CN117242073A - PRMT5 inhibitors and uses thereof - Google Patents

PRMT5 inhibitors and uses thereof Download PDF

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Publication number
CN117242073A
CN117242073A CN202280013815.6A CN202280013815A CN117242073A CN 117242073 A CN117242073 A CN 117242073A CN 202280013815 A CN202280013815 A CN 202280013815A CN 117242073 A CN117242073 A CN 117242073A
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alkyl
membered
cycloalkyl
alkoxy
deuterium
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李瑶
张国彪
黄世林
张浩亮
张晓波
王耀羚
郑登宇
王龙
唐平明
余彦
张晨
严庞科
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Tibet Haisike Pharmaceutical Co ltd
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Haisco Pharmaceutical Group Co Ltd
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Abstract

There is provided a compound of formula (I), stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, or a pharmaceutical composition containing the same, and the use thereof as a PRMT5 inhibitor in the manufacture of a medicament for the treatment of a related disorder.

Description

PRMT5 inhibitors and uses thereof Technical Field
The invention belongs to the field of medicines, and particularly relates to a derivative of a protein arginine methyltransferase inhibitor, a stereoisomer, a pharmaceutically acceptable salt, a solvate, a eutectic or a deuterated substance thereof, and application thereof in preparing medicines for treating PRMT 5-mediated related diseases.
Background
Protein arginine methyltransferase (PRMT) is capable of methylating a variety of proteins, including histones and nonhistones, and has an effect on a variety of biological processes, such as involvement in gene transcription, cell signaling, protein stability, cell proliferation, differentiation, apoptosis, and tumor formation, among others. Currently, 11 PRMT family members have been found, which can be classified into three categories depending on the manner in which arginine methylation is catalyzed: PRMT1-4, PRMT6, PRMT8 belong to type I, the catalytic forms are monomethyl and asymmetric dimethyl; PEMT5 and PRMT9 belong to type II, and the catalytic form is symmetrical dimethyl; PRMT7 belongs to type III and is capable of monomethyl catalysis.
Protein arginine methyltransferase 5 (PRMT 5) is commonly present in the cytoplasm and nucleus, and can specifically catalyze the symmetrical methylation of numerous substrates such as histones and nonhistones, thereby affecting multiple target genes and multiple signal pathway paths and playing multiple biological functions. In various malignant tumors of human beings (lung cancer, ovarian cancer, colorectal cancer, breast cancer, melanoma, leukemia and glioblastoma), the expression of PRMT5 is up-regulated, which fully indicates that PRMT5 plays an important role in the development of tumor formation. In addition, PRMT5 has been identified as a therapeutic target for mantle cell lymphoma, so the study of its small molecule inhibitors has become a hotspot in the development of antitumor drugs.
Disclosure of Invention
The invention aims to provide a novel PRMT5 inhibitor with high activity, small side effect, high bioavailability and high selectivity.
The compound provided by the invention and stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectic crystals thereof have the inhibiting effect on PRMT5, can inhibit cell proliferation, have good pharmacokinetic characteristics, high bioavailability, good safety, small toxic and side effects, and have the advantages of oral administration, quick absorption, high clearance and the like.
The invention provides a compound shown in a formula (I), and stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectic crystals thereof,
wherein,
ring a is selected from phenyl or 5-6 membered heteroaryl;
R 1 、R 2 、R 3 、R 4 each independently selected from hydrogen, deuterium, hydroxy, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, -C (O) C 1-6 Alkyl, -C (O) NHC 1-6 Alkyl, -C (O) NH 2 、-NHC(O)C 1-6 Alkyl, -N (C) 1-6 Alkyl) C (O) C 1-6 Alkyl, optionally substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, C 1-6 Substitution of the alkoxy group;
alternatively, R 1 、R 2 Together with the attached carbon atom, form a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
alternatively, R 3 、R 4 Together with the attached carbon atom, form a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
R 5 selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, -C (O) C 1-6 Alkyl, -C (O) NH 2 、-C(O)NHC 1-6 Alkyl, optionally substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, C 1-6 Substitution of the alkoxy group;
R 8 selected from hydrogen, deuterium, hydroxy, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 An alkoxy group;
R 6 selected from deuterium, halogen, cyano, nitro, cyano, amino, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -O-C 3-8 Cycloalkyl, -O- (3-8 membered heterocycloalkyl), -NH-C 3-8 Cycloalkyl, -NH- (3-8 membered heterocycloalkyl), -S-C 3-8 Cycloalkyl, -S- (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR 6a R 6b 、-NR 6a C(＝O)-R 6b 、-NR 6a R 6b 、-C(＝O)-R 6a 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Alkyl, said CH 2 Optionally further substituted with 1 to 5 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
R 6a selected from the group consisting ofHydrogen, deuterium, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally being substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, C 1-6 An alkoxy group;
R 6b selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, -S (O) 2 C 1-6 Alkyl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl being optionally substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
x is selected from the group consisting of bond, -O-, -S (O) 2 -、-CR xa R xb -or-NR xa -；
Y is selected from the group consisting of bond, -O-, -S (O) 2 -、-CR ya R yb -、-NR ya -or-CR ya -；
Z is selected from the group consisting of bond, -O-, -S (O) 2 -、-CR za R zb -、-NR za -、-CR za -or-N-;
provided X, Y, Z is not both a bond;
represents a single bond or a double bond;
X 1 selected from-CR x1a -or-N-;
X 2 selected from-CR x2a -or-N-;
X 3 selected from-CR x3a -or-N-;
X 7 selected from-CR x7a -or-N-;
X 4 selected from-O-, -S-, -CR x4a R x4b -or-NR x4a -；
X 5 Selected from-O-, -S-, -CR x5a R x5b -or-NR x5a -；
X 6 Selected from bonds, -O-, -S-, -CR x6a R x6b -or-NR x6a -；
R x1a 、R x2a 、R x3a 、R x7a Each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, -L-R 7 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (3-12 membered heterocycloalkyl), -O-C 3-12 Cycloalkyl, -O- (3-12 membered heterocycloalkyl), -NH-C 3-12 Cycloalkyl, -NH- (3-12 membered heterocycloalkyl), -S-C 3-12 Cycloalkyl, -S- (3-12 membered heterocycloalkyl), 5-12 membered heteroaryl, 6-12 membered aryl, -C (=o) NR xaa R xab 、-NR xaa C(＝O)-R xab 、-NR xaa R xab 、-C(＝O)-R xaa 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Alkyl, said CH 2 Optionally further substituted with 1 to 5 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
R xa 、R xb 、R ya 、R yb 、R za 、R zb 、R x4a 、R x4b 、R x5a 、R x5b 、R x6a 、R x6b each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (3-12 membered heterocycloalkyl), -O-C 3-12 Cycloalkyl, -O- (3-12 membered heterocycloalkyl), -NH-C 3-12 Cycloalkyl, -NH- (3-12 membered heterocycloalkyl), -S-C 3-12 Cycloalkyl, -S- (3-12 membered heterocycloalkyl), 5-12 membered heteroaryl, 6-12 membered aryl, -C (=o) NR xaa R xab 、-NR xaa C(＝O)-R xab 、-NR xaa R xab 、-C(＝O)-R xaa 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Alkyl, said CH 2 Optionally further substituted with 1 to 5 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
R xaa 、R xab each independently selected from hydrogen, deuterium, amino, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, deuterated C 1-6 An alkoxy group;
alternatively, R's bound to the same carbon atom xa And R is xb 、R ya And R is yb 、R za And R is zb 、R x4a And R is x4b 、R x5a And R is x5b Or R is x6a And R is x6b Together with the attached carbon atom, form =o, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
alternatively, R x4a And R is R x6a Together form-CH 2 -or-CH 2 CH 2 -；
L is selected from bond, -NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-、-NR La C(O)-(CH 2 ) p -O-、-O-(CH 2 ) p -C(O)NR La -、-NR La C(O)-NR La -、-O-、-S-、-S(O) 2 NR La -、-NR La S(O) 2 -；
R La Selected from hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 An alkyl group;
R 7 selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (4-12 membered heterocycloalkyl), - (CH) 2 ) r - (5-12 membered heteroaryl), - (CH) 2 ) r - (6-12 membered aryl) said CH 2 Optionally further substituted with 1 to 5 groups selected from deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-6 Alkyl, = O, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -SF 5 、-(CH 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -O-C 3-8 Cycloalkyl, -O- (3-8 membered heterocycloalkyl), -NH-C 3-8 Cycloalkyl, -NH- (3-8 membered heterocycloalkyl), -S-C 3-8 Cycloalkyl, -S- (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 The groups of the alkyl groups are substituted.
R cya 、R cyb Each independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 An alkyl group;
alternatively, -L-R 7 Selected from hydrogen, deuterium, amino, hydroxy, halogen, cyano, and C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1- 6 Alkoxy, halo C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 An alkoxy group;
m is selected from 0, 1, 2, 3 or 4;
p is selected from 0, 1 or 2;
r is selected from 0, 1, 2 or 3;
with the proviso that the compound of formula (I) is not selected from the following compounds:
in another technical scheme, the compound shown in the formula (I) has a structure shown in the formula (II), (III), (IV) and (V):
wherein,
ring a is selected from phenyl, 5 membered heteroaryl, or 6 membered heteroaryl;
x is selected from the group consisting of bond, -O-, -S (O) 2 -、-CR xa R xb -or-NR xa -；
Y is selected from the group consisting of bond, -O-, -S (O) 2 -、-CR ya R yb -、-NR ya -or-CR ya -；
Z is selected from the group consisting of bond, -O-, -S (O) 2 -、-CR za R zb -、-NR za -、-CR za -or-N-;
provided X, Y, Z is not both a bond;
X 4 selected from-O-, -S-, -CR x4a R x4b -or-NR x4a -；
X 5 Selected from-O-, -S-, -CR x5a R x5b -or-NR x5a -；
X 6 Selected from bonds, -O-, -S-, -CR x6a R x6b -or-NR x6a -；
X 1 Selected from-CR x1a -or-N-;
X 2 selected from-CR x2a -or-N-;
X 3 selected from-CR x3a -or-N-;
X 7 selected from-CR x7a -or-N-;
R x1a 、R x2a 、R x3a 、R x7a each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 The alkyl, alkoxy is optionally further substituted with 1 to 3 groups selected from F, cl, deuterium, nitro, cyano, amino, hydroxy, C 1-2 Alkyl, C 1-2 Alkoxy, halo C 1-2 Alkyl, halogenated C 1-2 Alkoxy, deuterated C 1-2 Alkyl, deuterated C 1-2 Substitution of the alkoxy group;
R xa 、R xb 、R ya 、R yb 、R za 、R zb 、R x4a 、R x4b 、R x5a 、R x5b 、R x6a 、R x6b each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-6 Monocyclic cycloalkyl, - (CH) 2 ) r -C 5-10 Bicyclic cycloalkyl, - (CH) 2 ) r - (3-6 membered monocyclic heterocycloalkyl), - (CH) 2 ) r - (5-to 10-membered bicycloheterocycloalkyl), -O-C 3-6 Monocyclic cycloalkyl, -O-C 5-10 Bicyclic cycloalkyl, -O- (3-6 membered monocyclic heterocycloalkyl), -O- (5-10 membered bicyclic heterocycloalkyl), -NH-C 3-6 Monocyclic cycloalkyl, -NH-C 5-10 Bicyclic cycloalkyl, -NH- (3-6 membered monocyclic heterocycloalkyl), -NH- (5-10 membered bicyclic heterocycloalkyl), 5-to 6-membered heteroaryl, -phenyl, -C (=o) NR xaa R xab 、-NR xaa C(＝O)-R xab 、-NR xaa R xab 、-C(＝O)-R xaa The CH is 2 Optionally further substituted with 1 to 3 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Substitution of the alkoxy group;
R xaa 、R xab each independently selected from hydrogen, deuterium, amino, hydroxy, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, deuterated C 1-4 An alkoxy group;
alternatively, R's bound to the same carbon atom xa And R is xb 、R ya And R is yb 、R za And R is zb 、R x4a And R is x4b 、R x5a And R is x5b Or R is x6a And R is x6b Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
alternatively, R x4a And R is R x6a Together form-CH 2 -or-CH 2 CH 2 -；
Provided that when-L-R 7 When hydrogen, R x3a Selected from hydrogen;
other groups are as described in any of the preceding claims.
In another embodiment, the compounds of formula (I), (II) of the present invention, stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, have the structure of formula (II-a), (II-b), (II-c):
X 1 selected from-CR x1a -or-N-;
X 2 selected from-CR x2a -or-N-;
X 3 selected from-CR x3a -or-N-;
R x1a 、R x2a 、R x3a each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-4 Alkyl, C 1- 4 Alkoxy, said alkyl, alkoxy optionally further being selected from the group consisting of F, cl, deuterium, nitro, cyano, amino, hydroxy, C 1-2 Alkyl, C 1-2 Alkoxy, halo C 1-2 Alkyl, halogenated C 1-2 Alkoxy, deuterated C 1-2 Alkyl, deuterated C 1-2 Substitution of the alkoxy group;
x is selected from-O-or-CR xa R xb -；
R xa 、R xb Each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl optionally further substituted with 1 to 3 groups selected from halogen, deuterium, hydroxy, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Substitution of the alkoxy group;
alternatively, R's bound to the same carbon atom xa And R is xb Together with the attached carbon atoms, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 3-membered heterocycleAlkyl, 4 membered heterocycloalkyl, 5 membered heterocycloalkyl;
other group definitions are consistent with any of the previous technical schemes.
In another embodiment, a compound of the invention, a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, wherein
R 1 、R 2 Each independently selected from hydrogen, deuterium, alternatively R 1 、R 2 Together with the attached carbon atoms, form a 3-membered cycloalkyl, 4-membered cycloalkyl or 5-membered cycloalkyl; and/or
R 5 Selected from hydrogen, deuterium, C 1-4 Alkyl, halogenated C 1-4 An alkyl group; and/or
R x1a 、R x2a 、R x3a 、R x7a Each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, and C 1-4 Alkyl, C 1-4 An alkoxy group;
other group definitions are consistent with any of the technical schemes described above.
In another embodiment, a compound of the invention, a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, wherein
L is selected from bond, -NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-、-O-、-NR La C(O)-CH 2 -O-；
R La Selected from hydrogen, deuterium, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 An alkyl group; or alternatively
L is selected from the group consisting of bond, -NH-,
Other groups are as described in any of the preceding claims.
In another embodiment, a compound of the invention, a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, wherein
R 7 Selected from- (CH) 2 ) r - (5-6 membered monocyclic heteroaryl), - (CH) 2 ) r - (4-6 membered monocyclic heterocycloalkyl), - (CH) 2 ) r - (6-to 10-membered bicycloheterocycloalkyl), - (CH) 2 ) r - (3-6 membered monocyclic cycloalkyl), - (CH) 2 ) r - (6-to 10-membered bicyclocycloalkyl) said Cy optionally being further substituted with 1, 2, 3, 4, 5 groups selected from deuterium, halogen, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r -C 3-8 Heterocycloalkyl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya The CH is 2 Optionally further substituted with 1, 2, 3, 4, 5 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Substitution of the alkoxy group;
r is selected from 0 or 1;
R cya 、R cyb each independently selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 An alkyl group; or alternatively
R 7 Selected from the group consisting of
Other groups are as described in any of the preceding claims.
In another embodiment, a compound of the invention, a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, wherein
R 7 L-is selected from F, cl, br, cyano, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 An alkoxy group; or alternatively
R 7 L-is selected from F, cl, br, cyano, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, -CH 2 F、-CHF 2 、-CF 3 、-OCH 2 F、-OCHF 2 、-OCF 3 、-CH 2 D、-CHD 2 、-CD 3 、-OCH 2 D、-OCHD 2 、-OCD 3 。
In another embodiment, a compound of the invention, a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, wherein
m is selected from 0, 1, 2; and/or
R 6 Selected from deuterium, halogen, cyano, C 1-4 Alkyl, - (CH) 2 ) r -C 3-6 Cycloalkyl, - (CH) 2 ) r -C 3-6 Heterocycloalkyl, -C (=o) NR 6a R 6b 、-NR 6a C(＝O)-R 6b 、-NR 6a R 6b 、-C(＝O)-R 6a The CH is 2 Optionally alkyl, cycloalkyl, heterocycloalkylFurther by 1, 2, 3, 4, 5 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Substitution of the alkoxy group;
r is selected from 0 or 1;
R 6a selected from hydrogen, deuterium, C 1-2 Alkyl optionally substituted with 1, 2, 3 groups selected from halogen, deuterium, hydroxy, amino, cyano, C 1-2 Substitution of the alkoxy group;
R 6b selected from hydrogen, deuterium, C 1-4 Alkyl optionally substituted with 1, 2, 3 groups selected from halogen, deuterium, hydroxy, amino, cyano, C 1-2 Substitution of the alkoxy group; or alternatively
m is selected from 0, 1;
R 6 selected from deuterium, F, cl, br, cyano, methyl, ethyl, propyl, isopropyl, t-butyl, 2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, azetidinyl, -CH 2 -azetidinyl, -CH 2 Azacyclopentyl, -CH 2 -an azacyclohexyl group, an oxetanyl group, -a CH 2 -oxetanyl, -CH 2 -oxacyclopentyl, -CH 2 -oxacyclohexyl, -C (O) NHCH 3 、-NHC(O)CH 3 、-N(CH 3 )C(O)CH 3 、-NHC(O)CH 2 CH 3 、-N(CH 3 )C(O)CH 2 CH 3 、-NH 2 、-NHCH 3 、-C(O)CH3、-C(O)CH 2 CH 3 The groups are further substituted by 1, 2 and 3 groups selected from F and deuterium;
other groups are as described in any of the preceding claims.
The invention relates to a compound shown in a formula (I), and stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectic crystals thereof,
wherein,
ring a is selected from phenyl or 5-6 membered heteroaryl;
R 1 、R 2 、R 3 、R 4 each independently selected from hydrogen, deuterium, hydroxy, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, -C (O) C 1-6 Alkyl, -C (O) NHC 1-6 Alkyl, -C (O) NH 2 、-NHC(O)C 1-6 Alkyl, -N (C) 1-6 Alkyl) C (O) C 1-6 Alkyl, optionally substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, C 1-6 Substitution of the alkoxy group;
alternatively, R 1 、R 2 Together with the attached carbon atom, form a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
alternatively, R 3 、R 4 Together with the attached carbon atom, form a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
R 5 selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, -C (O) C 1-6 Alkyl, -C (O) NH 2 、-C(O)NHC 1-6 Alkyl, optionally substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, C 1-6 Substitution of the alkoxy group;
R 8 selected from hydrogen, deuterium, hydroxy, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 An alkoxy group;
R 6 selected from deuterium, halogen, cyano, nitro, cyano, amino, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -O-C 3-8 Cycloalkyl, -O- (3-8 membered heterocycloalkyl), -NH-C 3-8 Cycloalkyl, -NH- (3-8 membered heterocycloalkyl), -S-C 3-8 Cycloalkyl, -S- (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR 6a R 6b 、-NR 6a C(＝O)-R 6b 、-NR 6a R 6b 、-C(＝O)-R 6a 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Alkyl, said CH 2 Optionally further substituted with 1 to 5 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
R 6a selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally being substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, C 1-6 Substitution of the alkoxy group;
R 6b selected from hydrogenDeuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, -S (O) 2 C 1-6 Alkyl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl being optionally substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
x is selected from the group consisting of bond, -O-, -S (O) 2 -、-CR xa R xb -or-NR xa -；
Y is selected from the group consisting of bond, -O-, -S (O) 2 -、-CR ya R yb -、-NR ya -or-CR ya -；
Z is selected from the group consisting of bond, -O-, -S (O) 2 -、-CR za R zb -、-NR za -、-CR za -or-N-;
provided X, Y, Z is not both a bond;
represents a single bond or a double bond;
X 1 selected from-CR x1a -or-N-;
X 2 selected from-CR x2a -or-N-;
X 3 selected from-CR x3a -or-N-;
X 7 selected from-CR x7a -or-N-;
X 4 selected from-O-, -S-, -CR x4a R x4b -orR-NR x4a -；
X 5 Selected from-O-, -S-, -CR x5a R x5b -or-NR x5a -；
X 6 Selected from bonds, -O-, -S-, -CR x6a R x6b -or-NR x6a -；
R x1a 、R x2a 、R x3a 、R x7a Each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, -L-R 7 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (3-12 membered heterocycloalkyl), -O-C 3-12 Cycloalkyl, -O- (3-12 membered heterocycloalkyl), -NH-C 3-12 Cycloalkyl, -NH- (3-12 membered heterocycloalkyl), -S-C 3-12 Cycloalkyl, -S- (3-12 membered heterocycloalkyl), 5-12 membered heteroaryl, 6-12 membered aryl, -C (=o) NR xaa R xab 、-NR xaa C(＝O)-R xab 、-NR xaa R xab 、-C(＝O)-R xaa 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Alkyl, said CH 2 Optionally further substituted with 1 to 5 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
R xa 、R xb 、R ya 、R yb 、R za 、R zb 、R x4a 、R x4b 、R x5a 、R x5b 、R x6a 、R x6b each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (3-12 membered heterocycloalkyl), -O-C 3-12 Cycloalkyl, -O- (3-12 membered heterocycloalkyl), -NH-C 3-12 Cycloalkyl, -NH- (3-12 membered heterocycloalkyl), -S-C 3-12 Cycloalkyl, -S- (3-12 membered heterocycloalkyl), 5-12 membered heteroaryl, 6-12 membered aryl, -C (=o) NR xaa R xab 、-NR xaa C(＝O)-R xab 、-NR xaa R xab 、-C(＝O)-R xaa 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Alkyl, said CH 2 Optionally further substituted with 1 to 5 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
R xaa 、R xab each independently selected from hydrogen, deuterium, amino, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, deuterated C 1-6 An alkoxy group;
alternatively, R's bound to the same carbon atom xa And R is xb 、R ya And R is yb 、R za And R is zb 、R x4a And R is x4b 、R x5a And R is x5b Or R is x6a And R is x6b Together with the attached carbon atom, form =o, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
alternatively, R is attached to adjacent carbon atoms xa And R is za Together with the attached carbon atom, form =o, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
alternatively, R x4a And R is R x6a Together form-CH 2 -or-CH 2 CH 2 -；
L is selected from bond, -NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-、-NR La C(O)-(CH 2 ) p -O-、-O-(CH 2 ) p -C(O)NR La -、-NR La C(O)-NR La -、-O-、-S-、-S(O) 2 NR La -、-NR La S(O) 2 -；
R La Selected from hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 An alkyl group;
R 7 selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (4-12 membered heterocycloalkyl), - (CH) 2 ) r - (5-12 membered heteroaryl), - (CH) 2 ) r - (6-12 membered aryl) said CH 2 Optionally further substituted with 1 to 5 groups selected from deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-6 Alkyl, = O, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -SF 5 、-(CH 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -O-C 3-8 Cycloalkyl, -O- (3-8 membered heterocycloalkyl), -NH-C 3-8 Cycloalkyl, -NH- (3-8 membered heterocycloalkyl), -S-C 3-8 Cycloalkyl, -S- (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Substitution of the alkyl group;
R cya 、R cyb each independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 An alkyl group;
alternatively, -L-R 7 Selected from hydrogen, deuterium, amino, hydroxy, halogen, cyano, and C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1- 6 Alkoxy, halo C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 An alkoxy group;
m is selected from 0, 1, 2, 3 or 4;
p is selected from 0, 1 or 2;
r is selected from 0, 1, 2 or 3;
with the proviso that the compound of formula (I) is not selected from the following compounds:
in another embodiment, the compound of formula (I) of the present invention, stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, has the structure of formula (II-1), (II-2), (II-3), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15):
Wherein,
ring a is selected from phenyl, 5 membered heteroaryl, or 6 membered heteroaryl;
ring B is selected from 5 membered heteroaryl or 6 membered heteroaryl;
the E ring is 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
the H ring is 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
R 11 、R 12 、R 13 、R 15 、R 17 、R 18 、R 19 、R 110 、R 111 、R 112 、R 113 、R 114 、R 115 、R 21 、R 22 、R 23 、R 25 、R 27 、R 28 、R 29 、R 210 、R 211 、R 212 、R 213 、R 214 、R 215 、R 31 、R 32 、R 33 、R 35 、R 36 、R 37 、R 38 、R 39 、R 310 、R 311 、R 312 、R 313 、R 314 、R 315 、R 41 、R 42 、R 43 、R 45 、R 46 、R 47 、R 48 、 R 49 、R 410 、R 411 、R 412 、R 413 、R 414 、R 415 each independently selected from hydrogen, deuterium, hydroxy, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally substituted with 1 to 3 groups selected from halogen, deuterium, hydroxy;
alternatively, R's bound to the same carbon atom 11 And R is 21 、R 31 And R is 41 、R 12 And R is 22 、R 32 And R is 42 、R 13 And R is 23 、R 33 And R is 43 、R 15 And R is 25 、R 35 And R is 45 、R 36 And R is 46 、R 17 And R is 27 、R 37 And R is 47 、R 18 And R is 28 、R 38 And R is 48 、R 19 And R is 29 、R 39 And R is 49 、R 110 And R is 210 、R 310 And R is 410 、R 111 And R is 211 、R 311 And R is 411 、R 112 And R is 212 、R 312 And R is 412 、R 112 And R is 213 、R 313 And R is 413 、R 114 And R is 214 、R 314 And R is 414 、R 115 And R is 215 Or R 315 And R is 415 Each independently form together with the attached carbon atom a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl group;
R 51 、R 52 、R 53 、R 55 、R 56 、R 57 、R 58 、R 59 、R 510 、R 511 、R 512 、R 513 、R 514 、R 515 each independently selected from hydrogen, deuterium, C 1-4 An alkyl group optionally substituted with 1 to 3 groups selected from halogen, deuterium, hydroxy;
R 81 、R 82 、R 83 、R 85 、R 86 、R 87 、R 88 、R 89 、R 810 、R 811 、R 812 、R 813 、R 814 、R 815 each independently selected from hydrogen, deuterium, hydroxy, and halogen;
r being bound to the same carbon atom 9a1 And R is 9b1 、R 9a2 And R is 9b2 Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl; or alternatively
R 9a1 And R is 9a2 Interlinking to form-CH 2 -、-CH 2 CH 2 -；
R 61 、R 63 、R 65 、R 66 、R 67 、R 68 、R 69 、R 610 、R 611 、R 612 、R 613 、R 614 、R 615 、R 616 、R 617 Each independently selected from deuterium, halogen, cyano, nitro, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -O-C 3-8 Cycloalkyl, -O- (3-8 membered heterocycloalkyl), -NH-C 3-8 Cycloalkyl, -NH- (3-8 membered heterocycloalkyl), -S-C 3-8 Cycloalkyl, -S- (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR 6a R 6b 、-NR 6a C(＝O)-R 6b 、-NR 6a R 6b 、-C(＝O)-R 6a 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Alkyl, said CH 2 Optionally further substituted with 1 to 5 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
R 62 is deuterium, halogen, - (CH) 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -C (=o) NR 6a R 6b 、-NR 6a C(＝O)-R 6b 、-NR 6a R 6b 、-C(＝O)-R 6a The CH is 2 Optionally further substituted with 1 to 3 groups selected from halogen, deuterium, cyano, hydroxy, = O, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Substitution of the alkoxy group;
R 6a selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally being substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, C 1-6 Substitution of the alkoxy group;
R 6b selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, -S (O) 2 C 1-6 Alkyl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl being optionally substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
X 81 、X 83 、X 86 、X 88 、X 89 、X 810 、X 811 、X 813 、X 814 、X 815 each independently selected from the group consisting of-O-, -S-, and S (O) -, -S (O) 2 -、-CR xa R xb -or-NR xa -；
X 87 Selected from the group consisting of-O-, -S (O) -, -S (O) 2 -、-CR xa R xb -or-NR xa -；
X 812 Selected from the group consisting of-O-, -S-, and S (O) -, -S (O) 2 -、-CR xa2 R xb2 -or-NR xa -；
X 82 Selected from the group consisting of-O-, -S-, and S (O) -, -S (O) 2 -、-CR xa1 R xb1 -or-NR xa -；
Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 Each independently selected from the group consisting of bond, -CR ya R yb -、-NR ya -or-CR ya -；
