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HK1195557B - Benzamides - Google Patents

Benzamides Download PDF

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Publication number
HK1195557B
HK1195557B HK14109011.0A HK14109011A HK1195557B HK 1195557 B HK1195557 B HK 1195557B HK 14109011 A HK14109011 A HK 14109011A HK 1195557 B HK1195557 B HK 1195557B
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HK
Hong Kong
Prior art keywords
het
compound
piperazin
tolyl
cyc
Prior art date
Application number
HK14109011.0A
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Chinese (zh)
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HK1195557A1 (en
Inventor
H.余
J.李
T．E．理查德森
P．巴拉迪
B．H．希斯利
A．古托普鲁斯
Original Assignee
默克专利有限公司
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Priority claimed from PCT/US2012/047038 external-priority patent/WO2013012848A1/en
Publication of HK1195557A1 publication Critical patent/HK1195557A1/en
Publication of HK1195557B publication Critical patent/HK1195557B/en

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Description

Benzamide derivatives
Priority requirement
This patent application claims priority from united states provisional patent application No. 61/508,861 filed on 7/18/2011 and from united states provisional patent application No. 61/526,342 filed on 23/8/2011.
Technical Field
The invention relates to compounds of general formula (I) and/or physiologically acceptable salts thereof,
in the formula, W1、W2、R1To R7、R8X and Y have the meanings given in the claims. The compounds of formula (I) are useful as positive allosteric modulators of the Follicle Stimulating Hormone Receptor (FSHR). The object of the invention also relates to pharmaceutical compositions comprising the compounds of formula (I) and to the use of the compounds of formula (I) for the treatment of fertility disorders.
Background
Gonadotropins play important roles in many bodily functions including metabolism, thermoregulation and reproductive processes. Gonadotropins act on specific types of gonadal cells to initiate ovarian and testicular differentiation and steroid production. The gonadotropin FSH (follicle stimulating hormone) is released from the anterior pituitary under the influence of gonadotropin releasing hormone and □ hormone, and from the placenta during pregnancy. FSH is a heterodimeric glycoprotein hormone with a structure similar to Luteinizing Hormone (LH) and Thyroid Stimulating Hormone (TSH), which are produced in the pituitary gland, and Chorionic Gonadotropin (CG), which is produced in the placenta. FSH plays a central role in stimulating follicular development and maturation in women, and furthermore, it is the major hormone regulating □ hormone secretion, whereas LH induces ovulation. FSH in males is responsible for the integrity of the tubules and acts on sertoli cells to support gametogenesis.
Hormones are relatively large (28-38kDa), consisting of a common α -subunit linked in a non-covalent manner to different β -subunits, which confer receptor binding specificity. The cellular receptors for these hormones were expressed on testis sertoli cells and ovarian granulosa cells. The FSH receptor is known to be a member of a class of membrane-bound receptors that bind to G-proteins and, when activated, stimulate an increase in the activity of adenylyl cyclase. This results in increased levels of the intracellular second messenger adenosine 3', 5' -monophosphate (cAMP), which in turn leads to increased steroid synthesis and secretion. Hydropathic analysis curves of the amino acid sequences of these receptors show three general domains: a hydrophilic amino-terminal region, which is considered to be the amino-terminal extracellular domain; 7 hydrophobic segments of transmembrane length, which are considered transmembrane domains; and a carboxy-terminal region, which contains potential phosphorylation sites (serine, threonine, and tyrosine residues), known as the carboxy-terminal intracellular or cytoplasmic domain. The glycoprotein hormone receptor family differs from other G protein-binding receptors (e.g., β -2-adrenoceptors, rhodopsin receptors, and substance K receptors) in that the size of the hydrophilic amino-terminal domain involved in hormone binding is large.
Every year, 2.4 million couples in the united states are suffering from infertility and need to be treated. The skilled person applies a protein product made of FSH extracted from urine or FSH produced by recombinant DNA technology parenterally to induce ovulation and to control ovarian hyperstimulation. Whereas ovulation induction is the achievement of single follicle ovulation, controlled ovarian hyperstimulation is the harvesting of multiple oocytes for various in vitro assisted reproductive techniques, such as In Vitro Fertilization (IVF). FSH is also used clinically for the treatment of male hypogonadism and male infertility, such as certain types of spermatogenesis-incapable disorders.
FSHR is a highly specific target during follicular growth and is expressed only in the ovary. However, the use of FSH is limited for the following reasons: expensive, lack of oral dosage forms and need for close monitoring by specialized physicians. Therefore, it would be desirable to be able to develop and identify a non-peptide small molecule that replaces FSH for oral administration. Low molecular weight FSH mimetics with agonist properties have been disclosed in international patent applications WO2002/09706 and WO2010/136438 and in US patent US6,653,338. Furthermore, WO2009/105435 relates to 3- (amido or sulfonamido) -4- (4-substituted-azinyl) -benzamides, which are useful as inhibitors of the chemokine receptor CXCR3, and which are useful in the prevention or treatment of diseases mediated by CXCR3, such as inflammation. There remains a need for low molecular weight hormone mimetics that selectively activate FSHR.
Disclosure of Invention
The object of the present invention was to find novel compounds with valuable properties, in particular compounds which can be used for the preparation of medicaments.
It has surprisingly been found that the compounds of the invention and their salts have high pharmaceutical properties and at the same time are highly tolerated. In particular, they act as FSHR agonists. The invention relates to a compound shown in a general formula (I),
in the formula (I), the compound is shown in the specification,
W1，W2each independently represents N or CR8Provided that W is1Or W2At least one ofOne represents N;
R1is represented by- (CY)2)n-E-(CY2)n-Het3、-(CY2)n-Cyc-Het3、-(CY2)n-NY-Het3、-(CY2)n-CONH-Het3、-(CY2)n-NHCO-Het3、-(CY2)n-C(Y)(OH)-(CY2)n-Het3、-(CY2)n-Het1、-(CY2)n-CONH-Het1、-(CY2)n-NHCO-Het1、-(CY2)n-Ar、-Cyc-Ar、-(CY2)n-NY-Ar、-(CY2)n-CONH-Ar、-(CY2)n-NHCO-Ar、-(CY2)n-C(Y)(OH)-(CY2)n-Ar、-(CY2)n-Cyc、-(CY2)n-NY-Cyc、-(CY2)n-CONH-Cyc、-(CY2)n-NHCO-Cyc、-(CY2)n-NHCO-NH-Cyc、Y、-(CYR8)n-OY、-(CY2)n-COOY、-(CY2)n-SO2Y、-(CYR8)n-CO-(CY2)n-N(R8)2、-(CY2)n-[C(Y)(OH)]m-(CYR8)n-NY2、[-(CY2)n-O]m-(CYR8)n-NYCOY、-(CY2)n-NYCOOY、-(CY2)n-NYSO2Y、-(CY2)n-NYCON(R8)2、-(CY2)n-NHCO-CH=CH2、-(CY2)n-NHCO-NH-(CY2)n=CH2Or- (CY)2)n-CN；
R2Represents Y;
R1，R2together also denotes- (CY)2)p-NH-(CY2)p-、-(CY2)p-NHCO-(CY2)p-、-(CY2)p-CONH-(CY2)p-、-(CY2)p-N(COA)-(CY2)p-、-(CY2)p-N(COOA)-(CY2)p-、-(CY2)p-C(Y)(Het3)-(CY2)p-、
R3Is represented by- (CY)2)n-Het1、-(CY2)n-Het3、-(CY2)n-Ar, -C (Y) (OY) -Ar, Y or- (CY)2)n-Cyc；
R4Denotes Y, COY or SO2Y；
R5Represents E-Ar, NY-Ar, Cyc, Y, OY, NYY, NYCOOY, NYCOY, COY, COOY, SO2Y、Het1Or Het3；
R6，R7Each independently represents H;
R6，R7together also denotes- (CY)2)p-；
R8Represents Y or Ar;
x and E each independently represent- (CY)2)m-, O, CO, -COO-or SO2；
Y represents H or A;
a represents a linear or branched alkyl group containing 1 to 10 carbon atoms, wherein 1 to 7 hydrogen atoms may each independently be substituted by Hal, = O and/or OH;
cyc represents cycloalkyl having 3 to 7 carbon atoms, wherein 1 to 4 hydrogen atoms may each independently be replaced by Hal and/or OH;
ar represents an unsaturated or aromatic monocyclic or bicyclic carbocyclic ring containing 3 to 10 carbon atoms, which carbocyclic ring may be substituted by at least one substituent selected from the group consisting of: a, Hal, - (CY)2)n-OY、COOY、CONH2、NHCOY、-(CY2)n-NYCOOY、-(CY2)n-NY2、NO2、SO2Y、SO2NY2、NYSO2Y、-(CY2)n-CN、-(CY2)n-Het2And Cyc, or may be fused to Cyc;
Het1represents an unsaturated or aromatic monocyclic or bicyclic heterocycle containing from 1 to 10 carbon atoms and from 1 to 4N, O and/or S atoms, which heterocycle may be substituted by at least one substituent selected from the following group: hal, A, Cyc, OY, = O, COOY, CONH2、NHCOY、-(CY2)n-NY2、SO2Y、SO2NY2、NHSO2Y, CN, Ar and- (CY)2)n-Het3；
Het2Represents a saturated or unsaturated monocyclic 5-or 6-membered heterocycle containing 1 to 4 carbon atoms and 1 to 4N, O and/or S atoms, which heterocycle may be substituted by a and/or = O;
Het3represents a saturated monocyclic or bicyclic heterocycle containing 3 to 7 carbon atoms and 1 to 4N, O and/or S atoms, which heterocycle may be substituted by at least one substituent selected from the group consisting of: = O, A, Hal, - (CY)2)n-Cyc、-(CY2)n-OY、COY、COOY、CONY2、NHCOY、-(CY2)n-NY2、CN、SO2Y and- (CY)2)n-Ar；
Hal represents F, Cl, Br or I;
m, n each independently represent 0, 1,2,3,4, 5 or 6; and
p represents 1,2 or 3;
and/or a physiologically acceptable salt thereof,
with the proviso that the following compounds are excluded:
3- (3-chloro-benzoylamino) -N- [2- (2, 4-dichloro-phenyl) -ethyl ] -4- (4-ethyl-piperazin-1-yl) -benzamide;
3- (3-chloro-benzoylamino) -N- [2- (2, 4-dichloro-phenyl) -ethyl ] -4- [4- (1-methyl-piperidin-4-yl) -piperazin-1-yl ] -benzamide; and
4- [1,4'] bipiperidinyl-1' -yl-3- (3-chloro-benzoylamino) -N- [2- (4-chloro-phenyl) -ethyl ] -benzamide.
In particular, the invention relates to compounds of formula (I),
in the formula (I), the compound is shown in the specification,
W1，W2each independently represents N or CH, provided that W1Or W2At least one of them represents N;
R1is represented by- (CY)2)n-E-Het3、-(CY2)n-Cyc-Het3，-(CY2)n-Het1、-(CY2)n-CONH-Het1、-(CY2)n-NHCO-Het1、-(CY2)n-Ar、-(CY2)n-Cyc、-(CY2)n-CONH-Cyc、-(CY2)n-NHCO-Cyc、A、-(CYR8)n-OY、-(CY2)n-COOY、-(CY2)n-SO2Y、-(CYR8)n-CONY2、-(CYR8)n-NY2、-(CYR8)n-NYCOY、-(CY2)n-NYCOOY、-(CY2)n-NYCONY2Or-(CY2)n-NHCO-CH=CH2；
R1，R2Together also denotes- (CY)2)p-NH-(CY2)p-、-(CY2)p-NHCO-(CY2)p-、-(CY2)p-CONH-(CY2)p-、-(CY2)p-N(COA)-(CY2)p-、-(CY2)p-N(COOA)-(CY2)p-、
R3Is represented by- (CY)2)n-Het1、-(CY2)n-Het3、-(CY2)n-Ar, H, A or- (CY)2)n-Cyc；
R4Represents Y;
R5represents E-Ar, H, A, COOY, SO2Y、Het1Or Het3；
R2，R6，R7Each independently represents H;
R6，R7together also denotes- (CY)2)p-；
R8Represents H, A or Ar;
x and E each independently represent- (CY)2)m-, O, CO, -COO-or SO2；
Y represents H or A;
a represents a linear or branched alkyl group containing 1 to 10 carbon atoms, wherein 1 to 7 hydrogen atoms may each independently be substituted by Hal and/or = O;
cyc represents a cycloalkyl group having 3 to 7 carbon atoms, wherein 1 to 4 hydrogen atoms may each independently be substituted by Ha;
ar represents an unsaturated or aromatic monocyclic or bicyclic carbocyclic ring containing 3 to 10 carbon atoms, which carbocyclic ring may be substituted by at least one substituent selected from the group consisting of: A. hal, OY, COOY, CONH2、NHCOY、NY2、NO2、SO2Y, CN and Het2Or may be fused to Cyc;
Het1represents an unsaturated or aromatic monocyclic or bicyclic heterocycle containing from 1 to 10 carbon atoms and from 1 to 4N, O and/or S atoms, which heterocycle may be substituted by at least one substituent selected from the following group: hal, A, Cyc, OY, COOY, CONH2、NHCOY、NY2、SO2Y、SO2NY2、NHSO2Y, CN and Ar;
Het2represents an unsaturated monocyclic 5-membered heterocyclic ring containing 1 to 3 carbon atoms and 2 to 4N and/or S atoms, which heterocyclic ring may be substituted by A;
Het3represents a saturated monocyclic or bicyclic heterocycle containing 3 to 7 carbon atoms and 1 to 4N, O and/or S atoms, which heterocycle may be substituted by at least one substituent selected from the group consisting of: = O, A, Hal, - (CY)2)n-Cyc、-(CY2)n-OY、COY、COOY、CONY2、NHCOY、NY2、CN、SO2Y and- (CY)2)n-Ar；
Hal represents F, Cl, Br or I;
m, n each independently represent 0, 1,2,3,4, 5 or 6; and
p represents 1,2 or 3;
and/or physiologically acceptable salts
With the proviso that the following compounds are excluded:
3- (3-chloro-benzoylamino) -N- [2- (2, 4-dichloro-phenyl) -ethyl ] -4- (4-ethyl-piperazin-1-yl) -benzamide;
3- (3-chloro-benzoylamino) -N- [2- (2, 4-dichloro-phenyl) -ethyl ] -4- [4- (1-methyl-piperidin-4-yl) -piperazin-1-yl ] -benzamide; and
4- [1,4'] bipiperidinyl-1' -yl-3- (3-chloro-benzoylamino) -N- [2- (4-chloro-phenyl) -ethyl ] -benzamide.
