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CN115594680A - TEAD inhibitor - Google Patents

TEAD inhibitor Download PDF

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Publication number
CN115594680A
CN115594680A CN202210804201.1A CN202210804201A CN115594680A CN 115594680 A CN115594680 A CN 115594680A CN 202210804201 A CN202210804201 A CN 202210804201A CN 115594680 A CN115594680 A CN 115594680A
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ring
methyl
group
compound
membered
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张学军
常少华
李学强
叶大炳
胡文兵
孙红娜
张辛
李莉娥
杨俊�
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Humanwell Healthcare Group Co ltd
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Humanwell Healthcare Group Co ltd
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Abstract

The invention provides a compound shown as a formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:
Figure DDA0003735878700000011
the definition of each group in formula I is as described in the invention; the compounds are useful as TEAD inhibitors for the prevention and/or treatment of diseases associated with increased TEAD expression, such as cell proliferative disorders.

Description

TEAD inhibitor
The present invention claims priority from a prior application entitled "a TEAD inhibitor" filed on 7.7.7.2021 by the intellectual property office of china, patent application No. 202110767020.1. The entire contents of this prior application are incorporated herein by reference.
Technical Field
The invention belongs to the field of medicines, and particularly relates to a TEAD inhibitor, and a preparation method and application thereof.
Background
The Hippo signal pathway is a highly conserved signal pathway composed of a series of kinase cascades and participates in the regulation of physiological processes such as cell proliferation, cell differentiation, cell dryness, extracellular matrix deposition, injury repair, organ development and the like. Activation of the Hippo signaling pathway by upstream GPCR, mechanical stress, etc., signals causes NF2 (neurofibrillatory type 2, neurofibrillary 2) to activate MST1/2 (mammarian stereo 20-like kinase 1/2), MST1/2 to activate LAST1/2 (large tumor promoter kinase 1/2), activated LATS1/2 to phosphorylate YAP (Yes Associated Protein)/TAZ (Transcriptional activator with PDZ binding motif), phosphorylated YAP/TAZ to localize in the cytoplasm and degrade in a ubiquitin-dependent manner, the non-phosphorylated YAP/TAZ is transferred to the nucleus and combined with several nuclear transcription factors including TEADs to form a transcription complex, and induces the expression of several downstream target genes including CTGF (Connective tissue growth factor), cyr61 (cysteine rich angiogenesis inducer 61) and AXL (receptor tyrosine kinase AXL), thereby promoting the physiological and pathological processes of the body.
TEADs (Transcriptional Enhanced Association Domains) are the final effectors of the Hippo signaling pathway and have four family members, TEAD1, TEAD2, TEAD3 and TEAD4, respectively, all TEADs subtypes have a DNA-binding TEA domain at the N-terminus and a YAP/TAZ-binding domain at the C-terminus, the DNA-binding and YAP/TAZ-binding Domains are highly conserved in mammals but differ greatly in the linker connecting the TEA domain and the transactivation domain, and the overall homology of the four TEADs subtypes is between 61% and 73%. The function of TEADs is mediated by its interaction with nuclear co-activators, YAP being the major nuclear co-activator of TEADs interaction.
YAP/TAZ-TEADs are activated to promote tumor development, and inhibition of YAP/TAZ interaction with TEADs has the potential to treat tumors. In some cancers, such as malignant mesothelioma, ovarian cancer, and cholangiocarcinoma, the YAP/TAZ-TEADs complex is often over-activated or overexpressed, leading to cancer progression. This overactivation is usually caused by alterations of genes upstream of the Hippo signaling pathway, especially in malignant mesothelioma patients, 40-50% of tumor NF2 mutations or deletions, <25% of tumor MST1 or LAST1/2 mutations or deletions, 70% of YAP high expression, and overactivation of the YAP/TAZ-TEADs complex helps to promote tumor cell proliferation, metastasis, epithelial-to-mesenchymal transition (EMT) and maintenance of tumor stem cells. The interaction of YAP and TEADs is crucial for initiating the transcription process to drive tumorigenesis and proliferation, and DNA binding domain deficient TEADs are able to block tumor formation mediated by mutations in genes upstream of the Hippo signaling pathway, suggesting that inhibition of YAP/TAZ interaction with TEADs has an anti-tumor effect. The Invenva Pharma patent shows that the inhibition of YAP/TAZ interaction with TEADs can obviously inhibit the proliferation of tumor cells (WO 2017064277). Other researches also show that the downstream proteins CTGF and CYR61 of YAP/TAZ-TEADS can induce tumor cells to generate drug resistance to paclitaxel and other therapeutic drugs, and the YAP/TAZ-TEADS becomes an alternative survival path of drug-resistant cancer cells. These all indicate that inhibition of YAP/TAZ interaction with TEADs has potential for the treatment of tumours, particularly tumours which are overactivated or mutated upstream of the Hippo signalling pathway.
Some YAP/TAZ interaction inhibitors with TEADs (VT-01, IK-930) have now entered clinical stage, and YAP/TAZ interaction inhibition with TEADs may be a promising new anti-tumor chemotherapeutic.
Disclosure of Invention
The invention provides a compound for a TEAD inhibitor, which can obviously inhibit the activity of TEADs transcription as the TEAD inhibitor and can be used for preventing and/or treating diseases related to the increase of TEAD expression.
In a first aspect of the present invention, there is provided a compound of formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof:
Figure BDA0003735878680000021
wherein W represents CH or N;
R 1 is hydrogen or a substituent selected from:
Figure BDA0003735878680000022
R 11 、R 12 、R 13 each independently hydrogen or a substituent selected from: c 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl, 4-6 membered heterocycloalkyl;
R 2 is hydrogen or a substituent selected from:
Figure BDA0003735878680000023
halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl;
V 1 、V 2 、V 3 、V 4 each independently represents C, CH or a heteroatom;
the heteroatom is selected from N, O or S;
and V is 1 、V 2 、V 3 、V 4 Containing 1,2 or 3 of said heteroatoms; when the number of heteroatoms is 2 or 3, the heteroatoms are the same or different;
l is O, -NH-Z-or-CH 2 -Z-；
Z is absent or C 1 -C 3 An alkylene group;
said L is optionally substituted by C 1 -C 3 Alkyl substitution;
ring A is a benzene ring, a 5-6 membered heteroaromatic ring or a 3-8 membered cycloalkyl group;
ring B is a 4-8 membered ring;
ring AOptionally substituted by one or more R 3 Substitution; when the substituent R is 3 When there are plural, R is 3 The same or different;
said R is 3 Selected from: halogen, C 1 -C 6 Alkyl, 3-6 membered cycloalkyl, C 1 -C 6 Alkoxy, -SF 5 、-CF 2 -O-R 31 ；
R 31 Is C 1 -C 6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
said R is 3 C in 1 -C 6 Alkyl, 3-6 membered cycloalkyl, C 1 -C 6 Alkoxy radical, R 31 Optionally substituted with a substituent selected from the group consisting of: halogen, hydroxy, amino, C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy radical, C 3 -C 6 A cycloalkyloxy group;
said ring B is optionally substituted by one or more R 4 Substitution; when the substituent R is 4 When there are plural, R is 4 The same or different;
R 4 selected from the group consisting of: halogen, hydroxy, oxo
Figure BDA0003735878680000024
C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, 3-6 membered cycloalkyl, -NH-C (O) -R 41 、-C(O)-NH-R 42 ；
R 41 、R 42 Each independently is C 1 -C 6 Alkyl radical, C 1 -C 6 An alkoxy group;
said R is 4 C in 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, 3-6 membered cycloalkyl, R 41 、R 42 Optionally substituted with a substituent selected from: halogen, hydroxy, C 1 -C 3 An alkoxy group.
In a preferred embodiment of the invention, W represents C or N;
R 1 is hydrogen or a substituent selected from:
Figure BDA0003735878680000031
R 11 、R 12 each independently hydrogen or a substituent selected from: c 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl, 4-6 membered heterocycloalkyl;
R 2 is hydrogen or a substituent selected from:
Figure BDA0003735878680000032
halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl;
V 1 、V 2 、V 3 、V 4 each independently represents C or a heteroatom;
the heteroatom is selected from N, O or S;
and V is 1 、V 2 、V 3 、V 4 Containing 1,2 or 3 of said heteroatoms; when the number of heteroatoms is 2 or 3, the heteroatoms are the same or different;
l is-NH-Z-or-CH 2 -Z-；
Z is absent or C 1 -C 3 An alkylene group;
said L is optionally substituted by C 1 -C 3 Alkyl substitution;
ring A is a benzene ring or a 5-6 membered heteroaromatic ring;
ring B is a 4-8 membered ring;
ring A is optionally substituted with one or more R 3 Substitution; when the substituent R 3 When there are plural, R is 3 The same or different;
the R is 3 Selected from: halogen, C 1 -C 6 Alkyl, 3-6 membered cycloalkyl, C 1 -C 6 Alkoxy, -SF 5 、-CF 2 -O-R 31 ；
R 31 Is C 1 -C 6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
the R is 3 C in 1 -C 6 Alkyl, 3-6 membered cycloalkyl, C 1 -C 6 Alkoxy radical, R 31 Optionally substituted with a substituent selected from: halogen, hydroxy, amino, C 1 -C 3 Alkyl radical, C 1 -C 3 An alkoxy group;
said ring B is optionally substituted by one or more R 4 Substitution; when the substituent R is 4 When there are plural, R is 4 The same or different;
R 4 selected from: halogen, hydroxy, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, 3-6 membered cycloalkyl, -NH-C (O) -R 41 、-C(O)-NH-R 42 ；
R 41 、R 42 Each independently is C 1 -C 6 Alkyl radical, C 1 -C 6 An alkoxy group;
the R is 4 C in 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, 3-to 6-membered cycloalkyl, R 41 、R 42 Optionally substituted with a substituent selected from the group consisting of: halogen, hydroxy, C 1 -C 3 An alkoxy group.
In a preferred embodiment of the invention, the group
Figure BDA0003735878680000033
Has a structure
Figure BDA0003735878680000034
In a preferred embodiment of the invention, in the group
Figure BDA0003735878680000035
In the formula, the ring B is a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring; preferably, ring B is a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring.
In a preferred embodiment of the present invention, ring B is selected from the group consisting of a tetrahydropyrrole ring, a morpholine ring, a cyclopentane ring, a piperazine ring, a piperidine ring, an oxazolidine ring, a 2-azabicyclo [3.1.0] hexane ring.
In a preferred embodiment of the invention, the group
Figure BDA0003735878680000036
Has a structure
Figure BDA0003735878680000037
Wherein M represents an N, O, S atom or group
Figure BDA0003735878680000041
In a preferred embodiment of the invention, 1) the radical
Figure BDA0003735878680000042
Has a structure
Figure BDA0003735878680000043
Figure BDA0003735878680000044
Wherein Y is 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 Each independently selected from CH and CH 2 N, O, S atoms;
and Y is 1 、Y 2 、Y 3 At most one of them is not CH, CH 2 ；
And Y is 4 、Y 5 、Y 6 、Y 7 At most one of them is not CH, CH 2 ；
Or,
2) Radical (I)
Figure BDA0003735878680000045
Has a structure
Figure BDA0003735878680000046
Wherein Q 1 、Q 2 、Q 3 、Q 4 、Q 5 Each independently selected from CH and CH 2 Or group
Figure BDA0003735878680000047
And Q 1 、Q 2 In which at most one is not CH, CH 2 ；
And Q 3 、Q 4 、Q 5 In which at most one is not CH, CH 2 ；
Preferably, the group
Figure BDA0003735878680000048
Selected from the group consisting of:
Figure BDA0003735878680000049
wherein;
m' represents CH, CH 2 N, O or S.
In a preferred embodiment of the present invention, V 1 、V 2 、V 3 、V 4 Each independently represents C, CH or a heteroatom selected from N, O, S; and V is 1 、V 2 、V 3 、V 4 Contains at least one N atom; preferably, V 1 、V 2 、V 3 、V 4 Containing 2 heteroatoms.
In a preferred embodiment of the present invention, when V 1 When is N, V 2 Is C, V 3 Is N, V 4 Is CH;
when V is 1 When is N, V 2 Is N, V 3 Is C, V 4 Is CH;
when V is 1 When is N, V 2 Is C, V 3 Is C, V 4 Is O or S;
when V is 1 When is CH, V 2 Is N, V 3 Is C, V 4 Is N.
In a preferred embodiment of the present invention,
Figure BDA00037358786800000410
selected from the group consisting of:
Figure BDA00037358786800000411
Figure BDA00037358786800000412
Figure BDA0003735878680000051
in a preferred embodiment of the invention, the formula I has structure Ia:
Figure BDA0003735878680000052
in a preferred embodiment of the invention, the group
Figure BDA0003735878680000053
Has a structure
Figure BDA0003735878680000054
Preferably, the group
Figure BDA0003735878680000055
Is composed of
Figure BDA0003735878680000056
In a preferred embodiment of the invention, in the group
Figure BDA0003735878680000057
In the formula (I), the ring B is a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring; preferably, ring B is a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring.
In a preferred embodiment of the invention, the group
Figure BDA0003735878680000058
Has a structure
Figure BDA0003735878680000059
Wherein M represents an N, O, S atom or group
Figure BDA00037358786800000510
In a preferred embodiment of the invention, L is-NH-or-CH 2 -; the-NH-or-CH 2 -optionally with C 1 -C 3 Alkyl substitution; preferably, L is-NH-.
In a preferred embodiment of the present invention, ring A is a benzene ring, a 5-6 membered N containing heteroaromatic ring or a 5-8 membered cycloalkyl group; preferably, the first and second air flow paths are arranged in parallel, ring A is benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, pyrazole, imidazole, triazole, cyclohexane,
Figure BDA0003735878680000061
Figure BDA0003735878680000062
More preferably, ring a is a benzene ring, pyridine or pyrimidine.
In a preferred embodiment of the invention, R 1 Is hydrogen,
Figure BDA0003735878680000063
R 11 、R 12 、R 13 Each independently hydrogen or a substituent selected from: c 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 1 -C 6 A haloalkyl group;
preferably, R 11 、R 12 Each independently hydrogen, methyl, ethyl, propyl;
more preferably, R 11 Is hydrogen, R 12 Is a methyl group. Or, more preferably, R 13 Is a vinyl group.
In a preferred embodiment of the invention, R 2 Is hydrogen or a substituent selected from: c 1 -C 6 Alkyl radical, C 1 -C 6 A haloalkyl group.
In a preferred embodiment of the invention, the group
Figure BDA0003735878680000064
Has a structure
Figure BDA0003735878680000065
Wherein Z is 1 、Z 2 、Z 3 、Z 4 、Z 5 Each is independently selected from CH or N; and Z is 1 、Z 2 、Z 3 、Z 4 、Z 5 There are at most two N in.
In a preferred embodiment of the invention, ring A is optionally substituted with 1 or 2R 3 Substitution; when the substituent R is 3 When there are 2, the R 3 The same or different;
said R is 3 Selected from: c 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, -SF 5 、-CF 2 -O-R 31 (ii) a Wherein R is 31 Is C 1 -C 6 Alkyl, 3-6 membered cycloalkyl;
said R is 3 C in 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, R 31 Optionally substituted with a substituent selected from the group consisting of: halogen, hydroxy, C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy radical, C 3 -C 6 A cycloalkyloxy group.
In a preferred embodiment of the present invention, R is 3 Selected from the group consisting of: -CF 3 、-OCF 3 、-SF 5 、
Figure BDA0003735878680000066
Figure BDA0003735878680000067
In a preferred embodiment of the invention, said ring B is optionally substituted by 1 or 2R 4 Substitution; when the substituent R is 4 When there are 2, the R 4 The same or different;
the R is 4 Is a substituent selected from the group consisting of: fluorine, chlorine, hydroxy, oxo
Figure BDA0003735878680000068
C 1 -C 6 Alkyl, -NH-C (O) -R 41 、-C(O)-NH-R 42 ；R 41 、R 42 Each independently of each otherIndependently is C 1 -C 6 Alkyl radical, C 1 -C 6 An alkoxy group;
said R is 4 C in 1 -C 6 Alkyl radical, R 41 、R 42 Optionally substituted with a substituent selected from: fluorine, chlorine, hydroxy, C 1 -C 3 An alkoxy group;
preferably, R 4 Is a substituent selected from the group consisting of: fluorine, chlorine, hydroxy, oxo
Figure BDA0003735878680000069
Methyl, ethyl, propyl, -NH-C (O) -R 41 、-C(O)-NH-R 42 (ii) a Wherein R is 41 、R 42 Each independently selected from: methyl, ethyl, propyl, methoxy, ethoxy, propoxy.
Preferably, R 4 Is a substituent selected from the group consisting of: CH (CH) 3 F, OH, oxo
Figure BDA00037358786800000610
-CHF 2 、CF 3 、
Figure BDA00037358786800000611
Figure BDA00037358786800000612
In a preferred embodiment of the present invention, the compound of formula I comprises:
Figure BDA0003735878680000071
Figure BDA0003735878680000081
Figure BDA0003735878680000091
Figure BDA0003735878680000101
in a second aspect of the present invention, there is provided a process for preparing a compound of formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof, according to the first aspect of the present invention, comprising:
1) Reacting the intermediate B-1 with the intermediate B-2 under the condition of a palladium catalyst to obtain a compound shown in a formula I;
Figure BDA0003735878680000102
2) The intermediate B-3 and the intermediate B-4 react to obtain a compound shown in a formula I;
Figure BDA0003735878680000111
wherein,
g is a boronic acid or boronic ester group;
x is halogen;
ring A is optionally substituted with one or more R 3 Substitution; when the substituent R is 3 When there are plural, R is 3 The same or different;
ring B is optionally substituted with one or more R 4 Substitution; when the substituent R 4 When there are plural, R is 4 The same or different;
w, L, ring A, ring B, R 1 、R 2 、R 3 、R 4 Is as defined in the first aspect of the invention.
In a preferred embodiment of the invention, the process is carried out in an inert solvent.
The inert solvents include, but are not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.
The compounds provided herein, including intermediates useful in the preparation of the compounds provided herein, contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and include protected derivatives thereof. "protected derivatives" are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as protecting groups). Suitable protecting groups for the carboxyl moiety include benzyl, t-butyl, and the like, as well as isotopes and the like. Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable hydroxy protecting groups include benzyl and the like.
In a third aspect of the invention, there is provided a pharmaceutical composition comprising: a compound of formula I as described in the first aspect of the invention, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof; and a pharmaceutically acceptable carrier.
In a fourth aspect of the present invention, there is provided a use of a compound of formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof, as described in the first aspect of the present invention, or a use of a pharmaceutical composition as described in the third aspect, the use comprising:
preparing a medicament, pharmaceutical composition or formulation for the prevention and/or treatment of a disease associated with increased TEAD expression; and/or the presence of a gas in the gas,
preparing a medicament, pharmaceutical composition or formulation for reducing/inhibiting TEAD expression, increased TEAD activity; and/or the presence of a gas in the gas,
preparing a medicament, a pharmaceutical composition or a preparation for reducing/inhibiting the Hippo signalling pathway.
In a preferred embodiment of the present invention, the TEAD comprises: TEAD1, TEAD2, TEAD3, and TEAD4.
In a preferred embodiment of the invention, the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.
The present invention also provides a method of treating a disease comprising administering to a patient a therapeutically effective amount of at least one compound of formula (I), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, a prodrug, or a pharmaceutical composition thereof.
In a preferred embodiment of the invention, the disease is a disease associated with increased expression of TEAD.
In a preferred embodiment of the invention, the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.
In a preferred embodiment of the invention, the patient is a mammal, preferably a human.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Advantageous effects
The present inventors have conducted extensive and intensive studies and have unexpectedly developed a compound represented by formula I, which is useful as a TEAD inhibitor. The compound can obviously inhibit the activity of TEADs transcription as a TEAD inhibitor, can obviously inhibit the proliferation of NCI-H226 (ATCC, cat # CRL 5826), has obvious effect of inhibiting the growth of NCI-H226 mesothelioma, shows excellent pharmacokinetic property and has good drug success rate.
The TEAD inhibitor can be used for preparing a medicament, a pharmaceutical composition or a preparation for preventing and/or treating diseases related to the increase of the TEAD expression; and/or, for the manufacture of a medicament, pharmaceutical composition or formulation for reducing/inhibiting TEAD expression, increased TEAD activity; and/or, for the manufacture of a medicament, pharmaceutical composition or formulation for reducing/inhibiting the Hippo signalling pathway. Wherein the TEAD comprises: TEAD1, TEAD2, TEAD3, and TEAD4; the disease is preferably a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.
Definition and description of terms
Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present specification.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definition in this section controls.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," "including," and other forms, such as "includes," "including," and "containing," are not limiting.
Definitions for the terms of the standardization can be found in the references including Carey and Sundberg "ADVANCED ORGANIC chemistry 4. Thed." vols. A (2000) and B (2001), plenum Press, new York). Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods. Unless a specific definition is set forth, the terms used herein in the pertinent description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using instructions from the manufacturer for use of the kit, or in a manner known in the art or as described herein. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.
When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, CH 2 O is equal to OCH 2 . As used herein, the term "a" or "an" refers to,
Figure BDA0003735878680000121
or
Figure BDA0003735878680000122
Indicates the attachment site of the group. As used herein, "R" refers to a group of atoms 1 "," R1 "and" R 1 "have the same meaning and are interchangeable. For R 2 And the like, and like definitions are intended to be the same.
As used herein, in chemical structure
Figure BDA0003735878680000131
Denotes an unsaturated or partially saturated ring, e.g. aromatic, which includes carbocyclic or heterocyclic rings. For example, in
Figure BDA0003735878680000132
Can be represented as a benzene ring, and,
Figure BDA0003735878680000133
can be represented as a pyridine, and can be represented as,
Figure BDA0003735878680000134
can be expressed as
Figure BDA0003735878680000135
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
In addition to the foregoing, the following terms, when used in the specification and claims of this application, have the meanings indicated below, unless otherwise specifically indicated.
As used herein, the term "halogen", alone or as part of another substituent, refers to fluorine, chlorine, bromine, iodine.
As used herein, the term "amino", alone or as part of another substituent, means-NH 2 。
As used herein, the term "hydroxy", alone or as part of another substituent, denotes — OH.
As used herein, the term "alkyl", alone or as part of another substituent, means a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, free of unsaturation, having, for example, from 1to 6 carbon atoms, and attached to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. An alkyl group may be unsubstituted or substituted with one or more suitable substituents. The alkyl group may also be an isotopic isomer of the naturally abundant alkyl group enriched in carbon and/or hydrogen isotopes (i.e., deuterium or tritium). As used herein, the term "alkenyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched, monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.
The term "C" alone or as part of another substituent 1 -C 6 Alkyl "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1,2,3, 4,5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropylPropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl or 1, 2-dimethylbutyl, and the like, or isomers thereof. In particular, the radicals have 1,2 or 3 carbon atoms ("C) 1 -C 3 Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.
The term "C" alone or as part of another substituent 1 -C 6 Alkoxy "is understood to mean a straight-chain or branched, saturated monovalent hydrocarbon radical having 1,2,3, 4,5 or 6 carbon atoms and an oxygen atom, or C 1 -C 6 alkyl-O-C 1 -C 6 The alkyl group is as defined in the specification, and the oxygen atom may be bonded to C 1 -C 6 Alkyl groups are linear or on any of the carbon atoms of the linear chain. Including but not limited to: methoxy (CH) 3 -O-), ethoxy (C) 2 H 5 -O-), propoxy (C) 3 H 7 -O-), butoxy (C) 4 H 9 -O-)。
The term "cycloalkyl", "carbocyclyl" or "alkane ring", alone or as part of another substituent, refers to a cyclic alkyl group. The term "m-n membered cycloalkyl" or "C m -C n Cycloalkyl "is understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms. For example, "3-8 membered cycloalkyl" refers to a cyclic alkyl group containing 3 to 8 carbon atoms, which may contain 1to 2 rings. The cyclic alkyl group includes a monocyclic ring, a bicyclic ring, a spiro ring, or a bridged ring. Examples of unsubstituted cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The cycloalkyl group may be substituted with one or more substituents.
The term "heterocycle" or "heterocycloalkyl" or "heterocyclyl", alone or as part of another substituent, refers to a cyclic hydrocarbon group (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl) in which one or more (in some embodiments, 1-3) carbon atoms are replaced with a heteroatom, such as, but not limited to, N, O, S, and P. The term "m-n membered heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms. For example, the term "4-6 membered heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having from 4 to 6 atoms. In some embodiments, the heterocycloalkyl group can be a heterocycloalkyl group fused to an aryl or heteroaryl group. When a prefix, such as 4-6 membered, is used to denote heterocycloalkyl, the number of carbons is also meant to include heteroatoms. Non-limiting examples of heterocycles include, but are not limited to, dihydropyridazine, dihydropyrazine, including substituted forms thereof, such as heterocyclyl including, but not limited to, 6-oxo-1, 6-dihydropyridazin-3-yl, 4-methyl-5-oxo-4, 5-dihydropyrazin-2-yl, and the like.