Z 1 、Z 2 、Z 3 、Z 4 、Z 5 、Z 6 Each independently selected from the group consisting of bond, -CR za R zb -、-NR za -、-CR za -or-N-;
X 41 、X 42 、X 43 、X 44 each independently selected from-CR x4a R x4b -or-NR x4a -；
X 51 、X 52 、X 53 、X 54 Each independently selected from-CR x5a R x5b -or-NR x5a -；
X 61 、X 62 、X 63 、X 64 Each independently selected from the group consisting of bond, -CR x6a R x6b -or-NR x6a -；
X 11 、X 12 、X 13 、X 15 、X 16 、X 17 、X 18 、X 19 、X 110 、X 113 、X 114 、X 115 Each independently selected from-CR x1a -or-N-;
X 21 、X 22 、X 23 、X 25 、X 26 、X 27 、X 28 、X 29 、X 211 、X 213 、X 214 、X 215 each independently selected from-CR x2a -or-N-;
X 31 、X 32 、X 33 、X 35 、X 36 、X 37 、X 38 、X 39 、X 310 、X 311 each independently selected from-CR x3a -or-N-;
X 710 、X 711 、X 713 、X 714 、X 715 each independently selected from-CR x7a -or-N-;
X 112 selected from-CR x1b -；
X 212 Selected from-CR x2b -；
X 712 Selected from-CR x7b -；
R x1a 、R x2a 、R x3a 、R x7a Each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 The alkyl, alkoxy is optionally further substituted with 1 to 3 groups selected from F, cl, deuterium, nitro, cyano, amino, hydroxy, C 1-2 Alkyl, C 1-2 Alkoxy, halo C 1-2 Alkyl, halogenated C 1-2 Alkoxy, deuterated C 1-2 Alkyl, deuterated C 1-2 Substitution of the alkoxy group;
R xa 、R xb 、R xa2 、R xb2 、R ya 、R yb 、R za 、R zb 、R x4a 、R x4b 、R x5a 、R x5b 、R x6a 、R x6b each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-6 Monocyclic cycloalkyl, - (CH) 2 ) r -C 5-10 Bicyclic cycloalkyl, - (CH) 2 ) r - (3-6 membered monocyclic heterocycloalkylyl), - (CH) 2 ) r - (5-to 10-membered bicycloheterocycloalkyl), -O-C 3-6 Monocyclic cycloalkyl, -O-C 5-10 Bicyclic cycloalkyl, -O- (3-6 membered monocyclic heterocycloalkyl), -O- (5-10 membered bicyclic heterocycloalkyl), -NH-C 3-6 Monocyclic cycloalkyl, -NH-C 5-10 Bicyclic cycloalkyl, -NH- (3-6 membered monocyclic heterocycloalkyl), -NH- (5-10 membered bicyclic heterocycloalkyl), 5-to 6-membered heteroaryl, -phenyl, -C (=o) NR xaa R xab 、-NR xaa C(＝O)-R xab 、-NR xaa R xab 、-C(＝O)-R xaa The CH is 2 Optionally further substituted with 1 to 3 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Substitution of the alkoxy group;
R xa1 、R xb1 each independently selected from hydrogen, deuterium, cyano, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-6 Monocyclic cycloalkyl, - (CH) 2 ) r -C 5-10 Bicyclic cycloalkyl, - (CH) 2 ) r - (3-6 membered monocyclic heterocycloalkyl), - (CH) 2 ) r - (5-10 membered bicycloheterocycloalkyl), 5-to 6-membered heteroaryl, phenyl, said CH 2 Optionally further substituted with 1 to 3 groups selected from halogen, deuterium, cyano, hydroxy, = O, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Substitution of the alkoxy group;
R xaa 、R xab each independently selected from hydrogen, deuterium, amino, hydroxy, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, deuteriumSubstitute C 1-4 An alkoxy group;
R x1b 、R x2b 、R x7b each independently selected from H, deuterium, nitro, cyano, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 The alkyl, alkoxy is optionally further substituted with 1 to 3 groups selected from F, cl, deuterium, nitro, cyano, amino, hydroxy, C 1-2 Alkyl, C 1-2 Alkoxy, halo C 1-2 Alkyl, halogenated C 1-2 Alkoxy, deuterated C 1-2 Alkyl, deuterated C 1-2 Substitution of the alkoxy group;
provided that R x1b 、R x2b 、R x7b Not simultaneously H;
alternatively, when R x1b 、R x2b 、R x7b At the same time selected from H, -L 12 -R 712 Selected from H;
alternatively, R's bound to the same carbon atom xa And R is xb 、R xa1 And R is xb1 、R ya And R is yb 、R za And R is zb 、R x4a And R is x4b 、R x5a And R is x5b Or R is x6a And R is x6b Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
alternatively, R is attached to adjacent carbon atoms xa And R is za Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
alternatively, R x4a And R is R x6a Together form-CH 2 -or-CH 2 CH 2 -；
L 1 Selected from the group consisting of-C (O) NR La -、*-NR La C(O)-、*-NR La C(O)-(CH 2 ) p -O-、*-O-(CH 2 ) p -C(O)NR La -、-NR La C(O)-NR La -、-S-、*-S(O) 2 NR La -、*-NR La S(O) 2 -, represents L 1 And R is R 71 A linking site;
L 2 selected from-NR La -、-C(O)-、-C(O)NR La -**、-NR La C(O)-(CH 2 ) p -O-**、-O-(CH 2 ) p -C(O)NR La -**、-NR La C(O)-NR La -**、-S-、-S(O) 2 NR La -**、-NR La S(O) 2 A method for producing a composite material x-ray in the sense that, represents L 2 And R is R 72 A linking site;
L 3 、L 5 、L 6 each independently selected from the group consisting of bond, -NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-、-NR La C(O)-(CH 2 ) p -O-、-O-(CH 2 ) p -C(O)NR La -、-NR La C(O)-NR La -、-O-、-S-、-S(O) 2 NR La -、-NR La S(O) 2 -；
L 7 、L 8 、L 9 、L 10 、L 11 、L 12 、L 13 、L 14 、L 15 Each independently selected from-NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-、-NR La C(O)-(CH 2 ) p -O-、-O-(CH 2 ) p -C(O)NR La -、-NR La C(O)-NR La -、-O-、-S-、-S(O) 2 NR La -、-NR La S(O) 2 -；
R La Selected from hydrogen, deuterium, halogenated C 1-4 Alkyl, deuterated C 1-4 An alkyl group;
R 71 selected from- (CH) 2 ) r - (4-12 membered heterocycloalkyl), - (CH) 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (5-12 membered heteroaryl), - (CH) 2 ) r - (6-12 membered aryl) said CH 2 Optionally further substituted with 1 to 3 groups selected from deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-4 Alkyl, = O, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya 、-S-C 1-4 Alkyl, -S (O) -C 1-4 Alkyl, -S (O) 2 -C 1-4 Substitution of the alkyl group; or alternatively
L 1 Selected from-NR La -，R 71 Selected from 5-12 membered heteroaryl, - (CH) 2 ) r - (6-12 membered aryl) said CH 2 Optionally further substituted with 1 to 3 groups selected from deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-4 Alkyl, = O, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya 、-S-C 1-4 Alkyl, -S (O) -C 1-4 Alkyl, -S (O) 2 -C 1-4 Substitution of the alkyl group;
R 72 selected from C 2-6 Alkenyl, -SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (4-12 membered heterocycloalkyl), 5-12 membered heteroaryl, 6-12 membered aryl, said CH 2 Optionally further substituted with 1 to 5 groups selected from deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-6 Alkyl, = O, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, - (CH) 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -O-C 3-8 Cycloalkyl, -O- (3-8 membered heterocycloalkyl), -NH-C 3-8 Cycloalkyl, -NH- (3-8 membered heterocycloalkyl), -S-C 3-8 Cycloalkyl, -S- (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Substitution of the alkyl group;
provided that when L 2 Selected from-NH-, R 72 Selected from- (CH) 2 ) r -4-12 membered heterocycloalkyl, 6-12 membered aryl or- (CH) 2 ) r -C 3-12 Cycloalkyl, one of the following conditions is satisfied: m is not 0, or X 12 、X 32 One selected from N, or R x2a 、R x3a Not simultaneously H; or alternatively
L 2 Selected from-NR La C(O)-**，R 72 Selected from C 2-6 Alkenyl, -SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (4-12 membered saturated heterocycloalkyl), 6-12 membered aryl, said CH 2 Optionally further substituted with 1 to 5 groups selected from deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-6 Alkyl, = O, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, - (CH) 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -O-C 3-8 Cycloalkyl, -O- (3-8 membered heterocycloalkyl), -NH-C 3-8 Cycloalkyl, -NH- (3-8 membered heterocycloalkyl), -S-C 3-8 Cycloalkyl, -S- (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Substitution of the alkyl group;
alternatively, -L 2 -R 72 Selected from CN, -C (O) N (C) 1-4 Alkyl group 2 A 5-membered heteroaryl, a 7-12 membered heteroaryl, said heteroaryl optionally being further substituted with 1 to 3 deuterium, halogen, hydroxy, amino, cyano, C 1-4 Alkyl, = O, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya Is substituted by a group of (2);
R 73 、R 75 、R 76 、R 77 、R 78 、R 79 、R 710 、R 711 、R 712 、R 713 、R 714 、R 715 each independently selected from deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (4-12 membered heterocycloalkyl), - (CH) 2 ) r - (5-12 membered heteroaryl), - (CH) 2 ) r - (6-12 membered aryl) said CH 2 Optionally further substituted with 1 to 5 groups selected from R f Is substituted by a group of (2);
alternatively, -L 7 -R 77 、-L 13 -R 713 Each independently selected from halogen, 5-12 membered heteroaryl, said heteroaryl optionally further being selected from R by 1-5 f Is substituted by a group of (2);
alternatively, -L 8 -R 78 、-L 9 -R 79 、-L 10 -R 710 、-L 11 -R 711 Each independently selected from SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (4-12 membered heterocycloalkyl), - (CH) 2 ) r - (5-12 membered heteroaryl), - (CH) 2 ) r - (6-12 membered aryl) said CH 2 Optionally further substituted with 1 to 5 groups selected from R f Is substituted by a group of (2);
each R f Each independently selected from deuteriumHalogen, nitro, cyano, amino, hydroxy, C 1-6 Alkyl, = O, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -SF 5 、-(CH 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -O-C 3-8 Cycloalkyl, -O- (3-8 membered heterocycloalkyl), -NH-C 3-8 Cycloalkyl, -NH- (3-8 membered heterocycloalkyl), -S-C 3-8 Cycloalkyl, -S- (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 An alkyl group;
R cya 、R cyb each independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 An alkyl group;
other groups are as described in any of the preceding claims.
In another embodiment, the compounds of the invention, stereoisomers, deuterated, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, wherein,
R 11 、R 12 、R 13 、R 15 、R 17 、R 18 、R 19 、R 110 、R 111 、R 112 、R 113 、R 114 、R 115 、R 21 、R 22 、R 23 、R 25 、R 27 、R 28 、R 29 、R 210 、R 211 、R 212 、R 213 、R 214 、R 215 、R 31 、R 32 、R 33 、R 35 、R 36 、R 37 、R 38 、R 39 、R 310 、R 311 、R 312 、R 313 、R 314 、R 315 、R 41 、R 42 、R 43 、R 45 、R 46 、R 47 、R 48 、R 49 、R 410 、R 411 、R 412 、R 413 、R 414 、R 415 each independently selected from hydrogen, deuterium, C 1-4 An alkyl group optionally substituted with 1 to 3 groups selected from halogen, deuterium;
alternatively, R's bound to the same carbon atom 11 And R is 21 、R 31 And R is 41 、R 12 And R is 22 、R 32 And R is 42 、R 13 And R is 23 、R 33 And R is 43 、R 15 And R is 25 、R 35 And R is 45 、R 36 And R is 46 、R 17 And R is 27 、R 37 And R is 47 、R 18 And R is 28 、R 38 And R is 48 、R 19 And R is 29 、R 39 And R is 49 、R 110 And R is 210 、R 310 And R is 410 、R 111 And R is 211 、R 311 And R is 411 、R 112 And R is 212 、R 312 And R is 412 、R 112 And R is 213 、R 313 And R is 413 、R 114 And R is 214 、R 314 And R is 414 、R 115 And R is 215 Or R 315 And R is 415 Each independently form together with the attached carbon atom a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl group;
R 51 、R 52 、R 53 、R 55 、R 56 、R 57 、R 58 、R 59 、R 510 、R 511 、R 512 、R 513 、R 514 、R 515 each independently selected from hydrogen, deuterium, C 1-4 An alkyl group optionally substituted with 1 to 3 groups selected from halogen, deuterium;
R 81 、R 82 、R 83 、R 85 、R 86 、R 87 、R 88 、R 89 、R 810 、R 811 、R 812 、R 813 、R 814 、R 815 Each independently selected from hydrogen, deuterium;
r being bound to the same carbon atom 9a1 And R is 9b1 、R 9a2 And R is 9b2 Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl; or alternatively
R 9a1 And R is 9a2 Interlinking to form-CH 2 -；
R 61 、R 63 、R 65 、R 66 、R 67 、R 68 、R 69 、R 610 、R 611 、R 612 、R 613 、R 614 、R 615 、R 616 、R 617 Each independently selected from deuterium, halogen, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR 6a R 6b 、-NR 6a C(＝O)-R 6b 、-NR 6a R 6b 、-C(＝O)-R 6a The CH is 2 Optionally further substituted with 1 to 3 groups selected from halogen, deuterium, C 1-4 Substitution of the alkyl group;
R 62 is deuterium, halogen, - (CH) 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -C (=o) NR 6a R 6b 、-NR 6a C(＝O)-R 6b 、-NR 6a R 6b 、-C(＝O)-R 6a The CH is 2 Optionally further substituted, by 1 to 3 groups selected from halogen, deuterium, = O, C 1-4 Alkyl, C 1-4 Substitution of the alkoxy group;
R 6a selected from hydrogen, deuterium, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally being substituted with 1 to 3 substituents selected from halogen, deuterium, C 1-4 Substitution of the alkoxy group;
R 6b selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl optionally being substituted with 1 to 3 groups selected from halogen, deuterium, C 1-4 Alkyl, C 1-4 Substitution of the alkoxy group;
X 81 、X 83 、X 86 、X 88 、X 89 、X 810 、X 811 、X 813 、X 814 、X 815 each independently selected from-O-, -S-, -CR xa R xb -or-NR xa -；
X 87 Selected from-O-, -CR xa R xb -or-NR xa -；
X 812 Selected from-O-, -S-, -CR xa2 R xb2 -or-NR xa -；
X 82 Selected from-O-, -S-, -CR xa1 R xb1 -or-NR xa -；
Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 Each independently selected from the group consisting of bond, -CR ya R yb -or-NR ya -；
Z 1 、Z 2 、Z 3 、Z 4 、Z 5 、Z 6 Each independently selected from the group consisting of bond, -CR za R zb -or-NR za -；
X 41 、X 42 、X 43 、X 44 Each independently selected from-CR x4a R x4b -or-NR x4a -；
X 51 、X 52 、X 53 、X 54 Each independently selected from-CR x5a R x5b -or-NR x5a -；
X 61 、X 62 、X 63 、X 64 Each independently selected from the group consisting of bond, -CR x6a R x6b -or-NR x6a -；
X 11 、X 12 、X 13 、X 15 、X 16 、X 17 、X 18 、X 19 、X 110 、X 113 、X 114 、X 115 Each independently selected from-CR x1a -or-N-;
X 21 、X 22 、X 23 、X 25 、X 26 、X 27 、X 28 、X 29 、X 211 、X 213 、X 214 、X 215 each independently selected from-CR x2a -or-N-;
X 31 、X 32 、X 33 、X 35 、X 36 、X 37 、X 38 、X 39 、X 310 、X 311 each independently selected from-CR x3a -or-N-;
X 710 、X 711 、X 713 、X 714 、X 715 each independently selected from-CR x7a -or-N-;
X 112 selected from-CR x1b -；
X 212 Selected from-CR x2b -；
X 712 Selected from-CR x7b -；
R x1a 、R x2a 、R x3a 、R x7a Each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further being 1 to 3 groups selected from F, cl, deuterium, hydroxy, C 1-2 Alkyl, C 1-2 Substitution of the alkoxy group;
R xa 、R xb 、R xa2 、R xb2 、R ya 、R yb 、R za 、R zb 、R x4a 、R x4b 、R x5a 、R x5b 、R x6a 、R x6b each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) r -C 3-6 Monocyclic cycloalkyl, - (CH) 2 ) r -C 5-10 Bicyclic cycloalkyl, - (CH) 2 ) r - (3-6 membered monocyclic heterocycloalkyl), - (CH) 2 ) r - (5-10 membered bicycloheterocycloalkyl), 5-to 6-membered heteroaryl, phenyl, -C (=o) NR xaa R xab 、-NR xaa C(＝O)-R xab 、-NR xaa R xab 、-C(＝O)-R xaa The CH is 2 Optionally further substituted with 1 to 3 groups selected from halogen, deuterium, C 1-4 Alkyl, C 1- 4 Substitution of the alkoxy group;
R xa1 、R xb1 each independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) r -C 3-6 Monocyclic cycloalkyl, - (CH) 2 ) r -C 5-10 Bicyclic cycloalkyl, - (CH) 2 ) r - (3-6 membered monocyclic heterocycloalkyl), - (CH) 2 ) r - (5-10 membered bicycloheterocycloalkyl), 5-to 6-membered heteroaryl, phenyl, said CH 2 Optionally further substituted with 1 to 3 groups selected from halogen, deuterium, C 1-4 Alkyl, C 1-4 Substitution of the alkoxy group;
R xaa 、R xab each independently selected from hydrogen, deuterium, C 1-4 An alkyl group;
R x1b 、R x2b 、R x7b each independently selected from H, deuterium, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further being 1 to 3 groups selected from F, cl, deuterium, hydroxy, C 1-2 Alkyl, C 1-2 Substitution of the alkoxy group;
provided that R x1b 、R x2b 、R x7b Not simultaneously H;
alternatively, when R x1b 、R x2b 、R x7b At the same time selected from H, -L 12 -R 712 Selected from H;
alternatively, R's bound to the same carbon atom xa And R is xb 、R xa1 And R is xb1 、R ya And R is yb 、R za And R is zb 、R x4a And R is x4b 、R x5a And R is x5b Or R is x6a And R is x6b Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
alternatively, R is attached to adjacent carbon atoms xa And R is za Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
Alternatively, R x4a And R is R x6a Together form-CH 2 -or-CH 2 CH 2 -；
Other groups are as described in any of the preceding claims.
In another embodiment, the compounds of the present invention, stereoisomers, deuterated, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or co-crystals thereof, have the structure of formula (III-1), (III-2), (III-3), (III-5), (III-6), (III-7), (III-8), (III-9):
ring E is 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
the H ring is 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
selected from the following A, B, C or D structure,
R 52 selected from hydrogen, deuterium, C 1-4 An alkyl group optionally substituted with 1 to 3 groups selected from halogen, deuterium;
r being bound to the same carbon atom 9a1 And R is 9b1 、R 9a2 And R is 9b2 Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl; or alternatively
R 9a1 And R is 9a2 Interlinking to form-CH 2 -；
R 69 Selected from deuterium, halogen, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further substituted with 1 to 3 groups selected from halogen, deuterium, hydroxy;
R 62 selected from deuterium, halogen, C 3-6 Cycloalkyl, 3-5 membered heterocycloalkyl, -C (=o) NR 6a R 6b 、-NHC(＝O)-R 6b 、-NR 6a R 6b 、-C(＝O)-R 6a The cycloalkyl, heterocycloalkyl, optionally further substituted with 1 to 3 groups selected from halogen, deuterium, = O, C 1-4 Substitution of the alkyl group;
R 6a selected from hydrogen, deuterium, C 1-4 An alkyl group optionally substituted with 1 to 3 groups selected from halogen, deuterium;
R 6b selected from hydrogen, deuterium, C 1-4 An alkyl group optionally substituted with 1 to 3 groups selected from halogen, deuterium;
X 81 、X 87 、X 88 、X 89 each independently selected from-O-, -CR xa R xb -or-NR xa -；
X 82 Selected from-O-, -CR xa1 R xb1 -or-NR xa -；
X 12 Selected from-CR x1a -or-N-;
X 22 selected from-CR x2a -or-N-;
X 32 selected from-CR x3a -or-N-;
R x1a 、R x2a 、R x3a each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further substituted with 1 to 3 groups selected from F, cl, deuterium;
R xa 、R xb each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further substituted with 1 to 3 groups selected from F, cl, deuterium;
R xa1 、R xb1 each independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further substituted with 1 to 3 groups selected from F, cl, deuterium;
Alternatively, R's bound to the same carbon atom xa And R is xb Together with the attached carbon atoms, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl;
L 1 selected from-NR La 、*-C(O)NR La -、*-NR La C (O) -, represents L 1 And R is R 71 A linking site;
L 2 selected from-NR La 、-C(O)-、-C(O)NR La -**、-NR La C(O)-(CH 2 ) p -O-**、-O-(CH 2 ) p -C(O)NR La A method for producing a composite material x-ray in the sense that, represents L 2 And R is R 72 Is a ligation site of (2);
L 3 、L 5 、L 6 each independently selected from the group consisting of bond, -NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-；
L 7 、L 8 、L 9 Each independently selected from-NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-；
R La Selected from hydrogen, deuterium, C 1-4 An alkyl group;
R 71 selected from 5-membered heteroaryl or 6-membered heteroaryl, said heteroaryl optionally being further substituted with 1 to 3 groups selected from deuterium, halogen, C 1-4 Substitution of the alkyl group;
R 72 selected from C 3-6 Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-8 membered heteroaryl, 6-9 membered aryl, said cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally being further substituted with 1 to 3 groups selected from deuterium, halogen, hydroxy, amino, cyano, C 1-4 Alkyl, = O, C 1-4 Alkoxy, halo C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya Is substituted by a group of (2);
provided that when L 2 Selected from-NH-, R 72 Selected from- (CH) 2 ) r -4-12 membered heterocycloalkyl, 6-12 membered aryl or- (CH) 2 ) r -C 3-12 Cycloalkyl, one of the following conditions is satisfied: m is not 0, or X 12 、X 32 One selected from N, or R x2a 、R x3a Not simultaneously H; or alternatively
L 2 Selected from-NR La C(O)-**，R 72 Selected from C 3-6 Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 6-9 membered aryl, said cycloalkyl, heterocycloalkyl, aryl optionally being further substituted with 1 to 3 groups selected from deuterium, halogen, cyano, amino, hydroxy, C 1-4 Alkyl, = O, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -C (=o) -R cya Is substituted by a group of (2);
alternatively, -L 2 -R 72 Selected from CN, -C (O) N (C) 1-4 Alkyl group 2 A 5 membered heteroaryl group, said heteroaryl group optionally being further substituted with 1 to 3 deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya Is substituted by a group of (2);
R 73 、R 75 、R 76 、R 77 、R 78 、R 79 each independently selected from deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-8 membered heteroaryl, 6-9 membered aryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally being further substituted with 1 to 3 groups selected from R f Is substituted by a group of (2);
alternatively, -L 7 -R 77 Each independently selected from halogen, 5-9 membered heteroaryl, said heteroaryl optionally further substituted with 1-3 groups selected from R f Is substituted by a group of (2);
alternatively, -L 8 -R 78 、-L 9 -R 79 Each independently selected from C 3-6 Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-8 membered heteroaryl, 6-9 membered aryl, said cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally being further selected from 1 to 3R f Is substituted by a group of (2);
each R f Each independently selected from deuterium, halogen, cyano, amino, hydroxy, C 1-4 Alkyl, = O, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-8 membered heteroaryl, 6-8 membered aryl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya ；
R cya 、R cyb Each independently selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 An alkyl group;
other groups are as described in any of the preceding claims.
In another embodiment, the compounds of the present invention, stereoisomers, deuterated, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or co-crystals thereof, have the structure of formula (III-1), (III-2), (III-3), (III-5), (III-6), (III-7), (III-8), (III-9): wherein the method comprises the steps of
m is selected from 0, 1 or 2;
R 62 selected from deuterium, halogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, -C (O) NHCH 3 、-NHC(O)CH 3 、-N(CH 3 )C(O)CH 3 、-NHC(O)CH 2 CH 3 、-N(CH 3 )C(O)CH 2 CH 3 、-NH 2 、-NHCH 3 、-C(O)CH3、-C(O)CH 2 CH 3 The groups are further substituted by 1, 2 and 3 groups selected from F and deuterium;
R 69 selected from deuterium, F, cl, br, methyl, ethyl, propyl optionally further substituted with 1, 2, 3 groups selected from F, deuterium;
other groups are as described in any of the preceding claims.
In another embodiment, the compound of the present invention, stereoisomers, deuterated, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or co-crystals thereof, has the structure of formula (IV-1):
L 10 selected from-NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-；
R La Selected from hydrogen, deuterium;
R 710 selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-8 membered heteroaryl, 6-9 membered aryl, said cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally being further selected from 1 to 3R f Is substituted by a group of (2);
alternatively, -L 10 -R 710 Selected from C 3-6 Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-8 membered heteroaryl, 6-9 membered aryl, said cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally being further selected from 1 to 3R f Is substituted by a group of (2);
each R f Each independently selected from deuterium, halogen, C 1-4 Alkyl, =o;
other groups are as described in any of the preceding claims.
In another embodiment, the compound of the present invention, stereoisomers, deuterated, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or co-crystals thereof, has the structure of formula (V-1):
L 11 Selected from-NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-；
R La Selected from hydrogen, deuterium;
R 711 selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, - (CH) 2 ) 0-2 -5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-8 membered heteroaryl, 6-9 membered aryl, said cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally being further substituted by 1 to 3 groups selected from deuterium, halogen, C 1-4 Alkyl, =o, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya Is substituted by a group of (2);
R cya 、R cyb each independently selected from methyl, ethyl, propyl, butyl, -CH 2 F、-CH 2 CH 2 F、-CHF 2 、-CF 3 、-CH 2 CHF 2 、-CH 2 CHF 3 、-CH 2 D、-CH 2 CH 2 D、-CHD 2 、-CD 3 、-CH 2 CHD 2 、-CH 2 CHD 3 ；
Other groups are as described in any of the preceding claims.
In another embodiment, the compounds of the present invention, stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or co-crystals thereof, have the structure of formula (VI-1), (VI-2), (VI-3), (VI-4), (VI-5):
X 812 selected from-O-, -CR xa2 R xb2 -or-NR xa -；
X 813 、X 814 、X 815 Each independently selected from-O-, -CR xa R xb -or-NR xa -；
X 112 Selected from-CR x1b -；
X 212 Selected from-CR x2b -；
X 712 Selected from-CR x7b -；
R xa 、R xb 、R xa2 、R xb2 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further substituted with 1 to 3 groups selected from halogen, deuterium;
R x1b 、R x2b 、R x7b each independently selected from H, deuterium, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further substituted with 1 to 3 groups selected from F, cl, deuterium, hydroxy;
Provided that R x1b 、R x2b 、R x7b Not simultaneously selected from H;
alternatively, when R x1b 、R x2b 、R x7b At the same time selected from H, -L 12 -R 712 Selected from H;
alternatively, R's bound to the same carbon atom xa And R is xb Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
L 12 、L 13 、L 14 、L 15 each independently selected from-NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-；
R La Selected from hydrogen, deuterium;
R 712 、R 713 、R 714 、R 715 each independently selected from H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-8 membered heteroaryl, 6-9 membered aryl, said alkylOptionally further substituted with 1 to 3 groups selected from R f Is substituted by a group of (2);
alternatively, -L 13 -R 713 Selected from F, cl, 5-8 membered heteroaryl, optionally further substituted with 1 to 3 groups selected from R f Is substituted by a group of (2);
each R f Each independently selected from deuterium, halogen, hydroxy, C 1-6 Alkyl, = O, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya ；
R cya 、R cyb Each independently selected from methyl, ethyl, propyl, butyl, -CH 2 F、-CH 2 CH 2 F、-CHF 2 、-CF 3 、-CH 2 CHF 2 、-CH 2 CHF 3 、-CH 2 D、-CH 2 CH 2 D、-CHD 2 、-CD 3 、-CH 2 CHD 2 、-CH 2 CHD 3 ；
Other groups are as described in any of the preceding claims.
In another embodiment, a compound of the invention, a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, wherein
L 1 Selected from the group consisting of-NH-,* Represents L 1 And R is R 71 Linking site, R 71 Selected from the group consisting of
L 2 Selected from the group consisting of-NH-,* Represents L 2 And R is R 72 Is the connecting site of R 72 Selected from the group consisting of
Provided that when L 2 Selected from-NH-, R 72 Selecting When one of the following conditions is satisfied: m is not 0, or X 12 、X 32 One selected from N, or R x2a 、R x3a Not simultaneously H; or alternatively
L 2 Selected from the group consisting of* Represents L 2 And R is R 72 Is the connecting site of R 72 Selected from the group consisting of
Alternatively, -L 2 -R 72 Selected from CN, -C (O) N (CH) 3 ) 2 、
L 3 、L 5 、L 6 Each independently selected from the group consisting of-NH-,R 73 、R 75 、R 76 each independently selected from
L 7 、L 8 、L 9 Each independently selected from the group consisting of-NH-,R 77 、R 78 、R 79 Each independently selected from
Alternatively, -L 7 -R 77 Selected from F, br,
Alternatively, -L 8 -R 78 、-L 9 -R 79 Each independently selected from
-L 10 -R 710 Selected from the group consisting of
L 11 Each independently selected from the group consisting of-NH-,R 711 selected from the group consisting of
L 12 、L 13 、L 14 、L 15 Each independently selected from the group consisting of-NH-,R 712 、R 713 、R 714 、R 715 each independently selected from
Alternatively, -L 13 -R 713 Selected from F,
Other groups are as described in any of the preceding claims.
