IAP inhibitors and their use in medicine
阅读说明：本技术 Iap抑制剂及其在药物中的应用 (IAP inhibitors and their use in medicine ) 是由 谢洪明 寇玉辉 蒋海港 黄仕海 张英俊 张健存 于 2019-01-21 设计创作，主要内容包括：一种抑制IAP的新化合物及其用途。具体涉及一种可作为IAP抑制剂的化合物,或其立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药。还涉及所述化合物和其药物组合物在制备用于治疗或预防IAP紊乱所致疾病的药物中的用途,尤其是在制备用于治疗或预防癌症或者乙型肝炎病毒感染的药物中的用途。(A novel compound for inhibiting IAP and its application are provided. In particular to a compound which can be used as an IAP inhibitor, or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. Also relates to application of the compound and the pharmaceutical composition thereof in preparing medicaments for treating or preventing diseases caused by IAP (oral administration diseases), in particular to application in preparing medicaments for treating or preventing cancer or hepatitis B virus infection.)
A compound having a structure represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the structure represented by formula (I),
wherein the content of the first and second substances,
m and n are each independently 1,2,3,4, 5,6 or 7;
r1and r2Each independently is 0, 1,2 or 3;
each R1aIndependently D, F, Cl, Br, oxo, cyano, COOH, haloAlkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, -NR8R9Aryloxy, carbocyclyl, heterocyclyl, -C (═ O) -R7、-S(＝O)-R7、-S(＝O)2-R7Aryl or alkyl; or, two R1aAnd the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring; wherein said haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, aryloxy, carbocyclyl, heterocyclyl, aryl, alkyl, 3-7 membered carbocycle and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, alkyl, carbocyclyl, heterocyclyl, alkoxy and aryl;
each R1bIndependently D, H, F, Cl, Br, oxo, cyano, hydroxy, COOH, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, -NR8R9Aryloxy, carbocyclyl, heterocyclyl, -C (═ O) -R7、-OC(＝O)-R7、-S(＝O)-R7、-S(＝O)2-R7Aryl, alkoxy or alkyl; or, two R1bAnd the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring; wherein said haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, aryloxy, carbocyclyl, heterocyclyl, aryl, alkoxy, alkyl, 3-7 membered carbocycle and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, alkyl, carbocyclyl, heterocyclyl, alkoxy and aryl;
ring a and ring B are each independently aryl or heteroaryl;
each R10aAnd R10bIndependently, D, F, Cl, Br, hydroxyl, cyano, COOH, amino, alkyl, alkynyl, carbocyclyl, heterocyclyl, alkoxy, aryl, -C (═ O) -R7、-NR8S(＝O)2-R7、-S(＝O)-R7Or S (═ O)2-R7；
R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6aAnd R6bEach independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, or carbocyclyl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, and carbocyclyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from the group consisting of D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl, and amino;
each R7Independently amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said amino, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl and amino; and
each R8And R9Independently H, D, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said amino, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl and amino.
The compound of claim 1, wherein each R1aIndependently D, F, Cl, Br, oxo, cyano, COOH, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl, -NR8R9、C6-10Aryloxy, 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, -C (═ O) -R7、-S(＝O)-R7、-S(＝O)2-R7、C6-10Aryl or C1-6An alkyl group; or, two R1aAnd the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring; wherein said C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl radical, C6-10Aryloxy group, 3-to 7-membered carbocyclic group, 3-to 7-membered heterocyclic group, C6-10Aryl radical, C1-6Alkyl, 3-7 membered carbocycle and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, C1-4Alkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, C1-4Alkoxy and C6-10Aryl is substituted by a substituent; and
each R1bIndependently D, H, F, Cl, Br, oxo, cyano, hydroxy, COOH, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl, -NR8R9、C6-10Aryloxy, 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, -C (═ O) -R7、-OC(＝O)-R7、-S(＝O)-R7、-S(＝O)2-R7、C6-10Aryl radical, C1-6Alkoxy or C1-6An alkyl group; or, two R1bAnd the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring; wherein said C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl radical, C6-10Aryloxy group, 3-to 7-membered carbocyclic group, 3-to 7-membered heterocyclic group, C6-10Aryl radical, C1-6Alkoxy radical, C1-6Alkyl, 3-7 membered carbocycle and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, C1-4Alkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, C1-4Alkoxy and C6-10Aryl is substituted by a substituent;
each R7Independently of one another is amino, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; wherein said amino group, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently optionally substituted by 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Aryl and amino;
each R8And R9Independently H, D, amino, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; wherein said amino group, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently optionally substituted by 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Aryl and amino.
The compound according to claim 1 or 2, wherein,
has a sub-structural formula:
has a sub-structural formula:
wherein each R is1a1And R1a2Independently D, F, Cl, Br, oxo, cyano, COOH. Trifluoromethyl, trifluoromethoxy, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, -NR8R9、-C(＝O)-R7、-S(＝O)-R7、-S(＝O)2-R10Phenoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, morpholinyl, piperazinyl, imidazolidinyl, phenyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; wherein said hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, phenoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, morpholinyl, piperazinyl, imidazolidinyl, phenyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, Isobutoxy, tert-butoxy and phenyl;
each R1b1And R1b2Independently D, H, F, Cl, Br, oxo, cyano, hydroxy, COOH, trifluoromethyl, trifluoromethoxy, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, -NR8R9、-C(＝O)-R7、-OC(＝O)-R7、-S(＝O)-R7、-S(＝O)2-R7Phenoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, morpholinyl, piperazinyl, imidazolidinyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; wherein said hydroxymethyl and hydroxy groupsEthyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, phenoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, morpholinyl, piperazinyl, imidazolidinyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, and the like, N-butoxy, iso-butoxy, tert-butoxy and phenyl;
each R7Independently amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopentyl, piperidinyl, or phenyl;
each R8And R9Independently H, D, amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopentyl, piperidinyl, or phenyl;
Q1a、Q2aand Q3aEach independently a bond, -CR11R12-、O、NR11Or S, and Q1a、Q2a、Q3aNot being a bond at the same time;
Q1b、Q2band Q3bEach independently a bond, -CR11R12-、O、NR11Or S, and Q1b、Q2b、Q3bNot being a bond at the same time;
R11and R12Each independently is H, D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanylA group selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and phenyl;
t1aand t1bEach independently is 0, 1 or 2; and
t2aand t2bEach independently is 0, 1,2 or 3.
The compound according to any one of claims 1 to 3, wherein,
has a sub-structural formula:
has a sub-structural formula:
the compound of any one of claims 1-4, ring A and ring B are each independently C6-10Aryl or 5-6 membered heteroaryl; and
each R10aAnd R10bIndependently D, F, Cl, Br, hydroxyl, cyano, COOH, amino, C1-4Alkyl radical, C2-4Alkynyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, C1-4Alkoxy, phenyl, -C (═ O) -R7、-NR8S(＝O)2-R7、-S(＝O)-R7Or S (═ O)2-R7。
The compound of any one of claims 1-5, ring a and ring B are each independently of the following subformula:
each R10aAnd R10bIndependently D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, ethynyl, propynyl, cyclopropyl, hydrofuranyl, pyrrolidinyl, phenyl, -C (═ O) CH3、-NHS(＝O)2CH3、-NCH3S(＝O)2CH3、-S(＝O)CH3Or S (═ O)2CH3。
The compound of any one of claims 1-6, wherein R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6aAnd R6bEach independently is H, D, C1-6Alkyl radical, C1-6Heteroalkyl group, C2-6Alkenyl radical, C2-6Alkynyl, C6-10Aryl, 5-6 membered heteroaryl, 3-7 membered heterocyclyl or 3-7 membered carbocyclyl, wherein said C1-6Alkyl radical, C1-6Heteroalkyl group, C2-6Alkenyl radical, C2-6Alkynyl, C6-10Aryl, 5-6 membered heteroaryl, 3-7 membered heterocyclyl and 3-7 membered carbocyclyl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical,C6-10Aryl, 5-6 membered heteroaryl and amino.
The compound of any one of claims 1-7, wherein R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6aAnd R6bEach independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxymethyl, ethoxymethyl, methylthiomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, phenyl, or pyridinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxymethyl, ethoxymethyl, methylthiomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and pyridinyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, methoxy, ethoxy, n-propoxy, isopropoxy, phenyl, imidazole, pyridine, and amino.
The compound of any one of claims 1-8, having a structure as shown in formula (II), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound having a structure as shown in formula (II),
the compound according to any one of claims 1 to 9, which has a structure represented by formula (II-1), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the compound having the structure represented by formula (II-1),
the compound of any one of claims 1-9, having a structure as shown in formula (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X),
the compound according to any one of claims 1 to 11, which has a structure as shown in formula (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1) or (X-1), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of a compound having a structure as shown in formula (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1) or (X-1),
the compound of any one of claims 1-12, having a structure of one of, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,
a pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and pharmaceutically acceptable adjuvants thereof.
Use of a compound of any one of claims 1-13 or a pharmaceutical composition of claim 14 for the manufacture of a medicament for the prevention or treatment of a disease caused by an IAP disorder.
The use of claim 15, wherein the disease caused by a disorder of IAP is cancer or a hepatitis b virus infection.
A compound of any one of claims 1-13 or a pharmaceutical composition of claim 14 for use in preventing or treating a disease in a subject caused by an IAP disorder.
The compound or pharmaceutical composition of claim 17, wherein the disease caused by a disorder of IAP is cancer or a hepatitis b virus infection.
A method for preventing or treating a disease caused by an IAP disorder comprising administering to a patient a therapeutically effective amount of a compound of any one of claims 1-13 or a pharmaceutical composition of claim 14.
The method of claim 19, wherein the disease caused by a disorder of IAP is cancer or hepatitis b virus infection.
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied, unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York,1994.
Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.
Unless otherwise defined herein, for any variable that occurs more than one time in any substituent or compound or any general structure described herein, its definition on each occurrence is independent of, and does not affect, its definition occurring anywhere else. Furthermore, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A stable compound is one that can be isolated from the reaction mixture in a useful purity.
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, such as compounds of the general formula above, or as specifically exemplified, sub-classified and encompassed within the examples. It is understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the terms "substituted" or "substituted" mean that one or more hydrogen atoms in a given structure are replaced with a particular substituent. In some embodiments, "optionally substituted" means that the group may be substituted or unsubstituted. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituents may be, but are not limited to, D, F, Cl, Br, hydroxyl, cyano, COOH, amino, alkyl, carbocyclyl, heterocyclyl, heteroaryl, alkoxy, and aryl, etc.
In addition, unless otherwise explicitly indicated, the descriptions of "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that specific items expressed between the same symbols do not affect each other in different groups or that specific items expressed between the same symbols in the same groups do not affect each other. For example, structural formulaAnd structural formulaQ between the three1aThe specific options of (a) are not affected; each Q2aThe specific options of (a) are not affected; each Q3aThe specific options of (a) are not affected; structure "- (R)1a)mIn each R1aAre not affected by each other.
In the description of the parts, the invention disclosesThe substituents are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "C" used alone as a prefixm-nA "group" means any group having m to n carbon atoms, e.g., C1-6Haloalkyl represents any group having 1 to 6 carbon atoms; c1-4Alkyl represents any group having 1 to 4 carbon atoms.
The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. In some embodiments, the alkyl group contains 1 to 10 carbon atoms; in some embodiments, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. In some specific structures, when an alkyl group is explicitly represented as a linking group, then the alkyl group represents a linked alkylene group, e.g., formula (C)6-10Aryl group) - (C1-6C in alkyl) -, C1-6Alkyl is understood to mean C1-6An alkylene group.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl (Et-CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Tert-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) 2-ethyl-1-butyl (-CH)2CH(CH2CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3) N-heptyl, n-octyl, and the like.
The term "heteroalkyl" means an alkyl chain interrupted by one or more heteroatoms, wherein the alkyl group and the heteroatoms have the same structure as described hereinMeaning. Unless otherwise specified, the heteroalkyl group contains from 1 to 10 carbon atoms, in other embodiments from 1 to 8 carbon atoms, in other embodiments from 1 to 6 carbon atoms, in other embodiments from 1 to 4 carbon atoms, and in other embodiments from 1 to 3 carbon atoms. Examples include, but are not limited to, CH3OCH2-、CH3CH2OCH2-、CH3SCH2-、CH3SCH2CH2-、(CH3)2NCH2-，(CH3)2CH2OCH2-、CH3OCH2CH2-、CH3CH2OCH2CH2-and the like.
The term "amino" refers to "-NH2”。
The term "hydroxy" refers to "-OH".
The term "cyano" refers to "-CN" or "-C ≡ N".
The term "halogen" refers to F, Cl, Br or I.
The term "oxo" refers to ═ O.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp2A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 10 carbon atoms; in one embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)2) Allyl (-CH)2CH＝CH2) Propenyl (-CHCH)3) Isopropenyl (-C (CH)3)＝CH2) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atomsWherein there is at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. In one embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, in one embodiment, the alkynyl group contains 2-10 carbon atoms; alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)2C.ident.CH), 1-propynyl (-C.ident.C-CH)3) And so on.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)3) Ethoxy (EtO, -OCH)2CH3) 1-propoxy (n-PrO, n-propoxy, -OCH)2CH2CH3) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)3)3) 1-pentyloxy (n-pentyloxy, -OCH)2CH2CH2CH2CH3) 2-pentyloxy (-OCH (CH)3)CH2CH2CH3) 3-pentyloxy (-OCH (CH))2CH3)2) 2-methyl-2-butoxy (-OC (CH))3)2CH2CH3) 3-methyl-2-butoxy (-OCH (CH)3)CH(CH3)2)，3-Methyl-l-butoxy (-OCH)2CH2CH(CH3)2) 2-methyl-l-butoxy (-OCH)2CH(CH3)CH2CH3) And so on.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a mono-, bi-or tricyclic ring containing 3 to 12 ring atoms, at least one ring atom being selected from nitrogen, sulfur and oxygen, and which may be fully saturated or contain one or more degrees of unsaturation, but not one aromatic ring. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. In some embodiments, heterocyclyl is a 3-7 membered heterocyclyl; in other embodiments, the heterocyclyl is a 4-7 membered heterocyclyl; in other embodiments, heterocyclyl is a 3-6 membered heterocyclyl; in other embodiments, heterocyclyl is a 4-6 membered heterocyclyl; in other embodiments, the heterocyclyl is a 5-6 membered heterocyclyl; in other embodiments, the heterocyclyl is a 5-membered heterocyclyl; in other embodiments, the heterocyclyl is a 6-membered heterocyclyl; in other embodiments, the heterocyclyl is a 7-membered heterocyclyl. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, 1, 3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, dioxanyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, 1, 4-oxazepanyl, thiepanyl, oxazepanyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, 1, 3-dioxolyl, 2-dioxolanyl, dithiopyranylRadical, diazaRadical, S-N-azaRadicals, indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-oxo-azepanyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane, 1-dioxothiomorpholinyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.
The term "carbocyclyl" or "carbocycle" denotes a monovalent or multivalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbocyclic and fused carbocyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. In some embodiments, a "carbocyclyl" is a cycloalkyl. In some embodiments, "carbocyclyl" or "carbocycle" is C3-10Carbocyclyl or 3-10 membered carbocycle; in other embodiments, "carbocyclyl" or "carbocycle" is C3-7Carbocyclyl or 3-7 membered carbocycle; in other embodiments, "carbocyclyl" or "carbocycle" is C4-7Carbocyclyl or a 4-7 membered carbocyclic ring; in still other embodiments, "carbocyclyl" or "carbocycle" is C4-6In yet other embodiments, "carbocyclyl" or "carbocycle" is C3-6Carbocyclyl or 3-6 membered carbocycle. Such examples further include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl (1-cyclopentyl-1-alkenyl, 1-cyclopentylAlkenyl-2-yl, 1-cyclopentyl-3-yl), cyclopentadienyl (2, 4-cyclopentadienyl, 1, 3-cyclopentadienyl), cyclohexyl, cyclohexenyl (1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl), cyclohexadienyl (1, 3-cyclohexadienyl, 1, 4-cyclohexadienyl), cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. The carbocyclyl group may be optionally substituted with one or more substituents described herein.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. In some embodiments, cycloalkyl contains 3 to 6 carbon atoms, i.e., C3-6A cycloalkyl group. Specific examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.
The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more attachment points to the rest of the molecule. In some embodiments, the aryl group contains 6 to 10 carbon atoms, i.e., C6-10And (4) an aryl group. Examples of the aryl group may include phenyl, naphthyl, and anthracene. The aryl group may independently be optionally substituted with one or more substituents described herein.
The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms (heteroatoms comprise nitrogen, phosphorus, oxygen or sulfur), wherein each ring system contains a ring of 5 to 7 atoms and has one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl group is a 5-6 membered heteroaryl; in other embodiments, the heteroaryl group is a 5-membered heteroaryl; in other embodiments, the heteroaryl group is a 6 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), and the like, 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.
The term "aryloxy" means that the aryl group is attached to the rest of the molecule through an oxygen atom. Wherein the aryl group has the meaning as described in the present invention. In one embodiment, the aryloxy group contains 6 to 10 carbon atoms, i.e., C6-10An aryloxy group. Examples of aryloxy groups include, but are not limited to: phenoxy, naphthoxy, and the like. The aryloxy group may be optionally substituted with one or more substituents described herein.
The term "haloalkyl" denotes an alkyl group substituted with one or more halogens. In some embodiments, haloalkyl group represents a haloalkyl group containing 1-6 carbon atoms, i.e., C1-6A haloalkyl group; in still other embodiments, haloalkyl groups represent haloalkyl containing 1-4 carbon atoms, i.e., C1-4A haloalkyl group; in still other embodiments, haloalkyl groups represent haloalkyl containing 1-3 carbon atoms, i.e., C1-3A haloalkyl group. Examples include, but are not limited to, trifluoromethyl, difluoromethyl, monofluoromethyl, 1, 2-dichloroethyl, 1, 2-difluoroethyl, and the like.
The term "hydroxyalkyl" denotes an alkyl group substituted with one or more hydroxyl groups. In some embodiments, a hydroxyalkyl group represents a hydroxyalkyl group containing 1-6 carbon atoms, i.e., C1-6A hydroxyalkyl group; in still other embodiments, the hydroxyalkyl group represents a haloalkyl group containing 1 to 4 carbon atoms, i.e., C1-4A hydroxyalkyl group; in still other embodiments, the hydroxyalkyl group represents a hydroxyalkyl group containing 1 to 3 carbon atoms, i.e., C1-3A hydroxyalkyl group. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, 1-hydroxypropyl, 2-hydroxy-2 methylpropyl, hydroxybutyl, and the like.
The term "alkoxyalkyl" denotes an alkyl group substituted with one or more alkoxy groups. In some embodiments, the alkoxyalkyl group is represented by one C1-6Alkoxy-substituted C1-6Alkyl radicals, i.e. C1-6Alkoxy radical C1-6An alkyl group; in other embodiments, the alkoxyalkyl group is represented by a C1-4Alkoxy-substituted C1-4Alkyl radicals, i.e. C1-4Alkoxy radical C1-4An alkyl group; in other embodiments, the alkoxyalkyl group is represented by a C1-3Alkoxy-substituted C1-3Alkyl radicals, i.e. C1-3Alkoxy radical C1-3An alkyl group; in other embodiments, the alkoxyalkyl group is represented by a C1-3Alkoxy-substituted C1-4Alkyl radicals, i.e. C1-3Alkoxy radical C1-4An alkyl group. Examples include, but are not limited to, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, methoxypropyl, and the like.
The term "haloAlkoxy "means an alkoxy group substituted with one or more halogens. In some embodiments, the haloalkoxy group represents a haloalkyl group containing 1 to 6 carbon atoms, i.e., C1-6A haloalkyl group; in still other embodiments, haloalkyl groups represent haloalkyl containing 1-4 carbon atoms, i.e., C1-4A haloalkyl group; in still other embodiments, haloalkyl groups represent haloalkyl containing 1-3 carbon atoms, i.e., C1-3A haloalkyl group. Examples include, but are not limited to, trifluoromethoxy, difluoromethoxy, monofluoro-substituted methoxy, 1, 2-difluoroethoxy, and the like.
