CN114369094B - Trifluoromethyl substituted sulfonamide selective BCL-2 inhibitors - Google Patents

Trifluoromethyl substituted sulfonamide selective BCL-2 inhibitors Download PDF

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CN114369094B
CN114369094B CN202210006210.6A CN202210006210A CN114369094B CN 114369094 B CN114369094 B CN 114369094B CN 202210006210 A CN202210006210 A CN 202210006210A CN 114369094 B CN114369094 B CN 114369094B
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alkyl
pharmaceutically acceptable
stereoisomer
acceptable salt
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CN114369094A (en
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刘飞
丰巍伟
王斌
徐宏江
汪纪楠
张喜全
王善春
施伟
张健青
姚绎炎
刘彦龙
李洋
刘利民
顾红梅
杨玲
董平
田心
陈智林
周浩
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms

Abstract

The present application relates to trifluoromethyl substituted sulfonamide selective BCL-2 inhibitors, in particular to compounds of formula I, stereoisomers or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing these compounds. The application is also directed to the use of these compounds and pharmaceutical compositions comprising these compounds in the treatment of diseases associated with the anti-apoptotic protein BCL-2, such as cancer.

Description

Trifluoromethyl substituted sulfonamide selective BCL-2 inhibitors
The application is a divisional application of the following application: 29 th 2019, 03; application number: 201980021318.9; the application name is as follows: "trifluoromethyl substituted sulfonamide selective BCL-2 inhibitors".
Cross Reference to Related Applications
The present application claims the priority and equity of chinese patent application No. 201810297914.7 filed 3/30/2018 to the chinese state intellectual property office, and the priority and equity of chinese patent application No. 201811161184.4 filed 9/30/2018 to the chinese state intellectual property office, the disclosures of which are incorporated herein by reference in their entirety.
Technical Field
The present application relates to compounds that selectively inhibit the anti-apoptotic protein BCL-2, methods of their preparation, pharmaceutical compositions containing the compounds, and their use in the treatment of diseases associated with the anti-apoptotic protein BCL-2, such as cancer.
Background
BCL-2 proteins are divided into three families: BCL-2 family (family members include BCL-2, BCL-XL, etc.), BAX family, and BH3-only family, wherein BCL-2 family plays an anti-apoptotic role and members of the latter two families play a pro-apoptotic role.
Anti-apoptotic BCL-2 family proteins are associated with many diseases and are being investigated as potential therapeutic drug targets. These targets for interventional therapies include, for example, BCL-2 family proteins BCL-2 and BCL-XL, among others. Recently, inhibitors of BCL-2 family proteins have been reported in WO2012071374, WO2010138588, WO2010065865. Although inhibitors with high binding to the target protein are taught therein, the compound binding affinity is only one of many parameters to be considered. One goal is to produce such compounds: which preferentially binds to, i.e., is selective for, one protein over another. To show this selectivity, it is well known that compounds show high binding affinity for a specific protein, and lower binding affinity for another member.
BCL-2 inhibitors have been disclosed which are not highly selective with respect to anti-apoptotic BCL-XL proteins and anti-apoptotic BCL-2 proteins and thus produce a greater likelihood of side effects, characterized by inhibiting anti-apoptotic BCL-XL proteins, producing side effects such as thrombocytopenia.
The compound disclosed by the application has higher selectivity and better performance in inhibiting the activity of anti-apoptosis BCL-2 protein compared with anti-apoptosis BCL-2 protein and anti-apoptosis BCL-XL protein. Meanwhile, the preparation method also has better liver microsome stability and optimized pharmacokinetic parameters, and has better patent medicine prospect.
Detailed Description
In one aspect, the present application relates to a compound of formula i,
wherein, the liquid crystal display device comprises a liquid crystal display device,
E 1 or B is a 1 Selected from-NHR 0 or-NR 1 R 2 The other is selected from H;
R 0 selected from 5-6 membered cycloalkyl optionally substituted by 5-6 membered heterocycloalkyl, or optionally by C 1-6 Alkyl substituted 5-6 membered heterocycloalkyl;
R 1 selected from H or C 1-6 Alkyl, R 2 Selected from C 1-6 Alkyl, or R 1 And R is 2 Together with the N atom to which they are attached form a 5-6 membered nitrogen containing heterocycloalkyl, said R 2 Optionally substituted with one, two or three groups selected from: -SR (sequence of events) a 、-COOR b Phenyl, hydroxy, 5-6 membered cycloalkyl optionally substituted by 5-6 membered heterocycloalkyl, optionally C 1-6 Alkyl-substituted 5-6 membered heterocycloalkyl, or-NR e R f The method comprises the steps of carrying out a first treatment on the surface of the The R is 1 And R is 2 The 5-to 6-membered nitrogen containing heterocycloalkyl groups formed together with the N atom to which they are attached are optionally substituted with C 1-6 Alkyl or-COOR b Substitution;
R a 、R b 、R e 、R f Each independently selected from C optionally substituted with phenyl 1-6 An alkyl group.
In one embodiment, the present application relates to a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
x is selected from N or O, and when X is selected from O, R 1 Absence of;
R 1 selected from hydrogen or C 1-6 An alkyl group;
R 2 selected from-R 3 or-C 1-6 Alkylene group-R 3 ；
R 3 Selected from-NHC 1-6 Alkyl, -N (C) 1-6 Alkyl group 2 、-COOC 1-6 Alkyl or optionally C 1-6 Alkyl, -OC 1-6 Alkyl, -COC 1-6 Alkyl, -COC 1-6 alkyl-OC 1-6 Alkyl, -COC 1-6 alkyl-NH (C) 1-6 Alkyl), -COC 1-6 alkyl-N (C) 1-6 Alkyl group 2 or-SO 2 C 1-6 An alkyl substituted 5-6 membered ring selected from heterocycloalkyl or cycloalkyl.
In a further embodiment, the present application relates to a compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
x is selected from N;
R 1 selected from hydrogen or C 1-6 An alkyl group;
R 2 selected from-C 1-6 Alkylene group-R 3 ；
R 3 Selected from-N (C) 1-6 Alkyl group 2 、-COOC 1-6 Alkyl or optionally C 1-6 Alkyl substituted 5-6 membered heterocycloalkyl.
In some embodiments, the heteroatoms in the heterocycloalkyl group are selected from oxygen, nitrogen, or sulfur, with a preferred number of heteroatoms being 1 or 2.
In some embodiments, the heteroatoms in the heterocycloalkyl group are selected from oxygen, nitrogen, with a preferred number of heteroatoms being 1 or 2.
In some embodiments, the heteroatoms in the heterocycloalkyl group are selected from oxygen, with a preferred number of heteroatoms being 1 or 2.
In some embodiments, the 5-6 membered ring is selected from 6 membered rings.
In some embodiments, the 5-6 membered ring is selected from dioxane, morpholine, piperidine, tetrahydropyran, tetrahydrothiopyran, tetrahydropyrrole, tetrahydrofuran, or cyclohexane.
In some embodiments, the 5-6 membered ring is selected from dioxane, morpholine, piperidine, tetrahydropyran, tetrahydrothiopyran, tetrahydrofuran, or cyclohexane.
In some embodiments, the 5-6 membered ring is selected from dioxane, morpholine, piperidine, tetrahydropyran, tetrahydrothiopyran, or cyclohexane.
In some embodiments, the 5-6 membered ring is selected from dioxane, morpholine, piperidine, or tetrahydropyran.
In some embodiments, the 5-6 membered ring is selected from dioxane, or tetrahydropyran.
In some embodiments, X is selected from N.
In some embodiments, X is selected from O, and R 1 Is not present.
In some embodiments, R 1 Selected from hydrogen.
In some embodiments, R 1 Selected from C 1-4 An alkyl group.
In some embodiments, R 1 Selected from methyl and ethyl.
In some embodiments, R 2 C in (C) 1-6 Alkylene is selected from C 1-4 An alkylene group; in some embodiments, C above 1-6 Alkylene is selected from C 1-3 An alkylene group; in some embodiments, C above 1-6 Alkylene is selected from-CH 2 -、-CH 2 CH 2 -、-CH 2 (CH 3 ) -or-CH 2 CH 2 CH 2 -。
In some embodiments, R 2 Selected from- (CH) 2 ) n -R 3 Wherein n is selected from 0, 1, 2, 3 or 4; or n is selected from 1, 2 or 3; or n is selected from 1 or 2.
In some embodiments, R 3 Selected from-N (C) 1-4 Alkyl group 2 、-COOC 1-4 Alkyl or optionally C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 1-4 alkyl-OC 1-4 Alkyl, -COC 1-4 alkyl-N (C) 1-4 Alkyl group 2 or-SO 2 C 1-4 An alkyl substituted 5-6 membered ring selected from heterocycloalkyl or cycloalkyl.
In some embodiments, R 3 Selected from optionally covered by C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 1-4 alkyl-OC 1-4 Alkyl, -COC 1-4 alkyl-N (C) 1-4 Alkyl group 2 or-SO 2 C 1-4 An alkyl substituted 5-6 membered ring selected from heterocycloalkyl or cycloalkyl; in some embodiments, R 3 Selected from optionally covered by C 1-4 Alkyl, -COC 1-4 Alkyl, or-COC 1-4 alkyl-OC 1-4 An alkyl substituted 5-6 membered ring, said ring being selected from heterocycloalkyl.
In some embodiments, R 3 Selected from-N (CH) 3 ) 2 、-N(CH 2 CH 3 ) 2 、-COOCH 2 CH 3 Or optionally methyl, ethyl, -OCH 3 、-COCH 3 、-COCH(CH 3 ) 2 、-COCH 2 OCH 3 、-COCH 2 N(CH 3 ) 2 or-SO 2 CH 3 A substituted 5-6 membered ring, said 5-6 membered ring being selected from heterocycloalkyl or cycloalkyl.
In some embodiments, R 3 Selected from optionally methyl, ethyl, -OCH 3 、-COCH 3 、-COCH(CH 3 ) 2 、-COCH 2 OCH 3 、-COCH 2 N(CH 3 ) 2 or-SO 2 CH 3 A substituted 5-6 membered ring, said 5-6 membered ring being selected from heterocycloalkyl or cycloalkyl.
In some embodiments, R 3 Selected from-N (C) 1-3 Alkyl group 2 、-COOC 1-3 Alkyl or optionally C 1-3 Alkyl, -OC 1-3 Alkyl, -COC 1-3 Alkyl, -COC 1-2 alkyl-OC 1-3 Alkyl, -COC 1-3 alkyl-N (C) 1-3 Alkyl group 2 or-SO 2 C 1-3 Alkyl substitutedA 5-6 membered ring selected from heterocycloalkyl or cycloalkyl; preferably the ring is selected from dioxane, morpholine, piperidine, tetrahydropyran, tetrahydrothiopyran, tetrahydropyrrole, tetrahydrofuran or cyclohexane.
In some embodiments, R 3 Selected from-N (CH) 3 ) 2 、-N(CH 2 CH 3 ) 2 、-COOCH 2 CH 3 Or optionally methyl, ethyl, -OCH 3 、-COCH 3 、-COCH(CH 3 ) 2 、-COCH 2 OCH 3 、-COCH 2 N(CH 3 ) 2 or-SO 2 CH 3 A substituted 5-6 membered ring, said 5-6 membered ring being selected from dioxane, morpholine, piperidine, tetrahydropyran, tetrahydrothiopyran, tetrahydropyrrole, tetrahydrofuran or cyclohexane.
In some embodiments, R 3 Selected from-N (CH) 3 ) 2 、-N(CH 2 CH 3 ) 2 、-COOCH 2 CH 3 Dioxane, tetrahydropyran, tetrahydrofuran, tetrahydrothiopyran.
In some embodiments, R 3 Selected from-N (CH) 3 ) 2 、-N(CH 2 CH 3 ) 2 、-COOCH 2 CH 3 。
In some embodiments, R 3 Selected from dioxane, tetrahydropyran, tetrahydrothiopyran, and tetrahydrofuran.
In some embodiments, R 3 Selected from optionally covered by C 1-3 Alkyl, -OC 1-3 Alkyl, -COC 1-3 Alkyl, -COC 1-2 alkyl-OC 1-3 Alkyl or-SO 2 C 1-3 Alkyl substituted dioxane or tetrahydropyran.
In some embodiments, R 3 Selected from optionally methyl, ethyl, -OCH 3 、-COCH 3 、-COCH(CH 3 ) 2 、-COCH 2 OCH 3 or-SO 2 CH 3 Substituted dioxane.
In some embodiments, R 3 Selected from dioxane or tetrahydropyran.
In some embodiments, R 3 Selected from optionally covered by C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 1-4 alkyl-OC 1-4 Alkyl, -COC 1-4 alkyl-N (C) 1-4 Alkyl group 2 or-SO 2 C 1-4 Alkyl substituted morpholines, piperidines, tetrahydropyrroles or cyclohexanes.
In some embodiments, R 3 Selected from optionally methyl, ethyl, -OCH 3 、-COCH 3 、-COCH(CH 3 ) 2 、-COCH 2 OCH 3 、-COCH 2 N(CH 3 ) 2 or-SO 2 CH 3 Substituted morpholines, piperidines, tetrahydropyrroles or cyclohexanes.
In some embodiments, R 3 Selected from optionally covered by C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 1-4 alkyl-OC 1-4 Alkyl, -COC 1-4 alkyl-N (C) 1-4 Alkyl group 2 or-SO 2 C 1-4 Alkyl substituted morpholines, piperidines.
In some embodiments, R 3 Selected from optionally methyl, ethyl, -OCH 3 、-COCH 3 、-COCH(CH 3 ) 2 、-COCH 2 OCH 3 、-COCH 2 N(CH 3 ) 2 or-SO 2 CH 3 Substituted morpholines, piperidines.
In some embodiments, R 3 Selected from optionally covered by C 1-4 Alkyl, -COC 1-4 Alkyl, or-COC 1-4 alkyl-OC 1-4 Alkyl substituted morpholines.
In some embodiments, R 3 Selected from optionally methyl, ethyl, -COCH 3 、-COCH(CH 3 ) 2 or-COCH 2 OCH 3 Substituted morpholines.
In some embodiments, R 3 Selected from optionally covered by C 1-4 Alkyl, -COC 1-4 Alkyl, -COC 1-4 alkyl-OC 1-4 Alkyl, -COC 1-4 alkyl-N (C) 1-4 Alkyl group) 2 or-SO 2 C 1-4 Alkyl substituted piperidines.
In some embodiments, R 3 Selected from optionally methyl, ethyl, -COCH 3 、-COCH(CH 3 ) 2 、-COCH 2 OCH 3 、-COCH 2 N(CH 3 ) 2 or-SO 2 CH 3 Substituted piperidines.
In some embodiments, when morpholine, piperidine or tetrahydropyrrole is substituted, the substitution site is on the N of its ring.
In some embodiments, R 3 Selected from the group consisting of
In some embodiments of the present invention, in some embodiments,the moiety is selected from the following structures:
in some embodiments, the->The moiety is selected from the following structures:
in some embodiments, the building blockSelected from->
In some embodiments, X is selected from N, R 1 Selected from hydrogen, R 2 Is- (CH) 2 ) n -R 3 Wherein n is selected from 0, 1, 2, 3 or 4, R 3 Selected from hydroxy, 5-6 membered cycloalkyl optionally substituted by 5-6 membered heterocycloalkyl, optionally C 1-4 Alkyl-substituted 5-6 membered heterocycloalkyl, or di-C 1-4 An alkylamino group.
In some embodiments, X is selected from N, R 1 Selected from hydrogen, R 2 Is- (CH) 2 ) n -R 3 Wherein R is 3 Selected from hydroxy, cyclohexane, morpholine-substituted cyclohexane, piperidine, methyl-substituted piperidine, tetrahydropyran, morpholine, piperazine, dimethylamino, or diethylamino. Wherein n is selected from 0, 1, 2 or 3; or n is selected from 1, 2 or 3.
In some embodiments, X is selected from N, R 1 Selected from hydrogen, R 2 Is- (CH) 2 ) n -R 3 Wherein R is 3 Selected from cyclohexane, cyclohexane substituted with morpholine, piperidine substituted with methyl, or tetrahydropyran; n is selected from 0 or 1.
In some embodiments, X is selected from N, R 1 Selected from hydrogen, R 2 Is- (CH) 2 ) n -R 3 Wherein n is selected from 0, 1, 2, 3 or 4, R 3 Selected from 5-6 membered cycloalkyl optionally substituted by 5-6 membered heterocycloalkyl, optionally by C 1-4 Alkyl-substituted 5-6 membered heterocycloalkyl, or-N (C) 1-4 Alkyl group 2 。
In some embodiments, X is selected from N, R 1 Selected from hydrogen, R 2 Is- (CH) 2 ) n -R 3 Wherein n is selected from 0, 1, 2, 3 or 4, R 3 Selected from optionally being C 1-4 Alkyl substituted 5-6 membered heterocycloalkyl.
In some embodiments, X is selected from N, R 1 Selected from hydrogen, R 2 Is- (CH) 2 ) n -R 3 Wherein n is selected from 0, 1, or 2, R 3 Selected from 5-6 membered heterocycloalkyl.
