CN115353512A - Heterocyclic urea compound and preparation method and application thereof - Google Patents

Heterocyclic urea compound and preparation method and application thereof Download PDF

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CN115353512A
CN115353512A CN202210897430.2A CN202210897430A CN115353512A CN 115353512 A CN115353512 A CN 115353512A CN 202210897430 A CN202210897430 A CN 202210897430A CN 115353512 A CN115353512 A CN 115353512A
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membered
alkyl
heteroaryl
heterocyclyl
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温俏冬
宋云龙
寇红艳
何为
高芳
蒋春华
陈丽光
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Shanghai Yishi Pharmaceutical Technology Co ltd
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract

The invention provides a compound with a novel structure, and a prodrug, a tautomer, an optical isomer, a solvate, an isotopic derivative or a pharmaceutically acceptable salt thereof. The compounds with novel structures designed by the invention provide a new direction for the development of the drugs of the POLQ inhibitors. The research on the in vitro enzyme activity inhibition activity shows that the compounds have stronger inhibition effect on the POLQ enzyme and can be used as prospect compounds for treating diseases mediated by the POLQ inhibitor.

Description

Heterocyclic urea compound and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a heterocyclic urea compound serving as a POLQ inhibitor, and a preparation method and application of the compound.
Background
Defects in DNA repair have become an effective strategy against cancer. It has become increasingly apparent over the past decades that selective deletions of the DNA repair pathway occur in a wide variety of tumors from 40% to 50%. DNA repair deletions promote tumor cell proliferation, leading to genetic instability and/or increased mutation rates, driving the evolution of tumors. Cancers deficient in DNA repair often rely on alternate DNA repair pathways, which have been targeted and successful in developing inhibitors of Poly ADP Ribose Polymerase (PARP) for the treatment of BRCA deficient breast and ovarian cancer. However, the need for new therapeutic approaches that exploit other DNA repair deficiencies remains urgent to overcome the acquired and innate resistance to PARP inhibitors (PARPi). DNA polymerase θ (POLQ)) is involved in DNA repair, not only synergizing with PARP inhibitors, but also has broader utility in cancer therapy. POLQ has been the major focus of drug development, and it is also a significant reason that it is not substantially expressed in normal cells, but is increased in many cancers, whether accompanied by a defect in Homologous Recombination (HRD).
POLQ is a key component of the POLQ alt-EJ pathway, also known as the microhomology-mediated end joining (MMEJ) pathway, involved in DNA double strand break repair, and the MMEJ can be paralleled by the HR and NHEJ pathways (Truong et al, PNAS 2003, 110 (19), 7720-7725). POLQ is less expressed in normal tissues but is up-regulated in many tumor types, such as breast, ovary, HNSCC, and lung. POLQ inhibitors have the potential to be used in a wide range of clinical settings, particularly in HR deficient tumors such as breast and ovarian cancers, or in combination with DNA damaging agents (chemotherapy and radiotherapy). Mechanistically, the indications can also be expanded in combination with PARP1 inhibitors.
POLQ overexpression is observed in a number of cancers, and the up-regulated levels correlate with poor prognosis. For example, about 70% of breast cancers show 5-fold or more high expression of POLQ, and this high expression is observed in both normal and deficient HR functioning breast cancers. In addition, POLQ is highly expressed in cancer cells and is resistant to ionizing radiation and chemotherapeutic drugs. Aberrant expression of POLQ also promotes survival of cells deficient in homologous recombination, a feature commonly observed in cells mutated in the BRCA1 or BRCA2 genes. Therefore, POLQ is considered as a promising new cancer target, and novel POLQ inhibitors will become part of new anticancer therapies.
Disclosure of Invention
The invention aims to provide a compound with a heterocyclic urea structure as a POLQ inhibitor, a preparation method of the compound and application of the compound in treating diseases mediated by POLQ.
In a first aspect of the present invention, there is provided a compound represented by the following formula (I), or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, having the following structure:
Figure BDA0003769482940000011
wherein X is selected from O and S;
w and V are independently selected from N or C (R) w )；R w Represents hydrogen, halogen or C 1-6 An alkyl group;
a is selected from hydrogen, halogen, amino, cyano, hydroxy, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Hydroxyalkyl, halo C 1-6 Alkyl radical, C 1-6 Alkylamino, -CO-C 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -NHCO-C 1-6 Alkyl, -CH 2 CONR a1 R a2 ；R a1 And R a2 Independently selected from H and C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Hydroxyalkyl, halo C 1-6 An alkyl group;
ring B is selected from C 6-14 Aryl, 5-16 membered heteroaryl and 5-16 membered heterocyclyl, said C 6-14 Aryl, 5-16 membered heteroaryl and 5-16 membered heterocyclyl is optionally substituted with n R b Substituted when multiple R b At the same time, each R b May be the same or different; wherein n is selected from 0, 1,2,3,4 and 5;
R b selected from halogen, cyano, hydroxy, nitro, amino, oxo, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -C 1-6 alkyl-C 3-8 Cycloalkyl, -C 1-6 Alkyl-4-10 membered heterocyclyl, -C 1-6 alkyl-C 6-12 Aryl radical, -C 1-6 Alkyl-5-10 membered heteroaryl, -NH-C 3-8 Cycloalkyl, -NH-4-10 membered heterocyclyl, -NH-C 6-12 Aryl, -NH-5-10 membered heteroaryl, -NH-C 1-6 alkyl-C 3-8 Cycloalkyl, -NH-C 1-6 Alkyl-4-10 membered heterocyclyl, -NH-C 1-6 alkyl-C 6-12 Aryl, -NH-C 1-6 Alkyl-5-10 membered heteroaryl, -O-C 1-6 alkyl-C 3-8 Cycloalkyl, -O-C 1-6 Alkyl-4-10 membered heterocyclyl, -O-C 1-6 alkyl-C 6-12 Aryl and-O-C 1-6 Alkyl-5-10 membered heteroaryl; said C is 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, -C 1-6 alkyl-C 3-8 Cycloalkyl, -C 1-6 Alkyl-4-10 membered heterocyclyl, -C 1-6 alkyl-C 6-12 Aryl radical, -C 1-6 Alkyl-5-10 membered heteroaryl, -NH-C 3-8 Cycloalkyl, -NH-4-10 membered heterocyclyl, -NH-C 6-12 Aryl, -NH-5-10 membered heteroaryl, -NH-C 1-6 alkyl-C 3-8 Cycloalkyl, -NH-C 1-6 Alkyl-4-10 membered heterocyclyl, -NH-C 1-6 alkyl-C 6-12 Aryl, -NH-C 1-6 Alkyl-5-10 membered heteroaryl, -O-C 1-6 alkyl-C 3-8 Cycloalkyl, -O-C 1-6 Alkyl-4-10 membered heterocyclyl, -O-C 1-6 alkyl-C 6-12 Aryl and-O-C 1-6 Alkyl-5-10 membered heteroaryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, nitro, oxo, -NH (C) 1-3 Alkyl), -N (C) 1-3 Alkyl) (C 1-3 Alkyl), -C 1-3 alkyl-NH 2 、-NH-C(O)C 1-3 Alkyl, -C (O) C 1-3 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl;
R 1 is selected from C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Hydroxyalkyl, halo C 1-6 Alkyl radical, C 1-6 Alkylamino radical, -CO-C 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -NHCO-C 1-6 Alkyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, C 6-12 An aryl group; said C is 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Hydroxyalkyl, halogeno C 1-6 Alkyl radical, C 1-6 Alkylamino radical, -CO-C 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -NHCO-C 1-6 Alkyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, C 6-12 Aryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, nitro, oxo, -NH (C) 1-3 Alkyl), -N (C) 1-3 Alkyl) (C 1-3 Alkyl), -C 1-3 alkyl-NH 2 、-NH-C(O)C 1-3 Alkyl, -C (O) C 1-3 Alkyl, halo C 1-6 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl, -C 1-3 alkyl-N (C) 1-3 Alkyl) C 1-3 Alkyl radical, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl;
R 2 and R 3 Independently selected from H, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy radical, C 1-4 Halogenoalkoxy, C 3-8 A cycloalkyl group; or R 2 And R 3 Together with the atoms to which they are attached form a 5-or 6-membered heterocyclic ring;
unless otherwise specified, the heteroatoms in the heterocyclic groups and heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1,2,3 or 4.
In a first aspect of the present invention, there is provided a compound represented by the following formula (I), or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, having the following structure:
Figure BDA0003769482940000021
wherein X is selected from O and S;
w and V are independently selected from N or C (R) w )；R w Represents hydrogen, halogen or C 1-6 An alkyl group;
a is selected from hydrogen, halogen, amino, cyano, hydroxy, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Hydroxyalkyl, halo C 1-6 Alkyl radical, C 1-6 Alkylamino, -CO-C 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -NHCO-C 1-6 Alkyl, -CH 2 CONR a1 R a2 ；R a1 And R a2 Independently selected from H and C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Hydroxyalkyl, halo C 1-6 An alkyl group;
ring B is selected from C 6-12 Aryl, 5-16 membered heteroaryl and 5-16 membered heterocyclyl, C 6-12 Aryl, 5-16 membered heteroaryl and 5-16 membered heterocyclyl are optionally substituted with n R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different; wherein n is selected from 0, 1,2,3,4 and 5;
R b selected from halogen, cyano, hydroxy, nitro, amino, oxo, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -C 1-6 alkyl-C 3-8 Cycloalkyl, -C 1-6 Alkyl-4-10 membered heterocyclyl, -C 1-6 alkyl-C 6-12 Aryl radical, -C 1-6 Alkyl-5-10 membered heteroaryl, -NH-C 3-8 Cycloalkyl, -NH-4-10 membered heterocyclyl, -NH-C 6-12 Aryl, -NH-5-10 membered heteroaryl, -NH-C 1-6 alkyl-C 3-8 Cycloalkyl, -NH-C 1-6 Alkyl-4-10 membered heterocyclyl, -NH-C 1-6 alkyl-C 6-12 Aryl, -NH-C 1-6 Alkyl-5-10 membered heteroaryl, -O-C 1-6 alkyl-C 3-8 Cycloalkyl, -O-C 1-6 Alkyl-4-10 membered heterocyclyl, -O-C 1-6 alkyl-C 6-12 Aryl and-O-C 1-6 Alkyl-5-10 membered heteroaryl; said C is 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -C 1-6 alkyl-C 3-8 Cycloalkyl, -C 1-6 Alkyl-4-10 membered heterocyclyl, -C 1-6 alkyl-C 6-12 Aryl radical, -C 1-6 Alkyl-5-10 membered heteroaryl, -NH-C 3-8 Cycloalkyl, -NH-4-10 membered heterocyclyl, -NH-C 6-12 Aryl, -NH-5-10 membered heteroaryl, -NH-C 1-6 alkyl-C 3-8 Cycloalkyl, -NH-C 1-6 Alkyl-4-10 membered heterocyclyl, -NH-C 1-6 alkyl-C 6-12 Aryl, -NH-C 1-6 Alkyl-5-10 membered heteroaryl, -O-C 1-6 alkyl-C 3-8 Cycloalkyl, -O-C 1-6 Alkyl-4-10 membered heterocyclyl, -O-C 1-6 alkyl-C 6-12 Aryl and-O-C 1-6 Alkyl-5-10 membered heteroaryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, nitro, oxo, -NH (C) 1-3 Alkyl), -N (C) 1-3 Alkyl) (C 1-3 Alkyl), -C 1-3 alkyl-NH 2 、-NH-C(O)C 1-3 Alkyl, -C (O) C 1-3 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl;
R 1 is selected from C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Hydroxyalkyl, halogeno C 1-6 Alkyl radical, C 1-6 Alkylamino, -CO-C 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -NHCO-C 1-6 Alkyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, C 6-12 An aryl group; said C is 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Hydroxyalkyl, halo C 1-6 Alkyl radical, C 1-6 Alkylamino, -CO-C 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -NHCO-C 1-6 Alkyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, C 6-12 Aryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, nitro, oxo, -NH (C) 1-3 Alkyl), -N (C) 1-3 Alkyl) (C 1-3 Alkyl), -C 1-3 alkyl-NH 2 、-NH-C(O)C 1-3 Alkyl, -C (O) C 1-3 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl;
R 2 and R 3 Independently selected from H, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy radical, C 1-4 Halogenoalkoxy, C 3-8 A cycloalkyl group; or R 2 And R 3 Together with the atoms to which they are attached form a 5-or 6-membered heterocyclic ring;
unless otherwise specified, the heteroatoms in the heterocyclic groups and heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1,2,3 or 4.
In a preferred embodiment of the invention, W and V are both selected from N.
In a preferred embodiment of the invention, A is selected from hydrogenHalogen, amino, cyano, hydroxy, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Hydroxyalkyl, halo C 1-6 An alkyl group; more preferably, a is selected from hydrogen, halogen, amino, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, cyclopropyl, methoxy; most preferably, a is selected from hydrogen.
In a preferred embodiment of the invention, ring B is selected from C 6-14 Aryl, 5-14 membered heteroaryl and 5-14 membered heterocyclyl, said C 6-14 Aryl, 5-14 membered heteroaryl and 5-14 membered heterocyclyl is optionally substituted with n R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different; wherein n is selected from 0, 1,2,3 and 4; more preferably, ring B is selected from C 6 Aryl, 6-14 membered heteroaryl and 6-14 membered heterocyclyl, said C 6 Aryl, 6-14 membered heteroaryl and 6-14 membered heterocyclyl is optionally substituted with n R b Substituted when multiple R b At the same time, each R b May be the same or different; wherein n is selected from 0, 1,2 and 3.
In a preferred embodiment of the invention, ring B is selected from C 6-10 Aryl, 5-12 membered heteroaryl and 5-14 membered heterocyclyl, said C 6-10 Aryl, 5-12 membered heteroaryl and 5-14 membered heterocyclyl are optionally substituted with n R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different; wherein n is selected from 0, 1,2,3 and 4; more preferably, ring B is selected from phenyl, 8-10 membered heteroaryl and 9-14 membered heterocyclyl, the heteroatoms in the heteroaryl, heterocyclyl being independently selected from O or N, the number of heteroatoms being 1,2 or 3, the phenyl, 8-10 membered heteroaryl and 9-14 membered heterocyclyl being optionally substituted by N R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different, wherein n is selected from 0, 1,2 and 3; more preferably, ring B is selected from phenyl, 9-10 membered bicyclic heterocyclyl wherein the heteroatom is N, the number of heteroatoms is 1 or 2, said phenyl, 9-10 membered bicyclic heterocyclyl optionally substituted with N R b The substitution is carried out by the following steps,when a plurality of R b When occurring simultaneously, each R b Which may be the same or different, wherein n is selected from 0, 1 and 2.
In a preferred embodiment of the present invention, ring B is selected from the group consisting of 6-12 membered bicyclic heteroaryl, 6-14 membered bicyclic heterocyclyl and 12-14 membered tricyclic heterocyclyl, said 6-12 membered bicyclic heteroaryl, 6-14 membered bicyclic heterocyclyl and 12-14 membered tricyclic heterocyclyl being optionally substituted with n R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different, wherein n is selected from 0, 1,2,3 and 4; more preferably, ring B is selected from 9-10 membered bicyclic heteroaryl, 9-10 membered bicyclic heterocyclyl and 14 membered tricyclic heterocyclyl, the heteroatoms in the heteroaryl, heterocyclyl are independently selected from O or N, the number of heteroatoms is 1,2 or 3, the 9-10 membered bicyclic heteroaryl, 9-10 membered bicyclic heterocyclyl and 14 membered tricyclic heterocyclyl are optionally substituted with N R b Substituted when multiple R b At the same time, each R b May be the same or different, wherein n is selected from 0, 1,2 and 3; more preferably, ring B is selected from 9-10 membered bicyclic heteroaryl and 9-10 membered bicyclic heterocyclyl, wherein the heteroatom in the heteroaryl or heterocyclyl is O or N and the number of heteroatoms is 1,2 or 3, wherein the 9-10 membered bicyclic heteroaryl and 9-10 membered bicyclic heterocyclyl are optionally substituted with N R b Substituted when multiple R b At the same time, each R b May be the same or different, wherein n is selected from 1,2 and 3; more preferably, ring B is selected from 9-10 membered bicyclic heterocyclic group, wherein the heteroatom in said heterocyclic group is N and the number of heteroatoms is 1, said 9-10 membered bicyclic heterocyclic group being optionally substituted by N R b Substituted when multiple R b When occurring simultaneously, each R b Which may be the same or different, wherein n is selected from 1 and 2.
In a preferred embodiment of the invention ring B is selected from 9-10 membered bicyclic heteroaryl, wherein the heteroatoms in said heteroaryl are independently selected from O or N, the number of heteroatoms is 1,2 or 3, said 9-10 membered bicyclic heteroaryl is optionally substituted by N R b Substituted when multiple R b At the same time, each R b Which may be the same or different, wherein n is selected from 1,2 and 3.
In a preferred embodiment of the invention, the ringB is selected from the group consisting of 5-membered/6-membered bicyclic fused heteroaryl, 6-membered/5-membered bicyclic fused heteroaryl, 6-membered/6-membered bicyclic fused heteroaryl, 5-membered/6-membered bicyclic fused heterocyclyl, 6-membered/5-membered bicyclic fused heterocyclyl, 6-membered/6-membered bicyclic fused heterocyclyl, wherein the heteroatom in the heteroaryl or heterocyclyl is O or N, the number of heteroatoms is 1,2 or 3, and the 5-membered/6-membered bicyclic fused heteroaryl, 6-membered/5-membered bicyclic fused heteroaryl, 6-membered/6-membered bicyclic fused heteroaryl, 5-membered/6-membered bicyclic fused heterocyclyl, 6-membered/5-membered bicyclic fused heterocyclyl, 6-membered/6-membered bicyclic fused heterocyclyl is optionally substituted with N R b Substituted when multiple R b At the same time, each R b Which may be the same or different, wherein n is selected from 1,2 and 3.
In a preferred embodiment of the invention, ring B is selected from C 6-10 Aryl radical, said C 6-10 Aryl is optionally substituted by n R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different; wherein n is selected from 1,2,3 and 4; more preferably, ring B is selected from phenyl optionally substituted by n R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different, wherein n is selected from 1,2 and 3; more preferably, ring B is selected from phenyl optionally substituted by n R b Substituted when more than one R b When occurring simultaneously, each R b Which may be the same or different, wherein n is selected from 1 and 2.
Preferably, ring B is monocyclic, bicyclic or tricyclic, including spiro, fused and bridged rings; more preferably, ring B is monocyclic or bicyclic; more preferably, ring B is bicyclic.
Preferably, ring B is selected from phenyl, 5-7 membered monocyclic heteroaryl, 5-7 membered monocyclic heterocyclyl, naphthyl, phenanthryl, anthracyl, 8-14 membered bicyclic heteroaryl, 8-14 membered bicyclic heterocyclyl, 9-14 membered tricyclic heteroaryl, 9-14 membered tricyclic heterocyclyl.
Preferably, ring B is selected from 8-14 membered bicyclic fused ring heteroaryl, 8-14 membered bicyclic fused ring heterocyclyl, 9-14 membered fused ring tricyclic heteroaryl, 9-14 membered fused ring tricyclic heterocyclyl.
Further preferably, ring B is selected from C 6 Aryl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 7-membered monocyclic heteroaryl<xnotran> ,5 ,6 ,7 ,6 /6 ,4 /4 ,4 /5 ,5 /4 ,5 /5 ,5 /6 ,6 /5 ,4 /6 ,6 /4 ,6 /6 ,4 /4 ,4 /5 ,5 /4 ,5 /5 ,5 /6 ,6 /5 ,4 /6 ,6 /4 ,6 /6 ,5 /6 /6 ,6 /5 /6 ,6 /6 /5 ,5 /5 /6 ,5 /6 /5 ,6 /5 /5 ,6 /6 /6 ,5 /6 /6 ,6 /5 /6 ,6 /6 /5 ,5 /5 /6 ,5 /6 /5 , </xnotran> 6-membered/5-membered tricyclic fused heterocyclic group, 6-membered/6-membered tricyclic fused aryl group, wherein hetero atoms in the heterocyclic group and the heteroaryl group are independently selected from O, N or S, and the number of hetero atoms is 1,2 or 3; the above groups are optionally substituted by n R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different; wherein n is selected from 0, 1,2 and 3.
Preferably, ring B is selected from the following structures, optionally substituted by n R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different, wherein n is selected from 0, 1,2 and 3:
Figure BDA0003769482940000051
even more preferably, ring B is selected from the following structures, optionally substituted by n R b Substituted when multiple R b Go out at the same timeAt the occurrence of each R b May be the same or different, wherein n is selected from 0, 1,2 and 3:
Figure BDA0003769482940000061
even more preferably, ring B is selected from the following structures optionally substituted by n R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different, wherein n is selected from 1,2 and 3:
Figure BDA0003769482940000062
even more preferably, ring B is selected from
Figure BDA0003769482940000063
Said structure is optionally substituted by n R b Substituted when more than one R b At the same time, each R b May be the same or different, wherein n is selected from 1 or 2.
Preferably, R b -ring B is selected from the following structures:
Figure BDA0003769482940000071
even more preferably, R b -ring B is selected from the following structures:
Figure BDA0003769482940000081
in a preferred embodiment of the invention, R b Selected from halogen, cyano, hydroxy, nitro, amino, oxo, C 1-4 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-to 10-membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -C 1-4 alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-4-10 membered heterocyclyl, -C 1-4 alkyl-C 6-12 Aryl radical, -C 1-4 Alkyl-5-10 membered heteroaryl, -NH-C 3-8 Cycloalkyl, -NH-4-10 membered heterocyclyl, -NH-C 6-12 Aryl, -NH-5-10 membered heteroaryl, -NH-C 1-4 alkyl-C 3-8 Cycloalkyl, -NH-C 1-4 Alkyl-4-10 membered heterocyclyl, -NH-C 1-4 alkyl-C 6-12 Aryl, -NH-C 1-4 Alkyl-5-10 membered heteroaryl, -O-C 1-4 alkyl-C 3-8 Cycloalkyl, -O-C 1-4 Alkyl-4-10 membered heterocyclyl, -O-C 1-4 alkyl-C 6-12 Aryl and-O-C 1-4 Alkyl-5-10 membered heteroaryl; said C is 1-4 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-to 10-membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, -C 1-4 alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-4-10 membered heterocyclyl, -C 1-4 alkyl-C 6-12 Aryl radical, -C 1-4 Alkyl-5-10 membered heteroaryl, -NH-C 3-8 Cycloalkyl, -NH-4-10 membered heterocyclyl, -NH-C 6-12 Aryl, -NH-5-10 membered heteroaryl, -NH-C 1-4 alkyl-C 3-8 Cycloalkyl, -NH-C 1-4 Alkyl-4-10 membered heterocyclyl, -NH-C 1-4 alkyl-C 6-12 Aryl, -NH-C 1-4 Alkyl-5-10 membered heteroaryl, -O-C 1-4 alkyl-C 3-8 Cycloalkyl, -O-C 1-4 Alkyl-4-10 membered heterocyclyl, -O-C 1-4 alkyl-C 6-12 Aryl and-O-C 1-4 Alkyl-5-10 membered heteroaryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, nitro, oxo, -NH (C) 1-3 Alkyl), -N (C) 1-3 Alkyl) (C) 1-3 Alkyl), -C (O) C 1-3 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 A hydroxyalkyl group.
Further preferably, R b Selected from halogen, cyano, hydroxy, nitro, amino, oxo, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, -C 1-4 alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-4-10 membered heterocyclyl, -C 1-4 Alkyl-5-10 membered heteroaryl, -NH-C 3-8 Cycloalkyl, -NH-4-10 membered heterocyclyl, -NH-5-10 membered heteroaryl, -NH-C 1-4 alkyl-C 3-8 Cycloalkyl, -NH-C 1-4 Alkyl-4-10 membered heterocyclyl, -NH-C 1-4 Alkyl-5-10 membered heteroaryl, -O-C 1-4 alkyl-C 3-8 Cycloalkyl, -O-C 1-4 Alkyl-4-10 membered heterocyclyl and-O-C 1-4 Alkyl-5-10 membered heteroaryl; said C is 1-4 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, -C 1-4 alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-4-10 membered heterocyclyl, -C 1-4 Alkyl-5-10 membered heteroaryl, -NH-C 3-8 Cycloalkyl, -NH-4-10 membered heterocyclyl, -NH-5-10 membered heteroaryl, -NH-C 1-4 alkyl-C 3-8 Cycloalkyl, -NH-C 1-4 Alkyl-4-10 membered heterocyclyl, -NH-C 1-4 Alkyl-5-10 membered heteroaryl, -O-C 1-4 alkyl-C 3-8 Cycloalkyl, -O-C 1-4 Alkyl-4-10 membered heterocyclyl and-O-C 1-4 Alkyl-5-10 membered heteroaryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, nitro, oxo, -NH (C) 1-3 Alkyl), -N (C) 1-3 Alkyl) (C 1-3 Alkyl), -C (O) C 1-3 Alkyl radical, C 1-6 Alkyl radical, C 1-6 A hydroxyalkyl group.
Further preferably, R b Selected from halogen, cyano, hydroxy, nitro, amino, oxo, C 1-4 Alkyl radical, C 5-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, 7-8 membered bicyclic heterocyclyl, -C 1-4 alkyl-C 3-6 Cycloalkyl, -C 1-4 Alkyl-4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -NH-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkenyl, -NH-C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl; the heteroatom in the heterocycloalkyl, heterocycloalkenyl, heterocyclyl or heteroaryl is O or N, and the number of heteroatoms is 1,2 or 3; said C is 1-4 Alkyl radical, C 5-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, 7-8 membered bicyclic heterocyclyl, -C 1-4 alkyl-C 3-6 Cycloalkyl, -C 1-4 Alkyl-4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -NH-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkenyl, -NH-C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, nitro, oxo, -NH (C) 1-3 Alkyl), -N (C) 1-3 Alkyl) (C 1-3 Alkyl), -C (O) C 1-3 Alkyl radical, C 1-4 Alkyl radical, C 1-3 A hydroxyalkyl group.
Further preferably, R b Selected from halogen, cyano, hydroxy, nitro, amino, oxo, C 1-4 Alkyl radical, C 5-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, 7-8 membered bicyclic heterocyclyl, -C 1-4 alkyl-C 3-6 Cycloalkyl, -C 1-4 Alkyl-4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -NH-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkenyl, -NH-C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl; the heteroatom in the heterocycloalkyl, the heterocycloalkenyl, the heterocyclyl and the heteroaryl is O or N, and the number of the heteroatoms is 1 or 2; said C is 1-4 Alkyl radical、C 5-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, 7-8 membered bicyclic heterocyclyl, -C 1-4 alkyl-C 3-6 Cycloalkyl, -C 1-4 Alkyl-4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -NH-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkenyl, -NH-C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, nitro, oxo, -NHCH 3 、-N(CH 3 )(CH 3 )、-C(O)CH 3 Methyl, ethyl, hydroxymethyl.
Further preferably, R b Selected from the group consisting of halogen, cyano, hydroxy, nitro, amino, oxo, methyl, ethyl, n-propyl, isopropyl, methoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-10 membered heterocyclyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -4-6 membered heterocyclyl, -CH 2 -5-6 membered heteroaryl, -NHCH 2 -cyclopropyl, -NHCH 2 -cyclobutyl, -NHCH 2 -cyclopentyl, -NHCH 2 -4-6 membered heterocyclyl, -NHCH 2 -5-6 membered heteroaryl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-4-6 membered heterocyclyl, -NH-5-6 membered heteroaryl, -OCH 2 -cyclopropyl, -OCH 2 -cyclobutyl, -OCH 2 -cyclopentyl, -OCH 2 -4-6 membered heterocyclyl and-OCH 2 -5-6 membered heteroaryl, said methyl, ethyl, n-propyl, isopropyl, methoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-10 membered heterocyclyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -4-6 membered heterocyclyl, -CH 2 -5-6 membered heteroaryl, -NHCH 2 -cyclopropyl, -NHCH 2 -cyclobutyl, -NHCH 2 -cyclopentyl, -NHCH 2 -4-6 membered heterocyclyl, -NHCH 2 -5-6 membered heteroaryl, -NH-cyclopropyl, -NH-cyclobutanRadical, -NH-cyclopentyl, -NH-4-6 membered heterocyclyl, -NH-5-6 membered heteroaryl, -OCH 2 -cyclopropyl, -OCH 2 -cyclobutyl, -OCH 2 -cyclopentyl, -OCH 2 -4-6 membered heterocyclyl and-OCH 2 -5-6 membered heteroaryl is unsubstituted or substituted by one or more of the following substituents, respectively: halogen, cyano, hydroxy, nitro, oxo, -NHCH 3 、-N(CH 3 )(CH 3 )、-C(O)CH 3 Methyl, ethyl, hydroxymethyl.
Preferably, R b Selected from the following structures: halogen, cyano, hydroxy, nitro, amino, oxo, methyl, ethyl, n-propyl, isopropyl, methoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure BDA0003769482940000101
Said above structure being unsubstituted or substituted by one or more of the following substituents, respectively: halogen, cyano, hydroxy, nitro, oxo, -NHCH 3 、-N(CH 3 )(CH 3 )、-C(O)CH 3 Methyl, ethyl, hydroxymethyl.
Further preferably, R b Selected from halogen, cyano, hydroxy, nitro, amino, oxo, methyl ethyl, n-propyl, isopropyl methoxy, methylthio, methoxy-N-methyl,
Figure BDA0003769482940000102
Figure BDA0003769482940000103
Further preferably, R b Selected from the group consisting of halogen, cyano, hydroxy, nitro, amino, oxo, methyl ethyl, n-propyl, isopropyl, methoxy, methylthio, methyl,
Figure BDA0003769482940000111
Figure BDA0003769482940000112
Most preferably, R b Selected from the group consisting of halogen, cyano, hydroxy, nitro, amino, oxo, methyl ethyl, n-propyl, isopropyl, methoxy, methylthio, methyl,
Figure BDA0003769482940000113
Figure BDA0003769482940000121
In a preferred embodiment of the invention, ring B is selected from 9-10 membered bicyclic heteroaryl and 9-10 membered bicyclic heterocyclyl, said 9-10 membered bicyclic heteroaryl and 9-10 membered bicyclic heterocyclyl being optionally substituted by n R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different, wherein n is selected from 1 or 2; r b Selected from halogen, oxo, C 1-6 Alkyl, -C 1-4 Alkyl-4-6 membered heterocycloalkyl, C 5-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl, said C 1-6 Alkyl, -C 1-4 Alkyl-4-6 membered heterocycloalkyl, C 5-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, C 1-4 An alkyl group; the heteroatom in the heterocycloalkyl and heteroaryl is O or N, and the number of the heteroatoms is 1 or 2.
In a preferred embodiment of the invention, ring B is selected from 9-10 membered bicyclic heteroaryl and 9-10 membered bicyclic heterocyclyl, said 9-10 membered bicyclic heteroaryl and 9-10 membered bicyclic heterocyclyl being optionally substituted by n R b Substituted when multiple R b At the same time, each R b May be the same or different, wherein n is selected from 1 or 2; r b Selected from halogen, oxo, C 1-4 Alkyl, -C 1-4 Alkyl-4-6 membered heterocycloalkyl, C 5-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl, said C 1-6 Alkyl, -C 1-4 Alkyl-4-6 membered heterocycloalkyl, C 5-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, methyl; the heteroatom in the heterocycloalkyl and heteroaryl is O or N, and the number of the heteroatoms is 1 or 2.
In a preferred embodiment of the invention, R 1 Selected from 4-12 membered heterocyclyl, 5-12 membered heteroaryl; the 4-12 membered heterocyclyl, 5-12 membered heteroaryl are unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, -NH-C (O) C 1-3 Alkyl, halo C 1-6 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl, -C 1-3 alkyl-N (C) 1-3 Alkyl) C 1-3 Alkyl radical, C 1-6 Alkyl radical, C 3-8 Cycloalkyl, C 1-6 Alkoxy radical, C 1-6 A hydroxyalkyl group.
Preferably, R 1 Selected from 5-10 membered heterocyclyl, 6-10 membered heteroaryl; the 5-10 membered heterocyclyl, 6-10 membered heteroaryl are unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, -NH-C (O) C 1-3 Alkyl, halo C 1-6 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl, -C 1-3 alkyl-N (C) 1-3 Alkyl) C 1-3 Alkyl radical, C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 1-3 Alkoxy radical, C 1-3 A hydroxyalkyl group.
Further preferably, R 1 Selected from the group consisting of 5-6 membered heterocycloalkyl, 9-10 membered bicyclic heterocyclyl, 6 membered monocyclic heteroaryl, 9-10 membered bicyclic heteroaryl; the heteroatom in the heterocycloalkyl, the heterocyclic group and the heteroaryl is O or N, and the number of the heteroatoms is 1,2 or 3; the 5-6 membered heterocycloalkyl, 9-10 membered bicyclic heterocyclyl, 6 membered monocyclic heteroaryl, 9-10 membered bicyclic heteroaryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, -NH-C (O) C 1-3 Alkyl, halo C 1-3 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl, -C 1-3 alkyl-N (C) 1-3 Alkyl) C 1-3 Alkyl radical, C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 1-3 Alkoxy radical, C 1-3 A hydroxyalkyl group.
Further preferably, R 1 Selected from the group consisting of 5-6 membered heterocycloalkyl, 5-membered/6-membered bicyclic fused heterocyclyl, 6-membered/5-membered bicyclic fused heterocyclyl, 6-membered/6-membered bicyclic fused heterocyclyl, 6-membered monocyclic heteroaryl, 5-membered/6-membered bicyclic fused heteroaryl, 6-membered/5-membered bicyclic fused heteroaryl, 6-membered/6-membered bicyclic fused heteroaryl; the heteroatom in the heterocycloalkyl, the heterocyclic group and the heteroaryl is O or N, and the number of the heteroatoms is 1,2 or 3; the 5-6 membered heterocycloalkyl group, the 5-membered/6-membered bicyclic fused heterocyclic group, the 6-membered/5-membered bicyclic fused heterocyclic group, the 6-membered/6-membered bicyclic fused heterocyclic group, the 6-membered monocyclic heteroaryl group, the 5-membered/6-membered bicyclic fused heteroaryl group, the 6-membered/5-membered bicyclic fused heteroaryl group, the 6-membered/6-membered bicyclic fused heteroaryl group are unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, -NH-C (O) CH 3 、-CH 2 NHCH 3 Trifluoromethyl, difluoromethyl, monofluoromethyl, hydroxymethyl.
