CN107793412A - The selective depressants of Bcl 2 and its preparation and use - Google Patents

The selective depressants of Bcl 2 and its preparation and use Download PDF

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Publication number
CN107793412A
CN107793412A CN201610800391.4A CN201610800391A CN107793412A CN 107793412 A CN107793412 A CN 107793412A CN 201610800391 A CN201610800391 A CN 201610800391A CN 107793412 A CN107793412 A CN 107793412A
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cancer
acid
compound
pharmaceutically acceptable
prodrug
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Inventor
王虎庭
朱岩
商现星
胡远东
何伟男
张慧
彭勇
韩永信
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Centaurus Biopharma Co Ltd
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Centaurus Biopharma Co Ltd
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Priority to CN201610800391.4A priority Critical patent/CN107793412A/en
Priority to CN201780053177.XA priority patent/CN109641897B/en
Priority to PCT/CN2017/100226 priority patent/WO2018041248A1/en
Publication of CN107793412A publication Critical patent/CN107793412A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the selective depressants of Bcl 2 and its preparation and use.It is related to formula (I) compound or its pharmaceutically acceptable salt, solvate, polymorph or prodrug, further relates to the pharmaceutical composition comprising formula (I) compound and its application in the medicine for treating the disease related to the protein expressions of anti-apoptotic Bcl 2 is prepared.

Description

Bcl-2 selective inhibitors, their preparation and use
Technical Field
The invention relates to compounds for selectively inhibiting the activity of Bcl-2 anti-apoptotic proteins, and also relates to a preparation method, a pharmaceutical composition and application of the compounds.
Background
Apoptosis plays an important role in ensuring a balance between proliferation and apoptosis of cells of an organism. Disorders of this pathway lead to a variety of diseases. Anti-apoptotic Bcl-2 proteins play an important role in the regulation of apoptosis, and are associated with a number of diseases, and in a variety of cancer and immune system disorders, the overexpression of Bcl-2 proteins is associated with tolerance to chemotherapy, disease progression, and overall prognosis, and there is a need in the therapeutic arts for active compounds that inhibit the anti-apoptotic protein Bcl-2. The relationship of Bcl-2 proteins to the following cancers is described in patents WO2005049593 and WO 2005024636: bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphocytic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer, and the like.
Inhibitors with high activity against target proteins have been reported in the art, but lack of selectivity often leads to severe side effects, such as inhibition of Bcl-XLResulting in thrombocytopenia (Andrew J Souers, Joel D Leverson, Erwin R Boghaert et al Nature Medicine, 2013, 19, 202-. Currently, only the Bcl-2 selective inhibitor, ABT-199, is approved by the FDA in the united states for the treatment of chronic lymphocytic leukemia.
The invention comprises a series of compounds having the anti-apoptotic protein Bcl-2Higher activity and higher selectivity (relative to the anti-apoptotic protein Bcl-X)L)。
Summary of The Invention
The present invention relates to compounds, or pharmaceutically acceptable salts, solvates, polymorphs, or prodrugs thereof, useful as inhibitors of one or more anti-apoptotic protein family members, which are useful for treating diseases associated with the expression of anti-apoptotic Bcl-2 proteins. The invention also relates to a preparation method of the compound or the pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, and application of the compound or the pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof in preparing medicines for treating diseases related to expression of the anti-apoptotic Bcl-2 protein.
Also disclosed are methods of treating diseases associated with the expression of anti-apoptotic Bcl-2 proteins using the compounds of the present invention, or pharmaceutically acceptable salts, solvates, polymorphs, or prodrugs thereof.
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, as described below:
wherein,
is a single bond or a double bond;
ar is selected from aryl and heteroaryl groups, which are optionally selected from halogen, amino, hydroxy, (═ O), and C1-6Radical substitution of alkyl;
x is selected from the group consisting of-O-, -S-and-NR3-；
R is selected from C1-6Alkoxy, monoalkylamino, dialkylamino, C3-8Cycloalkyl and C3-8Heterocycloalkyl, said cycloalkyl and heterocycloalkyl being optionally selected from halogen, amino, hydroxy, (═ O), - (CO) (CH)2)mNR4R5、-(CO)(CH2)mOR6And C1-6Radical substitution of alkyl;
R1、R2、R3、R4、R5and R6Each independently selected from H and C1-6An alkyl group;
m is independently 0, 1, 2, 3, 4, 5 or 6;
n is 0, 1, 2, 3, 4, 5 or 6.
In some embodiments, Ar is selected from 6-10 membered aryl and 5-10 membered heteroaryl, which are optionally selected from halogen, amino, hydroxy, (═ O), and C1-6Radical substitution of alkyl; preferably, the heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S; preferably, said aryl and heteroaryl groups are optionally selected from halogen, amino, (═ O) and C1-6Alkyl groups.
In some embodiments, X is selected from the group consisting of-O-and-NR3-, wherein R3Selected from H and C1-6An alkyl group.
In some embodiments, X is selected from the group consisting of-O-and-NH-.
In some embodiments, R1、R2And R3Is H.
In some embodiments, R4、R5And R6Is H.
In some embodiments, R is selected from C1-6Alkoxy radical, C3-8Cycloalkyl and C3-8Heterocycloalkyl, said ringAlkyl and heterocycloalkyl are optionally selected from halogen, amino, hydroxy, (═ O), - (CO) (CH)2)mNR4R5、-(CO)(CH2)mOR6And C1-6Radical substitution of alkyl, wherein R4、R5And R6Each independently selected from H and C1-6Alkyl, m is independently 0, 1, 2, 3, 4, 5 or 6.
In some embodiments, R is selected from C1-6Alkoxy radical, C3-8Cycloalkyl and C3-8Heterocycloalkyl, said cycloalkyl and heterocycloalkyl being optionally selected from halogen, amino, hydroxy, (═ O), - (CO) (CH)2)mNH2、-(CO)(CH2)mOH and C1-6Alkyl, and m is independently 0, 1, 2, 3, 4, 5, or 6.
In some embodiments, R is selected from C1-6Alkoxy radical, C3-8Cycloalkyl and C3-8Heterocycloalkyl, said cycloalkyl and heterocycloalkyl being optionally selected from halogen, amino, hydroxy, (═ O), - (CO) (CH)2)mNR4R5、-(CO)(CH2)mOR6And C1-6Radical substitution of alkyl, wherein R4、R5And R6Each independently selected from H and C1-6Alkyl, m is independently 0, 1, 2, 3 or 4.
In some embodiments, R is selected from C1-6Alkoxy radical, C3-8Cycloalkyl and C3-8Heterocycloalkyl, said cycloalkyl and heterocycloalkyl being optionally selected from halogen, amino, hydroxy, (═ O), - (CO) (CH)2)mNH2、-(CO)(CH2)mOH and C1-6Alkyl, and m is independently 0, 1, 2, 3, or 4.
In some embodiments, R is selected from C1-6Alkoxy radical, C3-8Cycloalkyl and C3-8Heterocycloalkyl, said cycloalkyl and heterocycloalkyl optionally being substituted by halogen or C1-6Alkyl substitution.
In some embodiments, n is 0, 1, 2, 3, or 4.
In some embodiments, the compounds of the present invention are selected from
In another aspect, the present invention also relates to a pharmaceutical composition comprising an effective amount of the above-described compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. Such compositions may comprise at least one of adjuvants, excipients, preservatives, absorption retarders, fillers, binders, adsorbents, buffers, disintegrants, solubilizers, other carriers, and other inert ingredients. In some embodiments, such compositions can treat diseases associated with expression of anti-apoptotic Bcl-2 proteins. Preferably, the disease is an autoimmune disease and cancer. More preferably, the disease is cancer. Most preferably, the cancer is bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphocytic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer.
In another aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, in the manufacture of a medicament for the treatment of a disease associated with expression of anti-apoptotic Bcl-2 protein. Preferably, the disease is an autoimmune disease and cancer. More preferably, the disease is cancer. Most preferably, the cancer is bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphocytic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer.
In another aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, for use as a medicament for treating a disease associated with expression of an anti-apoptotic Bcl-2 protein. Preferably, the disease is an autoimmune disease and cancer. More preferably, the disease is cancer. Most preferably, the cancer is bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphocytic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer.
In another aspect, the present invention provides a method of treating a disease associated with expression of an anti-apoptotic Bcl-2 protein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, a pharmaceutically acceptable salt, solvate, polymorph, or prodrug thereof, or a composition thereof. Preferably, the disease is an autoimmune disease and cancer. More preferably, the disease is cancer. Most preferably, the cancer is bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphocytic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer.
In another aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, as described above, in the manufacture of a pharmaceutical composition for the treatment of a disease associated with expression of an anti-apoptotic Bcl-2 protein. Preferably, the disease is an autoimmune disease and cancer. More preferably, the disease is cancer. Most preferably, the cancer is bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphocytic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer.
In another aspect, the present invention relates to a process for the preparation of the above-mentioned compounds of the present invention or pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof.
Detailed Description
Exemplary embodiments utilizing the principles of the present invention are set forth in the following detailed description of the invention. The features and advantages of the present invention may be better understood by reference to the following summary.
It should be understood that the scope of the various aspects of the invention is defined by the claims and that methods and structures within the scope of these claims and their equivalents are intended to be covered thereby.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, explanatory and are not restrictive of any inventive subject matter. The use of the singular forms also includes the plural unless specifically stated otherwise. The use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are not limiting.
Certain chemical terms
The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". And, optionally substituted groups may be unsubstituted (e.g.: CH)2CH3) Fully substituted (e.g.: -CF2CF3) Monosubstituted (e.g.: -CH2CH2F) Or any level between mono-and fully substituted (e.g.: -CH2CHF2、-CF2CH3、-CFHCHF2Etc.). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.
Definitions for the terms of the standardization body can be found in the references including Carey and Sundberg, fourth edition of advanced organic chemistry, volume a (2000) and volume B (2001), pleinan Press, new york. Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, nuclear magnetism, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy, and pharmacological methods. Unless specific definitions are set forth, the nomenclature used herein in the analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry, as well as the laboratory procedures and techniques, are those known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.
When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, -CH2O-is equivalent to-OCH2-。
As used herein, the terms "group", "chemical group" or "chemical group" refer to a particular portion or functional group of a molecule. Chemical groups are often considered as chemical entities embedded in or attached to a molecule.
Some of the chemical groups named herein may be referred to by a shorthand notation for the total number of carbon atoms. E.g. C1-C6Alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated by shorthand notation does not include carbon atoms on possible substituents.