In some embodiments, X is selected from N, R 1 Selected from hydrogen, R 2 Is- (CH) 2 ) n -R 3 Wherein R is 3 Selected from cyclohexane, piperidine substituted with methyl, tetrahydropyran, morpholine, dimethylamino, or diethylamino. Wherein n is selected from 0, 1, 2 or 3; or n is selected from 1, 2 or 3.
In some embodiments, X is selected from N, R 1 Selected from hydrogen, R 2 Is- (CH) 2 ) n -R 3 Wherein R is 3 Selected from cyclohexane, piperidine substituted with methyl, or tetrahydropyran; n is selected from 0 or 1.
In some embodiments of the present application, in some embodiments,the moiety is selected from the following structures:
in some embodiments, the->The moiety is selected from the following structures:
the present application relates to compounds of formula II, stereoisomers or pharmaceutically acceptable salts thereof,
therein, X, R 1 、R 2 Is as defined above for the compounds of formula I.
The present application provides the following compounds, stereoisomers or pharmaceutically acceptable salts thereof:
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the present application provides the following compounds, or pharmaceutically acceptable salts thereof:
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in another aspect, the present application relates to a pharmaceutical composition comprising a compound of formula (I) or formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to the application. In some embodiments, the pharmaceutical compositions of the present application further comprise pharmaceutically acceptable excipients.
In another aspect, the application features a method of treating a disorder associated with the anti-apoptotic protein BCL-2 in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I) or formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the application.
In another aspect, the present application describes the use of a compound of formula (I) or formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, according to the application, for the manufacture of a medicament for the prevention or treatment of a disease associated with the anti-apoptotic protein BCL-2.
In another aspect, the application describes the use of a compound of formula (I) or formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, according to the application, for the prevention or treatment of a disease associated with the anti-apoptotic protein BCL-2.
In another aspect, the present application describes a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application for use in the prevention or treatment of a disease associated with the anti-apoptotic protein BCL-2.
Wherein the disease associated with anti-apoptotic protein BCL-2 is selected from cancer. The cancer is selected from chronic lymphocytic leukemia (CLL, chronic lymphocytic leukemia) or B-cell lymphoma.
Definition of the definition
The following terms used in the present application have the following meanings unless otherwise indicated. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.
The term "optionally" or "optionally" means 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, ethyl "optionally" substituted with halogen means that ethyl may be unsubstituted (-CH) 2 CH 3 ) Monosubstituted (e.g. -CH 2 CH 2 F) Polysubstituted (e.g. -CHFCH 2 F、-CH 2 CHF 2 Etc.) or fully substituted (-CF) 2 CF 3 ). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
C herein m-n It is that the moiety has an integer number of carbon atoms in the given range. For example“C 1-6 By "is meant that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
The term "alkylene" refers to a divalent group formed by removing 1 hydrogen at any position of an alkyl group. For example, the term "C 1-6 Non-limiting examples of alkylene groups include, but are not limited to, methylene, ethylene, methyl methylene, dimethyl methylene, 1, 3-propylene, and the like.
The term "alkyl" refers to a compound of the formula C n H 2n+1 Is a hydrocarbon group of (a). The alkyl group may be linear or branched. For example, the term "C 1-6 Alkyl "refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio have the same definition as above. For another example, the term "C 1-4 Alkyl "refers to an alkyl group containing 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl).
The term "cycloalkyl" refers to a carbocycle that is fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, and the like.
The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3 to 7 membered ring containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen and/or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, ethylene oxide, ethylene nitride, non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thiaalkyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepinyl, thiepanyl. Preferred are monocyclic heterocycloalkyl groups having 5 or 6 ring atoms.
The term "treating" means administering a compound or formulation of the application to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) Preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state, but has not been diagnosed as having the disease state;
(ii) Inhibiting a disease or disease state, i.e., inhibiting its progression;
(iii) The disease or condition is alleviated, even if the disease or condition subsides.
The term "therapeutically effective amount" means an amount of a compound of the application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and disclosure.
The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like can be mentioned.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the application to an organism.
The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
The words "comprise" or "include" and their english variants such as comprises, comprising, contains or containing, etc. are to be understood in an open, non-exclusive sense, i.e. "including but not limited to.
The compounds and intermediates of the application may also exist in different tautomeric forms and all such forms are included within the scope of the application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine isomerisation. A specific example of a proton tautomer is an imidazole moiety, where a proton can migrate between two ring nitrogens. Tautomers include tautomers by recombination of some of the bond-forming electrons.
The application also includes those which are the same as those described herein, but in which one or more atoms are replaced by an atomic weight or mass number different from that commonly found in natureIsotopically-labeled compounds of the present application having a plurality of atom substitutions. Examples of isotopes that can be incorporated into compounds of the application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as, respectively 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 123 I、 125 I and 36 cl, and the like.
Certain isotopically-labeled compounds of the application (e.g., with 3 H is H 14 C-labeled) can be used in compound and/or substrate tissue distribution analysis. Tritiation (i.e 3 H) And carbon-14 (i.e 14 C) Isotopes are particularly preferred for ease of preparation and detectability. Positron emitting isotopes, such as 15 O、 13 N、 11 C and C 18 F can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples below by substituting an isotopically-labeled reagent for an non-isotopically-labeled reagent.
In addition, the use of heavier isotopes (such as deuterium (i.e. 2 H) Substitution may provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances, where deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium.
The compounds of the application may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included in the present application, such as enantiomers and diastereomers. The compounds of the application containing asymmetric carbon atoms can be isolated in optically pure or racemic form. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The pharmaceutical compositions of the present application may be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.
Typical routes of administration of the compounds of the application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present application may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, and the like.
In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms, and the like.
In all methods of administration of the compounds described herein, the dosage administered per day is from 0.01 to 200mg/kg body weight, either alone or in divided doses.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application. The chemical reactions of the embodiments of the present application are accomplished in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already present.
An important consideration in the art of synthetic route planning is the selection of suitable protecting groups for reactive functionalities (e.g., hydroxyl groups in the present application), for example, refer to Greene's Protective Groups in Organic Synthesis (4 th Ed.) Hoboken, new Jersey: john Wiley & Sons, inc.
In some embodiments, the compounds of formula I of the present application can be prepared by one skilled in the art of organic synthesis by the following routes using standard methods in the art:
Route 1:
route 2:
wherein R is 1 、R 2 X andx is as defined above 1 A leaving group selected from halogen and the like.
Detailed Description
Abbreviations in the present application, for example: DMF represents N, N-dimethylformamide; boc represents t-butoxycarbonyl; naOAc represents sodium acetate; meOH represents methanol; tBu represents tert-butyl; TBS represents tert-butyldimethylsilyl.
The application is further illustrated by examples, which are not intended to limit the scope of the application, for clarity. All reagents used in the present application are commercially available and can be used without further purification.
Example 1 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydro-2H-pyran-4-ylmethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 1-b
Phosphorus oxychloride was added dropwise to a solution of DMF (173.7 g) and dichloromethane (460 mL) at 0deg.C, and after the completion of the addition, the temperature was raised to 20deg.C and stirred for 1h, the temperature was lowered to 0deg.C, 3-dimethylcyclohexanone (1-a) (200 g) was added dropwise, and the mixture was heated to reflux overnight. The reaction was added dropwise to a solution containing NaOAc (86.7 g), naCl (80 g), water (1.2L) and dichloromethane (600 mL) with stirring, stirred at room temperature for 20min, the aqueous phase was extracted with dichloromethane (500 mL), the organic phases were combined, and the mixture was purified using a solvent containing K 3 PO 4 (40g) A water (1L) solution of NaCl (90 g) was washed once, dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 1-b (249 g).
2) Preparation of Compounds 1-c
Compound 1-b (120 g), tetrabutylammonium bromide (224.1 g) and acetonitrile (240 mL) were mixed, stirred, and K was added 2 CO 3 (192.1 g) in water (720 mL) was further added 4-trifluoromethylphenylboronic acid (138.6 g), palladium acetate (3.1 g), N 2 Protection, reaction at 40 DEG COvernight. 1L (containing 5wt% NaHCO) 3 +2wt% L-cysteine) aqueous solution and 1L ethyl acetate were added to the reaction solution, stirred for 0.5h, filtered, separated, the aqueous phase was extracted with ethyl acetate 0.8L.times.2, the organic phases were combined, and the resulting organic phase was successively washed with 1L (containing 5wt% NaHCO) 3 +2wt% L-cysteine) aqueous solution, saturated NaCl aqueous solution, anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain the compound 1-c (196 g).
3) Preparation of Compounds 1-d
Compound 1-c (196 g), 1-Boc-piperazine (155.3 g) was dissolved in a mixed solution of toluene (680 mL) and tetrahydrofuran (680 mL), and the mixture was stirred, cooled to 0℃and sodium triacetoxyborohydride (235.7 g) was added in portions and stirred at room temperature for 5 hours. After the completion of the reaction, 25% aqueous sodium chloride (2L) was added to the reaction mixture and stirred for 15min, followed by separation of the organic phase with 10% aqueous citric acid, 5% NaHCO 3 Washing with water solution and saturated sodium chloride water solution, concentrating the organic phase, adding acetonitrile (450 mL) into the concentrate, heating to 80 ℃ to stir the solution, cooling for crystallization, filtering, and drying to obtain the compound 1-d (160.5 g).
Compound 1-d: 1 H NMR(500MHz,DMSO-d 6 ),δ:7.67(d,2H),7.27(d,2H),3.24(m,4H),2.72(s,2H),2.20(t,2H),2.07(m,4H),2.00(s,2H),1.43(t,2H),1.36(s,9H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d 6 ),δ:153.6,147.6,134.1,129.4,128.9,126.9,126.7,124.9,124.8,78.5,59.7,52.3,46.1,34.7,28.8,27.9,27.8,25.1.ESI-MS:m/z＝453.4[M+H] + .
4) Preparation of Compounds 1-e
Compounds 1-d (100 g), isopropanol (800 mL) and hydrochloric acid (concentration 36-38 wt%,65 mL) were mixed and heated to 65℃for 3h. Cooling to precipitate a solid, filtering and drying to obtain the compound 1-e (95 g).
Compound 1-e: 1 H NMR(500MHz,DMSO-d 6 ),δ:11.79(br,1H),9.97(br,1H),9.95(br,1H),7.74(d,2H),7.37(d,2H),3.55(m,8H),2.96(s,2H),2.46(s,2H),2.06(m,2H),1.48(t,2H),0.97(s,6H).
13 C NMR(125MHz,DMSO-d 6 ),δ:146.5,129.3,128.3,128.0,126.1,125.8,123.6,58.8,48.4,47.0,34.9,29.1,28.4,26.3.ESI-MS:m/z＝353.3[M+H] + .
5) Preparation of Compounds 1-g
Compounds 1-e (95 g) were treated with K 3 PO 4 Dissolving in water, extracting with ethyl acetate, washing the organic layer with water, drying, filtering, concentrating to dryness, concentrating the concentrate (85 g), 2- [ (1-tert-butyldimethylsilylpyrrolo [2,3-b ]) to obtain a solution]Pyridin-5-yl) oxy]-tert-butyl 4-bromobenzoate (1-f) (110.4 g), tris (dibenzylideneacetone) dipalladium (1.5 g), [ (4- (N, N-dimethylamino) phenyl ]]Di-tert-butylphosphine (0.9 g), sodium tert-butoxide (105 g), toluene (310 mL) and tetrahydrofuran (460 mL) were mixed, stirred, nitrogen-protected, and heated to 55℃for reaction for 4h. With a solution containing L-cysteine (100 g) and NaHCO 3 (150g) The reaction mixture was washed 2 times (750 mL. Times.2) with 1.5L of aqueous solution of NaCl, then washed with saturated aqueous solution of anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain 1-g (185 g) of the compound.
Compound 1-g: 1 H NMR(500MHz,DMSO-d 6 ),δ:7.95(d,1H),7.66(m,3H),7.40(d,1H),7.24(m,3H),6.76(d,1H),6.48(s,2H),3.28(m,4H),2.75(s,2H),2.22(m,6H),2.00(s,2H),1.42(t,2H),1.23(s,9H),0.95(s,6H),0.85(s,9H),0.61(s,6H).
13 C NMR(125MHz,DMSO-d 6 ),δ:163.9,156.3,154.6,149.8,149.3,147.6,134.0,133.1,132.9,132.6,129.5,128.9,124.9,122.2,113.9,113.3,109.7,106.3,102.8,79.6,59.6,52.0,46.6,46.0,34.7,28.8,27.8,27.5,26.2,25.7,25.1,18.5.ESI-MS:m/z＝775.4205[M+H] + .
6) Preparation of Compounds 1-h
A mixture of 1-g (170 g) of the compound, toluene (1.7L) and trifluoroacetic acid (100 mL) was heated to 45℃and reacted for 5 hours. The reaction mixture was concentrated, ethyl acetate (1.5L) was added thereto, and saturated NaHCO was used 3 Washing with water solution and saturated sodium chloride water solution, drying with anhydrous sodium sulfate, filtering, concentrating, adding 1L toluene and 200mL ethyl acetate, heating to dissolve, cooling to precipitate solid, filtering, and drying to obtain compound 1-h (80 g).
Compound 1-h: 1 H NMR(500MHz,DMSO-d 6 ),δ:12.14(br,1H),11.60(br,1H),7.99(d,1H),7.75(d,1H),7.65(d,2H),7.46(t,1H),7.40(d,1H),7.26(d,2H),6.72(dd,1H),6.36(m,2H),3.11(m,4H),2.73(s,2H),2.20(m,6H),1.99(s,2H),1.41(t,2H),0.94(s,6H).
13 C NMR(125MHz,DMSO-d 6 ),δ:166.4,158.9,155.2,148.9,148.2,145.4,135.1,134.6,133.8,130.0,129.5,128.1,127.8,127.5,125.9,125.5,123.7,120.2,116.6,112.1,109.5,105.3,100.3,60.2,52.6,47.1,46.6,35.3,29.4,28.4,27.2,25.7.ESI-MS:m/z＝605.2724[M+H] + .
7) Reference WO2014165044 to the preparation of Compounds 1-k
8) 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydro-2H-pyran-4-ylmethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide (compound I-1)
Compound 1-h (6.1 g) and methylene chloride (100 mL) were mixed and stirred at room temperature, 4-dimethylaminopyridine (2.5 g) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.8 g) were added, and 3-nitro-4- [ [ (tetrahydropyran-4-yl) methyl group were added thereto and dissolved with stirring]Amino group]Benzenesulfonamide (1-k) (3.2 g) and triethylamine (3.1 g) were reacted at room temperature for 3 hours. Sequentially washing with 5wt% hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, anhydrous Na 2 SO 4 Drying, filtering, concentrating, adding dichloromethane (100 mL), meOH (10 mL) and petroleum ether (100 mL), heating to reflux, dissolving, naturally cooling to precipitate solid, filtering, and drying to obtain the compound I-1 (6.3 g).
Compound I-1: 1 H NMR(500MHz,DMSO-d 6 ),δ:11.69(s,1H),11.45(br,1H),8.53(m,2H),8.01(d,1H),7.78(dd,1H),7.64(d,2H),7.49(m,3H),7.24(d,2H),7.05(d,1H),6.65(dd,1H),6.36(dd,1H),6.19(d,1H),3.84(m,2H),3.28(m,4H),3.07(m,4H),2.77(s,2H),2.22(m,6H),1.97(m,2H),1.61(m,2H),1.39(t,2H),1.25(m,3H),0.93(s,6H).
13 C NMR(125MHz,DMSO-d 6 ),δ:157.5,154.1,147.5,147.0,145.2,135.2,134.0,132.0,129.5,129.0,127.5,127.2,127.0,126.7,125.4,125.0,123.2,119.7,117.5,114.7,108.8,99.8,66.6,59.7,59.5,51.9,47.9,46.5,46.1,34.7,33.8,30.1,28.8,27.8,25.2,20.7,14.0.ESI-MS:m/z＝902.4[M+H] + .
example 2 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (2- (1-methylpiperidin-4-yl) ethoxy ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 2-k
Compound 1-methyl-4- (hydroxyethyl) piperidine (1.45 g) was dissolved in tetrahydrofuran (20 mL), the solution was cooled down in an ice bath, sodium hydride (1 g) was added in portions, and after stirring for 0.5h, compound 3-nitro-4-chlorobenzenesulfonamide (2 g) was added and stirred at room temperature for 4h. Quenching with dilute hydrochloric acid, extracting with ethyl acetate, washing with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, filtering, and concentrating. The compound 2-k (2 g) is obtained by column chromatography separation and purification. Compound 2-k: ESI-MS: m/z=342.1 [ M-H ]] - 。
2) Preparation of Compound I-2
Compound 1-h (6.1 g) and methylene chloride (100 mL) were mixed and stirred at room temperature, 4-dimethylaminopyridine (2.5 g) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.8 g) were added, and the mixture was dissolved with stirring, and compound 2-k (3.4 g) and triethylamine (3.1 g) were added and reacted at room temperature for 3 hours. Sequentially washing with 5wt% hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, anhydrous Na 2 SO 4 Drying, filtering, concentrating, and separating and purifying by column chromatography to obtain compound I-2 (6.3 g).
