CN117836278A - SOS1 inhibitor, preparation method and application thereof - Google Patents

SOS1 inhibitor, preparation method and application thereof Download PDF

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Publication number
CN117836278A
CN117836278A CN202280054761.8A CN202280054761A CN117836278A CN 117836278 A CN117836278 A CN 117836278A CN 202280054761 A CN202280054761 A CN 202280054761A CN 117836278 A CN117836278 A CN 117836278A
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alkyl
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李东升
高善云
刘财路
蔡亚磊
杨茂志
屠汪洋
于冰
谢晴
张毅翔
李乐平
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Shanghai Haihe Pharmaceutical Co Ltd
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Abstract

An SOS1 inhibitor, and its preparation method and application are provided. The compound has a structural formula shown in a formula (I), wherein each symbol and variable are defined in the specification, has SOS1 inhibitor activity, and can be used for treating head and neck cancer, lung cancer, mediastinum tumor, gastrointestinal tumor, prostate cancer, testicular cancer, gynecological tumor, breast cancer, kidney and bladder cancer, endocrine system tumor, soft tissue sarcoma, osteosarcoma, rhabdoid tumor, mesothelioma, skin cancer, peripheral nervous system tumor, central nervous system tumor, lymphoma, leukemia, unknown primary cancer, noonan syndrome, heart face skin syndrome, hereditary gum fibromatosis and related syndromes thereof.

Description

SOS1 inhibitor, preparation method and application thereof Technical Field
The present invention belongs to the field of pharmaceutical chemistry. In particular, the present invention relates to a novel class of compounds, stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them, which are having SOS1 inhibitor activity.
Background
RAS proteins include KRAS (V-Ki-RAS 2 Kirsten rat sarcoma viral oncogene homolog), HRAS (neuroblastoma RAS viral oncogene homolog) and NRAS (Harvey murine sarcoma virus oncogene), where KRAS has two variable shear isomers KRAS4A and KRAS4B. The RAS proteins are mainly distributed inside the cell membrane, and membrane localization is a key step in activating RAS. Membrane localization of RAS proteins requires prenylation and palmitoylation at their C-terminus, but KRAS4B, due to the lack of palmitoylation sites, relies on electrostatic interactions between the polybasic domain composed of lysine and the plasma membrane (Ahearn et al, 2011;Wright and Philips,2006). RAS proteins belong to the small GTPase family, which exist in cells either as GTP-bound or as GDP-bound. Activation of RAS proteins requires their transition from GDP-binding to GTP-binding, a process catalyzed by guanylate-exchange factors GEFs (guanine nucleotide exchange factors), such as SOS1 (Son of Sevenless 1) (Chardin et al, 1993). RAS activation promotes activation of the downstream effector RAF, PI3K (Phosphoinositide 3-kinase) and RalGDS (Ral guanine nucleotide dissociation stimulator) to affect biological processes such as proliferation, growth, metabolism, migration, angiogenesis, etc. of cells (Rodriguez-Viciana and McCormick,2005; young et al, 2009). RAS proteins have intrinsic hydrolytic activity and can convert GTP to GDP. GTPase activating proteins GAPs (GTPase activating proteins), such as NF1, can increase their rate of hydrolysis to inactivate the RAS. Under normal conditions, GAPs and GEFs tightly regulate RAS protein inactivation and activation, but after RAS protein mutation, the regulatory mechanisms are deregulated. RAS mutations occur predominantly at the G12, G13 and Q61 positions in tumor cells, mutations at these positions attenuate endogenous and GAPs-mediated hydrolytic activity, and G13 and Q61 site mutations also increase GEFs-mediated GTP exchange rates (Simansu et al, 2017; smith et al, 2013). Analysis of biochemical data in recent years has shown that mutant RAS still has some intrinsic hydrolytic activity, and that the stronger the intrinsic hydrolytic activity of a RAS mutein, the stronger the inhibition of its activity by its upstream protein SHP2 (Hunter et al 2015;Mainardi et al, 2018).
SOS1 proteins have two important motifs, the allosteric binding site and the catalytic binding site, RAS Exchanger Motif (REM) and CDC25 homology domain (homologdomain), respectively. Wherein CDC25 binds RAS-GDP to promote exchange of GDP and GTP, REM binds RAS-GTP to further increase catalytic activity of SOS1 (Freedman et al, 2006;Pierre et al, 2011). SOS1 has a key role in KRAS mutant tumors, and knocking down SOS1 results in reduced proliferation and viability of KRAS mutant tumor cells, but has no effect on KRAS wild-type cells (Jeng et al 2012). SOS1 plays an important role in activating RAS signal paths. Activation of the tyrosine kinase receptor RTKs activates SHP2, which binds to the adaptor protein Grb2, promoting the formation of the Grb2 and SOS1 complex to activate SOS1, thereby activating the RAS protein (Baltanas et al 2020). SOS1 mutations are present in tumor cells, such as embryonal rhabdomyosarcoma, lung adenocarcinoma, etc. (Denayer et al, 2010), whereas SOS1 overexpression is present in bladder and prostate cancers (Timofeeva et al, 2009;Watanabe et al, 2000). In addition, SOS1 also has mutations in Noonan syndrome Noonan Syndrome (NS), cardio-facial skin syndrome, card-faco-cutaneous syndrome (CFC), and hereditary gingival fibromatosis hereditary gum fibromatosis and its related syndromes (Pierre et al 2011).
The homolog of SOS1, SOS2, also activates RAS proteins as GEFs, both of which are functionally redundant. Knockout of SOS1 in mice resulted in embryonic lethality (Qian et al, 2000), while conditional knockout of SOS1 in adult mice survived (Baltanas et al, 2013). While knockout of SOS2 in mice did not have a distinct phenotype (Esteban et al, 2000). If SOS1 and SOS2 are knocked out simultaneously in adult mice, the mice die quickly (Baltanas et al, 2013). Selective inhibition of individual SOS subtypes, such as SOS1, may be more effective in treating SOS1-RAS activated disease. Inhibition of SOS1 catalytic site binding to RAS can prevent SOS 1-mediated RAS-GTP production to inhibit RAS signaling pathways. In RAS-dependent tumors, such compounds are theoretically capable of disrupting RAS and SOS binding, inhibiting cellular ERK phosphorylation, and exerting an anti-tumor effect. Compounds that inhibit SOS1 and RAS interactions, which inhibit RAS activity, are useful for treating head and neck cancer, lung cancer, mediastinal tumor, gastrointestinal tumor, prostate cancer, testicular cancer, gynecological tumor, breast cancer, kidney and bladder cancer, endocrine system tumor, soft tissue sarcoma, osteosarcoma, rhabdoid tumor, mesothelioma, skin cancer, peripheral nervous system tumor, central nervous system tumor, lymphoma, leukemia, unknown primary cancer, noonan syndrome, cardiac skin syndrome, hereditary gingival fibromatosis and related syndromes thereof.
Disclosure of Invention
The present invention provides a compound of formula (I), an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:
wherein,
ring A is C 6-10 Aryl, 5-to 10-membered heteroaryl, or 4-to 10-membered heterocyclyl;
m(R 3 ) Represents that m R's which are the same or different are present at any position of the A ring 3 A substituent;
m is 0 to 5; preferably, m is 1, 2 or 3; more preferably, m is 1 or 2;
each R 3 The substituents are independently selected from: hydrogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 Alkynyl, 4-to 6-membered heterocyclyl, halogen, cyano, amino, or divalent substituent = O; the substitution means substitution by one or more substituents selected from halogen, hydroxy, cyano and amino; when ring A is C 6-10 In the case of aryl radicals, R 3 Not divalent substituent = O;
Q 1 is N or CR 4 ，Q 2 Is N or CR 5 ，Q 3 Is N or CR 6 ，Q 4 Is N or CR 1 The method comprises the steps of carrying out a first treatment on the surface of the And Q is 1 、Q 2 、Q 3 、Q 4 At least one of which is N;
R 1 is hydrogen, halogen, C which is unsubstituted or substituted by substituents of group A1 1-6 Alkyl, C unsubstituted or substituted by substituents of group A1 3-6 Cycloalkyl, C unsubstituted or substituted by substituents of group A1 1-6 Alkoxy, -CN, -COOH, unsubstituted or substituted by C 1-6 alkyl-substituted-CONH 2 Or unsubstituted or substituted by C 1-6 An alkyl-substituted amino group;
R 4 、R 5 、R 6 each independently is C which is unsubstituted or substituted by group A1 1-10 Alkyl, C unsubstituted or substituted by group A1 6-10 Aryl, 4-to 10-membered heterocyclic group unsubstituted or substituted by group A1, hydroxy, C 1-10 Alkoxy, -NH 2 、-CN、-COOH、-CONH 2 Or halogen;
R 2 c being hydrogen, unsubstituted or substituted by substituents of group A1 1-6 Alkyl, C unsubstituted or substituted by substituents of group A1 3-6 Cycloalkyl;
substituted by substituents of group A1 means by substituents selected from C 1-6 Alkyl, hydroxyOne or more substituents selected from the group consisting of a halogen, a cyano, an amino and a carboxyl group;
x is oxygen, NH, S, -SO 2 -, -ch=ch-, or X is absent;
b is-L 1 -Ring C-L 2 -R 9 ；
L 1 And L 2 Identical or different, each independently selected from- (CR) 7 R 8 ) n -、-(CR 7 R 8 ) n -CO-、-(CR 7 R 8 ) n -SO 2 -、-(CR 7 R 8 ) n -NH-CO-、-(CR 7 R 8 ) n -CO-NH-、-(CR 7 R 8 ) n -NH-SO 2 -、-(CR 7 R 8 ) n -SO 2 -NH-；
Ring C is substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, substituted or unsubstituted 4-to 10-membered heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkyl, or ring C is absent;
n is an integer from 0 to 10;
R 7 and R is 8 Each independently selected from hydrogen, hydroxy, halogen and C 1-3 An alkyl group;
R 9 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, substituted or unsubstituted 4-to 10-membered heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkyl;
R 9 and the substitution in ring C means substitution with one or more substituents selected from the group consisting of: -R 10 、C 1-6 Alkoxy, halogen, cyano, hydroxy, carboxy, -CO-R 10 、-NH-CO-R 10 、-CO-NH-R 10 、-SO 2 -R 10 、-NH-SO 2 -R 10 、-SO 2 -NH-R 10 or-CO- (CH) 2 ) i -O-R 10 I is an integer of 0 to 3; wherein R is 10 C being unsubstituted or substituted by one or more substituents selected from group A2 1-6 Alkyl or C 3-6 Cycloalkyl, group A2 substituents are selected from: halogen, C 1-3 Alkoxy, hydroxy, cyano and C 3-6 Cycloalkyl;
provided that B is not hydrogen, unsubstituted C 1-2 Alkyl, difluoromethyl and trifluoromethyl.
In one embodiment, the present invention provides a compound of formula (I) above, an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein:
ring A is phenyl;
m(R 3 ) Represents that m R's which are the same or different are present at any position of the A ring 3 A substituent;
m is 1 or 2;
each R 3 The substituents are independently selected from: hydrogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 Alkynyl, 4-to 6-membered heterocyclyl, halogen, cyano or amino; the substitution means substitution by one or more substituents selected from halogen, hydroxy, cyano, amino, preferably R 3 Selected from hydrogen, substituted or unsubstituted C 1-4 Alkyl and halogen, more preferably R 3 Selected from C substituted by halogen 1-4 Alkyl and halogen, further preferably R 3 Selected from fluorine and difluoromethyl.
In one embodiment, the present invention provides a compound of formula (I) above, an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein:
b is-L 1 -R 9 ；
L 1 Is- (CR) 7 R 8 ) n -、-(CR 7 R 8 ) n -CO-、-(CR 7 R 8 ) n -SO 2 -、-(CR 7 R 8 ) n -NH-CO-、-(CR 7 R 8 ) n -CO-NH-、-(CR 7 R 8 ) n -NH-SO 2 -or- (CR) 7 R 8 ) n -SO 2 -NH-；
R 9 Is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted 5-to 6-membered heteroaryl, substituted or unsubstituted 4-to 6-membered heterocyclyl, substituted or unsubstituted C 3-6 Cycloalkyl;
R 9 wherein said substitution means substitution with one or more substituents selected from the group consisting of: -R 10 、C 1-6 Alkoxy, halogen, cyano, hydroxy, carboxy, -CO-R 10 、-CO-C 3-6 Cycloalkyl, -NH-CO-R 10 、-CO-NH-R 10 、-SO 2 -R 10 、-NH-SO 2 -R 10 、-SO 2 -NH-R 10 、-CO-(CH 2 ) i -O-R 10 I is an integer of 0 to 3; wherein R is 10 C being unsubstituted or substituted by one or more substituents selected from group A2 1-6 Alkyl, group A2 substituents include: halogen, C 1-3 Alkoxy, hydroxy, cyano, C 3-6 Cycloalkyl;
provided that B is not hydrogen, unsubstituted C 1-2 Alkyl, difluoromethyl and trifluoromethyl.