In a preferred embodiment of the invention, R 1 Selected from the group consisting of 4-12 membered heterocyclyl, 5-12 membered heteroaryl, and C 6-12 An aryl group; the 4-12 membered heterocyclic group, 5-12 membered heteroaryl group and C 6-12 Aryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, amino, hydroxy, nitro, oxo, -NH (C) 1-3 Alkyl), -N (C) 1-3 Alkyl) (C 1-3 Alkyl), -C 1-3 alkyl-NH 2 、-NH-C(O)C 1-3 Alkyl, -C (O) C 1-3 Alkyl, halo C 1-3 Alkyl radical, C 1-3 Alkyl radical, C 3-8 Cycloalkyl radical, C 1-3 Alkoxy radical, C 1-3 Alkylthio radical, C 1-3 A hydroxyalkyl group.
Preferably, R 1 Selected from the group consisting of 5-10 membered heterocyclyl, 6-10 membered heteroaryl and C 6-10 An aryl group; the 5-to 10-membered heterocyclic group, 6-to 10-membered heteroaryl group and C 6-10 Aryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, nitro, oxo, -NHCH 3 、-N(CH 3 )(CH 3 )、-NH-C(O)CH 3 、-C(O)CH 3 Methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, methylthio, trifluoromethyl, difluoromethyl, monofluoromethyl.
Preferably, R 1 Is monocyclic, bicyclic or tricyclic, including spiro and fused rings; more preferably, ring B is monocyclic or bicyclic.
Preferably, R 1 Selected from phenyl, 5-7 membered monocyclic heteroaryl, 5-7 membered monocyclic heterocyclyl, naphthyl, 8-14 membered bicyclic heteroaryl, 8-14 membered bicyclic heterocyclyl.
Preferably, R 1 Selected from phenyl, 5-7 membered monocyclic heteroaryl, 5-7 membered monocyclic heterocyclyl, naphthyl, 8-14 membered bicyclic fused ring heteroaryl, 8-14 membered bicyclic fused ring heterocyclyl.
Further preferably, R 1 Is selected from C 6 Aryl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 7-membered monocyclic heteroaryl, 5-membered monocyclic heterocyclyl, 6-membered monocyclic heterocyclyl, 7-membered monocyclic heterocyclyl, 6/6-membered bicyclic fused aryl, 4-membered/4-membered bicyclic fused heteroaryl, 4-membered/5-membered bicyclic fused heteroaryl, 5-membered/4-membered bicyclic fused heteroaryl, 5-membered/5-membered bicyclic fused heteroaryl, 5-membered/6-membered bicyclic fused heteroaryl, 6-membered/5-membered bicyclic fused heteroaryl, 4-membered/6-membered bicyclic fused heteroaryl, 6-membered/4-membered bicyclic fused heteroaryl, 6-membered/6-membered bicyclic fused heteroaryl, 4-membered/4-membered bicyclic fused heterocyclyl, 4-membered/5-membered bicyclic fused heterocyclyl, 5-membered/4-membered bicyclic fused heterocyclyl, 5-membered/6-membered bicyclic fused heterocyclyl, 6-membered/5-membered bicyclic fused heterocyclyl, 4-membered/6-membered bicyclic fused heterocyclyl, 6-membered/6-membered bicyclic fused heterocyclyl, heteroaryl, O, N is 1 heteroatom selected from 1 or N is 3; r is as defined above 1 The group is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, nitro, oxo, -NHCH 3 、-N(CH 3 )(CH 3 )、-NH-C(O)CH 3 、-C(O)CH 3 Methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, methylthio, trifluoromethyl, difluoromethyl, monofluoromethyl.
Even more preferably, R 1 Selected from the following structures, which are unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, nitro, oxo, -NHCH 3 、-N(CH 3 )(CH 3 )、-NH-C(O)CH 3 、-C(O)CH 3 Methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, methylthio, trifluoromethyl, difluoromethyl, monofluoromethyl:
Figure BDA0003769482940000141
even more preferably, R 1 Selected from the following structures:
Figure BDA0003769482940000142
most preferably, R 1 Selected from the following structures:
Figure BDA0003769482940000143
in a preferred embodiment of the invention, R 1 Selected from 6-membered monocyclic heteroaryl, 9-10-membered bicyclic heteroaryl; the heteroatom in the heteroaryl is O or N, and the number of the heteroatoms is 1,2 or 3; the 6-membered monocyclic heteroaryl and the 9-10-membered bicyclic heteroaryl are unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, -NH-C (O) C 1-3 Alkyl, halo C 1-3 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl, -C 1-3 alkyl-N (C) 1-3 Alkyl) C 1-3 Alkyl radical, C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-3 Alkoxy radical, C 1-3 A hydroxyalkyl group.
Preference is given toOf (A) R 1 Selected from 6-membered monocyclic heteroaryl, 9-membered bicyclic heteroaryl; the heteroatom in the heteroaryl is N, and the number of the heteroatoms is 1 or 2; the 6-membered monocyclic heteroaryl and the 9-membered bicyclic heteroaryl are unsubstituted or substituted by one or more of the following substituents, respectively: which is unsubstituted or substituted, respectively, by one or more of the following substituents: halogen, hydroxy, halogeno C 1-3 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl radical, C 1-3 Alkyl radical, C 1-3 A hydroxyalkyl group.
Further preferably, R 1 Selected from 6-membered monocyclic heteroaryl, 5-membered/6-membered bicyclic fused heteroaryl, 6-membered/5-membered bicyclic fused heteroaryl, 6-membered/6-membered bicyclic fused heteroaryl; the heteroatom in the heteroaryl is N, and the number of the heteroatoms is 1 or 2; the 5-membered/6-membered bicyclic fused heteroaryl, 6-membered/5-membered bicyclic fused heteroaryl, 6-membered/6-membered bicyclic fused heteroaryl is unsubstituted or substituted with one or more of the following substituents, respectively: which is unsubstituted or substituted, respectively, by one or more of the following substituents: halogen, -C 1-3 alkyl-NH-C 1-3 Alkyl radical, C 1-3 Alkyl radical, C 1-3 A hydroxyalkyl group.
Further preferably, R 1 Selected from the following structures
Figure BDA0003769482940000151
Which is unsubstituted or substituted, respectively, by one or more of the following substituents: fluorine, chlorine, bromine, -CH 2 NHCH 3 Methyl, hydroxymethyl.
Further preferably, R 1 Selected from the following structures:
Figure BDA0003769482940000152
in a preferred embodiment of the invention, R 2 And R 3 Independently selected from hydrogen, methyl; or R 2 And R 3 Together with the atoms to which they are attached form a 5-or 6-membered heterocyclic ring.
Preferably, the first and second liquid crystal materials are,R 2 and R 3 Independently selected from hydrogen, methyl; or R 2 And R 3 Together with the atoms to which they are attached form a 5-membered heterocycloalkyl group in which the heteroatom is N, or a 6-membered heterocycloalkyl group, the number of heteroatoms being 2.
Further preferably, R 2 And R 3 Independently selected from hydrogen, methyl; or R 2 And R 3 Together with the atoms to which they are attached form a 5-membered heterocycloalkyl or a 6-membered heterocycloalkyl in which the heteroatom is N, the number of heteroatoms is 2, and X is S.
In a preferred embodiment of the invention, ring B is selected from phenyl optionally substituted by n R b Substituted when more than one R b When occurring simultaneously, each R b May be the same or different, wherein n is selected from 1,2 and 3; r is 1 Selected from 5-10 membered bicyclic heterocyclyl, 6-10 membered bicyclic heteroaryl; the 5-10 membered bicyclic heterocyclyl, 6-10 membered bicyclic heteroaryl are unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, -NH-C (O) C 1-3 Alkyl, halo C 1-6 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl, -C 1-3 alkyl-N (C) 1-3 Alkyl) C 1-3 Alkyl radical, C 1-6 Alkyl radical, C 3-8 Cycloalkyl, C 1-6 Alkoxy radical, C 1-6 A hydroxyalkyl group.
Preferably, ring B is selected from phenyl optionally substituted by n R b Substituted when more than one R b At the same time, each R b May be the same or different, wherein n is selected from 1,2 and 3; r is 1 Selected from 9-10 membered bicyclic heterocyclyl, 9-10 membered bicyclic heteroaryl; the 9-10 membered bicyclic heterocyclic group, 9-10 membered bicyclic heteroaryl group are unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, -NH-C (O) C 1-3 Alkyl, halo C 1-6 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl, -C 1-3 alkyl-N (C) 1-3 Alkyl) C 1-3 Alkyl radical, C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 1-3 Alkoxy radical, C 1-3 A hydroxyalkyl group.
Further preferably, ring B is selected from phenyl optionally substituted by n R b Substituted when more than one R b At the same time, each R b May be the same or different, wherein n is selected from 1,2 and 3; r 1 Selected from the group consisting of 5-membered/6-membered bicyclic fused heterocyclic group, 6-membered/5-membered bicyclic fused heterocyclic group, 6-membered/6-membered bicyclic fused heterocyclic group, 5-membered/6-membered bicyclic fused heteroaryl group, 6-membered/5-membered bicyclic fused heteroaryl group, 6-membered/6-membered bicyclic fused heteroaryl group; the heteroatom in the heterocyclic group and the heteroaryl group is O or N, and the number of the heteroatoms is 1,2 or 3; the 5-membered/6-membered bicyclic fused heterocyclic group, the 6-membered/5-membered bicyclic fused heterocyclic group, the 6-membered/6-membered bicyclic fused heterocyclic group, the 5-membered/6-membered bicyclic fused heteroaryl group, the 6-membered/5-membered bicyclic fused heteroaryl group, the 6-membered/6-membered bicyclic fused heteroaryl group are unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, -NH-C (O) CH 3 、-CH 2 NHCH 3 Trifluoromethyl, difluoromethyl, monofluoromethyl, hydroxymethyl.
In a preferred embodiment of the invention ring B is selected from phenyl optionally substituted with 2R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different; r b Selected from methyl,
Figure BDA0003769482940000161
R 1 Is selected from C 1-3 And (b) one or more optionally substituted pyridyl groups in the alkyl group.
Preferably, R b -ring B is selected from the following structures:
Figure BDA0003769482940000162
R 1 is selected from pyridyl optionally substituted by one or more of methyl.
In a preferred embodiment of the present invention, the compound represented by formula (I), or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure BDA0003769482940000163
Figure BDA0003769482940000171
Figure BDA0003769482940000181
Figure BDA0003769482940000191
Figure BDA0003769482940000201
Figure BDA0003769482940000211
Figure BDA0003769482940000221
Figure BDA0003769482940000231
Figure BDA0003769482940000241
Figure BDA0003769482940000251
the invention also aims to provide a method for preparing the compound shown in the formula (I) or a prodrug, a tautomer, a stereoisomer, a solvate, an isotopic derivative or a pharmaceutically acceptable salt thereof.
The compounds can be prepared by the following procedure.
The method comprises the following general steps:
Figure BDA0003769482940000252
a general step two:
Figure BDA0003769482940000261
a third general step:
Figure BDA0003769482940000262
wherein, in the preparation method, each substituent group in the compound is defined as the above.
The invention also provides a pharmaceutical composition which comprises the compound shown in the formula (I) shown in the invention, or a prodrug, a tautomer, a stereoisomer, a solvate, an isotopic derivative or a pharmaceutically acceptable salt thereof.
The invention also provides a medicinal composition which comprises the compound shown in the formula (I) shown in the invention, or a prodrug, a tautomer, a stereoisomer, a solvate, an isotope derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary material.
Administration of a compound of the present invention or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, can be carried out in pure form or in the form of a suitable pharmaceutical composition by any acceptable mode of administration which provides the drug for analogous use. The pharmaceutical compositions of the present invention may be prepared by combining a compound of the present invention with suitable pharmaceutically acceptable excipients. The pharmaceutical compositions of the present invention may be formulated as solid, semi-solid, liquid or gaseous formulations.
The invention also aims to provide the application of the compound shown in the formula (I) in the invention, or a prodrug, a tautomer, a stereoisomer, a solvate, an isotopic derivative or a pharmaceutically acceptable salt thereof in preparing medicines for treating diseases mediated by the POLQ.
In some embodiments, the POLQ-mediated disease is cancer or a tumor-associated disease.
Further, the present invention provides the use wherein the cancer or tumor comprises a solid tumor and a hematological tumor; the solid tumors comprise breast cancer, colorectal cancer, cervical cancer, ovarian cancer, prostatic cancer, gastric cancer (comprising gastrointestinal junction cancer), esophageal cancer, head and neck cancer and lung cancer; the hematologic tumors include lymphomas and leukemias.
An object of the present invention also includes providing a method for preventing and/or treating a disease mediated by POLQ, which comprises administering to a patient a therapeutically effective dose of a compound represented by the general formula (I), or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention; further, the POLQ-mediated disease is cancer or a tumor-related disease; further, the present invention provides the use wherein the cancer or tumor comprises a solid tumor and a hematological tumor; the solid tumors comprise breast cancer, colorectal cancer, cervical cancer, ovarian cancer, prostatic cancer, gastric cancer (comprising gastrointestinal junction cancer), esophageal cancer, head and neck cancer and lung cancer; the hematologic tumors include lymphomas and leukemias.
The compound represented by the general formula (I) of the present invention, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, may be administered in combination with one, two, or more additional anticancer agents or immune checkpoint modulators for treating cancer or tumor.
Further, the additional anti-cancer agents or immune checkpoint modulators for the treatment of cancer or tumor comprise PARP inhibitors, ATR inhibitors, ATM inhibitors, WEE1 inhibitors, topoisomerase inhibitors and DNA damaging chemotherapeutic agents.
Further, the DNA damage chemotherapeutic drug comprises cisplatin, bleomycin, gemcitabine and docetaxel; the topoisomerase inhibitor comprises etoposide and irinotecan.
The compound shown in the general formula (I) or a prodrug, a tautomer, a stereoisomer, a solvate, an isotope derivative or a pharmaceutically acceptable salt thereof can be used in combination with one or two or more other treatment means (such as radiotherapy) for treating cancer or tumors.
When the compound of the present invention, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, is administered in combination with another anticancer agent or immune checkpoint inhibitor for the treatment of cancer or tumor, the compound of the present invention, or a pharmaceutically acceptable salt thereof, may provide enhanced anticancer effects.
Definition of
The terms "optional," "any," "optionally," or "optionally" refer to a subsequently described event or circumstance which may, but need not, occur, and include instances where said event or circumstance occurs and instances where it does not.
The term "oxo" means that two hydrogen atoms at the same substitution position are replaced by the same oxygen atom to form a double bond, i.e. = O.
Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1-20 carbon atoms, preferably 1-10 carbon atoms (i.e., C) 1-10 Alkyl group), further preferably containing 1 to 8 carbon atoms (C) 1-8 Alkyl), more preferably containing 1 to 6 carbon atoms (i.e., C) 1-6 Alkyl) such as "C 1-6 By alkyl is meant that the group is alkyl and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1,2,3,4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropylAlkyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl and the like.
Unless otherwise specified, the term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one double bond. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C) 2-10 Alkenyl), further preferably containing 2 to 8 carbon atoms (C) 2-8 Alkenyl), more preferably containing 2 to 6 carbon atoms (i.e., C) 2-6 Alkenyl), 2-5 carbon atoms (i.e., C) 2-5 Alkenyl), 2-4 carbon atoms (i.e., C) 2-4 Alkenyl), 2-3 carbon atoms (i.e., C) 2-3 Alkenyl), 2 carbon atoms (i.e., C) 2 Alkenyl) such as "C 2-6 By alkenyl "is meant that the group is alkenyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2,3,4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1, 3-butadienyl, and the like.
Unless otherwise specified, the term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one triple bond consisting of carbon atoms and hydrogen atoms. Alkynyl groups may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C) 2-10 Alkynyl) and further preferably contains 2 to 8 carbon atoms (C) 2-8 Alkynyl) and more preferably contains 2 to 6 carbon atoms (i.e., C) 2-6 Alkynyl), 2-5 carbon atoms (i.e., C) 2-5 Alkynyl), 2-4 carbon atoms (i.e., C) 2-4 Alkynyl), 2-3 carbon atoms (i.e., C) 2-3 Alkynyl), 2 carbon atoms (i.e., C) 2 Alkynyl), for example "C 2-6 Alkynyl "means that the group is alkynyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2,3,4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.
Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic radical having the specified number of carbon atoms, preferably comprising 3 to 12 carbon atoms (i.e., C) 3-12 Cycloalkyl), more preferably containing 3 to 10 carbon atoms (C) 3-10 Cycloalkyl radicals) Further, 3 to 6 carbon atoms (C) are preferable 3-6 Cycloalkyl), 4 to 6 carbon atoms (C) 4-6 Cycloalkyl), 5 to 6 carbon atoms (C) 5-6 Cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.
Unless otherwise specified, the term "alkoxy" refers to an-O-alkyl group, as defined above, i.e. containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1,2,3,4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2-dimethylpropoxy, 1-ethylpropoxy, and the like.
Unless otherwise specified, the term "alkylthio" refers to the replacement of the oxygen in the above-mentioned "alkoxy" by sulfur, i.e., -S-alkyl, which is as defined above, i.e., contains 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1,2,3,4, 5 or 6). Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1-methylpropylthio, tert-butylthio, pentylthio, 1-dimethylpropylthio, 1, 2-dimethylpropylthio, and the like. .
The term "halogen" or "halo" means, unless otherwise specified, F, cl, br, I. The term "haloalkyl" means an alkyl group as defined above wherein one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen. Representative examples of haloalkyl groups include CCl 3 、CF 3 、CHCl 2 、CH 2 Cl、CH 2 Br、CH 2 I、CH 2 CF 3 、CF 2 CF 3 And the like.
Unless otherwise specified, the term "heterocyclyl" means a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon substituent, which isA non-aromatic structure comprising 3 to 20 ring atoms, wherein 1,2,3 or more ring atoms are selected from N, O or S, the remaining ring atoms being C. Preferably 3 to 12 ring atoms, further preferably 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 4 to 6 ring atoms, or 5 to 6 ring atoms. The heteroatoms are preferably 1-4, more preferably 1-3 (i.e. 1,2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like. Bicyclic or polycyclic heterocyclic groups include heterocyclic groups that are spiro, fused, and bridged. "Heterocyclyl" bicyclic or polycyclic rings include those wherein one ring is aromatic and the other ring is non-aromatic, including spiro, fused and bridged rings. Heterocyclyl groups may be monocyclic (monocyclic heterocyclyl) ring systems, or fused (fused or heterofused ring groups), bridged (heterobridged or bridged heterocyclyl) or spiro-connected (heterospiro or spiroheterocyclyl) ring systems, such as bicyclic ring systems (bicyclic heterocyclyl), and may be saturated or partially unsaturated. Bicyclic heterocyclic groups may contain one or more heteroatoms in one or both rings. In some embodiments, heterocyclyl also includes ring systems in which heterocyclyl as defined above is fused to one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring; alternatively, in some embodiments, heterocyclyl further includes a ring system wherein heterocyclyl is fused to one or more aryl/heteroaryl groups as defined above, wherein the point of attachment is on the aryl/heteroaryl or heterocyclyl ring; alternatively, in some embodiments, a heterocyclyl group as defined above is a fused ring system of one or more heterocyclyl groups as defined above wherein the point of attachment is on any heterocyclyl ring. In the above case, the number of elements of the heterocyclic ring system is the number of ring atoms of the ring system after fusion. In some embodiments, a heterocyclyl is optionally substituted, e.g., unsubstituted (unsubstituted heterocyclyl) or substituted (substituted heterocyclyl) with one or more substituents. Exemplary 3-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, aziridinyl (aziridyl), oxacyclopropaneyl (oxarenyl), and thiacyclopropanyl (thiorenyl). Containing 1 hetero atomExemplary 4-membered heterocyclic groups of (a) include, but are not limited to, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and 2, 5-dioxopyrrolidinyl. Exemplary 5-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiacyclopentane, dithiolane, each 2-oxooxazolidinyl. Exemplary 5-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and tetrahydrothiopyranyl (thianyl). Exemplary 6-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazinylalkyl (triazinanyl), oxadiazinylalkyl (oxadiazinanyl), thiadiazinylalkyl (thiadiazinanyl), oxathiazinoalkyl (oxathiazinanyl), and dioxazinylalkyl (dioxazinanyl). Exemplary 7-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepinyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azacyclooctyl, oxocyclooctyl, and thiacyclooctyl. Condensed to a C 6 Exemplary 5-membered heterocyclic groups on the aryl ring (also referred to herein as 5, 6-bicyclic heterocyclic groups) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolonyl, and the like. Condensed to a C 6 Exemplary 6-membered heterocyclyl groups on the aryl ring (also referred to herein as 6, 6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
Unless otherwise specified, the terms "fused ring group" and "fused ring" refer to aromatic, nonaromatic, saturated or partially unsaturated ring systems formed from two or more ring structures that share two adjacent atoms with each other. Illustrative examples of "fused rings" include (but are not limited to)
Figure BDA0003769482940000291
And the like.
Unless otherwise specified, the terms "fused heterocyclic group", "fused ring heterocyclic group", and "fused ring heterocyclic group" refer to a non-aromatic, saturated, or partially unsaturated ring system formed by two or more ring structures sharing two adjacent atoms with each other, the ring atoms containing one or more heteroatoms independently selected from oxygen, nitrogen, and sulfur, the number of heteroatoms being 1,2,3, or more. Illustrative examples of "fused ring heterocyclyl" include (but are not limited to)
Figure BDA0003769482940000292
Figure BDA0003769482940000293
And the like.
Unless otherwise specified, the terms "fused ring heteroaryl", "fused heteroaryl group" and "fused heteroaryl group" refer to an aromatic ring system formed by two or more ring structures sharing two adjacent atoms with each other, the ring atoms containing one or more heteroatoms independently selected from oxygen, nitrogen and sulfur, the number of heteroatoms being 1,2,3 or more. Illustrative examples of "fused ring heteroaryl" include (but are not limited to)
Figure BDA0003769482940000294
And the like.
Unless otherwise specified, the terms "spirocyclic group", "spirocyclic ring" and "spirocyclic ring" refer to a saturated, monovalent aliphatic hydrocarbon group containing only one spiro carbon atom, which may contain from 6 to 14, preferably from 7 to 10, ring carbon atoms. Spiro ring groups include 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, and 5-membered/6-membered spiro ring groups, etc., in which spiro atoms are respectively counted as the number of elements in each ring. Illustrative examples of spiro ring groups include (but are not limited to)
Figure BDA0003769482940000295
And so on.
Unless otherwise specifiedThe terms "heterospirocyclic group", "spirocyclic heterocyclyl" refer to a saturated, monovalent aliphatic group containing only one spiro carbon atom, which may contain 6 to 14 ring atoms, preferably 7 to 10 ring atoms, of which 1 to 4 ring heteroatoms, preferably 1 to 3 (i.e. 1,2 or 3) ring heteroatoms, are included, and the heteroatoms are independently selected from N, O and S. Heterospirocyclic groups include 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, and 5-membered/6-membered heterospirocyclic groups, etc., in which the number of spiro atoms is counted individually for each ring. Illustrative examples of heterocyclic groups include (but are not limited to)
Figure BDA0003769482940000296
And so on.
Unless otherwise specified, the terms "bridged ring group", "bridged ring" refer to a polycyclic, monovalent aliphatic hydrocarbon group in which any two rings share two ring carbon atoms not directly connected, which may contain from 5 to 20 ring carbon atoms, preferably from 6 to 14 ring carbon atoms, more preferably from 7 to 10 ring carbon atoms, and may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. The bridged ring group includes a bicyclic, tricyclic, tetracyclic or polycyclic bridged ring group, preferably a bicyclic, tricyclic or tetracyclic bridged ring group, more preferably a bicyclic or tricyclic bridged ring group. Illustrative examples of bridge ring groups include (but are not limited to)
Figure BDA0003769482940000301
Unless otherwise specified, the terms "heterobridged cyclic group", "bridged heterocyclic group" refer to a polycyclic, monovalent aliphatic group in which any two rings share two ring atoms which are not directly connected, which may contain 5 to 14 ring atoms, preferably 6 to 14 ring atoms, more preferably 7 to 10 ring atoms, of which 1 to 4 ring heteroatoms, preferably 1 to 3 (i.e., 1,2, or 3) ring heteroatoms, are independently selected from N, O, and S, and may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Heterobridged ring groups include bicyclic, tricyclic, tetracyclic or polycyclic heterobridged ring groups, preferably bicyclic, tricyclic or tetracyclic heterobridged ring groups, more preferably bicyclic or tricyclicHeterobridged ring radicals. Illustrative examples of heterobridged ring groups include (but are not limited to)
Figure BDA0003769482940000302
Unless otherwise specified, "heterocycloalkyl" means a monocyclic, saturated "heterocyclyl" or "heterocycle" as defined above, the ring atoms being as defined above, i.e. comprising from 3 to 20 ring atoms ("3-20 membered heterocycloalkyl"), the number of heteroatoms being from 1 to 4 (1, 2,3 or 4), preferably from 1 to 3 (1, 2 or 3), wherein the heteroatoms are each independently selected from N, O or S. Preferably 3 to 12 ring atoms ("3-12 membered heterocycloalkyl"), more preferably 3 to 10 ring atoms ("3-10 membered heterocycloalkyl"), even more preferably 3 to 8 ring atoms ("3-8 membered heterocycloalkyl"), even more preferably 4 to 7 ring atoms ("4-7 membered heterocycloalkyl"), even more preferably 5 to 10 ring atoms ("5-10 membered heterocycloalkyl"), even more preferably 5 to 6 ring atoms ("5-6 membered heterocycloalkyl"). In certain embodiments, each instance of heterocycloalkyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted (a "substituted heterocycloalkyl") with one or more substituents. The "heterocyclyl" or "heterocyclic" moieties above have given some exemplary "heterocycloalkyl" and also include, but are not limited to, aziridinyl, oxacyclopropaneyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxacyclohexylyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiacyclohexyl, oxazolidinyl, dioxanyl, dithiacyclohexyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolinidinyl, and the like.
Unless otherwise specified, the term "aryl" denotes monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems containing from 6 to 16 carbon atoms, or from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms, or from 6 to 10 carbon atoms, preferably from 6 to 10 carbon atoms, and the term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, pyrenyl, or the like.
Unless otherwise specified, the term "heteroaryl" denotes an aromatic monocyclic, bicyclic or polycyclic ring system containing a 5-16 membered structure, preferably a 5-14 membered structure, a 5-12 membered structure, a 5-10 membered structure, a 5-8 membered structure, more preferably a 5-6 membered structure, wherein 1,2,3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, the number of heteroatoms being preferably 1,2 or 3. Bicyclic or polycyclic heterocyclic groups include fused ring heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, phthalizinyl, pyrrolo [2,3-b ] pyridyl, imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.
Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, particularly humans, without excessive toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio, such as the medically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent.
The term "isotopic derivative" means, unless otherwise specified, that a compound of the present invention can exist in an isotopically labeled or enriched form, containing one or more atoms having an atomic mass or mass number different from the most naturally found atomThe atomic mass or mass number of a plurality of atoms. The isotope may be a radioactive or non-radioactive isotope. Isotopes commonly used as isotopic labels are: an isotope of hydrogen, 2 h and 3 h; carbon isotope: 13 c and 14 c; chlorine isotope: 35 cl and 37 cl; fluorine isotope: 18 f; iodine isotope: 123 i and 125 i; nitrogen isotope: 13 n and 15 n; oxygen isotope: 15 O, 17 o and 18 isotopes of O and sulfur 35 And S. These isotopically labeled compounds can be used to study the distribution of pharmaceutically acceptable molecules in tissues. In particular to 3 H and 13 c, because they are easy to label and convenient to detect, they are more widely used. Certain heavy isotopes, such as heavy hydrogen (c: (b)) 2 H) The substitution of (2) can enhance the metabolic stability and prolong the half-life period, thereby achieving the aim of reducing the dosage and providing the curative effect advantage. Isotopically-labeled compounds are generally synthesized by known synthetic techniques as are non-isotopically-labeled compounds, starting from a starting material which has been labeled.
Unless otherwise specified, the terms "solvate," "solvate," and "solvate" mean a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In certain instances, the solvate will be able to be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular arrangement and/or a disordered arrangement. Solvates may comprise stoichiometric or non-stoichiometric amounts of solvent molecules. "solvate" encompasses both solution phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
Unless otherwise specified, the term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like. Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
Unless otherwise specified, the term "tautomer" refers to structural isomers that have different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons.
Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): such as R, S configuration containing asymmetric centers, (Z), (E) isomers of double bonds, and conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention.
The term "prodrug" refers to a drug that is converted in vivo to the parent drug, unless otherwise specified. Prodrugs are often useful, which may improve some determined, undesirable physical or biological property. Physical properties are often associated solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too rapid metabolism or poor bioavailability, which may itself be associated with physicochemical properties. For example, they can be bioavailable by oral administration, whereas the parent cannot. The prodrug also has improved solubility in pharmaceutical compositions compared to the parent drug. An example, without limitation, of a prodrug would be any compound of the invention administered as an ester ("prodrug") to facilitate transport across a cell membrane, where water solubility is detrimental to mobility, but once intracellular water solubility is beneficial, it is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to show an active moiety.
The term "optionally substituted" means, unless otherwise specified, that the hydrogen of the substitutable site of the group is unsubstituted or substituted with one or more substituents, preferably selected from the group consisting of: halogen, hydroxy, mercapto, cyano, nitro, amino, azido, oxo, carboxy, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-to 10-membered heteroaromatic ring group, wherein, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-to 10-membered heteroaromatic ring radicals optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, said oxo means that two H at the same substitution position are replaced by the same O to form a double bond.
Unless otherwise specified, the term "treatment" encompasses any treatment of a disease, disorder, or condition in a patient, including: (a) Inhibiting the symptoms of, i.e., arresting the development of, diseases, disorders, and conditions; or (b) alleviating the symptoms of the disease, disorder, and condition, i.e., causing regression of the disease or symptoms; or (c) ameliorating or eliminating a disease, disorder, and condition or one or more symptoms associated with the disease.
The beneficial effects of the invention are as follows:
the invention designs a compound with a novel structure, and provides a new direction for the development of the drugs of the POLQ inhibitor class. The research on the in vitro enzyme activity inhibition activity shows that the compound has stronger inhibition effect on the POLQ enzyme and can be used as a prospect compound for treating the POLQ-mediated diseases. The hERG test shows that the compound has no obvious inhibition effect on hERG channel and has relatively low cardiac toxicity. In addition, the invention researches a specific synthesis method, and the synthesis method has the advantages of simple process and convenient operation, and is beneficial to large-scale industrial production and application.
The abbreviations used in the preparation examples, examples and elsewhere herein are:
DPPA Azidophosphoric acid Diphenyl ester
TEA Triethylamine
DCM dichloromethane
TFA trifluoroacetic acid
XPhos 2-dicyclohexylphos-2 ',4',6' -triisopropylbiphenyl
DMF N, N' -dimethylformamide
B 2 Pin 2 Biboric acid pinacol ester
Pd(dppf)Cl 2 [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
Dioxane Dioxane
MsCl methanesulfonyl chloride
Boc 2 Di-tert-butyl O dicarbonate
DCE 1, 2-Dichloroethane
THF tetrahydrofuran
TBDPSCl tert-butyldiphenylchlorosilane
DMP dimethyl phthalate
TBAF tetrabutylammonium fluoride
DMSO dimethyl sulfoxide
NBS N-bromosuccinimide
Tert-Butyl Tert-Butyl Tert-Butyl ester
DMAP N, N-dimethylpyridin-4-amine
EDCl 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
LAH lithium aluminum hydride
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples are generally performed under conventional conditions or conditions recommended by the manufacturers. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials are described herein for illustrative purposes only.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass spectrometry (LC-MS) or/and liquid chromatography (HPLC). NMR was measured using a Wuhan Zhongke Niujin Magnetic Resonance Technigy Co., ltd Quan tum-I,400MHz; the instrument used for LC-MS was Agilent,1290Infinity II; the instrument used for HPLC was Thermo, ultimate 3000.
Preparative HPLC condition one (ammonium bicarbonate as additive): the instrument comprises the following steps: a SHIMADZU; a pump: LC-20AP; a detector: SPD-20A; wavelength: 214nm and 254nm; column type: ultimate XB-C18, 50 × 250mm,10um (PARP-05); mobile phase: a:10mM ammonium bicarbonate, B: acetonitrile; operating time: 30min; flow rate: 70mL/min.
Preparative HPLC condition two (formic acid as additive): the instrument comprises the following steps: a SHIMADZU; a pump: LC-20AP; a detector: SPD-20A; wavelength: 214nm and 254nm; column type: ultimate XB-C18, 50 × 250mm,10um (PARP-05); mobile phase: a:0.1% formic acid, B: acetonitrile; operating time: 30min; flow rate: 70mL/min.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
Preparation of an intermediate:
an intermediate A: preparation of 1- (6-chloropyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea
Figure BDA0003769482940000331
The first step is as follows: 6-methylpyridine-3-carboxylic acid (10.00g, 72.9mmol, 1.0eq) was dissolved in dichloromethane (500 mL), and triethylamine (22.08g, 218.7mmol, 3.0eq) and cascade were added in this orderDiphenyl azophoshate (26.60g, 109.4mmol, 1.5eq), reacted at room temperature overnight, diluted with ethyl acetate (200 mL), the organic phase washed with saturated aqueous ammonium chloride (60mL. Times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography (PE: EA =4:1 to 1) to obtain compound A1 (9.78 g, yield: 100%). MS (ESI): M/z 135.1 (M + H) + .
The second step is that: compound A1 (5.00g, 37.27mmol, 1.0eq) and 6-chloropyrazine-2-amine (5.30g, 41.00mmol, 1.1eq) were dissolved in toluene (200 mL), argon was replaced, and the reaction mixture was heated to 110 ℃ and stirred for 6 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove toluene, washed with ethyl acetate, filtered, and dried to give intermediate A1- (6-chloropyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea (6.23 g, yield: 63.4%). MS (ESI) M/z 264.0 (M + H) + .