The term "heteroaryl/heteroaryl ring", alone or as part of another substituent, refers to a heteroaromatic system comprising 1to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5-or 6-membered. Non-limiting examples of heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and the like, and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and/or phenoxazinyl and the like.
The term "halo", alone or as part of another substituent, is used interchangeably with the term "halogen substituted". "haloalkyl" or "halogen-substituted alkyl" is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl.
The term "5-6 membered heteroaromatic ring" alone or as part of another substituent is to be understood as an aromatic ring group having 5 or 6 ring atoms and comprising 1-3 heteroatoms independently selected from N, O and S. The term "5-6 membered heteroaromatic ring" is understood to mean an aromatic ring radical having 5 or 6 ring atoms-and which contains 1-3 heteroatoms independently selected from N, O and S. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl.
In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.
In the present application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
"pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids which retain the biological effectiveness of the free base without other side effects. "pharmaceutically acceptable base addition salts" refers to salts with inorganic or organic bases which maintain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are also contemplated by the present invention. They may serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the invention.
The term "stereoisomer" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformers.
Depending on the choice of starting materials and processes, the compounds according to the invention may be present in the form of one of the possible isomers or of a mixture thereof, for example as pure optical isomers, or as isomer mixtures, for example as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (-) are the symbols used to specify the rotation of plane polarized light by a compound, where (-) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.
When the bond to a chiral carbon in the formula of the invention is depicted as a direct line, it is to be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are encompassed within the formula. The illustrations of racemic or enantiomerically pure compounds herein are from Maehr, j.chem.ed.1985, 62. The absolute configuration of a stereocenter is represented by wedge bonds and dashed bonds.
The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; whereas in phenol the enol type predominates. The present invention encompasses all tautomeric forms of the compounds.
In the present application, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of active ingredients and exert biological activity.
As used herein, a "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that is approved by the relevant governmental regulatory agency for human or livestock use.
In this application, the term "solvate" means that the compound of the invention or salt thereof includes stoichiometric or non-stoichiometric amounts of solvent bound by non-covalent intermolecular forces, and when the solvent is water, it is a hydrate.
In the present application, the term "prodrug" refers to a compound of the invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds, which modifications may be routinely made or removed in vivo to give the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy or amino group is attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy or a free amino group, respectively.
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioisotopes, such as deuterium (g) ((R)) 2 H) Tritium (A) 3 H) Iodine-125 (I) 125 I) Or C-14 ( 14 C) .1. The All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
In the present application, the term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of classes of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients enhance the handling characteristics of the pharmaceutical formulation, i.e., make the formulation more amenable to direct compression by increasing flowability and/or cohesiveness.
The term "treatment" and other similar synonyms as used herein include the following meanings:
(i) Preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is predisposed to the disease or condition but has not yet been diagnosed as having the disease or condition;
(ii) Inhibiting the disease or disorder, i.e., arresting its development;
(iii) Alleviating the disease or condition, i.e., causing the state of the disease or condition to resolve; or
(iv) Alleviating the symptoms caused by the disease or disorder.
Drawings
FIG. 1 is a graph of the inhibition of NCI-H226 mesothelioma growth by compounds I-39 and I-41.
Detailed Description
The present invention is further illustrated by the following examples. It is to be understood that the following description is only the most preferred embodiment of the present invention, and should not be taken as limiting the scope of the invention. In the following examples, the experimental methods without specific conditions, usually according to the conventional conditions or according to the conditions suggested by the manufacturers, can be modified by those skilled in the art without essential changes, and such modifications should be considered as included in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Preparation of intermediate A1
The synthetic route is as follows:
Figure BDA0003735878680000161
the first step is as follows: synthesis of 3-bromo-4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (A1-2)
Figure BDA0003735878680000162
To a solution of 1- (4-methoxyphenyl) -N-methylmethanamine (6.63g, 43.9mmol) and diisopropylethylamine (9.58mL, 54.8mmol) in dichloromethane (100 ml) was added dropwise 3-bromo-4-fluorobenzene-1-sulfonyl chloride (A1-1) (10g, 36.6mmol) at 0 ℃ under nitrogen protection. The reaction mixture was stirred at 0 ℃ for 0.5h under nitrogen. Then the temperature is raised to 25 ℃ and the mixture is stirred for 2 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was diluted with 100mL of dichloromethane, the organic phase was washed with an aqueous hydrochloric acid solution (0.5M, 150mL), the organic phase was collected, and anhydrous Na was added 2 SO 4 Drying, filtration and concentration gave crude product which was slurried with petroleum ether/methyl tert-butyl ether (10/1, v/v) (100 mL) to give 3-bromo-4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (A1-2) (12 g, 70.6% yield). The second step is that: synthesis of 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (A1)
Figure BDA0003735878680000163
To a solution of 3-bromo-4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (A1-2) (12g, 30.9mmol) and bis-pinacol boronate (11.77g, 46.4mmol) in 1, 4-dioxane (20 mL) was added anhydrous potassium acetate (6.07g, 61.8mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (2.262g, 3.09mmol) under nitrogen protection at 25 ℃. The reaction mixture was stirred at 110 ℃ for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated to give a crude product, which was isolated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) =100: 1-1).
Preparation of intermediate A2
The synthetic route is as follows:
Figure BDA0003735878680000164
the first step is as follows: 3-bromo-N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (A2-1)
Figure BDA0003735878680000171
To a solution of 5- (trifluoromethyl) pyridin-2-amine (1.0g, 6.17mmol) in N, N-dimethylformamide (25 mL) at 0 ℃ was added NaH (1.03g, 25.7mmol, 60%) in portions, and then 3-bromo-4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (A1-2) (2.0g, 5.14mmol) was added to the reaction solution. The reaction solution was stirred at 25 ℃ for 18 hours. After completion of the reaction, the reaction mixture was slowly dropped into 200mL of an ice-water mixture, the mixture was extracted with ethyl acetate (100mL. Times.3), and the organic phase was collected and washed with 200mL of saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) =100: 1-1) to give 3-bromo-N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (A2-1) (2.2 g, yield 80%).
The second step is that: n- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- ((5- (trifluoromethyl) pyridin-2) -yl) amino) benzenesulfonamide
Figure BDA0003735878680000172
To a solution of 3-bromo-N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (A2-1) (2g, 3.77mmol) and bis (pinacolato) borate (1.44g, 5.65mmol) in 1, 4-dioxane (25 mL) was added anhydrous potassium acetate (1.04g, 7.54mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.28g, 0.377mmol) under nitrogen at 25 ℃. The reaction mixture was stirred at 110 ℃ for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the reaction solution was filtered with celite, and the filtrate was concentrated to give a crude product, which was isolated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) =100: 1-1).
Preparation of intermediate A3
The synthetic route is as follows:
Figure BDA0003735878680000173
the first step is as follows: synthesis of 3-bromo-N- (4- (trifluoromethyl) phenyl) pyridin-2-amine (A3-2)
Figure BDA0003735878680000181
3-bromo-2-aminopyridine (A3-1) (10g, 57.8mmol), 4-trifluoromethyliodobenzene (10.48g, 38.5mmol), cuprous iodide (1.47g, 7.7mmol) and potassium tert-butoxide (8.63g, 77mmol) were dissolved in anhydrous 1, 4-dioxane (100 mL), heated to 100 ℃ under nitrogen protection for 24 hours, and cooled to room temperature. Quenching was performed by adding ice water (100 mL), followed by extraction with ethyl acetate (100 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) = 5) to give 3-bromo-N- (4- (trifluoromethyl) phenyl) pyridin-2-amine (A3-2) as a yellow solid (7.9 g, yield 64.7%).
The second step is that: synthesis of 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -N- (4 (trifluoromethyl) phenyl) pyridin-2-amine (A3)
Figure BDA0003735878680000182
3-bromo-N- (4- (trifluoromethyl) phenyl) pyridin-2-amine (A3-2) (5g, 15.8mmol), pinacol diboron diboride (6 g,23.6 mmol), [1, 1-bis (diphenylphosphino) ferrocene ] palladium dichloride (1.15g, 1.58mmol) and anhydrous potassium acetate (3.1g, 31.6 mmol) were dissolved in dioxane (50 mL), replaced with nitrogen three times, warmed to 90 ℃ and stirred for reaction for 20h. The reaction solution was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (80 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 5) to give 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -N- (4 (trifluoromethyl) phenyl) pyridin-2-amine (A3) as a yellow oil (3.8 g, yield 66.2%).
Preparation of intermediate A4
The synthetic route is as follows:
Figure BDA0003735878680000183
the first step is as follows: synthesis of 1, 2-bis (6-fluoropyridin-3-yl) disulfide (A4-2)
Figure BDA0003735878680000184
5-bromo-2-fluoropyridine (A4-1) (50.0 g, 284mmol) was dissolved in tetrahydrofuran (500 mL), nitrogen was replaced, the temperature was lowered to-40 ℃, a tetrahydrofuran solution of isopropyl magnesium chloride-lithium chloride (1.30M, 120.2mL) was slowly added dropwise, and after the dropwise addition, the temperature was slowly raised to room temperature and stirred for 2 hours. The reaction solution was cooled to-40 ℃ and sulfur powder (5.08g, 158mmol) dispersed in toluene (500 mL) was slowly added dropwise to the reaction solution. After the completion of the dropwise addition, the reaction system was slowly warmed to room temperature and stirred for 1 hour. After completion of the reaction, the reaction mixture was poured into a mixed aqueous solution (1000 mL) of potassium ferricyanide (46.8g, 142mmol) and potassium hydroxide (15.9g, 284mmol) and stirred at room temperature overnight under a nitrogen atmosphere. Extraction with ethyl acetate (500 mL × 3), combining the organic phases, then washing with saturated brine (1000 mL), drying the organic phase with anhydrous sodium sulfate, filtration, and concentration gave a crude product, which was purified by normal-phase flash silica gel column separation (petroleum ether: ethyl acetate (V/V) = 3) to give 1, 2-bis (6-fluoropyridin-3-yl) disulfide (A4-2) as a yellow solid (15 g, yield 39.14%).
The second step: 5- (chlorotetrafluoro-lambda) 6 Synthesis of (A4-3) -sulfanyl) -2-fluoropyridine
Figure BDA0003735878680000191
Dried potassium fluoride (7.25g, 125mmol), trichloroisocyanuric acid (14.5g, 62.4 mmol) and 1, 2-bis (6-fluoropyridin-3-yl) disulfide (A4-2) (1.00g, 3.90mmol) were dissolved in dried acetonitrile (20.0 mL) and trifluoroacetic acid (44.5mg, 390. Mu. Mol) was added thereto, followed by sealing and stirring at room temperature for reaction for 16 hours. And taking out the reaction supernatant in a nitrogen atmosphere after the reaction is finished, blowing acetonitrile by the nitrogen to obtain a white solid mixture, and immediately and directly using the white solid mixture in the next step.
The third step: 2-fluoro-5- (pentafluoro-lambda) compounds 6 Synthesis of (A4-4) sulfanyl) pyridine
Figure BDA0003735878680000192
Operating in a glove box, and adding the crude 5- (chlorotetrafluoro-lambda) in the previous step into a tetrafluoro-sealed tank 6 -sulfanyl) -2-fluoropyridine (A4-3) (1.00g, 4.17mmol) was dissolved in 5mL of dichloromethane and silver fluoride (1.06g, 8.35mmol) was added. After the addition of the materials, the reaction is carried out for 48 hours under the sealed condition at 120 ℃. Cooling to room temperature after the reaction is completed, filtering off solids containing 2-fluoro-5- (pentafluoro-lambda) 6 The reaction mixture of the (e) -sulfanyl) pyridine (A4-4) was used as it was in the next step.
The fourth step: 5- (pentafluoro- λ) 6 Synthesis of (A4) sulfanyl) pyridin-2-amines
Figure BDA0003735878680000193
The reaction mixture obtained in the previous step was dissolved in methylene chloride (50.0 mL), aqueous ammonia (50.0 mL, 181mmol) was added, and the mixture was heated to 105 ℃ in a closed pot and reacted for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, water (50.0 mL) was added, extraction was performed with methyl tert-butyl ether (50.0 mL. Times.3), and the mixture was washed with brine (100 mL. Times.2), dried and concentrated to obtain a crude product, which was then purified by silica gel chromatographyGel column separation and purification (petroleum ether: ethyl acetate (V/V) = 2) to obtain 5- (pentafluoro- λ) 6 -sulfanyl) pyridin-2-amine (A4) (0.51 g, 21% yield).
1 H NMR(400MHz,CDCl 3 _d)δ8.44(d,1H),7.74(dd,1H),6.46(d,1H),4.95(br s,2H)。
19 F NMR(400MHz,CDCl 3 _d):δ85.83(q,1F),66.25(br d,4F)。
LCMS:M/Z(ESI):221.0[M+H] + 。
Intermediate A5:
Figure BDA0003735878680000194
example 1: preparation of Compound I-1
The synthetic route is shown as follows:
Figure BDA0003735878680000201
the first step is as follows: synthesis of 2- (2-oxopyrrolidin-1-yl) acetamide (B1-2)
Figure BDA0003735878680000202
Methyl 2- (2-oxopyrrolidin-1-yl) acetate (22.0 g, 140mmol) was dissolved in methanol (30.0 mL), and aminomethanol (7M, 220mL) was added to the reaction mixture and the mixture was reacted at 60 ℃ for 4 hours. The reaction mixture was directly concentrated to give crude 2- (2- (2-oxopyrrolidin-1-yl) acetamide (B1-2) (19.5 g, yield 98.0%).
The second step is that: synthesis of 2-bromo-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B1-3)
Figure BDA0003735878680000203
2- (2-Oxypyrrolidone-1-yl) acetamide (19.5g, 137mmol) was dissolved in acetonitrile (300 mL), and tribromooxyphosphorus (43.3g, 151mmol) was added under nitrogen protection to react at 70 ℃ for 2 hours. The reaction mixture was added with a saturated potassium carbonate solution (500 mL), followed by extraction with ethyl acetate (500 mL), and the organic phase was washed with a saturated brine (500 mL), dried over sodium sulfate, and concentrated to give crude 2-bromo-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B1-3) (19.0 g, yield 74.1%).
The third step: synthesis of 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4-fluoro-N- [ (4-methoxyphenyl) methyl ] -N-methylbenzenesulfonamide (B1-4)
Figure BDA0003735878680000204
2-bromo-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B1-3) (500mg, 2.67mmol) and 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) benzenesulfonamide (A1) (1.02g, 2.43mmol) were dissolved in acetonitrile (10.0 mL) and water (5.00 mL), potassium carbonate (672mg, 4.86mmol) and 1, 1-bis (diphenylphosphine) ferrocene palladium chloride (178mg, 243. Mu. Mol) were added, and then the reaction was stirred at 95 ℃ for 10 hours under nitrogen protection. The reaction solution was concentrated to give a crude product, which was isolated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
The fourth step: synthesis of 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2) -yl) amino) benzenesulfonamide (B1-5)
Figure BDA0003735878680000211
5- (trifluoromethyl) pyridin-2-amine (187mg, 1.16mmol) and 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (400mg, 963. Mu. Mol) were dissolved in tetrahydrofuran (5.00 mL) and reacted at 0 ℃ with sodium hydride (58.0 mg, 1.44mmol) under nitrogen at 25 ℃ for 2 hours. The reaction was added dropwise to water (30.0 mL), followed by extraction with ethyl acetate (40.0 mL), and the organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, and concentrated to give the crude product. Separation was then performed by reverse phase high performance liquid chromatography using (column: 3. Mu. Phenomenex Luna C1875. Multidot. 30mm. Multidot. 3um; solvent: A = water + formic acid (0.05%), B = acetonitrile; gradient: 40% -70%,7 min.) to give 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2) -yl) amino) benzenesulfonamide (B1-5) (100 mg, 18.6% yield).
The fifth step: 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-1)
Figure BDA0003735878680000212
3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2) -yl) amino) benzenesulfonamide (100mg, 179. Mu. Mol) was dissolved in trifluoroacetic acid (204mg, 1.79mmol, 133. Mu.L) and reacted at 40 ℃ for 1 hour. The reaction mixture was added to water (30.0 mL), neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (40.0 mL), and the organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, and concentrated to give the crude product. Then separated by reverse phase high performance liquid chromatography by (column: 3. Mu. Phenomenex Luna C18. About. 25mm. 10. Mu.m; solvent: A = water + formic acid (0.05%), B = acetonitrile; gradient: 21% -51%,10 min) to give 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-1) (10.0 mg, yield 6.20%).
1 H NMR(400MHz,DMSO-d 6 )δ12.25(s,1H),8.88(d,1H),8.55(s,1H),7.98(d,1H),7.70(dt,2H),7.35(s,1H),6.93(d,1H),4.29-4.21(m,1H),4.10(t,2H),3.16-3.08(m,1H),3.04-2.97(m,2H),2.71(d,1H),2.68(d,3H)。
1 H NMR(400MHz,DMSO-d 6 )δ:12.30(s,1H),8.71(m,1H),8.60(s,1H),8.02(d,1H),7.96(m,1H),7.76(s,1H),7.58(m,1H),7.29(d,1H),7.06(d,1H),4.07(m,2H),2.89-2.96(m,2H),2.44(s,2H),2.43(s,3H)
LC-MS,M/Z(ESI):438.2[M+H] + 。
Example 2: preparation of Compound I-2
The synthetic route is shown as follows:
Figure BDA0003735878680000221
the first step is as follows: synthesis of methyl 2- (3-oxomorpholine) acetate (B2-2)
Figure BDA0003735878680000222
Morpholin-3-one (10.0 g,98.9 mmol) was dissolved in tetrahydrofuran (100 mL), and sodium hydrogen (4.35g, 109mmol) was added to the reaction solution in portions and reacted at 25 ℃ for 1 hour. Methyl bromoacetate (16.6 g, 109mmol) was added to the reaction mixture and reacted at 25 ℃ for 9 hours. Water (200 mL) was added to the reaction mixture, followed by extraction with dichloromethane (200 mL), and the organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to give crude methyl 2- (3-oxomorpholine) acetate (B2-2) (15.0 g, yield 87.6%). The second step: synthesis of 2- (3-oxomorpholine) acetamide (B2-3)
Figure BDA0003735878680000223
Methyl 2- (3-oxomorpholine) acetate (3.00g, 17.3mmol) was dissolved in methanol (10.0 mL), and aminomethanol (7M, 30mL) was added to the reaction mixture and reacted at 60 ℃ for 4 hours. The reaction was directly concentrated to give crude 2- (3-oxomorpholine) acetamide (B2-3) (1.20 g, yield 43.8%).
The third step: synthesis of 2-bromo-6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazine (B2-4)
Figure BDA0003735878680000224
2- (3-Oxomorphine) acetamide (B2-3) (1.00g, 6.32mmol) was dissolved in acetonitrile (10.0 mL), and phosphorus oxybromide (9.06g, 31.6 mmol) was added thereto under nitrogen protection to react at 90 ℃ for 2 hours. The reaction mixture was added with a saturated potassium carbonate solution (100 mL), followed by extraction with ethyl acetate (100 mL), and the organic phase was washed with a saturated brine (100 mL), dried over sodium sulfate, and concentrated to give crude 2-bromo-6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazine (B2-4) (800 mg, yield 62.3%).
LC-MS,M/Z(ESI):203.0[M+H] + 。
The fourth step: synthesis of 3- (6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B2-5)
Figure BDA0003735878680000231
2-bromo-6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazine (B2-4) (476mg, 2.34mmol) and 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (1.02g, 2.34mmol) were dissolved in acetonitrile (10.0 mL) and water (5.00 mL), potassium carbonate (648mg, 4.69mmol) and 1, 1-bis (diphenylphosphino) ferrocene palladium chloride (171mg, 234. Mu. Mol) were added, and the reaction was stirred at 95 ℃ for 10 hours under nitrogen. The reaction was concentrated to give a crude product, which was then separated by reverse phase high performance liquid chromatography (column: 3 phenomenex Luna c18 150 x 40mm x 15um; solvent: a = water + trifluoroacetic acid (0.05%), B = acetonitrile; gradient: 20% -50%,11 min) to give 3- (6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B2-5) (200 mg, yield 19.8%).
The fifth step: synthesis of 3- (6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B2-6)
Figure BDA0003735878680000232
5- (trifluoromethyl) pyridin-2-amine (147mg, 904. Mu. Mol) and 3- (5, 6-dihydro-8H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B2-5) (195mg, 452. Mu. Mol) were dissolved in N, N-dimethylformamide (5.0 mL), and sodium hydride (27.1mg, 678mol) was added thereto at 0 ℃ and reacted at 20 ℃ for 1 hour under nitrogen. The reaction was added dropwise to 1M hydrochloric acid (100 mL), neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, and concentrated to give the crude product. Then, the product was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 50.
And a sixth step: 3- (6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-2)
Figure BDA0003735878680000233
3- (6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (200mg, 349. Mu. Mol) was dissolved in trifluoroacetic acid (7.70mg, 67.5mmol, 5.00mL) and reacted at 60 ℃ for 2 hours. The reaction solution was added to water (40.0 mL), neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (40.0 mL), and the organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, and concentrated to give the crude product. Separation was then performed by reverse phase high performance liquid chromatography using (column: 3% phenomenex Luna c18 × 25mm × 10um; solvent: a = water + formic acid (0.05%), B = acetonitrile; gradient: 32% -62%,9 min) to give 3- (6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-2) (35.0 mg, yield 31.4%).
1 H NMR(400MHz,DMSO-d 6 )δ11.99(s,1H),8.71(d,1H),8.60(s,1H),8.06(d,1H),7.96(dd,1H),7.83(s,1H),7.60(dd,1H),7.31(d,1H),7.09(d,1H),4.92(s,2H),4.17-4.12(m,2H),4.10-4.05(m,2H),2.44(3H)。
LC-MS,M/Z(ESI):454.0[M+H] + 。
Example 3: preparation of Compound I-3
The synthetic route is as follows:
Figure BDA0003735878680000241
the first step is as follows: synthesis of methyl 2- (2-methyl-5-oxopyrrolidin-1-yl) acetate (B3-2)
5-methylpyrrolidin-2-one (10.0 g, 101mmol) was dissolved in tetrahydrofuran (50.0 mL), sodium hydride (4.44g, 111mmol) was added in portions at 0 ℃ under nitrogen protection, and the mixture was reacted at 0 ℃ for 1 hour, and methyl 2-bromoacetate (18.5 g, 121mmol) was added dropwise to the reaction mixture and reacted at 25 ℃ for 1 hour. The reaction solution was added to water (50 mL), followed by extraction with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to give a crude product, which was subjected to separation and purification on a silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
1 H NMR(400MHz,DMSO-d 6 )δ4.11(d,1H)3.87(d,1H)3.66-3.72(m,1H)3.65(s,3H)2.13-2.32(m,3H)1.48-1.56(m,1H)1.13(d,3H)
The second step is that: synthesis of 2- (2-methyl-5-oxopyrrolidin-1-yl) acetamide (B3-3)
Methyl 2- (2-methyl-5-oxopyrrolidin-1-yl) acetate (B3-2) (1.30g, 2.64mmol) was dissolved in aminomethanol (7M, 50.0 mL) and the mixture was reacted in a jar at 50 ℃ for 1 hour. The reaction mixture was concentrated to give 2- (2-methyl-5-oxopyrrolidin-1-yl) acetamide (B3-3) (3.20 g, 92.3% yield).
1 H NMR(400MHz,DMSO-d 6 )δ7.33(s,1H)7.04(s,1H)3.90(d,1H)3.64-3.70(m,1H)3.53(d,1H)2.11-2.27(m,3H)1.46-1.53(m,1H)1.11(d,3H)
The third step: synthesis of 2-bromo-5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B3-4)
2- (2-methyl-5-oxopyrrolidin-1-yl) acetamide (B3-3) (3.10g, 19.9mmol) was dissolved in acetonitrile (30.0 mL), and phosphorus oxybromide (11.4g, 39.7mmol) was added, followed by stirring at 90 ℃ for 2 hours under nitrogen. The reaction mixture was added to a saturated aqueous potassium carbonate solution to adjust the pH to 7 to 8, followed by extraction with ethyl acetate (200 mL), washing of the organic phase with saturated brine (100 mL), drying over sodium sulfate, and concentration to give a crude product, which was subjected to separation and purification with a silica gel column (petroleum ether: ethyl acetate (V/V) = 1-5) to give 2-bromo-5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B3-4) (2.50 g, yield 62.6%).