As described herein, the substituent (R)1b)nThe ring system formed by a ring bound to the center (as shown in formula f) represents n substituents R1bThe substitution can be made at any substitutable or any reasonable position on the ring. For example, the formula f represents the ring in any possible substituted position by n substituents R1bAnd (4) substitution.
As described herein, substituent R10aThe ring system formed by ring A with one bond connected to the center (shown as formula h) represents substituent R10aThe substitution can be made at any substitutable or any reasonable position on ring a. For example, the formula h represents that any possible substituted position on the ring A may be substituted by a substituent R10aAnd the specific substitution conditions are shown as formulas h1, h2, h3 and h 4.
As described herein, unless otherwise specified, a ring substituent may be attached to the rest of the molecule through any available position on the ring. For example, piperidinyl includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl.
Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention.
Unless otherwise indicated, the structural formulae depicted herein and the compounds depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, geometric or conformational isomers), nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Thus, compounds that are individual stereochemically isomeric forms, enantiomeric forms, diastereomeric forms, geometric forms, conformational forms, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention are also within the scope of the present invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.
The term "protecting group" or "Pg" refers to a substituent that when reacted with other functional groups, is typically used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2-(p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005。
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs in Design and Clinical Applications, Nature Review Delivery, 2008,7,255 and 270, S.J.Herer et al, Prodrugs of pharmaceuticals and pharmaceuticals, Journal of chemical Chemistry,2008,51,2328 and 5.
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York,1994.
The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereo structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. 50:50 are referred to as racemic mixtures or racemates, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.
"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
The term "tautomer" or "tautomeric form" means that isomers of structures of different energies may be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include tautomers that move through protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include tautomers that recombine into bond electrons.
"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.
"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanate, p-toluenesulfonic acidSalts, undecanoate salts, pentanoate salts, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates and aromatic sulfonates.
The "hydrate" of the present invention means an association of solvent molecules with water.
"nitroxide" in the context of the present invention means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March, pages). In particular, the N-oxide may be prepared by the method of L.W.Deady (Syn.Comm.1977,7,509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H，3H，11C，13C，14C，15N，17O，18O，18F，31P，32P，35S，36Cl and125I。
in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present3H，14C and18those compounds of F, or in which a non-radioactive isotope is present, e.g.2H and13C. the isotopically enriched compounds can be used for metabolic studies (use)14C) Reaction kinetics study (using, for example2H or3H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.18F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.
In another aspect, the invention relates to intermediates for the preparation of compounds of formula (I), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1) or (X-1).
In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound of formula (I), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1) or (X-1).
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and pharmaceutically acceptable adjuvants thereof. In some embodiments, adjuvants of the present invention include, but are not limited to, carriers, excipients, diluents, vehicles, or combinations thereof. In some embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.
In addition, heavier isotopes are, in particular, deuterium (i.e.,2substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the context of the present invention is to be considered as a substituent of a compound of formula (I), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1) or (X-1). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has, for each designated deuterium atom, at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D2O, acetone-d6、DMSO-d6Those solvates of (a).
Description of the Compounds of the invention
The compounds of the present invention, as IAP inhibitors, are effective in treating diseases caused by IAP disorders, and can be used for the preparation of medicaments for the prevention and treatment of cancer or hepatitis B virus infection.
In one aspect, the invention provides a compound having a structure shown in formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (I),
wherein m, n, r1、r2、R1a、R1bRing A, ring B, R10a、R10b、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6aAnd R6bHaving the definitions as described in the present invention.
In some embodiments of the present invention, the substrate is,
m and n are each independently 1,2,3,4, 5,6 or 7;
r1and r2Each independently is 0, 1,2 or 3;
each R1aIndependently D, F, Cl, Br, oxo (═ O), cyano, COOH, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, -NR8R9Aryloxy, carbocyclyl, heterocyclyl, -C (═ O) -R7、-S(＝O)-R7、-S(＝O)2-R7Aryl or alkyl; or, two R1aAnd the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring;wherein said haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, aryloxy, carbocyclyl, heterocyclyl, aryl, alkyl, 3-7 membered carbocycle and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, alkyl, carbocyclyl, heterocyclyl, alkoxy and aryl;
each R1bIndependently D, H, F, Cl, Br, oxo (═ O), cyano, hydroxy, COOH, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, -NR8R9Aryloxy, carbocyclyl, heterocyclyl, -C (═ O) -R7、-OC(＝O)-R7、-S(＝O)-R7、-S(＝O)2-R7Aryl, alkoxy or alkyl; or, two R1bAnd the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring; wherein said haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, aryloxy, carbocyclyl, heterocyclyl, aryl, alkoxy, alkyl, 3-7 membered carbocycle and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, alkyl, carbocyclyl, heterocyclyl, alkoxy and aryl;
ring a and ring B are each independently aryl or heteroaryl;
each R10aAnd R10bIndependently, D, F, Cl, Br, hydroxyl, cyano, COOH, amino, alkyl, alkynyl, carbocyclyl, heterocyclyl, alkoxy, aryl, -C (═ O) -R7、-NR8S(＝O)2-R7、-S(＝O)-R7Or S (═ O)2-R7；
R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6aAnd R6bEach independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, or carbocyclyl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, and carbocyclyl are each independently optionally substituted with 1,2.3 or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl and amino;
each R7Independently amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said amino, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl and amino;
each R8And R9Independently H, D, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said amino, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl and amino.
In some embodiments, each R is1aIndependently D, F, Cl, Br, oxo (═ O), cyano, COOH, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, -NR8R9Aryloxy, carbocyclyl, heterocyclyl, -C (═ O) -R7、-S(＝O)-R7、-S(＝O)2-R7Aryl or alkyl, wherein said haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, aryloxy, carbocyclyl, heterocyclyl, aryl and alkyl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, alkyl, carbocyclyl, heterocyclyl, alkoxy and aryl; or the like, or, alternatively,
has a sub-structural formula:
wherein Q1a、Q2aAnd Q3aEach independently a bond, -CR11R12-、O、NR11Or S, and Q1a、Q2a、Q3aNot being a bond at the same time;
R11and R12Each independently is H, D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and phenyl.
In some embodiments, each R is1aIndependently D, F, Cl, Br, oxo (═ O), cyano, COOH, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, -NR8R9Aryloxy, carbocyclyl, heterocyclyl, -C (═ O) -R7、-S(＝O)-R7、-S(＝O)2-R7Aryl or alkyl, wherein said haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, aryloxy, carbocyclyl, heterocyclyl, aryl and alkyl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, alkyl, carbocyclyl, heterocyclyl, alkoxy and aryl.
In some embodiments of the present invention, the substrate is,has a sub-structural formula:
wherein Q1a、Q2aAnd Q3aEach independently a bond, -CR11R12-、O、NR11Or S, and Q1a、Q2a、Q3aNot being a bond at the same time;
R11and R12Each independently is H, D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and phenyl.
In some embodiments, each R is1bIndependently D, H, F, Cl, Br, oxo (═ O), cyano, hydroxy, COOH, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, -NR8R9Aryloxy, carbocyclyl, heterocyclyl, -C (═ O) -R7、-OC(＝O)-R7、-S(＝O)-R7、-S(＝O)2-R7Aryl, alkoxy or alkyl; or, two R1bAnd the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring; wherein said haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, aryloxy, carbocyclyl, heterocyclyl, aryl, alkoxy, alkyl, 3-7 membered carbocycle and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, alkyl, carbocyclyl, heterocyclyl, alkoxy and aryl.
In some embodiments, ring a and ring B are each independently aryl or heteroaryl.
In some embodiments, each R is10aAnd R10bIndependently, D, F, Cl, Br, hydroxyl, cyano, COOH, amino, alkyl, alkynyl, carbocyclyl, heterocyclyl, alkoxy, aryl, -C (═ O) -R7、-NR8S(＝O)2-R7、-S(＝O)-R7Or S (═ O)2-R7。
In some embodiments, R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6aAnd R6bEach independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, or carbocyclyl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, and carbocyclyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from the group consisting of D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl, and amino.
In some embodiments, each R is7Independently amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said amino, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl and amino.
In some embodiments, each R is8And R9Independently H, D, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said amino, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl and amino.
In some embodiments, each R is1aIndependently D, F, Cl, Br, oxo (═ O), cyano, COOH, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl, -NR8R9、C6-10Aryloxy, 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, -C (═ O) -R7、-S(＝O)-R7、-S(＝O)2-R7、C6-10Aryl or C1-6An alkyl group; or, two R1aAnd the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring; wherein said C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl radical, C6-10Aryloxy group, 3-to 7-membered carbocyclic group, 3-to 7-membered heterocyclic group, C6-10Aryl radical, C1-6Alkyl, 3-7 membered carbocycle and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, C1-4Alkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, C1-4Alkoxy and C6-10Aryl is substituted by a substituent; and
each R1bIndependently D, H, F, Cl, Br, oxo (═ O), cyano, hydroxy, COOH, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl, -NR8R9、C6-10Aryloxy, 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, -C (═ O) -R7、-OC(＝O)-R7、-S(＝O)-R7、-S(＝O)2-R7、C6-10Aryl radical, C1-6Alkoxy or C1-6An alkyl group; or, two R1bAnd the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring; wherein said C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl radical, C6-10Aryloxy group, 3-to 7-membered carbocyclic group, 3-to 7-membered heterocyclic group, C6-10Aryl radical, C1-6Alkoxy radical, C1-6Alkyl, 3-7 membered carbocycle and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, C1-4Alkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, C1-4Alkoxy and C6-10Aryl is substituted by a substituent;
each R7Independently of one another is amino, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; wherein said amino group, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently optionally substituted by 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Substituents of aryl and amino groupsSubstituted;
each R8And R9Independently H, D, amino, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; wherein said amino group, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently optionally substituted by 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Aryl and amino.
In some embodiments, each R is1aIndependently D, F, Cl, Br, oxo (═ O), cyano, COOH, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl, -NR8R9、C6-10Aryloxy, 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, -C (═ O) -R7、-S(＝O)-R7、-S(＝O)2-R7、C6-10Aryl or C1-6An alkyl group; wherein said C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl radical, C6-10Aryloxy group, 3-to 7-membered carbocyclic group, 3-to 7-membered heterocyclic group, C6-10Aryl and C1-6Each alkyl is independently optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, C1-4Alkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, C1-4Alkoxy and C6-10Aryl is substituted by a substituent; or
Has a sub-structural formula:
wherein Q1a、Q2aAnd Q3aEach independently a bond, -CR11R12-、O、NR11Or S, and Q1a、Q2a、Q3aNot being a bond at the same time;
R11and R12Each independently is H, D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and phenyl.
In some embodiments, each R is1aIndependently D, F, Cl, Br, oxo (═ O), cyano, COOH, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl, -NR8R9、C6-10Aryloxy, 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, -C (═ O) -R7、-S(＝O)-R7、-S(＝O)2-R7、C6-10Aryl or C1-6An alkyl group; wherein said C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl radical, C6-10Aryloxy group, 3-to 7-membered carbocyclic group, 3-to 7-membered heterocyclic group, C6-10Aryl and C1-6Each alkyl is independently optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, C1-4Alkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, C1-4Alkoxy and C6-10Aryl group.
In some embodiments of the present invention, the substrate is,
wherein Q1a、Q2aAnd Q3aEach independently a bond, -CR11R12-、O、NR11Or S, and Q1a、Q2a、Q3aNot being a bond at the same time;
R11and R12Each independently is H, D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and phenyl.
In some embodiments, each R is1bIndependently D, H, F, Cl, Br, oxo (═ O), cyano, hydroxy, COOH, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl, -NR8R9、C6-10Aryloxy, 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, -C (═ O) -R7、-OC(＝O)-R7、-S(＝O)-R7、-S(＝O)2-R7、C6-10Aryl radical, C1-6Alkoxy or C1-6An alkyl group; or, two R1bAnd the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring; wherein said C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl radical, C6-10Aryloxy group, 3-to 7-membered carbocyclic group, 3-to 7-membered heterocyclic group, C6-10Aryl radical, C1-6Alkoxy radical, C1-6Alkyl, 3-7 membered carbocycle and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, C1-4Alkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, C1-4Alkoxy and C6-10Aryl group.
In some embodiments, each R is7Independently of one another is amino, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; wherein said amino group, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently optionally substituted by 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Aryl and amino.
In some embodiments, each R is8And R9Independently H, D, amino, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; wherein said amino group, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently optionally substituted by 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Aryl and amino.
In some embodiments of the present invention, the substrate is,
has a sub-structural formula:
wherein each R is1a1And R1a2Independently D, F, Cl, Br, oxo (═ O), cyano, COOH, trifluoromethyl, trifluoromethoxy, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, -NR8R9、-C(＝O)-R7、-S(＝O)-R7、-S(＝O)2-R10Phenoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, morpholinyl, piperazinyl, imidazolidinyl, phenyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; wherein said hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, phenoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, morpholinyl, piperazinyl, imidazolidinyl, phenyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, Isobutoxy, tert-butoxy and phenyl;
each R1b1And R1b2Independently D, H, F, Cl, Br, oxo (═ O), cyano, hydroxy, COOH, trifluoromethyl, trifluoromethoxy, hydroxymethyl, hydroxyethyl, methoxymethylEthyl, ethoxymethyl, ethoxyethyl, -NR8R9、-C(＝O)-R7、-OC(＝O)-R7、-S(＝O)-R7、-S(＝O)2-R7Phenoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, morpholinyl, piperazinyl, imidazolidinyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; wherein said hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, phenoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, morpholinyl, piperazinyl, imidazolidinyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, cyclopropyl, cyclopentyl, cyclohexyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexyl, Ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and phenyl;
each R7Independently amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopentyl, piperidinyl, or phenyl;
each R8And R9Independently H, D, amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopentyl, piperidinyl, or phenyl;
Q1a、Q2aand Q3aEach independently a bond, -CR11R12-、O、NR11Or S, and Q1a、Q2a、Q3aNot being a bond at the same time;
Q1b、Q2band Q3bEach independently is a bond,-CR11R12-、O、NR11Or S, and Q1b、Q2b、Q3bNot being a bond at the same time;
R11and R12Each independently is H, D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and phenyl;
t1aand t1bEach independently is 0, 1 or 2; and
t2aand t2bEach independently is 0, 1,2 or 3.
In some embodiments of the present invention, the substrate is,
has a sub-structural formula:
in some embodiments, ring a and ring B are each independently C6-10Aryl or 5-6 membered heteroaryl; and
each R10aAnd R10bIndependently D, F, Cl, Br, hydroxyl, cyano, COOH, amino, C1-4Alkyl radical, C2-4Alkynyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, C1-4Alkoxy, phenyl, -C (═ O) -R7、-NR8S(＝O)2-R7、-S(＝O)-R7Or S (═ O)2-R7。
In some embodiments, ring a and ring B are each independently of the following subformula:
and
each R10aAnd R10bIndependently D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, ethynyl, propynyl, cyclopropyl, hydrofuranyl, pyrrolidinyl, phenyl, -C (═ O) CH3、-NHS(＝O)2CH3、-NCH3S(＝O)2CH3、-S(＝O)CH3Or S (═ O)2CH3。
In some embodiments, R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6aAnd R6bEach independently is H, D, C1-6Alkyl radical, C1-6Heteroalkyl group, C2-6Alkenyl radical, C2-6Alkynyl, C6-10Aryl, 5-6 membered heteroaryl, 3-7 membered heterocyclyl or 3-7 membered carbocyclyl, wherein said C1-6Alkyl radical, C1-6Heteroalkyl group, C2-6Alkenyl radical, C2-6Alkynyl, C6-10Aryl, 5-6 membered heteroaryl, 3-7 membered heterocyclyl or 3-7 membered carbocyclyl each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Aryl, 5-6 membered heteroaryl and amino.
In some embodiments, R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6aAnd R6bEach independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxymethyl, ethoxymethyl, methylthiomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, phenyl, or pyridinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxymethyl, ethoxymethyl, methylthiomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, phenyl, and pyridinyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, methoxy, ethoxy, n-propoxy, isopropoxy, phenyl, imidazole, pyridine, and amino.
In some embodiments, the compounds of the invention have a structure as shown in formula (Ia), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of the structure shown in formula (Ia),
in some embodiments, the compounds of the present invention have a structure as shown in formula (Ia-1), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of the structure shown in formula (Ia-I),
in some embodiments, the compounds of the present invention have a structure as shown in formula (II), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of the structure shown in formula (II),
in some embodiments, the compounds of the present invention have a structure as shown in formula (II-1), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of the structure shown in formula (II-1),
in some embodiments, the compounds of the present invention have a structure as shown in formula (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound having a structure as shown in formula (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X),
in some embodiments, the compounds of the present invention have a structure as shown in formula (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1) or (X-1), or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound having a structure as shown in formula (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1) or (X-1),
in some embodiments, the compounds of the invention have a structure as shown in formula (IIIa), (IIIb), (IVa), (Va), (VIa) or (VIIa), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound having a structure as shown in formula (IIIa), (IIIb), (IVa), (Va), (VIa) or (VIIa)),
in some embodiments, the compounds of the invention have a structure as shown in formula (IIIa-1), (IIIb-1), (IVa-1), (Va-1), (VIa-1) or (VIIa-1), or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound having a structure as shown in formula (IIIa-1), (IIIb-1), (IVa-1), (Va-1), (VIa-1) or (VIIa-1),
in some embodiments, the compounds of the present invention have the structure of one of, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
in another aspect, the invention provides a pharmaceutical composition comprising any one of the compounds of the invention as described herein and pharmaceutically acceptable adjuvants therefor.
In another aspect, the invention provides the use of any one of the compounds of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of a disease caused by an IAP disorder.
In another aspect, the invention provides a compound of the invention or a pharmaceutical composition of the invention for use in the prevention or treatment of a disease caused by an IAP disorder.
In one aspect, the invention provides a method for treating or preventing a disease caused by an IAP disorder, the method comprising administering to a patient having a disease caused by an IAP disorder a pharmaceutically acceptable therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention.
In some embodiments, the disease caused by a disorder of IAPs described herein is cancer or hepatitis b virus infection.
In some embodiments, the cancers of the present invention include, but are not limited to, rectal cancer, renal cancer, ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, melanoma, glioblastoma, acute myeloid leukemia, small cell lung cancer, non-small cell lung cancer, rhabdomyosarcoma, basal cell carcinoma, and the like.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.
Nitroxides of the compounds of the present invention are also included within the scope of the present invention. The nitroxides of the compounds of the present invention may be prepared by oxidation of the corresponding nitrogen-containing basic species using a common oxidizing agent (e.g. hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperature, or by reaction with a peracid in a suitable solvent, for example peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
If the compounds of the invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Or using organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranonic acids, such as glucuronic acid and galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, and the like.
If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali or alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine, piperazine and the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
Compounds of the invention and pharmaceutical compositions, formulations and administrations thereof
According to another aspect, a feature of the pharmaceutical composition of the invention includes a compound of formula (I), (Ia-1), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1), (X-1), (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa), (IIIa-1), (IIIb-1), (IVa-1), (Va-1), (VIa-1) or (VIIa-1), a compound listed in the invention, or a compound of the examples. The amount of compound in the compositions of the invention is effective to treat or ameliorate a disease caused by a disorder of IAP in a subject, including cancer, hepatitis b virus infection.
As described herein, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants, as used herein, including any solvents, diluents, or other liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, and the like, as appropriate for the particular target dosage form. As described in the following documents: in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of this document, indicates that different adjuvants can be used In The preparation of pharmaceutically acceptable compositions and their well-known methods of preparation. Except insofar as any conventional adjuvant is incompatible with the compounds of the present invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, their use is contemplated by the present invention.