Compound I-2: 1 H NMR(500MHz,DMSO-d6),δ:11.83(br,1H),11.74(s,1H),8.40(s,1H),8.11(d,1H),8.05(s,1H),7.70(d,2H),7.58(s,1H),7.54(m,2H),7.47(d,1H),7.30(d,2H),6.72(d,1H),6.42(s,1H),6.26(s,1H),4.29(t,2H),3.42(t,4H),3.10(m,4H),2.91(m,4H),2.79(s,2H),2.76(s,3H),2.23(m,2H),2.04(s,2H),1.93(m,2H),1.73(m,3H),1.47(s,2H),1.39(t,2H),0.96(s,6H). 13 C NMR(125MHz,DMSO-d6),δ:164.1,158.7,158.5,155.4,154.2,146.8,146.0,138.7,135.7,134.2,132.7,131.3,129.3,128.4,126.0,125.7,120.3,118.6,116.2,116.1,109.5,103.3,100.5,68.3,58.6,54.0,51.1,46.9,44.4,43.1,34.7,34.4,30.3,29.4,29.1,28.3,25.7,25.2.ESI-MS:m/z＝928.6[M-H] - .
example 3 (S) -4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4-methylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 3-k
3-nitro-4-chlorobenzenesulfonamide (2.0 g), (S) -4-methyl-2-morpholinemethylamine (1.3 g) and N, N-diisopropylethylamine (2.7 g) were dissolved in acetonitrile (20 mL), heated to 80℃and reacted for 5 hours, cooled at room temperature, left to stand overnight, and suction filtered to give compound 3-k (1.9 g). Compound 3-k: ESI-MS: m/z=329.1 [ M-H ]] - .
2) Preparation of Compound I-3
Reference example 2 the preparation of compound I-2 in step 2) was carried out by changing the compound 2-k into the compound 3-k to obtain the compound I-3.
Compound I-3: 1 H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.71(s,1H),8.66(br,1H),8.59(s,1H),8.04(s,1H),7.86(d,1H),7.70(m,2H),7.56(m,1H),7.53(m,2H),7.31(m,2H),7.18(d,1H),6.72(d,1H),6.41(s,1H),6.27(s,1H),4.09(t,2H),3.96(m,1H),3.71(t,4H),3.58(m,3H),3.51(d,2H),3.40(d,2H),3.04(m,3H),2.93(t,2H),2.84(s,3H),2.23(m,2H),2.05(s,2H),1.48(m,2H),0.96(s,6H). 13 C NMR(125MHz,DMSO-d6),δ:164.0,159.2,158.9,158.6,158.3,154.0,147.8,146.8,146.3,145.9,141.9,135.6,134.3,132.6,130.6,129.2,128.3,128.1,128.0,126.1,125.5,122.6,120.3,118.5,117.6,115.8,115.3,114.0,109.6,103.5,100.5,72.2,64.0,58.5,54.6,52.4,51.0,46.9,44.5,44.2,43.3,34.7,29.1,28.3,25.2.ESI-MS:m/z＝917.6[M+H] + .
example 4 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1, 4-dioxan-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 4-k
3-nitro-4-chlorobenzenesulfonamide (2.0 g), 1, 4-dioxane-2-methylamine (1.2 g) and N, N-diisopropylethylamine (2.7 g) were dissolved in acetonitrile (20 mL), heated to 80℃and reacted for 5 hours, cooled at room temperature, left to stand overnight, and suction-filtered to give compound 4-k (2.0 g). Compound 4-k: ESI-MS: m/z=316.1 [ M-H ] ] - 。
2) Preparation of Compound I-4
Reference example 2 the preparation of compound I-2 in step 2) was carried out by changing the compound 2-k into the compound 4-k to obtain the compound I-4.
Compound I-4: 1 H NMR(500MHz,DMSO-d6),δ:11.71(s,1H),11.68(s,1H),8.59(t,1H),8.57(d,1H),8.04(d,1H),7.83(dd,1H),7.71(d,2H),7.55(d,1H),7.53(m,2H),7.30(m,2H),7.12(d,1H),6.72(dd,1H),6.40(dd,1H),6.27(d,1H),3.79(m,3H),3.65(m,6H),3.50(m,2H),3.41(m,2H),3.34(m,2H),3.03(m,2H),2.78(m,2H),2.22(m,2H),2.05(s,2H),1.48(m,2H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,158.9,158.6,158.2,154.0,147.9,146.9,146.2,145.9,142.0,135.6,134.3,132.6,130.2,129.2,128.3,128.2,126.1,125.1,123.7,122.5,120.3,118.4,117.3,115.7,115.0,114.1,109.6,103.5,100.4,73.4,68.5,66.4,66.2,58.5,51.0,46.9,44.2,43.9,34.6,29.1,28.3,25.2.ESI-MS:m/z＝904.6[M+H] + .
example 5 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (2- (1-methylpiperidin-4-yl) ethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 5-k
3-nitro-4-chlorobenzenesulfonamide (2.0 g), N-methyl-4- (2-aminoethyl) piperidine (1.4 g) and N, N-diisopropylethylamine (2.7 g) were dissolved in acetonitrile (20 mL), heated to 80℃and reacted for 5h, cooled at room temperature, allowed to stand overnight, and suction filtered to give compound 5-k (2.1 g). Compound 5-k: ESI-MS: m/z=341.1 [ M-H ]] - 。
2) Preparation of Compound I-5
Reference example 2 the preparation of compound I-2 in step 2) was carried out by changing the compound 2-k into the compound 5-k to obtain the compound I-5.
Compound I-5: 1 H NMR(500MHz,DMSO-d6),δ:8.58(t,1H),8.57(d,1H),8.04(d,1H),7.84(dd,1H),7.71(d,2H),7.55(d,1H),7.52(m,2H),7.30(m,2H),7.08(d,1H),6.72(dd,1H),6.40(dd,1H),6.27(d,1H),3.58(m,2H),3.42(m,4H),3.27(m,4H),3.04(m,4H),2.90(t,2H),2.75(s,3H),2.23(m,2H),2.04(s,2H),1.94(d,2H),1.57(m,2H),1.47(t,2H),1.35(m,2H),1.24(m,1H),0.96(s,6H). 13 C NMR(125MHz,DMSO-d6),δ:164.0,159.2,158.9,158.6,158.4,158.2,154.0,147.6,146.8,146.3,145.9,141.9,135.6,134.4,132.6,130.1,129.2,128.3,126.0,125.8,124.8,123.7,122.6,120.3,118.4,117.6,115.4,115.3,114.1,109.6,58.4,53.9,51.0,46.9,44.2,43.1,34.7,34.3,30.8,29.4,29.1,28.3,25.2.ESI-MS:m/z＝929.7[M+H] + .
example 6 4- (4- { [2- (2-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydro-2H-pyran-4-ylmethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
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1) Preparation of Compound 6-c
Compounds 1-b (5.16 g), 4-triphenylphosphine palladium (0.17 g), K 3 PO 4 (12.74 g), DMF (60 mL) and water (60 mL) were mixed and stirred for 10min, and 2-trifluoromethylphenylboronic acid (6.27 g) and N were further added 2 Protecting, reacting for 6 hours at 100 ℃, and completely reacting. 30mL (containing 5wt% NaHCO) 3 +2wt% L-cysteine) aqueous solution and 50mL ethyl acetate were added to the reaction solution, stirred for 0.5h, filtered, separated, the aqueous phase was extracted with 60mL X2 ethyl acetate, the organic phases were combined, the resulting organic phase was washed with saturated aqueous NaCl solution, anhydrous Na 2 SO 4 Drying, filtering, concentrating, and column chromatography to obtain compound 6-c (2 g).
2) Preparation of Compound 6-e
2- [ (1H-pyrrolo [2, 3-b)]Pyridin-5-yl) oxy]-tert-butyl 4-bromobenzoate (compound 1-f) (77.8 g), boc-piperazine (55.8 g), tris (dibenzylideneacetone) dipalladium (9 g), [ (4- (N, N-dimethylamino) phenyl)]Di-tert-butylphosphine (5.2 g), sodium tert-butoxide (96.1 g), toluene (800 mL) and tetrahydrofuran (300 mL) were mixed, stirred, nitrogen-protected, and heated to 60℃for 24 hours. With a solution containing L-cysteine (100 g) and NaHCO 3 (150g) The reaction mixture was washed 2 times (750 mL. Times.2) with an aqueous solution (1.5L) of saturated NaCl, and with anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain the compound 6-e (40 g). Compound 6-e: ESI-MS: m/z=495.4 [ M+H ] ]+.
3) Preparation of Compound 6-f
Compound 6-e (40 g), 800mL of tetrahydrofuran, 270mL of ethanol and 15mL of water were mixed, stirred, KOH (45.3 g) solid was added, the temperature was raised to 80℃and the mixture was refluxed for 8 hours with stirring, and the reaction was complete. 500mL of water was added thereto and stirred, pH was adjusted to 5 to 6 with dilute hydrochloric acid, the mixture was filtered, slurried with water (1L) 2 times (500 mL. Times.2), and dried to give Compound 6-f (35 g).
4) Preparation of Compound 6-h
Compound 6-f (35 g) and methylene chloride (100 mL) were mixed and stirred at room temperature, 4-dimethylaminopyridine (38.5 g) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (65.8 g) were added, and 3-nitro-4- [ [ (tetrahydropyran-4-yl) methyl group was added thereto and dissolved with stirring]Amino group]Benzenesulfonamide (compound 1-k) (25.2 g) was reacted at room temperature for 3 hours. Ei-yiWashing with 5wt% hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, anhydrous Na 2 SO 4 Drying, filtration, concentration, adding dichloromethane (200 mL) at room temperature stirring for 2h, filtration, drying to obtain compound 6-h (40 g).
5) Preparation of Compound 6-i
The compound 6-h is added into 500ml of isopropanol and stirred, 50ml of concentrated HCl is added, the temperature is raised to 65 ℃ and stirred for 8h, and the reaction is complete. Filtering, dissolving the filter cake in 300ml of water, dripping saturated sodium bicarbonate to adjust the pH to 6-7, filtering, drying, pulping the obtained solid with 200ml of ethyl acetate, filtering and drying to obtain the compound 6-i (27 g).
6) Preparation of Compound I-6
Compound 6-c (1 g) and compound 6-i (2.25 g) were dissolved in 20mL of methanol, stirred, sodium borohydride (0.27 g) was added, and stirred for 6 hours, to complete the reaction. Quenched by adding 10mL of saturated aqueous ammonium chloride solution, extracted twice with 20mL of ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried Na 2 SO 4 Drying, filtering, concentrating the filtrate, and performing column chromatography to obtain the compound I-6 (200 mg).
Compound I-6: 1 H NMR(500MHz,DMSO-d6),δ:11.73(s,1H),11.68(s,1H),8.61(m,1H),8.57(d,1H),8.04(d,1H),7.81(dd,1H),7.72(d,1H),7.61(m,1H),7.56(d,1H),7.50(dd,3H),7.25(d,1H),7.12(d,1H),6.72(dd,1H),6.40(m,1H),6.26(d,1H),3.84(dd,3H),3.61(d,2H),3.25(m,6H),3.12(d,2H),2.31(d,1H),1.88(m,5H),1.54(d,2H),1.51(m,1H),1.43(m,1H),1.23(m,4H),0.96(s,3H),0.92(s,3H).
13 C NMR(125MHz,DMSO-d6),δ:163.9,158.8,158.5,158.2,153.9,147.9,146.8,145.9,140.2,135.6,134.3,133.3,132.5,131.0,130.0,128.4,128.3,126.8,125.6,124.7,120.3,118.4,115.5,114.1,109.7,103.4,100.4,67.0,58.9,48.4,47.0,44.2,34.6,34.3,30.6,29.1,29.0,28.8,27.6,24.6.ESI-MS:m/z＝902.6[M+H] + .
example 7 4- (4- { [2- (3-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydro-2H-pyran-4-ylmethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 7-c
Compounds 1-b (5.16 g), 4-triphenylphosphine palladium (0.17 g), K 3 PO 4 (12.74 g), DMF (60 mL) and water (60 mL) were mixed and stirred for 10min, and 3-trifluoromethylphenylboronic acid (6.27 g) and N were further added 2 Protecting, reacting for 6 hours at 100 ℃, and completely reacting. 30mL (containing 5wt% NaHCO) 3 +2wt% L-cysteine) aqueous solution and 50mL ethyl acetate were added to the reaction solution, stirred for 0.5h, filtered, separated, the aqueous phase was extracted with 60mL X2 ethyl acetate, the organic phases were combined, the resulting organic phase was washed with saturated aqueous NaCl solution, anhydrous Na 2 SO 4 Drying, filtering, concentrating, and column chromatography to obtain compound 7-c (1.5 g).
2) Preparation of Compound I-7
Compound 7-c (1 g) and compound 6-i (2.25 g) were dissolved in 20mL of methanol, stirred, sodium borohydride (0.27 g) was added, and stirred for 6 hours, to complete the reaction. Quenched by adding 10mL of saturated aqueous ammonium chloride solution, extracted twice with 20mL of ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried Na 2 SO 4 Drying, filtering, concentrating the filtrate, and performing column chromatography to obtain the compound I-7 (100 mg).
Compound I-7: 1 H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.67(s,1H),8.61(m,1H),8.57(d,1H),8.04(d,1H),7.80(dd,1H),7.63(d,1H),7.51(m,4H),7.37(m,2H),7.12(d,1H),6.70(dd,1H),6.39(m,1H),6.25(d,1H),3.84(dd,2H),3.58(s,4H),3.24(m,6H),3.05(s,2H),,2.22(s,2H),2.06(s,2H),1.88(m,1H),1.60(d,2H),1.46(m,2H),1.22(m,4H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:163.9,158.8,158.5,158.2,153.9,147.9,146.8,145.9,142.9,135.6,134.3,132.5,130.2,130.0,129.9,129.7,128.3,125.6,124.7,124.4,123.4,122.7,120.3,118.4,115.5,114.1,109.6,103.4,100.4,67.0,58.3,50.9,48.4,46.9,44.1,34.6,34.3,30.6,29.1,29.0,28.3,25.2.ESI-MS:m/z＝902.6[M+H] + .
example 8 (R) -4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1, 4-dioxan-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 8-k
3-nitro-4-chlorobenzenesulfonamide (0.64 g), (R) - (1, 4-dioxane) -2-methylamine hydrochloride (0.5 g) and N, N-diisopropylethylamine (1.6 g) were dissolved in acetonitrile (10 mL), heated to 85℃and reacted for 6.5 hours, cooled at room temperature, left to stand overnight, filtered to give compound 8-k (0.65 g). Compound 8-k: ESI-MS: m/z=316.2 [ M-H ]] - .
2) Preparation of Compound I-8
Compound 1-h (0.61 g) and methylene chloride (15 mL) were mixed and stirred at room temperature, 4-dimethylaminopyridine (0.24 g) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.38 g) were added, dissolved in stirring, and compound 8-k (0.61 g) and triethylamine (0.30 g) were added to react at room temperature for 12 hours. Sequentially washing with 5wt% hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, anhydrous Na 2 SO 4 Drying, filtering, concentrating, and separating and purifying by column chromatography to obtain compound I-8.
Compound I-8: 1 H NMR(500MHz,DMSO-d6),δ:11.72(d,2H),8.59(br,1H),8.04(s,1H),7.84(d,1H),7.71(d,2H),7.55(m,1H),7.53(m,2H),7.30(d,2H),7.12(d,1H),6.72(d,1H),6.40(s,1H),6.28(s,1H),3.80(t,3H),3.65(m,3H),3.58(m,2H),3.50(d,2H),3.40(m,2H),3.33(t,2H),3.04(m,2H),2.78(m,2H),2.23(m,2H),2.05(s,2H),1.48(t,2H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,158.9,158.6,158.3,158.2,154.0,147.9,146.8,146.3,145.9,141.9,135.6,134.3,132.6,130.2,129.2,128.3,128.2,127.9,126.0,125.8,125.2,123.7,122.6,120.3,118.4,117.7,115.7,115.4,114.1,109.6,103.5,100.4,51.0,46.9,44.3,43.9,34.7,29.1,28.3,25.2.ESI-MS:m/z＝904.6[M+H] + .
example 9 (S) -4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1, 4-dioxan-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 9-k
3-nitro-4-fluorobenzenesulfonamide (0.6 g), (S) -2- (aminomethyl) -1, 4-dioxane hydrochloride (0.5 g) and N, N-diisopropylethylamine (1.6 g) were dissolved in acetonitrile (20 mL), heated to 85℃and reacted for 5 hours, cooled at room temperature, left to stand overnight, and suction-filtered to give compound 9-k (0.39 g). Compound 9-k: ESI-MS: m/z=316.1 [ M-H ]] - 。
2) Preparation of Compound I-9
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 9-k to give compound I-9.
