CN116621859A - Tri-fused ring KAT6 inhibitors - Google Patents

Tri-fused ring KAT6 inhibitors Download PDF

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Publication number
CN116621859A
CN116621859A CN202310130950.5A CN202310130950A CN116621859A CN 116621859 A CN116621859 A CN 116621859A CN 202310130950 A CN202310130950 A CN 202310130950A CN 116621859 A CN116621859 A CN 116621859A
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alkyl
alkoxy
cyano
amino
hydroxy
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刘斌
陈博
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Shandong Xuanzhu Pharma Co Ltd
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Xuanzhu Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention belongs to the technical field of medicines. In particular, the present invention relates to a class of tricyclic KAT6 inhibitor compounds, pharmaceutically acceptable salts thereof, deuterated compounds thereof, or stereoisomers thereof, containing said compounds, pharmaceutically acceptable salts thereof, deuterated compounds thereof, or stereoisomers thereofPharmaceutical compositions and formulations, methods of preparing the compounds, pharmaceutically acceptable salts thereof, deuterated compounds thereof, or stereoisomers thereof, and uses of the compounds, pharmaceutically acceptable salts thereof, deuterated compounds thereof, or stereoisomers thereof in the manufacture of medicaments for the treatment and/or prevention of KAT 6-mediated diseases and related diseases.

Description

Tri-fused ring KAT6 inhibitors
Technical Field
The invention belongs to the technical field of medicines. In particular, the invention relates to a class of tricyclic compounds useful as KAT6 inhibitors, pharmaceutically acceptable salts thereof, deuterated compounds thereof and stereoisomers thereof, pharmaceutical compositions and formulations containing the compounds, pharmaceutically acceptable salts thereof, deuterated compounds thereof and stereoisomers thereof, and uses of the compounds, pharmaceutically acceptable salts thereof, deuterated compounds thereof and stereoisomers thereof.
Background
Lysine acetyltransferases (Lysine acetyl transferases, KATs) catalyze the acetylation of lysine on histones and nonhistones. Histone acetylation is a key epigenetic regulator controlling chromosomal structure and gene transcription, affecting a variety of important cellular processes and phenotypes. In addition, acetylation of many non-histones is involved in a number of critical cellular processes including transcription, DNA damage repair, and signal transduction, among others. Acetylation affects protein function through a variety of mechanisms, including regulation of protein stability, enzymatic activity, subcellular localization, cross-talk with other post-translational modifications, and regulation of protein-protein and protein-DNA interactions. Based on sequence similarity, known mammalian histone acetyltransferases fall into three major classes, respectively: MYST family, p300/CBP family and Gcn5 related acetyltransferase family (Gcn 5/PCAF, also known as KAT2A/KAT 2B). The MYST family is the largest KAT family, named by the initiating member in yeast and mammals: MOZ, ybf2/Sas3, sas2 and TIP60. The MYST family includes five family members: KAT5 (TIP 60), KAT6A (MOZ or MYST 3), KAT6B (MORF and MYST 4), KAT7 (HBO 1 and MYST 2), KAT8 (MOF and MYST 1). These members all have a highly conserved MYST domain consisting of an acetyl coa binding sequence and a PHD (plant homologous domain) zinc finger domain.
KAT6A and its paralog KAT6B are proteins with 2004 and 2073 amino acids, respectively, which have 60% amino acid identity and 66% similarity. KAT6A and KAT6B consist of an N-terminal portion containing a NEMM domain, a double PHD zinc finger domain, a MYST domain, and a C-terminal region of glutamate/aspartate rich region and a serine/methionine rich region. Of these, NEMM domains play an important role in chromatin nuclear localization; the PHD zinc finger domain is the binding region for substrate histone H3; a MYST domain confers HAT activity; the serine/methionine rich domain has transcriptional activation activity.
KAT6 proteins play a key role in the regulation of gene expression by modifying histone lysine residues to regulate chromatin organization. KAT6A Histone Acetyltransferase (HAT) has been shown to be required for acetylation of lysine residues of histone H3 (H3K 9, H3K 23), KAT6B has also been shown to be required for normal acetylation of H3K23 in vivo. It is worth emphasizing that these histone modifications are associated with transcriptionally active genes. In addition to acetylation, KAT6A and KAT6B were also found to affect other acylations of histones, including crotonylation, propionylbutyrylation, and propionylation. KAT6A and KAT6B undergo H3K23 acetylation by forming a complex with BRPF1/2/3 and the other two proteins ING4/5 and MEAF 6.
KAT6A is a target for recurrent chromosomal translocation of acute myeloid leukemia and is locally amplified in lung, breast, ovarian, endometrial, bladder and esophageal cancers. In addition, KAT6B chromosomal translocation has been identified in a variety of cancers and is locally amplified in breast, ovarian, uterine, gastric, bladder and lung cancers. Therefore, KAT6 inhibitors have great potential in the aspect of treating cancers or other related diseases, and no small molecule inhibitors with the target point are marketed at present, so that the development of high-efficiency low-toxicity KAT6 inhibitors has important clinical significance.
Disclosure of Invention
The invention aims to provide a compound with a novel structure and good inhibition effect on KAT 6. Furthermore, the compounds can be used for preparing medicines for treating and/or preventing KAT6 mediated diseases or related diseases.
The technical scheme of the invention is as follows:
in one aspect, the present invention provides a compound of the following formula (I), a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof,
wherein ,
represents a single bond or a double bond; when->X represents a single bond 1 、X 2 Each independently selected from C, CH or N; when- >X represents a double bond 1 、X 2 All are C;
X 3 selected from CR 2 Or N;
L 1 selected from-CR 3 R 3’ -、-N(R 4 ) -, -O-, -S-; -C (O) -, -S (O) -or-S (O) 2 -；
L 2 Selected from-CR 5 R 5’ -、-N(R 7 ) -or not present;
ring A and X to which it is attached 1 、X 2 Together form the following optionally substituted with 1 to 4Q 1 groups: 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl;
each Q1 is independently selected fromHalogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy, - (CH) 2 ) m -3-10 membered cycloalkyl, - (CH) 2 ) m -3-10 membered heterocycloalkyl, - (CH) 2 ) m -5-to 10-membered heteroaryl or- (CH) 2 ) m -6-10 membered aryl;
ring B is selected from 3-10 membered cycloalkyl optionally substituted with 1-4Q 2, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl;
each Q2 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy or is optionally substituted with 1-2R 6 Substituted as follows: c (C) 1-6 Alkyl, C 1-6 Alkoxy, - (CH) 2 ) m -3-10 membered cycloalkyl, - (CH) 2 ) m -3-10 membered heterocycloalkyl, - (CH) 2 ) m -5-to 10-membered heteroaryl, - (CH) 2 ) m -6-10 membered aryl;
R 1 selected from C optionally substituted with 1-4Q 3 s 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkoxy-C 1-6 Alkyl, - (CH) 2 ) m -3-10 membered cycloalkyl, - (CH) 2 ) m -3-10 membered heterocycloalkyl, - (CH) 2 ) m -5-to 10-membered heteroaryl or- (CH) 2 ) m -6-10 membered aryl; each Q3 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl;
R 2 selected from hydrogen, halogen, hydroxy, amino, nitroRadical, cyano, carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy, - (CH) 2 ) m -3-10 membered cycloalkyl, - (CH) 2 ) m -3-10 membered heterocycloalkyl, - (CH) 2 ) m -5-to 10-membered heteroaryl or- (CH) 2 ) m -6-10 membered aryl;
R 3 、R 3’ 、R 4 、R 5 、R 5’ each R 6 、R 7 Are each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy or cyano C 1-6 An alkoxy group;
each m is independently selected from 0, 1, 2, 3 or 4.
In certain embodiments, the compounds of the foregoing general formula (I), pharmaceutically acceptable salts thereof, deuterated compounds thereof, or stereoisomers thereof, wherein,
represents a single bond or a double bond; when->X represents a single bond 1 、X 2 Each independently selected from C, CH or N; when->X represents a double bond 1 、X 2 All are C;
X 3 selected from CR 2 Or N;
L 1 selected from-CR 3 R 3’ -、-N(R 4 ) -, -O-or-S-;
L 2 selected from-CR 5 R 5’ -、-N(R 7 ) -or not present;
ring A and X to which it is attached 1 、X 2 Together form the following optionally substituted with 1 to 4Q 1 groups: 5-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 5-8 membered heteroaryl or phenyl;
each Q1 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy, - (CH) 2 ) m -3-6 membered cycloalkyl, - (CH) 2 ) m -3-6 membered heterocycloalkyl, - (CH) 2 ) m -5-8 membered heteroaryl or- (CH) 2 ) m -phenyl;
ring B is selected from 3-6 membered cycloalkyl optionally substituted with 1-4Q 2, 3-10 membered heterocycloalkyl (preferably 3-6 membered heterocycloalkyl), 5-10 membered heteroaryl (preferably 5-8 membered heteroaryl) or phenyl;
Each Q2 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy or is optionally substituted with 1-2R 6 Substituted as follows: c (C) 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) m -3-6 membered cycloalkyl, - (CH) 2 ) m -3-6 membered heterocycloalkyl, - (CH) 2 ) m -5-8 membered heteroaryl or- (CH) 2 ) m -phenyl;
R 1 selected from C optionally substituted with 1-4Q 3 s 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkoxy-C 1-4 Alkyl, - (CH) 2 ) m -5-8 membered cycloalkyl, - (CH) 2 ) m -5-8 membered heterocycloalkyl, - (CH) 2 ) m -5-8 membered heteroaryl or- (CH) 2 ) m -phenyl;
each Q3 is respectively independentIs selected from halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-8 membered heteroaryl or phenyl;
R 2 selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy, - (CH) 2 ) m -3-8 membered cycloalkyl, - (CH) 2 ) m -3-8 membered heterocycloalkyl, - (CH) 2 ) m -5-8 membered heteroaryl or- (CH) 2 ) m -phenyl;
R 3 、R 3’ 、R 4 、R 5 、R 5’ each R 6 、R 7 Are each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy or cyano C 1-4 An alkoxy group;
each m is independently selected from 0, 1, 2, 3 or 4.
In certain embodiments, ring a and the X to which it is attached 1 、X 2 Together form the following groups optionally substituted with 1 to 3Q 1: 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, 5-7 membered heteroaryl or phenyl; each Q1 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy, - (CH) 2 ) m -3-6 membered cycloalkyl, - (CH) 2 ) m -3-6 membered heterocycloalkyl, - (CH) 2 ) m -5-8 membered heteroaryl or- (CH) 2 ) m -phenyl.
In certain embodiments, ring a and the X to which it is attached 1 、X 2 Together form the following groups optionally substituted with 1 to 3Q 1: 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl; each Q1 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy, - (CH) 2 ) m -3-6 membered cycloalkyl, - (CH) 2 ) m -3-6 membered heterocycloalkyl, - (CH) 2 ) m -5-8 membered heteroaryl or- (CH) 2 ) m -phenyl.
In certain embodiments, each Q1 is independently selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 An alkoxy group.
In certain embodiments, ring B is selected from 3-6 membered cycloalkyl optionally substituted with 1-4Q 2, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, or phenyl; each Q2 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy or is optionally substituted with 1-2R 6 Substituted as follows: c (C) 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) m -3-6 membered cycloalkyl, - (CH) 2 ) m -3-6 membered heterocycloalkyl, - (CH) 2 ) m -5-8 membered heteroaryl or- (CH) 2 ) m -phenyl.
In certain embodiments, ring B is selected from the group consisting of optionally substituted with 1-3Q 25-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl; each Q2 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy or is optionally substituted with 1-2R 6 Substituted as follows: c (C) 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) m -3-6 membered cycloalkyl, - (CH) 2 ) m -3-6 membered heterocycloalkyl, - (CH) 2 ) m -5-8 membered heteroaryl or- (CH) 2 ) m -phenyl.
In certain embodiments, each Q2 is independently selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group.
In certain embodiments, R 1 Selected from C optionally substituted with 1-3Q 3 s 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkoxy-C 1-2 Alkyl, - (CH) 2 ) m -5-6 membered heteroaryl or- (CH) 2 ) m -phenyl; each Q3 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl.
In certain embodiments, R 2 Selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy or cyano C 1-4 An alkoxy group.
In certain embodiments, R 3 、R 3’ 、R 4 、R 5 、R 5’ Each R 6 、R 7 Respectively and independently select From hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy or halo C 1-4 An alkoxy group.
In certain embodiments, R 3 、R 3’ 、R 4 、R 5 、R 5’ Each R 6 、R 7 Are independently selected from hydrogen, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy or halo C 1-4 An alkoxy group.
In certain embodiments, the compounds of the foregoing general formula (I), pharmaceutically acceptable salts thereof, deuterated compounds thereof, or stereoisomers thereof, wherein,
represents a single bond or a double bond; when->X represents a single bond 1 、X 2 Each independently selected from C or N; when->X represents a double bond 1 、X 2 All are C;
X 3 selected from CR 2 Or N;
L 1 selected from-CR 3 R 3’ -、-N(R 4 ) -, -O-or-S-;
L 2 selected from-CR 5 R 5’ -、-N(R 7 ) -or not present;
ring A and X to which it is attached 1 、X 2 Together form the following optionally substituted with 1-2Q 1 groups:
each Q1 is independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, carboxy, hydroxy, amino, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, - (CH) 2 ) m -3-6 membered cycloalkyl, - (CH) 2 ) m -3-6 membered heterocycloalkyl, - (CH) 2 ) m -5-6 membered heteroaryl or- (CH) 2 ) m -phenyl;
ring B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, aziridinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, phenyl, pyridinyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, thiopyranyl, oxazinyl, indazolyl or quinolinyl optionally substituted with 1 to 3Q 2;
each Q2 is independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, carboxyl, or is optionally substituted with 1-2R 6 Substituted as follows: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, propoxy, isopropoxy, - (CH) 2 ) m -cyclopropyl, - (CH) 2 ) m -cyclobutyl, - (CH) 2 ) m Cyclopentyl, - (CH) 2 ) m -cyclohexyl, - (CH) 2 ) m -an oxetanyl, - (CH) 2 ) m -oxetanyl, - (CH) 2 ) m Tetrahydrofuranyl, - (CH) 2 ) m Azacyclobutyl, - (CH) 2 ) m Pyrrolidinyl, - (CH) 2 ) m Pyrazolidinyl, - (CH) 2 ) m Piperidinyl, - (CH) 2 ) m Piperazinyl, - (CH) 2 ) m Pyrazinyl, - (CH) 2 ) m Pyrrolyl, - (CH) 2 ) m Pyrazolyl, - (CH) 2 ) m Imidazolyl, - (CH) 2 ) m -pyridinyl, - (CH) 2 ) m Pyrimidinyl, - (CH) 2 ) m Pyridazinyl or- (CH) 2 ) m -phenyl;
R 1 selected from C optionally substituted with 1-3Q 3 s 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxymethyl, C 1-4 Alkoxyethyl, - (CH) 2 ) m Pyrazinyl, - (CH) 2 ) m Pyrrolyl, - (CH) 2 ) m Imidazolyl, - (CH) 2 ) m Pyrazolyl, - (CH) 2 ) m -1,2, 3-triazolyl, - (CH) 2 ) m -1,2, 4-triazolyl, - (CH) 2 ) m -pyridinyl, - (CH) 2 ) m Pyrimidinyl, - (CH) 2 ) m Pyridazinyl, - (CH) 2 ) m Furyl, - (CH) 2 ) m Thienyl, - (CH) 2 ) m -oxazolyl, - (CH) 2 ) m Pyranyl, - (CH) 2 ) m Thiopyranyl or- (CH) 2 ) m -phenyl;
each Q3 is independently selected from fluoro, chloro, bromo, iodo, cyano, carboxy, hydroxy, amino, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl or pyrrolidinyl;
R 2 Selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, carboxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxyA radical, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
R 3 、R 3’ 、R 4 、R 5 、R 5’ each R 6 、R 7 Each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each m is independently selected from 0, 1 or 2.
In certain embodiments, the compounds of the foregoing general formula (I), pharmaceutically acceptable salts thereof, deuterated compounds thereof, or stereoisomers thereof, wherein,
represents a single bond or a double bond; when->X represents a single bond 1 、X 2 Each independently selected from C or N; when->X represents a double bond 1 、X 2 All are C;
X 3 selected from CR 2 Or N;
L 1 Selected from-CH 2 -, -NH-; -O-or-S-;
L 2 selected from-CH 2 -、-N(R 7 ) -or not present;
ring A and X to which it is attached 1 、X 2 Together form the following optionally substituted with 1-2Q 1 groups:
each Q1 is independently selected from fluorine, chlorine, bromine, iodine, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indazolyl or quinolinyl optionally substituted with 1-3Q 2;
each Q2 is independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, carboxyl, or is optionally substituted with 1-2R 6 Substituted as follows: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, propoxy, isopropoxy;
R 1 Selected from C optionally substituted with 1-3Q 3 s 1-4 Alkoxy, C 1-4 Alkoxymethyl, C 1-4 Alkoxyethyl, - (CH) 2 ) m Pyrrolyl, - (CH) 2 ) m Imidazolyl, - (CH) 2 ) m Pyrazolyl, - (CH) 2 ) m -1,2, 3-triazolyl or- (CH) 2 ) m -1,2, 4-triazolyl;
each Q3 is independently selected from fluorine, chlorine, bromine, iodine, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, or pyrrolidinyl;
R 2 selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, carboxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each R 6 、R 7 Each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
Each m is independently selected from 0, 1 or 2.
In certain embodiments, R 1 Selected from methoxy, ethoxy, propoxy, isopropoxy, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, - (CH) optionally substituted with 1-3Q 3 groups 2 ) m Pyrrolyl, - (CH) 2 ) m Imidazolyl or- (CH) 2 ) m Pyrazolyl.
In certain embodiments, the compound of formula (I), a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof, further has a structure according to formula (II):
wherein t is selected from 0, 1 or 2;
ring B is selected from 5-6 membered cycloalkyl optionally substituted with 1-3Q 2, 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl or phenyl;
each Q2 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy or is optionally substituted with 1-2R 6 Substituted as follows: c (C) 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) m -3-6 membered cycloalkyl, - (CH) 2 ) m -3-6 membered heterocycloalkyl, - (CH) 2 ) m -5-8 membered heteroaryl or- (CH) 2 ) m -phenyl;
X 1 、X 2 、X 3 、L 2 ring A, Q, Q3, R 2 、m、R 5 、R 5’ 、R 6 、R 7 、As in any of the preceding schemes.
In certain embodiments, the compound of formula (I), a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof, further has a structure according to formula (II-1) as follows:
Wherein t is selected from 0, 1 or 2;
ring B is selected from 5-6 membered cycloalkyl optionally substituted with 1-3Q 2, 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl or phenyl;
each Q2 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy or is optionally substituted with 1-2R 6 Substituted as follows: c (C) 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) m -3-6 membered cycloalkyl, - (CH) 2 ) m -3-6 membered heterocycloalkyl, - (CH) 2 ) m -5-8 membered heteroaryl or- (CH) 2 ) m -phenyl;
X 1 、X 2 、L 2 ring A, Q, Q3, R 2 、m、R 5 、R 5’ 、R 6 、R 7 、As in any of the preceding schemes.
In certain embodiments, the compounds of the foregoing general formula (I), general formula (II) or general formula (II-1), pharmaceutically acceptable salts thereof, deuterides thereof, or stereoisomers thereof, wherein,
ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indazolyl or quinolinyl optionally substituted with 1-3Q 2;
each Q2 is independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, carboxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
X 1 、X 2 、L 2 Ring A, Q, Q3, R 2 、R 7 、m、t、As in any of the preceding schemes.
In certain embodiments, ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, phenyl, or indolyl optionally substituted with 1-3Q 2.
