was diluted with EA (30mL) and washed with brine (30 mL. times.3). Anhydrous Na for organic phase2SO4And (5) drying. The residue was purified by Pre-TLC to give (R) -N- ((R) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine]-2-yl) -2-methylpropane-2-sulfinamide (18mg, 11%) as an off-white solid.
Step g: to the compound (R) -N- ((R) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3, 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine]To a solution of (2-yl) -2-methylpropane-2-sulfinamide (18mg, 0.03mmol) in 1, 4-dioxane (2mL) was added HCl/1, 4-dioxane (4mol/L, 2 mL). After stirring for 30min, concentrate and wash twice with EA. Drying the solid in high vacuum to obtain the compound (R) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) 4-dihydro-2H-spiro [ naphthalene-1, 4' -piperidine]-2-amine (14mg, 88%) as an off-white solid. MS: 468(M + H)+.
Example 4
(R) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5, 6-dihydrospiro [ cyclopenta [ b ] pyridine-7, 4' -piperidine ] -6-amine
Step a: NaHMDS (38mL, 2mol/L in THF) was added to a solution of the compound 2-fluoro-3-methylpyridine (5.56g, 50.00mmol) and 1-tert-butyl 4-piperidine-1, 4-dicarboxylate (14.15 g, 55.00mmol) in toluene (50mL) at 0 deg.C, warmed to 20 deg.C naturally and stirred for 24 h. The reaction was quenched with brine (100 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 4- (3-methylpyridin-2-yl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (6.32g, 36%) as a yellow oil. MS: 349(M + H)+.
Step b: a solution of compound 4- (3-methylpyridin-2-yl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (4.80g, 13.78 mmol) and LDA (2mol/L, 17mL) in THF (48mL) was stirred at 0 ℃ for 0.5 h. The volatiles were removed by concentration under reduced pressure. The residue was purified by column chromatography to give 6-oxo-5, 6-dihydrospiro [ cyclopenta [ b ] as a red oil]Pyridine-7, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (0.95g, 23%). MS: 303(M + H)+.
Step c: to 6-oxo-5, 6-dihydrospiro [ cyclopenta [ b ]]Pyridine-7, 4' -piperidines]To a solution of tert-butyl (1' -carboxylate) (0.94g, 3.11 mol) in ethyl titanate (5mL) was added (R) -2-methylpropane-2-sulfinamide (1.13g, 9.33 mmol). Stirring was carried out at 80 ℃ for 1 h. EA (30mL) and water (20mL) were added to the reaction. Filtering, and collecting an organic phase in the filtrate. The aqueous phase was extracted with EA (10 mL. times.2). The combined organic phases were washed with brine (50mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (R, Z) -6- ((tert-butylsulfinyl) imino) -5, 6-dihydrospiro [ cyclopenta [ b ]]Pyridine-7, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (2.51g, crude). The reaction was directly put to the next step without further purification. MS: 406(M + H)+.
Step d: the compound (R, Z) -6- ((tert-butylsulfinyl) imino) -5, 6-dihydrospiro [ cyclopenta [ b ]]Pyridine-7, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (2.12g, crude) in THF (20mL)Stirring at-50 ℃. Reacting NaBH4(176mg, 4.66mmol) was added to the reaction and the temperature was allowed to rise to RT naturally. The reaction was quenched with saturated ammonium chloride solution (30 mL). The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give (R) -6- (((S) -tert-butylsulfinyl) amino) -5, 6-dihydrospiro [ cyclopenta [ b ] as a yellow solid]Pyridine-7, 4' -piperidines]Tert-butyl (1' -carboxylate) (0.21g, 17%, two-step yield). MS: 408(M + H)+.
Step e: the compound (R) -6- (((S) -tert-butylsulfinyl) amino) -5, 6-dihydrospiro [ cyclopenta [ b ]]Pyridine-7, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (204mg, 0.50mmol) and CF3A mixture of COOH (1mL) in DCM (10mL) was stirred at 25 ℃ for 1.5 h. The reaction was concentrated under reduced pressure. The residue was dissolved in NMP (10mL), 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (144mg, 0.50mmol) and K were added2CO3(0.82g, 6.00mmol) and stirred at 95 ℃ for 16 h. Addition of H2O (50mL), extracted with EA (30 mL. times.2). The combined organic phases were washed with brine (50mL) over anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain the compound (S) -N- ((R) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5, 6-dihydrospiro [ cyclopenta [ b ] b]Pyridine-7, 4' -piperidines]-6-yl) -2-methylpropane-2-sulfinamide (302mg, crude). The reaction was directly put to the next step without further purification. MS: 559 (M + H)+.
Step f: to the compound (S) -N- ((R) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) pyridine-7, 4' -piperidine]To a solution of (6-yl) -2-methylpropane-2-sulfinamide (302mg, 0.54mmol) in DCM (10mL) was added HCl/1, 4-dixoane (4mol/L, 1 mL). The system was stirred at 25 ℃ for 1h and filtered. The filter cake was dissolved in MeOH (2mL), DCM (15mL) was added, stirred for 0.5h, and filtered to give the compound (R) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5, 6-dihydrospiro [ cyclopenta [ b ] as a yellow solid]Pyridine-7, 4' -piperidines]-6-amine (163mg, 71%, two-step yield). MS: 455(M + H)+.1HNMR(600MHz，MeOH-d4)δ8.69 (d，1H)，8.54(d，1H)，7.92-7.96(m，1H)，7.88(s，1H)，7.75(d，1H)，6.58(d，1H)，4.54-4.67(m，3H)， 3.89-3.95(m，1H)，3.37-3.61(m，3H)，2.79-2.86(m，1H)，1.93-2.20(m，3H).
Example 5
(S) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -6-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine ] -1-amine
Step a: mixing 6-methoxy-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (557mg, 1.68 mmol) and (R) -2-methylpropane-2-sulfinamide (610mg, 5.04mmol) in Ti (OEt)4The solution (5mL) was stirred at 100 ℃ for 16 h. After cooling to RT, the reaction was diluted with EA (20mL) and water (30 mL). Filter through a pad of celite, rinsing with EA. The filtrate was washed with brine (1X 50mL) and dried over anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain (R, Z) -1- ((tert-butylsulfinyl) imino) -6-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]Tert-butyl (0.98g) -1' -carboxylate, which was used in the next step without further purification. MS: m/z 435(M + H)+.
Step b: to (R, Z) -1- ((tert-butylsulfinyl) imino) -6-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine](ii) -1' -Carboxylic acid tert-butyl ester (0.98g, 2.25mmol) in THF (10mL) NaBH was added4(0.17g, 4.51 mmol). The mixture was warmed to RT and stirred for 24 h. The reaction was diluted with EA (50mL) and water (50mL), the organic phase was separated, washed with brine (1X 50mL), anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 5, v/v) to give (S) -1- (((R) -tert-butylsulfinyl) amino) -6-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1＇-carboxylic acid tert-butyl ester (380 mg). MS: m/z437(M + H)+.
Step c: to (S) -1- (((R) -tert-butylsulfinyl) amino) -6-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]To a solution of tert-butyl (380mg, 0.87mmol) of the-1' -carboxylate in DCM (10mL) was added TFA (2mL) and the mixture was stirred at RT for 1.5 h. The system was concentrated under reduced pressure. The residue was dissolved in NMP (10mL), 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (301mg, 1.04mmol) and K were added2CO3(601mg, 4.35 mmol). The system was stirred at 100 ℃ for 16 h. After cooling to RT, the reaction was diluted with water (50mL) and EA (50 mL). The aqueous phase was separated and the organic phase was washed with brine (2X 50mL) over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM ═ 1: 20, v/v) to give (R) -N- ((S) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-3-yl) -2-methylpropane-2-sulfinamide (254 mg). MS: m/z588(M + H)+.
Step d: to (R) -N- ((S) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-3-yl) -2-methylpropane-2-sulfinamide (254mg, 0.43mmol) in 1, 4-dioxane (3mL) HCl (4M in 1, 4-dioxane, 3mL) was added dropwise and stirred at RT for 30 min. Filtering and drying the collected precipitate in a vacuum oven to obtain (S) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -6-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-amine (221mg, hydrochloride salt). MS: m/z484(M + H)+.1H NMR(600MHz，MeOH-d4)δ7.90(s，1H)，7.76(d，1H)，7.28(d，1H)，7.12(d，1H)，6.95 -6.89(m，1H)，6.58(d，1H)，4.35-4.50(m，3H)，3.82(s，3H)，3.40-3.49(m，2H)，3.08-3.16(m， 2H)，1.66-2.01(m，4H).