The terms "halogen", "halo" or "halide" refer to bromine, chlorine, fluorine or iodine.
The terms "aromatic", "aromatic ring", "aromatic" and "aromatic-cyclic" as used herein refer to a planar ring portion of one or more rings having a delocalized electron-conjugated system of 4n +2 electrons, where n is an integer. The aromatic ring may be formed of 5, 6, 7, 8, 9 or more atoms. The aromatic compound may be optionally substituted and may be monocyclic or fused-ring polycyclic. The term aromatic compound includes all carbocyclic rings (e.g., benzene rings) and rings containing one or more heteroatoms (e.g., pyridine).
The term "heteroatom" or "hetero" as used herein alone or as part of another component refers to atoms other than carbon and hydrogen. The heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.
The terms "fused" or "fused ring" as used herein, alone or in combination, refer to a cyclic structure in which two or more rings share one or more bonds.
The term "spiro" or "spirocyclic" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
The term "alkyl" as used herein alone or as part of another component (e.g., monoalkylamino) refers to an optionally substituted straight or optionally substituted branched chain monovalent saturated hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3 methylhexyl, n-octyl, n-nonyl, n-decyl, and the like.
The term "alkoxy" as used herein refers to-ORaGroup, wherein RaIs an alkyl group as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
The term "cycloalkyl" as used herein alone or as part of another ingredient refers to a stable monovalent non-aromatic monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms, and may include fused, spiro or bridged ring systems containing from 3 to 15 ring-forming carbon atoms, preferably from 3 to 10 ring-forming carbon atoms, more preferably from 3 to 8 ring-forming carbon atoms, which may or may not be saturated, attached to the rest of the molecule by single bonds. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexonyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2, 3-dihydroindenyl, 1, 2, 3, 4-tetrahydronaphthyl, 5, 6, 7, 8-tetrahydronaphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6, 7, 8, 9-tetrahydro-5H-benzocycloheptenyl, 5, 6, 7, 8, 9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 7-dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [2.2.2] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2 ] octenyl, bicyclo [3.2.1] octenyl, adamantyl, cyclooctenyl, Octahydro-4, 7-methylidene-1H-indenyl, octahydro-2, 5-methylidene-pentalenyl, bornyl, decahydronaphthyl, and the like. The heterocyclic group of the present invention includes preferably 3 to 8 carbon atoms, more preferably cyclopentyl, cyclohexyl, cyclohexanone group or cycloheptyl group.
The terms "heterocyclyl", "heterocycloalkyl", "heterocycle", as used herein alone or as part of another ingredient, refer to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specified, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused, spiro or bridged ring systems, the nitrogen, carbon or sulfur of the heterocyclyl group may optionally be oxidized, the nitrogen atom may optionally be quaternized, and the heterocyclyl group may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule through a single bond via a carbon or heteroatom in the ring. The heterocyclic group containing fused rings may contain one or more aromatic or heteroaromatic rings, provided that the atoms on the non-aromatic ring are attached to the rest of the molecule. For purposes of this application, a heterocyclyl group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, oxazolidinyl, 1-oxo-thiomorpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, phthalimidyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, thiazolidinyl, thieno [1, 3] dithianyl, thiomorpholinyl, trithianyl, and the like.
The terms "aromatic ring", "aromatic ring group", "aromatic group", "aryl" or the prefix "aryl" (as in "aralkyl") as used herein alone or as part of another ingredient refer to a hydrocarbon ring system containing hydrogen, 6 to 18 ring-forming carbon atoms, preferably 6 to 10 ring-forming carbon atoms, and at least one aromatic ring. For purposes of this invention, an aromatic ring group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused or bridged ring systems. The aryl carbon atom may be attached to the rest of the molecule by a single bond. Non-limiting examples of aryl groups include phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2-benzoxazolonyl, 2H-1, 4-benzoxazol-3 (4H) -on-7-yl, and the like. In the present invention, the aryl group is preferably C6-C10More preferably phenyl.
The term "heteroaryl" as used herein alone or as part of another ingredient refers to a 5-16 membered cyclic system comprising 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, at least one aromatic ring. Unless otherwise specified, heteroaryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic systems, which may contain fused or bridged ring systems, provided that the point of attachment to the rest of the molecule is an aromatic ring atom. The nitrogen, carbon and sulfur atoms of the heteroaromatic ring may optionally be oxidized and the nitrogen atoms may optionally be quaternized. For the purposes of the present invention, heteroaryl groups are preferably stable 4-11 membered monocyclic aromatic rings containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-8 membered monocyclic aromatic rings containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azapinyl, benzimidazolyl, benzindolyl, 1, 4-benzodioxanyl, benzo [6] [1, 4] dioxepinyl, benzodioxinyl, benzodioxolyl, benzofuranonyl, benzofuranyl, benzo [4, 6] imidazo [1, 2-a ] pyridinyl, benzonaphthofuranyl, benzopyranonyl, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, carbazolyl, carbolinyl, o-diazonaphthyl, dibenzofuranyl, dibenzothienyl, furanonyl, furanyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, isoindolyl, isoquinolyl, isothiazolyl, dihydroindolyl, etc, Isoxazolyl, naphthyridinyl, oxadiazolyl, oxatriazolyl, oxazolyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-oxopyridyl, 1-oxopyrimidinyl, oxiranyl, 2-oxazepinyl, oxopyridyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, 1-phenyl-1H-pyrrolyl, naphthyridinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, 1H-pyridin-2-yl, 1H-pyridin-4-yl, 1H-pyridin-2-one-4-yl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, quinuclidinyl, tetrahydroquinolyl, 4, 5, 6, 7-tetrahydrobenzo [ b ] thiophenyl, Tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl and the like. In the present application, heteroaryl is preferably 5-8 membered heteroaryl comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridyl, pyrimidinyl, thiazolyl, oxopyridyl, 1H-pyridin-2-one-4-yl or thienyl.
The term "polymorph" or "polymorph" as used herein means that the compounds of the present invention have multiple lattice morphologies. Some of the compounds of the present invention may have more than one crystal form, and the present invention encompasses all polymorphic forms or mixtures thereof.
Intermediate compounds of the present invention and polymorphs thereof are also within the scope of the present invention.
Unless otherwise specified, the compounds of the present invention contain olefinic double bonds including E and Z isomers.
It is understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in the R or S configuration. It will be apparent to those skilled in the art that some of the compounds of the present invention may also exhibit cis-trans isomerism. It is to be understood that the compounds of the present invention include their individual geometric and stereoisomers as well as mixtures thereof, including racemic mixtures. These isomers may be separated from their mixtures by carrying out or modifying known methods such as chromatographic techniques and recrystallization techniques, or they may be prepared separately from the appropriate isomers of their intermediates.
The term "pharmaceutically acceptable salts" as used herein includes both acid and base salts.
"pharmaceutically acceptable acid addition salts" refers to those which retain the biological potency and properties of the free base of the compound, are not biologically or otherwise undesirable, and are associated with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethylsulfonic acid, 2-hydroxyoxalic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, heptonic acid, gluconic acid, glucuronic acid, and the like, Glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid and the like. "pharmaceutically acceptable salt to be added to base" refers to those salts that retain the biological potency and properties of the free acid of the compound and are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic or organic base. Salts formed by reaction with an inorganic base include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.
Salt-forming organic bases include, but are not limited to, primary, secondary, tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylaminoethanol, 2-dimethylethanolamine, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benzphetamine, benzathine, ethylenediamine, glucosamine, meglumine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine
Crystallization often produces solvates of the compounds of the present invention. The term "solvate" as used herein refers to a combination of one or more molecules of the compound of the present invention and one or more molecules of a solvent.
The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent may be used. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may also retain water only by chance or a mixture of water and some other solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
Prodrugs of the compounds of the invention are also contemplated by the present invention. "prodrug" means a compound that can be converted, either physiologically or by solvation, into a biologically active compound of the invention. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention, which prodrug may be inactive when administered to a desired subject, but which converts to an active compound of the invention in vivo. Prodrugs are generally rapidly converted to the parent compounds of the present invention in vivo, for example, by hydrolysis in blood. Prodrugs often have advantages in terms of solubility, tissue compatibility, or delayed release in mammalian organisms. Prodrugs include amino protecting groups and carboxy protecting groups, all of which are well known to those skilled in the art. Reference may be made to methods for preparing specific prodrugs, for example, Saulnier, m.g., et al, bioorg.med.chem.lett.1994, 4, 1985-; greenwald, r.b., et al, j.med.chem.2000, 43, 475.
The term "pharmaceutical composition" as used herein refers to a formulation mixed with a compound of the present invention and a vehicle generally accepted in the art for delivering biologically active compounds to a mammal, such as a human. Such media comprise all pharmaceutically acceptable carriers.
As used herein, the term "acceptable" in reference to a formulation, composition or ingredient means that there is no lasting deleterious effect on the overall health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.
"pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant governmental authorities for use in humans and domestic animals.
The terms "subject," "patient," or "individual" as used herein refer to an individual having a disease, disorder, or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment related to the methods and compositions provided herein, the mammal is a human.
The term "treatment" as used herein refers to the treatment of a disease or condition associated with a mammal, particularly a human, and includes
(i) Preventing the development of a disease or condition in a mammal, particularly a mammal that has previously been exposed to the disease or condition but has not been diagnosed as having the disease or condition;
(ii) inhibiting the disease or disorder, i.e., controlling its development;
(iii) alleviating the disease or condition, i.e., causing regression of the disease or condition;
(iv) relieving symptoms caused by the disease or disorder.
The terms "disease" and "condition" as used herein may be used interchangeably and may have different meanings, as certain specific diseases or conditions have no known causative agent (and therefore the cause of the disease is not yet clear) and therefore are not considered as a disease but can be considered as an unwanted condition or syndrome, with more or less specific symptoms being confirmed by clinical researchers.
The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.
The terms "administering," "administration," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
In general, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be administered by forming an appropriate pharmaceutical composition with one or more pharmaceutically acceptable carriers. The pharmaceutical composition of the present invention may be formed into preparations in solid, semi-solid, liquid or gaseous form, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
The pharmaceutical composition of the present invention can be prepared by using a method well known in pharmacology. For example, pharmaceutical compositions for administration by injection may be prepared by combining a compound of the present invention with sterile, distilled water to form a solution. Surfactants may be added to help form a homogeneous solution or suspension. The actual methods of preparing these dosage forms are known or will be apparent to those skilled in the art.