Compound I-9: 1 H NMR(500MHz,DMSO-d6),δ:8.59(t,1H),8.57(d,1H),8.04(d,1H),7.89(d,1H),7.84(dd,1H),7.70(d,1H),7.54(d,1H),7.52(m,2H),7.40(m,1H),7.11(d,1H),6.75(dd,1H),6.40(dd,1H),6.29(d,1H),3.79(m,4H),3.66(m,2H),3.62(m,2H),3.49(m,2H),3.39(t,2H),3.33(m,2H),3.03(m,5H),2.27(m,1H),2.21(m,1H),1.96(d,3H),1.48(t,2H),1.24(m,1H),0.97(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,159.0,158.7,158.2,154.0,147.9,146.8,146.3,145.9,142.0,135.6,134.3,132.6,130.2,129.2,128.3,128.2,128.0,126.0,125.8,125.1,123.7,122.6,120.3,118.4,117.3,115.7,115.0,114.1,109.6,103.5,100.5,73.4,68.5,66.4,66.2,58.5,51.0,46.9,44.2,43.8,34.7,29.1,28.3,25.2.ESI-MS:m/z＝905.4[M+H] + .
example 10 (R) -4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4-methoxyacetyl morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 10-k
3-nitro-4-fluorobenzenesulfonamide (0.36 g), (R) -2- (aminomethyl) -4-methoxyacetyl morpholine hydrochloride (0.45 g) and N, N-diisopropylethylamine (0.97 g) were dissolved in acetonitrile (20 mL), heated to 85℃and reacted for 5 hours, cooled at room temperature, left to stand overnight, and suction filtered to give compound 10-k (0.39 g). Compound 10-k: ESI-MS: m/z=387.1 [ M-H ] ] - 。
2) Preparation of Compound I-10
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 10-k to give compound I-10.
Compound I-10: 1 H NMR(500MHz,DMSO-d6),δ:8.64(m,1H),8.58(d,1H),8.05(d,1H),7.83(dd,1H),7.71(d,2H),7.56(d,1H),7.52(m,2H),7.30(m,2H),7.16(m,1H),6.72(dd,1H),6.40(dd,1H),6.27(d,1H),4.22(m,3H),3.47(m,3H),3.27(m,5H),3.17(m,1H),3.00(m,2H),2.77(m,3H),2.64(m,1H),2.22(m,2H),2.05(m,3H),1.48(t,2H),1.24(m,4H),0.96(s,9H).ESI-MS:m/z＝976.4[M+H] + .
example 11 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1- (2-methoxyacetyl) piperidin-4-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 11-k
3-nitro-4-fluorobenzenesulfonamide (1.56 g), [ (4-methoxyacetyl piperidin-2-yl) methyl]Amine (1.56 g) and N, N-diisopropylethylamine (2.30 g) were dissolved in acetonitrile (10 mL), heated to 85℃and reacted for 6h, cooled at room temperature, left standing overnight, and suction filtered to give compound 11-k (1.92 g). Compound 11-k: ESI-MS: m/z=387.0 [ M+H ]] + .
2) Preparation of Compound I-11
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 11-k to give compound I-11.
Compound I-11: 1 H NMR(500MHz,DMSO-d6),δ:11.74(s,2H),8.64(t,1H),8.58(d,1H),8.05(d,1H),7.82(d,1H),7.70(d,2H),7.54(d,3H),7.28(d,2H),7.14(d,1H),6.73(d,1H),6.40(s,1H),6.30(s,1H),4.35(d,1H),4.06(dd,2H),3.71(m,5H),3.32(t,4H),3.28(s,3H),2.93(m,5H),2.23(s,1H),2.06(d,3H),1.90(m,1H),1.73(d,2H),1.48(t,2H),1.17(m,3H),0.96(d,6H).
13 C NMR(125MHz,DMSO-d6),δ:167.3,164.0,159.3,159.0,158.7,158.2,154.0,147.9,146.8,146.3,145.9,142.0,135.6,134.3,132.6,130.1,129.2,128.4,128.2,126.0,125.8,124.8,123.6,122.6,120.4,118.5,117.3,115.6,115.0,114.1,109.6,103.4,100.5,71.2,58.7,58.4,51.0,48.0,46.9,44.4,44.2,41.4,35.3,34.6,30.3,29.6,29.1,28.3,25.2.ESI-MS:m/z＝973.4[M+H] + .
example 12 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (3-dimethylaminopropyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 12-k
3-nitro-4-fluorobenzenesulfonamide (3.59 g), N 1 ,N 1 -dimethyl-1, 3-propanediamine (2.00 g) and N, N-diisopropylethylamine (5.28 g) were dissolved in acetonitrile (20 mL), heated to 85℃and reacted for 6h, cooled at room temperature, left standing overnight, and suction filtered to give compound 12-k (4.15 g). Compound 12-k: ESI-MS: m/z=301.1 [ M-H ]] - .
2) Preparation of Compound I-12
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 12-k to give compound I-12.
Compound I-12: 1 H NMR(500MHz,DMSO-d6),δ:11.56(s,1H),11.53(s,1H),8.53(m,1H),8.45(d,1H),7.95(d,1H),7.71(m,1H),7.65(dd,2H),7.57(d,1H),7.44(m,1H),7.34(d,1H),7.26(dd,2H),6.87(d,1H),6.63(d,1H),6.32(m,1H),6.23(m,1H),3.41(dd,3H),3.01(m,4H),2.86(m,2H),2.72(d,2H),2.58(m,6H),2.18(m,5H),1.98(m,2H),1.87(m,2H),1.40(m,2H),0.94(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:157.1,153.6,149.0,148.1,146.3,145.3,135.4,135.0,134.6,132.6,130.1,130.0,129.5,127.6,127.4,127.2,126.5,125.9,125.5,125.4,123.8,120.1,116.9,114.1,109.6,105.4,100.2,60.2,55.7,55.4,52.7,47.7,46.6,43.7,35.3,29.4,28.4,25.7,24.5.ESI-MS:m/z＝889.4[M+H] + .
example 13 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (3-diethylaminopropyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 13-k
3-nitro-4-fluorobenzenesulfonamide (2.82 g), N 1 ,N 1 Diethyl-1, 3-propanediamine (2.00 g) and N, N-diisopropylethylamine (4.14 g) were dissolved in acetonitrile (20 mL), heated to 85℃and reacted for 6 hours, cooled at room temperature, left standing overnight, and suction filtered to give compound 13-k (3.59 g). Compound 13-k: ESI-MS: m/z=329.1 [ M-H ]] - .
2) Preparation of Compound I-13
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 13-k to give compound I-13.
Compound I-13: 1 H NMR(500MHz,DMSO-d6),δ:11.54(s,2H),8.48(m,1H),8.44(d,1H),7.94(d,1H),7.71(m,1H),7.65(dd,2H),7.58(d,1H),7.44(m,1H),7.33(d,1H),7.26(dd,2H),6.89(d,1H),6.62(d,1H),6.31(m,1H),6.24(m,1H),3.42(dd,3H),3.01(m,4H),2.96(m,5H),2.73(d,2H),2.18(m,6H),1.99(m,2H),1.88(m,2H),1.40(m,2H),1.11(t,6H),0.94(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:157.0,153.5,148.1,146.2,145.2,135.4,135.1,134.5,132.6,130.1,130.0,129.5,127.6,127.4,126.3,125.9,125.5,123.8,120.1,116.8,114.0,109.6,105.7,100.2,60.2,55.4,52.7,49.4,47.7,46.8,46.6,35.3,29.4,28.4,25.7,9.7.ESI-MS:m/z＝917.4[M+H] + .
example 14 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydro-2H-pyran-4-ylmethyl) oxy ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 14-k
4-hydroxymethyl tetrahydropyran (0.50 g) was dissolved in tetrahydrofuran (20 mL) (0 ℃ C.), sodium hydride (purity 60%) (0.34 g) was slowly added, followed by 3-nitro-4-fluorobenzenesulfonamide (0.79 g), reacted at room temperature for 5 hours, 20mL of 10% aqueous sodium chloride solution was added, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to give compound 14-k (0.56 g). Compound 14-k: ESI-MS: m/z=315.0 [ M-H ]] - .
2) Preparation of Compound I-14
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 14-k to give compound I-14.
Compound I-14: 1 H NMR(500MHz,DMSO-d6),δ:11.65(s,2H),8.36(m,1H),8.04(m,2H),7.65(dd,2H),7.52(m,3H),7.40(m,1H),7.25(dd,2H),6.67(d,1H),6.40(m,1H),6.20(m,1H),4.08(m,1H),3.89(m,2H),3.33(m,6H),3.09(m,3H),2.83(m,2H),2.28(m,2H),2.18(m,2H),2.01(m,3H),1.64(m,2H),1.41(m,2H),1.35(dd,2H),0.94(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:158.3,155.1,154.8,147.9,147.2,145.9,138.5,135.7,134.2,132.6,129.5,128.2,127.5,127.3,125.9,125.5,123.7,120.3,118.3,115.7,109.3,103.1,100.4,74.5,67.0,60.0,52.4,46.8,46.6,35.2,34.6,29.3,29.2,28.4,25.6.ESI-MS:m/z＝903.3[M+H] + .
example 15 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (2-dimethylaminoethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 15-k
3-nitro-4-fluorobenzenesulfonamide (2.08 g), N 1 ,N 1 Dimethyl ethylenediamine (1.00 g) and N, N-diisopropylethylamine (3.06 g) were dissolved in acetonitrile (20 mL), heated to 85℃and reacted for 6 hours, cooled at room temperature, left standing overnight, and suction filtered to give compound 15-k (2.40 g). Compound 15-k: ESI-MS: m/z=287.1 [ M-H ]] - .
2) Preparation of Compound I-15
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 15-k to give compound I-15.
Compound I-15: 1 H NMR(500MHz,DMSO-d6),δ:11.61(s,1H),11.59(s,1H),8.53(m,1H),8.51(d,1H),7.99(d,1H),7.79(m,1H),7.65(dd,2H),7.53(d,1H),7.46(m,1H),7.43(d,1H),7.26(dd,2H),6.98(d,1H),6.65(d,1H),6.35(m,1H),6.22(m,1H),5.76(m,1H),3.54(m,2H),3.04(m,4H),2.85(m,2H),2.73(d,2H),2.47(m,5H),2.19(m,6H),1.99(m,2H),1.41(m,2H),0.94(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:157.7,154.3,148.1,146.7,145.6,135.5,134.8,132.6,130.3,130.0,129.5,127.9,127.4,127.2,125.9,125.4,123.7,120.2,117.5,114.9,109.4,104.3,100.3,60.2,56.3,55.4,52.6,47.4,46.6,44.5,35.3,29.4,28.4,25.7.ESI-MS:m/z＝875.3[M+H] + .
example 16 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (2-diethylaminoethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 16-k
3-nitro-4-fluorobenzenesulfonamide (1.58 g), N 1 ,N 1 Diethyl ethylenediamine (1.00 g) and N, N-diisopropylethylamine (2.32 g) were dissolved in acetonitrile (20 mL), heated to 85℃and reacted for 6 hours, cooled at room temperature, left standing overnight, and suction filtered to give compound 16-k (1.93 g). Compound 16-k: ESI-MS: m/z=315.1 [ M-H ]] - .
2) Preparation of Compound I-16
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 16-k to give compound I-16.
Compound I-16: 1 H NMR(500MHz,DMSO-d6),δ:11.61(s,1H),11.52(s,1H),8.62(m,1H),8.52(d,1H),8.00(d,1H),7.80(m,1H),7.65(dd,2H),7.53(d,1H),7.46(m,1H),7.44(d,1H),7.25(dd,2H),6.97(d,1H),6.64(d,1H),6.35(m,1H),6.21(m,1H),3.51(m,3H),3.04(m,4H),2.91(m,2H),2.77(d,3H),2.72(m,2H),2.19(m,6H),1.98(m,2H),1.40(m,2H),1.06(t,6H),0.94(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:157.7,154.3,148.1,146.7,145.6,135.6,134.8,134.6,132.5,130.2,130.0,129.5,127.9,127.4,127.3,127.2,125.9,125.5,125.4,123.7,120.2,117.6,115.0,109.4,104.1,100.3,60.2,52.6,50.3,47.4,46.7,46.6,35.3,29.4,28.4,25.7,11.1.ESI-MS:m/z＝903.4[M+H] + .
example 17 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydro-2H-pyran-3-ylmethyl) oxy ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 17-k
3-hydroxymethyl tetrahydropyran (0.50 g) was dissolved in tetrahydrofuran (20 mL) (0 ℃ C.), sodium hydride (purity 60%) (0.34 g) was slowly added, followed by 3-nitro-4-fluorobenzenesulfonamide (0.79 g), reacted at room temperature for 5 hours, 20mL of 10% aqueous sodium chloride solution was added, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to give compound 17-k (0.52 g). Compound 17-k: ESI-MS: m/z=315.0 [ M-H ]] - .
2) Preparation of Compound I-17
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 17-k to give compound I-17.
Compound I-17: 1 H NMR(500MHz,DMSO-d6),δ:11.69(s,1H),11.56(s,1H),8.37(m,1H),8.05(m,2H),7.66(dd,2H),7.52(m,3H),7.40(d,1H),7.25(dd,2H),6.67(d,1H),6.40(m,1H),6.21(m,1H),4.10(m,1H),3.87(m,1H),3.74(m,1H),3.35(m,6H),3.10(m,4H),2.83(m,2H),2.28(m,3H),2.18(m,2H),1.98(m,2H),1.62(m,1H),1.43(m,3H),1.24(m,1H),0.94(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:158.3,155.0,154.8,147.9,147.1,145.9,138.4,135.7,134.2,132.7,129.5,128.2,127.5,127.3,125.9,125.6,123.7,120.3,118.2,115.7,109.3,100.4,71.6,69.6,68.0,60.0,52.4,46.8,46.6,35.6,35.2,29.3,28.4,25.6,24.9.ESI-MS:m/z＝903.3[M+H] + .
example 18 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (ethoxycarbonylmethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 18-k
Dissolving 3-nitro-4-fluorobenzenesulfonamide (2.63 g), glycine ethyl ester hydrochloride (2.00 g) and N, N-diisopropylethylamine (6.95 g) in acetonitrile (30 mL), heating to 85 ℃, reacting for 6h, cooling at room temperature, standing overnight, and suction filtering to obtain the final productCompound 18-k (3.26 g). Compound 18-k: ESI-MS: m/z=302.1 [ M-H ]] - .
2) Preparation of Compound I-18
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 18-k to give compound I-18.
Compound I-18: 1 H NMR(500MHz,DMSO-d6),δ:11.68(s,1H),8.79(m,1H),8.69(d,1H),8.05(d,1H),7.86(m,1H),7.65(dd,2H),7.56(d,1H),7.50(m,2H),7.25(dd,2H),6.99(d,1H),6.67(d,1H),6.39(m,1H),6.18(m,1H),4.32(d,2H),4.19(m,2H),3.07(m,4H),2.76(m,2H),2.21(m,4H),2.17(m,2H),1.98(m,2H),1.40(m,2H),1.24(m,4H),0.94(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:169.7,158.4,155.0,148.0,147.2,146.9,145.9,135.8,134.4,132.6,130.5,129.5,128.2,127.9,127.2,125.5,123.7,120.2,118.5,116.0,109.2,102.7,100.4,61.6,60.0,52.5,46.9,46.6,44.8,35.2,29.3,28.4,25.6,14.5.ESI-MS:m/z＝890.3[M+H] + .
example 19 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (2- (N-methylpyrrolidin-2-yl) ethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 19-k
3-nitro-4-fluorobenzenesulfonamide (2.86 g), N-methyl-2- (2-aminoethyl) -pyrrolidine (2.00 g) and N, N-diisopropylethylamine (4.20 g) were dissolved in acetonitrile (30 mL), heated to 85℃and reacted for 6 hours, cooled at room temperature, left to stand overnight, and suction filtered to give compound 19-k (2.00 g). Compound 19-k: ESI-MS: m/z=327.1 [ M-H ]] - .
2) Preparation of Compound I-19
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 19-k to give compound I-19.
Compound I-19： 1 H NMR(500MHz,DMSO-d6),δ:11.73(s,2H),8.64(m,1H),8.59(d,1H),8.04(d,1H),7.87(m,1H),7.70(dd,2H),7.56(d,1H),7.52(m,2H),7.30(dd,2H),7.16(d,1H),6.72(d,1H),6.40(m,1H),6.27(m,1H),3.55(m,6H),3.08(m,6H),2.83(m,5H),2.23(m,4H),1.91(m,5H),1.46(m,4H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,159.3,159.0,158.4,158.3,154.0,147.5,146.8,146.3,145.9,141.9,135.6,134.5,132.6,130.4,129.2,128.3,128.2,127.9,126.0,125.8,122.6,118.5,117.5,115.4,115.2,114.1,109.6,103.5,100.5,82.7,66.6,58.4,55.6,51.0,46.9,44.2,39.1,34.7,29.4,29.3,29.1,28.3,27.0,25.2,21.5.ESI-MS:m/z＝915.4[M+H] + .
Example 20 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydro-2H-pyran-4-yl) oxy ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
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1) Preparation of Compound 20-k
4-Hydroxytetrahydropyran (0.50 g) was dissolved in tetrahydrofuran (20 mL) (0 ℃ C.), sodium hydride (purity 60%) (0.39 g) was slowly added, followed by 3-nitro-4-fluorobenzenesulfonamide (0.90 g), reacted at room temperature for 5 hours, 20mL of a 10% aqueous sodium chloride solution was added, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to give compound 20-k (0.52 g). Compound 20-k: ESI-MS: m/z=301.1 [ M-H ]] - .
2) Preparation of Compound I-20
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 20-k to give compound I-20.