The following examples were synthesized with the corresponding intermediate a and intermediate B, according to the methods described above.
The following examples are in the form of the free base or a pharmaceutically acceptable salt thereof.
Example 82
(S) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4' -piperidine ] -7-amine
Step a: reacting 7-oxo-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]A solution of tert-butyl (936mg, 3.10mmol) of the-1' -carboxylic acid and (R) -2-methylpropane-2-sulfinamide (1045mg, 8.62mmol) in ethyl titanate (8mL) was stirred at 100 ℃ for 2 h. After cooling to RT, the reaction was diluted with EA (50mL) and water (50 mL). Filter through a pad of celite and rinse the filter cake with EA. Separating organic phase from filtrate, and adding anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain (R, Z) -7- ((tert-butylsulfinyl) imino) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (1.41 g). MS: m/z406(M + H)+.
Step b: to-40 deg.C of (R, Z) -7- ((tert-butylsulfinyl) imino) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines](ii) -1' -Carboxylic acid tert-butyl ester (1.41g, 3.48mmol) in THF (50mL) was added BH3(1M in THF, 10.00mL, 10.00 mmol). The mixture was warmed to RT and stirred for 1 h. The reaction was quenched with brine (100 mL). The organic phases were collected, the aqueous phase was extracted with EA (1X 60mL), the organic phases were combined and washed with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (100mL) and stirred at 80 ℃ for 15 h. After cooling to RT, the reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM ═ 1: 60, v/v) to give (S) -7- (((R) -tert-butylsulfinyl) amino) -5, 7-dihydrospiro [ cyclopenta [ b ] amine]Pyridine-6, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (309 mg). MS: m/z 408(M + H)+.
Step c: to (S) -7- (((R) -tert-butylsulfinyl) amino) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]To a solution of tert-butyl (1) -carboxylate (309mg, 0.76mmol) in DCM (20mL) was added HCl (4M in EA, 2mL, 8.00mmol) and stirred at RT for 1.5 h. Concentrating under reduced pressure to obtain (S) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-7-amine (227 mg). MS: m/z204(M + H)+.
Step d: reacting (S) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-7-amine (HCl salt, 227mg, 0.73 mmol), 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (249mg, 0.86mmol), K2CO3A mixture of (1149 mg, 8.31mmol) and acetonitrile (15mL) was stirred at reflux for 44 h. After cooling to RT, the reaction was diluted with brine (100mL) and extracted with EA (2X 50 mL). The organic phases were combined and washed with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM ═ 1: 6, v/v) to give (S) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) pyrimidin-5-yl) thio) pyrazin-2-yl) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-7-amine (77 mg). MS: m/z 455(M + H)+.1H NMR(400MHz，MeOH-d4)δ 8.51(s，1H)，7.81(d，1H)，7.63(s，1H)，7.38(s，1H)，5.94(d，1H)，4.49-4.30(m，3H)，3.37-3.09 (m，4H)，2.05-1.95(m，1H)，1.85-1.70(m，2H)，1.60-1.50(m，1H).
The following examples were synthesized with the corresponding intermediate a and intermediate B, according to the methods described above.
In step a of example 82, tert-butylsulfinamide was used instead of (R) -2-methylpropane-2-sulfinamide to give the corresponding racemic product.
The following examples are in the form of the free base or a pharmaceutically acceptable salt thereof.
Example 133
(S) -4- ((5- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -3-chloropyridin-2-ol
Step a-c: (R) -N- ((S) -1 '- (5- ((3-chloro-2-methoxypyridin-4-yl) thio) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) was obtained by the procedure of example 5 (a-c)]-1-yl) -2-methylpropane-2-sulfinamide MS: m/z 558(M + H)+.
Step d: reacting (R) -N- ((S) -1 '- (5- ((3-chloro-2-methoxypyridin-4-yl) thio) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]A mixture of-1-yl) -2-methylpropane-2-sulfinamide (112mg, 0.20mmol), DCM (5mL) and HCl (4M in 1, 4-dioxane, 10mL) was stirred at RT for 17 h. The mixture was concentrated under reduced pressure, the residue dissolved in MeOH (10mL), and stirred at 60 ℃ for an additional 23 h. After cooling to RT, the reaction was concentrated under reduced pressure. The residue was dispersed in MeOH (2mL) and EA (20mL), and the precipitate was collected by filtration and dried under reduced pressure to give (S) -4- ((5- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) pyrazin-2-yl) thio) -3-chloropyridin-2-ol (73 mg). MS: m/z440(M + H)+.1H NMR(400MHz，DMSO-d6)δ8.51(s，1H)，8.34(s，1H)，7.59(d，1H)，7.28-7.37(m， 3H)，7.23(d，1H)，5.52(d，1H)，4.28-4.40(m，3H)，3.21-3.38(m，3H)，3.02-2.99(d，1H)，1.75-1.82(m，2H)，1.52-1.60(m，2H).
The following examples were synthesized by the above-described method using the corresponding starting materials. .
The following examples are in the form of their free bases or pharmaceutically acceptable salts.
Watch 18
Example 137
(S) -1-amino-1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ] -6-ol
(S) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -6-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]To a solution of (74mg, 0.14mmol) of (E) -1-amine in DCM (2mL) was added BBr3(1M in DCM, 0.71 mL). The system was stirred at RT for 6 h. Concentrating under reduced pressure to remove volatiles, dispersing the residue in water, filtering off the solid, and diluting with saturated NaHCO3The aqueous solution adjusted the pH of the filtrate to 7. The resulting precipitate was collected by filtration and dried in a vacuum oven to give (S) -1-amino-1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-6-ol (7 mg). MS: m/z 470(M + H)+.
The following examples were synthesized by the above-described method using the corresponding starting materials.
Watch 19
Example 139
1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5-methyl-5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4' -piperidine ] -5-amine
Step a: synthesis of (R, Z) -5- ((tert-butylsulfinyl) imino) -5, 7-dihydrospiro [ cyclopenta [ b ] with reference to step a of example 5]Pyridine-6, 4' -piperidines]-1' -carboxylic acid tert-butyl ester. MS: m/z406(M + H)+.
Step b: to-60 aC of (R, Z) -5- ((tert-butylsulfinyl) imino) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]To a solution of tert-butyl (1.49g, 3.67mmol) of (E) -1' -carboxylate in THF (15mL) was added dropwise methyllithium (1.3M in diethyl ether, 14mL, 18.20 mmol). The mixture was warmed to RT and stirred for 20 h. Dilute with water (10mL) and EA (20 mL). The aqueous phase was separated and NaOH (1.00g, 25.00mmol) and (Boc) were added2O (0.50 mL). The mixture was stirred at RT for 1.5 h. Extraction with EA (2X 50mL), combining the organic phases, washing with brine (1X 30mL), over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA: Hex ═ 1: 1, v/v) to give 5- (((R) -tert-butylsulfinyl) amino) -5-methyl-5, 7-dihydrospiro [ cyclopenta [ b ] amine]Pyridine-6, 4' -piperidines]-1' -carboxylic acid tert-butyl ester (823 mg). MS: m/z 422(M + H)+.
Step (c-d): reference exampleStep (c-d) of 5 Synthesis of 1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -5-methyl-5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]5-amine (71mg). MS: m/z469(M + H)+.1H NMR(400MHz，MeOH-d4)δ8.50-8.44(m，1H)，7.93-7.87(m，1H)，7.67-7.61(m，2H)， 7.41-7.35(m，1H)，5.97(d，1H)，4.54(m，2H)，3.35(d，1H)，3.23-3.08(m，3H)，1.92-1.78(m， 2H)，1.57-1.48(m，2H)，1.44(s，3H).
Example 140
1-amino-1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3H-spiro [ indolizine-2, 4' -piperidin ] -7(1H) -one
Step a: to-10 ℃ 1-hydroxy-7-oxo-1, 7-dihydro-3H-spiro [ indolizine-2, 4' -piperidine]To a solution of tert-butyl (1' -carboxylate) (100mg, 0.31mmol), triethylamine (157mg, 1.55mmol) in THF (10mL) and DCM (2mL) was added MsCl (66mg, 0.58 mmol). The resulting solution was stirred at RT for 1 h. The reaction was diluted with water (50mL) and extracted with DCM (3X 50 mL). The combined organic phases were passed over anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to give 1- ((methylsulfonyl) oxy) -7-oxo-1, 7-dihydro-3H-spiro [ indolizine-2, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (155 mg). MS: m/z399(M + H)+.