When available for treatment, a therapeutically effective amount of a compound of the invention, especially a compound of formula (I), (Ia-1), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1), (X-1), (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa), (IIIa-1), (IIIb-1), (IVa-1), (Va-1), (VIa-1) or (VIIa-1), and pharmaceutically acceptable salts thereof, may be administered as an unprocessed chemical, can also be provided as an active ingredient of a pharmaceutical composition. Accordingly, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, especially of formula (I), (Ia-1), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1), (X-1), (VIII-1), (IX-1), (X-1), (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa), (IIIa-1), (IIIb-1), (IVa-1), (Va-1), A compound of (VIa-1) or (VIIa-1) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable adjuvants including, but not limited to, carriers, diluents, or excipients, and the like. The term "therapeutically effective amount" as used herein refers to the total amount of each active component sufficient to show meaningful patient benefit (e.g., cancer cell reduction). When the active ingredient alone is used for separate administration, the term refers only to that ingredient. When used in combination, the term refers to the combined amounts of the active ingredients that, when combined, administered sequentially or simultaneously, result in a therapeutic effect. Compounds of the invention, in particular of the formulae (I), (Ia-1), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (III-1), (IV-1), (V-1), compounds of (VI-1), (VII-1), (VIII-1), (IX-1), (X-1), (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa), (IIIa-1), (IIIb-1), (IVa-1), (Va-1), (VIa-1) or (VIIa-1) and pharmaceutically acceptable salts thereof are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to a further aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation, which process comprises contacting a compound of the invention, especially of formula (I), (Ia-1), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1), (X-1), (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa), (IIIa-1), (IIIb-1), (IVa-1), (Va-1), Mixing the (VIa-1) or (VIIa-1) compound or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to 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 patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
The amount of active ingredient that is combined with one or more adjuvants to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. The amount of active ingredient which is admixed to prepare a single dosage form for the preparation of a single dosage form of the compound of formula (I), (Ia-1), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (VIII), (IX), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (IX-1), (X-1), (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa), (IIIa-1), (IIIb-1), (IVa-1), (Va-1), (VIa-1) or (VIIa-1) depending on the disease to be treated, The severity of the disease, the time of administration, the route of administration, the rate of excretion of the compound used, the time of treatment and the age, sex, weight and condition of the patient. Preferred unit dosage forms are those containing a daily or divided dose or suitable fraction thereof of the active ingredient described herein above. Treatment can be initiated with small doses, which are clearly below the optimal dose of the compound. Thereafter, the dosage is increased in smaller increments until the optimum effect is achieved in this case. In general, the compounds are most desirably administered at concentration levels that generally provide effective results in antitumor terms without causing any harmful or toxic side effects.
The pharmaceutical compositions comprise from about 1% to about 95%, preferably from about 20% to about 90% of the active ingredient. The pharmaceutical compositions of the present invention may be, for example, in unit dosage form such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules.
The compounds of the present invention or pharmaceutical compositions thereof are preferably administered in an effective amount. An effective amount is the amount of the formulation that alone or in combination with other agents produces the desired response. This may include only temporarily slowing the progression of the disease, but preferably includes permanently arresting the progression of the disease or delaying the onset of the disease or preventing the occurrence of the disease or condition. This can be monitored by conventional means. In general, the dosage of active compound should be from about 0.01mg/kg per day to 1000mg/kg per day. It is contemplated that administration is preferably daily via intravenous, intramuscular or intradermal and that dosage ranges of 50-500 mg/kg, once or several times, are suitable. Administration of a compound of the invention or a pharmaceutical composition thereof may be performed simultaneously with, after, or before chemotherapy or radiation, as long as the chemotherapeutic agent or radiation sensitizes the system to the compound of the invention or pharmaceutical composition thereof.
In general, routine experimentation in clinical trials will determine a specific range of optimal therapeutic effect for each therapeutic agent and each dosing regimen, and adjust administration to a specific patient to within an effective and safe range depending on the patient's condition and responsiveness to initial administration. However, the final dosage regimen will be adjusted according to the judgment of the attending physician in view of factors such as age, condition and size of the patient, efficacy of the compound of the invention or its pharmaceutical composition, duration of treatment and severity of the disease being treated. For example, the dosage regimen of the compound of the present invention or its pharmaceutical composition may be 1mg to 2000mg per day, preferably 1 to 1000mg per day, more preferably 50 to 600mg per day, orally administered in 2 to 4 (preferably 2) divided doses per day to reduce tumor growth. Intermittent therapy (e.g., one of three weeks or three of four weeks) may also be used.
The pharmaceutical compositions provided by the present invention comprise a therapeutically effective amount of one or more compounds of formula (I), (Ia-1), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1), (X-1), (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa), (IIIa-1), (IIIb-1), (IVa-1), (Va-1), (VIa-1) or (VIIa-1) provided by the invention, for use in the prevention, treatment or amelioration of one or more symptoms of a disease caused by a disorder of IAP or a condition associated with caspase activity, including caspase-9 activity. Such diseases or disorders include, but are not limited to, hyperproliferative diseases, autoimmune diseases, psoriasis, hyperplasia, and restenosis. The autoimmune diseases include HIV virus infection and hepatitis B virus infection.
The pharmaceutical compositions are suitable for administration by any suitable route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by mixing the active ingredient with a carrier or excipient. Oral administration or injection administration is preferred.
In addition, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (e.g., glucose or beta-lactose), corn sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth or sodium alginate), carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. For example, tablets are prepared by making a powder mixture, granulating or slugging, adding a lubricant and a disintegrant, and compressing into tablets. The powdered mixture is prepared by mixing the appropriately comminuted compound with a diluent or base as described above, optionally with a binder (for example carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone), a dissolution inhibitor (for example paraffin), an absorption accelerator (quaternary salt) and/or an absorbent (for example bentonite, kaolin or dicalcium phosphate). The powdered mixture may be granulated by wetting with a binder such as syrup, starch slurry, acacia slurry (acadia mucilage) or a solution of cellulosic or polymeric material and pressure sieving. An alternative to granulation is to pass the powder mixture through a tablet press, with the result that poorly formed agglomerates are broken up into granules. The granules may be lubricated by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the dies of the tablet press. The lubricated mixture is then compressed into tablets. The compounds of the present disclosure may also be combined with a free-flowing inert carrier and compressed into tablets without going through a granulation or pre-compression step. Transparent or opaque protective coating materials may be provided which consist of a shellac coating, a sugar coating or a coating of a polymeric material and a waxy polishing coating (wax). Dyes may be added to these coatings to distinguish different unit doses.
It will be appreciated that in addition to the ingredients particularly mentioned above, the formulations may include other ingredients conventional in the art having regard to the type of formulation in question, for example, such formulations which are suitable for oral administration may include flavouring agents.
Use of the Compounds and pharmaceutical compositions of the invention
The pharmaceutical composition of the invention is characterized by comprising compounds of formula (I), (Ia-1), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1), (X-1), (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa), (IIIa-1), (IIIb-1), (IVa-1), (Va-1), (VIa-1) or (VIIa-1), the compounds listed in the invention, or the compound of the examples, and pharmaceutically acceptable adjuvants such as carriers, adjuvants or excipients, and the like. The compounds of the compositions of the invention are useful in the prevention and treatment of diseases caused by IAP disorders.
Diseases caused by IAP disorders are, but not limited to, hyperproliferative diseases, autoimmune diseases, psoriasis, hyperplasia, and restenosis. Wherein the autoimmune disease comprises HIV virus infection and hepatitis B virus infection; proliferative diseases include neoplastic diseases (or cancers) (and/or any metastases).
The compound or the pharmaceutical composition thereof can be used for preparing medicaments particularly suitable for treating cancers, including tumors, such as skin cancer, breast cancer, brain cancer, neck cancer, testicular cancer and the like. It is particularly useful for the treatment of metastatic or malignant tumors. More particularly, cancers that may be treated by the compositions and methods of the present invention include, but are not limited to, the following tumor types: such as astrocytic, breast, neck, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid cancers, as well as sarcomas. More particularly, these compounds are useful in the treatment of: cancer in the heart region: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancer: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, hamartoma, mesothelioma; cancer in the gastrointestinal tract: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, reoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract cancer: renal cancer (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urinary tract cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); cancer of the liver site: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone-related cancers: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrosarcoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell chordoma, osteochondromatoma (osteoectochondromy wart), benign chondroma, chondroblastoma-like fibroma (chondroblastoma), osteoid osteoma, and giant cell tumor; cancers of the nervous system: cranial cancers (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meningeal cancers (meningioma, meningiosarcoma (menigiospora), glioma), brain cancers (astrocytoma, neuroblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); gynecological cancer: uterine cancer (endometrial cancer), cervical cancer (neck cancer, pre-neoplastic cervical dysplasia), ovarian cancer (serous cyst adenocarcinoma, mucinous cyst adenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors (granulosa-thecal tumors), sertoli cell tumors, dysgerminoma, malignant teratoma), vulval cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (rhabdomyosarcoma), fallopian tube tumor (carcinoma), hematologic cancer: leukemia (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, pre-tumor cervical dysplasia, cervical cancer (cervical cancer, pre-malignant cyst-cervical cancer), uterine cancer-cervical cancer (serous cyst adenocarcinoma, mucinous cyst adenocarcinoma, sarcoidosis, dysgerminoma, malignant teratoma), vulval cancer (squamous cell carcinoma, botryoid sarcoma, botryoid, Non-hodgkin lymphoma (malignant lymphoma); skin cancer: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal cancer, neuroblastoma. Thus, the term "cancer cell" as provided herein includes cells having any or related of the above-identified conditions.
The compound or the pharmaceutical composition thereof can also be used for preparing medicaments for treating HIV infection and hepatitis B virus infection diseases. The compound or the pharmaceutical composition thereof can effectively inhibit the expression of IAPs (apoptosis protein inhibitors) in liver cells and promote the elimination of HBV DNA and HBV surface antigen mediated by virus-specific T cells, thereby curing chronic HBV infection.
In the broad sense of the present invention, a proliferative disease may also be a hyperproliferative condition such as leukemia, hyperplasia, fibrosis (especially pulmonary fibrosis, but also other types of fibrosis such as renal fibrosis), angiogenesis, psoriasis, atherosclerosis and smooth muscle hyperplasia in blood vessels such as stenosis or restenosis following angioplasty.
When referring to a tumor, a tumor disease, a cancer or a cancer, additionally or alternatively metastases at the original organ or tissue and/or any other site are implied, irrespective of the site of the tumor and/or metastases.
The compounds of the present invention may be administered alone or in combination with other anti-cancer agents, such as compounds that inhibit tumor angiogenesis, e.g., protease inhibitors, epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, and the like; cytotoxic drugs such as antimetabolites, e.g., purine and pyrimidine mimetic antimetabolites; antimitotic agents such as microtubule stabilizing agents and antimitotic alkaloids; a platinum coordination complex; anti-tumor antibiotics; alkylating agents such as nitrogen mustards and nitrosoureas; endocrine drugs such as adrenocorticosteroids, androgens, antiandrogens, estrogens, antiestrogens, aromatase inhibitors, gonadotropin-releasing hormone agonists and somatostatin analogues and compounds targeting enzymes or receptors that are overexpressed and/or involved in specific metabolic pathways that are upregulated in tumor cells, for example inhibitors of ATP and GTP phosphodiesterase, inhibitors of histone deacetylase, inhibitors of protein kinases such as serine, threonine and tyrosine kinases, for example, Abelson protein tyrosine kinase and various growth factors, their receptors and kinase inhibitors such as epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, fibroblast growth factor inhibitors, insulin-like growth factor receptor inhibitors, platelet derived growth factor receptor kinase inhibitors, and the like; methionine aminopeptidase inhibitors, proteasome inhibitors, and cyclooxygenase inhibitors, e.g., cyclooxygenase-1 or-2 inhibitors.
In some embodiments, when administered in combination, there are two modes: 1) the compound or the pharmaceutical composition and other combinable active medicaments are respectively prepared into separate preparations, and the two preparations can be the same or different and can be used sequentially or simultaneously; when used sequentially, the first medicament does not lose its effective effect in vivo when the second medicament is administered; 2) the compound or pharmaceutical composition of the present invention and other active agents that can be combined are formulated into a single formulation and administered simultaneously.
The invention further relates to a method of promoting apoptosis in rapidly proliferating cells, the method comprising contacting the rapidly proliferating cells with an apoptosis-promoting effective amount of a polypeptide of formula (I), (Ia-1), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1), (X-1), (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa) of the invention that binds to the Smac binding site of a XIAP and/or cIAP protein, (IIIa-1), (IIIb-1), (IVa-1), (Va-1), (VIa-1) or (VIIa-1).
In another embodiment of the invention, a compound or composition of the invention may be administered with a chemotherapeutic agent and/or with radiation therapy, immunotherapy and/or photodynamic therapy to promote apoptosis and enhance the effectiveness of said chemotherapy, radiation therapy, immunotherapy and/or photodynamic therapy.
An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The compounds and compositions according to the methods of the present invention can be administered in any amount and by any route effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein.
General Synthesis of Compounds of the invention
In general, the compounds of the invention can be prepared by the processes described in the present invention, unless otherwise stated, where the substituents are as defined for the formulae (I), (Ia-1), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (VIII), (IX-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1), (X-1), (IX-1), (VIII-1), (IX-1), (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa), (IIIa-1), (IIIb-1), (IVa-1), (Va-1), (VIa-1) or (VIIa-1). The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Lingkai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.
The anhydrous tetrahydrofuran is obtained by refluxing and drying the metallic sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, N, N-dimethylacetamide and petroleum ether were used dried over anhydrous sodium sulfate in advance.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. Nuclear magnetic resonance spectroscopy with CDC13Or DMSO-d6As solvent (reported in ppm) TMS (0ppm) or chloroform (7.25ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broadene)d, broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).
Low resolution Mass Spectral (MS) data were measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.
Low resolution Mass Spectral (MS) data were determined by Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.
Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B).
Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm, 10min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.
The following acronyms are used throughout the invention:
DCM dichloromethane
DAST diethylaminosulfur trifluoride
THF tetrahydrofuran
LiOH lithium hydroxide
H2O water
DMF N, N-dimethylformamide
NaBH4Sodium borohydride
BF3.Et2Boron trifluoride diethyl etherate solution
EtMgBr Ethyl magnesium bromide
Tol. toluene
NBS N-bromosuccinimide
NCS N-chlorosuccinimide
(dppf)2PdCl21,1' -bis (diphenylphosphino) ferrocene palladium dichloride
Na2CO3Sodium carbonate
Pd/C Palladium/carbon
H2Hydrogen gas
EA, EtOAc ethyl acetate
Et3N-Triethylamine
DMT-MM 4- (4, 6-dimethoxytriazine) -4-methylmorpholine chloride
EDC.HCl 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
[ Ir (OMe) (COD) 2 bis (1, 5-cyclooctadiene) bis-mu-methoxydiiridium (I)
TFA trifluoroacetic acid
MeOH,CH3OH methanol
EtOH,CH3CH2OH ethanol
Cbz benzyloxycarbonyl
Ac acetyl group
OAc acetoxy
mL of
Microliter of μ L
g
mg of
mmol, mM mmol
DEG C, DEG C
r.t, rt Room temperature
min for
h hours
TLC thin layer chromatography
HPLC high performance liquid chromatography
HPLC-MS high performance liquid chromatography-mass spectrometry combined technology
Boc tert-butyloxycarbonyl group
PE Petroleum Ether
M mol/L, mol/L
DDQ 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone
The following synthetic schemes describe the steps for preparing the compounds disclosed herein. Unless otherwise stated, m, n, r1、r2、R1a、R1bRing A, ring B, R10a、R10b、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6aAnd R6bHaving the definitions as described in the present invention.
Synthesis scheme 1
When in useAnd
Synthesis scheme 2
When in useAndin the same fragment, the compound of formula (IIIA) can be obtained according to the synthetic procedure of scheme 2. Wherein each Pg is independently an amino protecting group, preferably Cbz; hal is Cl, Br, preferably Br; alkyl is C1-4Alkyl, preferably tert-butyl. The compound of formula (IIIA-1) is reacted with oxalyl chloride, and then the resulting acid chloride product is reacted with compound (IIIA-2) under the action of a Grignard reagent such as ethylmagnesium bromide to give compound (IIIA-3). The compound (IIIA-3) is reacted with a reducing agent such as sodium borohydride to give compound (IIIA-4). The compound (IIIA-4) is subjected to the action of a halogenating agent such as NBS to give the compound (IIIA-5). Compound (IIIA-5) and compound (IIIA-6) in the presence of a catalyst (e.g. (dppf)2PdCl2) And carrying out coupling reaction under the action of the compound (IIIA-7). Compound (IIIA-7) under appropriate conditions (e.g., H)2Pd/C catalyzed under the condition) to obtain a compound (IIIA-8) through deamination protection. The compound (IIIA-8) and the compound (IIIA-9) are subjected to coupling reaction under the action of a coupling agent (such as DMT-MM) to obtain the compound (IIIA-10). Deamination of compound (IIIA-10) under acidic conditions (e.g., TFA) affords compound (IIIA-11). Compound (IIIA-11) is subjected to basic conditions (e.g., LiOH) to give compound (IIIA).
Synthesis scheme 3
When in useAnd
Synthesis scheme 4
When in use
Synthesis scheme 5
When in use
Synthesis scheme 6
When in use
Example 1: synthesis of Compound 1
Step 1: synthesis of Compound 1-2
Ethyl glyoxylate (12.1g,118mmol) was added to 83mL of DCM, sodium sulfate (25.5g,179.5mmol) was added further, and R (+) -alpha-methylbenzylamine (14.9g,124mmol) was added dropwise at 0 ℃ and reacted at 0 ℃ for 5 h. After the reaction is finished, the extraction rate is increased, the filtrate is dried by spinning, and the mixture is passed through a column, and PE/EA (polyethylene/EA) 20/1 is used as an eluent, so that 23.5g of a yellow liquid product is obtained.
1H NMR(600MHz,CDCl3)7.75(d,J＝0.4Hz,1H),7.40–7.34(m,4H),7.30(dd,J＝8.7,4.1Hz,1H),4.63(q,J＝6.7Hz,1H),4.42–4.31(m,2H),1.63(dd,J＝12.1,6.8Hz,3H),1.40–1.33(m,3H)。
MS(ESI,pos.ion)m/z:206.1[M+H]+。
Step 2: synthesis of Compounds 1-3
Compound 1-2(7.6g, 37mmol) was added to 26mL DMF and CF was added3COOH (4.3g,37.7mmol), cyclopentadiene (5.0g, 74mmol) and a catalytic amount of water were added and reacted at room temperature overnight. The reaction was stopped, it was poured into 50mL of saturated sodium bicarbonate solution, the organic phase was separated, the aqueous phaseExtraction with DCM (25mL × 2), combining the organic phases, concentration and column chromatography of the residue with PE/EA ═ 20:1 as eluent, cross-over and column chromatography again gave 4.35g of yellow liquid product.
1H NMR(400MHz,CDCl3)7.30(t,J＝6.7Hz,2H),7.25–7.14(m,3H),6.43(d,J＝2.8Hz,1H),6.28(d,J＝5.6Hz,1H),4.33(s,1H),3.83(dtt,J＝10.7,7.2,3.6Hz,2H),3.06(q,J＝6.4Hz,1H),2.92(s,1H),2.23(s,1H),2.15(d,J＝8.3Hz,1H),1.43(d,J＝6.6Hz,4H),0.97(t,J＝7.1Hz,3H)。
MS(ESI,pos.ion)m/z:272.2[M+H]+。
Step 3: synthesis of Compounds 1-4
Compound 1-3(10.1g, 36.85mmol) was added to a 30mL mixed solvent of ethanol and ethyl acetate (V/V ═ 1/2), and 0.7g Pd/C was further added, and the reaction was carried out for 38 hours under a hydrogen atmosphere of 15 bar. Pd/C is extracted at the extraction rate, the filtrate is dried by a column, and PE/EA (5/1) and ethanol are sequentially used as eluent, so that 4.05g of an orange liquid product is obtained.