In some embodiments, the compounds of the invention, stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or co-crystals thereof, wherein the compounds are selected from any one of the structures having the formula (VII-1), formula (VII-2),
X 82 selected from-CR xa1 R xb1 -，R xa1 、R xb1 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Optionally further substituted by 1 to 3 groups selected from halogen, deuterium, R xa1 、R xb1 Capable of forming, together with the carbon atoms to which they are attached, a 3-to 5-membered cycloalkyl group, preferably R xa1 、R xb1 Forms a 3-membered cycloalkyl group with the carbon atom to which both are attached;
X 12 selected from-CR x1a -，X 32 Selected from-CR x3a -；
R x1a 、R x3a Each independently selected from hydrogen, deuterium, halogen, C 1-4 Any one of the group consisting of alkyl groups;
L 2 is-C (O) -, R 72 Selected from-NR cya R cyb 4-12 membered heterocycloalkyl, 6-12 membered aryl, heterocycloalkyl, 6-12 membered aryl optionally further substituted with 1 to 3 groups selected from halogen, deuterium, cyano, C 1-4 Alkoxy, halo C 1-4 Alkoxy, deuterated C 1-4 Alkoxy, =o, -C (=o) -R cya R is substituted by radicals of formula (I) cya 、R cyb Each independently selected from C 1-2 Alkyl, halogenated C 1-2 Alkyl, deuterated C 1-2 An alkyl group; or alternatively
L 2 is-NH-, -C (O) NR La A method for producing a composite material x-ray in the sense that, represents L 2 And R is R 72 Linking site, R 72 Selected from C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, 5-12 membered heteroaryl, 6-12 membered aryl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally further substituted with 1 to 3 groups selected from deuterium, halogen, nitro, cyano, =o, -C (=o) -R cya R is substituted by radicals of formula (I) cya Selected from C 1-2 Alkyl, halogenated C 1-2 Alkyl, deuterated C 1-2 An alkyl group; or alternatively
L 2 is-NR La C (O) -, represents L 2 And R is R 72 Linking site, R 72 Selected from C 3-12 Cycloalkyl, 4-12 membered saturated heterocycloalkyl, cycloalkyl, saturated heterocycloalkyl optionally further substituted with 1 to 3 groups selected from deuterium, halogen, nitro, cyano, =o, -C (=o) -R cya R is substituted by radicals of formula (I) cya Selected from C 1-2 Alkyl, halogenated C 1-2 Alkyl, deuterated C 1-2 An alkyl group;
as a means ofSelect, -L 2 -R 72 Selected from H or CN;
provided that when L 2 Selected from-NH-, R x3a Is not H;
X 715 selected from-CR x7a -or-N-, R x7a Selected from hydrogen, deuterium, halogen;
X 815 selected from-O-or-CR xa R xb -；R xa 、R xb Each independently selected from hydrogen, deuterium, halogen, C 1-4 An alkyl group optionally further substituted with 1 to 3 groups selected from halogen, deuterium, R xa 、R xb Capable of forming, together with the carbon atoms to which they are attached, a 3-to 5-membered cycloalkyl group, preferably R xa 、R xb Together with the carbon atoms to which they are attached, form a 3-membered cycloalkyl or 4-membered cycloalkyl;
Z 6 selected from a bond or-CR za R zb -，R za 、R zb Each independently selected from hydrogen;
L 15 selected from-NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-；
R 715 Selected from 4-12 membered heterocycloalkyl, 5-12 membered heteroaryl, optionally further substituted with 1 to 3 groups selected from C 1-2 Alkyl, = O, C 1-2 Alkoxy, halo C 1-2 Alkyl, halogenated C 1-2 Alkoxy, deuterated C 1-2 Alkyl, deuterated C 1-2 Alkoxy, -NR cya R cyb 、-C(＝O)-R cya R is substituted by radicals of formula (I) cya 、R cyb Each independently selected from C 1-2 Alkyl, halogenated C 1-2 Alkyl, deuterated C 1-2 An alkyl group.
In some embodiments, a compound of the invention, a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein
L 2 Is thatR 72 is-NR cya R cyb 、 Any one of the group consisting of wherein R' is selected from hydrogen, deuterium, halogen and C 1-4 Optionally further substituted with 1 to 3 groups selected from halogen, deuterium, optionally R' is H, deuterium, methyl, ethyl, propyl, butyl, -CH 2 F、-CH 2 CH 2 F、-CHF 2 、-CF 3 Any one of the group consisting of; r' is optionally methyl, ethyl, -CH 2 F、-CHF 2 、-CF 3 ；R cya 、R cyb Each independently is H, deuterium, methyl, ethyl, propyl, butyl, -CH 2 F、-CH 2 CH 2 F、-CHF 2 、-CF 3 、-CH 2 CHF 2 、-CH 2 CHF 3 、-CH 2 D、-CH 2 CH 2 D、-CHD 2 、-CD 3 、-CH 2 CHD 2 、-CH 2 CHD 3 Any one of the group consisting of R as an alternative cya 、R cyb Each independently is methyl, ethyl, -CH 2 F、-CHF 2 、-CF 3 ；
Or L 2 Is that* Represents L 2 And R is R 72 Linking site, R 72 Is that
Or L 2 Is that* Represents L 2 And R is R 72 Linking site, R 72 Is that
R xa1 、R xb1 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Optionally further substituted by 1 to 3 groups selected from halogen, deuterium, R xa 、R xb Capable of forming, together with the carbon atoms to which they are attached, a 3-to 5-membered cycloalkyl group, preferably R xa 、R xb Forms a 3-membered cycloalkyl group with the carbon atom to which both are attached;
-X 815 -Z 6 -is-O-CR xa R xb -or-CR xa R xb -，R xa 、R xb Each independently selected from hydrogen, deuterium, halogen, C 1-4 An alkyl group optionally further substituted with 1 to 3 groups selected from halogen, deuterium, R xa 、R xb Capable of forming, together with the carbon atoms to which they are attached, a 3-to 5-membered cycloalkyl group, preferably R xa 、R xb Together with the carbon atoms to which they are attached, form a 3-membered cycloalkyl or 4-membered cycloalkyl;
L 15 selected from-NH-, R 715 Is that
In some embodiments, a compound of the invention, a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein
In the above formula (VII-1), X 82 is-CH 2 -、C(CH 3 ) 2 Or cyclopropyl, X 12 Selected from-CH-, X 32 Selected from-CH-; l (L) 2 Is thatR 72 Is N (R) cya R cyb )、 Any one of the group consisting of R cya 、R cyb Each independently is methyl, ethyl, -CH 2 F、-CHF 2 、-CF 3 ；
Or L 2 Is that* Represents L 2 And R is R 72 Linking site, R 72 Is that
Or L 2 Is that* Represents L 2 And R is R 72 Linking site, R 72 Is that
In some embodiments, a compound of the invention, a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein
In the above formula (VII-2), -X 815 -Z 6 -is-O-CR xa R xb ，R xa 、R xb Each independently selected from any one of the group consisting of hydrogen, deuterium, and halogen; l (L) 15 Selected from-NH-, R 715 Is that
In some embodiments, the compounds of the present invention, stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or co-crystals thereof, wherein the compounds are selected from any one of the structures having the formula (VII-3), formula (VII-4)
Wherein X is 818 is-CR xa R xb -，R xa 、R xb Each independently selected from hydrogen, deuterium, halogen, C 1-4 An alkyl group, said alkyl group optionally being further substituted with 1 to 3 groups selected from halogen, deuterium, said R xa 、R xb Capable of forming, together with the carbon atoms to which they are attached, a 3-to 5-membered cycloalkyl group, preferably said R xa 、R xb Together with the carbon atoms to which they are attached, form a 3-membered cycloalkyl or 4-membered cycloalkyl;
L 18 selected from-NH-, R 718 Is that
L 7 Selected from-NH-, R 77 Is thatAlternatively L 7 Attached to the meta carbon atom of the five-membered heterocyclic ring of the benzene ring.
A compound of the invention, stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, wherein the compound is selected from the following structures:
a compound of the invention, stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, wherein the compound is selected from the following structures:
the invention also provides a pharmaceutical composition, which is characterized by comprising the compound in any one of the technical schemes, stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof and pharmaceutically acceptable carriers and/or excipients.
The invention also relates to the use of a compound according to any one of the preceding claims, a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or co-crystal thereof, or a composition thereof, in the manufacture of a medicament for the treatment of a PRMT5 mediated disorder; the PRMT5 mediated disease is a tumor.
Synthetic route
The compounds of the invention can be prepared by the person skilled in the art in combination with the WO2019173804A1 document and the known organic synthesis techniques starting from commercially available chemicals and/or compounds described in the chemical literature. "commercially available chemicals" are obtained from regular commercial sources and include: taitan technology, an Naiji chemistry, shanghai de moer, chengdu Kelong chemical, shaoguan chemical technology, nanjing medical stone, ming Kangde and Budweiser technologies.
The art references and monographs describe in detail the synthesis of reactants useful in the preparation of the compounds described herein or articles describing the preparation process are provided for reference. These references and monographs include: "Synthetic Organic Chemistry", john Wiley & Sons, inc., new York; S.R. Sandler et al, "Organic Functional Group Preparations,"2nd Ed., "Academic Press, new York,1983; h.o. house, "Modern Synthetic Reactions",2nd Ed., W.A.Benjamin, inc.Menlo Park, calif 1972; gilchrist, "Heterocyclic Chemistry",2nd Ed., john Wiley & Sons, new York,1992; march, "Advanced Organic Chemistry: reactions, mechanisms and Structure",4th Ed., wiley-Interscience, new York,1992; fuhrhop, J.and Penzlin G. "Organic Synthesis: peptides, methods, starting Materials", second, revised and Enlarged Edition (1994) John Wiley & Sons ISBN:3-527-29074-5; hoffman, R.V. "Organic Chemistry, an Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations"2nd Edition (1999) Wiley-VCH, ISBN:0-471-19031-4; march, J. "Advanced Organic Chemistry: reactions, mechanisms, and Structure"4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN:3-527-29871-1; patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN:0-471-93022-9; solomons, T.W.G. "Organic Chemistry"7th Edition (2000) John Wiley & Sons, ISBN:0-471-19095-0; stowell, J.C. "Intermediate Organic Chemistry"2nd Edition (1993) Wiley-Interscience, ISBN:0-471-57456-2; "Industrial Organic Chemicals: starting Materials and Intermediates An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN:3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.
Specific and similar reactants can be selectively identified by indexes of known chemicals prepared by american chemical abstracts, which are available in most public and university libraries and online. Chemicals known but not commercially available in catalogs are optionally prepared by custom chemical synthesis plants, many of which provide custom synthesis services (e.g., those listed above). References to the preparation and selection of pharmaceutically acceptable salts of the compounds described herein are p.h.stahl & c.g.weruth "Handbook of Pharmaceutical Salts", verlag Helvetica Chimica Acta, zurich,2002.
Terminology
Unless otherwise indicated herein, the terms of the present invention have the following meanings:
the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention include isotopes thereof, and the groups and compounds of the inventionThe carbon, hydrogen, oxygen, sulfur, nitrogen or halogen in question are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, sulfur include 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, fluorine 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
C x-y the expression group refers to a group containing from x to y carbon atoms, such as "C 1-6 Alkyl "refers to an alkyl group containing 1 to 6 carbon atoms.
"halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), iodine (I) or isotopes thereof.
"halo" or "halogen substituted" means that the hydrogen atom is substituted with one or more selected from F, cl, br, I or their isotopes, the upper limit of the number of halogen substituents being equal to the sum of the number of hydrogens that can be substituted by a substituent group, the number of halogen substituents being, without special limitation, any integer from 1 to the upper limit, preferably 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, 1 halogen substitution; when the number of halogen substituents is greater than 1, the same or different halogens may be substituted.
"halo C 1-6 Alkyl "refers to an alkyl group in which one or more hydrogens of the alkyl group containing 1-6 carbon atoms are replaced with one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine), the upper limit of the number of halogen substituents being equal to the sum of the number of hydrogens that may be substituted in the alkyl group, the number of halogen substituents being, without special limitation, any integer between 1 and this upper limit, preferably 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, or 1 halogen substitution; when the number of halogen substituents is greater than 1, which may be the same or different, halogen; including but not limited to-CF 3 、-CH 2 Cl、-CH 2 CF 3 、-CCl 2 、CF 3 Etc.
"deuterium" refers to the isotope deuterium of hydrogen (H).
"deuterated" or "deuterated" refers to the case where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl, alkynyl, etc., group is substituted with at least one deuterium atom, the upper limit of the number of deuterations being equal to the sum of the numbers of hydrogens that the substituted group may be substituted with, and the number of deuterations is any integer between 1 and this upper limit, preferably 1-20 deuterium atom substitutions, 1-10 deuterium atom substitutions, 1-6 deuterium atom substitutions, 1-3 deuterium atom substitutions, 1-2 deuterium atom substitutions, or 1 deuterium atom substitutions, without special limitation.
"alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, and unless otherwise specified, is an alkyl group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, still more preferably an alkyl group of 1 to 4 carbon atoms, and yet more preferably an alkyl group of 1-2 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like; the alkyl group may be further substituted with an optional substituent.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, the alkyl group being as defined above.
"alkenyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond (c=c), and unless otherwise specified, is predominantly comprised of 2 to 18 (e.g., 2 to 8, further such as 2 to 6, still further such as 2 to 4) carbon atoms, including but not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-pentadienyl, 1, 4-pentadiene, and the like; the alkenyl group may be optionally further substituted with any group.
"alkynyl" refers to a hydrocarbon group containing at least one carbon-carbon triple bond (C.ident.C) straight chain hydrocarbon group, branched hydrocarbon group, the backbone comprising from 2 to 18 (e.g., from 2 to 8, further such as from 2 to 6, still further such as from 2 to 4) carbon atoms. Ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl and the like; the alkynyl group may optionally be further substituted with any substituent.
"alkoxy" or "alkyloxy" refers to-O-alkyl, where not specifically defined, is-O-C 1-8 Alkyl, preferably-O-C 1-6 Alkyl, more preferably-O-C 1-4 Alkyl, more preferably-O-C 1-2 An alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy groups, and the like; the alkoxy group may optionally be further substituted with any substituent.
"haloalkoxy" means-O-haloalkyl, not specifically defined, and is-O-haloC 1-8 Alkyl, preferably-O-halo C 1-6 Alkyl, more preferably-O-halo C 1-4 Alkyl, more preferably-O-halo C 1-2 An alkyl group; the upper limit of the number of halogen substituents is equal to the sum of the numbers of hydrogens which the substituted group may be substituted, and the number of halogen substituents is any integer from 1 to the upper limit, preferably 1 to 5 halogen substitutions, 1 to 3 halogen substitutions, 1 to 2 halogen substitutions, 1 halogen substitution, without being particularly limited; when the number of halogen substituents is greater than 1, the same or different halogens are substituted; non-limitingExamples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.
"cycloalkyl" refers to a hydrocarbon ring which is a substituted or unsubstituted, saturated, partially unsaturated or fully unsaturated, non-aromatic ring, which may be monocyclic, bicyclic or polycyclic, and bicyclic or polycyclic may be a fused, spiro or bridged ring, and typically has 3 to 20 carbon atoms unless otherwise specified; when monocyclic cycloalkyl, preferably 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, still more preferably 3 to 4 carbon atoms; in the case of a bicyclic or polycyclic cycloalkyl group, preferably 4 to 12 carbon atoms, preferably 4 to 11 carbon atoms, more preferably 5 to 11 carbon atoms, more preferably 6 to 11 carbon atoms, still more preferably 6 to 10 carbon atoms; non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl, Etc.
"heterocycloalkyl" means a substituted or unsubstituted, saturated, partially unsaturated or fully unsaturated, non-aromatic ring containing at least one heteroatom, where unless otherwise specified, heterocycloalkyl is a 3 to 20 membered ring, preferably 3 to 15 membered, preferably 3 to 10 membered, more preferably 3 to 8 membered, even more preferably 3 to 6 membered, when a monocyclic heterocycloalkyl; when a bicyclic or polycyclic heterocycloalkyl group, it is preferably 4 to 12 membered, preferably 4 to 11 membered, more preferably 5 to 11 membered, still more preferably 6 to 10 membered; heterocycloalkyl may be monocyclic, bicyclic or polycyclic being bridged, fused and spiro, wherein the heteroatom is selected from N, S, O, P, si heteroatom and its oxidation state; when the heterocycloalkyl group is a double ring or a multiple ring, at least one of the rings contains at least one heteroatom, and the heterocyclic ring can be a double ring or a multiple ring formed by a ring containing the heteroatom and a ring not containing the heteroatom; when attached to other groups, it may be a heteroatom or a carbon atom as the point of attachment; non-limiting examples include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, pyranyl, azacyclopentenyl, azahexenyl, oxapentenyl, oxahexenyl, and the like.
"aryl" refers to a substituted or unsubstituted 5 to 15 membered aromatic carbocyclic ring, including monocyclic and fused ring aromatic groups. Preferably a 5-to 10-membered aromatic ring, further preferably a 5-to 8-membered aromatic ring; the aryl ring may be fused to a non-aryl ring (such as a heteroaryl, heterocycloalkyl, or cycloalkyl ring) wherein the aryl ring is a linking site, non-limiting examples include phenyl, naphthyl, anthracenyl, phenanthrenyl,
The aryl group may be optionally further substituted with any substituent.
"heteroaryl" or "heteroaryl" refers to a substituted or unsubstituted aromatic ring containing at least one heteroatom or group selected from N, S, O, P, si heteroatoms and oxidation state thereof, which may be monocyclic, bicyclic or polycyclic, and which may be bridged, fused or spiro; when bicyclic or polycyclic, it may be a heteroaryl to non-heteroaryl ring such as cycloalkyl, heterocycloalkyl, aryl fused, or heteroaryl to heteroaryl fused, wherein the heteroaryl ring is the attachment site; non-limiting examples include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, purinyl, Etc.; the heteroaryl group may be optionally further substituted with any substituent.
"carboxyl" refers to-C (=o) -OH.
"spiro" refers to a 5-to 20-membered polycyclic group between substituted or unsubstituted rings that shares a single carbon atom (referred to as a spiro atom), which may contain from 0 to 5 double bonds, and which may contain from 0 to 5 heteroatoms or groups selected from N, O, S, P, si and their oxidation states. Preferably 6 to 14 membered, more preferably 6 to 12 membered, even more preferably 6 to 10 membered spiro ring; the spiro ring may be formed between cycloalkyl, heterocycloalkyl; preferably trispirotriose (representing a ternary ring of a ternary ring screw), trispirotriose, trispirohexa, tetraspirohexa, pentaspiraohexa or pentaspiraohexa; non-limiting examples of rings include
The spiro ring may be optionally further substituted with any substituent.
"fused ring" means a polycyclic group wherein the rings share two adjacent atoms with the rings, wherein one or more of the rings may contain 0 or more double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain from 0 to 5 heteroatoms selected from N, S, O, P, si and oxidation states thereof. Preferably 5 to 20 membered, more preferably 5 to 14 membered, still more preferably 5 to 12 membered, still more preferably 5 to 10 membered. Preferably a tri-and tetra-ring (meaning that the tri-and tetra-rings form A three-membered ring as a basic ring or a four-membered ring as a basic ring according to IUPC naming rules, and the same shall apply hereinafter), a three-membered five-membered ring, a three-membered six-membered ring, non-limiting examples of tetratetracyclic, tetrapentacyclic, tetrahexacyclic, pentapentacyclic, pentahexacyclic, hexahexacyclic include purines, quinolines, isoquinolines, benzopyrans, benzofurans, benzothiophenes, The depicted acenes may optionally be further substituted with any substituent.
"bridged ring" means that two rings share two non-adjacent atoms, may contain 0 or more double bonds, and may be substituted or unsubstituted, wherein one or more of the rings may contain 0 to 5 heteroatoms selected from N, S, O, P, si and oxidation states thereof; the ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, further preferably 5 to 12, still further preferably 5 to 10; non-limiting examples include adamantane
The heteroatom according to the invention is selected from N, O, S, si, P atoms and their oxidized forms.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl may be, but is not necessarily, substituted with F, and is intended to include both cases where the alkyl is substituted with F and cases where the alkyl is not substituted with F.
The groups described herein are substituted with substituents, which are not specifically described as being substituted at positions where chemical theory permits, the number of substituents conforming to the rules of chemical bonding.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the invention which retain the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base.
"pharmaceutical composition" means a mixture of one or more compounds described herein or stereoisomers, solvates, pharmaceutically acceptable salts, co-crystals, deuterides, and other constituent ingredients thereof, wherein the other ingredients comprise a physiologically/pharmaceutically acceptable carrier and/or excipient.
"vector" means: non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc., which do not significantly stimulate the organism and do not eliminate the biological activity and properties of the administered compound, and which alter the manner and distribution of the drug into the body, control the release rate of the drug and deliver the drug to the targeted organ.
"excipient" means: which are not therapeutic agents per se, act as diluents, adjuvants, binders and/or vehicles for addition to pharmaceutical compositions to improve their handling or storage properties or to allow or facilitate the formation of unit dosage forms of the compound or pharmaceutical composition for administration. As known to those skilled in the art, pharmaceutically acceptable excipients may provide various functions and may be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutically acceptable excipients include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and croscarmellose (e.g., sodium croscarmellose); (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) a pH buffer solution; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances for use in pharmaceutical formulations.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
"solvate" refers to a substance formed by a chemical or non-chemical solvent to which a compound of the invention or a salt thereof is non-covalently bound to an intermolecular force. When the solvent is water, it is a hydrate.
"co-crystals" refers to crystals of Active Pharmaceutical Ingredient (API) and co-crystal former (CCF) that are bound by hydrogen bonds or other non-covalent bonds, wherein the pure states of the API and CCF are both solid at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.
Detailed Description
The following will describe the content of the present invention in detail by way of examples. The experimental procedures were carried out under conventional conditions without specifying the specific conditions in the examples. The examples are presented for better illustration of the present invention but are not to be construed as limiting the present invention to only the examples presented. Those skilled in the art will appreciate that various modifications and adaptations of the embodiments described above are possible and can be made without departing from the scope of the invention.
Test method
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR shift (. Delta.) is given in units of 10-6 (ppm). NMR was performed using a (Bruker Avance III and Bruker Avance 300) magnetonuclear instrument with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) and an internal standard of Tetramethylsilane (TMS);
MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X14.6mm, 3.5. Mu.M);
the thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;
column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.
Intermediate 1:
6-bromo-2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -3, 4-dihydroisoquinolin-1 (2H) -one (intermediate 1)
6-bromo-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
The first step:
6-bromo-2- (oxiran-2-ylmethyl) -3, 4-dihydroisoquinolin-1 (2H) -one (1 b)
6-bromo-2-(oxiran-2-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one
1a (2.26 g,10 mmol) was dissolved in dry N.N-dimethylformamide (30 mL), cooled to 0℃under nitrogen, sodium hydrogen (0.44 g,11mmol,60% wt) was added in portions, and after the addition was completed, bromomethyl ethylene oxide (1.64 g,12 mmol) was added dropwise to the system after 30 minutes of reaction. After the addition, the reaction was carried out at room temperature for 1 hour. The reaction was quenched with water (100 mL), extracted with ethyl acetate (100 ml×2), the organic phases combined, washed with saturated brine (100 ml×1), dried over anhydrous sodium sulfate, filtered, and the residue concentrated under reduced pressure was separated by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =2:1) to give the target compound 6-bromo-2- (oxiran-2-ylmethyl) -3, 4-dihydroisoquinolin-1 (2H) -one (1 b) (1.8 g, 64% yield).
LCMS m/z＝282.0/284.0[M+H] + .
And a second step of:
6-bromo-2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -3, 4-dihydroisoquinolin-1 (2H) -one (intermediate 1)
6-bromo-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
Compound 1b (1.8 g,6.4 mmol) was dissolved in isopropanol (20 mL), and 1,2,3, 4-tetrahydroisoquinoline (0.85 g,6.4 mmol) was added and reacted overnight at room temperature. After the reaction was completed, the mixture was filtered, and the cake was washed with a small amount of isopropyl alcohol and dried in vacuo to give the title compound 6-bromo-2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -3, 4-dihydroisoquinolin-1 (2H) -one (intermediate 1) (1.76 g, yield 66%).
LCMS m/z＝415.1/417.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.92(d,1H),7.47(dd,1H),7.35(d,1H),7.17-7.07(m,3H),7.03–6.96(m,1H),4.17-4.08(m,1H),3.90–3.58(m,6H),3.43(dd,1H),3.01–2.70(m,5H),2.68-2.62(m,1H),2.58-2.49(m,1H).
Intermediate 1 was prepared via chiral SFC to give two isomers.
Intermediate 1, isomer 1:
LCMS m/z＝415.1/417.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.92(d,1H),7.47(dd,1H),7.35(d,1H),7.17-7.07(m,3H),7.03–6.96(m,1H),4.17-4.08(m,1H),3.89–3.57(m,6H),3.43(dd,1H),3.01–2.70(m,5H),2.68-2.62(m,1H),2.58-2.48(m,1H).
intermediate 1, isomer 2:
LCMS m/z＝415.1/417.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.92(d,1H),7.47(dd,1H),7.35(d,1H),7.17-7.07(m,3H),7.03–6.95(m,1H),4.17-4.08(m,1H),3.90–3.58(m,6H),3.43(dd,1H),3.01–2.71(m,5H),2.68-2.62(m,1H),2.58-2.49(m,1H).
the preparation conditions are as follows: instrument Waters SFC 350, preparative column DAICEL CHIRALPAK AD (250 mm. Times.50 mm,10 μm), mobile phase A for CO 2 And B for IPA+ACN (0.1% NH) 3 ·H 2 O), gradient of 80% phase B, flow rate of 180mL/min, back pressure of 100bar, column temperature of 35 ℃, wavelength of 220nm, circulation time of 8.2min, sample pretreatment, dissolving compound in methanol dichloromethane system, concentration of 40mg/mL, injection of 10mL per needle.
The analysis method comprises the following steps: the apparatus was SHIMADZU LC-30ADsf, column: chiralpak AD-3.50X4.6 mm I.D.,3 μm, mobile phase: A for CO 2 And B for IPA+ACN (0.05% DEA), gradient: 40% phase B, flow rate: 3mL/min, back pressure: 100bar, column temperature: 35 ℃, wavelength: 220nm. Retention time: isomer 1: tr=1.02 min; isomer 2: tr=1.45 min.
Intermediate 2:
the synthesis of intermediate 2 is described in WO 2014100719.
Example 1: (R) -5-bromo-2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) isoindol-1-one (Compound 1)
(R)-5-bromo-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)isoindolin-1-one
(Compound 1)
The first step: 4-bromo-2- (bromomethyl) benzoic acid methyl ester (1B)
methyl 4-bromo-2-(bromomethyl)benzoate(1B)
1A (3 g,13.10 mmol) was dissolved in carbon tetrachloride (50 mL), N-bromosuccinimide (2.45 g,13.77 mmol) and dibenzoyl peroxide (0.9 g,3.72 mmol) were added under nitrogen and reacted at 80℃for 2h. The mixture was cooled to room temperature, most of the solvent was removed by rotary evaporation under reduced pressure, 40mL of water was added to the residue, extraction was performed with ethyl acetate (20 ml×3), the organic layers were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =10:1) to give the title compound 1B (3.3 g, 81%).
LC-MS(ESI):m/z＝308.9[M+H] + .
And a second step of: (R) -5-bromo-2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) isoindol-1-one (Compound 1)
(R)-5-bromo-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)isoindolin-1-one
(Compound 1)
1B (0.5 g,1.62 mmol), intermediate 2 (0.5 g,2.43 mmol) and N, N-diisopropylethylamine (1.05 g,8.10 mmol) were dissolved in DMF (20 mL) and reacted at 80℃for 16h under nitrogen. Cooled to room temperature, 30mL of water was added, extracted with ethyl acetate (15 ml×5), the organic layers were combined, dried over anhydrous sodium sulfate, and the residue after concentration was purified by column chromatography on silica gel (dichloromethane: methanol (v/v) =20:1) to give the title compound 1 (0.22 g, 34%).
1 H NMR(400MHz,CD 3 OD)δ7.70(d,J＝8.8Hz,1H),7.51–7.44(m,2H),7.21–7.11(m,4H),4.58(d,J＝12.0,1H),4.35(d,J＝12.0,1H),4.16–4.08(m,1H),3.87–3.73(m,3H),3.58–3.46(m,2H),2.95–2.82(m,3H),2.79–2.62(m,3H).
LC-MS(ESI):m/z＝401.1[M+H] + .
Example 2 2- (3, 4-Dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-6-carbonitrile (Compound 2, single isomer)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile(Compound 2,single isomer)
Intermediate 1, isomer 2 (0.20 g,0.48 mmol) was dissolved in N, N-dimethylformamide (10 mL), and zinc cyanide (0.11 g,0.96 mmol) and 4- (triphenylphosphine) palladium (0.10 g,0.086 mmol) were added and reacted at 100℃for 3 hours after the addition. Cooled to room temperature, filtered, water (80 mL) was added, extracted with ethyl acetate (20 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane: methanol (v/v) =20:1-10:1) to give the title compound 2 (0.10 g, 57.6%).
LC-MS(ESI):m/z＝362.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.17–8.15(m,1H),7.64–7.62(m,1H),7.51(s,1H),7.18–7.10(m,3H),7.01–6.99(m,1H),4.20–4.14(m,1H),3.94–3.65(m,5H),3.46–3.41(m,1H),3.07–2.91(m,5H),2.82–2.68(m,2H),2.60–2.54(m,1H).
Example 3, 2- (3, 4-Dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -3, 4-Dihydroisoquinolin-1 (2H) -one (Compound 3, single isomer)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
(Compound 3,single isomer)
Intermediate 1, isomer 2 (0.20 g,0.48 mmol) was dissolved in methanol (10 mL), palladium on carbon (0.05 g, 10%) was added and reacted at room temperature under hydrogen atmosphere for 24 hours. Filtration, concentration, and purification of the residue by silica gel column chromatography (dichloromethane: methanol (v/v) =20:1-10:1) gave the title compound 3 (0.10 g, 61.9%).
LC-MS(ESI):m/z＝337.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.08–8.06(m,1H),7.44–7.32(m,2H),7.19–7.09(m,4H),7.01–6.99(m,1H),4.19–4.13(m,1H),3.92–3.64(m,5H),3.51–3.46(m,1H),3.02–2.86(m,5H),2.80–2.75(m,1H),2.71–2.67(m,1H),2.61–2.56(m,1H).
Example 4, 2- (3, 4-Dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -N, N-dimethyl-1-oxo 1,2,3, 4-tetrahydroisoquinoline-6-carboxamide (Compound 4, single isomer)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-N,N-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Compound 4,single isomer)
The first step: 2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid (4A, single isomer)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid(4A,single isomer)
Compound 2 (1.7 g,4.87 mmol) was dissolved in methanol (10 mL), concentrated hydrochloric acid (20 mL) was added, and the tube was sealed after the addition was completed and reacted at 80℃for 16 hours. Cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) =20:1-10:1) to give the title compound 4A (1.2 g, 62.5%).
LC-MS(ESI):m/z＝381.2[M+H] + .