In certain embodiments, the compounds of the foregoing general formula (I), general formula (II) or general formula (II-1), pharmaceutically acceptable salts thereof, deuterides thereof, or stereoisomers thereof, wherein,
represents a single bond or a double bond; when->X represents a single bond 1 、X 2 Each independently selected from C or N; when->X represents a double bond 1 、X 2 All are C;
L 2 selected from-CH 2 -, -NH-or absent;
ring A and X to which it is attached 1 、X 2 Together form the following optionally substituted with 1-2Q 1 groups:
each Q1 is independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 An alkoxy group;
each Q2 is independently selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 An alkoxy group;
each Q3 is independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 An alkoxy group;
R 2 selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 An alkoxy group.
In certain embodiments, the compounds of the foregoing general formula (I), general formula (II) or general formula (II-1), pharmaceutically acceptable salts thereof, deuterides thereof, or stereoisomers thereof, wherein,
each Q1 is independently selected from fluorine, chlorine, bromine, iodine, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each Q2 is independently selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each Q3 is independently selected from fluorine, chlorine, bromine, iodine, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
R 2 Selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, the compound of formula (I), a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof, further has a structure according to formula (III):
wherein s is selected from 0, 1, 2 or 3; t is selected from 0, 1 or 2;
X 1 、X 2 、L 2 ring A, Q, Q2, Q3, R 2 、R 6 、R 7 、m、As in any of the preceding schemes.
In certain embodiments, the compound of formula (I), a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof, further has a structure according to formula (III-1) as follows:
wherein s is selected from 0, 1, 2 or 3; t is selected from 0, 1 or 2;
X 1 、X 2 、L 2 ring A, Q, Q2, Q3, R 2 、R 6 、R 7 、m、As in any of the preceding schemes.
In certain embodiments, ring a and the X to which it is attached 1 、X 2 Together form the following optionally substituted with 1-2Q 1 groups:
in certain embodiments, ring a and the X to which it is attached 1 、X 2 Together form the following optionally substituted with 1-2Q 1 groups:
In certain embodiments, ring a and the X to which it is attached 1 、X 2 Together form the following optionally substituted with 1-2Q 1 groups:
in certain embodiments, each Q1 is independently selected from halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group; preferably, each Q1 is independently selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl.
In certain embodiments, L 2 Is not present.
In certain embodiments, each Q2 is independently selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.
In certain embodiments, each Q2 is independently selected from fluoro, chloro, methyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.
In certain embodiments, each Q3 is independently selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.
In certain embodiments, R 2 Selected from hydrogen, halogen, methyl, ethyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, R 2 Is hydrogen.
In certain embodiments, R 3 、R 3’ 、R 4 、R 5 、R 5’ Each independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
In certain embodiments, each R 6 Each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, or carboxy.
In certain embodiments, R 7 Is hydrogen or C 1-4 An alkyl group.
In certain embodiments, t is 0.
The technical schemes in the invention can be mutually combined to form new technical schemes, and the formed new technical schemes are also included in the scope of the invention.
In certain embodiments, the compound of formula (I), formula (II-1), formula (III) or formula (III-1), a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof, is selected from the group consisting of:
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In another aspect, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), formula (II-1), formula (III) or formula (III-1), a pharmaceutically acceptable salt thereof, a deuteride thereof or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or diluents; the pharmaceutical composition can be prepared into any clinically or pharmaceutically acceptable dosage form, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays and the like.
In certain embodiments of the present invention, the above-described pharmaceutical formulations may be administered orally, parenterally, rectally, or pulmonary, etc., to a patient or subject in need of such treatment. For oral administration, the pharmaceutical composition may be formulated into oral preparations, for example, into conventional oral solid preparations such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparation such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. may be added. For parenteral administration, the pharmaceutical preparations may also be formulated as injections, including injectable solutions, injectable sterile powders and injectable concentrated solutions. When the injection is prepared, the conventional method in the existing pharmaceutical field can be adopted for production, and when the injection is prepared, no additive can be added, and the proper additive can be added according to the property of the medicine. For rectal administration, the pharmaceutical composition may be formulated as suppositories and the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalant or spray, etc.
The pharmaceutically acceptable carrier and/or diluent useful in the pharmaceutical composition or pharmaceutical formulation of the present invention may be any conventional carrier and/or diluent in the pharmaceutical formulation arts, and the choice of the particular carrier and/or diluent will depend on the mode of administration or type and state of disease for the particular patient being treated. The preparation of suitable pharmaceutical compositions for specific modes of administration is well within the knowledge of those skilled in the pharmaceutical arts.
In a further aspect, the invention also relates to the use of a compound of the aforementioned general formula (I), general formula (II-1), general formula (III) or general formula (III-1), a pharmaceutically acceptable salt thereof, a deuterated compound thereof or a stereoisomer thereof for the manufacture of a medicament for the prevention and/or treatment of diseases and related disorders mediated by KAT6, which medicament can be used in combination with one or more other medicaments for the prevention or treatment of diseases and related disorders mediated by KAT 6. The disease and related conditions are selected from cancers, including carcinoma in situ and metastatic cancers, or benign tumors. Further, the cancers include, but are not limited to, lung cancer (small cell lung cancer, non-small cell lung cancer), squamous cell cancer, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, renal cancer, esophageal adenocarcinoma, esophageal squamous cell cancer, prostate cancer, thyroid cancer, female genital tract cancer, lymphoma, neurofibroma, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, leukemia, glioma, sarcoma, or the like.
In certain embodiments, the KAT6 is KAT6A and/or KAT6B.
In certain embodiments, the cancer is breast cancer, prostate cancer, lung cancer (small cell lung cancer, non-small cell lung cancer); in certain embodiments, the breast cancer is ER + Breast cancer; at the position ofIn certain embodiments, the breast cancer is ER + /HER2 - Breast cancer. In certain embodiments, the lung cancer is non-small cell lung cancer. Wherein er+ breast cancer is estrogen receptor positive breast cancer; HER2 - Breast cancer is human epidermal growth factor receptor 2 negative breast cancer.
Furthermore, the application also relates to the use of the compounds of the aforementioned general formula (I), general formula (II-1), general formula (III) or general formula (III-1), pharmaceutically acceptable salts thereof, deuterated products thereof or stereoisomers thereof for the preparation of a medicament for the treatment and/or prophylaxis of diseases and related conditions mediated by KAT6 in combination with one or more medicaments.
In another aspect, the application relates to a compound of the aforementioned general formula (I), general formula (II-1), general formula (III) or general formula (III-1), a pharmaceutically acceptable salt thereof, a deuterated compound thereof or a stereoisomer thereof, which can be administered alone or in combination with one or more second therapeutically active agents for use in combination with KAT6 inhibitor compounds of the application in the treatment and/or prevention of diseases and related conditions mediated by KAT 6. Thus, in certain embodiments, the pharmaceutical composition further comprises one or more second therapeutically active agents. In certain embodiments, the second therapeutically active agent is selected from the group consisting of anticancer agents including mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal agents, angiogenesis inhibitors, cytostatic agents, targeting antibodies, cytotoxins, antihormins, antiandrogens, HMG-CoA reductase inhibitors, and prenyl protein transferase inhibitors.
In certain embodiments, the individual components to be combined (e.g., a compound of the invention, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, and a second therapeutically active agent) can be administered simultaneously or sequentially and separately administered in sequence. For example, the second therapeutically active agent may be administered before, simultaneously with, or after administration of the compound of the invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Furthermore, the individual components to be combined can also be administered jointly in the form of the same formulation or in the form of separate different formulations.
In another aspect, the invention relates to a compound of formula (I), formula (II-1), formula (III) or formula (III-1), a pharmaceutically acceptable salt thereof, a deuterated compound thereof or a stereoisomer thereof as described above, for use in combination with radiation therapy or chemotherapy in the treatment of cancer or benign tumors.
In another aspect, the invention also provides a method of treating KAT6 mediated diseases and related conditions, comprising administering to a patient in need thereof an effective amount of a compound of formula (I), formula (II-1), formula (III) or formula (III-1), a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof, a formulation or a pharmaceutical composition as described above; the KAT6 mediated disease and related conditions are as defined above.
By "effective amount" is meant an amount of a drug capable of alleviating, delaying, inhibiting or curing a condition in a subject. The size of the dose administered is determined by the mode of administration of the drug, the pharmacokinetics of the agent, the severity of the disease, the individual sign (sex, weight, height, age) of the subject, etc.
[ Definitions and general terms ]
In the description and claims of the present application, compounds are named according to chemical structural formulas, and if the same compounds are represented, the named and chemical structural formulas of the compounds are not identical, the chemical structural formulas are used as references.
In the present application, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art, however, for a better understanding of the present application, the following definitions of some terms are provided. When the definition and interpretation of terms provided by the present application are not identical to the meanings commonly understood by those skilled in the art, the definition and interpretation of terms provided by the present application is in control.
"halogen" as used herein refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
"C" as described in the present application 1-6 Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms and includes, for example," C 1-4 Alkyl "," C 1-3 Alkyl "," C 1-2 Alkyl "," C 2-6 Alkyl "," C 2-5 Alkyl "," C 2-4 Alkyl "," C 2-3 Alkyl "," C 3-6 Alkyl "," C 3-5 Alkyl "," C 3-4 Alkyl ", and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl (propyl), isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" as described in the present invention 1-4 Alkyl "means C 1-6 Specific examples of the alkyl group include 1 to 4 carbon atoms.
"C" as described in the present invention 1-6 Alkoxy "means" C 1-6 alkyl-O- ", said" C 1-6 Alkyl "is as defined above. "C" as described in the present invention 1-4 Alkoxy "means" C 1-4 alkyl-O- ", said" C 1-4 Alkyl "is as defined above.
"C" as described in the present invention 1-6 alkoxy-C 1-6 Alkyl "means" C 1-6 alkyl-O-C 1-6 Alkyl ", as used herein," C 1-4 alkoxy-C 1-4 Alkyl "means" C 1-4 alkyl-O-C 1-4 Alkyl ", said" C 1-6 Alkyl, C 1-4 Alkyl "is as defined above.
The invention relates to a hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halogenated C 1-6 Alkyl, carboxyl C 1-6 Alkyl "means C 1-6 One or more hydrogens in the alkyl groupEach substituted with one or more hydroxy, amino, halogen or carboxyl groups. The said "C 1-6 Alkyl "is as defined above.
The invention relates to the hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, halo C 1-6 Alkoxy "means" C 1-6 One or more hydrogens in the alkoxy "are substituted with one or more hydroxy, amino, or halogen groups.
"C" as described in the present invention 1-6 Alkylamino, C 1-6 Alkoxyamino, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl group, C 1-6 Alkylthio carbonyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylamide group, di (C) 1-6 Alkyl) amino, di (C) 1-6 Alkyl) aminocarbonyl "refers to C 1-6 alkyl-NH-, C 1-6 alkyl-O-NH-, C 1-6 alkyl-C (O) -, C 1-6 alkoxy-C (O) -, C 1-6 alkylthio-C (O) -, C 1-6 alkyl-S (O) 2 -、C 1-6 alkyl-C (O) -NH-,
The "6-10 membered aryl" described herein includes "6-8 membered monocyclic aryl" and "8-10 membered condensed ring aryl".
"6-8 membered monocyclic aryl" as used herein refers to monocyclic aryl groups containing 6-8 ring carbon atoms, examples of which include, but are not limited to: phenyl, cyclooctatetraenyl, and the like; phenyl is preferred.
The term "8-to 10-membered condensed ring aryl" as used herein refers to an unsaturated, aromatic cyclic group containing 8 to 10 ring carbon atoms, preferably "9-to 10-membered condensed ring aryl", which is formed by sharing two or more adjacent atoms with each other by two or more cyclic structures, and specific examples thereof are naphthyl and the like.
The "5-10 membered heteroaryl" as used herein includes "5-8 membered monocyclic heteroaryl" and "8-10 membered fused heteroaryl".
"5-8 membered monocyclic heteroaryl" as used herein refers to a monocyclic cyclic group having aromaticity which contains 5-8 ring atoms, at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. "5-8 membered monocyclic heteroaryl" includes, for example, "5-7 membered monocyclic heteroaryl", "5-6 membered nitrogen containing monocyclic heteroaryl", "6 membered nitrogen containing monocyclic heteroaryl", etc., wherein the heteroatoms in the "nitrogen containing heteroaryl" contain at least one nitrogen atom, for example, only 1 or 2 nitrogen atoms, or contain one nitrogen atom and 1 or 2 other heteroatoms (for example, oxygen and/or sulfur atoms), or contain 2 nitrogen atoms and 1 or 2 other heteroatoms (for example, oxygen and/or sulfur atoms). Specific examples of "5-8 membered monocyclic heteroaryl" include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepanyl, 1, 3-diazinoheptenyl, azocyclotetraenyl and the like. The "5-6 membered heteroaryl" refers to a specific example in which 5-8 membered heteroaryl contains 5-6 ring atoms.
The "8-to 10-membered fused heteroaryl group" as used herein refers to an unsaturated aromatic ring structure containing 8 to 10 ring atoms (at least one of which is a heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom) formed by two or more ring structures sharing two adjacent atoms with each other. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. Including "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", "9-10 membered fused heteroaryl containing 1-2 heteroatoms selected from nitrogen, oxygen or sulfur" and the like, which may be fused in such a manner as to be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and the like; specific examples include, but are not limited to: pyrrolopyrroles, pyrrolofurans, pyrazolopyrroles, pyrazolothiophenes, furanthiophenes, pyrazolooxazoles, benzofuranyl, benzisofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolonyl, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, and the like.
The "3-10 membered cycloalkyl" as used herein includes "3-7 membered monocyclic cycloalkyl" and "8-10 membered fused ring cycloalkyl".
"3-7 membered monocyclic cycloalkyl" as used herein refers to a saturated or partially saturated and non-aromatic monocyclic ring group containing 3-7 ring atoms, including "3-6 membered monocyclic cycloalkyl", "5-6 membered monocyclic cycloalkyl", specific examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexene, or the like.
"8-10 membered fused ring cycloalkyl" as used herein refers to a saturated or partially saturated, non-aromatic cyclic group containing 8-10 ring atoms formed by two or more cyclic structures sharing two adjacent atoms with each other, examples of which include, but are not limited to: etc.
As used herein, "3-8 membered cycloalkyl" refers to a specific example of "3-10 membered cycloalkyl" containing 3-8 ring carbon atoms.
The "3-10 membered heterocyclic group" as used herein includes "3-7 membered single heterocyclic group" and "8-10 membered condensed heterocyclic group".
"3-7 membered heterocyclic group" as used herein refers to a saturated or partially saturated and non-aromatic monocyclic ring group containing at least one heteroatom (e.g., containing 1,2, 3,4 or 5) and having 3 to 7 ring atoms, the heteroatom being a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom in the ring structure (e.g., carbon atom, nitrogen atom or sulfur atom) may be oxo. The "3-7 membered monocyclic group" described in the present invention includes "3-7 membered saturated monocyclic group" and "3-7 membered partially saturated monocyclic group". Preferably, the "3-7 membered mono-heterocyclic group" according to the present invention contains 1-3 heteroatoms; preferably, the "3-7 membered mono-heterocyclic group" according to the present invention contains 1-2 hetero atoms, and the hetero atoms are selected from nitrogen atoms and/or oxygen atoms; preferably, the "3-7 membered mono-heterocyclic group" according to the present invention contains 1 nitrogen atom. The "3-7 membered mono-heterocyclic group" is preferably "3-6 membered mono-heterocyclic group", "4-7 membered mono-heterocyclic group", "4-6 membered mono-heterocyclic group", "6-8 membered mono-heterocyclic group", "5-7 membered mono-heterocyclic group", "5-6 membered mono-heterocyclic group", "3-6 membered saturated mono-heterocyclic group", "5-6 membered saturated mono-heterocyclic group", "3-6 membered nitrogen-containing mono-heterocyclic group", "3-6 membered saturated nitrogen-containing mono-heterocyclic group", "5-6 membered saturated nitrogen-containing mono-heterocyclic group" or the like. For example, containing only 1 or 2 nitrogen atoms, or containing one nitrogen atom and 1 or 2 other heteroatoms (e.g., oxygen and/or sulfur atoms). Specific examples of "3-7 membered mono-heterocyclyl" include, but are not limited to: aziridinyl, 2H-aziridinyl, diazabicycloalkyl, 3H-diazapropenyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuranyl, dihydropyrrole, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidonyl, tetrahydropyridinonyl, dihydropyridinonyl, piperazinyl, morpholinyl, 4, 5-dihydro-oxazolyl, 4, 5-dihydro-isoxazolyl, 2, 3-dihydro-isoxazolyl, oxazolidinyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl, and the like.
The "8-10 membered fused heterocyclic group" as used herein refers to a saturated or partially saturated, non-aromatic cyclic group containing 8 to 10 ring atoms and at least one ring atom being a heteroatom, formed by two or more cyclic structures sharing two adjacent atoms with each other, wherein one of the rings may be an aromatic ring, but the whole of the fused ring is not aromatic, and the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo, including, but not limited to, "8-9 membered fused heterocyclic group", "9-10 membered fused heterocyclic group", and the like; specific examples of the "8-to 10-membered fused heterocyclic group" include, but are not limited to: pyrrolidinyl-cyclopropyl, cyclopentylazacyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-piperidyl, pyrrolidinyl-piperazinyl, pyrrolidinyl-morpholinyl, piperidinyl-morpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, pyrimidotetrahydropyranyl; tetrahydroimidazo [4,5-c ] pyridinyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, benzo [ d ] [1,3] dioxolyl, 2H-chromene-2-onyl, 4H-chromene, 4H-chromen-4-onyl, 4H-1, 3-benzoxazolyl, 4, 6-dihydro-1H-furo [3,4-d ] imidazolyl, 3a,4,6 a-tetrahydro-1H-furo [3,4-d ] imidazolyl, 4, 6-dihydro-1H-thieno [3,4-d ] imidazolyl, 4, 6-dihydro-1H-pyrrolo [3,4-d ] imidazolyl, octahydro-benzo [ d ] imidazolyl, decahydroquinolinyl, hexahydrothienoimidazoyl, hexahydrofuroimidazoyl, 4,5,6, 7-tetrahydro-1H-benzo [3,4-d ] imidazolyl, octahydro-pyrrolo [3,4-d ] pyrrolyl, and the like.
The term "carbon atom, nitrogen atom or sulfur atom is oxo" as used herein means that a c= O, N = O, S =o or SO is formed 2 Is a structure of (a).
The invention relates to L 2 Absence "means that the sulfonyl group is directly attached to ring B.
"optionally substituted" as used herein refers to both cases where one or more atoms on the substituted group may be "substituted" or "unsubstituted" with one or more substituents. The book is provided withThe term "pharmaceutically acceptable salt" as used herein refers to the acidic functional groups present in the compound (e.g., -COOH, -OH, -SO 3 H, etc.) with suitable inorganic or organic cations (bases), including salts with alkali metals or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and basic functional groups present in the compounds (e.g. -NH 2 Etc.) with suitable inorganic or organic anions (acids), including salts with inorganic or organic acids (e.g., carboxylic acids, etc.).
"deuterated" as used herein refers to one or more of the structures of the compound 1 H quilt 2 H (also denoted as "D") replaces the structure formed.
"stereoisomers" as used herein refers to compounds of the invention which contain one or more asymmetric centers and are thus useful as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention may have asymmetric centers that each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. The compounds of the present invention, if they contain olefinic double bonds, include cis-isomers and trans-isomers unless specified otherwise. The compounds described herein may exist in tautomeric (one of the functional group isomers) forms having different points of attachment of hydrogen through displacement of one or more double bonds, for example, the keto and enol forms thereof are keto-enol tautomers. Each tautomer and mixtures thereof are included within the scope of the present invention. Enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of all compounds are included within the scope of the present invention.
The term "dosage form" as used herein refers to a form of a medicament formulated for clinical use, including, but not limited to, powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injectable solutions, injectable sterile powders and injectable concentrated solutions), sprays, aerosols, powder sprays, lotions, liniments, ointments, plasters, pastes, patches, gargles or suppositories, more preferably powders, tablets, granules, capsules, solutions, injections, ointments, gargles or suppositories.