1H NMR(400MHz,CDCl3)4.20(q,J＝7.1Hz,2H),3.60(s,1H),3.37(s,1H),2.66(s,1H),1.56(dddd,J＝31.5,28.6,17.6,7.2Hz,5H),1.30(t,J＝7.2Hz,4H)。
MS(ESI,pos.ion)m/z:170.2[M+H]+。
And 4, step 4: synthesis of Compounds 1-5
Compound 1-4(3.83g,22mmol) was added to 18mL THF, sodium carbonate (3.6g,34mmol) and 8mL water were added, and Cbz-Cl (4.8g, 26mmol) was added dropwise at 0 deg.C. After the addition was complete, the reaction was carried out at room temperature for 2h, and after completion of the reaction, the reaction mixture was poured into water and extracted with DCM (20 mL. times.3). The organic phases are combined, concentrated and separated by column chromatography, and the eluent PE/EA is 20/1, so that 4.85g of colorless liquid is obtained.
1H NMR(400MHz,CDCl3)7.51–7.29(m,5H),5.14(ddd,J＝49.5,24.7,10.4Hz,2H),4.40(d,J＝26.7Hz,1H),4.26–4.03(m,2H),3.87(d,J＝23.2Hz,1H),2.72(s,1H),1.97(d,J＝10.0Hz,1H),1.87–1.65(m,3H),1.57–1.49(m,1H),1.30(dd,J＝13.4,6.3Hz,3H),1.18(d,J＝7.1Hz,1H)。
MS(ESI,pos.ion)m/z:304.2[M+H]+。
And 5: synthesis of Compounds 1-6
Compound 1-5(4.13g,14mmol) was added to 21mL of methanol solution, followed by addition of 10mL of water and LiOH. H2O (0.735g,17.38mmol), stirred at rt for 4h, poured into water, adjusted to PH 3, extracted with DCM (30mL × 3), combined organic phases, dried over sodium sulphate, spin dried, column separated, and eluted sequentially with PE/EA 5/1 and EA to give 3.4g of a colourless liquid.
1H NMR(400MHz,CDCl3)7.52–7.29(m,5H),5.23(s,2H),4.30(s,1H),3.93(s,1H),3.01(s,1H),2.00–1.75(m,2H),1.69(dd,J＝9.7,4.4Hz,2H),1.54–1.35(m,2H)。
MS(ESI,pos.ion)m/z:276.2[M+H]+。
Step 6: synthesis of Compounds 1-7
Compound 1-6(0.6g,2.1mmol) was added to 11mL of toluene, a catalytic amount of DMF was added, oxalyl chloride (0.34g,2.6mmol) was added dropwise at 0 ℃ and, after completion of the addition, the reaction was carried out at room temperature for 3 hours. The sample was dropped on a methanol dot plate for analysis, the reaction was completed, and the solvent was spin-dried to obtain 0.63g of a product, which was used directly in the next reaction.
And 7: synthesis of Compounds 1-8
6-fluoroindole (0.51g,4.0mmol) was added to 11mL of toluene, 4.1mL of 1M ethylmagnesium bromide was added dropwise at 0 ℃ to complete the reaction for one hour, and then 5mL of a toluene solution of the compound 1-7(0.63g,2.1mmol) was added dropwise. After dropping at 0 deg.C, the reaction solution was allowed to react for one hour and then transferred to room temperature for 4 hours. Poured into 10mL of water, extracted with EA (10mL × 3), the organic phases are combined, concentrated and separated on a column, PE/EA-2/1 is used as eluent, yielding 0.58g of white solid product.
1H NMR(400MHz,CDCl3)9.63(s,1H),7.97(dd,J＝8.7,5.5Hz,1H),7.72(d,J＝59.5Hz,1H),7.40(dt,J＝21.6,7.0Hz,3H),7.16–6.99(m,2H),6.90(d,J＝9.1Hz,1H),6.84(t,J＝9.1Hz,1H),5.13(ddd,J＝ 77.3,37.4,12.6Hz,2H),4.61–4.41(m,2H),2.72(d,J＝17.9Hz,1H),2.15(d,J＝9.6Hz,1H),1.87–1.73(m,2H),1.68(s,1H),1.29(d,J＝6.9Hz,2H)。
MS(ESI,pos.ion)m/z:393.3[M+H]+。
And 8: synthesis of Compounds 1-9
Compound 1-8(203mg,0.51mmol) was added to 11mL THF, sodium borohydride (25mg,0.61mmol) was added at 0 ℃,0.1 mL boron trifluoride ether was added dropwise, reaction was carried out at 60 ℃ for 3 hours, the reaction mixture was cooled slightly and poured into ammonium chloride solution, extraction was carried out with EA (10mL × 3), the organic phases were combined, concentrated, column separation was carried out, and PE/EA-4/1 was used as an eluent, whereby 0.18g of a colorless oily product was obtained.
1H NMR(400MHz,CDCl3)7.96(d,J＝13.4Hz,1H),7.77(dd,J＝8.4,5.4Hz,1H),7.50–7.35(m,4H),7.18(dd,J＝8.4,5.3Hz,1H),7.02(t,J＝7.1Hz,1H),6.95–6.88(m,1H),6.65(t,J＝9.2Hz,1H),5.22(s,2H),4.30(d,J＝18.2Hz,1H),3.60(d,J＝10.5Hz,1H),3.47(d,J＝10.8Hz,1H),3.40(d,J＝12.2Hz,1H),3.23(d,J＝11.5Hz,1H),2.56(dd,J＝24.6,13.5Hz,1H),2.34(s,1H),1.95(t,J＝10.5Hz,1H),1.71(dd,J＝22.9,13.2Hz,1H),1.34–1.27(m,2H)；
MS(ESI,pos.ion)m/z:379.1[M+H]+。
And step 9: synthesis of Compounds 1-10
Compounds 1-9(205mg,0.53mmol) were dissolved in 2mL EA, cooled to-2 deg.C, and then 4mL of cold trifluoroacetic acid was added dropwise, followed by reaction at 2-4 deg.C for 8 hours. And slowly adding the mixture into a mixed solvent of 20mL of ethyl acetate and 10mL of 25% potassium carbonate dropwise to separate an organic phase, washing the organic phase once with a saturated sodium carbonate solution, concentrating the organic phase to obtain an intermediate 200mg, adding 8mL of EA and 90mg of DDQ, reacting the intermediate at room temperature for 4 hours, directly concentrating the intermediate on a column for separation, and using PE/EA-10/1 as an eluent to obtain a white solid product 170 mg.
1H NMR(400MHz,CDCl3)11.38(s,2H),7.57–7.32(m,14H),6.91(t,J＝7.9Hz,2H),5.37(q,J＝12.4Hz,4H),4.37(s,2H),3.55(dd,J＝23.3,8.1Hz,6H),2.96(d,J＝12.3Hz,2H),2.55(s,2H),2.25(d,J＝9.9Hz,2H),1.49(d,J＝9.8Hz,4H),1.28(t,J＝9.5Hz,4H)；
MS(ESI,pos.ion)m/z:755.50[M+H]+。
Step 10: synthesis of Compounds 1-11
Adding the compound 1-10(172mg,0.23mmol) into 11mL of EA/EtOH mixed solvent, adding 50mg of 10% Pd/C, reacting at room temperature for 5 hours under a 14bar hydrogen atmosphere, stopping the reaction, filtering out Pd/C, spin-drying the filtrate, separating by using a column, and sequentially using PE/EA-1/2 and MeOH as eluent to obtain 84mg of a white solid product.
1H NMR(400MHz,DMSO-d6)8.67(s,2H),7.65(s,2H),7.19(d,J＝9.9Hz,2H),6.97(s,2H),3.88(s,2H),2.94(dd,J＝19.0,9.7Hz,4H),2.12(dd,J＝10.0,5.0Hz,2H),2.00(dd,J＝14.5,6.6Hz,1H),1.70–1.44(m,7H),1.39–1.29(m,2H),1.24(s,4H)。
MS(ESI,pos.ion)m/z:487.2[M+H]+。
Step 11: synthesis of Compounds 1-12
Compound 1-11(174mg,0.35mmol), compound 11-10(250mg,0.88mmol), ethyl 2-oxime cyanoacetate (70mg,0.5mmol) were added to 10mL of dichloromethane, a solution of EDCI (173mg,0.89mmol) in 5mL of DCM was added dropwise at room temperature, TLC monitored for completion of the reaction of the raw materials, the reaction solution was poured into water, the organic phase was washed with water 3 times, concentrated, column-separated, PE/EA ═ 2/1 as an eluent, to give 230mg of a yellow solid product.
1H NMR(400MHz,CDCl3)11.79(d,J＝65.1Hz,2H),7.42(dd,J＝11.6,7.9Hz,2H),7.05–6.78(m,4H),4.87–4.79(m,2H),4.68(s,1H),4.56(s,2H),4.43(s,1H),3.81–3.57(m,4H),2.92(s,2H),2.82(s,6H),2.56(s,1H),2.33(d,J＝10.2Hz,1H),2.04–1.88(m,3H),1.86–1.69(m,5H),1.69–1.57(m,3H),1.54– 1.45(m,21H),1.42(d,J＝7.2Hz,4H),1.04(td,J＝7.3,3.2Hz,4H),1.00–0.90(m,6H)。
MS(ESI,pos.ion)m/z:1027.5[M+H]+。
Step 12: synthesis of Compound 1
Compounds 1-12(101mg,0.097mmol) were added to 5mL DCM, followed by 1.2mL 4M EA/HCl and reacted at room temperature for 22 h. Spin-drying the solvent to give a yellow solid, washing with 5mL ethyl acetate, suction filtration, dissolving the solid with 5mL water, adjusting pH to 8 with sodium carbonate solution, extraction with EA (10 mL. times.3), drying the organic phase with anhydrous sodium sulfate, and spin-drying to give 75mg of the product as a pale yellow solid.
MS(ESI,pos.ion)m/z:827.5[M+H]+；
1H NMR(400MHz,CDCl3)11.97(d,J＝71.0Hz,2H),8.31(d,J＝7.9Hz,1H),8.04(d,J＝8.1Hz,1H),7.66–7.49(m,2H),7.43(dd,J＝8.7,5.1Hz,2H),6.91(dd,J＝16.0,7.4Hz,2H),4.81(ddd,J＝26.7,13.7,6.9Hz,2H),4.67(s,1H),4.43(s,1H),3.86–3.55(m,4H),3.20(dd,J＝16.6,11.0Hz,2H),2.97–2.80(m,2H),2.61(s,3H),2.53(s,3H),2.38–2.27(m,2H),2.02(dd,J＝15.5,7.2Hz,2H),1.89–1.78(m,4H),1.62(dd,J＝15.7,10.4Hz,6H),1.43(d,J＝6.9Hz,3H),1.35(dd,J＝6.8,2.0Hz,3H),1.28(t,J＝7.1Hz,4H),1.05(t,J＝7.6Hz,6H)。
Example 2: synthesis of Compound 2
Step 1: synthesis of Compound 2-2
Compound 2-1(340mg,0.47mmol, synthesis prepared by reacting compound 1-9 with compound (S) -benzyl 2- ((6-fluoro-1H-indol-3-yl) methyl) pyrrolidine-1-carboxylate under trifluoroacetic acid conditions, EA (10mL), MeOH (15mL), Pd/C (10%) (83mg) were sequentially added to the reaction flask, as was prepared for the synthesis of compounds 1-10 of reference example 1. H2Catalytic, rt stirring reaction. TLC monitored the starting material reaction complete. Filtration, EA, EtOH washing, spin drying to give the crude product, column chromatography separation, EA as eluent gave 140mg of a pale yellow solid in 65% yield. MS (ESI, pos.ion) M/z 461.3[ M + H ]]+。
Step 2: synthesis of Compounds 2-3
Compound 2-2(140mg,0.30mmol), compound 11-10(268mg,0.93mmol), ethyl 2-oxime cyanoacetate (238mg,1.67mmol) were added sequentially to the reaction flask, EDC.HCl (310mg,1.62mmol) was dissolved in DCM (20mL) and added slowly over 5min, and the reaction was stirred at rt. TLC monitored the starting material reaction complete. Concentrating the reaction solution, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V: V) ═ 1:1, obtaining light yellow solid 195mg with 64 percent of yield.
MS(ESI,pos.ion)m/z:1001.8[M+H]+。
And step 3: synthesis of Compound 2
Compound 2-3(195mg,0.19mmol), DCM (6mL), TFA (2.0mL) were added to the flask in sequence and the reaction stirred at rt. TLC monitored the starting material reaction complete. Saturated sodium bicarbonate solution (50mL) was added. EA extraction (25mL × 3), drying, spin-drying and column chromatography with EA/MeOH 5:1 as eluent gave 56mg of yellow solid in 36% yield.
MS(ESI,pos.ion)m/z:801.6[M+H]+；
1H NMR(400MHz,CDCl3)11.8-12.0(m,2H),8.28(m,1H),8.01(d,J＝7.8Hz,1H),7.60-7.51(m,2H),7.42-7.39(m,2H),6.85(m,2H),4.80-4.60(m,2H),4.35(m,1H),3.80(m,2H),3.71(m,1H),3.65(m,1H),3.55(m,2H),3.15(m,2H),2.86(m,2H),2.56(m,3H),2.50(m,3H),2.32(m,2H),2.10(m,2H),1.80-1.70(m,4H),1.65-1.58(m,4H),1.46(m,4H),1.37(m,3H),1.30(m,3H),1.20(m,2H),1.04(m,3H),1.01(m, 3H)。
Example 3: synthesis of Compound 3
Step 1: synthesis of Compound 3-2
Synthesis of Compound 3-2 can be prepared by the synthesis of step 6 of reference example 11, in which starting material 11-6 is replaced with starting material 3-1.
Step 2 Synthesis of Compound 3-3
Compound 3-2(1040mg,1.32mmol), EA (20mL), MeOH (30mL), Pd/C (10%) (202mg) were added to the reaction flask in order. H2Catalytic, rt stirring reaction. TLC monitored the starting material reaction complete. Filtration, solid EA, EtOH washed sequentially and the filtrate was spin dried to give 640mg of a pale yellow solid in 93% yield.
MS(ESI,pos.ion)m/z:518.9[M+H]+；
1H NMR(400MHz,CDCl3)13.85(s,1H),12.93(s,1H),7.47(m,2H),7.02(m,2H),6.86(m,2H),5.37(m, 1H),3.79(s,1H),3.72(m,1H),3.27(m,2H),3.20(m,1H),3.09(m,1H),3.04-2.90(m,2H),2.83(m,1H),2.59(m,1H),2.46(s,1H),2.06(s,3H),1.98(d,J＝10.0Hz,1H),1.90-1.72(m,4H),1.53(m,2H),1.41(m,2H)。
And step 3: synthesis of Compounds 3-4
Compounds 3-3(640mg,1.234mmol), compounds 11-10(1260mg,4.37mmol), ethyl 2-oxime cyanoacetate (817mg,5.75mmol) were added sequentially to a reaction flask, EDC.HCl (1800mg,9.38mmol) was dissolved in DCM (40mL) and added slowly over 10min, and rt was stirred for reaction. TLC monitored the starting material reaction complete. Concentrating the reaction solution, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate ═ 1.5: 1,2 product spots of very close polarity were collected and HPLC-MS verified as isomers (4.85min/5.02min ═ 1:1), yielding 1.1g of oil in 80% yield.
MS(ESI,pos.ion)m/z:1059.6[M+H]+。
And 4, step 4: synthesis of Compounds 3-5
Compounds 3-4(1100mg,1.039mmol), DCM (6mL), and TFA (2.0mL) were added to the flask in sequence, and the reaction stirred at rt. TLC monitored the starting material reaction complete. Saturated sodium bicarbonate solution (35mL) was added. EA extraction (25 mL. times.3), drying, spin-drying afforded 850mg of a pale yellow solid in 95% yield. HPLC-MS verified as isomer (2.76min/2.94min ═ 1: 1).
MS(ESI,pos.ion)m/z:859.2[M+H]+。
And 5: synthesis of Compound 3
Compounds 3-5(770mg,0.896mmol), MeOH (40mL), NaOH (1N) (6.2mL) were added sequentially to the reaction flask and stirred at rt. TLC monitored the starting material reaction complete. 45mL of saturated ammonium chloride solution was added, EA extracted (30 mL. times.4), dried, and concentrated to give 800mg of crude product for reverse phase HPLC preparative chromatography to give 249mg of compound 3 in 34% yield.
1H NMR(600MHz,CDCl3)11.83(s,1H),11.79(s,1H),8.28(dd,J＝19.9,8.4Hz,2H),7.72(dd,J＝8.6,5.2Hz,1H),7.57(m,2H),7.40(dd,J＝8.6,5.1Hz,1H),6.88(m,2H),4.74(m,2H),4.68(m,1H),4.43(d,J＝9.9Hz,1H),4.41(s,1H),4.04(dd,J＝11.0,4.3Hz,1H),3.78(m,2H),3.65(m,1H),3.59(m,1H),3.54(m,1H),3.12(m,2H),2.89(dd,J＝14.9,11.6Hz,1H),2.58(s,3H),2.56(s,3H),2.31(d,J＝10.1Hz,1H),2.21(d,J＝14.0Hz,1H),2.06-1.91(m,4H),1.87-1.81(m,2H),1.76(m,2H),1.66-1.59(m,4H),1.40(d,J＝1.8Hz,3H),1.38(d,J＝1.8Hz,3H),1.26(m,2H),1.06(m,6H)；
13C NMR(151MHz,CDCl3)175.24,175.03,172.34,171.74,160.99(d,J＝8.2Hz),159.42(d,J＝8.4Hz),137.27(dd,J＝13.0,7.9Hz),128.34(dd,J＝14.7,3.4Hz),125.98(d,J＝5.9Hz),119.53,119.46,118.39,118.33,108.37(d,J＝7.8Hz),108.15(d,J＝9.9Hz),98.38(dd,J＝25.9,17.0Hz),71.87,66.78,60.88,60.83,60.13,58.95,56.42,51.25,51.20,39.84,36.58,35.75,35.40,31.73,29.84,28.24,27.58,26.98,26.62,26.14,22.83,20.20,20.10,14.26,9.82,9.70；
HPLC 99.1％；
MS(ESI,pos.ion)m/z:817.1[M+H]+。
Example 4: synthesis of Compound 4
Step 1: synthesis of Compound 4-2
Compound 4-1(160mg,0.22mmol, Synthesis prepared by the synthesis of Compounds 1-10 of reference example 1 using (S) -6- ((6-fluoro-1H-indol-3-yl) methyl) -5-azaspiro [ 2.4%]Prepared by reacting benzyl heptane-5-carboxylate with benzyl (S) -2- ((6-fluoro-1H-indol-3-yl) methyl) pyrrolidine-1-carboxylate in trifluoroacetic acid, EA (10mL), and Pd/C (10%) (53mg) were sequentially added to the reaction flask. H2Gas catalyzed, rt stirred overnight. Filtration, EA, EtOH wash, spin-dry and column chromatography with EA/MeOH (V/V) ═ 7:1 as eluent gave 82mg of a pale yellow solid in 81% yield.
MS(ESI,pos.ion)m/z:461.3[M+H]+。
Step 2: synthesis of Compound 4-3
Compound 4-2(46mg,0.10mmol), DMT-MM (105mg,0.38mmol), compound 11-10(116mg,0.40mmol), EA (8mL) were sequentially added to the reaction flask, N-methylmorpholine (0.13mL,1.20mmol) was added slowly, and the addition was completed for 5 min. After 20min, rt was stirred overnight. Concentrating, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V/V) ═ 1:1, 95mg of oil is obtained with a yield of 95%.
MS(ESI,pos.ion)m/z:1001.6[M+H]+。
And step 3: synthesis of Compound 4
Compounds 4-3(90mg,0.09mmol), DCM (3.5mL), and TFA (0.75mL) were added sequentially to the flask and the reaction stirred at rt. TLC monitored the starting material reaction complete. Saturated sodium bicarbonate solution (25mL) was added. EA extraction (15mL × 3), drying, spin-drying and column chromatography with EA/MeOH (V/V) ═ 8:1 as eluent gave 38mg of a pale yellow solid in 53% yield.