For clarity, the fusion of a carbocycle with Cyc in the Ar definition refers to a fused ring system wherein another ring system is constructed on a monocyclic or bicyclic carbocycle, forming a bicyclic or tricyclic carbocycle. Furthermore, the disclaimer above is valid for any embodiment of the invention, if applicable.
Detailed Description
Within the meaning of the present invention, compounds are defined to include pharmaceutically usable derivatives, solvates, prodrugs, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures in any ratio.
The term "pharmaceutically acceptable derivatives" is used to indicate, for example, salts of the compounds of the invention and so-called prodrug compounds. The term "solvate of a compound" is used to indicate an adduct of such a compound with an inert solvent molecule formed by the attractive forces of each other. Solvates are, for example, mono-or bis-hydrates or alcoholates. Of course, the invention also relates to solvates of salts of the compounds of the invention. The term "prodrug" is intended to mean a compound of the invention modified with, for example, an alkyl or acyl group, a sugar or an oligopeptide, which is rapidly cleaved in vivo to form the active form of the compound of the invention. These also include biodegradable polymeric derivatives of the compounds of the invention, see, for example, int.115,61-67 (1995). Likewise, the compounds of the present invention may be formulated in any desired prodrug form, such as esters, carbonates, carbamates, ureas, amides or phosphates, in which case the only form actually biologically active isIs released by metabolism. Any compound that can be converted in vivo to a biologically active agent (e.g., a compound of the invention) is a prodrug within the scope and meaning of the invention. Various forms of prodrugs are known and described in the art (e.g., WermuthCG et al, Chapter 31: 671-. All documents mentioned are incorporated herein by reference. It is further known that chemical substances are converted in vivo into metabolites which, under suitable conditions, can likewise induce the desired biological action-in some cases, exert the desired biological action in an even more pronounced manner. The metabolic conversion of any compound of the invention to any biologically active compound in vivo is a metabolite within the scope and meaning of the invention.
The compounds of the invention may be in the form of their double bond isomers (e.g. pure E or Z isomers), or in the form of mixtures of these double bond isomers. The compounds of the invention may, if possible, be in tautomeric form, such as keto-enol tautomers. The present invention contemplates that all stereoisomers of the compounds of the invention may be in the form of a mixture, pure or substantially pure. Any carbon atom in the compounds of the present invention may have an asymmetric center. They may therefore be present in their racemic form, in the form of pure enantiomers and/or diastereomers, or in the form of mixtures of these enantiomers and/or diastereomers. The mixture may have a desired mixing ratio of stereoisomers. Thus, for example, the compounds of the invention having one or more chiral centers and being present as racemates or diastereomeric mixtures can be resolved into their optically pure isomers, i.e. enantiomers or diastereomers, by methods known per se. Resolution of the compounds of the invention can be achieved by column resolution for chiral or achiral phases, or recrystallization in an optional optically active solvent, or derivatization with an optically active acid or base, or with an optically active agent (e.g., an optically active alcohol) followed by removal of the groups.
The invention also relates to the use of mixtures of the compounds according to the invention, for example mixtures of two diastereomers, for example in a mixing ratio of 1: 1,1: 2,1: 3,1: 4,1: 5,1: 10,1: 100 or 1: 1000. these mixtures are particularly preferably mixtures of stereoisomeric compounds.
The terms used in the present specification to define compounds, especially the compounds of the invention, are generally based on the IUPAC organisation rules for compounds, especially organic compounds. The terms used to explain the above-mentioned compounds of the invention always have the following meanings, unless otherwise indicated in the specification or claims.
The term "unsubstituted" means that the corresponding radical, group or moiety has no substituents. The term "substituted" refers to corresponding radicals, groups or moieties having one or more substitutions. If a radical has multiple substituents and a selected plurality of substituents is specified, the selected substituents are independent of each other and need not be the same. Even if a radical has a plurality of specified substituents (e.g. Y)2Or YY), the substituents may be represented differently from each other (e.g., methyl and ethyl). Thus, it is understood that certain substitutions of any one of the radicals of the present invention may involve the same or different radicals. Thus, if each radical occurs several times in a compound, the radicals apply the meaning given above and are each independently of the other. If there are multiple substitutions, the radicals can be represented alternately by R', R "" and the like.
The term "alkyl" or "A" denotes acyclic, saturated or unsaturated hydrocarbon radicals which are straight-chain or branched and preferably have 1,2,3,4, 5,6, 7, 8, 9 or 10 carbon atoms, i.e.C1-10-an alkyl group. Examples of alkyl are methyl, ethyl, propyl, isopropyl, 1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 2-or 1,2, 2-trimethylpropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-, 2-or 3-methylbutyl, 1-, 1,2-,1,3-, 2,2-, 2, 3-or 3, 3-dimethylbutyl, 1-or 2-ethylbutyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-, 2-, 3-or 4-methylpentyl, hexyl, 2-hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl, docosyl.
In a preferred embodiment of the present invention A is a straight-chain or branched alkyl radical having from 1 to 10 carbon atoms, wherein from 1 to 7 hydrogen atoms may be substituted independently of one another by Hal and/or OH. A is more preferably a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, where 1 to 4 hydrogen atoms may be substituted independently of one another by Hal and/or OH. In a most preferred embodiment of the invention, A is a straight-chain or branched alkyl group having 1 to 5 carbon atoms, wherein 1 to 3 hydrogen atoms may be substituted independently of one another by Hal or OH. It is highly preferred that A is a straight-chain or branched alkyl radical having 1 to 5 carbon atoms, wherein 1 to 3 hydrogen atoms may be substituted independently of one another by F and/or Cl. A particular choice is C1-4-an alkyl group. C1-4Alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1, 1-trifluoroethyl or bromomethyl, in particular methyl, ethyl, propyl or trifluoromethyl. A highly preferred embodiment of the invention is where "A" represents methyl. It goes without saying that the respective meanings of A in any of the radicals of the invention are independent of one another.
The term "cycloalkyl" or "Cyc" in the sense of the present invention denotes saturated and partially unsaturated non-aromatic cyclic hydrocarbon radicals having 1 to 3 rings and comprising 3 to 20, preferably 3 to 12, particularly preferably 3 to 9, carbon atoms. Cycloalkyl groups may be part of a bicyclic or polycyclic ring system in which, for example, the cycloalkyl group is fused to an aryl, heteroaryl or heterocyclic group through any possible and desired ring member. The attachment to the compounds of formula (I) may be through any ring member of the cycloalkyl group. Examples of suitable cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclopentenyl, cyclohexenyl and cyclooctadienyl.
In a preferred embodiment of the invention Cyc is cycloalkyl having 3 to 6 carbon atoms, wherein 1 to 4 hydrogen atoms may be replaced by OH. More preferably C3-C6Cycloalkyl, i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In addition, the definition of A also includes cycloalkyl, which applies to Cyc. It is to be understood that the corresponding meanings of Cyc in any of the groups of the invention are each independently.
The term "aryl" or "carboaryl" in the sense of the present invention denotes monocyclic or polycyclic aromatic hydrocarbon systems having 3 to 14 carbon atoms, preferably 5 to 10 carbon atoms, particularly preferably 6 to 8 carbon atoms, which may be optionally substituted. The term "aryl" also includes aromatic rings that are part of a bicyclic or polycyclic saturated, partially unsaturated, and/or aromatic system, for example, when the aromatic ring is fused to an aryl, cycloalkyl, heteroaryl, or heterocyclyl group as defined herein via any desirable and possible ring atom of the aryl group. The attachment to the compounds of the general formula (I) can be carried out via any ring atom of the aryl group. Examples of suitable aryl radicals are phenyl, biphenyl, naphthyl, 1-naphthyl, 2-naphthyl and anthryl, and likewise indanyl, indenyl, 1,2,3, 4-tetrahydronaphthyl. Preferred carboaryl groups of the present invention are phenyl, naphthyl and biphenyl groups which may be optionally substituted, more preferred are monocyclic carboaryl groups having 6 to 8 carbon atoms which may be optionally substituted, and most preferred is phenyl which may be optionally substituted.
In another embodiment of the present invention, carbocycles include, but are not limited to, carboaryl, defined as "Ar". Examples of suitable Ar groups are phenyl, o-, m-or p-tolyl, o-, m-or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m-or p-isopropylphenyl, o-, m-or p-tert-butylphenyl, o-, m-or p-hydroxyphenyl, o-, m-or p-methoxyphenyl, o-, m-or p-ethoxyphenyl, o-, m-or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m-or p-chlorophenyl, o-, m-or p-sulfonylaminophenyl, o-, m-or p- (N-methylsulphonylamino) phenyl, o-, m-or p-sulphonylamido, o-, m-or p- (N, N-dimethyl-sulfonylamino) phenyl, o-, m-or p- (N-ethyl-N-methyl-sulfonylamino) phenyl, o-, m-or p- (N, N-diethyl-sulfonylamino) phenyl, in particular 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dibromophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4, 6-or 3,4, 5-trichlorophenyl, 2,4, 6-trimethoxyphenyl, 2-hydroxy-3, 5-dichlorophenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2, 5-dichloro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl or 2, 5-dimethyl-4-chlorophenyl.
Ar preferably represents an unsaturated or aromatic monocyclic or bicyclic carbocyclic ring containing from 3 to 10 carbon atoms, which carbocyclic ring may be substituted by at least one ring selected from A, Hal, OY, COOY, CONH2、NHCOY、NY2、NO2、SO2Y, CN and Het2Or may be fused to Cyc. In a more preferred embodiment of the invention, Ar represents an unsaturated or aromatic monocyclic or bicyclic carbocyclic ring containing 5 to 10 carbon atoms, which carbocyclic ring may be substituted by at least one ring selected from A, Hal, OY, COOY, CONH2、NHCOY、NY2、NO2CN and Het2Is substituted with the substituent(s). Most preferably, Ar represents an aromatic monocyclic carbocyclic ring containing 6 to 8 carbon atoms, which carbocyclic ring may be substituted by at least one member selected from A, Hal, OA, CONH2、NY2、NO2And CN. In another aspect of the invention, Ar preferably represents an unsaturated or aromatic monocyclic or bicyclic carbon ring containing 3 to 10 carbon atoms, which is substituted by at least one ring selected from A, Hal, - (CY)2)n-OY、COOY、CONH2、NHCOY、-(CY2)n-NYCOOY、-(CY2)n-NY2、NO2、SO2Y、SO2NY2、NYSO2Y、-(CY2)n-CN、-(CY2)n-Het2And Cyc, or may be fused to Cyc. In another more preferred embodiment of the invention, Ar represents an unsaturated or aromatic monocyclic or bicyclic carbocyclic ring containing 5 to 10 carbon atoms, which carbocyclic ring is substituted by at least one ring selected from A, Hal, OY, COOY, CONH2、NHCOY、-(CH2)n-NY2、SO2NH2、NO2CN and Het2Is substituted with the substituent(s). In another preferred embodiment of the invention, Ar represents an aromatic monocyclic carbocyclic ring containing 6 to 8 carbon atoms, which carbocyclic ring is substituted by at least one member selected from A, Hal, OY, CONH2、-(CH2)n-NY2、SO2NH2And Het2The substituent(s) of (a) is mono-or di-substituted. In a highly preferred embodiment of the invention, Ar represents phenyl, which phenyl may be mono-substituted with A, Hal or OA. Particularly preferred Ar represents phenyl which may be monosubstituted by A. It is to be understood that the corresponding meanings of Ar in any of the groups of the present invention are each independently.