Typical routes of administration of these pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal and intranasal. For example, suitable dosage forms for oral administration include capsules, tablets, granules and syrups. The compounds of the present invention included in these dosage forms may be solid powders or granules; a solution or suspension in an aqueous or non-aqueous solvent; oil drop in water, emulsion of water drop in oil, etc. The above-mentioned dosage forms can be prepared from the active compound and one or more carriers or adjuvants by customary pharmaceutical methods. The carrier should be compatible with the active compound or other adjuvants. For solid formulations, non-toxic carriers that are commonly used include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Liquid formulation carriers include, but are not limited to, water, physiological saline, dextrose, ethylene glycol, aqueous polyethylene glycol solutions, and the like. The active compound may be in solution or in suspension with the above carrier. The particular route of administration and dosage form will depend on the physical/chemical characteristics of the compound itself and the severity of the condition being treated and may be determined routinely by those skilled in the art.
Preparation of the Compounds of the invention
The following reaction scheme illustrates a process for preparing the compounds of the present invention.
It will be appreciated that in the following description, combinations of substituents and/or variables of the formula are permitted only in the context of forming stable compounds.
It will also be appreciated by those skilled in the art that in the schemes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. These functional groups include hydroxyl, amino, mercapto and carboxyl groups. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butylmethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable amino, amidino and guanidine protecting groups include t-butyloxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for the mercapto group include-C (O) -R "(R" represents alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable carboxyl protecting groups include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed by standard techniques known to those skilled in the art.
Detailed Description
The compounds of the present invention, methods for their preparation and uses are exemplified below with reference to the examples.
Synthesis method
Scheme 1
Scheme 2
The compounds of the present invention can be prepared according to the routes described in scheme 1 or scheme 2. Each of the products of the reactions of scheme 1 or scheme 2 may be obtained by conventional separation techniques including, but not limited to, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials may be synthesized by themselves or purchased from commercial establishments (such as, but not limited to, Adrich or Sigma). These materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described herein may be synthesized as a single isomer or as a mixture of isomers.
In scheme 1, starting material 1 and starting material 2 are reacted using methanesulfonyl chloride, a base to provide intermediate 3. Hydrolysis of intermediate 3 affords intermediate 4. And carrying out condensation reaction on the intermediate 4 and the raw material 5 to obtain a target compound 6.
In scheme 2, starting material 7 is reacted with starting material 2 using a reducing agent (e.g., sodium triacetoxyborohydride) to provide intermediate 3. Hydrolysis of intermediate 3 affords intermediate 4. And carrying out condensation reaction on the intermediate 4 and the raw material 5 to obtain a target compound 6.
Examples
The following non-limiting examples are illustrative only and do not limit the invention in any way.
Unless otherwise indicated, temperatures are in degrees celsius. Reagents were purchased from commercial suppliers such as national drug group chemical reagents beijing ltd, Alfa Aesar (Alfa Aesar), or beijing carbofuran technologies ltd, and these reagents were used directly without further purification unless otherwise specified.
Unless otherwise stated, the following reactions are carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or argon, or using a drying tube; the reaction bottle is provided with a rubber diaphragm so as to add the substrate and the reagent through an injector; glassware was dried and/or heat dried.
Unless otherwise stated, column chromatography purification was performed using 200-300 mesh silica gel from Qingdao oceanic plants; preparation of thin-layer chromatography silica gel precast slab (HSGF254) produced by Nicoti chemical industry research institute was used; MS is measured by a ThermoLCQ fly model (ESI) liquid chromatography-mass spectrometer; the optical rotation was measured by using an SGW-3 automatic polarimeter, Shanghai Spanish Meter, Ltd.
Nuclear magnetic data (1H NMR) was run at 400MHz using a Varian instrument. The solvent used for nuclear magnetic data is CDCl3、CD3OD、D2O, DMSO-d6, etc., based on tetramethylsilane (0.00ppm) or as a residueSolvent-based (CDCl)3：7.26ppm；CD3OD：3.31ppm；D2O: 4.79 ppm; d 6-DMSO: 2.50 ppm). When indicating the diversity of the peak shapes, the following abbreviations represent the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). If the coupling constant is given, it is given in Hertz (Hz).
Abbreviations:
example one
2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide
Step A: 5-bromo-1- (triisopropylsilyl) -1H-pyrrolo [2, 3-b ] pyridine
5-bromo-1H-pyrrolo [2, 3-b ] pyridine (3.94g, 0.02mol) was dissolved in anhydrous tetrahydrofuran (60mL), cooled to 0 ℃, a tetrahydrofuran solution of LiHMDS (2.2mL, 0.022mol) was added, and after 10 minutes, triisopropylchlorosilane (4.24g, 0.022mol) was added, and the mixture was gradually warmed to room temperature and stirred for 40 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to obtain a product (7.0g, 99%).
1H NMR(400MHz，CDCl3)δ8.27(d，J＝2.4Hz，1H)，7.98(d，J＝2.4Hz，1H)，7.31(d，J＝3.6Hz，1H)，6.49(d，J＝3.6Hz，1H)，1.78～1.89(m，3H)，1.12(d，J＝7.6Hz，18H)。
And B: (1- (Triisopropylsilyl) -1H-pyrrolo [2, 3-b ] pyridin-5-yl) boronic acid dimethyl ester
5-bromo-1- (triisopropylsilyl) -1H-pyrrolo [2, 3-b ] pyridine (5.37g, 0.015mol) was dissolved in anhydrous tetrahydrofuran (100mL) under nitrogen, cooled to-78 deg.C, and a solution of n-butyllithium in n-hexane (7.5mL, 0.018mol) was added, after 5 minutes, trimethyl borate (2.33g, 0.0225mol) was added, slowly warmed to room temperature, and stirred for 1 hour. The reaction was quenched by addition of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed and directly fed to the next step.
And C: 1- (triisopropylsilyl) -1H-pyrrolo [2, 3-b ] pyridin-5-ol
The dimethyl (1- (triisopropylsilyl) -1H-pyrrolo [2, 3-b ] pyridin-5-yl) borate obtained in the previous step was dissolved in tetrahydrofuran (50mL) at room temperature, cooled to 0 ℃, added with an aqueous sodium hydroxide solution (15mL, 0.015mol) and an aqueous 30% hydrogen peroxide solution (3mL), and kept at 0 ℃ for further stirring for 1 hour. Excess sodium sulfite was added and stirred until no color development was observed on a starch potassium iodide paper, the pH was adjusted to 4 with 1N hydrochloric acid, ethyl acetate was extracted, the ethyl acetate phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was chromatographed on a silica gel column, eluting with dichloromethane, to give an oily product (3.1g, 71%).
1H NMR(400MHz，CDCl3)δ7.96(d，J＝2.8Hz，1H)，7.33(d，J＝2.8Hz，1H)，7.29(d，J＝3.2Hz，1H)，6.44(d，J＝3.6Hz，1H)，4.53(br，1H)，1.79～1.87(m，3H)，1.12(d，J＝7.6Hz，18H)。
Step D: 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4-bromobenzoic acid methyl ester
1- (Triisopropylsilyl) -1H-pyrrolo [2, 3-b ] pyridin-5-ol (1.00g, 0.0035mol), methyl 4-bromo-2-fluorobenzoate (0.885g, 0.0038mol), and potassium carbonate (0.967g, 0.007mol) were added to N, N-dimethylformamide (10mL) at room temperature, heated to 80 ℃ and stirred for 1 hour. Cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate/dichloromethane (5/1), to give the product (0.48g, 40%).
1H NMR(400MHz，CDCl3)δ9.34(br，1H)，8.11(d，J＝2.8Hz，1H)，7.72(d，J＝8.4Hz，1H)，7.56(d，J＝2.4Hz，1H)，7.32～7.34(t，J＝2.8Hz，1H)，7.17～7.20(m，1H)，6.89(d，J＝2.0Hz，1H)，6.42～6.44(m，1H)，3.82(s，3H)。
Step E: 4- (3- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (methoxycarbonyl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
4- (4, 4, 5) at room temperature5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (493mg, 1.6mmol), 2- ((1H-pyrrolo [2, 3-b)]Pyridin-5-yl) oxy) -4-bromobenzoic acid methyl ester (460mg, 1.3mmol), potassium phosphate (552mg, 2.6mmol) and Pd (dppf) Cl2(106mg, 0.13mmol) was added to a mixture (6mL) of ethylene glycol dimethyl ether/water (5/1), heated to 80 ℃ under nitrogen, and stirred overnight. Cooling to room temperature, addition of water, extraction with ethyl acetate, combination of the ethyl acetate phases, washing with saturated brine, drying over anhydrous sodium sulfate, concentration, chromatography of the residue on a silica gel column and elution with dichloromethane/ethyl acetate (4/1) gave the product as a white solid (440mg, 75%).
1H NMR(400MHz，CDCl3)δ9.42(br，1H)，8.17(d，J＝2.4Hz，1H)，7.90(d，J＝8.4Hz，1H)，7.56(d，J＝2.4Hz，1H)，7.36(t，J＝3.2Hz，1H)，7.13～7.16(m，1H)，6.86(d，J＝1.6Hz，1H)，6.45～6.46(m，1H)，5.99～6.03(m，1H)，4.00(br，2H)，3.86(s，3H)，3.55(t，J＝1.6Hz，2H)，2.38(br，2H)，1.45(s，9H)。
Step F: methyl 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1, 2, 3, 6-tetrahydropyridin-4-yl) benzoate
Tert-butyl 4- (3- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (methoxycarbonyl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (220mg, 0.49mmol) was dissolved in dichloromethane (2mL), cooled to 0 ℃ and trifluoroacetic acid (1mL) was added. After the addition was completed, stirring was continued for 3 hours while maintaining at 0 ℃ and a saturated aqueous sodium carbonate solution was added, followed by extraction with methylene chloride, organic phase combination, washing with saturated brine, drying over anhydrous sodium sulfate and removal of the solvent to obtain the objective product (170mg, 100%).
1H NMR(400MHz，CDCl3)δ10.56(br，1H)，8.06(d，J＝2.4Hz，1H)，7.89(d，J＝8Hz，1H)，7.64(d，J＝3.6Hz，1H)，7.42(br，1H)，7.10(br，1H)，6.75(s，1H)，6.47(d，J＝2.8Hz，1H)，5.96(br，1H)，3.92(br，3H)，3.78(br，2H)，3.35(t，J＝5.2Hz，2H)，2.63(br，2H)。
Step G: 4, 4-dimethyl-2-oxocyclohexane-1-carboxylic acid methyl ester
Sodium hydrogen (16g, 0.4mol) was suspended in fresh dry tetrahydrofuran (500mL) and dimethyl carbonate (85mL, 1mol) was added. The reaction mixture was heated to reflux, and a solution of 3, 3-dimethylcyclohexan-1-one (25g, 0.2mol) in tetrahydrofuran (200mL) was added dropwise. After the addition, the reaction was continued under reflux for 2 hours. Cooled to 0 ℃, poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent removed, the residue chromatographed on a silica gel column eluting with petroleum ether/ethyl acetate (40/1) to give the product (34g, 93%).