Step b: mixing 1- ((methylsulfonyl) oxy) -7-oxo-1, 7-dihydro-3H-spiro [ indolizine-2, 4' -piperidine]A mixture of tert-butyl (155mg, 0.39mmol) 1' -carboxylate, sodium azide (136mg, 2.09mmol) and DMF (5mL) was stirred at 75 ℃ for 1h and 85 ℃ for 4 h. After cooling to RT, the reaction was diluted with EA (30mL), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM ═ 1: 10, v/v) to give 1-azido-7-oxo-1, 7-dihydro-3H-spiro [ indolizine-2, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (32 mg). MS: m/z346(M + H)+.
Step c: 1-azido-7-oxo-1, 7-dihydro-3H-spiro [ indolizine-2, 4' -piperidine]A solution of tert-butyl (32mg, 0.093mmol) of-1' -carboxylate, Pd/C (10%, 15mg) in EtOH (6mL) was stirred under hydrogen for 3 h. Filtering the reaction system, leaching the filter cake with EtOH, and concentrating the filtrate under reduced pressure to obtain 1-amino-7-oxo-1, 7-dihydro-3H-spiro [ indolizine-2, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (26 mg). MS: m/z 320(M + H)+.
Step d: to 1-amino-7-oxo-1, 7-dihydro-3H-spiro [ indolizine-2, 4' -piperidine]To a solution of tert-butyl (1' -carboxylate) (26mg, 0.081 mmol) in DCM (2mL) was added TFA (2mL) and stirred at room temperature for 30 min. The system was concentrated under reduced pressure. The residue was dissolved in NMP (2.5mL), 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (46mg, 0.16mmol) and K were added2CO3(395mg, 2.86mmol) and stirred at 95 ℃ for 16 h. After cooling to RT, it was diluted with DCM (30mL), filtered and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with MeOH: DCM ═ 1: 3, v/v) to give 1-amino-1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3H-spiro [ indolizine-2, 4' -piperidine]-7(1H) -one (2 mg). MS: m/z471(M + H)+.
The following examples were synthesized by the above-described method using the corresponding starting materials.
Watch 20
Example 142
3- ((2-amino-3-chloropyridin-4-yl) thio) -6- (1-imino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) pyrazin-2-amine
Step a: synthesis of (R, Z) -1- ((tert-butylsulfinyl) imino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine by step a of example 5]-1' -carboxylic acid tert-butyl ester MS: m/z 405(M + H)+.
Step b: to (R, Z) -1- ((tert-butylsulfinyl) imino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]To a solution of tert-butyl (405mg, 1.00mmol) of-1' -carboxylate in DCM (10mL) was added TFA (1mL) and stirred at RT for 1.5 h. The system was concentrated under reduced pressure. The residue was dissolved in NMP (10mL), 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (288mg, 1.00mmol) and K were added2CO3(1.38g, 10.00 mmol). The system was stirred at 100 ℃ for 18 h. After cooling to RT, it was diluted with water (50mL) and extracted with EA (3X 30 mL). The combined organic phases were washed with brine (1X 100mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH: DCM ═ 1: 5, v/v) to give 3- ((2-amino-3-chloropyridin-4-yl) thio) -6- (1-imino-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) pyrazin-2-amine (50 mg). MS: m/z452(M + H)+.1H NMR(400 MHz，MeOH-d4)δ7.83(d，1H)，7.37-7.74(m，5H)，5.96(d，1H)，4.43-4.58(m，2H)，3.12-3.28 (m，4H)，2.01-2.06(m，2H)，1.56-1.60(m，2H).
The following examples were synthesized with the corresponding starting materials in accordance with the above procedure.
TABLE 21
Example 148
1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -7-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine ] -1-amine
Step a: to 7-methoxy-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine]To a solution of tert-butyl (552mg, 1.07 mmol) of (E) -1' -carboxylate in MeOH (10mL) were added hydroxylamine hydrochloride (348mg, 5.01mmol) and AcONa (822 mg, 10.02 mmol). The system was stirred at RT for 4 h. The reaction was concentrated under reduced pressure. The residue was dissolved in EA (15mL) and water (15mL), the organic phase was separated, washed with brine (1X 15mL), dried over anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain (Z) -1- (hydroxyimino) -7-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine of yellow solid]-1' -Carboxylic acid tert-butyl ester (520 mg). MS: m/z347(M + H)+.
Step b: mixing (Z) -1- (hydroxyimino) -7-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (510 mg, 1.47mmol), PtO2A mixture of (30mg) and AcOH (10mL) was stirred under hydrogen at 60 ℃ for 17 h. After cooling to RT, the reaction was diluted with EA (45mL) and water (45mL), the aqueous phase was separated and washed with K2CO3The solid adjusted the pH to 10. The system was extracted with DCM (2X 30mL), and the combined organic phases were washed with brine (1X 50mL) and anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain colorless oily 1-amino-7-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (202 mg). MS: m/z333(M + H)+.
Step c: to 1-amino-7-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]To a solution of tert-butyl (199mg, 0.60 mmol) of-1' -carboxylate in DCM (10mL) was added TFA (1mL) and stirred at RT for 1.5 h. The system was concentrated under reduced pressure. The residue was dissolved in NMP (5mL) and 3- ((2-amino-3-chloropyridin-4-yl) thio) -6-chloropyrazin-2-amine (144mg, 0.50mmol) and K were added2CO3(691mg, 5.90 mmol). The system was stirred at 95 ℃ for 3 h. After cooling to RT, the reaction was diluted with water (50mL) and EA (1)X 50 mL). The organic phase was washed with brine (1X 50mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with MeOH: DCM ═ 1: 5, v/v) to give 1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -7-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-amine (20 mg). MS: m/z484(M + H)+.1H NMR(400MHz，DMSO-d6)6 7.66(s，1H)，7.64(d，1H)，7.36-7.28(m，1H)，6.90(d，1H)，6.88(d，1H)，5.75(d，1H)，4.29(s，1H)， 4.20(d，1H)，4.09(d，1H)，3.83(s，3H)，3.30-3.15(m，2H)，3.10(d，1H)，2.96(d，1H)，1.87-1.76 (m，1H)，1.70-1.54(m，2H)，1.41(d，1H).
The following examples were synthesized with the corresponding starting materials in accordance with the above procedure.
TABLE 22
Example 150
(S) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-methoxy-4, 6-dihydrospiro [ cyclopenta [ d ] thiazole-5, 4' -piperidine ] -4-amine
Step (a-b): synthesis of (S) -4- (((R) -tert-butylsulfinyl) amino) -2-chloro-4, 6-dihydrospiro [ cyclopenta [ d ] with reference to step (a-b) of example 5]Thiazole-5, 4' -piperidines]-1' -carboxylic acid tert-butyl ester. MS: m/z448(M + H)+.
Step c: (S) -4- (((R) -tert-butylsulfinyl) amino) -2-chloro-4, 6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (403mg, 0.90mmol), NaOHA mixture of (358mg, 8.95mmol) and MeOH (15mL) was stirred at 65 ℃ for 5 h. After cooling to RT, the volatiles were removed by concentration under reduced pressure. The residue was dissolved in water and the pH adjusted to 7 by addition of saturated aqueous citric acid. The system was extracted with EA (3X 30mL) and the combined organic phases were passed over anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to give (S) -4- (((R) -tert-butylsulfinyl) amino) -2-methoxy-4, 6-dihydrospiro [ cyclopenta [ d ] as a brown oil]Thiazole-5, 4' -piperidines]-1' -carboxylic acid tert-butyl ester (360 mg). MS: m/z 444(M + H)+.
Step (d-e): synthesis of (S) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-methoxy-4, 6-dihydrospiro [ cyclopenta [ d ] with reference to step (c-d) of example 5]Thiazole-5, 4' -piperidines]-4-amine. MS: m/z 491(M + H)+.
Example 151
(S) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -4, 6-dihydrospiro [ cyclopenta [ d ] thiazole-5-, 4' -piperidine ] -4-amine
Step (a-b): synthesis of (S) -4- (((R) -tert-butylsulfinyl) amino) -2-chloro-4, 6-dihydrospiro [ cyclopenta [ d ] with reference to step (a-b) of example 5]Thiazole-5, 4' -piperidines]-1' -carboxylic acid tert-butyl ester. MS: m/z448(M + H)+.
Step c: (S) -4- (((R) -tert-butylsulfinyl) amino) -2-chloro-4, 6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5, 4' -piperidines]A mixture of tert-butyl-1' -carboxylate (2.50g, 5.58mmol), TEA (2mL), Pd/C (10%, 690mg) and MeOH (50mL) was stirred under hydrogen at 40 ℃ for 24 h. Filtration was carried out and Pd/C (10%, 1.32 g) was added to the filtrate. Stirring for another 16h at 50 ℃ under hydrogen atmosphere. Filtering, and concentrating the filtrate under reduced pressure. Chromatography on silica gel (with EA: Hex)1: 1, v/v) to give (S) -4- (((R) -tert-butylsulfinyl) amino) -4, 6-dihydrospiro [ cyclopenta [ d ] amino)]Thiazole-5, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (1.28 g). MS: m/z414(M + H)+.