The fourth step: synthesis of 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) benzenesulfonamide (B3-5)
2-bromo-5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B3-4) (2.64g, 13.1mmol) and 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (5.20g, 12.0mmol) were dissolved in acetonitrile (30.0 mL) and water (30.0 mL), and potassium carbonate (3.30g, 23.9mmol) and 1, 1-bis (diphenylphosphino) ferrocenepalladium chloride (874mg, 1.19mmol) were added, followed by stirring at 95 ℃ for 10 hours under nitrogen protection. The reaction solution was concentrated to give a crude product, which was isolated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
The fifth step: synthesis of N- (4-methoxybenzyl) -N-methyl-3- (5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B3-6)
5- (trifluoromethyl) pyridin-2-amine (1.66g, 10.2mmol) and 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) benzenesulfonamide (B3-5) (4.00g, 9.31mmol) were dissolved in tetrahydrofuran (30.0 mL), and potassium hydroxide (1.05mg, 18.6 mmol) was added at 0 ℃ and reacted at 70 ℃ for 2 hours under nitrogen. The reaction was added dropwise to water (200 mL), followed by extraction with ethyl acetate (200 mL), washing of the organic phase with saturated brine (200 mL), drying over sodium sulfate, and concentration to give the crude product. Separation and purification by silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
LC-MS,M/Z(ESI):572.3[M+H] +
And a sixth step: synthesis of the compound N-methyl-3- (5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-3)
Figure BDA0003735878680000251
N- (4-methoxybenzyl) -N-methyl-3- (5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B3-6) (3.00g, 5.25mmol) was dissolved in trifluoroacetic acid (46.2g, 405mmol,30.0 mL) and reacted at 70 ℃ for 2 hours. The reaction mixture was added to water (200 mL), followed by extraction with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to give the crude product. Purification by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 50.
1 H NMR(400MHz,DMSO-d 6 )δ12.43(s,1H)8.74(d,1H)8.60(s,1H)8.03(d,1H)7.96(dd,1H)7.86(s,1H)7.58(dd,1H)7.29(d,1H)7.06(d,1H)4.43(s,1H)2.86-3.02(m,2H)2.77(ddt,1H)2.43(d,3H)2.11-2.22(m,1H)1.47(d,3H)
LC-MS,M/Z(ESI):451.8[M+H] +
Example 4: preparation of Compound I-4
Figure BDA0003735878680000252
The compound 3- (6-fluoro-6, 7-dihydro-5H-pyrrolo [1,2-a ]]Imidazol-2-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) aminoThe synthesis method of the group) benzenesulfonamide (I-4) refers to I-1, LC-MS, M/Z (ESI): 456.1[ M ] +H ]] + 。
Example 5: preparation of Compound I-5
The synthetic route is as follows:
Figure BDA0003735878680000261
the first step is as follows: synthesis of methyl 2- (2-methyl-5-oxopyrrolidin-1-yl) acetate (B5-2)
4-methylpyrrolidin-2-one (5.00g, 50.4 mmol) was dissolved in tetrahydrofuran (50.0 mL), sodium hydrogen (3.03g, 75.6 mmol) was added in portions at 0 ℃ under nitrogen protection, and the reaction was carried out at 0 ℃ for 1 hour, and methyl 2-bromoacetate (9.26g, 60.5 mmol) was added dropwise to the reaction solution and reacted at 25 ℃ for 1 hour. The reaction solution was added to water (50 mL), followed by extraction with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to give a crude product, which was subjected to separation and purification on a silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
The second step: synthesis of 2- (4-methyl-2-oxopyrrolidin-1-yl) acetamide (B5-3)
Methyl 2- (2-methyl-5-oxopyrrolidin-1-yl) acetate (B5-2) (3.00g, 2.64mmol) was dissolved in aminomethanol (7M, 50.0mL), and the solution was reacted at 50 ℃ for 1 hour in a jar. The reaction mixture was subjected to column chromatography to give 2- (4-methyl-2-oxopyrrolidin-1-yl) acetamide (B5-3) (2.70 g, 98.7% yield).
The third step: synthesis of 2-bromo-6-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B5-4)
2- (4-methyl-2-oxopyrrolidin-1-yl) acetamide (B5-3) (2.70g, 17.2mmol) was dissolved in acetonitrile (30.0 mL), phosphorus oxybromide (9.91g, 34.6 mmol) was added, and the reaction was stirred at 90 ℃ for 2 hours under nitrogen. The reaction mixture was added to a saturated aqueous potassium carbonate solution to adjust the pH to 7 to 8, followed by extraction with ethyl acetate (200 mL), washing of the organic phase with saturated brine (100 mL), drying over sodium sulfate, and concentration to give a crude product, which was subjected to separation and purification with a silica gel column (petroleum ether: ethyl acetate (V/V) = 1-5) to give 2-bromo-6-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B5-4) (1.30 g, yield 37.4%).
The fourth step: synthesis of 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (6-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) benzenesulfonamide (B5-5)
2-bromo-6-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B5-4) (1.30g, 6.47mmol) and 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (3.00g, 6.89mmol) were dissolved in acetonitrile (30.0 mL) and water (30.0 mL), and potassium carbonate (1.90g, 13.8mmol) and 1, 1-bis (diphenylphosphino) ferrocene palladium chloride (504mg, 689. Mu. Mol) were added, followed by stirring at 95 ℃ for 10 hours under nitrogen protection. The reaction solution was concentrated to give a crude product, which was isolated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
LC-MS,M/Z(ESI):429.9[M+H] +
The fifth step: synthesis of N- (4-methoxybenzyl) -N-methyl-3- (6-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B5-6)
4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (6-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) benzenesulfonamide (B5-5) (1.00g, 2.32mmol) and 5- (trifluoromethyl) pyridin-2-amine (415mg, 2.56mmol) were dissolved in dimethyl sulfoxide (10.0 mL), and cesium carbonate (2.28g, 6.98mmol) was added at 0 ℃ and reacted at 60 ℃ for 5 hours under nitrogen. The reaction was added dropwise to water (200 mL), followed by extraction with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to give the crude product. Purification by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 50.
LC-MS,M/Z(ESI):571.9[M+H] +
And a sixth step: n-methyl-3- (6-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-5)
Figure BDA0003735878680000271
N- (4-methoxybenzyl) -N-methyl-3- (6-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B5-6) (600mg, 1.05mmol) was dissolved in trifluoroacetic acid (10.0 mL) and reacted at 70 ℃ for 2 hours. The reaction mixture was added to water (200 mL), followed by extraction with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to give the crude product. Separation and purification by silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
1 H NMR(400MHz,DMSO-d 6 )δ12.27(s,1H)8.69(d,1H)8.60(s,1H)8.02(d,1H)7.97(dd,1H)7.75(s,1H)7.58(dd,1H)7.30(d,1H)7.06(d,1H)4.23(dd,1H)3.61-3.70(m,1H)3.06-3.17(m,2H)2.54(br s,1H)2.43(d,3H)1.23(d,3H)
LC-MS,M/Z(ESI):452.0[M+H] +
Example 6: preparation of Compound I-6
Figure BDA0003735878680000272
The compound N-methyl-3- (6-hydroxy-6, 7-hydro-5H-pyrrole [1, 2-a)]Synthesis method of imidazol-2-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-6) with reference to I-1, LC-MS, M/Z (ESI): 454.1[ M ] +H ], (ESI)] + 。
Example 7: preparation of Compound I-7
The synthetic route is as follows:
Figure BDA0003735878680000281
the first step is as follows: synthesis of nitroso-L-proline (B7-2)
L-proline (8.00g, 69.4 mmol) was dissolved in concentrated hydrochloric acid (40.0 mL), and an aqueous solution (40.0 mL) of sodium nitrite (4.79g, 69.4 mmol) was added dropwise at 0 ℃ under nitrogen protection, and after the addition was completed, the temperature was slowly raised to room temperature for 1 hour. The reaction solution was extracted with ethyl acetate (300 mL), and the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to give crude nitroso-L-proline (B7-2) (3.70 g, 36.9% yield). 1 H NMR(400MHz,CDCl 3 )δ3.79-3.59(m,1H),2.48-2.32(m,2H),2.31-1.99(m,4H)。
The second step is that: synthesis of 3a,4,5, 6-tetrahydro-3-oxo-3H-pyrrolo [1,2-c ] [1,2,3] oxadiazol-7-ium ylide (B7-3)
nitroso-L-proline (B7-2) (3.00g, 20.8 mmol) was dissolved in dichloromethane (30.0 mL), trifluoroacetic anhydride (4.37g, 20.8 mmol) was added dropwise at 0 deg.C, then slowly warmed to room temperature, and reacted at room temperature for 2 hours. Potassium carbonate (10.3g, 74.9mmol) was added, stirred for 1 hour, filtered, washed, and the filtrate was concentrated to give 3a,4,5, 6-tetrahydro-3-oxo-3H-pyrrolo [1,2-c ] [1,2,3] oxadiazol-7-ium ylide (B7-3) (3.23 g, crude product).
1 H NMR(400MHz,DMSO-d 6 )δ4.49(t,2H),2.76-2.70(m,2H),2.67-2.57(m,2H)
LC-MS,M/Z:127.0[M+H] +
The third step: synthesis of 2- (tributylstannyl) -5, 6-dihydro-4H-pyrrolo [1,2-B ] pyrazole (B7-4)
3a,4,5, 6-tetrahydro-3-oxo-3H-pyrrolo [1,2-c ] [1,2,3] oxadiazol-7-ium ylide (B7-3) (3.23g, 25.6 mmol) was dissolved in xylene (30.0 mL), tributyl (ethynyl) stannane (10.0 g,25.6 mmol) was added and the reaction was stirred at 140 ℃ for 42 hours under nitrogen protection. The reaction solution was added to an aqueous potassium fluoride solution, stirred for half an hour, then extracted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (50.0 mL), dried over sodium sulfate, and concentrated to give a crude product, which was subjected to separation and purification with a silica gel column (petroleum ether: ethyl acetate (V/V) = 1-10) to give 2- (tributylstannyl) -5, 6-dihydro-4H-pyrrolo [1,2-B ] pyrazole (B7-4) (110 mg, yield 1.08%).
LC-MS,M/Z:399.2[M+H] + .
The fourth step: synthesis of 3- (5, 6-dihydro-4H-pyrrolo [1,2-B ] pyrazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B7-5)
2- (tributylstannyl) -5, 6-dihydro-4H-pyrrolo [1,2-B ] pyrazole (B7-4) (70.0mg, 131. Mu. Mol) and 3-bromo-N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (A2) (78.0mg, 196. Mu. Mol) were dissolved in dioxane (1.00 mL), and lithium chloride and tetrakis (triphenylphosphine) palladium (15.2mg, 13.2. Mu. Mol) were added, followed by stirring at 100 ℃ for 12 hours under nitrogen protection. The reaction solution was added to water (10.0 mL), extracted with ethyl acetate (10.0 mL), the organic phase was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated to give a crude product, which was isolated and purified with a silica gel chromatography plate (petroleum ether: ethyl acetate (V/V) = 2).
LC-MS,M/Z:558.2[M+H] + .
The fifth step: synthesis of 3- (5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-7)
Figure BDA0003735878680000291
3- (5, 6-dihydro-4H-pyrrolo [1,2-B ] pyrazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B7-5) (32.0 mg, 57.3. Mu. Mol) was added to trifluoroacetic acid (1.00 mL) at 0 ℃ and reacted at 70 ℃ for 2 hours under nitrogen protection. Adjusting pH to 8 by adding aqueous sodium bicarbonate solution, extracting with ethyl acetate (5.00 mL), washing the organic phase with saturated brine (5.00 mL), drying over sodium sulfate, and concentrating to give crude product, which is column Waters Xbridge150 × 25mm × 5um; solvent: a = water +0.225 vol% ammonia (99%), B = acetonitrile; gradient: 45% -75%, 9min, purification yielded 3- (5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-7) (10.0 mg, 22.7% yield).
1 H NMR(400MHz,DMSO-d 6 )δ11.23(s,1H),8.72(d,1H),8.61(s,1H),8.07(d,1H),7.99(dd,8.9Hz,1H),7.66(dd,8.9Hz,1H),7.35(q,1H),7.14(d,1H),6.57(s,1H),4.25(t,2H),2.94(t,2H),2.61(d,2H),2.43(d,3H)
LC-MS,M/Z(ESI):438.1[M+H] + 。
Example 8: preparation of Compound I-8
Figure BDA0003735878680000292
The compound 3- (5, 6-dihydro-4H-cyclopentane [ d ]]Synthesis method of oxazol-2-yl) -N-methyl-4- (5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-8) is described with reference to I-1, LC-MS, M/Z (ESI): 439.2[ M ] +H ], [] + 。
Example 9: preparation of Compound I-9
Figure BDA0003735878680000293
The compound 3- (5, 6-dihydro-4H-cyclopentane [ d ]]Synthesis of thiazol-2-yl) -N-methyl-4- (5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-9) reference is made to I-1, LC-MS, M/Z (ESI): 455.1[ M ] +H ], (ESI)] + 。
Example 10: preparation of Compound I-10
The synthetic route is as follows:
Figure BDA0003735878680000301
the first step is as follows: synthesis of 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((6- (trifluoromethoxy) pyridin-3-yl) amino) benzenesulfonamide (B10-2)
3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B1-4) (212mg, 510. Mu. Mol), 6- (trifluoromethoxy) pyridin-3-amine (100mg, 561. Mu. Mol) were dissolved in tetrahydrofuran (1.00 mL), potassium hydroxide (57.2mg, 1.02mmol) was added, and then slowly raised to 70 ℃ for 12 hours. The reaction was quenched with water (10.0 mL), extracted with ethyl acetate (15.0 mL), and the organic phase was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated to give 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((6- (trifluoromethoxy) pyridin-3-yl) amino) benzenesulfonamide (B10-2) (200 mg, crude).
LC-MS,M/Z:574.0[M+H] + .
The second step is that: synthesis of 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N-methyl-4- ((6- (trifluoromethoxy) pyridin-3-yl) amino) benzenesulfonamide (I-10)
Figure BDA0003735878680000302
3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((6- (trifluoromethoxy) pyridin-3-yl) amino) benzenesulfonamide (B10-2) (200mg, 348. Mu. Mol) was dissolved in trifluoroacetic acid (2.00 mL) and the reaction was stirred at 70 ℃ for 2 hours under nitrogen. The reaction was adjusted to pH 8 by adding aqueous sodium bicarbonate, then extracted with ethyl acetate (10 mL), the organic phase washed with saturated brine (5 mL), dried over sodium sulfate, and concentrated to give crude product, which was purified using column Waters Xbridge150 x 25mm x 5um; solvent: a = water +0.225 vol% ammonia (99%), B = acetonitrile; gradient: isolation and purification of 32% to 62% gave 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N-methyl-4- ((6- (trifluoromethoxy) pyridin-3-yl) amino) benzenesulfonamide (I-10) (30.3 mg, 19.0% yield).
1 H NMR(400MHz,DMSO-d 6 )δ10.74(s,1H),8.25(d,1H),7.97(d,1H),7.87(dd,1H),7.70(s,1H),7.46(dd,1H),7.32-7.19(m,3H),4.04(t,2H),2.85(t,2H),2.59-2.54(m,2H),2.41(d,3H)
LC-MS,M/Z(ESI):454.2[M+H] + 。
Example 11: preparation of Compound I-11
The synthetic route is as follows:
Figure BDA0003735878680000311
the first step is as follows: synthesis of 2- (5-bromopyridin-2-yl) propan-2-ol (B11-2)
Methyl 5-bromopyridine-2-carboxylate (3.00g, 13.9mmol) was dissolved in tetrahydrofuran (30.0 ml), and methyl magnesium bromide (3M, 13.8mL) was added dropwise at 0 ℃ and after completion of the addition, nitrogen gas was replaced, and the mixture was slowly warmed to room temperature and reacted for 12 hours. The reaction solution was quenched with saturated ammonium chloride at 0 ℃ (60.0 mL), extracted with ethyl acetate (150 mL), and the organic phase was washed with saturated brine (120 mL), dried over sodium sulfate, concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 1-10) to give 2- (5-bromopyridin-2-yl) propan-2-ol (B11-2) (1.60 g, 53.3% yield). LC-MS, M/Z:217.1[ 2 ], [ M + H ]] + .
The second step: synthesis of 2- (5- ((diphenylmethylene) amino) pyridin-2-yl) propan-2-ol (B11-3)
2- (5-Bromopyridin-2-yl) propan-2-ol (B11-2) (700mg, 3.24mmol), diphenylmethanimine (763mg, 4.21mmol) was dissolved in dioxane (7.00 mL), tris (dibenzylideneacetone) dipalladium (148mg, 161. Mu. Mol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (187mg, 323. Mu. Mol), cesium carbonate (3.17g, 9.72mmol) was added, and the reaction was slowly raised to 100 ℃ for 12 hours. The reaction solution was quenched with water (10.0 mL), extracted with ethyl acetate (15.0 mL), and the organic phase was washed with saturated brine (10.0 mL), dried over sodium sulfate, concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 10.
LC-MS,M/Z:317.2[M+H] + .
The third step: synthesis of 2- (5-aminopyridin-2-yl) propan-2-ol (B11-4)
2- (5- ((diphenylmethylene) amino) pyridin-2-yl) propan-2-ol (B11-3) (500mg, 1.58mmol) was dissolved in dichloromethane (5.00 mL), hydrochloric acid (4M, 5.00mL) was added, and the reaction was stirred under nitrogen at 25 ℃ for 2 hours. The reaction mixture was added with aqueous sodium bicarbonate to adjust the pH to 8, followed by extraction with ethyl acetate (10.0 mL), washing of the organic phase with saturated brine (5.00 mL), drying over sodium sulfate, and concentration to give the crude product, 2- (5-aminopyridin-2-yl) propan-2-ol (B11-4) (210 mg, 87.3% yield).
LC-MS,M/Z:153.1[M+H] + .
The fourth step: synthesis of 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((6- (2-hydroxypropan-2-yl) pyridin-3-yl) amino) -N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B11-5)
Reacting 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ]]Imidazol-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B10-1) (212mg, 510. Mu. Mol), 2- (5-aminopyridin-2-yl) propan-2-ol (B11-4) (80.5 mg, 529. Mu. Mol) were dissolved in tetrahydrofuran (1.00 mL), potassium hydroxide (81.0 mg, 1.44mmol) was added, and the reaction was slowly raised to 70 ℃ for 12 hours. The reaction mixture was quenched with water (10.0 mL), extracted with ethyl acetate (15.0 mL), and the organic phase was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated to give 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] salt]Imidazol-2-yl) -4- ((6- (2-hydroxypropan-2-yl) pyridin-3-yl) amino) -N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B11-5) (200 mg, crude). LC-MS, M/Z:548.2[ M + H ]] + .
The fifth step: synthesis of 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((6- (2-hydroxypropan-2-yl) pyridin-3-yl) amino) -N-methylbenzenesulfonamide (I-11)
Figure BDA0003735878680000321
3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((6- (2-hydroxypropan-2-yl) pyridin-3-yl) amino) -N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B11-5) (70.0 mg, 127. Mu. Mol) was dissolved in trifluoroacetic acid (1.00 mL), and the reaction was stirred at 70 ℃ for 2 hours under nitrogen protection. The reaction was adjusted to pH 8 by adding aqueous sodium bicarbonate, then extracted with ethyl acetate (10.0 mL), the organic phase was washed with saturated brine (5.00 mL), dried over sodium sulfate, concentrated to give crude product, which was purified by column Waters Xbridge150 × 25mm × 5um; solvent: a = water +0.225 vol% ammonia (99%), B = acetonitrile; gradient: 21% -51%,9min, isolation and purification gave 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((6- (2-hydroxypropan-2-yl) pyridin-3-yl) amino) -N-methylbenzenesulfonamide (I-11) (11.0 mg, 19.6% yield).
1 H NMR(400MHz,DMSO-d 6 )δ10.75(s,1H),8.38(d,1H),7.92(d,1H),7.70(s,1H),7.68-7.64(m,1H),7.64-7.60(m,1H),7.43(dd,1H),7.22(d,1H),7.20-7.10(m,1H),5.18(s,1H),4.05(t,2H),2.86(t,2H),2.59-2.55(m,2H),2.40(s,3H),1.44(s,6H)
LC-MS,M/Z:428.1[M+H] + .
Example 12: preparation of Compound I-12
The synthetic route is shown as follows:
Figure BDA0003735878680000322
the first step is as follows: synthesis of 2- (4-aminopyridin-2-yl) propan-2-ol (B12-2)
Methyl 4-aminopyridine-2-carboxylate (2.00g, 13.1mmol) was dissolved in tetrahydrofuran (20.0 mL), methylmagnesium bromide (3M, 13.1mL) was added at 0 ℃ under nitrogen blanket, after which nitrogen was replaced and the reaction was slowly raised to 25 ℃ for 12 hours. The reaction solution was quenched with saturated ammonium chloride solution (60.0 mL) at 0 ℃, extracted with ethyl acetate (90.0 mL), and the organic phase was washed with saturated brine (60.0 mL), dried over sodium sulfate, and concentrated to give crude 2- (4-aminopyridin-2-yl) propan-2-ol (B12-2) (1.10 g, 54.9% yield).
1 H NMR(400MHz,DMSO-d 6 )δ8.10(d,1H),7.10(d,1H),6.66(dd,1H),6.31(s,2H),2.53(s,6H)
LC-MS,M/Z:153.3[M+H] + .
The second step is that: synthesis of 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) -N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B12-3)
Reacting 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ]]Imidazol-2-yl) -4-fluoro-N- (4-methoxyBenzyl) -N-methylbenzenesulfonamide (B10-1) (200mg, 481. Mu. Mol), 2- (4-aminopyridin-2-yl) propan-2-ol (B12-2) (80.5 mg, 529. Mu. Mol) were dissolved in tetrahydrofuran (2.00 mL), potassium hydroxide (81.0 mg, 1.44mmol) was added, and then slowly raised to 70 ℃ for 12 hours. The reaction mixture was quenched with water (10.0 mL), extracted with ethyl acetate (15.0 mL), and the organic phase was washed with saturated brine (10.0 mL), dried over sodium sulfate, concentrated, and separated and purified with a silica gel plate (petroleum ether: ethyl acetate (V/V) = 1/1) to give 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] complex]Imidazol-2-yl) -4- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) -N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B12-3) (51.0 mg, 19.3% yield). LC-MS, M/Z:532.3[ M-16 ]] + .
The third step: synthesis of 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) -N-methylbenzenesulfonamide (I-12)
Figure BDA0003735878680000331
3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) -N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B12-3) (50.0 mg, 94.3. Mu. Mol) was dissolved in trifluoroacetic acid (1.00 mL), and the reaction was stirred at 70 ℃ for 2 hours under nitrogen protection. Adding aqueous sodium bicarbonate solution into the reaction solution to adjust the pH value to 8, extracting with ethyl acetate (10.0 mL), washing an organic phase with saturated saline (5.00 mL), drying by sodium sulfate, concentrating to obtain a crude product, and using a column Waters Xbridge150 × 25mm × 5um; solvent: a = water +0.225 vol% ammonia (99%), B = acetonitrile; gradient: from 18% to 48%, isolated and purified for 9min to give 3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) -N-methylbenzenesulfonamide (I-12) (6.47 mg, 14.4% yield).
1 H NMR(400MHz,DMSO-d 6 )δ10.72(s,1H),8.23(d,1H),8.05(d,1H),7.68(s,1H),7.63-7.58(m,1H),7.57-7.52(m,1H),7.35-7.28(m,2H),6.92(dd,1H),5.17(s,1H),4.04(t,2H),2.87(t,2H),2.59-2.56(m,2H),2.44(d,3H),1.41(s,6H)
LC-MS,M/Z:428.1[M+H] + .
Example 13: preparation of Compound I-13
The synthetic route is shown as follows:
Figure BDA0003735878680000332
the first step is as follows: synthesis of imidazo [1,2-a ] pyrazin-8 (7H) -one (B13-2)
8-Chloroimidazo [1,2-a ] pyrazine (9.00g, 58.6 mmol) was dissolved in water (50.0 mL), hydrochloric acid (5M, 139mL) was added under nitrogen protection, nitrogen was replaced after the addition, and the temperature was slowly raised to 80 ℃ for reaction for 12 hours. The reaction solution was concentrated to give imidazo [1,2-a ] pyrazin-8 (7H) -one (B13-2) (9.10 g, crude product).