The term "heteroaryl" in the sense of the present invention denotes a 1-15-membered, preferably 1-9-membered, particularly preferably 5-, 6-or 7-membered monocyclic or polycyclic aromatic hydrocarbon radical which comprises at least one, if appropriate also 2,3,4 or 5, heteroatom(s), which may be identical or different, in particular nitrogen, oxygen and/or sulfur. The number of nitrogen atoms is preferably 0, 1,2,3 or 4, and the number of oxygen atoms and sulfur atoms is independently 0 or 1. The term "heteroaryl" includes systems in which the aromatic ring is part of a bicyclic or polycyclic saturated, partially unsaturated, and/or aromatic system, for example, when the aromatic ring is fused to an aryl, cycloalkyl, heteroaryl, or heterocyclyl group as defined herein via any desirable and possible ring atom of the heteroaryl group. The attachment to the compounds of the general formula (I) can be made via any ring atom of the heteroaryl group. Examples of suitable heteroaryl groups are pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, phthalazinyl, indazolyl, indolizinyl, quinoxalinyl, quinazolinyl, pteridinyl, carbazolyl, phenazinyl, phenoxazinyl, phenothiazinyl and acridinyl.
Heteroaryl in "Het1"preferably means in the sense of a compound having from 1 to 10 carbon atoms and from 1 to 4N, O and/or sulfur atomsSaturated or aromatic monocyclic or bicyclic heterocycles which may be substituted by at least one substituent selected from Hal, A, Cyc, OY, = O, COOY, CONH2、NHCOY、-(CY2)n-NY2、SO2Y、SO2NY2、NHSO2Y, CN, Ar and- (CY)2)n-Het3Is substituted with the substituent(s). In a more preferred embodiment of the invention, Het1Denotes an unsaturated or aromatic monocyclic or bicyclic heterocycle having 1 to 10 carbon atoms and 1 to 4N, O and/or sulfur atoms, which may be substituted by at least one substituent selected from Hal, A, Cyc, OY, COOY, CONH2、NHCOY、NY2、SO2Y、SO2NY2、NHSO2Y, CN and Ar. In a most preferred embodiment of the invention, Het1Denotes an unsaturated or aromatic monocyclic or bicyclic heterocycle having 1 to 9 carbon atoms and 1 to 3N, O and/or sulfur atoms, which is substituted by at least one substituent selected from Hal, A, Cyc, OY, CONH2、NHCOY、-(CH2)n-NY2、SO2NY2、NHSO2Y, CN and Ar, wherein the substituents are mono-or di-substituted. In another most preferred embodiment of the invention, Het1Denotes an unsaturated or aromatic monocyclic heterocycle having 1 to 6 carbon atoms and 1 to 3N, O and/or sulfur atoms, which is substituted by at least one substituent selected from Hal, A, Cyc, OA, CONH2、NHCOA、NHA、SO2NH2And CN, or an aromatic bicyclic heterocycle having 6 to 9 carbon atoms and 1 to 3N and/or sulfur atoms, which may be mono-substituted by A. Highly preferred are, Het1Represents pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazinyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, indolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl or quinoxalinyl, which may be monosubstituted by Hal, a or Cyc. Particularly preferred is Het1Represents pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazinyl, thiadiazolyl, tetrazolyl, pyridyl or pyrimidinyl, which may be Hal, Cyc or- (CH)2)n-NA2One is substituted. It is to be understood that Het in any of the groups of the invention1Are each independently.
Heteroaryl in "Het2"in the sense of" preferably means a saturated or unsaturated monocyclic 5-or 6-membered heterocyclic ring having 1 to 4 carbon atoms and 1 to 4N, O and/or S atoms, which may be substituted by a and/or = O. In a more preferred embodiment of the invention, Het2Represents an unsaturated monocyclic 5-membered heterocyclic ring having 1 to 3 carbon atoms and 2 to 4N and/or S atoms, which may be substituted by A. In the most preferred embodiment of the invention, Het2Represents imidazolyl, pyrazinyl, thiazinyl or tetrazolyl, which may be monosubstituted by methyl. In a highly preferred embodiment of the invention, Het2Represents a tetrazolyl group.
The term "heterocycle" or "heterocyclyl" in the sense of the present invention denotes a mono-or polycyclic ring system having 3 to 20 ring atoms, preferably 3 to 14 ring atoms, particularly preferably 3 to 10 ring atoms, comprising carbon atoms and 1,2,3,4 or 5 identical or different heteroatoms, in particular nitrogen, oxygen and/or sulfur. The ring system may be saturated or mono-or polyunsaturated. In the case of a ring system consisting of at least two rings, the rings can be joined together by fusion or screwing. These heterocyclic groups may be attached through any ring atom. The term "heterocyclyl" includes systems in which the heterocyclic ring is part of a bicyclic or polycyclic saturated, partially unsaturated and/or aromatic system, for example, when the heterocyclic ring is fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl group as defined herein via any desirable and possible atom in the heterocyclic group. The attachment to the compounds of formula (I) may be made via any ring atom of the heterocyclyl group. Examples of suitable heterocyclic groups are: pyrrolidinyl, thiopyrrolidinyl, piperidinyl, pyrazinyl, oxazinyl, oxapiperidinyl, oxadiazolyl, tetrahydrofuranyl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl, morpholinyl, tetrahydrothiophenyl, dihydropyranyl.
In a preferred embodiment of the invention, the term "Het3"denotes a saturated mono-group having 3 to 7 carbon atoms and 1 to 4N, O and/or sulfur atomsA ring or bicyclic heterocycle which may be substituted by at least one member selected from the group consisting of = O, A, Hal, - (CY)2)n-Cyc、-(CY2)n-OY、COY、COOY、CONY2、NHCOY、-(CH2)n-NY2、CN、SO2Y and- (CY)2)n-substituents of Ar. In a more preferred embodiment of the invention, Het3Denotes a saturated monocyclic heterocycle having 3 to 6 carbon atoms and 1 to 3N, O and/or O atoms, which may be substituted by at least one substituent selected from the group consisting of = O, A, Hal, - (CY)2)n-Cyc、-(CY2)n-OY、COY、COOY、CONY2、NHCOY、NY2、CN、SO2Y and- (CY)2)n-Ar is monosubstituted, disubstituted or trisubstituted. In the most preferred embodiment of the invention, Het3Represents a saturated monocyclic heterocycle having 3 to 6 carbon atoms and 1 to 3N, O and/or O atoms, which may be substituted by at least one member selected from the group consisting of = O, A, Cyc, OY, COA, COOA, CONHA and SO2The substituent of A is mono-substituted, di-substituted or tri-substituted. Most preferably, Het3Represents pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, or thiomorpholinyl, which may be mono-substituted with = O. Particularly preferred is that3Represents pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, or thiomorpholinyl, which is monosubstituted with = O. It is to be understood that Het in any of the groups of the invention3Are each independently.
The terms "halogen", "halogen atom", "halogen substituent" or "Hal" in the sense of the present invention denote one or several fluorine (F), bromine (Br), chlorine (Cl) or iodine (I) atoms. The terms "dihalo", "trihalo" and "perhalo" refer to two, three and four substituents, respectively, each of which may be independently selected from F, Cl, Br or I. Halogen preferably represents an atom of F, Cl or Br. F and Cl are particularly preferred, especially when halogen is substituted in an alkyl (haloalkyl) or alkoxy group (e.g. CF)3And CF3O) above. It is to be understood that the corresponding meaning of "Hal" in any group of the invention is independent of each other.
The preferred embodiment of the present invention is W1And W2Both represent N.
In another more preferred embodiment of the invention, the benzene ring in the skeleton of formula (I) is in the meta position-NXR3R4Part is substituted by-CONR1R2And (4) substitution.
According to the invention, R1Is- (CY)2)n-E-Het3、-(CY2)n-Cyc-Het3、-(CY2)n-Het1、-(CY2)n-NHCO-Het1、-(CY2)n-Ar、-(CY2)n-Cyc、-(CY2)n-CONH-Cyc、A、-(CYR8)n-OY、-(CY2)n-COOY、-(CYR8)n-NY2、-(CYR8)n-NYCOY、-(CY2)n-NYCOOY or- (CY)2)n-NHCO-CH=CH2More preferred is- (CY)2)n-E-Het3、-(CY2)n-Cyc-Het3、-(CY2)n-Het1、-(CY2)n-NHCO-Het1、-(CY2)n-Ar、-(CY2)n-Cyc、-(CY2)n-CONH-Cyc、A、-(CYR8)n-OH、-(CY2)n-COOA、-(CYR8)n-NY2、-(CYR8)n-NACOA、-(CY2)n-NHCOOA or- (CY)2)n-NHCO-CH=CH2Most preferred is- (CY)2)n-E-Het3、-(CY2)n-Cyc-Het3、-(CY2)n-Het1、-(CY2)n-NHCO-Het1、-(CY2)n-Ar、-(CY2)n-Cyc or- (CY)2)n-CONH-Cyc, highly preferred is- (CY)2)n-E-Het3、-(CY2)n-Het1Or- (CY)2)n-Ar, particularly preferably- (CY)2)n-Het3。
According to the invention, R1Is- (CY)2)n-E-(CY2)n-Het3、-(CY2)n-Cyc-Het3、-(CY2)n-NHCO-Het3、-(CY2)n-C(Y)(OH)-(CY2)n-Het3、-(CY2)n-Het1、-(CY2)n-NHCO-Het1、-(CY2)n-Ar、-(CY2)n-C(Y)(OH)-(CY2)n-Ar、-(CY2)n-Cyc、-(CY2)n-CONH-Cyc、A、-(CYR8)n-OY、-(CY2)n-COOY、-(CYR8)n-CO-(CY2)n-N(R8)2、-(CY2)n-[C(Y)OH]]m-(CYR8)n-NY2、[-(CY2)n-O]m-(CYR8)n-NYCOY、-(CY2)n-NYCOOY、-(CY2)n-NYCON(R8)2、-(CY2)n-NHCO-CH=CH2Or- (CY)2)n-NHCO-NH-(CY2)n=CH2More preferred is- (CY)2)n-E-Het3、-(CY2)n-Cyc-Het3、-(CY2)n-NHCO-Het3、-(CY2)n-C(Y)(OH)-(CY2)n-Het3、-(CY2)n-Het1、-(CY2)n-NHCO-Het1、-(CY2)n-Ar、-(CY2)n-C(Y)(OH)-(CY2)n-Ar、-(CY2)n-Cyc、-(CY2)n-CONH-Cyc、A、-(CYR8)n-OY、-(CY2)n-COOY、-(CY2)n-CO-NY2、-(CYR8)n-NY2、-(CYR8)n-NYCOY、-(CY2)n-NYCOOY、-(CY2)n-NYCON(R8)2、-(CY2)n-NHCO-CH=CH2Or- (CY)2)n-NHCO-NH-(CY2)n=CH2。
According to the invention, R1Is- (CY)2)n-E-(CY2)n-Het3、-(CY2)n-NHCO-Het3、-(CY2)n-C(Y)(OH)-(CY2)n-Het3、-(CY2)n-Het1、-(CY2)n-Ar、-(CY2)n-C(Y)(OH)-(CY2)n-Ar、-(CY2)n-Cyc、-(CYR8)n-CO-(CY2)n-N(R8)2、[-(CY2)n-O]m-(CYR8)n-NYCOY、-(CY2)n-NYCON(R8)2Or- (CY)2)n-NHCO-NH-(CY2)n=CH2Most preferred is- (CY)2)n-Het3、-(CY2)n-NHCO-Het3、-(CY2)n-C(Y)(OH)-(CY2)n-Het3、-(CY2)n-Het1、-(CY2)n-Ar、-(CY2)n-C(Y)(OH)-Ar、Cyc、-(CY2)n-CO-NY2、(CY2)n-NYCOY、-(CY2)n-NYCONY2Or- (CY)2)n-NHCO-NH-(CY2)n=CH2。
According to the invention, R2The preferred embodiment of (a) is H.
In another preferred embodiment, R1And R2Together represent- (CY)2)p-NH-(CY2)p-、-(CY2)p-NHCO-(CY2)p-、-(CY2)p-CONH-(CY2)p-、-(CY2)p-N(COA)-(CY2)p-、-(CY2)p-N(COOA)-(CY2)p-、
According to the invention, R3Is a preferred embodiment of Het1、Het3Ar, H, A or Cyc, more preferably Het1、Het3Or Ar, highly preferred is Het1Or Het3Highly particularly preferred are Het1。
According to the invention, R4The preferred embodiment of (A) is Y, more preferably H.
According to the invention, R5Preferred examples of (a) are E-Ar, H, A, COOA or Het1More preferably E-Ar, H or COOA. According to the invention, R5Is E-Ar or Het1Most preferred is E-Ar, and highly preferred is Ar.