In one embodiment, B is -(CR 7 R 8 ) n -R 9 。
In one embodiment, R 7 、R 8 Each independently is H or C 1-3 Alkyl, preferably H or methyl.
In one embodiment, L 1 And L 2 N in (2) are each independently 0, 1 or 2.
In one embodiment, R 9 Is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkyl;
the heteroaryl is selected from:
the heterocyclic group is selected from:
wherein said substitution means substitution with one or more substituents selected from the group consisting of: -R 10 、C 1-6 Alkoxy, halogen, cyano, hydroxy, carboxy, -CO-R 10 、-CO-C 3-6 Cycloalkyl, -NH-CO-R 10 、-CO-NH-R 10 、-SO 2 -R 10 、-NH-SO 2 -R 10 、-SO 2 -NH-R 10 、-CO-(CH 2 ) i -O-R 10 I is an integer of 0 to 3; wherein R is 10 C being unsubstituted or substituted by one or more substituents selected from group A2 1-6 Alkyl, group A2 substituents include: halogen, C 1-3 Alkoxy, hydroxy, cyano, C 3-6 Cycloalkyl;
provided that B is not hydrogen, unsubstituted C 1-2 Alkyl, difluoromethyl, trifluoromethyl.
In one embodiment, R 9 Is a substituted or unsubstituted phenyl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted C 3-8 Cycloalkyl;
The heteroaryl is selected from:
the heterocyclic group is selected from:
wherein said substitution means substitution with one or more substituents selected from the group consisting of: -R 10 、C 1-6 Alkoxy, halogen, cyano, hydroxy, carboxy, -CO-R 10 、-CO-C 3-6 Cycloalkyl, -NH-CO-R 10 、-CO-NH-R 10 、-SO 2 -R 10 、-NH-SO 2 -R 10 、-SO 2 -NH-R 10 、-CO-(CH 2 ) i -O-R 10 I is an integer of 0 to 3; wherein R is 10 Is unsubstituted or substituted by one of the substituents selected from group A2One or more substituted C 1-6 Alkyl, group A2 substituents include: halogen, C 1-3 Alkoxy, hydroxy, cyano, C 3-6 Cycloalkyl groups.
In one embodiment, R 9 Is unsubstituted or substituted by C 1-6 Alkoxy, cyano or-NH-CO-R 10 Substituted phenyl, wherein R 10 Is C 1-6 An alkyl group.
In one embodiment, R 9 A heteroaryl group, substituted or unsubstituted, selected from the group consisting of: preferablyAnd said substitution means by one or more members selected from R 10 Is substituted by a substituent of (2).
In one embodiment, R 9 Is a substituted or unsubstituted heterocyclic group selected from Preferably More preferably
Wherein said substitution means substitution with one or more substituents selected from the group consisting of: -CO-R 10 、-CO-C 3-6 Cycloalkyl, -SO 2 -R 10 、-CO-(CH 2 ) i -O-R 10 I is an integer of 0 to 3; wherein R is 10 C being unsubstituted or substituted by one or more substituents selected from group A2 1-6 Alkyl, group A2 substituents include hydroxy and cyano.
In one embodiment, R 2 Is C 1-4 Alkyl or halo C 1-4 An alkyl group; preferably, R 2 Is methyl or ethyl.
In one embodiment, the compound of formula (I) has the structure of formula (I-1-1), (I-1-2), (I-1-3), (I-1-4), (I-1-5) as follows:
wherein,
R 1 、R 2 、R 3 、R 5 and m, X and B are defined as above.
In one embodiment, the compound of formula (I) has the structure of formula (I-2-1), (I-2-2), (I-2-3) as follows:
wherein R is 1 、R 2 、R 5 X, B are as defined above; r is R 31 、R 32 、R 33 、R 34 、R 35 Each independently selected from: hydrogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 Alkynyl, 4-to 6-membered heterocyclyl, halogen, cyano, amino; the substitution is selected from C 1-6 One or more substituents selected from the group consisting of alkyl, halogen, hydroxy, cyano and amino; preferably, R 31 Is halogen, R 32 Is halogenated C 1-6 Alkyl, R 33 、R 34 、R 35 Are all hydrogen;
in one embodiment, R 1 Is hydrogen or C 1-6 Alkyl groups, preferably methyl groups.
Preferably, the compound of formula (I) has the structure of formula (I-3) or formula (I-4), wherein R 2 Not hydrogen:
of these, the structure of formula (I-4) is a more preferable structure.
Specifically, the compound of formula (I) is selected from the following compounds:
in another aspect of the present invention, there is provided a pharmaceutical composition comprising:
(1) A therapeutically effective amount of the compound of formula (I), an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof, as an active ingredient; and
(2) A pharmaceutically acceptable carrier.
In another aspect of the invention there is provided the use of said compound of formula (I), an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof, or said pharmaceutical composition, in the preparation of an SOS1 inhibitor.
In another aspect of the invention there is provided the use of a compound of formula (I), an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof, or said pharmaceutical composition, in the manufacture of a medicament for the prevention and/or treatment of a disease associated with SOS1 mutation, activity or expression level.
Wherein the SOS1 mutation, activity or expression level related diseases include head and neck cancer, lung cancer, mediastinum tumor, gastrointestinal tumor, prostate cancer, testis cancer, gynecological tumor, breast cancer, kidney and bladder cancer, endocrine system tumor, soft tissue sarcoma, osteosarcoma, rhabdoid tumor, mesothelioma, skin cancer, peripheral nervous system tumor, central nervous system tumor, lymphoma, leukemia, unknown primary cancer, noonan syndrome, heart and face skin syndrome, hereditary gingival fibromatosis and related syndromes thereof.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. Each feature disclosed in the description may be replaced by alternative features serving the same, equivalent or similar purpose. And are limited to a space, and are not described in detail herein.
Terminology
In the present invention, when the valence of the group is carried with a wavy lineWhen, for example, inThe wavy line indicates the point of attachment of this group to the rest of the molecule.
In the present invention, the halogen is F, cl, br or I.
In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.
In the present invention, the term "C 1-6 "means having 1, 2, 3, 4, 5 or 6 carbon atoms," C 1-8 "means having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on. "3-to 8-membered" heterocyclic group means that the heterocyclic group has 3 to 8 ring atoms, and so on "4-to 10-membered heterocyclic group" and the like.
In the present invention, the term "alkyl" means a saturated linear or branched hydrocarbon moiety, e.g., the term "C 1-10 Alkyl "refers to a straight or branched chain alkyl group having 1 to 10 carbon atoms and includes, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like; methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are preferred. In the present invention, the above-mentioned C 1-10 Alkyl is preferably C 1-6 Alkyl, more preferably C 1-4 An alkyl group.
In the present invention, the term "alkoxy" means-O- (C) 1-6 Alkyl) groups. For example, the term "C 1-6 Alkoxy "refers to straight or branched chain alkoxy groups having 1 to 6 carbon atoms and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.
In the present invention, the term "alkenyl" means a straight or branched hydrocarbon moiety containing at least one double bond, e.g., the term "C 2-6 Alkenyl "refers to a straight or branched alkenyl group having 2 to 6 carbon atoms containing one double bond and includes, without limitation, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.
In the present invention, the term"cycloalkyl" means a saturated cyclic hydrocarbyl moiety, e.g., the term "C 3-8 Cycloalkyl "refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like.
The term "aryl" as used herein refers to a carbocyclic hydrocarbon group consisting of one ring or a plurality of fused rings, such as two, wherein at least one ring is an aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and the like.
In the present invention, the term "heterocyclyl" denotes a cyclic group comprising at least one carbon atom and at least one (e.g. 1-3) ring heteroatom selected from N, O, S, in particular one or more ring carbons on a cycloalkyl group as defined herein is selected from-O-, -n=, -NR-, -C (O) -, -S (O) -and-S (O) 2 -partial substitution of the groups formed, wherein R is hydrogen, C 1-4 Alkyl or nitrogen protecting groups (e.g., benzyloxycarbonyl, p-methoxybenzylcarbonyl, t-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-phenyl, 3, 4-dimethoxybenzyl, etc.). "heterocyclyl" includes bicyclic structures such as monocyclic, bridged, spiro, etc., e.g., 3-to 8-membered heterocyclyl, 3-to 6-membered heterocyclyl, etc.; such as tetrahydrofuranyl, pyrrolidinyl, oxetanyl, aziridinyl, thietanyl, 1, 2-dithianyl, 1, 3-dithianyl, azepanyl, oxetanyl, and the like.
In the present invention, the term "5-to-10-membered heteroaryl" refers to a monocyclic or bicyclic or fused polycyclic, cyclic aromatic hydrocarbon group having 5 to 10 ring atoms, for example, 5, 6 or 7 ring atoms (i.e., 5-to 7-membered heteroaryl), which contains at least one (e.g., 1 to 3) ring heteroatom independently selected from N, O and S (e.g., N) in the ring, the remaining ring atoms being carbon atoms; such as imidazolyl, pyridyl, pyrrolyl, thiazolyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, pyrimidinyl, 1,2, 4-triazolyl, and the like; five membered heteroaryl groups are preferred, such as imidazolyl, isoxazolyl, 1,2, 4-triazolyl. Bicyclic heteroaryl groups include, for example, benzoxazolyl, imidazopyridinyl, triazolopyridinyl, benzofuranyl, pyrazolopyrimidinyl, benzodioxolyl, indolyl, quinolinyl, isoquinolinyl, and the like.
In the present invention, the substitution is mono-substitution or poly-substitution, and the poly-substitution is di-substitution, tri-substitution, tetra-substitution, or penta-substitution. The disubstitution means having two substituents and so on. In the case of polysubstitution, the substituents may be identical to or different from one another.
The pharmaceutically acceptable salts of the present invention may be salts of anions with positively charged groups on the compounds of formula (I). Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methylsulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate or maleate. Similarly, salts may be formed from cations with negatively charged groups on the compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium and ammonium ions, such as tetramethylammonium.
In another preferred embodiment, "pharmaceutically acceptable salt" refers to salts of the compounds of formula (I) with an acid selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalacetic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid, and the like; or salts of the compounds of formula (I) with inorganic bases, for example sodium, magnesium, potassium, calcium, aluminum, manganese or ammonium salts; or salts of the compounds of formula (I) with organic bases such as the methylamine, ethylamine or ethanolamine salts.
"safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of active ingredient per dose, more preferably 10-200mg of active ingredient per dose. Preferably, the "one dose" is a tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatibility" as used herein means that the components of the composition are capable of blending with and between the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g.) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and the like.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like. In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredient, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the invention may be administered alone or in combination with other therapeutic agents, such as antineoplastic agents.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 20 to 500mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions (e.g.those described in Sambrook et al, molecular cloning: A laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989)) or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
General synthetic method
The synthesis of the compounds of the general formula (I) according to the invention can be carried out by the following synthetic route. In the synthetic routes described below, the information concerning solvents, acids, bases, coupling catalysts, and ligands is based on existing organic chemistry knowledge and name reactions.
In the present application, when the name of the compound is inconsistent with the structural formula, the structural formula of the compound is subject.
The invention relates to synthesis of chiral amine intermediates, and the main synthesis route is shown in a synthesis route 1:
synthetic route 1:
containing R 3 The substituted aromatic bromo (I-a) and tin reagent are cleaved under acidic conditions by Stille coupling reaction to give compound (I-d). Or by containing R 3 The substituted aromatic carboxylic acid (I-b) and dimethylhydroxylamine hydrochloride are subjected to condensation reaction to obtain Weinreb amide (I-c), and then reacted with Grignard reagent to obtain corresponding ketone (I-d). The ketone (I-d) and (S) - (-) -tert-butylsulfinamide react to form the corresponding ketimine (I-e), which is reduced stereoselectively to give (I-f). Finally, the sulfinyl group is removed in a hydrogen chloride system to give the hydrochloride (I-g) of the chiral amine intermediate.
The synthesis of the target compound is described in detail in synthetic schemes 2 to 5.
Synthetic route 2:
the objective compound (II-d) can be produced by the following method:
when R is 1 When the alkyl group is an alkyl group, the raw material (II-a) containing the B moiety, the alkyl group (R 1 ) The formamidine hydrochloride and the methyl formate are obtained by two steps of synthesis operation: the C-2 position is R 1 Substituted pyrimidinones (II-b). The compound (II-b) is chloridized in a phosphorus oxychloride system to obtain a 4-chloropyrimidine compound (II-c), and the 4-chloropyrimidine compound and a chiral amine intermediate (I-g) undergo substitution reaction under alkaline conditions to obtain a target compound (II-d).