1H NMR(400MHz，CDCl3)δ12.12(s，1H)，3.76(s，3H)，2.23～2.27(m，2H)，2.06(s，2H)，1.37～1.40(m，2H)，0.96(s，6H)。
Step H: 4, 4-dimethyl-2- (((trifluoromethyl) sulfonyl) oxy) cyclohex-1-ene-1-carboxylic acid methyl ester
Sodium hydrogen (11.8g, 0.3mol) was suspended in dichloromethane (1L), cooled to 0 deg.C and methyl 4, 4-dimethyl-2-oxocyclohexane-1-carboxylate (27g, 0.15mol) was added. The reaction was allowed to continue at 0 ℃ for 30 minutes, then cooled to-78 ℃ and trifluoromethanesulfonic anhydride (27mL, 0.16mol) was added. After the addition, the reaction was warmed to room temperature for 40 hours. Then poured into water, extracted with dichloromethane, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to obtain a product (46g, 99%).
1H NMR(400MHz，CDCl3)δ3.80(s，3H)，2.48～2.52(m，2H)，2.17(s，2H)，1.42～1.45(m，2H)，1.00(s，6H)。
Step I: 4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-carboxylic acid methyl ester
Under nitrogen protection, methyl 4, 4-dimethyl-2- (((trifluoromethyl) sulfonyl) oxy) cyclohex-1-ene-1-carboxylate (43g, 0.14mol), p-chlorobenzoic acid (23.4g, 0.15mol), potassium phosphate (57.7g, 0.27mol), Pd (dppf) Cl2(10g, 0.014mol) was reacted in a mixed solvent (700mL) of ethylene glycol dimethyl ether/methanol/water (5/1/1) at 70 ℃ for 20 hours. After cooling to room temperature, it was poured into water, extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed, and purified by column chromatography, eluting with petroleum ether/dichloromethane (3/1), to give the product (29g, 77%).
1H NMR(400MHz，CDCl3)δ7.27(d，J＝8.0Hz，2H)，7.03(d，J＝8.0Hz，2H)，3.46(s，3H)，2.43～2.48(m，2H)，2.12～2.13(m，2H)，1.47～1.50(m，2H)，0.99(s，6H)。
Step J: (4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -diphenyl ] -2-yl) methanol
Methyl 4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -diphenyl ] -2-carboxylate (650mg, 2.3mmol) was dissolved in tetrahydrofuran (20mL), a solution of lithium borohydride (3.5mL, 14mmol) was added, and then methanol (2.4mL) was slowly added dropwise. After the addition, the reaction was stirred at room temperature overnight. The reaction was quenched with 1N hydrochloric acid and then extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed, and purified by column chromatography, eluting with dichloromethane, to give a product (330mg, 57%).
1H NMR(400MHz，CDCl3)δ7.17～7.20(m，2H)，6.95～6.98(m，2H)，3.84(s，2H)，2.18～2.22(m，2H)，1.94(s，2H)，1.37～1.40(m，2H)，0.88(s，6H)。
Step K: methyl 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) benzoate
(4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methanol (120mg, 0.48mmol) was dissolved in dichloromethane (3mL) at room temperature, cooled to 0 deg.C, triethylamine (98mg, 0.96mmol), methanesulfonyl chloride (60mg, 0.58mmol) were added, and stirring was continued at 0 deg.C for 30 minutes. The reaction system was added to a solution of methyl 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1, 2, 3, 6-tetrahydropyridin-4-yl) benzoate (168mg, 0.48mmol) in dichloromethane (2mL) and stirred at room temperature overnight. Water was added, extraction was performed with dichloromethane, and organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was separated on a preparative thin-layer plate using methylene chloride/methanol (20/1) as a developing solvent to give the desired product (30mg, 11%).
1H NMR(400MHz，CDCl3)δ10.69(br，1H)，8.15(d，J＝2.0Hz，1H)，7.88(d，J＝8.4Hz，1H)，7.57(d，J＝2.4Hz，1H)，7.39(t，J＝2.4Hz 1H)，7.22(d，J＝8.0Hz，2H)，7.02(d，J＝8.0Hz，1H)，6.93(d，J＝8.4Hz，2H)，6.78(s，1H)，6.45(br，1H)，5.86(br，1H)，3.85(s，3H)，3.22(br，4H)，2.73(br，2H)，2.44(s，2H)，2.36(s，2H)，2.01(s，2H)，1.45(t，J＝5.6Hz，2H)，0.94(s，6H)。
Step L: 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) benzoic acid
Methyl 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) benzoate (30mg, 0.05mmol) was dissolved in 1, 4-dioxane (6mL), an aqueous sodium hydroxide solution (1.5mL, 1.5mmol) was added, and the mixture was heated to 50 ℃ and stirred for 2 hours. Saturated aqueous solution of sodium dihydrogenphosphate was added to adjust the pH to 6, extraction was performed with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to obtain the objective product (30mg, 100%).
1H NMR(400MHz，CDCl3)δ10.96(br，2H)，8.02(br，1H)，7.77(t，J＝8.8Hz，1H)，7.45(s，1H)，7.16～7.22(m，3H)，6.88～6.94(m，3H)，6.75(d，J＝14Hz，1H)，6.24(s，1H)，5.77(d，J＝19.2Hz，1H)，3.18(br，2H)，3.09(br，2H)，2.59～2.63(m，2H)，2.30(br，4H)，1.96(s，2H)，1.35～1.43(m，2H)，0.90(s，6H)。
Step M: 3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) benzenesulfonamide
4-chloro-3-nitrobenzenesulfonamide (2.36g, 10mmol) and (tetrahydro-2H-pyran-4-yl) methylamine (1.61g, 14mmol) were dissolved in acetonitrile (30mL) and diisopropylethylamine (5.3mL, 30mmol) was added. Heating and refluxing overnight, cooling, pouring into water, stirring thoroughly, and filtering. The solid was washed with ethyl acetate and dried to give the product (3.0g, 95%).
1H NMR(400MHz，d6-DMSO)δ8.56(t，J＝6.0Hz，1H)，8.44(d，J＝1.6Hz，1H)，7.78～7.81(m，1H)，7.27～7.31(m，3H)，3.81～3.85(m，2H)，3.31～3.35(m，2H)，3.21～3.27(m，2H)，1.87～1.92(m，1H)，1.57～1.61(m，2H)，1.23～1.29(m，2H)。
And step N: 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide
2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) benzoic acid (30mg, 0.05mmol) and triethylamine (10mg, 0.1mmol) were mixed, and a solution of 3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) benzenesulfonamide (17mg, 0.05mmol), EDCI (13mg, 0.07mmol), DMAP (12mg, 0.1mmol) in dichloromethane was added and stirred at room temperature overnight. Dilute with dichloromethane, wash with water and saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate the residue on preparative thin layer plates using dichloromethane/methanol as developing solvent (15/1) to give the desired product (20mg, 44%).
1H NMR(400MHz，CD3OD)δ9.50(br，1H)，8.93(d，J＝2.0Hz，1H)，8.55(t，J＝7.2Hz，1H)，8.17～8.21(m，2H)，8.05(d，J＝8.4Hz，1H)，7.71(d，J＝2.0Hz，2H)，7.49(t，J＝2.8Hz，1H)，7.24(d，J＝8.4Hz，2H)，7.10(d，J＝8.4Hz，1H)，6.93～6.96(m，2H)，6.67(s，1H)，6.56～6.57(m，1H)，5.90(br，1H)，4.03～4.07(m，2H)，3.41～3.47(m，2H)，3.27～3.30(m，2H)，2.97(br，4H)，2.19～2.58(m，7H)，2.01(s，3H)，1.74～1.78(m，2H)，1.43～1.48(m，4H)，0.96(s，6H)。
Example two
2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl-N- ((4- ((2-methoxyethyl) amino) -3-nitrophenyl) sulfonyl) benzamide
Step A: 4- ((2-methoxyethyl) amino) -3-nitrobenzenesulfonamide
4-chloro-3-nitrobenzenesulfonamide (570mg, 2.4mmol), 2-methoxyethylamine (250mg, 3.3mmol) and triethylamine (900mg, 7.2mmol) were dissolved in acetonitrile (5mL) at room temperature, heated to 80 ℃ and stirred overnight. The solvent was removed, water was added to precipitate a solid, which was washed with water and ethanol to give the product as a yellow solid (450mg, 68%).
1H NMR(400MHz，CDCl3)δ8.76(d，J＝2.0Hz，1H)，8.57(br，1H)，7.89～7.92(m，1H)，6.98(d，J＝7.2Hz，1H)，4.82(br，2H)，3.69～3.72(m，2H)，3.54～3.58(m，2H)，3.44(s，3H)。
And B: 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl-N- ((4- ((2-methoxyethyl) amino) -3-nitrophenyl) sulfonyl) benzamide
2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) benzoic acid (30mg, 0.05mmol) and triethylamine (10mg, 0.1mmol) were mixed and a solution of 4- ((2-methoxyethyl) amino) -3-nitrobenzenesulfonamide (15mg, 0.05mmol), EDCI (13mg, 0.07mmol), DMAP (12mg, 0.1mmol) in dichloromethane (2mL) was added, stirred at room temperature overnight, diluted with dichloromethane, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was separated on preparative thin layer plates in dichloromethane/methanol (15/1) to give the desired product (20mg, 46%).