The second step: synthesis of 6, 7-dihydroimidazo [1,2-a ] pyrazin-8 (5H) -one (B13-3)
Imidazo [1,2-a ] pyrazin-8 (7H) -one (B13-2) (9.00g, 66.6 mmol) was dissolved in methanol (60.0 mL), palladium on carbon (900mg, 845. Mu. Mol) was added under nitrogen protection, after which hydrogen was replaced, and the temperature was slowly raised to 50 ℃ to react for 12 hours. The reaction solution was filtered through celite and concentrated to give 6, 7-dihydroimidazo [1,2-a ] pyrazin-8 (5H) -one (B13-3) (4.50 g, 49.2% yield).
1 H NMR(400MHz,CH 3 OH-d 4 )δ7.81-7.78(m,1H),7.77-7.73(m,1H),4.61-4.47(m,2H),3.93-3.81(m,2H)
The third step: synthesis of 2, 3-dibromo-6, 7-dihydroimidazo [1,2-a ] pyrazin-8 (5H) -one (B13-4)
Reacting 6, 7-dihydroimidazo [1,2-a ]]Pyrazine-8 (5H) -one (B13-3) (2.30g, 16.7 mmol) was dissolved in N, N-dimethylformamide (30.0 mL), N-bromosuccinimide (2.98g, 16.7 mmol) was added at-10 deg.C, and the reaction was slowly raised to 25 deg.C for 12 hours. The reaction mixture was quenched with water (20.0 mL), extracted with ethyl acetate (60.0 mL), and the organic phase was washed with saturated brine (40.0 mL), dried over sodium sulfate, and concentrated to give 2, 3-dibromo-6, 7-dihydroimidazo [1,2-a ] salt]Pyrazin-8 (5H) -one (B13-4) (1.10 g, crude). LC-MS, M/Z:296.1[ 2 ], [ M + H ]] + .
The fourth step: synthesis of 2-bromo-6, 7-dihydroimidazo [1,2-a ] pyrazin-8 (5H) -one (B13-5)
2, 3-dibromo-6, 7-dihydroimidazo [1,2-a ] pyrazin-8 (5H) -one (B13-4) (1.10g, 3.73mmol) was dissolved in tetrahydrofuran (11.0 mL), isopropylmagnesium chloride (2M, 2.98mL) was added dropwise at 0 ℃ under nitrogen protection, and the reaction was stirred slowly to room temperature for 2 hours. The reaction was quenched at 0 ℃ with saturated aqueous ammonium chloride, then extracted with ethyl acetate (15.0 mL), the organic phase was washed with saturated brine (15.0 mL), dried over sodium sulfate, and concentrated to give crude 2-bromo-6, 7-dihydroimidazo [1,2-a ] pyrazin-8 (5H) -one (B13-5) (1.70 g, crude).
1 H NMR(400MHz,DMSO-d 6 )δ8.19(br s,1H),7.53(s,1H),4.21-4.16(m,2H),3.57-3.52(m,2H)
LC-MS,M/Z:215.9[M+H] + .
The fifth step: synthesis of 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (8-oxo-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-2-yl) benzenesulfonamide (B13-6)
4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) benzenesulfonamide (A1) (3.93g, 9.03mmol), 2-bromo-6, 7-dihydroimidazo [1,2-a ] is added]Pyrazine-8 (5H) -one (B13-5) (1.50g, 6.94mmol) was dissolved in acetonitrile (20.0 mL), and aqueous solution (10.0 mL) of potassium carbonate (1.92g, 13.8 mmol) and [1, 1-bis (diphenylphosphine) ferrocene were added under nitrogen protection]Palladium dichloride dichloromethane mixture (453mg, 555. Mu. Mol), after the addition was complete, nitrogen was replaced and the reaction was slowly raised to 90 ℃ for 12 hours. The reaction solution was quenched with water (40.0 mL), extracted with ethyl acetate (90.0 mL), and the organic phase was washed with saturated brine (60.0 mL), dried over sodium sulfate, concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =10]Pyrazin-2-yl) benzenesulfonamide (B13-6) (140 mg, 4.54% yield). LC-MS, M/Z:445.1[ M + H ]] + .
And a sixth step: synthesis of N- (4-methoxybenzyl) -N-methyl-3- (8-oxo-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B13-7)
4-fluoro-N- (4-methoxy)Benzyl) -N-methyl-3- (8-oxo-5, 6,7, 8-tetrahydroimidazo [1,2-a ]]Pyrazin-2-yl) benzenesulfonamide (B13-6) (70.0 mg, 157. Mu. Mol), 5- (trifluoromethyl) pyridin-2-amine (28.0 mg, 173. Mu. Mol) were dissolved in tetrahydrofuran (1.00 mL), potassium hydroxide (26.5 mg, 472. Mu. Mol) was added, and the reaction was slowly raised to 70 ℃ for 12 hours. The reaction mixture was quenched with water (10.0 mL), extracted with ethyl acetate (15.0 mL), and the organic phase was washed with saturated brine (10.0 mL), dried over sodium sulfate, and concentrated to give N- (4-methoxybenzyl) -N-methyl-3- (8-oxo-5, 6,7, 8-tetrahydroimidazo [1,2-a ] -2]Pyrazin-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B13-7) (42.0 mg, crude). LC-MS, M/Z:587.1, [ M ] +H] + .
The seventh step: synthesis of N-methyl-3- (8-oxo-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-13)
Figure BDA0003735878680000351
N- (4-methoxybenzyl) -N-methyl-3- (8-oxo-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B13-7) (70.0 mg, 119. Mu. Mol) was dissolved in trifluoroacetic acid (1.00 mL), and the reaction was stirred at 70 ℃ for 2 hours under nitrogen. The reaction was adjusted to pH 8 by adding aqueous sodium bicarbonate, then extracted with ethyl acetate (10.0 mL), the organic phase was washed with saturated brine (5.00 mL), dried over sodium sulfate, concentrated to give crude product, which was purified by column Waters Xbridge150 × 25mm × 5um; solvent: a = water +0.225 vol% ammonia (99%), B = acetonitrile; gradient: 20% -50%,10min, separation and purification to obtain N-methyl-3- (8-oxo-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-13) (0.83 mg, 1.36% yield).
1 H NMR(400MHz,DMSO-d 6 )δ12.03(s,1H),8.72(d,1H),8.61(s,1H),8.38(br s,1H),8.13(d,1H),8.09(s,1H),8.04(dd,1H),7.65(dd,1H),7.41-7.29(m,1H),6.98(d,1H),4.35-4.30(m,2H),3.63(br s,2H),2.44(br s,3H)
LC-MS,M/Z:467.1[M+H] + .
Example 14: preparation of Compound I-14
The synthetic route is as follows:
Figure BDA0003735878680000352
the first step is as follows: synthesis of methyl (R) 2- ((tert-butoxycarbonyl) amino) -3-methoxypropionate (B14-2)
Methyl (R) -2- ((t-butoxycarbonyl) amino) -3-hydroxypropionate (15.0g, 68.4mmol,18.5mL, 1.00eq) and silver oxide (50.7g, 218mmol, 3.20eq) were dissolved in acetonitrile (400 mL) and replaced with nitrogen three times, and iodomethane (48.5g, 342mmol,21.3mL, 5.00eq) was added dropwise at 0 ℃. And reacted at 25 ℃ for 24 hours. After the reaction was completed, the reaction mixture was directly filtered and concentrated to obtain a colorless oil, which was purified by column chromatography (petroleum ether/ethyl acetate =100/1to 10/1) to obtain methyl (R) -2- ((tert-butoxycarbonyl) amino) -3-methoxypropionate (B14-2) (15.2 g, yield 95.24%).
1 HNMR(400MHz,CDCl 3 )δ5.48-5.23(m,1H),4.53-4.33(m,1H),3.86-3.79(m,1H),3.77(s,3H),3.61–3.58(m,1H),3.35(s,3H),1.46(s,9H)
The second step is that: synthesis of (S) - (1-hydroxy-3-methoxypropan-2-yl) carbamic acid tert-butyl ester (B14-3)
Methyl (R) -2- ((t-butoxycarbonyl) amino) -3-methoxypropionate (B14-2) (15.0 g,68.4mmol,18.5mL, 1.00eq) was dissolved in tetrahydrofuran under nitrogen protection, and lithium borohydride (4M, 34.2mL, 2.00eq) was slowly added dropwise at 0 ℃ and reacted at 25 ℃ for 2 hours after completion of the addition. After completion of the reaction, the reaction mixture was slowly added to ice water (50.0 mL), quenched, extracted with ethyl acetate 150mL (50.0 mL × 3), dried and concentrated to give a colorless oily substance, and purified by column chromatography (petroleum ether/ethyl acetate =100/1to 2/1) to give tert-butyl (S) - (1-hydroxy-3-methoxypropan-2-yl) carbamate (B14-3) (13.5 g, yield 96.1%).
1 HNMR(400MHz,CDCl 3 )δ5.10(s,1H),3.78-3.66(m,2H),3.63-3.61(m,1H),3.52-3.44(m,2H),3.30(s,3H),2.61(s,1H),1.38(s,9H)
The third step: synthesis of methyl (S) -3-bromo-1- (2- ((tert-butoxycarbonyl) amino) -3-methoxy-3-oxopropyl) -1H-pyrazole-5-carboxylate (B14-4)
Methyl 3-bromo-1H-pyrazole-5-carboxylate (1.00g, 4.88mmol, 1.00eq), (S) - (1-hydroxy-3-methoxypropan-2-yl) carbamic acid tert-butyl ester (B14-3) (1.30g, 6.34mmol, 1.30eq) and triphenylphosphine (2.56g, 9.76mmol, 2.00eq) were dissolved in toluene (10.0 mL), and diisopropyl azodicarboxylate (1.28g, 6.33mmol, 1.30eq) was added dropwise under nitrogen protection at 10 ℃ and reacted at 20 ℃ for 2 hours after the addition was completed. After completion of the reaction, the reaction mixture was added to ice water (50 mL), extracted with 150mL (50ml × 3), dried and filtered to give an oil, and purified by column chromatography (petroleum ether/ethyl acetate =100/1to 1/1) to give (S) -methyl 3-bromo-1- (2- ((tert-butoxycarbonyl) amino) -3-methoxy-3-oxopropyl) -1H-pyrazole-5-carboxylate (B14-4) (1.75 g, yield 91.4%).
1 HNMR(400MHz,CDCl 3 )δ6.89-6.77(m,1H),5.09-5.04(m,1H),5.02-4.96(m,2H),4.66-4.56(m,1H),3.89(s,3H),3.51-3.40(m,2H),3.35(s,3H),1.36(s,9H)
The fourth step: synthesis of (S) -2-bromo-6- (methoxymethyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one (B14-5)
(S) -3-bromo-1- (2- ((tert-butoxycarbonyl) amino) -3-methoxy-3-oxopropyl) -1H-pyrazole-5-carboxylic acid methyl ester (B14-4) (1.45g, 3.69mmol) was dissolved in ethyl acetate (10.0 mL), ethyl acetate hydrochloride was added dropwise under nitrogen protection, and the reaction was carried out at 25 ℃ for 2 hours, after completion of the reaction, it was directly concentrated and added to toluene (20.0 mL), nitrogen was substituted three times, triethylamine (1.39g, 13.6mmol, 1.91mL) was further added to the reaction solution, and the reaction was carried out at 100 ℃ for 12 hours. After completion of the reaction, concentration and purification by column chromatography (petroleum ether/ethyl acetate =100/1to 1/1) gave (S) -2-bromo-6- (methoxymethyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one (B14-5) (1.05 g, yield 88.4%).
1 HNMR(400MHz,CDCl 3 )δ6.86(s,1H),5.01-4.95(m,2H),4.41-4.36(m,1H),4.24-4.17(m,1H),3.58-3.52(m,1H),3.51-3.45(m,1H),3.41(s,3H)
LC-MS,M/Z(ESI):260.0[M+H] +
The fifth step: synthesis of (S) -2- (2-aminopyridin-3-yl) -6- (methoxymethyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one (B14-6)
(S) -2- (2-Aminopyridin-3-yl) -6- (methoxymethyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one (B14-5) (250mg, 961. Mu. Mol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (233mg, 1.06mmol, 1.1eq), potassium phosphate (408mg, 1.92mmol) and 1, 3-bis (diphenylphosphino) propalladium (11.3mg, 19.2. Mu. Mol) were dissolved in dioxane (5.00 mL), replaced with nitrogen three times and reacted at 90 ℃ for 12 hours. After the reaction was completed, it was used in the next step.
LC-MS,M/Z(ESI):274.2[M+H] +
And a sixth step: synthesis of (S) -6- (methoxymethyl) -2- (2- ((4- (trifluoromethyl) phenyl) amino) pyridin-3-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one (I-14)
Figure BDA0003735878680000371
The reaction solution of the previous step, 1-iodo-4- (trifluoromethyl) benzene (199mg, 731. Mu. Mol), tris (dibenzylideneacetone) dipalladium (33.5mg, 36.5. Mu. Mol), cesium carbonate (476 mg, 1.46mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (42.3 mg, 73.1. Mu. Mol) were dissolved in N, N-dimethylformamide (5.00 mL) and stirred at 100 ℃ for 2 hours under nitrogen protection, after completion of the reaction, (S) -6- (methoxymethyl) -2- (2- ((4- (trifluoromethyl) phenyl) amino) pyridin-3-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one (30.0 mg) was obtained by direct filtration and concentration.
H NMR(400MHz,DMSO-d 6 )δ10.77(s,0.5H 1H),8.50(br s,0.5H 1H),8.33-8.22(m,2H),8.06-8.04(m,2H),7.66-7.64(m,2H),7.49-7.48(m,1H),7.05-6.99(m,1H),4.71-4.59(m,1H),4.52-4.40(m,1H),4.18-4.07(m,2H),3.54-3.41(m,2H),3.30(s,3H)
LC-MS,M/Z(ESI):418.2[M+H] +
Example 15: preparation of Compound I-15
Figure BDA0003735878680000372
The compound (S) -6- (methoxymethyl) -2- (2- ((4- (trifluoromethyl) phenyl) amino) pyridin-3-yl) -6, 7-dihydroimidazo [1,2-a ]]Synthesis method of pyrazine-8 (5H) -ketone (I-15) refers to I-14, LC-MS, M/Z (ESI): 418.2[ M ] +H] + 。
Example 16: preparation of Compound I-16
Figure BDA0003735878680000373
The compound (R) -N- (2- (2- ((4- (trifluoromethyl) phenyl) amino) pyridin-3-yl) -5, 6-dihydro-4H-pyrrolo [1, 2-b)]Synthesis of pyrazol-4-yl) acetamide (I-16) is described in reference to I-14, LC-MS, M/Z (ESI): 402.2[ M ] +H] + 。
Example 17: preparation of Compound I-17
Figure BDA0003735878680000381
The compound (R) - (2- (2- ((4- (trifluoromethyl) phenyl) amino) pyridin-3-yl) -5, 6-dihydro-4H-pyrrolo [1, 2-b)]Synthesis method of pyrazole-4-yl) methyl carbamate (I-17) refers to I-14, LC-MS, M/Z (ESI): 418.2[ M + H ], [ M ], [] + 。
Example 18: preparation of Compound I-18
Figure BDA0003735878680000382
The compound (R) - (2- (2- ((4- (trifluoromethyl) phenyl) amino) pyridin-3-yl) -6, 7-dihydro-5H-pyrrolo [1, 2-a)]Synthesis method of imidazol-7-yl) methyl carbamate (I-18) refer to I-1, LC-MS, M/Z (ESI): 418.2, [ M + H ], [2 ]] + 。
Example 19: preparation of Compound I-19
Figure BDA0003735878680000383
Synthesis procedure for Compound I-19 referring to I-1, 5- (difluoro (methoxy) methyl) pyridin-2-amino was substituted for 5- (trifluoromethyl) pyridin-2-amino to give 4- ((5- (difluoro (methoxy) methyl) pyridin-2-yl) amino) -3- (6, 7-dihydro-5H-pyrrolo [1,2-a ] n]Imidazol-2-yl) -N-methylbenzenesulfonamide (I-19); LC-MS, M/Z (ESI) 450.2[ 2 ], [ M + H ]] + 。
Example 20: preparation of Compound I-20
Figure BDA0003735878680000384
Synthesis of Compound I-20 referring to I-1, 5- (trifluoromethyl) pyridin-2-amino was replaced with 5- (cyclopropyloxydifluoromethyl) pyridin-2-amino to give the compound 4- ((5- (cyclopropyloxydifluoromethyl) pyridin-2-yl) amino) -3- (6, 7-dihydro-5H-pyrrolo [1, 2-a)]Imidazol-2-yl) -N-methylbenzenesulfonamide (I-20); LC-MS, M/Z (ESI) 476.2[ M ] +H] + 。
Example 21: preparation of Compound I-21
Figure BDA0003735878680000391
The compound 5- (6, 7-dihydro-5H-pyrrolo [1,2-a ]]Imidazol-2-yl) -N-methyl-6- ((4- (pentafluoro- λ) 6 Synthesis method of (sulfanyl) phenyl) amino) pyridine-3-sulfonamide (I-21) refers to I-1, LC-MS, M/Z (ESI): 496.2[ M ] +H] + 。
Example 22: preparation of Compound I-22
Figure BDA0003735878680000392
Synthesis of Compound I-22 with reference to I-1, 5- (pentafluoro-Lambda) 6 -sulfanyl) -2-aminopyridine (A4) instead of 5- (trifluoromethyl) pyridin-2-amino to give the compound 3- (6, 7-dihydro-5H-pyrrolo [1, 2-a)]Imidazol-2-yl) -N-methyl-4- ((5- (pentafluoro- λ) 6 -sulfanyl) pyridin-2-yl) amino) benzeneSulfonamide (I-22); LC-MS, M/Z (ESI) 496.1[ M ] +H] + 。
Example 23: preparation of Compound I-23
The synthetic route is shown as follows:
Figure BDA0003735878680000401
the first step is as follows: synthesis of 2, 3-dibromo-5, 6-dihydro-7H-pyrrolo [1,2-a ] imidazol-7-one (B23-2)
5, 6-dihydro-7H-pyrrolo [1,2-a ] imidazol-7-one (5.00g, 40.9 mmol) was dissolved in N, N-dimethylformamide (100 mL), and N-bromosuccinimide (14.9 g,83.9 mmol) was added in portions to the reaction solution at 0 ℃ and reacted at 25 ℃ for 5 hours. Water (300 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (300 mL), and the organic phase was washed with saturated brine (300 mL), dried over sodium sulfate, and concentrated to give the crude product. Then, the compound was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 50.
LC-MS,M/Z(ESI):280.9[M+H] + 。
The second step: synthesis of 2, 3-dibromo-7, 7-difluoro-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B23-3)
2, 3-dibromo-5, 6-dihydro-7H-pyrrolo [1,2-a ] imidazol-7-one (B23-2) (10.0g, 35.7mmol) was dissolved in methylene chloride (50.0 mL), 0 was added, diethylaminosulfur trifluoride (10.0g, 179mmol) was added to the reaction solution, and the reaction was carried out at 20 ℃ for 2 hours. Water (500 mL) was added to the reaction mixture, followed by extraction with dichloromethane (500 mL), and the organic phase was washed with saturated brine (300 mL), dried over sodium sulfate, and concentrated to give the crude product. Then, the product was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 50.
LC-MS,M/Z(ESI):302.9[M+H] + 。
The third step: synthesis of 2-bromo-7, 7-difluoro-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B23-4)
2, 3-dibromo-7, 7-difluoro-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B23-3) (1.00g, 3.31mmol) was dissolved in tetrahydrofuran (15.0 mL), and n-butyllithium (318mg, 3.31mmol) was added under nitrogen protection and reacted at-40 ℃ for 1 hour. The reaction solution was added with water (300 mL), followed by extraction with ethyl acetate (300 mL), and the organic phase was washed with saturated brine (300 mL), dried over sodium sulfate, and concentrated to give a crude product, which was then purified by separation with a silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
1 H NMR(400MHz,DMSO-d 6 )δ7.58(s,1H)4.23-4.29(m,2H)3.11(tt,2H)
LC-MS,M/Z(ESI):223.0[M+H] + 。
Referring to the preparation of the other compounds herein, 2-bromo-7, 7-difluoro-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B23-4) (320mg, 1.43mmol) and 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) benzenesulfonamide (622mg, 1.43mmol) were reacted to give 3- (7, 7-difluoro-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B23-5) (420 mg, 65.3% yield).
LC-MS,M/Z(ESI):452.1[M+H] + 。
5- (trifluoromethyl) pyridin-2-amine (A5) (165mg, 1.02mmol) and 3- (7, 7-difluoro-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B23-5) (420mg, 2.04mmol) were reacted to give 3- (7, 7-difluoro-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B23-6) (220 mg, 39.8% yield).
LC-MS,M/Z(ESI):594.3[M+H] + 。
3- (7, 7-difluoro-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B23-6) (220mg, 370. Mu. Mol) was stripped of the PMB group in trifluoroacetic acid (20.0 mL) to give 3- (7, 7-difluoro-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-23) (15.0 mg, 8.55% yield).
Figure BDA0003735878680000411
1 H NMR(400MHz,DMSO-d 6 )δppm 11.03(s,1H),8.58(s,1H),8.47(s,1H),8.14(d,1H),7.97-8.02(m,2H),7.67(dd,1H),7.38(q,1H),7.01(d,1H),4.31-4.38(m,2H),3.18-3.27(m,2H),2.45(d,3H)
LC-MS,M/Z(ESI):474.1[M+H] +
Example 24: preparation of Compound I-24
The synthetic route is shown as follows:
Figure BDA0003735878680000412
the first step is as follows: synthesis of 2, 3-dibromo-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine (B24-2)
5,6,7,8-tetrahydroimidazo [1,2-a ] pyridine (900mg, 7.37mmol) was dissolved in dichloromethane (10 mL), N-bromosuccinimide (3.27g, 18.42mmol) was added, stirring was performed at room temperature for 2h, followed by concentration, and the crude product was purified with a silica gel chromatography column (petroleum ether: ethyl acetate =10: 1-3.
LC-MS,M/Z(ESI):231.0[M+H] + 。
The second step: synthesis of 2-bromo-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine (B24-3)
2, 3-dibromo-5, 6,7, 8-tetrahydroimidazo [1,2-a ]]Pyridine (B24-2) (550mg, 1.96mmol) was dissolved in tetrahydrofuran (10 mL), and after cooling to-78 ℃ and 2.5M n-butyllithium (0.78ml, 1.96mmol) was added dropwise, after stirring for 1 hour, a saturated ammonium chloride solution (10 mL) was added, followed by extraction with ethyl acetate (10mL. Times.3), and the organic phase was collected and washed with 10mL of saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =10:1-3a]Pyridine (B24-3) (0.3 g, 76% yield).
LC-MS,M/Z(ESI):201.0[M+H] + 。
Referring to the preparation of the other compounds herein, 2-bromo-5,6,7,8-tetrahydroimidazo [1,2-a ] pyridine (B24-3) (0.3 g, 1.49mmol) was dissolved in 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3-dioxan-2-yl) benzenesulfonamide (653mg, 1.49mmol)' and reacted to give 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-2-yl) benzenesulfonamide (B24-4) (500 mg, yield: 78%).
LC-MS,M/Z(ESI):430.1[M+H] + 。
4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-2-yl) benzenesulfonamide (B24-4) (300mg, 0.70mmol) was reacted with 5- (trifluoromethyl) pyridin-2-amine (226mg, 1.40mmol) to give N- (4-methoxybenzyl) -N-methyl-3- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B24-5) (200 mg, yield: 50.1%).
LC-MS,M/Z(ESI):572.1[M+H] + 。
N- (4-methoxybenzyl) -N-methyl-3- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B24-4) (50mg, 0.087mmol) was freed of the PMB group in trifluoroacetic acid (1 mL) to give N-methyl-3- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-24) (20 mg, yield: 50.6%).