Advantageous effects of the invention
(1) The compound, the pharmaceutically acceptable salt or the stereoisomer thereof has excellent KAT-6 inhibitory activity, and can be used for treating KAT-6 mediated diseases and related diseases;
(2) The compound, the pharmaceutically acceptable salt or the stereoisomer thereof has good pharmacokinetic properties, longer action and high bioavailability;
(3) The compound, the pharmaceutically acceptable salt or the stereoisomer thereof has good safety;
(4) The compound has simple preparation process, high medicine purity and stable quality.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be construed that the scope of the invention is limited to the following examples. All techniques that can be realized based on the above-described aspects of the present invention are within the scope of the present invention.
Preparation example of the Compounds of the invention
Intermediate 1: preparation of 5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine
Preparation of 4-bromo-2-fluoro-6-hydroxybenzonitrile (1 b)
4-bromo-2, 6-difluorobenzonitrile (21.8 g,100.0 mmol) was added to acetonitrile (500 mL), potassium acetate (10.8 g,110.0 mmol) and 18-crown-6 (29.1 g,110.0 mmol) were added, the reaction was left to react at 90 ℃ for 16 hours, the system was quenched with water, the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to dryness, and the title compound 18.2g was obtained by normal phase purification (ethyl acetate: petroleum ether=1:4), yield: 84.3%.
Preparation of 2- (allyloxy) -4-bromo-6-fluorobenzonitrile (1 c)
4-bromo-2-fluoro-6-hydroxybenzonitrile (24.8 g,114.8 mmol) was added to N, N-dimethylformamide (260 mL), and after potassium carbonate (15.1 g,109.3 mmol) and bromopropene (13.3 g,110.0 mmol) were added, the mixture was reacted at 40℃for 6 hours. The system was quenched with water, the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by normal phase (ethyl acetate: petroleum ether=1:9) to give 26g of the target compound, yield: 88.4%.
Preparation of 3-allyl-4-bromo-6-fluoro-2-hydroxybenzonitrile (1 e)
2- (allyloxy) -4-bromo-6-fluorobenzonitrile (5.6 g,21.9 mmol) was dissolved in 1, 2-dichlorobenzene (30 mL) and the mixture was reacted at 200℃for 2 hours under microwave. The reaction solution was concentrated and dried, and purified by normal phase (ethyl acetate: petroleum ether=1:9) to give 4.7g of the objective compound, yield: 83.9%.
4.preparation of 4-bromo-6-fluoro-2-hydroxy-3- (3-hydroxypropyl) benzonitrile (1 f)
3-allyl-4-bromo-6-fluoro-2-hydroxybenzonitrile (4.0 g,15.6 mmol) was added to tetrahydrofuran (50 mL), borane tetrahydrofuran solution (1M, 17.2 mL) was added, the reaction was continued for 1 hour, hydrogen peroxide (35% wt,4 mL) and saturated sodium bicarbonate solution (4 mL) were added, and the mixture was then reacted at 10℃for 16 hours. The system was quenched by adding saturated aqueous sodium thiosulfate, the pH was adjusted to about 2 with dilute hydrochloric acid, the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by normal phase (ethyl acetate: petroleum ether=1:3) to give the objective compound 2.2g, yield: 51.4%.
Preparation of 5.5-bromo-7-fluorochroman-8-carbonitrile (1 g)
4-bromo-6-fluoro-2-hydroxy-3- (3-hydroxypropyl) benzonitrile (2.2 g,8.0 mmol) and triphenylphosphine (2.1 g,8.0 mmol) were added to tetrahydrofuran (80 mL) at 0deg.C, diethyl azodicarboxylate (1.4 g,8.0 mmol) was added dropwise, and stirring was continued for 30 min. The system was quenched with water, the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to dryness, and purified in normal phase (ethyl acetate: petroleum ether=1:10) to give 2.0g of the target compound, yield: 97.3%.
Preparation of methyl 8-cyano-7-fluorochroman-5-carboxylate (1 h)
5-bromo-7-fluorochroman-8-carbonitrile (2.3 g,9.0 mmol) was added to N, N-dimethylacetamide (56 mL) and methanol (20 mL), triethylamine (4.6 g,45.5 mmol) was added, and the mixture was reacted under carbon monoxide at 90℃for 16 hours. After the reaction, the reaction was quenched with water, extracted with ethyl acetate, the organic phase was concentrated, and purified on a silica gel column (petroleum ether: ethyl acetate=7:1) to give the objective compound 1.8g, yield: 85.2%.
Preparation of 7.7-fluoro-5- (hydroxymethyl) chroman-8-carbonitrile (1 i)
Methyl 8-cyano-7-fluorochroman-5-carboxylate (1.8 g,7.7 mmol) was dissolved in tetrahydrofuran (50 mL), and a solution of lithium borohydride in tetrahydrofuran (2M, 7.7mL,15.4 mmol) was added thereto, and the reaction was continued at 70℃for 3 hours. The reaction was quenched with water, extracted with ethyl acetate, the organic phase concentrated, and purified on a silica gel column (petroleum ether: ethyl acetate=1:1) to give 1.5g of the title compound, yield: 94.6%.
8.5 preparation of- ((1H-pyrazol-1-yl) methyl) -7-fluorochroman-8-carbonitrile (1 j)
7-fluoro-5- (hydroxymethyl) chroman-8-carbonitrile (1.4 g,6.8 mmol) was added to acetonitrile (70 mL), 1- (methylsulfonyl) -1H-pyrazole (1.2 g,8.2 mmol) and cesium carbonate (2.7 g,8.3 mmol) were added and reacted at 70℃for 2 hours. After the reaction, water was added to quench the reaction, ethyl acetate was used for extraction, the organic phase was concentrated, and the target compound was obtained by silica gel column purification (petroleum ether: ethyl acetate=1:1) in a yield of 92.0%.
9.5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine preparation (Int-1)
5- ((1H-pyrazol-1-yl) methyl) -7-fluorochroman-8-carbonitrile (310 mg,1.2 mmol) was added to N, N-dimethylformamide (35 mL), potassium tert-butoxide (404 mg,3.6 mmol) was added thereto, stirring was continued for 1 hour, acetohydroxamic acid (270 mg,3.6 mmol) was added, and the mixture was allowed to react at 45℃for 16 hours. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated and purified by silica gel column (petroleum ether: ethyl acetate=1:1) to give 60mg of the title compound in 18.4% yield.
Intermediate 2: preparation of 4- ((1H-pyrazol-1-yl) methyl) -2, 3-dihydrobenzofuran [7,6-d ] isoxazol-8-amine
Preparation of 4-bromo-6-fluoro-2-hydroxy-3- (2-oxoethyl) benzonitrile (2 b)
3-allyl-4-bromo-6-fluoro-2-hydroxybenzonitrile (2.0 g,7.8 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0deg.C, a solution of potassium osmium dihydrate (52 mg,0.16 mmol) in water (20 mL) was added, stirred for 30 minutes, and a solution of sodium periodate (4.2 g,19.6 mmol) in water (20 mL) was added. The reaction was carried out at 20℃for 0.5 hour. Ethyl acetate (50 mL) and water (50 mL) were added for extraction, and concentrated and purified in normal phase (ethyl acetate: petroleum ether=1:5) to give 1.5g of the target compound, yield: 74.4%.
Preparation of 4-bromo-6-fluoro-2-hydroxy-3- (2-hydroxyethyl) benzonitrile (2 c)
4-bromo-6-fluoro-2-hydroxy-3- (2-oxoethyl) benzonitrile (1.5 g,5.8 mmol) was dissolved in methanol (30 mL), cooled to 0 ℃, sodium borohydride (442 mg,11.6 mmol) was added, the reaction was continued for 1 hour, quenched with water (5 mL), concentrated, pH was adjusted to about 2 with dilute hydrochloric acid, extracted with ethyl acetate (30 mL), concentrated, and purified by normal phase (ethyl acetate: petroleum ether=1:2) to give the title compound 1.0g, yield: 66.1%.
Preparation of 4-bromo-6-fluoro-2, 3-dihydrobenzofuran-7-carbonitrile (2 d)
4-bromo-6-fluoro-2-hydroxy-3- (2-hydroxyethyl) benzonitrile (1.5 g,5.8 mmol) and triphenylphosphine (1.6 g,6.1 mmol) were added to tetrahydrofuran (50 mL), cooled to 0deg.C, diethyl azodicarboxylate (1.1 g,6.3 mmol) was added dropwise, and stirring was continued for 1 hour. The system was quenched with water, the organic phase was extracted with ethyl acetate (30 mL), concentrated, and purified in normal phase (ethyl acetate: petroleum ether=1:9) to give the title compound 1.3g, yield: 93.1%.
Preparation of methyl 7-cyano-6-fluoro-2, 3-dihydrobenzofuran-4-carboxylate (2 e)
4-bromo-6-fluoro-2, 3-dihydrobenzofuran-7-carbonitrile (1.3 g,5.4 mmol) was added to N, N-dimethylacetamide (15 mL) and methanol (5 mL), pd (dppf) Cl was added 2 (390 mg,0.53 mmol) and triethylamine (1.6 g,15.8 mmol) were purged 3 times with carbon monoxide and reacted at 90℃for 16 hours in a carbon monoxide atmosphere. After the reaction, the reaction was quenched with water, extracted with ethyl acetate (30 mL), the organic phase concentrated, and purified on a silica gel column (petroleum ether: ethyl acetate=3:1) to give the objective compound 1.0g, yield: 84.2%.
Preparation of 6-fluoro-4- (hydroxymethyl) -2, 3-dihydrobenzofuran-7-carbonitrile (2 f)
7-cyano-6-fluoro-2, 3-dihydrobenzofuran-4-carboxylic acid methyl ester (1.0 g,4.5 mmol) was dissolved in tetrahydrofuran (30 mL), lithium borohydride in tetrahydrofuran (2M, 4.6mL,9.2 mmol) was added, and the mixture was reacted at 70℃for 3 hours. The reaction was quenched with water, extracted with ethyl acetate (30 mL), the organic phase concentrated, and purified on a silica gel column (petroleum ether: ethyl acetate=1:2) to give 700mg of the title compound in yield: 80.1%.
6.4- ((1H-pyrazol-1-yl) methyl) -6-fluoro-2, 3-dihydrobenzofuran-7-carbonitrile preparation (2 g)
6-fluoro-4- (hydroxymethyl) -2, 3-dihydrobenzofuran-7-carbonitrile (700 mg,3.6 mmol) was added to acetonitrile (30 mL), 1- (methylsulfonyl) -1H-pyrazole (640 mg,4.4 mmol) and cesium carbonate (1.5 g,4.6 mmol) were added and reacted at 70℃for 2 hours. After the reaction, the reaction was quenched with water, extracted with ethyl acetate (30 mL), the organic phase was concentrated, and purified on a silica gel column (petroleum ether: ethyl acetate=1:2) to give 700mg of the target compound, yield: 79.4%.
7.4 preparation of- ((1H-pyrazol-1-yl) methyl) -2, 3-dihydrobenzofuran [7,6-d ] isoxazol-8-amine (Int-2)
4- ((1H-pyrazol-1-yl) methyl) -6-fluoro-2, 3-dihydrobenzofuran-7-carbonitrile (300 mg,1.2 mmol) was dissolved in acetonitrile (30 mL)/water (3 mL), tetramethylguanidine (280 mg,7.2 mmol) and acetohydroxamic acid (280 mg,3.7 mmol) were added and reacted at 100℃for 40 hours. The reaction was quenched with water, extracted with ethyl acetate (30 mL), the organic phase concentrated, purified by column on silica gel (petroleum ether: ethyl acetate=1:2), and the crude product purified by column on C18 (methanol/water=0-60%) to give 50mg of the title compound, yield: 15.8%.
Intermediate 3: preparation of 4- ((1H-pyrazol-1-yl) methyl) -2-methyl-2, 3-dihydrobenzofuran [7,6-d ] isoxazol-8-amine
Preparation of 4-bromo-6-fluoro-2-methyl-2, 3-dihydrobenzofuran-7-carbonitrile (3 b)
To a solution of 4-bromo-6-fluoro-2-hydroxy-3- (2-hydroxypropyl) benzonitrile (3.5 g,12.8 mmol) and triphenylphosphine (5.1 g,19.4 mmol) in tetrahydrofuran (80 mL) at 0deg.C was added dropwise diethyl azodicarboxylate (3.4 g,19.5 mmol) followed by stirring for 30 min. The system was quenched with water, the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by normal phase (ethyl acetate: petroleum ether=10%) to give 2.5g of the target compound in 76.4% yield.
Preparation of methyl 7-cyano-6-fluoro-2-methyl-2, 3-dihydrobenzofuran-4-carboxylate (3 c)
To a solution of 4-bromo-6-fluoro-2-methyl-2, 3-dihydrobenzofuran-7-carbonitrile (2.3 g,9.0 mmol) in N, N-dimethylacetamide (20 mL) and methanol (20 mL) was added triethylamine (1.8 g,17.8 mmol) and Pd (dppf) Cl 2 (700 mg,0.96 mmol) was reacted at 90℃for 16 hours in a carbon monoxide atmosphere. After the reaction, the reaction was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated and purified by silica gel column (ethyl acetate: petroleum ether=10%) to give 1.8g of the target compound in 85.2% yield.
Preparation of 6-fluoro-4- (hydroxymethyl) -2-methyl-2, 3-dihydrobenzofuran-7-carbonitrile (3 d)
To a solution of methyl 7-cyano-6-fluoro-2-methyl-2, 3-dihydrobenzofuran-4-carboxylate (1.7 g,7.2 mmol) in tetrahydrofuran (50 mL) was added lithium borohydride (320 mg,14.7 mmol), and the mixture was reacted at 20℃for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, the organic phase concentrated, and purified on a silica gel column (petroleum ether: ethyl acetate=1:1) to give 1.3g of the target compound in 86.8% yield.
4.4 preparation of- ((1H-pyrazol-1-yl) methyl) -6-fluoro-2-methyl-2, 3-dihydrobenzofuran-7-carbonitrile (3 e)
To a solution of 6-fluoro-4- (hydroxymethyl) -2-methyl-2, 3-dihydrobenzofuran-7-carbonitrile (1.2 g,5.8 mmol) in acetonitrile (100 mL) was added 1- (methylsulfonyl) -1H-pyrazole (1.0 g,6.8 mmol) and cesium carbonate (2.6 g,8.0 mmol) and reacted at 70℃for 2 hours. After the reaction, water was added to quench the reaction, ethyl acetate was used for extraction, the organic phase was concentrated, and the target compound was obtained by silica gel column purification (petroleum ether: ethyl acetate=1:1) in an yield of 87.2%.
5.4 preparation of- ((1H-pyrazol-1-yl) methyl) -2-methyl-2, 3-dihydrobenzofuran [7,6-d ] isoxazol-8-amine (Int-3)
To a solution of 4- ((1H-pyrazol-1-yl) methyl) -6-fluoro-2-methyl-2, 3-dihydrobenzofuran-7-carbonitrile (1.2 g,4.7 mmol) in N, N-dimethylformamide (50 mL) and water (5 mL) at 20℃were added potassium carbonate (2.6 g,18.8 mmol) and acetohydroxamic acid (1.4 g,18.6 mmol), and the mixture was reacted at 45℃for 16 hours. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase concentrated and purified on a silica gel column (MeOH: dcm=10%) to give 1.1g of the title compound in 87.3% yield.
Intermediate 4: preparation of 5- (2-methoxyethyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine
Preparation of 7-fluoro-5- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) chroman-8-carbonitrile (4 b)
5-bromo-7-fluorochroman-8-carbonitrile (700 mg,2.8 mmol), potassium 2- (tetrahydro-2H-pyran-2-yloxy) ethyltrifluoroborate (991 mg,4.2 mmol), palladium acetate (94 mg,0.42 mmol), n-butylbis (1-adamantyl) phosphine (150 mg,0.42 mmol) and cesium carbonate (2.7 g,8.4 mmol) were dissolved in 1, 4-dioxane (20 mL) and water (5 mL), replaced with nitrogen, and reacted at elevated temperature to 100℃for 12 hours. After the reaction, water and ethyl acetate were added for extraction, and the organic phase was collected, dried by spin-drying, and purified by silica gel column chromatography (PE: ea=2:1) to give 840mg of the objective compound in 98.4% yield.
Preparation of 7-fluoro-5- (2-hydroxyethyl) chroman-8-carbonitrile (4 c)
7-fluoro-5- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) chroman-8-carbonitrile (816 mg,2.7 mmol) and p-toluenesulfonic acid monohydrate (608 mg,3.2 mmol) were dissolved in MeOH (30 mL) at 30℃and stirred for 30min, after which the reaction was checked. Concentrating under reduced pressure, and purifying with silica gel column (ethyl acetate: petroleum ether=1:1) to obtain the title compound 580mg, yield: 97.2%.
Preparation of 7-fluoro-5- (2-methoxyethyl) chroman-8-carbonitrile (4 d)
7-fluoro-5- (2-hydroxyethyl) chroman-8-carbonitrile (500 mg,2.3 mmol) was dissolved in DMF (20 mL), naH (184 mg,4.6 mmol) was added and reacted at 0℃for 30min, methyl iodide (4813 mg,3.4 mmol) was added dropwise and reacted for 5h. LCMS detects the end of the reaction. Washing with water, extraction with ethyl acetate, and purification on a silica gel column (petroleum ether: ethyl acetate=3:5) gave 167mg of the title compound, yield: 30.9%.
4.5 preparation of- (2-methoxyethyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine (Int-4)
7-fluoro-5- (2-methoxyethyl) chroman-8-carbonitrile (100 mg,0.43 mmol), acetohydroxamic acid (124 mg,1.7 mmol), potassium carbonate (235 mg,1.7 mmol) was dissolved in DMF (10 mL) and H 2 O (1 mL) was reacted at 70℃for 40h. LCMS detects the end of the reaction. Washing with water, extraction with ethyl acetate, and purification on a silica gel column (petroleum ether: ethyl acetate=1:2) gave 70mg of the title compound, yield: 66.3%.
Intermediate 5: preparation of 5- (4-methoxy-1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine
Preparation of 4-methoxy-1- (methylsulfonyl) -1H-pyrazole (5 b)
Triethylamine (304 mg,3.0 mmol) and methylsulfonyl chloride (138 mg,1.2 mmol) were added to a solution of 4-methoxy-1H-pyrazole (100 mg,1.0 mmol) in DCM (5 mL) at 0deg.C, reacted for 2H at 25deg.C, TLC (PE: EA=2:1) showed that the reaction was complete, the reaction solution was diluted with water, extracted with DCM, and the organic phase was dried by spin to give 180mg of crude product.
2.7 preparation of fluoro-5- (4-methoxy-1H-pyrazol-1-yl) methyl) chromane-8-carbonitrile (5 c)
To a reactor were added 7-fluoro-5- (hydroxymethyl) chroman-8-carbonitrile (200 mg,0.97 mmol), 4-methoxy-1- (methylsulfonyl) -1H-pyrazole (180 m, crude product of the above step), cesium carbonate (470 mg,1.5 mmol) and acetonitrile (10 mL), reacted at 70℃for 10 hours, LC-MS showed completion of the reaction, the reaction solution was diluted with water, EA extracted, the organic phase was dried by spin, and the residue was purified by column chromatography (SiO 2 PE: ea=80:20-50:50) to yield 180mg of product in 64.9% yield.
3.5 preparation of (4-methoxy-1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine (Int-5)
Into a reactor, 7-fluoro-5- (4-methoxy-1H-pyrazol-1-yl) methyl) chromium-8-carbonitrile (180 mg,0.63 mmol), acetohydroxamic acid (237 mg,3.2 mmol), potassium carbonate (435 mg,3.1 mmol), DMF (5 mL) and water (1 mL) were charged, the reaction was carried out at 70℃for 20 hours, LC-MS showed completion of the reaction, the reaction solution was filtered, the filtrate was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=80:20-20:80) to yield 170mg of crude target compound.