And a second step of: 2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -N, N-dimethyl-1-oxo 1,2,3, 4-tetrahydroisoquinoline-6-carboxamide (Compound 4, single isomer)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-N,N-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Compound 4,single isomer)
4A (0.12 g,0.32 mmol) was dissolved in dichloromethane (10 mL), dimethylamine (0.055 g,0.38 mmol), N, N-diisopropylethylamine (0.12 g,0.96 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.16 g,0.42 mmol) were added and reacted at room temperature for 1 hour after the addition. Concentration and purification of the residue by column chromatography on silica gel (dichloromethane: methanol (v/v) =40:1-10:1) gave the title compound 4 (0.05 g, 38.3%).
LC-MS(ESI):m/z＝408.3[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.09–8.07(m,1H),7.35–7.33(m,1H),7.26(s,1H),7.17–7.09(m,3H),7.02–7.00(m,1H),4.68–4.63(m,1H),4.20–4.14(m,1H),3.92–3.65(m,5H),3.50–3.44(m,1H),3.12–2.91(m,10H),2.81–2.76(m,1H),2.72–2.68(m,1H),2.61–2.55(m,1H).
Example 5, N- (3, 3-Difluorocyclobutyl) -2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-6-carboxamide (Compound 5, single isomer)
N-(3,3-difluorocyclobutyl)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Compound 5,single isomer)
The intermediate 4A and 3, 3-difluoro-cyclobutylamine are taken as raw materials, and the compound 5 is synthesized by referring to the synthesis method of the compound 4.
LC-MS(ESI):m/z＝470.4[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.07–8.05(m,1H),7.65–7.62(m,2H),7.17–7.09(m,3H),7.01–6.99(m,1H),6.60–6.58(m,1H),4.52–4.42(m,1H),4.19–4.13(m,1H),3.93–3.64(m,5H),3.46–3.41(m,1H),3.16–2.90(m,7H),2.80–2.75(m,1H),2.70–2.54(m,4H).
Example 6, 2- (3, 4-Dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -6- (piperazine-1-carbonyl) -3, 4-Dihydroisoquinolin-1 (2H) -one (Compound 6, single isomer)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(piperazine-1-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one(Compound 6,single isomer)
The first step: tert-butyl 4- (2- (3- (3- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-6-carbonyl) piperazine-1-carboxylate (6A)
tert-butyl 4-(2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)piperazine-1-carboxylate(6A)
The title compound 6A was synthesized using intermediate 4A and N-Boc piperazine as starting materials with reference to the synthesis of compound 4.
And a second step of: 2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -6- (piperazine-1-carbonyl) -3, 4-dihydroisoquinolin-1 (2H) -one (Compound 6, single isomer)
(R)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(piperazine-1-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one(Compound 6,single isomer)
6A (0.20 g,0.36 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added, and the reaction was carried out at room temperature for 3 hours after the addition was completed. Concentration and purification of the residue by silica gel column chromatography (dichloromethane: methanol (v/v) =20:1-10:1) gave the title compound 6 (0.11 g, 68.1%).
LC-MS(ESI):m/z＝449.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.10–8.08(m,1H),7.33–7.31(m,1H),7.26(s,1H),7.17–7.09(m,3H),7.01–6.99(m,1H),4.18–4.12(m,1H),3.92–3.63(m,7H),3.49–3.39(m,3H),3.04–2.73(m,10H),2.70–2.65(m,1H),2.59–2.53(m,1H).
Example 7, 6- (3-oxa-8-azabicyclo [3.2.1] octane-8-carbonyl) -2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -3, 4-dihydroisoquinolin-1 (2H) -one (Compound 7, single isomer)
6-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one(Compound 7,single isomer)
The compound 7 is synthesized by taking an intermediate 4A and 3-oxa-8-azabicyclo [3.2.1] octane hydrochloride as raw materials and referring to a synthesis method of the compound 4.
LC-MS(ESI):m/z＝476.3[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.11–8.09(m,1H),7.41–7.39(m,1H),7.36(s,1H),7.17–7.09(m,3H),7.01–6.99(m,1H),4.73(s,1H),4.19–4.13(m,1H),3.93–3.59(m,10H),3.49–3.44(m,1H),3.05–2.90(m,5H),2.80–2.75(m,1H),2.71–2.67(m,1H),2.60–2.55(m,1H),2.06–1.97(m,4H).
Example 8, N- (1-Acetylpiperidin-4-yl) -2- (3, 4-dihydro-isoquinolin-2 (1H) -yl) -2-hydroxypropyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-6-carboxamide (Compound 8, single isomer)
N-(1-acetylpiperidin-4-yl)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Compound 8,single isomer)
The intermediate 4A and 1-acetylpiperidin-4-amine are used as raw materials, and the compound 8 is synthesized by referring to the synthesis method of the compound 4.
LC-MS(ESI):m/z＝505.3[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.10–8.08(m,1H),7.66–7.65(m,2H),7.17–7.09(m,3H),7.01–6.99(m,1H),6.33–6.32(m,1H),4.63–4.59(m,1H),4.25–4.14(m,2H),3.92–3.65(m,6H),3.47–3.41(m,1H),3.26–3.19(m,1H),3.06–2.92(m,5H),2.81–2.67(m,3H),2.60–2.55(m,1H),2.18–2.03(m,5H),1.49–1.39(m,2H).
Example 9, 2- (3, 4-Dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -1-oxo-N- (pyridazin-4-yl) -1,2,3, 4-tetrahydroisoquinoline-6-carboxamide (Compound 9, single isomer)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-N-(pyridazin-4-yl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Compound 9,single isomer)
The intermediate 4A and 4-aminopyridazine are taken as raw materials, and the compound 9 is synthesized by referring to a synthesis method of the compound 4.
LC-MS(ESI):m/z＝458.3[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ9.58(s,1H),9.49–9.48(m,1H),9.02–9.00(m,1H),8.29–8.27(m,1H),7.96–7.94(m,1H),7.80–7.78(m,2H),7.18–7.09(m,3H),7.01–6.99(m,1H),4.23–4.17(m,1H),3.91–3.69(m,5H),3.45–3.40(m,1H),3.03–2.83(m,6H),2.74–2.70(m,1H),2.65–2.59(m,1H).
Example 10: 1-acetyl-N- (2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinolin-6-yl) piperidine-4-carboxamide (Compound 10, single isomer)
1-acetyl-N-(2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperidine-4-carboxamide(Compound 10,single isomer)
The first step: 6-amino-2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -3, 4-dihydroisoquinolin-1 (2H) -one (10A, single isomer)
6-amino-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
Intermediate 1, isomer 2 (0.41 g,1.0 mmol), benzophenone imine (0.27 g,1.5 mmol), bis (2-diphenylphosphinophenyl) ether (54 mg,0.1 mmol), pd 2 (dba) 3 (47 mg,0..05 mmol) and sodium t-butoxide (0.19 g,2 mmol) were dissolved in dry 1, 4-dioxane (20 mL) and reacted at 105℃for 2 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate (80 mL), and saturated NaHCO was added 3 The solution (80 mL) was separated, the aqueous phase was extracted with ethyl acetate (80 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was concentrated and added to tetrahydrofuran (20 mL) and hydrochloric acid (10 mL,1N aqueous solution) and stirred for 1 hour. The pH was adjusted to alkaline with saturated sodium bicarbonate and extracted with ethyl acetate (80 mL). Washing with saturated saline, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating by silica gel column chromatography (methanol: dichloromethane (v/v) =0:1-1:30) to obtain the target compound 6-amino-2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -3, 4-dihydroisoquinolin-1 (2H) -one (10A) (0.21 g, yield 60%).
LCMS m/z＝352.2[M+H] + .
And a second step of: 1-acetyl-N- (2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinolin-6-yl) piperidine-4-carboxamide (Compound 10, single isomer)
1-acetyl-N-(2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperidine-4-carboxamide
10A (0.21 g,0.6 mmol) was dissolved in acetonitrile (10 mL) and 1-acetyl-4-piperidinecarboxylic acid (0.1 g,0.6 mmol) and N-methylimidazole (0.25 g,3 mmol) were added sequentially. After stirring uniformly, N, N, N ', N' -tetramethyl chloroformidine hexafluorophosphate (0.20 g,0.72 mmol) was added, and after the addition, the reaction was carried out at room temperature for 1 hour. Water (30 mL) was added, extracted with ethyl acetate (60 mL. Times.2), the organic phase was washed with saturated aqueous sodium chloride (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated by silica gel column chromatography (DCM: meOH (v/v) =10:1) to give compound 10 (0.13 g, yield 43%).
LCMS m/z＝505.3[M+H] + .
1 H NMR(400MHz,CD 3 OD)δ7.89(d,1H),7.64(d,1H),7.47(dd,1H),7.17–6.99(m,4H),4.58(d,1H),4.28-4.20m,1H),4.03(d,1H),3.90(dd,1H),3.83–3.68(m,4H),3.44–3.34(m,1H),3.28–3.15(m,1H),3.08–2.99(m,2H),2.99–2.84(m,4H),2.82–2.59(m,4H),2.14(s,3H),1.99–1.88(m,2H),1.84–1.60(m,2H).
Example 11:2- (3- (6, 7-Dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) -2-hydroxypropyl) -7- (pyridazin-4-ylamino) -3, 4-Dihydroisoquinolin-1 (2H) -one (Compound 11)
2-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-7-(pyridazin-4-ylamino)-3,4-dihydroisoquinolin-1(2H)-one
The first step: 1-chloro-3- (6, 7-dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) propan-2-ol (11B)
1-chloro-3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)propan-2-ol
11A (1.4 g,10.06 mmol) and epichlorohydrin (0.93 g,10.06 mmol) were dissolved in isopropanol (20 mL) at room temperature and stirred overnight at room temperature, TLC monitored complete reaction of starting material and dried by spin-drying (PE: EA=2:1) to give compound 11B (1.6 g, 68% yield).
LCMS m/z＝232.1[M+H] + .
And a second step of: 7-bromo-2- (3- (6, 7-dihydrothieno [3,2-C ] pyridin) -5 (4H) -yl) -2-hydroxypropyl) -3, 4-dihydroisoquinolin-1 (2H) -one (11C)
7-bromo-2-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
7-bromo-3, 4-dihydro-2H-isoquinolin-1-one (1.6 g,6.9 mmol) was added in portions to a suspension of sodium hydrogen in DMF (10 mL) at 0deg.C, and after completion of the addition, a solution of 11B (1.56 g,6.9 mmol) in DMF (10 mL) was added dropwise and reacted at 70deg.C for 5H. 300mL of water were added, extracted twice with ethyl acetate, the combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 11C (0.8 g, yield 28%) by silica gel column chromatography (DCM: meOH=20:1).
LCMS m/z＝421.0/423.0[M+H] + .
And a third step of: 2- (3- (6, 7-Dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) -2-hydroxypropyl) -7- (pyridazin-4-ylamino) -3, 4-Dihydroisoquinolin-1 (2H) -one (Compound 11)
2-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-7-(pyridazin-4-ylamino)-3,4-dihydroisoquinolin-1(2H)-one
Reaction 11C (0.5 g,1.19 mmol), 4-aminopyridazine (0.23 g,2.38 mmol) was dissolved in 1, 4-dioxane (50 mL), to which was added sodium t-butoxide (0.23 g,2.38 mmol), pd 2 (dba) 3 (0.22 g,0.24 mmol), xantphos (0.28 g,0.48 mmol), nitrogen blanket, 100℃for 1h. After the reaction cooled to room temperature and concentrated under reduced pressure, DCM (10 mL) was added to the residue, celite was filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography (DCM/CH 3 Oh=0% -20%) to give the target compound 11 (0.1 g, 20% yield).
LCMS m/z＝436.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.89(d,1H),8.65(dd,1H),7.91(d,1H),7.66(s,1H),7.33-7.30(m,1H),7.21-7.19(m,1H),7.09(d,1H),6.97-6.95(m,1H),6.70(d,1H),4.19-4.13(m,1H),3.92–3.71(m,4H),3.61-3.57(m,1H),3.49-3.44(m,1H),3.01-2.97(m,4H),2.90-2.87(m,2H),2.85-2.79(m,1H),2.75-2.70(m,1H),2.61-2.55(m,1H).
Example 12:7' - ((1-Acetylpiperidin-4-yl) amino) -2' - (3- (6, 7-dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) -2-hydroxypropyl) -2',3' -dihydro-1 ' H-spiro [ cyclopropan-1, 4' -isoquinolin-1 ' -one (compound 12)
7'-((1-acetylpiperidin-4-yl)amino)-2'-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
The first step: 5- (oxiran-2-ylmethyl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine (12A)
5-(oxiran-2-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
11A (0.4 g,2.88 mmol) and epibromohydrin (0.59 g,4.32 mmol) were dissolved in THF (20 mL) at room temperature, potassium carbonate (1.2 g,8.64 mmol) was added thereto, stirred overnight at room temperature, TLC monitored complete reaction of the starting materials, and the reaction solution was concentrated and then separated by column chromatography (PE: EA=4:1) to give compound 12A (0.4 g, 71% yield).
LCMS m/z＝232.1[M+H] + .
And a second step of: 7' - ((1-Acetylpiperidin-4-yl) amino) -2' - (3- (6, 7-dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) -2-hydroxypropyl) -2',3' -dihydro-1 ' H-spiro [ cyclopropan-1, 4' -isoquinolin-1 ' -one (compound 12)
7'-((1-acetylpiperidin-4-yl)amino)-2'-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
12B (synthesized in reference to WO 2020259478) (0.2 g,0.64 mmol) was added in portions to a suspension of sodium hydrogen (23 mg,0.96 mmol) in DMF (10 mL) at 0deg.C, and after the addition was completed, the reaction was continued at 0The reaction was carried out at a temperature of 0.5h, a solution of 12A (0.12 g,0.64 mmol) in DMF (2 mL) was added dropwise, and the mixture was allowed to react overnight at room temperature after completion of the dropwise addition. The reaction was quenched by addition of 10mL of saturated aqueous ammonium chloride, the residue was extracted twice with ethyl acetate, the combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the column chromatographed (DCM: CH 3 Oh=4:1) to give the objective compound 12 (20 mg, yield 6%).
LCMS m/z＝509.3[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.34-7.33(m,1H),7.15(d,1H),6.73(d,1H),6.67-6.65(m,2H),4.50-4.47(m,1H),4.28-4.27(m,1H),3.80-3.75(m,3H),3.60-3.53(m,5H),3.23-3.17(m,3H),3.04-2.81(m,6H),2.10(s,3H),1.33-1.25(m,5H),0.97-0.91(m,4H).
Example 13 (R) -5- ((1-Acetylpiperidin-4-yl) amino) -2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) isoindolin-1-one (Compound 13)
(R)-5-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)isoindolin-1-one(Compound 13)
Compound 1 (0.50 g,1.25 mmol) was dissolved in dry dioxane (20 mL) and 1-acetylpiperidin-4-amine (0.36 g,2.50 mmol), sodium t-butoxide (0.36 g,3.75 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.58 g,1.01 mmol) and bis-dibenzylideneacetone palladium (0.14 g,0.25 mmol) were added sequentially. After 3 hours of reaction at 100 ℃ under nitrogen protection, filtration and concentration, the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) =10:1) to give the title compound 13 (15 mg, 2.6%).
LC-MS(ESI):m/z＝463.3[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.63–7.61(m,1H),7.17–7.09(m,3H),7.01–6.99(m,1H),6.64–6.61(m,1H),6.57(s,1H),4.53–4.50(m,3H),4.17–4.10(m,1H),3.97–3.95(m,1H),3.89–3.77(m,3H),3.70–3.66(m,1H),3.60–3.55(m,2H),3.26–3.20(m,1H),3.00–2.90(m,3H),2.87–2.78(s,2H),2.73–2.69(m,1H),2.63–2.57(m,1H),2.16–2.07(m,5H),1.45–1.33(m,2H).
Example 14:2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -6- (2-methoxy-7-azaspiro [3.5] nonane-7-carbonyl) -3, 4-dihydroisoquinolin-1 (2H) -one (Compound 14, single isomer)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(2-methoxy-7-azaspiro[3.5]nonane-7-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one(Compound 14)
The compound 14 is synthesized by taking 4A and 2-methoxy-7-azaspiro [3.5] nonane as raw materials and referring to a synthesis method of the compound 4.
LC-MS(ESI):m/z＝518.3[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.08–8.06(m,1H),7.31–7.29(m,1H),7.23(s,1H),7.16–7.09(m,3H),7.01–6.99(m,1H),4.18–4.12(m,1H),3.92–3.63(m,8H),3.49–3.44(m,1H),3.27–3.23(m,5H),3.05–2.89(m,5H),2.82–2.74(m,1H),2.70–2.66(m,1H),2.59–2.54(m,1H),2.23(s,2H),1.75–1.53(m,6H).
EXAMPLE 15 7- (2- (3, 4-Dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-6-carbonyl) -7-azaspiro [3.5] nonane-2-carbonitrile (Compound 15, single isomer)
7-(2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)-7-azaspiro[3.5]nonane-2-carbonitrile(Compound 15)
The compound 15 is synthesized by taking 4A and 7-azaspiro [3.5] nonane-2-nitrile as raw materials and referring to a synthesis method of the compound 4.
LC-MS(ESI):m/z＝513.3[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.09–8.07(m,1H),7.30–7.28(m,1H),7.23(s,1H),7.18–7.10(m,3H),7.02–7.01(m,1H),4.23–4.18(m,1H),3.93–3.87(m,2H),3.84–3.68(m,5H),3.51–3.46(m,1H),3.29(s,1H),3.14–2.95(m,6H),2.91–2.84(m,1H),2.77–2.73(m,1H),2.67–2.61(m,1H),2.34–2.20(m,5H),1.81–1.66(m,4H).
EXAMPLE 16 7' - ((1-Acetylpiperidin-4-yl) amino) -2' - (2-hydroxy-3- (isoindolin-2-yl) propyl) -2',3' -dihydro-1 ' H-spiro [ cyclopropane-1, 4' -isoquinoline ] -1' -one (compound 16)
7'-((1-acetylpiperidin-4-yl)amino)-2'-(2-hydroxy-3-(isoindolin-2-yl)propyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one(Compound 16)
The first step: 7' -Nitro-2 ' - (oxiran-2-ylmethyl) -2',3' -dihydro-1 ' H-spiro [ cyclopropane-1, 4' -isoquinoline ] -1' -one (16B)
7'-nitro-2'-(oxiran-2-ylmethyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
16A (synthesized in reference to WO 2020259478) (0.50 g,2.29 mmol) was dissolved in N, N-dimethylformamide (10 mL), sodium hydride (0.18 g,4.58 mmol) was added at 0deg.C, and then ethylene oxide bromide (0.62 g,4.58 mmol) was added and the reaction was resumed at room temperature for 3 hours. The reaction was quenched with water, extracted with ethyl acetate (20 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane: methanol (v/v) =40:1-20:1) to give the title compound 16B (0.3 g, 47.7%).
And a second step of: 2' - (2-hydroxy-3- (isoindolin-2-yl) propyl) -7' -nitro-2 ',3' -dihydro-1 ' H-spiro [ cyclopropane-1, 4' -isoquinoline ] -1' -one (16C)
2'-(2-hydroxy-3-(isoindolin-2-yl)propyl)-7'-nitro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
16B (0.20 g,0.73 mmol) was dissolved in isopropanol (10 mL) and isoindoline (0.17 g,1.46 mmol) was added and reacted at room temperature for 16 hours. Concentration and purification of the residue by column chromatography on silica gel (dichloromethane: methanol (v/v) =20:1-10:1) gave the title compound 16C (0.2 g, 69.6%).
LC-MS(ESI):m/z＝394.2[M+H] + .
And a third step of: 7' -amino-2 ' - (2-hydroxy-3- (isoindolin-2-yl) propyl) -2',3' -dihydro-1 ' H-spiro [ cyclopropane-1, 4' -isoquinoline ] -1' -one (16D)
7'-amino-2'-(2-hydroxy-3-(isoindolin-2-yl)propyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
16C (0.20 g,0.51 mmol) was dissolved in methanol (10 mL), and palladium on carbon (0.050 g, 10%) was added and reacted at room temperature under a hydrogen atmosphere for 16 hours. Filtration and concentration gave the title compound 16D (0.12 g, 64.7%).
LC-MS(ESI):m/z＝364.2[M+H] + .
Fourth step: 7' - ((1-Acetylpiperidin-4-yl) amino) -2' - (2-hydroxy-3- (isoindolin-2-yl) propyl) -2',3' -dihydro-1 ' H-spiro [ cyclopropane-1, 4' -isoquinoline ] -1' -one (compound 16)
7'-((1-acetylpiperidin-4-yl)amino)-2'-(2-hydroxy-3-(isoindolin-2-yl)propyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
Intermediate 16D (0.12 g,0.33 mmol) was dissolved in dichloromethane (10 mL), 1-acetylpiperidin-4-amine (0.14 g,0.99 mmol) was added, then acetic acid (0.0099 g,0.17 mmol) was added, reacted at room temperature for 8 hours, sodium triacetoxyborohydride (0.21 g,0.99 mmol) was added, reacted at room temperature for 1 hour, and then concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) =40:1-10:1) to give the title compound 16 (0.065 g, 40.3%).
LC-MS(ESI):m/z＝489.3[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.37–7.35(m,1H),7.25–7.20(m,4H),6.67–6.66(m,2H),4.50–4.47(m,1H),4.19–4.13(m,3H),4.07–4.04(m,2H),3.84–3.78(m,2H),3.62–3.53(m,4H),3.24–3.17(m,1H),2.99–2.92(m,2H),2.89–2.81(m,1H),2.15–2.05(m,6H),1.38–1.32(m,2H),0.99–0.93(m,3H).
EXAMPLE 17 6- ((1-Acetylpiperidin-4-yl) amino) -2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -7-fluoro-3, 4-dihydroisoquinolin-1 (2H) -one (Compound 17)
6-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one(Compound 17)
The first step: 6-bromo-7-fluoro-1, 2,3, 4-tetrahydroisoquinoline (17B)
6-bromo-7-fluoro-1,2,3,4-tetrahydroisoquinoline
6-bromo-7-fluoroisoquinoline 17A (2.5 g,11.06 mmol) was dissolved in glacial acetic acid (55 mL) at 0deg.C, sodium borohydride (0.46 g,12.1 mmol) was added in portions, and the mixture was warmed to room temperature and stirred for 3h. The reaction solution was then slowly added dropwise to a saturated aqueous sodium bicarbonate solution (200 mL) to quench the reaction solution, the residue was extracted with dichloromethane, the separated layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 17B (2.1 g, 82.52%) as a pale yellow oily solid which was used in the next reaction without further purification.
LC-MS(ESI):m/z＝230.1[M+H] + .
And a second step of: 1- (6-bromo-7-fluoro-3, 4-dihydroisoquinolin-2 (1H) -yl) ethan-1-one (17C)
methyl 1-(6-bromo-7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one
Compound 17B (1.0 g,4.35 mmol) was dissolved in a dichloromethane solvent mixture (0.84 g,6.5 mmol), acetyl chloride (0.41 g,5.22 mmol) was slowly added dropwise, and the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was poured into water, and the separated organic phase was washed with saturated aqueous sodium bicarbonate, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 17C (1.2 g, 100%) as a yellowish brown solid which was used further in the next step without purification.
LC-MS(ESI):m/z＝272.2[M+H] + .
And a third step of: 2-acetyl-6-bromo-7-fluoro-3, 4-dihydroisoquinolin-1 (2H) -one (17D)
2-acetyl-6-bromo-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one
17C (1.08 g,3.97 mmol) was dissolved in dichloromethane (20 mL), potassium permanganate (1.26 g,8.0 mmol) was added sequentially, benzyl trimethyl ammonium bromide (0.18 g,0.79 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction solution was added dropwise to 1N diluted hydrochloric acid (100 mL), vigorously stirred for 15min, extracted with dichloromethane (50×3 mL), the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product as a yellow oil, which was purified by flash column chromatography on silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =5:1-3:1) to give 17D (0.5 g, 44.02%) as a white solid.
LC-MS(ESI):m/z＝286.1[M+H] + .
Fourth step: 6-bromo-7-fluoro-3, 4-dihydroisoquinolin-1 (2H) -one (17E)
6-bromo-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one
17D (0.5 g,1.75 mmol) was dissolved in methanol (10 mL) and sodium methoxide (0.28 g,3.52 mmol) was slowly added and the reaction stirred at room temperature for 1 hour. The reaction solvent was removed by concentration under reduced pressure, the residue was added to 50mL of water, ph=7 was adjusted with dilute hydrochloric acid, extracted with dichloromethane (20×3 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane: methanol (v/v) =100:1 to 50:1) to give 17E (0.4 g, 93.65%) as a yellow solid.
LC-MS(ESI):m/z＝243.9[M+H] + .
Fifth step: 6-bromo-7-fluoro-2- (oxiran-2-ylmethyl) -3, 4-dihydroisoquinolin-1 (2H) -one (17F)
6-bromo-7-fluoro-2-(oxiran-2-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one
17E (0.40 g,1.64 mmol) was dissolved in N, N-dimethylformamide (10 mL), sodium hydride (0.13 g,3.28 mmol) was added, the reaction was stirred for 15min, then epibromohydrin (0.27 g,1.97 mmol) was added, and the reaction was resumed at room temperature for 3 hours. The reaction was quenched with water, extracted with ethyl acetate (20 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane: methanol (v/v) =60:1-40:1) to give the title 17F (0.27 g, 54.86%) as a yellow oil.
LC-MS(ESI):m/z＝300.0[M+H] + .
Sixth step: 6-bromo-7-fluoro-2- (2-hydroxy-3- (1, 2,3, 4-tetrahydronaphthalen-2-yl) propyl) -3, 4-dihydroisoquinolin-1 (2H) -one (17G)
6-bromo-7-fluoro-2-(2-hydroxy-3-(1,2,3,4-tetrahydronaphthalen-2-yl)propyl)-3,4-dihydroisoquinolin-1(2H)-one
In a 50mL single port flask, compound 17F (1.04 g,3.47 mmol), 1,2,3, 4-tetrahydroisoquinoline (0.46 g,3.47 mmol) was dissolved in isopropyl alcohol (10 mL) and the reaction stirred at room temperature for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) =40:1-20:1) to give compound 17G (0.6G, 53.33%) as a white solid.
LC-MS(ESI):m/z＝478.3[M+H] + .
Seventh step: 6- ((1-Acetylpiperidin-4-yl) amino) -2- (3, 4-dihydro-isoquinolin-2 (1H) -yl) -2-hydroxypropyl) -7-fluoro-3, 4-dihydro-isoquinolin-1 (2H) -one (Compound 17)
6-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one(Compound 17)
17G (0.6G, 1.39 mmol) was dissolved in dry dioxane (20 mL), 1-acetylpiperidin-4-amine (0.24G, 1.67 mmol), sodium t-butoxide (0.4G, 4.17 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.26G, 0.36 mmol), bis-dibenzylideneacetone palladium (0.1G, 0.17 mmol), nitrogen blanket, and reacted at 100℃for 3 hours. After the reaction was cooled to room temperature, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) =20:1) to give racemate of compound 17 (300 mg, 43.7%).
Resolution of the racemate of compound 17 by chiral HPLC gave compound 17, isomer 1 (retention time: 4.117min,72mg, 10.5%) and compound 17, isomer 2 (retention time: 4.260min,76mg, 11.07%), chiral HPLC separation and purification conditions were as follows: instrument name Waters 150Mgm; chromatographic column DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm) mobile phase A for CO 2 and B for EtOH(0.1％NH 3 ·H 2 O); gradient 30%phase B isocratic elution; the flow rate is 130mL/min; column pressure 100bar; column temperature is 35 ℃; the absorption wavelength is 220nm; cycle time: about 9.5 min).
Compound 17, isomer 1: LC-MS (ESI) m/z=495.3 [ M+H ]] + .
1 H NMR(400MHz,CDCl 3 -d)δ7.66–7.58(m,1H),7.24–7.16(m,2H),7.17–7.11(m,1H),7.06–7.01(m,1H),6.44–6.37(m,1H),4.55–4.44(m,1H),4.33(s,1H),4.23–4.15(m,1H),4.15–4.06(m,1H),3.99–3.95(m,1H),3.88–3.76(m,2H),3.73(t,J＝6.6Hz,2H),3.61–3.50(m,2H),3.29–3.17(m,2H),3.14–3.04(m,3H),2.96–2.84(m,5H),2.20–2.04(m,5H),1.53–1.37(m,2H).
Compound 17, isomer 2: LC-MS (ESI) m/z=495.3 [ M+H ]] + .
1 H NMR(400MHz,CDCl 3 -d)δ7.64–7.56(m,1H),7.25–7.18(m,2H),7.18–7.13(m,1H),7.08–7.01(m,1H),6.46–6.37(m,1H),4.57–4.47(m,1H),4.44(s,1H),4.28–4.07(m,3H), 3.89–3.80(m,1H),3.80–3.70(m,3H),3.66–3.52(m,2H),3.38–3.19(m,3H),3.15–3.06(m,3H),3.06–2.78(m,5H),2.17–2.03(m,5H),1.50–1.39(m,2H).
Example 18:6- (4-Acetylpiperazine-1-carbonyl) -2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -3, 4-dihydroisoquinolin-1 (2H)) -one (Compound 18, single isomer)
6-(4-acetylpiperazine-1-carbonyl)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
The intermediate 4A and 1-acetylpiperazine are used as raw materials, and the compound 18 is synthesized by referring to a synthesis method of the compound 4.
1 H NMR(400MHz,CDCl 3 )δ8.12–8.10(m,1H),7.35–7.32(m,1H),7.27(s,1H),7.16–7.09(m,3H),7.02–7.00(m,1H),4.20–4.14(m,1H),3.93–3.73(m,6H),3.69–3.65(m,2H),3.61–3.53(m,2H),3.49–3.44(m,2H),3.05–3.02(m,2H)3.00–2.91(m,3H),2.81–2.76(m,1H),2.72–2.68(m,1H),2.61–2.55(m,1H),2.13(s,3H),1.95–1.76(m,2H).