An intermediate B: preparation of 6- (3-methyl-4- ((3-methyloxetan-3-yl) methoxy) phenyl) pyrazin-2-amine
Figure BDA0003769482940000341
The first step is as follows: 4-bromo-2-methylphenol (1.00g, 5.35mmol, 1.0eq) was dissolved in N, N' -dimethylformamide (20 mL), sodium hydride (235mg, 9.63mmol,60% pure, 1.0eq) was slowly added at 0 ℃, and after stirring for 10 minutes, 3- (chloromethyl) -3-methyloxetane (709mg, 5.89mmol, 1.1eq) was added, and the mixture was heated to 100 ℃ and stirred overnight. The reaction was cooled to room temperature, quenched with ice water (50 mL), the aqueous phase extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography (PE 100% to PE: EA = 4). MS (ESI) M/z 271.1 (M + H) + .
The second step is that: compound B1 (2.20g, 8.11mmol, 1.0eq), pinacol diboron ester (3.09g, 12.2mmol, 1.5eq), potassium acetate (2.39g, 24.3mmol, 3.0eq) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (290mg, 0.4mmol, 0.05eq) was added to dioxane (40 mL) and stirred at 100 ℃ under argon. Concentrating the reaction mixture under reduced pressure, separating the residue by flash silica gel column chromatography (PE)100% to PE: EA = 10) to obtain compound B2 (2.58 g, yield: 100.0%). MS (ESI) M/z 319.2 (M + H) + .
The third step: compound B2 (4.69g, 14.77mmol, 1.0eq), 6-chloropyrazin-2-amine (1.91g, 14.77mmol, 1.0eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (1.08g, 1.48mmol, 0.1eq) and anhydrous sodium carbonate (3.13g, 29.54mmol, 2.0eq) were sequentially added to a mixed solution of dioxane/water (200 mL/50 mL), replaced with argon for 3 times, and the mixture was heated to 90 ℃ and stirred for 6 hours. After the reaction was cooled to room temperature, water (30 mL) was added, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by flash silica gel chromatography (PE: EA =4:1 to 1) to give intermediate B6- (3-methyl-4- ((3-methyloxetan-3-yl) methoxy) phenyl) pyrazin-2-amine (2.80 g, yield: 66.6%). MS (ESI): M/z 286.2 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ8.22(s,1H),7.86–7.74(m,3H),7.05(d,J＝9.2Hz,1H),6.42(s,2H),4.54(d,J＝6.0Hz,2H),4.33(d,J＝5.6Hz,2H),4.08(s,2H),2.22(s,3H),1.39(s,3H).
An intermediate C: preparation of 6- (3-methyl-4- ((3-methyloxetan-3-yl) methoxy) phenyl) pyrazine-2-carboxylic acid
Figure BDA0003769482940000342
6-chloropyrazine-2-carboxylic acid (249mg, 1.57mmol, 1eq) and compound B2 (5009 mg,1.57mmol, 1eq), sodium carbonate (332mg, 3.14mmol, 2eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (57mg, 0.079mmol, 0.05eq) was added to a mixed solution of dioxane (10 mL) and water (1 mL), nitrogen gas was replaced, and the reaction solution was heated to 100 ℃ and stirred for 16 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to flash silica gel column chromatography (DCM: meOH = 1) to give intermediate C6- (3-methyl-4- ((3-methyloxetan-3-yl) methoxy) phenyl) pyrazine-2-carboxylic acid (200 mg, yield: 40.8%). MS (ESI) M/z 315.1 (M + H) + .
Example 1
Synthesis of 1- (6- (1- ((3-methyloxetan-3-yl) methyl) -1H-indol-5-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000351
the first step is as follows: 5-bromo-1H-indole (534mg, 2.72mmol, 1eq) was dissolved in N, N-dimethylformamide (20 mL), cooled in an ice water bath to 0 ℃ and sodium hydride (131mg, 3.27mmol,60% pure, 1.2eq) was added. After 30 minutes of reaction in an ice bath, 3- (chloromethyl) -3-methyloxetane (361mg, 3.00mmol, 1.1eq) was added thereto, and after the addition, the reaction mixture was heated to 90 ℃ and stirred for 18 hours. The reaction solution was poured into 100mL of ice water, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to flash silica gel column chromatography (PE: EA =10:1 to 5). MS (ESI) M/z 280.0 (M + H) + .
The second step is that: compound 1a (310mg, 1.11mmol, 1eq), potassium acetate (327mg, 3.33mmol, 3eq), pinacol ester diboron (423mg, 1.67mmol, 1.5eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (40mg, 0.055mmol, 0.05eq) was added to dioxane (10 mL) in sequence, replaced with argon three times and heated to 100 deg.C for reaction overnight. The reaction solution was concentrated, and the residue was subjected to flash silica gel column chromatography (PE: EA = 3). MS (ESI) M/z 328.2 (M + H) + .
The third step: intermediate A (285mg, 1.08mmol, 1eq), compound 1b (354mg, 1.08mmol, 1eq), potassium carbonate (299mg, 2.16mmol, 2eq) were added in this order to a mixed solution of dioxane (5 mL) and water (0.5 mL), and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (35mg, 0.11mmol, 0.1eq) was replaced with argon three times, and then the temperature was raised to 100 ℃ to react for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was refluxed with 3mL of ethanol for 30 minutes, slowly cooled to room temperature, filtered and dried to give the title compound, 1- (6- (1- ((3-methyloxetan-3-yl) methyl) -1H-indol-5-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea (55 mg, yield: 11.9%). MS (ESI):m/z 429.2(M+H) + . 1 H NMR(400MHz,DMSO-d 6 )δ9.96(s,1H),9.77(s,1H),8.87(s,1H),8.85(s,1H),8.53(d,J＝2.4Hz,1H),8.34(s,1H),7.94–7.89(m,2H),7.73(d,J＝8.4Hz,1H),7.51(d,J＝3.2Hz,1H),7.23(d,J＝8.4Hz,1H),6.62(d,J＝3.2Hz,1H),4.62(d,J＝6.0Hz,2H),4.46(s,2H),4.23(d,J＝5.6Hz,2H),2.43(s,3H),1.21(s,3H).
example 2
Synthesis of 1- (6- (1- ((3-methyloxetan-3-yl) methyl) -1H-indazol-5-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000361
the first step is as follows: 3-methyl-3-oxetanylmethanol (4 g,39.17mmol, 1eq) and triethylamine (5.95g, 58.76mmol,1.5 eq) were dissolved in dichloromethane (50 mL), methanesulfonyl chloride (4.71g, 41.13mmol, 1.05eq) was slowly added dropwise at 0 ℃ and reacted at 25 ℃ for 2 hours after completion of the addition. The reaction mixture was spun and pumped to dryness by an oil pump to obtain Compound 2a (5.6 g,31.07mmol, 79.3%). 1 HNMR(400MHz,CDCl 3 )δ4.52(d,J＝6.4Hz,2H),4.43(d,J＝6.4Hz,2H),4.32(s,2H),3.08(s,3H),1.40(s,3H).
The second step: 5-bromoindazole (1g, 5.08mmol, 1eq), compound 2a (1.01g, 5.58mmol, 1.1eq) and potassium carbonate (2.1g, 15.23mmol, 3eq) were dissolved in N, N-dimethylformamide (20 mL), and the reaction mixture was heated to 50 ℃ for 16 hours. The reaction mixture was diluted with water (100 mL), the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (PE: EA = 10). MS (ESI) M/z 281.0 (M + H) + . 1 HNMR(400MHz,CDCl 3 )δ7.86(s,1H),7.78(d,J＝1.2Hz,1H),7.78(d,J＝1.2Hz,1H),7.37(dd,J＝8.8,1.6Hz,1H),7.20(d,J＝8.8Hz,1H),4.70(d,J＝6.0Hz,2H),4.45(s,2H),4.34(d,J＝6.0Hz,2H),1.15(s,3H).
The third step: compound 2b (100mg, 0.35mmol, 1eq) was dissolved in dioxane (5 mL), and potassium acetate (70mg, 0.71mmol, 2eq) and pinacol diboron (18 mg,0.71mmol, 2eq) were added in that order0mg,0.71mmol, 2eq) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (13mg, 0.018mmol, 0.05eq) was purged with nitrogen, and the reaction mixture was heated to 90 ℃ and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to flash silica gel chromatography (PE: EA = 5. MS (ESI): M/z 329.2 (M + H) + .
The fourth step: compound 2c (120mg, 0.37mmol, 0.8eq), intermediate A (120mg, 0.46mmol, 1eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (1695g, 0.02mmol, 0.05eq) and sodium carbonate (97mg, 0.91mmol, 2eq) were sequentially added to a mixed solvent of dioxane (5 mL) and water (0.5 mL), nitrogen gas was replaced, and the reaction solution was heated to 100 ℃ and stirred for 16 hours. The reaction liquid was concentrated under reduced pressure, and the residue was subjected to flash silica gel chromatography (DCM: meOH = 10. MS (ESI) M/z 430.2 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ9.76–9.75(m,2H),8.95(s,1H),8.92(s,1H),8.54–8.52(m,2H),8.26(d,J＝0.8Hz,1H),8.15(dd,J＝8.8,1.6Hz,1H),7.92–7.89(m,2H),7.24(d,J＝8.4Hz,1H),4.71–4.70(m,4H),4.28(d,J＝6.0Hz,2H),2.43(s,3H),1.15(s,3H).
Example 3
Synthesis of 1- (6- (1- ((3-methyloxetan-3-yl) methyl) -1,2,3, 4-tetrahydroquinolin-6-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000371
the first step is as follows: 6-bromo-1, 2,3, 4-tetrahydroquinoline (1.00g, 4.71mmol, 1eq) was dissolved in N, N' -dimethylformamide (10 mL), sodium hydride (302mg, 7.54mmol,60% by volume purity,1.6 eq) was added to the above solution, and after stirring at room temperature for 30 minutes, 3- (chloromethyl) -3-methyloxyethane (852mg, 7.07mmol, 1.5eq) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched by slowly adding 25mL of ice water. Extracted with ethyl acetate, washed once with brine (15 mL), once with water (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the desired compoundCompound 3a (1.39 g, yield: 99.6%). MS (ESI) M/z 296.0 (M + H) + .
The second step is that: compound 3a (1.38g, 4.66mmol, 1eq), pinacol diboron diborate (1.77g, 6.99mmol, 1.5eq), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (205mg, 0.28mmol, 0.06eq) and potassium acetate (1.37g, 13.98mmol, 3eq) were added in sequence to anhydrous dioxane (25 mL), replaced with argon three times, and the reaction solution was warmed to 80 ℃ and stirred overnight. The reaction solution was directly concentrated under reduced pressure, and the residue was subjected to flash silica gel column chromatography (PE: EA = 6. MS (ESI) M/z 344.2 (M + H) + .
The third step: compound 3b (200mg, 0.58mmol, 1eq), intermediate A (184.35mg, 0.7mmol, 1.2eq), potassium carbonate (161.05mg, 1.17mmol, 2eq) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (42mg, 0.058mmol, 0.1eq) was added in this order to a mixed solution of dioxane (5 mL) and water (1 mL), and the mixture was heated to 90 ℃ under argon and stirred overnight. After the reaction mixture was cooled, water (5 mL) was added, the aqueous phase was extracted with dichloromethane, and the organic phase was concentrated under reduced pressure. The residue was separated by flash silica gel chromatography (DCM: meOH = 10). MS (ESI) M/z 445.3 (M + H) + . 1 HNMR(400MHz,DMSO-d 6 )δ9.95(s,1H),9.64(s,1H),8.67(s,1H),8.66(s,1H),8.49(d,J＝2.4Hz,1H),7.88(dd,J＝8.4,2.8Hz,1H),7.74–7.62(m,2H),7.20(d,J＝8.4Hz,1H),6.70(d,J＝8.8Hz,1H),4.53(d,J＝5.6Hz,2H),4.18(d,J＝6.0Hz,2H),3.50(s,2H),3.28–3.21(m,2H),2.77(t,J＝6.2Hz,2H),2.40(s,3H),1.90–1.85(m,2H),1.29(s,3H).
Example 4
Synthesis of 1- (6- (1- ((3-methyloxetan-3-yl) methyl) indolin-5-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000381
the first step is as follows: 5-bromo-2, 3-dihydro-1H-indole (1.00g, 5.05mmol, 1.0eq) was dissolved in methylene chloride (10 mL), 3-methyl-3-formyl-1-oxetane (606 mg,6.05mmol, 1.2eq) and acetic acid (1 mL) were sequentially added, and after the reaction solution was stirred at room temperature for 30 minutes, sodium borohydride acetate (2.14g, 10.10mmol, 2.0eq) was added, and stirring was continued at room temperature overnight. The reaction mixture was washed with a saturated sodium bicarbonate solution (20 mL) and a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography (PE: DCM = 3. MS (ESI) M/z 282.0 (M + H) + .
The second step is that: compound 4a (480mg, 1.71mmol, 1.0eq), pinacol diboron ester (651mg, 2.56mmol, 1.5eq), potassium acetate (419mg, 4.27mmol, 2.5eq) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (125mg, 0.17mmol, 0.1eq) was added to dioxane (4 mL) in sequence and heated to 100 ℃ under argon atmosphere and stirred for 3 hours. After the reaction solution was cooled to room temperature, it was filtered through celite, and concentrated under reduced pressure. The residue was separated by preparative thin layer chromatography (PE: EA = 4. MS (ESI) M/z 330.2 (M + H) + .
The third step: compound 4b (213mg, 0.65mmol,1.0 eq), intermediate A (188mg, 0.71mmol, 1.1eq), sodium carbonate (137mg, 1.29mmol,2.0 eq) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (47mg, 0.06mmol, 0.1eq) was sequentially added to a mixed solution of dioxane/water (5mL, 4/1), replaced with argon gas 3 times, heated to 90 ℃ and stirred for 3 hours. Ethyl acetate (20 mL) was added for dilution, celite was filtered, and the filtrate was concentrated under reduced pressure. Washed with ethyl acetate (15 mL) and dried to give compound 4- (6- (1- ((3-methyloxetan-3-yl) methyl) indolin-5-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea (32.71 mg, yield: 11.7%). MS (ESI) M/z 431.2 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ10.36(s,1H),9.83(s,1H),8.81(d,J＝1.6Hz,1H),8.69(s,1H),8.54(d,J＝2.8Hz,1H),7.89(dd,J＝8.4,2.8Hz,1H),7.81–7.78(m,2H),7.22(d,J＝8.4Hz,1H),6.62(d,J＝9.2Hz,1H),4.49(d,J＝6.0Hz,2H),4.28(d,J＝5.6Hz,2H),3.45(t,J＝8.8Hz,2H),3.36(s,2H),3.04(t,J＝8.4Hz,2H),2.42(s,3H),1.34(s,3H).
Examples 5 and 6
Synthesis of 1- (6- (1- ((3-methyloxetan-3-yl) methyl) -1H-benzo [ d ] imidazol-5-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea (compound 5):
synthesis of 1- (6- (1- ((3-methyloxetan-3-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea (compound 6):
Figure BDA0003769482940000391
synthesis of Compounds 5 and 6 As in example 1, the first step was performed using 5-bromo-1H-benzimidazole in place of 5-bromo-1H-indole to give two isomers, and the last step was purified by reverse phase preparative chromatography pre-HPLC (0.01% FA in water, meCN) to give the title compounds 5 and 6.
Compound 5: MS (ESI) M/z 430.2 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ9.85(s,1H),9.77(s,1H),8.93(d,J＝0.4Hz,1H),8.92(s,1H),8.55–8.51(m,1H),8.42(d,J＝1.6Hz,2H),8.04(dd,J＝8.4,1.6Hz,1H),7.92(dd,J＝8.4,2.4Hz,1H),7.89–7.83(m,1H),7.23(d,J＝8.4Hz,1H),4.61(d,J＝6.0Hz,2H),4.55(s,2H),4.26(d,J＝6.0Hz,2H),2.43(s,3H),1.25(s,3H).
Compound 6: MS (ESI): M/z 430.2 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ9.77(s,1H),9.72(s,1H),8.97(s,1H),8.95(s,1H),8.54(d,J＝2.4Hz,1H),8.44(s,2H),7.98(dd,J＝8.4,1.6Hz,1H),7.90(dd,J＝8.4,2.4Hz,1H),7.82(d,J＝8.4Hz,1H),7.23(d,J＝8.4Hz,1H),4.62(d,J＝6.0Hz,2H),4.58(s,2H),4.27(d,J＝6.0Hz,2H),2.43(s,3H),1.25(s,3H).
Example 7
Synthesis of 1- (6- (1- ((3-methyloxetan-3-yl) methyl) -2-carbonyl-1, 2,3, 4-tetrahydroquinolin-6-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000392
synthesis of Compound 7 the same procedure as in example 1 was used, substituting 6-bromo-1, 2,3, 4-tetrahydro-2-quinolinone for 5-bromo-1H-indole in the first step. Compound 7: MS (ESI) M/z 459.2 (M + H) + . 1 H NMR(400MHz,DMSO-d6)δ9.72(s,2H),8.93(s,1H),8.84(s,1H),8.52(s,1H),8.01–7.87(m,3H),7.40(d,J＝8.4Hz,1H),7.22(d,J＝8.4Hz,1H),4.53(d,J＝5.6Hz,2H),4.16(s,2H),4.06(d,J＝5.6Hz,2H),3.02–2.92(m,2H),2.71–2.60(m,2H),2.43(s,3H),1.27(s,3H).
Example 8
Synthesis of 1- (6- (1- ((3-methyloxetan-3-yl) methyl) -2-carbonyl-1, 2-dihydroquinolin-6-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000393
the synthesis of compound 8 was performed as in example 1, substituting 6-bromoquinolin-2-one for 5-bromo-1H-indole in the first step. Compound 8: MS (ESI) M/z 457.3 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ9.76(s,1H),9.67(s,1H),9.02(s,1H),8.94(s,1H),8.53(d,J＝2.8Hz,1H),8.50(d,J＝2.0Hz,1H),8.28(dd,J＝8.8,2.0Hz,1H),8.06(d,J＝9.6Hz,1H),7.90(dd,J＝8.4,2.4Hz,1H),7.75(d,J＝9.2Hz,1H),7.23(d,J＝8.4Hz,1H),6.76(d,J＝9.6Hz,1H),4.57(d,J＝6.4Hz,2H),4.40(s,2H),4.09(d,J＝6.0Hz,2H),2.43(s,3H),1.38(s,3H).
Example 9
Synthesis of 1- (6-methylpyridin-3-yl) -3- (6- (2- (tetrahydrofuran-3-yl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyrazin-2-yl) urea:
Figure BDA0003769482940000401
the first step is as follows: 6-bromo-1, 2,3, 4-tetrahydroisoquinoline (400mg, 1.89mmol, 1eq), dihydro-3 (2H) -furanone (195mg, 2.27mmol, 1.2eq), zinc chloride (26mg, 0.189mmol, 0.1eq) were added to methanol (15 mL), and sodium cyanoborohydride was added thereto at room temperature(226mg, 3.78mmol, 2eq) and stirring continued at room temperature for 1 hour. The reaction was poured into saturated sodium bicarbonate solution (100 mL), the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over sodium sulfate and concentrated. The residue was subjected to flash silica gel chromatography (PE/EA = 3/1) to give compound 9a (570 mg, yield: 106.9%). MS (ESI) M/z 282.1 (M + H) + . 1 H NMR(400MHz,CDCl 3 )δ7.26–7.19(m,2H),6.89(d,J＝7.9Hz,1H),4.05–3.94(m,2H),3.83(dd,J＝16.0,8.1Hz,1H),3.73(dd,J＝8.6,6.8Hz,1H),3.65(d,J＝14.9Hz,1H),3.54(d,J＝14.9Hz,1H),3.23–3.10(m,1H),2.88(t,J＝5.8Hz,2H),2.83–2.74(m,1H),2.71–2.62(m,1H),2.21–2.08(m,1H),2.01–1.87(m,1H).
The second step: to 1,4-dioxane (10 mL) was added at room temperature the compound 9a (580mg, 2.06mmol, 1eq), pinacol diboron (0.78g, 3.08mmol, 1.5eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (150mg, 0.21mmol, 0.1eq) and potassium acetate (610mg, 6.17mmol, 3eq). The mixture was heated to 100 ℃ under nitrogen and stirred for 2 hours. The reaction solution was concentrated, and the residue was subjected to flash silica gel chromatography (PE/EA = 3/1) to obtain compound 9b (500 mg, yield: 73.7%). MS (ESI) M/z 330.2 (M + H) + .
The third step: intermediate A (150mg, 0.54mmol, 1eq), compound 9b (225mg, 0.68mmol, 1.2eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (40mg, 0.054mmol, 0.1eq) and sodium carbonate (180.88mg, 1.71mmol, 3eq) were dissolved in dioxane (4 mL) and water (2 mL) and stirred at 100 ℃ for 2 hours under nitrogen. Water (200 mL) was poured into the reaction mixture, extracted with ethyl acetate, and the organic phase was dried over sodium sulfate and concentrated. The residue was subjected to flash silica gel column chromatography (DCM/MeOH = 10/1) to give a crude product, which was further purified by preparative reverse-HPLC (0.01% FA in water, meCN) to give the title compound 9 (10 mg, yield: 4.1%). MS (ESI) M/z 431.3 (M + H) + . 1 H NMR(400MHz,MeOD)δ8.73(s,2H),8.57(d,J＝2.5Hz,1H),8.04(dd,J＝8.5,2.6Hz,1H),7.93–7.88(m,2H),7.37–7.30(m,2H),4.15–3.94(m,5H),3.83(dd,J＝16.0,8.1Hz,1H),3.64–3.56(m,1H),3.24–3.11(m,4H),2.53(s,3H),2.41–2.32(m,1H),2.17–2.07(m,1H).
Example 10
1- (6-methylpyridin-3-yl) -3- (6- (2- (oxetan-3-yl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) pyrazin-2-yl) urea
Figure BDA0003769482940000411
The synthesis of compound 10 was performed as in example 9, substituting 3-oxetanone for dihydro-3 (2H) -furanone in the first step. Compound 10: MS (ESI) M/z 417.3 (M + H) + . 1 H NMR(400MHz,MeOD)δ8.71(s,1H),8.69(s,1H),8.59(d,J＝2.5Hz,1H),8.03(dd,J＝8.5,2.6Hz,1H),7.90–7.82(m,2H),7.34–7.26(m,2H),4.83(t,J＝6.7Hz,2H),4.75(t,J＝6.3Hz,2H),3.83–3.76(m,1H),3.67(s,2H),3.09(t,J＝6.0Hz,2H),2.76(t,J＝6.0Hz,2H),2.53(s,3H).
Example 11
Synthesis of (R) -1- (6-methylpyridin-3-yl) -3- (6- (1, 2,4a, 5-tetrahydro-4H-benzo [ b ] [1,4] oxadiazyl [4,3-d ] [1,4] oxazin-8-yl) pyrazin-2-yl) urea:
Figure BDA0003769482940000412
the first step is as follows: (S) -2-hydroxymethylmorpholine hydrochloride (900mg, 5.86mmol, 1eq), 1, 2-difluoro-4-nitrobenzene (932mg, 5.86mmol, 1eq) were dissolved in dimethyl sulfoxide (100 mL), and potassium hydroxide (1.64g, 29.29mmol, 4eq) was added. The mixture was stirred at room temperature for 3 hours and then warmed to 60 ℃ for 18 hours. The reaction mixture was cooled, poured into water (300 mL), and extracted with ethyl acetate. The combined organic phases were washed with water, brine (100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to flash silica gel column chromatography (PE: EA = 20. MS (ESI) M/z 237.1 (M + H) + .
The second step is that: compound 11a (560mg, 2.37mmol, 1eq) and di-tert-butyl dicarbonate (776mg, 3.56mmol, 1.5eq) were sequentially added to methanol (20 mL), palladium on carbon (60mg, 10%) was added, hydrogen gas was substituted three times, and the mixture was reacted at room temperature overnight. The reaction mixture was filtered and concentrated to give compound 11b (660 mg, yield: 90.9％)。MS(ESI):m/z 307.2(M+H) + .
The third step: compound 11b (720mg, 2.35mmol, 1eq) was dissolved in methylene chloride (3 mL), trifluoroacetic acid (3 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The solvent was dried and then dissolved in dichloromethane (30 mL), a saturated sodium bicarbonate solution (50 mL) was added, the mixture was stirred for half an hour and then the layers were separated, the organic phase was dried and then dried, and the crude product was separated by flash chromatography on silica gel (PE: EA =5:1 to 1) to obtain compound 11c (360 mg, yield: 74.3%). MS (ESI): M/z 207.2 (M + H) + . 1 HNMR(400MHz,DMSO-d 6 )δ6.49(d,J＝8.4Hz,1H),6.30–5.93(m,2H),4.45(s,1H),4.05(d,J＝10.4Hz,1H),3.85(d,J＝11.2Hz,1H),3.74(d,J＝9.4Hz,1H),3.59–3.44(m,1H),3.35(d,J＝12.4Hz,2H),3.09(t,J＝10.5Hz,1H),2.82(d,J＝9.2Hz,1H).
The fourth step: compound 11c (360mg, 1.75mmol, 1eq) was added to water (10 mL), hydrobromic acid (0.6 mL,48% aqueous solution) was added, and the mixture was cooled to 0 ℃ in an ice bath and stirred for 0.5 hour. An aqueous solution (0.5 mL) of sodium nitrite (133mg, 1.92mmol, 1.05eq) was added dropwise. After 0 ℃ reaction for 0.5 hour, cuprous bromide (751mg, 5.24mmol, 3eq) was added and the reaction was carried out at 0 ℃ for 2 hours. Saturated sodium bicarbonate solution (50 mL) was added, extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to flash silica gel column chromatography (PE: EA =10:1 to 5). MS (ESI) M/z 270.0 (M + H) + .
The fifth step: compound 11d (75mg, 0.28mmol, 1eq), potassium acetate (55mg, 0.56mmol, 2eq), pinacol diboron (106mg, 0.42mmol, 1.5eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (8mg, 0.03mmol, 0.1eq) was sequentially added to dioxane (2 mL), replaced with argon three times, and then heated to 100 ℃ for reaction overnight. The reaction solution was concentrated, and the residue was subjected to flash silica gel column chromatography (PE: EA = 4). MS (ESI) M/z 318.2 (M + H) + .
And a sixth step: intermediate A (53mg, 0.2mmol, 1eq), compound 11e (63mg, 0.2mmol, 1eq), and sodium carbonate (43mg, 0.4mmol, 2eq) were added to a mixed solvent of dioxane (1 mL) and water (0.2 mL) in this order, and [1,1' -bis (diphenylphosphino) ferrocene was added]Palladium dichloride (5mg, 0.02mm)ol,0.1 eq), replacement with argon three times, and reaction at 100 ℃ for 18 hours. After the reaction mixture was cooled, ethyl acetate (20 mL) was added, and the mixture was washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated and purified by preparative thin layer chromatography (EA/PE = 9). MS (ESI): M/z 419.2 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ10.32(s,1H),9.88(s,1H),8.91(s,1H),8.74(s,1H),8.55–8.49(m,1H),7.93–7.85(m,1H),7.60(dd,J＝8.4,2.0Hz,1H),7.47(d,J＝2.0Hz,1H),7.21(d,J＝8.4Hz,1H),7.01(d,J＝8.8Hz,1H),4.30–4.27(m,1H),4.00–3.96(m,1H),3.95–3.85(m,2H),3.73(d,J＝11.6Hz,1H),3.66–3.56(m,1H),3.27–3.14(m,2H),2.79(dd,J＝12.0,3.6Hz,1H),2.42(s,3H).
Example 12
Synthesis of (S) -1- (6-methylpyridin-3-yl) -3- (6- (1, 2,4a, 5-tetrahydro-4H-benzo [ b ] [1,4] oxadiazanyl [4,3-d ] [1,4] oxazin-8-yl) pyrazin-2-yl) urea:
Figure BDA0003769482940000421
synthesis of Compound 12 the same procedure as in example 11 was used, except that in the first step, (R) -2-hydroxymethylmorpholine hydrochloride was used instead of (S) -2-hydroxymethylmorpholine hydrochloride. Compound 12: MS (ESI): M/z 419.2 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ10.41(s,1H),9.91(s,1H),8.93(s,1H),8.74(s,1H),8.54(d,J＝2.4Hz,1H),7.88(dd,J＝8.4,2.8Hz,1H),7.60(dd,J＝8.4,2.0Hz,1H),7.47(d,J＝2.0Hz,1H),7.21(d,J＝8.4Hz,1H),7.01(d,J＝8.4Hz,1H),4.30–4.26(m,1H),4.00–3.96(m,1H),3.95–3.87(m,2H),3.77–3.68(m,1H),3.64–3.58(m,1H),3.25–3.16(m,2H),2.83–2.76(m,1H),2.42(s,3H).
Example 13
Synthesis of 1- (6- (3-methyl-4- ((3-methyloxetan-3-yl) methoxy) phenyl) pyrazin-2-yl) -3- (pyrazolo [1,5-a ] pyridin-6-yl) urea:
Figure BDA0003769482940000431
the first step is as follows: reacting 6-bromopyrazolo [1,5-a ]]Pyridine (500mg, 2.5mmol, 1eq) was dissolved in toluene (4 mL), and tert-butyl carbamate (2.6 g,22mmol, 8.7eq), palladium acetate (62mg, 0.28mmol, 0.1eq), cesium carbonate (1.6 g,5mmol, 2eq) and XPhos (120mg, 0.25mmol, 0.1eq) were added. The nitrogen gas was replaced three times, and the reaction mixture was heated to 110 ℃ and stirred for 16 hours. The reaction was concentrated, and the residue was separated by flash column chromatography on silica gel (DCM: meOH = 10) to give compound 13a (873 mg, yield: 100%). MS (ESI) M/z 234.1 (M + H) + .
The second step is that: compound 13a (873mg, 3.73mmol, 1eq) was added to trifluoroacetic acid (3 mL), and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated, and the residue was separated by flash silica gel column chromatography (DCM: meOH = 10) to obtain compound 13b (100 mg, yield: 20%). MS (ESI) M/z 134.1 (M + H) + .
The third step: intermediate C (157mg, 0.5mmol, 1eq) was dissolved in toluene (5 mL), and compound 13b (100mg, 0.75mmol, 1.5eq), triethylamine (152mg, 1.5mmol, 3eq), and diphenylphosphorylazide (275.2mg, 1.0mmol, 2eq) were added. The mixture was heated to 100 ℃ and stirred for 5 hours. The reaction solution was concentrated, and the residue was purified by preparative reverse phase chromatography pre-HPLC (0.01% FA in water, meCN) to give the title compound 13 (8 mg, yield: 3.6%). MS (ESI) M/z 445.1 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ9.81–9.79(m,2H),9.15–9.14(m,1H),8.90(s,1H),8.81(s,1H),7.97–7.92(m,3H),7.71(dd,J＝9.6,0.8Hz,1H),7.18–7.14(m,1H),7.12(dd,J＝9.2,2.0Hz,1H),6.60(dd,J＝2.2,1.0Hz,1H),4.56(d,J＝5.6Hz,2H),4.35(d,J＝6.0Hz,2H),4.14(s,2H),2.27(s,3H),1.41(s,3H).
Example 14
Synthesis of 1- (imidazo [1,2-a ] pyridin-6-yl) -3- (6- (3-methyl-4- ((3-methyloxetan-3-yl) methoxy) phenyl) pyrazin-2-yl) urea:
Figure BDA0003769482940000432
reacting imidazo [1,2-a ]]Pyridine-6-carboxylic acid (100mg, 0.62mmol, 1eq), intermediate B (194mg, 0.68mmol, 1.1eq),diphenyl azidophosphate (339mg, 1.24mmol, 2eq) and triethylamine (187mg, 1.85mmol, 3eq) were added to toluene (5 mL) and stirred at 90 ℃ for 5 h. The reaction was concentrated, and the residue was separated by flash column chromatography on silica gel (DCM: meOH = 10) to give the title compound 14 (7.8 mg, yield: 3.2%). MS (ESI): M/z 445.2 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ9.78(s,1H),9.76(s,1H),9.09–9.07(m,1H),8.91(s,1H),8.81(s,1H),8.03(s,1H),7.96–7.94(m,2H),7.59–7.57(m,1H),7.54–7.53(m,1H),7.17–7.15(m,1H),7.10(dd,J＝9.6,2.0Hz,1H),4.56(d,J＝5.6Hz,2H),4.35(d,J＝5.6Hz,2H),4.14(s,2H),2.27(s,3H),1.41(s,3H).
Example 15
Synthesis of 1- (imidazo [1,2-a ] pyridin-7-yl) -3- (6- (3-methyl-4- ((3-methyloxetan-3-yl) methoxy) phenyl) pyrazin-2-yl) urea:
Figure BDA0003769482940000441
synthesis of Compound 15 the same as in example 14, using imidazo [1,2-a ]]Pyridine-7-carboxylic acid instead of imidazo [1,2-a ]]Pyridine-6-carboxylic acid. Compound 15: MS (ESI) M/z 445.1 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),9.84(s,1H),8.92(s,1H),8.80(s,1H),8.47(d,J＝7.2Hz,1H),7.98–7.92(m,2H),7.85–7.80(m,2H),7.44(s,1H),7.14(d,J＝9.2Hz,1H),6.90(d,J＝7.2Hz,1H),4.54(d,J＝5.6Hz,2H),4.33(d,J＝6.0Hz,2H),4.12(s,2H),2.26(s,3H),1.40(s,3H).
Example 16
Synthesis of 1- (2-methyl-2H-indazol-6-yl) -3- (6- (3-methyl-4- ((3-methyloxetan-3-yl) methoxy) phenyl) pyrazin-2-yl) urea:
Figure BDA0003769482940000442
compound 16 was synthesized according to the same procedure as in example 13, except that 2-methyl-6-amino-2H-indazole was used instead of compound 13b in the third step. Compound 16: MS (ESI) M/z 459.2 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ10.42(s,1H),9.93(s,1H),9.02(s,1H),8.78(s,1H),8.25(s,1H),7.96–7.92(m,3H),7.66–7.62(m,1H),7.15(d,J＝9.2Hz,1H),7.02(dd,J＝8.8,1.6Hz,1H),4.56(d,J＝5.6Hz,2H),4.35(d,J＝5.6Hz,2H),4.13(s,2H),4.12(s,3H),2.28(s,3H),1.41(s,3H).
Example 17
Synthesis of 1- (6- (4- ((3-methyloxyethan-3-yl) methyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000443
the first step is as follows: 2-amino-5-bromophenol (2.00g, 10.64mmol, 1.0eq) was dissolved in 1, 2-dichloroethane (50 mL), and 3-methoxyethane-3-carbaldehyde (1.06g, 10.64mmol, 1.0eq) and sodium cyanoborohydride (2.00g, 31.91mmol, 3.0eq) were added and stirred at room temperature for 8 hours. The system was poured into ice water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was separated by flash silica gel column chromatography (100% PE-PE: EA = 10) to obtain compound 17a (1.29 g, yield: 44.6%). MS (ESI) M/z 272.0 (M + H) + .