Step (d-e): synthesis of (S) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -4, 6-dihydrospiro [ cyclopenta [ d ] with reference to step (c-d) of example 5]Thiazole-5, 4' -piperidines]-4-amine. MS: m/z461(M + H)+.1H NMR (400MHz，DMSO-d6)δ8.94(s，1H)，7.63-7.66(m，2H)，5.76(d，1H)，3.99-4.07(m，2H)，3.87(s， 1H)，3.28-3.38(m，2H)，2.78-2.93(m，2H)，1.47-1.87(m，4H).
In step a of example 5, tert-butylsulfinamide was used instead of (R) -2-methylpropane-2-sulfonamide to give the corresponding racemic product.
The following examples were synthesized with the corresponding starting materials in accordance with the above procedure.
TABLE 23
EXAMPLE 155
(S) -1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -4, 6-dihydrospiro [ cyclopenta [ d ] thiazole-5, 4' -piperidine ] -6-amine
Step a: synthesis of (R, Z) -6- ((tert-butylsulfinyl) imino) -2-chloro-4, 6-dihydrospiro [ cyclopenta [ d ] with reference to step a of example 5]Thiazole-5, 4' -piperidines]-1' -carboxylic acid tert-butyl ester. MS: m/z 446(M + H)+.
Step b: to (R, Z) -6- ((tert-butylsulfinyl) imino) -2-chloro-4, 6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5, 4' -piperidines](iv) -1' -Carboxylic acid tert-butyl ester (4.25g, 9.53mmol) in THF (30mL) was added BH3(1M in THF, 30.00mL, 30.00 mmol). The mixture was warmed to RT and stirred for 18 h. The reaction was quenched with brine (50 mL). The organic phase was separated off and washed with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with (EA: Hex ═ 1: 2, v/v) to give (S) -6- (((R) -tert-butylsulfinyl) amino) -4, 6-dihydrospiro [ cyclopenta [ d ] amine]Thiazole-5, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (1.12 g). MS: m/z414(M + H)+.
Step (c-d): synthesis of (S) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -4, 6-dihydrospiro [ cyclopenta [ d ] with reference to step (c-d) of example 5]Thiazole-5, 4' -piperidines]-6-amine.1H NMR(400MHz，DMSO-d6)δ 9.01(s，1H)，7.63-7.66(m，2H)5.76(d，1H)，4.19-4.23(m，2H)，4.09(s，1H)，3.15-3.32(m，2H)， 2.80-2.93(m，2H)，1.60-1.87(m，4H).MS：m/z 461(M+H)+.
The following examples were synthesized with the corresponding starting materials in accordance with the above procedure.
Watch 24
Example 157
(S) -1 '- (6-amino-5- ((3-fluoro-1H-indol-4-yl) thio) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ] -1-amine
(S) -1- (4- ((3-amino-5- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) pyrazine-2-yl) thio) -3, 3-difluoroindolin-1-yl) ethan-1-one (86mg, 0.16mmol) was dissolved in MeOH (8mL) and NaOH (17mg, 0.43mmol) was added. The system was stirred for a further 21h at 65 ℃. After cooling to RT, the reaction was concentrated under reduced pressure. The residue was diluted with water (10mL) and EA (20 mL). The separated organic phase was washed with brine (10mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. Adding EA (5mL) and Hex (3mL) for pulping, filtering, collecting precipitate, and drying under reduced pressure to obtain (S) -1' - (6-amino-5- ((3-fluoro-1H-WIndol-4-yl) thio) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-amine (14 mg).1HNMR(400MHz，DMSO-d6)δ7.59(s，1H)，7.37-7.21(m，5H)，7.13(d，1H)，7.00 -6.93(m，1H)，6.40(d，1H)，4.18(d，2H)，3.97(s，1H)，3.09(m，3H)，2.72(m，1H)，1.77-1.62(m， 2H)，1.50-1.47(m，1H)，1.20-1.16(m，1H)MS：461(M+H)+.
Example 158
(S) -1- (1-amino-1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -6-yl) ethan-1-one
Step a-b: synthesis of (S) -1- (((R) -tert-butylsulfinyl) amino) -6-cyano-1, 3-dihydrospiro [ indene-2, 4' -piperidine) with reference to step (a-b) of example 5]-1' -carboxylic acid tert-butyl ester. MS: m/z 432(M + H)+.
Step c: to-50 deg.C (S) -1- (((R) -tert-butylsulfinyl) amino) -6-cyano-1, 3-dihydrospiro [ indene-2, 4' -piperidine]Methyl magnesium bromide (3M solution in THF/Hex, 0.50mL, 1.50mmol) was added dropwise to a solution of tert-butyl (1' -carboxylate) (430mg, 1.00mmol) in THF (10 mL). Naturally warming to room temperature and stirring for 24 h. The reaction was quenched with brine (10 mL). Separating the organic phase with anhydrous Na2SO4Drying, filtering and concentrating under reduced pressureCondensing to obtain (S) -6-acetyl-1- (((R) -tert-butylsulfinyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]Tert-butyl (0.72g) -1' -carboxylate, which was used in the next step without further purification. MS: m/z 449(M + H)+.
Step d-e: synthesis of (S) -1- (1-amino-1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) with reference to step (c-d) of example 5]-6-yl) ethan-1-one. MS: 496(M + H)+.
The following examples were synthesized with the corresponding starting materials in accordance with the above procedure.
TABLE 25
The following examples can be synthesized using the methods described above and suitable starting materials:
watch 26
Pharmacological testing
Example a phosphatase activity assay (single dose):
single dose inhibition assay PTP was activated by co-incubation of 6, 8-difluoro-4-methylumbelliferone phosphate (DiFMUP) as substrate for 30min with SHP2 enzyme solution (diluted to 0.5nM in the reaction medium) and dPEG8 peptide in reaction medium (60mM dimethyl 3, 3-glutarate (pH7.2), 75mM NaCl, 75mM KCl, 1mM EDTA, 0.05% Tween 20, 2mM Dithiothreitol (DTT)). DMSO (0.5% (V/V) or compound (100nM) was added to the mixture, incubation was continued at room temperature for 30min, DiFMUP (12. mu.M, total volume of reaction solution 100. mu.L) was added, the reaction was started, after incubation for 30min, the fluorescence intensity of the reaction solution (excitation light 340nM, emission light 450nM) was measured using 2104-0020envision xcite Multilabel Reader (PerkinElmer), three wells were set for each dose, the fluorescence value of the control well (DMSO) was set to 100%, the inhibitory activity of the compound-treated wells was expressed as a percentage of the control wells, and the inhibitory activity of the compound of the present invention against SHP2 is shown in Table A.
TABLE A
Phosphatase activity assay (IC50 assay):
IC50value detection, PTP was activated by incubating 6, 8-difluoro-4-methylumbelliferone phosphate (DiFMUP) as a reaction substrate with SHP2 enzyme solution (diluted to 0.5nM in the reaction solution) and dPEG8 peptide in a reaction solution (60mM3, dimethyl-3-glutarate (pH7.2), 75mM NaCl, 75mM KCl, 1mM EDTA, 0.05% Tween 20, 2mM Dithiothreitol (DTT)) for 30 minutes. DMSO (0.5% (V/V) or a compound (concentration: 0.3 nM-1. mu.M) was added to the mixture, incubation was continued at room temperature for 30min, DiFMUP (12. mu.M, total volume of the reaction solution: 100. mu.L) was added to start the reaction, after incubation for 30min, the fluorescence intensity (excitation light 340nM, emission light 450nM) of the reaction solution was measured with 2104-0020EnVision Xcite Multilabel Reader (Perkinelmer). The IC of the present invention, in which the compound inhibits the enzymatic activity of SHP2, was used50See table B.
TABLE B
Example C cell proliferation assay:
MV-4-11 cells (4000 cells/well) were plated in 96-well plates in a medium of 100. mu.L/well (IMDM containing 3% Fetal Bovine Serum (FBS), from Gibco). After 24 hours of incubation, compounds of the invention formulated to different concentrations were added. On day 8, 30. mu.L of MTS/PMS reagent (purchased from Promega, Sigma, respectively) was added to each well, and absorbance was measured according to the protocol (Promega). IC of the Compounds of the invention50The values are shown in Table C.