LC-MS(ESI):m/z＝491.3[M+H] + .
Example 19 (R) -6- ((1-Acetylpiperidin-4-yl) amino) -2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) isoindolin-1-one (Compound 19)
(R)-6-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)isoindolin-1-one
The compound 19 is obtained by taking 2-methyl-5-bromomethyl benzoate (19A) as a raw material and referencing the synthesis method of the compound 1 to obtain 19C, and then taking 19C as a raw material and referencing the synthesis method of the compound 13.
1 H NMR(400MHz,CDCl 3 )δ7.22–7.11(m,4H),7.02–7.00(m,2H),6.79–6.76(m,1H),4.55–4.52(m,2H),4.26–4.19(m,1H),3.97–3.93(m,1H),3.84–3.76(m,3H),3.65–3.55(m,2H),3.24–3.18(m,1H),3.07–2.92(m,4H),2.87–2.79(m,2H),2.71–2.66(m,1H),2.21–2.08(m,5H),1.37–1.27(m,3H).
LC-MS(ESI):m/z＝463.3[M+H] + .
Example 20:7- ((1-Acetylpiperidin-4-yl) amino) -2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -5-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (Compound 20)
7-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
The first step: 5-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (20B)
5-methyl-3,4-dihydroisoquinolin-1(2H)-one
5-bromo-3, 4-dihydroisoquinolin-1 (2H) -one (20A) (5.0 g,22.1 mmol) was dissolved in dioxane (100 mL), and methylboronic acid (3.98 g,66.4 mmol), sodium carbonate (7.04 g,66.4 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (4.8 g,6.64 mmol) were added sequentially, water (10 mL) was reacted for 3 hours at 100deg.C, filtered, concentrated and the residue was purified by silica gel column chromatography (PE: EA (v/v) =5:1-1:1) to give the title compound 20B (3.1 g, 88.5%).
LC-MS(ESI):m/z＝162.1[M+H] + .
And a second step of: 5-methyl-7-nitro-3, 4-dihydroisoquinolin-1 (2H) -one (20C)
5-methyl-7-nitro-3,4-dihydroisoquinolin-1(2H)-one
20B (3.1 g,19.3 mmol) was dissolved in concentrated sulfuric acid (10 mL), and potassium nitrate (2.33 g,23.1 mmol) was added at 0deg.C and reacted at 0deg.C for 1 hour. Water (30 mL) was added, filtered and dried to give the title compound 20C (3.2 g, 80.7%).
LC-MS(ESI):m/z＝207.1[M+H] + .
And a third step of: 7-amino-5-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (20D)
7-amino-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
20C (3.2 g,15.5 mmol) was dissolved in methanol (20 mL), palladium on carbon (0.3 g, 10%) was added, and after reaction at room temperature under hydrogen atmosphere for 8 hours, filtration and concentration gave the title compound 20D (2.6 g, 96.2%).
LC-MS(ESI):m/z＝177.2[M+H] + .
Fourth step: 7-amino-5-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (20E)
7-amino-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
20D (0.50 g,2.84 mmol) was dissolved in DMF (10 mL), 2, 5-hexanedione (0.65 g,5.68 mmol) and p-toluenesulfonic acid (0.24 g,1.42 mmol) were added, reacted for 3 hours at 100℃with water (30 mL), EA (30X 3 mL) was added, the combined organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (PE: EA (v/v) =5:1-1:1) to give the title compound 20E (0.6 g, 83.1%).
LC-MS(ESI):m/z＝255.2[M+H] + .
Fifth step: 7- (2, 5-dimethyl-1H-pyrrol-1-yl) -5-methyl-2- (oxiran-2-ylmethyl) -3, 4-dihydroisoquinolin-1 (2H) -one (20F)
7-(2,5-dimethyl-1H-pyrrol-1-yl)-5-methyl-2-(oxiran-2-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one
20E (0.50 g,1.97 mmol) was dissolved in DMF (10 mL), sodium hydride (0.16 g,3.94 mmol) was added at 0deg.C, after stirring for 30 min, epibromohydrin (0.54 g,3.94 mmol) was added, reacted for 2 hours at 0deg.C, water (30 mL) was added, EA (30X 3 mL) was extracted, and the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give the title compound 20F (0.4 g, 65.4%).
LC-MS(ESI):m/z＝311.2[M+H] + .
Sixth step: 2- (3, 4-Dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -7- (2, 5-dimethyl-1H-pyrrol-1-yl) -5-methyl-3, 4-Dihydroisoquinolin-1 (2H) -one (20G)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-7-(2,5-dimethyl-1H-pyrrol-1-yl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
20F (0.30G, 0.97 mmol) was dissolved in isopropanol (10 mL), 1,2,3, 4-tetrahydroisoquinoline (0.26G, 1.94 mmol) was added, reacted at room temperature for 16 hours, concentrated, and the residue was purified by silica gel column chromatography (PE: EA (v/v) =5:1-1:1) to give the title compound 20G (0.3G, 69.7%).
LC-MS(ESI):m/z＝444.3[M+H] + .
Seventh step: 7-amino-2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -5-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (20H)
7-amino-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
20G (0.30G, 0.68 mmol) was dissolved in ethanol (15 mL), hydroxylamine (0.22G, 6.80 mmol) and hydroxylamine hydrochloride (0.28G, 4.08 mmol) were added, reacted at 80℃for 24 hours, water (30 mL) was added, and EA (30X 3 mL) was added for extraction. The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give the title compound 20H (0.2 g, 80.5%).
LC-MS(ESI):m/z＝366.3[M+H] + .
Eighth step: 7- ((1-Acetylpiperidin-4-yl) amino) -2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -5-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (Compound 20)
7-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
20H (0.20 g,0.55 mmol) was dissolved in dichloromethane (10 mL), 1-acetylpiperidin-4-amine (0.23 g,1.65 mmol) was added, then acetic acid (0.017 g,0.28 mmol) was added, reacted at room temperature for 8 hours, sodium triacetoxyborohydride (0.23 g,1.65 mmol) was added, reacted at room temperature for 1 hour, and then concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) =40:1-10:1) to give the title compound 20 (0.03 g, 11.1%).
1 H NMR(400MHz,CDCl 3 )δ7.21–7.20(m,1H),7.18–7.10(m,3H),7.02–7.00(m,1H),6.57–6.55(m,1H),4.50–4.47(m,1H),4.23–4.14(m,1H),3.90–3.67(m,6H),3.60–3.49(m,2H),3.24–3.17(m,1H),3.02–2.93(m,3H),2.87–2.80(m,4H),2.75–2.61(m,2H),2.22(s,3H),2.15–2.04(m,5H),1.38–1.29(m,2H).
LC-MS(ESI):m/z＝491.3[M+H] + .
Example 21:7- ((1-Acetylpiperidin-4-yl) amino) -2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -6-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (Compound 21)
7-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-methyl-3,4-dihydroisoquinolin-1(2H)-one
The first step: 6-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (21A)
6-methyl-3,4-dihydroisoquinolin-1(2H)-one
6-bromo-3, 4-dihydroisoquinolin-1 (2H) -one (1A) (5.00 g,22.12 mmol) was dissolved in dioxane (100 mL), and methylboric acid (3.98 g,66.36 mmol), sodium carbonate (7.04 g,66.36 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (5.42 g,6.64 mmol) were sequentially added, water (10 mL), after 3 hours reaction at 100deg.C, filtration and concentration were carried out, and the residue was purified by silica gel column chromatography (PE: EA (v/v) =5:1-1:1) to give the title compound 21A (3.1 g, 88.5%).
LC-MS(ESI):m/z＝162.2[M+H] + .
And a second step of: 7-iodo-6-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (21B)
7-iodo-6-methyl-3,4-dihydroisoquinolin-1(2H)-one
21A (3.20 g,19.85 mmol) was dissolved in trifluoroacetic acid (20 mL), N-iodosuccinimide (4.91 g,21.84 mmol) was added at 0deg.C, reacted for 24 hours at room temperature, concentrated, and the residue was purified by silica gel column chromatography (PE: E A (v/v) =5:1-2:1) to give the title compound 21B (3.5 g, 61.4%).
LC-MS(ESI):m/z＝288.0[M+H] + .
And a third step of: 7-iodo-6-methyl-2- (oxiran-2-ylmethyl) -3, 4-dihydroisoquinolin-1 (2H) -one (21C)
7-iodo-6-methyl-2-(oxiran-2-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one
21B (3.00 g,10.45 mmol) was dissolved in DMF (20 mL), sodium hydride (0.84 g,20.90 mmol) was added at 0deg.C, and after stirring for 30 min, epibromohydrin (2.12 g,15.67 mmol) was added and reacted at 0deg.C for 2 hours. Water (50 mL) was added, EA (30X 3 mL) was extracted, the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give the title compound 21C (2.3 g, 64.1%).
LC-MS(ESI):m/z＝344.0[M+H] + .
Fourth step: 2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -7-iodo-6-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (21D)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-7-iodo-6-methyl-3,4-dihydroisoquinolin-1(2H)-one
21C (0.50 g,1.46 mmol) was dissolved in isopropanol (10 mL), and 1,2,3, 4-tetrahydroisoquinoline (0.29 g,2.19 mmol) was added and reacted at room temperature for 16 hours. Concentration and purification of the residue by column chromatography on silica gel (DCM: meOH (v/v) =40:1-10:1) gave the title compound 21D (0.45 g, 64.7%).
LC-MS(ESI):m/z＝477.2[M+H] + .
Fifth step: 7- ((1-Acetylpiperidin-4-yl) amino) -2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -6-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (Compound 21)
7-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-methyl-3,4-dihydroisoquinolin-1(2H)-one
21D (0.30 g,0.63 mmol) was dissolved in dry dioxane (20 mL), 1-acetylpiperidin-4-amine (0.13 g,0.95 mmol), sodium t-butoxide (0.18 g,1.89 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.29 g,0.50 mmol), bis-dibenzylideneacetone palladium (0.072 g,0.13 mmol), nitrogen blanket, and reacted at 100℃for 3 hours. After the reaction was cooled to room temperature, filtered, concentrated, and the residue was purified by silica gel column chromatography ((dichloromethane: methanol (v/v) =10:1) to give the title compound 21 (120 mg, 39.0%). Compound 21 was prepared by chiral SFC to give two isomers.
The preparation conditions are as follows:
instrument, waters 150mgm, preparative column DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm), mobile phase A for CO 2 And B for IPA+ACN (0.1% NH) 3 ·H 2 O), gradient of 45% phase B, flow rate of 120mL/min, back pressure of 100bar, column temperature of 35 ℃, wavelength of 220nm, cycle time of 8min, sample pretreatment, compound dissolution in ethanol, concentration of 5mg/mL, injection of 6mL per needle.
The analysis method comprises the following steps:
the apparatus SHIMADZU LC-30ADsf, column: chiralpak AD-3.50X4.6 mm I.D.,3 μm, mobile phase: A for CO2 and B for IPA+ACN (0.05% DEA), gradient: 40% phase B, flow rate: 3mL/min, back pressure: 100bar, column temperature: 35 ℃, wavelength: 220nm. Retention time: isomer 1: tr=1.237; isomer 2: tr=1.485.
Compound 21, isomer 1:
1 H NMR(400MHz,CDCl 3 )δ7.28(s,1H),7.24–7.13(m,3H),7.05–7.04(m,1H),6.90(s,1H),4.52–4.49(m,1H),4.42–4.34(m,1H),4.18–4.14(m,1H),4.05–4.01(m,1H),3.85–3.76(m,2H),3.74–3.64(m,3H),3.57–3.51(m,1H),3.27–3.21(m,3H),3.14–3.04(m,2H),2.91–2.83(m,5H),2.21–2.18(m,1H),2.14(s,3H),2.11–2.09(m,4H),1.41–1.33(m,2H).
LCMS m/z＝491.3[M+H] + .
compound 21, isomer 2:
1 H NMR(400MHz,CDCl 3 )δ7.28(s,1H),7.23–7.13(m,3H),7.05–7.04(m,1H),6.90(s,1H),4.53–4.49(m,1H),4.41–4.32(m,1H),4.17–4.13(m,1H),4.05–4.01(m,1H),3.85–3.76(m,2H),3.74–3.63(m,3H),3.56–3.48(m,1H),3.27–3.20(m,3H),3.13–3.03(m,2H),2.99–2.83(m,5H),2.21–2.18(m,1H),2.14(s,3H),2.11–2.09(m,4H),1.41–1.32(m,2H).
LCMS m/z＝491.3[M+H] + .
example 22:7- ((1-Acetylpiperidin-4-yl) amino) -2- (3- (6, 7-dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) -2-hydroxypropyl-3, 4-dihydroisoquinolin-1 (2H) -one (Compound 22)
7-((1-acetylpiperidin-4-yl)amino)-2-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
The first step:
11C chiral resolution method: (Instrument name: waters 150Mgm; column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm) mobile phase: A for CO) 2 and B for EtOH(0.1％NH 3 ·H 2 O); gradient 45%phase B isocratic elution; the flow rate is 105mL/min; column pressure 100bar; column temperature is 35 ℃; the absorption wavelength is 220nm; cycle time: 4.8 min). Retention time of compound 22A: 0.918min; retention time of compound 22B: 1.127min, compounds 22A and 22B were enantiomers of each other.
And a second step of:
22A (0.5 g,1.19 mmol) and 1-acetylpiperidin-4-amine (0.34 g,2.38 mmol) were dissolved in 1,4 dioxane (50 mL) and sodium tert-butoxide (0.23 g,2.38 mmol) and Pd were added sequentially thereto 2 (dba) 3 (0.22 g,0.24 mmol), xantphos (0.28 g,0.48 mmol). The reaction is carried out for 1h at 100 ℃ under the protection of nitrogen replacement. TLC and LC-MS showed complete reaction of starting material, concentrated, spin-dried, dissolved in DCM, suction filtered through celite, and the filtrate was concentrated to give a residue which was separated by column chromatography (DCM/CH 3 Oh=0% -20%) to give compound 22, isomer 1 (20 mg, yield 6%).
1 H NMR(400MHz,CDCl 3 )δ7.30(d,1H),7.11(d,1H),6.98(d,1H),6.73-6.65(m,2H),4.51-4.48(m,1H),4.22-4.20(m,1H),3.88-3.70(m,6H),3.57-3.50(m,3H),3.24-3.17(m,1H),3.10-3.08(m,1H),2.97-2.85(m,5H),2.73-2.67(m,1H),2.10(s,3H),1.33-1.25(m,4H).
LCMS m/z＝483.6[M+H] + .
With reference to the above synthesis method, compound 22, isomer 2, was obtained starting from 22B.
1 H NMR(400MHz,CDCl 3 )δ7.29(d,1H),7.11(d,1H),6.98(d,1H),6.74-6.66(m,2H),4.51-4.48(m,1H),4.22-4.20(m,1H),3.88-3.70(m,5H),3.57-3.50(m,3H),3.24-3.17(m,2H),3.10-3.08(m,3H),2.94-2.80(m,6H),2.73-2.67(m,1H),2.10(s,3H),1.33-1.25(m,4H).
LCMS m/z＝483.6[M+H] + .
Example 23:7' - ((1-Acetylpiperidin-4-yl) amino) -2' - (3- (6, 7-dihydrothieno [3,2-c ] pyridinyl-5 (4H) -yl) -2-hydroxypropyl) -2',3' -dihydro-1 ' H-spiro [ cyclopropane-1, 4' -isoquinolin-1 ' -one (Compound 12, isomer 1 and isomer 2)
7'-((1-acetylpiperidin-4-yl)amino)-2'-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
Compound 12 was resolved by chiral HPLC to give compound 12, isomer 1 and isomer 2, resolution conditions as follows: instrument name Waters 150Mgm; chromatographic column DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm) mobile phase A for CO 2 and B for EtOH(0.1％NH 3 ·H 2 O); gradient 50%phase B isocratic elution; the flow rate is 80mL/min; column pressure 100bar; column temperature is 38 ℃; the absorption wavelength is 220nm; cycle time: about 9.5 min). Isomer 1 retention time: 5.891min; isomer 2 retention time: 9.420min.
Compound 12, isomer 1: 1 H NMR(400MHz,CDCl 3 )δ7.34(s,1H),7.06(d,1H),6.73(d,1H),6.67(s,2H),4.50-4.47(m,1H),4.28-4.27(m,1H),3.83-3.78(m,2H),3.76-3.74(m,1H),3.66-3.48(m,5H),3.23-3.17(m,5H),3.04-2.81(m,7H),2.10(s,3H),1.33-1.26(m,5H),1.00-0.83(m,4H).
LCMS m/z＝509.3[M+H] + .
compound 12, isomer 2: 1 H NMR(400MHz,CDCl 3 )δ7.35(s,1H),7.10(d,1H),6.73(d,1H),6.67(s,2H),4.50-4.47(m,1H),4.28-4.27(m,1H),3.83-3.78(m,3H),3.66-3.48(m,5H),3.23-3.17(m,3H),3.04-2.81(m,6H),2.10(s,3H),1.33-1.26(m,5H),1.00-0.83(m,4H).
LCMS m/z＝509.3[M+H] + .
example 24:8- (2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-6-carbonyl) -2, 8-diazaspiro [4.5] decan-3-one (Compound 24, single isomer)
8-(2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)-2,8-diazaspiro[4.5]decan-3-one
Compound 4A (0.1 g,0.26 mmol) was dissolved in dichloromethane (10 mL), 2, 8-diazaspiro [4.5] decan-3-one (0.049 g,0.32 mmol), N, N-diisopropylethylamine (0.05 g,0.4 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.12 g,0.31 mmol) were added, and the reaction was continued at room temperature with stirring for 3 hours after the addition was completed. The reaction was poured into 50mL of water, extracted with dichloromethane (40 ml×3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane: methanol (v/v) =40:1-20:1) to give the title compound 24 (0.060 g, 44.18%).
1 H NMR(400MHz,CDCl 3 )δ8.12–8.08(m,1H),7.49–7.47(m,1H),7.38(s,1H),7.20–7.13(m,3H),7.07–7.03(m,1H),4.81-4.75(m,1H),4.51-4.48(m,2H),4.32(s,1H),4.07–4.03(m,1H),3.92–3.84(m,7H),3.82–3.79(m,1H),3.75–3.71(m,1H),3.60–3.53(m,1H),3.16-3.12(m,1H),3.06-3.04(m,5H),2.95-2.88(m,1H),2.83-2.77(m,1H),2.35–1.87(m,5H).
LC-MS(ESI):m/z＝517.3[M+H] + .
Example 25:2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyrazine-7-carbonyl) -3, 4-dihydroisoquinolin-1 (2H) -one (Compound 25, single isomer)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one
Compound 25 was obtained according to the above synthetic route, referring to the synthetic procedure for compound 4, starting from intermediate 4A and 5,6,7, 8-tetrahydroimidazo [1,2-a ] pyrazine.
1 H NMR(400MHz,CDCl 3 )δ8.14–8.12(m,1H),7.41–7.39(m,1H),7.30(s,1H),7.15–7.12(m,3H),7.04–7.00(m,2H),6.89–6.88(m,1H),4.78(s,2H),4.17–4.01(m,4H),3.92–3.65(m,6H),3.52–3.49(m,2H),3.05–2.92(m,5H),2.79–2.77(m,1H),2.72-2.68(m,1H),2.60–2.55(m,1H).
LC-MS(ESI):m/z＝486.2[M+H] + .
Example 26:2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -6- (2-methyl-2, 4,5, 6-tetrahydropyrrole [3,4-c ] pyrazole-5-carbonyl) -3, 4-dihydroisoquinolin-1 (2H) -one (Compound 26, single isomer)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(2-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one
Compound 26 was obtained according to the above synthetic route, starting from intermediate 4A and 2-methyl-2, 4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazole, referring to the synthetic procedure for compound 4.
1 H NMR(400MHz,CDCl 3 )δ8.10–8.08(m,1H),7.33–7.30(m,1H),7.25(s,1H),7.17–7.10(m,3H),7.02–7.00(m,1H),5.71(s,1H),4.24–4.18(m,1H),3.93–3.87(m,2H),3.85–3.71(m,3H),3.51–3.46(m,2H),3.25(s,2H),3.05–3.01(m,3H),2.97–2.94(m,2H),2.88–2.83(m,1H),2.80(s,2H),2.77–2.73(m,1H),2.67–2.62(m,1H),1.76–1.64(m,3H).
LC-MS(ESI):m/z＝486.3[M+H] + .
Example 27:6- (5-Acetyloctahydropyrrolo [3,4-c ] pyrrole-2-carbonyl) -2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -3, 4-dihydroisoquinolin-1 (2H) -one (Compound 27)
(6-(5-acetyloctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
The first step: 5-Acetylhexahydropyrrole [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (Compound 27B)
tert-butyl 5-acetylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
2-BOC-octahydropyrrolo [3,4-C ] pyrrole 27A (1.06 g,5 mmol) was dissolved in dichloromethane (20 mL) at 0deg.C, triethylamine (0.76 g,7.5 mmol) was added, acetyl chloride (0.47 g,6 mmol) was added dropwise, and the mixture was allowed to warm to room temperature and stirred for 1h. The reaction was slowly added dropwise to a saturated aqueous sodium hydrogencarbonate solution (200 mL) to quench the reaction, the aqueous phase was extracted with dichloromethane, the layers were separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 27B (1.2 g, 94.5%) which was used in the next reaction without further purification.
LC-MS(ESI):m/z＝199.1[M-55] + .
And a second step of: 1- (hexahydropyrrolyl [3,4-C ] pyrrol-2 (1H) -yl) ethan-1-one hydrochloride (Compound 27C)
1-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-one hydrochloride
27B (0.6 g,1.54 mmol) was dissolved in dichloromethane (20 mL), methanol hydrochloride (5 mL) was added, and after completion of the addition, the reaction was performed at room temperature for 3 hours and concentrated to give the title compound 27C (0.6 g, 99%). The reaction mixture was used in the next reaction without purification.
LC-MS(ESI):m/z＝155.2[M+H] + .
And a third step of: 6- (5-Acetyloctahydropyrrolo [3,4-c ] pyrrole-2-carbonyl) -2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -3, 4-dihydroisoquinolin-1 (2H) -one (Compound 27)
(6-(5-acetyloctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
Compound 4A (0.1 g,0.26 mmol) was dissolved in dichloromethane (10 mL), compound 27C (0.06 g,0.32 mmol), N, N-diisopropylethylamine (0.1 g,0.8 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.12 g,0.31 mmol) were added, and the reaction was continued to stir at room temperature for 3 hours after the addition was completed. The reaction was poured into 50mL of water and extracted with dichloromethane (20 mL. Times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane: methanol (v/v) =40:1-20:1) to give the title compound 27 (0.050 g, 36.8%).
1 H NMR(400MHz,CDCl 3 -d)δ8.03–8.01(m,1H),7.42–7.40(m,1H),7.33(s,1H),7.30–7.17(m,3H),7.10–7.08(m,1H),4.66-4.64(m,1H),4.48-4.37(m,2H),3.97-3.91(m,1H),3.85–3.75(m,5H),3.71–3.63(m,5H),3.54–3.43(m,4H),3.33–3.26(m,6H),3.10–2.92(m,5H),2.08–2.05(m,3H),1.57–1.52(m,2H),1.46–1.44(m,2H).
LC-MS(ESI):m/z＝517.3[M+H] + .
Example 28:2- (-3- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -6- ((3 aR,5R,6 aS) -5-methoxyoctahydrocyclopenta [ c ] pyrrole-2-carbonyl) -3, 4-dihydroisoquinolin-1 (2H) -one (Compound 28)
2-(-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((3aR,5R,6aS)-5-methoxyoctahydrocyclopenta[c]pyrrole-2-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one
The first step: (3 aR,5r,6 aS) -5-Hydroxyhexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (28B)
tert-butyl(3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
At 0 ℃, cis-5-oxo hexahydrocyclopenta [ C]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester 28A (1.3 g,5.77 mmol) was dissolved in methanol (20 mL) and NaBH was slowly added 4 (0.288 g,6 mmol) was warmed to room temperature and stirred for 1h. The reaction solution was poured into water, extracted with ethyl acetate (100 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 28B (1.3 g, 99.11%) which was used in the next reaction without further purification.
LC-MS(ESI):m/z＝172.2[M-55] + .
And a second step of: (3 aR,5r,6 aS) -5-methoxyoctahydrocyclopenta [ C ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (28C)
tert-butyl(3aR,5r,6aS)-5-methoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
28B (1.3 g,5.72 mmol) was dissolved in N, N-dimethylformamide (20 mL), sodium hydride (0.28 g,7 mmol) was added at 0deg.C, stirring was continued for 1 hour, methyl iodide (1.0 g,7 mmol) was added dropwise thereto, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was slowly poured into ice water, extracted with ethyl acetate (100 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 28C (1.3 g, 94.2%). The reaction mixture was used in the next reaction without purification.
LC-MS(ESI):m/z＝186.2[M-55] + .
And a third step of: (3 aR,5r,6 aS) -5-methoxyoctahydrocyclopenta [ c ] pyrrole hydrochloride (28D)
(3aR,5r,6aS)-5-methoxyoctahydrocyclopenta[c]pyrrole hydrochloride
28C (1.3 g,1.54 mmol) was dissolved in dichloromethane (20 mL), methanol hydrochloride (5 mL) was added, and after completion of the addition, the reaction was performed at room temperature for 3 hours and concentrated under reduced pressure to give the title compound 28D (0.9 g, 94%). The reaction mixture was used in the next reaction without purification.
LC-MS(ESI):m/z＝142.2[M+H] + .
Fourth step: 2- (-3- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -6- ((3 aR,5R,6 aS) -5-methoxyoctahydrocyclopenta [ c ] pyrrole-2-carbonyl) -3, 4-dihydroisoquinolin-1 (2H) -one (Compound 28)
2-(-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((3aR,5R,6aS)-5-methoxyoctahydrocyclopenta[c]pyrrole-2-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one
Compound 4A (0.1 g,0.26 mmol) was dissolved in dichloromethane (10 mL), compound 28D (0.06 g,0.33 mmol), N, N-diisopropylethylamine (0.1 g,0.8 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.12 g,0.31 mmol) were added, and the reaction was continued to stir at room temperature for 3 hours after the addition was completed. The reaction was poured into 50mL of water, extracted with dichloromethane (20 ml×3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane: methanol (v/v) =40:1-20:1) to give the title compound 28 (0.050 g, 37.7%).
1 H NMR(400MHz,CDCl 3 )δ7.94–7.92(m,1H),7.37–7.34(m,1H),7.30(s,1H),7.23–7.14(m,3H),7.08–7.06(m,1H),4.40–4.39(m,1H),4.29–4.09(m,2H),3.87–3.63(m,2H),3.59–3.55(m,3H),3.35–3.29(m,3H),3.27(s,4H),3.16–3.08(m,3H),3.05–3.00(m,3H),2.71–2.61(m,2H),2.15–1.99(m,1H),1.68–1.44(m,5H).
LC-MS(ESI):m/z＝504.3[M+H] + .
Example 29: (R) -2' - (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -6' - (2-methoxy-7-azaspiro [3.5] nonane-7-carbonyl) -2',3' -dihydro-1 ' H-spiro [ cyclopropane-1, 4' -isoquinolin-1 ' -one (Compound 29)
(R)-2'-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6'-(2-methoxy-7-azaspiro[3.5]nonane-7-carbonyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
29A (see patent US 20120225857) (1.00 g,3.97 mmol) was dissolved in N, N-dimethylformamide (10 mL), sodium hydride (0.32 g,7.97 mmol) was added at 0deg.C, and after 30min (R) - (-) -glycidyl p-nitrobenzenesulfonate (1.54 g,5.96 mmol) was added and reacted for 1 hour. Water (80 mL) was added and extracted with ethyl acetate (20 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 29B (1.0 g, 81.7%).
LC-MS(ESI):m/z＝310.0[M+H] + .
Compound 29 was obtained by a synthesis method of reference compound 14 using 29B as a starting material.
1 H NMR(400MHz,CDCl 3 )δ8.11-8.09(m,1H),7.25-7.24(m,1H),7.19-7.11(m,3H),7.03-7.00(m,1H),6.88(s,1H),4.26-4.21(m,1H),3.97-3.87(m,2H),3.86-3.82(m,1H),3.79-3.75(m,1H),3.71-3.50(m,5H),3.31-3.23(m,5H),3.11-2.97(m,4H),2.82-2.67(m,2H),2.28-2.16(m,2H),1.76-1.64(m,4H),1.56-1.46(m,2H),1.12-1.05(m,4H).
LC-MS(ESI):m/z＝544.3[M+H] + .
Example 30: (R) -7- (2 ' - (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -1' -oxo-2 ',3' -dihydro-1 ' H-spiro [ cyclopropane-1, 4' -isoquinoline ] -6' -carbonyl) -7-azaspiro [3.5] nonane-2-carbonitrile (compound 30)
(R)-7-(2'-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-6'-ylcarbonyl)-7-azaspiro[3.5]nonane-2-carbonitrile
The compound 30 is synthesized by a synthesis method taking 29E and 7-azaspiro [3.5] nonane-2-nitrile as raw materials and referencing the compound 29.
1 H NMR(400MHz,CDCl 3 )δ8.12–8.10(m,1H),7.24–7.23(m,1H),7.18–7.10(m,3H),7.02–7.00(m,1H),6.87(s,1H),4.22–4.17(m,1H),3.93–3.83(m,2H),3.74–3.47(m,6H),3.32–3.19(m,2H),3.13–2.94(m,4H),2.90–2.62(m,4H),2.35–2.18(m,5H),1.71–1.62(m,2H),1.12–1.02(m,4H).
LC-MS(ESI):m/z＝539.3[M+H] + .