Figure BDA0003735878680000421
1 H NMR(400MHz,DMSO-d 6 )δ12.46(s,1H),8.72(d,1H),8.57(s,1H),7.99(d,1H),7.95(d,1H),7.67(s,1H),7.54(q,1H),7.27(q,1H),7.03(d,1H),4.01-4.04(m,2H),2.87-2.90(m,2H),2.48(d,3H),1.88-1.93(m,4H)
LC-MS,M/Z(ESI):452.1[M+H] + 。
Example 25: preparation of Compound I-25
The synthetic route is shown as follows:
Figure BDA0003735878680000431
the first step is as follows: synthesis of 5, 6-dibromo-2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazole (B25-2)
2,4, 5-tribromo-1H-imidazole (5 g, 16.41mmol) was dissolved in tetrahydrofuran (50 mL), cooled to-78 deg.C, 2.5M n-butyllithium (6.56mL, 16.41mmol) was added dropwise, 2-methyloxirane (11.48mL, 164mmol) was added after stirring for 1H, gradually warmed to room temperature, and stirred for 12H. Saturated ammonium chloride solution (50 mL) was added, extracted with ethyl acetate (50mL. Times.3), and the organic phase was collected and washed with 50mL of saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =10: 1-3)]Oxazole (B25-2) (4 g, 86.3% yield). LC-MS, M/Z (ESI): 282.8[ M ] +H] + 。
The second step is that: synthesis of 6-bromo-2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazole (B25-3)
Reacting 5, 6-dibromo-2-methyl-2, 3-dihydroimidazo [2,1-b ]]Oxazole (B25-2) (1g, 3.55mmol) was dissolved in tetrahydrofuran (10 mL), cooled to-78 deg.C, 2.5M n-butyllithium (1.49ml, 3.72mmol) was added dropwise, stirred for 1h, then saturated ammonium chloride solution (10 mL) was added, extracted with ethyl acetate (10mL. Times.3), the organic phase was collected and washed with 10mL saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =10: 1-3)]Oxazole (B25-3) (0.6 g, 83.3% yield). LC-MS, M/Z (ESI): 202.8[ M ] +H] + 。
Referring to the preparation of other compounds herein, 6-bromo-2-methyl-2, 3-dihydroimidazo [2,1-b ] is prepared]Oxazole (B25-3) (0.6 g, 2.96mmol) was reacted with 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3-dioxan-2-yl) benzenesulfonamide (A1) (1.29g, 2.96mmol) to give 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-b ]]Oxazol-6-yl) benzenesulfonamide (B25-4) (700 mg, yield: 54.9%). LC-MS, M/Z (ESI): 432.1[ M ] +H] + 。
Reacting 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-b ]]Oxazol-6-yl) benzenesulfonamide (B25-4) (200mg, 0.464mmol) was reacted with 5- (trifluoromethyl) pyridin-2-amine (113mg, 0.695mmol) to give N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2, 1-B: (meth) acrylic acid)]Oxazol-6-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B25-5) (150 mg, yield: 56.4%). LC-MS, M/Z (ESI): 574.1, [ M ] +H] + 。
N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B25-5) (70mg, 0.122mmol) was stripped of the PMB group in trifluoroacetic acid (1 ml) to give N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-25) (50 mg, yield: 90%).
Figure BDA0003735878680000441
1 H NMR(400MHz,DMSO-d 6 )δ11.3(s,1H),8.54(s,1H),8.50(d,1H),7.96(d,1H),7.91(d,1H),7.55(d,1H),7.54(s,1H),7.42(q,1H),6.96(d,1H),5.43-5.52(m,1H),4.35-4.40(m,1H),3.83-3.87(m,1H),2.41(d,3H),1.53(d,3H)
LC-MS,M/Z(ESI):454.1[M+H] + 。
Example 26: preparation of Compound I-26
The synthetic route is as follows:
Figure BDA0003735878680000442
the first step is as follows: synthesis of 5-bromo-6-chloro-N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (B26-2)
5-bromo-6-chloropyridine-3-sulfonyl chloride (8.60g, 29.6 mmol) was dissolved in dichloromethane (50.0 mL), triethylamine (8.97g, 88.7 mmol) and 1- (4-methoxyphenyl) -N-methylmethanamine (4.56g, 30.15mmol) were added, and reaction was carried out at 25 ℃ for 1 hour to give 5-bromo-6-chloro-N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (B26-2) (11.0 g, 91.7% yield).
The second step is that: synthesis of 5-bromo-N- (4-methoxybenzyl) -N-methyl-6- (4- (trifluoromethyl) phenoxy) pyridine-3-sulfonamide (B26-3)
5-bromo-6-chloro-N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (B26-2) (4.17g, 10.3mmol) was dissolved in tetrahydrofuran (50.0 mL), and cesium carbonate (16.8g, 30.8mmol) and 4- (trifluoromethyl) phenol (2.00g, 12.3mmol) were added and reacted at 45 ℃ for 2 hours. Water (200 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to give 5-bromo-N- [ (4-methoxyphenyl) methyl ] -N-methyl-6- [4- (trifluoromethyl) phenoxy ] pyridine-3-sulfonamide (B26-3) (5.00 g, 91.5% yield).
The third step: synthesis of (5- (N- (4-methoxybenzyl) -N-methylsulfonyl) -2- (4- (trifluoromethyl) phenoxy) pyridin-3-yl) boronic acid (B26-4)
5-bromo-N- [ (4-methoxyphenyl) methyl ] -N-methyl-6- [4- (trifluoromethyl) phenoxy ] pyridine-3-sulfonamide (B26-3) (3.00g, 5.65mmol) was dissolved in tetrahydrofuran (30.0 mL), N-butyllithium (2.50M, 2.71mL, 6.78mmol) was added at-70 deg.C, and the reaction was stirred at-70 deg.C for 1 hour, triisopropyl borate (5.31g, 28.2mmol) was added, and the reaction was stirred at-70 deg.C for 2 hours. The reaction solution was added to water (200 mL), followed by extraction with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to give a crude product, which was isolated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
The fourth step: synthesis of (R) -N- (4-methoxybenzyl) -N-methyl-5- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -6- (4- (trifluoromethyl) phenoxy) pyridine-3-sulfonamide (B26-5)
(5- (N- (4-methoxybenzyl) -N-methylsulfamoyl) -2- (4- (trifluoromethyl) phenoxy) pyridin-3-yl) boronic acid (B26-4) (100mg, 201. Mu. Mol) and (R) -6-bromo-2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazole (61.4 mg, 302. Mu. Mol) were dissolved in dioxane (10.0 mL), and [1, 1-bis (diphenylphosphino) ferrocene ] dichloropalladium (73.7 ug, 1.01. Mu. Mol), potassium carbonate (55.7 mg, 403. Mu. Mol) were added, and the reaction was stirred at 105 ℃ for 6 hours. The reaction solution was added to water (100 mL), followed by extraction and concentration with ethyl acetate (100 mL) to give crude (R) -N- (4-methoxybenzyl) -N-methyl-5- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -6- (4- (trifluoromethyl) phenoxy) pyridine-3-sulfonamide (B26-5) (25.0 mg, 5.70% yield).
LC-MS,M/Z(ESI):575.1[M+H] +
The fifth step: synthesis of (R) -N-methyl-5- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -6- (4- (trifluoromethyl) phenoxy) pyridine-3-sulfonamide (I-26)
Figure BDA0003735878680000451
Reacting (R) -N- (4-methoxybenzyl) -N-methyl-5- (2-methyl-2, 3-dihydroimidazo [2,1-b ]]Oxazol-6-yl) -6- (4- (trifluoromethyl) phenoxy) pyridine-3-sulfonamide (B26-5) (200 mg, μmol) was dissolved in trifluoroacetic acid (15.0 mL) and reacted at 60 ℃ for 2 hours. The reaction mixture was added to a saturated aqueous potassium carbonate solution to adjust the pH to 7-8, followed by extraction with ethyl acetate (100 mL), washing of the organic phase with a saturated brine (200 mL), drying over sodium sulfate, and concentration to give a crude product. Then separated by reversed-phase high performance liquid chromatography (column: YMC Triart C18 25mm. Multidot.5um; solvent: A = water, B = acetonitrile; gradient: 21% -51%,10 minutes) to give (R) -N-methyl-5- (2-methyl-2, 3-dihydroimidazo [2,1-B ] in the form of a salt]Oxazol-6-yl) -6- (4- (trifluoromethyl) phenoxy) pyridine-3-sulfonamide (I-26). LC-MS, M/Z (ESI) 455.1[ 2 ] M + H] + 。
Example 27: preparation of Compound I-27
The synthetic route is as follows:
Figure BDA0003735878680000452
the first step is as follows: synthesis of methyl 2- (3-methyl-2-oxopyrrolidin-1-yl) acetate (B27-2)
3-methylpyrrolidone (4.5g, 45.4 mmol) was dissolved in tetrahydrofuran (50 ml), and the temperature was reduced to 0 ℃ to add sodium hydride (2.18g, 54.5mmol, 60%), followed by stirring for 0.5h, addition of methyl 2-bromoacetate (7.64g, 49.9mmol), gradual warming to room temperature, and stirring for 2h. Saturated ammonium chloride solution (50 mL) was added, extracted with ethyl acetate (50mL. Times.3), and the organic phase was collected and washed with 50mL saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =10: 1-1) to give methyl 2- (3-methyl-2-oxopyrrolidin-1-yl) acetate (B27-2) (5 g, 64.3% yield). LC-MS, M/Z (ESI) 172.1[ 2 ], [ M + H ]] + 。
The second step is that: synthesis of 2- (3-methyl-2-oxopyrrolidin-1-yl) acetamide (B27-3)
Methyl 2- (3-methyl-2-oxopyrrolidin-1-yl) acetate (B27-2) (5 g, 3.55mmol) was dissolved in 7M methanolic ammonia (50 ml) and the mixture was stirred at 60 ℃ for 12h. Spin-drying gave 2- (3-methyl-2-oxopyrrolidin-1-yl) acetamide (B27-3) (5 g, 100% yield). LC-MS, M/Z (ESI) 157.1[ 2 ] M + H] + 。
The third step: synthesis of 2-bromo-7-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B27-4)
2- (3-methyl-2-oxypyrrolidin-1-yl) acetamide (B27-3) (1g, 6.40mmol) was placed in a 100mL single-neck flask, tribromooxyphosphorus (3.67g, 12.81mmol) was added, heated to 80 ℃ to melt the tribromooxyphosphorus, and stirred for 3h. After the reaction mixture was cooled, water (30 mL) was slowly added, extracted with ethyl acetate (30mL. Times.3), and the organic phase was collected and washed with 10mL of saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =50: 1-10) to give 2-bromo-7-methyl-6, 7-dihydro-5H-pyrrole [1,2-a]Imidazole (B27-4) (700 mg, 54.4% yield).
LC-MS,M/Z(ESI):201.1[M+H] + 。
Referring to the preparation of the other compounds herein, 2-bromo-7-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] is prepared]Imidazole (B27-4) (0.7g, 3.48mmol) and 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3-dioxan-2-yl) benzenesulfonamide (A1) (1.52g, 3.48mmol) to give 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (7-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] s]Imidazol-2-yl) benzenesulfonamide (B27-5) (500 mg, yield: 33.4%). LC-MS, M/Z (ESI) 430.1[ M ] +H] + 。
Reacting 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (7-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ]]Imidazol-2-yl) benzenesulfonamide (B27-5) (300mg, 0.6988 mmol) was reacted with 5- (trifluoromethyl) pyridin-2-amine (340mg, 2.095mmol) to give N- (4-methoxybenzyl) -N-methyl-3- (7-methyl-6, 7-dihydro-5H-pyrrole [1,2-a ] -pyrrole]Imidazol-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B27-6) (100 mg, yield: 25.0%). LC-MS, M/Z (ESI) 572.1[ 2 ], [ M + H ]] + 。
N- (4-methoxybenzyl) -N-methyl-3- (7-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B27-6) (100mg, 0.175mmol) was freed of the PMB group in trifluoroacetic acid (1 ml) to give N-methyl-3- (7-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-27) (50 mg, yield: 63.3%).
Figure BDA0003735878680000461
1 H NMR(400MHz,DMSO-d 6 )δ12.41(s,1H),8.70(d,1H),8.57(s,1H),7.99(d,1H),7.94(q,1H),7.71(s,1H),7.56(q,1H),7.27(d,1H),7.01(d,1H),4.01-4.13(m,1H),3.94-3.99(m,1H),3.25-3.34(m,1H),2.76-2.78(m,1H),2.48(d,3H),2.14-2.17(m,1H),1.34(d,3H)
LC-MS,M/Z(ESI):452.1[M+H] + 。
Example 28: preparation of Compound I-28
Figure BDA0003735878680000471
Synthesis of Compound I-28 reference is made to I-1, LC-MS, M/Z (ESI): 450.2[ 2 ], [ M ] +H] +
Example 29: preparation of Compound I-29
The synthetic route is as follows:
Figure BDA0003735878680000472
the first step is as follows: synthesis of methyl 2- (4, 4-dimethyl-2-oxopyrrolidin-1-yl) acetate (B29-2)
4, 4-Dimethylpyrrolidone (3 g,26.5 mmol) was dissolved in tetrahydrofuran (50 ml), and then the solution was cooled to 0 ℃ and sodium hydride (1.27g, 31.8mmol, 60%) was added thereto, followed by stirring for 0.5h, further methyl 2-bromoacetate (4.87g, 31.8 mmol) was added thereto, the temperature was gradually raised to room temperature, and the mixture was stirred for 2h. Saturated ammonium chloride solution (50 mL) was added, extracted with ethyl acetate (50mL. Times.3), the organic phase was collected and washed with 50mL saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =10: 1-1) to give methyl 2- (4, 4-dimethyl-2-oxopyrrolidin-1-yl) acetate (B29-2) (4.2 g, 86% yield). LC-MS, M/Z (ESI): 186.1[ M ] +H] + 。
The second step is that: synthesis of 2- (4, 4-dimethyl-2-oxopyrrolidin-1-yl) acetamide (B29-3)
Methyl 2- (4, 4-dimethyl-2-oxopyrrolidin-1-yl) acetate (B29-2) (4.2g, 22.68mmol) was dissolved in 7M methanolic ammonia (50 ml), stirred at 60 ℃ for 12h. Spin-drying gave 2- (4, 4-dimethyl-2-oxopyrrolidin-1-yl) acetamide (B29-3) (3.5 g, 91% yield). LC-MS, M/Z (ESI): 171.1[ M ] +H] + 。
The third step: synthesis of 2-bromo-6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B29-4)
2- (4, 4-dimethyl-2-oxopyrrolidin-1-yl) acetamide (B29-3) (1.2g, 7.05mmol) was placed in a 100ml single-neck flask, phosphorus oxybromide (4.04g, 14.10 mmol) was added, the mixture was heated to 80 ℃ to melt the phosphorus oxybromide, and the mixture was stirred for 3h. After the reaction mixture was cooled, water (30 mL) was slowly added, and extracted with ethyl acetate (30mL × 3), and the organic phase was collected and washed with 10mL of saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering, and concentrating to obtainTo obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =50: 1-10) to give 2-bromo-6, 6-dimethyl-6, 7-dihydro-5H-pyrrole [1,2-a]Imidazole (B29-4) (500 mg, 33% yield).
LC-MS,M/Z(ESI):215.1[M+H] + 。
Referring to the preparation of the other compounds herein, 2-bromo-6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] is prepared]Imidazole (B29-4) (0.5g, 2.32mmol) was reacted with 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3-dioxan-2-yl) benzenesulfonamide (A1) (1.02g, 2.32mmol) to give 3- (6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] -a]Imidazol-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B29-5) (460 mg, yield: 44.6%). LC-MS, M/Z (ESI): 444.1[ M ] +H] + 。
Reacting 3- (6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [1,2-a ]]Imidazol-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B29-5) (460mg, 1.04mmol) was reacted with 5- (trifluoromethyl) pyridin-2-amine (504mg, 3.11mmol) to give 3- (6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] B]Imidazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B29-6) (60 mg, yield: 9.88%). LC-MS, M/Z (ESI): 586.1[ M ] +H] + 。
3- (6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B29-6) (60mg, 0.102mmol) was deputy of the PMB group in trifluoroacetic acid to give 3- (6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-29) (25 mg, yield: 52.4%).
Figure BDA0003735878680000481
1 H NMR(400MHz,DMSO-d 6 )δ12.23(s,1H),8.65(d,1H),8.57(s,1H),8.00(d,1H),7.94(q,1H),7.73(s,1H),7.56(q,1H),7.25(d,1H),7.02(d,1H),3.60(s,2H),2.75(s,2H),2.40(d,3H),1.24(s,6H)
LC-MS,M/Z(ESI):466.1[M+H] + 。
Example 30: preparation of Compound I-30
The synthetic route is as follows:
Figure BDA0003735878680000482
the first step is as follows: synthesis of 5, 6-dibromo-2, 2-dimethyl-2, 3-dihydroimidazo [2,1-B ] oxazole (B30-2)
2,4,5-tribromo-1H-imidazole (5.00g, 16.41mmol) was dissolved in tetrahydrofuran (50.0 mL), cooled to-78 deg.C, to which n-butyllithium (7.22mL, 18.05mmol, 2.5M) was slowly added dropwise, after stirring at that temperature for 30min, methyl propylene oxide (11.83g, 164.06mmol) was slowly added dropwise, and after the addition, the temperature was slowly raised to 25 deg.C for reaction for 16 hours. After the reaction was completed, the reaction mixture was quenched by addition of saturated ammonium chloride solution (20.0 mL), extracted three times with ethyl acetate (50.0 mL), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by separation and purification on a silica gel column (petroleum ether: ethyl acetate (V/V) = 3)]Oxazole (B30-2) (4.51 g, 92.9% yield). LC-MS, M/Z (ESI): 297.0[ M ] +H] + 。
The second step is that: synthesis of 6-bromo-2, 2-dimethyl-2, 3-dihydroimidazo [2,1-B ] oxazole (B30-3)
Reacting 5, 6-dibromo-2, 2-dimethyl-2, 3-dihydroimidazo [2,1-b ]]Oxazole (B30-2) (4.50g, 15.20mmol) was dissolved in tetrahydrofuran (50.0 mL), cooled to-78 deg.C, n-butyllithium (6.08mL, 15.20mmol, 2.5M) was slowly added dropwise thereto, and after stirring at that temperature for 30min, saturated ammonium chloride solution (20.0 mL) was added thereto for quenching, extraction was performed three times with ethyl acetate (50.0 mL), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by separation and purification with a silica gel column (petroleum ether: ethyl acetate (V/V) = 3)]Oxazole (B30-3) (2.21 g, 67.0% yield). LC-MS, M/Z (ESI): 217.0[ M + H ]] + 。
Referring to the method of the other examples, the compound 6-bromo-2, 2-dimethyl-2, 3-dihydroimidazo [2,1-b ]]Oxazole (B30-3) (2.00g, 9.21mmol) was reacted with 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (A5, 4.01g, 9.21mmol) to give 3- (2, 2-dimethyl-2, 3-dihydroimidazo [2, 1-B)]Oxazol-6-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B30-4) (3.18 g, 77.5% yield). LC-MS, M/Z (ESI): 446.1[ M ] +H] + 。
Reacting 3- (2, 2-dimethyl-2, 3-dihydroimidazo [2,1-b ]]Reaction of oxazol-6-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B30-4) (1.00g, 2.24mmol) with 5- (trifluoromethyl) pyridin-2-amine (A5) (1.09g, 6.73mmol) gave 3- (2, 2-dimethyl-2, 3-dihydroimidazo [2, 1-B)]Oxazol-6-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin) -2-yl) amino) benzenesulfonamide (B30-5) (230 mg, 17.4% yield). LC-MS, M/Z (ESI) 588.0[ M + H ]] + 。
3- (2, 2-dimethyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin) -2-yl) amino) benzenesulfonamide (B30-5) (200mg, 0.34mmol) was stripped of the PMB group in trifluoroacetic acid to give 3- (2, 2-dimethyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-30) (85 mg, 53.4% yield).
Figure BDA0003735878680000491
1 H NMR(400MHz,CDCl 3 )δ11.72(s,1H),8.88(d,1H),8.52(s,1H),7.94(d,1H),7.68(ddd,2.4Hz,2H),7.00(s,1H),6.91(d,1H),3.96(s,2H),2.66(d,3H),1.69(s,6H).
LC-MS,M/Z(ESI):468.1[M+H] + 。
Example 31: preparation of Compound I-31
The synthetic route is shown as follows:
Figure BDA0003735878680000501
the first step is as follows: synthesis of (S) -5, 6-dibromo-2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazole (B31-2)
2,4, 5-tribromo-1H-imidazole (20g, 65.6 mmol) is dissolved in tetrahydrofuran (200 mL), the temperature is reduced to-78 ℃,2.5M n-butyllithium (26.2mL, 65.6 mmol) is added dropwise, after stirring for 1H, (S) -2-methyloxirane (45.9mL, 656mmol) is added, the temperature is gradually increased to the room temperature, and the stirring is carried out for 12H. Saturated ammonium chloride solution (200 mL) was added, extracted with ethyl acetate (200mL. Times.3), and the organic phase was collected and washed with 200mL saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =10: 1-3)]Oxazole (B31-2) (12.5 g, 67.6% yield). LC-MS, M/Z (ESI): 282.8[ M ] +H] + 。
The second step is that: synthesis of (S) -6-bromo-2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazole (B31-3)
Reacting (S) -5, 6-dibromo-2-methyl-2, 3-dihydroimidazole [2,1-b ]]Oxazole (B31-2) (12.5g, 44.3 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to-78 deg.C, 2.5M n-butyllithium (18.6 mL,46.5 mmol) was added dropwise, after stirring for 1h, saturated ammonium chloride solution (100 mL) was added, extracted with ethyl acetate (100mL. Times.3), the organic phase was collected and washed with 100mL saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =10: 1-3) to give (S) -6-bromo-2-methyl-2, 3-dihydroimidazo [2,1-b]Oxazole (B31-3) (8.0 g, 88.7% yield).
LC-MS,M/Z(ESI):202.8[M+H] + 。
Referring to the method of the other examples, (S) -6-bromo-2-methyl-2, 3-dihydroimidazo [2,1-b ]]Oxazole (B31-3) (0.5g, 2.3mmol) was reacted with 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3-dioxan-2-yl) benzenesulfonamide (A1) (1.0g, 2.3mmol) to give (S) -4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] to give]Oxazol-6-yl) benzenesulfonamide (B31-4) (500 mg, yield: 50.4%). LC-MS, M/Z (ESI) 432.1[ 2 ], [ M + H ]] + 。
Reacting (S) -4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-b ]]Oxazol-6-yl) benzenesulfonamide (B31-4) (400mg, 0.9mmol) was reacted with 5- (trifluoromethyl) pyridin-2-amine (226mg, 1.4 mmol) to give (S) -N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2, 1-B)]Oxazol-6-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B31-5) (150 mg, yield: 28.2%). LC-MS, M/Z (ESI): 574.1, [ M ] +H] + 。
(S) -N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B31-5) (140mg, 0.2mmol) was stripped of the PMB group in trifluoroacetic acid to give (S) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-31) (75 mg, yield: 67.8%).
Figure BDA0003735878680000511
1 H NMR(400MHz,DMSO-d 6 )δ11.3(s,1H),8.52(t,2H),7.96(d,1H),7.91(d,1H),7.55(d,1H),7.54(s,1H),7.42(q,1H),6.96(d,1H),5.43-5.52(m,1H),4.35-4.40(m,1H),3.83-3.87(m,1H),2.41(d,3H),1.53(d,3H)
LC-MS,M/Z(ESI):454.1[M+H] + 。
Example 32: preparation of Compound I-32
The synthetic route is as follows:
Figure BDA0003735878680000512
the first step is as follows: synthesis of N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((6- (trifluoromethoxy) pyridin-3-yl) amino) benzenesulfonamide (B32-1)
Reacting 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-b ]]Dissolving oxazole-6-yl benzenesulfonamide (B25-4) (600mg, 1.391mmol) in DMF (5 ml), cooling to 0 deg.C, adding sodium hydride (278mg, 6.95mmol, 60%), stirring for 0.5h,6- (trifluoromethoxy) pyridin-3-amine (297mg, 1.669mmol) was added, the temperature was gradually raised to room temperature and stirred for 12h. The reaction mixture was added to water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was collected and washed with 10mL of saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =20: 1-3) to give N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazole [2,1-b]Oxazol-6-yl) -4- ((6- (trifluoromethoxy) pyridin-3-yl) amino) benzenesulfonamide (B32-1) (500 mg, 61.0% yield).
LC-MS,M/Z(ESI):590.1[M+H] + 。
The second step is that: synthesis of N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -4- ((6- (trifluoromethoxy) pyridin-3-yl) amino) benzenesulfonamide (I-32)
Figure BDA0003735878680000513
N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((6- (trifluoromethoxy) pyridin-3-yl) amino) benzenesulfonamide (B32-1) (500mg, 0.848mmol) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (1 ml) was added, and stirring was carried out for 12h. Spin-dried, and the crude was purified by silica gel chromatography (petroleum ether: ethyl acetate =20: 1-1) to give N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -4- ((6- (trifluoromethoxy) pyridin-3-yl) amino) benzenesulfonamide (I-32) (250 mg, 62.8% yield).