MS(ESI,pos.ion)m/z:801.6[M+H]+；
1H NMR(400MHz,CDCl3)11.88(s,1H),11.70(s,1H),8.15(m,2H),7.63(m,1H),7.52-7.40(m,3H),6.80(m,2H),4.70(m,3H),4.40(m,2H),4.00(m,1H),3.82(m,2H),3.63(m,2H),3.52(m,2H),3.15-3.08(m,3H),2.58(s,3H),2.55(s,3H),2.23(m,2H),2.02-1.90(m,4H),1.88-1.70(m,3H),1.40(s,1H),1.36(m,6H),1.20(m,1H),1.03(m,6H),0.88(m,2H),0.68(m,1H),0.58(m,1H)；
HPLC 86.4％。
Example 7: synthesis of Compound 7
Step 1: synthesis of Compound 7-2
Synthesis of Compound 7-2 can be prepared by the synthesis of step 6 of reference example 11, in which starting material 11-6 is replaced with starting material 7-1.
Step 2: synthesis of Compound 7-3
Compound 7-2(290mg,0.369mmol), EA (14mL), Pd/C (10%) (153mg) were added to the reaction flask in sequence. H2Catalyzed, rt stirred overnight. Filtering, washing a filter cake EA and EtOH in sequence, and spin-drying the filtrate to obtain a light yellow solid 165mg with the yield of 86.3%.
MS(ESI,pos.ion)m/z:519.0[M+H]+。
And step 3: synthesis of Compound 7-4
The compound 7-3(165mg,0.318mmol), DMT-MM (280mg,1.012mmol), compound 11-10(330mg,1.15mmol) and EA (16mL) were sequentially added to a reaction flask, N-methylmorpholine (0.10mL,0.91mmol) was added slowly, and the addition was completed for 5-10 min. After 10min, rt was stirred overnight. Concentrating, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V: V) ═ 1.5: 1, 207mg of oil was obtained, yield 61%.
MS(ESI,pos.ion)m/z:1059.6[M+H]+；
1H NMR(400MHz,CDCl3)11.77(s,1H),11.50(s,1H),7.56-7.26(m,5H),6.88(t,J＝9.1Hz,3H),5.49(s,1H),4.68(m,5H),4.50(m,2H),4.18(m,1H),3.86(t,J＝13.3Hz,2H),3.61-3.46(m,4H),3.33(m,1H),3.18(m,1H),2.89(d,J＝8.0Hz,6H),2.81(m,1H),2.33(s,3H),2.09(s,1H),1.94(m,2H),1.77(m,2H),1.51(s,18H),1.39(t,J＝7.4Hz,6H),1.02(m,6H),0.88(m,2H),0.63(m,2H)。
And 4, step 4: synthesis of Compound 7-5
Compounds 7-4(207mg,0.195mmol), DCM (6mL), TFA (0.96mL) were added to the flask in sequence, and the reaction stirred at rt.
TLC monitored the starting material reaction complete. Saturated sodium bicarbonate solution (25mL) was added. EA extraction (15 mL. times.3), drying, spin-drying gave 182mg of crude product, quantitative yield, directly put into the next reaction.
MS(ESI,pos.ion)m/z:859.3[M+H]+。
And 5: synthesis of Compound 7
Compounds 7-5(182mg,0.212mmol), MeOH (12mL), and LiOH (1N) (4.0mL) were added sequentially to the reaction flask and after 5min, stirred at rt. TLC monitored the starting material reaction complete. Quenching reaction was added with 0.4mL of acetic acid, 15mL of saturated sodium bicarbonate solution was added, EA extraction (15mL × 3), drying, concentration of the residue by silica gel column chromatography, eluent ethyl acetate: methanol (V: V) ═ 5:1, 100mg of product is obtained in 58% yield.
1H NMR(400MHz,CDCl3)11.91(s,1H),11.75(s,1H),8.26(dd,J＝12.6,8.5Hz,2H),7.72(dd,J＝8.6,5.3Hz,1H),7.57(m,2H),7.44(dd,J＝8.6,5.1Hz,1H),6.87(m,2H),4.72(m,3H),4.44(m,2H),4.03(dd,J＝11.4,4.7Hz,1H),3.82(dd,J＝27.2,10.5Hz,2H),3.69(m,2H),3.50(m,2H),3.19-3.09(m,3H),2.55(d,J＝6.1Hz,6H),2.19(d,J＝13.8Hz,1H),2.01-1.91(m,4H),1.85-1.75(m,9H),1.42(s,1H),1.38(d,J＝6.9Hz,6H),1.25(m,1H),1.05(m,6H),0.86(m,2H),0.66(m,1H),0.56(m,1H)；
MS(ESI,pos.ion)m/z:817.4[M+H]+；
HPLC 91.9％。
Example 9: synthesis of Compound 9
Step 1: synthesis of Compound 9-2
Synthesis of Compound 9-2 can be prepared by the synthesis of step 6 of reference example 11, in which starting material 11-6 is replaced with starting material 9-1.
Step 2: synthesis of Compound 9-3
Compound 9-2(221mg,0.275mmol), EA (15mL), Pd/C (10%) (104mg) were added to the reaction flask in that order. H2Catalyzed, rt stirred overnight. Filtering, washing a filter cake EA and EtOH in sequence, and spin-drying the filtrate to obtain 146mg of light yellow solid with the yield of 99.0%.
MS(ESI,pos.ion)m/z:537.3[M+H]+；
1H NMR(400MHz,CDCl3)13.09(d,overlap,2H),7.45(dd,J＝8.4,5.4Hz,2H),7.04(m,2H),6.86(m,2H),5.37(s,1H),3.71(m,2H),3.48(d,J＝6.8Hz,2H),3.42(s,3H),3.29-3.18(m,4H),3.10(m,2H),2.95(m,3H),2.63-2.50(m,3H),2.36(m,1H),2.05(s,3H),1.87(m,1H),1.38(m,1H)。
And step 3: synthesis of Compound 9-4
Compound 9-3(223mg,0.416mmol), DMT-MM (362mg,1.31mmol), compound 11-10(393mg,1.36mmol), EA (15mL) were added to the reaction flask in sequence, N-methylmorpholine (0.31mL,2.80mmol) was added slowly, and the addition was completed over 20 min. After 40min, rt was stirred overnight. Concentrating, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V: V) ═ 3:1, 288mg of oil is obtained, yield 64%.
MS(ESI,pos.ion)m/z:1077.8[M+H]+；
1H NMR(400MHz,CDCl3)11.72(s,1H),11.49(s,1H),7.55-7.40(m,5H),6.88(m,3H),5.48(m,1H),4.84(dd,J＝13.2,6.5Hz,1H),4.74(s,1H),4.66(dd,J＝13.9,6.9Hz,2H),4.49(t,J＝9.5Hz,1H),4.30(m,1H),4.19(m,1H),3.84(d,J＝12.3Hz,2H),3.55(m,2H),3.44(m,2H),3.40(s,3H),3.33(m,1H),2.95(m, 1H),2.90(s,3H),2.88(s,3H),2.43(m,1H),2.32(s,4H,overlap),2.28(s,1H),2.07(m,2H),1.96(m,2H),1.83(m,3H),1.51(s,9H),1.49(s,9H),1.40(m,6H),1.01(m,6H)。
And 4, step 4: synthesis of Compounds 9-5
Compound 9-4(720mg,0.668mmol), DCM (6mL), TFA (1.50mL) were added to the flask in sequence and the reaction stirred at rt. TLC monitored the starting material reaction complete. Saturated sodium bicarbonate solution (60mL) was added. EA extraction (30 mL. times.3), drying, spin-drying 630mg of crude product, quantitative yield, directly into the next reaction.
MS(ESI,pos.ion)m/z:877.3[M+H]+。
And 5: synthesis of Compound 9
Compounds 9-5(630mg,0.718mmol), MeOH (15mL), NaOH (1N) (5.0mL) were added sequentially to the reaction flask and stirred at rt. TLC monitored the starting material reaction complete. Quenching reaction was added with 0.6mL of acetic acid, 25mL of saturated sodium bicarbonate solution was added, EA was extracted (35 mL. times.3), dried, and the residue was concentrated by silica gel column chromatography, eluting with ethyl acetate: methanol (V: V) ═ 8:1, 500mg of product is obtained with a yield of 83%.
1H NMR(400MHz,CDCl3)11.84(s,1H),11.74(s,1H),8.38(d,J＝8.0Hz,1H),8.30(d,J＝8.4Hz,1H),7.74(dd,J＝8.5,5.3Hz,1H),7.56-7.48(m,3H),6.87(m,2H),4.85(dd,J＝13.0,6.6Hz,1H),4.73(m,1H),4.64(m,1H),4.41(t,J＝9.3Hz,1H),4.28(dd,J＝16.6,8.0Hz,1H),4.09(m,1H),3.99(dd,J＝11.1,4.5Hz,1H),3.89(m,1H),3.79(m,1H),3.70(m,1H),3.62(m,1H),3.51(m,2H),3.42(m,2H),3.37(s,3H),3.14(m,2H),2.91(m,1H),2.57(s,3H),2.56(s,3H),2.38(m,6H),2.19(d,J＝13.8Hz,1H),2.07-1.92(m,2H),1.82(m,2H),1.39(m,6H),1.04(m,6H)；
MS(ESI,pos.ion)m/z:835.4[M+H]+；
HPLC 93.0％。
Example 10: synthesis of Compound 10
Step 1: synthesis of Compound 10-2
Synthesis of Compound 10-2 can be prepared by the synthesis of step 6 of reference example 11, in which starting material 11-6 is replaced with starting material 10-1.
Step 2: synthesis of Compound 10-3
Compound 10-2(670mg,0.841mmol), EA (28mL), Pd/C (10%) (356mg) were added to the reaction flask in that order. H2Catalyzed, rt stirred overnight. Filtering, washing a filter cake EA and EtOH in sequence, and spin-drying the filtrate to obtain a light yellow solid of 470mg with quantitative yield, and directly putting the light yellow solid into the next reaction.
MS(ESI,pos.ion)m/z:529.2[M+H]+。
And step 3: synthesis of Compound 10-4
Compound 10-3(160mg,0.303mmol), DMT-MM (290mg,1.048mmol), compound 11-10(321mg,1.113mmol), EA (16mL) were added to the reaction flask in sequence, N-methylmorpholine (0.15mL,1.40mmol) was added slowly, and the addition was completed over 5-10 min. After 40min, rt was stirred overnight. Concentrating, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V: V) ═ 1.5: 1, 258mg of oil was obtained, yield 79%.
MS(ESI,pos.ion)m/z:1091.6[M+Na]+；
1H NMR(400MHz,CDCl3)11.58(s,1H),11.31(s,1H),7.56-7.50(m,4H),7.02(m,1H),6.96-6.86(m,3H),5.49(t,J＝5.0Hz,1H),4.75-4.57(m,5H),4.47(m,1H),4.35-4.18(m,2H),3.84(d,J＝12.4Hz,1H),3.55(d,J＝14.1Hz,2H),3.38-3.18(m,2H),2.88(d,J＝2.5Hz,6H),2.59(t,J＝14.6Hz,1H),2.33(s,3H),2.29(m,1H),2.10(m,1H),1.96(m,2H),1.82-1.73(m,4H),1.52(d,J＝2.5Hz,18H),1.40-1.37(m,6H),1.03(m,6H)。
And 4, step 4: synthesis of Compound 10-5
Compound 10-4(258mg,0.241mmol), DCM (8mL), TFA (1.20mL) were added to the flask in sequence, and the reaction stirred at rt. TLC monitored the starting material reaction complete. Saturated sodium bicarbonate solution (25mL) was added. EA extraction (15 mL. times.3), drying, spin-drying 238mg of crude product, quantitative yield, directly into the next reaction.
MS(ESI,pos.ion)m/z:869.5[M+H]+。
And 5: synthesis of Compound 10
Compounds 10-5(450mg,0.518mmol), MeOH (25mL), LiOH (1N) (7.5mL) were added sequentially to the reaction flask and stirred at rt. TLC monitored the starting material reaction complete. Quenching reaction was added with 0.4mL of acetic acid, 25mL of saturated sodium bicarbonate solution was added, EA extraction (25mL × 3), drying, concentration of the residue by silica gel column chromatography, eluent ethyl acetate: methanol (V: V) ═ 6:1, 240mg of product is obtained with a yield of 56%.
1H NMR(400MHz,CDCl3)11.81(s,1H),11.42(s,1H),8.28(d,J＝8.5Hz,1H),8.14(d,J＝8.3Hz,1H),7.74(dd,J＝8.6,5.3Hz,1H),7.59-7.47(m,3H),6.89(m,2H),4.72(dd,J＝13.6,7.7Hz,1H),4.66(s,1H),4.59(m,2H),4.40(t,J＝9.2Hz,1H),4.31(m,1H),4.12(m,1H),4.02(dd,J＝11.2,4.6Hz,1H),3.79(d,J＝11.1Hz,1H),3.62(m,2H),3.52(m,1H),3.21(d,J＝13.0Hz,1H),3.12(m,2H),2.56(d,J＝3.5Hz,6H),2.52(m,1H),2.19(d,J＝13.7Hz,2H),2.05-1.94(m,6H),1.86-1.79(m,2H),1.38(t,J＝7.2Hz,6H),1.07(m,6H)；
MS(ESI,pos.ion)m/z:827.5[M+H]+；
HPLC 95.8％。
Example 11: synthesis of Compound 11
Synthesis of intermediate Compound 11-7
Compounds 11-7a (410mg,1.0mmol), [ Ir (OMe) (COD) 2(33mg,0.05mmol), 4 '-di-tert-butyl-2, 2' -bipyridine (27mg,0.1mmol), and diboron pinacol ester (508mg,2.0mmol) were mixed, anhydrous THF (20mL) was added, and the reaction was refluxed overnight under nitrogen. Suction filtration, washing of the filter cake with ethyl acetate (50mL), removal of the solvent, chromatography on silica gel column 1 time, eluent petroleum ether: ethyl acetate (V: V) ═ 9: 1, obtaining a yellow white solid 161mg with the yield of 30 percent.
1H NMR(400MHz,CDCl3)8.39–7.45(m,7H),7.04–6.56(m,2H),5.07(d,J＝108.2Hz,3H),4.30(s,1H),3.92(d,J＝40.7Hz,1H),3.68–3.15(m,3H),2.12(s,3H),1.64(s,2H),1.36(d,J＝5.0Hz,12H).
MS(ESI,pos.ion)m/z:537.2[M+H]+。
Step 1 Synthesis of Compound 11-2
Compound 11-1(18g,64.4mmol) was dissolved in DCM (200mL), DAST (26mL,193.3mmol) was added dropwise at-78 deg.C, and after addition was complete, the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with saturated sodium bicarbonate solution (80mL), extracted with DCM (150mL), washed with saturated sodium chloride solution (150mL), dried over anhydrous sodium sulfate, and the residue was chromatographed on silica gel with petroleum ether as eluent: ethyl acetate (V: V) ═ 2: 1, 11g of colorless oil was obtained, yield 60.8%.
MS(ESI,pos.ion)m/z:282.15[M+H]+；
1H NMR(400MHz,CDCl3)7.46–7.27(m,5H),5.45–5.02(m,3H),4.60(dd,J＝30.0,9.6Hz,1H),3.99–3.54(m,5H),2.72–2.21(m,2H)。
Step 2: synthesis of Compound 11-3
Compound 11-2(11g,39mmol) was dissolved in THF (60mL), an aqueous solution of lithium hydroxide (60mL) was added dropwise (2.7g of lithium hydroxide monohydrate was dissolved in 60mL of water), and after completion of the addition, the mixture was allowed to stand at room temperature for overnight reaction. The reaction mixture was transferred to a separatory funnel, and water (100mL) and ethyl acetate (150mL) were added for extraction. Discarding the organic phase, adjusting pH of the aqueous phase to 3 with dilute hydrochloric acid at 0 ℃, adding ethyl acetate (200mL) for extraction three times, combining the organic phases, drying, spinning out the solvent, performing silica gel column chromatography on the residue, and eluting PE: EA (V: V) ═ 1:1, 10g of pale yellow oil is obtained, yield 95%.
MS(ESI,pos.ion)m/z:290.15[M+Na]+；
1H NMR(400MHz,CDCl3)7.37(m,5H),5.46–5.04(m,3H),4.63(m,1H),4.00–3.49(m,2H),2.80–2.20(m,2H)。
And step 3: synthesis of Compound 11-4
Compound 11-3(10g,37.4mmol) was dissolved in DCM (60mL), DMF (0.5mL) was added, and oxalyl chloride (10mL,112mmol) was slowly added dropwise at 0 deg.C. After the dropwise addition, the mixture is transferred to room temperature to react for 6 hours, the solvent is spun out, and DCM (30mL) is added to obtain solution A for later use. 6-fluoroindole (10g,74.9mmol) is dissolved in anhydrous toluene (80mL), ethyl magnesium bromide ether solution (25mL,3mol/L) is added dropwise at the temperature of-5 ℃, and after the dropwise addition is finished, the reaction is carried out for 3 hours under the condition of heat preservation, thus obtaining solution B. Slowly dripping the solution A into the solution B at the temperature of minus 5 ℃, preserving the temperature for reaction for 3 hours after finishing dripping, and then transferring to room temperature for reaction overnight. The reaction was quenched with water (100mL), adjusted to PH 3 with 1M dilute hydrochloric acid, extracted with ethyl acetate (300mL), washed with saturated sodium chloride solution (150mL), the organic layer was separated, dried, the solvent was spun off, and the residue was chromatographed on silica gel with petroleum ether: ethyl acetate (V: V) ═ 3:1, obtaining yellow white solid 3g with the yield of 20 percent.
MS(ESI,pos.ion)m/z:385.1[M+H]+；
1H NMR(400MHz,DMSO)12.08(s,1H),8.56–7.95(m,2H),7.49–6.78(m,7H),5.51–4.74(m,4H),3.98–3.57(m,2H),2.98–2.57(m,1H),2.42–2.16(m,1H)。
And 4, step 4: synthesis of Compound 11-5
Dissolving the compound 11-4(0.8g,2.1mmol) in THF (16mL), adding sodium borohydride (0.19g,2.4mmol) at the temperature of-3 ℃, dropwise adding boron trifluoride ether solution (0.52mL,4.2mmol), and after dropwise adding, keeping the temperature for reaction for 10 min. Slowly heating to 60 ℃ and reacting for 3 h. And (2) dropwise adding a saturated ammonium chloride solution (15mL) at the temperature of 0 ℃ to quench the reaction, adding ethyl acetate (50mL) to extract twice, drying, spinning out the solvent, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V: V) ═ 10:1, colorless oil 0.50g, yield 65%.
MS(ESI,pos.ion)m/z:371.2[M+H]+；
1H NMR(400MHz,CDCl3)8.20–7.32(m,6H),7.25–6.55(m,3H),5.29–5.08(m,2H),4.29(dt,J＝39.4,8.2Hz,1H),3.93(dd,J＝18.0,8.4Hz,1H),3.45(ddd,J＝66.9,12.3,9.8Hz,1H),2.89(t,J＝12.5Hz,1H),2.34–2.12(m,1H),2.02–1.92(m,1H)。
And 5: synthesis of Compound 11-6
Dissolve compound 11-5(0.5g,1.3mmol) in DCM (20mL), add NBS (0.24g,1.3mmol) at-3 deg.C and incubate for 1 h. Extraction with DCM (20mL), washing with saturated sodium chloride solution (20mL), drying, removal of the solvent, chromatography on silica gel column, eluent petroleum ether: ethyl acetate (V: V) ═ 5:1, colorless oily substance 0.5g was obtained, yield 80%.
MS(ESI,pos.ion)m/z:451.1[M+H]+；
1H NMR(400MHz,CDCl3)8.50(d,J＝7.3Hz,1H),7.86–6.57(m,8H),5.47–5.04(m,3H),4.47–4.22(m,1H),4.06–3.53(m,2H),3.34(ddd,J＝89.8,13.7,3.5Hz,1H),3.08–2.80(m,1H),2.22(t,J＝16.9Hz,1H),2.04–1.85(m,1H)。
Step 6: synthesis of Compounds 11-8
Compound 11-6(0.5g,1.1mmol), 11-7(0.72g,1.34mmol), 1' -bis (diphenylphosphino) ferrocene dichloropalladium dichloromethane complex (0.18g,0.22mmol) and sodium carbonate (0.30g,2.78mmol) were mixed, DMF (12mL) and water (3mL) were added, vacuum was applied, nitrogen gas was purged, and the temperature was raised to 90 ℃ for reaction overnight. Cooling, filtering with celite, adding water (15mL) to the filtrate, adding ethyl acetate (45mL), extracting three times, combining the organic phases, washing with saturated sodium chloride solution (15mL), drying, spinning off the solvent, performing silica gel column chromatography on the residue, and adding petroleum ether: ethyl acetate (V: V) ═ 10:1, 0.45g of white solid was obtained, yield 52%.