Compound I-20: 1 H NMR(500MHz,DMSO-d6),δ:11.75(s,2H),8.40(m,1H),8.06(m,2H),7.70(dd,2H),7.56(m,4H),7.30(dd,2H),6.72(d,1H),6.42(m,1H),6.26(m,1H),3.79(m,2H),3.67(m,2H),3.54(m,5H),3.28(m,2H),3.04(m,2H),2.77(m,2H),2.23(m,2H),2.04(m,2H),1.97(m,2H),1.65(m,2H),1.47(m,2H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,159.1,158.9,158.6,158.5,153.9,146.7,146.3,146.0,139.5,135.7,133.9,132.6,131.3,129.2,128.4,126.1,125.9,123.7,122.6,120.4,118.7,117.6,116.9,115.3,113.8,109.5,103.2,100.5,74.4,64.2,58.5,51.0,46.9,44.2,34.7,31.3,29.1,28.3,25.2.ESI-MS:m/z＝889.3[M+H] + .
example 21 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((tetrahydrofuran-3-yl) methyl) oxy ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 21-k
3-hydroxymethyl tetrahydrofuran (0.50 g) was dissolved in tetrahydrofuran (20 mL) (0 ℃ C.), sodium hydride (purity 60%) (0.39 g) was slowly added, followed by 3-nitro-4-fluorobenzenesulfonamide (0.90 g), reacted at room temperature for 5 hours, 20mL of 10% aqueous sodium chloride solution was added, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to give compound 21-k (0.64 g). Compound 21-k: ESI-MS: m/z=301.1 [ M-H ]] - .
2) Preparation of Compound I-21
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 21-k to give compound I-21.
Compound I-21: 1 H NMR(500MHz,DMSO-d6),δ:11.74(s,2H),8.40(m,1H),8.09(m,1H),8.05(m,1H),7.70(dd,2H),7.57(m,1H),7.53(m,1H),7.46(m,1H),7.30(dd,2H),6.72(d,1H),6.42(m,1H),6.27(m,1H),4.20(m,1H),4.16(m,2H),3.78(m,2H),3.75(m,2H),3.58(m,3H),3.04(m,6H),2.79(m,1H),2.23(m,2H),2.02(m,3H),1.68(m,2H),1.47(m,2H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,159.2,158.9,158.6,158.4,155.4,154.1,146.7,146.3,146.0,142.0,138.6,135.7,134.2,132.7,131.3,129.2,128.4,128.2,126.1,125.7,123.7,122.6,120.4,118.6,117.5,116.1,115.2,113.8,109.6,103.2,100.5,71.9,69.8,67.3,58.5,51.0,46.9,44.2,38.3,34.7,29.1,28.7,28.3,25.2.ESI-MS:m/z＝889.3[M+H] + .
example 22 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [2- (morpholin-4-yl) ethyl ] amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 22-k
3-nitro-4-fluorobenzenesulfonamide (1.41 g), N-2-aminoethylmorpholine (1.00 g) and N, N-diisopropylethylamine (2.07 g) were dissolved in acetonitrile (20 mL), heated to 85℃and reacted for 6 hours, cooled at room temperature, left to stand overnight, and suction filtered to give compound 22-k (2.00 g). Compound 22-k: ESI-MS: m/z=329.1 [ M-H ] ] - .
2) Preparation of Compound I-22
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 22-k to give compound I-22.
Compound I-22: 1 H NMR(500MHz,DMSO-d6),δ:11.76(s,2H),8.69(m,1H),8.60(d,1H),8.04(d,1H),7.90(m,1H),7.70(dd,2H),7.57(d,1H),7.52(m,2H),7.30(dd,2H),7.20(d,1H),6.72(d,1H),6.40(m,1H),6.27(m,1H),4.00(m,3H),3.86(m,3H),3.68(m,3H),3.58(m,5H),3.38(m,2H),3.06(m,6H),2.23(m,2H),2.05(m,2H),1.47(m,2H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,159.2,159.0,158.7,158.4,154.1,147.2,146.8,146.3,145.9,135.7,134.5,132.6,131.1,129.2,128.4,128.1,126.1,125.8,123.7,122.6,118.5,117.7,115.4,115.3,113.9,109.5,103.4,100.5,63.8,58.5,54.3,51.8,51.0,46.9,44.2,37.3,34.7,29.1,28.3,25.2.ESI-MS:m/z＝917.4[M+H] + .
example 23 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1-methoxycyclohex-4-yl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 23-k
3-nitro-4-fluorobenzenesulfonamide (0.71 g), 4-methoxycyclohexylamine (0.50 g) and N, N-diisopropylethylamine (1.04 g) were dissolved in acetonitrile (20 mL), heated to 85℃and reacted for 6 hours, cooled at room temperature, left to stand overnight, and suction-filtered to give compound 23-k (0.63 g). Compound 23-k: ESI-MS: m/z=328.1 [ M-H ]] - .
2) Preparation of Compound I-23
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 23-k to give compound I-23.
Compound I-23: 1 H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.69(s,1H),8.57(d,1H),8.24(d,1H),8.05(d,1H),7.82(m,1H),7.70(dd,2H),7.55(d,1H),7.52(m,2H),7.30(dd,2H),7.16(d,1H),6.72(d,1H),6.40(m,1H),6.27(m,1H),3.65(m,3H),3.59(m,2H),3.26(m,6H),3.04(m,2H),2.78(m,2H),2.22(m,2H),2.05(m,6H),1.47(m,4H),1.32(m,2H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,159.2,158.9,158.6,158.4,158.2,154.0,147.0,146.8,146.2,145.9,142.0,135.6,134.4,132.5,130.0,129.2,128.4,128.3,128.2,126.1,125.8,124.9,123.6,122.5,120.3,118.5,117.2,115.8,114.9,114.2,109.6,103.5,100.5,77.6,58.5,55.6,51.0,50.9,46.9,44.3,34.6,29.8,29.6,29.1,28.3,25.2.ESI-MS:m/z＝916.4[M+H] + .
example 24 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((1 r,4 r) -1-methoxycyclohex-4-yl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 24-k
3-nitro-4-fluorobenzenesulfonamide (0.71 g), trans-4-methoxycyclohexanamine (0.50 g) and N, N-diisopropylethylamine (1.04 g) were dissolved in acetonitrile (20 mL), heated to 85℃and reacted for 6 hours, cooled at room temperature, left to stand overnight, and suction-filtered to give compound 24-k (0.87 g). ESI-MS: m/z=328.1 [ M-H ]] - .
2) Preparation of Compound I-24
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 24-k to give compound I-24.
Compound I-24: 1 H NMR(500MHz,DMSO-d6),δ:11.70(s,2H),,8.57(d,1H),8.24(d,1H),8.04(d,1H),7.82(m,1H),7.70(dd,2H),7.54(d,1H),7.51(m,2H),7.30(dd,2H),7.16(d,1H),6.72(d,1H),6.40(m,1H),6.27(m,1H),3.65(m,3H),3.58(m,2H),3.26(m,4H),3.18(m,1H),3.03(m,2H),2.78(m,2H),2.23(m,2H),2.05(m,6H),1.46(m,4H),1.32(m,3H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,158.9,158.6,158.2,154.0,147.0,146.8,146.3,145.9,142.0,135.6,134.4,132.5,130.0,129.2,128.4,128.3,128.2,126.1,125.0,124.9,123.7,122.5,120.3,118.5,117.5,115.8,114.2,109.6,103.5,100.5,77.6,58.5,55.6,51.0,50.9,46.9,44.3,34.7,29.8,29.6,29.1,28.3,25.2.ESI-MS:m/z＝916.4[M+H] + .
example 25 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((N-ethylpiperidin-4-yl) methyl) oxy ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 25-k
N-ethyl-4-hydroxymethylpiperidine (0.50 g) was dissolved in tetrahydrofuran (20 mL) (0 ℃ C.) and sodium hydride was slowly added(purity 60%) (0.28 g), then 3-nitro-4-fluorobenzenesulfonamide (0.64 g) was added thereto, reacted at room temperature for 5 hours, 20mL of 10wt% aqueous sodium chloride solution was added thereto, extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to give compound 25-k (0.72 g). Compound 25-k: ESI-MS: m/z=342.1 [ M-H ] ] - .
2) Preparation of Compound I-25
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 25-k to give compound I-25.
Compound I-25: 1 H NMR(500MHz,DMSO-d6),δ:11.76(s,2H),8.41(d,1H),8.12(m,1H),8.05(d,1H),7.70(dd,2H),7.54(d,2H),7.52(m,2H),7.30(dd,2H),6.72(d,1H),6.41(m,1H),6.27(m,1H),4.15(m,2H),3.58(m,5H),3.10(m,6H),2.92(m,4H),2.23(m,2H),2.05(m,3H),1.97(m,2H),1.57(m,2H),1.46(m,2H),1.23(m,4H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,159.2,158.9,158.7,158.4,155.3,154.1,146.7,146.3,146.0,141.9,138.6,135.7,134.3,132.7,131.4,129.2,128.4,128.2,127.9,126.0,125.8,125.7,123.7,122.6,120.4,118.6,117.5,116.1,115.2,113.7,112.9,109.5,103.3,100.5,73.5,58.4,51.0,47.9,46.9,44.2,34.7,33.3,29.1,29.0,28.3,26.1,25.2.ESI-MS:m/z＝930.4[M+H] + .
example 26 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((N-methylpyrrolidin-3-yl) methyl) oxy ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 26-k
1-methyl-3-pyrrolidinemethanol (0.50 g) was dissolved in tetrahydrofuran (20 mL) (0 ℃ C.), sodium hydride (60% purity) was slowly added (0.35 g), followed by 3-nitro-4-fluorobenzenesulfonamide (0.80 g), reacted at room temperature for 5 hours, 20mL of 10wt% aqueous sodium chloride solution was added, and ethyl acetate (50 mL. Times.3) was usedThe organic phases were extracted, combined, dried over anhydrous sodium sulfate, filtered off with suction, and concentrated under reduced pressure to give compound 26-k (0.68 g). Compound 26-k: ESI-MS: m/z=314.1 [ M-H ]] - .
2) Preparation of Compound I-26
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 26-k to give compound I-26.
Compound I-26: 1 H NMR(500MHz,DMSO-d6),δ:11.87(m,1H),11.74(m,1H),8.44(d,1H),8.15(d,1H),8.04(d,1H),7.70(dd,2H),7.54(m,3H),7.46(m,1H),7.30(dd,2H),6.72(d,1H),6.42(m,1H),6.27(m,1H),4.28(m,7H),3.61(m,6H),2.87(m,4H),2.23(m,3H),2.05(m,2H),1.48(m,2H),1.24(m,4H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.1,159.1,158.9,158.6,158.4,158.3,155.3,154.2,146.8,146.3,146.0,138.5,135.7,134.4,132.6,131.7,130.1,129.3,128.4,128.2,127.9,126.0,125.9,125.8,123.7,118.5,116.2,115.7,113.9,113.4,109.5,103.3,100.5,71.2,58.5,57.2,57.0,55.4,55.0,51.0,46.9,44.3,34.7,29.3,28.3,25.2.ESI-MS:m/z＝902.4[M+H] + .
example 27 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydro-2H-thiopyran-4-yl) oxy ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 27-k
tetrahydro-2H-thiopyran-4-ol (1.00 g) was added to tetrahydrofuran (10 mL) (0deg.C), naH (1.13 g) was slowly added, 3-nitro-4-fluorobenzenesulfonamide (1.56 g) was then added and reacted at room temperature for 5H, 10wt% aqueous NaCl solution (20 mL) was added, extracted with EA (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was dried to give compound 27-k (1.85 g). Compound 27-k: ESI-MS: m/z=319.4 [ M+H ]] + .
2) Preparation of Compound I-27
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 27-k to give compound I-27.
Compound I-27: 1 H NMR(500MHz,DMSO-d6),δ:11.83(s,1H),11.74(s,1H),8.40(s,1H),8.07(d,2H),7.70(d,2H),7.59(s,1H),7.54(m,3H),7.30(d,2H),6.72(d,1H),6.43(s,1H),6.25(s,1H),3.68(m,2H),3.57(s,2H),3.27(m,2H),3.04(m,2H),2.80(t,4H),2.58(t,2H),2.23(s,2H),2.08(s,3H),2.04(s,2H),1.93(m,2H),1.48(s,2H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.1,158.7,158.5,154.1,153.8,146.7,146.3,146.0,139.4,135.8,134.0,132.6,131.3,129.2,128.4,128.2,126.0,125.9,125.8,123.6,120.4,118.7,116.8,113.8,109.5,103.2,100.5,75.7,58.5,51.0,46.9,44.3,34.7,32.0,29.1,25.2,24.5.ESI-MS:m/z＝905.5[M+H] + .
example 28 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydro-2H-thiopyran-4-yl) methoxy ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 28-k
Tetrahydrothiopyran-4-methanol (1.12 g) was added to tetrahydrofuran (10 mL) (0 ℃ C.), naH (1.13 g) was slowly added, 3-nitro-4-fluorobenzenesulfonamide (1.56 g) was then added and reacted at room temperature for 5 hours, 10wt% aqueous NaCl solution (20 mL) was added, extracted with EA (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was dried to give compound 28-k (1.88 g). Compound 28-k: ESI-MS: m/z=333.4 [ M+H ] ] + .
2) Preparation of Compound I-28
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 28-k to give compound I-28.
Compound I-28: 1 H NMR(500MHz,DMSO-d6),δ:11.83(s,1H),11.74(s,1H),8.40(s,1H),8.09(d,1H),8.05(s,1H),7.71(d,2H),7.58(s,1H),7.54(m,2H),7.45(d,1H),7.30(d,2H),6.72(d,1H),6.42(s,1H),6.26(s,1H),4.07(d,2H),3.68(m,2H),3.56(s,3H),3.27(m,2H),3.05(m,2H),2.65(m,4H),2.23(s,2H),2.06(d,4H),1.86(m,1H),1.46(m,4H),1.24(m,1H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,158.7,158.4,155.5,154.1,146.7,146.3,146.0,138.6,135.7,134.2,132.6,131.2,129.2,128.3,127.9,126.0,125.8,125.7,123.7,120.3,118.6,116.0,113.8,109.6,103.3,100.5,75.0,58.5,51.0,46.9,44.3,36.8,34.7,32.0,30.4,29.1,28.3,27.7,25.2.ESI-MS:m/z＝919.5[M+H] + .
example 29 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydrofuran-2-yl) methoxy ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 29-k
Tetrahydrofurfuryl alcohol (0.87 g) was added to tetrahydrofuran (10 mL) (0 ℃ C.), naH (1.13 g) was slowly added, followed by 3-nitro-4-fluorobenzenesulfonamide (1.56 g) which was reacted at room temperature for 5 hours, 10wt% aqueous NaCl solution (20 mL) was added, extracted with EA (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was dried to give compound 29-k (1.71 g). Compound 29-k: ESI-MS: m/z=303.0 [ M+H ]] + .
2) Preparation of Compound I-29
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 29-k to give compound I-29.
Compound I-29: 1 H NMR(500MHz,DMSO-d6),δ:11.82(s,1H),11.72(s,1H),8.39(s,1H),8.09(d,1H),8.06(s,1H),7.71(d,2H),7.58(s,1H),7.53(m,2H),7.49(d,1H),7.30(d,2H),6.72(d,1H),6.42(s,1H),6.27(s,1H),3.77(m,2H),3.68(m,3H),3.56(s,3H),3.28(m,2H),3.04(m,2H),2.78(m,2H),2.23(s,2H),2.06(m,4H),1.86(m,2H),1.76(m,1H),1.48(m,2H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,158.7,158.4,155.4,154.1,146.7,146.3,146.0,138.8,135.7,134.1,132.7,131.3,130.1,129.2,128.3,128.2,126.0,125.8,125.6,120.3,118.6,116.2,115.7,113.7,109.6,103.3,100.5,76.4,72.6,68.2,58.5,51.0,46.9,44.3,34.7,31.8,29.6,29.5,29.3,29.1,28.3,27.7,25.8,25.2.ESI-MS:m/z＝889.3[M+H] + .
example 30 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydrofuran-3-yl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 30-k
3-nitro-4-fluorobenzenesulfonamide (1.56 g), 3-aminotetrahydrofuran (0.74 g) and N, N-diisopropylethylamine (2.30 g) were dissolved in acetonitrile (10 mL), heated to 85℃and reacted for 6 hours, cooled at room temperature, left to stand overnight, and suction-filtered to give compound 30-k (1.63 g). Compound 30-k: ESI-MS: m/z=288.1 [ M+H ]] + .
2) Preparation of Compound I-30
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 30-k to give compound I-30.