According to the invention, R1、R3、R5Are expressed independently of one another (CY)2)n-Het3、-(CY2)n-Het1、-(CY2)n-Ar or Cyc, highly particularly preferred is- (CY)2)n-Het3、Het1Or Ar. The disclaimer above applies.
According to the invention, R8、R7Is that they together represent- (CY2)p-。
According to the invention, R8The preferred embodiment of (A) is Y, more preferably H. It is to be understood that R in any of the groups of the present invention8Are each independently.
According to the invention, R2、R4、R8In another more preferred embodiment, H is represented independently of each other, more preferably H.
According to the invention, the preferred embodiment of X is- (CY)2)m-, CO or SO2More preferably CO, SO2Or a single bond, most preferably CO or SO2. According to the invention, another preferred embodiment of X is- (CY)2)m-or CO. Highly preferred X is CO.
According to the invention, the preferred embodiment of E is- (CY)2)m-, CO, -COO-or SO2More preferably, - (CY)2)m-, CO or SO2Most preferably, - (CY)2)m-. It is to be understood that the corresponding meanings of E in any group of the invention are each independently.
In one aspect of the invention, Y represents H or a. It is to be understood that the corresponding meanings of Y in any group of the invention are each independently. .
According to the invention, preferred embodiments of the index m are 0, 1,2 or 3, more preferably 0, 1 or 2, most preferably 0 or 1.
According to the invention, preferred embodiments of the index n are 0, 1,2,3,4 or 5, more preferably 0, 1,2,3 or 4, most preferably 0, 1,2 or 3. It is to be understood that the corresponding meaning of n in any group of the invention is independent of each other.
According to the invention, the preferred embodiment of the index p is 1,2 or 3, more preferably 2 or 3, most preferably 2. It is to be understood that the corresponding meaning of p in any group of the invention is independent of each other.
In the preferred embodiment of the present invention, W1And W2Represents N, R6And R7Together represent- (CY)2)p-, p represents 2.
The subject of the present invention is therefore compounds of the general formula (I) in which at least one of the abovementioned radicals has the meaning indicated above, in particular to carry out the preferred embodiments described above. Groups not designated in more detail in any of the examples of the general formula (I), its sub-formulae or other residues thereon should be understood to have the meaning indicated in the general formula (I) disclosed herein for the purpose of the present invention. This means that the above groups can take all the meanings assigned to them, as described above or below, including any preferred embodiments, without being bound thereto, and independently in further particular cases. It is to be specifically understood that each embodiment of a group can be combined with each embodiment of one or more other groups.
In another preferred embodiment of the present invention, there is provided a benzamide derivative represented by the sub-formula (I-A),
in the formula (I), the compound is shown in the specification,
R1is represented by- (CY)2)n-E-(CY2)n-Het3、-(CY2)n-Cyc-Het3、-(CY2)n-NHCO-Het3、-(CY2)n-C(Y)(OH)-(CY2)n-Het3、-(CY2)n-Het1、-(CY2)n-NHCO-Het1、-(CY2)n-Ar、-(CY2)n-C(Y)(OH)-(CY2)n-Ar、-(CY2)n-Cyc、-(CY2)n-CONH-Cyc、A、-(CYR8)n-OY、-(CY2)n-COOY、-(CYR8)n-CO-(CY2)n-N(R8)2、-(CY2)n-[C(Y)OH]]m-(CYR8)n-NY2、[-(CY2)n-O]m-(CYR8)n-NYCOY、-(CY2)n-NYCOOY、-(CY2)n-NYCON(R8)2、-(CY2)n-NHCO-CH=CH2Or- (CY)2)n-NHCO-NH-(CY2)n=CH2；
R3Represents Het1、Het3Ar, H, A or Cyc;
R5represents E-Ar, H, A, COOA or Het1；
R8Each Y independently represents H or A;
x represents CO or- (CY)2)m；
E represents- (CY)2)m-, CO, -COO-or SO2；
A represents a straight-chain or branched alkyl group having 1 to 10 carbon atoms, wherein 1 to 7 hydrogen atoms may each
Independently by Hal and/or OH;
cyc represents a cycloalkyl group having 3 to 7 carbon atoms, wherein 1 to 4 hydrogen atoms may be independently substituted
Hal and/or OH substitution;
ar represents an unsaturated or aromatic monocyclic or bicyclic carbocyclic ring containing 5 to 10 carbon atoms, which carbocyclic ring may be substituted by at least one substituent selected from the group consisting of: A. hal, OY, COOY, CONH2、NHCOY、-(CH2)n-NY2、SO2NH2、NO2CN and Het2；
Het1Represents an unsaturated or aromatic monocyclic or bicyclic heterocycle containing from 1 to 9 carbon atoms and from 1 to 3N, O and/or S atoms, which heterocycle may be mono-or disubstituted by at least one substituent selected from the group consisting of: hal, A, Cyc, OY, CONH2、NHCOY、-(CH2)n-NY2、SO2NY2、NHSO2Y, CN and Ar;
Het2represents imidazolyl, pyrazinyl, thiazolyl or tetrazolyl, which may be mono-substituted by methyl;
Het3represents a saturated monocyclic heterocycle containing 3 to 6 carbon atoms and 1 to 3N, O and/or S atoms, which heterocycle may be mono-, di-or tri-substituted by at least one substituent selected from the group consisting of: = O, A, Hal, - (CY)2)n-Cyc、-(CY2)n-OY、COY、COOY、CONY2、NHCOY、NY2、CN、SO2Y and- (CY)2)n-Ar；
Hal represents F, Cl, Br or I; and
m, n each independently represent 0, 1,2 or 3;
and/or a physiologically acceptable salt thereof,
with the proviso that the following compounds are excluded:
3- (3-chloro-benzoylamino) -N- [2- (2, 4-dichloro-phenyl) -ethyl ] -4- (4-ethyl-piperazin-1-yl) -benzamide.
In another preferred embodiment of the present invention, there is provided a benzamide derivative represented by the sub-formula (I-B),
in the formula (I), the compound is shown in the specification,
R1is represented by- (CY)2)n-Het3、-(CY2)n-NHCO-Het3、-(CY2)n-C(Y)(OH)-(CY2)n-Het3、-(CY2)n-Het1、-(CY2)n-Ar、-(CY2)n-C(Y)(OH)-Ar、Cyc、-(CY2)n-CO-NY2、-(CY2)n-NYCOY、-(CY2)n-NYCONY2Or- (CY)2)n-NHCO-NH-(CY2)n=CH2；
Y represents H or A;
a represents a linear or branched alkyl group having 1 to 6 carbon atoms, wherein 1 to 4 hydrogen atoms may each be independently
Is substituted on site by Hal and/or OH;
cyc represents a cycloalkyl group having 3 to 6 carbon atoms, wherein 1 to 4 hydrogen atoms may be substituted by OH;
ar represents an aromatic monocyclic carbocyclic ring containing 6 to 8 carbon atoms, which carbocyclic ring may be mono-or disubstituted by at least one substituent selected from the group consisting of: A. hal, OY, CONH2、-(CH2)n-NA2、SO2NH2And Het2；
Het1Represents an unsaturated or aromatic monocyclic heterocycle containing from 1 to 6 carbon atoms and from 1 to 3N, O and/or S atoms, which heterocycle may be mono-or disubstituted by at least one substituent selected from the group consisting of: hal, A, Cyc and- (CH)2)n-NA2；
Het2Represents a tetrazolyl group;
Het3represents a saturated monocyclic heterocycle containing 3 to 6 carbon atoms and 1 to 3N, O and/or S atoms, which heterocycle may be mono-, di-or tri-substituted by at least one substituent selected from the group consisting of: = O, A and OY;
hal represents F, Cl or Br; and
n represents 0, 1,2 or 3;
and/or physiologically acceptable salts.
In still another preferred embodiment of the present invention, there is provided a benzamide derivative represented by the sub-formula (I-C),
in the formula (I), the compound is shown in the specification,
R1is represented by- (CY)2)n-E-Het3、-(CY2)n-Cyc-Het3、-(CY2)n-Het1、-(CY2)n-NHCO-Het1，-(CY2)n-Ar、-(CY2)n-Cyc、-(CY2)n-CONH-Cyc、A、-(CYR8)n-OY、-(CY2)n-COOY、-(CYR8)n-NY2、-(CYR8)n-NYCOY、-(CY2)n-NYCOOY or- (CY)2)n-NHCO-CH=CH2；
R3Represents Het1、Het3Ar, H, A or Cyc;
R5represents E-Ar, H, A, COOA or Het1；
R8Each Y independently represents H or A;
e represents- (CY)2)m-, CO, -COO-or SO2；
A represents a linear or branched alkyl group containing 1 to 10 carbon atoms, wherein 1 to 7 hydrogen atoms may each independently be substituted by Hal and/or OH;
cyc represents cycloalkyl having 3 to 7 carbon atoms, wherein 1 to 4 hydrogen atoms may each independently be replaced by Hal;
ar represents an unsaturated or aromatic monocyclic or bicyclic carbocyclic ring containing 5 to 10 carbon atoms, which carbocyclic ring may be substituted by at least one substituent selected from the group consisting of: A. hal, OY, COOY, CONH2、NHCOY、NY2、NO2CN and Het2；
Het1Represents an unsaturated or aromatic monocyclic or bicyclic heterocycle containing from 1 to 9 carbon atoms and from 1 to 3N, O and/or S atoms, which heterocycle may be mono-or disubstituted by at least one substituent selected from the group consisting of: hal, A, Cyc, OY, CONH2、NHCOY、NY2、SO2NY2、NHSO2Y, CN and Ar;
Het2represents imidazolyl, pyrazinyl, thiazolyl or tetrazolyl, which may be mono-substituted by methyl;
Het3represents a saturated monocyclic heterocycle containing 3 to 6 carbon atoms and 1 to 3N, O and/or S atoms, which heterocycle may be mono-, di-or tri-substituted by at least one substituent selected from the group consisting of: = O, A, Hal, - (CY)2)n-Cyc、-(CY2)n-OY、COY、COOY、CONY2、NHCOY、NY2、CN、SO2Y and- (CY)2)n-Ar；
Hal represents F, Cl, Br or I; and
m, n each independently represent 0, 1,2 or 3;
and/or a physiologically acceptable salt thereof,
with the proviso that the following compounds are excluded:
3- (3-chloro-benzoylamino) -N- [2- (2, 4-dichloro-phenyl) -ethyl ] -4- (4-ethyl-piperazin-1-yl) -benzamide.
In still another preferred embodiment of the present invention, there is provided a benzamide derivative represented by the sub-formula (I-D),
in the formula (I), the compound is shown in the specification,
y represents H or A;
a represents a linear or branched alkyl group containing 1 to 6 carbon atoms, wherein 1 to 4 hydrogen atoms may each independently be substituted by Hal and/or OH;
cyc represents a cycloalkyl group having 3 to 6 carbon atoms;
ar represents an aromatic monocyclic carbocyclic ring containing 6 to 8 carbon atoms, which carbocyclic ring may be mono-or disubstituted by at least one substituent selected from the group consisting of: A. hal, OA, CONH2、NY2、NO2And CN;
Het1represents an unsaturated or aromatic monocyclic heterocycle containing from 1 to 6 carbon atoms and from 1 to 3N, O and/or S atoms, which heterocycle may be mono-or disubstituted by at least one substituent selected from the group consisting of: hal, A, Cyc, OA, CONH2、NHCOA、NHA、SO2NH2And CN, or an aromatic bicyclic heterocycle containing 6 to 9 carbon atoms and 1 to 3N and/or S atoms, said heterocycle being optionally substituted by A;
Het3represents a saturated monocyclic heterocycle containing 3 to 6 carbon atoms and 1 to 3N, O and/or S atoms, which heterocycle may be mono-or disubstituted by at least one substituent selected from the group consisting of: = O, A, Cyc, OY, COA, COOA, CONHA and SO2A；
Hal represents F, Cl or Br; and
n represents 0, 1,2 or 3;
and/or physiologically acceptable salts.
The teaching of the present description above with respect to compounds of the general formula (I), including the radical definitions and preferred examples thereof, is valid and applicable, if reasonable, without being restricted to compounds of the sub-formulae (I-A), (I-B) and salts thereof.
Tables 1 and 2 list the most preferred examples of compounds of formula (I), (I-A), (I-B) and (I-C).
Table 1: compounds represented by the general formula (I), (I-A), (I-B) and (I-C).
Analytical test a: example 10; analytical test B: example 11.
Table 2: other compounds represented by the general formulae (I), (I-A), (I-B) and (I-C).
Analytical test a: example 10; analytical test B: example 11.
Highly preferred embodiments are compounds selected from the following group:
and/or physiologically acceptable salts thereof.
The benzamide derivatives of the general formula (I) and their starting materials for their preparation are prepared by respective known methods, as described in the literature (for example in standard publications such as Houben-Weyl, Methodenderorganschel chemistry [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart) and/or known to the person skilled in the art, i.e. under reaction conditions which are known and suitable for the reaction in question.