Intermediate 6: preparation of 5- (methoxymethyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine
Preparation of 7-fluoro-5- (methoxymethyl) chroman-8-carbonitrile (6 b)
To a solution of 7-fluoro-5- (hydroxymethyl) chroman-8-carbonitrile (2.0 g,9.7 mmol) in DMF (20 mL) was added NaH (60%, 776mg,19.4 mmol), reacted at 0℃for 0.5h, methyl iodide (6.9 g,48.6 mmol) was added, reacted at 0℃for 1h, and LC-MS showed completion of the reaction. The reaction mixture was diluted with water, extracted with EA, the organic phase was dried by spinning, and the residue was purified by column chromatography (SiO 2 PE: EA=80:20-60:40) to afford the title compound in a yield of 93.7% at 2.0 g.
Preparation of 5- (methoxymethyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine (Int-6)
7-fluoro-5- (methoxymethyl) chroman-8-carbonitrile (2.0 g,9.0 mmol), acetohydroxamic acid (2.7 g,36.0 mmol), potassium carbonate (5.0 g,36.2 mmol) were dissolved in DMF (40 mL) and water (4 mL), the reaction was heated to 70℃for 16h, the reaction solution was filtered, the filtrate was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=80:20-30:70), and pulping the crude product by EA to obtain 1.5g of the target compound with a yield of 70.8%.
Intermediate 7: preparation of 5- (ethoxymethyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine
Preparation of 5- (ethoxymethyl) -7-fluorochroman-8-carbonitrile (7 b)
7-fluoro-5- (hydroxymethyl) chroman-8-carbonitrile (200 mg,0.97 mmol) was dissolved in 10mL DMF, 60% NaH (100 mg,2.5 mmol) was added at 0deg.C and stirred for 10min, and then ethyl iodide (300 mg,1.92 mmol) was added to react for 2 h. Water quenching, ethyl acetate extraction, concentration, and column chromatography (EA: pe=60%) of the residue gave 160mg of the target product in a yield of 70.4%.
Preparation of 5- (ethoxymethyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine (Int-7)
5- (ethoxymethyl) -7-fluorochroman-8-carbonitrile (140 mg,0.59 mmol) was dissolved in DMF (10 mL) and water (1 mL), potassium carbonate (210 mg,1.5 mmol) and acetohydroxamic acid (110 mg,1.5 mmol) were added, the reaction was completed at 75℃for 8h, the ethyl acetate extract was separated, concentrated, and the objective product was obtained by column chromatography (EA: PE=50%) in a yield of 81.2%.
Intermediate 8: preparation of 4- ((1H-pyrazol-1-yl) methyl) - [1,3] dioxol [4',5':5,6] benzo [1,2-d ] isoxazol-8-amine
Preparation of 5-fluoro-7-iodobenzo [ d ] [1,3] dioxol-4-amine (8 b)
At 30 ℃, to 5-fluorobenzo [ d ]][1,3]Dioxa (dioxa)To a solution of cyclopentene-4-amine (900 mg,5.8 mmol) in methanol (5 mL) and methylene chloride (10 mL) was added calcium carbonate (639 mg,6.4 mmol) and benzyl trimethyl ammonium dichloroiodate (2.2 g,6.3 mmol), and the reaction was continued at 30℃for 4h, and LC-MS showed completion of the reaction. The reaction solution was filtered, the filtrate was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=10:1) to give 1.5g of the target product, yield 92.0%.
Preparation of methyl 7-amino-6-fluorobenzo [ d ] [1,3] dioxole-4-carboxylate (8 c)
Weighing 5-fluoro-7-iodobenzo [ d ]][1,3]Dioxacyclopenten-4-amine (1.6 g,5.7 mmol), pd (dppf) Cl 2 (417 mg,0.57 mmol), triethylamine (1.2 g,11.9 mmol), DMA (20 mL) and methanol (5 mL), CO was replaced three times, the reaction was carried out at 90℃for 10h, LC-MS showed the reaction was completed, the reaction solution was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=90:10-75:25) to yield 850mg of product in 70.0% yield.
Preparation of methyl 6-fluoro-7-iodobenzo [ d ] [1,3] dioxole-4-carboxylate (8 d)
To 7-amino-6-fluorobenzo [ d ]][1,3]To acetonitrile (20 mL) of dioxole-4-carboxylic acid methyl ester (850 mg,4.0 mmol), copper iodide (762 mg,4.0 mmol), sodium iodide (600 mg,4.0 mmol) and tert-butyl nitrite (823mg, 8.0 mmol) were added and reacted at 70℃for 2 hours. After the completion of the reaction, the reaction mixture was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=90:10-80:20) to yield 1.0g of the desired product in 77.4% yield.
Preparation of methyl 7-cyano-6-fluorobenzo [ d ] [1,3] dioxole-4-carboxylate (8 e)
Adding 6-fluoro-7-iodobenzo [ d ] to a reactor][1,3]Dioxacyclopentene-4-carboxylic acid methyl ester (1.0 g,3.1 mmol), cuprous cyanide (833 mg,9.3 mmol) and NMP (10 mL) were reacted for 1h at 170℃and LC-MS showed the reaction was complete. The reaction solution was filtered, the filtrate was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=90:10-75:25) to afford 500mg of the desired product in 72.6% yield.
Preparation of 5.5-fluoro-7- (hydroxymethyl) benzo [ d ] [1,3] dioxole-4-carbonitrile (8 f)
To 7-cyano-6-fluorobenzo [ d ]][1,3]Dioxolane-4-carboxylic acid methyl ester (300 mg,1.3 mmol) in THF (15 m)L) solution was added with lithium borohydride (142 mg,6.5 mmol), reacted at 70℃for 1h, LC-MS showed the reaction was completed, the reaction solution was diluted with water, EA extracted, the organic phase was dried by spinning, and the residue was purified by column chromatography (SiO 2 PE: EA=80:20-60:40) to yield 250mg of the desired product in 95.3% yield.
6.preparation of 7- (1H-pyrazol-1-yl) methyl) -5-fluorobenzo [ d ] [1,3] dioxole-4-carbonitrile (8 g)
Adding 5-fluoro-7- (hydroxymethyl) benzo [ d ] to a reactor][1,3]Dioxacyclopentene-4-carbonitrile (250 mg,1.3 mmol), 1- (methylsulfonyl) -1H pyrazole (228 mg,1.6 mmol), cesium carbonate (635 mg,1.9 mmol) and acetonitrile (8 mL), reacted at 70℃for 2H, the reaction solution was filtered, the filtrate was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=60:40) to yield 250mg of the desired product in 79.6% yield.
7.4 preparation of- ((1H-pyrazol-1-yl) methyl) - [1,3] dioxolo [4',5':5,6] benzo [1,2-d ] isoxazol-8-amine (Int-8)
Potassium tert-butoxide (1.1 g,9.8 mmol) was added to DMF (50 mL) of acetohydroxamic acid (750 mg,10.0 mmol), reacted at 30℃for 2H, followed by 7- (1H-pyrazol-1-yl) methyl) -5-fluorobenzo [ d ] ][1,3]Dioxacyclopentene-4-carbonitrile (200 mg,0.82 mmol) was reacted at 90℃for 2h, and the reaction was terminated by LC-MS detection. The reaction mixture was diluted with water, extracted with EA, the organic phase was dried by spinning, and the residue was purified by column chromatography (SiO 2 PE: EA=1:1) to yield 40mg of the desired product in 19.0% yield.
Intermediate 9: preparation of 5- ((1H-pyrazol-1-yl) methyl) -6,7,8, 9-tetrahydronaphtho [1,2-d ] isoxazol-1-amine
Preparation of 4-iodo-5, 6,7, 8-tetrahydronaphthalen-1-amine (9 b)
5,6,7, 8-tetrahydronaphthalen-1-amine (10.0 g,67.9 mmol) was dissolved in 350mL of acetic acid, iodine chloride (11.0 g,67.8 mmol) was added, and after the addition, the reaction was completed at 30℃for 4.0 hours. The residue was concentrated and subjected to column chromatography to give 11.0g of the desired product in 59.3% yield.
Preparation of methyl 4-amino-5, 6,7, 8-tetrahydronaphthalene-1-carboxylate (9 c)
4-iodo-5, 6,7, 8-tetrahydronaphthalen-1-amine (11.0 g,40.3 mmol) was dissolved in DMA (70 mL) and methanol 130mL, pd (dppf) Cl was added 2 (5.8 g,7.9 mmol) and triethylamine (8.1 g,80.0 mmol) were reacted at 90℃for 2.0 h. After concentration, the target product was obtained by column chromatography (EA: pe=15%) 8.1g, yield 97.9%.
Preparation of methyl 4-acetamido-5, 6,7, 8-tetrahydronaphthalene-1-carboxylate (9 d)
Methyl 4-amino-5, 6,7, 8-tetrahydronaphthalene-1-carboxylate (4.0 g,19.5 mmol) was dissolved in 100mL THF, triethylamine (4.0 g,39.5 mmol), DMAP (500 mg) and acetic anhydride (2.6 g,25.5 mmol) were added and reacted at 30℃for 8.0h. After completion of the reaction, water was added to quench, and after concentration, 3.5g of the target product was obtained by column chromatography (EA: pe=65%) with a yield of 72.6%.
Preparation of 4-acetamido-3-fluoro-5, 6,7, 8-tetrahydronaphthalene-1-carboxylic acid methyl ester (9 e)
Methyl 4-acetamido-5, 6,7, 8-tetrahydronaphthalene-1-carboxylate (3.5 g,14.2 mmol) was dissolved in 50mL and Select F (10.0 g,28.2 mmol) was added and the reaction was completed at 80℃for 6.0 h. Column chromatography (EA: pe=70%) of the residue after concentration gave 1.0g of the target product, yield: 26.6%.
Preparation of methyl 4-amino-3-fluoro-5, 6,7, 8-tetrahydronaphthalene-1-carboxylate (9 f)
Methyl 4-acetamido-3-fluoro-5, 6,7, 8-tetrahydronaphthalene-1-carboxylate (1.0 g) was dissolved in 10mL of methanol, concentrated sulfuric acid (4 mL) was added, the reaction was completed at 80 ℃ for 4 hours, water was used, ethyl acetate was extracted, concentrated, and the residue was subjected to column chromatography (EA: pe=10%) to give 350mg of the objective product with a yield of 41.1%.
Preparation of methyl 4-amino-3-fluoro-5, 6,7, 8-tetrahydronaphthalene-1-carboxylate (9 g)
Methyl 4-amino-3-fluoro-5, 6,7, 8-tetrahydronaphthalene-1-carboxylate (550 mg,2.4 mmol) was dissolved in 50mL acetonitrile, cuprous iodide (510 mg,2.7 mmol), sodium iodide (440 mg,2.9 mmol) and tert-butyl nitrite (550 mg,5.3 mmol) were added, after the addition, the reaction was completed at 80℃for 2 hours, concentrated, and the residue was subjected to column chromatography (EA: PE=10%) to give 350mg of the objective product with a yield of 43.1%.
Preparation of methyl 4-cyano-3-fluoro-5, 6,7, 8-tetrahydronaphthalene-1-carboxylate (9 h)
Methyl 4-amino-3-fluoro-5, 6,7, 8-tetrahydronaphthalene-1-carboxylate (350 mg,1.0 mmol) was dissolved in 5mL NMP, cuprous cyanide (220 mg,2.5 mmol) was added, the reaction was completed at 170℃for 3 hours, and the residue was concentrated and subjected to column chromatography (EA: PE=10%) to give 200mg of the target product with a yield of 81.9%.
8.2 preparation of fluoro-4- (hydroxymethyl) -5,6,7, 8-tetrahydronaphthalene-1-carbonitrile (9 i)
Methyl 4-cyano-3-fluoro-5, 6,7, 8-tetrahydronaphthalene-1-carboxylate (175 mg,0.75 mmol) was dissolved in 10mL THF, lithium borohydride (35 mg,1.6 mmol) was added, the reaction was completed at 30℃for 3 hours, and the residue was concentrated to directly carry out the next reaction.
9.4- ((1H-pyrazol-1-yl) methyl) -2-fluoro-5, 6,7, 8-tetrahydronaphthalene-1-carbonitrile preparation (9 j)
The crude product of the above step was dissolved in 20mL of acetonitrile, cesium carbonate (550 mg,1.7 mmol) and 1- (methylsulfonyl) -1H-pyrazole (145 mg,0.99 mmol) were added, and after the addition, the reaction was completed at 30℃for 3 hours, and the desired product was obtained by concentration and column chromatography of the residue (EA: PE=65%) in 130mg, with a two-step yield of 67.9%.
10.5 preparation of- ((1H-pyrazol-1-yl) methyl) -6,7,8, 9-tetrahydronaphtho [1,2-d ] isoxazol-1-amine (Int-9)
4- ((1H-pyrazol-1-yl) methyl) -2-fluoro-5, 6,7, 8-tetrahydronaphthalene-1-carbonitrile (100 mg,0.39 mmol) was dissolved in 10mL of DMF and water (1 mL), potassium carbonate (550 mg,4.0 mmol) and acetohydroxamic acid (300 mg,4.0 mmol) were added, the addition was completed, the reaction was completed at 80℃for 3 hours, and the aimed product was obtained in a yield of 66.6% by concentration and column chromatography of residue (EA: PE=65%).
Intermediate 10: preparation of 5- ((1H-pyrazol-1-yl) methyl) -2, 3-dihydro- [1,4] dioxino [2',3':5,6] benzo [1,2-d ] isoxazol-9-amine
Preparation of 6-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin (10 b)
4-fluorobenzene-1, 2-diol (23.7 g,185.0 mmol) and cesium carbonate (150.7 g,462.6 mmol) were added to DMF (200 mL) and 1, 2-dibromoethane (52.1 g,277.3 mmol) and reacted at 80℃for 16 hours. After the reaction of the system is finished, EA and water are added for extraction and separation, an organic phase is concentrated, and residues are separated through silica gel column chromatography (PE: EA=12:1) to obtain 10.0g of target product with the yield of 35.1 percent.
Preparation of 6-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxine-5-carboxylic acid (10 c)
6-fluoro-2, 3-dihydrobenzo [ b ]][1,4]Dicyclohexene (9.0 g,58.4 mmol) was added to THF (100 mL), LDA (2M, 43.8mL,87.6 mmol) was added dropwise at-78℃and the reaction was carried out at-78℃for 1h. Dry ice (7.7 g,175.0 mmol) was then added in portions and the reaction was slowly warmed to 25℃for 1 hour. And after the reaction is finished, adding EA and water into the system for extraction and separation. The aqueous phase was adjusted to pH 4 by addition of 2N HCl, the EA extract was separated, the organic phase was dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (SiO 2 DCM: meoh=25:1) to afford the desired product 4.5g in 38.9% yield.
3. Preparation of tert-butyl (6-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) carbamate (10 d)
6-fluoro-2, 3-dihydrobenzo [ b ]][1,4]Dicyclohexene-5-carboxylic acid (4.0 g,20.2 mmol), DPPA (6.1 g,22.2 mmol), et 3 N (6.1 g,60.3 mmol) and t-butanol (4 mL) were added to 1, 4-dioxane (40 mL) and reacted at 100deg.C under nitrogen for 4h. LC-MS showed that the reaction was completed, the reaction solution was filtered, the filtrate was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=4:1) to give 3.2g of the desired product in 58.9% yield.
Preparation of 6-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-amine (10 e)
Tert-butyl (6-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) carbamate (3.1 g,11.5 mmol) was added to a solution of TFA (4 mL) and dichloromethane (15 mL) and reacted at 25℃for 4h. After the reaction, the reaction solution was concentrated, pH was adjusted to 8 by adding aqueous sodium hydrogencarbonate, the resultant was separated by EA extraction, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give 1.7g of the objective product in a yield of 87.4%.
Preparation of 6-fluoro-8-iodo-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-amine (10 f)
6-fluoro-2, 3-dihydrobenzo [ b ]][1,4]Dioxetan-5-amine (1.5 g,8.9 mmol) was added to a solution of methanol (15 mL) and methylene chloride (30 mL), and calcium carbonate (1.3 g,13.0 mmol) and benzyltrimethylammonium dichloroiodate (2.2 g,6.3 mmol) were added and reacted at 25℃for 1h. LC-MS showed that the reaction was completed, and the concentrated residue of the reaction solution was purified by column chromatography (SiO 2 PE: EA=5:1) to yield 2.1g of the desired product in 80.0% yield.
Preparation of methyl 8-amino-7-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxine-5-carboxylate (10 g)
Adding 6-fluoro-8-iodo-2, 3-dihydrobenzo [ b ] to a reactor][1,4]Dioxetan-5-amine (2.0 g,6.8 mmol), pd (dppf) Cl 2 (4966 mg,0.68 mmol), triethylamine (2.1 g,20.8 mmol), DMA (45 mL) and methanol (5 mL), CO was replaced three times, the reaction was completed at 90℃for 16h, LC-MS showed that the reaction was completed, the reaction solution was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=4:1) to yield 1.2g of the desired product in 77.7% yield.
Preparation of 7.7-fluoro-8-iodo-2, 3-dihydrobenzo [ b ] [1,4] dioxine-5-carboxylic acid methyl ester (10 h)
To 8-amino-7-fluoro-2, 3-dihydrobenzo [ b ]][1,4]To methyl dioxin-5-carboxylate (1.1 g,4.8 mmol) in acetonitrile (30 mL) were added cuprous iodide (910 mg,4.8 mmol), sodium iodide (720 mg,4.8 mmol) and tert-butyl nitrite (1.5 g,14.5 mmol) and reacted at 80℃for 2 hours. Vacuum filtering, adding water and EA to the filtrate, concentrating the organic phase, and subjecting the residue to column chromatography (SiO 2 PE: EA=6:1) to yield 1.1g of product in 67.8% yield.
Preparation of methyl 8-cyano-7-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxine-5-carboxylate (10 i)
Adding 7-fluoro-8-iodo-2, 3-dihydrobenzo [ b ] to a reactor][1,4]Dioxetane-5-carboxylic acid methyl ester (1.0 g,3.0 mmol), cuprous cyanide (795 mg,9.0 mmol) and NMP (15 mL) were reacted at 170deg.C for 1h, LC-MS showed the reaction was completed, the reaction solution was filtered, the filtrate was separated by adding water and EA extraction, the organic phase was concentrated, and the residue was purified by column chromatography (SiO 2 PE: EA=3:1) to yield 430mg of the desired product in 60.4% yield.
9.6 preparation of 6-fluoro-8- (hydroxymethyl) -2, 3-dihydrobenzo [ b ] [1,4] dioxine-5-carbonitrile (10 j)
To 8-cyano-7-fluoro-2, 3-dihydrobenzo [ b ]][1,4]Lithium borohydride (147 mg,6.7 mmol) was added to a solution of methyl dioxane-5-carboxylate (400 mg,1.7 mmol) in THF (15 mL), the reaction was continued at 70℃for 4h, LC-MS showed complete reaction, the reaction solution was diluted with water, EA was extracted, the organic phase was dried by spin-on, and the residue was purified by column chromatography (SiO 2 PE: EA=2:1) to yield 300mg of the desired product in 84.4% yield.
10.8- ((1H-pyrazol-1-yl) methyl) -6-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxine-5-carbonitrile preparation (10 k)
Adding 6-fluoro-8- (hydroxymethyl) -2, 3-dihydrobenzo [ b ] to a reactor][1,4]Dioxetane-5-carbonitrile (279 mg,1.3 mmol), 1- (methylsulfonyl) -1H pyrazole (234 mg,1.6 mmol), cesium carbonate (847 mg,2.6 mmol) and acetonitrile (15 mL) were reacted at 70℃for 2 hours, the reaction solution was filtered, the filtrate was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=1:1) to yield 250mg of the desired product in 74.2% yield.