1 H NMR(400MHz,DMSO-d 6 )δ9.81(s,1H),8.19(d,1H),7.92(d,1H),7.80(q,1H),7.45(d,1H),7.38(s,1H),7.22-7.28(m,3H),5.41-5.47(m,1H),4.33-4.38(m,1H),3.80-3.84(m,1H),2.38(d,3H),1.50(d,3H)
LC-MS,M/Z(ESI):470.1[M+H] + 。
Example 33: preparation of Compound I-33
The synthetic route for compound I-33 is shown below:
Figure BDA0003735878680000521
the first step is as follows: synthesis of (R) -5, 6-dibromo-2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazole (B33-2)
Dissolving 2,4, 5-tribromo-1H-imidazole (17.74g, 58.2mmol) in anhydrous tetrahydrofuran (85 mL), adding n-butyl lithium (2.5M, 23.3mL, 58.2mmol) dropwise at-78 deg.C under the protection of nitrogen, stirring at-78 deg.C for 45 min, adding (R) -2-methyloxirane (33.8g, 582mmol), naturally returning to room temperature, stirring, reacting for 2 days, adding 40mL saturated ammonium chloride at 0 deg.C, quenching reaction, extracting with ethyl acetate (100mL x 3), and extracting the organic phase with anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3) to give (R) -5, 6-dibromo-2-methyl-2, 3-dihydroimidazo [2,1-b]Oxazole (B33-2) (13.01 g, 79% yield). LC-MS, M/Z (ESI) 282.80[ 2 ] M + H] + 。
The second step is that: synthesis of (R) -6-bromo-2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazole (B33-3)
Reacting (R) -5, 6-dibromo-2-methyl-2, 3-dihydroimidazo [2,1-b ]]Oxazole (B33-2) (13.0g, 46.1mmol) was dissolved in anhydrous tetrahydrofuran (72 mL), n-butyllithium (2.5M, 18.4mL, 46.1mmol) was added dropwise at-78 deg.C, the reaction was carried out at-78 deg.C for 2 hours, the reaction was quenched with 25mL of saturated ammonium chloride at 0 deg.C, ethyl acetate (50mL. Times.3) was extracted, and the organic phase was extracted with anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3) to give (R) -6-bromo-2-methyl-2, 3-dihydroimidazole [2,1-b]Oxazole (B33-3) (6.88 g, 73.4% yield). LC-MS, M/Z (ESI): 202.9[ M ] +H] + 。
Referring to the procedure of the other example, 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (A1) (2.28g, 5.25mmol) and (R) -6-bromo-2-methyl-2, 3-dihydroimidazo [2, 1-b)]Oxazole (B33-3) (1.06g, 5.25mmol) to give (R) -4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazole [2, 1-B)]Oxazol-6-yl) benzenesulfonamide (B33-4) (1.104 g, yield: 48.8%). LC-MS, M/Z (ESI): 432.3[ M ] +H] + 。
Reaction of (R) -4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) benzenesulfonamide (B33-4) with 5- (trifluoromethyl) pyridin-2-amine gave (R) -N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((5- (trifluoromethyl)) pyridin-2-yl) amino) benzenesulfonamide (B33-5) (0.8 g, yield: 54.5%).
LC-MS,M/Z(ESI):574.10[M+H] + 。
(R) -N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((5- (trifluoromethyl)) pyridin-2-yl) amino) benzenesulfonamide (B33-5) (0.69g, 1.21mmol) was stripped of the PMB group in trifluoroacetic acid to give (R) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-33). (251 mg, yield: 45.7%).
Figure BDA0003735878680000531
1 H NMR(400MHz,DMSO)δ11.32(s,1H),8.56(s,1H),8.53(d,1H),7.98(d,1H),7.93(dd,1H),7.56(dd,1H),7.44(s,1H),7.31(q,1H),6.99(d,1H),5.54–5.45(m,1H),4.40(dd,1H),3.87(dd,1H),2.42(d,3H),1.55(d,3H).
LC-MS,M/Z(ESI):454.2[M+H] + 。
Example 34: preparation of Compound I-34
The synthetic route for the target compound I-34 is shown below:
Figure BDA0003735878680000532
the first step is as follows: synthesis of 4-nitrosomorpholine-3-carboxylic acid (B34-2)
Morpholine-3-formate salt (8.00g, 47.7 mmol) was dissolved in water (100 mL), and sodium nitrite (4.94g, 71.6 mmol) was added in portions to the reaction solution at 0 ℃ and reacted at 0 ℃ for 3 hours. Water (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (300 mL), and the reaction mixture was washed with saturated brine (200 mL)The organic phase was dried over sodium sulfate and concentrated to give the crude product. Then, the residue was purified by separation with a silica gel column (petroleum ether: ethyl acetate (V/V) = 50. LC-MS, M/Z (ESI) 161.1[ 2 ] M + H] + 。
The second step is that: synthesis of 6, 7-dihydro-4H- [1,2,3] oxadiazolo [4,3-c ] [1,4] oxazin-8-n-3-ol anion (B34-3)
4-nitrosomorpholine-3-carboxylic acid (B34-2) (7.60g, 47.4 mmol) was dissolved in toluene (100 mL), and trifluoroacetic anhydride (15.0 g, 71.2mmol) was added to the reaction mixture at 0 ℃ to react at 20 ℃ for 10 hours. Water (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to give the crude product. Then, the compound 6, 7-dihydro-4H- [1,2,3]Oxadiazole-o [4,3-c ] s][1,4]Oxazin-8-dianion-3-ol anion (B34-3) (6.00 g, 88.9% yield). LC-MS, M/Z (ESI): 143.2[ M ] +H] + 。
The third step: synthesis of 2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazine (B34-4)
Reacting 6, 7-dihydro-4H- [1,2,3]Oxadiazole-o [4,3-c ] s][1,4]Oxazin-8-n-3-ol anion (B34-3) (1.50g, 10.5 mmol) was dissolved in xylene (15.0 mL), and 2-ethynyl-4, 5-tetramethyl-1, 3, 2-dioxaborolane (2.10g, 13.7 mmol) was added to the solution, and the reaction was carried out at 120 ℃ for 8 hours. The reaction solution was added with water (50.0 mL), followed by extraction with ethyl acetate (100 mL), the organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to give a crude product, which was then isolated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 1-1) to give 2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydro-4H-pyrazolo [5, 1-c)][1,4]Oxazine (B34-4) (1.60 g, 60.6% yield). LC-MS, M/Z (ESI) 251.3[ 2 ], [ M + H ]] + 。
The fourth step: synthesis of 3-bromo-N- (4-methoxybenzyl) -N-methyl-4- ((4- (trifluoromethyl) phenyl) amino) benzenesulfonamide (B34-5)
3-bromo-4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (A1-2) (5.00g, 12.8mmol) and 4- (trifluoro-benzyl) are mixedMethyl) aniline (2.28g, 14.1mmol) was dissolved in N, N-dimethylformamide (50.0 mL), and potassium carbonate (12.6 g,38.6 mmol) was added, followed by stirring at 80 ℃ for 2 hours under nitrogen. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to give a crude product, which was then separated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 10. LC-MS, M/Z (ESI): 530.1[ M ] +H] + 。
The fifth step: synthesis of 3- (6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazin-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((4- (trifluoromethyl) phenyl) amino) benzenesulfonamide (B34-6)
3-bromo-N- (4-methoxybenzyl) -N-methyl-4- ((4- (trifluoromethyl) phenyl) amino) benzenesulfonamide (B34-5) (2.00g, 3.78mmol) and 2- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) -6, 7-dihydro-4H-pyrazolo [5, 1-c)][1,4]Oxazine (B34-4) (945mg, 3.78mmol) was dissolved in dioxane (30.0 mL) and water (10.0 mL), and potassium carbonate (1.57g, 11.3mmol) and 1, 1-bis (diphenylphosphino) ferrocene palladium chloride (276 mg, 377. Mu. Mol) were added and reacted at 100 ℃ for 8 hours under nitrogen. Then, water (50.0 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to give the crude product. Then, the product was purified by separation with a silica gel column (petroleum ether: ethyl acetate (V/V) =50 1-1) to give 3- (6, 7-dihydro-4H-pyrazolo [5,1-c][1,4]Oxazin-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((4- (trifluoromethyl) phenyl) amino) benzenesulfonamide (B34-6) (1.50 g, 69.3% yield). LC-MS, M/Z (ESI): 573.2[ M ] +H] + 。
And a sixth step: 3- (6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazin-2-yl) -N-methyl-4- ((4- (trifluoromethyl) phenyl) amino) benzenesulfonamide (I-34)
Figure BDA0003735878680000541
3- (6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazin-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((4- (trifluoromethyl) phenyl) amino) benzenesulfonamide (B34-6) (1.00g, 1.75mmol) was dissolved in trifluoroacetic acid (10.0 mL) and reacted at 60 ℃ for 2 hours. The reaction mixture was added to water (50.0 mL), then adjusted to neutral pH with potassium carbonate, and then extracted with ethyl acetate (50.0 mL), and the organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, and concentrated to give a crude product. Separation was then performed by reverse phase high performance liquid chromatography using (column: phenomenex luna C18 250 x 80mm x 10um; solvent: a = water + formic acid (0.05%), B = acetonitrile; gradient: 50% -80%,20 min) to give 3- (6, 7-dihydro-4H-pyrazolo [5,1-C ] [1,4] oxazin-2-yl) -N-methyl-4- ((4- (trifluoromethyl) phenyl) amino) benzenesulfonamide (I-34) (434 mg, 53.2% yield).
1 H NMR(DMSO-d 6 )δ9.99(s,1H),8.07(d,1H),7.66(d,2H),7.56-7.63(m,2H),7.40(d,2H),7.33(d,1H),6.61(s,1H),4.88(s,2H),4.22-4.29(m,2H),4.09-4.17(m,2H),2.43(d,3H)
LC-MS,M/Z(ESI):453.1[M+H] +
Example 35: preparation of Compound I-35
The synthetic route is as follows:
Figure BDA0003735878680000551
the first step is as follows: synthesis of methyl 2- (2-methyl-5-oxomorpholine) acetate (B35-2)
6-methylmorpholin-3-one (3g, 26.1mmol) is dissolved in tetrahydrofuran (30 ml), cooled to 0 ℃ and sodium hydride (1.25g, 31.3mmol, 60%) is added, stirring is carried out at 0 ℃ for 30 minutes, methyl 2-bromoacetate (4.78g, 31.3mmol) is added and stirring is carried out at 0 ℃ for 2h. Water (100 mL) was added, extracted with ethyl acetate (100mL. Times.3), and the organic phase was collected and washed with 100mL of saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 50.
LC-MS,M/Z(ESI):188.0[M+H] + 。
The second step is that: synthesis of 2- (2-methyl-5-oxomorpholine) acetamide (B35-3)
Methyl 2- (2-methyl-5-oxomorpholine) acetate (B35-2) (3g, 16.03mmol) was dissolved in methanol (5 ml), and 7M ammonia in methanol (25 ml) was added, followed by stirring at 60 ℃ for 4 hours in a stuffy pot. Direct spin-drying gave 2- (2-methyl-5-oxomorpholine) acetamide (B35-3) (2.76 g, 100% yield). LC-MS, M/Z (ESI): 173.0[ M ] +H] + 。
The third step: synthesis of 2-bromo-6-methyl-5, 6-dihydro-8H-imidazo [2,1-c ] [1,4] oxazine (B35-4)
2- (2-methyl-5-oxomorpholine) acetamide (B35-3) (1.5 g, 8.71mmol) and phosphorus oxybromide (5 g, 17.42mmol) were placed in a 50ml single-neck flask and heated to 80 ℃ for 1 hour. After completion of the reaction, the reaction mixture was slowly added to ice water (30 mL), extracted with ethyl acetate (100mL. Times.3), and the organic phase was collected and washed with 100mL of saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =10: 1-3)][1,4]Oxazine (B35-4) (0.8 g, 42.3% yield)
LC-MS,M/Z(ESI):217.0[M+H] + 。
Referring to the procedure of the other example, compound B35-4 (359mg, 1.65mmol) was reacted with intermediate A1 (0.6g, 1.38mmol) to give the compound 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (6-methyl-5, 6-dihydro-8H-imidazo [2,1-c ] [1,4] oxazin-2-yl) benzenesulfonamide (B35-5) (450 mg, 73.3% yield).
LC-MS,M/Z(ESI):446.1[M+H] + 。
Reaction of Compound B35-5 (450mg, 1.01mmol) with intermediate A5 (327mg, 2.02mmol) gave N- (4-methoxybenzyl) -N-methyl-3- (6-methyl-5, 6-dihydro-8H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B35-6) (200 mg, yield: 33.7%)
LC-MS,M/Z(ESI):588.1[M+H] + 。
Compound B35-6 was freed of the PMB group in trifluoroacetic acid to give N-methyl-3- (6-methyl-5, 6-dihydro-8H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-35) (50 mg, yield: 31.4%)
Figure BDA0003735878680000561
1 H NMR(400MHz,DMSO-d 6 )δ12.02(s,1H),8.69(d,1H),8.57(s,1H),8.03(d,1H),7.94(d,1H),7.59(s,1H),7.57(d,1H),7.27(d,1H),7.05(d,1H),5.00(d,1H),4.82(d,1H),4.15-4.19(m,1H),4.05-4.07(m,1H),3.68-3.79(m,1H),2.40(d,3H),1.29(d,3H)
LC-MS,M/Z(ESI):468.1[M+H] + 。
Example 36: preparation of Compound I-36
The synthetic route is shown as follows:
Figure BDA0003735878680000562
the first step is as follows: synthesis of (2S, 4S) -4-fluoro-1-nitrosopyrrolidine-2-carboxylic acid (B36-2)
(2S, 4S) -4-fluoropyrrolidine-2-carboxylate (9.00g, 53.1mmol) was dissolved in water (50.0 mL), and sodium nitrite (3.66g, 53.1mmol) was added to the reaction mixture in portions at 0 ℃ to react at 20 ℃ for 4 hours. Water (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (400 mL), and the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to give crude (2S, 4S) -4-fluoro-1-nitrosopyrrolidine-2-carboxylic acid (B36-2) (8.00 g, 93.0% yield).
LC-MS,M/Z(ESI):163.1[M+H] + 。
The second step is that: synthesis of (5R) -5-fluoro-5, 6-dihydro-4H-pyrrolo [1,2-c ] oxadiazol-7-zwitterion-3-ol anion (B36-3)
(2S, 4S) -4-fluoro-1-nitrosopyrrolidine-2-carboxylic acid (B36-2) (8.00g, 49.3mmol) was dissolved in toluene (100 mL), and trifluoroacetic anhydride (15.6g, 74.0 mmol) was added to the reaction solution at 0 ℃ to react at 20 ℃ for 2 hours. The reaction solution was concentrated to give a crude product. Then, the compound was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 3.
LC-MS,M/Z(ESI):145.0[M+H] + 。
The third step: synthesis of (R) -5-fluoro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydro-4H-pyrrolo [1,2-B ] pyrazole (B36-4)
(5R) -5-fluoro-5, 6-dihydro-4H-pyrrolo [1,2-c ] oxadiazol-7-carbonium-3-ol anion (B36-3) (2.00g, 13.6 mmol) was dissolved in xylene (15.0 mL), and 2-ethynyl-4, 5-tetramethyl-1, 3, 2-dioxolane (2.70g, 17.8mmol) was added to the solution and reacted at 160 ℃ for 2 hours under microwave. Water (50.0 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to give crude (R) -5-fluoro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydro-4H-pyrrolo [1,2-B ] pyrazole (B36-4) (2.80 g of crude, 81.2% yield).
LC-MS,M/Z(ESI):253.1[M+H] + 。
The fourth step: synthesis of (R) -3- (5-fluoro-5, 6-dihydro-4H-pyrrolo [1,2-B ] pyrazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B36-5)
3-bromo-N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (A2) (3.58g, 6.74mmol) and (R) -5-fluoro-2- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) -5, 6-dihydro-4H-pyrrolo [1,2-B ] pyrazole (B36-4) (1.70g, 6.74mmol) were dissolved in dioxane (20.0 mL) and water (10.0 mL), potassium carbonate (2.80g, 20.23mmol) and 1, 1-bis (diphenylphosphino) ferrocene palladium chloride (493mg, 674. Mu. Mol) were added and reacted at 100 ℃ for 5 hours under nitrogen protection. Then, water (20.0 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (80.0 mL), and the organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to give the crude product. Then, the compound was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) = 10.
LC-MS,M/Z(ESI):573.2[M+H] + 。
The fifth step: (R) -3- (5-fluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-36)
Figure BDA0003735878680000571
(R) -3- (5-fluoro-5, 6-dihydro-4H-pyrrolo [1,2-B ] pyrazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B36-5) (600mg, 1.04mmol) was dissolved in trifluoroacetic acid (4.00 mL) and reacted at 60 ℃ for 1 hour. The reaction mixture was added to water (50.0 mL), and the pH was adjusted to neutral with potassium carbonate, followed by extraction with ethyl acetate (50.0 mL), and the organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, and concentrated to give a crude product. Separation was then performed by reverse phase high performance liquid chromatography using (column: phenomenex C18 x 30mm 3um; solvent: a = water + formic acid, B = acetonitrile; gradient: 35% -65%,7 min) to give (R) -3- (5-fluoro-5, 6-dihydro-4H-pyrrolo [1,2-B ] pyrazol-2-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-36) (23.8 mg, 4.96% yield).
1 H NMR(CDCl 3 )δ:8.54(s,1H),8.29(d,1H),7.72-7.85(m,4H),7.13-7.26(m,1H),6.83(d,1H),5.75(br s,1H),4.43-4.60(m,2H),4.32(br d,1H),3.00-3.44(m,2H),2.74(d,3H)
LC-MS,M/Z(ESI):456.0[M+H] +
Example 37: preparation of Compound I-37
The synthetic route is as follows:
Figure BDA0003735878680000581
the first step is as follows: synthesis of 2,4, 5-tribromo-1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-imidazole (B37-2)
2,4, 5-tribromo-1H-Imidazole (3g, 9.84mmol) was dissolved in DMF (30 ml), and (2-bromoethoxy) (tert-butyl) dimethylsilane (2.83g, 11.81mmol) and cesium carbonate (9.62g, 29.5 mmol) were added and stirred at 60 ℃ for 3h. Water (100 mL) was added, extracted with ethyl acetate (100mL. Times.3), and the organic phase was collected and washed with 100mL of saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =50: 1-3) to give 2,4,5-tribromo-1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H imidazole (B37-2) (3.6 g, 79.0% yield).
LC-MS,M/Z(ESI):460.8[M+H] + 。
The second step is that: synthesis of 2- (2, 4, 5-tribromo-1H-imidazol-1-yl) ethan-1-ol (B37-3)
2,4, 5-tribromo-1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-imidazole (B37-2) (3.6 g, 7.77mmol) was dissolved in dioxane (15 ml), 4M hydrogen chloride dioxane solution (15 ml) was added, stirred at room temperature for 1H, and spun dry to give 2- (2, 4, 5-tribromo-1H-imidazol-1-yl) ethan-1-ol (B37-3) (2.71 g, 100% yield).
LC-MS,M/Z(ESI):346.8[M+H] + 。
The third step: synthesis of 5, 6-dibromo-2, 3-dihydroimidazo [2,1-B ] oxazole (B37-4)
2- (2, 4, 5-tribromo-1H-imidazol-1-yl) ethan-1-ol (B37-3) (2.62g, 7.51mmol) was dissolved in DMF (25 ml), cooled to 0 deg.C, sodium hydride (601mg, 15.02mmol, 60%) was added, and stirred at 0 deg.C for 2H. After completion of the reaction, the reaction mixture was slowly added to water (100 mL), extracted with ethyl acetate (100mL. Times.3), and the organic phase was collected and washed with 100mL of saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =50: 1-3)]Oxazole (B37-4) (2 g, 99.4% yield).
LC-MS,M/Z(ESI):266.8[M+H] + 。
The fourth step: synthesis of 6-bromo-2, 3-dihydroimidazo [2,1-B ] oxazole (B37-5)
Reacting 5, 6-dibromo-2, 3-dihydroimidazole [2,1-b ]]Oxazole (B37-4) (2g, 7.47mmol) was dissolved in tetrahydrofuranTo 30ml of furan was cooled to-78 ℃ and 2.5M n-butyllithium (3.28ml, 8.21mmol) was added and stirred at-78 ℃ for 1h. The reaction mixture was slowly added to saturated ammonium chloride (100 mL), extracted with ethyl acetate (100mL. Times.3), and the organic phase was collected and washed with 100mL of saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =10: 1-3)]Oxazole (B37-5) (0.8 g, 56.7% yield).
LC-MS,M/Z(ESI):189.0[M+H] + 。
Referring to the procedures of the other examples, compound B37-5 (347mg, 1.84mmol) was reacted with intermediate A1 (0.8g, 1.84mmol) to give Compound 3- (2, 3-dihydroimidazo [2, 1-B)]Oxazol-6-yl) -4-fluoro-N- (4-methoxybenzyl) -N-toluenesulfonamide (B37-6) (0.2 g, yield: 26.1%). LC-MS, M/Z (ESI) 418.1[ 2 ], [ M + H ]] + 。
Reaction of Compound B37-6 (200mg, 0.479mmol) with intermediate A5 (155mg, 0.958mmol) gave 3- (2, 3-dihydroimidazo [2,1-B ]]Oxazol-6-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B37-7) (50 mg, yield: 18.6%). LC-MS, M/Z (ESI) 588.1[ 2 ], [ M + H ]] + 。
Compound B37-7 (50mg, 0.089mmol) removal of the PMB group in trifluoroacetic acid gave 3- (2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-37) (20 mg, 50% yield)
Figure BDA0003735878680000591
1 H NMR(400MHz,DMSO-d 6 )δ11.24(s,1H),8.54(s,1H),8.49(d,1H),7.96(d,1H),7.91(d,1H),7.56(d,1H),7.54(s,1H),6.99(d,1H),6.96(d,1H),5.06(t,2H),4.25(t,2H),2.41(d,3H)
LC-MS,M/Z(ESI):440.1[M+H] + 。
Example 38: preparation of Compound I-38
The synthetic route is shown as follows:
Figure BDA0003735878680000592
the first step is as follows: synthesis of methyl 2- (3-oxomorpholino) acetate (B38-2)
Morpholine-3-one (10.0 g,98.9 mmol) is dissolved in tetrahydrofuran (100 mL), sodium hydrogen (4.75g, 118mmol) is added in portions at 0 ℃ under the protection of nitrogen, reaction is carried out at 0 ℃ for 1 hour, and methyl 2-bromoacetate (18.2g, 118mmol) is added dropwise to the reaction solution and reaction is carried out at 25 ℃ for 1 hour. The reaction mixture was added to water (100 mL), followed by extraction with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to give a crude product, which was isolated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
LC-MS,M/Z(ESI):174.1[M+H] +
The second step is that: synthesis of 2- (3-oxomorpholino) acetamide (B38-3)
Methyl 2- (3-oxomorpholino) acetate (B38-2) (5.00g, 28.8mmol) was dissolved in aminomethanol (7M, 50.0mL), and the reaction was carried out at 60 ℃ for 8 hours in a jar. The reaction mixture was concentrated to give 2- (3-oxomorpholino) acetamide (B38-3) (3.30 g, yield 72.3%).
The third step: synthesis of 2-bromo-6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazine (B38-4)
2- (3-Oxomorpholino) acetamide (B38-3) (1.50g, 9.48mmol) was dissolved in acetonitrile (15.0 mL), and phosphorus oxybromide (2.99g, 10.4 mmol) was added, followed by stirring at 90 ℃ for 2 hours under nitrogen. The reaction mixture was added to a saturated aqueous potassium carbonate solution to adjust the pH to 7 to 8, followed by extraction with ethyl acetate (200 mL), washing of the organic phase with a saturated brine (100 mL), drying over sodium sulfate, concentration to give a crude product, and separation and purification with a silica gel column (petroleum ether: ethyl acetate (V/V) =50][1,4]Oxazine (B38-4) (1.00 g, 51.9% yield). LC-MS, M/Z (ESI) 202.8[ 2 ], [ M + H ]] +
Referring to the method of the other example, compound B38-4 (466 mg, 2.30mmol) was reacted with intermediate A1 (1)00g, 2.30mmol) to give the compound 3- (6, 8-dihydro-5H-imidazo [2, 1-c)][1,4]Oxazin-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B38-5) (300 mg, 30.2% yield). LC-MS, M/Z (ESI): 432.3[ M ] +H] + 。
Reaction of Compound B38-5 (284mg, 658. Mu. Mol) with intermediate A5 (160mg, 987. Mu. Mol) gave 3- (6, 8-dihydro-5H-imidazo [2, 1-c)][1,4]Oxazin-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B38-6) (300 mg, 79.5% yield). LC-MS, M/Z (ESI) 574.1[ 2 ], [ M + H ]] + 。
Compound B38-6 (200mg, 349 μmol) was stripped of the PMB group in trifluoroacetic acid to give 3- (6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-38) (53.7 mg, 32.9% yield).