The second step is that: compound 17a (1g, 3.67mmol, 1eq) was dissolved in N, N-dimethylformamide (50 mL), and potassium carbonate (1.50g, 11.02mmol, 3eq) was added at room temperature, followed by 1, 2-dibromoethane (2.0g, 11.02mmol, 3eq). The mixture was heated to 100 ℃ and stirred overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with water, brine and the organic phase was dried over anhydrous sodium sulfate. After concentration, the residue was separated by flash silica gel chromatography (PE: EA = 9). MS (ESI) M/z 298.0 (M + H) + .
The third step: the compound 17b (483mg, 1.62mmol, 1.0eq), pinacol diboron ester (617mg, 2.43mmol, 1.5eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (118mg, 0.16mmol, 0.1eq) and potassium acetate (3970 mg,4.05mmol, 2.5eq) were sequentially added to dioxane (5 mL), replaced with argon gas for 3 times, and the temperature was raised toAfter stirring at 100 ℃ for 2 hours, the mixture was filtered through celite, concentrated under reduced pressure, and the residue was chromatographed on flash silica gel (PE: EA = 10. MS (ESI): M/z 346.2 (M + H) + .
The fourth step: compound 17c (227mg, 0.66mmol, 1.0eq), intermediate A (191mg, 0.72mmol, 1.1eq), cesium carbonate (428mg, 1.315mmol, 2.0eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (48mg, 0.07mmol, 0.1eq) was sequentially added to a mixed solution of dioxane-water (4, 1,5mL), replaced with argon gas 3 times, and heated to 100 ℃ for reaction for 2 hours. After the system was cooled to room temperature, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, washed with methanol, filtered, the cake was collected, and dried under vacuum to give the title compound 17 (177.77 mg, yield: 60.3%). MS (ESI) M/z 447.2 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ9.86(s,1H),9.65(s,1H),8.75(s,1H),8.70(s,1H),8.50(s,1H),7.90(d,J＝8.4Hz,1H),7.53(d,J＝8.0Hz,1H),7.44(s,1H),7.22(d,J＝8.0Hz,1H),6.87(d,J＝8.8Hz,1H),4.55(d,J＝5.2Hz,2H),4.23(d,J＝6.0Hz,4H),3.53(s,2H),3.36(s,2H),2.43(s,3H),1.32(s,3H).
Example 18
Synthesis of 1- (6- (4- ((3-methyloxyethan-3-yl) methyl) -3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000451
the first step is as follows: 7-bromo-2H-benzo [ b ]][1,4]Oxazin-3 (4H) -one (301mg, 1.32mmol, 1eq) was dissolved in N, N-dimethylformamide (10 mL), sodium hydride (60%, 106mg,2.64mmol, 2eq) was added under ice-bath, and after 30 minutes of incubation, 3- (chloromethyl) -3-methyloxetane (175mg, 1.45mmol, 1.1eq) was added, and after completion of the addition, the temperature was raised to 80 ℃ for 18 hours. The reaction was cooled and poured into ice water (50 mL), the aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on flash silica gel (PE: EA =10:1 to 5)19a (160 mg, yield: 38.8%). MS (ESI) M/z 312.0 (M + H) + .
The second step is that: compound 19a (160mg, 0.51mmol, 1eq), potassium acetate (100mg, 1.02mmol, 2eq), pinacol ester diboron (194mg, 0.77mmol, 1.5eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (15mg, 10%) was sequentially added to dioxane (5 mL), replaced with argon three times, and heated to 100 ℃ for reaction overnight. The reaction solution was subjected to flash silica gel chromatography (EA: PE = 3. MS (ESI): M/z 360.2 (M + H) + .
The third step: intermediate A (74mg, 0.28mmol, 1eq), compound 19b (151mg, 0.42mmol, 1.5eq), and sodium carbonate (60mg, 0.56mmol, 2eq) were sequentially added to a mixed solvent of dioxane (5 mL) and water (0.5 mL), and [1,1' -bis (diphenylphosphino) ferrocene was added]Palladium dichloride (15mg, 10%) was substituted with argon three times, and then the mixture was heated to 100 ℃ to react for 3 hours. The reaction solution was cooled, ethyl acetate (20 mL) was added, the organic phase was washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and spun dry, and the crude product was purified by flash chromatography on silica gel (EA) to give a crude product, which was further purified by preparative Pre-HPLC (C18, 0.01% HCOOH in water, meCN) to give the title compound 19 (30 mg, yield: 23.3%). MS (ESI) M/z 461.2 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ9.74(s,1H),9.71(s,1H),8.97(s,1H),8.87(s,1H),8.52(d,J＝2.4Hz,1H),7.89(dd,J＝8.4,2.8Hz,1H),7.79(dd,J＝8.4,2.0Hz,1H),7.76(d,J＝2.0Hz,1H),7.50(d,J＝8.8Hz,1H),7.23(d,J＝8.4Hz,1H),4.77(s,2H),4.54(d,J＝6.0Hz,2H),4.17(s,2H),4.10(d,J＝6.0Hz,2H),2.43(s,3H),1.30(s,3H).
Example 19
Synthesis of 1- (6- {1- [ trans-2-hydroxychloropentyl ] -2, 3-dihydro-1H-indol-5-yl } pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000461
the first step is as follows: zinc chloride (1.62g, 11.89mmol, 2eq) was dissolved in water (20 mL), and 5-bromo-2, 3-indoline (1.77g, 8.92mmol,1.5 eq) and 1, 2-cyclopentane oxide were slowly added(500mg, 5.94mmol, 1equiv) in acetonitrile (10 mL), heating to 90 ℃ under nitrogen, and stirring for 2 hours. Ethyl acetate (50 mL) was added to dilute the reaction mixture, the layers were separated by extraction, the organic phase was concentrated to give a crude product, which was purified by flash chromatography on silica gel (EA% = 0-30%) to give compound 49a (900 mg, yield: 53.7%). MS (ESI) M/z 282.1 (M + H) + . 1 H NMR(400MHz,CDCl 3 )δ7.16–7.09(m,2H),6.41(d,J＝8.9Hz,1H),4.24(q,J＝6.8Hz,1H),3.70(dd,J＝15.3,8.2Hz,1H),3.48–3.31(m,2H),2.95(t,J＝8.3Hz,2H),2.05–1.76(m,4H),1.71–1.58(m,3H).
The second step is that: in a 100mL flask, compound 49a (900mg, 3.19mmol, 1eq), pinacoldiboron diborate (1.21g, 4.78mmol, 1.5eq), potassium acetate (939mg, 9.57mmol, 3eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (233mg, 0.32mmol, 0.1eq) and dioxane (20 mL) were heated to 100 ℃ under nitrogen and stirred for 2 hours. The reaction mixture was diluted with water (100 mL) and ethyl acetate (300 mL), the layers were separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated. Flash chromatography on silica gel (EA% = 0-70%) gave compound 49b (500 mg, yield: 47.6%). MS (ESI): M/z 330.2 (M + H) + .
The third step: compound 49b (100mg, 0.304mmol, 1eq), intermediate A (160.17mg, 0.608mmol, 2eq), sodium carbonate (64.12mg, 0.608mmol, 2eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (44.59mg, 0.0609mmol, 0.2eq) was added to a mixed solution of dioxane (5 mL) and water (0.5 mL), nitrogen gas was replaced, and the reaction solution was heated to 100 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated by rotary evaporation, dissolved in 10mL of N, N-dimethylformamide, and filtered again, and sent to preparative treatment. The residue was purified by reverse phase preparative chromatography Prep-HPLC to give the title compound 49 (18.80 mg, yield: 14.4%). MS (ESI) M/z 430.5 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ10.05(s,1H),9.72(s,1H),8.73(s,1H),8.72(s,1H),8.59(d,J＝2.4Hz,1H),7.98–7.95(m,1H),7.84–7.76(m,2H),7.32(d,J＝8.4Hz,1H),6.66(d,J＝8.4Hz,1H),4.93(s,1H),4.17–4.10(m,1H),3.81–3.75(m,1H),3.64–3.57(m,2H),3.04(t,J＝8.4Hz,2H),2.49(s,3H),1.96–1.84(m,2H),1.80–1.73(m,1H),1.69–1.53(m,3H)
Example 20
Synthesis of 1- (6- {1- [ trans-4-hydroxypyrrolidin-3-yl ] -2, 3-dihydro-1H-indol-5-yl } pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000471
the first step is as follows: 5-Bromoindoline (1.00g, 5.05mmol, 1eq) and THF (20 mL) were charged in a 50mL single-neck flask, sodium hydride (60%, 404mg,10.10mmol, 2eq) was added under ice-cooling, and t-butyl 6-oxa-3-azabicyclo [3.1.0 ] was added under stirring for 20 minutes]Hexane-3-carboxylate (1.40g, 7.57mmol, 1.5eq) was reacted at 95 ℃ for 6 hours. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated and separated by flash silica gel chromatography (PE: EA =10, 1 to 4. MS (ESI) M/z 383.1 (M + H) + . 1 H NMR(400MHz,CDCl 3 )δ7.15(s,2H),6.37(d,J＝8.9Hz,1H),4.39(dd,J＝10.7,5.2Hz,1H),3.90(dd,J＝11.7,5.5Hz,1H),3.73–3.69(m,2H),3.55–3.21(m,4H),2.96(t,J＝8.3Hz,2H),2.35(s,1H),1.46(s,9H).
The second step is that: in a 100mL single-neck flask, compound 50a (500mg, 1.30mmol, 1eq), pinacol diboron (398mg, 1.57mmol, 1.2eq), pd (dppf) Cl 2 (191mg, 0.26mmol, 0.2eq), potassium acetate (512mg, 5.22mmol, 4eq) and 1,4-dioxane (30 mL). The reaction system was purged with nitrogen three times and stirred at 90 ℃ for 8 hours. Diluted with water, filtered, the filtrate was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by flash silica gel chromatography (PE: EA = 4. MS (ESI): M/z 431.4 (M + H) + .
The third step: the compound 50b (279mg, 0.65mmol, 1eq), the intermediate A (167.2mg, 0.65mmol, 1eq), and the [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (92.83mg, 0.13mmol, 0.2eq) and anhydrous sodium carbonate (137.73mg, 1.3mmol, 2eq) were added sequentially to a mixture of dioxane/water (15 mL/1.5 mL)Mixing the solution, heating to 100 ℃ under the protection of nitrogen, and stirring for 16 hours. The organic layer was washed with saturated brine (30 mL), and then dried over anhydrous sodium sulfate. Filtering to remove insoluble substances, and concentrating the organic phase under reduced pressure to obtain a crude product. The crude product was separated by flash chromatography on silica gel (PE: EA =4: 1), and the resulting fraction was subjected to rotary evaporation under reduced pressure to remove the solvent, to obtain compound 50c (200 mg, yield: 57.9%). MS (ESI): M/z 531.8 (M + H) + .
The fourth step: 4M dioxane hydrochloride (4 mL,1mmol, 2.63eq) was added to a solution of compound 50c (200mg, 0.38mmol, 1eq) in dichloromethane (5 mL) with nitrogen and stirring at 25 ℃ for 2 h. The reaction solution was concentrated, and the residue was purified by reverse phase preparative chromatography Prep-HPLC to give the title compound 50 (59 mg, yield: 36.0%). MS (ESI) M/z 432.2 (M + H) + . 1 H NMR(400MHz,MeOD)δ8.55(s,1H),8.52–8.49(m,2H),8.43(s,1H),8.07–8.04(m,1H),7.79–7.76(m,2H),7.29(d,J＝8.4Hz,1H),6.74(d,J＝8.4Hz,1H),4.61–4.60(m,1H),4.11–4.08(m,1H),3.74–3.69(m,1H),3.58–3.47(m,4H),3.28(d,J＝2.4Hz,1H),3.09(t,J＝8.4Hz,2H),2.50(s,3H).
Example 21
Synthesis of 1- (6- (1- ((3-hydroxyoxetan-3-yl) methyl) indol-5-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000481
the first step is as follows: a solution of 3-oxetanone (2.1g, 29.1mmol) in dry tetrahydrofuran (100 mL) was cooled to 0 ℃ under nitrogen, maintaining the internal temperature below 10 ℃, and vinylmagnesium bromide (1M in THF,50mL,50.0 mmol) was added dropwise. The reaction mixture was stirred for 10 minutes, then allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured into saturated ammonium chloride (200 mL). The mixture was stirred for 5 minutes, and the layers were separated and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the crude product. The crude product was separated by flash chromatography on silica gel (PE/EA = 3/2) to obtain compound 52a (600 mg, yield: 20.6%). 1 H NMR(400MHz,CDCl 3 )δ6.36–6.26(m,1H),5.47–5.40(m,1H),5.30–5.27(m,1H),4.74–4.68(m,4H),3.55(s,1H).
The second step: a solution of compound 52a (450mg, 4.49mmol) in dichloromethane (5 mL) and methanol (45 mL) was bubbled with a stream of ozone at-78 deg.C for 20 minutes, after which triphenylphosphine (3.0 g) was added and the mixture was stirred at-78 deg.C for 6 hours. After completion of the reaction, the temperature was raised to room temperature, filtered, and the filtrate was concentrated under reduced pressure to remove the excess reagent to give compound 52b (3.2 g, crude) which was used directly in the next step.
The third step: to a 100mL flask were added compound 52b (2.06g, 20.2mmol, 20.0eq), 5-bromo-2, 3-dihydro-1H-indole (200mg, 1.01mmol, 1.0eq), dichloromethane (30 mL) and glacial acetic acid (0.2 mL) in this order, followed by stirring at room temperature for 30 minutes. Sodium triacetoxyborohydride (428.03mg, 2.02mmol,2.0 eq) was added to the reaction solution, followed by stirring at room temperature for 30 minutes. After the reaction was completed, water (2 mL) was added to quench the reaction, and the reaction was concentrated under reduced pressure to remove excess reagents to obtain a crude product. The crude product was separated by flash chromatography on silica gel (PE/EA = 3/2) to obtain compound 52c (180 mg, yield: 62%). MS (ESI) M/z 283.8 (M + H) + . 1 H NMR(400MHz,CDCl 3 )δ7.27–7.15(m,2H),6.46(d,J＝8.4Hz,1H),4.73(d,J＝7.2Hz,2H),4.57(d,J＝7.2Hz,2H),3.43(s,2H),3.37(t,J＝8.4Hz,2H),3.10(s,1H),3.00(t,J＝8.4Hz,2H).
The fourth step: under nitrogen protection, compound 52c (198mg, 0.7mmol, 1.0eq), 4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-ylboronic acid (265.42mg, 1.05mmol, 1.5eq), potassium acetate (136.77mg, 1.39mmol, 2.0eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (51.57mg, 0.105mmol, 0.1eq) and dioxane (5 mL). The mixture was stirred at 100 ℃ for 3 hours. After the reaction is finished, cooling to room temperature, and carrying out reduced pressure concentration to remove redundant reagents to obtain a crude product. The crude product was separated by flash chromatography on silica gel (PE/EA = 1/1) to obtain compound 52d (150 mg, yield: 64%). MS (ESI) M/z 332.0 (M + H) + . 1 H NMR(400MHz,CDCl 3 )δ7.59(d,J＝8.0Hz,1H),7.57(s,1H),6.59(d,J＝8.0Hz,1H),4.74(d,J＝7.2Hz,2H),4.59(d,J＝7.2Hz,2H),3.51(s,2H),3.39(t,J＝8.4Hz,2H),3.08(s,1H),3.02(t,J＝8.4Hz,2H),1.33(s,12H).
The fifth step: to compound 52d (129.17mg, 0.39mmol, 1.0eq), intermediate A (92.55mg, 0.35mmol, 0.9eq) and [1,1' -bis (diphenylphosphino) ferrocene, under nitrogen protection]To a solution of palladium dichloride (20.43mg, 0.035mmol, 0.01eq) in dioxane (3 mL) and water (0.3 mL) was added sodium carbonate (82.67mg, 0.79mmol,2.0 eq). The resulting mixture was reacted at 100 ℃ for 3 hours. After the reaction was complete, it was cooled to room temperature. The reaction mixture was diluted with water (50 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine (150 mL), followed by drying over anhydrous sodium sulfate. Filtering to remove insoluble substances, and concentrating the organic phase under reduced pressure to obtain a crude product. The crude product was chromatographed on flash silica gel (DCM/MeOH = 10/1) to give the title compound 52 (80 mg, yield: 45%). MS (ESI) M/z 432.8 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ9.98(s,1H),9.70(s,1H),8.72(d,J＝8.8Hz,2H),8.53(d,J＝2.4Hz,1H),7.94–7.89(m,1H),7.83–7.79(m,2H),7.25(d,J＝8.4Hz,1H),6.70(d,J＝8.4Hz,1H),5.95(s,1H),4.53–4.43(m,4H),3.61(t,J＝8.4Hz,2H),3.46(s,2H),3.04(t,J＝8.4Hz,2H),2.45(s,3H).
Example 22
Synthesis of 1- [6- (1- { [3- (hydroxymethyl) oxetan-3-yl ] methyl } -2, 3-dihydro-1H-indol-5-yl) pyrazin-2-yl ] -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000491
the first step is as follows: 3, 3-bis-hydroxymethyl-1-oxetane (1g, 8.46mmol, 1eq) was dissolved in tetrahydrofuran (60 mL), stirred at 0 ℃, sodium hydrogen (60%, 338mg,8.46mmol, 1eq) was added, stirred at room temperature for 30 minutes under nitrogen protection, tert-butyldiphenylchlorosilane (2.33g, 8.46mmol, 1.0eq) was added at 0 ℃, and stirred at room temperature for 1 hour. Quenched with water, extracted 3 times with dichloromethane and concentrated under reduced pressure. The residue was chromatographed on flash silica gel (100% PE to PE: EA = 63) to give compound 53a (2.0 g, yield: 66.2%). 1 H NMR(400MHz,CDCl 3 )δ7.71–7.65(m,4H),7.40–7.47(m,6H),4.50–4.39(m,4H),3.95(s,4H),2.46(s,1H),1.09(s,9H).
The second step is that: compound 53a (1.0 g,0.28mmol, 1eq) was dissolved in dichloromethane (5 mL), and dessimutan reagent (2.37g, 5.60mmol, 2eq) was added thereto, and the reaction was stirred at 0 ℃ for 1 hour. The reaction mixture was transferred with methylene chloride, and rotary evaporation was carried out to obtain compound 53b (0.90 g). 1 H NMR(400MHz,DMSO-d 6 )δ9.84(s,1H),7.65–7.61(m,5H),7.51–7.47(m,5H),4.68(d,J＝6.4Hz,2H),4.45(d,J＝6.4Hz,2H),4.17(s,2H),1.00(s,9H).
The third step: 5-bromo-2, 3-dihydro-1H-indole (335mg, 1.69mmol, 1eq) was dissolved in methylene chloride (6 mL), and compound 53b (0.90g, 2.54mmol, 1.5eq) and acetic acid (0.6 mL) were added at 0 ℃ to replace nitrogen and stirred at 30 ℃ for 30 minutes, and sodium borohydride acetate (716mg, 3.38mmol, 2eq) was added and stirred at 30 ℃ for 17 hours. The reaction solution was filtered, concentrated, and sampled, and separated by flash chromatography on silica gel (PE: EA = 79. MS (ESI): M/z 535.8 (M + H) + .
The fourth step: compound 53c (800mg, 1.49mmol, 1eq), pinacol diboron (757mg, 2.98mmol, 2eq), potassium acetate (366mg, 3.74mmol, 2.5eq) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (218mg, 0.299mmol, 0.2eq) was dissolved in 1,4-dioxane (8 mL), and the mixture was stirred at 100 ℃ for 4 hours while displacing nitrogen gas. Celite filtration, and the filtrate was separated by flash silica gel chromatography (PE: EA = 4). MS (ESI) M/z 583.8 (M + H) + .
The fifth step: compound 53d (300mg, 0.51mmol, 1eq), intermediate A (135mg, 0.51mmol, 1eq), sodium carbonate (109mg, 1.028mmol, 2eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (75mg, 0.103mmol, 0.2eq) was added to a mixed solution of dioxane (10 mL) and water (1 mL), nitrogen gas was replaced, and the reaction solution was heated to 100 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, filtered, and rotary-distilled to dryness to give compound 53e (300 mg, yield: 85.2%) which was used directly in the next reaction. MS (ESI) M/z 684.8 (M + H) + .
And a sixth step: compound 53e (250mg, 0.365mmol, 1eq) and tetrabutylammonium fluoride (0.73mL, 0.73mmol, 2eq) were dissolved in tetrahydrofuran (1)0 mL) was stirred at room temperature under a nitrogen blanket for 2 hours. Concentration, dissolution in 10mL of N, N-dimethylformamide, filtration and purification by reverse phase preparative chromatography Pre-HPLC gave the title compound 53 (61.19 mg, yield: 37.0%). MS (ESI) M/z 447.2 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ9.93(s,1H),9.67(s,1H),8.72(s,1H),8.69(s,1H),8.51(d,J＝2.4Hz,1H),7.90–7.88(m,1H),7.80–7.77(m,2H),7.23(d,J＝8.4Hz,1H),6.63(d,J＝8.8Hz,1H),5.02–4.98(m,1H),4.42–4.37(m,4H),3.67(d,J＝5.2Hz,2H),3.49(t,J＝8.4Hz,2H),3.41(s,2H),3.03(t,J＝8.4Hz,2H),2.43(s,3H).
Example 23
Synthesis of 1- (6- (1- ((3-methyloxoalk-3-yl) methyl) -2, 3-dihydro-1H-indol-5-yl) pyrazin-2-yl) -3- (pyrazolo [1,5-a ] pyridin-6-yl) urea:
Figure BDA0003769482940000501
the first step is as follows: to 1.4-dioxane (30 mL) of compound 4b (2.5g, 7.59mmol, 1.0eq) and water (3 mL) were added 6-chloropyrazine-2-carboxylic acid (1.44g, 9.11mmol, 1.2eq), sodium carbonate (2.01g, 18.9mmol, 2.5eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (648mg, 0.8mmol, 0.1eq). Stirring for 3 hours at 100 ℃ under the protection of nitrogen, filtering, and concentrating. The residue was chromatographed on flash silica gel (DCM/MeOH = 10/1) to give compound 59a (1.1 g, yield: 44.5%). MS (ESI): M/z 326.0 (M + H) + .
The second step is that: to toluene (10 mL) containing compound 59a (110mg, 0.34mmol,1.0 eq) was added compound 13b (50mg, 0.37mmol, 1.1eq), triethylamine (105mg, 1.03mmol,3.0 eq), diphenyl phosphorazidate (189mg, 0.69mmol,2.0 eq). Stirring was carried out at 100 ℃ for 15 hours under nitrogen. The reaction solution was concentrated, and the residue was purified by reverse phase preparative chromatography Prep-HPLC to give the title compound 59 (15 mg, yield: 9.7%). MS (ESI) M/z 456.3 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ9.93(s,1H),9.74(s,1H),9.16(s,1H),8.76(s,1H),8.72(s,1H),7.95(d,J＝2.4Hz,1H),7.82–7.81(m,2H),7.73(d,J＝9.6Hz,1H),7.12(dd,J＝9.6,2.0Hz,1H),6.65–6.63(m,1H),6.62–6.61(m,1H),4.51(d,J＝5.6Hz,2H),4.31(d,J＝5.6Hz,2H),3.48(t,J＝8.4Hz,2H),3.39(s,2H),3.07(t,J＝8.4Hz,2H),1.36(s,3H).
Example 24
Synthesis of 1- (6- (1- ((3-methyloxoalk-3-yl) methyl) -2, 3-dihydro-1H-indol-5-yl) pyrazin-2-yl) -3- (4, 5,6, 7-tetrahydropyrazol [1,5-a ] pyridin-6-yl) urea:
Figure BDA0003769482940000511
the first step is as follows: to 6-bromopyrazolo [1,5-a ]]To a solution of pyridine (2.5g, 12.69mmol, 1.0eq), dimethyl sulfoxide (1.66g, 21.19mmol, 1.67eq) and triethylamine (3.85g, 38.07mmol, 3.0eq) in methanol (50 mL) was added bis-triphenylphosphine palladium dichloride (891mg, 3.807mmol, 0.1eq). The reaction mixture was stirred at 100 ℃ under carbon monoxide (16 atm) for 16 hours. After completion of the reaction, the reaction solution was cooled to 25 ℃. The reaction solution was concentrated and then separated by flash silica gel chromatography (PE/EA = 1/1) to obtain compound 60a (2.0 g, yield: 89%). MS (ESI): M/z 177.0 (M + H) + . 1 H NMR(400MHz,CDCl 3 )δ9.20(s,1H),8.22(d,J＝2.0Hz,1H),7.79(d,J＝8.0Hz,1H),7.62–7.55(m,1H),6.76(s,1H),3.90(s,3H).
The second step: to a solution of compound 60a (700mg, 3.97mmol,1.0 eq) in methanol (5 mL) was added a solution of sodium hydroxide (794.69mg, 19.87mmol,3.0 eq) in water (5 mL). The reaction mixture was stirred at 110 ℃ for 1 hour. After completion of the reaction, the reaction solution was cooled to 25 ℃. Methanol was removed by rotary evaporation under reduced pressure, and diluted with water (20 mL), the reaction solution pH =4 was adjusted with 1M dilute hydrochloric acid, the precipitate was filtered, the cake was washed with water, and the cake was dried by rotary drying to give compound 60b (500 mg, yield: 77%). 1 H NMR(400MHz,DMSO-d 6 )δ13.29(s,1H),9.15(s,1H),8.19(d,J＝2.0Hz,1H),7.77(d,J＝4.0Hz,1H),7.60–7.55(m,1H),6.74(s,1H).
The third step: to a solution of compound 60b (500mg, 3.08mmol,1.0 eq) in methanol (5 mL) was added palladium on carbon (140mg, 10% wet palladium on carbon). The reaction solution was stirred and reacted at 40 ℃ for 16 hours under hydrogen conditions. After completion of the reaction, the reaction solution was cooled to 25 ℃. Inverse directionThe reaction solution was filtered through a Celite layer, and the filtrate was spin-dried to give compound 60c (500 mg, yield: 97%). 1 H NMR(400MHz,DMSO-d 6 )δ12.82(s,1H),7.34(d,J＝1.6Hz,1H),6.02–5.94(m,1H),4.27–4.20(m,1H),4.15–4.07(m,1H),3.11–3.00(m,1H),2.87–2.69(m,2H),2.17–2.05(m,1H),1.94–1.81(m,1H).
The fourth step: in a 100mL single-neck flask, compound 4b (2g, 6.07mmol, 1eq) was added to a mixed solvent of 1,4-dioxane (30 mL) and water (3 mL), and 6-chloropyrazin-2-amine (1.97g, 15.17mmol, 2.5eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (500mg, 0.60mmol, 0.1eq), sodium carbonate (1.28g, 12.12mmol, 2.0eq), the reaction system was purged with nitrogen and then stirred at 100 ℃ for 16 hours. The reaction solution was filtered, concentrated, and pooled, and separated by flash silica gel chromatography (PE: EA = 1) to obtain compound 60d (1.5 g, yield: 83.4%). MS (ESI): M/z 297.0 (M + H) + .
The fifth step: to a solution of compound 60c (100mg, 0.34mmol, 1.0eq), compound 60d (112.14mg, 0.68mmol, 2.0eq) and triethylamine (102.22mg, 1.02mmol, 3.0eq) in toluene (4 mL) was added diphenylphosphorylazide (112.15mg, 0.68mmol, 2.0eq). The reaction solution was stirred at 100 ℃ under nitrogen for 16 hours. After completion of the reaction, the reaction solution was cooled to 25 ℃. Filtration and spin-drying of the filtrate gave a crude product which was purified by preparative reverse phase preparative chromatography per-HPLC to give the title compound 60 (30 mg, yield: 19.4%). MS (ESI) M/z459.8 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ9.41(s,1H),8.61(s,1H),8.59(s,1H),7.93(d,J＝6.0Hz,1H),7.69–7.67(m,1H),7.65–7.60(m,1H),7.40(d,J＝2.0Hz,1H),6.56(d,J＝8.4Hz,1H),6.05(d,J＝1.6Hz,1H),4.48(d,J＝5.6Hz,2H),4.36–4.25(m,4H),4.05–4.00(m,1H),3.43(t,J＝8.4Hz,2H),3.36–3.34(m,2H),3.01(t,J＝8.4Hz,2H),2.92–2.85(m,2H),2.10–2.04(m,1H),2.03–1.93(m,1H),1.32(s,3H).
Example 25
Synthesis of 1- (1H-indazol-6-yl) -3- (6- (3-methyl-4- ((3-methyloxy-3-yl) methoxy) phenyl) pyrazin-2-yl) urea:
Figure BDA0003769482940000521
compound 70 was synthesized according to the same method as that of example 13, except for using 6-aminoindazole in place of compound 13b in the third step. Compound 70: MS (ESI): M/z 445.2 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ12.89(s,1H),10.02(s,1H),9.73(s,1H),8.90(s,1H),8.80(s,1H),8.06(s,1H),7.98–7.94(m,3H),7.70(d,J＝8.4Hz,1H),7.17(d,J＝9.2Hz,1H),6.96(dd,J＝8.8,1.6Hz,1H),4.56(d,J＝5.6Hz,2H),4.35(d,J＝5.6Hz,2H),4.14(s,2H),2.28(s,3H),1.42(s,3H).
Example 26
Synthesis of 1- (6- (3-methyl-4- (methyl ((1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) amino) phenyl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000531
the first step is as follows: 2-chloropyridine-3-amino-formaldehyde (2.00g, 14.13mmol, 1eq) was dissolved in 3M hydrochloric acid (4 mL), 30% hydrogen peroxide (0.5 mL) was added, stirring was carried out at 100 ℃ under microwave for 2 hours, LCMS indicated that the reaction was complete, the reaction solution was adjusted to pH7 with sodium bicarbonate solid, a solid precipitated, filtered, and recrystallized with a small amount of ethanol to give compound 109a (1.20 g, yield: 69%). MS (ESI) M/z 124.1 (M + H) + .
The second step: compound 109a (1.70g, 13.81mmol, 1eq) was dissolved in N, N-dimethylformamide (20 mL), cesium carbonate (9.00g, 27.62mmol, 2eq) was added, and after stirring for 20 minutes, iodomethane (3.92mL, 27.62mmol, 2eq) was added, and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete, and the reaction was directly concentrated to dryness under reduced pressure and then stirred with silica gel and chromatographed on flash silica gel (DCM: meOH = 10. MS (ESI) M/z 138.1 (M + H) + .
The third step: compound 109b (1.10g, 8.02mmol, 1eq) and 4-bromo-2-methylaniline (2.98g, 16.04mmol, 2eq) were dissolved in methanol (20 mL), and sodium cyanoborohydride (960mg, 16.04mmol, 2eq) was added in portions, and stirred at room temperature overnight. LCMS shows complete reaction, reaction solution, quick silica gelChromatographic separation (DCM: meOH = 10) gave compound 109c (1.3 g, yield: 52.8%). MS (ESI) M/z 307.0 (M + H) + .
The fourth step: compound 109c (300mg, 0.98mmol, 1eq), cesium carbonate (636mg, 1.95mmol, 2eq) were dissolved in N, N-dimethylformamide (3 mL), stirred at room temperature for 30 minutes, iodomethane (208mg, 1.46mmol, 1.5eq) was added dropwise, and stirred at room temperature overnight. LCMS showed the reaction was complete, and the reaction was directly concentrated to dryness under reduced pressure and separated by flash silica gel chromatography (PE: EA = 10) to obtain compound 109d (150 mg, yield: 45.2%). MS (ESI) M/z 321.0 (M + H) + .
The fifth step: compound 109d (130mg, 0.4mmol, 1eq), pinacol diboron (154mg, 0.61mmol, 1.5eq), potassium acetate (80mg, 0.81mmol, 2eq) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (30mg, 0.04mmol, 0.1eq) was added to dioxane (5 mL) in sequence and stirred overnight at 100 deg.C under argon. LCMS showed the reaction was complete, and the reaction was directly concentrated to dryness under reduced pressure and directly separated by flash silica gel chromatography (PE: EA = 1) to obtain compound 109e (80 mg, yield: 53.7%). MS (ESI) M/z 369.3 (M + H) + .
And a sixth step: compound 109e (80mg, 0.22mmol, 1eq), intermediate A (52mg, 0.2mmol, 0.9eq), cesium carbonate (142mg, 0.43mmol, 2eq) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (1695g, 0.022mmol, 0.1eq) was added to a mixed solution of dioxane (5 mL) and water (0.5 mL) in that order, and stirred overnight at 100 ℃ under argon. LCMS showed reaction completion, and the reaction was filtered and purified by silica gel prep plate (EA: PE =9, 1, uv254nm) to give crude product, which was further purified by reverse phase preparative chromatography Pre-HPLC to give the title compound 109 (3.61 mg, yield: 3.5%). MS (ESI) M/z 470.2 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ9.97(s,1H),9.78(s,1H),8.88(s,1H),8.79(s,1H),8.53(d,J＝2.4Hz,1H),7.92–7.85(m,3H),7.63(dd,J＝6.8,2.0Hz,1H),7.44(dd,J＝6.8,2.0Hz,1H),7.23(d,J＝8.4Hz,1H),7.18(d,J＝8.4Hz,1H),6.24(t,J＝6.8Hz,1H),3.97(s,2H),3.46(s,3H),2.71(s,3H),2.43(s,3H),2.34(s,3H).
Example 27
Synthesis of 1- (6- (3-methyl-4- (methyl ((1-methyl-1H-pyrazol-3-yl) methyl) amino) phenyl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000541
the first step is as follows: 1-methyl-1H-pyrazole-3-carbaldehyde (5.00g, 45.41mmol, 1.0eq) and 4-bromo-2-methylaniline (8.45g, 45.41mmol, 1.0eq) were dissolved in methanol (200 mL), and sodium cyanoborohydride (7.13g, 113.52mmol, 2.5eq) was added in portions under an ice-water bath, warmed to room temperature, and reacted overnight. LCMS monitoring showed the product formed, the reaction was concentrated under reduced pressure and separated by flash silica gel chromatography (PE: EA =10, 1 to 4. MS (ESI) M/z 280.0 (M + H) + .