Known variants thereof may also be used and will not be described in detail here. If desired, the starting materials can be formed in situ, leaving them in the crude reaction mixture in an unseparated state, but immediately converting them into the compounds of the invention. On the other hand, the reaction may be carried out stepwise.
The reaction is preferably carried out under basic conditions. Suitable bases are metal oxides, such as alumina; alkali metal hydroxides (potassium hydroxide, sodium hydroxide, and lithium hydroxide); alkaline earth metal hydroxides (barium hydroxide and calcium hydroxide); alkali metal alkoxides (potassium ethoxide or sodium propoxide); and various organic bases (piperidine or diethanolamine).
The reaction is usually carried out in an inert solvent. Suitable inert solvents are, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid, acetic acid or trifluoroacetic acid (TFA); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate; or mixtures of said solvents. Particularly preferred are TFA, water, THF, tert-butanol, tert-amyl alcohol, triethylamine or dioxane.
Depending on the conditions used, the reaction time is between a few minutes and 14 days and the reaction temperature is between-30 ℃ and 140 ℃, usually between-10 ℃ and 130 ℃, particularly suitably between 30 ℃ and 125 ℃.
The invention also relates to a process for the preparation of a compound of general formula (I) comprising the steps of:
(a) a compound of the general formula (II)
Wherein W1、W2、R3To R7、R6X and Y have the meanings indicated above,
reacting with a compound of the general formula (III) in the presence of a crosslinking agent and a solvent,
wherein R is1And R2Having the meaning indicated above, and which,
carrying out reaction to obtain the compound of the general formula (I),
wherein W1、W2、R1To R7、R8X and Y have the meanings indicated above,
and optionally
(b) Converting a base or acid of the compound of formula (I) into a salt thereof.
The benzamide derivative represented by the general formula (I) can be obtained by the above-mentioned route. The starting materials, including the compounds of the general formulae (II) and (III), are generally known to the person skilled in the art or they can be prepared by known methods. Thus, any of the compounds of formula (II) and (III) may be purified as intermediates and used as starting materials for the preparation of the compounds of formula (I). Process step (a) is preferably carried out in the presence of a crosslinking agent which is a carbodiimide derivative, in particular 1-ethyl-3- [ 3-dimethylaminopropyl ] carbodiimide hydrochloride (EDC), and/or a solvent which is an organic acid, in particular TFA. More preferably, process step (a) is carried out in the presence of EDC and TFA. In addition to tert-butyl carbamate (BOC), the person skilled in the art knows that other protecting groups can be used in the compounds of the formula (III).
The compounds of formula (I) may be modified, for example by hydrogenation or metal reduction, to remove chlorine, or by substitution, and/or by conversion to a salt with an acid or base, preferably a strong acid. Many documents and methods are now available for the skilled person for use and reference with respect to inorganic chemistry, chemical strategies and strategies, synthetic routes, protection of intermediates, cleavage and purification procedures, isolation and characterization, etc. General chemical modifications are known to those skilled in the art. Halogenation of aryl or hydroxy groups with halogens of acids, alcohols, phenols and tautomeric structures may be preferably carried out using POCl3Or SOCl2、PCl5、SO2Cl2The process is carried out. In some cases, oxalyl chloride may also be used. The temperature may vary from 0 ℃ to reflux temperature depending on the halogenated pyridone structure or the carboxylic or sulfonic acid. The time may range from minutes to hours, even overnight. Similarly, alkylation, ether formation, ester formation, amide formation are well known to those skilled in the art. The arylation with arylboronic acids may be carried out in the presence of a palladium catalyst and a suitable ligand and base, preferably a carbonate, phosphate or borate of sodium, potassium or caesium. Organic bases such as triethylamine, DIPEA or more basic DBU may also be used. The solvent may be toluene, dioxane, THF, diglyme, glyme, alcohols, DMF, DMA, NMP, acetonitrile, in some cases even water and other solvents may be used. A commonly used catalyst is Pd (PPh) as a precursor of the PdO catalyst3)4Or Pd (OAc)2、PdCl2They are more favorable than many complex catalysts and are more efficient ligands. In C-C arylation, instead of using boronic acids and esters (Stille coupling), aryl-potassium trifluoroborate salts (Suzuki-Miyaura coupling), organosilanes (Hiyama coupling), Grignard reagents (Kumada), zinc organyl groups (Negishi coupling) and tin organyl groups (Stille coupling) can be used. This experience can be shifted to N-and O-alkylation reactions. Even the N-alkylation of electron deficient anilines (Biscoe et al, JACS 130: 6686 (2008)) using aryl chlorides and anilines (forset al, jacs130: 13552(2008) and O-alkylation with copper and palladium catalysts have been described in numerous documents, and many of these methods can be used by those skilled in the art.
In the last step of the above process, salts of the compounds of the formulae (I) to (III), preferably of the formula (I), are optionally provided. The compounds of the present invention may be used in non-salt final forms, but on the other hand, the present invention also includes the use of these compounds in the form of their pharmaceutically acceptable salts, which can be prepared from various organic and inorganic acids and bases by methods known in the art. In most cases, pharmaceutically acceptable salts of the compounds of the present invention are prepared primarily by conventional methods. If the compounds of the present invention contain a carboxyl group, the corresponding base addition salts may be obtained by reacting the compounds with a suitable base to form a suitable salt thereof. Such bases are, for example, alkali metal hydroxides (such as potassium hydroxide, sodium hydroxide and lithium hydroxide), alkaline earth metal hydroxides (such as barium hydroxide and calcium hydroxide) and alkali metal alkoxides (such as potassium ethoxide and sodium propoxide), and various organic bases such as piperidine, diethanolamine and N-methylglutamide. Also included are aluminum salts of the compounds of the present invention. For certain compounds of the invention, these compounds may be reacted with pharmaceutically acceptable organic or inorganic acids, such as hydrogen halides, e.g., hydrogen chloride, hydrogen bromide, or hydrogen iodide, to form acid addition salts; other mineral acids and their corresponding salts, such as sulfates, nitrates or phosphates, etc., and alkyl or monoaryl sulfonates, such as ethanesulfonate, p-toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts, such as acetates, trifluoroacetates, tartrates, maleates, succinates, citrates, benzoates, salicylates, ascorbates, etc. Pharmaceutically acceptable acid addition salts of the compounds of the invention thus include: acetate, adipate, alginate, arginine, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, hydrobromide, butyrate, camphorate, camphorsulfonate, caprylate, hydrochloride, chlorobenzoate, citrate, cyclopentylpropionate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethylsulfonate, fumarate, galactarate (from mucic acid), galacturonate, glucoheptonate, gluconic acid, glutamate, glycerophosphate, hemisuccinate, monosulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, hydrogen sulfonate, hydrogen sulfite, hydrogen carbonate, hydrogen, Malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, hydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but these examples do not represent a limitation of the salts.
In relation to the above description, it will be seen that the terms "pharmaceutically acceptable salt" and "physiologically acceptable salt" in this specification are interchangeable and are used herein to indicate an active ingredient comprising a compound of the invention in the form of a salt, particularly if such salt form imparts improved pharmacokinetic properties to the active ingredient compared to the free form of the active ingredient. The pharmaceutically acceptable salt form of the active ingredient may also for the first time impart desirable pharmacokinetic properties to such active ingredient and may even have a positive impact on the pharmacodynamics of the therapeutic effect of this active ingredient in vivo.
The invention also relates to the use of compounds of the general formula (I) and/or physiologically acceptable salts thereof for modulating FSH receptors, in particular in the presence of FSH. The term "modulation" means any change in FSHR-mediated signal transduction based on the action of a particular compound of the invention, which is capable of interacting with the FSHR target, enabling recognition, binding and activation. The compounds are characterized by a high affinity for FSHR, ensuring reliable binding, preferably positive allosteric modulation of FSHR. More preferably, the substance is monospecific to ensure unique and direct recognition of a single FSHR target. In the context of the present invention, the term "recognition" -without limitation-relates to any kind of interaction between a specific compound and a target, in particular covalent or non-covalent binding or association, such as covalent bonds, hydrophilic/hydrophobic interactions, van der waals forces, ion pairs, hydrogen bonds, ligand-receptor interactions and the like. Such association may also comprise the presence of other molecules (e.g. peptides, proteins or nucleotide sequences). The receptor/ligand interactions of the present invention are characterized by high affinity, high selectivity, and minimal to no cross-reactivity with other target molecules, thereby precluding unhealthy and deleterious effects on the treated subject.
A preferred object of the present invention relates to a method for modulating an FSH receptor, preferably in a positive allosteric manner, wherein a system capable of expressing an FSH receptor, preferably in the presence of FSH, is contacted with at least one compound of the general formula (I) according to the invention and/or a physiologically acceptable salt thereof under conditions such that said FSH receptor is modulated, in particular in a positive allosteric manner. Although cell systems are preferred within the scope of the present invention, in vitro translation systems based on protein synthesis, which do not require living cells, may alternatively be employed. A cell system is defined as any subject, provided that the subject comprises cells. Thus, the cell system may be selected from the group consisting of single cells, cell culture media, tissues, organs, and animals. The teaching of the present specification above with respect to compounds of formula (I), including any preferred embodiments thereof, is valid and applicable, but is not limited to compounds of formula (I) and salts thereof when used in methods of modulating FSHR.
The compounds of the invention preferably exhibit advantageous biological activities which are readily demonstrated in cell culture media assays, such as those described in the present specification or in the prior art (see, e.g., WO2002/09706, incorporated herein by reference). In the assay, the compounds of the invention preferably express and elicit agonist effects. Preferably, the compounds of the invention have FSHR agonist activity as EC50Standard expression, EC50Less than 10. mu.M, more preferably less than 1. mu.M, most preferably less than 0.5. mu.M, and highly preferably less than 0.1. mu.M. "EC50"is the effective concentration of the compound at which half of the maximum FSH response is achieved.
As mentioned above, these signal transduction pathways are associated with various diseases, preferably fertility disorders. Thus, the compounds of the invention are enabled to prevent and/or treat diseases that depend on one or more of said signal transduction pathways by interacting with said signal transduction pathway. The present invention therefore relates to compounds according to the invention for use as modulators, preferably agonists, more preferably positive allosteric modulators of the signal transduction pathways, preferably FSHR mediated signal transduction pathways, described in the present specification. It is believed that the compounds of the invention are capable of binding to the intracellular receptor domain without competitive interaction with FSH, but they act as positive allosteric enhancers of FSH at their receptors. Non-competitive interactions refer to the property of agonist activity exhibited by the compounds of the invention in which the compounds activate FSHR without significantly reducing the binding strength of FSH to FSHR.
The methods of the invention may be performed in vitro or in vivo. Sensitivity to treatment of particular cells with the compounds of the invention can be determined in vitro assays during research and clinical use. The cell culture is typically incubated with the various concentrations of the compound of the invention for a time sufficient for the active agent to modulate FSHR activity, often for an incubation period of between 1 hour and 1 week. In vitro treatment may be performed with cultured cells of a biopsy sample or cell line. In a preferred aspect of the invention, the follicular cell is stimulated to mature. Viable cells remaining after treatment are then counted and further processed.
The host or patient may be of a mammal, such as a primate, particularly a human; rodents, including mice, rats, and hamsters; rabbits, horses, cattle, dogs, cats, etc. Animal models of interest for experimental studies can provide models for the treatment of human diseases.
In order to identify signal transduction pathways and to detect interactions between various signal transduction pathways, many scientists have developed appropriate models or model systems, such as cell culture models and transgenic animal models. To detect certain stages of the signal transduction cascade, interacting compounds may be used to modulate the signal. The compounds of the invention may be used as reagents to detect FSHR-dependent signal transduction pathway status in animal models and/or cell culture models or in clinical diseases as mentioned in the present application.
The use described in the preceding paragraphs of this specification may be performed in an in vitro or in vivo model. The adjustment is monitored by techniques described in the context of this specification. In vitro use is preferably used on human samples suffering from fertility disorders. By testing a number of specific compounds and/or derivatives thereof, the active ingredient which is most suitable for the treatment of human patients can be selected. The in vivo dosage rate of the selected derivative is preferably matched to the susceptibility to FSHR and/or the severity of the patient's disease in view of the in vitro (experimental) data, thereby significantly enhancing the therapeutic effect. Furthermore, the teachings of the present specification that follow in relation to the use of compounds of general formula (1) and derivatives thereof in the manufacture of a medicament for the prevention, or treatment and/or control of the progression of disease are effective and applicable and may not be limited, if deemed appropriate, to the use of the compounds of the invention to modulate FSHR activity.
The invention also relates to medicaments containing at least one compound according to the invention and/or pharmaceutically usable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios. The invention also relates to medicaments comprising at least one compound according to the invention and/or physiologically acceptable salts thereof.