Watch C
Example D p-measurement of ERK cellular levels
The level of activation of ERK1/2 was detected by immunoblotting using an antibody against p-ERK 1/2. Briefly, MV-4-11 human leukemia cells were incubated with a range of compounds (concentrations from 0.3nM to 100nM) for 2 hours. Cells were lysed using RIPA buffer (Thermo Fisher Scientific, Rockford, IL, USA) containing a cocktail of Halt protease inhibitors and total cellular protein was recovered. mu.L of total protein was separated by SDS-PAGE under reducing conditions and transferred to PVDF membrane (Bio-Rad). After blocking with Tris buffered saline solution containing 5% BSA, the membrane was incubated with primary antibody overnight at 4 ℃ followed by incubation with horseradish peroxidase (HRP) labeled secondary antibody for 1 hour. The bound secondary antibody is detected using chemiluminescence.
Example E MV-4-11 xenograft tumor model
MV-4-11 cell culture was expanded, collected and injected subcutaneously into 5-8 week old female NOD/SCID mice (5X 10)6One cell per mouse, n-6-10 per group). When the average tumor volume is about 100-3At that time, oral gavage (0.1-10 mpk/dose) is initiated. During the treatment period (once or twice a day)For 2-4 weeks), tumor volume was measured using a vernier caliper. Differences in tumor volume between groups were counted using a one-way ANOVA analysis. The solvent is a negative control.
The compounds provided herein are preferably formulated into pharmaceutical compositions for administration by various routes. Most preferably, the pharmaceutical composition is for oral administration, such pharmaceutical compositions and methods for their preparation are well known in the art, see, e.g., remington: pharmaceutical science and practice (edited by a jennaro et al, 19 th edition, macpress, 1995) [ REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al, eds., 19)thed.，Mack Publishing Co.，1995)]The compounds of formula I, II, III or IV are generally effective over a wide dosage range.
In summary, most of the compounds listed in this invention are very potent and selective with an IC50 of less than 10 nM. They also show good antitumor effects in vivo models. For example, daily dosages typically fall within the range of about 0.2mg to 100mg dosages, preferably 0.2mg to 50mg dosages, more preferably 0.2mg to 20mg dosages. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed. The above dosage ranges do not limit the scope of the invention in any way. It will be understood that the actual amount of the compound administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's condition.

Claims (51)

1. A compound represented by structural formula I:
the method is characterized in that:
each R1Are all independently selected from-H, halogen, -NH2-CN, substituted or unsubstituted-C1-6Alkoxy, or substituted or unsubstituted-C1-6An alkyl group;
R2selected from-H, halogen, -NH2、-CN、-OH、-NHC1-6Alkyl, -N (C)1-6Alkyl radical)2Substituted or unsubstituted-C1-6Alkoxy, substituted or unsubstituted-C1-6Alkyl or-C5-10A heterocyclic group; or
R2To adjacent R1Are linked together with the carbon atom to which they are each attached to form a 6-10 membered aromatic ring, a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring, and each ring system independently may be optionally unsubstituted or substituted with 1, 2 or 3 halogens, -NH2、-CN、-C1-6Alkyl or-CO-C1-6Alkyl substitution;
each Y1Independently selected from N or CH;
R3is selected from-H or-NH2；
Each R4aAnd R4bAre all independently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy or-C1-6An alkyl group;
or
R4aAnd R4bTogether with the carbon atom to which they are both attached form CO, C ═ NH, or C ═ N-OH;
p is 0, 1, 2 or 3;
each R5aAnd R5bAre all independently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy or-C1-6An alkyl group; or
R5aAnd R5bTogether with the carbon atom to which they are both attached, form a 3-5 membered heterocyclyl or C ═ NH;
q is 0, 1, 2, 3 or 4;
w is absent, O, S or NRw(ii) a And R iswis-H, halogen, -NH2、-CN、-OH、-NO2Carboxy, -C1-6alkyl-O-C1-6Alkoxy, substituted or unsubstituted-C1-6Alkoxy, or substituted or unsubstituted-C1-6An alkyl group;
ring A is absent or is a 3-10 membered ring;
represents a single bond or a double bond;
when ring A is absent, Y2Is CR2aR2b、NR2aOr O, and Y3Is CR3aR3b、NR3aOr O;
when ring A is a 3-to 10-membered ring:
i) when in useWhen represents a single bond, Y2Is CR2aOr N, and Y3Is CH or N; or
ii) whenWhen representing a double bond, Y2Is C, and Y3Is C;
each R2a、R2b、R3aAnd R3bAre all independently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy, substituted or unsubstituted-C1-6Alkoxy, or substituted or unsubstituted-C1-6An alkyl group;
each R6Independently selected from-H, halogen, -NR6aR6b、-CN、-OH、-NO2Oxo, ═ O, carboxyl, -C1-6Alkoxy, -C1-6Alkyl, -C1-6alkenyl-NR6aR6b、-C1-6alkenyl-O-C1-6Alkyl, -C1-6Alkenyl, -CO-OR6a、-C1-6alkenyl-C3-10Heterocyclyl radical, -C1-6alkenyl-C5-10Heteroaryl, -C1-6alkenyl-CO-NR6aR6b、-C1-6alkenyl-NR6a-CO-NR6aR6b、-C1-6alkenyl-NR6a-CO-C1-6Alkyl, -CO-NR6aR6b、-CO-CO-NR6aR6b、-C3-10Carbocyclyl, -C3-10Heterocyclyl, -CO-C1-6Alkyl, -CO-C1-6alkenyl-NR6aR6b、-CO-NR6a-C3-10heterocyclyl-CO-NR6a-C3-10Heterocyclyl, -CO-C3-10Heterocyclyl, -O-C1-6alkenyl-CO-OR6a、-O-C1-6alkenyl-CO-NR6aR6b、-O-C1-6alkenyl-NR6aR6b、-O-C3-10Carbocyclyl, -O-C3-10Heterocyclyl radical, -NR6a-CO-C1-6Alkyl, -NR6a-CO-NR6aR6b、-NR6a-CO-C5-10Heteroaryl, -NR6a-C1-6olefin-NR6aR6b、-NR6a-C1-6olefin-C3-10Heterocyclyl radical, -NR6a-C1-6olefin-C5-10Heteroaryl, -NR6a-SO2C1-6Alkyl, -S-C1-6Alkyl, -SONR6aR6b、-SO2NR6aR6b、-SO-C1-6Alkyl, -SO2C1-6Alkyl, -PO (C)1-6Alkyl radical)2、-PO(C1-6Alkoxy group)2、-C3-10Heterocyclyl or-C5-10A heteroaryl group; each R6Each independently optionally substituted or unsubstituted with 1, 2 or 3 substituents; and n is 0, 1, 2, 3, 4, 5 or 6; or
Two adjacent R6Taken together and together with the carbon atoms to which they are respectively attached form a 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, -C3-6Heterocyclyl or-C3-6Carbocyclyl, and each ring system independently is optionally substituted or unsubstituted with one or more substituents;
each R6aAnd R6bAre all independently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy, substituted or unsubstituted-C1-6Alkoxy, or substituted or unsubstituted-C1-6An alkyl group.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: each R1Independently selected from-H; -F; -Cl; -Br; -NH2；-CN；-OH；-NO2(ii) a A carboxyl group; -C1-6An alkyl group; -C1-6An alkoxy group; by 1, 2 or 3 halogens, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkyl or-C1-3alkoxy-substituted-C1-6An alkyl group; or by 1, 2 or 3 halogens, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkyl or-C1-3alkoxy-substituted-C1-6An alkoxy group.
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that: each R1Independently selected from-H; -F; -Cl; -Br; -NH2；-CN；-OH；-NO2(ii) a A carboxyl group; a methyl group; an ethyl group; propyl; isopropyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; by 1, 2 or 3-F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted-C1-3An alkyl group; or by 1, 2 or 3 of-F, -Cl, -Br, -NH2、-CN、-OH、-NO2C substituted by carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy1-3An alkoxy group.
4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein: each R1Independently selected from-H; -F; -Cl; -Br; -NH2(ii) a -CN; -OH; a methyl group; an ethyl group; propyl; isopropyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; or methyl substituted with 1, 2 or 3 substituents, and each substituent is independently selected from-F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, whereinCharacterized in that: r2Is selected from-H; -F; -Cl; -Br; -NH2；-CN；-OH；-NO2；-N3(ii) a A carboxyl group; -C1-3An alkyl group; -C1-3An alkoxy group; -NHC1-3An alkyl group; -N (C)1-3Alkyl radical)2；-CONH2；-CONHC1-3An alkyl group; -CON (C)1-3Alkyl radical)2；-COC1-3An alkyl group; -NHCOC1-3An alkyl group; -N (C)1-3Alkyl) -CO-C1-3An alkyl group; -C5-10A heterocyclic group; is substituted by 1, 2 or 3 substituents selected from-F, -Cl, -Br, -I, -NH2-C substituted by a substituent of-CN or-OH1-3An alkyl group; or is substituted by 1, 2 or 3 groups selected from-F, -Cl, -Br, -I, -NH2-C substituted by a substituent of-CN or-OH1-3An alkoxy group.