In order to conveniently synthesize the target compound (II-d), a compound with a benzyl group in the B part can be synthesized on the basis of the route, and the compound is subjected to catalytic hydrogenation reduction to obtain a common intermediate pyrimidine phenol (II-e). The B moiety of the target compound (II-d) can be obtained by reacting the starting material of the terminal moiety which is a halide or other leaving group (e.g., p-toluenesulfonyloxy, methanesulfonyloxy) with the intermediate pyrimidinol (II-e) via S N 2, constructing a reaction; can also be obtained by Mitsunobu reaction of a raw material with a hydroxyl structure at the end group part and an intermediate pyrimidine phenol (II-e); or can be obtained by epoxy ring opening under alkaline condition by using raw materials with end groups of a cyclohexane structure.
R of the target compound (II-d) 1 Portions may also be synthesized by the following pathways: 2, 4-dichloropyrimidine-5-alcohol (II-f) is taken as a raw material, and a chiral amine intermediate (I-g) is subjected to substitution reaction under alkaline conditions to obtain a compound (II-g). The compound (II-h) obtained after the introduction of the part B by the aforementioned method is a target compound having different substituents by a coupling reaction in the presence of a metal catalyst, which involves a coupling reaction such as: suzuki, stille, buchwald, chan-lam or an insertion carbonyl reaction. The target compounds (II-d) also relate to a series of derivatives obtained by reducing, hydrolyzing and substituting the compounds obtained by the coupling reaction. The reduction reactions involved in this section are, for example: catalytic hydrogenation of cyano groups or lithium aluminum hydride reduction to give aminomethylenesThe derivative, carboxylic ester compound is reduced by lithium aluminum hydride to obtain a hydroxymethylene derivative; the hydrolysis reaction involved in this section is as follows: hydrolyzing cyano into amide under the conditions of hydrogen peroxide and sodium hydroxide, and hydrolyzing carboxylic esters to obtain corresponding carboxylic acids; the substitution reactions involved in this section are as follows: alkylation of the above-mentioned terminal amino or hydroxyl compound under basic conditions.
Synthetic route 3:
the target compound (III-e) can be prepared by the following method:
2, 4-dichloropyrimidine-5-nitro (III-a) is used as a starting material to carry out substitution reaction with chiral amine intermediate (I-g) to obtain (III-b), and then catalytic hydrogenation reaction is carried out to obtain amino-containing compound (III-c). The B part of the compound (III-d) can be obtained by reacting raw materials with end groups of acyl chloride, sulfonyl chloride and isocyanate with the compound (III-c); or starting materials which are halides or other leaving groups (e.g. p-toluenesulfonyloxy, methanesulfonyloxy) via the terminal moiety and the intermediate pyrimidylamine (III-d) via S N 2, constructing a reaction; or is obtained by epoxy ring opening under alkaline condition by using a raw material with a terminal group of a cyclohexane structure. The compounds (III-d) are obtained by coupling reaction in the presence of metal catalysts to give compounds having different R 1 The target compound (III-e) of substituent, the coupling reaction involved in this step is as follows: suzuki, stille, buchwald, chan-lam or an insertion carbonyl reaction. The target compound (III-e) also relates to a compound which is obtained through the coupling reaction, and the compound is shown in the general formula I after reduction, hydrolysis and substitution. The reduction reactions involved in this section are, for example: catalytic hydrogenation of cyano or reduction of lithium aluminum hydride to obtain an aminomethylene derivative, and reduction of carboxylic ester compounds by lithium aluminum hydride to obtain a hydroxymethylene derivative; the hydrolysis reaction involved in this section is as follows: hydrolyzing cyano group into amide under hydrogen peroxide and sodium hydroxide, such as carboxylate water Obtaining corresponding carboxylic acid by decomposition; the substitution reactions involved in this section are as follows: alkylation of the above-mentioned terminal amino or hydroxyl compound under basic conditions. Specific syntheses are described in the examples.
The compound (III-f) is used as a raw material, the compound (III-g) is obtained through substitution reaction, and the compound (III-e) is obtained through Buchwald reaction between the compound (III-f) and a raw material with an amino structure at the end group;
the compound (III-h) is used as a raw material, the compound (III-i) is obtained through substitution reaction, and the compound (III-e) is prepared by further carrying out acylation reaction with raw materials with end groups of acyl chloride, sulfonyl chloride and isocyanate or carrying out substitution reaction with raw materials with end groups of halogeno compounds or other leaving groups (such as p-toluenesulfonyloxy and methanesulfonyloxy).
Synthetic route 4:
the alpha-amino acetal (IV-a) and the ethyl oxamate are subjected to two-step reaction of reflux in an alcohol solution and reflux in acid water to obtain a 2, 3-dihydroxypyrazine compound (IV-b), and then chloridized in a phosphorus oxychloride system to obtain the 2, 3-dichloropyrazine compound (IV-c). The compound (IV-c) and the compound (B-X) undergo substitution reaction under alkaline conditions to obtain a compound (IV-d). The compound (IV-d) and chiral amine intermediate (I-g) are subjected to Buchwald reaction to obtain the target compound (IV-e).
Synthetic route 5:
2,3, 5-trichloropyridazine is taken as a raw material (V-a), and different substrates are adopted: the chiral amine intermediate (I-g) or the compound B-X-H is subjected to substitution reaction to obtain a compound (V-B) or (V-e), respectively. Compound (V-B) or (V-e) is substituted with compound B-X-H or chiral amine intermediate (I-g) or Buch, respectivelywald reaction gives the corresponding products (V-c) and (V-f). The latter is introduced into R by catalytic hydrogenation or metal-catalyzed coupling reaction 1 The group to give the target compounds (V-d) and (V-g).
Synthetic route 6:
4, 5-dihalogen substituted pyrimidine (VI-a), halogen can be chlorine or bromine respectively, and the halogen and chiral amine intermediate (I-g) are subjected to substitution reaction to generate a compound (VI-B), and the compound and a B part with an end group containing an olefinic bond are synthesized into the target compound (VI) through heck reaction. The target compound also comprises a compound shown in the general formula I, which is obtained by the reaction, the hydrolysis or deprotection of the compound, the acylation, the sulfonylation, the alkylation and the metal-catalyzed coupling reaction. Specific syntheses are described in the examples.
Examples
EXAMPLE 1 Synthesis of Compound Int-1
The synthetic route is as follows:
step one:
into a dry 3L round bottom flask was added the compound Int-1-a (100 g,0.49 mol) and anhydrous tetrahydrofuran (1L). The solution was cooled to 0deg.C and diethylaminosulfur trifluoride (120 g,0.17 mol) was added dropwise under nitrogen protection. After the addition, the reaction temperature was raised to room temperature and stirring was continued for 16 hours. After TLC monitoring the end of the reaction, the reaction was poured into ice water, extracted with ethyl acetate (500 ml x 3), the organic phases were combined, dried, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/1) to give 1-bromo-3- (difluoromethyl) -2-fluorobenzene Int-1-b (90 g, pale yellow oil), yield: 82%. 1 H NMR(CDCl 3 ,400MHz):δ7.69–7.65(m,1H)，7.56–7.52(m,1H)，7.14(t,J＝8.0Hz,1H)，6.88(t,J＝54.8Hz,1H).
Step two:
into a dry 2L single neck round bottom flask was added, in order, the compound Int-1-b (90 g,0.40 mol), tributyl (1-ethoxyvinyl) stannane (173 g,0.48 mol) and anhydrous dioxane (900 mL), triethylamine (101 g,1.0 mol) and bis (triphenylphosphine) palladium (II) chloride (2.8 g,4.0 mmol) with stirring. The reaction system was replaced with argon, heated to 80℃and stirred for reaction for 12 hours. After TLC monitoring the reaction, the residue was concentrated, saturated potassium fluoride solution (300 mL) was added, stirred for 1 hour, filtered, the filtrate was extracted with ethyl acetate (300 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to give 1- (difluoromethyl) -3- (1-ethoxyvinyl) -2-fluorobenzene Int-1-c (100 g, brown oil), the crude product was directly used in the next step.
Step three:
into a dry 1L single neck round bottom flask was added sequentially the compound Int-1-c (100 g, crude) and anhydrous dioxane (200 mL). The solution was cooled to 0deg.C and diluted hydrochloric acid (200 mL,0.40mol, 2M) was added dropwise under nitrogen protection. After the completion of the dropwise addition, the reaction was warmed to room temperature and stirred for a further 12 hours. After TLC monitoring the end of the reaction, the reaction was poured into water, the filtrate was extracted with dichloromethane (300 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give 1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-one Int-1-d (53 g, pale yellow oil), yield: 50% in two steps. 1 H NMR(CDCl 3 ,400MHz):δ7.69–7.98(m,1H)，7.81–7.77(m,1H)，7.36–7.33(m,1H)，6.95(t,J＝54.8Hz,1H)，2.68(d,J＝4.2Hz,3H).
Step four:
into a dry 1L single neck round bottom flask were successively added the compound Int-1-d (17 g,90 mmol), (S) -2-methylpropane-2-sulfinamide (16 g,0.14 mol) and anhydrous tetrahydrofuran (200 mL), titanium tetraethyloxide (62 g,0.27 mol) was added with stirring, and the reaction was stirred at 80℃under argon protectionAnd 16 hours. After TLC monitoring the reaction, the residue was concentrated, saturated brine (100 mL), extracted with ethyl acetate (100 mL x 3), the combined organic phases dried over anhydrous sodium sulfate, and the concentrated organic phase was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to give (S, Z) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylene) -2-methylpropane-2-sulfinamide Int-1-e (23.7 g, yellow oil), yield: 90%. LCMS (ESI): m/z 292.1[ M+H ]] + .
Step five:
into a dry 1L three-necked flask, dichloro (p-methylisopropylbenzene) ruthenium (II) dimer (1.4 g,2.3 mmol), (1S, 2R) -1-amino-2, 3-dihydro-1H-inden-2-ol (0.70 g,4.5 mmol), 4A molecular sieve (50 g) and isopropyl alcohol (100 mL) were successively added, and the mixture was stirred under argon at 90℃for 20 minutes. The reaction was cooled to 40℃and a solution of the compound Int-1-e (13 g,45 mmol) in isopropanol (450 mL) and a solution of potassium tert-butoxide in isopropanol (113 mL,11mmol, 0.1M) were added in sequence and reacted at 40℃for 2 hours. The reaction was monitored by TLC, the system was concentrated, and the residue was taken up in saturated brine (100 mL), extracted with ethyl acetate (100 mL. Times.3), and the organic phases combined and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/2) to give (S) -N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide Int-1-f (12.5 g, yellow oil), yield: 95%. 1 H-NMR(CDCl 3 ,400MHz):δ7.54–7.51(m,2H)，7.24–7.23(m,1H)，6.90(t,J＝54.8Hz,1H),4.87–4.80(m,1H)，3.55(d,J＝5.2Hz,1H)，1.55(t,J＝6.4Hz,3H)，1.23(s,9H).
Step six:
into a dry 1L single neck round bottom flask was added sequentially the compound Int-1-f (12.5 g,43 mmol) and anhydrous dioxane (100 mL). The solution was cooled to 0deg.C and a dioxane solution of dilute hydrochloric acid (50 mL,0.20mol, 4M) was added dropwise under nitrogen protection. After the completion of the dropwise addition, the reaction temperature was raised to room temperature, and stirring was continued for 12 hours. After the completion of the reaction, which was monitored by LC-MS, the reaction mixture was concentrated, methyl t-butyl ether (200 mL) was added to the residue, the mixture was stirred for 2 hours, the precipitated product was filtered, and dried to give (R) -1- (3- (difluoro)Methyl) -2-fluorophenyl) ethylamine hydrochloride Int-1 (8.7 g, white solid), yield: 92%. 1 H NMR(CDCl 3 ,400MHz):δ8.87(s,3H),7.98–7.94(m,1H)，7.67–7.64(m,1H)，7.45–7.41(m,1H)，7.25(t,J＝54.8Hz,1H),4.64(m,1H),1.55(t,d＝6.4Hz,3H).Chiral HPLC:98.5％.
EXAMPLE 2 Synthesis of Compound Int-2
The synthetic route is as follows:
step one:
into a dry 1000mL round bottom flask was added the compound Int-2-a (25 g,13 mmol), anhydrous tetrahydrofuran (250 mL). NaH (6.7 g,0.17mol,60% pure) was added at 0deg.C under nitrogen, followed by ethyl formate (9.5 g,0.13 mol), heated to 65deg.C, and refluxed for 2 hours. After the completion of the TLC monitoring, the reaction solution was concentrated under reduced pressure, and the obtained residue was used in the next step.