The second step is that: compound 111a (150mg, 0.54mmol, 1eq) was added to N, N-dimethylformamide (5 mL), replaced with argon, sodium hydride (60%, 43mg,1.087mmol, 2eq) was added while cooling on ice, the reaction was maintained for half an hour, iodomethane (152mg, 1.07mmol, 2eq) was added, the tube sealed, and the temperature was raised to 90 ℃ for 3 hours. The reaction solution was cooled to room temperature, quenched with water (30 mL), extracted with ethyl acetate, washed with water, washed with brine, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was separated by flash chromatography on silica gel (PE: EA =10 1 to 3) to obtain compound 111b (150 mg, yield: 71%). MS (ESI) M/z 294.0 (M + H) + .
The third step: compound 111b (135mg, 0.46mmol, 1eq), potassium acetate (135mg, 1.38mmol, 3eq), pinacol diboron (175mg, 0.69mmol, 1.5eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (14mg, 10%) was added to dioxane (5 mL) in this order, replaced with argon three times, and then heated to 100 ℃ for 18 hours. LCMS monitored the product formation, the reaction was cooled and filtered through celite, and the silica gel was stirred and chromatographed on flash silica gel (PE: EA =3, 20-3. MS (ESI) M/z 342.2 (M + H) + .
The fourth step: intermediate A (61mg, 0.23mmol, 1eq), compound 111c (118mg, 0.35mmol, 1.5eq), and sodium carbonate (73mg, 0.69mmol, 3eq) were added in this order to a mixed solvent of dioxane (1.8 mL) and water (0.2 mL), and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (10mg, 10%) was replaced by argon three times and then increasedThe temperature is increased to 100 ℃ and the reaction is carried out for 5 hours. The starting material was reacted completely by LCMS and the reaction was washed once with ethyl acetate (10 mL), saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and spun dry. The crude product was purified by reverse phase preparative chromatography Pre-HPLC to give the title compound 111 (5 mg, yield: 4.9%). MS (ESI) M/z 443.3 (M + H) + . 1 H NMR(400MHz,DMSO-d 6 )δ9.87(s,1H),9.75(s,1H),8.86(s,1H),8.79(s,1H),8.53(s,1H),7.94–7.83(m,3H),7.59(d,J＝2.4Hz,1H),7.24(d,J＝8.4Hz,1H),7.16(d,J＝8.4Hz,1H),6.09(d,J＝2.4Hz,1H),4.03(s,2H),3.79(s,3H),2.67(s,3H),2.43(s,6H).
Example 28
Synthesis of 1- (6-methylpyridin-3-yl) -3- {6- [1- (pyrrolidin-3-yl) -2, 3-dihydro-1H-indol-5-yl ] pyrazin-2-yl } urea hydrochloride:
Figure BDA0003769482940000551
the first step is as follows: 5-Bromobinoindole (2.00g, 10.1mmol, 1equiv.), 1-t-butoxycarbonyl-3-pyrrolidone (2.81g, 15.15mmol, 1.5equiv.) was dissolved in methanol (100 mL). The reaction was stirred at room temperature for 2 hours, acetic acid (3 mL) was added, and then sodium cyanoborohydride (3.02g, 50.49mmol, 5equ.) was added in portions. The reaction was stirred overnight. LCMS showed reaction completion, solvent was spun off, dissolved in water, extracted with ethyl acetate, organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by flash chromatography on silica gel to give compound 114a (3.3 g, yield: 89%). MS (ESI) M/z 367.19 (M + H) + ； 1 H NMR(400MHz,CDCl 3 )δ7.14(s,2H),6.33(d,J＝8.8Hz,1H),4.10–3.93(m,1H),3.76–3.46(m,2H),3.44–3.25(m,4H),2.94(t,J＝8.3Hz,2H),2.17–1.96(m,2H),1.44(s,9H).
The second step is that: compound 114a (1.00g, 2.72mmol, 1equiv.), pinacol diboron (830mg, 3.27mmol, 1.2equiv.), pd (dppf) Cl 2 (398mg, 0.55mmol, 0.2equiv.), and potassium acetate (1.069g, 10.89mmol, 4equiv.) were added to 1,4-dioxane (30 mL). The reaction system was purged with nitrogen three times and stirred at 90 ℃ for 8 hours. Spin-drying solvent, dissolving in water, extracting with ethyl acetate, and drying with anhydrous sodium sulfateThen, the mixture was filtered, concentrated, and purified by flash silica gel chromatography (PE: EA =20:1 to 10). MS (ESI) M/z 415.42 (M + H) + ； 1 H NMR(400MHz,CDCl 3 ):δ7.67–7.48(m,2H),6.48(t,J＝9.6Hz,1H),4.34–4.14(m,1H),3.75–3.50(m,2H),3.50–3.29(m,4H),2.96(t,J＝8.3Hz,2H),2.20–2.05(m,2H),1.45(s,9H),1.35–1.29(m,12H).
The third step: 114b (512mg, 1.24mmol, 1equiv.), intermediate A, pd (dppf) Cl, was added to a 100mL single-neck flask 2 (342mg, 0.12mmol, 0.1equiv.), potassium carbonate (342mg, 2.47mmol, 2equiv.), 1,4-dioxane (20 mL) and water (5 mL). The reaction system was purged with nitrogen three times and stirred at 90 ℃ for 4 hours. The solvent was dried by evaporation, dissolved in water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and prepared by reverse phase preparative chromatography pre-HPLC to give compound 114c (330 mg, yield: 50%). MS (ESI) M/z 516.38 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ8.54(s,2H),8.39(s,1H),8.02(d,J＝8.7Hz,1H),7.80–7.70(m,2H),7.28(d,J＝8.6Hz,1H),6.65(d,J＝8.3Hz,1H),4.31(d,J＝7.7Hz,1H),3.70–3.49(m,4H),3.40(dd,J＝11.1,6.4Hz,2H),3.05(t,J＝8.1Hz,2H),2.49(d,J＝9.1Hz,3H),2.17(d,J＝8.6Hz,2H),1.48(d,J＝2.3Hz,9H).
The fourth step: compound 114c (100mg, 0.19mmol, 1equiv.) and an ethyl hydrogen chloride acetate solution (4M, 10mL) were added to a 10mL single-necked flask, and stirred at room temperature for 2 hours, LCMS showed completion of the reaction, followed by filtration, washing the filter cake with ethyl acetate (20 mL), and drying to obtain the title compound 114 (39.40 mg, yield: 46%). MS (ESI) M/z 416.39 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ11.25(s,1H),10.07(s,1H),9.51(d,J＝31.3Hz,2H),9.07–8.89(m,2H),8.79(s,1H),8.31(dd,J＝8.7,2.3Hz,1H),7.85(dd,J＝18.3,8.2Hz,3H),6.70(d,J＝8.4Hz,1H),4.50–4.45(m,1H),3.64–3.48(m,2H),3.47–3.28(m,2H),3.19(m,2H),3.03(t,J＝8.3Hz,2H),2.69(s,3H),2.26–1.97(m,2H).
Example 29
Synthesis of 3- (6-chloropyridin-3-yl) -1- (6- {1- [ (3-methyloxacyclohexan-3-yl) methyl ] -2, 3-dihydro-1H-indol-5-yl } pyrazin-2-yl) urea:
Figure BDA0003769482940000561
the first step is as follows: to 5-bromo-2, 3-dihydro-1H-indole (1g, 5.05mmol, 1.0equiv.) in dichloromethane (20 mL) was added 3-methyloxetane-3-carbaldehyde (606 mg,6.06mmol, 1.2equiv.), glacial acetic acid (0.1mL, 1.67mmol, 0.33equiv.), sodium triacetoxyborohydride (2.13g, 10.1mmol, 2.0equiv.). Stirring at 25 ℃ for 15 hours under the protection of nitrogen. LCMS showed the reaction was complete and the reaction was quenched by addition of water (30 mL), extracted with ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated. The residue was purified by flash chromatography on silica gel (PE/EtOAc = 8/1) to give compound 115a (1.4 g, yield: 98%). MS (ESI) M/z 283.8 (M + H) + ； 1 H NMR(400MHz,CDCl 3 )：δ7.17-7.15(m,2H),6.32(d,J＝8.0Hz,1H),4.60(d,J＝5.6Hz,2H),4.45(d,J＝5.6Hz,2H),3.40(t,J＝8.4Hz,2H),3.24(s,2H),3.00(t,J＝8.4Hz,2H),1.43(s,3H).
The second step: to a solution of compound 115a (1.4g, 4.96mmol, 1.0equiv.) in 1.4-dioxane (20 mL) were added diboronanol ester (1.9g, 7.44mmol, 1.5equiv.), potassium acetate (1.2g, 12.4mmol, 2.5equiv.), and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (3970 mg,0.49mmol, 0.1equiv.). After stirring at 100 ℃ for 3 hours under nitrogen, LCMS indicated complete reaction, cooling to room temperature, water (30 mL) was added to the reaction, extracted with ethyl acetate, dried over innumerable sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (PE/EtOAc = 3/1) to give compound 115b (900 mg, yield: 55%). MS (ESI): M/z 330.0 (M + H) + ； 1 H NMR(400MHz,CDCl 3 )：δ7.55(d,J＝7.8Hz,1H),7.51(s,1H),6.41(d,J＝7.8Hz,1H),4.57(d,J＝5.8Hz,2H),4.40(d,J＝5.8Hz,2H),3.40(t,J＝8.4Hz,2H),3.29(s,2H),3.00(t,J＝8.4Hz,2H),1.37(s,3H),1.31(s,12H).
The third step: to 1.4-dioxane (30 mL) of compound 115b (2.5g, 7.59mmol,1.0 equiv.) and water (3 mL) were added 6-chloropyrazine-2-carboxylic acid (1.44g, 9.11mmol,1.2 equiv.), sodium carbonate (2.01g, 18.9mm)ol,2.5 equiv.), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (648mg, 0.8mmol, 0.1equiv.). Stirring was carried out at 100 ℃ for 3 hours under nitrogen. LCMS showed reaction complete, filtered and filtrate concentrated. The residue was purified by flash chromatography on silica gel (DCM/MeOH = 10/1) to give compound 115c (1.1 g, yield: 44.5%). MS (ESI): M/z 326.0 (M + H) + 。
The fourth step: to toluene (Tol, 2 mL) of compound 115c (50mg, 0.15mmol, 1.0equiv.), 6-chloropyridin-3-amine (24mg, 0.18mmol, 1.2equiv.), triethylamine (47mg, 0.46mmol, 3.0equiv.), diphenylphosphorylazide (85mg, 0.31mmol, 2.0equiv.) was added. Stirring is carried out for 15 hours at 100 ℃ under the protection of nitrogen. LCMS showed the reaction was complete, the reaction was concentrated and the residue was purified by reverse phase preparative chromatography Prep-HPLC to give the title compound 115 (12 mg, yield: 17.3%). MS (ESI) M/z 451.2 (M + H) + ； 1 H NMR(400MHz,DMSO)：δ10.07(s,1H),9.77(s,1H),8.76(s,1H),8.73(s,1H),8.52(d,J＝2.8Hz,1H),8.08(dd,J＝8.8,2.8Hz,1H),7.82-7.80(m,2H),7.51(d,J＝8.8Hz,1H),6.64(d,J＝9.2Hz,1H),4.51(d,J＝5.6Hz,2H),4.30(d,J＝5.6Hz,2H),3.47(t,J＝8.0Hz,2H),3.42(s,2H),3.08(d,J＝8.0Hz,2H),1.35(s,3H).
Example 30
Synthesis of 1- (6- { 7-methoxy-1- [ (3-methyloxyethan-3-yl) methyl ] -1H-indazol-5-yl } pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000571
the first step is as follows: to acetonitrile (10 mL) containing 2-methoxy-6-methylaniline (1.0 g,7.29mmol,1.0 equiv.) was added N-bromosuccinimide (1.69g, 9.48mmol,1.3 equiv.), and the mixture was stirred at 25 ℃ for 15 hours. LCMS showed reaction completion, water was added to the reaction, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE/EtOAc = 5/1) to give compound 116a (650 mg, yield 41.3%). MS (ESI): M/z 215.8 (M + H) + ； 1 H NMR(400MHz,CDCl 3 )：δ6.86(d,J＝1.2Hz,1H),6.81(d,J＝2.0Hz,1H),3.85(s,3H),2.16(s,3H).
The second step is that: glacial acetic acid (972mg, 16.2mmol,7.0 equiv.), potassium acetate (1.8g, 18.5mmol,8.0 equiv.), tert-butyl nitrite (358mg, 3.47mmol,1.5 equiv.) were added to toluene (20 mL) of compound 116a (500mg, 2.31mmol,1.0 equiv.). Stirring was carried out at 25 ℃ for 15 hours under nitrogen. LCMS showed reaction completion, water was added to the reaction, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE/EtOAc = 3/1) to give compound 116b (200 mg, yield: 38%). MS (ESI) M/z 229.0 (M + H) + ； 1 H NMR(400MHz,CDCl 3 )δ7.96(s,1H),7.47(d,J＝1.2Hz，1H),6.82(s,1H),3.97(s,3H).
The third step: to compound 116b (180mg, 0.79mmol,1.0 equiv.) in N, N-dimethylformamide (5 mL) was added sodium hydrogen (80mg, 2.0mmol,2.5equiv., purity 60%), 3- (chloromethyl) -3-methyloxyethane (144mg, 1.19mmol,1.5 equiv.) at 0 ℃. Stirring was carried out at 25 ℃ for 15 hours under nitrogen. LCMS showed reaction completion, water (20 mL) was added to the reaction, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE/EtOAc = 3/1) to give compound 116c (90 mg, yield: 36.5%). MS (ESI) M/z 310.8 (M + H) + ； 1 H NMR(400MHz,CDCl 3 )δ7.85(s,1H),7.42(d,J＝1.2Hz,1H),6.78(d,J＝1.2Hz,1H),4.79(s,2H),4.76(d,J＝6.0Hz,2H),4.33(d,J＝6.0Hz,2H),3.94(s,3H),1.20(s,3H).
The fourth step: to 1.4-dioxane (20 mL) of compound 116c (200mg, 0.64mmol, 1.0equiv.), diboronanol ester (243mg, 0.96mmol, 1.5equiv.), potassium acetate (157mg, 1.6mmol, 2.5equiv.), and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (49mg, 0.06mmol, 0.1equiv.). Stirring is carried out for 3 hours at 100 ℃ under the protection of nitrogen. LCMS showed reaction completion, water (30 mL) was added to the reaction, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE/EtOAc = 3/1) to give compound 116d (190 mg, yield: 82.5%)。MS(ESI):m/z 359.0(M+H) + ； 1 H NMR(400MHz,CDCl 3 )δ7.97(s,1H),7.87(s,1H),7.11(s,1H),4.87(s,2H),4.83(d,J＝6.0Hz,2H),4.36(d,J＝6.0Hz,2H),4.02(s,3H),1.39(s,12H),1.26(s,3H).
The fifth step: to 1.4-dioxane (10 mL) of compound 116d (190mg, 0.53mmol, 1.0equiv.) and water (2 mL) were added intermediate A (168mg, 0.64mmol, 1.2equiv.), sodium carbonate (140mg, 1.32mmol, 2.5equiv.), and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (40mg, 0.05mmol, 0.1equiv.). Stirring is carried out for 15 hours at 100 ℃ under the protection of nitrogen. LCMS showed reaction complete, filtered and the filtrate concentrated. The residue was purified by reverse phase preparative chromatography Prep-HPLC to give the title compound 116 (45 mg, yield: 18.9%). MS (ESI) M/z 460.3 (M + H) + ； 1 H NMR(EN1079-081-P)(400MHz,DMSO)：δ9.66-9.64(m,2H),8.93(s,1H),8.88(s,1H),8.48(d,J＝2.8Hz,1H),8.15(s,1H),8.05(s,1H),7.84(dd,J＝8.4,2.8Hz,1H),7.50(d,J＝1.2Hz,1H),7.20(d,J＝8.4Hz,1H),4.78(s,2H),4.60(d,J＝6.0Hz,2H),4.18(d,J＝6.0Hz,2H),4.00(s,3H),2.38(s,3H),1.09(s,3H).
Example 31
Synthesis of 1- (6- {1- [2- (dimethylamine) ethyl ] -2, 3-dihydro-1H-indol-5-yl } pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea formate:
Figure BDA0003769482940000581
the first step is as follows: 5-bromo-2, 3-dihydro-1H-indole (500mg, 2.52mmol, 1equiv.), 2- (dimethylamino) acetaldehyde hydrochloride (405.57mg, 3.28mmol, 1.3equiv.), zinc chloride (34.41mg, 0.25mmol, 0.1equiv.) were dissolved in methanol (10 mL NaHCO), stirred at room temperature for 2 hours, LCMS showed completion of the reaction, and the reaction was poured into saturated NaHCO 3 (200 mL), extracted with ethyl acetate, the combined organic phases dried over sodium sulfate, filtered, and the filtrate dried to give the crude product. The crude product was chromatographed on flash silica gel (PE/EtOAc = 3/1-DCM/MeOH = 10/1) to give compound 117a (260 mg, yield: 38.3%). MS (ESI) M/z 269.10 (M + H) + ； 1 H NMR(400MHz,CDCl 3 )δ7.19–7.10(m,2H),6.34(d,J＝8.8Hz,1H),3.40(t,J＝8.4Hz,2H),3.20(t,J＝7.0Hz,2H),2.95(t,J＝8.3Hz,2H),2.61(t,J＝7.0Hz,2H),2.37(s,6H).
The second step is that: to dioxane (6 mL) was added compound 117a (200mg, 0.74mmol, 1equ.), pinacol diboron (283.02mg, 1.11mmol, 1.5equ.), potassium acetate (218.75mg, 2.23mmol, 3equ.) and Pd (dppf) Cl2 (51.22mg, 0.07mmol, 0.1equ.). Heating to 100 ℃ under the protection of nitrogen, and stirring for 2 hours. The reaction was diluted with 50mL of ethyl acetate, filtered, and the filtrate was concentrated to give a crude product, which was separated by flash chromatography on silica gel (ethyl acetate/petroleum ether = 0-90% first, and methanol/dichloromethane = 0-11%) to give compound 117b (100 mg, crude product). MS (ESI) M/z 317.2 (M + H) + .
The third step: compound 117b (100mg, 0.32mmol, 1equiv.), intermediate a (91.71mg, 0.35mmol, 1.1equiv.), sodium carbonate (67.83mg, 0.64mmol, 2.0eq.) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (23.39mg, 0.03mmol, 0.1equiv.) was sequentially added to a mixed solution of dioxane and water (5mL, 4. Cooled to room temperature, diluted with ethyl acetate (50 mL), filtered, and the filtrate was concentrated to give a crude product, which was purified by C18 column (acetonitrile/water = 0-80%, aqueous phase containing 0.1 wt% formic acid) to give the title compound 117 (15 mg, yield: 11.2%). MS (ESI): M/z 418.2 (M + H) + ； 1 H NMR(400MHz,MeOD)δ8.56(s,1H),8.53(s,1H),8.52(s,1H),8.44(s,1H),8.03(dd,J＝8.4,2.7Hz,1H),7.78(d,J＝9.9Hz,2H),7.28(d,J＝8.5Hz,1H),6.73(d,J＝8.2Hz,1H),3.54(t,J＝8.4Hz,2H),3.47(t,J＝6.5Hz,2H),3.10(dd,J＝10.7,6.7Hz,4H),2.71(s,6H),2.50(s,3H).
Example 32
Synthesis of 1- (6- (1- (2-hydroxypropyl) indol-5-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000591
the first step is as follows: 5-Bromoindoline (1.00g, 5.0mmol, 1.0equiv.) was dissolved in anhydrous THF (10 mL)) To the solution, sodium hydride (0.4 g,10.0mmol,60% purity, 2equiv.) was added under nitrogen protection at 0 ℃ and after stirring for 10min, propylene oxide (0.44g, 7.5mmol,1.5 equiv.) was slowly added dropwise and allowed to warm to room temperature and stirred for 16 hours. The reaction was cooled to room temperature, quenched with ice water (10 mL), the aqueous phase extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The residue was subjected to flash silica gel chromatography (PE: EA = 5) to obtain compound 118a (800 mg, yield: 61.5%). 1 H NMR(400MHz,DMSO-d6)δ7.13(s,1H),7.09(d,J＝8.4Hz 1H),6.39(d,J＝8.4Hz,1H),4.69(d,J＝4.4Hz,1H),3.97–3.78(m,1H),3.55–3.40(m,2H),2.96-2.88(m,4H),1.14–1.07(d,J＝6.0Hz,3H).
The second step is that: compound 118a (871mg, 3,43mmol, 1.1equiv.), potassium acetate (611mg, 6.24mmol, 2.0equiv.), and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (226mg, 0.31mmol, 0.1equiv.) was added to a solution of 1,4-dioxane (10 mL) and the reaction stirred at 100 ℃ under nitrogen for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was separated by flash silica gel chromatography (PE: EA = 5. MS (ESI) M/z 304.0 (M + H) + .
The third step: to a solution of compound 118b (200mg, 0.66mmol,1.0 equiv.) in dioxane (10 mL) was added an aqueous solution (2 mL) of intermediate A (192mg, 0.73mmol,1.1 equiv.) and sodium carbonate (140mg, 1.32mmol,2.0 equiv.), and [1,1' -bis (diphenylphosphino) ferrocene ] was added under nitrogen protection]Palladium dichloride (51.2mg, 0.07mmol, 0.1equiv.) was reacted at 100 ℃ with stirring for 16 hours. LCMS showed reaction completion, the reaction was cooled to room temperature, concentrated, the residue was added with water (20 mL), extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by flash chromatography on silica gel (PE/EtOAc = 1/9) to give 100mg of crude title compound 118, which was then isolated and purified by reverse phase preparative chromatography Pre-HPLC to give title compound 118 (42.53mg, 0.105mmol, 16.9% yield). MS (ESI): M/z 405.2 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.69(s,1H),8.69(s,1H),8.67(s,1H),8.56(s,1H),7.93(d,J＝8.8Hz,1H),7.79-7.71(m,2H),7.30(d,J＝8.0Hz,1H),6.55(d,J＝8.0Hz,1H),4.73(s,1H),3.93-3.88(m,1H),3.58(t,J＝8.4Hz,2H),3.09-3.04(m,2H),3.01(t,J＝8.8Hz,2H),2.48(s,3H),1.11(d,J＝6.4Hz,3H).
Example 33
Synthesis of (S) -1- (6- (1- ((3-methyloxycyclohexan-3-yl) methyl) indol-5-yl) pyrazin-2-yl) -3- (piperidin-3-yl) urea:
Figure BDA0003769482940000601
the first step is as follows: in a 100mL single-necked flask, compound 60d (500mg, 1.69mmol, 1equiv.) was added to a solvent of toluene (10 mL), followed by addition of (3S) -1- [ (tert-butoxy) carbonyl group]Piperidine-3-carboxylic acid (580.2mg, 2.53mmol, 1.5eq), diphenylphosphorylazide (927.5mg, 3.37mmol, 2.0eq), triethylamine (511.5mg, 5.05mmol, 3.0eq), the reaction system was purged with nitrogen and then stirred at 100 ℃ for 16 hours. LCMS showed the reaction was complete, the reaction was filtered, concentrated, and chromatographed on flash silica gel (PE: EA = 1) to give compound 119a (370 mg, yield 42.0%). MS (ESI) M/z 523.0 (M + H) + .
The second step is that: in a 100mL single-neck flask, the compound 119a (100mg, 0.19mmol, 1equiv.) was added to a solvent of dichloromethane (10 mL), trifluoroacetic acid (2mL, 17.54mmol, 183.3eq) was further added dropwise, and the reaction system was purged with nitrogen and then stirred at 25 ℃ for 1 hour to obtain a red-brown liquid. LCMS showed reaction completion, which was dried and then dissolved in N, N-dimethylformamide and isolated and purified by reverse phase preparative chromatography Pre-HPLC (formic acid as additive) to give the title compound 119 (54.52 mg, 69.4% yield). MS (ESI) M/z 423.4 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ9.54(s,1H),8.61(s,1H),8.52(s,1H),8.22-8.12(m,1H),7.81-7.74(m,2H),6.61(d,J＝8.4Hz,1H),4.50(d,J＝5.6Hz,2H),4.30(d,J＝5.6Hz,2H),3.90–3.80(m,2H),3.37(s,2H),3.22-3.14(m,2H),3.08–2.92(m,3H),2.83–2.69(m,2H),1.96-1.86(m,1H),1.82-1.71(m,1H),1.66–1.48(m,2H),1.35(s,3H).
Example 34
Synthesis of 1- (6- {1- [ (3-methyloxoalk-3-yl) methyl ] -1H,2H,3H pyrrolo [2,3-b ] pyridin-5-yl ] pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000611
the first step is as follows: in the presence of 5-bromo-1H, 2H, 3H-pyrrolo [2,3-b ]]Pyridine (500mg, 2.52mmol,1.0 equiv.) in N, N' -dimethylformamide (10 mL) was added sodium hydride (202 mg, 60% purity, 5.05mmol,2.0 equiv.), stirred at room temperature for 30min, then 3-chloromethyl-3-methyloxetane (454mg, 3.77mmol,1.5 equiv.) was added, and stirred at 25 ℃ for 15 hours. LCMS showed the reaction was complete, and was slowly quenched by addition of ice water (10 mL), extracted with ethyl acetate, and the organic phases were combined, washed successively with saturated sodium chloride solution, water, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash chromatography on silica gel (eluent: PE/EA = 3/1) to give compound 120a (450 mg, yield: 63.3%). MS (ESI) M/z 282.9 (M + H) + ； 1 H NMR(400MHz,CDCl 3 )δ7.87(d,J＝1.2Hz,1H),7.26(d,J＝1.2Hz,1H),4.64(d,J＝6.0Hz,2H),4.42(d,J＝6.0Hz,2H),3.57–3.53(m,4H),3.03(t,J＝8.4Hz,2H),1.39(s,3H).
The second step is that: to 1.4-dioxane (15 mL) of compound 120a (300mg, 1.03mmol, 1.0equiv.) were added diboronanol ester (404mg, 1.59mmol, 1.5equiv.), potassium acetate (260mg, 2.65mmol, 2.5equiv.), and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (80mg, 0.1mmol, 0.1equiv.). Stirring is carried out for 3 hours at 100 ℃ under the protection of nitrogen. LCMS indicated complete reaction, suction filtered and concentrated to give crude compound 120b (310 mg, yield: 70.8%) which was used directly in the next step. MS (ESI) M/z 249.0 (M + H) + .
The third step: to 1.4-dioxane (10 mL) of compound 120b (300mg, 1.21mmol, 1.0equiv.) and water (1 mL), intermediate A (383mg, 1.45mmol, 1.2equiv.), sodium carbonate (320mg, 3.02mmol, 2.5equiv.), and [1,1' -bis (diphenylphosphino) ferrocene were added]Palladium dichloride dichloromethane complex (97mg, 0.12mmol, 0.1equiv.). Stirring is carried out for 15 hours at 100 ℃ under the protection of nitrogen. LCMS showed reaction complete, filtered and the filtrate concentrated. The residue was purified by reverse phase preparative chromatography Prep-HPLC to give the title compound 120 (11 mg, yield: 2.1%). MS (ESI) M/z 432.3 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ11.57(s,1H),9.15(s,1H),8.73(s,1H),8.66(d,J＝2.4Hz,1H),8.60(s,1H),8.46(s,1H),8.18(s,1H),7.94(dd,J＝8.8,2.4Hz,1H),7.19(d,J＝8.4Hz,1H),4.19(d,J＝12.8Hz,1H),4.02-3.96(m,3H),3.44-3.43(m,1H),3.40(s,2H),3.35-3.32(m,2H),3.23(d,J＝12.8Hz,1H),2.42(s,3H),1.05(s,3H).
Example 35
Synthesis of 3- (6-methylpyridin-3-yl) -1- {6- [1- (oxazolidin-3-yl) -2, 3-dihydro-1H-indol-5-yl ] pyrazin-2-yl } urea:
Figure BDA0003769482940000621
the first step is as follows: 5-bromo-2, 3-dihydro-1H-indole (500mg, 2.52mmol, 1equv.), oxazolidin-3-one (326mg, 3.79mmol, 1.5equv.), zinc chloride (34mg, 0.24mmol, 0.1equv.), and methanol (10ml, 100.0%) were added, sodium cyanoborohydride (302mg, 4.71mmol, 2equv.) was added at room temperature, and stirring was continued for 1 hour at room temperature. LCMS showed the reaction was complete and the reaction was quenched by pouring into saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was spun dry to give crude product which was chromatographed on flash silica gel (PE/EtOAc = 3/1) to give compound 121a (600 mg, yield: 88.8%). MS (ESI): M/z 268.10 (M + H) + ； 1 H NMR(400MHz,CDCl 3 )δ7.20–7.12(m,2H),6.36(d,J＝8.1Hz,1H),4.19(ddd,J＝14.9,7.5,4.4Hz,1H),4.24-4.15(m,1H),4.07-3.98(m,1H),3.89–3.84(m,1H),3.79(dd,J＝15.7,8.4Hz,1H),3.46(dd,J＝16.6,8.2Hz,1H),3.38(dd,J＝16.6,8.2Hz,1H),2.94(t,J＝8.3Hz,1H),2.25-2.13(m,1H),2.07–1.94(m,1H).
The second step is that: the compound 121a (600mg, 2.24mmol, 1equiv.), the bis-pinacol borate (852.31mg, 3.36mmol, 1.5equiv.), pd (dppf) Cl 2 (80 mg), KOAc (700 mg) was dissolved in 1,4-dioxane (10 ml, 100%), and reacted at 100 ℃ for 2 hours under nitrogen protection. LCMS shows complete reaction, the reaction is poured into water (100 mL), extracted with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, the filtrate is spun dry to give the crude product, which is then purified over silica gelChromatography (PE/EtOAc = 3/1) afforded compound 121b (400 mg, yield: 56.7%). MS (ESI) M/z 316.24 (M + H) + ；1H NMR(EN1084-59-P1A,CDCl 3 ,400MHz)δ7.56(d,J＝7.9Hz,1H),7.51(s,1H),6.47(d,J＝7.9Hz,1H),4.36–4.25(m,1H),4.06-3.96(m,1H),3.93(dd,J＝9.4,4.0Hz,1H),3.85(dd,J＝9.4,6.6Hz,1H),3.79(dd,J＝15.6,8.3Hz,1H),3.52–3.46(m,1H),3.44–3.36(m,1H),2.95(t,J＝8.4Hz,2H),2.26-2.13(m,1H),2.09–1.92(m,1H),1.31(s,12H).
The third step: compound 121b (200mg, 0.63mmol, 1eq), intermediate A (167.3mg, 0.63mmol, 1eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (92.7mg, 0.13mmol, 0.2eq) and anhydrous sodium carbonate (134.5mg, 1.27mmol, 2eq) were added in sequence to a mixed solution of dioxane/water (20 mL/2 mL), heated to 100 ℃ under nitrogen protection and stirred for 16 hours. LCMS shows the reaction is complete, the reaction is concentrated and the residue is purified by reverse phase preparative chromatography Prep-HPLC to give the title compound 121 (62.42 mg, yield: 23.6%). MS (ESI) M/z 417.0 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.67(s,1H),8.73(s,1H),8.69(s,1H),8.52(d,J＝2.4Hz,1H),7.90(dd,J＝8.4,2.8Hz,1H),7.80-7.78(m,2H),7.26(d,J＝8.4Hz,1H),6.68(d,J＝8.4Hz,1H),4.43-4.37(m,1H),3.91–3.89(m,1H),3.83–3.75(m,2H),3.71-3.65(m,1H),3.53–3.44(m,2H),2.98(t,J＝8.4Hz,2H),2.43(s,3H),2.19-2.13(m,1H),2.01–1.90(m,1H).
Example 36
Synthesis of (1- {6- [1- (2-methylpropyl) -2, 3-dihydro-1H-indol-5-yl ] pyrazin-2-yl } -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000631
the first step is as follows: 5-bromo-2, 3-dihydro-1H-indole (1.00g, 5.07mmol, 1eq) was dissolved in dichloromethane (15 mL), 2-methylpropionaldehyde (402mg, 5.58mmol, 1.1eq) and acetic acid (1 mL) were added to the above mixture, and after stirring at 25 ℃ for 30min, sodium triacetoxyborohydride (2.15g, 10.14mmol, 2eq) was added to the reaction mixture, and stirring was carried out at room temperature for 16 hours. LCMS showed reaction complete, dichloromethane extraction, brineAfter washing, washing with water and drying over anhydrous sodium sulfate, filtration was carried out, the filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel (PE: EA = 5). MS (ESI) M/z 254.9 (M + H) + .
The second step: compound 122a (450mg, 1.77mmol, 1.5eq), potassium acetate (290mg, 2.95mmol, 2.5eq) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (173mg, 0.24mmol, 0.2eq) was added to dioxane (4 mL) in sequence, warmed to 100 ℃ under nitrogen and stirred for 3 hours, LCMS showed reaction complete, after the reaction system cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure and separated by flash silica gel chromatography (PE: EA =4: 1) to give compound 122b (243 mg, yield: 68.3%). MS (ESI) M/z 302.0 (M + H) + .
The third step: compound 122b (100mg, 033mmol, 1.0eq), intermediate A (87.53mg, 0.33mmol, 1eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (48.53mg, 0.66mmol, 0.2eq) and anhydrous sodium carbonate (70.37mg, 0.66mmol,2.0 eq) are sequentially added into a mixed solution of dioxane/water (10 mL/1 mL), protected by nitrogen, heated to 100 ℃ and stirred for 16 hours. LCMS showed the reaction was complete, the reaction was concentrated and the residue was purified by reverse phase preparative chromatography Prep-HPLC to give the title compound 122 (16.13 mg, yield: 12.1%). MS (ESI): M/z 403.0 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.67(s,1H),8.70(s,1H),8.68(s,1H),8.53(d,J＝2.4Hz,1H),7.91(dd,J＝8.4,2.8Hz,1H),7.78-7.76(m,2H),7.26(d,J＝8.0Hz,1H),6.56(d,J＝8.4Hz,1H),3.49(t,J＝8.8Hz,2H),3.03(t,J＝8.8Hz,2H),2.94(d,J＝7.2Hz,2H),2.44(s,3H),1.99-1.94(m,1H),0.94(d,J＝6.4Hz,6H).