"drug" in the sense of the present invention is any agent in the pharmaceutical field, comprising one or more compounds of general formula (I) or a preparation thereof (e.g. a pharmaceutical composition or a pharmaceutical preparation), which can be used for the prevention, treatment, follow-up or post-treatment nursing of patients suffering from a disease associated with FSHR activity, said patients showing at least temporarily the overall condition or a pathological change in an individual part of the body of the patient.
The invention therefore also relates to pharmaceutical compositions comprising at least one compound of the general formula (I) according to the invention and/or a physiologically acceptable salt thereof as active compound, together with pharmaceutically tolerable adjuvants and/or excipients. It is understood that the compounds of the present invention are provided in effective amounts.
An "adjuvant" in the sense of the present invention means any substance which, when administered simultaneously, sequentially or in tandem, promotes, enhances or improves the specific response of the active ingredients of the invention. Known injection adjuvants are, for example: aluminum compositions such as aluminum hydroxide or aluminum phosphate; saponins, such as QS 21; muramyl dipeptide or tripeptide; proteins, such as gamma interferon or TNF; MF 59; squalene or a polyol.
In addition, the active ingredients may be administered alone or in combination with other treatments. The synergistic effect achieved by using one or more compounds □ according to the invention in a pharmaceutical composition is that a compound of formula (I) is combined with at least one further agent as active ingredient, which may be another compound of formula (I) or a compound having a different structural skeleton. The active ingredients may be used simultaneously or sequentially. The compounds of the invention are suitable for use in combination with known fertility inducers. Preferably, the additional active agent is selected from the group consisting of: FSH, α -FSH (gonalf), β -FSH, LH, hMG and 2- (4- (2-chloro-1, 2-diphenylvinyl) -phenoxy) -N, N-diethyl-citric acid ethylamine (clomiphene citrate). Other ovulation additives are known to those skilled in the art (see, for example, WO2002/09706, the contents of which are incorporated herein by reference) and may be used with the compounds of the present invention.
The invention also relates to a kit of parts consisting of an effective amount of a compound of the invention and/or pharmaceutically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, in a separately packaged form, together with an effective amount of other active ingredients. The kit comprises suitable containers, such as boxes, various bottles, bags or ampoules. For example, the kit may comprise separate ampoules, each containing an effective amount of a compound of the invention and/or pharmaceutically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in various proportions, in dissolved or lyophilized form, and an effective amount of a further pharmaceutically active compound.
The pharmaceutical formulations may be adapted for administration by any appropriate method as required, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared by various methods known to those skilled in the art of pharmacy, for example, by mixing the active ingredient with excipients or adjuvants.
The pharmaceutical compositions of the present invention are prepared in known manner using conventional pharmaceutical engineering solid or liquid carriers, diluents and/or additives in suitable dosages. The amount of excipient admixed with the active ingredient to prepare a unit dose will vary depending upon the individual treated and the mode of administration. Suitable excipients include organic or inorganic substances which are suitable for different routes of administration, for example enteral (e.g. oral), parenteral or topical administration, and which do not react with the compound of formula (I) or a salt thereof. Examples of such excipients are: water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, triacetin, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and vaseline.
Pharmaceutical formulations adapted for oral administration may be administered as separate units, for example, capsules or tablets; powder or granules; solutions or suspensions in water and non-aqueous liquids; edible foams or foam foods; or oil-in-water type liquid emulsion and water-in-oil type liquid emulsion.
Pharmaceutical formulations suitable for parenteral administration, including aqueous and non-aqueous sterile injection solutions, consisting of an antioxidant, a buffer, a bacteriostatic agent and a solute, by which means the formulation is rendered isotonic with the blood of the subject; also included are aqueous and non-aqueous sterile suspensions, which may include suspending media and thickening agents. The formulations may be administered in unit-dose or multi-dose containers, for example sealed ampoules and vials, and stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile carrier liquid, for example water for injections, immediately prior to use. Injections and suspensions may be formulated from sterile powders, granules and tablets.
It goes without saying that these preparations may also comprise, in addition to the ingredients specifically mentioned above, other substances customary to those skilled in the art in respect of the particular type of preparation, and that, for example, preparations suitable for oral administration may contain fragrances.
In a preferred embodiment of the invention, the pharmaceutical composition is suitable for oral administration. The formulation may be sterilized or may contain adjuvants such as carrier proteins (e.g. serum albumin), lubricants, preservatives, stabilizers, fillers, chelating agents, antioxidants, solvents, binders, suspending agents, wetting agents, emulsifiers, salts (salts that affect osmotic pressure), buffer substances, colorants, fragrances and one or more other active substances (e.g. one or more vitamins). Additives are known in the art and may be used in a variety of different formulations.
The invention therefore also relates to a pharmaceutical composition for oral administration comprising, as active ingredient, at least one compound of general formula (I) according to the invention and/or a physiologically acceptable salt thereof, and a pharmaceutically tolerable adjuvant, optionally in combination with at least one other active pharmaceutical ingredient. The two pharmaceutically active ingredients are especially provided in effective amounts. The above teachings of the specification regarding the route of administration and the combination product are valid and applicable and may not be limited to the combination of the two features if it seems reasonable.
The terms "effective amount" or "effective dose" or "dose" are used interchangeably herein to refer to the amount of a pharmaceutical compound that has a prophylactic or therapeutic effect on a disease or pathology, i.e., that is, that causes a biological or medical response in a tissue, system, animal or human that is sought or desired by a researcher or physician. "prophylactic action" is the possibility of reducing the progression of a disease or even preventing the onset of a disease. "therapeutically relevant effect" means to relieve to some extent one or more symptoms of a disease or to partially or completely reverse one or more or all of the physiological or biochemical parameters associated with or resulting in a change in a disease or pathology to a normal state. Furthermore, the term "therapeutically effective amount" means that the amount produces the following result compared to a corresponding patient who does not receive such amount: treating improves, cures, prevents or eliminates a disease, syndrome, condition, patient complaint, illness, or side effect or also slows the progression of a disease, complaint, or illness. The term "therapeutically effective amount" also encompasses an amount effective to enhance normal physiological function.
The pharmaceutical compositions of the present invention are administered at a dose or dose range that is sufficiently high to achieve the desired prophylactic or therapeutic effect in alleviating the above-mentioned diseases, cancers and/or fibrotic diseases. It will be understood that the specific dose level, frequency and period of administration for any particular human will depend upon a variety of factors including the activity of the specific compound selected, the age, body weight, general health, sex, diet, time and route of administration, rate of excretion, drug combination and the particular condition being treated and its severity. The exact dosage can be determined by one skilled in the art using routine experimentation, using known means and methods. The above teachings of the present specification are effective and applicable, if reasonable, without limitation to pharmaceutical compositions comprising compounds of formula (I).
The pharmaceutical preparations may be administered in the form of dosage units consisting of a predetermined amount of the active ingredient per unit dose. The prophylactic or therapeutic concentration of the active ingredient in the formulation may vary from 0.1 to 100 wt%. Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in a dose of about 0.5 to 1000mg, preferably 1mg to 700mg, especially preferably 5mg to 100 mg. Generally, such dosage ranges are appropriate for the total daily dose. In other words, the daily dose is preferably about 0.02 to 100mg/kg body weight. However, the specific dosage for each patient will depend upon a number of factors already described hereinabove in this specification (e.g., the condition being treated, the mode of administration, and the age, weight, and physical condition of the patient). Preferred dosage unit formulations comprise a daily dose or partial dose, or a fraction thereof, of the active ingredient as described above. In addition, pharmaceutical preparations of this type can be prepared by methods generally known to those skilled in the art of pharmacy.
While the therapeutically effective amount of a compound of the invention will ultimately be determined by an attending physician or veterinarian taking into account a number of factors (e.g., the age and weight of the animal, the precise condition to be treated and its severity, the nature of the formulation and the method of administration), the effective dose of a compound of the invention for treating the growth of tumors (e.g., colorectal or breast cancer) will generally be in the range of from 0.1 to 100mg/kg of the subject (mammal) body weight per day, and in particular will generally be in the range of from 1 to 10mg/kg of body weight per day. Thus, the actual daily dose for an adult mammal weighing 70kg is typically between 70 and 700mg, and this dose may be administered daily as a single dose or may be divided into partial doses for multiple administrations (e.g., two, three, four, five, six) per day, such that the total daily dose remains the same. An effective amount of a salt or solvate, or physiologically functional derivative thereof, may be determined as part of an effective amount of the compound itself. It is envisaged that similar dosages will be suitable for the treatment of the other symptoms mentioned above.
The pharmaceutical composition of the present invention can be used as a medicament for human and veterinary medicine. According to the invention, the compounds of the general formula (I) and/or their physiologically acceptable salts are suitable for the prophylaxis or treatment and/or monitoring of diseases which are caused, mediated and/or propagated by FSHR activity. In particular the disease is fertility disorders. It is understood that the host of the compound is included within the scope of the present invention.
Particularly preferred are stimulation of follicular development, ovulation induction, control of ovarian hyperstimulation, assisted reproductive techniques (including in vitro fertilization), male hypogonadism and male infertility, including certain classes of disorders where sperm production is not possible.
The invention also relates to the use of a compound of general formula (I) and/or a physiologically acceptable salt thereof for the prevention or treatment and/or monitoring of a disease caused, mediated and/or propagated by FSHR activity. The invention also relates to the use of a compound of general formula (I) and/or a physiologically acceptable salt thereof for the preparation of a medicament for the prevention or treatment and/or monitoring of a disease caused, mediated and/or propagated by FSHR activity. The compounds of the general formula (I) and/or their physiologically acceptable salts can also be used as intermediates for the preparation of other pharmaceutically active ingredients. The medicaments are preferably prepared non-chemically, for example by combining the active ingredient with at least one solid, liquid and/or semi-liquid carrier or excipient, optionally in admixture with one or more other active substances in suitable dosage forms.
Another object of the present invention are the compounds of general formula (I) according to the invention and/or their physiologically acceptable salts for use in the prevention or treatment and/or monitoring of diseases caused, mediated and/or propagated by FSHR activity. Another preferred object of the present invention relates to the use of the compounds of the general formula (I) according to the invention and/or their physiologically acceptable salts for the prophylaxis or treatment and/or monitoring of fertility disorders. The teachings of the present specification above relating to compounds of formula (1) and preferred embodiments thereof are effective and applicable and are not limited to the use of compounds of formula (1) and salts thereof for the prevention or treatment and/or monitoring of fertility disorders.
The compounds of the invention of formula (I) may be administered one or more times before or after onset of the disease as a treatment. The above compounds and medical products of the invention are particularly useful in therapeutic treatment. A therapeutically relevant effect is one in which one or more symptoms of a disease are relieved to some extent, or one or more physiological or biochemical parameters associated with or resulting in a change in a disease or pathology are partially or completely reversed into a normal state. Monitoring may be considered a treatment to enhance response and completely eradicate disease pathogens and/or symptoms, provided that the compounds are administered at different time intervals. The same or different compounds may be applied. Drugs may also be used to reduce the progression of the disease or even prevent the occurrence of conditions associated with FSHR activity in advance, or to treat the occurrence or persistence of the condition. The disease or condition to which the present invention relates is preferably fertility disorders.
In the sense of the present invention, it is advisable to administer a prophylactic treatment if the subject possesses a precondition for the above-mentioned physiological or pathological condition, such as a familial predisposition, a genetic defect, or a previous medical history.
It is a further object of the present invention to provide a method for the treatment of diseases which are induced, mediated and/or propagated by FSHR activity, wherein at least one compound of the general formula (I) according to the invention and/or a physiologically acceptable salt thereof is administered to a mammal in need of such treatment. It is a further object of the present invention to provide a method for the treatment of fertility disorders, wherein at least one compound of general formula (I) according to the invention and/or a physiologically acceptable salt thereof is administered to a mammal in need of such treatment. As noted above, the compound is preferably provided in an effective amount. The preferred treatment is oral administration. In another preferred aspect, the method of treatment consists in achieving ovulation induction and/or controlled ovarian hyperstimulation. In a further preferred aspect, the method of treatment forms the basis of a method of in vitro fertilization comprising the steps of: (a) treating a mammal with the above treatment, (b) collecting an egg from said mammal, (c) fertilizing said egg, and d) implanting said fertilized egg in a host mammal. The host mammal may be the mammal (i.e., patient) receiving the treatment or a surrogate. The teachings of the present invention and its embodiments are effective and applicable and may not be limited to the methods of the present invention if it seems reasonable.
Within the scope of the present invention, for the first time, novel benzamide compounds represented by the general formula (I) are provided. The low molecular weight compounds of the present invention are potent selective modulators of the FSH receptor. They are 10-fold selective for FSH receptors over LH receptors and even 100-fold selective for TSH receptors, while IC for unrelated G protein-bound receptors (GPCRs) or non-GPCR targets50The value does not exceed 10. mu.M. The invention includes the use of said benzamide derivatives to modulate and/or improve the FSHR signaling cascade, thereby providing a research tool for the diagnosis and/or treatment of any disease caused by FSHR signaling.