A fresh sodium ethoxide solution (150 mL,3.7g of metallic sodium dissolved in 150mL of absolute ethanol) was added to acetamidine hydrochloride (7.5 g,0.13 mol), and after stirring thoroughly, the reaction solution was poured into the above residue. The reaction was heated to 100 ℃ (oil bath) and reflux continued for 12 hours. After LCMS monitoring the reaction, hydrochloric acid solution (2N) was added to the reaction solution to adjust ph= -5, extracted with ethyl acetate (200 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to give 5- (benzyloxy) -2-methylpyrimidin-4 (3H) -one Int-2-b (2.5 g, white solid), yield: 9%. LCMS (ESI) m/z 217.0[ M+H ] ] + .
Step two:
to a dry 100mL single-necked round bottom flask was added sequentially the compound Int-2-b (2.3 g,11 mmol), phosphorus oxychloride (20 mL), and the mixture was stirred at 120℃for 3 hours under nitrogen protection. After completion of the LCMS reaction, the reaction solution was slowly added dropwise to a saturated sodium carbonate solution, and the solution was extracted with ethyl acetate (50 mL x3) The organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give 5- (benzyloxy) -4-chloro-2-methylpyrimidine Int-2-c (1.7 g, white solid), yield: 68%. LCMS: m/z 235.0[ M+H ]] + .
Step three:
to a dry 100mL jar was added, in order, the compound Int-2-c (1.7 g,7.2 mmol), int-1 (2.1 g,11 mmol), N, N-diisopropylethylamine (4.7 g,36 mmoL) and isopropanol (20 mL), and the mixture was stirred under nitrogen at 100deg.C for 12 hours. After LCMS monitored the end of the reaction, water (20 mL) was added to the reaction, extracted with ethyl acetate (50 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, the organic phase concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-5-benzyloxy-pyrimidine Int-2-d (1.5 g, white oil), yield: 53%. LCMS: m/z 388.0[ M+H ] ] + .
Step four:
into a dry 250mL single neck round bottom flask was added the compound Int-2-d (1.4 g,3.6 mmol), pd/C (0.14 g,10% Pd/C) and methanol (25 mL) in sequence. The reaction was replaced with hydrogen 3 times, and then stirred at 25℃under hydrogen balloon pressure for 12 hours. After LCMS monitoring the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=5/1) to give (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrimidin-5-ol Int-2 (0.6 g, white solid), yield: 60%. LCMS (ESI) m/z 298.0[ M+H ]] + ,1H NMR(DMSO-d 6 ,400MHz):δ9.76(br,1H),7.86–7.79(m,3H)，7.68–7.60(m,2H)，7.48(t,J＝6.8Hz,1H)，7.40–7.08(m,3H)，5.59–5.55(m,1H),2.19(s,3H),1.50(d,J＝6.4Hz,3H).
EXAMPLE 3 Synthesis of Compound Int-3
The synthetic route is as follows:
step one:
in a dry 250mL round bottom flask was added compound Int-3-a (8.5 g,35 mol), ethyl 2-bromo-2, 2-difluoroacetate (8.5 g,42 mol) and anhydrous dimethyl sulfoxide (100 mL), and activated copper powder (2.6 g,35 mol) was added with stirring. After the addition was completed, the reaction temperature was raised to 60℃and stirred under argon for 16 hours. After TLC monitoring the end of the reaction, the reaction was poured into ice water, ethyl acetate (50 ml x 3) extracted, the organic phase dried, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to give 2- (3-acetylphenyl) -2, 2-difluoroethyl acetate Int-3-b (3.1 g, pale yellow oil), yield: 36%. 1 H NMR(CDCl 3 ,400MHz):δ8.19(s,1H),8.11(d,J＝8.0Hz,1H),7.81(s,J＝8.0Hz,1H)，7.61–7.57(m,1H)，4.32(q,J＝7.2Hz,2H),2.64(s,3H),1.32(t,J＝7.2Hz,3H).
Step two:
to a dry 250mL single neck round bottom flask was added, in order, the compound Int-3-b (3.1 g,13 mmol), (S) -2-methylpropane-2-sulfinamide (2.3 g,19 mmol) and anhydrous tetrahydrofuran (40 mL), and tetraethyltitanyl (8.9 g,39 mmol) was added with stirring. The reaction was heated to 80℃and stirred under argon for 12 hours. After TLC monitoring the reaction, the residue was concentrated, saturated brine (50 mL) was added, ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to give (S, Z) -2- (3- (1- ((tert-butylsulfinyl) imino) ethyl) phenyl) -2, 2-difluoroethyl acetate Int-3-c (2.8 g, yellow oil), yield: 64%. 1 H NMR(DMSO-d6,400MHz):δ8.09(s,1H),8.01(d,J＝7.6Hz,1H),7.73(d,J＝8.0Hz,1H)，7.53(t,J＝8.0Hz,1H)，5.29–4.13(m,2H)，2.79(s,3H),1.33(s,9H),1.29(d,J＝6.4Hz,3H).
Step three:
into a dry 250mL three-necked flask was successively added dichloro (p-methylisopropylbenzene) ruthenium (II) dimer (0.18 g,0.29 mmol), (1S, 2R) -1-amino-2, 3-dihydro-1H-inden-2-ol (86 mg,0.58 mmo)l), 4A molecular sieves (5 g) and isopropanol (20 mL), under argon, were stirred at 90℃for 20 min. The reaction was cooled to 40℃and a solution of compound Int-3-c (2.0 g,5.8 mmol) in isopropanol (90 mL) and a solution of t Ding Jia in isopropanol (14.5 mL,1.45mmol, 0.1M) were added in this order and reacted at 40℃for 3 hours. After TLC monitoring the reaction, the residue was concentrated, saturated brine (50 mL) was added, ethyl acetate (50 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/2) to give isopropyl 2- (3- ((R) -1- (((S) -tert-butylsulfinyl) amino) ethyl) phenyl) -2, 2-difluoroacetate Int-3-d (1.4 g, yellow oil), yield: 70%. 1 H NMR(CDCl 3 ,400MHz):δ7.58(s,1H),7.55–7.51(m,2H),7.49–7.42(m,1H)，5.15–5.09(m,1H),4.60–4.59(m,1H),3.44(d,J＝2.0Hz,1H),1.53(d,J＝6.4Hz,1H),1.29(d,J＝6.0Hz,1H),1.24(s,9H).
Step four:
into a dry 50mL single neck round bottom flask was added sequentially the compound Int-3-d (1.4 g,4.8 mmol) and anhydrous dioxane (10 mL). The solution was cooled to 0deg.C and a dioxane solution of hydrochloric acid (5 mL,20mmol, 4M) was added dropwise under nitrogen protection. After the addition was completed, the reaction temperature was raised to room temperature and stirring was continued for 12 hours. After the completion of the reaction, the reaction mixture was concentrated by LC-MS, methyl t-butyl ether (20 mL) was added to the residue, the mixture was stirred for 2 hours, the supernatant was removed, and the oil was dried to give isopropyl (R) -2- (3- (1-aminoethyl) phenyl) -2, 2-difluoroacetate hydrochloride Int-3-e (1.1 g, pale yellow oil) and the crude product was used directly in the next step. LCMS (ESI) m/z 258.1[ M+H ]] + .
Step five:
to a dry 25mL single neck round bottom flask was added, in order, compound Int-3-e (50 mg,0.17 mmol) and absolute ethanol (1 mL). The solution was cooled to 0deg.C and sodium borohydride (10 mg,0.26 mol) was added under nitrogen. After the addition was completed, the reaction temperature was raised to room temperature and stirring was continued for 2 hours. After the completion of the reaction, which was monitored by LC-MS, the reaction mixture was concentrated, and the resulting residue was purified by high performance liquid chromatography to give ((R) -2- (3- (1-aminoethyl) phenyl) -2, 2-difluoroethane-1-ol formate Int-3 (10 mg, pale yellow oil), yield: 24％。LCMS(ESI):m/z 202.1[M+H] + . 1 H NMR(CDCl 3 ,400MHz):δ8.87(s,3H),7.98–7.94(m,1H)，7.67–7.64(m,1H)，7.45–7.41(m,1H)，7.25(t,J＝54.8Hz,1H),4.640(m,1H),3.40(m,1H),1.55(t,d＝6.4Hz,3H)；Chiral HPLC:98.5％.
EXAMPLE 4 Synthesis of Compound A-1
Synthetic route
Step one:
in a one-necked flask equipped with 60mL of N, N-dimethylformamide, compound A-1-a (4.4 g,50 mmol), sodium hydride (2.4 g,60 mmol) and methyl bromoacetate (7.1 mL,75 mmol) were charged, and the reaction was stirred at room temperature under nitrogen atmosphere overnight. The reaction solution was poured into water, extracted three times with ethyl acetate, the organic phase was washed with water (2 times), saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by chromatography to give the compound a-1-b (4.2 g, white solid) yield: 50.30%. LCMS (ESI) m/z 168.0[ M+H ]] + .
Step two:
a single-necked flask was charged with Compound A-1-b (2.2 g,13.17 mmol), 20mL of N, N-dimethylformamide and N, N-dimethylformamide dimethyl acetal (4.7 g,39.52 mmol), and the reaction was stirred under nitrogen at 130℃for 5 hours. The reaction solution was poured into water, extracted three times with ethyl acetate, the organic phase was washed 2 times with water, saturated brine 1 time, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to give the compound a-1-c (1.8 g, brown solid) in the yield: 61.64%. LCMS (ESI) m/z 223.2[ M+H ]] + .
Step three:
compound A-1-c (1 g,4.5 mmol) was dissolved in 20mL of anhydrous methanol, followed by sequential addition of sodium methoxide (2.43 g,45 mmol) and acetamidine hydrochloride (2.12 g,22.52 mmol), and stirred overnight at 100deg.C in a stirred tank. The reaction solution was filtered and concentrated, and purified by column chromatography to give Compound A-1-d (300 mg, white solid) ) Yield: 32.82%. LCMS (ESI) m/z 204.1[ M+H ]] + .
Step four:
compounds A-1-d (300 mg,1.48 mmol) were suspended in 5mL of phosphorus oxychloride and reacted under nitrogen at 100deg.C with stirring overnight. The reaction solution was concentrated, the residual solution was poured into water, ph= -8 was adjusted with sodium bicarbonate solution, then extracted three times with ethyl acetate, the organic phase was washed 2 times with water, saturated brine once, dried over anhydrous sodium sulfate, concentrated, and purified with chromatography plates to give compound a-1-e (70 mg, white solid) yield: 21.47%. LCMS (ESI) m/z 222.0[ M+H ]] + .
Step five:
to a one-necked flask containing 2mL of isopropyl alcohol was added compound A-1-e (70 mg,0.317 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamine (60 mg,0.317 mmol) and N-ethyldiisopropylamine (82 mg,0.633 mmol), and the reaction mixture was stirred at 100℃overnight. The reaction solution was concentrated, and the compound A-1 (27 mg, white solid) was obtained by reverse phase preparation, separation and purification in yield: 22.88%. LCMS (ESI) m/z 375.2[ M+H ]] + ； 1 H NMR(400MHz,MeOD):δ8.37(s,1H),8.34–8.24(m,1H),7.73(s,1H),7.53–7.44(m,2H),7.44–7.39(m,2H),7.21(t,J＝7.7Hz,1H),6.99(t,J＝54.9Hz,1H),5.70(q,J＝7.0Hz,1H),3.41–3.19(m,1H),2.37(s,3H),1.54(d,J＝7.1Hz,3H).
A-2 was synthesized in a similar manner to A-1.
EXAMPLE 5 Synthesis of Compound A-3
The synthetic route is as follows:
step one:
sequentially adding the materials into a dry 50mL three-neck flaskIntermediate Int-2 (50 mg,0.17 mmol), 2- (pyridin-2-yl) ethan-1-ol (21 mg,0.17 mmol), triphenylphosphine (57 mg,0.22 mmol) and anhydrous tetrahydrofuran (5 mL) were added, nitrogen displaced three times, heated to 75 ℃, and reacted with stirring for 10 minutes. Diisopropyl azodicarboxylate (44 mg,0.22 mmol) was added to the reaction system, and the reaction was continued with stirring at 75℃for 3 hours. After LCMS monitoring the reaction, diluted with water, extracted with ethyl acetate (50 ml×2), the combined organic phases washed with saturated brine (50 ml×2), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the resulting residue purified by thin layer chromatography (dichloromethane/methanol=20/1) to give (R) N- (1- (3- (difluoromethyl) -2-fluorobenzyl) ethyl) -2-methyl-5- (2- (pyridin-2-yl) ethoxy) pyrimidin-4-amine a-3 (10 mg, pale yellow oil), yield: 15%. LCMS (ESI) m/z 403.1[ M+H ] ] + ； 1 H NMR(DMSO-d 6 ,400MHz):δ8.50(d,J＝4.0Hz,1H),7.71–7.76(m,2H),7.57(t,J＝7.4Hz,1H),7.49(t,J＝6.8Hz,1H),7.42(d,J＝7.6Hz,1H),7.08–7.35(m,3H),6.94(d,J＝8.0Hz,1H),5.54(t,J＝7.4Hz,1H),4.38(t,J＝6.6Hz,2H),3.24(t,J＝6.6Hz,2H),2.21(s,3H),1.49(d,J＝7.2Hz,3H).