1H NMR(400MHz，CD3OD)δ9.84～9.90(m，1H)，8.87(d，J＝2.4Hz，1H)，8.δ0(t，J＝5.2Hz，1H)，8.12～8.15(m，1H)，8.08(s，1H)，7.99(d，J＝8.4Hz，1H)，7.66(d，J＝2.0Hz，1H)，7.46(t，J＝2.8Hz，1H)，7.21～7.24(m，2H)，7.01～7.05(t，J＝8.4Hz，1H)，6.91～6.97(m，3H)，6.62～6.64(d，J＝5.2Hz，1H)，6.52(t，J＝1.6Hz，1H)，5.82～5.85(m，1H)，3.69(t，J＝5.6Hz，2H)，3.52～3.56(m，2H)，3.44(s，3H)，3.01～3.29(m，4H)，2.56～2.88(m，3H)，2.25～2.42(m，4H)，2.02～2.09(m，2H)，1.42～1.47(m，2H)，0.95(d，J＝3.2Hz，6H)。
EXAMPLE III
2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -piperidin-4-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) sulfonyl) benzamide
Step A: 4- (3- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (methoxycarbonyl) phenyl) piperidine-1-carboxylic acid tert-butyl ester
Tert-butyl 4- (3- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (methoxycarbonyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (290mg, 0.64mmol) was dissolved in methanol (5mL) at room temperature, 10% palladium on charcoal (100mg) was added and stirred under 1atm hydrogen for 1 hour, then 6 drops of acetic acid were added and stirring continued under 1atm hydrogen overnight. Celite was filtered and the filtrate was concentrated to give the product as a white solid (288mg, 99%).
1H NMR(400MHz，CDCl3)δ10.09(br，1H)，8.10(d，J＝2.4Hz，1H)，7.89(d，J＝8.0Hz，1H)，7.61(d，J＝2.4Hz，1H)，7.39(s，1H)，7.00～7.02(m，1H)，6.71(s，1H)，6.48(d，J＝3.2Hz，1H)，4.20(br，2H)，3.88(s，3H)，2.69-2.75(m，2H)，2.54～2.60(m，1H)，1.73～1.77(m，2H)，1.50～1.54(m，2H)，1.44(s，9H)。
And B: 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (piperidin-4-yl) benzoic acid methyl ester
Tert-butyl 4- (3- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (methoxycarbonyl) phenyl) piperidine-1-carboxylate (288mg, 0.64mmol) was dissolved in dichloromethane (2mL), cooled to 0 deg.C, trifluoroacetic acid (1mL) was added and stirring was continued at 0 deg.C for 3H. Saturated aqueous sodium carbonate was added to pH 8, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to give the desired product (223mg, 99%).
1H NMR(400MHz，CDCl3)δ9.89(br，1H)，8.17(d，J＝2.4Hz，1H)，7.86(d，J＝8.0Hz，1H)，7.57(d，J＝2.4Hz，1H)，7.37(d，J＝3.2Hz，1H)，6.99(d，J＝8.0Hz，1H)，6.71(s，1H)，6.46(d，J＝3.2Hz，1H)，3.86(s，3H)，3.11～3.15(m，2H)，2.63～2.69(m，2H)，2.49～2.57(m，1H)，2.06(br，1H)，1.72～1.75(m，2H)，1.51～1.58(m，2H)。
And C: methyl 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -piperidin-4-yl) benzoate
(4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methanol (174mg, 0.69mmol) was dissolved in dichloromethane (3mL), cooled to 0 deg.C, triethylamine (140mg, 1.38mmol) and methanesulfonamide (91mg, 0.79mmol) were added, respectively, warmed to room temperature and stirred for 30 minutes, and the reaction was added dropwise to a solution of methyl 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (piperidin-4-yl) benzoate (242mg, 0.69mmol) in dichloromethane (2 mL). After the addition was complete, the mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was separated on a preparative thin-layer plate using methylene chloride/methanol (20/1) as a developing solvent to give the desired product (120mg, 30%).
1H NMR(400MHz，CDCl3)δ9.23(br，1H)，8.13(d，J＝1.2Hz，1H)，7.86(d，J＝8.0Hz，1H)，7.55(d，J＝0.2Hz，1H)，7.30～7.36(m，3H)，7.12(br，1H)，6.93(d，J＝8.0Hz，2H)，6.64(s，1H)，6.46(d，J＝0.5Hz，1H)，3.85(s，3H)，3.43(br，4H)，2.44～2.67(m，5H)，2.04(br，2H)，1.63～1.79(m，4H)，1.42(br，2H)，0.96(s，6H)。
Step D: 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) piperidin-4-yl) benzoic acid
Methyl-2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -piperidin-4-yl) benzoate (120mg, 0.20mmol) was dissolved in 1, 4-dioxane (12mL) at room temperature, a 1N aqueous solution of sodium hydroxide (3.0mL, 3.0mmol) was added, heating was carried out to 50 ℃ and stirring was carried out for 2 hours, after cooling to room temperature, a saturated aqueous solution of sodium dihydrogenphosphate was added to adjust the pH to 6, ethyl acetate was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed to obtain the objective product (110mg, 95%).
1H NMR(400MHz，d6-DMSO)δ12.7(br，1H)，11.68(s，1H)，8.00(d，J＝2.4Hz，1H)，7.73(d，J＝8.0Hz，1H)，7.49～7.51(m，2H)，7.34(d，J＝8.4Hz，2H)，7.03～7.05(m，3H)，6.70(d，J＝0.8Hz，1H)，6.39～6.40(m，1H)，3.21～3.28(m，2H)，2.73(br，4H)，2.38～2.32(m，1H)，2.12～2.15(m，2H)，1.95(br，2H)，1.58～1.62(m，2H)，1.43～1.49(br，2H)，1.38(t，J＝7.2Hz，2H)，0.92(s，6H)。
Step E: 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -piperidin-4-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) sulfonyl) benzamide
2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) piperidin-4-yl) benzoic acid (40mg, 0.070mmol) and 3-nitro-4- ((tetrahydro-2H-pyran-4-yl) methylamine) phenylmethanesulfonamide (27mg, 0.086mmol) were dissolved in dichloromethane (3mL), triethylamine (16mg, 0.16mmol), EDCI (20mg, 0.10mmol) and DMAP (20mg, 0.16mmol) were added and stirred at room temperature overnight. Washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was separated on a preparative thin layer plate using methylene chloride/methanol as a developing solvent (15/1) to obtain the objective product (26mg, 43%).
1H NMR(400MHz，d6-DMSO)δ12.19(br，1H)，11.73(br，1H)，8.74(br，1H)，8.55～8.61(m，2H)，8.01(s，1H)，7.82(d，J＝6.4Hz，1H)，7.62(br，1H)，7.53(s，1H)，7.47(d，J＝8.0Hz，1H)，7.39(d，J＝8.2Hz，2H)，7.07(d，J＝8.2Hz，2H)，6.93(d，J＝8.4Hz，1H)，6.51(s，1H)，6.41(s，1H)，3.81～3.84(m，2H)，3.47(br，2H)，3.21～3.28(m，6H)，2.52～2.67(m，5H)，2.16(br，2H)，1.99(br，2H)，1.84(m，1H)，1.74(br，2H)，1.57(d，J＝10.8Hz，2H)，1.42～1.44(m，2H)，1.22～1.25(m，2H)，0.92(s，6H)。
Example four
2- ((6-aminopyridin-3-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide
Step A: 2- ((6-Aminopyridin-3-yl) oxy) -4-bromobenzoic acid methyl ester
Methyl 4-bromo-2-fluorobenzoate (3.1g, 13.3mmol) and 6-aminopyridin-3-ol (1.76g, 16mmol) were dissolved in N, N-dimethylformamide (30mL), and potassium carbonate (3.67g, 26.6mmol) was added and reacted at 80 ℃ for 4 hours under nitrogen. After cooling to room temperature, the reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by column chromatography (dichloromethane/methanol-20/1) to give the product (0.9g, 21%).
1H NMR(400MHz，CDCl3)δ7.90(d，J＝2.8Hz，1H)，7.75(d，J＝8.4Hz，1H)，7.22～7.25(m，1H)，7.18～7.21(m，1H)，6.95(d，J＝1.6Hz，1H)，6.54(d，J＝9.2Hz，1H)，4.42(brs，2H)，3.88(s，3H)。
And B: 4- (3- ((6-Aminopyridin-3-yl) oxy) -4- (methoxycarbonyl) phenyl-3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
Under nitrogen protection, methyl 2- ((6-aminopyridin-3-yl) oxy) -4-bromobenzoate (850mg, 2.63mmol), tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (813mg, 2.63mmol), potassium phosphate (1.12g, 5.26mmol) and Pd (dppf) Cl2(190mg, 0.26mmol) was reacted in a mixed solvent of ethylene glycol dimethyl ether (30mL) and water (6mL) at 80 ℃ for 12 hours. Then poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane/methanol-20/1) to give the product (1.1g, 98%).
1H NMR(400MHz，CDCl3)δ7.87～7.91(m，2H)，7.19～7.22(m，1H)，7.12～7.15(m，1H)，6.85(d，J＝1.2Hz，1H)，6.53～6.55(m，1H)，6.04(brs，1H)，4.38(s，2H)，4.06(d，J＝2.8Hz，2H)，3.89(s，3H)，3.60(t，J＝5.6Hz，2H)，2.42(brs，2H)，1.49(s，9H)。
And C: 2- ((6-Aminopyridin-3-yl) oxy) -4- (1, 2, 3, 6-tetrahydropyridin-4-yl) benzoic acid methyl ester
Tert-butyl 4- (3- ((6-aminopyridin-3-yl) oxy) -4- (methoxycarbonyl) phenyl-3, 6-dihydropyridine-1 (2H) -carboxylate (1.2g, 2.82mmol) was dissolved in dichloromethane (5mL), cooled to 0 deg.C, 3mL trifluoroacetic acid was added and stirring was continued at 0 deg.C for 3 hours.
Step D: methyl 2- ((6-aminopyridin-3-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) benzoate
(4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methanol (231mg, 0.92mmol) was dissolved in dichloromethane (5mL) at room temperature, diisopropylethylamine (232mg, 1.8mmol) was added, cooled to 0 deg.C, and methanesulfonyl chloride (125mg, 1.1mmol) was added. The reaction was allowed to return to room temperature for 10 minutes, and methyl 2- ((6-aminopyridin-3-yl) oxy) -4- (1, 2, 3, 6-tetrahydropyridin-4-yl) benzoate (300mg, 0.92mmol) was added, stirred at room temperature overnight, then poured into water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product which was purified by thin layer chromatography (dichloromethane/methanol-40/1) to give the product (150mg, 29%).