MS(ESI,pos.ion)m/z:777.2[M-H]-；
1H NMR(400MHz,CDCl3)11.30(s,1H),11.23(s,1H),7.93–7.32(m,14H),6.92(tt,J＝9.3,4.7Hz,2H),5.63–5.18(m,6H),4.32(dd,J＝20.3,9.5Hz,2H),4.11–3.57(m,6H),3.51–3.32(m,2H),2.67–2.21(m,5H),2.16–1.85(m,2H)。
And 7: synthesis of Compounds 11-9
Compound 11-8(595mg,0.76mmol), Et3N (0.32mL,2.3mmol), EA (35mL), Pd/C (10%) (329mg) were added to the reaction flask in that order. H2Catalyzed, rt stirred overnight. Filtration, EA, EtOH wash, spin-dry to give 380mg of a pale yellow solid, 97% yield. MS (ESI, pos. ion) M/z 511.1[ M + H ]]+。
And 8: synthesis of Compounds 11-11
Compound 11-9(155mg,0.304mmol), DMT-MM (301mg,1.088mmol), compound 11-10(320mg,1.11mmol), EA (10.5mL) were sequentially added to the reaction flask, N-methylmorpholine (0.18mL,1.6mmol) was added slowly, and the addition was completed for 5-10 min. After 40min, rt was stirred overnight. Concentrating, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V: V) ═ 1.5: 1, obtaining oil 220mg with 68% yield.
MS(ESI,pos.ion)m/z:1073.5[M+Na]+；
1H NMR(400MHz,CDCl3)11.53(s,1H),11.46(s,1H),7.60(dd,J＝8.7,5.2Hz,1H),7.55(m,3H),7.17(m,1H),6.89(m,3H),5.52–5.35(m,2H),4.74–4.63(m,4H),4.51(dd,J＝20.2,9.4Hz,2H),4.22-4.10(m,2H),3.84(d,J＝12.3Hz,1H),3.56(d,J＝14.6Hz,2H),3.40–3.26(m,2H),2.88(s,6H),2.59–2.46(m,1H),2.33(s,3H),1.98(m,2H),1.80(m,3H),1.51(s,18H),1.39(s,3H),1.38(s,3H),1.04(dd,J＝17.0,7.5Hz,6H)。
And step 9: synthesis of Compounds 11-12
Compounds 11-11(450mg,0.428mmol), DCM (13mL), TFA (1.9mL) were added to the flask in sequence, and the reaction stirred at rt. TLC monitored the starting material reaction complete. Saturated sodium bicarbonate solution (25mL) was added. EA extraction (15 mL. times.3), drying, spin-drying yielded 400mg of crude product, quantitative yield, directly put into the next reaction.
MS(ESI,pos.ion)m/z:851.5[M+H]+。
Step 10: synthesis of Compound 11
Compounds 11-12(207mg,0.243mmol), MeOH (12mL), and LiOH (1N) (3.3mL) were added to the reaction flask in that order. After 5min, rt is stirred. TLC monitored the starting material reaction complete. Quenching reaction was added with 0.4mL of acetic acid, 15mL of saturated sodium bicarbonate solution was added, EA extraction (15mL × 3), drying, concentration of the residue by silica gel column chromatography, eluent ethyl acetate: methanol (V: V) ═ 5:1, 100mg of product was obtained in 51% yield.
1H NMR(400MHz,CDCl3)11.77(s,1H),11.59(s,1H),8.26(d,J＝8.5Hz,1H),8.16(d,J＝8.4Hz,1H),7.72(dd,J＝8.6,5.3Hz,1H),7.60-7.51(m,3H),6.92-6.85(m,2H),5.44(d,J＝52.6Hz,1H),4.75–4.69(m,3H),4.51(t,J＝9.3Hz,1H),4.42(t,J＝9.8Hz,1H),4.14(s,1H),4.07-4.00(m,2H),3.79(d,J＝11.3Hz,1H),3.63(t,J＝12.1Hz,2H),3.56(m,1H),3.32(m,1H),3.13(dd,J＝14.0,7.0Hz,2H),2.56(d,J＝3.7Hz,6H),2.46(m,1H),2.19(d,J＝14.1Hz,1H),2.05-1.95(m,4H),1.91-1.79(m,5H),1.39(t,J＝6.2Hz,6H),1.08(dd,J＝16.3,7.5Hz,6H)；
13C NMR(151MHz,CDCl3)175.30,175.19,172.40,172.28,161.03,159.44(d,J＝4.6Hz),137.33,137.24,128.50,128.48,128.33,128.30,125.98,125.86,119.58,119.51,119.06,119.00,108.57,108.46,108.40,108.37,108.20,107.54,98.36,98.28,98.19,98.11,94.87,93.70,71.82,60.80(d,J＝7.3Hz),60.03,59.67,56.41,54.30,54.15,51.32,51.24,36.56,35.67,34.71,34.58,29.84,28.25,27.76,26.11,25.99,20.11,20.09,9.97,9.82；
MS(ESI,pos.ion)m/z:809.5[M+H]+；
HPLC 96.2％。
Example 12: synthesis of Compound 12
Step 1: synthesis of Compound 12-2
Compound 12-1(12g,42.9mmol) was dissolved in DCM (120mL), DAST (17mL,128mmol) was added dropwise at-78 deg.C, and after the addition was complete, the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with saturated sodium bicarbonate solution (40mL), extracted with DCM (80mL), washed with saturated sodium chloride solution (80mL), dried over anhydrous sodium sulfate, and chromatographed on silica gel with petroleum ether as eluent: ethyl acetate (V/V) ═ 2: 1, 8.5g of colorless oil was obtained, yield 70%.
MS(ESI,pos.ion)m/z:282.2[M+H]+；
1H NMR(400MHz,CDCl3)7.47–7.11(m,5H),5.36–4.95(m,3H),4.62–4.38(m,1H),4.02–3.49(m,5H),2.73–2.02(m,2H)。
Step 2: synthesis of Compound 12-3
Compound 12-2(8.5g,30mmol) was dissolved in THF (50mL), an aqueous solution of lithium hydroxide (50mL) was added dropwise (2.1g of lithium hydroxide monohydrate in 50mL of water), and after completion of the addition, the reaction mixture was transferred to room temperature for 4 hours. The reaction mixture was transferred to a blocking funnel, and water (80mL) and ethyl acetate (120mL) were added for extraction. Discarding the organic phase, adjusting pH of the aqueous phase to 3 with dilute hydrochloric acid at 0 ℃, adding ethyl acetate (150mL) for extraction three times, combining the organic phases, drying, spinning out the solvent, performing silica gel column chromatography on the residue, and eluting with petroleum ether: ethyl acetate (V/V) ═ 1:1, 7.5g of pale yellow oil was obtained, yield 93%.
MS(ESI,pos.ion)m/z:268.2[M+H]+；
1H NMR(400MHz,CDCl3)9.09(s,1H),7.50–7.13(m,5H),5.34–4.96(m,3H),4.71–4.42(m,1H),4.10–3.90(m,1H),3.76–3.56(m,1H),2.79–2.54(m,1H),2.42–2.15(m,1H)。
And step 3: synthesis of Compound 12-4
Compound 12-3(7.5g,28mmol) was dissolved in DCM (60mL), DMF (0.5mL) was added, and oxalyl chloride (7.3mL,84mmol) was added dropwise at 0 deg.C. After the dropwise addition, the mixture is transferred to room temperature for reaction for 4 hours, the solvent is spun out, and DCM (30mL) is added to obtain solution A for later use. 6-fluoroindole (7.6g,56mmol) is dissolved in anhydrous toluene (80mL), ethyl magnesium bromide (18.6mL,3mol/L) is added dropwise at the temperature of-5 ℃, and after the dropwise addition is finished, the reaction is carried out for 2.5h under the condition of heat preservation, thus obtaining solution B. And (3) dripping the A liquid into the B liquid at the temperature of minus 5 ℃, preserving the temperature for reaction for 3 hours after finishing dripping, and transferring to room temperature for reaction for 3 hours. The reaction was quenched with water (100mL), adjusted to acidic pH with 1M dilute hydrochloric acid, extracted with ethyl acetate (300mL), washed with saturated sodium chloride solution (150mL), the organic layer separated, dried, the solvent spun off, and the residue was chromatographed on silica gel with petroleum ether as eluent: ethyl acetate (V/V) ═ 3:1, obtaining yellow white solid 6.2g with 58 percent of yield.
MS(ESI,pos.ion)m/z:385.1[M+H]+；
1H NMR(400MHz,DMSO)12.14(d,J＝10.6Hz,1H),8.56(d,J＝15.9Hz,1H),8.18(ddd,J＝17.4,8.7,5.6Hz,1H),7.50–6.82(m,7H),5.56–5.22(m,2H),5.12–4.99(m,2H),,3.89(td,J＝20.0,10.9Hz,1H),3.75–3.53(m,1H),2.83–2.57(m,1H),2.30–1.91(m,1H)。
And 4, step 4: synthesis of Compounds 12-5
Dissolving the compound 12-4(1.8g,4.7mmol) in THF (36mL), adding sodium borohydride (0.67g,18mmol) at the temperature of-3 ℃, dropwise adding boron trifluoride ether solution (1.7mL,14mmol), and after dropwise adding, keeping the temperature for reaction for 10 min. Slowly heating to 60 ℃ and reacting for 3 h. And (2) dropwise adding a saturated ammonium chloride solution (30mL) at the temperature of 0 ℃ to quench the reaction, adding ethyl acetate (100mL) to extract twice, drying, spinning out the solvent, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V/V) ═ 10:1, colorless oil 0.8g was obtained, yield 46%.
MS(ESI,pos.ion)m/z:371.2[M+H]+；
1H NMR(400MHz,CDCl3)8.39(s,1H),7.66–6.61(m,9H),5.54–5.18(m,2H),4.99(dd,J＝53.0,10.2Hz,1H),4.52–4.31(m,1H),4.10–3.77(m,1H),3.30(dt,J＝32.5,14.1Hz,2H),2.97(ddd,J＝78.6,14.1,8.0Hz,1H),2.33–2.15(m,1H),2.01–1.72(m,1H)。
And 5: synthesis of Compounds 12-6
Dissolve compound 12-5(0.8g,2.2mmol) in DCM (20mL), add NBS (0.38g,2.2mmol) at-3 deg.C and incubate for 1 h. Extraction with DCM (60mL), washing with saturated sodium chloride solution (30mL), drying, removal of solvent, chromatography on silica gel column, eluent petroleum ether: ethyl acetate ═ 5:1, colorless oil 0.78g, yield 77%.
MS(ESI,pos.ion)m/z:471.05[M+Na]+；
1H NMR(400MHz,CDCl3)8.82(s,1H),7.58–6.54(m,8H),5.52–4.86(m,3H),4.48(dd,J＝38.7,5.0Hz,1H),4.15–3.77(m,1H),3.63–3.12(m,2H),3.02–2.69(m,1H),2.24(dd,J＝25.9,13.3Hz,1H),2.07–1.89(m,1H)。
Step 6: synthesis of Compounds 12-7
Compounds 12-6(0.57g,1.27mmol), compounds 11-10(0.612g,1.14mmol, synthesis of intermediate compounds 11-7 in reference example 11), 1' -bis (diphenylphosphino) ferrocene dichloropalladium dichloromethane complex (0.207g,0.25mmol), and sodium carbonate (0.336g,3.17mmol) were mixed, DMF (10mL), water (2.5mL) were added, vacuum was applied with nitrogen, and the temperature was raised to 90 ℃ for reaction for 6 h. Cooling, filtering diatomaceous earth, adding saturated sodium chloride solution (30mL), adding ethyl acetate (90mL), extracting twice, combining organic phases, drying, spinning off solvent, performing silica gel column chromatography on the residue, eluting dichloromethane to obtain 0.7g white solid, and purifying with petroleum ether: ethyl acetate (V/V) ═ 1: 1(5mL) solvent slurried to give 0.56g of product in 56.7% yield and 98.69% purity (HPLC).
MS(ESI,pos.ion)m/z:780.2[M+H]+；
1H NMR(400MHz,CDCl3)11.26(d,J＝22.7Hz,2H),7.61–7.30(m,14H),6.91(t,J＝8.9Hz,2H),5.55–4.97(m,6H),4.36–3.92(m,4H),3.84–3.63(m,4H),3.51–2.86(m,2H),2.34(s,4H),2.25–1.94(m,3H).
And 7: synthesis of Compounds 12-8
Compounds 12-7(710mg,0.91mmol), EA (25mL), Pd/C (10%) (400mg) were added to the flask in that order. H2Catalyzed, rt stirred overnight. Filtration, EA, EtOH washing and spin-drying gave 465mg of a pale yellow solid with 100% yield.
MS(ESI,pos.ion)m/z:511.2[M+H]+。
And 8: synthesis of Compounds 12-9
Compound 12-8(200mg,0.39mmol), DMT-MM (361mg,1.30mmol), compound 11-10(433mg,1.50mmol), EA (12mL) were sequentially added to a reaction flask, N-methylmorpholine (0.25mL,2.3mmol) was added slowly, and the addition was completed for 10-15 min. After 50min, rt was stirred overnight. Concentrating, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V/V) ═ 1:1, light yellow solid 316mg is obtained, yield 77%.
MS(ESI,pos.ion)m/z:1073.6[M+Na]+；
1H NMR(400MHz,CDCl3)11.50(s,2H),7.53(dd,J＝8.9,5.0Hz,1H),7.41(m,2H),7.05(m,1H),6.88(m,2H),5.46–5.20(m,2H),4.76–4.60(m,4H),4.43(m,2H),4.11(m,2H),3.98(m,1H),3.83(d,J＝12.6Hz,1H),3.67(d,J＝12.8Hz,1H),3.32(m,1H),2.91(m,1H),2.87(s,6H),2.33(s,3H),2.22(m,2H),1.95-1.81(m,3H),1.51(s,18H),1.40-1.36(m,6H),1.02(m,6H)。
And step 9: synthesis of Compounds 12-10
Compounds 12-9(1110mg,1.06mmol), DCM (15mL), TFA (2.8mL) were added sequentially to the flask and the reaction stirred at rt. TLC monitored the starting material reaction complete. Concentrate and add saturated sodium bicarbonate solution (35 mL). EA extraction (15 mL. times.3), drying, spin-drying 900mg of crude product, quantitative yield, directly into the next reaction.
MS(ESI,pos.ion)m/z:851.5[M+H]+。
Step 10: synthesis of Compound 12
Compounds 12-10(890mg,1.05mmol), MeOH (15mL), LiOH (1N) (4.0mL) were added sequentially to the reaction flask, and after 5min, rt was stirred. TLC monitored the starting material reaction complete. Quenching reaction was added with 0.5mL of acetic acid, 25mL of saturated sodium bicarbonate solution was added, EA extraction (15mL × 3), drying, concentration of the residue by silica gel column chromatography, eluent ethyl acetate: methanol (V/V) ═ 5:1, obtaining light yellow solid 200mg with the yield of 23.5%.
1H NMR(600MHz,CDCl3)11.61(s,1H),11.58(s,1H),8.24(d,J＝8.4Hz,1H),8.01(d,J＝8.7Hz,1H),7.73(dd,J＝8.6,5.3Hz,1H),7.47(dd,J＝9.6,2.0Hz,1H),7.41(m,2H),6.86(m,2H),5.29(d,J＝52.2Hz,1H),4.72(m,2H),4.62(m,1H),4.42(m,2H),4.03-3.92(m,4H),3.80(d,J＝11.1Hz,1H),3.72(dd,J＝14.4,2.3Hz,1H),3.63(m,3H),3.52(dd,J＝14.4,12.0Hz,1H),3.27(m,2H),2.86(dd,J＝14.5,11.6Hz,1H),2.54(s,3H),2.47(s,3H),2.26(m,1H),2.15(m,1H),2.08(m,1H),2.00(m,1H),1.92(m,2H),1.81(m,2H),1.41(m,6H),1.05(m,6H)；
MS(ESI,pos.ion)m/z:809.5[M+H]+；
HPLC 91.3％。
Example 13: synthesis of Compound 13
Step 1: synthesis of Compound 13-2
Synthesis of Compound 13-2 can be prepared by reference to the synthesis of step 6 of example 11, in which starting material 11-6 is replaced with starting material 13-1, and starting material 11-7 is replaced with starting material 13-7 (Compound 13-7 can be referred to for the synthesis of Compound 11-7).
Step 2: synthesis of Compound 13-3
Compound 13-2(196mg,0.252mmol), EA (15mL), Pd/C (10%) (101mg) were added to the reaction flask in that order. H2Catalyzed, rt stirred overnight. Filtering, washing a filter cake EA and EtOH in sequence, concentrating the filtrate, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V: V) ═ 2: 1, obtaining light yellow solid 73mg with the yield of 56.8 percent.
MS(ESI,pos.ion)m/z:511.1[M+H]+。
And step 3: synthesis of Compound 13-4
Compound 13-3(73mg,0.143mmol), DMT-MM (132mg,0.477mmol), compound 11-10(173mg,0.600mmol), and EA (7mL) were sequentially added to a reaction flask, N-methylmorpholine (0.10mL,0.91mmol) was added slowly, and the addition was completed for 5-10 min. After 40min, rt was stirred overnight. Concentrating, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V: V) ═ 1.5: 1, 135mg of oily substance is obtained, and the yield is 89%.
MS(ESI,pos.ion)m/z:1073.3[M+Na]+。
And 4, step 4: synthesis of Compound 13-5
Compound 13-4(135mg,0.128mmol), DCM (9mL), TFA (0.95mL) were added to the flask in sequence, and the reaction stirred at rt. TLC monitored the starting material reaction complete. Saturated sodium bicarbonate solution (25mL) was added. EA extraction (10 mL. times.3), drying, spin-drying 120mg of crude product, quantitative yield, directly into the next reaction.
MS(ESI,pos.ion)m/z:851.3[M+H]+。
And 5: synthesis of Compound 13
Compounds 13-5(120mg,0.141mmol), MeOH (8mL), and LiOH (1N) (3.5mL) were added sequentially to the reaction flask and stirred at rt. TLC monitored the starting material reaction complete. Quenching reaction was added with 0.4mL of acetic acid, 15mL of saturated sodium bicarbonate solution was added, EA extraction (10mL × 3), drying, concentration of the residue by silica gel column chromatography, eluent ethyl acetate: methanol (V: V) ═ 8:1, 60mg of product is obtained with a yield of 52.6%.
1H NMR(400MHz,CDCl3)11.66(s,1H),11.17(s,1H),8.23(d,J＝8.5Hz,1H),7.91(d,J＝8.3Hz,1H),7.64-7.57(m,3H),7.01(m,1H),6.89(m,2H),5.42(d,J＝52.3Hz,1H),4.70(m,3H),4.52(m,2H),4.10-4.01(m,3H),3.79(m,2H),3.67(m,2H),3.55(m,2H),3.26(m,2H),3.12(q,J＝6.7Hz,2H),2.56(s,3H),2.48(s,3H),2.41(m,4H),2.19(d,J＝14.1Hz,1H),1.98(m,3H),1.37(m,6H),1.06(t,J＝7.3Hz,6H)；
MS(ESI,pos.ion)m/z:809.5[M+H]+；
HPLC 95.2％。
Example 14: synthesis of Compound 14
Step 1: synthesis of Compound 14-2
Synthesis of Compound 14-2 can be prepared by reference to the synthesis of step 6 of example 11, in which starting material 11-6 is replaced with starting material 13-1, and starting material 11-7 is replaced with starting material 14-7 (Compound 14-7 can be referred to for the synthesis of Compound 11-7).