For example, in vitro use of the compounds of the invention is a unique tool for understanding the biological effects of FSH, including the evaluation of a number of factors believed to influence FSH production and FSH-FSHR interaction (e.g., the mechanism of FSH signaling/receptor activation), as well as a number of factors influenced by FSH production and FSH-FSHR interaction. The compounds of the invention may also be used in the development of other compounds that interact with FSHR, since the compounds of the invention provide important structure-activity relationship (SAR) information for such development. The compounds of the invention bind to FSHR and are useful as reagents for detecting FSHR on living cells, on fixed cells, in biological fluids, in tissue homogenates, in pure natural materials, and the like. For example, by labeling the compound, one can identify cells having FSHR on their surface. In addition, due to their ability to bind FSHR, the compounds of the invention can be used in situ staining, FACS (fluorescence activated cell sorting), western blotting, ELISA (enzyme linked immunosorbent assay), receptor purification, or for purification of cells expressing FSHR on the cell surface or in permeabilized cells.
The compounds of the present invention are also useful as commercial research reagents for a variety of medical research and diagnostic applications. Such uses include, but are not limited to: as a calibration standard for quantifying the activity of a candidate FSH agonist in various functional assays; as a blocking agent in a random compound screen, i.e. in the search for a new family of FSH receptor ligands, the compounds may be used to block the recovery of the FSH compounds claimed in the present invention; use in co-crystallization with the FSHR receptor, i.e. the compounds of the invention allow the compound to bind to FSHR to form crystals, thus determining the receptor/compound structure by X-ray crystallography; for other research and diagnostic applications, where FSHR is preferably activated, or such activation can be conveniently calibrated against known amounts of FSH agonist; use as a probe in an assay to determine FSHR expression on the cell surface; and compounds for detecting the site of FSHR binding ligand in development assays.
The low molecular weight inhibitor may be applied or combined with physical means to diagnose the effect of the treatment. Medicaments and pharmaceutical compositions containing said compounds and the use of said compounds for the treatment of FSHR-mediated conditions are promising new approaches, applicable in a variety of different treatments, capable of improving the health status of humans or animals directly and in real time. The effect is particularly advantageous for the effective treatment of infertility, either alone or in combination with other fertility-inducing treatment regimens. In particular, the compounds of the invention potentiate the effects of native FSH in ovulation induction and assisted reproduction technologies. The oral bioavailability and novel active chemical substances of the present invention provide greater convenience to the patient and physician compliance.
The compounds of the invention are active in primary screens (CHO cells, with or without FSHR), selective in secondary screens (inactive or with very low activity towards TSHR and LHR) and effective in granulosa cell aromatase assay. No hERG or any toxic effects were observed in vitro.
The compounds of general formula (I) and their salts, isomers, tautomers, enantiomeric forms, diastereomers, racemates, derivatives, prodrugs and/or metabolites are characterized by high specificity and stability, low manufacturing costs and convenient handling. These features form the basis for reproducible action, including no cross-reactivity, and reliable and safe interaction with the target structure.
All documents cited in this specification are incorporated herein by reference.
It is to be understood that this invention is not limited to the particular compounds, pharmaceutical compositions, uses and methods described in this specification as these may vary. Furthermore, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention. This specification includes as used in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, those skilled in the art will recognize that reference to "a compound" includes a single or multiple compounds, which in turn may be the same or different; or to "a method," including a plurality of equivalent steps and methods. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The technique of the gist of the present invention is described in detail in this specification. Other techniques not described in detail correspond to standard methods known to the person skilled in the art or are described in detail in the cited documents, patent applications or standard documents. Although the methods and materials described herein can be used in the practice or testing of the present invention, suitable examples are set forth below. The following examples are given by way of illustration only and without any limiting effect. Standard reagents and buffers without any contamination (any practical occasion) were used in the examples. Embodiments are constructed which are not limited to the various combinations of features explicitly shown, but verified features may be combined without limitation if the problem of the invention is solved
In the following examples, "conventional detection" means: according to the final product, water is added if necessary, the pH is adjusted to 2-10, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporatedThe crude product is purified by silica gel chromatography and/or crystallization. Measuring R on silica gelfValues, eluent ethyl acetate/methanol 9: 1.
standard description of analytical devices
In a Varian equipped with an automated triple-broadband (ATB) probeUnityNMR spectra were taken on an Inova400mhz NMR spectrometer. Simultaneously adjust ATB probes to1H、19F and13C. for what is typical1HNMR spectra, with a pulse angle of 45 degrees, summed over 8 scans and a spectral width of 16ppm (-2ppm to 14 ppm). A total of 32768 complex points were collected over a 5.1 second acquisition time with the cycle delay set to 1 second. Spectra were collected at 25 ℃. Prior to Fourier transformation, it is usually processed with 0.2Hz line broadening and zero-filling of 131072 dots1HNMR spectroscopy.
Method a (fast LC): Shimadzushim-packXR-ODS, 3.0X30mm, 2.2 μm column, temperature 50 ℃, flow rate 1.5mL/min, injection of 2 μ L, mobile phase (A): water containing 0.1% formic acid and 1% acetonitrile, mobile phase (B): methanol with 0.1% formic acid; residence time is expressed in minutes. The method comprises the following specific steps: (I) flowing through a binary pump G1312B with UV/Vis diode array detector G1315C and Agilent6130 mass spectrometer in positive and negative ion electrospray mode, UV-detection at 220 and 254nm with mobile phase (B) gradient 15-95%, 2.2 min linear gradient; (II) hold 95% of (B) for 0.8 min; (III) mobile phase (B) decreased from 95% to 15%, 0.1 min linear gradient; and (IV) 15% hold of (B) for 0.29 minutes.
Method B (polar Stop-Gap): mu.L of mobile phase (A) was injected using an Agilent Zorbax Bonus RP, 2.1X50mm, 3.5 μm column, temperature 50 ℃, flow rate 0.8mL/min, 2 μ L: water containing 0.1% formic acid and 1% acetonitrile, mobile phase (B): methanol with 0.1% formic acid; residence time is expressed in minutes. The method comprises the following specific steps: (I) flowing through a binary pump G1312B with UV/Vis diode array detector G1315C and Agilent6130 mass spectrometer in positive and negative ion electrospray mode, UV-detection at 220 and 254nm with a gradient of 5-95% mobile phase (B), 2.5 min linear gradient; (II) hold 95% of (B) for 2.5 minutes; (III) mobile phase (B) decreased from 95% to 5%, 0.1 min linear gradient; and (IV) 5% of (B) for 0.29 min.
Preparative HPLC: preparative HPLC was performed using a system controlled by Chromeleon software and consisting of two varianpstar model 218 pumps, VarianProStar model 320UV/Vis detector, SEDEX55ELSD detector and Gilson215 liquid processor. Typical preparative HPLC-uses a mobile phase consisting of water and methanol. The standard column was a VarianDynamax21.4mm diameter MicroorbGuard-8C 18 column.
Rt: the residence time.
Example 1: synthetic route to furan-2-carboxylic acid [5- ((S) -1-phenyl-ethylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide (compound No. 11)
Scheme 1
Step 1
To a solution of 4-fluoro-3-nitro-benzoic acid (6.0g, 32.4mmol) in DMF (20mL) was added K2CO3(8.94g, 64.8mmol), 1-o-tolyl-piperazine (6.85g, 38.9mmol) was further added, and the reaction mixture was stirred at room temperature for 16 hours. DMF (5.0mL) was added and filtered. The solid was washed with methanol (300mL) and the methanol layer was evaporated to give an acid in the first step: 3-Nitro-4- (4-o-tolyl-piperazin-1-yl) -benzoic acid (4.0g, 36%).
Step 2
The compound acid 3-nitro-4- (4-o-tolyl-piperazin-1-yl) -benzoic acid (2.0g, 5.86mmol) was dissolved in a mixture of ethanol (100mL) and methanol (100mL) and evacuated (evacuated) for 5 minutes. The above solution was added under nitrogen atmosphere to a 3-neck flask containing Pd/C (0.2g, 5 wt%). The reaction mixture was evacuated, purged twice with nitrogen, and stirred under a hydrogen balloon for 4 hours. LC-MS showed the reaction was complete, the contents evacuated, purged with nitrogen, filtered through celite, and concentrated to give aniline 3-amino-4- (4-o-tolyl-piperazin-1-yl) -benzoic acid (1.7g, 94%).
Step 3
3-amino-4- (4-o-tolyl-piperazin-1-yl) -benzoic acid (1.5g, 4.8mmol) was dissolved in CH together with TEA (3.3mL, 24mmol)2Cl2(50mL) and cooled to 0 ℃. Is added dropwise to CH2Cl2Furoyl chloride (1.38g, 10.6mmol) in (5.0mL), the reaction was stirred at 0-25 ℃ for 6 hours. The reaction mixture was concentrated, dissolved in a mixture of methanol (20mL) and THF (20mL), and stirred with a solution of 2N NaOH (20mL) for 2 hours. The solvent was removed, the contents dissolved in water, and the solution was acidified to ph5.0 with 2n hcl. Filtering and drying to obtain the solid product 3- [ (furan-2-carbonyl) -amino group]-4- (4-o-tolyl-piperazin-1-yl) -benzoic acid (1.1g, 56%).
Step 4
To 3- [ (furan-2-carbonyl) -amino group]-4- (4-o-tolyl-piperazin-1-yl) -benzoic acid (0.1g, 0.247mmol) and HOBt (0.05g, 0.37mmol) in CH2Cl2(3.0mL) was added methylbenzylamine (0.035g, 0.296mmol) and EDC.HCl (0.05g, 0.321mmol) and the reaction mixture was stirred at room temperature for 3 hours. The crude product is substituted by CH2Cl2Diluting (10.0mL), washing with water, concentrating, purifying with silica gel column using CH2Cl2Methanol (10%) as eluent, gave a milky white solid which was treated with 5mL of a 2m hcl solution in dioxane and then ether. Filtration and drying gave the precipitated product (0.02g, 16% yield).
LCMS(ESI)509(M+H)；1HNMR(400MHz，DMSO-d6)ppm1.40-1.48(m，3H)2.28(brs，3H)3.05(s，9H)5.13(quin，J=7.42Hz，1H)6.69(dd，J=3.47,1.76Hz，1H)6.93-6.99(m，1H)7.06-7.11(m，1H)7.14-7.21(m，3H)7.26-7.31(m，3H)7.33-7.38(m，3H)7.69(dd，J=8.35,2.00Hz，1H)7.95-8.00(m，1H)8.57(d，J=2.00Hz，1H)8.74(d，J=8.05Hz，1H)9.42(s，1H)。
The following compounds were prepared using scheme 1:
following the same procedure as compound No. 11 starting from the intermediate acid 3- [ (furan-2-carbonyl) -amino group]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid [5- [2- (1H-indol-3-yl) -ethylcarbamoyl-2-carboxylic acid]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide (compound No. 10).
LCMS(ESI)548(M+H)；1HNMR (400MHz, methanol-d 4) ppm2.32(s, 3H)3.03-3.09(m, 2H)3.12(s, 8H)3.65(t, J =7.44Hz, 2H)6.67(dd, J =3.54,1.78Hz, 1H)6.93-7.00(m, 2H)7.02-7.08(m, 1H)7.10(s, 1H)7.13-7.18(m, 3H)7.27-7.33(m, 2H)7.37(d, J =8.30Hz, 1H)7.54-7.62(m, 2H)7.80(d, J =1.03Hz, 1H)8.64(d, J =2.05, 1H).
Following the same procedure as compound No. 11 starting from the intermediate acid 3- [ (furan-2-carbonyl) -amino group]Preparation of 4- [3- [ (furan-2-carbonyl) -amino ] -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid]-4- (4-o-tolyl-piperazin-1-yl) -benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (compound No. 49).
LCMS(ESI)588(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm1.36-1.42(m，1H)1.42-1.46(m，10H)1.59(brs，1H)1.93-2.08(m，2H)2.34(s，3H)2.90(t，J=11.27Hz，2H)3.07-3.22(m，8H)3.94-4.18(m，3H)6.10(d，J=7.76Hz，1H)6.60(dd，J=3.51,1.76Hz，1H)7.01(td，J=7.33,1.24Hz，1H)7.09-7.15(m，1H)7.17-7.24(m，3H)7.30-7.36(m，1H)8.80(d，J=2.10Hz，1H)9.43(s，1H)。
According to the followingPreparation of furan-2-carboxylic acid [5- (1-acetyl-piperidin-4-ylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl]-amide (compound No. 56): 4- [3- [ (furan-2-carbonyl) -amino group]-4- (4-o-tolyl-piperazin-1-yl) -benzoylamino]Tert-butyl (0.35g, 0.59mmol) piperidine-1-carboxylate with CH2Cl2A mixture of (5.0mL) and TFA (3.0mL) was stirred together for 6 hours. The reaction was concentrated to give an intermediate salt (0.225 g). Reacting furan-2-carboxylic acid [5- (piperidin-4-ylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl]TFA salt of the amide (0.06g, 0.123mmol) dissolved in CH2Cl2To (5.0mL) was added DIPEA (0.2mL, 1.23mmol) and acetic anhydride (0.062g, 0.615 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated and dissolved in methanol and purified by preparative HPLC using methanol/water as eluent to give the product (0.025g, 38%).