Figure BDA0003735878680000601
1 H NMR(400MHz,DMSO-d 6 )δ11.91-12.04(m,1H)8.67-8.74(m,1H)8.56-8.63(m,1H)8.04-8.09(m,1H)8.04-8.04(m,1H)7.91-8.01(m,1H)7.81-7.85(m,1H)7.57-7.65(m,1H)7.25-7.37(m,1H)7.03-7.14(m,1H)4.87-5.05(m,2H)4.79-4.87(m,1H)4.11-4.19(m,2H)4.04-4.10(m,2H)2.43-2.45(m,3H)。
1 H NMR(400MHz,DMSO-d 6 )δ＝11.99(s,1H),8.71(d,1H),8.60(s,1H),8.06(d,1H),7.96(dd,1H),7.83(s,1H),7.60(dd,1H),7.31(d,1H),7.09(d,1H),4.92(s,2H),4.17-4.12(m,2H),4.10-4.05(m,2H),2.44(d,3H)。
LC-MS,M/Z(ESI):454.0[M+H] + 。
Example 39: preparation of Compound I-39
The synthetic route is as follows:
Figure BDA0003735878680000611
the first step is as follows: synthesis of (R) -N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((4- (trifluoromethyl)) phenyl) amino) benzenesulfonamide (B39-1)
4- (trifluoromethyl) aniline (0.47g, 2.92mmol) was dissolved in N, N-dimethylformamide (15 mL) under nitrogen, sodium hydrogen (60%, 0.35g, 8.76mmol) was added at 0 deg.C, stirred for 30 minutes, and (R) -4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) benzenesulfonamide (B33-4) (0.43g, 1.00mmol) was added and allowed to return to room temperature for one day. The reaction was quenched by the addition of water (45 mL) at 0 deg.C, extracted with ethyl acetate (40 mL. Times.3), and the organic phases were combined, washed with water (15 mL), washed with saturated brine (15 mL), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether: ethyl acetate =2: 1-1) gave (R) -N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((4- (trifluoromethyl)) phenyl) amino) benzenesulfonamide (B39-1) (0.26 g, 46.6% yield).
LC-MS,M/Z(ESI):573.2[M+H] + 。
The second step: synthesis of (R) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -4- ((4- (trifluoromethyl) phenyl) amino) benzenesulfonamide (I-39)
Figure BDA0003735878680000612
(R) -N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((4- (trifluoromethyl)) phenyl) amino) benzenesulfonamide (B39-1) (0.26g, 0.45mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (4 mL) was added, and stirring was carried out at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated, and then dissolved in ethyl acetate (50 mL), washed with a saturated sodium bicarbonate solution to pH 7-8 of the aqueous phase, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1) to obtain (R) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -4- ((4- (trifluoromethyl) phenyl) amino) benzenesulfonamide (I-39) (96.3 mg, yield 46.9%).
1 H NMR(400MHz,DMSO)δ9.92(s,1H),8.00(s,1H),7.61(s,1H),7.58(s,1H),7.50(s,2H),7.36(s,1H),7.32–7.27(m,1H),7.25(d,2H),5.51–5.40(m,1H),4.36(dd,1H),3.83(dd,1H),2.42(d,3H),1.53(d,3H).
LC-MS,M/Z(ESI):453.1[M+H] + 。
Example 40: preparation of Compound I-40
The synthetic route is shown as follows:
Figure BDA0003735878680000621
the first step is as follows: synthesis of methyl 1- (4-methoxybenzyl) -5-oxopyrrolidine-3-carboxylate (B40-2)
Dimethyl 2-methylenesuccinate (25.0 g, 158mmol) was dissolved in methanol (300 mL), and (4-methoxyphenyl) methylamine (21.6 g, 158mmol) was added to the reaction solution and reacted at 80 ℃ for 2 hours. The reaction solution was concentrated, followed by addition to water (500 mL), followed by extraction with ethyl acetate (500 mL), washing of the organic phase with saturated brine (200 mL), drying over sodium sulfate, and concentration to give a crude product, which was isolated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
The second step is that: synthesis of 4- (hydroxymethyl) -1- (4-methoxybenzyl) pyrrolidin-2-one (B40-3)
Methyl 1- (4-methoxybenzyl) -5-oxopyrrolidine-3-carboxylate (B40-2) (30.0 g, 114mmol) was dissolved in ethanol (500 mL), sodium borohydride (43.1g, 1.14mol) was added slowly at 0 ℃ and the reaction was carried out at 20 ℃ for 6 hours. The reaction solution was quenched with water (500 mL) and concentrated, followed by extraction with ethyl acetate (500 mL), and the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to give a crude product, which was isolated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
LC-MS,M/Z(ESI):236.2[M+H] +
The third step: synthesis of 1- (4-methoxybenzyl) -5-oxopyrrolidine-3-carbaldehyde (B40-4)
Oxalyl chloride (21.6 g, 170mmol) was dissolved in dichloromethane (200 mL), dimethyl sulfoxide (18.2 g, 233mmol) was added, the reaction was stirred at-70 ℃ under nitrogen for 1 hour, 4- (hydroxymethyl) -1- (4-methoxybenzyl) pyrrolidin-2-one (B40-3) (25.0 g, 106mmol) was added, the reaction was stirred at-70 ℃ for 1 hour, triethylamine (32.2 g, 318mmol) was added, and the reaction was stirred at-70 ℃ for 1 hour. The reaction solution was added with water (100 mL), followed by extraction with dichloromethane (400 mL), the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to give a crude product, which was isolated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
The fourth step: synthesis of 4- (difluoromethyl) -1- (4-methoxybenzyl) pyrrolidin-2-one (B40-5)
1- (4-methoxybenzyl) -5-oxopyrrolidine-3-carbaldehyde (B40-4) (18.0g, 77.2mmol) was dissolved in methylene chloride (200 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (34.1g, 154mmol) was added at 0 ℃ and the reaction was stirred at 0 ℃ for 1 hour. The reaction solution was diluted with water (100 mL), followed by extraction with dichloromethane (400 mL), and the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to give a crude product, which was isolated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
LC-MS,M/Z(ESI):256.2[M+H] +
The fifth step: synthesis of 4- (difluoromethyl) pyrrolidin-2-one (B40-6)
4- (difluoromethyl) -1- (4-methoxybenzyl) pyrrolidin-2-one (B40-5) (5.00g, 19.6 mmol) was dissolved in acetonitrile (30.0 mL) and water (30.0 mL), and cerium ammonium nitrate (11.8 g,21.5 mmol) was added thereto at 0 ℃ to react at 25 ℃ for 5 hours. The reaction was added dropwise to water (100 mL), followed by extraction with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to give the crude product. Separation and purification by a silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
LC-MS,M/Z(ESI):136.2[M+H] +
And a sixth step: synthesis of methyl 2- (4- (difluoromethyl) -2-oxopyrrolidin-1-yl) acetate (B40-7)
4- (difluoromethyl) pyrrolidin-2-one (B40-6) (1.80g, 13.3mmol) was dissolved in tetrahydrofuran (20.0 mL), sodium hydrogen (586 mg,14.6 mmol) was added in portions at 0 ℃ under nitrogen protection, and reacted at 0 ℃ for 1 hour, and methyl 2-bromoacetate (2.45g, 15.9mmol) was added dropwise to the reaction mixture and reacted at 0 ℃ for 2 hours. The reaction solution was added to water (50 mL), followed by extraction with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to give a crude product, which was isolated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
The seventh step: synthesis of 2- (4- (difluoromethyl) -2-oxopyrrolidin-1-yl) acetamide (B40-8)
Methyl 2- (4- (difluoromethyl) -2-oxopyrrolidin-1-yl) acetate (1.80g, 8.69mmol) was dissolved in methanolic ammonia (7M, 20.0 mL) and reacted in a tank at 85 ℃ for 1 hour. The reaction solution was concentrated to give 2- (4- (difluoromethyl) -2-oxopyrrolidin-1-yl) acetamide (B40-8) (1.50 g, 89.8% yield).
Eighth step: synthesis of 2-bromo-6- (difluoromethyl) -6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B40-9)
2- (4- (difluoromethyl) -2-oxopyrrolidin-1-yl) acetamide (B40-8) (1.50g, 7.81mmol) was dissolved in acetonitrile (15.0 mL), phosphorus oxybromide (2.24g, 7.81mmol) was added, and the reaction was stirred at 85 ℃ for 1 hour under nitrogen. The reaction mixture was added to a saturated aqueous potassium carbonate solution to adjust the pH to 7 to 8, followed by extraction with ethyl acetate (100 mL), washing of the organic phase with a saturated brine (100 mL), drying over sodium sulfate, and concentration to give a crude product, which was separated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 1-1) to give 2-bromo-6- (difluoromethyl) -6, 7-dihydro-5H-pyrrolo [1,2-a]Imidazole (B40-9) (0.90 g, 48.6% yield). LC-MS, M/Z (ESI) 238.4[ 2 ], [ M + H ]] +
Referring to the preparation method of the other compounds, 2-bromo-6- (difluoromethyl) -6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B40-9) (0.80g, 3.37mmol) and 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) benzenesulfonamide (A1) were reacted to give 3- (6- (difluoromethyl) -6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B40-10) (800 mg, 51.2% yield).
LC-MS,M/Z(ESI):466.1[M+H] +
Reacting 3- (6- (difluoromethyl) -6, 7-dihydro-5H-pyrrolo [1,2-a ]]Imidazol-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B40-10) (750mg, 1.61mmol) and 5- (trifluoromethyl) pyridin-2-amine (A5) (287mg, 1.77mmol) were reacted to give 3- (6- (difluoromethyl) -6, 7-dihydro-5H-pyrrolo [1,2-a ] a]Imidazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B40-11) (200 mg, 20.4% yield). LC-MS, M/Z (ESI): 608.2[ M ] +H] +
3- (6- (difluoromethyl) -6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B40-11) (100mg, 164. Mu. Mol) was dissolved in trifluoroacetic acid (5.0 mL) to remove the PMB group to give 3- (6- (difluoromethyl) -6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-40) (8.00 mg, 9.77% yield).
Figure BDA0003735878680000641
1 H NMR(CDCl 3 )δ11.84-12.05(m,1H),8.78(d,1H),8.40-8.56(m,1H),7.90(d,1H),7.59-7.69(m,2H),7.28(s,2H),6.85(d,1H),5.77-6.09(m,1H),4.17-4.26(m,1H),4.07-4.16(m,2H),3.11-3.23(m,1H),2.94-3.05(m,1H),2.60(d,3H)
LC-MS,M/Z(ESI):488.2[M+H] +
Example 41: preparation of Compound I-41
The synthetic route is as follows:
Figure BDA0003735878680000642
the first step is as follows: synthesis of (R) -N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((6- (trifluoromethoxy)) pyridin-3-yl) amino) benzenesulfonamide (B41-1)
6- (trifluoromethoxy) pyridin-3-amine (0.62g, 3.48mmol) was dissolved in N, N-dimethylformamide (30 mL), nitrogen protected, sodium hydrogen (60%, 0.42g, 10.43mmol) was added at 0 deg.C, stirred for 30 minutes, (R) -4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) benzenesulfonamide (B33-4) (1.5g, 3.48mmol) was added, and the reaction was allowed to return to room temperature naturally for one day. The reaction was quenched by the addition of water (45 mL) at 0 deg.C, extracted with ethyl acetate (40 mL. Times.3), and the organic phases were combined, washed with water (15 mL), washed with saturated brine (15 mL), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether: ethyl acetate =2: 1-1.
LC-MS,M/Z(ESI):590.3[M+H] + 。
The second step is that: synthesis of (R) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -4- ((6- (trifluoromethoxy) pyridin-3-yl) amino) benzenesulfonamide (I-41)
Figure BDA0003735878680000643
(R) -N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((6- (trifluoromethoxy)) pyridin-3-yl) amino) benzenesulfonamide (B41-1) (1.51g, 2.56mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (10 mL) was added, and stirring was carried out at room temperature for 3 hours. After the reaction was completed, it was concentrated, and then dissolved in ethyl acetate (50 mL), washed with a saturated sodium bicarbonate solution to a pH of 7-8 of the aqueous phase, and the crude product was purified by silica gel chromatography (dichloromethane: methanol =20: 1) to give (R) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -4- ((6- (trifluoromethoxy) pyridin-3-yl) amino) benzenesulfonamide (I-41) (0.72 g, yield 60%).
1 H NMR(400MHz,DMSO)δ9.82(s,1H),8.21(d,1H),7.94(d,1H),7.81(dd,1H),7.46(dd,1H),7.39(d,1H),7.26(dt,3H),5.51–5.41(m,1H),4.37(dd,1H),3.84(dd,1H),2.41(d,3H),1.53(d,3H).
LC-MS,M/Z(ESI):470.2[M+H] + 。
Example 42: preparation of Compound I-42
The synthetic route is as follows:
Figure BDA0003735878680000651
the first step is as follows: synthesis of methyl 2- (2-oxo-4- (trifluoromethyl) pyrrolidin-1-yl) acetate (B42-2)
4-trifluoromethyl-pyrrolidin-2-one (3.60g, 23.5 mmol) was dissolved in tetrahydrofuran (30.0 mL), sodium hydride (1.03g, 25.9 mmol) was added in portions at 0 ℃ under nitrogen protection, and the mixture was reacted at 0 ℃ for 1 hour, and then methyl 2-bromoacetate (9.26g, 60.5 mmol) was added dropwise to the reaction mixture and reacted at 25 ℃ for 1 hour. The reaction solution was added to water (50 mL), followed by extraction with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to give a crude product, which was isolated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 50.
The second step: synthesis of 2- (4-trifluoromethyl-2-oxopyrrolidin-1-yl) acetamide (B42-3)
Methyl 2- (2-trifluoromethyl-5-oxopyrrolidin-1-yl) acetate (2.70g, 2.64mmol) was dissolved in aminomethanol (7M, 20.0mL), and the mixture was subjected to a jar reaction at 70 ℃ for 1 hour. The reaction mixture was subjected to column chromatography to give 2- (4-trifluoromethyl-2-oxopyrrolidin-1-yl) acetamide (B42-3) (2.50 g, 99.2% yield).
The third step: synthesis of 2-bromo-6-trifluoromethyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B42-4)
2- (4-trifluoromethyl-2-oxopyrrolidin-1-yl) acetamide (B42-3) (1.700g, 8.09mmol) was dissolved in acetonitrile (30.0 mL), phosphorus oxybromide (2.78g, 9.71mmol) was added, and the reaction was stirred at 85 ℃ for 1 hour under nitrogen. The reaction solution was added to a saturated aqueous potassium carbonate solution to adjust the pH to 7 to 8, followed by extraction with ethyl acetate (200 mL), washing of the organic phase with saturated brine (100 mL), drying over sodium sulfate, and concentration to give a crude product, which was subjected to separation and purification with a silica gel column (petroleum ether: ethyl acetate (V/V) = 1-5) to give 2-bromo-6-trifluoromethyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (B42-4) (1.70 g, yield 82.4%).
Referring to the preparation method of other compounds, 2-bromo-6-trifluoromethyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] is prepared]Imidazole (B42-4) (1.52g, 5.97mmol) and 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) benzenesulfonamide (A1) (2.60g, 5.97mmol) react to give 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (6-trifluoromethyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] pyrrole [1,2-a ]]Imidazol-2-yl) benzenesulfonamide (B42-5) (900 mg, 31.2% yield). LC-MS, M/Z (ESI): 484.1[ M ] +H] +
4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (6-trifluoromethyl-6, 7-dihydro-5H-pyrrolo [1, 2-a)]Imidazol-2-yl) benzenesulfonamide (B42-5) (640mg, 1.32mmol) and 5- (trifluoromethyl) pyridin-2-amine (236mg, 1.46mmol) were reacted to give N- (4-methoxybenzyl) -N-methyl-3- (6-trifluoromethyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] -c]Imidazol-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B42-6) (400 mg, 48.3% yield). LC-MS, M/Z (ESI): 626.2[ M ] +H] +
N- (4-methoxybenzyl) -N-methyl-3- (6-trifluoromethyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B42-6) (400mg, 639 μmol) was stripped of the PMB group in trifluoroacetic acid (10.0 mL) to give N-methyl-3- (6-trifluoromethyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-42) (28.6 mg, 8.50% yield).
Figure BDA0003735878680000661
1 H NMR(400MHz,DMSO-d 6 )δ11.90(s,1H)8.66(dd,1H)8.59(s,1H)8.04(s,1H)7.97(d,1H)7.78(s,1H)7.60(d,1H)7.32(q,1H)7.08(d,1H)4.44(dd,1H)4.18-4.25(m,1H)4.06-4.17(m,1H)3.39(d,1H)3.08(dd,1H)2.41-2.44(m,3H)
LC-MS,M/Z(ESI):506.2[M+H] +
Example 43: preparation of Compound I-43
The synthetic route is as follows:
Figure BDA0003735878680000662
the first step is as follows: synthesis of (R) -6-bromo-2, 5-dimethyl-2, 3-dihydroimidazo [2,1-B ] oxazole (B43-1)
Reacting (R) -5, 6-dibromo-2-methyl-2, 3-dihydroimidazole [2,1-b ]]Oxazole (B33-2) (2.2g, 7.80mmol) was dissolved in tetrahydrofuran (10 ml), cooled to-78 deg.C, 2.5M n-butyllithium (3.12ml, 7.80mmol) was added dropwise, stirred for 1h, iodomethane (0.488 ml) was added, and stirring was continued for 1h. Saturated ammonium chloride solution (10 mL) was added, extraction was performed with ethyl acetate (10 mL × 3), and the organic phase was collected and washed with 10mL of saturated brine. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =10: 1-3) to give (R) -6-bromo-2, 5-dimethyl-2, 3-dihydroimidazole [2,1-b]Oxazole (B43-1) (1.4 g, 82.6% yield). LC-MS, M/Z (ESI) 217.0[ M + H ]] + 。
Referring to the preparation method of the other compounds, (R) -6-bromo-2, 5-dimethyl-2, 3-dihydroimidazo [2,1-B ] oxazole (B43-1) (1.20g, 5.51mmol) was reacted with 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3-dioxan-2-yl) benzenesulfonamide (2.4g, 5.51mmol) to give (R) -3- (2, 5-dimethyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B43-2) (2 g, yield 81.4%).
LC-MS,M/Z(ESI):446.1[M+H] + 。
Mixing (R) -3- (2, 5-dimethyl-2, 3-dihydroimidazole [2,1-b ]]Oxazol-6-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B43-2) (200mg, 0.449mmol) and 5- (trifluoromethyl) pyridin-2-amine (109mg, 0.673mmol) are reacted to give (R) -3- (2, 5-dimethyl-2, 3-dihydroimidazole [2,1-B ]]Oxazol-6-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B43-3) (100 mg,yield 37.8%). LC-MS, M/Z (ESI) 588.1[ M ] +H] + 。
N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B43-3) (70mg, 0.122mmol) was stripped of the PMB group in trifluoroacetic acid (1 ml) to give N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (I-43) (50 mg, 90% yield).
Figure BDA0003735878680000671
1 H NMR(400MHz,DMSO-d 6 )δ11.3(s,1H),8.54(s,1H),8.50(d,1H),7.96(d,1H),7.91(d,1H),7.55(d,1H),7.54(s,1H),7.42(q,1H),5.43-5.52(m,1H),4.35-4.40(m,1H),3.83-3.87(m,1H),2.41(d,3H),2.23(d,3H),1.53(d,3H)
LC-MS,M/Z(ESI):468.1[M+H] +
Example 44: preparation of Compound I-44
The synthetic route is shown as follows:
Figure BDA0003735878680000672
the first step is as follows: synthesis of 2- (3-oxomorpholino) acetamide (B44-2)
Methyl 2- (3-oxomorpholino) acetate (5.00g, 28.9 mmol) was dissolved in aminomethanol (50.0 mL) and reacted at 25 ℃ for 2 hours to give 2- (3-oxomorpholino) acetamide (B44-2) (3.70 g, 81.0% yield).
The second step is that: synthesis of 2-bromo-5, 6-dihydro-8H-imidazo [2,1-c ] [1,4] oxazine (B44-3)
2- (3-Oxomorpholino) acetamide (B44-2) (2.70g, 2.64mmol) was dissolved in acetonitrile (50.0 mL), and phosphorus oxybromide (7.38g, 25.7 mmol) was added and reacted at 25 ℃ for 2 hours. The reaction mixture was added to a saturated aqueous solution of potassium carbonate, the pH was adjusted to 7 to 8 with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to give 2-bromo-5, 6-dihydro-8H-imidazo [2,1-c ] [1,4] oxazine (B44-3) (2.00 g, 42.1% yield).
Referring to the preparation method of other compounds, 2-bromo-5, 6-dihydro-8H-imidazo [2,1-c ]][1,4]Oxazine (B44-3) (2.00g, 9.85mmol) was reacted with 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) benzenesulfonamide (4.29g, 9.85mmol) to give 3- (5, 6-dihydro-8H-imidazo [2,1-c ] m][1,4]Oxazin-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B44-4) (2.10 g, 49.4% yield). LC-MS, M/Z (ESI): 432.1[ M ] +H] +
Reacting 3- (5, 6-dihydro-8H-imidazo [2, 1-c)][1,4]Oxazin-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B44-4) (1.00g, 2.32mmol) and 4- (trifluoromethyl) aniline (560mg, 3.48mmol) reacted to give 3- (5, 6-dihydro-8H-imidazo [2,1-c ] amine][1,4]Oxazin-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((4- (trifluoromethyl) phenyl) amino) benzenesulfonamide (B44-5) (140 mg, 10.6% yield). LC-MS, M/Z (ESI): 573.3[ M ] +H] +
3- (5, 6-dihydro-8H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- ((4- (trifluoromethyl) phenyl) amino) benzenesulfonamide (B44-5) (140mg, 244.50. Mu. Mol) was dissolved in trifluoroacetic acid (15.0 mL) to remove the PMB group to give 3- (5, 6-dihydro-8H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -N-methyl-4- ((4- (trifluoromethyl) phenyl) amino) benzenesulfonamide (I-44) (35.0 mg, 30.4% yield).
Figure BDA0003735878680000681
1 H NMR(400MHz,CDCl 3 )δ10.75(s,1H)7.98(d,1H)7.55-7.63(m,3H)7.48(d,1H)7.35(s,1H)7.33(s,2H)4.92(s,2H)4.19-4.24(m,1H)4.15(s,4H)2.70(d,3H)
LC-MS,M/Z(ESI):453.2[M+H] +
Example 45: preparation of Compound I-45
The synthetic route is as follows:
Figure BDA0003735878680000682
2-chloro-3-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (1.52g, 5.97mmol) and 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) benzenesulfonamide (A1) (2.60g, 5.97mmol) were dissolved in N-butanol (40.0 mL), potassium phosphate (1.65g, 12.0mmol) and (2-dicyclohexylphosphino-2 ',6' -dimethoxybibiphenyl) [2- (2 '-amino-1, 1' -bibiphenyl) ] palladium (II) (437mg, 597. Mu. Mol) were added, and then the reaction was stirred at 60 ℃ for 10 hours under nitrogen protection. The reaction solution was concentrated to give a crude product, which was isolated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) =50: 1-5) to give 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (3-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) benzenesulfonamide (B45-1) (900 mg, yield 31.2%).
LC-MS,M/Z(ESI):430.1[M+H] +
Referring to the preparation method of other compounds, 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (3-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] is]Imidazol-2-yl) benzenesulfonamide (B45-1) (500mg, 1.16mmol) and 5- (trifluoromethyl) pyridin-2-amine (226mg, 1.40mmol) reacted to give N- (4-methoxybenzyl) -N-methyl-3- (3-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] amine]Imidazol-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B45-2) (500 mg, 37.6% yield). LC-MS, M/Z (ESI): 572.1[ 2 ], [ M + H ]] + 。
N- (4-methoxybenzyl) -N-methyl-3- (3-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonamide (B45-2) (500mg, 874 μmol) was stripped of the PMB group in trifluoroacetic acid (10.0 mL) to give N-methyl-3- (3-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -4- [ [5- (trifluoromethyl) -2-pyridinyl ] amino ] benzenesulfonamide (I-45) (10.0 mg, 2.41% yield).
Figure BDA0003735878680000691
1 H NMR(400MHz,CDCl 3 )δ8.49-8.58(m,1H)8.42(s,1H)7.76(d,1H)7.68(dd,1H)7.58-7.64(m,1H)6.85-6.94(m,1H)3.94(t,2H)2.92-3.01(m,2H)2.62-2.71(m,2H)2.60(d,3H)2.29(s,3H)。
LC-MS,M/Z(ESI):452.1[M+H] + 。
Examples 46 to 51:
preparation of Compounds I-46, I-47, I-48, I-49, I-50, I-51 reference is made to the preparation of Compound I-26.