Example 31:7- ((1-Acetylpiperidin-4-yl) amino) -2- (3, 4-dihydro-isoquinolin-2 (1H) -yl) -2-hydroxypropyl) -5-methyl-3, 4-dihydro-isoquinolin-1 (2H) -one (Compound 20 isomer 1, isomer 2, both enantiomers)
7-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one(R and S enantiomer of Compound 20)
The first step:
7-amino-5-bromo-3, 4-dihydroisoquinolin-1 (2H) -one 31A (synthesized as described in reference to patent WO 2021028806) (5.00 g,20.74 mmol) was dissolved in DMF (50 mL), 2, 5-hexanedione (4.73 g,41.49 mmol) and p-toluenesulfonic acid (0.36 g,2.07 mmol) were added and reacted at 100℃for 3 hours. After the reaction was cooled to room temperature, the reaction solution was poured into ice water, filtered and dried to give the title compound 31B (6.5 g, 97.7%).
LC-MS(ESI):m/z＝321.0[M+H] + .
And a second step of:
31B (6.50 g,20.37 mmol) was dissolved in DMF (50 mL), sodium hydride (1.63 g,40.74 mmol) was added at 0deg.C, and after stirring for 30 min, epibromohydrin (4.19 g,30.56 mmol) was added and reacted at 0deg.C for 2 hours. Quench with water (150 mL), extract EA (50X 3 mL), wash the combined organic phases with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate to give the title compound 31C (7.2 g, 94.7%).
LC-MS(ESI):m/z＝375.0[M+H] + .
And a third step of:
31C was dissolved in isopropyl alcohol (80 mL), tetrahydroisoquinoline (7.66 g,57.6 mmol) was added and reacted at room temperature for 16 hours. Concentration and purification of the residue by silica gel column chromatography (PE: EA (v/v) =2:1-1:3) gave the title compound 31D (7.8 g, 82.1%).
LC-MS(ESI):m/z＝508.1[M+H] + .
Fourth step:
intermediate 31D (18.01 g,5.96 mmol) was prepared via chiral SFC to give two isomers 31E and 31F (enantiomers of each other).
Chiral separation conditions: instrument, waters 350mgm, preparation column, DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm), mobile phase, A for CO 2 And B for EtOH+ACN (0.1% NH) 3 ·H 2 O), gradient 40%Phase B isocratic elution, flow rate 180mL/min, back pressure 100bar, column temperature 35 ℃, wavelength 220nm, cycle time 3.8min, sample pretreatment, compound dissolution in ethanol, concentration 12mg/mL, injection 1.5mL per needle.
The analysis method comprises the following steps: the apparatus was SHIMADZU LC-30AD sfc, column: chiralpak AD-3.50X4.6 mm I.D.,3 μm, mobile phase: A for CO 2 And B for EtOH+ACN (0.05% DEA), gradient: 40% phase B, flow rate: 3mL/min, back pressure: 100bar, column temperature: 35 ℃, wavelength: 220nm. Retention time: isomer 1 (31E): t is tR=0.92 min; isomer 2 (31F): tr=1.409 min.
Fifth step:
31E was dissolved in dioxane (100 mL), and methyl boric acid (3.98 g,66.4 mmol), sodium carbonate (7.04 g,66.4 mmol), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (4.8 g,6.64 mmol), water (10 mL) were added in this order and reacted at 100℃for 3 hours. After the reaction was cooled to room temperature, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE: EA (v/v) =5:1-1:1) to give the title compound 20G-1 (3.1G, 72.1%).
LC-MS(ESI):m/z＝444.3[M+H] + .
Taking 31F as a raw material, and synthesizing 20G-2 by referring to a synthesis method of 20G-1.
LC-MS(ESI):m/z＝444.3[M+H] + .
Sixth step:
20H-1 was synthesized by the seventh synthesis method of reference example 20 using 20G-1 as the starting material.
20H-2 was synthesized by the seventh synthesis method of reference example 20 using 20G-2 as the starting material.
Seventh step:
the eighth step of the synthesis method of reference example 20 was performed using 20H-1 as a starting material to obtain compound 20, isomer 1.
1 H NMR(400MHz,CDCl 3 )δ7.21-7.20(m,1H),7.17-7.09(m,3H),7.02-7.00(m,1H),6.57-6.55(m,1H),4.50-4.46(m,1H),4.23-4.14(m,1H),3.90-3.67(m,6H),3.60-3.49(m,2H),3.24-3.17(m,1H),3.02-2.93(m,3H),2.87-2.80(m,4H),2.75-2.61(m,2H),2.22(s,3H),2.14-2.04(m,5H),1.35-1.29(m,2H).
LC-MS(ESI):m/z＝491.3[M+H] + .
The eighth step of the synthesis method of reference example 20 was performed using 20H-2 as a starting material to obtain compound 20, isomer 2.
1 H NMR(400MHz,CDCl 3 )δ7.21-7.20(m,1H),7.17-7.10(m,3H),7.02-7.00(m,1H),6.57-6.55(m,1H),4.50-4.47(m,1H),4.23-4.13(m,1H),3.90-3.68(m,6H),3.59-3.49(m,2H),3.24-3.17(m,1H),3.02-2.93(m,3H),2.87-2.80(m,4H),2.75-2.61(m,2H),2.22(s,3H),2.15-2.04(m,5H),1.37-1.29(m,2H).
LC-MS(ESI):m/z＝491.3[M+H] + .
Example 32: (R) -7' - ((1-acetylpyridin-4-yl) amino) -2' - (3- (6, 7-dihydrothiophene [3,2-c ] pyridin-5 (4H) -yl) -2-hydroxypropyl) -2',3' -dihydro-1 ' H-spiro [ cyclobutane-1, 4' -isoquinolin-1 ' -one (Compound 32)
(R)-7'-((1-acetylpiperidin-4-yl)amino)-2'-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinolin]-1'-one
The first step:
7 '-nitro-2', 3 '-dihydro-1' H-spiro [ cyclobutane-1, 4 '-isoquinoline ] -1' -one (32A) (synthesized as described in reference to patent CN 112125886) (0.6 g,2.58 mmol) was dissolved in N, N-dimethylformamide (10 mL), 60% sodium hydride (0.15 g,3.87 mmol) was added and stirred for 15min, then (R) - (-) -glycidyl p-nitrobenzenesulfonate (0.27 g,1.97 mmol) was added and the reaction mixture was warmed to room temperature for 3 h. The reaction was quenched with water, extracted with ethyl acetate (20 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane: methanol (v/v) =95:5) to give the title compound 32B (0.31 g, 41.63%).
LC-MS(ESI):m/z＝289.2[M+H] + .
And a second step of:
in a 50mL single-necked flask, compound 32B (0.31 g,1.08 mmol), 4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridine (0.15 g,1.08 mmol) was dissolved in isopropanol (10 mL) in this order, and the reaction was continued with stirring at room temperature for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) =96:4) to give compound 32C (0.30 g, 65.26%).
LC-MS(ESI):m/z＝428.3[M+H] + .
And a third step of:
to a 50mL single-necked flask, 32C (0.30 g,0.7 mmol), 10% palladium on carbon (0.15 g), methanol (20 mL) and hydrogen were sequentially added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was filtered through celite, and concentrated under reduced pressure to give compound 32D (0.24 g, 86.03%) which was used in the next reaction without further purification.
LC-MS(ESI):m/z＝398.3[M+H] + .
Fourth step:
to a 50mL single-necked flask, 32D (0.24 g,0.6 mmol), 1-acetylpiperidin-4-one (0.12 g,0.84 mmol), methylene chloride (3 mL), acetic acid (5 mL) were sequentially added, and the reaction was stirred at room temperature for 10min, followed by addition of sodium triacetoxyborohydride (0.18 g,0.84 mmol) and stirring was continued for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude product as a yellow oil, methylene chloride was added to the crude product, a saturated aqueous sodium hydrogencarbonate solution was extracted, the organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution, dried over organic anhydrous sodium sulfate, filtered, and concentrated to give the crude product as a yellow oil which was separated by silica gel column chromatography (methylene chloride: methanol (v/v) =10:1) to give the objective compound 32 (0.18 g, 57.04%).
1 H NMR(400MHz,CDCl 3 -d)δ7.30-7.28(m,2H),7.11-7.10(m,1H),6.78-6.75(m,1H),6.73-6.71(m,1H),4.50-4.47(m,1H),4.23-4.18(m,1H),3.97-3.77(m,3H),3.74(s,2H),3.68-3.53(m,4H),3.23-3.18(m,1H),3.09-3.05(m,1H),2.93-2.78(m,5H),2.69-2.53(m,1H),2.30-2.22(m,3H),2.15-1.94(m,11H).
LC-MS(ESI):m/z＝523.2[M+H] + .
Example 33:7- (2- (3, 4-dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -4, 4-dimethyl-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-6-carbonyl) -7-azaspiro [3.5] nonane-2-carbonitrile (Compound 33)
7-(2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)-7-azaspiro[3.5]nonane-2-carbonitrile
The first step:
6-bromo-4, 4-dimethyl-3, 4-dihydroisoquinolin-1 (2H) -one 33A (synthesized as described in patent WO 2019094312) (0.5 g,1.97 mmol) was dissolved in N, N-dimethylformamide (15 mL) at 0deg.C, 60% sodium hydride (0.12 g,3.0 mmol) was added and the reaction stirred for 1H. Bromopropane oxide (0.32 g,2.36 mmol) was added, and after the addition was completed, the reaction was stirred at room temperature for 2 hours. The reaction solution was poured into 100mL of water, the aqueous phase was extracted three times with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =3:1-1:1) to give the title compound 33B (0.3 g, 49.16%).
LC-MS(ESI):m/z＝310.1[M+H] + .
And a second step of:
in a 50mL single-necked flask, compound 33B (0.3 g,0.97 mmol), 1,2,3, 4-tetrahydroisoquinoline (0.14 g,1.06 mmol) was successively stirred in isopropanol (10 mL) at room temperature for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) =40:1-20:1) to give compound 33C (0.35 g, 81.62%).
LC-MS(ESI):m/z＝443.3[M+H] + .
And a third step of:
compound 33C was resolved by chiral HPLC to give isomer 33C-1 and isomer 33C-2 (enantiomers of each other) under the following purification conditions: (Instrument name: waters 350; chromatographic column: DAICEL CHIRALCEL AD (250 mm. Times.30 mm,10 μm) mobile phase: A for CO) 2 and B for IPA (Neu) gradient 45%phase B isocratic elution; the flow rate is 200mL/min; column pressure 100bar; column temperature is 35 ℃; the absorption wavelength is 220nm; cycle time: -7 min). Isomer 33C-1 retention time: 2.265min; isomer 33C-2 retention time: 2.579min. The absolute configuration of isomer 33C-1 and isomer 33C-2 is not defined.
Fourth step:
compound 33C-1 (0.42 g,0.95 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (80 mg) and triethylamine (424 m g,4.2 mmol) were added to a mixed solvent of methanol (20 mL) and dichloromethane (20 mL), and reacted at 110℃for 3 hours under carbon monoxide (20 MPa) atmosphere. After the reaction liquid was cooled to room temperature, filtration was performed, and the filtrate was concentrated under reduced pressure, followed by column chromatography to give Compound 33D-1 (0.34 g, 85%).
LC-MS(ESI):m/z＝423.2[M+H] + .
Taking 33C-2 as a raw material, and synthesizing to obtain 33D-2 by referring to the synthesis method.
Fifth step:
compound 33D-1 (0.34 g,0.8 mmol) was dissolved in methanol (3 mL), tetrahydrofuran (3 mL) and water (6 mL), lithium hydroxide monohydrate (0.17 g,4.02 mmol) was added, and the reaction was stirred at room temperature for 2 hours. Dilute hydrochloric acid was added to adjust the pH to 5-6, water (50 mL) and dichloromethane (20 x 3 mL) were added to extract, and the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 33E-1 (0.26 g, 79.1%) which was used in the next reaction without purification.
LC-MS(ESI):m/z＝409.1[M+H] + .
Taking 33D-2 as a raw material, and synthesizing to obtain 33E-2 by referring to the synthesis method.
Sixth step:
compound 33E-1 (0.08 g,0.20 mmol) was dissolved in dichloromethane (10 mL), 7-azaspiro [3.5] nonane-2-carbonitrile hydrochloride (0.048 g,0.24 mmol), N, N-diisopropylethylamine (0.12 g,0.96 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.09 g,0.24 mmol) were added and reacted at room temperature for 1 hour after the addition. Concentration and purification of the residue by column chromatography on silica gel (dichloromethane: methanol (v/v) =40:1-10:1) gave compound 33, isomer 1 (0.04 g, 38.7%).
1 H NMR(400MHz,CDCl 3 )δ8.10-8.08(m,1H),7.33-7.32(m,1H),7.30-7.28(m,1H),7.19-7.11(m,3H),7.03-7.00(m,1H),4.23-4.21(m,1H),3.93-3.87(m,2H),3.76-3.70(m,4H),3.60-3.47(m,3H),3.31-3.24(m,2H),3.10-2.64(m,10H),2.31-2.24(m,5H),1.35(m,6H).
LC-MS(ESI):m/z＝541.3[M+H] + .
Compound 33, isomer 2, was synthesized using 33E-2 as a starting material by the above synthesis method.
1 H NMR(400MHz,CDCl 3 )δ8.09-8.08(m,1H),7.33-7.31(m,1H),7.30-7.27(m,1H),7.19-7.12(m,3H),7.05-7.00(m,1H),4.23-4.21(m,1H),3.93-3.85(m,2H),3.76-3.71(m,4H),3.60-3.47(m,3H),3.31-3.24(m,2H),3.10-2.64(m,10H),2.32-2.24(m,5H),1.35(m,6H).
LC-MS(ESI):m/z＝541.2[M+H] + .
Example 34:2- (3, 4-Dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -6- (2-methoxy-7-azaspiro [3.5] nonane-7-carbonyl) -4, 4-dimethyl-3, 4-dihydroisoquinolin-1 (2H) -one (Compound 34)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(2-methoxy-7-azaspiro[3.5]nonane-7-carbonyl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one
33E-1 (0.08 g,0.19 mmol) was dissolved in dichloromethane (8 mL), compound 34A (synthesized as described in reference to WO 2021088992) (0.045 g,0.24 mmol), N, N-diisopropylethylamine (0.06 g,0.48 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.09 g,0.24 mmol) were added and reacted at room temperature for 1 hour after the addition. Concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) =40:1-10:1) to give the title compound 34, isomer 1 (16 mg, 15%).
1 H NMR(400MHz,CDCl 3 )δ8.08-8.06(m,1H),7.33-7.32(m,1H),7.31-7.28(m,1H),7.20-7.13(m,3H),7.04-7.02(m,1H),4.35-4.33(m,1H),4.09-4.05(m,1H),3.93-3.84(m,3H),3.69-3.60(m,2H),3.59-3.52(m,3H),3.23-3.18(m,6H),3.05-2.80(m,6H),2.25-2.22(m,2H),1.75-1.68(m,6H),1.35(s,6H).
LC-MS(ESI):m/z＝546.3[M+H] + .
The compound 34, isomer 2, was synthesized using 33E-2 as a starting material by referring to the above synthesis method.
1 H NMR(400MHz,CDCl 3 )δ 1 H NMR(400MHz,CDCl 3 )δ8.08-8.05(m,1H),7.33-7.32(m,1H),7.32-7.28(m,1H),7.20-7.13(m,3H),7.04-7.02(m,1H),4.35-4.33(m,1H),4.09-4.06(m,1H),3.93-3.84(m,3H),3.70-3.61(m,2H),3.59-3.52(m,3H),3.23-3.18(m,6H),3.05-2.82(m,6H),2.26-2.22(m,2H),1.76-1.68(m,6H),1.35(s,6H).
LC-MS(ESI):m/z＝546.3[M+H] + .
Example 35:2- (3, 4-Dihydroisoquinolin-2 (1H) -yl) -2-hydroxypropyl) -6- (2- (trifluoromethoxy) -7-azaspiro [3.5] nonane-7-carbonyl) -3, 4-dihydroisoquinolin-1 (2H) -one (Compound 35)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(2-(trifluoromethoxy)-7-azaspiro[3.5]nonane-7-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one
Compound 4A (0.1 g,0.26 mmol) was dissolved in dichloromethane (10 mL), compound 35A (synthesized according to the method of document WO 2017001660) (0.066 g,0.32 mmol), N, N-diisopropylethylamine (0.1 g,0.8 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.12 g,0.31 mmol) were added, and the reaction was continued at room temperature with stirring for 3 hours after the addition. The reaction was poured into 50mL of water, extracted with dichloromethane (20 ml×3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane: methanol (v/v) =40:1-20:1) to give the title compound 35 (0.030 g, 20%).
1 H NMR(400MHz,CDCl 3 )δ8.07-8.05(m,1H),7.31-7.28(m,1H),7.23(s,1H),7.19-7.12(m,2H),7.04-7.02(m,1H),4.76-4.74(m,1H),4.29-4.27(m,1H),4.07-3.95(m,1H),3.89-3.75(m,3H),3.74-3.68(m,2H),3.55-3.50(m,1H),3.33-3.30(m,2H),3.09-2.97(m,6H),2.86-2.72(m,3H),2.39-2.32(m,2H),2.08-2.05(m,2H),1.69-1.59(m,6H).
LC-MS(ESI):m/z＝572.3[M+H] + .
Example 36: (R) -7- ((1-Acetylpiperidin-4-yl) amino) -2- (3- (6, 7-dihydrothiophene [3,2-c ] pyridin-5 (4H) -yl) -2-hydroxypropyl) -4, 4-dimethyl-3, 4-dihydroisoquinolin-1 (2H) -one (Compound 36)
(R)-7-((1-acetylpiperidin-4-yl)amino)-2-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one
The first step:
compound 36A (5.00 g,28.54 mmol) was dissolved in dimethylsulfoxide (100 mL), cesium carbonate (27.9 g,85.62 mmol) was added under nitrogen and stirred at room temperature for 30min. Methyl iodide (8.91 g,62.79 mmol) was slowly added dropwise and stirred overnight at room temperature. After completion of TLC reaction, 300mL of water was added, extraction was performed with ethyl acetate (300 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 36B (5.60 g, 96.58%).
LC-MS(ESI):m/z＝204.1[M+H] + .
And a second step of:
compound 36B (5.6 g,27.55 mmol) was dissolved in methanol 100 (mL), cobalt dichloride (14.31 g,110.2 mmol) was added under nitrogen, cooled to 0-10deg.C, stirred for 30min, sodium borohydride (6.25 g,165.3 mmol) was added slowly in portions, then warmed to room temperature and stirred, and TLC monitored the reaction. After the reaction is completed, the mixture is filtered, and the filter cake is washed with a small amount of methanol. After concentrating the filtrate under reduced pressure, water (200 mL) was added to the residue, and extracted with ethyl acetate (300 ml×3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the residue obtained after concentration was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =50:1-10:1) to give compound 36C (3.8 g, 78.71%).
LC-MS(ESI):m/z＝176.2[M+H] + .
And a third step of:
compound 36C (3.6 g,20.54 mmol) was dissolved in concentrated sulfuric acid (30 mL). Stirring for 30min in ice bath and nitrogen atmosphere, controlling the temperature at 0-10deg.C, slowly adding concentrated nitric acid (6 mL) dropwise, stirring for 30min after the dropwise addition, and TLC monitoring reaction. After completion of the reaction, the reaction mixture was slowly poured into ice water (100 mL) and extracted with ethyl acetate (300 ml×3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 36D (2.6 g, 57.48%).
LC-MS(ESI):m/z＝221.1[M+H] + .
Fourth step:
Compound 36D (1.00 g,4.50 mmol) was dissolved in DMF (20 mL). Sodium hydride (0.16 g,6.75 mmol) was added thereto under nitrogen atmosphere at 0℃and stirring was continued for 30min. A solution of (R) - (-) -glycidyl p-nitrobenzenesulfonate (1.17 g,4.50 mmol) in DMF (20 mL) was added dropwise, and after completion of the dropwise addition, TLC monitored the reaction. After completion of the reaction, 50mL of water was added, extracted with ethyl acetate (50 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 36E (0.60 g, 48.26%).
LC-MS(ESI):m/z＝277.1[M+H] + .
Fifth step:
compound 36E (1.24 g,4.46 mmol) was dissolved in isopropanol (60 mL), N-diisopropylethylamine (1.73 g,13.38 mmol) was added under nitrogen, and after stirring for 30min, 4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride (0.86 g,4.91 mmol) was added and the temperature was raised to 100℃for 3 hours. After the reaction was cooled to room temperature, it was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) =99:1-10:1) to give compound 36F (1.1 g, 59.07%).
LC-MS(ESI):m/z＝416.2[M-H] - .
Sixth step:
iron powder (0.96 g,17.22 mmol) and ammonium chloride (0.92 g,17.22 mmol) were added as a solid to 80mL of ethanol and water (1:1), stirred at 60℃for 30min, compound 36F (1.10 g,2.65 mmol) was added, and the temperature was raised to 80℃for 1 hour. After the reaction was cooled to room temperature, it was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) =99:1-10:1) to give compound 36G (0.75G, 73.41%).
LC-MS(ESI):m/z＝386.2[M+H] + .
Seventh step:
compound 36G (300 mg,0.77 mmol) was dissolved in 20mL of acetic acid, 1-acetylpiperidin-4-one (0.13G, 0.92 mmol) and sodium triacetoxyborohydride (0.33G, 1.54 mmol) were added under nitrogen and stirred at room temperature for 3 hours. LC-MS monitoring reaction completion, reaction liquid was directly concentrated, and the obtained residue was purified by reverse phase silica gel column chromatography (water: acetonitrile (v/v) =99:1-65:35) to obtain compound 36 (220 mg, 55.73%).
1 H NMR(400MHz,DMSO-d6)δ7.25(d,1H),7.18-7.03(m,2H),6.83-6.69(m,2H),5.59(d,1H),4.17(dd,3H),4.00-3.70(m,5H),3.48-3.39(m,2H),3.31(d,1H),3.25-3.14(m,2H),2.78(s,4H),2.00(s,3H),1.85(s,6H),1.20(d,6H).
LC-MS(ESI):m/z＝511.3[M+H] + .
Example 37: (R) -7'- ((1-Acetylpiperidin-4-yl) amino) -2' - (3- (6, 7-dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) -2-hydroxypropyl) -2',3' -dihydro-1H-spiro [ cyclopropane-1, 4'- [2,6] naphthyridine ] -1' -one (compound 37)
(R)-7'-((1-acetylpiperidin-4-yl)amino)-2'-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,6]naphthyridin]-1'-one
The first step:
37A (10 g,42.29 mmol) was dissolved in 100mL of dichloromethane, cooled to 0deg.C, oxalyl chloride (5.90 g,46.52 mmol) and a drop of DMF were added and the reaction was warmed to room temperature and stirred overnight. 20mL of ethanol was added thereto, the mixture was reacted for half an hour, and after concentration, the mixture was separated by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =5:1) to give compound 37B (10 g, yield: 94.40%).
LCMS m/z＝265.3[M+H] +
And a second step of:
compound 37B (22.00 g,83.18 mmol), methyl boronic acid (7.47 g,124.77 mmol), potassium phosphate (61.80 g,291.13 mmol) and tricyclohexylphosphorus (4.67 g,16.68 mmol) were dissolved in 200mL toluene and 10mL water, nitrogen blanketed, and palladium acetate (1.87 g,8.32 mmol) was added and reacted at 100deg.C for 16 hours. LC-MS showed complete reaction, cooling, filtration, washing the filter cake twice with ethyl acetate, and separating the crude product obtained after concentration of the filtrate by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =5:1) to give compound 37C (9.7 g, yield: 58.42%).
LCMS m/z＝200.1[M+H] +
And a third step of:
compound 37C (5.14 g,27.69 mmol) was dissolved in carbon tetrachloride (50 mL), NBS (4.93 g,27.7 mmol) was added, benzoyl peroxide (1 g,4.13 mmol) was reacted overnight at 80 ℃. LCMS monitored completion of the reaction, cooled, concentrated under reduced pressure to remove the reaction solvent, then extracted with water and ethyl acetate, the organic phase washed 2 times with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =5:1) to give compound 37D (3.8 g, yield: 53.15%).
LCMS m/z＝279.3[M+H] +
Fourth step:
TMSCN (6.41 g,64.62 mmol) was dissolved in anhydrous acetonitrile (200 mL) and tetrabutylammonium fluoride (21.12 g,80.78 mmol) was added. To the reaction solution was slowly added dropwise a solution of Compound 37D (15.00 g,53.85 mmol) in acetonitrile (10 mL), and the reaction was carried out for 3 hours after completion of the dropwise addition. LCMS monitored completion of the reaction, and the reaction solution was filtered through celite, water was added to the filtrate, extracted with ethyl acetate, the organic phase was washed 2 times with saturated sodium chloride, dried over anhydrous sodium sulfate, and the organic phase was concentrated and separated by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =4:1) to give compound 37E (10.3 g, yield: 85.15%).
LCMS m/z＝225.4[M+H] +
Fifth step:
ethyl 2-chloro-5- (cyanomethyl) isonicotinate (37E) (1.6 g,7.12 mmol) was dissolved in anhydrous DMF (25 mL) and 1, 2-dibromoethane (2.0 g,10.65 mmol) and cesium carbonate (4.64 g,14.24 mmol) were added sequentially. Stirring was carried out at room temperature under nitrogen atmosphere for 16 hours. After completion of LCMS monitoring reaction, water was added, extracted with ethyl acetate, the organic phase was washed 2 times with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (petroleum ether: ethyl acetate (v/v) =3:1) to give compound 37F (1.3 g, yield: 73.03%).
LCMS m/z＝251.1[M+H] +
Sixth step:
compound 37F (0.01 g,0.042 mmol) was dissolved in anhydrous 1, 4-dioxane (3 mL), 1-acetylpiperidin-4-amine (0.006g, 0.042 mmol), cesium carbonate (0.041 g,0.13 mmol), palladium (II) chloride (0.0033 g,0.0042 mmol), 2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2-aminoethyl) phenyl ], and reacted overnight at 90 ℃. LCMS monitored completion of the reaction, cooled, concentrated and separated by column chromatography (dichloromethane: methanol (v/v) =10:1) to give compound 37G (10 mg, yield: 66.80%).
LCMS m/z＝357.2[M+H] +
Seventh step:
compound 37G (0.2G, 0.56 mmol) was dissolved in 10mL of ammonia in methanol, and 1G of Raney nickel was added and reacted under hydrogen atmosphere for 2 hours. TLC showed completion of the reaction, filtration, washing of the cake with 10mL of dichloromethane/methanol (10:1) three times, and concentration of the filtrate gave 37H (0.17 g, yield: 95.00%).
Eighth step:
compound 37H (0.22 g,0.7 mmol) was dissolved in 10mL anhydrous N, N-dimethylformamide, sodium hydride (0.042 g,1.05 mmol) was added and stirred for half an hour. Glycidyl (R) - (-) -4-nitrobenzenesulfonate (0.22 g,0.84 mmol) was added and reacted for half an hour, TLC showed complete reaction, concentrated, washed three more times with DCM and concentrated to give 37I (0.12 g, 46.28%).
Ninth step:
4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine hydrochloride (0.084 g,0.48 mmol) and DIPEA (0.12 g,0.96 mmol) were dissolved in 5mL of isopropanol. Half an hour of reaction, compound 37I (60 mg,0.16 mmol) was added, and the mixture was stirred at 110℃for 1 hour. After cooling, concentration, the residue was purified by reverse phase preparation column (acetonitrile: water (v/v) =35:65) to give the objective compound 37 (5 mg, yield: 6.10%).
LCMS m/z＝510.3[M+H] +
Example 38:7- [ (1-Acetylpiperidin-4-yl) amino ] -4- [ (2R) -2-hydroxy-3- (4H, 5H,6H, 7H-thiophene [3,2-c ] pyridin-5-yl) propyl ] -2,3,4, 5-tetrahydro-1, 4-azepin-5-one (Compound 38)
7-[(1-acetylpiperidin-4-yl)amino]-4-[(2R)-2-hydroxy-3-(4H,5H,6H,7H-thieno[3,2-c]pyridin-5-yl)propyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one
The first step:
3, 4-dihydro-1, 4-benzooxazepin-5 (2H) -one (2.00 g,12.25 mmol) was placed in acetic acid (20 mL). Liquid bromine (2.15 g,13.48 mmol) was added thereto, and the temperature was raised to 60℃for reaction for 6 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the reaction mixture was concentrated, and the obtained residue was purified by a silica gel column (ethyl acetate: petroleum ether=0 to 100%) to give compound 38B (1.08 g, yield 36.42%)
LC-MS(ESI):m/z＝242.1[M+H] +
And a second step of:
compound 38B (500 mg,2.07 mmol) was placed in N, N-dimethylformamide (40 mL). Sodium hydride (99 mg,4.14 mmol) was added under nitrogen at 0-10 ℃. After stirring for 30 minutes, a solution of glycidyl (R) - (-) -4-nitrobenzenesulfonate (560 mg,2.28 mmol) in N, N-dimethylformamide (10 mL) was slowly added to the reaction mixture, and the reaction was warmed to room temperature and stirred for 30 minutes. The reaction mixture was concentrated to 2mL, isopropanol (20 mL) was added, and after concentrating again to 2mL, isopropanol (100 mL) was added, N-diisopropylethylamine (800 mg,6.21 mmol) and 4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine hydrochloride (580 mg,4.14 mmol) were sequentially added, and after nitrogen substitution, the temperature was raised to 100℃for reaction for 3 hours. After the reaction was completed, cooled to room temperature, the reaction solution was concentrated to dryness by filtration, and the residue was purified by silica gel column (methanol: dichloromethane=0 to 10%), to give compound 38C (720 mg, yield 79.53%).