Step 2: synthesis of Compound 14-3
Compound 14-2(280mg,0.38mmol), Et3N (0.22mL,1.6mmol), EA (30mL), Pd/C (10%) (170mg) were added to the reaction flask in that order. H2Catalyzed, rt stirred overnight. Filtering, washing a filter cake EA and EtOH in sequence, and spin-drying the filtrate to obtain a light yellow solid 161mg with the yield of 90%.
MS(ESI,pos.ion)m/z:471.3[M+H]+。
And step 3: synthesis of Compound 14-4
Compound 14-3(103mg,0.219mmol), DMT-MM (205mg,0.741mmol), compound 11-10(208mg,0.722mmol), EA (8.0mL) were sequentially added to the reaction flask, N-methylmorpholine (0.12mL,1.1mmol) was added slowly, and the addition was completed for 5-10 min. After 20min, rt was stirred overnight. Concentrating, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V: V) ═ 1.5: 1, 172mg of oil was obtained, yield 77%.
MS(ESI,pos.ion)m/z:1011.6[M+H]+；
1H NMR(400MHz,CDCl3)11.43(s,2H),7.60(dd,J＝8.5,5.2Hz,2H),7.52(m,2H),6.93–6.88(m,2H),5.52(s,1H),5.39(s,1H),4.74(s,1H),4.67(dd,J＝14.3,7.0Hz,2H),4.53(t,J＝9.1Hz,2H),4.14(m,2H),4.08(m,2H),3.55(d,J＝14.1Hz,2H),3.33(t,J＝13.2Hz,2H),2.88(s,6H),2.53(m,2H),1.99(dd,J＝13.9,6.9Hz,2H),1.81(m,2H),1.69(d,J＝11.4Hz,2H),1.52(s,18H),1.39(s,3H),1.38(s,3H),1.32(m,3H),1.05(t,J＝7.3Hz,6H)。
And 4, step 4: synthesis of Compound 14
Compound 14-4(418mg,0.413mmol), DCM (12mL), TFA (2.3mL) were added to the flask in sequence, and the reaction stirred at rt. TLC monitored the starting material reaction complete. Saturated sodium bicarbonate solution (30mL) was added. EA extraction (15mL × 3), drying, concentration of the residue by silica gel column chromatography, eluent ethyl acetate: methanol (V: V) ═ 10:1, 229mg of product was obtained in 68.3% yield.
1H NMR(400MHz,CDCl3)11.64(s,2H),8.15(d,J＝8.4Hz,2H),7.62-7.52(M,4H),6.90(m,2H),5.52(s,1H),5.39(s,1H),4.66(dd,J＝14.0,7.7Hz,2H),4.51(t,J＝9.3Hz,2H),4.16(m,1H),4.08(m,2H),3.62(m,2H),3.36–3.29(m,2H),3.16-3.09(m,4H),2.56(s,6H),2.46(m,2H),1.97(m,3H),1.91-1.82(m,4H),1.41-1.38(m,6H),1.09(t,J＝7.4Hz,6H)；
13C NMR(151MHz,CDCl3)175.25,172.47,171.33,161.06,159.49,137.35,137.27,128.40,125.82,119.10(d,J＝9.9Hz),108.65,108.49,107.74,98.38,98.20,94.89,93.72,60.77,59.69,54.32,51.16,45.86,35.64,27.78,25.98,21.20,9.98,8.73；
MS(ESI,pos.ion)m/z:811.5[M+H]+；
HPLC 97.4％。
Example 15: synthesis of Compound 15
Step 1: synthesis of Compound 15-3
Compound 11-9(85mg,0.167mmol, prepared by the synthesis in step 7 of example 11), DMT-MM (159mg,0.575mmol), compound 15-2(204mg,0.596mmol), and EA (6mL) were sequentially added to a reaction flask, followed by N-methylmorpholine (0.10mL,0.91mmol) and then added slowly over 5-10 min. After 40min, rt was stirred overnight. Concentrating, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V: V) ═ 1.5: 1, 140mg of oil is obtained with a yield of 72%.
MS(ESI,pos.ion)m/z:1159.5[M+H]+。
Step 2: synthesis of Compound 15-4
Compound 15-3(140mg,0.121mmol), DCM (12mL), TFA (0.90mL) were added to the flask in sequence, and the reaction stirred at rt. TLC monitored the starting material reaction complete. Saturated sodium bicarbonate solution (25mL) was added. EA extraction (10 mL. times.3), drying, spin-drying 130mg of crude product, quantitative yield, directly into the next reaction.
MS(ESI,pos.ion)m/z:959.8[M+H]+。
And step 3: synthesis of Compound 15
Compounds 15-4(130mg,0.136mmol), MeOH (11mL), and LiOH (1N) (3.0mL) were added sequentially to the reaction flask and stirred at rt. TLC monitored the starting material reaction complete. Quenching reaction was added with 0.4mL of acetic acid, 15mL of saturated sodium bicarbonate solution was added, EA extraction (10mL × 3), drying, concentration of the residue by silica gel column chromatography, eluent ethyl acetate: methanol (V: V) ═ 10:1, 79mg of product are obtained, yield 63.6%.
1H NMR(400MHz,CDCl3)11.83(s,1H),11.65(s,1H),8.09(dd,J＝24.3,8.9Hz,2H),7.74(dd,J＝8.3,5.3Hz,1H),7.61-7.53(m,3H),6.88(dd,J＝18.3,8.9Hz,2H),5.35(m,1H),4.60(m,2H),4.51(m,2H),4.41(m,1H),4.20(m,1H),4.12(m,2H),3.83(d,J＝11.2Hz,1H),3.59(m,4H),3.33(m,2H),3.11(m,2H),2.52(d,J＝4.1Hz,6H),2.43(m,1H),2.18-2.04(m,6H),1.96-1.90(m,6H),1.79(m,4H),1.70(m,2H),1.38(t,J＝6.5Hz,6H),1.25(m,4H),1.14(m,4H)；
MS(ESI,pos.ion)m/z:917.3[M+H]+；
HPLC 95.5％。
Example 27: synthesis of Compound 27
Step 1: synthesis of Compound 27-2
Compound 27-1(2g,8mmol) was dissolved in DCM (20mL), DMF (0.2mL) was added, and oxalyl chloride (2.2mL) was slowly added dropwise at 0 deg.C. After the dropwise addition, the reaction mixture was transferred to room temperature for reaction for 3 hours. The solvent was spun off and DCM (5mL) was added to give solution A for use. Dissolving 1H-benzindole (1.4g,8.2mmol) in toluene (20mL), dropwise adding ethyl magnesium bromide (2.7mL,3mol/L) at-5 ℃, and after dropwise adding, keeping the temperature for reaction for 3H to obtain solution B. Dripping the A liquid into the B liquid at the temperature of minus 5 ℃, and separating out solids in the dripping process. After the dropwise addition, the reaction is carried out for 3 hours under the condition of heat preservation. Hydrochloric acid was added to adjust PH to 3, water (30mL) was added, the organic layer was separated, the insoluble solid on the wall of the flask was dissolved in DCM (100mL), washed, dried, the solvent was spun off, and suction filtration was carried out to obtain 1.05g of a gray solid with a yield of 32%.
MS(ESI,pos.ion)m/z:399.2[M+H]+；
1H NMR(400MHz,DMSO-d6)12.92(d,J＝3.4Hz,1H),8.59–8.41(m,2H),8.31(dd,J＝18.4,8.7Hz,1H),7.99(dd,J＝7.9,4.2Hz,1H),7.65(m,2H),7.50(t,J＝7.5Hz,1H),7.42–6.94(m,5H),5.31(m,1H),5.02(m,2H),3.55(m,2H),2.46–2.31(m,1H),1.90(dd,J＝14.2,7.7Hz,3H)。
Step 2: synthesis of Compound 27-3
Compound 27-2(0.6g,1.5mmol) and sodium borohydride (0.22g,5.7mmol) were added to THF (15mL) and boron trifluoride ether solution (0.56mL,4.5mmol) was added dropwise at-8 ℃ and, after the addition was complete, the temperature was raised to 60 ℃ for reaction for 3 hours. Cooling, transferring the reaction liquid to a low temperature condition, dropwise adding a saturated ammonium chloride solution (20mL) to quench the reaction, extracting with ethyl acetate (50mL), extracting the water phase with ethyl acetate (50mL) once, combining the organic phases, washing with a saturated sodium chloride solution (20mL), drying, spinning out the solvent, performing silica gel column chromatography on the residue, and eluting with petroleum ether: ethyl acetate (V/V) ═ 6:1, the solvent was spun off to obtain 0.39g of a white foamy substance in a yield of 67%.
MS(ESI,pos.ion)m/z:385.1[M+H]+；
1H NMR(400MHz,CDCl3)8.98(s,1H),8.09–7.80(m,2H),7.59–7.31(m,9H),7.01(d,J＝26.9Hz,1H),5.29(s,2H),4.27(dd,J＝32.3,5.1Hz,1H),3.61–3.20(m,3H),2.84(ddd,J＝23.5,11.9,8.0Hz,1H),1.89–1.89(m,4H)。
And step 3: synthesis of Compound 27-4
Compound 27-3(0.83g,2.2mmol) was dissolved in DCM (25mL), NBS (0.38g,2.2mmol) was added at 0 deg.C and the reaction was incubated for 0.5 h. The reaction was quenched with saturated ammonium chloride solution (20mL), extracted with DCM (40mL), dried, the solvent spun off, column chromatographed on silica gel, eluent petroleum ether: ethyl acetate (V/V) ═ 10:1, colorless oily substance 0.92g is obtained, yield 92%.
MS(ESI,pos.ion)m/z:485.1[M+Na]+；
1H NMR(400MHz,CDCl3)8.98(s,1H),8.10–7.30(m,11H),5.36–5.09(m,2H),4.31(d,J＝44.7Hz,1H),3.63–3.13(m,3H),2.90–2.72(m,1H),2.01–1.72(m,4H)。
And 4, step 4: synthesis of Compound 27-5
Compound 27-4(0.40g,0.86mmol), compound 11-7(0.50g,0.93mmol, synthesis of intermediate compound 11-7 in reference example 11), sodium carbonate (0.23g,2.16mmol), 1' -bis (diphenylphosphino) ferrocene dichloropalladium dichloromethane complex (0.14g,0.17mmol) were mixed, DMF (10mL), water (2.5mL) were added, nitrogen was added, and the mixture was heated to 90 ℃ for reaction overnight. Cooling, passing through diatomaceous earth, adding water (15mL), adding ethyl acetate (50mL), extracting three times, combining the organic phases, washing with saturated sodium chloride solution (30mL), drying, spinning off the solvent, performing silica gel column chromatography, eluting with petroleum ether: ethyl acetate (V/V) ═ 10:1, obtaining white solid 0.16g, yield 23% and purity 95%.
1H NMR(400MHz,CDCl3)11.20(s,1H),10.91(s,1H),9.42–6.77(m,19H),5.50–5.21(m,5H),4.33(dt,J＝18.4,9.0Hz,4H),4.02–3.09(m,5H),3.53–3.02(m,3H),2.33–2.17(s,4H),2.12–1.97(m,3H),1.89–1.77(m,2H)。
And 5: synthesis of Compounds 27-6
Compounds 27-5(460mg,0.58mmol), EA (25mL), Pd/C (10%) (110mg) were added to the reaction flask in that order. H2Catalyzed, rt stirred overnight. Filtration, EA, EtOH washing and spin drying gave 305mg of a pale yellow solid with 100% yield.
MS(ESI,pos.ion)m/z:525.3[M+H]+。
Step 6: synthesis of Compounds 27-7
At 0 deg.C, compounds 27-6(350mg,0.67mmol), DMT-MM (621mg,2.24mmol), compounds 11-10(601mg,2.09mmol), and EA (21mL) were added to the reaction flask in sequence, and N-methylmorpholine (0.48mL,4.4mmol) was added slowly over 10 min. After 40min at 0 ℃ the mixture was stirred at room temperature overnight. Concentrating, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V/V) ═ 1:1, obtaining 470mg of oily matter with 66 percent of yield.
MS(ESI,pos.ion)m/z:1065.6[M+H]+；
1H NMR(400MHz,CDCl3)11.38(s,1H),11.17(s,1H),7.89(m,1H),7.61(m,2H),7.56(m,2H),7.43(m,2H),6.88(m,2H),5.50–5.32(m,2H),4.64–4.50(m,4H),4.46(m,2H),4.20-4.12(m,2H),3.83(m,2H),3.63(m,2H),3.50(m,2H),3.36–3.20(m,2H),2.80(s,6H),2.50–2.40(m,4H),2.28(s,3H),1.90(m,2H),1.76(m,3H),1.50(m,18H),1.33(s,3H),1.30(s,3H),1.02(m,6H)。
And 7: synthesis of Compounds 27-8
Compounds 27-7(470mg,0.44mmol), DCM (6mL), TFA (1.3mL) were added sequentially to the reaction flask and the reaction stirred at rt. TLC monitored the starting material reaction complete. Saturated sodium bicarbonate solution (35mL) was added. EA extraction (15 mL. times.3), drying, spin-drying 382mg crude product, quantitative yield, directly into the next reaction.
MS(ESI,pos.ion)m/z:865.5[M+H]+。
And 8: synthesis of Compound 27
Compounds 27-8(110mg,0.13mmol), MeOH (6mL), and LiOH (1N) (2.0mL) were added in that order. After 5min, rt is stirred. TLC monitored the starting material reaction complete. Saturated sodium bicarbonate solution 15mL was added, EA extracted (15mL × 3), dried, concentrated residue was column chromatographed on silica gel, eluent ethyl acetate: methanol (V/V) ═ 8:1, obtaining light yellow solid 45mg with 43 percent yield.
MS(ESI,pos.ion)m/z:823.5[M+H]+；
1H NMR(400MHz,CDCl3)11.83(s,1H),11.56(s,1H),8.26-8.15(m,3H),7.71(m,2H),7.58-7.45(m,4H),6.85(m,2H),4.70(m,1H),4.68(s,1H),4.54(m,2H),4.39(m,1H),4.30(m,1H),4.10(m,1H),4.00(m,1H),3.72(m,1H),3.60(m,2H),3.50(m,1H),3.19(m,1H),3.13(m,2H),2.59(s,3H),2.56(s,3H),2.50(m,1H),2.15-2.10(m,4H),2.00-1.90(m,6H),1.82(m,2H),1.40(t,J＝7.1Hz,6H),1.04(m,6H)；
HPLC 91.8％。
Example 28: synthesis of Compound 28
Step 1: synthesis of Compound 28-2
Compound 28-1(500mg,0.595 mmol) was synthesized as in compound 27-5 of reference example 27, using (2R,4S) -4-acetoxy-2- ((2-bromo-5, 6-dihydro-4H-pyrrolo [3,2, 1-ij) as starting material 27-4]Quinolin-1-yl) methyl) pyrrolidine-1-carboxylic acid benzyl ester, EA (25mL), and Pd/C (10%, 200mg) were added to the reaction flask in that order. H2Catalyzed, rt stirred overnight. Filtration, EA, EtOH wash, spin-dry, column chromatography, EA as eluent gave 250mg of a pale yellow solid, 73% yield.
MS(ESI,pos.ion)m/z:573.2[M+H]+。
Step 2 Synthesis of Compound 28-3
At 0 deg.C, compound 28-2(168mg,0.279mmol), DMT-MM (210mg,0.759mmol), compound 11-10(313mg,1.086mmol), and EA (8mL) were added sequentially to a reaction flask, and N-methylmorpholine (0.21mL,1.90mmol) was added slowly over 10 min. After 50min at 0 ℃ the mixture was stirred at room temperature overnight. Concentrating, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V: V) ═ 1: 1.5, 186mg of oil are obtained with a yield of 60%.
MS(ESI,pos.ion)m/z:1135.6[M+Na]+；
1H NMR(400MHz,CDCl3)10.78(s,1H),8.07(m,1H),7.99(m,1H),7.63(m,1H),7.17-7.11(m,2H),7.03-6.90(m,3H),5.31(m,1H),4.72-4.53(m,4H),4.41(m,1H),4.31-4.12(m,2H),3.86(m,1H),3.80(m,2H),3.52(m,2H),3.35-3.11(m,2H),2.80(m,2H),2.72(s,3H),2.76(s,3H),2.71(m,4H),2.50(m 1H),2.10(s,3H),2.05(s,3H),2.23(m,1H),2.12(m,1H),1.98(m,2H),1.81-1.70(m,4H),1.51(m,18H),1.42(m,6H),0.99(m,6H)。
And step 3: synthesis of Compound 28-4
Compound 28-3(186mg,0.167mmol), DCM (5mL), TFA (0.92mL) were added to the flask in sequence, and the reaction stirred at rt. TLC monitored the starting material reaction complete. Saturated sodium bicarbonate solution (20mL) was added. EA extraction (12 mL. times.3), drying, spin-drying 153mg of crude product, quantitative yield, directly into the next reaction.
MS(ESI,pos.ion)m/z:913.5[M+H]+。
And 4, step 4: synthesis of Compound 28
Compounds 28-4(150mg,0.164mmol), MeOH (10mL), and LiOH (1N) (3.0mL) were added in that order, and stirred at rt. TLC monitored the starting material reaction complete. 0.5mL of acetic acid was added to quench the reaction, 20mL of saturated sodium bicarbonate solution was added, EA was extracted (20 mL. times.3), dried, and the residue was concentrated by silica gel column chromatography, eluting with ethyl acetate: methanol (V/V) ═ 5:1, obtaining light yellow solid 70mg with 51 percent of yield.
1H NMR(600MHz,CDCl3)11.18(s,1H),7.98(m,1H),7.88(d,J＝8.4Hz,1H),7.64(d,J＝8.2Hz,1H),7.31(d,J＝8.0Hz,1H),7.12(m,1H),6.92(m 4H),6.77(d,J＝7.0Hz,1H),4.56(m,4H),4.40(m,1H),4.30-4.10(m,2H),3.81(m,2H),3.76(m,2H),3.50(m,2H),3.30(m,2H),2.77(m,2H),2.46(s,3H),2.43(s,3H),2.70(m,4H),2.45(m 1H),2.20(m,1H),2.11(m,1H),1.92(m,2H),1.80-1.65(m,4H),1.33(m,6H),0.94(m,6H)；
MS(ESI,pos.ion)m/z:829.5[M+H]+；
HPLC 95.2％。
Example 29: synthesis of Compound 29
Step 1: synthesis of Compound 29-2
Compound 29-1(312mg,0.394mmol, see example 12 synthetic preparation of compound 12-7 wherein compound 11-7 is replaced with benzyl (2R,4S) -4-acetoxy-2- ((6-fluoro-1-methyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-3-yl) methyl) pyrrolidine-1-carboxylate), EA (15mL), Pd/C (10%) (193mg), were added sequentially. H2Catalyzed, rt stirred overnight. Filtration, EA, EtOH wash, spin-dry, column chromatography gave 82mg of a pale yellow solid in 40% yield.
MS(ESI,pos.ion)m/z:525.2[M+H]+。
Step 2: synthesis of Compound 29-3
At 0 ℃, compound 29-2(57mg,0.109mmol), DMT-MM (99mg,0.358mmol), compound 11-10(111mg,0.385mmol), and EA (6mL) were sequentially added to a reaction flask, N-methylmorpholine (0.07mL,0.60mmol) was added slowly, and the addition was completed within 5-10 min. After 50min at 0 ℃ the mixture was stirred at room temperature overnight. Concentrating, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate ═ 1:1, obtaining 78mg of light yellow solid with the yield of 71 percent.
MS(ESI,pos.ion)m/z:1065.5[M+H]+。
And step 3: synthesis of Compound 29-4
Compound 29-3(78mg,0.073mmol), DCM (8mL), TFA (0.95mL) were added sequentially to the flask, the reaction stirred at rt, and TLC monitored the completion of the starting material reaction. Saturated sodium bicarbonate solution (25mL) was added. EA extraction (10 mL. times.3), drying, spin-drying 64mg of crude product, quantitative yield, directly into the next reaction.