Example 37
Synthesis of 1- (6- (1- (3-methyloxyethane-3-carbonyl) indol-5-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000641
the first step is as follows: 3-methyl-3-carboxy-1-oxetane (100mg, 0.86mmol, 1equiv.) was added to N, N-dimethyl formamideTo a solvent of amide (6 mL) was added 5-bromo-2, 3-dihydro-1H-indole (255.85mg, 1.29mmol,1.5 equiv.), N, N-dimethylpyridin-4-amine (126.25mg, 1.03mmol, 1.2eq), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (294.12mg, 1.89mmol, 2.2eq) and the reaction system was stirred at 25 ℃ for 16 hours after replacing nitrogen. LCMS showed the reaction was complete, and the reaction was filtered and concentrated, and separated by flash silica gel chromatography (PE: EA = 1) to obtain compound 123a (110 mg, yield: 43.2%). MS (ESI): M/z 295.8 (M + H) + .
The second step is that: the compound 123a (110mg, 0.37mmol, 1equiv.) was added to a solvent of 1,4-dioxane (8 mL), followed by addition of pinacol diboron (188.64mg, 0.74mmol, 2.0equiv.), potassium acetate (91mg, 0.93mmol, 2.5eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (27mg, 0.037mmol, 0.1eq) was stirred at 100 ℃ for 3 hours after nitrogen gas was replaced in the reaction system. LCMS showed the reaction was complete, the reaction was filtered and concentrated, and flash chromatography on silica gel (PE: EA = 1) was used to isolate compound 123b (120 mg, yield: 94.5%). MS (ESI) M/z 344.0 (M + H) + .
The third step: compound 123b (120mg, 0.35mmol, 1equiv.) is added to a mixed solvent of 1,4-dioxane (8 mL) and water (0.8 mL), followed by addition of 3- (6-chloropyrazin-2-yl) -1- (6-methylpyridin-3-yl) urea (138mg, 0.52mmol, 1.5eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (26mg, 0.035mmol, 0.1eq), sodium carbonate (74mg, 0.70mmol,2.0 eq), and the reaction system was purged with nitrogen and then stirred at 100 ℃ for 16 hours. LCMS showed the reaction was complete, the reaction was filtered through celite, concentrated and purified by reverse phase preparative chromatography Pre-HPLC to give the title compound 123 (9.11 mg, yield: 6%). MS (ESI): M/z 445.6 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ9.80-9.73(m,2H),8.92(s,1H),8.82(s,1H),8.51(d,J＝2.4Hz,1H),8.01(s,1H),7.98-7.94(m,1H),7.91-7.87(m,1H),7.64-7.52(m,1H),7.23(d,J＝8.4Hz,1H),4.99(d,J＝6.0Hz,1H),4.29(d,J＝5.6Hz,1H),3.88(t,J＝8.2Hz,1H),3.22(t,J＝8.0Hz,1H),2.43(s,3H),1.71(s,3H).
Example 38
Synthesis of 1- {6- [1- (2-hydroxy-2-methylpropyl) -2, 3-dihydro-1H-indol-5-yl ] pyrazin-2-yl } -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000642
the first step is as follows: a50 mL single-neck flask was charged with 5-bromoindoline (1g, 5.05mmol, 1equiv.) and THF (20mL, 100%), ice-cooled, sodium hydride (404mg, 10.10mmol, 2equiv.), stirred for 2 minutes, added with methyl propylene oxide (546mg, 7.57mmol, 1.5equiv.), and reacted at room temperature overnight. LCMS showed the reaction was complete, and water (30 mL) was added to quench the reaction, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, filtered, the filtrate was concentrated, and the compound 124a (1109 mg, yield: 90.4%) was isolated and purified by flash silica gel chromatography (PE: EA = 10. MS (ESI) M/z 270.11 (M + H) + ； 1 H NMR(400MHz,CDCl3)δ7.15(s,1H),7.13(dd,J＝8.3,2.1Hz,1H),6.40(d,J＝8.3Hz,1H),3.52(t,J＝8.5Hz,2H),3.06–2.91(m,4H),1.28(s,6H).
The second step is that: compound 124a (500mg, 1.85mmol, 1equiv.), pinacol diboron (563.96mg, 2.22mmol, 1.2equiv.), pd (dppf) Cl was added to a 100mL single-necked flask 2 (271mg, 0.37mmol, 0.2equiv.), potassium acetate (726.51mg, 7.4mmol, 4equiv.) and 1,4-dioxane (40 mL). The reaction system was purged with nitrogen three times and stirred at 90 ℃ for 8 hours. LCMS showed the reaction was complete, the solvent was dried, dissolved with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and separated by flash chromatography on silica gel (PE: EA =20 1-10) to give compound 124b (152 mg, yield: 26%). MS (ESI) M/z 318.25 (M + H) + ； 1 H NMR(400MHz,CDCl 3 )δ7.56(d,J＝7.9Hz,1H),7.53(s,1H),6.53(d,J＝7.9Hz,1H),3.56(t,J＝8.5Hz,2H),3.05(s,2H),3.01(t,J＝8.5Hz,2H),1.32(s,12H),1.29(s,6H).
The third step: compound 124b (123mg, 0.39mmol, 1.0eq), intermediate A (102.24mg, 0.39mmol, 1.0eq), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (56.74mg, 0.078mmol, 0.2eq) and anhydrous sodium carbonate (82.19mg, 0.78mmol, 2.0eq) were sequentially added to a mixed solution of dioxane/water (10 mL/1 mL), nitrogen gas was substituted for 3 times, and the temperature was raised toStirred at 100 ℃ for 16 hours. LCMS showed the reaction was complete, the reaction was concentrated and the residue was purified by reverse phase preparative chromatography Prep-HPLC to give the title compound 124 (53.7 mg, yield 33.5%). MS (ESI) M/z 419.3 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ10.00(s,1H),9.68(s,1H),8.69(s,1H),8.68(s,1H),8.53(d,J＝2.8Hz,1H),7.93-7.90(m,1H),7.77-7.76(m,2H),7.25(d,J＝8.4Hz,1H),6.59(d,J＝8.8Hz,1H),4.48(s,1H),3.66(t,J＝8.8Hz,2H),3.06–3.02(m,3H),2.44(s,3H),1.18(s,6H).
Example 39
Synthesis of 3- (6- {1- [ (3-methyloxoalk-3-yl) methyl ] -2, 3-dioxy-2, 3-dihydro-1H-indol-5-yl ] pyrazin-2-yl) -1- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000651
the first step is as follows: 5-bromo-2, 3-dihydro-1H-indole-2, 3-dione (2.0g, 8.85mmol, 1equiv.), potassium carbonate (1.47g, 10.62mmol, 1.2equiv.), and N, N-dimethylformamide (20 mL) were subjected to nitrogen substitution, followed by stirring at 70 ℃ for 1 hour, followed by addition of potassium iodide (734.42mg, 4.42mmol, 0.5equiv.), and 3-chloromethyl-3-methyloxetane (1.28g, 10.62mmol, 1.2equiv.), 70 ℃ and stirring at 1.5 hours. The reaction solution was cooled to room temperature, then water (20 mL) was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by flash chromatography on silica gel (PE: EA = 3) to obtain compound 125a (1.4 g, yield: 51%). MS (ESI) M/z 312.0 (M + H) + 。
The second step: compound 125a (100mg, 0.32mmol, 1equiv.) is dissolved in 1,4-dioxane (2 mL), pinacol diboron (106.44mg, 0.42mmol, 1.3equiv.), potassium acetate (94mg, 0.96mmol, 3.0equiv.), and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (12mg, 0.02mmol, 0.05equiv.) was purged with nitrogen and then stirred at 100 ℃ for 3 hours. The reaction solution was cooled to room temperature, followed by filtration, and the filtrate was spin-dried to obtain crude compound 125b (110 mg, yield: 94%). MS (ESI): M/z 358.3 (M + H) + . Used in the next step without purification。
The third step: compound 125b (110mg, 0.31mmol, 1equiv.) was dissolved in 1,4-dioxane (1 mL)/water (0.1 mL), intermediate A (73.08mg, 0.28mmol, 0.9equiv.), sodium carbonate (82mg, 0.78mmol, 2.5equiv.), and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (22mg, 0.03mmol, 0.1equiv.) was purged with nitrogen and then stirred at 100 ℃ for 2 hours. LCMS showed the reaction was complete, the reaction liquid was cooled to room temperature, filtered and then isolated and purified by reverse phase preparative chromatography Pre-HPLC to give the title compound 125 (7.79 mg, yield: 5.5%). MS (ESI) M/z 459.1 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ9.76(s,1H),9.57(s,1H),9.00(s,1H),8.92(s,1H),8.53(d,J＝2.4Hz,1H),8.42–8.35(m,1H),8.27(d,J＝1.6Hz,1H),7.95–7.85(m,1H),7.45(d,J＝8.4Hz,1H),7.23(d,J＝8.4Hz,1H),4.61(d,J＝6.0Hz,2H),4.21(d,J＝6.0Hz,2H),3.93(s,2H),2.43(s,3H),1.37(s,3H).
Example 40
Synthesis of 3- (6- {1- [ (3-methyloxetan-3-yl) methyl ] -2-oxo-2, 3-dihydro-1H-indol-5-yl } pyrazin-2-yl) -1- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000661
the first step is as follows: a microwave tube was charged with compound 125a (600mg, 1.93mmol, 1equiv.) and hydrazine hydrate (6.0 mL), followed by nitrogen bubbling and stirring at 120 ℃ for 1 hour. After the reaction solution was cooled to room temperature, water (10 mL) was added to dilute the solution, the solution was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by flash chromatography on silica gel (PE: EA = 1) to obtain compound 126a (180 mg, yield: 31.5%). MS (ESI) M/z 297.8 (M + H) + .
The second step: compound 126a (100mg, 0.34mmol, 1equiv.) is dissolved in 1,4-dioxane (2 mL), and pinacol diboron (111.47mg, 0.44mmol, 1.3equiv.), potassium acetate (100mg, 1.02mmol, 3.0equiv.) and [1,1' -bis (diphenylphosphino) ferrocene are added]Palladium dichloride (12mg, 0.02mmol, 0.05equiv.) was purged with nitrogen and then stirred at 100 ℃ for 3 hours. LC (liquid Crystal)MS showed the reaction was complete, the reaction solution was cooled to room temperature, then filtered, and the filtrate was spin-dried to give crude compound 126b (110 mg, yield: 94.3%). MS (ESI): M/z 344.0 (M + H) + . Was used in the next step without further purification.
The third step: compound 126b (110mg, 0.32mmol, 1equiv.) is dissolved in 1,4-dioxane (1mL, 90.91%)/water (0.1mL, 9.09%), intermediate A (76.05mg, 0.29mmol, 0.9equiv.), sodium carbonate (85mg, 0.8mmol, 2.5equiv.) and [1,1' -bis (diphenylphosphino) ferrocene ] are added]Palladium dichloride (22mg, 0.03mmol, 0.1equiv.) was purged with nitrogen and then stirred at 100 ℃ for 2 hours. LCMS shows the reaction is complete, the reaction is cooled to room temperature, filtered, the filtrate is concentrated and purified by reverse phase preparative chromatography Pre-HPLC to afford the title compound 126 (46.8 mg, yield: 32%). MS (ESI) M/z 445.1 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ9.73(s,1H),9.71(s,1H),8.92(s,1H),8.83(s,1H),8.54(d,J＝2.4Hz,1H),8.05–8.00(m,2H),7.95–7.85(m,1H),7.30–7.20(m,2H),4.60(d,J＝6.0Hz,2H),4.19(d,J＝6.0Hz,2H),3.89(s,2H),3.74(s,2H),2.44(s,3H),1.33(s,3H).
EXAMPLE 41
Synthesis of 1- (6- (1- ((1-methyl-1H-pyrazol-3-yl) methyl) indol-5-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000671
the first step is as follows: 5-bromo-2, 3-dihydro-1H-indole (500mg, 2.52mmol, 1equiv.), 1-methyl-1H-pyrazole-3-carbaldehyde (416.96mg, 3.79mmol, 1.5equiv.), zinc chloride (34.41mg, 0.25mmol, 0.1equiv.) were added to methanol (10 mL), sodium cyanoborohydride (302.03mg, 5.05mmol, 2equiv.) was added at room temperature, and stirring was continued for 1 hour at room temperature. LCMS showed the reaction was complete and the reaction was quenched by pouring into saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, filtered and the filtrate spun dry to give crude product which was chromatographed on flash silica gel (PE/EtOAc = 3/1) to give compound 127a (600 mg, yield: 88.8%). MS (ESI) M/z =2.231 (M + H) + ； 1 H NMR(400MHz,CDCl 3 )δ7.27(d,J＝2.2Hz,1H),7.15–7.11(m,2H),6.48–6.43(m,1H),6.12(d,J＝2.2Hz,1H),4.23(s,2H),3.87(s,3H),3.37(t,J＝8.4Hz,2H),2.92(t,J＝8.4Hz,2H).
The second step: the compound 127a (600mg, 2.05mmol, 1equiv.), bisphenonal borate (782.24mg, 3.08mmol, 1.5equiv.), pd (dppf) Cl 2 (150 mg), potassium acetate (604.62mg, 6.16mmol, 3equiv.), dissolved in dioxane (10 mL) and reacted at 90 ℃ for 3 hours under nitrogen. LCMS showed the reaction was complete, the reaction was poured into water (100 mL), extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product, which was purified by flash chromatography on silica gel (PE/EtOAc = 3/1) to give compound 127b (650 mg, yield: 93.5%). MS (ESI): M/z 340.30 (M + H) + ； 1 H NMR(CDCl 3 ,400MHz)δ7.57(d,J＝7.9Hz,1H),7.50(s,1H),7.25(d,J＝2.1Hz,1H),6.59(d,J＝7.9Hz,1H),6.11(d,J＝2.2Hz,1H),4.32(s,2H),3.86(s,3H),3.41(t,J＝8.4Hz,2H),2.94(t,J＝8.4Hz,2H),1.31(s,12H).
The third step: intermediate A (150mg, 0.54mmol, 1equiv.), compound 127b (289.48mg, 0.85mmol, 1.5equiv.), and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (40 mg), sodium carbonate (180.88mg, 1.71mmol,3 equiv.) were dissolved in dioxane (4 mL) and water (2 mL) and stirred at 100 ℃ for 3 hours under nitrogen. LCMS showed reaction complete, pour reaction into water (200 mL), filter with celite, wash celite with ethyl acetate; celite was then soaked with dichloromethane (30 mL) and methanol (8 mL), filtered, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product which was isolated and purified by flash chromatography on silica gel (DCM/MeOH = 10/1) to give the title compound 127 (78.41 mg). MS (ESI) M/z 441.36 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ9.95(s,1H),9.67(s,1H),8.71(s,1H),8.68(s,1H),8.51(s,1H),7.89(d,J＝6.8Hz,1H),7.83–7.71(m,2H),7.59(s,1H),7.22(d,J＝8.3Hz,1H),6.75(d,J＝8.2Hz,1H),6.13(s,1H),4.31(s,2H),3.79(s,3H),3.46(t,J＝8.3Hz,2H),2.97(t,J＝8.0Hz,2H),2.42(s,3H).
Example 42
Synthesis of 1- (6- (1- ((1H-pyrazol-3-yl) methyl) indol-5-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000681
synthesis of compound 128 the same as in example 127 was used, except that 1H-pyrazole-3-carbaldehyde was used in the first step instead of 1-methyl-1H-pyrazole-3-carbaldehyde. Compound 128: MS (ESI) M/z 427.36 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ12.58(brs,1H),9.93(s,1H),9.67(s,1H),8.72(s,1H),8.69(s,1H),8.52(d,J＝2.6Hz,1H),7.89(dd,J＝8.4,2.6Hz,1H),7.82–7.75(m,2H),7.59(s,1H),7.23(d,J＝8.4Hz,1H),6.77(d,J＝8.3Hz,1H),6.17(d,J＝2.1Hz,1H),4.38(s,2H),3.46(t,J＝8.5Hz,2H),2.98(t,J＝8.4Hz,2H),2.43(s,3H).
Example 43
Synthesis of 1- (6- (1- ((1-methyl-1H-pyrazol-5-yl) methyl) indol-5-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000682
synthesis of compound 129 the same procedure used in example 127 was followed, the first step being the use of 1-methyl-1H-pyrazole-5-carbaldehyde instead of 1-methyl-1H-pyrazole-3-carbaldehyde. Compound 129: MS (ESI) M/z 441.33 (M + H) + ； 1 H NMR(400MHz,MeOD)δ8.58(s,1H),8.56(d,J＝2.4Hz,1H),8.46(s,1H),8.03(dd,J＝8.5,2.7Hz,1H),7.80(d,J＝5.8Hz,2H),7.40(d,J＝1.9Hz,1H),7.30(d,J＝8.4Hz,1H),6.79(d,J＝8.8Hz,1H),6.26(d,J＝1.9Hz,1H),4.45(s,2H),3.88(s,3H),3.40(t,J＝8.4Hz,2H),3.07(t,J＝8.3Hz,2H),2.50(s,3H).
Example 44
Synthesis of 1- (6- (1-isobutyl-1H-indazol-5-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000683
the first step is as follows: 5-bromo-1H-indazole (200mg, 1.02mmol, 1.0equiv.) and potassium carbonate (211mg, 1.53mmol, 1.5equiv.) were placed in a two-port reaction flask, then 10mL of DMF was added, and finally bromoisobutane (210mg, 1.53mmol, 1.5equiv.) was added dropwise with stirring. The reaction solution was heated to 120 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, 10mL of distilled water was added, followed by extraction with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (PE: EA = 10) to give compound 130a (154 mg, yield: 59.9%). MS (ESI): M/z 252.8 (M + H) + ； 1 H NMR(400MHz,CDCl 3 ):δ7.93(d,J＝0.8Hz,1H),7.86(dd,J＝2.0,0.4Hz,1H),7.43(dd,J＝8.8,2.0Hz,1H),7.28(d,J＝8.8Hz,1H),4.15(d,J＝7.2Hz,2H),2.38-2.27(m,1H),0.91(d,J＝6.8Hz,6H).
The second step is that: compound 130a (130mg, 0.52mmol, 1.0equiv.), pinacol diboron ester (197mg, 0.77mmol, 1.5equiv.), potassium acetate (101mg, 1.03mmol, 2.0equiv.), and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (37mg, 0.05mmol, 0.1equiv.) was added to a dioxane (10 mL) solution and the reaction stirred at 100 ℃ for 5 hours under nitrogen. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was chromatographed on flash silica gel (PE: EA = 10). MS (ESI) M/z301.0 (M + H) + ； 1 H NMR(400MHz,CDCl 3 ):δ8.27(s,1H),8.00(s,1H),7.78(d,J＝8.4Hz,1H),7.38(d,J＝8.4Hz,1H),4.17(d,J＝7.2Hz,2H),2.34-2.29(m,1H),1.37(s,12H),0.91(d,J＝6.8Hz,6H).
The third step: to a solution of compound 130b (70mg, 0.24mmol,1.0 equiv.) in 1,4-dioxane (10 mL) under nitrogen, intermediate A (71mg, 0.27mmol,1.1 equiv.) and [1,1' -bis (diphenylphosphino) ferrocene were added]Palladium dichloride (17.1mg, 0.023mmol, 0.1equiv.), and finally an aqueous solution (1 mL) of sodium carbonate (59mg, 0.49mmol,2.0 equiv.) were added. The reaction solution was heated to 100 ℃ and stirred for 16 hours. LCMS shows the reaction is complete, the reaction solution is cooled to room temperature, concentrated, the residue is added with water (20 mL), extracted with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, the filtrate is concentrated, and the residue is purified by chromatographySeparation by flash chromatography on silica gel (DCM: meOH = 15) gave the title compound 130 (35.54 mg, yield: 36.8%). MS (ESI) M/z 402.2 (M + H) + ； 1 H NMR(400MHz,CDCl 3 ):δ9.86(s,1H),9.84(s,1H),8.94(s,1H),8.89(s,1H),8.53–8.51(m,2H),8.21(s,1H),8.11(d,J＝8.8Hz,1H),7.89(dd,J＝8.0,2.4Hz,1H),7.85(d,J＝8.8Hz,1H),7.23(d,J＝8.4Hz,1H),4.26(d,J＝7.2Hz,2H),2.42(s,3H),2.28-2.21(m,1H),0.87(d,J＝6.4Hz,6H).
Example 45
Synthesis of 1- {6- [1- (2-cyano-2, 2-dimethylethyl) -2, 3-dihydro-1H-indol-5-yl ] pyrazin-2-yl } -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000691
the first step is as follows: reacting 5-bromo-1- [ (3- { [ (tert-butyldiphenylsilyl) oxy)]Methyl } oxoalk-3-yl) methyl]-2, 3-dihydro-1H-indole (180mg, 0.64mmol, 1eq), pinacol diboron (327.45mg, 1.29mmol, 2eq), potassium acetate (158.19mg, 1.61mmol, 2.5eq) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (93.66mg, 0.128mmol, 0.2eq) was dissolved in 3mL of 1,4-dioxane, and the mixture was stirred at 85 ℃ for 3 hours after replacement of nitrogen. LCMS showed the reaction was complete, filtered over celite, the filtrate was concentrated, and separated by flash silica gel chromatography (PE: EA = 100. MS (ESI): M/z 327.2 (M + H) + 。
The second step is that: compound 131a (50mg, 0.153mmol, 1eq) and intermediate A (80.82mg, 0.307mmol, 2eq), sodium carbonate (32.54mg, 0.307mmol, 2eq) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (22.46mg, 0.0307mmol, 0.2eq) was added to a mixed solution of dioxane (2 mL) and water (0.2 mL), nitrogen gas was replaced, and the reaction solution was heated to 100 ℃ and stirred for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated by rotary evaporation, dissolved in 3mL of N, N-dimethylformamide, filtered again, and purified by reverse phase preparative chromatography pre-HPLC to give the title compound 131 (37.1 mg, yield: 25.7%). MS (ESI) M/z 428.2 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ9.93(s,1H),9.69(s,1H),8.75(s,1H),8.72(s,1H),8.54(d,J＝2.4Hz,1H),7.92(dd,J＝8.4,2.4Hz,1H),7.82-7.78(m,2H),7.27(d,J＝8.4Hz,1H),6.78(d,J＝9.2Hz,1H),3.69(t,J＝8.8Hz,2H),3.36(s,2H),3.08(t,J＝8.4Hz,2H),2.44(s,3H),1.40(s,6H).
Example 46
Synthesis of 3- (6- { 7-fluoro-1- [ (3-methyloxetan-3-yl) methyl ] -2, 3-dihydro-1H-indol-5-yl } pyrazin-2-yl) -1- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000701
the first step is as follows: 7-fluoro-1H-indole (3g, 22.2mmol, 1equ.) was added to acetic acid (22 mL) and sodium cyanoborohydride (2.79g, 44.4mmol, 2equ.) was added portionwise. The reaction was allowed to proceed overnight at room temperature, LCMS showed completion, the reaction system was poured into NaOH solution (2M, 270ml), extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and subjected to flash chromatography on silica gel (PE) to give compound 132a (1914 mg, yield: 62.9%). MS (ESI) M/z 138.07 (M + H) + ； 1 H NMR(400MHz,CDCl3)δ6.90(dd,J＝7.3,0.9Hz,1H),6.82–6.77(m,1H),6.63(ddd,J＝8.1,7.4,4.7Hz,1H),3.61(t,J＝8.4Hz,2H),3.07(t,J＝8.4Hz,2H).
The second step is that: compound 132a (1.5 g,10.94mmol, 1equiv.) was added to acetonitrile (80 mL), and a solution of N-bromosuccinimide (1.95g, 10.94mmol, 1equiv.) in acetonitrile (15 mL) was added dropwise under ice-cooling, followed by reaction at room temperature for 2 hours. LCMS showed the reaction was complete, the solvent was dried and flash chromatography on silica gel (PE: EA = 33. MS (ESI) M/z 216.04 (M + H) + ； 1 H NMR(400MHz,CDCl3)δ7.01(dd,J＝1.6,0.8Hz,1H),6.99–6.91(m,1H),3.62(t,J＝8.5Hz,2H),3.06(t,J＝8.5Hz,2H).
The third step: compound 132b (500mg, 2.31mmol, 1equiv.), 3-methyloxetane-3-carbaldehyde (348mg, 3.47mmol, 1equiv.), acetic acid (1 mL) was added to methanol (20 mL), followed by addition of sodium cyanoborohydride (727mg, 11.57mmol, 5equiv.) in portions. The reaction system is stirred at room temperatureAnd (4) at night. LCMS showed the reaction was complete, and water (50 mL) was added to quench the reaction, the organic solvent was dried, then extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by flash chromatography on silica gel to give compound 132c (304 mg, yield: 43.8%). 1 H NMR(400MHz,CDCl3)δ7.03–6.84(m,2H),4.61(d,J＝5.8Hz,2H),4.38(d,J＝5.8Hz,2H),3.46(s,2H),3.37(t,J＝8.7Hz,2H),3.02(t,J＝8.6Hz,2H),1.42(s,3H).
The fourth step: compound 132c (304mg, 1.01mmol, 1equiv.), pinacol diboron (309mg, 1.22mmol, 1.2equiv.), pd (dppf) Cl2 (148mg, 0.203mmol, 0.2equiv.), and potassium acetate (398mg, 4.05mmol, 4equiv.) were added to 1,4-dioxane (20 mL). The reaction system was purged with nitrogen three times and stirred at 90 ℃ for 8 hours. LCMS showed the reaction was complete, the solvent was dried, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by filtration, and separated by flash chromatography on silica gel (PE: EA =33 1-20) to give compound 132d (200 mg, yield: 56.9%). MS (ESI): M/z 348.28 (M + H) + ； 1 H NMR(400MHz,CDCl3)δ7.03(s,1H),6.94(s,1H),4.64(d,J＝5.7Hz,2H),4.37(d,J＝5.7Hz,2H),3.39(s,2H),3.23(t,J＝8.7Hz,2H),2.96(t,J＝8.6Hz,2H),2.25(s,3H),1.49(s,3H).
The fifth step: compound 132d (100mg, 0.288mmol, 1equiv.), intermediate A (84mg, 0.32mmol, 1.1equiv.), pd (dppf) Cl2 (21mg, 0.029mmol, 0.1equiv.), and potassium carbonate (80mg, 0.58mmol, 2equiv.) were added to 1,4-dioxane (6 mL) and water (1.5 mL). The reaction system was purged with nitrogen three times and stirred at 90 ℃ for 4 hours. LCMS showed the reaction was complete, the solvent was dried, and flash chromatography on silica gel (DCM: meOH = 15). MS (ESI) M/z 449.32 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ9.74(s,1H),9.66(s,1H),8.80(s,1H),8.73(s,1H),8.51(s,1H),7.89(d,J＝8.5Hz,1H),7.64(d,J＝13.0Hz,2H),7.23(d,J＝8.3Hz,1H),4.52(d,J＝5.5Hz,2H),4.27(d,J＝5.5Hz,2H),3.54(s,2H),3.47(t,J＝8.6Hz,2H),3.09(t,J＝8.5Hz,2H),2.43(s,3H),1.36(s,3H).
Example 47
Synthesis of 3- { imidazo [1,2-a ] pyridin-7-yl } -1- (6- {1- [ (3-methyloxyethan-3-yl) methyl ] -2, 3-dihydro-1H-indol-5-yl } pyrazin-2-yl) urea:
Figure BDA0003769482940000711
under the protection of nitrogen and with stirring, compound 60d (182.77mg, 0.62mmol, 1.0eq.), imidazo [1,2-a ] was added]To a solution of pyridine-7-carboxylic acid (150mg, 0.93mmol, 1.5eq.) and azido diphenyl phosphate (254.57mg, 0.93mmol, 1.5eq.) in toluene (5.0 mL) was added triethylamine (187.21mg, 1.85mmol, 3.0eq.). The reaction was stirred at 110 ℃ for 16 h, LCMS showed complete reaction, solvent was spun dry, and separated by TLC plate (dichloromethane: methanol =8 f = 0.5) to obtain the title compound 133 (8.63 mg, yield: 3.2%). MS (ESI) M/z 456.2 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ10.04(s,1H),9.68(s,1H),8.77(s,1H),8.71(s,1H),8.49(d,J＝7.6Hz,1H),7.83-7.80(m,4H),7.46(s,1H),6.93-6.88(m,1H),6.63(d,J＝8.8Hz,1H),4.50(d,J＝5.6Hz,2H),4.29(d,J＝5.6Hz,2H),3.47(t,J＝8.8Hz,2H),3.37(s,2H),3.06(t,J＝8.4Hz,2H),1.34(s,3H).
Example 48
Synthesis of 1- (6- (1- (2-hydroxypropyl) -1H-indazol-5-yl) pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000712
compound 134 was synthesized as in example 118, substituting 5-bromo-1H-indazole for 5-bromoindoline in the first step. Compound 134: MS (ESI) M/z 404.2 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ9.76(s,2H),8.94(s,1H),8.91(s,1H),8.52(d,J＝2.8Hz,1H),8.51(s,1H),8.20(s,1H),8.11(dd,J＝8.8,1.6Hz,1H),7.91(dd,J＝8.4,2.6Hz,1H),7.84(d,J＝8.8Hz,1H),7.24(d,J＝8.4Hz,1H),4.92(d,J＝4.8Hz,1H),4.41–4.31(m,2H),4.14-4.08(m,1H),2.43(s,3H),1.10(d,J＝6.4Hz,3H).
Example 49
Synthesis of 1- (6- {1- [ (3S, 4S) -4-hydroxy-1-methylpyrrolidin-3-yl ] -2, 3-dihydro-1H-indol-5-yl } pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000721
compound 50 (30mg, 0.07mmol, 1equiv.), sodium triacetoxyborohydride (42mg, 0.198, 3eq), aqueous formaldehyde (0.3ml, 37wt.% in H 2 O) was added to the methanol solution (3 mL) in turn, under nitrogen, and stirred at 25 ℃ for 1 hour. LCMS indicated complete reaction and flash chromatography on silica gel afforded the title compound 135 (4.91 mg, yield: 15.7%). MS (ESI) M/z 446.3 (M + H) + ； 1 H NMR(400MHz,DMSO-d6):δ9.95(s,1H),9.67(s,1H),8.72(s,1H),8.68(s,1H),8.51(d,J＝2.4Hz,1H),7.90-7.88(m,1H),7.78-7.76(m,2H),7.23(d,J＝8.4Hz,1H),6.71(d,J＝8.4Hz,1H),5.18(s,1H),4.25-4.23(m,1H),3.92-3.88(m,1H),3.57-3.52(m,2H),2.98(t,J＝8.4Hz,2H),2.87-2.83(m,1H),2.72-2.62(m,2H),2.43(s,3H),2.28-2.25(m,1H),2.23(s,3H).
Example 50
Synthesis of 3- (6- { 7-methyl-1- [ (3-methyloxetan-3-yl) methyl ] -2, 3-dihydro-1H-indol-5-yl } pyrazin-2-yl) -1- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000722
the first step is as follows: 7-methyl-1H-indole (2g, 15.25mmol, 1equiv.) was added to acetic acid (15 mL) and sodium cyanoborohydride (1.92g, 30.49mmol, 2equiv.) was added in portions. The reaction was allowed to react overnight at room temperature, LCMS showed completion, the reaction was quenched by pouring into aqueous NaOH (190ml, 2m), extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and separated by flash chromatography on silica gel (PE: EA =33: 1) to give compound 136a (1678 mg, yield: 91.8%). MS (ESI) M/z 134.12 (M + H) + ； 1 H NMR(400MHz,CDCl3)δ7.01(d,J＝7.3Hz,1H),6.88(d,J＝7.5Hz,1H),6.68(t,J＝7.4Hz,1H),3.58(t,J＝8.4Hz,2H),3.07(t,J＝8.4Hz,2H),2.16(s,3H).
The second step is that: compound 136a (1.678g, 12.60mmol, 1equiv.) was added to acetonitrile (80 mL), and a solution of N-bromosuccinimide (2.24g, 12.60mmol, 1equiv.) in acetonitrile (30 mL) was added dropwise under ice-cooling, and the mixture was reacted at room temperature for 2 hours. LCMS showed completion of the reaction, solvent was dried by rotation, and flash column chromatography gave compound 136b (1401 mg, yield: 52.4%). MS (ESI) M/z 212.06 (M + H) + ； 1 H NMR(400MHz,CDCl3)δ7.07(s,1H),6.98(s,1H),3.58(m,2H),3.05(m,2H),2.09(s,3H).
The third step: compound 136b (1.2g, 5.66mmol, 1equiv.), 3-methyloxetane-3-carbaldehyde (850mg, 8.49mmol, 1.5equiv.) was added to methanol (50 mL), and sodium cyanoborohydride (711mg, 11.32mmol, 2equiv.) was added in portions and reacted at room temperature for 4 hours. LCMS shows the reaction is complete, water (50 mL) is added to quench the reaction, organic solvent is spun off, extracted with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, the filtrate is concentrated, and the residue is chromatographed on flash silica gel to give compound 136c (587 mg, yield: 35%). MS (ESI) M/z 296.11 (M + H) + ； 1 H NMR(400MHz,CDCl3)δ7.03(s,1H),6.94(s,1H),4.64(d,J＝5.7Hz,2H),4.37(d,J＝5.7Hz,2H),3.39(s,2H),3.23(t,J＝8.7Hz,2H),2.96(t,J＝8.6Hz,2H),2.25(s,3H),1.49(s,3H).
The fourth step: compound 136c (323mg, 1.09mmol, 1equiv.), pinacolate diboron (332mg, 1.31mmol, 1.2equiv.), pd (dppf) Cl2 (160mg, 0.218mmol, 0.2equiv.), and potassium acetate (428mg, 4.36mmol, 4equiv.) were added to 1,4-dioxane (20 mL). The reaction system was purged with nitrogen three times and stirred at 90 ℃ for 8 hours. LCMS showed the reaction was complete, after solvent was dried, dissolved in water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and separated by flash chromatography on silica gel (PE: EA =20: 1-15) to give compound 136d (174 mg, yield: 46%). MS (ESI) M/z 344.36 (M + H) + ； 1 H NMR(400MHz,CDCl3)δ7.39(s,1H),7.32(s,1H),4.65(d,J＝5.7Hz,2H),4.38(d,J＝5.8Hz,2H),3.53(s,2H),3.31–3.19(m,2H),2.97(t,J＝8.7Hz,2H),2.30(s,3H),1.48(s,3H),1.32(s,12H).