LC-MS(ESI):m/z＝437.0[M+H] +
And a third step of:
compound 38C (200 mg,0.46 mmol), 1-acetylpiperidin-4-amine (78 mg,0.55 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (43 mg,0.069 mmol), sodium t-butoxide (88 mg,0.92 mmol) were added sequentially to toluene (10 mL). After 3 nitrogen substitutions, tris (dibenzylideneacetone) dipalladium (51 mg,0.055 mmol) was added, and after 3 nitrogen substitutions again, the temperature was raised to 80 ℃ for reaction overnight. After the reaction is completed, cooling to room temperature, filtering, separating and purifying the residue obtained after the filtrate is dried by a liquid phase preparation column (liquid phase preparation condition: C18 reverse phase preparation column, mobile phase is deionized water (A) containing 0.1% ammonia water, acetonitrile (B), gradient elution, B content = 5% -50%, elution time 15min, flow rate 12mL/min, column temperature: 30 ℃); compound 38 (10 mg, yield 4.36%, retention time about 4.47 min) was obtained.
LC-MS(ESI):m/z＝499.3[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ9.87(s,1H),7.50(d,1H),6.99-6.69(m,4H),5.86(s,1H),4.54(s,1H),4.38-4.15(m,8H),3.78(m,6H),3.18(m,4H),2.80(s,1H),2.00(s,5H),1.41-1.11(m,2H).
Biological testing:
1. PRMT5 enzyme activity test method
1 Xtest buffer (10mM Tris,1mM DTT,0.01%BSA,0.01%Tween-20, pH adjusted to 8.0) was prepared. Test compounds were dissolved in DMSO to make a 10mM stock solution, then diluted with DMSO to 100-fold final concentration, 100nL of compound was added to each well of the dosing group, and 100nL of DMSO solution was added to the blank well and the negative control well. Then, 5. Mu.L PRMT5/MEP50 (BPS, cat.31921) enzyme solution (final concentration 1 nM) was added to the dosing group and the negative control wells, and 5. Mu.L of 1 Xtest buffer was added to the blank wells and incubated at room temperature for 15 minutes. Mu. L H4 (1-21) S1ac (0.05. Mu.M; GL Biochem, custom) and SAM (1. Mu.M; sigma, cat. A7007) were added to each well and incubated for 1 hour at room temperature. 1X Epigenetics buffer (PerkinElmer, cat.AL008F) was formulated for dilution of acceptor microbeads with donor microbeads. Add 15. Mu.L of acceptor microbeads (final concentration) 10 μg/mL; perkinElmer, cat.AL150C) and donor microbeads (final concentration 10 μg/mL; perkinElmer, cat.AS106M) were incubated for 1 hour at room temperature in the absence of light and detected using the Alpha module in an Enspire microplate reader. The inhibition ratio was calculated in Excel from the data obtained: inhibition (%) = (maximum value) Negative control -detection signal value)/(maximum value Negative control -minimum value Blank control ) 100, fitting IC using XL-Fit 50 Values.
Test results: the compounds of the present invention show inhibitory activity against PRMT5 receptor, and the IC50 values of the compounds of the examples for PRMT5 enzyme activity are in the range of 0.01-1000 nM. The test results of some examples are shown in table 1:
table 1 Compound PRMT5 enzyme Activity
Numbering of compounds IC50(nM)
Compound 1 95
Compound 2 38
Compound 3 51
Compound 5 53
Compound 6 72
Compound 7 69
Compound 8 53
Compound 9 31
Compound 10 24
Compound 11 18
Compound 12 23
Compound 13 26
Compound 14 27
Compound 15 24
Compound 16 13
Compound 17, isomer 2 17
Compound 18 85
Compound 19 27
Compound 20 39
Compound 22, isomer 1 18
Compound 22, isomer 2 61
Compound 12, isomer 1 15
Compound 12, isomer 2 15
Compound 24 65
Compound 25 80
Compound 26 54
Compound 27 76
Compound 29 13
Compound 30 16
Compound 20, isomer 1 90
Compound 20, isomer 2 30
Compound 32 31
Compound 33, isomer 1 54
Compound 34, isomer 1 45
Compound 34, isomer 2 40
Compound 35 22
Compound 36 31
Compound 37 36
Compound 38 7.7
Conclusion: the compounds of the present invention have an inhibitory effect on PRMT 5.
2. SW620 cell proliferation inhibition assay
SW620 cells were cultured in DMEM medium (ATCC, cat #30-2002, supplemented with 10% FBS and 1% diabody) until the confluency reached about 85% and cell plating was performed. The medium was discarded, rinsed with 1 XPBS, digested with pancreatin (Gibco, cat # 15400-054), and stopped when the cells became round and began to shedAfter the completion of centrifugation, the cells were blown down and transferred to a sterile centrifuge tube, centrifuged at 1000rpm for 3 minutes, and the supernatant was discarded. The cells were resuspended in medium and counted in a centrifuge tube. And (3) regulating the cell suspension to a proper concentration according to the counting result, pouring the cell suspension into a sample adding groove, adding the sample into a first 96-well cell plate (Corning, cat#3903), simultaneously paving 10 Day0 holes in a second 96-well cell plate, and marking cell information and paving date on the two 96-well cell plates. The compound was dissolved in DMSO to 10mM and stored for later use, and the compound stock solution was diluted 5-fold in sequence at the time of the experiment. After 24 hours of plating, diluted compound was added to the first 96-well cell plate at 9 concentrations of 3 wells each, and a DMSO vehicle control was set at 37 ℃ with 5% co 2 Culturing was continued for 6 days under the conditions. A second 96-well plate was plated with CELL VIABILITY reagent (Promega, cat#G7573) 24 hours later and the first 96-well plate was plated with CELL VIABILITY reagent on day 6 post-dose, incubated at room temperature for 30 minutes, gently shaken 5 times after incubation was completed, and chemiluminescent readings were detected with a microplate reader. The cell proliferation inhibition rate was calculated according to the following formula: [1- (T) Testing -T 0 /T Control -T 0 )]Formula x 100, then using origin9.2 software, using the doseResp function to calculate the GI of the compound to inhibit cell proliferation 50 Values.
Test results: the compounds of the invention show inhibitory activity against PRMT5 receptor, and the IC50 values of the compounds of the examples on SW620 cells are less than 100. Mu.M. Compound a (Compound a described in patent WO 2015198229), compound B (24 a described in patent WO 2019173804), wherein the test results of some of the examples are shown in table 2:
TABLE 2 cell proliferative Activity
Numbering of compounds IC50(μM)
Compound 12 0.5
Compound 14 0.21
Compound 15 0.25
Compound 16 0.73
Compound 12, isomer 2 0.036
Compound A 0.33
Compound B 0.11
Conclusion: the compounds of the present invention have proliferation inhibiting effect on SW620 cells.
3. MDA-MB-231 cell proliferation inhibition assay
MDA-MB-231 cells were incubated with DMEM medium (supplemented with 10% FBS and 1% diabody) until confluence reached about 85% and cell plating was performed. The medium was discarded, rinsed with 1 XPBS, digested with pancreatin (Gibco, cat # 15400-054), stopped when the cells became round and began to fall off, the cells were blown down and transferred to a sterile centrifuge tube, centrifuged at 1000rpm for 3 minutes, removed after centrifugation, and the supernatant discarded. The cells were resuspended in medium and counted in a centrifuge tube. The cell suspension was adjusted to an appropriate concentration according to the result of the counting, poured into a sample-adding well, and added to a first 96-well cell plate (Corning, cat#3903) while 10 Day0 wells were simultaneously plated In the second 96-well cell plate, cell information and plating date were noted on both 96-well cell plates. The compound was dissolved in DMSO to 10mM and stored for later use, and the compound stock solution was diluted 5-fold in sequence at the time of the experiment. After 24 hours of plating, diluted compound was added to the first 96-well cell plate at 9 concentrations of 3 wells each, and a DMSO vehicle control was set at 37 ℃ with 5% co 2 Culturing was continued for 6 days under the conditions. A second 96-well plate was plated with CELL VIABILITY reagent (Promega, cat#G7573) 24 hours later and the first 96-well plate was plated with CELL VIABILITY reagent on day 6 post-dose, incubated at room temperature for 30 minutes, gently shaken 5 times after incubation was completed, and chemiluminescent readings were detected with a microplate reader. The cell proliferation inhibition rate was calculated according to the following formula: [1- (T) Testing -T 0 /T Control -T 0 )]Formula x 100, then using origin9.2 software, using the doseResp function to calculate the GI of the compound to inhibit cell proliferation 50 Values.
TABLE 3 cell proliferative Activity
Numbering of compounds IC50(μM)
Compound 14 0.078
Compounds of formula (I)15 0.063
Compound 12, isomer 2 0.043
Compound 29 0.029
Compound 30 0.134
Compound 32 0.115
Compound 34, isomer 1 0.4
Compound 35 0.137
Compound 37 0.47
Compound A 0.21
Compound B 0.15
Conclusion: the compounds of the present invention have proliferation inhibiting effect on MDA-MB-231 cells.
4. Mouse pharmacokinetic test
The purpose of the experiment is as follows: the concentration of the test substance in the plasma of the mice was measured by administering the test substance to the BALB/c mice by intravenous and intragastric administration at a single dose, and the in vivo pharmacokinetic profile and bioavailability of the test substance in the mice were evaluated.
The experimental object: compound 12, isomer 2 of the present invention.
Test animals: male BALB/c mice, about 20-25 g, 6-8 weeks old, 18/compound. Purchased from Hunan Style Lekka laboratory animal Co.
The test method comprises the following steps: on the day of the trial, 18 BALB/c mice were randomized by body weight. The water is not forbidden for 12-14 h after 1 day of feeding, and the feed is fed for 4h after the feeding. Administration was according to table 4.
Table 4 dosing information
Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline; gastric lavage dosing vehicle: 0.5% MC
Isoflurane was anesthetized before and after dosing to obtain 0.08mL of blood via the orbit and placed in an EDTAK2 centrifuge tube. The plasma was collected by centrifugation at 5000rpm at 4℃for 10 min. Intravenous set blood collection time point: 0,5,15,30min,1,2,4,6,8,24h; time point of blood collection for the lavage group: 0,5,15,30min,1,2,4,6,8,24h. All samples were stored at-80 ℃ prior to analytical testing.
Pharmacokinetic parameters of the compounds of Table 5 in mice
Conclusion: compound 12, isomer 2, has excellent pharmacokinetic bioavailability.
5. Macaca fascicularis pharmacokinetic test
The purpose of the experiment is as follows: the concentration of the test substance in the blood plasma of the cynomolgus monkey is measured by single-dose intravenous and intragastric administration of the test substance to the cynomolgus monkey, and the in vivo drug substitution characteristics and bioavailability of the test substance in the cynomolgus monkey are evaluated.
The experimental object: the compounds of the examples of the present invention.
Test animals: about 3-5 kg of male cynomolgus monkey, 6 compounds/compound, purchased from experimental animals limited in western mountain, su.
The test method comprises the following steps: on the day of the experiment, 6 cynomolgus monkeys were randomly grouped by body weight. The water is not forbidden for 12-14 h after 1 day of feeding, and the feed is fed for 4h after the feeding. Administration was according to table 6.
TABLE 6 dosing information
Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline; gastric lavage dosing vehicle: 0.5% MC
Isoflurane was anesthetized before and after dosing by orbital blood sampling of 1ml and placed in an EDTAK2 centrifuge tube. The plasma was collected by centrifugation at 5000rpm at 4℃for 10 min. Intravenous set blood collection time point: 0,5,15,30min,1,2,4,6,8,10,12,24h; time point of blood collection for the lavage group: 0,5,15,30min,1,2,4,6,8,10,12,24h. All samples were stored at-80 ℃ prior to analytical testing.
Pharmacokinetic parameters of the compounds of Table 7 in cynomolgus monkeys
Conclusion: compound 12, isomer 2, monkey, has excellent pharmacokinetic bioavailability.

Claims (15)

  1. A compound of formula (I), stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
    wherein,
    ring a is selected from phenyl or 5-6 membered heteroaryl;
    R 1 、R 2 、R 3 、R 4 each independently selected from hydrogen, deuterium, hydroxy, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, -C (O) C 1-6 Alkyl, -C (O) NHC 1-6 Alkyl, -C (O) NH 2 、-NHC(O)C 1-6 Alkyl, -N (C) 1-6 Alkyl) C (O) C 1-6 Alkyl, optionally substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, C 1-6 Substitution of the alkoxy group;
    alternatively, R 1 、R 2 Together with the attached carbon atom, form a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
    alternatively, R 3 、R 4 Together with the attached carbon atom, form a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
    R 5 selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, -C (O) C 1-6 Alkyl, -C (O) NH 2 、-C(O)NHC 1-6 Alkyl, optionally substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, C 1-6 Substitution of the alkoxy group;
    R 8 selected from hydrogen, deuterium, hydroxy, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 An alkoxy group;
    R 6 selected from deuterium, halogen, cyano, nitro, cyano, amino, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -O-C 3-8 Cycloalkyl, -O- (3-8 membered heterocycloalkyl), -NH-C 3-8 Cycloalkyl, -NH- (3-8 membered heterocycloalkyl), -S-C 3-8 Cycloalkyl, -S- (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR 6a R 6b 、-NR 6a C(＝O)-R 6b 、-NR 6a R 6b 、-C(＝O)-R 6a 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Alkyl, said CH 2 Optionally further substituted with 1 to 5 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
    R 6a selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally being substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, C 1-6 Substitution of the alkoxy group;
    R 6b Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, -S (O) 2 C 1-6 Alkyl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl being optionally substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
    x is selected from the group consisting of bond, -O-, -S (O) 2 -、-CR xa R xb -or-NR xa -；
    Y is selected from the group consisting of bond, -O-, -S (O) 2 -、-CR ya R yb -、-NR ya -or-CR ya -；
    Z is selected from the group consisting of bond, -O-, -S (O) 2 -、-CR za R zb -、-NR za -、-CR za -or-N-;
    provided X, Y, Z is not both a bond;
    represents a single bond or a double bond;
    X 1 selected from-CR x1a -or-N-;
    X 2 selected from-CR x2a -or-N-;
    X 3 selected from-CR x3a -or-N-;
    X 7 selected from-CR x7a -or-N-;
    X 4 selected from-O-, -S-, -CR x4a R x4b -or-NR x4a -；
    X 5 Selected from-O-, -S-, -CR x5a R x5b -or-NR x5a -；
    X 6 Selected from bonds, -O-, -S-, -CR x6a R x6b -or-NR x6a -；
    R x1a 、R x2a 、R x3a 、R x7a Each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, -L-R 7 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (3-12 membered heterocycloalkyl), -O-C 3-12 Cycloalkyl, -O- (3-12 membered heterocycloalkyl), -NH-C 3-12 Cycloalkyl, -NH- (3-12 membered heterocycloalkyl), -S-C 3-12 Cycloalkyl, -S- (3-12 membered heterocycloalkyl), 5-12 membered heteroaryl, 6-12 membered aryl, -C (=o) NR xaa R xab 、-NR xaa C(＝O)-R xab 、-NR xaa R xab 、-C(＝O)-R xaa 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Alkyl, said CH 2 Optionally further substituted with 1 to 5 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
    R xa 、R xb 、R ya 、R yb 、R za 、R zb 、R x4a 、R x4b 、R x5a 、R x5b 、R x6a 、R x6b each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (3-12 membered heterocycloalkyl), -O-C 3-12 Cycloalkyl, -O- (3-12 membered heterocycloalkyl), -NH-C 3-12 Cycloalkyl, -NH- (3-12 membered heterocycloalkyl), -S-C 3-12 Cycloalkyl, -S- (3-12 membered heterocycloalkyl), 5-12 membered heteroaryl, 6-12 membered aryl, -C (=o) NR xaa R xab 、-NR xaa C(＝O)-R xab 、-NR xaa R xab 、-C(＝O)-R xaa 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Alkyl, said CH 2 Optionally further substituted with 1 to 5 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
    R xaa 、R xab each independently selected from hydrogen, deuterium, amino, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, deuterated C 1-6 An alkoxy group;
    alternatively, R's bound to the same carbon atom xa And R is xb 、R ya And R is yb 、R za And R is zb 、R x4a And R is x4b 、R x5a And R is x5b Or R is x6a And R is x6b Together with the attached carbon atom, form =o, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
    alternatively, R is attached to adjacent carbon atoms xa And R is za Together with the attached carbon atom, form =o, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
    alternatively, R x4a And R is R x6a Together form-CH 2 -or-CH 2 CH 2 -；
    L is selected from bond, -NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-、-NR La C(O)-(CH 2 ) p -O-、-O-(CH 2 ) p -C(O)NR La -、-NR La C(O)-NR La -、-O-、-S-、-S(O) 2 NR La -、-NR La S(O) 2 -；
    R La Selected from hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 An alkyl group;
    R 7 selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (4-12 membered heterocycloalkyl), - (CH) 2 ) r - (5-12 membered heteroaryl), - (CH) 2 ) r - (6-12 membered aryl) said CH 2 Optionally further substituted with 1 to 5 groups selected from deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-6 Alkyl, = O, C 1-6 Alkoxy group,C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -SF 5 、-(CH 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -O-C 3-8 Cycloalkyl, -O- (3-8 membered heterocycloalkyl), -NH-C 3-8 Cycloalkyl, -NH- (3-8 membered heterocycloalkyl), -S-C 3-8 Cycloalkyl, -S- (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Substitution of the alkyl group;
    R cya 、R cyb each independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 An alkyl group;
    alternatively, -L-R 7 Selected from hydrogen, deuterium, amino, hydroxy, halogen, cyano, and C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1- 6 Alkoxy, halo C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 An alkoxy group;
    m is selected from 0, 1, 2, 3 or 4;
    p is selected from 0, 1 or 2;
    r is selected from 0, 1, 2 or 3;
    with the proviso that the compound of formula (I) is not selected from the following compounds:
  2. the compound of formula (I) according to claim 1, which is a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, having the structure of formula (II-1), (II-2), (II-3), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15):
    Wherein,
    ring a is selected from phenyl, 5 membered heteroaryl, or 6 membered heteroaryl;
    ring B is selected from 5 membered heteroaryl or 6 membered heteroaryl;
    the E ring is 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
    the H ring is 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
    R 11 、R 12 、R 13 、R 15 、R 17 、R 18 、R 19 、R 110 、R 111 、R 112 、R 113 、R 114 、R 115 、R 21 、R 22 、R 23 、R 25 、R 27 、R 28 、R 29 、R 210 、R 211 、R 212 、R 213 、R 214 、R 215 、R 31 、R 32 、R 33 、R 35 、R 36 、R 37 、R 38 、R 39 、R 310 、R 311 、R 312 、R 313 、R 314 、R 315 、R 41 、R 42 、R 43 、R 45 、R 46 、R 47 、R 48 、R 49 、R 410 、R 411 、R 412 、R 413 、R 414 、R 415 each independently selected from hydrogen, deuterium, hydroxy, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally substituted with 1 to 3 groups selected from halogen, deuterium, hydroxy;
    alternatively, R's bound to the same carbon atom 11 And R is 21 、R 31 And R is 41 、R 12 And R is 22 、R 32 And R is 42 、R 13 And R is 23 、R 33 And R is 43 、R 15 And R is 25 、R 35 And R is 45 、R 36 And R is 46 、R 17 And R is 27 、R 37 And R is 47 、R 18 And R is 28 、R 38 And R is 48 、R 19 And R is 29 、R 39 And R is 49 、R 110 And R is 210 、R 310 And R is 410 、R 111 And R is 211 、R 311 And R is 411 、R 112 And R is 212 、R 312 And R is 412 、R 112 And R is 213 、R 313 And R is 413 、R 114 And R is 214 、R 314 And R is 414 、R 115 And R is 215 Or (b)R 315 And R is 415 Each independently form together with the attached carbon atom a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl group;
    R 51 、R 52 、R 53 、R 55 、R 56 、R 57 、R 58 、R 59 、R 510 、R 511 、R 512 、R 513 、R 514 、R 515 each independently selected from hydrogen, deuterium, C 1-4 An alkyl group optionally substituted with 1 to 3 groups selected from halogen, deuterium, hydroxy;
    R 81 、R 82 、R 83 、R 85 、R 86 、R 87 、R 88 、R 89 、R 810 、R 811 、R 812 、R 813 、R 814 、R 815 each independently selected from hydrogen, deuterium, hydroxy, and halogen;
    r being bound to the same carbon atom 9a1 And R is 9b1 、R 9a2 And R is 9b2 Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl; or alternatively
    R 9a1 And R is 9a2 Interlinking to form-CH 2 -、-CH 2 CH 2 -；
    R 61 、R 63 、R 65 、R 66 、R 67 、R 68 、R 69 、R 610 、R 611 、R 612 、R 613 、R 614 、R 615 、R 616 、R 617 Each independently selected from deuterium, halogen, cyano, nitro, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -O-C 3-8 Cycloalkyl, -O- (3-8 membered heterocycloalkyl), -NH-C 3-8 Cycloalkyl, -NH- (3-8 membered heterocycloalkyl), -S-C 3-8 Cycloalkyl, -S- (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR 6a R 6b 、-NR 6a C(＝O)-R 6b 、-NR 6a R 6b 、-C(＝O)-R 6a 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Alkyl, said CH 2 Optionally further substituted with 1 to 5 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
    R 62 is deuterium, halogen, - (CH) 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -C (=o) NR 6a R 6b 、-NR 6a C(＝O)-R 6b 、-NR 6a R 6b 、-C(＝O)-R 6a The CH is 2 Optionally further substituted with 1 to 3 groups selected from halogen, deuterium, cyano, hydroxy, = O, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Substitution of the alkoxy group;
    R 6a selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally being substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, C 1-6 Substitution of the alkoxy group;
    R 6b selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 Alkylamino, di (C) 1-6 Alkyl) amino, -S (O) 2 C 1-6 Alkyl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl being optionally substituted with 1 to 5 groups selected from halogen, deuterium, hydroxy, amino, cyano, = O, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Substitution of the alkoxy group;
    X 81 、X 83 、X 86 、X 88 、X 89 、X 810 、X 811 、X 813 、X 814 、X 815 each independently selected from the group consisting of-O-, -S-, and S (O) -, -S (O) 2 -、-CR xa R xb -or-NR xa -；
    X 87 Selected from the group consisting of-O-, -S (O) -, -S (O) 2 -、-CR xa R xb -or-NR xa -；
    X 812 Selected from the group consisting of-O-, -S-, and S (O) -, -S (O) 2 -、-CR xa2 R xb2 -or-NR xa -；
    X 82 Selected from the group consisting of-O-, -S-, and S (O) -, -S (O) 2 -、-CR xa1 R xb1 -or-NR xa -；
    Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 Each independently selected from the group consisting of bond, -CR ya R yb -、-NR ya -or-CR ya -；
    Z 1 、Z 2 、Z 3 、Z 4 、Z 5 、Z 6 Each independently selected from the group consisting of bond, -CR za R zb -、-NR za -、-CR za -or-N-;
    X 41 、X 42 、X 43 、X 44 each independently selected from-CR x4a R x4b -or-NR x4a -；
    X 51 、X 52 、X 53 、X 54 Each independently selected from-CR x5a R x5b -or-NR x5a -；
    X 61 、X 62 、X 63 、X 64 Each independently selected from the group consisting of bond, -CR x6a R x6b -or-NR x6a -；
    X 11 、X 12 、X 13 、X 15 、X 16 、X 17 、X 18 、X 19 、X 110 、X 113 、X 114 、X 115 Each independently selected from-CR x1a -or-N-;
    X 21 、X 22 、X 23 、X 25 、X 26 、X 27 、X 28 、X 29 、X 211 、X 213 、X 214 、X 215 each independently selected from-CR x2a -or-N-;
    X 31 、X 32 、X 33 、X 35 、X 36 、X 37 、X 38 、X 39 、X 310 、X 311 each independently selected from-CR x3a -or-N-;
    X 710 、X 711 、X 713 、X 714 、X 715 each independently selected from-CR x7a -or-N-;
    X 112 selected from-CR x1b -；
    X 212 Selected from-CR x2b -；
    X 712 Selected from-CR x7b -；
    R x1a 、R x2a 、R x3a 、R x7a Each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 The alkyl, alkoxy is optionally further substituted with 1 to 3 groups selected from F, cl, deuterium, nitro, cyano, amino, hydroxy, C 1-2 Alkyl, C 1-2 Alkoxy, halo C 1-2 Alkyl, halogenated C 1-2 Alkoxy, deuterated C 1-2 Alkyl, deuterated C 1-2 Substitution of the alkoxy group;
    R xa 、R xb 、R xa2 、R xb2 、R ya 、R yb 、R za 、R zb 、R x4a 、R x4b 、R x5a 、R x5b 、R x6a 、R x6b each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-6 Monocyclic cycloalkyl, - (CH) 2 ) r -C 5-10 Bicyclic cycloalkyl, - (CH) 2 ) r - (3-6 membered monocyclic heterocycloalkyl), - (CH) 2 ) r - (5-to 10-membered bicycloheterocycloalkyl), -O-C 3-6 Monocyclic cycloalkyl, -O-C 5-10 Bicyclic cycloalkyl, -O- (3-6 membered monocyclic heterocycloalkyl), -O- (5-10 membered bicyclic heterocycloalkyl), -NH-C 3-6 Monocyclic cycloalkyl, -NH-C 5-10 Bicyclic cycloalkyl, -NH- (3-6 membered monocyclic heterocycloalkyl), -NH- (5-10 membered bicyclic heterocycloalkyl), 5-to 6-membered heteroaryl, -phenyl, -C (=o) NR xaa R xab 、-NR xaa C(＝O)-R xab 、-NR xaa R xab 、-C(＝O)-R xaa The CH is 2 Optionally further substituted with 1 to 3 groups selected from halogen, deuterium, nitro, cyano, amino, hydroxy, = O, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Substitution of the alkoxy group;
    R xa1 、R xb1 each independently selected from hydrogen, deuterium, cyano, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-6 Monocyclic cycloalkyl, - (CH) 2 ) r -C 5-10 Bicyclic cycloalkyl, - (CH) 2 ) r - (3-6 membered monocyclic heterocycloalkyl), - (CH) 2 ) r - (5-10 membered bicycloheterocycloalkyl), 5-to 6-membered heteroaryl, phenyl, said CH 2 Optionally further substituted with 1 to 3 groups selected from halogen, deuterium, cyano, hydroxy, = O, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Substitution of the alkoxy group;
    R xaa 、R xab each independently selected from hydrogen, deuterium, amino, hydroxy, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, deuterated C 1-4 An alkoxy group;
    R x1b 、R x2b 、R x7b each independently selected from H, deuterium, nitro, cyano, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 The alkyl, alkoxy is optionally further substituted with 1 to 3 groups selected from F, cl, deuterium, nitro, cyano, amino, hydroxy, C 1-2 Alkyl, C 1-2 Alkoxy, halo C 1-2 Alkyl, halogenated C 1-2 Alkoxy, deuterated C 1-2 Alkyl, deuterated C 1-2 Substitution of the alkoxy group;
    provided that R x1b 、R x2b 、R x7b Not simultaneously H;
    alternatively, when R x1b 、R x2b 、R x7b At the same time selected from H, -L 12 -R 712 Selected from H;
    alternatively, R's bound to the same carbon atom xa And R is xb 、R xa1 And R is xb1 、R ya And R is yb 、R za And R is zb 、R x4a And R is x4b 、R x5a And R is x5b Or R is x6a And R is x6b Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
    alternatively, R is attached to adjacent carbon atoms xa And R is za Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
    alternatively, R x4a And R is R x6a Together form-CH 2 -or-CH 2 CH 2 -；
    L 1 Selected from the group consisting of-C (O) NR La -、*-NR La C(O)-、*-NR La C(O)-(CH 2 ) p -O-、*-O-(CH 2 ) p -C(O)NR La -、-NR La C(O)-NR La -、-S-、*-S(O) 2 NR La -、*-NR La S(O) 2 -, represents L 1 And R is R 71 A linking site;
    L 2 selected from-NR La -、-C(O)-、-C(O)NR La -**、-NR La C(O)-(CH 2 ) p -O-**、-O-(CH 2 ) p -C(O)NR La -**、-NR La C(O)-NR La -**、-S-、-S(O) 2 NR La -**、-NR La S(O) 2 A method for producing a composite material x-ray in the sense that, represents L 2 And R is R 72 A linking site;
    L 3 、L 5 、L 6 each independently selected from the group consisting of bond, -NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-、-NR La C(O)-(CH 2 ) p -O-、-O-(CH 2 ) p -C(O)NR La -、-NR La C(O)-NR La -、-O-、-S-、-S(O) 2 NR La -、-NR La S(O) 2 -；
    L 7 、L 8 、L 9 、L 10 、L 11 、L 12 、L 13 、L 14 、L 15 Each independently selected from-NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-、-NR La C(O)-(CH 2 ) p -O-、-O-(CH 2 ) p -C(O)NR La -、-NR La C(O)-NR La -、-O-、-S-、-S(O) 2 NR La -、-NR La S(O) 2 -；
    R La Selected from hydrogen, deuterium, halogenated C 1-4 Alkyl, deuterated C 1-4 An alkyl group;
    R 71 selected from- (CH) 2 ) r - (4-12 membered heterocycloalkyl), - (CH) 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (5-12 membered heteroaryl), - (CH) 2 ) r - (6-to 12-membered aryl),the CH is 2 Optionally further substituted with 1 to 3 groups selected from deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-4 Alkyl, = O, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya 、-S-C 1-4 Alkyl, -S (O) -C 1-4 Alkyl, -S (O) 2 -C 1-4 Substitution of the alkyl group; or alternatively
    L 1 Selected from-NR La -，R 71 Selected from 5-12 membered heteroaryl, - (CH) 2 ) r - (6-12 membered aryl) said CH 2 Optionally further substituted with 1 to 3 groups selected from deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-4 Alkyl, = O, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya 、-S-C 1-4 Alkyl, -S (O) -C 1-4 Alkyl, -S (O) 2 -C 1-4 Substitution of the alkyl group;
    R 72 selected from C 2-6 Alkenyl, -SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (4-12 membered heterocycloalkyl), 5-12 membered heteroaryl, 6-12 membered aryl, said CH 2 Cycloalkyl, heterocycloalkyl, heteroaryl,Aryl is optionally further substituted with 1 to 5 groups selected from deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-6 Alkyl, = O, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, - (CH) 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -O-C 3-8 Cycloalkyl, -O- (3-8 membered heterocycloalkyl), -NH-C 3-8 Cycloalkyl, -NH- (3-8 membered heterocycloalkyl), -S-C 3-8 Cycloalkyl, -S- (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Substitution of the alkyl group;
    provided that when L 2 Selected from-NH-, R 72 Selected from- (CH) 2 ) r -4-12 membered heterocycloalkyl, 6-12 membered aryl or- (CH) 2 ) r -C 3-12 Cycloalkyl, one of the following conditions is satisfied: m is not 0, or X 12 、X 32 One selected from N, or R x2a 、R x3a Not simultaneously H; or alternatively
    L 2 Selected from-NR La C(O)-**，R 72 Selected from C 2-6 Alkenyl, -SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (4-12 membered saturated heterocycloalkyl), 6-12 membered aryl, said CH 2 Optionally further substituted with 1 to 5 groups selected from deuterium,Halogen, nitro, cyano, amino, hydroxy, C 1-6 Alkyl, = O, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, - (CH) 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -O-C 3-8 Cycloalkyl, -O- (3-8 membered heterocycloalkyl), -NH-C 3-8 Cycloalkyl, -NH- (3-8 membered heterocycloalkyl), -S-C 3-8 Cycloalkyl, -S- (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 Substitution of the alkyl group;
    alternatively, -L 2 -R 72 Selected from CN, -C (O) N (C) 1-4 Alkyl group 2 A 5-membered heteroaryl, a 7-12 membered heteroaryl, said heteroaryl optionally being further substituted with 1 to 3 deuterium, halogen, hydroxy, amino, cyano, C 1-4 Alkyl, = O, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya Is substituted by a group of (2);
    R 73 、R 75 、R 76 、R 77 、R 78 、R 79 、R 710 、R 711 、R 712 、R 713 、R 714 、R 715 each independently selected from deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (4-12 membered heterocycloalkyl), - (CH) 2 ) r - (5-12 membered heteroaryl), - (CH) 2 ) r - (6-12 membered aryl) said CH 2 Optionally further substituted with 1 to 5 groups selected from R f Is substituted by a group of (2);
    alternatively, -L 7 -R 77 、-L 13 -R 713 Each independently selected from halogen, 5-12 membered heteroaryl, said heteroaryl optionally further being selected from R by 1-5 f Is substituted by a group of (2);
    alternatively, -L 8 -R 78 、-L 9 -R 79 、-L 10 -R 710 、-L 11 -R 711 Each independently selected from SF 5 、-(CH 2 ) r -C 3-12 Cycloalkyl, - (CH) 2 ) r - (4-12 membered heterocycloalkyl), - (CH) 2 ) r - (5-12 membered heteroaryl), - (CH) 2 ) r - (6-12 membered aryl) said CH 2 Optionally further substituted with 1 to 5 groups selected from R f Is substituted by a group of (2);
    each R f Each independently selected from deuterium, halogen, nitro, cyano, amino, hydroxy, C 1-6 Alkyl, = O, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -SF 5 、-(CH 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -O-C 3-8 Cycloalkyl, -O- (3-8 membered heterocycloalkylyl), -NH-C 3-8 Cycloalkyl, -NH- (3-8 membered heterocycloalkyl), -S-C 3-8 Cycloalkyl, -S- (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya 、-S-C 1-6 Alkyl, -S (O) -C 1-6 Alkyl, -S (O) 2 -C 1-6 An alkyl group;
    R cya 、R cyb each independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 An alkyl group.