MS(ESI,pos.ion)m/z:865.5[M+H]+。
And step 3: synthesis of Compound 29
Adding the compounds 29-5(54mg,0.063mmol), MeOH (6.5mL), and LiOH (1N) (2.0mL) in sequence into a reaction flask, stirring at rt, TLC monitoring the completion of the reaction of the starting materials, adding acetic acid 0.4mL, quenching, adding saturated sodium bicarbonate solution 25mL, EA extracting (20mL × 3), drying, concentrating the residue, performing silica gel column chromatography, eluting with ethyl acetate, methanol (V/V) 5:1 to obtain a pale yellow solid 35mg, yield 67%, MS (ESI, pos.ion) M/z 823.5[ M + H% ], yield 67%. M/z]+；
1H NMR(400MHz,CDCl3)11.27(s,1H),8.20(m,2H),7.70(m,1H),7.60(m,3H),6.90(m,2H),5.40(m,1H),4.70(m,3H),4.50(m,1H),4.41(m,1H),4.10(s,1H),4.05(m,2H),3.75-3.65(m,3H),3.52(m,1H),3.30(m,1H),3.11(m,2H),2.98(s,3H),2.59(s,3H),2.57(s,3H),2.41(m,1H),2.20(m,1H),2.08-1.90(m,4H),1.90-1.73(m,5H),1.38(t,J＝6.8Hz,6H),1.06(m,6H)；
HPLC 95.0％。
Example 30: synthesis of Compound 30
Step 1: synthesis of Compound 30-1
Compounds 11-5(1.87g,5.06mmol), EA (45mL), Pd/C (10%) (980mg) were added sequentially to the reaction flask. H2Gas catalyzed, rt stirred overnight. Filtration, EA, EtOH wash, spin-dry to give 1.15g of white solid, 96% yield.
MS(ESI,pos.ion)m/z:237.1[M+H]+。
Step 2: synthesis of Compound 30-3
At 0 ℃, compound 30-1(350mg,1.48mmol), DMT-MM (761mg,2.75mmol), compound 30-2(715mg,2.09mmol), EA (20mL) were added to the reaction flask in sequence, N-methylmorpholine (0.22mL,2.0mmol) was added slowly, and the addition was completed for 5 min. After 50min reaction at 0 ℃ rt was stirred overnight. Concentrating, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate (V: V) ═ 1: 2, obtaining a pale yellow solid 570mg with the yield of 68 percent.
MS(ESI,pos.ion)m/z:561.3[M+H]+；
1H NMR(400MHz,CDCl3)8.08(s,1H),7.82(dd,J＝8.6,5.4Hz,1H),7.02(m,2H),6.93–6.85(m,1H),6.76(s,broad,1H),5.29(m,1H),4.79(m,1H),4.57(m,1H),4.43(t,J＝8.3Hz,1H),4.06(m,1H),4.00(m, 1H),3.45(dd,J＝13.5,3.2Hz,1H),2.83(m,1H,overlap),2.80(s,3H),2.18(m,1H),1.91(m,1H),1.76(m,6H),1.66(m,3H),1.50(s,9H),1.47(m,1H),1.36(m,1H),1.32(d,J＝7.1Hz,3H)。
And step 3: synthesis of Compound 30-4
Dissolve compound 30-3(170mg,0.30mmol) in DCM (10mL), add NBS (55mg,0.31mmol) at-3 deg.C, and keep the temperature for 2 h. Extraction with DCM (25mL), washing with saturated sodium chloride solution (25mL), drying, removal of the solvent, chromatography on silica gel column, eluent petroleum ether: ethyl acetate (V: V) ═ 1:1, white solid 81mg was obtained with a yield of 41%.
MS(ESI,pos.ion)m/z:639.2[M+H]+；
1H NMR(400MHz,CDCl3)8.77(s,1H),7.78(dd,J＝8.6,5.3Hz,1H),6.96(m,1H),6.84(m,1H),5.26(d,J＝53.0Hz,1H),4.79(m,1H),4.58(m,1H),4.43(t,J＝8.2Hz,1H),4.11(m,2H),4.03(m,1H),3.91(m,1H),3.35(dd,J＝13.5,3.1Hz,1H),2.86m,1H),2.80(s,3H),2.16(m,1H),1.97(m,1H),1.83–1.72(m,5H),1.49(s,9H),1.31(m,3H),1.25(m,4H)。
And 4, step 4: synthesis of Compound 30-5
Compound 30-4(709mg,1.11mmol), compound 13-7(763mg,1.42mmol), 1' -bis (diphenylphosphino) ferrocene dichloropalladium dichloromethane complex (222mg,0.27mmol), sodium carbonate (298mg,2.81mmol) were mixed, DMF (20mL), water (5mL) were added, vacuum was applied, nitrogen gas was applied, and the mixture was heated to 90 ℃ for reaction overnight. Cooling, filtering with celite, adding water (25mL), extracting with ethyl acetate (50mL × 3), combining the organic phases, washing with saturated sodium chloride solution (25mL), drying, spinning off the solvent, chromatography on silica gel column, petroleum ether: ethyl acetate (V: V) ═ 3:1 as eluent, giving 458mg of pale yellow solid with a yield of 42%.
MS(ESI,pos.ion)m/z:969.3[M+H]+；
1H NMR(400MHz,CDCl3)11.15(d,J＝10.1Hz,2H),7.66(m,1H),7.48–7.38(m,5H),7.35(m,2H),7.00(m,1H),6.90(m,2H),5.37(s,1H),5.32(m,2H),4.65(s,broad,1H),4.52(m,2H),4.28(t,J＝9.3Hz,1H),4.16–4.02(m,2H),3.79–3.62(m,4H),3.40(m,1H),3.26(t,J＝12.9Hz,1H),3.03(m,1H),2.79(m,2H),2.42(t,J＝16.8Hz,1H),2.27(s,3H),2.02(m,2H),1.95(s,3H),1.84(m 4H),1.75(m,3H),1.67(m,2H),1.49(s,9H),1.33(d,J＝7.1Hz,3H),1.30(m,2H)。
And 5: synthesis of Compound 30-6
Compounds 30-5(458mg,0.47mmol), EA (25mL), Pd/C (10%) (236mg) were added in sequence. H2Catalyzed, rt stirred overnight. Filtration, EA, EtOH wash, concentration of the filtrate, column chromatography with EA as eluent gave 212mg of a pale yellow solid in 53% yield.
MS(ESI,pos.ion)m/z:835.2[M+H]+；
1H NMR(400MHz,CDCl3)13.53(s,1H),11.03(s,1H),7.68(dd,J＝8.7,5.3Hz,1H),7.32(d,J＝7.9Hz,1H),7.08–7.02(m,2H),6.92(m,2H),5.40(m,2H),4.72(s,broad,1H),4.52(m,2H),4.06(m,1H),3.83(m,1H),3.42(m,1H),3.36–3.22(m,3H),3.11(m,2H),2.87(s,3H),2.84–2.74(m,2H),2.67–2.53(m,2H),2.07(s,3H),1.91(m,2H),1.88(m,1H),1.80-1.69(m,10H),1.64(m,1H),1.51(s,9H),1.37(d,J＝7.1Hz,3H)。
Step 6: synthesis of Compounds 30-7
At 0 deg.C, compound 30-6(195mg,0.23mmol), DMT-MM (160mg,0.58mmol), compound 11-10(190mg,0.66mmol), EA (20mL) were added to the reaction flask in sequence, N-methylmorpholine (0.10mL,0.89mmol) was added slowly, and the addition was completed for 5 min. After 50min reaction at 0 ℃ rt was stirred overnight. Concentrating, performing silica gel column chromatography on the residue, and eluting petroleum ether: ethyl acetate ═ 1: 2, obtaining light yellow solid 200mg with 77% yield.
MS(ESI,pos.ion)m/z:1105.5[M+H]+；
1H NMR(600MHz,CDCl3)11.42(s,1H),11.19(s,1H),7.67(dd,J＝8.6,5.2Hz,1H),7.52(s,broad,1H),7.43(d,J＝8.0Hz,1H),7.36(m,1H),7.02(m,2H),6.91(m,2H),5.49(t,J＝5.1Hz,1H),5.41(d,J＝53.0Hz,1H),4.65(dd,J＝13.9,7.2Hz,2H),4.57–4.49(m,4H),4.17(m,1H),4.06(m,1H),3.83(d,J＝12.2Hz,1H),3.72(m,1H),3.58(m,1H),3.34(m,1H),3.27(m,1H),2.88(s,3H),2.86(s,3H),2.79(m,3H),2.46(m,1H),2.32(s,3H),2.29(s,1H),2.19(d,J＝14.0Hz,1H),1.93(m,2H),1.86(m,4H),1.75(m,4H),1.51(s,18H),1.45(m,2H),1.38(d,J＝7.2Hz,3H),1.35(d,J＝7.1Hz,3H),1.00(t,J＝7.3Hz,3H)。
And 7: synthesis of Compounds 30-8
Compounds 30-7(500mg,0.45mmol), DCM (12mL), TFA (1.8mL) were added sequentially to the reaction flask and the reaction stirred at rt. TLC monitored the starting material reaction complete. Saturated sodium bicarbonate solution (30mL) was added. EA extraction (20 mL. times.3), drying, spin-drying 410mg of crude product, quantitative yield, directly into the next reaction.
MS(ESI,pos.ion)m/z:905.5[M+H]+。
And 8: synthesis of Compound 30
Compounds 30-8(260mg,0.29mmol), MeOH (15mL), and LiOH (1N) (3.0mL) were added sequentially to the reaction flask and stirred at rt. TLC monitored the starting material reaction complete. Quenching reaction was added with 0.5mL of acetic acid, 25mL of saturated sodium bicarbonate solution was added, EA extraction (25mL × 3), drying, concentration of the residue by silica gel column chromatography, eluent ethyl acetate: methanol (V: V) ═ 7:1, obtaining light yellow solid 123mg with the yield of 50 percent.
1H NMR(400MHz,CDCl3)11.65(s,1H),11.20(s,1H),8.28(d,J＝8.4Hz,1H),7.83(d,J＝8.9Hz,1H),7.69–7.53(m,3H),6.97(m,1H),6.88(m,2H),5.38(d,J＝53.6Hz,1H),4.70(dd,J＝13.4,7.4Hz,1H),4.62(s,1H),4.51(t,J＝8.1Hz,2H),4.43(t,J＝10.0Hz,1H),4.15(m,1H),4.05(m,1H),3.96(dd,J＝11.0,4.6Hz,1H),3.78(d,J＝11.5Hz,2H),3.65(m,1H),3.53(m,1H),3.26(m,1H),3.19–3.06(m,3H),2.56(s,3H),2.45(s,3H),2.39(m,2H),2.17(m,2H),1.98(m,2H),1.94–1.82(m,5H),1.78(m,3H),1.68(m,1H),1.39(d,J＝6.9Hz,3H),1.36(d,J＝6.9Hz,3H),1.32(m,2H),1.27(m,1H),1.04(t,J＝7.4Hz,3H)；
MS(ESI,pos.ion)m/z:863.3[M+H]+；
HPLC 97.8％。
Examples 5,6, 8, 16, 17, 19, 20, 21, 22, 25, 26, 31 to 44
The compounds of examples 5,6, 8, 16, 17, 19, 20, 21, 22, 25, 26, 31-44 were prepared according to synthetic methods using the corresponding starting materials and intermediates, the specific structures and characterization data being as follows:
examples of biological Activity test
Biological Activity example 1
Firstly, the purpose of experiment is as follows:
the CTG method was used to test the 50% inhibitory concentration of compounds on cell proliferation in SK-OV-3 human ovarian cancer and in MDA-MB-231 human breast cancer (IC 50).
Secondly, the used experimental reagents and test products are as follows:
1)CellTiter-Glo(CTG)(Promega)
2) l15 Medium (Gibco)
3) DMEM medium (Hyclone)
4) McCoy's 5a medium (Gibco)
5) FBS (fetal bovine serum) (Gibco)
6) 0.25% pancreatin-EDTA (Gibco)
7)DMSO(Sigma)
8) 96-well cell culture plate, white wall transparent bottom (Corning)
9) The cell strain SK-OV-3 is purchased from Shanghai Life sciences research institute of Chinese academy of sciences
10) Cell line MDA-MB-231 was purchased from ATCC
Thirdly, experimental steps:
1) cell seeding
Cells in exponential growth phase were collected and counted for viable cells using a Vi-Cell XR Cell counter. The cell suspension is adjusted to the appropriate concentration with the corresponding medium. Add 90. mu.L of cell suspension to each well in 96-well cell culture plates to a final cell concentration of 2000 cells/well.
2) Adding chemicals for treatment
Each test compound was dissolved in DMSO as a 20mM stock. 4X series of gradient dilutions were prepared from stock solutions and the corresponding solvents. Then diluted 100-fold each with medium. Finally, 10 μ L of corresponding 10-fold solution is added to each well of each cell, each drug concentration is 3 multiple wells, and the concentration range of the test compound used in the final test is 0.153-10000 nM: test compounds were diluted to a final DMSO concentration of 0.1% per well. Standing at 37 deg.C for 5% CO2Incubate for 72 hours.
3) Read plate detection
After 72 hours of drug treatment, 50. mu.l (1/2 culture volume) of CTG solution previously thawed and equilibrated to room temperature was added to each well according to the CTG protocol, mixed well for 2 minutes using a microplate shaker, allowed to stand at room temperature for 10 minutes, and then the fluorescence signal value was measured using an Envision2104 plate reader.
4) Data analysis
Cell viability using the formula: Vsample/Vvehicle control x 100% calculation. Where Vsample is the reading for the drug treated group and Vvehicle control is the mean value for the solvent control group. Sigmoidal dose-survival curves were plotted using a non-linear regression model using GraphPad Prism 5.0 software and IC50 values were calculated.
Fourthly, the experimental results are as follows:
TABLE 1 inhibitory Activity of the Compounds of the present invention on SK-OV-3 human ovarian cancer cell proliferation
In addition, the compounds 1,2 and 4of the invention also have strong inhibitory activity on the proliferation of SK-OV-3 human ovarian cancer cells, and the IC50 values are all 1-10 nM. Therefore, the compound has stronger inhibitory activity on the proliferation of SK-OV-3 human ovarian cancer cells.
TABLE 2 inhibitory Activity of the Compounds of the invention on MDA-MB-231 human Breast cancer cell proliferation
Table 2 shows that the compound has strong inhibitory activity on MDA-MB-231 human breast cancer cell proliferation.
B: biological Activity example 2
Firstly, the purpose of experiment is as follows:
the compound was tested by the CTG method for 50% inhibitory concentration of cell proliferation in Molm13 human acute myelomonocytic leukemia (IC 50).
Secondly, the used experimental reagents and test products are as follows:
11)CellTiter-Glo(CTG)(Promega)
12) DMEM medium (Hyclone)
13) RPMI medium (Gibco)
14) FBS (fetal bovine serum) (Gibco)
15) 0.25% pancreatin-EDTA (Gibco)
16)DMSO(Sigma)
17) 96-well cell culture plate, white wall transparent bottom (Corning)
18) Cell line Molm13 derived DSMZ, Beijing Kaokang gift
Thirdly, experimental steps:
1) cell seeding
Cells in the exponential growth phase were collected and viable cell counts were performed using a cell counter. The cell suspension is adjusted to the appropriate concentration with the corresponding medium. Add 90. mu.L of cell suspension to each well in 96-well cell culture plates to a final cell concentration of 3000 cells/well.
2) Adding chemicals for treatment
Each test compound was dissolved in DMSO as a 10mM stock solution. 3X series of gradient dilutions were prepared from stock solutions and the corresponding solvents. Then diluted 100-fold each with medium. Finally, 10 μ L of corresponding 10-fold solution is added to each cell well, each drug concentration is 3 multiple wells, and the concentration range of the test compound used in the final test is 1.52-10000 nM: test compounds were diluted to a final DMSO concentration of 0.1% per well. Standing at 37 deg.C for 5% CO2Incubate for 72 hours.
3) Read plate detection
After 72 hours of drug treatment, according to the CTG operation instruction, 50 μ l (1/2 culture volume) of CTG solution which is pre-melted and balanced to room temperature is added into each well, mixed evenly for 2 minutes by a microplate shaker, and placed at room temperature for 10 minutes, and then a fluorescence signal value is measured by a multifunctional microplate reader.
4) Data analysis
Cell viability using the formula: Vsample/Vvehicle control x 100% calculation. Where Vsample is the reading for the drug treated group and Vvehicle control is the mean value for the solvent control group. Sigmoidal dose-survival curves were plotted using a non-linear regression model using GraphPad Prism 5.0 software and IC50 values were calculated.
Fourthly, the experimental results are as follows:
TABLE 3 inhibitory Activity of the Compounds of the present invention on the proliferation of Molm13 human acute myelomonocytic leukemia cells
Compound (I)
Molm13,IC50(nM)
Birinapant
63
Compound 3
18
Compound 9
4
Compound 10
1
Compound 13
6
Compound 27
33
Table 3 shows that the compound has strong inhibitory activity on proliferation of Molm13 human acute myelomonocytic leukemia cells.
Biological Activity example 3
The inhibitory effect of the compounds on the cIAP1-BIR3 target was evaluated based on fluorescence polarization binding experiments.
The inhibition effect of the small molecule compound on the binding capacity of the cIAP1-BIR3 protein and a fluorescent marker SM5F (AbuRPF-K (5-Fam) -NH2) is detected by a drug screening system based on a fluorescence polarization binding experiment. The protein is combined with the fluorescent marker to generate fluorescence polarization, and an Envision microplate reader is used for detecting a fluorescence polarization value (mP) to reflect the combination degree of the protein and the fluorescent marker. Experimental procedure a) to a 384 reaction plate (6008260, Perkinelmer) was added 8. mu.L/well of cIAP1-BIR3 protein solution (prepared in 2.2.1.2 procedures) and centrifuged at 1000rpm for use. b) The positive compound birinapag (10mM stock) was diluted 10-fold to 1000 μ M with 100% DMSO, the test compound (10mM stock) was diluted 100-fold to 100 μ M, and the concentration of the test compound in 384 dilution plates (3657, corning) was adjusted at 1: 3, carrying out equal ratio dilution so that the gradient concentration of the positive compound is as follows: 1000,333.3,111.1,37.04,12.34,4.12,1.37,0.46,0.15,0.051,0 μ M. Gradient concentration of test compound: 100,33.3,11.1,3.704,1.234,0.412,0.137,0.046,0.015,0.005,0 μ M. c) Transfer 5. mu.L of compound solution (prepared in step b) to 384 dilution plates containing 45. mu.L of 1 Xreaction buffer, shake and mix well and centrifuge at 1000 rpm. d) mu.L of the compound solution (prepared in step c) was transferred to 384 reaction plates (prepared in step a), centrifuged at 1000rpm and incubated for 15 minutes at 25 ℃. e) Transfer 10. mu.L of fluorescent label (prepared in step 2.2.1.3) to 384 reaction plates, centrifuge at 1000rpm and incubate at 25 ℃ for 60 min. The final concentration gradient of the positive compound and the test compound in the reaction system is 10000,3333.3,1111.1,370.3,123.5,41.4,13.7,4.6,1.5,0.51 and 0 nM. 1000,333.3,111.1,37.04,12.34,4.12,1.37,0.46,0.15,0.051,0 nM. The final concentration of DMSO is 1%. f) The mP value was read using an Envision multifunctional plate reader. The mP value size is used to characterize the extent to which the cIAP1-BIR3 protein binds to the fluorescent marker SM 5F. g) IC50 (half maximal inhibitory concentration) for compounds was obtained using a non-linear fit formula. The results of the specific experiments are shown in table 4.
TABLE 4 inhibitory Activity of the Compounds of the invention against the cIAP1-BIR3 target
Table 4 shows that the compounds of the present invention have strong inhibitory activity against cIAP1-BIR3 protein.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that those skilled in the art can make changes, modifications, substitutions and alterations to the above embodiments without departing from the principle and spirit of the present invention, the scope of which is defined by the appended claims and their equivalents.
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