1H NMR(400MHz，CDCl3)δ7.87(d，J＝2.8Hz，1H)，7.84(d，J＝8.0Hz，1H)，7.25～7.29(m，1H)，7.17～7.20(m，1H)，7.05～7.07(m，1H)，7.02(d，J＝8.0Hz，1H)，6.96～6.98(m，2H)，6.78(s，1H)，6.54(d，J＝8.8Hz，1H)，5.92(s，1H)，4.56(brs，2H)，3.86(s，3H)，3.20(brs，4H)，2.74(brs，2H)，2.27～2.48(m，4H)，2.04(s，2H)，1.46～1.51(m，2H)，0.98(s，6H)。
Step E: 2- ((6-aminopyridin-3-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) benzoic acid
Methyl 2- ((6-aminopyridin-3-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) benzoate (80mg, 0.14mmol) was dissolved in 1, 4-dioxane (6mL) at room temperature, 1N aqueous sodium hydroxide (3mL, 1.5mmol) was added, and the mixture was warmed to 50 ℃ and stirred for 2 hours. After cooling to room temperature, a saturated aqueous solution of sodium dihydrogenphosphate was added to adjust the pH to 6, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to give the product (78mg, 100%).
Step F: 2- ((6-aminopyridin-3-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide
A solution of 2- ((6-aminopyridin-3-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) benzoic acid (78mg, 0.14mmol) and triethylamine (28mg, 0.28mmol) in dichloromethane (1mL) was added to a solution of 3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) benzenesulfonamide (136mg, 0.43mmol), EDCI (35mg, 0.18mmol), DMAP (34mg, 0.28mmol) in dichloromethane (3mL) and stirred at room temperature overnight. Diluted with dichloromethane, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was separated on a preparative thin layer plate using dichloromethane/methanol as a developing solvent (20/1) to obtain the desired product (62mg, 51%).
1H NMR(400MHz，d6-DMSO)δ8.60(brs，1H)，8.55(s，1H)，7.84～7.86(m，1H)，7.69(d，J＝2.0Hz，1H)，7.45(d，J＝8.0Hz，1H)，7.36(d，J＝8.4Hz，2H)，7.15～7.20(m，2H)，7.04～7.11(m，3H)，6.67(s，1H)，6.47(d，J＝8.8Hz，1H)，5.93～5.97(m，3H)，3.82～3.86(m，2H)，3.22～3.34(m，8H)，2.36～2.49(m，4H)，2.19(s，2H)，1.96～2.02(m，2H)，1.89～1.92(m，1H)，1.60～1.63(m，2H)，1.42～1.46(m，2H)，1.26～1.30(m，2H)，0.95(s，6H)。
EXAMPLE five
4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -2- (2-fluorophenoxy) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide
Step A: 4-bromo-2- (2-fluorophenoxy) benzoic acid methyl ester
2-Phenoxyphenol (3.00g, 0.27mol), methyl 4-bromo-2-fluorobenzoate (6.7g, 0.29mol), and potassium carbonate (7.4g, 0.54mol) were dissolved in N, N-dimethylformamide (100mL) at room temperature, and heated to 80 ℃ and stirred for 1 h. Cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (petroleum ether/dichloromethane ═ 3/1) to give the product (3.3g, 38%).
1H NMR(400MHz，CDCl3)δ7.81(d，J＝8.4Hz，1H)，7.29～7.31(m，1H)，7.11～7.24(m，3H)，7.00～7.06(m，2H)，3.86(s，3H)。
And B: 4- (3- (2-fluorophenoxy) -4- (methoxycarbonyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (3.4g, 11mmol), 4-bromo-2- (2-fluorophenoxy) benzoic acid methyl ester (3g, 9.2mmol), potassium phosphate (3.9g, 18mmol) and Pd (dppf) Cl at room temperature2(0.68g, 0.93mmol) was dissolved in a mixed solvent (60mL) of ethylene glycol dimethyl ether/water (5/1), and the mixture was heated to 80 ℃ under nitrogen and stirred overnight. Cooling to room temperature, addition of water, extraction with ethyl acetate, combination of ethyl acetate phases, washing with saturated brine, drying over anhydrous sodium sulfate, concentration and purification by column chromatography (petroleum ether/ethyl acetate: 10/1) gave the product as a white solid (3.9g, 99%).
1H NMR(400MHz，CDCl3)δ7.92(d，J＝8.4Hz，1H)，7.17～7.21(m，2H)，7.06～7.11(m，2H)，6.90～6.93(m，2H)，6.08(br，1H)，4.05(d，J＝2.4Hz，2H)，3.82(s，3H)，3.60(t，J＝5.6Hz，2H)，2.43～2.44(m，2H)，1.47(s，9H)。
And C: 2- (2-fluorophenyl) -4- (1, 2, 3, 6-tetrahydropyridin-4-yl) benzoic acid methyl ester
Tert-butyl 4- (3- (2-fluorophenoxy) -4- (methoxycarbonyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (1g, 2.3mmol) was dissolved in dichloromethane (4mL), 4mL of trifluoroacetic acid was added and the mixture was stirred for 1H. Saturated aqueous sodium carbonate was added to pH 8, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to give the desired product (0.7g, 92%).
1H NMR(400MHz，CDCl3)δ7.91(d，J＝8.4Hz，1H)，7.15～7.22(m，2H)，7.04～7.08(m，2H)，6.94(d，J＝1.2Hz，1H)，6.87～6.91(m，1H)，6.15(br，1H)，3.81(s，3H)，3.53～3.54(m，2H)，3.01(t，J＝5.6Hz，2H)，2.40(br，2H)。
Step D: 4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -2- (2-fluorophenoxy) benzoic acid methyl ester
Methyl 2- (2-fluorophenyl) -4- (1, 2, 3, 6-tetrahydropyridin-4-yl) benzoate (57mg, 0.17mmol) and 2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-enecarbaldehyde (87mg, 0.35mmol) were dissolved in dichloromethane (5mL) at room temperature, 0.5mL of acetic acid was added, stirring was carried out for 30 minutes, sodium triacetoxyborohydride (144mg, 0.68mmol) was added, stirring was carried out at room temperature for 1 hour, sodium triacetoxyborohydride (144mg, 0.68mmol) was added, and the reaction was continued at room temperature for 1 hour. Then poured into water, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was separated on a preparative thin-layer plate using a developing solvent (petroleum ether/ethyl acetate: 4/1) to give the desired product (20mg, 21%).
1H NMR(400MHz，CDCl3)δ7.88(d，J＝8.4Hz，1H)，7.25(d，J＝6.8Hz，2H)，7.15～7.17(m，2H)，7.03～7.08(m，2H)，6.97(d，J＝8.8Hz 2H)，6.91(d，J＝1.6Hz，1H)，6.84～6.88(m，1H)，6.05(br，1H)，3.80(s，3H)，2.92～2.95(m，4H)，2.45～2.48(m，2H)，2.40(br，2H)，2.22～2.25(m，2H)，2.00(br，2H)，1.44(t，J＝6.4Hz，2H)，0.97(s，6H)。
Step E: 4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -2- (2-fluorophenoxy) benzoic acid
Methyl 4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -2- (2-fluorophenoxy) benzoate (20mg, 0.035mmol) was dissolved in 1, 4-dioxane (3mL) at room temperature, an aqueous sodium hydroxide solution (1.5mL, 1.5mmol) was added, and the mixture was heated to 50 ℃ and stirred for 2 h. After cooling to room temperature, a saturated aqueous solution of sodium dihydrogenphosphate was added to adjust the pH to 6, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to obtain the objective product (20mg, 100%).
1H NMR(400MHz，CDCl3)δ7.87(d，J＝8.0Hz，1H)，7.25(d，J＝8.4Hz，2H)，7.00～7.18(m，4H)，6.94(d，J＝8.0Hz，3H)，6.70(br，1H)，5.81(br，1H)，3.41(br，2H)，3.34(br，2H)，2.89(br，2H)，2.45(br，2H)，2.34(br，2H)，2.03(br，2H)，1.41(t，J＝6.4Hz，2H)，0.94(s，6H)。
Step F: 4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -2- (2-fluorophenoxy) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide
A solution (1mL) of 4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -2- (2-fluorophenoxy) benzoic acid (20mg, 0.035mmol) and TEA (10mg, 0.1mmol) in methylene chloride was added to a solution of 3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) benzenesulfonamide (11mg, 0.036mmol), EDCI (9mg, 0.05mmol), DMAP (9mg, 0.07mmol) in methylene chloride (2mL) and stirred at room temperature overnight, diluted with methylene chloride, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was separated on preparative thin layer plates using 15: 1 dichloromethane/methanol as developing solvent to give the desired product (7mg, 23%).
1H NMR(400MHz，CD3OD)δ8.92(d，J＝2.4Hz，1H)，8.55(t，J＝5.2Hz，1H)，8.17～8.19(m，1H)，8.04(d，J＝8.4Hz，1H)，7.28～7.33(m，2H)，7.24(d，J＝8.4Hz，4H)，7.01～7.03(m，1H)，6.93～6.96(m，3H)，6.62(br，1H)，5.84(br，1H)，4.01～4.05(m，2H)，3.39～3.46(m，2H)，3.27～3.30(m，6H)，2.32～2.42(m，6H)，2.04(br，3H)，1.73～1.76(m，2H)，1.45～1.50(m，4H)，0.97(s，6H)。
EXAMPLE six
2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- ((4-fluorotetrahydro-2H-pyran-4-yl) methoxy-3-nitrophenyl) sulfonyl) benzamide
Step A: 3- (tetrahydro-2H-pyran-4-yl) oxirane-2-carbonitriles
tetrahydro-4H-pyran-4-one (20g, 200mmol) and chloroacetonitrile (10.56g, 140mmol) were dissolved in t-butanol (20mL) and reacted at room temperature for 30 minutes. A suspension of potassium tert-butoxide (24.68g, 220mmol) suspended in tert-butanol (200mL) was then added slowly over a period of 30 minutes, and the reaction was continued at room temperature for 16 hours after addition. The reaction was then diluted with water (200mL) and quenched with 3N hydrochloric acid. Extraction with ether, washing of the organic phase with saturated brine, drying over anhydrous sodium sulfate and removal of the solvent gave the crude product (18g) which was used directly in the next step.
And B: 2- (4-Fluorotetrahydro-2H-pyran-4-yl) -2-hydroxyacetonitrile
The crude product from example six step A (18g) was dissolved in dichloromethane (60mL), stirred in a plastic bottle, and cooled to 0 ℃. After 70% pyridine hydrogen fluoride solution (18mL) was added, the temperature was returned to room temperature, and the reaction was allowed to proceed overnight. The reaction was then diluted with ethyl acetate (200mL) and neutralized with saturated sodium bicarbonate solution until no more gas evolution occurred. Extraction with ethyl acetate and washing of the organic phase with 1% dilute hydrochloric acid, saturated brine, drying over anhydrous sodium sulfate, concentration under reduced pressure and purification by column chromatography (dichloromethane/methanol-20/1) gave the product (8.2g, 37% over two steps).