Compound I-30: 1 H NMR(500MHz,DMSO-d6),δ:11.71(d,2H),8.57(d,1H),8.31(d,1H),8.03(d,1H),7.87(d,1H),7.71(d,2H),7.52(dd,3H),7.49(d,1H),7.13(d,2H),6.73(d,1H),6.38(s,1H),6.29(s,1H),4.36(m,1H),3.94(m,1H),3.88(m,1H),3.77(m,1H),3.72(m,3H),3.59(s,2H),3.29(m,2H),3.03(m,2H),2.78(m,2H),2.34(m,1H),2.23(s,2H),2.05(s,2H),1.91(m,1H),1.48(t,2H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,159.2,158.9,158.6,158.3,154.0,146.9,146.3,145.8,142.0,135.5,134.5,132.5,130.6,129.2,128.3,128.1,128.0,126.1,125.8,125.6,123.6,120.3,118.2,117.4,115.8,114.3,109.6,103.6,100.4,76.4,72.7,66.9,58.5,53.7,51.0,46.9,44.2,34.6,33.0,29.1,28.3,25.2.ESI-MS:m/z＝874.6[M+H] + .
example 31 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1-ethylpyrrolidin-3-yl) methoxy ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 31-k
(1-Ethylpyrrolidin-3-yl) methanol (0.52 g) was added to tetrahydrofuran (10 mL) (0 ℃ C.), naH (0.53 g) was slowly added thereto, followed by reaction at room temperature for 5 hours by adding 3-nitro-4-fluorobenzenesulfonamide (0.73 g), 10wt% aqueous NaCl solution (20 mL) was added, extracted with EA (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was dried by suction filtration to give compound 31-k (0.90 g). Compound 31-k: ESI-MS: m/z=330.1 [ M+H ] ] + .
2) Preparation of Compound I-31
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 31-k to give compound I-31.
Compound I-31: 1 H NMR(500MHz,DMSO-d6),δ:11.90(s,1H),11.74(s,1H),8.44(dd,1H),8.15(dd,1H),8.05(t,1H),7.71(d,2H),7.58(t,1H),7.54(m,1H),7.52(s,1H),7.47(dd,1H),7.30(d,2H),6.72(dd,1H),6.42(s,1H),6.26(s,1H),4.30(m,4H),3.63(m,2H),3.57(s,2H),3.23(m,4H),2.97(m,4H),2.78(m,2H),2.23(s,2H),2.04(s,2H),1.48(t,2H),1.24(m,4H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.1,159.2,158.8,158.6,158.4,154.1,146.7,146.3,146.0,138.6,135.7,134.5,132.6,130.2,129.2,128.4,126.0,123.7,120.3,118.5,118.0,116.2,115.7,109.5,103.4,100.5,71.1,58.5,55.0,54.9,53.1,52.7,51.0,49.9,49.7,46.9,44.3,36.0,35.8,34.7,29.1,28.3,26.5,26.0,25.2,11.1.ESI-MS:m/z＝916.2[M+H] + .
example 32 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydrofuran-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 32-k
3-nitro-4-chlorobenzenesulfonamide (1.43 g), tetrahydrofuranmethylamine hydrochloride (1.00 g) and N, N-diisopropylethylamine (3.53 g) were dissolved in acetonitrile (10 mL), heated to 85℃and reacted for 6 hours, cooled at room temperature, left to stand overnight, and suction-filtered to give compound 32-k (1.46 g). Compound 32-k: ESI-MS: m/z=302.3 [ M+H ]] + .
2) Preparation of Compound I-32
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 32-k to give compound I-32.
Compound I-32: 1 H NMR(500MHz,DMSO-d6),δ:11.73(s,1H),11.68(s,1H),8.64(t,1H),8.58(d,1H),8.05(d,1H),7.83(dd,1H),7.71(d,2H),7.53(m,3H),7.30(d,2H),7.12(d,1H),6.72(dd,1H),6.40(s,1H),6.27(s,1H),3.81(m,1H),3.71(m,1H),3.64(m,1H),3.59(s,2H),3.51(m,1H),3.38(m,2H),3.29(m,2H),3.03(m,2H),2.78(m,2H),2.58(m,1H),2.23(s,2H),2.04(s,2H),1.99(m,1H),1.64(m,1H),1.48(t,2H),1.24(m,2H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,159.2,158.9,158.6,158.4,158.2,154.0,147.8,146.8,146.2,145.8,142.0,135.6,134.3,132.5,130.1,129.2,128.3,128.2,126.0,125.8,124.9,123.6,122.5,120.4,118.5,117.2,116.2,115.5,109.6,103.5,100.5,70.8,67.3,58.5,51.0,46.9,45.8,44.2,38.0,34.6,29.8,29.1,28.3,25.2.ESI-MS:m/z＝888.5[M+H] + .
example 33 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1- (tetrahydro-2H-pyran-4-yl) ethoxy ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 33-k
4-Ethylenetetrahydro-2H-pyran (0.52 g) was added to tetrahydrofuran (10 mL) (0 ℃ C.), naH (0.53 g) was slowly added, followed by 3-nitro-4-fluorobenzenesulfonamide (0.73 g) reaction at room temperature for 5 hours, 10wt% aqueous NaCl solution (20 mL) was added, extracted with EA (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was dried to give compound 33-k (0.88 g). Compound 33-k: ESI-MS: m/z=331.1 [ M+H ]] + .
2) Preparation of Compound I-33
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 33-k to give compound I-33.
Compound I-33: 1 H NMR(500MHz,DMSO-d6),δ:11.79(s,1H),11.76(s,1H),8.39(s,1H),8.09(d,2H),7.71(d,2H),7.62(s,1H),7.53(m,3H),7.30(d,2H),6.72(d,1H),6.44(s,1H),6.25(s,1H),4.63(m,1H),3.88(d,2H),3.58(s,2H),3.29(m,4H),3.03(m,2H),2.78(m,2H),2.23(s,2H),2.04(s,2H),1.84(m,1H),1.69(d,1H),1.52(m,2H),1.35(m,2H),1.25(m,6H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,159.1,158.8,158.6,158.3,154.7,154.1,146.6,146.3,146.1,139.4,135.8,134.0,132.7,130.9,129.2,128.4,128.0,126.0,125.8,123.6,120.4,118.9,117.6,116.4,115.2,113.6,109.5,103.1,100.5,80.2,67.3,67.1,58.5,51.0,46.9,44.2,34.7,29.5,29.1,28.5,28.3,28.1,25.2,16.3.ESI-MS:m/z＝917.7[M+H] + .
example 34 (R) -4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4-methylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 34-k
3-nitro-4-chlorobenzenesulfonamide (0.38 g), (R) -4-methyl-2-morpholinemethylamine (0.25 g) and N, N-diisopropylethylamine (0.52 g) were dissolved in acetonitrile (10 mL), heated to 85℃and reacted for 6h, cooled at room temperature, left to stand overnight, and suction filtered to give compound 34-k (0.45 g). Compound 34-k: ESI-MS: m/z=331.1 [ M+H ] ] + .
2) Preparation of Compound I-34
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 34-k to give compound I-34.
Compound 34-k: 1 H NMR(500MHz,DMSO-d6),δ:11.72(s,2H),8.66(s,1H),8.59(s,1H),8.05(s,1H),7.86(d,1H),7.71(d,2H),7.53(m,3H),7.31(d,2H),7.18(d,1H),6.73(d,1H),6.41(s,1H),6.27(s,1H),3.97(m,2H),3.69(m,2H),3.51(m,2H),3.40(d,1H),3.06(m,3H),2.94(m,2H),2.84(s,3H),2.23(s,2H),2.04(s,2H),1.48(s,2H),1.35(m,3H),1.24(s,4H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,159.0,158.6,158.3,154.0,147.8,146.8,146.3,145.9,141.9,135.6,134.3,132.6,130.5,130.1,129.2,128.3,126.0,125.5,123.6,122.6,120.3,118.4,115.8,114.0,109.6,103.5,100.4,72.2,64.0,58.5,54.5,52.4,51.0,46.9,44.5,34.7,31.7,29.5,29.3,29.1,28.3,27.0,28.1,25.2,22.5.ESI-MS:m/z＝917.4[M+H] + .
example 35 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1-isobutyrylpiperidin-4-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 35-k
3-nitro-4-chlorobenzenesulfonamide (0.54 g), (1-isobutyrylpiperidin-4-yl) methylamine (0.5 g) and N, N-diisopropylethylAmine (0.73 g) was dissolved in acetonitrile (10 mL), heated to 85deg.C, reacted for 6h, cooled at room temperature, left to stand overnight, and suction filtered to give compound 34-k (0.78 g). Compound 34-k: ESI-MS: m/z=385.2 [ M+H ]] + .
2) Preparation of Compound I-35
Reference example 8 step 2) preparation of compound I-8, 8-k was changed to compound 35-k, to give compound I-35.
Compound I-35: 1 H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.67(s,1H),8.64(t,1H),8.58(d,1H),8.05(d,1H),7.82(dd,1H),7.70(d,2H),7.53(m,3H),7.30(d,2H),7.14(d,1H),6.72(dd,1H),6.40(s,1H),6.26(s,1H),4.41(d,1H),3.96(d,1H),3.56(s,3H),3.32(t,4H),2.98(t,3H),2.85(m,3H),2.23(s,2H),2.04(s,2H),1.91(m,1H),1.76(m,2H),1.48(t,2H),1.24(s,1H),1.14(m,1H),0.96(s,12H).
13 C NMR(125MHz,DMSO-d6),δ:174.5,164.0,158.7,158.5,158.3,154.0,147.9,146.8,146.3,146.0,135.7,134.3,132.6,130.1,129.2,128.3,128.2,127.9,126.0,125.8,124.8,123.6,120.3,118.4,118.3,115.9,115.6,114.1,109.6,103.4,100.4,58.5,51.0,48.0,46.9,45.0,44.3,41.4,35.5,34.7,30.7,29.7,29.5,29.1,28.3,25.2,20.0,19.9.ESI-MS:m/z＝971.7[M+H] + .
example 36 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydro-2H-pyran-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 36-k
3-nitro-4-chlorobenzenesulfonamide (1.20 g), 2-aminomethyltetrahydropyran (0.70 g) and N, N-diisopropylethylamine (1.64 g) were dissolved in acetonitrile (10 mL), heated to 85℃and reacted for 6 hours, cooled at room temperature, left to stand overnight, and suction-filtered to give compound 36-k (1.74 g). Compound 36-k: ESI-MS: m/z=316.0 [ M+H ]] + .
2) Preparation of Compound I-36
Reference example 8 step 2) preparation of compound I-8, 8-k was changed to compound 36-k, to give compound I-36.
Compound I-36: 1 H NMR(500MHz,DMSO-d6),δ:11.71(s,1H),11.67(s,1H),8.62(t,1H),8.57(d,1H),8.04(d,1H),7.82(dd,1H),7.70(d,2H),7.53(m,3H),7.30(d,2H),7.11(d,1H),6.72(dd,1H),6.40(s,1H),6.27(s,1H),3.58(m,4H),3.48(m,2H),3.36(m,3H),3.28(m,2H),3.03(m,2H),2.78(m,2H),2.22(s,2H),2.04(s,2H),1.80(d,1H),1.65(d,1H),1.48(m,4H),1.28(m,2H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,158.7,158.4,158.2,154.0,147.9,146.8,146.3,146.0,135.6,134.3,132.6,130.1,129.2,128.2,126.0,125.0,123.7,120.3,115.8,114.1,109.6,103.4,100.4,75.6,68.0,58.5,51.0,47.9,46.9,44.3,34.7,30.7,29.5,29.2,29.1,28.3,26.0,25.2,22.9.ESI-MS:m/z＝902.7[M+H] + .
example 37 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (3-morpholinopropyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 37-k
3-nitro-4-chlorobenzenesulfonamide (1.37 g), N- (3-aminopropyl) morpholine (1.0 g) and N, N-diisopropylethylamine (1.87 g) were dissolved in acetonitrile (10 mL), heated to 85℃and reacted for 6h, cooled at room temperature, left to stand overnight, and suction filtered to give compound 37-k (1.74 g). Compound 37-k: ESI-MS: m/z=345.1 [ M+H ]] + .
2) Preparation of Compound I-37
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 37-k to give compound I-37.
Compound I-37: 1 H NMR(500MHz,DMSO-d6),δ:11.74(s,1H),11.70(s,1H),8.67(t,1H),8.60(d,1H),8.05(d,1H),7.87(dd,1H),7.70(d,2H),7.53(m,3H),7.31(d,2H),7.14(d,1H),6.73(dd,1H),6.41(s,1H),6.27(s,1H),3.98(d,2H),3.65(t,3H),3.59(m,2H),3.52(m,2H),3.45(d,2H),3.30(m,2H),3.20(t,2H),3.07(m,4H),2.78(m,2H),2.23(m,2H),2.00(m,4H),1.47(t,2H),1.24(m,1H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,159.3,159.0,158.7,158.4,154.0,147.5,146.8,146.3,145.9,141.9,135.6,134.4,132.6,130.4,129.2,128.4,128.3,128.2,127.9,126.0,125.8,125.1,123.6,122.6,120.3,118.5,117.6,115.4,115.2,114.0,109.6,103.4,100.4,63.8,58.4,54.1,51.6,51.0,46.9,44.2,34.7,29.2,29.1,28.3,25.1,22.8.ESI-MS:m/z＝931.4[M+H] + .
example 38 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydro-2H-pyran-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 38-k
3-nitro-4-chlorobenzenesulfonamide (1.37 g), (tetrahydro-2H-pyran-3-yl) methylamine hydrochloride (0.85 g) and N, N-diisopropylethylamine (2.70 g) were dissolved in acetonitrile (10 mL), heated to 85℃and reacted for 6H, cooled at room temperature, left to stand overnight, and suction filtered to give compound 38-k (1.74 g). Compound 38-k: ESI-MS: m/z=316.1 [ M+H ]] + .
2) Preparation of Compound I-38
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 38-k to give compound I-38.
Compound I-38: 1 H NMR(500MHz,DMSO-d6),δ:11.73(s,1H),11.67(s,1H),8.58(d,2H),8.05(d,1H),7.83(d,1H),7.71(d,2H),7.53(m,3H),7.31(d,2H),7.11(d,1H),6.73(d,1H),6.40(s,1H),6.27(s,1H),3.72(m,6H),3.29(m,5H),3.05(m,2H),2.78(m,2H),2.23(m,2H),2.06(m,2H),1.84(m,2H),1.60(m,1H),1.48(m,3H),1.27(m,2H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,158.9,158.6,158.2,154.0,147.8,146.8,146.3,145.9,141.9,135.7,134.3,132.6,130.2,129.2,128.3,128.3,128.2,127.9,126.0,125.8,124.8,123.6,122.7,120.3,118.4,115.5,114.1,109.6,103.5,100.4,70.5,68.0,58.5,54.1,51.0,46.9,44.9,44.3,35.3,34.7,29.1,28.3,27.2,25.2,25.0.ESI-MS:m/z＝902.2[M+H] + .
example 39 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4-isobutyrylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 39-k
3-nitro-4-fluorobenzenesulfonamide (1.48 g), 4-isobutyryl-2-morpholinemethylamine (1.5 g) and N, N-diisopropylethylamine (2.20 g) were dissolved in acetonitrile (10 mL), heated to 85℃and reacted for 6h, cooled at room temperature, left to stand overnight, and suction filtered to give compound 39-k (2.2 g). Compound 39-k: ESI-MS: m/z=387.0 [ M+H ] ] + .
2) Preparation of Compound I-39
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 39-k to give compound I-39.
Compound I-39: 1 H NMR(500MHz,DMSO-d6),δ:11.76(s,2H),8.32(d,1H),8.06(d,1H),7.91(d,1H),7.87(s,1H),7.71(d,2H),7.59(s,1H),7.53(d,2H),7.30(d,2H),7.26(d,1H),6.73(d,1H),6.43(s,1H),6.26(s,1H),3.91(d,1H),3.68(m,1H),3.59(m,4H),3.29(m,1H),3.12(m,7H),2.79(t,3H),2.38(m,1H),2.23(s,2H),2.04(m,2H),1.47(m,2H),1.39(s,1H),1.24(s,1H),1.01(s,6H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:176.9,164.0,159.2,158.9,158.9,158.6,154.1,148.4,146.7,146.3,146.0,142.0,138.2,135.7,133.0,132.6,129.2,128.4,128.2,128.0,127.6,126.0,125.8,123.6,122.6,120.9,120.4,118.6,117.4,115.1,113.9,109.6,103.3,100.5,74.2,65.8,58.5,53.7,51.0,50.1,46.9,44.2,41.0,34.6,34.4,29.1,28.3,25.2,20.0.ESI-MS:m/z＝973.6[M+H] + .
example 40 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1-acetylpiperidin-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 40-k
3-nitro-4-chlorobenzenesulfonamide (1.31 g), 1-acetyl-3-piperidinemethylamine (1.30 g) and N, N-diisopropylethylamine (1.80 g) were dissolved in acetonitrile (10 mL), heated to 85℃and reacted for 6 hours, cooled at room temperature, left to stand overnight, and suction-filtered to give compound 40-k (2.10 g). Compound 40-k: ESI-MS: m/z=357.3 [ M+H ]] + .
2) Preparation of Compound I-40
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 40-k to give compound I-40.