Figure BDA0003735878680000692
Figure BDA0003735878680000701
Compound I-46, LC-MS, M/Z (ESI) 455.1, M + H] + 。
Compound I-47, LC-MS, M/Z (ESI) 439.1, M + H] + 。
Compound I-48, LC-MS, M/Z (ESI): 499.1, [ M ] +H] + 。
Compound I-49, LC-MS, M/Z (ESI): 513.1, [ M ] +H] + 。
Compound I-50, LC-MS, M/Z (ESI): 513.1, [ M ] +H] + 。
Compound I [ 51 ], [ LC-MS ], M/Z (ESI) ].1M + H] + 。
Examples 52 to 53
Preparation of Compounds I-52, I-53 reference is made to the preparation of Compound I-33.
Figure BDA0003735878680000702
Compound I-52, LC-MS, M/Z (ESI): 459.2[ M ] +H] + 。
Compound I-53, LC-MS, M/Z (ESI): 460.1, [ M ] +H] + 。
EXAMPLE 54 Synthesis of Compound I-54
The synthetic route is as follows:
Figure BDA0003735878680000703
the first step is as follows: synthesis of N- (2-bromo-4-nitrophenyl) -5- (trifluoromethyl) pyridin-2-amine (B54-2)
5- (trifluoromethyl) pyridin-2-amine (1.5g, 9.26mmol) was dissolved in dry tetrahydrofuran (30 mL), cooled to 0 ℃, naH (0.56g, 13.89mmol, 60%) was added, and after stirring for 30 minutes, 2-bromo-1-fluoro-4-nitrobenzene (1.70g, 7.72mmol) was added and the reaction was allowed to return to room temperature overnight. The reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL) and the organic phase collected. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography to give N- (2-bromo-4-nitrophenyl) -5- (trifluoromethyl) pyridin-2-amine (B54-2) (2.37 g, 85% yield).
LC-MS,M/Z(ESI):361.9[M+H] +
The second step: (R) -N- (2- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4-nitrophenyl) -5- (trifluoromethyl) pyridin-2-amine (B54-3)
N- (2-bromo-4-nitrophenyl) -5- (trifluoromethyl) pyridin-2-amine (B54-2) (0.5g, 1.38mmol) and (R) -2-methyl-6- (tributylstannyl) -2, 3-dihydroimidazo [2,1-B ]]Oxazole (0.54g, 1.31mmol) was dissolved in DMF (10 mL) in N 2 Under protection, [1,1' -bis (diphenylphosphino) ferrocene ] is added]Palladium dichloride (76mg, 0.11mmol). Reaction solution in N 2 Reacting for 12h at 130 ℃ under the atmosphere. To the reaction mixture were added water (30 mL) and ethyl acetate (30 mL), and the organic phase was collected. Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. Purifying the crude product with silica gel column chromatography to obtain (R) -N- (2- (2-methyl-2, 3-dihydroimidazole [2,1-b ]]Oxazol-6-yl) -4-nitrophenyl) -5- (trifluoromethyl) pyridin-2-amine (B54-3) (0.39 g, 70% yield)
LC-MS,M/Z(ESI):406.1[M+H] +
The third step: synthesis of (R) -2- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -N1- (5- (trifluoromethyl) pyridin-2-yl) benzene-1, 4-diamine (B54-4)
Mixing (R) -N- (2- (2-methyl-2, 3-dihydroimidazole [2,1-b ]]Oxazol-6-yl) -4-nitrophenyl) -5- (trifluoromethyl) pyridin-2-amine (B54-3) (0.39g, 0.96 mmol) was dissolved in tetrahydrofuran (8 mL), platinum carbon (30mg, 10% by weight) was added, and then reacted under hydrogen at room temperature for 6h. After completion of the reaction, water (20 mL) and ethyl acetate (20 mL) were added, and the organic phase was collected and washed with anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. Purifying the crude product with silica gel column chromatography to obtain (R) -2- (2-methyl-2, 3-dihydroimidazole [2,1-b ]]Oxazol-6-yl) -N1- (5- (trifluoromethyl) pyridin-2-yl) benzene-1, 4-diamine (B54-4) (0.29 g, 80% yield)
LC-MS,M/Z(ESI):376.2[M+H] +
The fourth step: (R) -N- (3- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -4- ((5- (trifluoromethyl) pyridin-2-ylamino) phenyl) acrylamide (I-58)
(R) -2- (2-methyl-2, 3-dihydroimidazo [2,1-b ] at 0 deg.C]Oxazol-6-yl) -N1- (5- (trifluoromethyl) pyridin-2-yl) benzene-1, 4-diamine (B54-4) (0.29g, 0.77mmol) was dissolved in dichloromethane (8 mL) and triethylamine (0.2ml, 1.45mmol), and acryloyl chloride (69 μ L,0.85 mmol) was slowly added dropwise. The reaction was carried out overnight at room temperature, after completion of the reaction, water (15 mL) and methylene chloride (20 mL) were added, and the organic phase was collected and treated with anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. Purifying the crude product with silica gel column chromatography to obtain (R) -N- (3- (2-methyl-2, 3-dihydroimidazole [2,1-b ]]Oxazol-6-yl) -4- ((5- (trifluoromethyl) pyridin-2-ylamino) phenyl) acrylamide (I-58) (0.14 g, 42% yield)
LC-MS,M/Z(ESI):430.2[M+H] +
Example 55: preparation of Compound I-55
Figure BDA0003735878680000711
Preparation of I-59 reference Compound I-58, LC-MS, M/Z (ESI): 431.2, [ M ] +H] + 。
In the test examples of the present invention, reference is made to patent WO2020243415A2 for the preparation of control compounds, the structure of which is as follows:
Figure BDA0003735878680000721
test example 1: TEADS-mediated transcriptional repression IC 50 Evaluation test
HEK293T-TEAD Reporter Assay was used to detect the transcription inhibition of small molecule compounds on TEADs mediation.
HEK293T-TEAD-LUC reporter cell line was cultured with DMEM +10% FBS +1% PS +200ug/ml Hygromycin as complete medium, cells in log phase were seeded in 384 well plates, 2500 cells/well/35ul, 37 ℃,5% CO 2 The incubation was overnight, and 5uL of the diluted compound (DMSO final concentration: 0.1%) was added to each well the next day while setting the positive control group to which only DMSO was added, and taking the Okacid acid signal value of 2. Mu.M as the signal of the negative control group, and then 5% CO at 37 ℃. (Co) 2 Incubating for 48h, and using after incubation
Figure BDA0003735878680000722
Fluorescence signal values were determined on an Envision 2104Multilabel Reader by luciferase assay system (Promega, E2550) and following the instructions provided by the supplier. Calculating the inhibition rate by the following formula, then drawing a curve by taking the Log value of the concentration of the inhibitor as an X axis and the inhibition rate as a Y axis, and calculating by Graphpad 7.0 to obtain the IC 50 。
Inhibition% = (positive control signal-test well signal)/(positive control signal-negative control signal) =100
TABLE 1 test Compounds for TEADS transcriptional repression Activity on HEK293T-TEAD-LUC reporter cell line cells
Test compounds IC 50 (nM)
Control Compounds 70
I-1 28
I-2 63
I-3 55.5
I-5 39.9
I-7 14
I-10 15.7
I-25 47.6
I-32 50.3
I-33 80.9
I-39 18.6
I-41 36.9
I-42 49.9
HEK293T-TEAD Reporter Assay results show that the compound can obviously inhibit the activity of TEADs transcription on HEK293T-TEAD-LUC Reporter cell line cells, and shows more excellent inhibition effect compared with a control compound.
Test example 2: test for inhibiting malignant mesothelioma cell proliferation
The NF2 mutant NCI-H226 cell proliferation test is adopted to detect the proliferation inhibition effect of the small molecular compound on malignant mesothelioma cells.
NCI-H226 (ATCC, cat # CRL 5826) was cultured with RPMI1640+10% FBS +1% PS as complete medium, the cells in log phase were seeded in 96-well plates, 800 cells/well/195ul, 37 ℃,5% CO 2 The incubation was overnight, and 5uL of the diluted compound (final DMSO concentration: 0.1%) was added to each well the next day while setting the positive control group to which only DMSO was added, and the Staurosporine signal value of 1. Mu.M was used as the signal for the negative control group, and then 5% CO was added at 37 ℃. (0.1%) 2 After 6 days of incubation, 100ul of the medium was aspirated, and the fluorescence signal was measured on an Envision 2104Multilabel Reader using the Celltiter Glo assay kit (Promega, G7573) and following the instructions from the supplier. Calculating the inhibition rate by the following formula, drawing a curve by taking the Log value of the concentration of the inhibitor as an X axis and the inhibition rate as a Y axis, and calculating by Graphpad 7.0 to obtain IC 50 。
Inhibition% = (positive control signal-test well signal)/(positive control signal-negative control signal) × 100
The results of the NCI-H226 cell proliferation test show that the compound can obviously inhibit the proliferation of NCI-H226 (ATCC, cat # CRL 5826).
TABLE 2 proliferation-inhibiting Activity of test Compounds on NCI-H226 cells
Test compounds IC 50 (nM)
Control Compounds 66
I-1 22
I-2 44
I-5 5.7
I-7 45.4
I-10 10.6
I-23 41.5
I-24 10.4
I-25 50
I-32 76.1
I-33 69.6
I-34 5.4
I-37 25.5
I-39 13
I-41 24.2
I-42 48.3
I-44 7.9
I-45 35
The test result of the compound on the proliferation inhibition of malignant mesothelioma cells shows that the compound can obviously inhibit the proliferation of NCI-H226 cells, and shows more excellent inhibition effect compared with a control compound.
Test example 3: pharmacokinetic testing
Mouse pharmacokinetic experiments using 3 male ICR mice, 20-25g, fasted overnight, orally gavaged (10 mg/kg). Blood was collected before and 15, 30 minutes and 1,2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800g at 2-8 ℃ for 6 minutes, and plasma was collected and stored at-80 ℃. And (3) adding 3-5 times of acetonitrile solution containing an internal standard into the plasma at each time point, mixing, carrying out vortex mixing for 1 minute, centrifuging at 4 ℃ for 10 minutes at 13000 rpm, taking supernatant, adding 3 times of water, mixing, and taking a proper amount of mixed solution to carry out LC-MS/MS analysis. The major pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model.
Table 3: results of mouse pharmacokinetic experiments
Figure BDA0003735878680000741
The results of mouse pharmacokinetic experiments show that the compound of the invention has excellent pharmacokinetic properties and good drug formation.
Test example 4: tumor-bearing efficacy test of NCI-H226 mesothelioma mice
Nu/Nu nude mice (CRL) were acclimatized for one week, then NCI-H226 cells at log phase were resuspended in PBS at 100. Mu.L/mouse at 5X 10 6 NCI-H226 cells are inoculated subcutaneously at the right back part of the mouse, the growth of the tumor is observed periodically, and the tumor grows to 80-100mm of the average volume 3 During treatment, the tumor size and the weight of a mouse are randomly divided into a model group and an administration group, the tumor volume and the animal weight are measured and recorded before administration and in the administration process, the model group is taken as a control group after treatment is finished, the growth inhibition effect of the administration group on the tumor is counted, and TGI is calculated.
The results of the tumor-bearing mouse pharmacodynamic tests show that (figure 1) the compound has a remarkable effect of inhibiting the growth of NCI-H226 mesothelioma.
The embodiments of the present invention have been described above by way of example. It should be understood that the scope of the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement or the like made by those skilled in the art within the spirit and principle of the present invention should be included in the protection scope of the claims of the present application.

Claims (22)

1. A compound of formula I, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs thereof:
Figure FDA0003735878670000011
wherein W represents CH or N;
R 1 is hydrogen or a substituent selected from:
Figure FDA0003735878670000012
R 11 、R 12 、R 13 each independently hydrogen or a substituent selected from:C 1 -C 6 alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl, 4-6 membered heterocycloalkyl;
R 2 is hydrogen or a substituent selected from:
Figure FDA0003735878670000013
halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl;
V 1 、V 2 、V 3 、V 4 each independently represents C, CH or a heteroatom;
the heteroatom is selected from N, O or S;
and V is 1 、V 2 、V 3 、V 4 Containing 1,2 or 3 of said heteroatoms; when the number of heteroatoms is 2 or 3, the heteroatoms are the same or different;
l is O, -NH-Z-or-CH 2 -Z-；
Z is absent or is C 1 -C 3 An alkylene group;
said L is optionally substituted by C 1 -C 3 Alkyl substitution;
ring A is a benzene ring, a 5-6 membered heteroaromatic ring or a 3-8 membered cycloalkyl group;
ring B is a 4-8 membered ring;
ring A is optionally substituted with one or more R 3 Substitution; when the substituent R is 3 When there are plural, R is 3 The same or different;
said R is 3 Selected from the group consisting of: halogen, C 1 -C 6 Alkyl, 3-6 membered cycloalkyl, C 1 -C 6 Alkoxy, -SF 5 、-CF 2 -O-R 31 ；
R 31 Is C 1 -C 6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
the R is 3 C in 1 -C 6 Alkyl, 3-6 membered cycloalkyl, C 1 -C 6 Alkoxy radical, R 31 Optionally, optionallySubstituted with a substituent selected from the group consisting of: halogen, hydroxy, amino, C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy radical, C 3 -C 6 A cycloalkyloxy group;
said ring B is optionally substituted by one or more R 4 Substitution; when the substituent R 4 When there are plural, R is 4 The same or different;
R 4 selected from the group consisting of: halogen, hydroxy, oxo
Figure FDA0003735878670000014
C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, 3-6 membered cycloalkyl, -NH-C (O) -R 41 、-C(O)-NH-R 42 ；
R 41 、R 42 Each independently is C 1 -C 6 Alkyl radical, C 1 -C 6 An alkoxy group;
the R is 4 C in 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, 3-6 membered cycloalkyl, R 41 、R 42 Optionally substituted with a substituent selected from: halogen, hydroxy, C 1 -C 3 An alkoxy group;
preferably, W represents C or N;
R 1 is hydrogen or a substituent selected from:
Figure FDA0003735878670000021
R 11 、R 12 each independently hydrogen or a substituent selected from: c 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl, 4-6 membered heterocycloalkyl;
R 2 is hydrogen or a substituent selected from:
Figure FDA0003735878670000022
halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, 3-6-membered cycloalkyl, 3-6 memberedA halocycloalkyl group;
V 1 、V 2 、V 3 、V 4 each independently represents C or a heteroatom;
the heteroatom is selected from N, O or S;
and V is 1 、V 2 、V 3 、V 4 Containing 1,2 or 3 of said heteroatoms; when the number of heteroatoms is 2 or 3, the heteroatoms are the same or different;
l is-NH-Z-or-CH 2 -Z-；
Z is absent or is C1-C3 alkylene;
said L is optionally substituted by C 1 -C 3 Alkyl substitution;
ring A is a benzene ring or a 5-6 membered heteroaromatic ring;
ring B is a 4-8 membered ring;
ring A is optionally substituted with one or more R 3 Substitution; when the substituent R is 3 When there are plural, R is 3 The same or different;
the R is 3 Selected from: halogen, C 1 -C 6 Alkyl, 3-6 membered cycloalkyl, C 1 -C 6 Alkoxy, -SF 5 、-CF 2 -O-R 31 ；
R 31 Is C 1 -C 6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
the R is 3 C in 1 -C 6 Alkyl, 3-6 membered cycloalkyl, C 1 -C 6 Alkoxy radical, R 31 Optionally substituted with a substituent selected from the group consisting of: halogen, hydroxy, amino, C 1 -C 3 Alkyl radical, C 1 -C 3 An alkoxy group;
said ring B is optionally substituted by one or more R 4 Substitution; when the substituent R 4 When there are plural, R is 4 The same or different;
R 4 selected from: halogen, hydroxy, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, 3-6 membered cycloalkyl, -NH-C (O) -R 41 、-C(O)-NH-R 42 ；
R 41 、R 42 Each is independent of othersThe standing is C 1 -C 6 Alkyl radical, C 1 -C 6 An alkoxy group;
said R is 4 C in 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, 3-to 6-membered cycloalkyl, R 41 、R 42 Optionally substituted with a substituent selected from the group consisting of: halogen, hydroxy, C 1 -C 3 An alkoxy group.
2. The compound of claim 1, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof, wherein a group
Figure FDA0003735878670000023
Has a structure
Figure FDA0003735878670000024
3. The compound of claim 1 or 2, wherein at the group consisting of tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof
Figure FDA0003735878670000025
In the formula, the ring B is a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring; preferably, ring B is a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring; more preferably, ring B is selected from the group consisting of a tetrahydropyrrole ring, a morpholine ring, a cyclopentane ring, a piperazine ring, a piperidine ring, an oxazolidine ring, a 2-azabicyclo [3.1.0]]And (5) a hexane ring.
4. The compound of claim 3, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof, wherein a group
Figure FDA0003735878670000026
Has a structure
Figure FDA0003735878670000027
Wherein M represents an N, O, S atom or group
Figure FDA0003735878670000028
5. The compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of claim 3 wherein 1) the group
Figure FDA0003735878670000036
Has a structure
Figure FDA0003735878670000037
Figure FDA0003735878670000038
Wherein, Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 Each independently selected from CH and CH 2 N, O, S atoms;
and Y is 1 、Y 2 、Y 3 In which at most one is not CH, CH 2 ；
And Y is 4 、Y 5 、Y 6 、Y 7 In which at most one is not CH, CH 2 ；
Or,
2) Radical (I)
Figure FDA0003735878670000039
Has a structure
Figure FDA00037358786700000310
Wherein Q is 1 、Q 2 、Q 3 、Q 4 、Q 5 Each independently selected from CH and CH 2 Or group
Figure FDA00037358786700000311
And Q 1 、Q 2 In which at most one is not CH, CH 2 ；
And Q 3 、Q 4 、Q 5 At most one of them is not CH, CH 2 ；
Preferably, the group
Figure FDA0003735878670000031
Selected from the group consisting of:
Figure FDA0003735878670000032
wherein; m' represents CH, CH 2 N, O or S;
preferably, the group
Figure FDA0003735878670000033
Selected from:
Figure FDA0003735878670000034
Figure FDA0003735878670000035
Figure FDA0003735878670000041
6. the compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 3, wherein V is 1 、V 2 、V 3 、V 4 Each independently represents C or a heteroatom selected from N, O, S;
and V is 1 、V 2 、V 3 、V 4 Contains at least one N atom;
preferably, V 1 、V 2 、V 3 、V 4 Contains 2 heteroatoms;
preferably, when V 1 When is N, V 2 Is C, V 3 Is N, V 4 Is CH;
when V is 1 When is N, V 2 Is N, V 3 Is C, V 4 Is CH;
when V is 1 When is N, V 2 Is C, V 3 Is C, V 4 Is O or S;
when V is 1 When is CH, V 2 Is N, V 3 Is C, V 4 Is N.
7. The compound of claim 1, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs thereof, wherein formula I has structure Ia
Figure FDA0003735878670000042
8. The compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 7, characterized in that the radicals
Figure FDA0003735878670000043
In the formula (I), the ring B is a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring; preferably, ring B is a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring.
9. The compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 7, wherein the group
Figure FDA0003735878670000044
Has a structure
Figure FDA0003735878670000045
Wherein M represents an N, O, S atom or group
Figure FDA0003735878670000046
10. The compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 7, wherein L is-NH-or-CH 2-;
said-NH-or-CH 2-being optionally substituted by C 1 -C 3 Alkyl substitution;
preferably, L is-NH-.
11. The compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 7, wherein ring a is a phenyl ring or a 5-6 membered N-containing heteroaromatic ring;
preferably, the first and second air flow paths are arranged in parallel, ring A is benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, pyrazole, imidazole or triazole, cyclohexane,
Figure FDA0003735878670000051
More preferably, ring a is a benzene ring, pyridine or pyrimidine.
12. The compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 7, wherein R is 1 Is hydrogen,
Figure FDA0003735878670000052
R 11 、R 12 、R 13 Each independently hydrogen or a substituent selected from: c 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 1 -C 6 A haloalkyl group;
preferably, R 11 、R 12 Each independently hydrogen, methyl, ethyl, propyl;
more preferably, R 11 Is hydrogen, R 12 Is methyl; or, more preferably, R 13 Is a vinyl group.
13. The compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 7, wherein R is 2 Is hydrogen or a substituent selected from: c 1 -C 6 Alkyl radical, C 1 -C 6 A haloalkyl group.
14. The compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 7, characterized in that the group
Figure FDA0003735878670000053
Has a structure
Figure FDA0003735878670000054
Wherein Z is 1 、Z 2 、Z 3 、Z 4 、Z 5 Each is independently selected from C or N;
and Z is 1 、Z 2 、Z 3 、Z 4 、Z 5 There are at most two N in.
15. The compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 7, wherein ring A is optionally substituted with 1 or 2R 3 Substitution;
when the substituent R is 3 When there are 2, the R 3 The same or different;
the R is 3 Selected from: c 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, -SF 5 、-CF 2 -O-R 31 ；
Wherein R is 31 Is C 1 -C 6 Alkyl, 3-6 membered cycloalkyl;
the R is 3 C in 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, R 31 Optionally substituted with a substituent selected from: halogen, hydroxy, C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy radical, C 3 -C 6 A cycloalkyloxy group;
preferably, R is 3 Selected from: -CF 3 、-OCF 3 、-SF 5 、
Figure FDA0003735878670000055
16. The compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 7, wherein ring B is optionally substituted by 1 or 2R 4 Substitution;
when the substituent R is 4 When there are 2, the R 4 The same or different;
said R is 4 Is a substituent selected from the group consisting of: fluorine, chlorine, hydroxy, oxo
Figure FDA0003735878670000056
C 1 -C 6 Alkyl, -NH-C (O) -R 41 、-C(O)-NH-R 42 ；
R 41 、R 42 Each independently is C 1 -C 6 Alkyl radical, C 1 -C 6 An alkoxy group;
the R is 4 C in 1 -C 6 Alkyl, R 41 、R 42 Optionally substituted with a substituent selected from the group consisting of: fluorine, chlorine, hydroxy, C 1 -C 3 An alkoxy group;
preferably, R 4 Is a substituent selected from the group consisting of: fluorine, chlorine, hydroxy, oxo
Figure FDA0003735878670000057
Methyl, ethyl,Propyl, -NH-C (O) -R 41 、-C(O)-NH-R 42 (ii) a Wherein R is 41 、R 42 Each independently selected from: methyl, ethyl, propyl, methoxy, ethoxy, propoxy;
preferably, R 4 Is a substituent selected from the group consisting of: CH (CH) 3 F, OH, oxo
Figure FDA0003735878670000058
-CHF 2 、CF 3 、
Figure FDA0003735878670000059
Figure FDA0003735878670000061
17. The compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, comprising:
Figure FDA0003735878670000062
Figure FDA0003735878670000071
Figure FDA0003735878670000081
Figure FDA0003735878670000091
18. a process for the preparation of a compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, according to claim 1, comprising:
1) Reacting the intermediate B-1 with the intermediate B-2 under the condition of a palladium catalyst to obtain a compound shown in a formula I;
Figure FDA0003735878670000092
or
2) The intermediate B-3 and the intermediate B-4 react to obtain a compound shown in a formula I;
Figure FDA0003735878670000101
wherein,
g is a boronic acid or boronic ester group;
x is halogen;
ring A is optionally substituted with one or more R 3 Substitution; when the substituent R 3 When there are plural, R is 3 The same or different;
ring B is optionally substituted with one or more R 4 Substitution; when the substituent R is 4 When there are plural, R is 4 The same or different;
w, L, ring A, ring B, R 1 、R 2 、R 3 、R 4 Is defined as in claim 1.
19. A pharmaceutical composition, comprising: a compound of any one of claims 1-17, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof; and a pharmaceutically acceptable carrier.
20. Use of a compound of any one of claims 1-17, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof, or use of a pharmaceutical composition of claim 19, comprising:
preparing a medicament, pharmaceutical composition or formulation for the prevention and/or treatment of a disease associated with increased TEAD expression; and/or the presence of a gas in the gas,
preparing a medicament, pharmaceutical composition or formulation for reducing/inhibiting TEAD expression, increased TEAD activity; and/or the presence of a gas in the gas,
preparing a medicament, a pharmaceutical composition or a preparation for reducing/inhibiting the Hippo signalling pathway.
21. The use of claim 20, wherein the TEAD comprises: TEAD1, TEAD2, TEAD3, and TEAD4.
22. The use of claim 20, wherein the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.
CN202210804201.1A 2021-07-07 2022-07-07 TEAD inhibitor Pending CN115594680A (en)

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