  3. The compound of claim 2, wherein the stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
    R 11 、R 12 、R 13 、R 15 、R 17 、R 18 、R 19 、R 110 、R 111 、R 112 、R 113 、R 114 、R 115 、R 21 、R 22 、R 23 、R 25 、R 27 、R 28 、R 29 、R 210 、R 211 、R 212 、R 213 、R 214 、R 215 、R 31 、R 32 、R 33 、R 35 、R 36 、R 37 、R 38 、R 39 、R 310 、R 311 、R 312 、R 313 、R 314 、R 315 、R 41 、R 42 、R 43 、R 45 、R 46 、R 47 、R 48 、R 49 、R 410 、R 411 、R 412 、R 413 、R 414 、R 415 each independently selected from hydrogen, deuterium, C 1-4 An alkyl group optionally substituted with 1 to 3 groups selected from halogen, deuterium;
    alternatively, R's bound to the same carbon atom 11 And R is 21 、R 31 And R is 41 、R 12 And R is 22 、R 32 And R is 42 、R 13 And R is 23 、R 33 And R is 43 、R 15 And R is 25 、R 35 And R is 45 、R 36 And R is 46 、R 17 And R is 27 、R 37 And R is 47 、R 18 And R is 28 、R 38 And R is 48 、R 19 And R is 29 、R 39 And R is 49 、R 110 And R is 210 、R 310 And R is 410 、R 111 And R is 211 、R 311 And R is 411 、R 112 And R is 212 、R 312 And R is 412 、R 112 And R is 213 、R 313 And R is 413 、R 114 And R is 214 、R 314 And R is 414 、R 115 And R is 215 Or R 315 And R is 415 Each independently form together with the attached carbon atom a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl group;
    R 51 、R 52 、R 53 、R 55 、R 56 、R 57 、R 58 、R 59 、R 510 、R 511 、R 512 、R 513 、R 514 、R 515 each independently selected from hydrogen, deuterium, C 1-4 An alkyl group optionally substituted with 1 to 3 groups selected from halogen, deuterium;
    R 81 、R 82 、R 83 、R 85 、R 86 、R 87 、R 88 、R 89 、R 810 、R 811 、R 812 、R 813 、R 814 、R 815 each independently selected from hydrogen, deuterium;
    R being bound to the same carbon atom 9a1 And R is 9b1 、R 9a2 And R is 9b2 Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl; or alternatively
    R 9a1 And R is 9a2 Interlinking to form-CH 2 -；
    R 61 、R 63 、R 65 、R 66 、R 67 、R 68 、R 69 、R 610 、R 611 、R 612 、R 613 、R 614 、R 615 、R 616 、R 617 Each independently selected from deuterium, halogen, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), 5-to 8-membered heteroaryl, 6-to 8-membered aryl, -C (=o) NR 6a R 6b 、-NR 6a C(＝O)-R 6b 、-NR 6a R 6b 、-C(＝O)-R 6a The CH is 2 Optionally further substituted with 1 to 3 groups selected from halogen, deuterium, C 1-4 Substitution of the alkyl group;
    R 62 is deuterium, halogen, - (CH) 2 ) r -C 3-8 Cycloalkyl, - (CH) 2 ) r - (3-8 membered heterocycloalkyl), -C (=o) NR 6a R 6b 、-NR 6a C(＝O)-R 6b 、-NR 6a R 6b 、-C(＝O)-R 6a The CH is 2 Optionally further substituted, by 1 to 3 groups selected from halogen, deuterium, = O, C 1-4 Alkyl, C 1-4 Substitution of the alkoxy group;
    R 6a selected from hydrogen, deuterium, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally being substituted with 1 to 3 substituents selected from halogen, deuterium, C 1-4 Substitution of the alkoxy group;
    R 6b selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl optionally being substituted with 1 to 3 groups selected from halogen, deuterium, C 1-4 Alkyl, C 1-4 Substitution of the alkoxy group;
    X 81 、X 83 、X 86 、X 88 、X 89 、X 810 、X 811 、X 813 、X 814 、X 815 each independently selected from-O-, -S-, -CR xa R xb -or-NR xa -；
    X 87 Selected from-O-, -CR xa R xb -or-NR xa -；
    X 812 Selected from-O-, -S-, -CR xa2 R xb2 -or-NR xa -；
    X 82 Selected from-O-, -S-, -CR xa1 R xb1 -or-NR xa -；
    Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 Each independently selected from the group consisting of bond, -CR ya R yb -or-NR ya -；
    Z 1 、Z 2 、Z 3 、Z 4 、Z 5 、Z 6 Each independently selected from the group consisting of bond, -CR za R zb -or-NR za -；
    X 41 、X 42 、X 43 、X 44 Each independently selected from-CR x4a R x4b -or-NR x4a -；
    X 51 、X 52 、X 53 、X 54 Each independently selected from-CR x5a R x5b -or-NR x5a -；
    X 61 、X 62 、X 63 、X 64 Each independently selected from the group consisting of bond, -CR x6a R x6b -or-NR x6a -；
    X 11 、X 12 、X 13 、X 15 、X 16 、X 17 、X 18 、X 19 、X 110 、X 113 、X 114 、X 115 Each independently selected from-CR x1a -or-N-;
    X 21 、X 22 、X 23 、X 25 、X 26 、X 27 、X 28 、X 29 、X 211 、X 213 、X 214 、X 215 each independently selected from-CR x2a -or-N-;
    X 31 、X 32 、X 33 、X 35 、X 36 、X 37 、X 38 、X 39 、X 310 、X 311 each independently selected from-CR x3a -or-N-;
    X 710 、X 711 、X 713 、X 714 、X 715 each independently selected from-CR x7a -or-N-;
    X 112 selected from-CR x1b -；
    X 212 Selected from-CR x2b -；
    X 712 Selected from-CR x7b -；
    R x1a 、R x2a 、R x3a 、R x7a Each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further being 1 to 3 groups selected from F, cl, deuterium, hydroxy, C 1-2 Alkyl, C 1-2 Substitution of the alkoxy group;
    R xa 、R xb 、R xa2 、R xb2 、R ya 、R yb 、R za 、R zb 、R x4a 、R x4b 、R x5a 、R x5b 、R x6a 、R x6b each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) r -C 3-6 Monocyclic cycloalkyl, - (CH) 2 ) r -C 5-10 Bicyclic cycloalkyl, - (CH) 2 ) r - (3-6 membered monocyclic heterocycloalkyl), - (CH) 2 ) r - (5-10 membered bicycloheterocycloalkyl), 5-to 6-membered heteroaryl, phenyl, -C (=o) NR xaa R xab 、-NR xaa C(＝O)-R xab 、-NR xaa R xab 、-C(＝O)-R xaa The CH is 2 Optionally further substituted with 1 to 3 groups selected from halogen, deuterium, C 1-4 Alkyl, C 1- 4 Substitution of the alkoxy group;
    R xa1 、R xb1 each independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) r -C 3-6 Monocyclic cycloalkyl, - (CH) 2 ) r -C 5-10 Bicyclic cycloalkyl, - (CH) 2 ) r - (3-6 membered monocyclic heterocycloalkyl), - (CH) 2 ) r - (5-10 membered bicycloheterocycloalkyl), 5-to 6-membered heteroaryl, phenyl, andthe CH is 2 Optionally further substituted with 1 to 3 groups selected from halogen, deuterium, C 1-4 Alkyl, C 1-4 Substitution of the alkoxy group;
    R xaa 、R xab each independently selected from hydrogen, deuterium, C 1-4 Substitution of the alkyl group;
    R x1b 、R x2b 、R x7b each independently selected from H, deuterium, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further being 1 to 3 groups selected from F, cl, deuterium, hydroxy, C 1-2 Alkyl, C 1-2 Substitution of the alkoxy group;
    provided that R x1b 、R x2b 、R x7b Not simultaneously H;
    alternatively, when R x1b 、R x2b 、R x7b At the same time selected from H, -L 12 -R 712 Selected from H;
    alternatively, R's bound to the same carbon atom xa And R is xb 、R xa1 And R is xb1 、R ya And R is yb 、R za And R is zb 、R x4a And R is x4b 、R x5a And R is x5b Or R is x6a And R is x6b Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
    alternatively, R is attached to adjacent carbon atoms xa And R is za Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
    Alternatively, R x4a And R is R x6a Together form-CH 2 -or-CH 2 CH 2 -。
  4. A compound according to claim 2 or 3, a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, having the structure of formula (III-1), (III-2), (III-3), (III-5), (III-6), (III-7), (III-8), (III-9):
    ring E is 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
    the H ring is 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
    selected from the following A, B, C or D structure,
    R 52 selected from hydrogen, deuterium, C 1-4 An alkyl group optionally substituted with 1 to 3 groups selected from halogen, deuterium;
    r being bound to the same carbon atom 9a1 And R is 9b1 、R 9a2 And R is 9b2 Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl; or alternatively
    R 9a1 And R is 9a2 Interlinking to form-CH 2 -；
    R 69 Selected from deuterium, halogen, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further substituted with 1 to 3 groups selected from halogen, deuterium, hydroxy;
    R 62 Selected from deuterium, halogen, C 3-6 Cycloalkyl, 3-5 membered heterocycloalkyl, -C (=o) NR 6a R 6b 、-NHC(＝O)-R 6b 、-NR 6a R 6b 、-C(＝O)-R 6a The cycloalkyl, heterocycloalkyl, optionally further substituted with 1 to 3 groups selected from halogen, deuterium, = O, C 1-4 Substitution of the alkyl group;
    R 6a selected from hydrogen, deuterium, C 1-4 An alkyl group optionally substituted with 1 to 3 groups selected from halogen, deuterium;
    R 6b selected from hydrogen, deuterium, C 1-4 An alkyl group optionally substituted with 1 to 3 groups selected from halogen, deuterium;
    X 81 、X 87 、X 88 、X 89 each independently selected from-O-, -CR xa R xb -or-NR xa -；
    X 82 Selected from-O-, -CR xa1 R xb1 -or-NR xa -；
    X 12 Selected from-CR x1a -or-N-;
    X 22 selected from-CR x2a -or-N-;
    X 32 selected from-CR x3a -or-N-;
    R x1a 、R x2a 、R x3a each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further substituted with 1 to 3 groups selected from F, cl, deuterium;
    R xa 、R xb each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further substituted with 1 to 3 groups selected from F, cl, deuterium;
    R xa1 、R xb1 each independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further substituted with 1 to 3 groups selected from F, cl, deuterium;
    alternatively, R's bound to the same carbon atom xa And R is xb Together with the attached carbon atoms, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl;
    L 1 Selected from-NR La 、*-C(O)NR La -、*-NR La C (O) -, represents L 1 And R is R 71 A linking site;
    L 2 selected from-NR La 、-C(O)-、-C(O)NR La -**、-NR La C(O)-(CH 2 ) p -O-**、-O-(CH 2 ) p -C(O)NR La A method for producing a composite material x-ray in the sense that, represents L 2 And R is R 72 Is a ligation site of (2);
    L 3 、L 5 、L 6 each independently selected from the group consisting of bond, -NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-；
    L 7 、L 8 、L 9 Each independently selected from-NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-；
    R La Selected from hydrogen, deuterium, C 1-4 An alkyl group;
    R 71 selected from 5-membered heteroaryl or 6-membered heteroaryl, said heteroaryl optionally being further substituted with 1 to 3 groups selected from deuterium, halogen, C 1-4 Substitution of the alkyl group;
    R 72 selected from C 3-6 Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-8 membered heteroaryl, 6-9 membered aryl, said cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally being further substituted with 1 to 3 groups selected from deuterium, halogen, hydroxy, amino, cyano, C 1-4 Alkyl, = O, C 1-4 Alkoxy, halo C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya Is substituted by a group of (2);
    provided that when L 2 Selected from-NH-, R 72 Selected from- (CH) 2 ) r -4-12 membered heterocycloalkyl, 6-12 membered aryl or- (CH) 2 ) r -C 3-12 Cycloalkyl, one of the following conditions is satisfied: m is not 0, or X 12 、X 32 One selected from N, or R x2a 、R x3a Not simultaneously H; or alternatively
    L 2 Selected from-NR La C(O)-**，R 72 Selected from C 3-6 Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 6-9 membered aryl, said cycloalkyl, heterocycloalkylThe radicals, aryl groups are optionally further substituted with 1 to 3 radicals selected from deuterium, halogen, cyano, amino, hydroxy, C 1-4 Alkyl, = O, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -C (=o) -R cya Is substituted by a group of (2);
    alternatively, -L 2 -R 72 Selected from CN, -C (O) N (C) 1-4 Alkyl group 2 A 5 membered heteroaryl group, said heteroaryl group optionally being further substituted with 1 to 3 deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya Is substituted by a group of (2);
    R 73 、R 75 、R 76 、R 77 、R 78 、R 79 each independently selected from deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-8 membered heteroaryl, 6-9 membered aryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally being further substituted with 1 to 3 groups selected from R f Is substituted by a group of (2);
    alternatively, -L 7 -R 77 Selected from halogen, 5-9 membered heteroaryl, said heteroaryl optionally further being selected from R by 1-3 f Is substituted by a group of (2);
    alternatively, -L 8 -R 78 、-L 9 -R 79 Each independently selected from C 3-6 Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-8 membered heteroaryl, 6-9 membered aryl, said cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally being further selected from 1 to 3R f Is substituted by a group of (2);
    each R f Each independently selected from deuterium, halogen, cyano, amino, hydroxy, C 1-4 Alkyl, = O, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-8 membered heteroaryl, 6-8 membered aryl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya ；
    R cya 、R cyb Each independently selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 An alkyl group.
  5. The compound of claim 4, a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein
    m is selected from 0, 1 or 2;
    R 62 selected from deuterium, halogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, -C (O) NHCH 3 、-NHC(O)CH 3 、-N(CH 3 )C(O)CH 3 、-NHC(O)CH 2 CH 3 、-N(CH 3 )C(O)CH 2 CH 3 、-NH 2 、-NHCH 3 、-C(O)CH3、-C(O)CH 2 CH 3 The groups are further substituted by 1, 2 and 3 groups selected from F and deuterium;
    R 69 selected from deuterium, F, cl, br, methyl, ethyl, propyl, optionally further substituted with 1, 2, 3 groups selected from F, deuterium.
  6. A compound according to claim 2 or 3, a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, said compound having the structure of formula (IV-1), (V-1):
    L 10 、L 11 each independently selected from-NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-；
    R La Selected from hydrogen, deuterium;
    R 710 selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-8 membered heteroaryl, 6-9 membered aryl, said cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally being further selected from 1 to 3R f Is substituted by a group of (2);
    alternatively, -L 10 -R 710 Selected from C 3-6 Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-8 membered heteroaryl, 6-9 membered aryl, said cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally being further selected from 1 to 3R f Is substituted by a group of (2);
    R f each independently selected from deuterium, halogen, C 1-4 Alkyl, =o;
    R 711 selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, - (CH) 2 ) 0-2 -5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-8 membered heteroaryl, 6-9 membered aryl, said cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally being further substituted by 1 to 3 groups selected from deuterium, halogen, C 1-4 Alkyl, =o, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya Is substituted by a group of (2);
    R cya 、R cyb each independently selected from methyl, ethyl, propyl, butyl, -CH 2 F、-CH 2 CH 2 F、-CHF 2 、-CF 3 、-CH 2 CHF 2 、-CH 2 CHF 3 、-CH 2 D、-CH 2 CH 2 D、-CHD 2 、-CD 3 、-CH 2 CHD 2 、-CH 2 CHD 3 。
  7. A compound according to claim 2 or 3, a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, said compound having the structure of formula (VI-1), (VI-2), (VI-3), (VI-4), (VI-5):
    X 812 Selected from-O-, -CR xa2 R xb2 -or-NR xa -；
    X 813 、X 814 、X 815 Each independently selected from-O-, -CR xa R xb -or-NR xa -；
    X 112 Selected from-CR x1b -；
    X 212 Selected from-CR x2b -；
    X 712 Selected from-CR x7b -；
    R xa 、R xb 、R xa2 、R xb2 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further substituted with 1 to 3 groups selected from halogen, deuterium;
    R x1b 、R x2b 、R x7b each independently selected from H, deuterium, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, said alkyl, alkoxy optionally further substituted with 1 to 3 groups selected from F, cl, deuterium, hydroxy;
    provided that R x1b 、R x2b 、R x7b Not simultaneously selected from H;
    alternatively, when R x1b 、R x2b 、R x7b At the same time selected from H, -L 12 -R 712 Selected from H;
    alternatively, R's bound to the same carbon atom xa And R is xb Together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
    L 12 、L 13 、L 14 、L 15 each independently selected from-NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-；
    R La Selected from hydrogen, deuterium;
    R 712 、R 713 、R 714 、R 715 each independently selected from H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl6-12 membered bicyclic heterocycloalkyl, 5-8 membered heteroaryl, 6-9 membered aryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally being further substituted with 1 to 3 groups selected from R f Is substituted by a group of (2);
    Alternatively, -L 13 -R 713 Selected from F, cl, 5-8 membered heteroaryl, optionally further substituted with 1 to 3 groups selected from R f Is substituted by a group of (2);
    each R f Each independently selected from deuterium, halogen, hydroxy, C 1-6 Alkyl, = O, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -C (=o) NR cya R cyb 、-NR cya C(＝O)-R cyb 、-NR cya R cyb 、-C(＝O)-R cya ；
    R cya 、R cyb Each independently selected from methyl, ethyl, propyl, butyl, -CH 2 F、-CH 2 CH 2 F、-CHF 2 、-CF 3 、-CH 2 CHF 2 、-CH 2 CHF 3 、-CH 2 D、-CH 2 CH 2 D、-CHD 2 、-CD 3 、-CH 2 CHD 2 、-CH 2 CHD 3 。
  8. The compound of any one of claims 2 to 7, stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or co-crystals thereof, wherein
    L 1 Selected from the group consisting of-NH-,* Represents L 1 And R is R 71 Linking site，R 71 Selected from the group consisting of
    L 2 Selected from the group consisting of-NH-,* Represents L 2 And R is R 72 Is the connecting site of R 72 Selected from the group consisting of
    Provided that when L 2 Selected from-NH-, R 72 Selecting When one of the following conditions is satisfied: m is not 0, or X 12 、X 32 One selected from N, or R x2a 、R x3a Not simultaneously H; or alternatively
    L 2 Selected from the group consisting of* Represents L 2 And R is R 72 Is the connecting site of R 72 Selected from the group consisting of
    Alternatively, -L 2 -R 72 Selected from CN, -C (O) N (CH) 3 ) 2 、
    L 3 、L 5 、L 6 Each independently selected from the group consisting of-NH-,R 73 、R 75 、R 76 each independently selected from
    L 7 、L 8 、L 9 Each independently selected from the group consisting of-NH-,R 77 、R 78 、R 79 Each independently selected from
    Alternatively, -L 7 -R 77 Selected from F, br,
    Alternatively, -L 8 -R 78 、-L 9 -R 79 Each independently selected from
    -L 10 -R 710 Selected from the group consisting of
    L 11 Each independently selected from the group consisting of-NH-, R 711 Selected from the group consisting of
    L 12 、L 13 、L 14 、L 15 Each independently selected from the group consisting of-NH-,R 712 、R 713 、R 714 、R 715 each independently selected from
    Alternatively, -L 13 -R 713 Selected from F,
  9. The compound according to claim 1, which is a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein the compound is selected from any one of the structures having the formula (VII-1), the formula (VII-2),
    X 82 selected from-CR xa1 R xb1 -，R xa1 、R xb1 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Optionally further substituted by 1 to 3 groups selected from halogen, deuterium, and optionally an alkyl group, R xa1 、R xb1 Capable of forming, together with the carbon atoms to which they are attached, a 3-to 5-membered cycloalkyl group, preferably said R xa1 、R xb1 Forms a 3-membered cycloalkyl group with the carbon atom to which both are attached;
    X 12 selected from-CR x1a -，X 32 Selected from-CR x3a -；
    R x1a 、R x3a Each independently selected from hydrogen, deuterium, halogen, C 1-4 Any one of the group consisting of alkyl groups;
    L 2 is-C (O) -, R 72 Selected from-NR cya R cyb 4-12 membered heterocycloalkyl, 6-12 membered aryl, said heterocycloalkyl, 6-12 membered aryl optionally being further substituted by 1 to 3 groups selected from halogen, deuterium, cyano, C 1-4 Alkoxy, halo C 1-4 Alkoxy, deuterated C 1-4 Alkoxy, =o, -C (=o) -R cya R is substituted by radicals of formula (I) cya 、R cyb Each independently selected from C 1-2 Alkyl, halogenated C 1-2 Alkyl, deuterated C 1-2 An alkyl group; or alternatively
    L 2 is-NH-, -C (O) NR La A method for producing a composite material x-ray in the sense that, represents L 2 And R is R 72 Linking site, R 72 Selected from C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, 5-12 membered heteroaryl, 6-12 membered aryl, said cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally being further substituted by 1 to 3 groups selected from deuterium, halogen, nitro, cyano, =o, -C (=o) -R cya R is substituted by radicals of formula (I) cya Selected from C 1-2 Alkyl, halogenated C 1-2 Alkyl, deuterated C 1-2 An alkyl group; or alternatively
    L 2 is-NR La C (O) -, represents L 2 And R is R 72 Linking site, R 72 Selected from C 3-12 Cycloalkyl, 4-12 membered saturated heterocycloalkyl, said cycloalkylThe saturated heterocycloalkyl group is optionally further substituted with 1 to 3 groups selected from deuterium, halogen, nitro, cyano, =o, -C (=o) -R cya R is substituted by radicals of formula (I) cya Selected from C 1-2 Alkyl, halogenated C 1-2 Alkyl, deuterated C 1-2 An alkyl group;
    alternatively, -L 2 -R 72 Selected from H or CN;
    provided that when L 2 Selected from-NH-, R x3a Is not H;
    X 715 selected from-CR x7a -or-N-, R x7a Selected from hydrogen, deuterium, halogen;
    X 815 selected from-O-or-CR xa R xb -；R xa 、R xb Each independently selected from hydrogen, deuterium, halogen, C 1-4 An alkyl group, said alkyl group optionally being further substituted with 1 to 3 groups selected from halogen, deuterium, said R xa 、R xb Capable of forming, together with the carbon atoms to which they are attached, a 3-to 5-membered cycloalkyl group, preferably said R xa 、R xb Together with the carbon atoms to which they are attached, form a 3-membered cycloalkyl or 4-membered cycloalkyl;
    Z 6 selected from a bond or-CR za R zb -，R za 、R zb Each independently selected from hydrogen;
    L 15 selected from-NR La 、-C(O)-、-C(O)NR La -、-NR La C(O)-；
    R 715 Selected from 4-12 membered heterocycloalkyl, 5-12 membered heteroaryl, said heterocycloalkyl, heteroaryl optionally further being selected from 1 to 3From C 1-2 Alkyl, = O, C 1-2 Alkoxy, halo C 1-2 Alkyl, halogenated C 1-2 Alkoxy, deuterated C 1-2 Alkyl, deuterated C 1-2 Alkoxy, -NR cya R cyb 、-C(＝O)-R cya R is substituted by radicals of formula (I) cya 、R cyb Each independently selected from C 1-2 Alkyl, halogenated C 1-2 Alkyl, deuterated C 1-2 An alkyl group.
  10. The compound of claim 9, a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein
    L 2 Is thatR 72 is-NR cya R cyb 、 Any one of the group consisting of wherein R' is selected from hydrogen, deuterium, halogen and C 1-4 Optionally further substituted with 1 to 3 groups selected from halogen, deuterium, optionally wherein R' is H, deuterium, methyl, ethyl, propyl, butyl, -CH 2 F、-CH 2 CH 2 F、-CHF 2 、-CF 3 Of the group consisting ofAny one of them; alternatively said R' is methyl, ethyl, -CH 2 F、-CHF 2 、-CF 3 ；R cya 、R cyb Each independently is H, deuterium, methyl, ethyl, propyl, butyl, -CH 2 F、-CH 2 CH 2 F、-CHF 2 、-CF 3 、-CH 2 CHF 2 、-CH 2 CHF 3 、-CH 2 D、-CH 2 CH 2 D、-CHD 2 、-CD 3 、-CH 2 CHD 2 、-CH 2 CHD 3 Any one of the group consisting of R as an alternative cya 、R cyb Each independently is methyl, ethyl, -CH 2 F、-CHF 2 、-CF 3 ；
    Or L 2 Is that* Represents L 2 And R is R 72 Linking site, R 72 Is that
    Or L 2 Is that* Represents L 2 And R is R 72 Linking site, R 72 Is that
    R xa1 、R xb1 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Optionally further substituted by 1 to 3 groups selected from halogen, deuterium, and optionally an alkyl group, R xa 、R xb Capable of forming, together with the carbon atoms to which they are attached, a 3-to 5-membered cycloalkyl group, preferably said R xa 、R xb Forms a 3-membered cycloalkyl group with the carbon atom to which both are attached;
    -X 815 -Z 6 -is-O-CR xa R xb -or-CR xa R xb -，R xa 、R xb Each independently selected from hydrogen, deuterium, halogen, C 1-4 An alkyl group, said alkyl group optionally being further substituted with 1 to 3 groups selected from halogen, deuterium, said R xa 、R xb Capable of forming, together with the carbon atoms to which they are attached, a 3-to 5-membered cycloalkyl group, preferably said R xa 、R xb Together with the carbon atoms to which they are attached, form a 3-membered cycloalkyl or 4-membered cycloalkyl;
    L 15 selected from-NH-, R 715 Is that
  11. The compound of claim 1 or 2, stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or co-crystals thereof, wherein said compound is selected from the following structures:
  12. the compound of claim 1 or 2, stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or co-crystals thereof, wherein said compound is selected from the following structures:
  13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier and/or excipient.
  14. Use of a compound according to any one of claims 1-12, a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, or a composition according to claim 13, for the preparation of a medicament for the treatment of a PRMT5 mediated disorder.
  15. The use according to claim 14, wherein the PRMT5 mediated disease is a tumour.
CN202280013815.6A 2021-04-02 2022-04-01 PRMT5 inhibitors and uses thereof Pending CN117242073A (en)

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