6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein: r2Is selected from-H; -F; -Cl; -Br; -NH2；-CN；-OH；-NO2；-N3(ii) a A carboxyl group; a methyl group; an ethyl group; propyl; isopropyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; -NHCH3；-N(CH3)2；-CONH2；-CONHCH3；-CON(CH3)2；-COCH3；-NH-COCH3；-N(CH3)-COCH3；Or methyl or ethyl by 1, 2 or 3 substituents selected from-F, -Cl, -Br, -NH2-CN or-OH.
7. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein: r2R adjacent thereto1Are linked and taken together with the carbon atom to which they are each linked to form a 5-membered heteroaryl, 6-membered aryl, 5-membered heterocyclyl or 6-membered heterocyclyl; and each of said hetero compoundsAryl or heterocyclyl contains 1 or 2 heteroatoms selected from N or O; and each said ring system is independently optionally substituted by-F, -Cl, -Br, -I, -NH2、-CN、-OH、-NO2Carboxy, oxo, ═ O, -CONH2Substituted or unsubstituted C1-3Alkoxy, substituted or unsubstituted C1-3Alkyl, -C1-3alkenyl-O-C1-3Alkyl, -C1-3alkenyl-COOH, -C1-3alkenyl-NHCONH2、-CO-N(C1-3Alkyl radical)2、-C1-3alkenyl-NHCO-C1-3Alkyl, -CO-CO-N (C)1-3Alkyl radical)2、-CO-C1-3Alkyl, -SONH2、-SO2NH2、-SOCH3or-SO2CH3Substituted or unsubstituted.
8. The compound according to any one of claims 1-4 or 7, or a pharmaceutically acceptable salt thereof, wherein: r2R adjacent thereto1Are linked and taken together with their respective linking carbon atoms to form a 5-membered heteroaryl, 6-membered aryl, 5-membered heterocyclyl or 6-membered heterocyclyl; and each heteroaryl or heterocyclyl group contains 1 heteroatom selected from N or O; and each ring system may be independently optionally substituted by-F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, oxo, ═ O, -CONH2Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CH2OCH3、-CH2COOH、-CH2NHCONH2、-CON(CH3)2、-CH2NHCOCH3、-CO-CON(CH3)2or-COCH3Substituted or unsubstituted.
9. The compound of any one of claims 1-4 or 7-8, or a pharmaceutically acceptable salt thereof, R2R adjacent thereto1Are linked and form together with the carbon atoms to which they are respectively linked
10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein: each R4aAnd R4bAre independently selected from-H, -F, -Cl, -Br, -I and-NH2、-CN、-OH、-NO2Carboxy or-C1-3An alkyl group; or
R4aAnd R4bTogether with the carbon atom to which they are both attached, form C-O, C-NH or C-N-OH.
11. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein: each R4aAnd R4bAre all independently selected from-H, -NH2-OH, methyl, ethyl, methoxy or ethoxy; or
R4aAnd R4bTogether with the carbon atom to which they are commonly attached, form C ═ O.
12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein: each R5aAnd R5bAre each independently selected from-H; -F; -Cl; -Br; -I; -NH2；-CN；-OH；-NO2(ii) a A carboxyl group; -C1-3An alkyl group; -C1-3An alkoxy group; is substituted by-F, -Cl, -Br, -I, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkyl or-C1-3alkoxy-substituted-C1-6An alkyl group; or by-F, -Cl, -Br, -I, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkyl or-C1-3alkoxy-substituted-C1-6An alkoxy group; or
R5aAnd R5bTogether with the carbon atom to which they are both attached, form C ═ NH, 3-membered heterocyclyl, 4-membered heterocyclyl, or 5-membered heterocyclyl; and each of said heterocyclyl groups independently optionally includes 1 or 2 heteroatoms selected from N or O; and each ring system may be independently optionally substituted by-H, -F, -Cl, -Br, -I, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkoxy or-C1-3Alkyl is substituted or unsubstituted.
13. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein: each R5aOr R5bAre all independently selected from-H, -NH2-OH, methyl, ethyl, methoxy or ethoxy; or
R5aAnd R5bTogether with the carbon atom to which they are commonly attached, form C ═ NH, 3-membered heterocyclyl, 4-membered heterocyclyl, or 5-membered heterocyclyl; and each of said heterocyclyl groups contains 1 heteroatom selected from N or O.
14. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein: w is NRwAnd R iswSelected from-H, -F, -Cl, -Br, -I, -NH2、-CN、-OH、-NO2Carboxy, -C1-3alkyl-O-C1-3Alkyl, -C1-3Alkoxy or-C1-3An alkyl group.
15. The compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein: w is NRwAnd R iswSelected from-H, -F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, methyl, ethyl, propyl, isopropyl, methoxyEthoxy, propoxy, isopropoxy, methyl-CO-methyl or methyl-CO-methoxy.
16. The compound according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein: ring a is selected from 6-membered aryl, 10-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 9-membered heterocyclyl, 10-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, 8-membered carbocyclyl, 9-membered carbocyclyl, or 10-membered carbocyclyl; and each heteroaryl or each heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S.
17. The compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein: ring a is selected from 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl; a 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, or 8-membered carbocyclyl; and each heteroaryl and each heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N, O or S.
18. The compound according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein: ring A is selected from
19. The compound according to any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein: each R2a、R2b、R3aAnd R3bAre all independently selected from-H, -F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkyl or-C1-3An alkoxy group.
20. The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein: each R2a、R2b、R3aAnd R3bAre all independently selected from-H, -F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy.
21. The compound according to claim 19 or 20, or a pharmaceutically acceptable salt thereof, wherein: r2aAnd R2bEach independently is-H or methyl, and R3aAnd R3bEach independently is-H.
22. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-21, characterized in that: each R6Are all independently selected from-H, -F, -Cl, -Br, -NR6aR6b-CN, -OH, oxo, - (O), carboxy, -C1-3Alkoxy, -C1-4Alkyl, -C1-3alkenyl-NR6aR6b、-C1-3alkenyl-O-C1-3Alkyl, -C1-3alkenyl-CO-OR6a、-C1-3alkenyl-C5-6Heterocyclyl radical, -C1-3alkenyl-C5-6Heteroaryl, -C1-3alkenyl-CO-NR6aR6b、-C1-3Alkenyl, -NR6a-CO-NR6aR6b、-CO-NR6aR6b、-CO-CO-NR6aR6b、-CO-C1-3Alkyl, -CO-NR6a-C5-6Heterocyclyl, -CO-C5-6Heterocyclyl, -O-C5-6Carbocyclyl, -O-C5-6Heterocyclyl radical, -NR6a-CO-C1-3Alkyl, -NR6a-CO-NR6aR6b、-NR6a-C1-3alkenyl-NR6aR6b、-NR6a-C1-6alkenyl-C3-6Heterocyclyl radical, -NR6a-SO2C1-3Alkyl, -S-C1-3Alkyl, -SO-C1-3Alkyl, -SO2NR6aR6b、-SO2C1-3Alkyl, -PO (C)1-3Alkyl radical)2、-PO(C1-3Alkoxy group)25-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl or 6-membered heteroaryl, and each R6Independently optionally substituted or unsubstituted with 1, 2 or 3 substituents selected from-F, -Cl, Br, -NH2-OH, carboxy, oxo, ═ O, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; each R is6aAnd R6bAre each independently selected from-H; -F; -Cl; br; i; -NH2；-CN；-OH；-NO2(ii) a A carboxyl group; -C1-3An alkoxy group; -C1-3Alkyl or substituted by 1, 2 or 3-H, halogen, -NH2-CN or-OH substituted-C1-3An alkyl group; or
Two adjacent R6Connected together and separately therefromCarbon atoms taken together form a 6-membered aryl, 5-membered carbocyclyl, 5-membered heteroaryl, or 5-membered heterocyclyl; and each heteroaryl or heterocyclyl group contains 1 or 2 heteroatoms selected from N, O or S; and each said ring system is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents, each said substituent being independently selected from-F, -Cl, -Br, -NH2、-CN、-OH、-NO2- (O), oxo, carboxy, -CONH2、-PO(CH3)2Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
23. The compound of any one of claims 1-19 or 22, or a pharmaceutically acceptable salt thereof, wherein: each R6Are each independently selected from-H; -F; -Cl; -Br; -NR6aR6b(ii) a -CN; -OH; an oxo group; o; a carboxyl group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; a methyl group; an ethyl group; propyl; isopropyl group; a tertiary butyl group; -C1-3alkenyl-NR6aR6b；-NR6a-CO-NR6aR6b；-CO-NR6aR6b；-CO-CO-NR6aR6b(ii) a -CO-methyl; -CO-ethyl; -CO-NR6a-C5-6A heterocyclic group; -CO-C5-6A heterocyclic group; -O-C5-6A carbocyclic group; -O-C5-6A heterocyclic group; -NR6a-CO-methyl; -NR6a-CO-NR6aR6b；-NR6a-C1-3alkenyl-NR6aR6b；-NR6a-C1-6alkenyl-C3-6A heterocyclic group; -NR6a-SO2-a methyl group; -NR6a-SO2-an ethyl group; -S-methyl; -S-ethyl; -SO-methyl; -SO-ethyl; -SO2NR6aR6b；-SO2A methyl group; -SO2An ethyl group; -PO (methyl)2(ii) a -PO (ethyl)2(ii) a -PO (methoxy)2(ii) a -PO (ethoxy)2(ii) a 5-membered heterocyclic groups containing 1, 2 or 3 heteroatoms(ii) a A6 membered heterocyclyl containing 1, 2 or 3 heteroatoms; a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms; or a6 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein each R6Each independently optionally substituted or unsubstituted with 1, 2 or 3 substituents selected from-F, -Cl, Br, -NH2-OH, carboxy, oxo, ═ O, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; each R6aAnd R6bAre each independently selected from-H; -F; -Cl; br; i; -NH2；-CN；-OH；-NO2(ii) a A carboxyl group; a methyl group; an ethyl group; a methoxy group; an ethoxy group; by 1, 2 or 3 of-H, F, Cl, Br, -NH2-CN or-OH substituted methyl; or by 1, 2 or 3 of-H, F, Cl, Br, -NH2Ethyl substituted by-CN or-OH; or
Two adjacent R6Taken together and together with the carbon atoms to which they are each attached form a phenyl group, a 5-membered carbocyclyl group, a 5-membered heteroaryl group containing 1 or 2N or O, or a 5-membered heterocyclyl group containing 1 or 2N or O; and each said ring system is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents, each said substituent being independently selected from-F, -Cl, -Br, -NH2、-CN、-OH、-NO2- (O), oxo, carboxy, -CONH2、-PO(CH3)2Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
24. The compound according to any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein: each R6Are independently selected from-F, -Cl, -Br, -O, -OH, -CN, -NH2、-SCH3、-SOCH3、-SO2CH3、-PO(CH3)2、-PO(OC2H5)2、-NHSO2CH3、-C(O)NH2Methyl, ethyl, isopropyl, methoxy, ethoxy, ═ O, oxo, -OH, -CN, -NH2、-Cl、-Br、-CF3、-OCF3、-SO2NH2、-SO2CH3、-CH2NH2、-SCH3、-NHCOCH3、-NHCONHCH3、Or
Two adjacent R6Are linked together and form together with the carbon atoms to which they are respectively attached
25. The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein: the compound is of formula II:
the method is characterized in that:
R3is selected from-H or-NH2；
Each R4aOr R4bAre all independently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy or substituted or unsubstituted-C1-3An alkyl group; or
R4aAnd R4bTogether with the carbon atom to which they are both attached form C ═ O, C ═ NH, or C ═ N-OH;
p is 0, 1, 2 or 3;
each R5aOr R5bAre all independently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy or substituted or unsubstituted-C1-3An alkyl group; or
R5aAnd R5bTogether with the carbon atom to which they are both attached form a 3-5 membered heterocyclyl; and each of said heterocyclyl groups is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents selected from-H, halogen, -NH2-CN or-OH;
q is 0, 1, 2, 3 or 4;
ring A is a 3-6 membered carbocyclic ring, a 3-6 membered heterocyclic ring, benzene, or a 5-6 membered heteroaromatic ring;
represents a single bond or a double bond; wherein the content of the first and second substances,
i) when in useWhen represents a single bond, Y2Is CR2aOr N, and Y3Is CH or N; or
ii) whenWhen representing a double bond, Y2Is C, and Y3Is C;
R2aselected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy or substituted or unsubstituted-C1-3An alkyl group;
each R6Independently selected from-H, halogen, -NR6aR6b、-CN、-OH、-NO2- (O), carboxyl group, -C1-3Alkoxy, -C1-4Alkyl, -CO-NR6aR6b、-CO-CO-NR6aR6b、-CO-C1-3Alkyl, -CO-NR6a-C3-10heterocyclyl-CO-NR6a-C3-10Heterocyclyl, -CO-C4-6Heterocyclyl, -O-C3-6Carbocyclyl, -O-C3-6Heterocyclyl radical, -NR6a-CO-C1-3Alkyl, -NR6a-CO-NR6aR6b、-NR6a-CO-C5-6Heteroaryl, -NR6a-SO2C1-3Alkyl, -S-C1-3Alkyl, -SONR6aR6b、-SO2NR6aR6b、-SO-C1-3Alkyl, -SO2-C1-3Alkyl, -PO (C)1-3Alkyl radical)2、-PO(C1-3Alkoxy group)2、-C3-6Heterocyclyl or-C5-6Heteroaryl, wherein each R6Each independently optionally substituted or unsubstituted with 1, 2 or 3 substituents; and n is 0, 1, 2 or 3; or
Two adjacent R6Taken together with the carbon atoms to which they are respectively attached to form a 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, C3-6Heterocyclyl or C3-6Carbocyclyl, each said ring system being independently optionally substituted or unsubstituted with 1, 2 or 3 substituents;
each R6aAnd R6bIndependently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy, or substituted or unsubstituted-C1-3An alkyl group.
26. The compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein: each R5aOr R5bIndependently selected from-H, -Cl, -Br,-NH2-OH, carboxyl, methyl, ethyl, methoxy or ethoxy; or
R5aAnd R5bTogether with the carbon atom to which they are jointly attached formAnd C represents said carbon atom and R5aAnd R5bAnd (4) connecting.
27. The compound of claim 25 or 26, or a pharmaceutically acceptable salt thereof, wherein: ring a is 6-membered phenyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, 9-membered heteroaryl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl; and each heteroaryl group independently comprises 1 or 2 heteroatoms selected from N, O or S; each of said heterocyclyl groups independently contains 1 or 2 heteroatoms selected from N or O.
28. The compound according to any one of claims 25-27, or a pharmaceutically acceptable salt thereof, wherein: ring A is selected from
29. The compound according to any one of claims 25-28, or a pharmaceutically acceptable salt thereof, wherein: r2aIs selected from-H; -F; -Cl; -Br; -NH2；-CN；-OH；-NO2(ii) a A carboxyl group; a methyl group; an ethyl group; propyl; isopropyl esterA group; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; is-F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted-C1-3An alkyl group; or by-F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substituted-C1-3An alkoxy group.
30. The compound according to any one of claims 25-29, or a pharmaceutically acceptable salt thereof, wherein: y is2Is CH or N, and Y3Is CH or N.
31. The compound according to any one of claims 25-29, or a pharmaceutically acceptable salt thereof, wherein: y is2Is C, and Y3Is C.
32. The compound according to any one of claims 25-31, or a pharmaceutically acceptable salt thereof, wherein: each R6Are all independently selected from-H, -F, -Cl, -Br, -NH2、-N(CH3)2-CN, -OH, oxo, - (O), carboxy, methoxy, ethoxy, methyl, ethyl, isopropyl, tert-butyl, -CH2NH2、-CH2CH2OCH3、-CH2-COOH、-CH2NH-CONHCH3、-CONH2、-CON(CH3)2、-CONHOH、-CONHCH2CH2OH、-CO-CON(CH3)2、-COCH3、-SO2NH2、-SO2CH3、-SCH3、-SOCH3、-PO(CH3)2、-PO(OC2H5)2、-NHSO2CH3、-NH-COCH3、-NH-CONHCH3、
Wherein each R6Independently optionally substituted by 1, 2 or 3-F, -Cl, -NH2-OH, oxo, ═ O, methyl, ethyl or propyl substituted or unsubstituted.
33. The compound according to any one of claims 25-32, or a pharmaceutically acceptable salt thereof, wherein: each R6aAnd R6bAre all independently selected from-H, -Cl, -Br and-NH2-OH, carboxyl, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, methyl substituted with-OH or ethyl substituted with-OH.