The following compounds were synthesized in a similar manner to A-3.
EXAMPLE 6 Synthesis of Compound A-12
The synthetic route is as follows:
to a dry 25mL round bottom flask was added in order intermediate Int-2 (50 mg,0.17 mmol), 3- (bromomethyl) benzonitrile (49 mg,0.25 mmol), potassium carbonate (46 mg,0.34 mmol) and acetonitrile (5 mL), and the reaction was stirred at 80℃for 12 hours under nitrogen. After completion of LCMS monitoring the reaction, water (5 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, the organic phase concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (dichloromethane/methanol=15/1) to give the product (R) -3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrimidin-5-yl) oxy) methyl) benzonitrile a-12 (15 mg, white solid), yield: 22%. LCMS (ESI): m/z 413.2[ M+H ]] + ； 1 H NMR(DMSO-d 6 ,400MHz):δ8.04(s,1H),7.86–7.79(m,3H),7.68–7.60(m,2H),7.48(t,J＝6.8Hz,1H),7.40–7.08(m,3H),5.60–5.57(m,1H),5.30–5.23(m,2H),2.19(s,3H),1.52(d,J＝7.2Hz,3H).
The following compounds were synthesized in a similar manner to A-12.
EXAMPLE 7 Synthesis of Compound A-20
The synthetic route is as follows:
step one:
in a dry 25mL three-necked flask, compound Int-2 (50 mg,0.17 mmol), 2-dimethyloxirane (12 mg,0.17 mmol), anhydrous potassium carbonate (93 mg,0.67 mmol), acetonitrile (1.5 mL) and H2O (0.5 mL) were added and reacted under argon atmosphere at 120℃under microwave irradiation for 1 hour. After LCMS monitoring the reaction, the reaction solution was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography (ethyl acetate/methanol=20/1) to give (R) -1- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrimidin-5-yl) oxy) -2-methylpropan-2-ol a-20 (10 mg, pale yellow solid), yield: 16%. LCMS (ESI) m/z 307.2[ M+H ] ] + ； 1 H NMR(DMSO-d 6 ,400MHz):δ7.67(s,1H),7.63(t,J＝7.2Hz,1H),7.51(t,J＝7.2Hz,1H),7.37–7.10(m,3H),5.64–5.57(m,1H),4.95(s,1H),3.77(d,2H),2.21(s,3H),1.53(t,J＝8.0Hz,3H),1.24(s,6H).
The following compounds were synthesized in a similar manner to A-20.
EXAMPLE 8 Synthesis of Compound A-24
The synthetic route is as follows:
step one:
in a dry 25mL three-necked flask, compound Int-2 (0.11 g,0.37 mmol), tert-butyl 3- (hydroxymethyl) azetidine-1-carboxylate (69 mg,0.37 mmol), triphenylphosphine (0.13 g,0.48 mmol) and anhydrous tetrahydrofuran (3 mL) were added, and the reaction was stirred for 10 minutes after the temperature had risen to 70℃under the protection of argon, diisopropyl azodicarboxylate (97 mg,0.48 mmol) was added and the reaction was continued with stirring at 70℃for 2 hours. After LCMS monitoring the reaction to completion, the reaction solution was cooled to room temperature, saturated ammonium chloride solution (10 mL), ethyl acetate extraction (15 ml×3), combined organic phases, washed with saturated brine (15 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (dichloromethane/methanol=20/1) to give (R) -3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrimidin-5-yl) oxy) methylazetidine-1-carboxylic acid tert-butyl ester a-24-a (94 mg, yellow solid), yield: 55%. LCMS (ESI) m/z 467.2[ M+H] + 。
Step two:
in a dry 25mL single-necked flask, compound A-24-a (94 mg,0.20 mmol), trifluoroacetic acid (0.5 mL) and dichloromethane (2.5 mL) were added, and the reaction was stirred at room temperature for 16 hours. LCMS monitored completion of reaction, saturated sodium bicarbonate solution pH-8 was added, extracted with dichloromethane (20 ml×3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (formic acid system) to give the product (R) -3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrimidin-5-yl) oxy) methylazetidine formate a-24 (15 mg, white solid), yield: 20%. LCMS (ESI) m/z 367.2[ M+H ] ] + ； 1 H NMR(DMSO-d 6 ,400MHz):δ8.38(s,2H),7.73–7.64(m,3H),7.48–7.50(t,J＝6.8Hz,1H),7.36–7.09(m,2H), 5.64–5.68(t,J＝7.2Hz,1H),4.11(s,2H),3.95(d,J＝8.0Hz,4H),3.26–3.22(m,1H),2.21(s,3H),1.55(d,J＝6.8Hz,3H).
The following compounds were synthesized in a similar manner to A-24.
EXAMPLE 9 Synthesis of Compound A-25
The synthetic route is as follows:
step one:
in a dry 25mL single-necked flask, compound A-24 (90 mg,0.25 mmol), 2-methoxyacetyl chloride (40 mg,0.37 mmol), potassium carbonate (0.10 g,0.73 mmol) and anhydrous N, N-dimethylformamide (2 mL) were added and the reaction stirred at room temperature for 16 hours. After LCMS monitoring the reaction, water (10 mL) was added, the ethyl acetate extracts (15 ml×3), the organic phases were combined, washed with saturated brine (15 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (dichloromethane/methanol=20/1) to give (R) -1- (3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrimidin-5-yl) oxy) methyl) azetidin-1-yl) -2-methoxyethan-1-one a-25 (12 mg, yellow solid), yield: 22%. LCMS (ESI) m/z 439.2[ M+H ]] + ； 1 H NMR(DMSO-d 6 ,400MHz):δ7.67(s,1H),7.51–7.45(m,2H),7.21(t,J＝8.0Hz,1H),7.07–6.78(m,1H),5.69–5.56(m,2H),6.50–6.44(m,1H),4.27–4.11(m,4H),3.99(d,J＝12.0Hz,3H),3.39(d,J＝8.0Hz,3H),3.14–3.09(m,1H),2.44(s,3H),1.60(d,J＝7.2Hz,3H).
The following compounds were synthesized in a similar manner to A-25.
EXAMPLE 10 Synthesis of Compound A-31
The synthetic route is as follows:
step one:
in a one-necked flask equipped with 10mL of N, N-dimethylformamide, compound A-31-a (500 mg,3.49 mmol), naH (67 mg,4.19 mmol) were successively added, and the mixture was stirred at room temperature for 15 minutes, then 1-bromo-2-methoxyethane (4815 g,3.49 mmol) was added to the system, and the reaction was carried out at room temperature under nitrogen atmosphere for 16 hours. Concentrating under reduced pressure, and purifying the residue by flash column chromatography to give compound a-31-b (350 mg, yellow oil) in the yield: 49.8%. 1 H NMR(400MHz,CD 3 OD):δ3.75(s,3H),3.72-3.70(m,1H),3.64-3.62(m,2H),3.53-3.50(m,3H),3.35(s,3H),3.26-3.22(m,1H),2.75-2.60(m,2H).
Step two:
into a single-necked flask, compound A-31-b (350 mg,1.74 mmol) was successively introduced, followed by dissolution in 3mL of ethanol. Sodium borohydride (99 mg,2.61 mmol) was slowly added at 0deg.C and reacted at room temperature under nitrogen for 4 hours. After completion of the reaction, ice water was added to the reaction solution, extraction and concentration was performed with ethyl acetate, and the residue was purified by silica gel chromatography to give compound a-31-c (170 mg, yellow oil) as a yield: 56.4%. 1 H NMR(400MHz,DMSO-d 6 ):δ4.75-4.72(m,1H),3.45-3.40(m,3H),3.385-3.32(m,2H),3.30-3.28(m,1H),3.23(s,3H),3.15-3.12(m,1H),2.33-2.31(m,3H),2.27-2.25(m,1H),2.02-1.97(m,1H).
Step three:
compound A-31-c is reacted with intermediate Int-2 to give compound A-31 in a similar manner to the synthesis of compound A-3.
EXAMPLE 11 Synthesis of Compound A-39
The synthetic route is as follows:
step one:
in a dry 50mL single-necked flask, compound A-39-a (0.50 g,4.4 mmol), p-toluenesulfonic acid (83 mg,0.44 mmol) and methanol (10 mL) were successively added, and the reaction was stirred at room temperature for 16 hours. After completion of TLC detection, saturated sodium bicarbonate solution (30 mL) was added, stirred for 0.5 hour, extracted with ethyl acetate (50 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate and concentrated to give (4-methoxytetrahydro-2H-pyran-4-yl) methanol A-39-b (0.41 g, colorless oil), crude product, which was used directly in the next step.
Step two:
in a dry 25mL three-necked flask, compound Int-2 (0.10 g,0.34 mmol), (4-methoxytetrahydro-2H-pyran-4-yl) methanol A-39-b2 (50 mg,0.34 mmol), triphenylphosphine (0.12 g,0.44 mmol) and toluene (5 mL) were added, and after stirring for 10 minutes under argon, diisopropyl azodicarboxylate (88 mg,0.44 mmol) was added and the reaction stirred for 5 hours at 120 ℃. After LCMS monitoring the reaction, the reaction solution was cooled to room temperature, concentrated, and the resulting residue was purified by thin layer chromatography (dichloromethane/methanol=20/1) to give (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -5- ((4-methoxytetrahydro-2H-pyran-4-yl) methoxy) -2-methylpyrimidin-4-amine a-39 (11.7 mg, yellow oily liquid), yield: 8 ％。LCMS(ESI):m/z 426.2[M+H] + ； 1 H NMR(DMSO-d 6 ,400MHz):δ7.80(s,1H),7.66(t,J＝7.2Hz,1H),7.50(t,J＝7.2Hz,1H),7.35–7.08(m,2H),6.77(d,J＝8.0Hz,1H),5.60(t,J＝7.6Hz,1H),4.01(s,2H),3.68–3.57(m,4H),3.20(s,3H),2.23(s,3H),1.83–1.70(m,4H),1.54(d,J＝6.8Hz,3H).
EXAMPLE 12 Synthesis of Compound A-54
The synthetic route is as follows:
step one:
in a dry 50mL round bottom flask was added compound A-54-c (0.50 g,3.2 mmol), triethylamine (0.64 g,6.4 mmol) and anhydrous dichloromethane (20 mL) in sequence. The reaction was cooled to 0℃and methylsulfonyl chloride (0.36 g,3.2 mmol) was added dropwise, then slowly raised to 25℃and stirring continued for 3 hours. After the TLC detection reaction was completed, water (5 mL) was added to the reaction solution, dichloromethane extraction (10 ml×3), the organic phases were combined, dried, and concentrated under reduced pressure to give the product (1-acetylpiperidin-4-yl) methylsulfonate a-54-d (0.53 g, white solid), yield: 71%.
1 H NMR(DMSO-d 6 ,400MHz):δ4.44(d,J＝13.2Hz,1H),4.13(d,J＝6.4Hz,2H),3.88(d,J＝13.6Hz,1H),3.24(s,3H)，3.15–3.04(m，1H),2.47(s，1H)，2.05–1.97(m，4H),1.75(t,J＝16Hz,2H),1.13–1.08(m,2H).
Step two:
to a dry 25mL single-necked flask, 5- (benzyloxy) -4-chloro-2-methylpyrimidine (0.14 g,0.61 mmol), int-3 (0.15 g,0.61 mmol), anhydrous potassium carbonate (0.17 g,1.2 mmol) and dimethyl sulfoxide (5 mL) were added sequentially, and the mixture was stirred under argon at 100℃for 16 hours. After completion of the LCMS monitoring reaction, the reaction mixture was diluted with water, extracted with ethyl acetate (40 mL. Times.3), the organic phases were combined, washed with saturated brine (20 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate)Purification of (R) -2- (3- (1- ((5- (benzyloxy) -2-methylpyrimidin-4-yl) amino) ethyl) phenyl) -2, 2-difluoroethane-1-ol a-54-a (35 mg, colorless solid) was obtained as a product in yield: 14%. LCMS (ESI) m/z 400.2[ M+H ] ] + .