11.5- ((1H-pyrazol-1-yl) methyl) -2, 3-dihydro- [1,4] dioxino [2',3':5,6] benzo [1,2-d ] isoxazol-9-amine preparation (Int-10)
Potassium tert-butoxide (307 mg,8.1 mmol) was added to acetohydroxamic acid (608 mg,8.1 mmol) in DMF (40 mL) and after reaction at 30℃for 2H, 8- ((1H-pyrazol-1-yl) methyl) -6-fluoro-2, 3-dihydrobenzo [ b ] was added][1,4]Dioxetane-5-carbonitrile (210 mg,0.81 mmol), the reaction was allowed to proceed at 90℃for 16h, LC-MS detection was complete, the reaction was diluted with water, EA was extracted, the organic phase was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=1:1) to yield 70mg of the desired product in 31.7% yield.
Intermediate 11:6- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H- [1,4] dioxepin [2',3':5,6] benzo [1,2-d ] isoxazol-10-amine
Preparation of 7-fluoro-3, 4-dihydro-2H-benzo [ b ] [1,4] dioxepin (11 b)
To 4-To a solution of fluorobenzene-1, 2-diol (15.0 g,117.1 mmol) in ethanol (700 mL) were added potassium carbonate (56.6 g,409.6 mmol) and 1, 3-dibromopropane (30.7 g,152.1 mmol), the reaction was continued at 90℃for 2 hours, the reaction solution was concentrated, the residue was diluted with water, EA extraction, the organic phase was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=90:10) to yield 14.0g of product in 71.1% yield.
Preparation of 7-fluoro-3, 4-dihydro-2H-benzo [ b ] [1,4] dioxepin-6-carboxylic acid (11 c)
To a solution of 7-fluoro-3, 4-dihydro-2H-benzo [ b ] [1,4] dioxepin (14.0 g,83.2 mmol) in THF (300 mL) was added LDA (2M, 100mL,200.0 mmol), reacted at-78℃for 1H, dry ice (18.3 g,415.9 mmol) was added, reacted at-78℃for 1H, then slowly warmed to 25℃for 1H, the reaction mixture was quenched with water, EA extracted (organic phase was discarded), the aqueous phase was pH adjusted to 1-2 with dilute hydrochloric acid, EA was extracted, and the organic phase was spin-dried to give 14.7g of crude product.
3. Preparation of tert-butyl (7-fluoro-3, 4-dihydro-2H-benzo [ b ] [1,4] dioxepin-6-yl) carbamate (11 d)
Weighing 7-fluoro-3, 4-dihydro-2H-benzo [ b ]][1,4]Dioxetane-6-carboxylic acid (14.0 g, crude product of the above step), DPPA (21.8 g,79.2 mmol), triethylamine (26.7 g,263.8 mmol), tert-butanol (100 mL) and dioxane (300 mL) were added to the reactor, nitrogen was replaced three times, the reaction was carried out at 100℃for 5h, LC-MS showed that the reaction was completed, the reaction solution was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=70:30) to give 7.5g of crude product.
Preparation of 7-fluoro-3, 4-dihydro-2H-benzo [ b ] [1,4] dioxepin-6-amine (11 e)
To (7-fluoro-3, 4-dihydro-2H-benzo [ b ]][1,4]Dioxahepten-6-yl) carbamic acid tert-butyl ester (7.5 g, crude product of the above step) in methanol (20 mL) was added with dioxane solution (4M, 40 mL) of hydrochloric acid, reacted at 30℃for 1h, LC-MS showed completion of the reaction, the reaction solution was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=70:30) to yield 6.9g of product.
Preparation of 7-fluoro-9-iodo-3, 4-dihydro-2H-benzo [ b ] [1,4] dioxepin-6-amine (11 f)
To 7-fluoro-3, 4-dihydro-2H-benzo [ b ] at 30 DEG C][1,4]Dioxohepten-6-amine (6.8 g,37.1 mmol) in methanol (20 mL) and methylene chloride (40 mL) were added calcium carbonate (4.1 g,41.0 mmol) and benzyltrimethylammonium dichloroiodate (14.2 g,40.8 mmol), reacted at 30℃for 3h, LC-MS showed the reaction was completed, the reaction solution was filtered, the filtrate was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=90:10) to yield 10.4g of product in 90.6% yield.
Preparation of methyl 9-amino-8-fluoro-3, 4-dihydro-2H-benzo [ b ] [1,4] dioxepin-6-carboxylate (11 g)
Weighing 7-fluoro-9-iodo-3, 4-dihydro-2H-benzo [ b ]][1,4]Dioxohepten-6-amine (10.4 g,33.6 mmol), pd (dppf) Cl 2 (2.5 g,3.4 mmol), triethylamine (10.2 g,100.8 mmol), DMA (80 mL) and methanol (20 mL) were added to the reactor, CO was replaced three times, the reaction was carried out at 90℃for 5h, LC-MS showed that the reaction was completed, the reaction solution was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=90:10-75:25) to yield 4.4g of product in 54.2% yield.
Preparation of methyl 8-fluoro-9-iodo-3, 4-dihydro-2H-benzo [ b ] [1,4] dioxepin-6-carboxylate (11H)
To 9-amino-8-fluoro-3, 4-dihydro-2H-benzo [ b ]][1,4]To methyl dioxepin-6-carboxylate (4.3 g,17.8 mmol) in acetonitrile (70 mL) were added cuprous iodide (3.7 g,19.4 mmol), sodium iodide (2.9 g,19.3 mmol) and tert-butyl nitrite (5.5 g,53.3 mmol), the reaction was allowed to react at 70℃for 1h, the reaction solution was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=90:10-80:20) to yield 5.5g of product in 87.6% yield.
Preparation of methyl 9-cyano-8-fluoro-3, 4-dihydro-2H-benzo [ b ] [1,4] dioxepin-6-carboxylate (11 i)
Weighing 8-fluoro-9-iodo-3, 4-dihydro-2H-benzo [ b ]][1,4]Dioxetane-6-carboxylic acid methyl ester (5.0 g,14.2 mmol), cuprous cyanide (3.8 g,42.4 mmol) and NMP (50 mL) were added to the reactor, reacted at 170℃for 1h, LC-MS showed the reaction was completed, the reaction solution was filtered, the filtrate was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=80:20) to yield 3.0g of product in 84.1% yield.
9.preparation of 7-fluoro-9- (hydroxymethyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] dioxepin-6-carbonitrile (11 j)
To 9-cyanogen1-8-fluoro-3, 4-dihydro-2H-benzo [ b ] ][1,4]A solution of methyl dioxy-6-carboxylate (3.2 g,12.7 mmol) in THF (50 mL) was added lithium borohydride (830 mg,38.1 mmol), reacted at 70℃for 2h, LC-MS showed the reaction was complete, the reaction solution was diluted with water, EA extracted, the organic phase was spun dry, and the residue was purified by column chromatography (SiO 2 PE: EA=80:20-50:50) to yield 2.7g of product in 95.0% yield.
10.9 preparation of- ((1H-pyrazol-1-yl) methyl) -7-fluoro-3, 4-dihydro-2H-benzo [ b ] [1,4] dioxepin-6-carbonitrile (11 k)
Weighing 7-fluoro-9- (hydroxymethyl) -3, 4-dihydro-2H-benzo [ b ]][1,4]Dioxetane-6-carbonitrile (2.7 g,12.1 mmol), 1- (methylsulfonyl) -1H pyrazole (3.5 g,23.9 mmol), cesium carbonate (7.9 g,24.2 mmol) and acetonitrile (60 mL) were added to the reactor and reacted at 85℃for 17H, the reaction solution was filtered, the filtrate was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: EA=50:50) to yield 3.0g of product in 90.7% yield.
11.6- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H- [1,4] dioxepin [2',3':5,6] benzo [1,2-d ] isoxazol-10-amine preparation (Int-11)
To 9- ((1H-pyrazol-1-yl) methyl) -7-fluoro-3, 4-dihydro-2H-benzo [ b ]][1,4]Dioxocycloheptene-6-carbonitrile (500 mg,1.8 mmol) in DMF (10 mL) and water (1 mL) were added acetohydroxamic acid (676 mg,9.0 mmol) and potassium carbonate (1.2 g,8.7 mmol), reacted at 90℃for 16h, the reaction solution was diluted with water, EA extract, the organic phase was dried by spin-drying, and the residue was purified by column chromatography (SiO 2 PE: ea=60:40-40:60) to yield 250mg of product in 47.4%.
Intermediate 12:4- ((1H-pyrazol-1-yl) methyl) - [1,3]Dioxolane [4',5':5,6]Benzo [1,2-d]Isoxazole-2, 2-d 2 Preparation of 8-amine
Using 5-fluorobenzo [ d ]][1,3]Dioxacyclopentene-2, 2-d 2 -4-amine as starting material, 4- ((1H-pyrazol-1-yl) methyl) - [1,3 was prepared using the same preparation method as intermediate 8]Dioxolane [4',5':5,6]Benzo [1,2-d]Isoxazol-2, 2-d 2-8-amine (Int-12).
Preparation example 1: preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -1-cyclohexylmethylsulfonamide (Compound 5)
1. Preparation of (cyclohexylmethyl) ethyl thioester
(bromomethyl) cyclohexane (2.0 g,11.3 mmol) and potassium thioacetate (1.9 g,16.9 mmol) were added to DMF (5 mL) and reacted at 70℃for 3h, and TLC (PE: EA=10:1) was monitored for completion of the reaction. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was washed with brine, dried, spun-dried, and the residue was purified by column chromatography (SiO 2 PE: ea=50:1-30:1) to yield 1.7g of pink oil in 87.4% yield.
2. Preparation of cyclohexylmethylsulfinyl chloride
(cyclohexylmethyl) ethyl thioate (300 mg,1.7 mmol) was dissolved in dichloromethane (10 mL), acetic anhydride (267 mg,2.6 mmol) was added, the mixture was then placed at-10℃and sulfonyl chloride (588 mg,4.4 mmol) was added dropwise, the reaction was continued for 1h, and the completion of the reaction was detected by LCMS. The reaction solution is spin-dried to obtain 500mg of crude target compound, which is directly used for the next reaction.
Preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -1-cyclohexylmethylsulfinamide
To a solution of 5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine (100 mg,0.37 mmol) in DMF (5 mL) at 10deg.C was added NaH (14.8 mg,0.37 mmol). After reaction at 10℃for 15 min, a solution of cyclohexylmethanesulfonyl chloride (500 mg, crude) in DMF (1 mL) was added dropwise and the reaction was continued for 2h, and LC-MS showed the reaction was complete. The reaction solution was quenched in water, extracted with ethyl acetate, and the organic phase was dried by spin-drying, followed by purification by silica gel column chromatography (EA: pe=0-100%) to give 40mg of the target compound in 26.1% yield.
Preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -1-cyclohexylmethylsulfonamide
N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -1-cyclohexylmethanesulfonamide (40 mg,0.096 mmol) was dissolved in dichloromethane (10 mL), 85% m-chloroperoxybenzoic acid (39 mg,0.19 mmol) was added, the reaction was continued for 2H at 25℃and completion of the reaction was detected by LCMS. Diluting with dichloromethane, washing with saturated sodium bicarbonate aqueous solution, spin-drying the organic phase, separating by silica gel column chromatography (EA: PE=3:2) to obtain crude product, and pulping with mixed solution of ethyl acetate and n-heptane (ethyl acetate: n-heptane=1:1) to obtain 8mg of product with a yield of 19.3%.
Molecular formula C 21 H 26 N 4 O 4 S molecular weight 430.2 LC-MS (M/z): 431.2 (M+H) + )
1 H-NMR(400MHz,DMSO)δ:7.79(s,1H),7.51(m,1H),6.48(m,1H),6.31(m,1H),5.42(s,2H),4.25(s,2H),3.33(s,1H),2.71-2.65(m,2H),2.10-1.91(m,4H),1.90-1.80(m,2H),1.69-1.51(m,4H),1.31-1.00(m,5H).
Preparation example 2: preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -2, 5-dimethoxybenzenesulfonamide (Compound 8)
To 5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] at 0deg.C]To N, N-dimethylacetamide (1 mL) of isoxazol-9-amine (50 mg,0.18 mmol) was added sodium hydride (60%, 14mg,0.35 mmol), reacted at 0℃for 0.5h, and then added a solution of 2, 5-dimethoxybenzenesulfonyl chloride (85 mg,0.36 mmol) in N, N-dimethylacetamide (0.5 mL), reacted at 0℃for 2h, with LCMS showing about 60% conversion. The reaction mixture was diluted with water, EA extracted (organic phase was discarded), the aqueous phase was pH adjusted to 3-4 with dilute hydrochloric acid (1M), EA extracted, the organic phase was spin-dried and the residue was subjected to prep-TLC (SiO) 2 ,100％EA,R f =0.3) to yield 15mg of the product in 17.2%.
Molecular formula C 22 H 22 N 4 O 6 S molecular weight 470.5. 470.5 LC-MS (M/z): 471.0 (M+H) + )
1 H-NMR(400MHz,CDCl 3 )δ:8.12(s,1H),7.65(d,J＝3.2,1H),7.56(d,J＝2.0,1H),7.36(d,J＝2.0,1H),7.08(t,J＝3.2,1H),6.90(d,J＝8.8,1H),6.56(s,1H),6.32(d,J＝2.0,1H),5.32(s,2H),4.37-4.30(m,2H),3.90(s,3H),3.85(s,3H),2.66-2.60(m,2H),2.17-2.10(m,2H).
Preparation example 3: preparation of N- (4- ((1H-pyrazol-1-yl) methyl) -2-methyl-2, 3-dihydrobenzofuran [7,6-d ] isoxazol-8-yl) -2-methoxybenzenesulfonamide (Compound 9)
To a solution of 4- ((1H-pyrazol-1-yl) methyl) -2-methyl-2, 3-dihydrobenzofuran [7,6-d ] isoxazol-8-amine (100 mg,0.37 mmol) in THF (10 mL) at 0deg.C were added sodium tert-butoxide (80 mg,0.83 mmol) and 2-methoxybenzenesulfonyl chloride (140 mg,0.68 mmol), and the mixture was left at 60deg.C for 8 hours. The reaction was quenched with water, extracted with ethyl acetate, and the aqueous phase was concentrated and purified by silica gel column (ethyl acetate=100%) to give 15mg of the target compound in 9.2% yield.
Molecular formula C 21 H 20 N 4 O 5 S molecular weight 440.5 LC-MS (M/e): 441.1 (M+H) + )
1 H-NMR(400MHz,CDCl 3 )δ:8.13(m,1H),7.74(s,1H),7.58-7.56(m,2H),7.39(s,1H),7.15-7.08(m,1H),6.99-6.95(s,1H),6.63(s,1H),6.32(s,1H),5.34(s,2H),5.18-5.15(m,1H),3.90(s,3H),3.20-3.10(m,1H),2.68-2.62(m,1H),1.56-1.54(s,3H).
Preparation example 4: preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -2-fluoro-5-methoxybenzenesulfonamide (Compound 11)
5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine (50 mg,0.18 mmol) was dissolved in THF (30 mL) at 0℃and then added to sodium tert-butoxide (52 mg,0.54 mmol), stirred for 1 hour, then 2-fluoro-5-methoxybenzenesulfonyl chloride (81 mg,0.36 mmol) was added dropwise to the above reaction system, stirred for 10 minutes, then moved to 60℃and stirred for 16 hours, after completion of the LC-MS detection reaction, water (50 mL) and ethyl acetate (50 mL. Times.1) were added thereto for extraction, the pH of the water phase was adjusted to 5-6 with 0.5N HCl, and then ethyl acetate (50 mL. Times.2) was used for extraction, the combined organic phase was dried over anhydrous sodium sulfate, and the resulting mixture was added with methanol (5 mL) for beating, and suction filtration to give the target compound (14 mg) in 17.0% yield.
Molecular formula C 21 H 19 FN 4 O 5 S molecular weight 458.5 LC-MS (M/e): 459.1 (M+H) + )
1 H-NMR(400MHz,DMSO-d 6 )δ:11.30(s,1H),7.79(d,1H,J＝2.1Hz),7.52(d,1H,J＝1.4Hz),7.39-7.37(m,1H),7.32-7.28(m,2H),6.47(s,1H),6.32-6.31(m,1H),5.42(s,2H),4.17-4.12(m,2H),3.77(s,3H),2.70-2.67(m,2H),1.99-1.95(m,2H).
Preparation example 5: preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -1-methyl-1H-indazole-7-sulfonamide (Compound 12)
Preparation of 1.1-methyl-1H-indazole-7-sulfonyl chloride
To a tetrahydrofuran solution of n-butyllithium (0.19 mL,0.48 mmol) was added a tetrahydrofuran solution of di-n-butylmagnesium (1.4 mL,1.4 mmol) at 25℃and after stirring for 30 minutes, cooled to-25℃and a tetrahydrofuran (2 mL) solution of 7-bromo-1-methylindazole (200 mg,0.95 mmol) was added thereto at that temperature. Heating to-10deg.C, and maintaining for 1 hr. The reaction solution was slowly added dropwise to a solution of sulfonyl chloride (390 mg,2.9 mmol) in toluene (5 mL) at-10℃and stirring was continued for 20 minutes. After the reaction, the reaction solution was dried by spin to obtain 500mg of crude product, which was directly used for the next reaction.
Preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -1-methyl-1H-indazole-7-sulfonamide
5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d]Isoxazol-9-amine (100 mg,0.37 mmol) was dissolved in tetralinTo hydrofuran (10 mL) was added 1-methyl-1H-indazole-7-sulfonyl chloride (440 mg, crude) and sodium t-butoxide (107 mg,1.1 mmol). Reacting at 60deg.C for 12 hr, detecting, extracting with water (50 mL) and ethyl acetate (50 mL. Times.1), adjusting pH of the aqueous phase to 5-6 with 0.5N HCl, extracting with ethyl acetate (50 mL. Times.2), mixing the organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography (SiO) 2 Dichloromethane: ethyl acetate=1:3) to give 15mg of the objective compound in 8.7% yield.
Molecular formula C 22 H 20 N 6 O 4 S molecular weight 464.5 LC-MS (M/e): 465.0 (M+H) + )
1 H-NMR(400MHz,DMSO-d 6 )δ:8.21(s,1H),8.00(d,J＝7.8Hz,1H),7.94(d,J＝7.28Hz,1H),7.72(d,J＝2.0Hz,1H),7.47(s,1H),7.19(t,J＝7.7Hz,1H),6.36(s,1H),6.27(s,1H),5.35(s,2H),4.45(s,3H),4.04(t,J＝4.7Hz,2H),2.62(t,J＝6.4Hz,2H),1.91(t,J＝5.8Hz,2H).
Preparation example 6: preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -2-fluoro-5-methoxybenzenesulfonamide (Compound 13)
1. Preparation of cyclohexane sulfinyl chloride
S-Cyclohexylethyl sulfate (1.0 g,6.3 mmol) was dissolved in dichloromethane (20 mL), acetic anhydride (643 mg,6.3 mmol) was added, the mixture was then placed at-10℃and sulfonyl chloride (1.1 mg,8.2 mmol) was added dropwise, the reaction was continued for 3h, LCMS detection was completed, the reaction solution was dried by spin to give 1.4g of crude target compound, which was directly used in the next reaction.
Preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) cyclohexanesulfinamide
To a solution of 5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine (100 mg,0.37 mmol) in DMF (10 mL) at-10deg.C was added NaH (30 mg,0.74 mmol). The reaction was carried out at-10℃for 15 minutes, a solution of cyclohexane sulfinyl chloride (300 mg, crude product) in DMF (1 mL) was added dropwise, the reaction was continued for 10 minutes, LC-MS showed that the reaction was completed, the reaction solution was poured into water for quenching, extracted with ethyl acetate, the organic phase was dried by spinning, and the target compound was purified by silica gel column chromatography (EA: PE=0-100%) to obtain 30mg of the target compound in 20.3% yield.
Preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) cyclohexanesulfonamide
N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) cyclohexanesulfinamide (30 mg,0.075 mmol) was dissolved in dichloromethane (10 mL), 85% m-chloroperoxybenzoic acid (26 mg,0.15 mmol) was added, the reaction was continued for 4H at 25℃and completion of the reaction was detected by LCMS. Diluting with dichloromethane, washing with saturated sodium bicarbonate aqueous solution, spin-drying the organic phase, separating by silica gel column chromatography (EA: PE=3:2) to obtain crude product of target compound, and pulping (ethyl acetate: n-heptane=1:1) to obtain 20mg of target compound with a yield of 64.1%.
Molecular formula C 20 H 24 N 4 O 4 S molecular weight 416.5 LC-MS (M/z): 417.2 (M+H) + )
1 H-NMR(400MHz,CDCl 3 )δ:7.57(s,1H),7.35(m,1H),7.30(brs,1H),6.62(m,1H),6.32(m,1H),5.34(s,2H),4.29(t,J＝5.04,2H),3.82–3.60(m,1H),2.71-2.65(m,2H),2.32-2.20(m,2H),2.10-2.01(m,2H),1.90-1.80(m,2H),1.69-1.51(m,2H),1.31-1.00(m,4H).
Preparation example 7: preparation of 5-fluoro-2-methoxy-N- (5- (2-methoxyethyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) benzenesulfonamide (Compound 14)
5- (2-methoxyethyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine (105 mg,0.42 mmol) was dissolved in DMA (5 mL) at 0deg.C, stirred for 0.5H, 5-fluoro-2-methoxybenzenesulfonyl chloride (175 mg,0.84 mmol) was added and stirred for 3H. LCMS detects the end of the reaction. Washing with water, extracting with ethyl acetate once, adding diluted hydrochloric acid to adjust the pH to 6-7, extracting with ethyl acetate, washing, drying and concentrating the organic phase, and purifying with a silica gel column (petroleum ether: ethyl acetate=1:2) to obtain the title compound 117mg, yield: 63.9%.
Molecular formula C 20 H 21 FN 2 O 6 S molecular weight 436.5 LC-MS (M/e): 437.5 (M+H) + )
1 H-NMR(400MHz,DMSO-d 6 )δ:10.29(s,1H),7.59-7.50(m,2H),7.30-7.20(m,1H),6.99(s,1H),4.18-4.14(m,2H),3.80(s,3H),3.60-3.52(m,2H),3.32-3.20(m,3H),2.90-2.80(m,2H),2.75-2.65(m,2H),2.05-1.90(m,2H).
Preparation example 8: preparation of 2-methoxy-N- (5- (methoxymethyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) benzenesulfonamide (Compound 15)
5- (methoxymethyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine (100 mg,0.43 mmol) was dissolved in DMA (5 mL) at 0deg.C, sodium hydrogen (69 mg,1.7 mmol) was added, stirred for 30min, then 2-methoxybenzenesulfonyl chloride (163 mg,0.86 mmol) was added, stirred for 3 hours, after completion of LCMS detection reaction, water (150 mL) and EA were added to extract once, pH was adjusted to 6-7 with dilute hydrochloric acid, extracted with EA, the organic phase was concentrated, and column chromatography was separated (petroleum ether (EA: DCM=85:15))=1:2, concentrating to give 96mg of the target compound in 55.3% yield.
Molecular formula C 19 H 20 N 2 O 6 S molecular weight 404.4 LC-MS (M/e): 405.1 (M+H) + )
1 H-NMR(400MHz,DMSO- d6 )δ:9.85(s,1H),7.83-7.81(m,1H),7.63-7.61(m,1H),7.23-7.20(m,1H),7.12-7.07(m,2H),4.45(s,2H),4.21-4.19(m,2H),3.82(s,3H),3.35(s,3H),2.67-2.63(m,2H),1.99-1.97(m,2H).
Preparation example 9: preparation of 5-fluoro-2-methoxy-N- (5- (4-methoxy-1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) benzenesulfonamide (Compound 16)
To 5- (4-methoxy-1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d at 0deg.C]To DMA (3 mL) of isoxazol-9-amine (170 mg crude), naH (60%, 91mg,2.3 mmol) was added, reacted at 0℃for 0.5h, then 5-fluoro-2-methoxybenzenesulfonyl chloride (256 mg,1.1 mmol) was added, reacted at 0℃for 2h, the reaction solution was diluted with water, EA was extracted (the organic phase was discarded), the aqueous phase was adjusted to pH 3-4 with dilute hydrochloric acid (1M), EA was extracted, the organic phase was spin-dried, and the residue was purified by column chromatography (SiO 2 PE: EA=80:20-60:40) to obtain a crude product of the target compound, and pulping with PE: EA=1:1 to obtain 55mg of the target compound.
Molecular formula C 22 H 21 FN 4 O 6 S molecular weight 488.5 LC-MS (M/z): 489.1 (M+H) + )
1 H-NMR(400MHz,DMSO-d 6 )δ:10.40(s,1H),7.58-7.48(m,3H),7.27-7.22(m,2H),6.54(s,1H),5.27(s,2H),4.17-4.14(m,2H),3.78(s,3H),3.64(s,3H),2.68-2.64(m,2H),1.98-1.95(m,2H).
Preparation example 10: preparation of N- (5- (methoxymethyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -5-fluoro-2-methoxybenzenesulfonamide (Compound 17)
5- (methoxymethyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine (160 mg,0.72 mmol) was dissolved in 10mL DMA, and 60% NaH (60 mg,1.5 mmol) and 5-fluoro-2-methoxybenzenesulfonyl chloride (330 mg,1.5 mmol) were added at 0deg.C and reacted for 2H. After completion of water quenching, ethyl acetate extraction, the aqueous phase was adjusted to pH 7 with 4M HCl, separated by ethyl acetate extraction, concentrated, and the residue was subjected to column chromatography (EA: pe=70%) to give the desired product in a yield of 125mg of 40.9%.
Molecular formula C 19 H 19 FN 2 O 6 S molecular weight 422.4 LC-MS (M/e): 423.1 (M+H) + )
1 H-NMR(400MHz,DMSO)δ:10.36(s,1H),7.58-7.56(m,2H),7.26-7.23(m,1H),7.09(s,1H),4.44(s,2H),4.17-4.15(m,2H),3.78(s,3H),3.34(s,3H),2.66-2.63(m,2H),1.98-1.96(m,2H).
Preparation example 11: preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -1-cyclohexylsulfamide (Compound 18)
1. Preparation of cyclohexylcarbamoyl chloride
To a solution of cyclohexylsulfamic acid (2.0 g,11.2 mmol) in toluene (20 ml) was added phosphorus pentachloride (2.3 g,11.2 mmol) and reacted at 90℃for 4 hours. After the reaction is finished, the temperature is reduced to 25 ℃, and the reaction liquid is dried by spinning to obtain 3.0g of crude product of the target compound, which is directly used for the next reaction.
Preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -1-cyclohexylsulfamide
5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d]Isoxazol-9-amine (100 mg,0.37 mmol) was dissolved in DMA (10 mL) and sodium hydride (60%in oil,44mg,1.1mmol) was added. The reaction was carried out at 25℃for 30 minutes, and cyclohexylcarbamoyl chloride (500 mg, crude product) was added thereto, and the reaction was carried out at 25℃for 1 hour. LCMS detected completion of the reaction, quenched the reaction with water. The mixture was extracted with ethyl acetate. The aqueous phase was retained, ph=3 was adjusted with 3M aqueous hydrochloric acid, extracted again with ethyl acetate, the organic phase was collected, dried by spin-drying, column chromatography (SiO 2 Petroleum ether ethyl acetate=1:1) to yield 80mg of the target compound in 50.1% yield.
Molecular formula C 20 H 25 N 5 O 4 S molecular weight 431.5 LC-MS (M/z): 432.2 (M+H) + )
1 H-NMR(400MHz,DMSO)δ:9.53(s,1H),7.78(s,1H),7.69-7.52(m,1H),7.50(s,1H),6.45(s,1H),6.30(s,1H),5.40(s,2H),4.40-4.29(m,2H),3.23–3.15(m,1H),2.71-2.52(m,2H),2.11-1.95(m,2H),1.79-1.56(m,4H),1.50-1.38(m,2H),1.35-0.92(m,4H).
Preparation example 12: preparation of 1-cyclohexyl-N- (5- (methoxymethyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) sulfamide (Compound 19)
To 5- (methoxymethyl) -3, 4-dihydro-2H-chroman [8,7-d ] at 0deg.C]To a solution of isoxazol-9-amine (100 mg,0.43 mmol) in DMA (3 mL) was added NaH (60%, 200mg,5.0 mmol), reacted at 25℃for 0.5h, cyclohexylsulfamoyl chloride (500 mg crude product) was added, reacted at 25℃for 2h, the reaction solution was diluted with water, EA was extracted (the organic phase was discarded), the pH of the aqueous phase was adjusted to 3-4 with dilute hydrochloric acid, EA was extracted, the organic phase was spin-dried, and the residue was purified by column chromatography (SiO 2 PE: EA=90:10-30:70) to yield 130mg of the title compound in 77.0% yield.
Molecular formula C 18 H 25 N 3 O 5 S molecular weight 395.5 LC-MS (M/z): 396.1 (M+H) + )
1 H-NMR(400MHz,DMSO-d 6 )δ:9.45(s,1H),7.57-7.54(m,1H),7.06(s,1H),4.44(s,2H),4.27-4.23(m,2H),3.33(s,3H),3.21-3.19(m,1H),2.66-2.62(m,2H),2.01-1.96(m,2H),1.95-1.71(m,2H),1.61-1.58(m,2H),1.48-1.44(m,1H),1.21-1.14(m,4H),1.10-1.01(m,1H).
Preparation example 13: preparation of N- (5- (ethoxymethyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -5-fluoro-2-methoxybenzenesulfonamide (Compound 20)
5- (ethoxymethyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine (110 mg,0.44 mmol) was dissolved in 10mL DMA, and 60% NaH (55 mg,1.4 mmol) and 5-fluoro-2-methoxybenzenesulfonyl chloride (230 mg,1.0 mmol) were added at 0deg.C and reacted for 2.0H. After completion of water quenching, ethyl acetate extraction, pH of the aqueous phase was adjusted to 7 with 4M HCl and ethyl acetate extraction was performed, and the residue was concentrated by separation and column chromatography (EA: PE=70%) to give 78mg of the target product in 40.3% yield.
Molecular formula C 20 H 21 FN 2 O 6 S molecular weight 436.5 LC-MS (M/e): 437.2 (M+H) + )
1 H-NMR (400 MHz, DMSO). Delta.10.30 (s, 1H), 7.58-7.51 (m, 2H), 7.26-7.23 (m, 1H), 7.09 (s, 1H), 4.48 (s, 2H), 4..17-4.15 (m, 2H), 3.78 (s, 3H), 3.55-3.50 (m, 2H), 2.66-2.63 (m, 2H), 1.98-1.96 (m, 2H), 1.20-1.15 (m, 3H). Preparation 14: n- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8, 7-d)]Preparation of isoxazol-9-yl) -2, 5-difluorobenzenesulfonamide (compound 21)
5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine (236 mg,1.1 mmol) was dissolved in DMA (10 mL) at 0deg.C, then NaH (118 mg,3.0 mmol) was added, stirred for 1 hour, then 2, 5-difluoro-benzenesulfonyl chloride (200 mg,0.74 mmol) was added dropwise to the above reaction system, stirred for 2 hours, after completion of LC-MS detection, water (50 mL) and ethyl acetate (50 mL. Times.1) were added to extract, the aqueous phase was adjusted to pH 5-6 with 0.5N HCl, ethyl acetate (50 mL. Times.2) was used to extract, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting mixture was added to methanol (5 mL) to slurry, and the yield was 36.3%.
The molecular formula: c (C) 20 H 16 F 2 N 4 O 4 S molecular weight: 446.4 LC-MS (M/e): 447.4 (M+H) + )
1 H-NMR(400MHz,DMSO- d6 )δ:7.87(s,1H),7.78-7.51(m,4H),6.48(s,1H),6.32-6.31(t,J＝1.88Hz,1H),5.41(s,2H),4.13-4.11(t,J＝4.96Hz,2H),2.70-2.67(m,2H),1.98-1.94(m,2H).
Preparation example 15: preparation of N- (5- (1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -5-fluoro-2-methylbenzenesulfonamide (Compound 22)
30℃to 5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d]Isoxazol-9-amine (300 mg)NaH (60%, 222mg,5.6 mmol) was added to a 1.1mmol solution of DMA (10 mL), reacted at 30℃for 0.5h, 5-fluoro-2-toluenesulfonyl chloride (348 mg,1.7 mmol) was added, reacted at 30℃for 2h, the reaction mixture was diluted with water, EA extraction (discarding the organic phase), the pH of the aqueous phase was adjusted to 3-4 with dilute hydrochloric acid (1M), EA extraction was carried out, the organic phase was spin-dried, and the residue was purified by column chromatography (SiO) 2 PE: ea=50:50) to obtain crude target compound, and pulping with EA: meoh=1:1 to obtain 27mg of target compound in 5.5% yield.
Molecular formula C 21 H 19 FN 4 O 4 S molecular weight 442.5 LC-MS (M/z) 443.1 (M+H) + )
1 H-NMR(400MHz,DMSO-d 6 ) Delta 11.1 (s, 1H), 7.78 (s, 1H), 7.78-7.64 (m, 1H), 7.51-7.40 (m, 3H), 6.47 (s, 1H), 6.32-6.20 (m, 1H), 5.41 (s, 2H), 4.19-4.16 (m, 2H), 2.71-2.67 (m, 2H), 2.59 (s, 3H), 2.01-1.94 (m, 2H). Preparation 16: n- (4- ((1H-pyrazol-1-yl) methyl) - [1,3]Dioxolano [4',5':5,6]Benzo [1,2-d]Preparation of isoxazol-8-yl) -2-methoxybenzenesulfonamide (Compound 23)
4- ((1H-pyrazol-1-yl) methyl) - [1,3 was added to the reactor]Dioxolano [4',5':5,6]Benzo [1,2-d]Isoxazol-8-amine (30 mg,0.12 mmol), 2-methoxybenzenesulfonyl chloride (124 mg,0.60 mmol), sodium t-butoxide (115 mg,1.2 mmol) and THF (5 mL), 90 ℃ (tube sealing) were reacted for 14h, the reaction solution was diluted with water, EA was extracted (the organic phase was discarded), the pH of the aqueous phase was adjusted to 3-4 with dilute hydrochloric acid, EA was extracted, the organic phase was dried by spinning, and the residue was purified by column chromatography (SiO 2 PE: EA=60:40) to yield 15mg of the desired product in 30.1% yield.
Molecular formula C 19 H 16 N 4 O 6 S molecular weight 428.4 LC-MS (M/z): 429.1 (M+H) + )
1 H-NMR(400MHz,DMSO-d 6 )δ:11.06(s,1H),7.82(d,J＝2.0,1H),7.73(d,J＝7.8,1H),7.62(t,J＝8.2,1H),7.47(s,1H),7.21(d,J＝8.4,1H),7.05(t,J＝7.6,1H),6.76(s,1H),6.28(s,1H),6.21(s,2H),5.41(s,2H),3.77(s,3H).
Preparation example 17: preparation of N- (5- (1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -5-fluoro-2-ethylbenzenesulfonamide (Compound 24)
Preparation of 1, 5-fluoro-2-ethylbenzenesulfonyl chloride
1-ethyl-4-fluorobenzene (1.24 g,0.01 mol) was placed in a 50ml reaction flask, chlorosulfonic acid (10.0 ml) was added to react for 1.0h at 50℃and cooled to 20-25℃and the reaction solution was slowly added to purified water (30.0 ml) at 0℃to extract methylene chloride (50.0 ml), the methylene chloride phase was concentrated under reduced pressure, and the residue was purified by column chromatography (n-heptane elution) to give 700mg of the objective compound in a yield of 31.5%.
Preparation of N- (5- (1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -5-fluoro-2-ethylbenzenesulfonamide
To a solution of 5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine (100 mg,0.37 mmol) in DMA (10 mL) was added NaH (60%, 80mg,2.0 mmol), reacted at 30℃for 0.5H, 5-fluoro-2-ethylbenzenesulfonyl chloride (700 mg,3.2 mmol) was added, reacted at 30℃for 2H, the reaction solution was diluted with water, EA extraction, the organic phase was dried, and the residue was separated by column chromatography (dichloromethane) to give 16mg of the objective compound in a yield of 9.5%.
Molecular formula C 22 H 21 FN 4 O 4 S molecular weight 456.5. 456.5 LC-MS (M/z): 457.1 (M+H) + )
1 H-NMR(400MHz,CDCl 3 )δ:8.07(s,2H),7.56(s,1H),7.52-7.15(m,2H),7.07-7.02(m,1H),6.59～6.55(m1H),6.32-6.26(m,1H),5.32(s,2H),4.28(m,2H),2.88-2.64(m,2H),2.61-2.36(m,2H),2.07-2.03(m,2H),1.28～1.11(m,3H).
Preparation example 18: preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) -2-fluoro-5-methylbenzenesulfonamide (Compound 25)
5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine (300 mg,1.2 mmol) was dissolved in THF (30 mL) at 0deg.C, followed by addition of sodium tert-amyl alcohol (221 mg,2.3 mmol), stirring for 1 hour, then 2-fluoro-5-methylbenzenesulfonyl chloride (120 mg,0.47 mmol) was added dropwise to the above reaction system, stirring for 10min, then shifting to 60deg.C, stirring for 16H, after completion of LCMS detection, water (50 mL) and ethyl acetate (50 mL. Times.1) were added for extraction, the pH of the aqueous phase was adjusted to 5-6 with 0.5N HCl, ethyl acetate (50 mL. Times.2) was used for extraction, the organic phase was combined, dried over anhydrous sodium sulfate, and the resultant mixture was added to methanol (5 mL) for beating, followed by suction filtration to give a yield of 10.0%.
Molecular formula C 20 H 17 FN 4 O 4 S molecular weight 428.4 LC-MS (M/e): 429.4 (M+H) + )
1 H-NMR(400MHz,DMSO- d6 )δ:7.77-7.70(m,2H),7.55(s,1H),7.39-7.35(m,1H),7.27-7.24(m,1H),6.59(s,1H),6.37(s,1H),5.42(s,2H),4.84-4.75(m,3H),3.11-3.06(m,2H),2.65(s,3H).
Preparation example 19: preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-yl) piperidine-1-sulfonamide (Compound 26)
5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chroman [8,7-d ] isoxazol-9-amine (500 mg,1.8 mmol) was dissolved in tetrahydrofuran (20 mL), piperidine-1-sulfonyl chloride (1.3 g,7.2 mmol) and sodium t-butoxide (719 mg,5.4 mmol) were added, and reacted at 60℃for 6 hours. LCMS detected completion of the reaction, spin-dried the reaction solution, and purified by column chromatography (SiO 2, petroleum ether: ethyl acetate=3:4) to yield 7.78% of the title compound at 60 mg.
Molecular formula C 19 H 23 N 5 O 4 S molecular weight 417.5. 417.5 LC-MS (M/z): 418.1 (M+H) + )
1 H-NMR(400mhz, dmso) delta 9.82 (s, 1H), 7.80 (s, 1H), 7.52 (s, 1H), 6.49 (s, 1H), 6.32 (s, 1H), 5.42 (s, 2H), 4.26 (t, j=4.9 hz, 2H), 3.32-3.12 (m, 4H), 2.79-2.59 (m, 2H), 2.11-1.95 (m, 2H), 1.62-1.35 (m, 6H). Preparation 20: n- (5- ((1H-pyrazol-1-yl) methyl) -6,7,8, 9-tetrahydronaphtho [1,2-d]Preparation of isoxazol-1-yl) -5-fluoro-2-methoxybenzenesulfonamide (Compound 27)
5- ((1H-pyrazol-1-yl) methyl) -6,7,8, 9-tetrahydronaphtho [1,2-d ] isoxazol-1-amine (50 mg,0.19 mmol) was dissolved in 10mL THF, sodium tert-butoxide (45 mg,0.47 mmol) and 5-fluoro-2-methoxybenzenesulfonyl chloride (100 mg,0.45 mmol) were added, the addition was completed, the reaction was completed at 80℃for 8 hours, and 17mg of the objective product was obtained by concentration and column chromatography of the residue (EA: PE=90%), with a yield of 20.0%.