34. The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein: the compound is represented by structural formula III:
the method is characterized in that:
each R1And R2Are all independently selected from-H, -F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkoxy or-C1-3An alkyl group; or
R1R adjacent thereto2Are linked and together with the carbon atom to which they are each linked form a 5-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N or O, and said 5-membered heterocyclic ring is optionally substituted by 1, 2 or 3 halogens, -NH2、-CN、-OH、-NO2Carboxy, oxo, ═ O, -CONH2or-CO-C1-3Alkyl substituted or unsubstituted;
Y1is selected from N or CH;
R3is selected from-H or-NH2；
Ring B is selected from a benzene ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, and each of said heteroaromatic ring groups or heterocyclic rings independently optionally comprises 1 or 2 heteroatoms selected from N or O;
i) when in useWhen represents a single bond, Y3Is CH or N; or
ii) whenWhen representing a double bond, Y3Is C;
R7selected from halogen, -NH2、-CN、-OH、-NO2Carboxy, oxo, ═ O, -CONH2、-NH-COCH3Substituted or unsubstituted-C1-6Alkoxy, or substituted or unsubstituted-C1-6An alkyl group; and m is 0, 1 or 2.
35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein: r1R adjacent thereto2Are linked and form together with the carbon atoms to which they are respectively linkedAnd said ring system is independently optionally substituted by 1 or 2-F or-COCH3Substituted or unsubstituted.
36. The compound of claim 34 or 35, or a pharmaceutically acceptable salt thereof, wherein: ring B is selected from
37. The compound according to any one of claims 34-36, or a pharmaceutically acceptable salt thereof, wherein: r7Is selected from-NH2-CN, oxo, - (O) -CONH2、-NH-COCH3Methyl or methoxy.
38. The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt thereof, characterized in that: the compound is represented by structural formula IV:
the method is characterized in that:
each R1And R2Are each independently selected from-H; -F; -Cl; -Br; -NH2；-CN；-OH；-NO2(ii) a A carboxyl group; -NHC1-3An alkyl group; -N (C)1-3Alkyl radical)2；-C1-3An alkoxy group; -C1-3Alkyl or 1, 2 or 3 halogen substituted-C1-3An alkyl group; or
R1R adjacent thereto2Are linked and taken together with the carbon atom to which they are each attached form a 6-membered carbocyclic ring, a 6-membered aryl ring, a 5-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, or a 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, and each of said ring systems is independently optionally substituted with 1, 2 or 3 halogens, -NH2、-CN、-OH、-NO2Carboxy, oxo, ═ O, and derivatives of formula IICONH2、-C1-3Alkoxy, -C1-3Alkyl or-CO-C1-3Alkyl substituted or unsubstituted;
Y1is N or CH;
R3is-H or-NH2；
Ring D is selected from 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, each of which independently optionally contains 1 or 2 heteroatoms selected from N, O or S;
represents a single bond or a double bond; and is
i) When in useWhen represents a single bond, Y2Is CR2aOr N, and Y3Is CR3aOr N; or
ii) whenWhen representing a double bond, Y2And Y3Are all C;
each R2aAnd R3aAre all independently selected from-H, halogen, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkoxy or-C1-3An alkyl group;
R8selected from halogen, -NH2、-CN、-OH、-NO2Carboxy, oxo, ═ O, C1-4Alkyl radical, C1-3Alkoxy, -SO2NR8aR8b、-S-C1-3Alkyl, -SO-C1-3Alkyl, -SO2-C1-3Alkyl, -CO-NR8aR8b、-PO(C1-3Alkyl radical)2、-PO(C1-3Alkoxy group)2、-NR8a-CO-C1-3Alkyl, -NR8a-CO-NR8aR8b-O-5 membered carbonCyclyl, -O-5 membered heterocyclyl, -O-6 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 5 membered heteroaryl, or 6 membered heteroaryl; and each R8Each independently optionally substituted by 1, 2 or 3 substituents selected from halogen, methyl, ethyl, methoxy, oxo, -NH2A substituent of-CN or-OH; and t is 0, 1, 2 or 3; or
Two adjacent R8Taken together with the carbon atoms to which they are respectively attached to form a 6-membered aryl or 5-membered heteroaryl, and each said ring system independently is optionally substituted or unsubstituted;
each R8aAnd R8bAre all independently selected from H, halogen, -NH2、-CN、-OH、-NO2Carboxy, -C1-3Alkoxy or-C1-3An alkyl group.
39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein: each R1And R2Are all independently selected from-H, -F, -Cl, -Br, -NH2、-CN、-OH、-NO2、-CF3Carboxy, -NHCH3、-N(CH3)2Methoxy, ethoxy, methyl or ethyl; or
R1R adjacent thereto2Are linked and taken together with the carbon atom to which they are each attached form a 6-membered carbocyclic ring, a 6-membered aryl group, a 5-membered heterocyclic group containing 1 heteroatom selected from N or O, or a 5-membered heteroaromatic ring including 1 heteroatom selected from N or O; and each said ring system is independently optionally substituted with 1, 2 or 3 substituents selected from-F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, oxo, ═ O, -CONH2Methoxy, ethoxy, methyl, ethyl, -CO-methyl or-CO-ethyl.
40. The compound of claim 38 or 39, or a pharmaceutically acceptable salt thereof, wherein: each R1And R2Are all independently selected from-H, -F, -Cl, -Br, -NH2、-CN、-OH、-NO2、-CF3Carboxy, -NHCH3、-N(CH3)2Methoxy, ethoxy, methyl or ethyl; or
R1R adjacent thereto2Are linked and form together with the carbon atoms to which they are respectively linkedAnd said ring systems are each independently optionally substituted by 1, 2 or 3 substituents selected from-F or-COCH3Substituted or unsubstituted.
41. The compound according to any one of claims 38-40, or a pharmaceutically acceptable salt thereof, wherein: ring D is selected from
42. The compound according to any one of claims 38-41, or a pharmaceutically acceptable salt thereof, wherein: each R2aAnd R3aAre each independently selected from-H, methyl or methoxy.
43. The compound according to any one of claims 38-42, or a pharmaceutically acceptable salt thereof, wherein: r8Selected from-F, -Cl, -Br, -NH2、-CN、-OH、-NO2Carboxy, oxo, ═ O, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, -CO-methyl, -SO2NR8aR8b-S-methyl, -S-ethyl, -SO-methyl, -SO-ethyl, -SO2-methyl, -SO2-ethyl, -CO-C3-6heterocyclyl-CO-NR8aR8b-PO (methyl)2-PO (ethyl)2-PO (methoxy)2-PO (ethoxy)2、-NR8a-CO-methyl, -NR8a-CO-ethyl, -NR8a-CO-NR8aR8b、-NR8a-SO2Methyl, -O-5 membered carbocyclyl, -O-5 membered heterocyclyl, -O-6 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 5 membered heteroaryl or 6 membered heteroaryl, each of said heterocyclyl or heteroaryl containing 1 or 2 heteroatoms selected from O, N or S; each R8Independently optionally substituted by 1, 2 or 3 substituents selected from-F, -Cl, -Br, -NH2-CN, -OH, oxo, -O, methoxy, ethoxy, methyl or ethyl.
44. The compound according to any one of claims 38-43, or a pharmaceutically acceptable salt thereof, wherein: r8Selected from-F, -Cl, -Br, -NH2-CN, -OH, carboxyl, oxo, - (O), methyl, ethyl, isopropyl, tert-butyl, CF3Methoxy, -SOCH3、-SO2CH3、-SCH3、P(O)(CH3)2、P(O)(OC2H5)2、NHS(O)2CH3、--CONH2、-NH-COCH3、-NH-CONHCH3、-NH-COCH3、Or
2R8Composition ofOr a benzene ring.
45. The compound according to any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein: the compound is selected from
46. A pharmaceutical composition comprising at least one compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
47. The pharmaceutical composition of claim 46, wherein: the weight ratio of the compound or the pharmaceutically acceptable salt thereof to the auxiliary material is 0.0001-10.
48. Use of a pharmaceutical composition according to claim 46 or 47 or a compound according to any one of claims 1-45 for the manufacture of a medicament.
49. Use according to claim 48, characterized in that: the medicament is useful for treating, preventing or preventing a disease or disorder mediated by SHP2 activity.
50. Use according to claim 48 or 49, characterized in that: the disease or disorder mediated by SHP2 activity is cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or vision disorder.
51. The use according to any one of claims 48 to 50, wherein: the disease or disorder mediated by SHP2 activity is selected from one or more of the following conditions: noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, stomach cancer, pancreatic cancer, and combinations thereof.
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