Step three:
in a dry 25mL single-necked flask, compound A-54-a (35 mg,0.09 mmol), palladium on carbon (10 mg, 10%) and methanol (2 mL) were sequentially added, and the reaction was stirred under hydrogen balloon pressure at 25℃for 12 hours. After LCMS monitoring the reaction, filtration and concentration of the filtrate under reduced pressure afforded crude product (R) -4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylpyrimidin-5-ol a-54-b (21 mg, colorless solid). LCMS (ESI) m/z 309.9[ M+H ]] + .
Step four:
into a dried 25mL round bottom flask was added compound A-54-b (20 mg,0.06 mmol), compound A-54-d (17 mg,0.71 mmol), potassium carbonate (18 mg,0.13 mmol) and acetonitrile (5 mL) in sequence, and stirred at 80℃for 12 hours under argon. After completion of LCMS monitoring reaction, water (5 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, and the resulting residue was concentrated under reduced pressure to give product ((R) -1- (4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylpyrimidin-5-yl) oxy) methyl) piperidin-1-one a-54 (2.0 mg, white solid), yield: 7%. LCMS (ESI) m/z 449.2[ M+H ]] + .HPLC:purity:98.57％(214nm),99.96％(254nm). 1 H NMR(DMSO-d 6 ,400MHz):δ7.72(s,1H),7.54(s,1H)，7.45(m,3H),5.80–5.76(m，1H),5.49–5.46(m，1H),5.35–5.33(m，1H),4.70–4.66(m,1H),4.01–3.85(m,5H),3.04–3.08(m,1H),2.59–2.49(m,4H),2.22(t,J＝7.6Hz,1H)，2.10(d,J＝12.5Hz,3H),2.01–2.00(m,2H),1.63(d,J＝8.0Hz,3H),0.90–0.84(m,2H).
EXAMPLE 13 Synthesis of Compound B-1
The synthetic route is as follows:
step one:
in a one-necked flask equipped with 20mL of N, N-dimethylformamide, compound B-1-a (1.0 g,6.71 mmol), potassium carbonate (1.85 g,13.42 mmol) and 3-hydroxypyridine (428 mg,6.71 mmol) were charged, and the reaction was stirred under nitrogen at 60℃for 12 hours. The reaction solution was poured into water, extracted three times with ethyl acetate, the organic phase was washed 2 times with water, saturated brine once, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to give the compound B-1-B (650 mg, yellow solid) in the yield: 46.7%. LCMS (ESI) m/z 208.1[ M+H ]] + .
Step two:
in a one-necked flask containing 10mL of toluene, compound B-1-B (219 g,1.06 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamine (200 mg,1.06 mmol), 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl (86 mg,0.21 mmol), tris (dibenzylideneacetone) dipalladium (192 mg,0.21 mmol) and cesium carbonate (690 mg,2.12 mmol) were charged, and the reaction was stirred under nitrogen atmosphere at 100℃for 16 hours. The reaction solution was poured into water, extracted three times with ethyl acetate, the organic phase was washed 2 times with water, saturated brine was once, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to give compound B-1 (75 mg, yellow solid), yield: 19.6%. LCMS (ESI) m/z 361.1[ M+H ] ] + ； 1 H NMR(400MHz,CD 3 OD):δ9.23–9.22(m,1H),8.89–8.87(m,1H),8.81–8.78(m,1H),8.29–8.26(m,1H),7.75–7.73(m,1H),7.69–7.68(m,1H),7.59–7.58(m,1H),7.40–7.39(m,1H),7.36–7.32(m,1H),7.05(t,J＝54.8,1H),5.56–5.54(m,1H),1.78(d,J＝7.2Hz,3H).
The following compounds were synthesized in a similar manner to B-1.
EXAMPLE 14 Synthesis of Compound B-4
The synthetic route is as follows:
step one:
to a solution of B-4-a (500 mg,2.72 mmol) and Int-1 (674 mg,2.99 mmol) in ethanol (10 mL) was added triethylamine (549 mg,5.44 mmol), and the reaction was stirred at 60℃for 12 hours. After the reaction was completed, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give compound B-4-B (236 mg, white solid) yield: 26%. LCMS m/z 336.0[ M+H ]] + .
Step two:
to a solution of B-4-B (156 mg,0.46 mmol), B-4-c (432 mg,2.32 mmol) and diisopropylethylamine (119 mg,0.92 mmol) in dimethyl sulfoxide (2 mL) was added cesium fluoride (458 mg,1.38 mmol), and the mixture was stirred at 130℃for 16 hours with argon substitution 3 times. After the reaction was completed, the reaction was diluted with water (30 mL), extracted with ethyl acetate (3×30 mL), the extract was washed with saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give compound B-4-d (144 mg, white solid) yield: 65%. LCMS: m/z 486.2[ M+H ]] + .
Step three:
to 1, 4-dioxane (1 ml) containing B-4-d (70 mg,0.14 mmol) was added hydrochloric acid/1, 4-dioxane solution (1 ml, 4M) and stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (water/acetonitrile=1:0 to 1:3) to give compound B-4 (3.9 mg, white solid) yield: 7%. LCMS: m/z 386.5[ M+H ] ] + . 1 H NMR(400MHz,DMSO-d 6 ):δ11.02(d,J＝15.0Hz,1H),9.20(d,J＝6.7Hz,1H),8.33(s,3H),7.72(d,J＝5.9Hz,1H),7.59(t,J＝6.9Hz,1H),7.11–7.38(m,2H),6.41(d,J＝6.2Hz,1H),5.22–5.12(m,1H),4.46(s,1H),4.24–4.07(m,1H),3.79(d,J＝9.5Hz,1H),2.98(s,2H),2.61(s,1H),1.66(d,J＝6.5Hz,3H).
The following compounds were synthesized in a similar manner to B-4.
EXAMPLE 15 Synthesis of Compound B-6
The synthetic route is as follows:
to a solution of B-5 (153 mg,0.37 mmol) in methanol (3 mL) was added palladium on carbon (15 mg, 10%), the hydrogen was replaced 3 times, and the reaction was stirred at 50℃for 12 hours under an atmosphere of hydrogen (15 psi). After the reaction was completed, the catalyst was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give compound B-6 (98.1 mg, white solid), yield: 70%. LCMS: m/z 381.1[ M+H ]] + . 1 H NMR(400MHz,CDCl 3 )δ:8.97(s,1H),8.18(s,1H),8.01(d,J＝6.4Hz,1H),7.67(t,J＝7.3Hz,1H),7.50(t,J＝7.0Hz,1H),7.18(t,J＝7.7Hz,1H),6.90(t,J＝54.9Hz,1H),6.17(d,J＝6.6Hz,1H),5.04(d,J＝6.6Hz,1H),3.93–3.84(m,2H),3.40–3.23(m,4H),2.13–2.03(m,1H),1.85(d,J＝6.8Hz,3H),1.75–1.66(m,2H),1.36–1.22(m,2H).
EXAMPLE 16 Synthesis of Compound B-7
The synthetic route is as follows:
to a solution of B-5 (10 mg,0.024 mmol), trimethylboroxine (15 mg,0.12 mmol) and N, N-diisopropylethylamine (31 mg,0.24 mmol) in N, N-dimethylformamide (1 mL) was added (BrettPhos) Pd (II) phenethylamine chloride (2 mg,0.002 mmol), argon was replaced 3 times, and the reaction was stirred for 12 hours at 100 ℃. After the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol=10:1) to givePurification of the crude product by reverse phase column chromatography (water: acetonitrile=1:0 to 1:3) afforded compound B-7 (3.9 mg, white solid) in yield: 41%. LCMS (ESI): m/z 395.2[ M+H ]] + . 1 H NMR(600MHz,CDCl 3 ):δ8.76(s,1H),7.60(t,J＝7.2Hz,1H),7.50(t,J＝6.9Hz,1H),7.20(t,J＝7.7Hz,1H),6.91(t,J＝55.0Hz,1H),5.87(s,1H),4.93(q,J＝6.7Hz,1H),3.92–3.87(m,2H),3.30(td,J＝11.7,1.7Hz,2H),3.00(s,2H),2.62(s,1H),2.41(s,3H),1.91–1.82(m,1H),1.72(d,J＝6.8Hz,3H),1.60(dd,J＝29.5,12.8Hz,2H),1.20(dddd,J＝16.2,12.4,8.3,4.1Hz,2H).
EXAMPLE 17 Synthesis of Compound C-1
The synthetic route is as follows:
step one:
to a dry flask was added, in order, compound C-1-a (1.0 g,6.0 mmol), bromomethylpyridine hydrobromide (2.3 g,9.1 mmol), potassium carbonate (2.1 g,15 mmol), sodium iodide (90 mg,0.6 mmol) and N, N-dimethylformamide (60 mL), and the mixture was reacted at room temperature under nitrogen for 24 hours. After completion of the reaction, the reaction solution was quenched with water and extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by normal phase preparation to give compound C-1-b (200 mg, yellow solid), yield: 13%.
Step two:
compound C-1-b (200 mg,0.78 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamine hydrochloride Int-1 (148 mg,0.78 mmol) and N, N-diisopropylethylamine (202 mg,1.56 mmol) were dissolved in tetrahydrofuran (5 mL) and refluxed overnight. After the reaction was completed, the reaction solution was cooled, concentrated under reduced pressure, and the residue was prepared from normal phase to give compound C-1 (110 mg, yellow oil), yield: 50%. LCMS (ESI) m/z 408.2[ M+H ]] + .
EXAMPLE 18 Synthesis of Compound C-2
The synthetic route is as follows:
step one:
into a 10mL microwave tube was charged 4mL of DMA, compound C-1 (50 mg,0.12 mmol), cyclopropylboronic acid (53 mg,0.62 mmol), [1,1' -bis (diphenylphosphino) ferrocene ]Palladium dichloride (18 mg,0.025 mmol) and potassium carbonate (42 mg,0.30 mmol) were bubbled with Bi Danqi for 2 minutes, the lid was closed and stirred at 110℃for 12 hours. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution under cooling, extracted with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel plate to give compound C-2 (5.9 mg, white solid), yield: 12%. LCMS (ESI) m/z=415.0 [ m+h ]] + ； 1 H NMR(400MHz,CD 3 OD):δ8.69(s,1H),8.53(d,J＝8.8Hz,1H),8.00(d,J＝7.6Hz,1H),7.65(s,1H),7.44-7.48(m,3H),7.21-7.17(m,1H),6.99(t,J＝55.2Hz,1H),5.41-5.45(m,1H),5.23(s,2H),1.74-1.81(m,1H),1.54(d,J＝6.8Hz,3H),0.93-0.99(m,1H),0.78-0.86(m,1H),0.70-0.64(m,1H),0.34-0.42(m,1H).
The following compounds were synthesized in a similar manner to C-2.
EXAMPLE 19 Synthesis of Compound C-4
The synthetic route is as follows:
step one:
compound C-3 (120 mg,0.32 mmol), zinc cyanide (112 mg,0.96 mmol), 1-bis (diphenylphosphorus) ferrocene (18 mg,0.03 mmol), zinc powder (6.2)mg,0.095 mmol), then solvent N, N-dimethylacetamide (3 mL), finally catalyst tris (dibenzylideneacetone) dipalladium (30 mg,0.03 mmol) was added, nitrogen sparged for 3 min, then capped quickly, reacted at 110℃for 7 hours, after completion of the reaction, the reaction cooled to room temperature, quenched with saturated ammonium chloride solution, extracted with ethyl acetate and the combined organic phases dried and concentrated under reduced pressure. Purification of the residue using a normal phase prep column gave the title compound C-4 (16.8 mg, white solid), yield: 14%. LCMS (ESI) m/z=363.1 [ m+h ] ] + ； 1 H NMR(400MHz,CD 3 OD):δ7.82(s,1H),7.60(t,J＝7.3Hz,1H),7.52(t,J＝6.9Hz,1H),7.28(t,J＝7.8Hz,1H),7.03(t,J＝54.9Hz,1H),5.62(q,J＝7.1Hz,1H),3.98–4.11(m,2H),1.65(d,J＝7.0Hz,3H),1.35–1.45(m,1H),0.65-0.75(m,2H),0.38–0.49(m,2H).
EXAMPLE 20 Synthesis of Compound C-5
The synthetic route is as follows:
step one:
compound C-4 (58 mg,0.16 mmol) was dissolved in tetrahydrofuran (6 mL), then a tetrahydrofuran solution of lithium aluminum oxide (0.096 mL,0.24mmol,2.5 mol/L) was added dropwise under nitrogen protection at 0deg.C, the reaction was stirred at 0deg.C for 2 hours, after completion of the reaction, water (0.2 mL) was added to the reaction solution, and pH= -12 was adjusted with sodium hydroxide solution (w/w=15%) and filtered, the filtrate was extracted with ethyl acetate, the organic phases were combined, dried and concentrated, and the residue was prepared by reverse phase to give compound C-5 (6.8 mg, white solid), yield: 20%. LCMS (ESI) m/z=367.2 [ m+h ]] + ； 1 H NMR(400MHz,CD 3 OD):δ7.56(s,1H),7.51(t,J＝8.0Hz,1H),7.38(t,J＝8.0Hz,1H),7.15(t,J＝8.0Hz,1H),7.03(t,J＝52.0Hz,1H),5.51–5.57(m,1H),3.79–3.84(m,2H),3.50–3.55(m,2H),1.51(d,J＝7.2Hz,3H),1.26–1.27(m,1H),0.54–0.53(m,2H),0.28–0.31(m,2H).