Compound I-40: 1 H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.67(s,1H),8.61(m,2H),8.05(d,1H),7.83(t,1H),7.71(d,2H),7.54(d,3H),7.30(d,2H),7.13(dd,1H),6.72(d,1H),6.40(s,1H),6.27(s,1H),4.10(dd,1H),3.69(m,3H),3.58(s,2H),3.31(m,4H),3.08(m,2H),2.91(t,1H),2.71(m,2H),2.23(s,2H),2.04(s,2H),1.98(d,3H),1.72(m,3H),1.48(m,2H),1.28(m,2H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:168.7,164.0,158.9,158.6,158.2,154.0,147.8,146.8,146.3,145.9,141.9,135.6,134.3,132.6,129.2,128.3,128.2,127.9,126.0,125.8,123.6,122.6,120.3,120.2,118.4,117.8,115.6,115.5,114.1,109.6,103.4,100.4,58.5,51.0,49.8,46.9,45.6,45.5,44.8,44.3,41.9,35.9,34.7,29.1,28.2,25.2,24.2,21.8.ESI-MS:m/z＝943.2[M+H] + .
example 41 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1- (methylsulfonyl) piperidin-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 41-k
3-nitro-4-fluorobenzenesulfonamide (1.57 g), 1-methylsulfonyl-3-piperidinemethylamine (1.65 g) and N, N-diisopropylethylamine (2.31 g) were dissolved in acetonitrile (10 mL), heated to 85℃and reacted for 6 hours, cooled at room temperature, left to stand overnight, and suction-filtered to give compound 41-k (2.40 g). Compound 41-k: ESI-MS: m/z=393.1 [ M+H ]] + .
2) Preparation of Compound I-41
Reference example 8 step 2) preparation of compound I-8, 8-k was changed to compound 41-k, to give compound I-41.
Compound 41-I: 1 H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.67(s,1H),8.61(m,2H),8.06(s,1H),7.84(s,1H),7.71(m,2H),7.54(d,3H),7.23(d,3H),6.73(s,1H),6.41(s,1H),6.28(s,1H),3.49(m,8H),3.04(m,2H),2.81(m,3H),2.55(m,4H),2.23(s,2H),2.05(m,2H),1.79(m,2H),1.48(s,2H),1.21(m,2H),0.96(s,9H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,158.9,158.6,158.3,154.0,147.8,146.8,146.3,146.0,141.9,135.7,134.4,132.6,130.2,129.2,128.3,126.0,125.0,123.7,120.3,118.4,118.0,115.6,114.1,109.6,103.4,100.5,58.5,51.0,49.3,46.9,46.4,45.7,44.3,35.1,34.7,34.5,29.1,28.3,27.4,25.2,24.1.ESI-MS:m/z＝979.6[M+H] + .
example 42 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (N-ethylmorpholin-3-yl) methyl ] amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 42-k
3-nitro-4-fluorobenzenesulfonamide (0.85 g), N-ethyl-3-aminomethylmorpholine (0.67 g) and N, N-diisopropylethylamine (1.25 g) were dissolved in acetonitrile (20 mL), heated to 85℃and reacted for 6 hours, cooled at room temperature, left to stand overnight, and suction-filtered to give compound 42-k (1.19 g). Compound 42-k: ESI-MS: m/z=343.1 [ M-H ]] - .
2) Preparation of Compound I-42
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 42-k to give compound I-42.
Compound I-42: 1 H NMR(500MHz,DMSO-d6),δ:11.73(s,2H),8.69(d,1H),8.60(d,1H),8.05(d,1H),7.92(m,1H),7.70(dd,2H),7.58(d,1H),7.52(m,2H),7.17(d,2H),6.72(d,2H),6.40(m,1H),6.27(m,1H),3.58(m,10H),3.30(m,3H),3.04(m,4H),2.77(m,3H),2.24(m,2H),2.05(m,2H),1.47(m,2H),1.23(m,4H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,159.2,159.0,158.7,158.4,154.0,146.8,146.3,145.9,141.9,135.7,132.6,131.3,129.2,128.4,128.1,126.1,125.8,122.6,120.4,118.6,115.3,113.9,109.5,103.4,100.5,58.4,51.0,46.9,44.2,34.7,29.1,28.3,25.2.ESI-MS:m/z＝931.4[M+H] + .
example 43 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4-acetylmorpholin-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
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1) Preparation of Compound 43-k
3-nitro-4-fluorobenzenesulfonamide (0.65 g), 4-acetyl-3-morpholinemethylamine (0.70 g) and N, N-diisopropylethylamine (0.95 g) were dissolved in acetonitrile (10 mL), heated to 85℃and reacted for 6 hours, cooled at room temperature, left to stand overnight, and suction filtered to give compound 43-k (0.95 g). Compound 43-k: ESI-MS: m/z =359.1[M+H] + .
2) Preparation of Compound I-43
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 43-k to give compound I-43.
Compound I-43: 1 H NMR(500MHz,DMSO-d6),δ:11.77(s,2H),8.33(d,1H),8.08(d,1H),7.91(d,1H),7.76(s,1H),7.71(d,2H),7.56(s,1H),7.51(d,2H),7.30(d,2H),7.27(d,1H),6.71(d,1H),6.45(s,1H),6.22(s,1H),3.75(d,1H),3.68(m,2H),3.58(m,7H),3.30(m,4H),3.08(m,2H),2.98(m,2H),2.27(s,2H),2.04(m,3H),1.47(m,2H),1.33(m,2H),1.24(m,1H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,159.1,158.7,158.2,154.0,147.9,146.5,146.2,145.8,142.0,135.6,134.4,132.7,130.2,129.4,128.2,126.0,125.5,123.7,122.6,120.2,118.5,115.9,114.1,109.7,103.3,100.4,58.5,54.6,52.5,51.1,46.8,44.6,34.8,31.5,29.6,29.3,29.1,28.3,27.0,25.2,22.5.
ESI-MS:m/z＝945.4[M+H] + .
example 44 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4-isobutyrylmorpholin-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 44-k
3-nitro-4-fluorobenzenesulfonamide (0.26 g), 4-isobutyryl-3-morpholinemethylamine (0.26 g) and N, N-diisopropylethylamine (0.38 g) were dissolved in acetonitrile (10 mL), heated to 85℃and reacted for 6h, cooled at room temperature, left to stand overnight, and suction filtered to give compound 44-k (0.40 g). Compound 44-k: ESI-MS: m/z=387.1 [ M+H ] ] + .
2) Preparation of Compound I-44
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 44-k to give compound I-44.
Compound I-44: 1 H NMR(500MHz,DMSO-d6),δ:11.72(s,2H),8.30(d,1H),8.06(d,1H),7.90(d,1H),7.77(s,1H),7.70(d,2H),7.54(s,1H),7.50(d,2H),7.30(d,2H),7.27(d,1H),6.72(d,1H),6.43(s,1H),6.21(s,1H),3.76(d,1H),3.69(m,2H),3.55(m,7H),3.31(m,4H),2.98(m,3H),2.27(s,2H),2.05(m,2H),1.47(m,2H),1.32(m,2H),1.23(m,1H),1.00(s,6H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:176.8,164.0,159.2,158.8,158.7,154.0,148.5,146.8,146.4,146.1,142.0,138.2,135.7,133.2,132.5,129.2,128.5,128.2,128.0,127.6,126.1,125.9,123.7,122.7,121.0,120.2,118.6,117.4,115.2,113.9,109.7,103.4,100.4,74.2,65.9,58.5,54.6,51.0,50.1,46.9,44.3,41.0,34.6,34.5,29.1,28.3,25.3,20.0.ESI-MS:m/z＝973.4[M+H] + .
example 45 4- (4- { [2- (4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (N-methoxyacetyl piperidin-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 45-k
3-nitro-4-fluorobenzenesulfonamide (1.03 g), N-methoxyacetyl-3-aminomethylpiperidine (1.04 g) and N, N-diisopropylethylamine (1.51 g) were dissolved in acetonitrile (20 mL), heated to 85℃and reacted for 6 hours, cooled at room temperature, left to stand overnight, and suction-filtered to give compound 45-k (1.53 g). Compound 45-k: ESI-MS: m/z=385.1 [ M-H ]] - .
2) Preparation of Compound I-45
Reference example 8 the preparation of compound I-8 of step 2) was followed by the exchange of compound 8-k for compound 45-k to give compound I-45.
Compound I-45: 1 H NMR(500MHz,DMSO-d6),δ:11.72(s,1H),11.66(s,1H),8.65(d,1H),8.59(d,1H),8.05(d,1H),7.83(m,1H),7.70(dd,2H),7.56(d,1H),7.51(m,2H),7.30(m,2H),7.14(d,1H),6.72(d,1H),6.40(m,1H),6.27(m,1H),4.07(m,4H),3.72(m,2H),3.58(m,3H),3.28(m,5H),3.11(m,1H),3.03(m,2H),2.78(m,4H),2.23(m,2H),2.06(m,2H),1.82(m,2H),1.67(m,1H),1.47(m,2H),1.28(m,2H),0.96(s,6H).
13 C NMR(125MHz,DMSO-d6),δ:164.0,158.8,158.6,158.3,154.0,147.8,146.8,146.3,146.0,141.9,135.7,134.3,132.6,130.2,129.2,128.3,128.2,126.1,125.8,123.7,120.3,118.4,115.5,115.4,114.1,109.6,103.4,100.5,71.6,71.2,58.7,58.5,51.0,48.6,46.9,45.6,45.4,45.1,44.3,42.2,36.0,35.3,34.7,29.1,28.3,25.2,24.9,24.5.ESI-MS:m/z＝973.4[M+H] + .
the following compounds were prepared according to the procedure for the preparation of reference example 45:
test example 1
1. In vitro protein binding inhibition Activity
1.1 screening for BCL-2/BAK binding inhibitory Activity
500nM of the Tag1-BCL-2 protein mother solution was diluted to 5nM with a dilution buffer in a kit (model: BCL-2/BAK (BH 3) BINDING ASSAY KITS, from cisbio), 20. Mu.M of the Tag2-BAK protein mother solution was diluted to 120nM, 5. Mu.L of the Tag1-BCL-2 protein dilution was added to each well, then the DMSO-dissolved test compound was added to the wells with a nanoliter-type-meter, a 4-fold gradient, 7 total concentrations were applied to give a final compound concentration of 2000nM-0.488nM, blank control wells (without enzyme) and negative control wells (containing enzyme, vehicle DMSO) were set, 2 replicate wells were set, and finally 5. Mu.L of the Tag2-BAK protein dilution was added to each well, followed by incubation at 25℃for 15min, followed by centrifugation and homogenization. 100 Xanti-Tag 1-Eu with detection buffer in kit 3+ Diluted to a 1X use concentration, while 100X anti-Tag2-XL665 was diluted to a 1X use concentration. anti-Tag1-Eu 3+ And anti-Tag2-XL665 at 1:1 mixing uniformly, adding in each holeAdding 5 mu L of the mixed solution, and reacting for 2 hours at 25 ℃ or more. PE Envision multifunctional enzyme-labeled instrument reader (excitation 620nm, emission 665 nm). Calculating IC by taking logarithm of compound concentration as abscissa, signal value as ordinate, four-parameter analysis and fitting of a quantitative response curve 50 . The results are shown in Table 1.
1.2 screening for BCL-XL/BAK binding inhibitory Activity
A300 nM solution of Tag1-BCL-XL protein was diluted to 2nM with a dilution buffer in a kit (model: BCL-XL/BAK (BH 3) BINDING ASSAY KITS, from cisbio), 10. Mu.M solution of Tag2-BAK protein was diluted to 80nM, 5. Mu.L of Tag1-BCL-XL protein dilution was added to each well, then different test compounds dissolved in DMSO were added to the wells with a nanoliter-type-meter, a 4-fold gradient was applied to a total of 7 concentrations to give a final concentration of 2000nM-0.488nM, a blank control well (without enzyme) and a negative control well (containing enzyme, with solvent DMSO) were set, 2 duplicate wells were set, and finally 5. Mu.L of Tag2-BAK protein dilution was added to each well, followed by centrifugation and incubation at 25℃for 15min. 100 Xanti-Tag 1-Eu with detection buffer in kit 3+ Diluted to a 1X use concentration, while 100X anti-Tag2-XL665 was diluted to a 1X use concentration. anti-Tag1-Eu 3+ And anti-Tag2-XL665 at 1:1, adding 5 mu L of mixed solution into each hole, and reacting for 2 hours or more at 25 ℃. PE instrument read plate (excitation 620nm, emission 665 nm). Calculating IC by taking logarithm of compound concentration as abscissa, signal value as ordinate, four-parameter analysis and fitting of a quantitative response curve 50 . The results are shown in Table 1.
The compounds of Table 1 inhibit BCL-2/BAK and BCL-XL/BAK binding Activity
2. Human platelet toxicity test (Caspase 3 Activity assay)
10mL of human whole blood was drawn using a heparin sodium anticoagulation tube, mixed well, centrifuged at 90g for 10min, the supernatant collected, and centrifuged at 1950g for 10min. Discarding supernatant, re-suspending with 4mL PBS, centrifuging 1190g for 5min, and discarding supernatantThe platelets were resuspended in PBS and the density was adjusted to 2-3X 10 8 And each mL. According to 2 to 3 multiplied by 10 7 The density of each mL is inoculated in a 96-well plate, 100 mu L/well, 50 mu L of control buffer is added to a negative control well, 50 mu L of compound with corresponding concentration is added to each compound well, and the final concentration of the compound is 2.5 mu M, 1.25 mu M or 1 mu M, and the mixture is incubated in an incubator at 37 ℃ for 90min. The liquids in the 96-well plates were transferred to 1.5mL centrifuge tubes, respectively. Centrifuging at 4deg.C for 5min at 6000g, removing supernatant, and placing on ice for use. The 5 Xlysate was diluted to 1 Xlysate with the water provided in the kit, and the protease inhibitor cocktail was added at a ratio of 1:200 to prepare a lysis mix ready for use. Adding 40 mu L of lysis mixed solution into each centrifuge tube, re-suspending platelets at the bottom by a pipette, carrying out lysis for 15-20 min on ice, centrifuging for 10min at the temperature of 14000g at the temperature of 4 ℃, and sub-packaging samples for later use. 10X of the test solution was diluted to 1X of the test solution with water supplied from the kit, and the substrate Ac-DEVD-AMC was added at a ratio of 1:600 to prepare a reaction mixture. A blank well was added with 5. Mu.L of detection buffer and 40. Mu.L of reaction mix. Sample negative control wells, 5 μl control platelet lysate, 40 μl reaction mix was added. In the compound group, 5. Mu.L of platelet lysate and 40. Mu.L of reaction mixture were added. Wherein 40. Mu.L of the reaction mixture is finally added, gently mixed, and read by a PE Envision multifunctional enzyme label instrument (excitation 360nm, emission 460 nm), and detected once every 10min for 6 times. Based on the magnitude of the fluorescence intensity of the released AMC, the activity of Caspase-3 can be determined, i.e., the slope of the fitted line corresponding to each well represents the magnitude of the Caspase activity (shown in Table 2).
Effects of the compounds of Table 2 on human platelet Caspase3 Activity
Note that: the data were normalized.
3. Compound pair DOHH-2 and RS4; proliferation inhibition of 11 cells
DOHH-2 cells (from DSMZ, germany) were cultured in RPMI 1640 medium (containing 5% FBS, 1% sodium pyruvate), 37℃in 5% CO 2 SaturationCulturing in a humid cell incubator. Taking DOHH-2 cells in a good exponential growth phase, collecting the cells to a centrifuge tube, centrifuging at a low speed table centrifuge at 1500 rpm for 3min, discarding the supernatant, and adding 5mL of the culture medium to resuspend the cells by a pipette. Counting with a cytometer, diluting with the above culture medium, and adjusting cell density to 8X10 4 And each mL. Inoculating 100 μl/well onto 96-well plate with a row gun, placing at 37deg.C, and containing 5% CO 2 Culturing in a saturated humidity cell incubator. After incubation for 24h, compound addition was performed using a nanoliter addition apparatus, 3-fold dilution was performed, 8 concentration gradients were added, 2 replicate wells were set for each concentration, the highest concentration was 10 μm, CCK-8, 10 μl/well was added after 72 hours, and absorbance was measured at 450nm with an Envision microplate reader after 4 hours, and inhibition (%) = (negative control group mean-experimental group mean)/(negative control group mean-blank group mean) ×100% was calculated, with the logarithm of compound concentration as abscissa, inhibition was ordinate, four-parameter analysis, and a fit-up curve.
RS4;11 cells (from Nanjac Bai) in PRMI1640 medium (containing 10% FBS), 37℃and 5% CO 2 Culturing in a saturated humidity cell incubator. Taking RS4 in a good exponential growth phase state; 11 cells were collected in a dish, centrifuged at 1500 rpm for 3min, and the supernatant was discarded, and 5mL of complete medium (RPMI basal medium+10% FBS) was added to the dish by a pipette for cell resuspension. Counting with a cytometer, diluting the complete medium, and adjusting the cell density to 2×10 5 The serum concentration is adjusted to 5% by adding equal amount of RPMI basic culture medium, and the cell density is 1×10 5 Each mL of the plate. Inoculating 100 μl/well onto 96-well plate with a row gun, placing at 37deg.C, and containing 5% CO 2 Culturing in a saturated humidity cell incubator. After incubation for 24h, compound addition was performed using a nanoliter applicator, 2 replicate wells were set for each concentration, cells without compound were used as negative control, CCK-8, 10. Mu.L/well was added after 72 h, absorbance was measured at 450nm using an Envision microplate reader after 4h, and inhibition was calculated as (%) = (average of negative control group)Values-experimental group mean)/(negative control group mean-blank group mean) ×100%, with log of compound concentration as abscissa, inhibition ratio as ordinate, four-parameter analysis, fitting of dose-response curve. The results are shown in Table 3.