Molecular formula C 22 H 21 FN 4 O 4 S molecular weight 456.5. 456.5 LC-MS (M/e): 457.1 (M+H) + )
1 H-NMR(400MHz,CDCl 3 )δ:7.81-7.71(m,1H),7.61(s,1H),7.56-7.54(m,1H),7.53(s,1H),7.51-7.50(m,1H),7.18-6.95(m,1H),6.62(s,1H),6.33(s,1H),5.35-5.19(m,2H),3.97(s,3H),3.31-3.29(m,2H),2.71-2.68(m,2H),1.91-1.81(m,4H).
Preparation example 21: preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -2, 3-dihydro- [1,4] dioxino [2,3':5,6] benzo [1,2-d ] isoxazol-9-yl) -2, 6-dimethoxybenzenesulfonamide (Compound 29)
Adding 5- ((1H-pyrazol-1-yl) methyl) -2, 3-dihydro- [1,4 to the reactor]Dicyclohexene [2',3':5,6]Benzo [1,2-d]Isoxazol-9-amine (35 mg,0.13 mmol), 2, 6-dimethoxybenzenesulfonyl chloride (91 mg,0.38 mmol), sodium tert-butoxide (37 mg,0.38 mmol) and THF (8 mL) were reacted at 95deg.C (tube sealing) for 48h. After the reaction, 5mL each of DCM and methanol are added into the system, the mixture is filtered under reduced pressure, the filtrate is concentrated and the residue is concentratedThe remainder passes through a silica gel big plate (SiO) 2 PE: EA=2:8) to give 3mg of the target product in a yield of 4.9%.
Molecular formula C 21 H 20 N 4 O 7 S molecular weight 472.5-LC-MS (M/z): 473.0 (M+H) + )
1 H-NMR(400MHz,CDCl 3 )δ:7.57(s,1H),7.50-7.47(m,1H),7.44-7.36(m,1H),6.64-6.60(m,2H),6.49(s,1H),6.32(s,1H),5.39(s,2H),4.49-4.32(m,4H),3.91(s,6H).
Preparation example 22: preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -2, 3-dihydro- [1,4] dioxino [2,3':5,6] benzo [1,2-d ] isoxazol-9-yl) -5-fluoro-2-methoxybenzenesulfonamide (Compound 30)
Adding 5- ((1H-pyrazol-1-yl) methyl) -2, 3-dihydro- [1,4 to the reactor]Dicyclohexene [2',3':5,6]Benzo [1,2-d]Isoxazol-9-amine (30 mg,0.11 mmol), 5-fluoro-2-methoxybenzenesulfonyl chloride (75 mg,0.33 mmol), sodium t-butoxide (32 mg,0.33 mmol) and THF (6 mL) were reacted at 95 ℃ (tube sealing) for 16h. After the reaction, 5mL each of DCM and methanol was added to the reaction system, the mixture was filtered under reduced pressure, the filtrate was concentrated, and the residue was purified by thin layer chromatography (SiO 2 PE: EA=2:8) to yield 7mg of the desired product in 13.8% yield.
Molecular formula C 20 H 17 FN 4 O 6 Molecular weight of S460.4 LC-MS (M/z): 461.0 (M+H) + )
1 H-NMR(400MHz,CDCl 3 )δ:7.90-7.80(m,2H),7.57(s,1H),7.48(s,1H),6.98-6.92(m,1H),6.52(s,1H),6.31(s,1H),5.38(s,2H),4.44-4.32(m,4H),3.93(s,3H).
Preparation example 23: preparation of N- (4- ((1H-pyrazol-1-yl) methyl) - [1,3] dioxolo [4',5':5,6] benzo [1,2-d ] isoxazol-8-yl) -2, 6-dimethoxybenzenesulfonamide (Compound 31)
To 4- ((1H-pyrazol-1-yl) methyl) - [1,3]Dioxolano [4',5':5,6]Benzo [1,2-d]Isoazol-8-amine (40 mg,0.15 mmol) in THF (5 mL) was added 2, 6-dimethoxybenzenesulfonyl chloride (178 mg,0.75 mmol) and sodium tert-butoxide (144 mg,1.5 mmol), reacted for 13h at 90 ℃ (tube sealing), the reaction solution was diluted with water, EA was extracted (organic phase was discarded), the aqueous phase was pH-adjusted to 3-4 with dilute hydrochloric acid, EA was extracted, the organic phase was dried by spinning, and the residue was purified by column chromatography (SiO 2 PE: EA=50:50-30:70) to yield 20mg of product in 28.2% yield.
Molecular formula C 20 H 18 N 4 O 7 S molecular weight 458.4 LC-MS (M/z): 459.0 (M+H) + )
1 H-NMR(400MHz,DMSO-d 6 )δ:10.72(s,1H),7.84(d,J＝2.0,1H),7.54-7.48(m,2H),6.79-6.76(m,3H),6.30-6.28(m,1H),6.22(s,2H),5.42(s,2H),3.76(s,6H).
Preparation example 24: preparation of N- (4- ((1H-pyrazol-1-yl) methyl) - [1,3] dioxolo [4',5':5,6] benzo [1,2-d ] isoxazol-8-yl) -5-fluoro-2-methoxybenzenesulfonamide (Compound 32)
To 4- ((1H-pyrazol-1-yl) methyl) - [1,3]Dioxolano [4',5':5,6]Benzo [1,2-d]Isoazol-8-amine (60 mg,0.23 mmol) in THF (8 mL) was added 5-fluoro-2-methoxybenzenesulfonyl chloride (258 mg,1.1 mmol) and sodium tert-butoxide (221 mg,2.3 mmol), reacted at 90℃for 15h (tube sealing), the reaction mixture was diluted with water, EA was extracted to give organic phase 1, the aqueous phase was pH-adjusted with dilute hydrochloric acid to 3-4, EA was extracted to give organic phase 2, the above two organic phases were combined, and the resultant residue was dried by column chromatography (SiO 2 PE: EA=50:50-30:70) and the crude product was slurried with a mixed solvent of EA and MeOH (EA: meOH=1:1), filtered and the filter cake dried to give 20mg of product in 19.3% yield.
Molecular formula C 19 H 15 FN 4 O 6 S molecular weight 446.4. 446.4 LC-MS (M/z): 447.0 (M+H) + )
1 H-NMR(400MHz,DMSO-d 6 )δ:11.30(s,1H),7.83(d,J＝2.0,1H),7.55-7.48(m,3H),7.27-7.20(m,1H),6.79(s,1H),6.30-6.28(m,1H),6.23(s,2H),5.42(s,2H),3.77(s,3H).
Preparation example 25: preparation of N- (6- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H- [1,4] dioxepin [2',3':5,6] benzo [1,2-d ] isoxazol-10-yl) -2-methoxybenzenesulfonamide (Compound 45)
Adding 6- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H- [1,4 to the reactor]Dioxepin [2',3':5,6]Benzo [1,2-d]Isoxazol-10-amine (50 mg,0.17 mmol), 2-methoxybenzenesulfonyl chloride (176 mg,0.85 mmol), sodium t-butoxide (163 mg,1.7 mmol) and THF (4 mL), 90 ℃ (tube sealing) were reacted for 14h, the reaction solution was diluted with water, EA was extracted (organic phase was discarded), the aqueous phase was pH-adjusted to 3-4 with dilute hydrochloric acid, EA was extracted, the organic phase was dried by spin, and the residue was purified by column chromatography (SiO 2 PE: ea=40:60) to yield 40mg of product in 50.2%.
Molecular formula C 21 H 20 N 4 O 6 S molecular weight 456.5. 456.5 LC-MS (M/z): 457.0 (M+H) + )
1 H-NMR(400MHz,DMSO-d 6 )δ:10.21(s,1H),7.82-7.79(m,2H),7.62(t,J＝7.5,1H),7.48(s,1H),7.22(d,J＝8.4,1H),7.09(t,J＝7.6,1H),6.73(s,1H),6.28(s,1H),5.39(s,2H),4.24-4.21(m,2H),4.06-4.03(m,2H),3.81(s,3H),2.18-2.14(m,2H).
Preparation example 26: preparation of N- (6- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H- [1,4] dioxepino [2',3':5,6] benzo [1,2-d ] isoxazol-10 yl) -2, 6-dimethoxybenzenesulfonamide (Compound 46)
6- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H- [1,4] -dioxepino [2',3':5,6] benzo [1,2-d ] isoxazol-10-amine (90 mg,0.31 mmol) was dissolved in THF (10 mL) at 0℃and then added to NaOtBu (154 mg,1.6 mmol), stirred for 1 hour, then 2-fluoro-5-methylbenzenesulfonyl chloride (372 mg,1.6 mmol) was added dropwise to the above reaction system, stirred for 10 minutes, then stirred for 16 hours at 60℃and extracted with LC-MS after completion of the detection reaction, the aqueous phase was adjusted to pH 5-6 with 0.5NHCl, then ethyl acetate (50 mL. Times.2) was used, the organic phase was combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting mixture was added to methanol (5 mL) and slurried, filtered to obtain 50mg, 32.7%.
Molecular formula C 22 H 22 N 4 O 7 S molecular weight 486.5 LC-MS (M/e): 487.1 (M+H) + )
1 H-NMR(400MHz,DMSO- d6 )δ:9.72(s,1H),7.82-7.80(m,1H),7.55-7.45(m,2H),6.80-6.75(d,J＝8.52Hz,3H),6.71(s,1H),6.30-6.25(m,1H),5.40(s,2H),4.35-4.25(m,2H),4.10-4.05(m,2H),3.78(s,6H),2.20-2.10(m,2H).
Preparation example 27: preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -2, 3-dihydro- [1,4] dioxine [2',3':5,6] benzo [1,2-d ] isoxazol-9-yl) -3-fluoro-2, 6-dimethoxybenzenesulfonamide (Compound 47)
Preparation of 1, 3-fluoro-2, 6-dimethoxy benzenesulfonyl chloride
Di-n-butylmagnesium (1.0M in THF,2.8ml,2.8mmol) was added to the n-butyllithium (2.5M in THF,0.60ml,1.4mmol) solution at 25℃and stirred for 30 minutes. A solution of 1-fluoro-3-iodo-2, 4-dimethoxybenzene (400 mg,1.4 mmol) in THF (2 mL) was added to the mixture after cooling to-25deg.C. After the addition, the temperature is raised to-10 ℃ and stirred for 1 hour. The reaction solution was added to a solution of sulfonyl chloride (756 mg,5.6 mmol) in toluene (5 mL) at-10deg.C and stirring was continued for 20 min. LC-MS showed completion of the reaction, spin-drying the reaction solution, and column chromatography (SiO 2 Petroleum ether ethyl acetate=3:1) to yield 250mg of product with a yield of 70.3%.
Preparation of N- (5- ((1H-pyrazol-1-yl) methyl) -2, 3-dihydro- [1,4] dioxine [2',3':5,6] benzo [1,2-d ] isoxazol-9-yl) -3-fluoro-2, 6-dimethoxybenzenesulfonamide
5- ((1H-pyrazol-1-yl) methyl) -2, 3-dihydro- [1,4]Dioxins [2',3':5,6]Benzo [1,2-d]Isoxazol-9-amine (100 mg,0.37 mmol) was dissolved in tetrahydrofuran (10 mL) and 3-fluoro-2, 6-dimethoxybenzenesulfonyl chloride (188 mg,0.74 mmol) and sodium t-butoxide (107 mg,1.1 mmol) were added. The reaction was carried out at 90℃for 6 hours. LCMS detected completion of the reaction, quenched the reaction with water. The mixture was extracted with ethyl acetate. The aqueous phase was retained, ph=3 was adjusted with 3M aqueous hydrochloric acid, extracted again with ethyl acetate, the organic phase was collected, dried by spin-drying, column chromatography (SiO 2 Petroleum ether ethyl acetate=3:4) to yield 20mg of product in 11.0% yield.
Molecular formula C 21 H 19 FN 4 O 7 S molecular weight 490.5 LC-MS (M/z): 491.1 (M+H) + )
1 H-NMR(400MHz,DMSO)δ:10.43(s,1H),7.81(s,1H),7.58-7.53(m,1H),7.50(s,1H),7.00-6.93(m,1H),6.47(s,1H),6.30(s,1H),5.38(s,2H),4.38-4.30(m,4H),3.81(s,3H),3.77(s,3H).
Preparation example 28: preparation of N- (4- ((1H-pyrazol-1-yl) methyl) - [1,3] dioxol [4',5':5,6] benzo [1,2-d ] isoxazol-8-yl) -3-fluoro-2, 6-dimethoxybenzenesulfonamide (Compound 48)
4- ((1H-pyrazol-1-yl) methyl) - [1,3]Dioxolane [4',5':5,6 ]Benzo [1,2-d]Isoxazol-8-amine (100 mg,0.39 mmol) was dissolved in tetrahydrofuran (10 mL) and 3-fluoro-2, 6-dimethoxybenzenesulfonyl chloride (508 mg,2.0 mmol) and sodium t-butoxide (375 mg,3.9 mmol) were added. The reaction was carried out at 90℃for 6 hours. LCMS detected completion of the reaction, quenched the reaction with water. The mixture was extracted with ethyl acetate. The aqueous phase was retained, ph=3 was adjusted with 3M aqueous hydrochloric acid, extracted again with ethyl acetate, the organic phase was collected, dried by spin-drying, column chromatography (SiO 2 Ethyl acetate) to yield 20mg of product in 11.0% yield.
Molecular formula C 20 H 17 FN 4 O 7 S molecular weight 476.4 LC-MS (M/z): 477.1 (M+H) + )
1 H-NMR(400MHz,DMSO)δ:11.21(s,1H),7.83(s,1H),7.58-7.52(m,1H),7.47(s,1H),7.00-6.93(m,1H),6.76(s,1H),6.28(s,1H),6.22(s,2H),5.41(s,2H),3.76(s,3H),3.74(s,3H).
Preparation example 29: n- (4- ((1H-pyrazol-1-yl) methyl) - [1,3]Dioxolane [4',5':5,6]Benzo [1,2-d]Isoxazol-8-yl-2, 2-d 2 ) Preparation of 2-methoxybenzenesulfonamide (Compound 50)
Weighing 4- ((1H-pyrazol-1-yl) methyl) - [1,3]Dioxolane [4',5':5,6]Benzo [1,2-d]Isoxazole-2, 2-d 2 8-amine (23 mg,0.088 mmol), 2-methoxybenzenesulfonyl chloride (91 mg,0.44 mmol), sodium t-butoxide (42 mg,0.44 mmol) and THF (10 mL), 90 ℃ (tube sealing) were reacted for 3h, the reaction solution was diluted with water, EA was extracted (organic phase was discarded), the aqueous phase was adjusted to pH 3-4 with dilute hydrochloric acid, EA was extracted, the organic phase was dried by spinning, and the residue was purified by column chromatography (SiO 2 PE: ea=60:40) to yield 10mg of product in 26.3% yield.
Molecular formula C 19 H 14 D 2 N 4 O 6 S molecular weight 430.4 LC-MS (M/z): 431.1 (M+H) + )
1 H-NMR(400MHz,CDCl 3 )δ:7.3(s,1H),7.59-7.55(m,3H),7.49(s,1H),7.08-7.04(m,2H),6.67(s,1H),6.30(s,1H),5.38(s,2H),4.02(s,3H).
The following compounds were prepared using the same or similar methods as in the preparation examples above:
2 test of pharmacological Activity of Compounds of the invention
The beneficial effects of the compounds of the present invention are further illustrated below by means of pharmacological test examples, but this should not be understood as the compounds of the present invention having only the following beneficial effects.
Abbreviations used in the following experiments represent the following meanings:
DMSO: dimethyl sulfoxide (Dimethyl sulfoxide)
[ 3 H]-Ac-CoA： 3 H-labelled acetyl-CoA
1 x of which "×": multiple times
BMG：PHERAstar FSX enzyme label instrument
HTRF: homogeneous time resolved fluorescence
Experimental example 1: in vitro enzymatic Activity of the Compounds of the invention
Test article: the compounds synthesized in the examples of the present invention.
Positive control wells: no addition of compounds
Negative control wells: without addition of enzymes
Experimental reagent:
reagent name Suppliers (suppliers) Kit for detecting a substance in a sample
KAT6B ACTIVE MOTIF 81224
KAT6A ACTIVE MOTIF 81223
Experiment consumable:
reagent name Suppliers (suppliers) Kit for detecting a substance in a sample
384 well plate Perkin Elmer SMP410A001PK
The experimental method comprises the following steps:
1. dilution of the Compounds
1) The compounds of the invention were formulated to 10mM using DMSO as assay stock.
2) The stock solution of the compound of the present invention was diluted 3-fold in gradient to 10 concentrations, the highest concentration being 10mM.
3) The diluted compounds of the invention were transferred separately to 384 well plates using Echo550, diluted 1000-fold, with 2 duplicate wells per concentration set and 1% DMSO final concentration.
4) The final concentrations of the test compounds were 10000nM, 3333nM, 1111nM, 370nM, 123nM, 41nM, 14nM, 4.6nM, 1.5nM, 0.51nM.
2. Enzyme reaction experiment
1) Enzyme solutions were prepared in 1 x test buffer. (modified Tris Buffer modified Tris buffer)
2) Preparation [ preparation ] 3 H]Diluting the mixture of Ac-CoA and polypeptide in a 1 Xtest buffer to obtain a substrate solutionAnd (3) liquid.
3) Transfer 10. Mu.L of enzyme solution and 1 Xreaction buffer into 384-well plates. The negative control wells were not added with enzyme, the positive control wells were not added with compound, and other operations were performed simultaneously with the test wells.
4) Incubate for 15 minutes at room temperature.
5) The reaction was started by adding 10. Mu.L of substrate solution per well.
6) KAT6A and KAT6B were incubated at room temperature for 60min and 120min, respectively.
7) A cold Ac-CoA preparation reaction stop solution was added to the 1 Xassay buffer.
8) The reaction was stopped by adding 10. Mu.L of stop solution to each well.
9) mu.L of the stopped liquid was pipetted from each well and transferred from the assay plate to the Flashplate.
10 Incubation for 1h at room temperature.
11 Plate read on Microbeta (liquid scintillation counter).
3. Data analysis
Inhibition (% inh) was calculated using the following formula:
inhibition％＝(Max-Signal)/(Max-Min)*100％
wherein, max represents: signal intensity of positive control wells without compound;
Min represents: signal intensity of negative control wells without enzyme;
signal represents: signal intensity of the test compound;
IC is calculated using the following formula 50 ：
Y＝Bottom+(Top-Bottom)/(1+(IC 50 /X)*HillSlope)
Y is inhibition, X is compound concentration.
4. Experimental results:
TABLE 1 inhibitory Activity of the inventive Compounds against KAT6A/KAT6B
From the above experimental results, it can be seen that the compounds of the present invention are effective in inhibiting the activity of KAT6A and KAT6B, and are effective KAT6A and KAT6B inhibitors.
Experimental example 2: in vitro enzymatic Activity of the Compounds of the invention
Test article: the compounds synthesized in the examples of the present invention.