EXAMPLE 21 Synthesis of Compound C-6
The synthetic route is as follows:
step one:
to a one-necked flask equipped with tetrahydrofuran and water (1:1, 2 mL) was added sodium hydroxide (30 mg,0.74 mmol), compound C-4 (90 mg,0.25 mmol), hydrogen peroxide (141 mg,1.24mmol, w/w=30%), and then reacted at 25℃for 6 hours under nitrogen. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined and washed with saturated sodium sulfite solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase preparation to give compound C-6 (50.2 mg, white solid), yield: 53%. LCMS (ESI) m/z=381.2 [ m+h ] ] + ； 1 H NMR(400MHz,CD 3 OD):δ7.83(s,1H),7.65(t,J＝8.0Hz,1H),7.49(t,J＝8.0Hz,1H),7.27(t,J＝8.0Hz,1H),7.12(t,J＝56.0Hz,1H),5.64–5.69(m,1H),4.00–4.02(m,2H),1.65(d,J＝8.0Hz,3H),1.34–1.39(m,1H),0.66–0.70(m,2H),0.40–0.44(m,2H).
EXAMPLE 22 Synthesis of Compound D-1
The synthetic route is as follows:
step one:
into a single-necked flask, 20mL of n-butanol, compound D-1-a (0.50 g,3.50 mmol) and Compound Int-1 (1.32 g,6.99 mmol) were successively added, and the mixture was stirred under nitrogen at 130℃for 16 hours. After the reaction, spin-drying, dispersing with water, extracting with ethyl acetate, drying the organic phase, concentrating, and passing through a column to obtain a compound D-1-b (300 mg), wherein the yield is as follows: 29%.
Step two:
15mL of four-necked flask was charged withHydrofuran, compound D-1-b (65 mg,0.219 mmol), then DIPEA (113 mg,0.8759 mmol) and cyclopropylcarbonyl chloride (57 mg,0.5475 mmol) were added and reacted for 16 hours at room temperature under argon atmosphere. After the reaction was completed, quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by flash silica gel column to give compound D-1 (35 mg, white solid), yield: 42%. LCMS (ESI) m/z=364.8 [ m+h ]] + ； 1 H NMR(400MHz,CD 3 OD):δ8.05(s,1H),7.60(t,J＝7.1Hz,1H),7.47(d,J＝6.6Hz,1H),7.24(t,J＝7.7Hz,1H),7.02(t,J＝54.9Hz,1H),5.65(d,J＝7.0Hz,1H),1.86(dd,J＝8.6,3.9Hz,1H),1.60(d,J＝7.0Hz,3H),1.03(td,J＝4.8,3.0Hz,2H),0.97–0.92(m,2H).
The following compounds were synthesized in a similar manner to D-1.
EXAMPLE 23 Synthesis of Compound D-3
The synthetic route is as follows:
step one:
15mL of tetrahydrofuran, compound D-1-b (65 mg,0.219 mmol) and then cyclopropyl isocyanate (45 mg,0.5475 mmol) were sequentially added to a single-necked flask, and the mixture was reacted at room temperature under argon atmosphere for 16 hours. After completion of the reaction, the mixture was separated into layers with water and ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, concentration and purification of the residue by flash column to give compound D-3 (16 mg, white solid), yield: 19%. LCMS (ESI) m/z=379.8 [ m+h ] ] + ； 1 H NMR(600MHz,CD 3 OD):δ7.83(s,1H),7.50(t,J＝7.4Hz,1H),7.37(t,J＝7.0Hz,1H),7.12(t,J＝7.7Hz,1H),6.90(t,J＝54.9Hz,1H),5.55(q,J＝7.0Hz,1H),2.52(tt,J＝7.0,3.6Hz,1H),2.24(s,3H),1.48(d,J＝7.0Hz,3H),0.67–0.61(m,2H),0.47(s,2H).
EXAMPLE 24 Synthesis of Compound D-4
The synthetic route is as follows:
step one:
5mL of isopropyl alcohol, compound D-4-a (72 mg,0.44 mmol), compound Int-1 (100 mg,0.44 mmol) and diisopropylethylamine (170 mg,1.32 mmol) were added sequentially to a single-port flask, and the mixture was stirred at 90℃for 12 hours. After completion of the reaction, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane/methanol=10:1) to give compound D-4-b (75 mg, white solid), yield: 54%. LCMS (ESI) m/z=316.0 [ m+h ]] + .
Step two:
to a solution of compound D-4-b (100 mg,0.32 mmol), compound D-4-c (104 mg,0.96 mmol) and cesium carbonate (312 mg,0.96 mmol) in toluene (3 mL) was added (BrettPhos) Pd (II) phenethylamine chloride (25 mg, 0.032 mmol), argon was substituted 3 times, and the reaction was stirred at 110℃for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give a crude product, which was further purified by reverse direction column chromatography (water/acetonitrile=1/0 to 1/3) to give compound D-4 (17 mg, white solid), yield: 14%. LCMS (ESI) m/z=388.2 [ m+h ]] + ； 1 H NMR(600MHz,CDCl 3 ):δ8.51(d,J＝1.4Hz,1H),8.40–8.36(m,1H),7.93(s,1H),7.65(t,J＝8.0Hz,2H),7.44(t,J＝6.8Hz,1H),7.17–7.12(m,2H),7.05(s,1H),6.88(t,J＝55.1Hz,1H),6.00(s,1H),5.74–5.69(m,1H),4.29–4.18(m,2H),2.39(s,3H),1.67(d,J＝7.0Hz,3H).
The following compounds were synthesized in a similar manner to D-4.
EXAMPLE 25 Synthesis of Compound D-19
The synthetic route is as follows:
in a one-necked flask containing 10mL of tetrahydrofuran was charged compound D-1-a (35 mg,0.118 mmol), followed by DIPEA (122 mg,0.9459 mmol) and methanesulfonic anhydride (62 mg,0.354 mmol) and reacted at room temperature under argon atmosphere for 16 hours. Then quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by flash column chromatography to give compound D-19 (5 mg, white solid) yield: 11%. LCMS (ESI) m/z=374.7 [ m+h ] ] + ； 1 H NMR(400MHz,CD 3 OD)δ7.71(s,1H),7.50(t,J＝7.5Hz,1H),7.38(t,J＝6.9Hz,1H),7.14(t,J＝7.7Hz,1H),6.90(t,J＝54.8Hz,1H),5.55(d,J＝7.0Hz,1H),2.88(s,3H),2.26(s,3H),1.50(d,J＝7.0Hz,3H).
The following compounds were synthesized in a similar manner to D-19.
EXAMPLE 26 Synthesis of Compound E-1
The synthetic route is as follows:
step one:
to a three-necked flask containing isopropyl alcohol (5 mL) was added compound E-1-a (200 mg,0.96 mmol), diisopropylethylamine (621.8 mg,4.8 mmol) and compound Int-1 (216.9 mg,0.96 mmol), and after mixing well, the mixture was reacted at 110℃under nitrogen atmosphere for 16 hours. After completion of the reaction, the reaction mixture was cooled and concentrated under reduced pressure, and the residue was purified by column chromatography to give compound E-1-b (300 mg, yellow oil), yield: 86.5%. LCMS (ESI) m/z=360.0 [ m+h ]] +
Step two:
to a solution of compound E-1-b (100 mg,0.27 mmol) in 1.4-dioxane (5 mL) under nitrogen was added ethyl acrylate (55.7 mg,0.54 mmol), triethylamine (84.4 mg,0.81 mmol), xphos (26.5 mg,0.054 mmol) and palladium acetate (25.5 mg,0.027 mmol), and after mixing uniformly, the reaction mixture was gradually warmed to 100℃under nitrogen to react overnight. After completion of the reaction, the reaction mixture was cooled, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography to give compound E-1-c (75 mg, yellow oil), yield: 70.8%. LCMS (ESI) m/z=380.1 [ m+h ] ] +
Step three:
to a three-necked flask containing ethanol (3 mL) was added sodium hydroxide (39.5 mg,0.95 mmol) and Compound E-1-c (75 mg,0.19 mmol) in this order. After mixing well, the mixture was reacted at 35℃for 2 hours. After the reaction is completed, the reaction solution is cooled to room temperature and added with HCl (1 mol/L) to adjust the pH to 6Concentration under reduced pressure afforded compound E-1-d (40 mg, yellow solid), yield: 57.5%. LCMS (ESI) m/z=352.1 [ m+h ]] +
Step four:
compound E-1-d (40 mg,0.11 mmol), cyclopropylamine (6.5 mg,0.11 mmol), HATU (43.3 mg,0.11 mmol) and N, N-diisopropylethylamine (44.1 mg,0.33 mmol) were dissolved in dichloromethane (3 mL) and reacted at room temperature under nitrogen for 2 hours. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution, then extracted with ethyl acetate, the combined organic phases were dried and concentrated under reduced pressure, and the residue was purified by reverse phase preparation to give compound E-1 (10.5 mg, white solid), yield: 23.6%. LCMS (ESI) m/z=391.2 [ m+h ]] + ； 1 H NMR(400MHz,CD 3 OD):δ8.16(s,1H),7.63(d,J＝16.0Hz,1H),7.57-7.53(m,1H),7.47(t,J＝8.0Hz,1H),7.24(t,J＝8.0Hz,1H),7.13(t,J＝52.0Hz,1H),6.47(d,J＝16.0Hz,1H),5.73-5.67(m,1H),3.31-3.30(m,1H),2.36(s,3H),1.61(s,3H),0.82-0.78(m,2H),0.58-0.54(m,2H)。
The following compounds were synthesized in a similar manner to E-1.
EXAMPLE 27 detection of KRAS-G12C/SOS1 inhibition by Compounds
The test purpose is to test the inhibition of KRAS-G12C/SOS1 by the test compound, IC 50 To characterize the inhibition ability of the compounds on KRAS-G12C/SOS1, IC 50 The lower the value, the greater its inhibition ability. BI-3406 was used as a positive control compound.
Experimental reagent: KRASG12C/SOS Binding kit (Cisbio, cat.63ADK000CB16 PEG); DMSO (Sigma, cat.D 8418-1L); 384-well white plate (Perkinelmer, cat.6007290)
The experimental method comprises the following steps:
1. compound preparation: the solution was dissolved in 100% DMSO to give a 10mM stock solution, and stored in a refrigerator in a dark place.
2. Kinase reaction process:
(1) Preparation of the compound: the test compound concentration was 5000nM, diluted to 200-fold final concentration of 100% DMSO in 384 well plates, 3-fold diluted compound, 10 concentrations. 50nL of compound at 200-fold final concentration was transferred to the destination plate 384-well-plate using a dispenser Echo 550. 50nL of 100% DMSO was added to each of the negative control wells and the positive control wells.
(2) Tag1-SOS1 solution was prepared with a Diluent buffer at 4-fold final concentration.
(3) 2.5. Mu.L of a 4-fold final concentration of Tag1-SOS1 solution was added to 384-well plates.
(4) Tag2-KRAS-G12C solution was prepared with a final concentration of 4 times using a Diluent buffer.
(5) 2.5. Mu.L of Tag2-KRAS-G12C solution with a final concentration of 4 times is added to each of the compound well and the positive control well; 2.5. Mu.L of a reagent buffer was added to the negative control wells.
(6) The 384-well plate was centrifuged at 1000rpm for 30 seconds, and incubated at room temperature for 15 minutes after shaking and mixing.
(7) The Detection buffer was used to prepare an Anti-Tag1-Tb3+ solution at a final concentration of 1 time and an Anti-Tag2-XL665 solution at a final concentration of 1 time, and the two solutions were mixed to obtain a Mix solution, and 5. Mu.L of Mix solution was added to each well.
(8) The 384-well plate was centrifuged at 1000rpm for 30 seconds, and incubated at 4℃for 120 minutes after shaking and mixing.
(9) Em665/620 was read with an Envision microplate reader.
Data analysis
Calculation formula
Inhibition％＝(Max signal-Compound signal)/(Max signal-Min signal)×100
Wherein Min signal is negative control Kong Junzhi and Max signal is positive control Kong Junzhi.
Fitting dose-response curve
The log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and a log (inhibitor) vs. response-Variable slope fit quantitative effect curve of analysis software GraphPadprism5 is adopted, so that the IC of each compound on the enzyme activity is obtained 50 Values.