The fifth step: compound 136d (174mg, 0.51mmol, 1equiv.), intermediate A (147mg, 0.56mmol, 1.1equiv.), pd (dppf) Cl 2 (37mg, 0.05mmol, 0.1equiv.), and potassium carbonate (140mg, 1.01mmol, 2equiv.) were added to 1,4-dioxane (8 mL) and water (2 mL). The reaction system was purged with nitrogen three times and stirred at 90 ℃ for 4 hours. LCMS showed the reaction was complete, the solvent was spun off, and flash chromatography on silica gel (DCM: meOH = 15). MS (ESI): M/z 445.37 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ10.01(s,1H),9.72(s,1H),8.70(s,1H),8.69(s,1H),8.53(d,J＝2.5Hz,1H),7.90(dd,J＝8.4,2.7Hz,1H),7.64(s,1H),7.58(s,1H),7.24(d,J＝8.4Hz,1H),4.56(s,1H),4.54(s,1H),4.28(s,1H),4.26(s,1H),3.55(s,2H),3.30(t,J＝8.7Hz,2H),3.00(t,J＝8.7Hz,2H),2.43(s,3H),2.34(s,3H),1.41(s,3H).
Example 51
Synthesis of 1- (6-methylpyridin-3-yl) -3- (6- (1- ((3-methyltetrahydrofuran-3-yl) methyl) indol-5-yl) pyrazin-2-yl) urea:
Figure BDA0003769482940000731
the first step is as follows: a solution of benzyl 3-methyloxazolidine-3-carboxylate (1g, 4.54mmol,1.0 equiv.) in tetrahydrofuran (10 mL) was slowly added dropwise under nitrogen to a solution of lithium aluminum hydride (431mg, 11.4mmol,2.5 equiv.) in tetrahydrofuran (10 mL) at-78 ℃ in a dry ice/acetone bath. The temperature was slowly raised to 25 ℃ and the reaction was stirred for 24 hours. LCMS showed the reaction was complete, water (20 mL) was slowly added dropwise, extracted with ethyl acetate, the organic phase was dried over sodium sulfate, concentrated, and the residue was separated by flash chromatography on silica gel (PE/EA = 1/1) to give compound 137a (700 mg, yield: 74.8%). 1 H NMR(400MHz,CDCl 3 )：δ7.40–7.30(m,5H),4.70(s,2H),3.93–3.84(m,2H),3.73(d,J＝8.4Hz,1H),3.49(s,2H),3.39(d,J＝8.4Hz,1H),1.90–1.85(m,1H),1.67–1.63(m,1H),1.15(s,3H).
The second step is that: in a solution of compound 137a (1.2g, 5.82mmol,1.0 equiv.) in ethanol (10 mL), N 2 10% Palladium on carbon (200 mg.), H, was added with protection 2 The reaction was stirred at 25 deg.C for 15 hours (15 psi). LCMS shows complete reaction, the reaction solution is filtered, the filtrate is concentrated, and compound 137b is isolated by flash chromatography on silica gel (450 mg, yield: 66.6%). 1 H NMR(400MHz,CDCl 3 )：δ3.93–3.81(m,2H),3.73(d,J＝8.8Hz,1H),3.51(s,2H),3.39(d,J＝8.8Hz,1H),1.90-1.83(m,1H),1.65–1.62(m,1H),1.13(s,3H).
The third step: to a solution of compound 137b (200mg, 1.72mmol,1.0 equiv.) in dichloromethane (10 mL) was added dess-martin reagent (1.46g, 3.33mmol,2.0 equiv.), and the reaction was stirred at 25 ℃ for 2 hours. LCMS showed reaction completion, the reaction was filtered, the filtrate was concentrated, and the residue was purified by flash silica gel chromatography (PE/EA = 1/1) to obtain compound 137c (30 mg, yield: 15.1%). 1 H NMR(400MHz,CDCl 3 ):δ9.57(s,1H),4.09(d,J＝9.2Hz,1H),3.95–3.85(m,2H),3.47(d,J＝9.2Hz,1H),2.35–2.28(m,1H),1.75–1.69(m,1H),1.24(s,3H).
The fourth step: to a solution of compound 137c (150mg, 1.31mmol,1.0 equiv.) in dichloromethane (5 mL) were added 5-bromoindole (260mg, 1.31mmol,1.0 equiv.), glacial acetic acid (8mg, 0.13mmol, 0.1equiv.), sodium triacetoxyborohydride (610mg, 2.62mmol,2.0 equiv.), and the reaction was stirred at 25 ℃ for 15 hours. LCMS showed completion of the reaction, the reaction was concentrated, and the residue was separated by flash chromatography on silica gel (PE/EA = 2/1) to obtain compound 137d (35 mg, yield: 9.0%). MS (ESI) M/z 298.0 (M + H) + .
The fifth step: to 1,4-dioxane (10 mL) of compound 137d (50mg, 0.17mmol, 1.0equiv.) was added diboron pinacol ester (64mg, 0.25mmol, 1.5equiv.), potassium acetate (42mg, 0.43mmol, 2.5equiv.), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (14mg, 0.02mmol, 0.1equiv.). Stirring was carried out at 100 ℃ for 3 hours under nitrogen. LCMS showed completion of the reaction, the reaction was filtered, the filtrate was concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 3/1) to give compound 137e (40 mg, yield: 69.0%). MS (ESI) M/z 343.4 (M + H) + .
And a sixth step: to compound 137e (40mg, 0.12mmol,1.0 equiv.) in 1,4-dioxane (10 mL) and water (1 mL) was added intermediate A (R)37mg,0.14mmol, 1.2equiv.), sodium carbonate (31mg, 0.29mmol, 2.5equiv.), and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (8mg, 0.01mmol, 0.1equiv.). Stirring was carried out at 100 ℃ for 3 hours under nitrogen. LCMS showed reaction complete, reaction filtered and filtrate concentrated. The residue was purified by preparative reverse phase chromatography pre-HPLC to give the title compound 137 (20 mg, yield: 34.3%). MS (ESI) M/z 444.8 (M + H) + ； 1 H NMR(400MHz,DMSO-d6):δ9.95(s,1H),9.68(s,1H),8.72(s,1H),8.69(s,1H),8.54(d,J＝2.4Hz,1H),7.92(dd,J＝8.4,2.8Hz,1H),7.79-7.77(m,2H),7.26(d,J＝8.4Hz,1H),6.60(d,J＝8.8Hz,1H),3.88-3.76(m,2H),3.59-3.52(m,3H),3.39-3.37(m,1H),3.17-3.11(m,2H),3.05(t,J＝8.8Hz,2H),2.44(s,3H),1.88-1.78(m,1H),1.74-1.65(m,1H),1.13(s,3H).
Example 52
Synthesis of 1- (6- (hydroxymethyl) pyridin-3-yl) -3- (6- (1- ((3-methyloxan-3-yl) methyl) indol-5-yl) pyrazin-2-yl) urea:
Figure BDA0003769482940000751
the first step is as follows: to a solution of the compound methyl 6- (hydroxymethyl) nicotinate (500mg, 2.99mmol, 1.0eq.) and Imidazole (Imidazole, 610.91mg,8.97mmol, 3.0eq.) in N, N-dimethylformamide (5.0 mL) was added tert-butyldiphenylchlorosilane (1.23g, 4.49mmol, 1.5eq.). The reaction was stirred at 30 ℃ for 16 hours, LCMS showed completion of the reaction, and the reaction was concentrated and purified by flash chromatography on silica gel (ethyl acetate/petroleum ether = 1/10) to obtain compound 138a (1.0 g, yield: 82%). 1 H NMR(400MHz,CDCl 3 )δ9.07(d,J＝1.6Hz,1H),8.35(dd,J＝8.4,2.0Hz,1H),7.79(d,J＝8.0Hz,1H),7.75–7.60(m,4H),7.46–7.42(m,1H),7.42–7.40(m,1H),7.37–7.30(m,4H),4.92(s,2H),3.95(s,3H),1.14(s,9H).
The second step is that: to a solution of compound 138a (200mg, 0.49mmol,1.0 eq.) in tetrahydrofuran (3.0 mL) and methanol (3.0 mL) was added a solution of lithium hydroxide monohydrate (62.14mg, 1.47mmol,3.0 eq.) in water (3.0 mL). The reaction solution is stirred and reacted for 2 hours at the temperature of 0DEG CThe reaction was run through TLC plate (ethyl acetate/petroleum ether =1/10 f =0.4, disappearance of starting material). After completion of the reaction, the reaction mixture was concentrated to obtain crude compound 138b (300 mg). MS (ESI): M/z 391.8 (M + H) + .
The third step: triethylamine (193.6 mg,1.9mmol, 5.0eq.) was added to a solution of the compound 138b (150mg, 0.38mmol, 1.0eq.) and the compound 60d (105.43mg, 0.38mmol, 1.0eq.) in toluene (5.0 mL) with stirring under nitrogen protection. The reaction was stirred at 110 ℃ for 16 h, LCMS showed completion, and the reaction was cooled to room temperature. The reaction solution was concentrated and purified by flash chromatography on silica gel (ethyl acetate/petroleum ether = 1/1) to obtain compound 138c (35 mg, yield: 13%). MS (ESI): M/z 684.8 (M + H) + ； 1 H NMR(400MHz,CDCl 3 )δ11.93(s,1H),9.48(s,1H),8.56(s,1H),8.49(d,J＝2.4Hz,1H),8.41(dd,J＝8.4,2.4Hz,1H),8.20(s,1H),7.73–7.66(m,7H),7.43–7.36(m,6H),6.56(d,J＝8.4Hz,1H),4.87(s,2H),4.60(d,J＝6.0Hz,2H),4.45(d,J＝6.0Hz,2H),3.53(t,J＝8.6Hz,2H),3.37(s,2H),3.14(t,J＝8.6Hz,2H),1.43(s,3H),1.15(s,9H).
The fourth step: to a solution of compound 138c (30mg, 0.04mmol,1.0 eq.) in tetrahydrofuran (1.0 mL) was added tetrabutylammonium fluoride in tetrahydrofuran (0.08mL, 0.08mmol,2.0 eq.) under nitrogen protection. The reaction was stirred at 20 ℃ for 1 hour, LCMS showed completion of the reaction, the reaction was filtered, and the filtrate was concentrated and purified by reverse phase preparative chromatography pre-HPLC to give the title compound 138 (11.46 mg, yield: 64.2%). MS (ESI) M/z 446.8 (M + H) + ； 1 H NMR(400MHz,DMSO-d 6 )：δ10.04(s,1H),9.72(s,1H),8.74(s,1H),8.70(s,1H),8.63(s,1H),8.05(dd,J＝8.4,2.0Hz,1H),7.81-7.76(m,2H),7.51(d,J＝8.8Hz,1H),6.63(d,J＝8.8Hz,1H),4.57(s,2H),4.49(d,J＝6.0Hz,2H),4.29(d,J＝5.6Hz,2H),3.50-3.36(m,4H),3.04(t,J＝8.4Hz,2H),1.34(s,3H).
Example 53
Synthesis of 1- (6- ((methylamino) methyl) pyridin-3-yl) -3- (6- (1- ((3-methyloxetan-3-yl) methyl) indolin-5-yl) pyrazin-2-yl) urea:
Figure BDA0003769482940000761
the first step is as follows: 6-formylpyridine-3-carboxylic acid methyl ester (500mg, 3.03mmol, 1equiv.) was added to methanol (20 mL), methylamine hydrochloride (224.86mg, 3.33mmol, 1.1equiv.) was added thereto, and after stirring for five minutes, sodium cyanoborohydride (382mg, 6.06mmol, 2equiv.) was added thereto, and after nitrogen substitution, stirring was carried out for ten minutes at 30 ℃. Saturated aqueous ammonium chloride (10 mL) was added, followed by di-tert-butyl dicarbonate (1.98g, 9.08mmol, 3equiv.) and stirring at 30 ℃ for 8 hours. Water (10 mL) and ethyl acetate (30 mL) were added to the reaction solution, and after separation, the organic phase was washed with saturated brine, and after concentration, was separated by flash silica gel chromatography (PE: EA = 5) to obtain compound 139a (320 mg, yield: 37.7%). MS (ESI) M/z 281.0 (M + H) + .
The second step: compound 139a (320mg, 1.14mmol, 1equiv.) was dissolved in methanol (5 mL)/tetrahydrofuran (5 mL), and lithium hydroxide monohydrate (143.5mg, 3.42mmol, 3equiv.) was dissolved in water (2.5 mL), and the mixture was added to the above system, and after nitrogen substitution, stirring was performed at 30 ℃ for 1 hour. The reaction solution was directly spin-dried to obtain crude compound 139b (lithium salt). MS (ESI) M/z 267.0 (M + H) + Used directly in the next step.
The third step: after adding compound 60d (350mg, 1.18mmol, 1equiv.), compound 139b (314.48 mg), and triethylamine (596mg, 5.9mmol, 5equiv.), to toluene (5 mL), diphenyl phosphorazidate (325mg, 1.18mmol, 1equiv.) was added dropwise, and the mixture was stirred at 110 ℃ for 4 hours after replacement with nitrogen gas. The reaction solution was subjected to reverse phase preparative chromatography Pre-HPLC) to separate and purify the reaction solution to obtain compound 139c (70 mg, yield: 10.6%). MS (ESI): M/z 560.8 (M + H) + .
The fourth step: compound 139c (70mg, 0.13mmol, 1equiv.) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise, followed by stirring at room temperature for half an hour at 30 ℃. The reaction solution was filtered, and the filtrate was purified by separation by preparative reverse phase chromatography pre-HPLC to give the title compound 139 (4.54 mg, yield: 7.3%). MS (ESI) M/z 460.2 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ10.02(s,1H),9.75(s,1H),8.93(s,1H),8.79(s,1H),8.77(d,J＝2.4Hz,1H),8.72(s,1H),8.10–8.00(m,1H),7.85–7.75(m,2H),7.48(d,J＝8.0Hz,1H),6.62(d,J＝8.0Hz,1H),4.55–4.45(m,2H),4.32–4.28(m,2H),4.26(s,2H),3.46(t,J＝8.0Hz,2H),3.37(s,2H),3.04(t,J＝8.0Hz,2H),2.63(s,3H),1.34(s,3H).
Example 54
Synthesis of 1-methyl-3- (6- (1- ((3-methyloxycyclohexan-3-yl) methyl) indol-5-yl) pyrazin-2-yl) -1- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000771
the first step is as follows: 6-methylpyridin-3-amine (1.00g, 9.25mmol, 1equiv.) and formaldehyde (833.09mg, 27.74mmol, 3equiv.) were dissolved in 20mL of methanol under nitrogen, and sodium methoxide (2.49g, 46.24mmol, 5equiv.) was added to the reaction mixture in portions, followed by heating to 50 ℃ and stirring for 16 hours. Then, sodium borohydride (1.05g, 27.74mmol,3 equiv.) was added in portions to the reaction solution under ice bath, and then the reaction was stirred at 30 ℃ for 5 hours. LCMS showed the reaction was complete, quenched with 20mL of water, then extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and purified by flash chromatography on silica gel (DCM: meOH = 19) to afford compound 140a (450 mg, yield: 39.8%). MS (ESI): M/z 123.2 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ7.80(d,J＝2.8Hz,1H),6.94(d,J＝8.4Hz,1H),6.79(dd,J＝8.4,2.8Hz,1H),5.58(s,1H),2.65(d,J＝5.2Hz,3H),2.28(s,3H).
The second step: under nitrogen protection, compound 140a (50.00mg, 0.41mmol, 1equiv.) and 4-nitrophenylcarbonyl chloride (164.98mg, 0.82mmol, 2equiv.) were placed in a 25mL two-necked flask, then 5mL of THF was added, and finally triethylamine (207.07mg, 2.05mmol, 5equiv.) was added dropwise to the reaction mixture, and the reaction was stirred at 30 ℃ for 3 hours. LCMS showed the reaction was complete, the reaction was concentrated and purified by TLC large plate (PE: EA = 1. MS (ESI): M/z 287.8 (M + H) + ； 1 H NMR(400MHz,CDCl 3 )δ8.54-8.52(m,1H),8.24-8.22(m,2H),7.56(s,1H),7.26–7.21(m,3H),3.41(s,3H),2.59(s,3H).
The third step: compound 60d (70.00mg, 0.24mmol, 1equiv.) was dissolved in 2mL of DMF under nitrogen, and sodium hydride (30.00mg, 0.71mmol,3equiv, 60%) was added to the reaction solution, and after stirring for 5 minutes, compound 140b (81.42mg, 0.28mmol, 1.2equiv.) was added to the reaction solution, and the reaction was stirred at 30 ℃ for 5 hours. LCMS showed the reaction was complete, and the reaction was quenched by addition of two drops of water and purified by reverse phase preparative chromatography pre-HPLC to give the title compound 140 (5.38 mg, yield: 5.1%). MS (ESI) M/z 445.2 (M + H) + ； 1 H NMR(400MHz,MeOD)δ8.84(s,1H),8.45(s,1H),8.36(d,J＝2.4Hz,1H),7.64(dd,J＝8.4,2.4Hz,1H),7.57(d,J＝8.8Hz,2H),7.29(d,J＝8.3Hz,1H),6.40(d,J＝8.0Hz,1H),4.52(d,J＝6.0Hz,2H),4.30(d,J＝6.0Hz,2H),3.37(t,J＝8.4Hz,2H),3.27(s,3H),3.22-3.20(m,2H),2.91(t,J＝8.4Hz,2H),2.47(s,3H),1.30(s,3H).
Example 55
Synthesis of 1- (6- {1- [ (3S, 4R) -4-hydroxyoxazolidin-3-yl ] -2, 3-dihydro-1H-indol-5-yl } pyrazin-2-yl) -3- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000781
the first step is as follows: 5-bromo-2, 3-dihydro-1H-indole (2g, 10.1mmol, 1equiv.) was dissolved in tetrahydrofuran (40 mL), sodium hydride (60%, 808mg,20.2mmol, 2.0equiv.) was added under ice-bath, and after stirring for 30 minutes, 3, 6-dioxabicyclo [3.1.0 ] was added]Hexane (1.3g, 15.15mmol, 1.5equiv.) was substituted with nitrogen, and the mixture was heated to 90 ℃ and stirred for 6 hours. LCMS showed the reaction was complete, and water (10 mL) was added to the reaction solution to quench, followed by extraction with ethyl acetate, and the organic phases were combined, backwashed with saturated brine, then dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and separated by flash chromatography on silica gel (PE: EA = 1) to obtain compound 141a (2.4 g, yield: 83.6%). MS (ESI) M/z =286.0 (M + H) + ； 1 H NMR(400MHz,CDCl 3 )δ7.19–7.12(m,2H),6.45–6.39(m,1H),4.50–4.40(m,1H),4.15–4.02(m,2H),4.01–3.95(m,1H),3.94–3.88(m,1H),3.72(dd,J＝10.8,3.2Hz,1H),3.52-3.36(m,2H),2.94(t,J＝8.4Hz,2H).
The second step is that: compound 141a (1g, 3.52mmol, 1equiv.) is dissolved in 1,4-dioxane (15 mL), and pinacol diboron ester (1.34g, 5.28mmol, 1.5equiv.), potassium acetate (862mg, 8.8mmol, 2.5equiv.) and [1,1' -bis (diphenylphosphino) ferrocene ] are added]Palladium dichloride (256mg, 0.35mmol, 0.1equiv.) was purged with nitrogen and then stirred at 100 ℃ for 3 hours. LCMS showed the reaction was complete, the reaction was filtered, the filtrate was concentrated, and then separated by flash silica gel column chromatography (PE: EA = 10) to give compound 141b (1.3 g, yield: 66.1%). MS (ESI): M/z 332.2 (M + H) + .
The third step: compound 141b (100mg, 0.3mmol, 1equiv.), intermediate a (119.42mg, 0.45mmol, 1.5equiv.), and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (44mg, 0.06mmol, 0.2eq) and anhydrous sodium carbonate (96mg, 0.90mmol, 3.0eq) were sequentially added to a mixed solution of dioxane/water (10 mL/1 mL), and the mixture was heated to 100 ℃ under nitrogen protection and stirred for 16 hours. LCMS showed the reaction was complete, the reaction was concentrated, and the residue was purified by reverse phase preparative chromatography Prep-HPLC to give the title compound 141 (22 mg, yield: 17.0%). MS (ESI) M/z 432.8 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)(EN1078-156-P):δ9.98(s,1H),9.67(s,1H),8.73(s,1H),8.70(s,1H),8.51(d,J＝2.8Hz,1H),7.91-7.88(m,1H),7.81–7.78(m,2H),7.24(d,J＝8.8Hz,1H),6.71(d,J＝8.0Hz,1H),5.39(d,J＝4.0Hz,1H),4.26-4.25(m,1H),3.98–3.88(m,4H),3.57–3.44(m,3H),2.98(t,J＝8.4Hz,2H),2.42(s,3H).
Example 56
Synthesis of 3- {6- [2- (2-hydroxypropyl) -2H-indazol-5-yl ] pyrazin-2-yl } -1- (6-methylpyridin-3-yl) urea:
Figure BDA0003769482940000782
the first step is as follows: compound 134a (200mg, 0.787mmol, 1.0equiv.), pinacol ester diborate (299.92mg, 1.181mmol, 1.5equiv.), potassium acetate (231.71mg, 2.361mmol, 3.0equiv.), and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (86.41mg, 0.118mmol, 0.15equiv.) was added to dioxane (10 mL) solutionIn the solution, the reaction was stirred at 100 ℃ for 16 hours under nitrogen protection. LCMS shows reaction complete, filtration and concentration of the filtrate under reduced pressure to give crude compound 142a (400 mg), MS (ESI): M/z 303.0 (M + H) + Used in the next step without further purification.
The second step is that: to a solution of compound 142a (200mg, 0662mmol, 1equiv.) in 1,4-dioxane (10 mL) were added intermediate A (261.78mg, 0.993mmol, 1.5equiv.) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (96.88mg, 0.066mmol, 0.1equiv) was added, and an aqueous solution (1 mL) of sodium carbonate (140.33mg, 1.324mmol, 2equiv.) was added, and the reaction was stirred at 100 ℃ for 16 hours under nitrogen. LCMS shows the reaction is complete, the reaction is cooled to room temperature, filtered off with suction, concentrated and the residue is purified by preparative HPLC to give the title compound 142 (2.88 mg, yield: 1.5%). MS (ESI) M/z 404.2 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ9.81(s,1H),9.78(s,1H),8.94(s,1H),8.89(s,1H),8.56(d,J＝2.8Hz,1H),8.51-8.49(m,2H),7.99-7.90(m,2H),7.76(d,J＝9.2Hz,1H),7.28(d,J＝8.8Hz,1H),5.05(s,1H),4.46-4.30(m,2H),4.18-4.15(m,1H),2.45(s,3H),1.11(d,J＝6.4Hz,3H).
Example 57
Synthesis of 3- {6- [1- (2-hydroxycyclopentyl) -2, 3-dihydro-1H-indol-5-yl ] pyrazin-2-yl } -1- [ (3S) -piperidin-3-yl ] urea:
Figure BDA0003769482940000791
the first step is as follows: 6-bromopyrazin-2-amine (900mg, 5.17mmol, 1equiv.), (3S) -1- [ (tert-butoxy) carbonyl]Piperidine-3-carboxylic acid (2.37g, 10.34mmol, 2equiv.), diphenylphosphorylazide (2.8g, 10.34mmol, 2equiv.), triethylamine (1.57g, 15.51mmol,3.0 equiv.) were added to toluene (15 mL). After nitrogen substitution, the mixture was stirred at 110 ℃ for 4 hours. LCMS showed reaction completion, the reaction was concentrated, dissolved in dichloromethane (10 mL) and separated by flash silica gel column chromatography (PE: EA = 1) to give (compound 143a (460 mg, yield: 21.4%). MS (ESI): M/z 344.0 (M + H) + .
The second step is that: compound 143a (100mg, 0.25mmol, 1equiv.) was dissolved in 1, 4-bisOxirane (1 mL)/water (0.1 mL), compound 49b (90.48mg, 0.27mmol, 1.1equiv.), sodium carbonate (22mg, 0.425mmol, 1.7equiv.) and [1,1' -bis (diphenylphosphino) ferrocene ] were added]Palladium dichloride (7 mg,0.018mmol, 0.07equiv.) was stirred at 100 ℃ for 3 hours, after nitrogen substitution. LCMS showed reaction completion, the reaction was filtered, the filtrate was concentrated, and was isolated and purified by TLC plate (DCM: meOH = 20. MS (ESI) M/z 523.2 (M + H) + .
The third step: compound 143b (30mg, 0.06mmol, 1equiv.) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.4 mL) was added dropwise slowly, and the mixture was stirred at 25 ℃ for 1 hour after replacement with nitrogen. LCMS showed the reaction was complete and the reaction was concentrated and purified by reverse phase preparative chromatography pre-HPLC to afford the title compound 143 (5.56mg, 0.01mmol, 22.7% yield). MS (ESI) M/z 423.3 (M + H) + ； 1 H NMR(400MHz,CD3OD)δ8.52(s,1H),8.47(s,1H),8.25(s,1H),7.66(d,J＝8.4Hz,1H),7.62(s,1H),6.62(d,J＝8.0Hz,1H),4.30–4.20(m,1H),4.10–3.95(m,1H),3.90–3.75(m,1H),3.65–3.45(m,3H),3.10–2.95(m,4H),2.30–2.12(m,1H),2.09–1.91(m,3H),1.90–1.59(m,6H).
Example 58
Synthesis of 3- (6- {1- [ (4R) -4-hydroxyoxazol-3-yl ] -2, 3-dihydro-1H-indol-5-yl } pyrazin-2-yl) -1- [ (3S) -piperidin-3-yl ] urea:
Figure BDA0003769482940000801
the first step is as follows: dissolving compound 143a (100mg, 0.25mmol, 1equiv.) in 1,4-dioxane (1 mL)/water (0.1 mL), adding compound 141b (91.02mg, 0.27mmol, 1.1equiv.), sodium carbonate (66mg, 0.63mmol, 2.5equiv.), and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (22mg, 0.03mmol, 0.1equiv.) was purged with nitrogen and then stirred at 100 ℃ for 3 hours. LCMS showed the reaction was complete, and after the reaction was filtered, the filtrate was concentrated and isolated and purified by TLC plate (DCM: meOH = 20). MS (ESI): M/z 525.2 (M + H) + .
The second step is that: compound 144a (30mg, 0.06mmol, 1equiv.) is dissolved inDichloromethane (2 mL) was added dropwise to trifluoroacetic acid (0.4 mL) slowly, and the mixture was stirred at 25 ℃ for 1.5 hours, with replacement by nitrogen. LCMS indicated complete reaction, the reaction was filtered and purified by reverse phase preparative chromatography pre-HPLC to give the title compound 144 (7.9 mg, yield: 30.5%). MS (ESI) M/z 425.3 (M + H) + ； 1 H NMR(400MHz,CD 3 OD)δ8.52(s,1H),8.51(s,1H),8.31(s,1H),7.71(d,J＝8.4Hz,1H),7.68(s,1H),6.69(d,J＝8.4Hz,1H),4.38(s,1H),4.12–4.05(m,2H),4.04–3.95(m,3H),3.71–3.67(m,1H),3.66–3.57(m,1H),3.55–3.47(m,2H),3.06–2.94(m,4H),2.25–2.15(m,1H),2.10–2.00(m,1H),1.94–1.69(m,2H).
Example 59
Synthesis of (3- (6- {1- [ (3-methyloxoalk-3-yl) methyl ] -2-oxo-2, 3-dihydro-1H-indol-5-yl ] pyrazin-2-yl) -1- [ (3S) -piperidin-3-yl ] urea:
Figure BDA0003769482940000802
the first step is as follows: compound 143a (210mg, 0.52mmol, 1equiv.) was dissolved in methylene chloride (2 mL), and trifluoroacetic acid (0.4 mL) was added dropwise thereto slowly, and the mixture was stirred at 20 ℃ for 1 hour after nitrogen substitution. LCMS showed the reaction was complete and the reaction was spin dried to give crude compound 145a (120 mg, yield: 66.3%) which was used in the next step without further purification. MS (ESI) M/z 302.1 (M + H) + .
The second step: compound 126b (100mg, 0.29mmol, 1equiv.) is dissolved in 1,4-dioxane (2 mL)/water (0.2 mL), compound 145a (104.94mg, 0.35mmol, 1.2equiv.) is added]]Sodium carbonate (77mg, 0.73mmol,2.5equiv. And [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (22mg, 0.03mmol, 0.1equiv.) was purged with nitrogen and then stirred at 100 ℃ for 3 hours. LCMS showed the reaction was complete, and the reaction was filtered and subjected to preparative reverse phase chromatography pre-HPLC to isolate and purify to obtain the title compound 145 (10.99 mg, yield: 8.6%). MS (ESI) M/z 437.3 (M + H) + ； 1 H NMR(400MHz,DMSO-d6)δ9.63(s,1H),8.72(s,1H),8.63(s,1H),8.29(s,1H),8.20(s,1H),8.09–8.03(m,2H),7.24(d,J＝8.0Hz,1H),4.59(d,J＝6.0Hz,2H),4.18(d,J＝5.6Hz,2H),3.88(s,2H),3.83–3.78(m,1H),3.73(s,2H),3.07–2.96(m,1H),2.85–2.72(m,2H),2.70–2.60(m,1H),1.85–1.62(m,2H),1.60–1.40(m,2H),1.32(s,3H).
Biological test evaluation
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
Test example 1
1. Purpose of the experiment:
the purpose of this experiment was to examine the ability of the inventive compounds to inhibit the activity of PolQ polymerase. Mixing the template and the primer according to the proportion of 1:1.1, carrying out heat treatment in a reaction buffer solution at 95 ℃ for 5 minutes, slowly cooling, treating the PolQ protein by using compounds with different concentrations, incubating at room temperature, measuring fluorescence in a 525/598nm module on an Envision instrument, and reading data. Four parameters were fitted to the processed data to obtain IC50 values, and thus the biological activity of the compound was calculated.
2. Experimental materials and equipment:
1) Material
Primer [ P ] 5 'GACGGGAAGG-3' (Shanghai Biotech)
5-TAMRA-CCTTCCTCTCCCTGTGTTGTACTGTACCTTCCGTCAGGAGGAAGG-BHQ-3' (Shanghai worker)
DNA-polymerase: POL theta (Shanghai Ruizi chemical)
2) Reagents & manufacturer:
·dNTP(10mM),
·MgCl 2 ,Thermo Fisher#R0971；
·NaCl,Sigma#10708976001
·BSA,Sigma#10％
·DTT,Sigma#10197777001；
3) Consumable material:
·Assay plate:
Figure BDA0003769482940000811
384well microplate(Cat#4514),store at RT
·Compound plate:96-well plate-V bottom(Haimen Qunchao,Cat#FPT019),store at RT
·Compound plate:384-LDV plate(LABCYTE,Cat#LP-0200),store at RT
4) Equipment:
·Liquid handler:Echo(LABCYTE Echo550)
·Plate reader:Envision multiple plate reader(Perkin Elmer)
cell Counter (Counter star-IC-1000)
·CO 2 Incubator MCO-15AC (Thermo Fisher)
Pipette tip 0.2-10. Mu.L, 5-50. Mu.L, 20-300. Mu.L
Centrifuge Thermo Centrifuge ST 40R
Millipore Milli-Q Reference system
A refrigerator: haier-20degree freezer
3. Experimental procedure
The polymerase active fragment of PolQ (amino acids 1-987) was expressed and purified in SF9 insect cell line, dispensed and stored in a-80 ℃ refrigerator. The reaction was carried out in a1 Xbuffer system (20mM Tris pH7.8, 10mM MgCl2, 50mM KCl,1mM DTT,0.01% Tween-20 and 0.01% BSA).
The compound powder was dissolved in DMSO to a concentration of 10mM. Compounds were diluted in 3-fold gradients at 11 concentrations tested, and transferred to 384-well reaction plates (Corning 4514) at 150nL using ECHO, with a maximum final concentration of 10 μ M, and 150nL of DMSO was added to each of the positive and negative controls. The content of DMSO in the final reaction system is 1%.
Form board
5-TAMRA-CCTTCCTCTCCTCCTGTGTTACCTCCGTCAGGAGGAAGG-BHQ-3 ' (SEQ IDNO 3) and primer 5' GACGGGAAGG-3' (SEQ IDNO 3) were mixed at a ratio of 1.1, heat-treated at 95 ℃ for 5 minutes in a heat-treatment reaction buffer (10 mM Tris (pH 8.0), 100mM NaCl and H2O), and slowly cooled. mu.L of a mixture of PolQ protein and dNTP was added to the reaction plate (final concentration of PolQ protein 2.5nM, final concentration of dNTP 48. Mu.M) and incubated for 15 min at room temperature. A DNA mixture (96 nM for the final reaction) was prepared, 5. Mu.L was transferred to the reaction plate and incubated for 60 min at room temperature. After the incubation, the fluorescence intensity was measured at 525/598nm on Envision and the data were recorded. IC50 values for compounds were determined by a four parameter dose response equation.
4. The experimental results are as follows:
Figure BDA0003769482940000821
Figure BDA0003769482940000831
remarking: a represents IC50<100n Μ.
The above data show that: the compound has strong inhibition effect on the POLQ enzyme.
Test example 2hERG assay
1. Experimental methods
1.1 storage of Compounds
After receiving the compound, the compound administrator dissolved the powder in 100% dmso to prepare a 20mM stock solution.
1.2 cell culture and treatment
CHO cells stably expressing hERG were cultured in 35mm diameter cell culture dishes at 37 ℃ in a 5% CO2 incubator. On the day of the experiment, the cell culture fluid was aspirated, washed once with the extracellular fluid, and then added with 0.25% of the total
Trypsin-EDTA solution, digested at room temperature for 3-5 minutes. The digestion solution was aspirated, resuspended in extracellular fluid and the cells transferred to a petri dish for electrophysiological recording.
1.3 preparation of Compounds
The compound stock solution was diluted with 100% DMSO, i.e., 10 μ L of the compound stock solution was added to 20 μ L DMSO and serially diluted 3-fold to an intermediate concentration.
Then, 10. Mu.L of the intermediate compound concentration was added to 4990. Mu.L of the extracellular fluid and diluted 500-fold to give the final concentration to be tested.
Positive control compound Cisapride preparation: mu.L of stock cisaprideDMSO at 150. Mu.M was added to 4990. Mu.L of extracellular fluid and diluted 500-fold to give the final concentration to be tested, 300nM. The final concentration of DMSO in the test concentration did not exceed 0.2%, and the concentration of DMSO had no effect on the hERG potassium channel.