Inhibition of DOHH-2 cell proliferation by the compounds of Table 3
4. In vitro solubility evaluation
In a final system of 1000. Mu.L, the ratio of 990. Mu.L of PBS buffer at pH7.4, 10. Mu.L (100. Mu.M) of test compound and organic solvent (acetonitrile) was 1% (volume ratio). After standing at 25℃for 16h, the mixture was centrifuged (12000 rpm,20 ℃) for 10min, 20. Mu.L of supernatant was removed, and the reaction was stopped with 400. Mu.L of acetonitrile containing an internal standard (diazepam 20 ng/mL). The supernatant was aspirated at 30. Mu.L, diluted with 150. Mu.L of 50% acetonitrile water, and analyzed by 0.5. Mu.L. The solubility of the compounds in PBS buffer at pH7.4 is shown in Table 4.
Solubility of the compounds of Table 4 in PBS buffer at pH7.4
Compounds of formula (I) Solubility (mu M)
I-1 1.2
5. In vitro liver microstation stability evaluation
300. Mu.L of the final incubation system contained 30. Mu.L of liver microsomes (protein concentration: 0.15 mg/mL), 30. Mu.L of NADPH+MgCl 2 3. Mu.L of test compound (final concentration 1. Mu.M in acetonitrile), 237. Mu.L of PBS buffer (pH 7.4). Wherein the organic matterThe ratio of the solvent (acetonitrile) was 1% (by volume). 2 parts per species (human, rat and mouse) were made, each 0.3mL. Mixing substrate and enzyme with total volume of 270 μL, pre-incubating NADPH at 37deg.C for 5min, adding 30 μL of NADPH+MgCl 2 Mix and withdraw 50 μl of glacial acetonitrile containing internal standard (diazepam) to stop the reaction at 0, 15, 30, 60min, respectively.
mu.L of the resulting incubated sample was taken, and 300. Mu.L of glacial acetonitrile containing an internal standard (diazepam 20 ng/mL) was added for precipitation, and after vortexing for 5min, centrifugation (12000 rpm,4 ℃) for 10min was performed. The supernatant was aspirated at 75. Mu.L, diluted with 75. Mu.L of ultrapure water, and analyzed by 0.5. Mu.L of sample. The results are shown in Table 5-1 and Table 5-2.
TABLE 5-1 in vitro human and rat liver microsomal metabolic stability (1. Mu.M)
Table 5-2 Compounds in vitro liver microsomal Metabolic stability (1. Mu.M)
6. Evaluation of in vitro CYP450 enzyme inhibition
In 500. Mu.L of the final incubation system, 50. Mu.L of liver microsomes (protein concentration: 0.2 mg/mL), 1. Mu.L of mixed CYP450 specific substrates (CYP 1A2, 2B6, 2C9, 2C19, 2D6, 3A 4), 398. Mu.L of PBS buffer (pH 7.4), 1. Mu.L of specific positive inhibitor (positive control group) or test compound, 50. Mu.L of NADPH+MgCl were contained 2 . Wherein the ratio of the organic solvent (acetonitrile) was 0.5% (by volume). 2 portions of each CYP450 subtype were used, each 0.5mL. Each tube was pre-incubated with a total volume of 450. Mu.L of substrate and enzyme and NADPH at 37℃for 5min, respectively, and 50. Mu.L of NADPH+MgCl was added 2 Mix and withdraw 50 μl of ice acetonitrile with internal standard (diazepam) for 30min to terminate the reaction. In addition, 2 blanks (KB) of 500. Mu.L each were prepared in parallel, and NADPH was not added as a negative control.
mu.L of the resulting incubated sample was aspirated, and 300. Mu.L of glacial acetonitrile containing an internal standard (diazepam) was added for precipitation, vortexed for 5min, and centrifuged (12000 rpm,4 ℃) for 10min. 50. Mu.L of the supernatant was aspirated, 100. Mu.L of ultrapure water was added thereto, and diluted and mixed well to give 1. Mu.L of sample for analysis.
7. In vitro protein binding Rate evaluation
Plasma sample preparation: and respectively sucking 450 mu L of blank plasma of corresponding species (rat, mouse, dog, monkey and human), and adding 50 mu L of corresponding test compound solution and positive control taxol to obtain a plasma sample solution, wherein the concentration of the compound plasma is respectively 1 mu M and 10 mu M, and the acetonitrile ratio of the organic solvent is 1% (volume ratio).
Placing the pretreated dialysis membrane in a balance dialysis device, sucking 100 mu L of plasma sample solution and PBS buffer solution, respectively adding the plasma sample solution and PBS buffer solution to two sides (sample side and buffer solution side) (n=3), sealing the balance device by using a film, then placing the balance device into a 37 ℃ incubator overnight (100 rpm), after the dialysis balance is achieved, respectively sucking 50 mu L of sample from the sample side and the buffer solution side, respectively adding equal volumes of blank PBS buffer solution and blank plasma, so that two matrixes are identical.
100. Mu.L of the resulting incubated sample was precipitated by adding 500. Mu.L of glacial acetonitrile containing an internal standard (diazepam), vortexed for 5min, and centrifuged (12000 rpm,4 ℃) for 10min. The supernatant was aspirated at 75. Mu.L, diluted with 75. Mu.L of ultrapure water, and analyzed by 1. Mu.L of sample.
8. In vivo pharmacokinetic evaluation in rats
SD rats weighing 180-220 g, after 3-5 days adaptation, randomly dividing into 2 groups, and respectively perfusing gastric samples according to 5mg/kg dose for 3 groups.
The animals (SD rats) were fasted for 12h before dosing and were fed with food 4h after dosing, with free water before, after and during the experiment.
After administration by gastric lavage, about 0.2mL of blood is taken from the orbit at 0min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h and 24h, EDTA-K2 is anticoagulated, and then the blood plasma is transferred to 4 ℃ within 30min, 4000rpm and centrifugally separated under the condition of 10 min. All plasma was collected and stored at-20℃immediately for testing.
And (3) sucking 50 mu L of the plasma sample to be detected obtained by the treatment, adding 300 mu L of acetonitrile solution containing an internal standard (diazepam 20 mg/mL), shaking and uniformly mixing for 5min, centrifuging at 12000rpm for 10min, taking 75 mu L of supernatant, adding 75 mu L of ultrapure water for dilution, uniformly mixing, sucking 2 mu L of the supernatant for LC/MS/MS measurement, and recording a chromatogram.
Oral exposure of test compounds was assessed by in vivo pharmacokinetic experiments in rats. The pharmacokinetic parameters for compound I-1 are shown in Table 6 below.
Table 6 in vivo drug substitution parameters in rats of Compound (I-1)
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Claims (46)

1. A compound of formula II, a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
Wherein, the liquid crystal display device comprises a liquid crystal display device,
x is selected from N or O, and when X is selected from O, R 1 Absence of;
R 1 selected from hydrogen;
R 2 selected from- (CH) 2 ) n -R 3 The method comprises the steps of carrying out a first treatment on the surface of the n is selected from 0, 1 or 2;
when n is 0, R 3 Selected from optionally covered by C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 1-4 alkyl-OC 1-4 Alkyl, -COC 1-4 alkyl-NH (C) 1-4 Alkyl), -COC 1-4 alkyl-N (C) 1-4 Alkyl group 2 or-SO 2 C 1-4 Alkyl substituted 5-6 membered rings;
when n is selected from 1 or 2, R 3 Selected from-NHC 1-4 Alkyl, -N (C) 1-4 Alkyl group 2 、-COOC 1-4 Alkyl or optionally C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 1-4 alkyl-OC 1-4 Alkyl, -COC 1-4 alkyl-NH (C) 1-4 Alkyl group),-COC 1-4 alkyl-N (C) 1-4 Alkyl group 2 or-SO 2 C 1-4 An alkyl-substituted 5-6 membered ring,
the ring is selected from heterocycloalkyl or cycloalkyl, the heteroatom of the heterocycloalkyl is selected from S, N or O, and the number of the heteroatoms is selected from 1 or 2.
2. The compound of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula II,
wherein, the liquid crystal display device comprises a liquid crystal display device,
x is selected from N;
R 1 selected from hydrogen;
R 2 selected from- (CH) 2 ) n -R 3 The method comprises the steps of carrying out a first treatment on the surface of the n is selected from 1 or 2;
R 3 selected from-N (C) 1-4 Alkyl group 2 、-COOC 1-4 Alkyl or optionally C 1-4 Alkyl substituted 5-6 membered heterocycloalkyl.
3. The compound of claim 1, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the R 3 The 5-6 membered ring of (C) is selected from dioxane, morpholine, piperidine, tetrahydropyran, tetrahydrothiopyran, tetrahydropyrrole, tetrahydrofuran or cyclohexane.
4. The compound of claim 1, a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is selected from O and R 1 Is not present.
5. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is selected from N, R 1 Selected from hydrogen, R when n is 0 3 Selected from optionally being C 1-4 Alkyl substituted 5-6 membered heterocycloalkyl, R when n is selected from 1 or 2 3 Selected from optionally being C 1-4 Alkyl-substituted 5-6 membered heterocycloalkyl, or-N (C) 1-4 Alkyl group 2 。
6. The compound of claim 5, a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is selected from 0, 1 or 2, r 3 Selected from optionally being C 1-4 Alkyl substituted 5-6 membered heterocycloalkyl.
7. The compound of claim 6, a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is selected from 0, 1, or 2, r 3 Selected from 5-6 membered heterocycloalkyl.
8. The compound of claim 1, a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is selected from N, R 1 Selected from hydrogen.
9. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n is selected from 1 or 2.
10. The compound of claim 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n is selected from 1.
11. The compound of claim 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n is selected from 2.
12. The compound of claim 1, a stereoisomer or pharmaceutically acceptable salt thereof, wherein when n is selected from 1 or 2, R 3 Selected from-N (C) 1-4 Alkyl group 2 、-COOC 1-4 Alkyl or optionally C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 1-4 alkyl-OC 1-4 Alkyl, -COC 1-4 alkyl-N (C) 1-4 Alkyl group 2 or-SO 2 C 1-4 Alkyl substituted 5-6 membered rings.
13. The compound of claim 12, stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 Selected from-N (C) 1-3 Alkyl group 2 、-COOC 1-3 Alkyl or optionally C 1-3 Alkyl, -OC 1-3 Alkyl, -COC 1-3 Alkyl, -COC 1-2 alkyl-OC 1-3 Alkyl, -COC 1-3 alkyl-N (C) 1-3 Alkyl group 2 or-SO 2 C 1-3 Alkyl substituted 5-6 membered rings.
14. The compound of claim 13, a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 Selected from-N (CH) 3 ) 2 、-N(CH 2 CH 3 ) 2 、-COOCH 2 CH 3 Or optionally methyl, ethyl, -OCH 3 、-COCH 3 、-COCH(CH 3 ) 2 、-COCH 2 OCH 3 、
-COCH 2 N(CH 3 ) 2 or-SO 2 CH 3 Substituted 5-6 membered rings.
15. The compound of claim 14, a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 Selected from-N (CH) 3 ) 2 、-N(CH 2 CH 3 ) 2 、-COOCH 2 CH 3 。
16. The compound of claim 1, stereoisomer or pharmaceutically acceptable salt thereof, wherein when n is selected from 0, 1 or 2, R 3 Selected from optionally methyl, ethyl, -OCH 3 、-COCH 3 、-COCH(CH 3 ) 2 、-COCH 2 OCH 3 、-COCH 2 N(CH 3 ) 2 or-SO 2 CH 3 Substituted 5-6 membered rings.
17. The compound of claim 14, a stereoisomer thereof, or a pharmaceutically acceptable salt thereofAn acceptable salt, wherein R 3 Selected from-N (CH) 3 ) 2 、-N(CH 2 CH 3 ) 2 、-COOCH 2 CH 3 Dioxane, tetrahydropyran, tetrahydrofuran or tetrahydrothiopyran.
18. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the 5-6 membered ring is selected from dioxane, morpholine, piperidine, tetrahydropyran, tetrahydrothiopyran, tetrahydropyran, tetrahydrofuran, or cyclohexane.
19. A compound according to claim 3, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein when the morpholine, piperidine or tetrahydropyrrole is substituted, the substitution site is on the N of its ring.
20. The compound of claim 1, stereoisomer or pharmaceutically acceptable salt thereof, wherein when n is selected from 0, 1 or 2, R 3 Selected from dioxane, tetrahydropyran, tetrahydrothiopyran, or tetrahydrofuran.
21. The compound of claim 1, stereoisomer or pharmaceutically acceptable salt thereof, wherein when n is selected from 0, 1 or 2, R 3 Selected from optionally covered by C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 1-4 alkyl-OC 1-4 Alkyl, -COC 1-4 alkyl-N (C) 1-4 Alkyl group 2 or-SO 2 C 1-4 Alkyl substituted morpholines, piperidines, tetrahydropyrroles or cyclohexanes.
22. The compound of claim 21, stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of optionally methyl, ethyl,
-OCH 3 、-COCH 3 、-COCH(CH 3 ) 2 、-COCH 2 OCH 3 、-COCH 2 N(CH 3 ) 2 or-SO 2 CH 3 Substituted morpholines, piperidines, tetrahydropyrroles or cyclohexanes.
23. The compound of claim 21, stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 Selected from optionally covered by C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 1-4 alkyl-OC 1-4 Alkyl, -COC 1-4 alkyl-N (C) 1-4 Alkyl group 2 or-SO 2 C 1-4 Alkyl substituted morpholines or piperidines.
24. The compound of claim 23, stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of optionally methyl, ethyl,
-OCH 3 、-COCH 3 、-COCH(CH 3 ) 2 、-COCH 2 OCH 3 、-COCH 2 N(CH 3 ) 2 or-SO 2 CH 3 Substituted morpholines or piperidines.
25. The compound of claim 23, stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 Selected from optionally covered by C 1-4 Alkyl, -COC 1-4 Alkyl, or-COC 1-4 alkyl-OC 1-4 Alkyl substituted morpholines.
26. The compound of claim 25, stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of optionally methyl, ethyl,
-COCH 3 、-COCH(CH 3 ) 2 or-COCH 2 OCH 3 Substituted morpholines.
27. The compound of claim 21, stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 Selected from optionally covered by C 1-4 Alkyl, -COC 1-4 Alkyl, -COC 1-4 alkyl-OC 1-4 Alkyl, -COC 1-4 alkyl-N (C) 1-4 Alkyl group 2 or-SO 2 C 1-4 Alkyl substituted piperidines.
28. The compound of claim 27, stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 Selected from optionally methyl, ethyl, -COCH 3 、-COCH(CH 3 ) 2 、-COCH 2 OCH 3 、-COCH 2 N(CH 3 ) 2 or-SO 2 CH 3 Substituted piperidines.
29. The compound of claim 1, stereoisomer or pharmaceutically acceptable salt thereof, wherein when n is selected from 0, 1 or 2, R 3 Selected from optionally covered by C 1-3 Alkyl, -OC 1-3 Alkyl, -COC 1-3 Alkyl, -COC 1-2 alkyl-OC 1-3 Alkyl or-SO 2 C 1-3 Alkyl substituted dioxane or tetrahydropyran.
30. The compound of claim 29, stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 Selected from optionally methyl, ethyl, -OCH 3 、-COCH 3 、-COCH(CH 3 ) 2 、-COCH 2 OCH 3 or-SO 2 CH 3 Substituted dioxane.
31. The compound of claim 29, stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 Selected from dioxane or tetrahydropyran.
32. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is selected from N, R 1 Selected from hydrogen, R 2 Is- (CH) 2 ) n -R 3 Wherein R is 3 Selected from cyclohexane, piperidine substituted with methyl, or tetrahydropyran; n is selected from 0 or 1.
33. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is selected from N, R 1 Selected from hydrogen, R 2 Is- (CH) 2 ) n -R 3 Wherein when n is 0, R 3 Selected from cyclohexane, piperidine substituted with methyl, tetrahydropyran or morpholine; when n is selected from 1 or 2, R 3 Selected from cyclohexane, piperidine substituted with methyl, tetrahydropyran, morpholine, dimethylamino, or diethylamino.
34. The compound of claim 32, a stereoisomer or pharmaceutically acceptable salt thereof, wherein X is selected from N, R 1 Selected from hydrogen, R 2 Is- (CH) 2 ) n -R 3 Wherein R is 3 Selected from cyclohexane, piperidine substituted with methyl, or tetrahydropyran; n is selected from 0 or 1.
35. The compound of claim 1, a stereoisomer or pharmaceutically acceptable salt thereof, wherein when n is selected from 1 or 2, R 3 Selected from the group consisting of
36. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein,the moiety is selected from the following structures:
37. the compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The moiety is selected from the following structures:
38. the compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein,the moiety is selected from the following structures:
39. the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:
40. the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:
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41. the following compounds or pharmaceutically acceptable salts thereof:
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42. a pharmaceutical composition comprising a compound of any one of claims 1-41, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
43. The pharmaceutical composition of claim 42, further comprising a pharmaceutically acceptable adjuvant.
44. Use of a compound according to any one of claims 1 to 41, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 42 or 43 for the manufacture of a medicament for the prevention or treatment of a disease associated with the anti-apoptotic protein BCL-2.
45. The use according to claim 44, wherein said disease associated with anti-apoptotic protein BCL-2 is selected from cancer.
46. The use of claim 45, wherein the cancer is selected from chronic lymphocytic leukemia or B-cell lymphoma.
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