The fitting formula is: y=bottom+ (Top-Bottom)/(1+10
The inhibitory activity of the compounds of the examples on KRAS-G12C/SOS1 interaction is shown in Table 1.
TABLE 1 inhibitory Activity of example Compounds against KRAS-G12C/SOS1 interaction
Numbering of compounds IC 50
A-1 C
A-2 C
A-3 B
A-4 B
A-5 D
A-6 B
A-7 A
A-8 B
A-9 B
A-10 B
A-11 B
A-12 B
A-13 B
A-14 A
A-15 A
A-16 B
A-17 B
A-18 B
A-19 A
A-20 B
A-21 A
A-22 B
A-23 A
A-24 A
A-25 A
A-26 A
A-27 A
A-28 A
A-29 A
A-30 A
A-31 B
A-32 B
A-33 A
A-34 A
A-35 A
A-36 A
A-37 D
A-38 B
A-39 B
A-40 B
A-41 B
A-42 A
A-43 D
A-44 A
A-45 A
A-46 A
A-47 A
A-48 A
A-49 C
A-50 A
A-51 B
A-52 B
A-53 B
A-54 A
B-1 D
B-2 D
B-3 B
B-4 B
B-5 A
B-6 A
B-7 A
C-1 B
C-2 B
C-3 C
C-4 B
C-5 B
C-6 C
D-1 B
D-2 B
D-3 D
D-4 A
D-5 A
D-6 B
D-7 A
D-8 A
D-9 A
D-10 B
D-11 A
D-12 A
D-13 A
D-14 A
D-15 A
D-16 A
D-17 A
D-18 A
D-19 D
D-20 D
D-21 D
D-22 A
D-23 A
D-24 A
D-25 A
D-26 A
E-1 C
E-2 A
E-3 A
Note that: IC (integrated circuit) 50 Wherein "A" represents IC 50 Less than or equal to 200nM, and "B" represents 200nM < IC 50 "C" means 2000nM < IC 50 Less than or equal to 5000nM, "D" means IC 50 > 5000nM, "//" indicates no measurement.

Claims (15)

  1. A compound of formula (I), an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:
    wherein,
    ring A is C 6-10 Aryl, 5-to 10-membered heteroaryl, or 4-to 10-membered heterocyclyl;
    m(R 3 ) Represents that m R's which are the same or different are present at any position of the A ring 3 A substituent;
    m is 0 to 5; preferably, m is 1, 2 or 3; more preferably, m is 1 or 2;
    each R 3 The substituents are independently selected from: hydrogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 Alkynyl, 4-to 6-membered heterocyclyl, halogen, cyano, amino, or divalent substituent = O; the substitution means substitution by one or more substituents selected from halogen, hydroxy, cyano and amino; when ring A is C 6-10 Aryl or 5-to 10-membered heteroaryl, R 3 Not divalent substituent = O;
    Q 1 is N or CR 4 ，Q 2 Is N or CR 5 ，Q 3 Is N or CR 6 ，Q 4 Is N or CR 1 The method comprises the steps of carrying out a first treatment on the surface of the And Q is 1 、Q 2 、Q 3 、Q 4 At least one of which is N;
    R 1 is hydrogen, halogen, C which is unsubstituted or substituted by substituents of group A1 1-6 Alkyl group,C unsubstituted or substituted by substituents of group A1 3-6 Cycloalkyl, C unsubstituted or substituted by substituents of group A1 1-6 Alkoxy, -CN, -COOH, unsubstituted or substituted by C 1-6 alkyl-substituted-CONH 2 Or unsubstituted or substituted by C 1-6 An alkyl-substituted amino group;
    R 4 、R 5 、R 6 each independently is C which is unsubstituted or substituted by group A1 1-10 Alkyl, C unsubstituted or substituted by group A1 6-10 Aryl, 4-to 10-membered heterocyclic group unsubstituted or substituted by group A1, hydroxy, C 1-10 Alkoxy, -NH 2 、-CN、-COOH、-CONH 2 Or halogen;
    R 2 c being hydrogen or unsubstituted or substituted by substituents of group A1 1-6 Alkyl, C unsubstituted or substituted by substituents of group A1 3-6 Cycloalkyl;
    substituted by substituents of group A1 means by substituents selected from C 1-6 One or more substituents selected from alkyl, hydroxy, halogen, cyano, amino and carboxyl groups;
    x is oxygen, NH, S, -SO 2 -, -ch=ch-, or X is absent;
    b is-L 1 -Ring C-L 2 -R 9 ；
    L 1 And L 2 Identical or different, each independently selected from- (CR) 7 R 8 ) n -、-(CR 7 R 8 ) n -CO-、-(CR 7 R 8 ) n -SO 2 -、-(CR 7 R 8 ) n -NH-CO-、-(CR 7 R 8 ) n -CO-NH-、-(CR 7 R 8 ) n -NH-SO 2 -、-(CR 7 R 8 ) n -SO 2 -NH-；
    Ring C is substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, substituted or unsubstituted 4-to 10-membered heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkyl or ring C is absent;
    n is an integer from 0 to 10;
    R 7 and R is 8 Each independently selected from hydrogen, hydroxy, halogen and C 1-3 An alkyl group;
    R 9 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, substituted or unsubstituted 4-to 10-membered heterocyclyl, substituted or unsubstituted C 3-8 Cycloalkyl;
    R 9 and the substitution in ring C means substitution with one or more substituents selected from the group consisting of: -R 10 、C 1-6 Alkoxy, halogen, cyano, hydroxy, carboxy, -CO-R 10 、-NH-CO-R 10 、-CO-NH-R 10 、-SO 2 -R 10 、-NH-SO 2 -R 10 、-SO 2 -NH-R 10 、-CO-(CH 2 ) i -O-R 10 I is an integer of 0 to 3; wherein R is 10 C being unsubstituted or substituted by one or more substituents selected from group A2 1-6 Alkyl or C 3-6 Cycloalkyl, group A2 substituents are selected from: halogen, C 1-3 Alkoxy, hydroxy, cyano and C 3-6 Cycloalkyl;
    provided that B is not hydrogen, unsubstituted C 1-2 Alkyl, difluoromethyl and trifluoromethyl.
  2. A compound of formula (I) according to claim 1, which is an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:
    wherein,
    b is-L 1 -R 9 ；
    L 1 Is- (CR) 7 R 8 ) n -、-(CR 7 R 8 ) n -CO-、-(CR 7 R 8 ) n -SO 2 -、-(CR 7 R 8 ) n -NH-CO-、-(CR 7 R 8 ) n -CO-NH-、-(CR 7 R 8 ) n -NH-SO 2 -or- (CR) 7 R 8 ) n -SO 2 -NH-；
    R 9 Is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted 5-to 6-membered heteroaryl, substituted or unsubstituted 4-to 6-membered heterocyclyl, substituted or unsubstituted C 3-6 Cycloalkyl;
    R 9 wherein said substitution means substitution with one or more substituents selected from the group consisting of: -R 10 、C 1-6 Alkoxy, halogen, cyano, hydroxy, carboxy, -CO-R 10 、-CO-C 3-6 Cycloalkyl, -NH-CO-R 10 、-CO-NH-R 10 、-SO 2 -R 10 、-NH-SO 2 -R 10 、-SO 2 -NH-R 10 、-CO-(CH 2 ) i -O-R 10 I is an integer of 0 to 3; wherein R is 10 C being unsubstituted or substituted by one or more substituents selected from group A2 1-6 Alkyl, group A2 substituents include: halogen, C 1-3 Alkoxy, hydroxyRadicals, cyano radicals, or C 3-6 Cycloalkyl;
    provided that B is not hydrogen, unsubstituted C 1-2 Alkyl, difluoromethyl and trifluoromethyl.
  3. A compound of formula (I) according to claim 2, which is an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:
    wherein,
    b is- (CR) 7 R 8 ) n -R 9 。
  4. A compound of formula (I) according to any one of claims 1-3, an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:
    wherein R is 7 、R 8 Each independently is H or C 1-3 Alkyl, preferably H or methyl.
  5. A compound of formula (I) according to any one of claims 1-4, an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:
    wherein L is 1 And L 2 N in (2) are each independently 0, 1 or 2.
  6. A compound of formula (I) according to any one of claims 1-5, an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:
    Wherein,
    R 9 is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl,Substituted or unsubstituted C 3-8 Cycloalkyl;
    the heteroaryl is selected from:
    the heterocyclic group is selected from:
    wherein said substitution means substitution with one or more substituents selected from the group consisting of: -R 10 、C 1-6 Alkoxy, halogen, cyano, hydroxy, carboxy, -CO-R 10 、-CO-C 3-6 Cycloalkyl, -NH-CO-R 10 、-CO-NH-R 10 、-SO 2 -R 10 、-NH-SO 2 -R 10 、-SO 2 -NH-R 10 、-CO-(CH 2 ) i -O-R 10 I is an integer of 0 to 3; wherein R is 10 C being unsubstituted or substituted by one or more substituents selected from group A2 1-6 Alkyl, group A2 substituents include: halogen, C 1-3 Alkoxy, hydroxy, cyano, C 3-6 Cycloalkyl;
    provided that B is not hydrogen, unsubstituted C 1-2 Alkyl, difluoromethyl andtrifluoromethyl.
  7. A compound of formula (I) according to claim 6, which is an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof: wherein:
    R 9 is unsubstituted or substituted by C 1-6 Alkoxy, cyano or-NH-CO-R 10 Substituted phenyl, wherein R 10 Is C 1-6 An alkyl group; or alternatively
    R 9 A heteroaryl group, substituted or unsubstituted, selected from the group consisting of: And said substitution means by one or more members selected from R 10 Is substituted by a substituent of (2); or alternatively
    R 9 Is a substituted or unsubstituted heterocyclic group selected from
    Wherein said substitution means substitution with one or more substituents selected from the group consisting of: -CO-R 10 、-CO-C 3-6 Cycloalkyl, -SO 2 -R 10 、-CO-(CH 2 ) i -O-R 10 I is an integer of 0 to 3; wherein R is 10 C being unsubstituted or substituted by one or more substituents selected from group A2 1-6 Alkyl, AGroup 2 substituents include hydroxy and cyano.
  8. A compound of formula (I) according to any one of claims 1-7, an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:
    wherein R is 2 Is methyl or ethyl.
  9. A compound of formula (I) according to any one of claims 1-8, an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:
    wherein ring A is phenyl;
    m(R 3 ) Represents that m R's which are the same or different are present at any position of the A ring 3 A substituent;
    m is 1 or 2;
    each R 3 The substituents are independently selected from: hydrogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 Alkynyl, 4-to 6-membered heterocyclyl, halogen, cyano or amino; the substitution refers to substitution by one or more substituents selected from halogen, hydroxyl, cyano and amino.
  10. A compound of formula (I) according to any one of claims 1-8, an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:
    wherein the compound of formula (I) has the structure of the following formulas (I-1-1), (I-1-2), (I-1-3), (I-1-4) and (I-1-5):
    wherein,
    R 1 、R 2 、R 3 、R 5 m, X, B are as defined in claims 1 to 8.
  11. A compound of formula (I) according to any one of claims 1-7, an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:
    the compound of the formula (I) has a structure of the formula (I-3) or the formula (I-4); wherein R is 2 Not hydrogen:
  12. a compound of formula (I) according to claim 1, which is an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:
    wherein the compound of formula (I) is selected from the following compounds:
  13. a pharmaceutical composition, the pharmaceutical composition comprising:
    (1) A therapeutically effective amount of a compound of formula (I) selected from the group consisting of enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates thereof, or pharmaceutically acceptable salts thereof, as an active ingredient, as defined in any one of claims 1 to 12; and
    (2) A pharmaceutically acceptable carrier.
  14. Use of a compound of formula (I), an enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof according to any one of claims 1-12, or a pharmaceutical composition according to claim 13, for the preparation of a medicament for the prevention and/or treatment of a disease associated with SOS1 mutation, activity or expression level.
  15. The use according to claim 14, wherein the diseases associated with SOS1 mutation, activity or expression level comprise head and neck cancer, lung cancer, mediastinal tumor, gastrointestinal tumor, prostate cancer, testicular cancer, gynecological tumor, breast cancer, kidney and bladder cancer, tumor of the endocrine system, soft tissue sarcoma, osteosarcoma, rhabdoid tumor, mesothelioma, skin cancer, tumor of the peripheral nervous system, tumor of the central nervous system, lymphoma, leukemia, unknown primary cancer, noonan syndrome, heart-face skin syndrome, hereditary gingival fibromatosis and related syndromes thereof.
CN202280054761.8A 2021-09-02 2022-07-28 SOS1 inhibitor, preparation method and application thereof Pending CN117836278A (en)

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