1.4 electrophysiological recording procedure
CHO cells stably expressing the hERG potassium channel were subjected to whole-cell patch clamp technique at room temperature to record the hERG potassium channel current. The glass microelectrode is formed by drawing a glass electrode blank (BF 150-86-10, sutter) by a drawing instrument, the tip resistance after filling the liquid in the electrode is about 2-5M omega, and the glass microelectrode can be connected to a patch clamp amplifier after being inserted into an amplifier probe. The clamped voltage and data recording is controlled and recorded by a pClamp 10 software through a computer, the sampling frequency is 10kHz, and the filtering frequency is 2kHz. After a whole cell record was obtained, the cells were clamped at-80 mV and the voltage at the step inducing the hERG potassium current (IhERG) was given a depolarization voltage of 2s from-80 mV to +20mV, repolarized to-50 mV, and returned to-80 mV after 1 s. This voltage stimulus was given every 10s and the dosing process was started after (1 min) the hERG potassium current was determined to be stable. The compounds were administered for at least 1 minute per concentration tested, with at least 2 cells tested per concentration (n.gtoreq.2).
1.5 data processing
The data analysis was performed using pClamp 10, graphPad Prism 5 and Excel software. The degree of inhibition of hERG potassium current (-50 mV induced hERG tail current peak) by different compound concentrations was calculated using the following equation: inhibition% = [1- (I/Io) ] x 100%
Where Inhibition% represents the percentage of Inhibition of the compound on the hERG potassium current, I and Io represent the magnitude of the hERG potassium current after and before dosing, respectively.
Compound IC50 was calculated using GraphPad Prism 5 software by equation fitting: y = Bottom + (Top-Bottom)/(1 +10^ ((LogicC 50-X) > HillSlope))
Wherein X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage under the corresponding concentration, and Bottom and Top are respectively the minimum and maximum inhibition percentages.
2. The experimental results are as follows:
the test results show that the compounds of the present application have an I of more than 30. Mu.MC 50 The value has no obvious inhibition effect on the hERG channel in the detection concentration range of the test, can reflect that the compound has lower cardiotoxicity to a certain extent, and has positive significance on drug safety evaluation.

Claims (13)

1. A compound of formula (I) or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, having the structure:
Figure FDA0003769482930000011
wherein X is selected from O and S;
w and V are independently selected from N or C (R) w )；R w Represents hydrogen, halogen or C 1-6 An alkyl group;
a is selected from hydrogen, halogen, amino, cyano, hydroxy, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Hydroxyalkyl, halo C 1-6 Alkyl radical, C 1-6 Alkylamino, -CO-C 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -NHCO-C 1-6 Alkyl, -CH 2 CONR a1 R a2 ；R a1 And R a2 Independently selected from H and C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Hydroxyalkyl, halo C 1-6 An alkyl group;
ring B is selected from C 6-14 Aryl, 5-16 membered heteroaryl and 5-16 membered heterocyclyl, said C 6-14 Aryl, 5-16 membered heteroaryl and 5-16 membered heterocyclyl are optionally substituted with n R b Substituted when more than one R b When occurring simultaneously, each R b May be the same or different; wherein n is selected from 0, 1,2,3,4 and 5;
R b selected from halogen, cyano, hydroxy, nitro, amino, oxo, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy radicalBase, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -C 1-6 alkyl-C 3-8 Cycloalkyl, -C 1-6 Alkyl-4-10 membered heterocyclyl, -C 1-6 alkyl-C 6-12 Aryl radical, -C 1-6 Alkyl-5-10 membered heteroaryl, -NH-C 3-8 Cycloalkyl, -NH-4-10 membered heterocyclyl, -NH-C 6-12 Aryl, -NH-5-10 membered heteroaryl, -NH-C 1-6 alkyl-C 3-8 Cycloalkyl, -NH-C 1-6 Alkyl-4-10 membered heterocyclyl, -NH-C 1-6 alkyl-C 6-12 Aryl, -NH-C 1-6 Alkyl-5-10 membered heteroaryl, -O-C 1-6 alkyl-C 3-8 Cycloalkyl, -O-C 1-6 Alkyl-4-10 membered heterocyclyl, -O-C 1-6 alkyl-C 6-12 Aryl and-O-C 1-6 Alkyl-5-10 membered heteroaryl; said C is 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, -C 1-6 alkyl-C 3-8 Cycloalkyl, -C 1-6 Alkyl-4-10 membered heterocyclyl, -C 1-6 alkyl-C 6-12 Aryl, -C 1-6 Alkyl-5-10 membered heteroaryl, -NH-C 3-8 Cycloalkyl, -NH-4-10 membered heterocyclyl, -NH-C 6-12 Aryl, -NH-5-10 membered heteroaryl, -NH-C 1-6 alkyl-C 3-8 Cycloalkyl, -NH-C 1-6 Alkyl-4-10 membered heterocyclyl, -NH-C 1-6 alkyl-C 6-12 Aryl, -NH-C 1-6 Alkyl-5-10 membered heteroaryl, -O-C 1-6 alkyl-C 3-8 Cycloalkyl, -O-C 1-6 Alkyl-4-10 membered heterocyclyl, -O-C 1-6 alkyl-C 6-12 Aryl and-O-C 1-6 Alkyl-5-10 membered heteroaryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, nitro, oxo, -NH (C) 1-3 Alkyl), -N (C) 1-3 Alkyl) (C 1-3 Alkyl), -C 1-3 alkyl-NH 2 、-NH-C(O)C 1-3 Alkyl, -C (O) C 1-3 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl;
R 1 is selected from C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Hydroxyalkyl, halogeno C 1-6 Alkyl radical, C 1-6 Alkylamino, -CO-C 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -NHCO-C 1-6 Alkyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, C 6-12 An aryl group; said C is 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Hydroxyalkyl, halo C 1-6 Alkyl radical, C 1-6 Alkylamino radical, -CO-C 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -NHCO-C 1-6 Alkyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, C 6-12 Aryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, nitro, oxo, -NH (C) 1-3 Alkyl), -N (C) 1-3 Alkyl) (C 1-3 Alkyl), -C 1-3 alkyl-NH 2 、-NH-C(O)C 1-3 Alkyl, -C (O) C 1-3 Alkyl, halo C 1-6 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl, -C 1-3 alkyl-N (C) 1-3 Alkyl) C 1-3 Alkyl radical, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl;
R 2 and R 3 Independently selected from H, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy radical, C 1-4 Halogenoalkoxy, C 3-8 A cycloalkyl group; or R 2 And R 3 Together with the atoms to which they are attached form a 5-or 6-membered heterocyclic ring;
unless otherwise specified, the heteroatoms in the above heterocyclic groups, heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1,2,3 or 4.
2. The compound of claim 1, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein W and V are both selected from N.
3. The compound of claim 1 or 2, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein a is selected from the group consisting of hydrogen, halogen, amino, cyano, hydroxy, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Hydroxyalkyl, halo C 1-6 An alkyl group; more preferably, a is selected from hydrogen, halogen, amino, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, cyclopropyl, methoxy; most preferably, a is selected from hydrogen.
4. The compound of any one of claims 1 to 3, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of phenyl, 5-7 membered monocyclic heteroaryl, 5-7 membered monocyclic heterocyclyl, naphthyl, phenanthryl, anthracenyl, 8-14 membered bicyclic heteroaryl, 8-14 membered bicyclic heterocyclyl, 9-14 membered tricyclic heteroaryl, 9-14 membered tricyclic heterocyclyl;
preferably, ring B is selected from 8-14 membered bicyclic fused ring heteroaryl, 8-14 membered bicyclic fused ring heterocyclyl, 9-14 membered fused ring tricyclic heteroaryl, 9-14 membered fused ring tricyclic heterocyclyl;
preferably, ring B is selected from C 6-12 Aryl, 5-14 membered heteroaryl and 5-14 membered heterocyclyl, said C 6-12 Aryl, 5-14 membered heteroaryl and 5-14 membered heterocyclyl are optionally substituted with n R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or differentThe same is carried out; wherein n is selected from 0, 1,2,3 and 4; more preferably, ring B is selected from C 6 Aryl, 6-14 membered heteroaryl and 6-14 membered heterocyclyl, said C 6 Aryl, 6-14 membered heteroaryl and 6-14 membered heterocyclyl is optionally substituted with n R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different; wherein n is selected from 0, 1,2 and 3;
further preferably, ring B is selected from C 6 <xnotran> ,5 ,6 ,7 ,5 ,6 ,7 ,6 /6 ,4 /4 ,4 /5 ,5 /4 ,5 /5 ,5 /6 ,6 /5 ,4 /6 ,6 /4 ,6 /6 ,4 /4 ,4 /5 ,5 /4 ,5 /5 ,5 /6 ,6 /5 ,4 /6 ,6 /4 ,6 /6 ,5 /6 /6 ,6 /5 /6 ,6 /6 /5 ,5 /5 /6 ,5 /6 /5 ,6 /5 /5 ,6 /6 /6 ,5 /6 /6 ,6 /5 /6 ,6 /6 /5 , </xnotran> 5-membered/6-membered tricyclic fused heterocyclic group, 5-membered/6-membered/5-membered tricyclic fused heterocyclic group, 6-membered/5-membered tricyclic fused heterocyclic group, 6-membered/6-membered tricyclic fused aryl group, wherein hetero atoms in the heterocyclic group and the heteroaryl group are independently selected from O, N or S, and the number of hetero atoms is 1,2 or 3; the above groups are optionally substituted by n R b Substituted when more than one R b When occurring simultaneously, each R b May be the same or different; wherein n is selected from 0, 1,2 and 3;
preferably, ring B is selected from the group consisting of 6-12 membered bicyclic heteroaryl, 6-14 membered bicyclic heterocyclyl and 12-14 membered bicyclic heteroarylA tricyclic heterocyclyl, said 6-12 membered bicyclic heteroaryl, 6-14 membered bicyclic heterocyclyl and 12-14 membered tricyclic heterocyclyl optionally substituted with n R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different, wherein n is selected from 0, 1,2,3 and 4; more preferably, ring B is selected from the group consisting of 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocyclyl and 14 membered tricyclic heterocyclyl, wherein the heteroatoms in the heteroaryl, heterocyclyl are independently selected from O or N, the number of heteroatoms is 1,2 or 3, and wherein the 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocyclyl and 14 membered tricyclic heterocyclyl are optionally substituted with N R b Substituted when multiple R b At the same time, each R b May be the same or different, wherein n is selected from 0, 1,2 and 3; more preferably, ring B is selected from 9-10 membered bicyclic heteroaryl and 9-10 membered bicyclic heterocyclyl, wherein the heteroatom in the heteroaryl or heterocyclyl is O or N and the number of heteroatoms is 1,2 or 3, wherein the 9-10 membered bicyclic heteroaryl and 9-10 membered bicyclic heterocyclyl are optionally substituted with N R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different, wherein n is selected from 0, 1,2 and 3; more preferably, ring B is selected from 9-10 membered bicyclic heterocyclic group, wherein the heteroatom in said heterocyclic group is N and the number of heteroatoms is 1, said 9-10 membered bicyclic heterocyclic group being optionally substituted by N R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different, wherein n is selected from 0, 1 and 2; preferably, ring B is selected from 9-10 membered bicyclic heteroaryl, wherein the heteroatoms in the heteroaryl are independently selected from O or N, the number of heteroatoms is 1,2 or 3, and the 9-10 membered bicyclic heteroaryl is optionally substituted with N R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different, wherein n is selected from 0, 1,2 and 3; preferably, ring B is selected from C 6-10 Aryl radical, said C 6-10 Aryl is optionally substituted by n R b Substituted when multiple R b At the same time, each R b May be the same or different; wherein n is selected from 0, 1,2,3 and 4; more preferably, ring B is selected from phenyl optionally substituted by n R b Substituted when more than one R b When occurring simultaneously, each R b Which may be the same or different from each other,wherein n is selected from 0, 1,2 and 3; more preferably, ring B is selected from phenyl optionally substituted by n R b Substituted when multiple R b At the same time, each R b May be the same or different, wherein n is selected from 0, 1 and 2;
even more preferably, ring B is selected from the following structures, optionally substituted by n R b Substituted when more than one R b When occurring simultaneously, each R b May be the same or different; wherein n is selected from 0, 1,2 and 3:
Figure FDA0003769482930000031
even more preferably, R b -ring B is selected from the following structures:
Figure FDA0003769482930000032
5. the compound of any one of claims 1-4, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R b Selected from halogen, cyano, hydroxy, nitro, amino, oxo, C 1-4 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-to 10-membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -C 1-4 alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-4-10 membered heterocyclyl, -C 1-4 alkyl-C 6-12 Aryl, -C 1-4 Alkyl-5-10 membered heteroaryl, -NH-C 3-8 Cycloalkyl, -NH-4-10 membered heterocyclyl, -NH-C 6-12 Aryl, -NH-5-10 membered heteroaryl, -NH-C 1-4 alkyl-C 3-8 Cycloalkyl, -NH-C 1-4 Alkyl-4-10 membered heterocyclyl, -NH-C 1-4 alkyl-C 6-12 Aryl, -NH-C 1-4 Alkyl-5-10 membered heteroaryl, -O-C 1-4 alkyl-C 3-8 Cycloalkyl, -O-C 1-4 Alkyl-4-10 membered heterocyclyl, -O-C 1-4 alkyl-C 6-12 Aryl and-O-C 1-4 Alkyl-5-10 membered heteroaryl; said C is 1-4 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-to 10-membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -C 1-4 alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-4-10 membered heterocyclyl, -C 1-4 alkyl-C 6-12 Aryl radical, -C 1-4 Alkyl-5-10 membered heteroaryl, -NH-C 3-8 Cycloalkyl, -NH-4-10 membered heterocyclyl, -NH-C 6-12 Aryl, -NH-5-10 membered heteroaryl, -NH-C 1-4 alkyl-C 3-8 Cycloalkyl, -NH-C 1-4 Alkyl-4-10 membered heterocyclyl, -NH-C 1-4 alkyl-C 6-12 Aryl, -NH-C 1-4 Alkyl-5-10 membered heteroaryl, -O-C 1-4 alkyl-C 3-8 Cycloalkyl, -O-C 1-4 Alkyl-4-10 membered heterocyclyl, -O-C 1-4 alkyl-C 6-12 Aryl and-O-C 1-4 Alkyl-5-10 membered heteroaryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, nitro, oxo, -NH (C) 1-3 Alkyl), -N (C) 1-3 Alkyl) (C) 1-3 Alkyl), -C (O) C 1-3 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 A hydroxyalkyl group;
further preferably, R b Selected from halogen, cyano, hydroxy, nitro, amino, oxo, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, -C 1-4 alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-4-10 membered heterocyclyl, -C 1-4 Alkyl-5-10 membered heteroaryl, -NH-C 3-8 Cycloalkyl, -NH-4-10 membered heterocyclyl, -NH-5-10 membered heteroaryl, -NH-C 1-4 alkyl-C 3-8 Cycloalkyl, -NH-C 1-4 Alkyl-4-10 membered heterocyclyl, -NH-C 1-4 Alkyl-5-10 membered heteroaryl, -O-C 1-4 alkyl-C 3-8 Cycloalkyl, -O-C 1-4 Alkyl-4-10 membered heterocyclyl and-O-C 1-4 Alkyl-5-10 membered heteroaryl; said C is 1-4 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, -C 1-4 alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-4-10 membered heterocyclyl, -C 1-4 Alkyl-5-10 membered heteroaryl, -NH-C 3-8 Cycloalkyl, -NH-4-10 membered heterocyclyl, -NH-5-10 membered heteroaryl, -NH-C 1-4 alkyl-C 3-8 Cycloalkyl, -NH-C 1-4 Alkyl-4-10 membered heterocyclyl, -NH-C 1-4 Alkyl-5-10 membered heteroaryl, -O-C 1-4 alkyl-C 3-8 Cycloalkyl, -O-C 1-4 Alkyl-4-10 membered heterocyclyl and-O-C 1-4 Alkyl-5-10 membered heteroaryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, nitro, oxo, -NH (C) 1-3 Alkyl), -N (C) 1-3 Alkyl) (C 1-3 Alkyl), -C (O) C 1-3 Alkyl radical, C 1-6 Alkyl radical, C 1-6 A hydroxyalkyl group;
further preferably, R b Selected from halogen, cyano, hydroxy, nitro, amino, oxo, C 1-4 Alkyl radical, C 5-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, 7-8 membered bicyclic heterocyclyl, -C 1-4 alkyl-C 3-6 Cycloalkyl, -C 1-4 Alkyl-4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -NH-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkenyl, -NH-C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl; the heteroatom in the heterocycloalkyl, heterocycloalkenyl, heterocyclyl or heteroaryl is O or N, and the number of heteroatoms is 1,2 or 3; said C is 1-4 Alkyl radical, C 5-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, 7-8 membered bicyclic heterocyclyl, -C 1-4 alkyl-C 3-6 Cycloalkyl, -C 1-4 Alkyl-4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -NH-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkenyl, -NH-C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, nitro, oxo, -NH (C) 1-3 Alkyl), -N (C) 1-3 Alkyl) (C 1-3 Alkyl), -C (O) C 1-3 Alkyl radical, C 1-4 Alkyl radical, C 1-3 A hydroxyalkyl group;
further preferably, R b Selected from halogen, cyano, hydroxy, nitro, amino, oxo, C 1-4 Alkyl radical, C 5-6 Cycloalkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, 7-8 membered bicyclic heterocyclyl, -C 1-4 alkyl-C 3-6 Cycloalkyl, -C 1-4 Alkyl-4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -NH-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkenyl, -NH-C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl; the heteroatom in the heterocycloalkyl, the heterocycloalkenyl, the heterocyclyl and the heteroaryl is O or N, and the number of the heteroatoms is 1 or 2; said C is 1-4 Alkyl radical, C 5-6 Cycloalkyl, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Hydroxyalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, 7-8 membered bicyclic heterocyclyl, -C 1-4 alkyl-C 3-6 Cycloalkyl, -C 1-4 Alkyl-4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -NH-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkyl, -NH-C 1-4 Alkyl-4-6 membered heterocycloalkenyl, -NH-C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, nitro, oxo, -NHCH 3 、-N(CH 3 )(CH 3 )、-C(O)CH 3 Methyl, ethyl, hydroxymethyl;
even more preferably, R b Selected from the group consisting of halogen, cyano, hydroxy, nitro, amino, oxo, methyl, ethyl, n-propyl, isopropyl, methoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-10 membered heterocyclyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -4-6 membered heterocyclyl, -CH 2 -5-6 membered heteroaryl, -NHCH 2 -cyclopropyl, -NHCH 2 -cyclobutyl, -NHCH 2 -cyclopentyl, -NHCH 2 -4-6 membered heterocyclyl, -NHCH 2 -5-6 membered heteroaryl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-4-6 membered heterocyclyl, -NH-5-6 membered heteroaryl, -OCH 2 -cyclopropyl, -OCH 2 -cyclobutyl, -OCH 2 -cyclopentyl, -OCH 2 -4-6 membered heterocyclyl and-OCH 2 -5-6 membered heteroaryl, said methyl, ethyl, n-propyl, isopropyl, methoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-10 membered heterocyclyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -4-6 membered heterocyclyl, -CH 2 -5-6 membered heteroaryl, -NHCH 2 -cyclopropyl, -NHCH 2 -cyclobutyl, -NHCH 2 -cyclopentyl, -NHCH 2 -4-6 membered heterocyclyl, -NHCH 2 -5-6 membered heteroaryl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-4-6 membered heterocyclyl, -NH-5-6 membered heteroaryl, -OCH 2 -cyclopropyl, -OCH 2 -cyclobutyl, -OCH 2 -cyclopentyl, -OCH 2 -4-6 membered heterocyclyl and-OCH 2 -5-6 membered heteroaryl is unsubstituted or substituted by one or more of the following substituents, respectively: halogen, cyano, hydroxy, nitro, oxo, -NH CH 3 、-N(CH 3 )(CH 3 )、-C(O)CH 3 Methyl, ethyl, hydroxymethyl;
most preferably, R b Selected from the group consisting of halogen, cyano, hydroxy, nitro, amino, oxo, methyl ethyl, n-propyl, isopropyl, methoxy, methylthio, methyl,
Figure FDA0003769482930000051
Figure FDA0003769482930000052
6. The compound of any one of claims 1-5, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of a 9-10 membered bicyclic heteroaryl and a 9-10 membered bicyclic heterocyclyl, said 9-10 membered bicyclic heteroaryl and 9-10 membered bicyclic heterocyclyl being optionally substituted with n R b Substituted when multiple R b At the same time, each R b May be the same or different, wherein n is selected from 1 or 2; r is b Selected from halogen, oxo, C 1-6 Alkyl, -C 1-4 Alkyl-4-6 membered heterocycloalkyl, C 5-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl, said C 1-6 Alkyl, -C 1-4 Alkyl-4-6 membered heterocycloalkyl, C 5-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, C 1-4 An alkyl group; the heteroatom in the heterocycloalkyl or heteroaryl is O or N, and the number of the heteroatoms is 1 or 2;
preferably, ring B is selected from 9-10 membered bicyclic heteroaryl and 9-10 membered bicyclic heterocyclyl, said 9-10 membered bicyclic heteroaryl and 9-10 membered bicyclic heterocyclyl being optionally substituted by n R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different, wherein n is selected from 1 or 2; r b Selected from halogen, oxo, C 1-4 Alkyl and substituted benzeneC 1-4 Alkyl-4-6 membered heterocycloalkyl, C 5-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl, said C 1-6 Alkyl, -C 1-4 Alkyl-4-6 membered heterocycloalkyl, C 5-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-4 Alkyl-5-6 membered heteroaryl, -O-C 1-4 Alkyl-4-6 membered heterocycloalkyl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, methyl; the heteroatom in the heterocycloalkyl and heteroaryl is O or N, and the number of the heteroatoms is 1 or 2.
7. The compound of any one of claims 1-6, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from phenyl, 5-7 membered monocyclic heteroaryl, 5-7 membered monocyclic heterocyclyl, naphthyl, 8-14 membered bicyclic heteroaryl, 8-14 membered bicyclic heterocyclyl;
preferably, R 1 Selected from phenyl, 5-7 membered monocyclic heteroaryl, 5-7 membered monocyclic heterocyclyl, naphthyl, 8-14 membered bicyclic fused ring heteroaryl, 8-14 membered bicyclic fused ring heterocyclyl;
preferably, R 1 Selected from the group consisting of 4-12 membered heterocyclyl, 5-12 membered heteroaryl and C 6-12 An aryl group; the 4-12 membered heterocyclic group, 5-12 membered heteroaryl group and C 6-12 Aryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, amino, hydroxy, nitro, oxo, -NH (C) 1-3 Alkyl), -N (C) 1-3 Alkyl) (C) 1-3 Alkyl), -C 1-3 alkyl-NH 2 、-NH-C(O)C 1-3 Alkyl, -C (O) C 1-3 Alkyl, halo C 1-3 Alkyl radical, C 1-3 Alkyl radical, C 3-8 Cycloalkyl radical, C 1-3 Alkoxy radical, C 1-3 Alkylthio radical, C 1-3 A hydroxyalkyl group;
preferably, R 1 Selected from 5-10 membered heterocyclyl, 6-10 membered heteroaryl; the 5-10 membered heterocyclyl, 6-10 membered heteroaryl are unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyanoHydroxy, amino, -NH-C (O) C 1-3 Alkyl, halo C 1-6 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl, -C 1-3 alkyl-N (C) 1-3 Alkyl) C 1-3 Alkyl radical, C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-3 Alkoxy radical, C 1-3 A hydroxyalkyl group;
preferably, R 1 Selected from the group consisting of 5-6 membered heterocycloalkyl, 8-10 membered bicyclic heterocyclyl, 6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl; the heteroatom in the heterocycloalkyl, the heterocyclic group and the heteroaryl is O or N, and the number of the heteroatoms is 1,2 or 3; the 5-6 membered heterocycloalkyl, 8-10 membered bicyclic heterocyclyl, 6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl are unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, -NH-C (O) C 1-3 Alkyl, halo C 1-3 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl, -C 1-3 alkyl-N (C) 1-3 Alkyl) C 1-3 Alkyl radical, C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 1-3 Alkoxy radical, C 1-3 A hydroxyalkyl group;
preferably, R 1 Selected from the group consisting of 5-6 membered heterocycloalkyl, 5-membered/6-membered bicyclic fused heterocyclic group, 6-membered/5-membered bicyclic fused heterocyclic group, 6-membered/6-membered bicyclic fused heterocyclic group, 6-membered monocyclic heteroaryl group, 5-membered/6-membered bicyclic fused heteroaryl group, 6-membered/5-membered bicyclic fused heteroaryl group, 6-membered/6-membered bicyclic fused heteroaryl group; the heteroatom in the heterocycloalkyl, heterocyclic group and heteroaryl is O or N, and the number of the heteroatoms is 1,2 or 3; the 5-6 membered heterocycloalkyl, 5-membered/6-membered bicyclic fused heterocyclic group, 6-membered/5-membered bicyclic fused heterocyclic group, 6-membered/6-membered bicyclic fused heterocyclic group, 6-membered monocyclic heteroaryl, 5-membered/6-membered bicyclic fused heteroaryl, 6-membered/5-membered bicyclic fused heteroaryl, 6-membered/6-membered bicyclic fused heteroaryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, -NH-C (O) CH 3 、-CH 2 NHCH 3 Trifluoromethyl, difluoromethyl, monofluoromethyl, hydroxymethyl;
more preferably, R 1 Selected from 5-10 membered heterocyclic groups6-10 membered heteroaryl and C 6-10 An aryl group; the 5-to 10-membered heterocyclic group, 6-to 10-membered heteroaryl group and C 6-10 Aryl is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, nitro, oxo, -NHCH 3 、-N(CH 3 )(CH 3 )、-NH-C(O)CH 3 、-C(O)CH 3 Methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, methylthio, trifluoromethyl, difluoromethyl, monofluoromethyl;
further preferably, R 1 Is selected from C 6 Aryl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 7-membered monocyclic heteroaryl, 5-membered monocyclic heterocyclyl, 6-membered monocyclic heterocyclyl, 7-membered monocyclic heterocyclyl, 6/6-membered bicyclic fused aryl, 4-membered/4-membered bicyclic fused heteroaryl, 4-membered/5-membered bicyclic fused heteroaryl, 5-membered/4-membered bicyclic fused heteroaryl, 5-membered/5-membered bicyclic fused heteroaryl, 5-membered/6-membered bicyclic fused heteroaryl, 6-membered/5-membered bicyclic fused heteroaryl, 4-membered/6-membered bicyclic fused heteroaryl, 6-membered/4-membered bicyclic fused heteroaryl, 6-membered/6-membered bicyclic fused heteroaryl, 4-membered/4-membered bicyclic fused heterocyclyl, 4-membered/5-membered bicyclic fused heterocyclyl, 5-membered/4-membered bicyclic fused heterocyclyl, 5-membered/6-membered bicyclic fused heterocyclyl, 6-membered/5-membered bicyclic fused heterocyclyl, 4-membered/6-membered bicyclic fused heterocyclyl, 6-membered/6-membered bicyclic fused heterocyclyl, the heteroatoms in the heterocyclic group and the heteroaryl group are independently selected from O, N or S, and the number of the heteroatoms is 1,2 or 3; r is as defined above 1 The group is unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, nitro, oxo, -NHCH 3 、-N(CH 3 )(CH 3 )、-NH-C(O)CH 3 、-C(O)CH 3 Methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, methylthio, trifluoromethyl, difluoromethyl, monofluoromethyl;
preferably, R 1 Selected from 6-membered monocyclic heteroaryl, 9-membered bicyclic heteroaryl; the heteroatom in the heteroaryl is N, and the number of the heteroatoms is 1 or 2; the 6-membered monocyclic heteroaryl and the 9-membered bicyclic heteroaryl are unsubstituted or substituted with one or more of the following substituents, respectively: which is unsubstituted or substitutedSubstituted with one or more of the following substituents: halogen, hydroxy, halogeno C 1-3 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl radical, C 1-3 Alkyl radical, C 1-3 A hydroxyalkyl group;
further preferably, R 1 Selected from 6-membered monocyclic heteroaryl, 5-membered/6-membered bicyclic fused heteroaryl, 6-membered/5-membered bicyclic fused heteroaryl, 6-membered/6-membered bicyclic fused heteroaryl; the heteroatom in the heteroaryl is N, and the number of the heteroatoms is 1 or 2; the 5-membered/6-membered bicyclic fused heteroaryl, 6-membered/5-membered bicyclic fused heteroaryl, 6-membered/6-membered bicyclic fused heteroaryl is unsubstituted or substituted with one or more of the following substituents, respectively: which is unsubstituted or substituted, respectively, by one or more of the following substituents: halogen, -C 1-3 alkyl-NH-C 1-3 Alkyl radical, C 1-3 Alkyl radical, C 1-3 A hydroxyalkyl group;
even more preferably, R 1 Selected from the following structures, which are unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, nitro, oxo, -NHCH 3 、-N(CH 3 )(CH 3 )、-NH-C(O)CH 3 、-C(O)CH 3 Methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, methylthio, trifluoromethyl, difluoromethyl, monofluoromethyl,
Figure FDA0003769482930000071
most preferably, R 1 Selected from the following structures:
Figure FDA0003769482930000081
8. a compound according to any one of claims 1 to 7, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, whichIn (c), ring B is selected from phenyl optionally substituted by n R b Substituted when multiple R b When occurring simultaneously, each R b May be the same or different, wherein n is selected from 0, 1,2 and 3; r 1 Selected from 5-10 membered bicyclic heterocyclyl, 6-10 membered bicyclic heteroaryl; the 5-10 membered bicyclic heterocyclyl, 6-10 membered bicyclic heteroaryl are unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, -NH-C (O) C 1-3 Alkyl, halo C 1-6 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl, -C 1-3 alkyl-N (C) 1-3 Alkyl) C 1-3 Alkyl radical, C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 A hydroxyalkyl group;
preferably, ring B is selected from phenyl optionally substituted by n R b Substituted when more than one R b When occurring simultaneously, each R b May be the same or different, wherein n is selected from 0, 1,2 and 3; r is 1 Selected from 8-10 membered bicyclic heterocyclic group, 8-10 membered bicyclic heteroaryl; the 8-10 membered bicyclic heterocyclyl, 8-10 membered bicyclic heteroaryl are unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, -NH-C (O) C 1-3 Alkyl, halo C 1-6 Alkyl, -C 1-3 alkyl-NH-C 1-3 Alkyl, -C 1-3 alkyl-N (C) 1-3 Alkyl) C 1-3 Alkyl radical, C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-3 Alkoxy radical, C 1-3 A hydroxyalkyl group;
further preferably, ring B is selected from phenyl optionally substituted with n R b Substituted when multiple R b At the same time, each R b May be the same or different, wherein n is selected from 1,2 and 3; r is 1 Selected from the group consisting of 5-membered/6-membered bicyclic fused heterocyclic group, 6-membered/5-membered bicyclic fused heterocyclic group, 6-membered/6-membered bicyclic fused heterocyclic group, 5-membered/6-membered bicyclic fused heteroaryl group, 6-membered/5-membered bicyclic fused heteroaryl group, 6-membered/6-membered bicyclic fused heteroaryl group; the heteroatom in the heterocyclic group and the heteroaryl group is O or N, and the number of the heteroatoms is 1,2 or 3; the 5-membered/6-membered bicyclic fused heterocyclic group, 6-membered/5-membered bicyclic fused heterocyclic group, 6-membered/6-membered bicyclic fused heterocyclic groupCyclyl, 5-membered/6-membered bicyclic fused heteroaryl, 6-membered/5-membered bicyclic fused heteroaryl, 6-membered/6-membered bicyclic fused heteroaryl are unsubstituted or substituted with one or more of the following substituents, respectively: halogen, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, -NH-C (O) CH 3 、-CH 2 NHCH 3 Trifluoromethyl, difluoromethyl, monofluoromethyl, hydroxymethyl;
preferably, ring B is selected from phenyl optionally substituted with 2R b Substituted when more than one R b When occurring simultaneously, each R b May be the same or different; r is b Selected from methyl,
Figure FDA0003769482930000082
R 1 Is selected from C 1-3 Pyridyl optionally substituted with one or more of alkyl;
preferably, R b -ring B is selected from the following structures:
Figure FDA0003769482930000083
R 1 is selected from pyridyl optionally substituted by one or more of methyl.
9. The compound of any one of claims 1-8, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 And R 3 Independently selected from hydrogen, methyl; or R 2 And R 3 Together with the atoms to which they are attached form a 5-or 6-membered heterocyclic ring; preferably, R 2 And R 3 Independently selected from hydrogen, methyl; or R 2 And R 3 Together with the atoms to which they are attached form a 5-membered heterocycloalkyl or 6-membered heterocycloalkyl group, in which the heteroatoms are N, the number of heteroatoms being 2.
10. A compound selected from the group consisting of:
Figure FDA0003769482930000091
Figure FDA0003769482930000101
Figure FDA0003769482930000111
Figure FDA0003769482930000121
Figure FDA0003769482930000131
Figure FDA0003769482930000141
Figure FDA0003769482930000151
Figure FDA0003769482930000161
Figure FDA0003769482930000171
11. a pharmaceutical composition comprising a compound of any one of claims 1 to 10, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof.
12. Use of a compound according to any one of claims 1 to 10, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the manufacture of a medicament for the treatment of a disease mediated by POLQ; preferably, the disease mediated by POLQ is cancer or a tumor-related disease; preferably, the cancer or tumor comprises a solid tumor and a hematological tumor; preferably, the solid tumor comprises breast cancer, colorectal cancer, cervical cancer, ovarian cancer, prostate cancer, gastric cancer (including gastrointestinal junction cancer), esophageal cancer, head and neck cancer, lung cancer; preferably, the hematological neoplasm comprises lymphoma and leukemia.
13. A compound according to any one of claims 1 to 10, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for use in combination with one, two or more additional anti-cancer agents or immune checkpoint modulators or therapeutic means (e.g. radiotherapy) for the treatment of cancer or tumors; preferably, the additional anti-cancer agent or immune checkpoint modulator for the treatment of cancer or tumor comprises a PARP inhibitor, an ATR inhibitor, an ATM inhibitor, a WEE1 inhibitor, a topoisomerase inhibitor and a DNA damaging chemotherapeutic; preferably, the DNA damaging chemotherapeutic comprises cisplatin, bleomycin, gemcitabine, docetaxel; the topoisomerase inhibitor comprises etoposide and irinotecan.
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