Positive control drug: PF-9363, its structural formula is shown below:
experimental reagent:
reagent name Suppliers (suppliers) Goods number
KAT6B ACTIVE MOTIF 81224
KAT6A ACTIVE MOTIF 81223
AcCOA SIGMA A2056-25MG
Bio-H3(1-21) GenScript /
Eu-Ab Perkin Elmer TRF0412-M
Ulight-SA Perkin Elmer TRF0102-M
Experiment consumable:
consumable name Suppliers (suppliers) Goods number
384 well plate Greiner 784075
96-well plate Nunc 249944
The experimental method comprises the following steps:
1. experimental procedure
1) The compounds of the invention were formulated to 10mM using DMSO as assay stock.
2) The stock solution of the compound of the invention is diluted 10 times firstly, then diluted 10 times by 4 times of gradient with a 96-well plate, and the highest concentration is 1mM; the positive drug pair was diluted 10-fold in stock solution, then diluted 10-fold in 3-fold gradient with 96-well plate, with the highest concentration being 1mM or 10mM.
3) 50nL of compound was transferred to 384 plates, each compound concentration containing 2 multiplex wells. Plates were assayed by centrifugation 384 at 1000 RPM.
4) The final concentrations of the test compounds were 1000nM, 250nM, 62.5nM, 15.625nM, 3.906nM, 0.977nM, 0.244nM, 0.061nM, 0.015nM, 0.004nM; the final concentration of the cationic drug-pair compound was 1000nM, 333.3nM, 111.1nM, 37.04nM, 12.35nM, 4.12nM, 1.37nM, 0.46nM, 0.15nM, 0.05nM when KAT6A was assayed; for KAT6B detection, the final concentration of the cationic drug-pair compound was 10. Mu.M, 3333nM, 1111nM, 370.4nM, 123.5nM, 41.2nM, 13.7nM, 4.6nM, 1.5nM, and 0.5nM.
5) mu.L of KAT6A or KAT6B was added to each well and incubated at 25℃for 10min.
6) Add 2.5. Mu.L of Bio-H per well 3 &C O A, incubation at 25℃for 90min.
7) mu.L of Eu-Ab & Ulight-SA working solution was added to each assay well, and 384 assay plates were centrifuged at 1000 RPM.
8) Incubate at 25℃for 60 min.
9) The BMG was used to read the HTRF signal 665nm/615nm ratio.
2. Data analysis
Compound inhibition (%) = (negative control signal-compound signal)/(negative control signal-positive control signal) ×100%;
the negative control signal is a signal reading from wells without compound (DMSO);
the positive control signal is the signal reading value of the highest concentration of the positive drug pair;
the compound signal is the signal reading of the test compound.
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*Hillslope))
Y is the ratio of 665nm/615nm, X is the Log value of the compound concentration.
3. Experimental results:
TABLE 2 inhibitory Activity of the inventive Compounds against KAT6A/KAT6B
From the above experimental results, it can be seen that the compounds of the present invention are effective in inhibiting the activity of KAT6A and/or KAT6B, and are effective KAT6A and/or KAT6B inhibitors.
Experimental example 3: in vitro cytological Activity of the Compounds of the invention
Test objects part of the compounds according to the invention are given in the preparation examples for their chemical names and structures.
Reagents and cell lines used in the experiments:
RPMI 1640: roswell Park Memorial Institute (RPMI) 1640 medium;
CTG: cellTiter-Glo cell viability detection kit;
FBS: fetal bovine serum;
cell line ZR-75-1: er+, her 2-human breast cancer cells.
Experimental method (CelltiterGlo assay)
1. Preparation of cells
1.1 cell culture:
ZR-75-1 cells are adherent cells, and the culture solution is RPMI 1640+10% FBS+1% PS.
1.2 preparation of cell suspension:
cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion, ensuring cell viability above 95%. To the appropriate concentration, 100. Mu.L of each cell suspension was added to a 96-well plate.
TABLE 3 cell seeding number
2. Formulation of test compounds
2.1 preparing a stock solution of test compound in DMSO, the stock solution concentration of test compound was 1000X.
2.2 preparation of test Compound working stock solution
Test compounds 1000 x solution, followed by 4-fold serial gradient dilutions using DMSO for a total of 9 concentrations. Then 2. Mu.L of DMSO gradient diluted compound was added to 198. Mu.L of culture medium (RPMI 1640+10% FBS+1% PS) and working stock solution of compound was 20X; 22.5. Mu.L of the compound working stock solution was 20X added to 125.5. Mu.L of the culture solution (RPMI 1640+10% FBS+1% PS) as a test compound working stock solution (compound working stock solution concentration 3 times the final concentration, the highest working stock solution concentration 3. Mu.M).
2.3 Compound treatment
mu.L of working stock solution of the compound (4-fold dilution, final DMSO concentration of 0.1%) was added to each well of a 96-well plate seeded with cells.
The final concentrations of the test compounds were: 1000.00nM,250.00nM,62.50nM,15.63nM,3.91nM,0.976nM,0.244nM,0.061nM,0.015nM.
2.4 control well settings
Solvent control: 0.1% dmso.
Blank control: non-medicated medium, 96 well plate detection reading
2.5 96 well plates were placed at 37℃in 5% CO 2 The cells were cultured in a cell incubator for 18 days.
3. Detection of
The CTG reagent was thawed and the 96-well plate was equilibrated to room temperature for 30 minutes, 60 μl of reagent (Celltiter Glo assay kit) was added to each well, shaken with a shaker for 2 minutes and mixed well (protected from light), and incubated at room temperature for 20 minutes (protected from light). The multifunctional enzyme label instrument reads the optical signal value.
4. Data processing
1) Inhibition (%) = (DMSO solvent control well reading-test substance well reading)/(DMSO solvent control well reading-blank control well reading) ×100%;
2) Plotting to obtain curve and IC 50 。
Experimental results
TABLE 4 in vitro cytological Activity of the Compounds of the invention
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Experimental example 4 in vitro cytological inhibitory Activity of the Compounds of the invention
1. Preparation of cells
1.1 cell culture:
ZR-75-1 cells are adherent cells, and the culture solution is RPMI 1640+10% FBS+1% PS.
1.2 preparation of cell suspension:
cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion, ensuring cell viability above 95%. To the appropriate concentration, 90. Mu.L of the cell suspension was added to each 96-well plate.
TABLE 5 cell seed number
2. Formulation of test compounds
2.1 preparing a stock solution of test compound in DMSO at a concentration of 10mM.
2.2 preparation of test Compound working stock solution
The test compound stock 10mM was diluted 10-fold with DMSO to 1mM, followed by 4-fold serial dilutions of 9 concentrations. Then 2. Mu.L of DMSO gradient diluted compound was added to 198. Mu.L of culture medium (RPMI 1640+10% FBS+1% PS) to give working stock of test compound (working stock concentration of compound 10 times final concentration, highest working stock concentration 10. Mu.M).
2.3 Compound treatment
mu.L of working stock solution of the compound (4-fold gradient dilution, final DMSO concentration of 0.1%) was added to each well of a 96-well plate seeded with cells.
The final concentrations of the test compounds were: 1000.00nM,250.00nM,62.50nM,15.63nM,3.91nM,0.976nM,0.244nM,0.061nM,0.015nM.
2.4 control well settings
Solvent control: 0.1% DMSO (2. Mu.L DMSO was added to 198. Mu.L of culture medium and diluted, and 10. Mu.L was added to the well plate).
Blank control: the medium was not dosed and the readings were measured in 96 well plates.
2.5 96 well plates were placed at 37℃in 5% CO 2 The cells were cultured in a cell incubator for 15 days.
3. Detection of
The CTG reagent was thawed and the 96-well plate was equilibrated to room temperature for 30 minutes, 60 μl of reagent (Celltiter Glo assay kit) was added to each well, shaken with a shaker for 2 minutes and mixed well (protected from light), and incubated at room temperature for 20 minutes (protected from light). The multifunctional enzyme label instrument reads the optical signal value.
4. Data processing
1) Inhibition (%) = (DMSO solvent control well reading-test substance well reading)/(DMSO solvent control well reading-blank control well reading) ×100%;
2) Plotting to obtain curve and IC 50 。
Experimental results
TABLE 6 in vitro cytological Activity of the Compounds of the invention
Conclusion of experiment:
from experimental examples 3 and 4, the compounds of the invention can effectively inhibit proliferation of ZR-75-1 cells, which shows that the compounds of the invention can obviously inhibit proliferation of ER+ and Her 2-breast cancer cells, and have clinical application potential for treating ER+ and Her 2-breast cancer diseases.

Claims (10)

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a deuterated compound thereof or a stereoisomer thereof,
wherein ,
represents a single bond or a double bond; when->X represents a single bond 1 、X 2 Each independently selected from C, CH or N; when->X represents a double bond 1 、X 2 All are C;
X 3 selected from CR 2 Or N;
L 1 selected from-CR 3 R 3’ -、-N(R 4 ) -, -O-, -S-; -C (O) -, -S (O) -or-S (O) 2 -；
L 2 Selected from-CR 5 R 5’ -、-N(R 7 ) -or not present;
ring A and X to which it is attached 1 、X 2 Together form the following optionally substituted with 1 to 4Q 1 groups: 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl;
each Q1 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy, - (CH) 2 ) m -3-10 membered cycloalkyl, - (CH) 2 ) m -3-10 membered heterocycloalkyl, - (CH) 2 ) m -5-to 10-membered heteroaryl or-CH 2 ) m -6-10 membered aryl;
ring B is selected from 3-10 membered cycloalkyl optionally substituted with 1-4Q 2, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl; each Q2 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy or is optionally substituted with 1-2R 6 Substituted as follows: c (C) 1-6 Alkyl, C 1-6 Alkoxy, - (CH) 2 ) m -3-10 membered cycloalkyl, - (CH) 2 ) m -3-10 membered heterocycloalkyl, - (CH) 2 ) m -5-to 10-membered heteroaryl, - (CH) 2 ) m -6-10 membered aryl;
R 1 selected from C optionally substituted with 1-4Q 3 s 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkoxy-C 1-6 Alkyl, - (CH) 2 ) m -3-10 membered cycloalkyl, - (CH) 2 ) m -3-10 membered heterocycloalkyl, - (CH) 2 ) m -5-to 10-membered heteroaryl or- (CH) 2 ) m -6-10 membered aryl; each Q3 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl;
R 2 selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy, - (CH) 2 ) m -3-10 membered cycloalkyl, - (CH) 2 ) m -3-10 membered heterocycloalkyl, - (CH) 2 ) m -5-to 10-membered heteroaryl or- (CH) 2 ) m -6-10 membered aryl;
R 3 、R 3’ 、R 4 、R 5 、R 5’ each R 6 、R 7 Are each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy or cyano C 1-6 An alkoxy group;
each m is independently selected from 0, 1, 2, 3 or 4.
2. The compound of claim 1, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof,
represents a single bond or a double bond; when->X represents a single bond 1 、X 2 Each independently selected from C, CH or N; when->X represents a double bond 1 、X 2 All are C;
X 3 selected from CR 2 Or N;
L 1 selected from-CR 3 R 3’ -、-N(R 4 ) -, -O-or-S-;
L 2 selected from-CR 5 R 5’ -、-N(R 7 ) -or not present;
ring A and X to which it is attached 1 、X 2 Together form the following optionally substituted with 1 to 4Q 1 groups: 5-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 5-8 membered heteroaryl or phenyl;
each Q1 is independently selected from halogen, hydroxyRadicals, amino radicals, nitro radicals, cyano radicals, carboxyl radicals, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy, - (CH) 2 ) m -3-6 membered cycloalkyl, - (CH) 2 ) m -3-6 membered heterocycloalkyl, - (CH) 2 ) m -5-8 membered heteroaryl or- (CH) 2 ) m -phenyl;
ring B is selected from 3-6 membered cycloalkyl optionally substituted with 1-4Q 2, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl or phenyl;
Each Q2 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy or is optionally substituted with 1-2R 6 Substituted as follows: c (C) 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) m -3-6 membered cycloalkyl, - (CH) 2 ) m -3-6 membered heterocycloalkyl, - (CH) 2 ) m -5-8 membered heteroaryl or- (CH) 2 ) m -phenyl;
R 1 selected from C optionally substituted with 1-4Q 3 s 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkoxy-C 1-4 Alkyl, - (CH) 2 ) m -5-8 membered cycloalkyl, - (CH) 2 ) m -5-8 membered heterocycloalkyl, - (CH) 2 ) m -5-8 membered heteroaryl or- (CH) 2 ) m -phenyl; each Q3 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-8 membered heteroaryl or phenyl;
R 2 selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy, - (CH) 2 ) m -3-8 membered cycloalkyl, - (CH) 2 ) m -3-8 membered heterocycloalkyl, - (CH) 2 ) m -5-8 membered heteroaryl or- (CH) 2 ) m -phenyl;
R 3 、R 3’ 、R 4 、R 5 、R 5’ each R 6 、R 7 Are each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy or cyano C 1-4 An alkoxy group;
each m is independently selected from 0, 1, 2, 3 or 4.
3. The compound of claim 1 or 2, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof,
represents a single bond or a double bond; when->X represents a single bond 1 、X 2 Each independently selected from C, CH or N; when->X represents a double bond 1 、X 2 All are C;
X 3 selected from CR 2 Or N;
L 1 selected from-CR 3 R 3’ -、-N(R 4 ) -, -O-or-S-;
L 2 selected from-CR 5 R 5’ -、-N(R 7 ) -or not present;
ring A and X to which it is attached 1 、X 2 Together form the following optionally substituted with 1-2Q 1 groups:
each Q1 is independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, carboxy, hydroxy, amino, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, - (CH) 2 ) m -3-6 membered cycloalkyl, - (CH) 2 ) m -3-6 membered heterocycloalkyl, - (CH) 2 ) m -5-6 membered heteroaryl or- (CH) 2 ) m -phenyl;
ring B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, aziridinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, phenyl, pyridinyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, thiopyranyl, oxazinyl, indazolyl or quinolinyl optionally substituted with 1 to 3Q 2;
each Q2 is independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, carboxyl, or is optionally substituted with 1-2R 6 Substituted as follows: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, propoxy, isopropoxy, - (CH) 2 ) m -cyclopropylRadical, - (CH) 2 ) m -cyclobutyl, - (CH) 2 ) m Cyclopentyl, - (CH) 2 ) m -cyclohexyl, - (CH) 2 ) m -an oxetanyl, - (CH) 2 ) m -oxetanyl, - (CH) 2 ) m Tetrahydrofuranyl, - (CH) 2 ) m Azacyclobutyl, - (CH) 2 ) m Pyrrolidinyl, - (CH) 2 ) m Pyrazolidinyl, - (CH) 2 ) m Piperidinyl, - (CH) 2 ) m Piperazinyl, - (CH) 2 ) m Pyrazinyl, - (CH) 2 ) m Pyrrolyl, - (CH) 2 ) m Pyrazolyl, - (CH) 2 ) m Imidazolyl, - (CH) 2 ) m -pyridinyl, - (CH) 2 ) m Pyrimidinyl, - (CH) 2 ) m Pyridazinyl or- (CH) 2 ) m -phenyl;
R 1 selected from C optionally substituted with 1-3Q 3 s 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxymethyl, C 1-4 Alkoxyethyl, - (CH) 2 ) m Pyrazinyl, - (CH) 2 ) m Pyrrolyl, - (CH) 2 ) m Imidazolyl, - (CH) 2 ) m Pyrazolyl, - (CH) 2 ) m -1,2, 3-triazolyl, - (CH) 2 ) m -1,2, 4-triazolyl, - (CH) 2 ) m -pyridinyl, - (CH) 2 ) m Pyrimidinyl, - (CH) 2 ) m Pyridazinyl, - (CH) 2 ) m Furyl, - (CH) 2 ) m Thienyl, - (CH) 2 ) m -oxazolyl, - (CH) 2 ) m Pyranyl, - (CH) 2 ) m Thiopyranyl or- (CH) 2 ) m -phenyl;
each Q3 is independently selected from fluoro, chloro, bromo, iodo, cyano, carboxy, hydroxy, amino, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl or pyrrolidinyl;
R 2 Selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, carboxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
R 3 、R 3’ 、R 4 、R 5 、R 5’ each R 6 、R 7 Each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each m is independently selected from 0, 1 or 2.
4. The compound of any one of claim 1 to 3, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof,
represents a single bond or a double bond; when->X represents a single bond 1 、X 2 Each independently selected from C, CH or N; when->X represents a double bond 1 、X 2 All are C;
X 3 selected from CR 2 Or N;
L 1 selected from-CH 2 -, -NH-; -O-or-S-;
L 2 selected from-CH 2 -、-N(R 7 ) -or not present;
ring A and X to which it is attached 1 、X 2 Together form the following optionally substituted with 1-2Q 1 groups:
each Q1 is independently selected from fluorine, chlorine, bromine, iodine, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indazolyl or quinolinyl optionally substituted with 1-3Q 2;
each Q2 is independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, carboxyl, or is optionally substituted with 1-2R 6 Substituted as follows: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, propoxy, isopropoxy;
R 1 Selected from C optionally substituted with 1-3Q 3 s 1-4 Alkoxy, C 1-4 Alkoxymethyl, C 1-4 Alkoxyethyl, - (CH) 2 ) m Pyrrolyl, - (CH) 2 ) m Imidazolyl, - (CH) 2 ) m Pyrazolyl, - (CH) 2 ) m -1,2, 3-triazolyl or- (CH) 2 ) m -1,2, 4-triazolyl;
each Q3 is independently selected from fluorine, chlorine, bromine, iodine, cyano, carboxyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, or pyrrolidinyl;
R 2 selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, carboxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
each R 6 、R 7 Each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
Each m is independently selected from 0, 1 or 2.
5. The compound of any one of claim 1 to 4, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof, having a structure according to formula (II-1),
wherein t is selected from 0, 1 or 2;
ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indazolyl or quinolinyl optionally substituted with 1-3Q 2;
each Q2 is independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, carboxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
X 1 、X 2 、L 2 ring A, Q, Q3, R 2 、R 7 、m、The method of any one of claims 1-4.
6. The compound of any one of claim 1 to 5, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof, having a structure according to formula (III) or formula (III-1),
Wherein s is selected from 0, 1, 2 or 3; t is selected from 0, 1 or 2;
X 1 、X 2 、L 2 ring A, Q, Q2, Q3, R 2 、R 6 、R 7 、m、The method of any one of claims 1-5.
7. The compound of claim 1, a pharmaceutically acceptable salt thereof, a deuterate thereof, or a stereoisomer thereof selected from the group consisting of:
8. a pharmaceutical formulation comprising a compound as defined in any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof, wherein the pharmaceutical formulation comprises one or more pharmaceutically acceptable excipients and is in any pharmaceutically acceptable dosage form.
9. A pharmaceutical composition comprising a compound of any one of claims 1-7, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof, comprising one or more second therapeutically active agents selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal agents, angiogenesis inhibitors, cytostatic agents, targeting antibodies, cytotoxins, antihormins, antiandrogens, HMG-CoA reductase inhibitors, and prenyl protein transferase inhibitors.
10. The compound of any one of claims 1-7, a pharmaceutically acceptable salt thereof, a deuterated or stereoisomers thereof, a pharmaceutical formulation of claim 8, or a pharmaceutical formulation of claim 9Use of a pharmaceutical composition in the manufacture of a medicament for the treatment and/or prophylaxis of diseases and conditions mediated by KAT6 selected from the group consisting of lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, thyroid cancer, female genital tract cancer, lymphoma, neurofibromas, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumors, mast cell tumors, multiple myeloma, melanoma, leukemia, glioma or sarcoma; preferably, the lung cancer is selected from small cell lung cancer and non-small cell lung cancer; the breast cancer is ER + Breast cancer or ER + /HER2 - Breast cancer.
CN202310130950.5A 2022-02-18 2023-02-17 Tri-fused ring KAT6 inhibitors Pending CN116621859A (en)

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CN202210150313X 2022-02-18
CN202210150313 2022-02-18
CN2022105764891 2022-05-25
CN202210576489 2022-05-25
CN202211087818 2022-09-07
CN2022110878182 2022-09-07

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