1H NMR(400MHz，CDCl3)δ4.37(d，J＝15.6Hz，1H)，3.92～3.96(m，2H)，3.68～3.77(m，2H)，3.37(s，1H)，1.81～2.02(m，4H)。
And C: (4-Fluorotetrahydro-2H-pyran-4-yl) -methanol
2- (4-Fluorotetrahydro-2H-pyran-4-yl) -2-hydroxyacetonitrile (8.2g, 51.5mmol) was dissolved in a mixed solution of isopropanol (160mL) and water (40mL), cooled to 0 deg.C, and sodium borohydride (2.89g, 76.4mmol) was added in portions, followed by warming to room temperature for reaction overnight. Then quenched by the addition of acetone and stirred for 1 hour. Extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed, and the product was purified by column chromatography (petroleum ether/ethyl acetate: 3/1) to obtain a product (2.8g, 41%).
1H NMR(400MHz，CDCl3)δ3.81～3.86(m，2H)，3.70～3.76(m，2H)，3.58～3.65(m，2H)，3.37(s，1H)，1.65～1.88(m，4H)。
Step D: 4- ((4-Fluorotetrahydro-2H-pyran-4-yl) methoxy) -3-nitrobenzenesulfonamide
(4-Fluorotetrahydro-2H-pyran-4-yl) -methanol (140mg, 1.04mmol), 4-chloro-3-nitrobenzenesulfonamide (225mg, 0.95mmol), 60% sodium hydrogen (114g, 2.85mmol) was stirred in tetrahydrofuran (5mL) at room temperature overnight. Then quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product which was purified by thin layer chromatography (dichloromethane/methanol-20/1) to give the product (120mg, 38%).
1H NMR(400MHz，d6-DMSO)δ8.31(d，J＝2.4Hz，1H)，8.05～8.08(m，1H)，7.60(d，J＝9.2Hz，1H)，7.52(s，2H)，4.42(d，J＝20.0Hz，2H)，3.76～3.80(m，2H)，3.56～3.62(m，2H)，1.80～1.90(m，4H)。
Step E: 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- ((4-fluorotetrahydro-2H-pyran-4-yl) methoxy-3-nitrophenyl) sulfonyl) benzamide
A solution of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) benzoic acid (50mg, 0.088mmol) and TEA (18mg, 0.176mmol) in methylene chloride (1mL) was added to a solution of 4- ((4-fluorotetrahydro-2H-pyran-4-yl) methoxy) -3-nitrobenzenesulfonamide (29mg, 0.088mmol), EDCI (22mg, 0.114mmol), DMAP (22mg, 0.176mmol) in methylene chloride (2mL), after stirring overnight at room temperature, it was diluted with dichloromethane, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was separated on a preparative thin-layer plate using dichloromethane/methanol-20/1 as a developing solvent to obtain the desired product (30mg, 39%).
1H NMR(400MHz，d6-DMSO)δ11.59(s，1H)，9.19(brs，1H)，8.21(s，1H)，7.88～7.95(m，2H)，7.50(d，J＝8.0Hz，1H)，7.44～7.46(m，1H)，7.40(s，1H)，7.34(d，J＝8.4Hz，2H)，7.24(br，1H)，7.07～7.09(m，3H)，6.75(s，1H)，6.33～6.34(m，1H)，5.94(br，1H)，4.28(d，J＝20.4Hz，2H)，3.73～3.77(m，2H)，3.53～3.60(m，2H)，2.85～3.07(m，4H)，2.32～2.43(m，4H)，2.16(s，2H)，2.00(s，2H)，1.79～1.87(m，4H)，1.41(s，2H)，0.92(s，6H)。
EXAMPLE seven
2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methoxy) amino-3-nitrophenyl) sulfonyl) benzamide
Step A: (4-Fluorotetrahydro-2H-pyran-4-yl) methyl methanesulfonate
(4-Fluorotetrahydro-2H-pyran-4-yl) -methanol (2.8g, 20.9mmol) and triethylamine (3.17g, 31.3mmol) were dissolved in dichloromethane and cooled to 0 ℃. Methanesulfonyl chloride (3.59g, 31.3mmol) was added dropwise, and after completion of the addition, the reaction was returned to room temperature for 2 hours. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to obtain a crude product (4.4g) which was used directly in the next step.
And B: 4- (azidomethyl) -4-fluorotetrahydro-2H-pyrane
The crude product from example seven step A (4.4g) was dissolved in N, N-dimethylformamide (60mL) and sodium azide (6.79g, 104.5mmol) and sodium bicarbonate (3.51g, 41.8mmol) were added. The temperature was raised to 120 ℃ and the reaction was carried out for 17 hours. Then cooled to room temperature, poured into water, extracted with ethyl acetate, the organic phase washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to about 30mL, and the ethyl acetate solution of the product was used directly in the next step.
And C: (4-Fluorotetrahydro-2H-pyran-4-yl) -methylamine
To the solution obtained in the seventh step B of example, 10% palladium on carbon (280mg) was added, and the mixture was stirred under hydrogen (1atm) at room temperature for 24 hours. Then filtered, concentrated in vacuo and purified by column chromatography (dichloromethane/methanol-10/1) to give the product (1.3g, 47% overall yield over three steps).
1H NMR(400MHz，CDCl3)δ3.80～3.85(m，2H)，3.68～3.74(m，2H)，2.80(d，J＝20.8Hz，2H)，1.60～1.84(m，4H)。
Step D: 4- (((4-Fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrobenzenesulfonamide
(4-Fluorotetrahydro-2H-pyran-4-yl) -methylamine (1.25g, 9.39mmol), 4-chloro-3-nitrobenzenesulfonamide (2.02g, 8.53mmol), diisopropylethylamine (3.3g, 25.6mmol) were dissolved in acetonitrile (30mL) and heated at reflux overnight. Then cooled to room temperature, poured into water, adjusted to pH 6 with 1N hydrochloric acid and extracted with ethyl acetate. Washing the organic phase with saturated saline solution, drying with anhydrous sodium sulfate, and vacuum concentrating to obtain a crude product. Ethyl acetate (10mL) was added to the crude product, which was stirred for 1 hour, filtered, washed with ethyl acetate, and dried to give the product (1.5g, 48%).
1H NMR(400MHz，D6-DMSO)δ8.58(t，J＝6.4Hz，1H)，8.48(d，J＝2.4Hz，1H)，7.82～7.84(m，1H)，7.41(d，J＝9.2Hz，1H)，7.33(s，1H)，3.74～3.81(m，4H)，3.50～3.56(m，2H)，1.76～1.86(m，4H)。
Step E: 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methoxy) amino-3-nitrophenyl) sulfonyl) benzamide
A solution (1mL) of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro- [1, 1' -biphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) benzoic acid (113mg, 0.20mmol) and TEA (40mg, 0.40mmol) in methylene chloride was added to a solution of 4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrobenzenesulfonamide (67mg, 0.20mmol), EDCI (50mg, 0.26mmol), DMAP (49mg, 0.40mmol) in methylene chloride (2mL), after stirring overnight at room temperature, it was diluted with dichloromethane, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was separated on a preparative thin-layer plate using dichloromethane/methanol-20/1 as a developing solvent to obtain the desired product (70mg, 40%).
1H NMR(400MHz，d6-DMSO)δ11.62(s，1H)，8.48～8.54(m，2H)，7.97(d，J＝2.4Hz，1H)，7.76(d，J＝8.4Hz，1H)，7.46～7.50(m，1H)，7.33(d，J＝8.4Hz，2H)，7.05～7.14(m，4H)，6.74(s，1H)，6.34～6.35(m，1H)，5.96(br，1H)，3.63～3.75(m，4H)，3.47～3.53(m，2H)，3.20(br，4H)，2.69(br，2H)，2.34(br，2H)，2.15(s，2H)，1.95～2.01(m，2H)，1.72～1.85(m，4H)，1.38～1.41(m，2H)，0.92(s，6H)。
Example eight
4- (1- ((2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-enyl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -2- (3-fluoro-1H-pyrrolo [2, 3-b ] pyridin-5-yloxy) -N- (3-nitro-4- ((tetrahydro-2H-pyran-4-yl) methylamino) phenylsulfonyl) benzamide
Step A: 4- (3- (3-fluoro-1H-pyrrolo [2, 3-b ] pyridin-5-yloxy) -4- (methoxycarbonyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
Tert-butyl 4- (3- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (methoxycarbonyl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (1.08g, 2.4mmol) and the selective fluoro reagent (1.02g, 2.9mmol) were dissolved in acetonitrile (30 mL)/water (6mL) and heated to 40 ℃ for 4H with stirring. Then cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography, eluting with dichloromethane/ethyl acetate 4/1 to give the desired product (165mg, 15%).
1H NMR(400MHz，CDCl3)δ8.88(s，1H)，8.20(d，J＝2.8Hz，1H)，7.94(d，J＝8Hz，1H)，7.52(d，J＝2.4Hz，1H)，7.19～7.22(m，1H)，7.12(t，J＝1.6Hz，1H)，6.91(d，J＝1.6Hz，1H)，6.05(br，1H)，4.03～4.04(br，2H)，3.85(s，3H)，3.59(t，J＝6.0Hz，2H)，2.42(br，2H)，1.47(s，9H)。
And B: 2- (3-fluoro-1H-pyrrolo [2, 3-b ] pyridin-5-yloxy) -4- (1, 2, 3, 6-tetrahydropyridin-4-yl) benzoic acid methyl ester
Tert-butyl 4- (3- (3-fluoro-1H-pyrrolo [2, 3-b ] pyridin-5-yloxy) -4- (methoxycarbonyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (165mg, 0.35mmol) was dissolved in dichloromethane (3mL), cooled to 0 deg.C and trifluoroacetic acid (3mL) added and stirring continued at 0 deg.C for 3H. Then, saturated sodium carbonate solution was added to adjust the pH to 9, followed by extraction with methylene chloride, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to obtain the objective product (130mg, 100%).
1H NMR(400MHz，CDCl3)δ8.98(br，1H)，8.20(d，J＝2.8Hz，1H)，7.92(d，J＝8.4Hz，1H)，7.50(d，J＝2.4Hz，1H)，7.20～7.22(m，1H)，7.10(d，J＝2.4Hz，1H)，6.92(d，J＝1.6Hz，1H)，6.14～6.15(m，1H)，3.84(s，3H)，3.50(d，J＝2.8Hz，2H)，3.06(t，J＝5.6Hz，2H)，2.36(br，2H)。
And C: 4- (1- ((2- (4-chlorophenyl) -4, 4-dimethylcyclohexyl-1-enyl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -2- (3-fluoro-1H-pyrrolo [2, 3-b ] pyridin-5-yloxy) benzoic acid methyl ester
Methyl 2- (3-fluoro-1H-pyrrolo [2, 3-b ] pyridin-5-yloxy) -4- (1, 2, 3, 6-tetrahydropyridin-4-yl) benzoate (120mg, 0-33mmol) and 2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-enecarbaldehyde (162mg, 0.65mmol) were dissolved in dichloromethane (5mL), acetic acid (0.5mL) was added at room temperature, and after stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (276mg, 1.30mmol) was added and stirred at room temperature overnight. Then, sodium carbonate solution was added to adjust the pH to 9, followed by extraction with methylene chloride, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was separated on a preparative thin-layer plate using 1/1% dichloromethane/ethyl acetate as developing solvent to give the product (70mg, 36%).
1H NMR(400MHz，CDCl3)δ10.09(br，1H)，8.17(d，J＝2.8Hz，1H)，7.89(d，J＝8.0Hz，1H)，7.51(d，J＝2.4Hz，1H)，7.24(d，J＝8.4Hz，2H)，7.09～7.12(m，2H)，6.95(d，J＝8.4Hz，2H)，6.84(d，J＝1.6Hz，1H)，5.95(br，1H)，3.83(s，3H)，3.11(br，4H)，2.66(br，2H)，2.43(br，2H)，2.30(br，2H)，2.01(br，2H)，1.44(t，J＝6.4Hz，2H)，0.95(s，6H)。
Step D: 4- (1- ((2- (4-chlorophenyl) -4, 4-dimethylcyclohexyl-1-enyl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -2- (3-fluoro-1H-pyrrolo [2, 3-b ] pyridin-5-yloxy) benzoic acid
Methyl 4- (1- ((2- (4-chlorophenyl) -4, 4-dimethylcyclohexyl-1-enyl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -2- (3-fluoro-1H-pyrrolo [2, 3-b ] pyridin-5-yloxy) benzoate (70mg, 0.12mmol) was dissolved in 1, 4-dioxane (3mL), and a 1N aqueous solution of sodium hydroxide (1.5mL, 1.5mmol) was added and stirred at 50 ℃ for 2 hours. Saturated aqueous solution of sodium dihydrogenphosphate was added to pH 6, extraction was performed with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to obtain the objective product (70mg, 100%).
1H NMR(400MHz，DMSO)δ12.87(br，1H)，11.52(br，1H)，8.08(d，J＝2.8Hz，1H)，7.79(d，J＝8.4Hz，1H)，7.50(t，J＝2.4Hz，1H)，7.49(d，J＝2.4Hz，1H)，7.47(d，J＝8.4Hz，2H)，7.27～7.29(m，1H)，7.07(d，J＝8.4Hz，2H)，6.97(d，J＝1.6Hz，1H)，6.16(br，1H)，2.83(br，4H)，2.31～2.36(m，4H)，2.15～2.18(m，2H)，1.97(br，2H)，1.39(t，J＝6.4Hz，2H)，0.94(s，6H)。
Step E: 4- (1- ((2- (4-chlorophenyl) -4, 4-dimethylcyclohexyl-1-enyl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -2- (3-fluoro-1H-pyrrolo [2, 3-b ] pyridin-5-yloxy) -N- (3-nitro-4- ((tetrahydro-2H-pyran-4-yl) methylamino) phenylsulfonyl) benzamide
A solution of 4- (1- ((2- (4-chlorophenyl) -4, 4-dimethylcyclohexyl-1-enyl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -2- (3-fluoro-1H-pyrrolo [2, 3-b ] pyridin-5-yloxy) benzoic acid (70mg, 0.12mmol) and triethylamine (30mg, 0.24mmol) in dichloromethane (1mL) was added to a solution of 3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) benzenesulfonamide (38mg, 0.12mmol), EDCI (30mg, 0.15mmol), DMAP (29mg, 0.24mmol) in dichloromethane (2mL), stirred overnight at room temperature, diluted with dichloromethane, washed with water several times, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was separated on a preparative thin layer plate using methylene chloride/methanol-15/1 as a developing solvent to give the product (20mg, 19%).
1H NMR(400MHz，DMSO)δ11.48(br，1H)，9.53(br，1H)，8.47(br，2H)，8.02～8.03(m，1H)，7.73～7.76(m，1H)，7.47～7.52(m，3H)，7.33(d，J＝8.4Hz，2H)，7.07～7.15(m，4H)，6.80(s，1H)，5.99(br，1H)，3.81～3.85(m，2H)，3.22～3.25(m，4H)，2.69～3.08(m，4H)，2.31～2.43(m，4H)，2.18(br，2H)，1.97～2.00(m，2H)，1.85(br，1H)，1.57～1.60(m，2H)，1.38～1.43(m，2H)，1.24～1.28(m，2H)，0.93(s，6H)。
Biological Activity assay
1. In vitro enzymatic activity assay of compounds:
the fluorescence polarization method is adopted to establish the Bcl2 and Bcl-xl enzymatic screening method. The basic principle is as follows: small molecule compounds compete with the fluorophore FITC labeled short peptide (FITC-Bim) for their binding site to Bcl2 or Bcl-xl. After FITC-Bim is combined with macromolecular substance Bcl2 or Bcl-xl, fluorescent substance FITC is irradiated by single plane blue polarized light (485nm), absorbed light energy jumps into an excited state, then returns to a ground state, and single plane polarized fluorescence (525nm) is emitted. Conversely, if FITC-Bim fails to bind to the macromolecular species Bcl2 or Bcl-xl, the small molecule rotates or flips at a fast rate and the emitted light will be depolarized relative to the plane of the excitation light. That is, when the compound competitively binds to Bcl2 or Bcl-xl, FITC-Bim exists in a free state, and the polarization value is reduced. Therefore, the binding ability of the compound to Bcl2 or Bcl-xl can be reflected by the change of the polarization value.
The specific operation is as follows: a10 mM stock of the compound was first diluted to 1mM or 0.1mM in DMSO, followed by a 3-fold gradient dilution in DMSO. mu.L of the compound diluted in a gradient was transferred to 96. mu.L of reaction buffer (PBS, pH 7.4; 50mM NaCl; 0.01% NP40 and 2mM Dithiothreitol (DTT)), and then this further diluted compound was added to a 384-well black round-bottom plateThen, 8. mu.L of an enzyme solution containing 2nM Bcl2 or Bcl-x in the reaction buffer was added. The above test mixture was then incubated at 23 ℃ for 30 minutes with shaking, after which 4. mu.L of reaction buffer containing 8nMFITC-Bim was added and incubation at room temperature was continued for 60 minutes. The measurement of the polarized light value was carried out by EnVision under Ex485/Em 530. Data were processed by data analysis software Prism and IC of the compound was obtained50The value is obtained.
2. Determination of cell proliferation activity of compounds:
using Promega corporationThe detection reagent establishes a suspension cell proliferation inhibition screening method.
Human follicular B lymphoma cells DOHH2 and human acute lymphoblastic leukemia cells Molt-4 supplemented with 10% fetal bovine serumRPMI-1640Culturing in a culture medium at 37 deg.C, 95% air and 5% CO2 in 25cm2 or 75cm2 plastic tissue culture bottleAnd in the middle, subculturing for 2-3 times in a week.
The cells were treated at 8X 103Cells/well (DOHH2) and 6X 103Cell/well (Molt-4) Density seeded in 96-well cell culture plates195. mu.L/well, at 37 ℃, 95% air and 5% CO2Culturing in the medium. After 24 hours, the test compound is added: compounds were diluted in DMSO in 3-fold gradients starting at 10mM (in DMSO) and taking 4. mu.l of each concentrationL was added to 96. mu.L of serum-free medium, and finally 5. mu.L of the diluted compound was added to the cell-seeded culture plate. The final concentration of DMSO in the cell culture medium was 0.1%, and the final concentration of the test compound was 0.3nM to 10. mu.M. The cells were incubated at 37 ℃ for 3 days.
After 3 days, cell viability was determined by CellTiter-blue (Promega) kit, and the semi-inhibitory concentration of the compound on cell proliferation, IC, was calculated by Prism program50The value is obtained.
Biological data of selected partial compounds
Selected compounds prepared as described above were analyzed according to the biological methods described herein. The results are shown in the following table:
enzymology data
Compound numbering Bcl2 IC50(nM) Bcl-xl IC50(nM)
ABT-199 2.75 567.9
1 ＜2 ＞500
2 ＜2 ＞1000
6 ＜1 ＞300
7 ＜1 ＞300
8 ＜2 ＞500
Cytological data

Claims (10)

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof,
wherein,
is a single bond or a double bond;
ar is selected from aryl and heteroaryl groups, which are optionally selected from halogen, amino, hydroxy, (═ O), and C1-6Radical substitution of alkyl;
x is selected from the group consisting of-O-, -S-and-NR3-；
R is selected from C1-6Alkoxy radical, C3-8Cycloalkyl and C3-8Heterocycloalkyl, said cycloalkyl and heterocycloalkyl being optionally selected from halogen, amino, hydroxy, (═ O), - (CO) (CH)2)mNR4R5、-(CO)(CH2)mOR6And C1-6Radical substitution of alkyl;
R1、R2、R3、R4、R5and R6Each independently selected from H and C1-6An alkyl group;
m is independently 0, 1, 2, 3, 4, 5, or 6;
n is 0, 1, 2, 3, 4, 5 or 6.
2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein Ar is selected from 6-10 membered aryl and 5-10 membered heteroaryl, optionally selected from halogen, amino, hydroxy, (═ O) and C1-6Alkyl groups.
3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein X is selected from-O-and-NH-, R1And R2Is H.
4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein R is selected from C1-6Alkoxy radical, C3-8Cycloalkyl and C3-8Heterocycloalkyl, said cycloalkyl and heterocycloalkyl optionally being substituted by halogen or C1-6Alkyl substitution.
5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein n is 0, 1, 2, 3 or 4.
6. A compound represented by any one of the following structures:
or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.
7. A pharmaceutical composition comprising at least one compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, and a pharmaceutically acceptable carrier.
8. Use of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, for the manufacture of a medicament for the treatment of a disease associated with expression of an anti-apoptotic Bcl-2 protein.
9. The use of claim 8, wherein the disease is cancer.
10. The use of claim 8, wherein the disease is bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphocytic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer.
CN201610800391.4A 2016-09-01 2016-09-01 The selective depressants of Bcl 2 and its preparation and use Pending CN107793412A (en)

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