LCMS(ESI)530(M+H)；1HNMR (400MHz, chloroform-d) ppm1.33-1.52(m, 3H)1.96-2.07(m, 1H)2.10(s, 3H)2.34(s, 3H)2.76(t, J =11.42Hz, 1H)3.12(dd, J =19.38,5.61Hz, 8H)3.19-3.25(m, 1H)3.82(d, J =12.15Hz, 1H)4.12-4.26(m, 1H)4.59(d, J =14.10Hz, 1H)6.23(d, J =7.71Hz, 1H)6.58(dd, J =3.47,1.76Hz, 1H)6.99-7.06(m, 1H)7.07-7.14(m, 1H) 7.21.21 = 32H (d = 5.32H) 7.31, 1.76Hz, 1H)7.19(d, 1H)7.31, 1H = 32H, 1H 2H (d, 1H) 2.5 Hz, 1H = 7.5H, 1H (d, 5H) 2Hz, 1H) 2.5H, 1.
Furan-2-carboxylic acid [5- (1-methanesulfonyl-piperidin-4-ylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl was prepared according to the following procedure]-amide (compound No. 58): furan-2-carboxylic acid [5- (piperidin-4-ylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide (0.35g, 0.59mmol) with CH2Cl2A mixture of (5.0mL) and TFA (3.0mL) was stirred together for 6 hours. The reaction was concentrated to give an intermediate salt (0.225 g). Reacting furan-2-carboxylic acid [5- (piperidin-4-ylcarbamoyl)2- (4-o-tolyl-piperazin-1-yl) -phenyl]-TFA salt of amide (0.06g, 0.123mmol) dissolved in CH2Cl2To (5.0mL) was added DIPEA (0.2mL, 1.23mmol) and acetic anhydride (0.062g, 0.615 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated and dissolved in methanol and purified by preparative HPLC using methanol/water as eluent to give the product (0.025g, 37%).
LCMS(ESI)566(M+H)；1HNMR(400MHz，DMSO-d6)ppm1.57(qd，J=11.93,3.69Hz，2H)1.87(d，J=10.74Hz，2H)2.26(s，3H)2.77-2.83(m，3H)2.84(s，3H)3.04(s，8H)3.54(d，J=11.91Hz，2H)6.70(dd，J=3.47,1.76Hz，1H)6.91-6.99(m，1H)7.05-7.11(m，1H)7.12-7.19(m，2H)7.30(d，J=2.88Hz，1H)7.35(d，J=8.35Hz，1H)7.61(dd，J=8.30，2.05Hz，1H)7.84-8.03(m，1H)8.27(d，J=7.76Hz，1H)8.55(d，J=2.00Hz，1H)9.42(s，1H)。
Following the same procedure as compound No. 11 starting from the intermediate acid 3- [ (furan-2-carbonyl) -amino group]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid [5- [ (S) -1- (4-chloro-phenyl) -2-methylamino-ethylcarbamoyl-2-carboxylic acid]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide (compound No. 55).
LCMS(ESI)570(M-H)；1HNMR (400MHz, methanol-d 4) ppm2.32(s, 3H)2.79(s, 3H)3.14(s, 8H)3.48-3.54(m, 2H)5.52(dd, J =8.79,5.86Hz, 1H)6.67(dd, J =3.47,1.71Hz, 1H)6.91-7.03(m, 1H)7.12-7.20(m, 3H)7.29(d, J =3.47Hz, 1H)7.38-7.49(m, 5H)7.70(dd, J =8.32,2.03Hz, 1H)7.81(s, 1H)8.71(d, J =2.00Hz, 1H).
Following the same procedure as compound No. 11 starting from the intermediate acid 3- [ (furan-2-carbonyl) -amino group]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzoic acidFuran-2-carboxylic acid [5- (4-chloro-benzylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide (compound No. 131).
LCMS(ESI)529(M+H)；1HNMR(400MHz，DMSO-d6)ppm2.26(s，3H)3.04(s，8H)4.42(d，J=5.76Hz，2H)6.70(dd，J=3.49,1.68Hz，1H)6.90-7.00(m，1H)7.06-7.11(m，1H)7.13-7.19(m，2H)7.26-7.40(m，6H)7.66(dd，J=8.35,2.00Hz，1H)7.98(d，J=1.61Hz，1H)8.61(d，J=2.00Hz，1H)8.99(t，J=6.08Hz，1H)9.41(s，1H)。
Following the same procedure as compound No. 11 starting from the intermediate acid 3- [ (furan-2-carbonyl) -amino group]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid [5- (3, 5-dimethoxy-benzylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl-2-carboxylic acid]Amide (compound No. 95).
LCMS(ESI)555(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm2.39(s，3H)3.19(d，J=9.71Hz，8H)3.75-3.80(m，6H)4.56(d，J=5.81Hz，2H)6.38(t，J=2.25Hz，1H)6.51(d，J=2.25Hz，2H)6.56-6.63(m，2H)6.98-7.08(m，1H)7.17-7.25(m，4H)7.33-7.40(m，1H)7.55-7.68(m，1H)8.87(d，J=2.05Hz，1H)9.44(s，1H)。
Following the same procedure as compound No. 11 starting from the intermediate acid 3- [ (furan-2-carbonyl) -amino group]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid [5- (2-methoxy-benzylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl-2-carboxylic acid]Amide (compound No. 124).
LCMS(ESI)525(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm2.36(s，3H)3.11-3.22(m，9H)3.88-3.92(m，3H)4.60(d，J=5.86Hz，2H)6.60(dd，J=3.47,1.76Hz，1H)6.79(t，J=5.54Hz，1H)6.89-6.96(m，2H)6.99-7.06(m，1H)7.12-7.38(m，6H)7.55-7.64(m，2H)8.82(d，J=2.10Hz，1H)9.43(brs，1H)。
Following the same procedure as compound No. 11 starting from the intermediate acid 3- [ (furan-2-carbonyl) -amino group]Preparation of furan-2-carboxylic acid [5- [ (naphthalen-1-ylmethyl) -carbamoyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide compound No. 96).
LCMS(ESI)545(M+H)；1HNMR(400MHz，DMSO-d6)ppm2.26(s，3H)3.04(s，8H)4.91(d，J=5.66Hz，2H)6.69(dd，J=3.49,1.73Hz，1H)6.92-6.98(m，1H)7.05-7.11(m，1H)7.15(d，J=7.37Hz，2H)7.29(d，J=3.22Hz，1H)7.36(d，J=8.35Hz，1H)7.43-7.47(m，2H)7.48-7.59(m，2H)7.70(dd，J=8.35,2.05Hz，1H)7.82(t，J=4.76Hz，1H)7.90-7.94(m，1H)7.98(d，J=1.12Hz，1H)8.16(d，J=8.10Hz，1H)8.64(d，J=2.05Hz，1H)8.99(t，J=5.74Hz，1H)9.41(s，1H)。
Following the same procedure as compound No. 11 starting from the intermediate acid 3- [ (furan-2-carbonyl) -amino group]Preparation of furan-2-carboxylic acid [5- ((S) -2-hydroxy-1-phenyl-ethylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid]Amide (compound No. 67).
LCMS(ESI)525(M+H)；1HNMR (400MHz, methanol-d)4)ppm2.35(s，3H)3.15(s，8H)3.87(d，J=6.59Hz，2H)5.18-5.24(m，1H)6.69(dd，J=3.51,1.81Hz，1H)6.95-7.02(m，1H)7.17(dd，J=3.73,1.93Hz，3H)7.24-7.29(m，1H)7.31(d，J=3.51Hz，1H)7.35(t，J=7.57Hz，2H)7.43(dd，J=7.74,3.25Hz，3H)7.69(d，J=2.15Hz，1H)7.81-7.83(m，1H)。
Following the same procedure as compound No. 11 starting from the intermediate acid 3- [ (furan-2-carbonyl) -amino group]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid [5- (3-methoxy-benzylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl-2-carboxylic acid]Amide (compound No. 93).
LCMS(ESI)525(M+H)；1HNMR (400MHz, dichloromethane-d 2) ppm2.45(s, 3H)3.29(d, J =10.20Hz, 8H)3.80(s, 3H)4.60(d, J =5.76Hz, 2H)6.56-6.63(m, 2H)6.80-6.86(m, 1H)6.88-6.99(m, 2H)7.05-7.14(m, 1H)7.26(dd, J =7.76,2.44Hz, 5H)7.40(s, 1H)7.59-7.62(m, 1H)7.63-7.69(m, 1H)8.86(s, 1H)9.41-9.49(m, 1H).
Following the same procedure as compound No. 11 starting from the intermediate acid 3- [ (furan-2-carbonyl) -amino group]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid Furan-2-carboxylic acid [2- (4-o-tolyl-piperazin-1-yl) -5- (4-trifluoromethyl-benzylcarbamoyl) -phenyl]Amide (compound No. 94).
LCMS(ESI)525(M+H)；1HNMR (400MHz, dichloromethane-d 2) ppm2.41(s, 3H)3.23(d, J =9.57Hz, 8H)4.70(d, J =5.91Hz, 2H)6.61(dd, J =3.49,1.78Hz, 1H)6.71-6.78(m, 1H)7.03-7.11(m, 1H)7.20-7.27(m, 4H)7.38(d, J =8.30Hz, 1H)7.51(d, J =8.00Hz, 2H)7.59-7.65(m, 3H)7.68(dd, J =8.30, 2.10Hz, 1H)8.89(d, J =2.05Hz, 1H)9.38-9.50(m, 1H).
2-cyclopropyl-oxazole-4-carboxylic acid {2- [4- (3-methyl-pyridin-2-yl) -piperazin-1-yl]-5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl]-phenyl } -amide.
LCMS(M+H)572；1HNMR (400MHz, dichloromethane-d)2)ppm1.01-1.19(m，4H)1.75(t，J=6.08Hz，2H)1.98-2.12(m，4H)2.33(s，3H)2.38(t，J=8.13Hz，2H)3.06-3.13(m，4H)3.32-3.45(m，9H)6.90(dd，J=7.30，4.91Hz，1H)7.27(d，J=8.25Hz，1H)7.47(d，J=6.83Hz，1H)7.64(dd，J=8.27,2.07Hz，2H)8.12(s，1H)8.18(dd，J=4.88,1.46Hz，1H)8.86(d，J=2.05Hz，1H)9.90(s，1H)。
2-cyclopropyl-oxazole-4-carboxylic acid [5- {3 ]-[ (tetrahydro-pyran-4-carbonyl) -amino]-propylcarbamoyl } -2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS(M+H)615；1HNMR (chloroform-d) ppm9.99(s, 1H), 8.89(d, J =1.9Hz, 1H), 8.13(s, 1H), 7.72(dd, J =8.3,2.0Hz, 1H), 7.32(d, J =8.2Hz, 1H), 7.20-7.26(m, 2H), 7.15-7.20(m, 1H), 7.02-7.09(m, 1H), 6.78(t, J =5.9Hz, 1H), 6.70(t, J =6.3Hz, 1H), 4.05(t, J =3.1Hz, 1H), 4.01(t, J =3.3Hz, 1H), 3.53(q, J =6.3Hz, 2H), 3.40-3.48(m, 2H), 3.33(q = 6.3.2H), 3.15.15H, 2H, 3.9H, 1H, 4.4.4.4.4.4.4.4.3 Hz, 1H), 3.53(q, 2H), 2H =6.3H, 2H), 1.70-1.78(m, 2H), 1.11-1.20(m, 4H).
2-cyclopropyl-oxazole-4-carboxylic acid [5- (3-propionylamino-propylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS(M+H)559；1HNMR (chloroform-d) ppm9.98(s, 1H), 8.90(d, J =1.9Hz, 1H), 8.13(s, 1H), 7.72(dd, J =8.2,2.0Hz, 1H), 7.31(d, J =8.2Hz, 1H), 7.20-7.26(m, 2H), 7.15-7.20(m, 1H), 7.02-7.08(m, 1H), 6.84(t, J =5.7Hz, 1H), 6.43-6.51(m, 1H), 3.53(q, J =6.2Hz, 2H), 3.34(q, J =6.2Hz, 2H), 3.17-3.23(m, 4H), 3.09-3.16(m, 4H), 2.38(s, 3H), 2.7H = 28, 7.2 Hz, 2H), 3.06 (J = 6.7H), 2H, 3.06H, 3.7H, 1H, 7H, 1H, 7H, 3.7H, 1H, 7H, 3.7，1.10-1.18(m，4H)。
Furan-2-carboxylic acid [5 ]-[3-(3-propyl-ureido) -propylcarbamoyl]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS(M+H)547；1HNMR (chloroform-d) ppm9.48(s, 1H), 8.88(d, J =1.9Hz, 1H), 7.68-7.80(m, 1H), 7.59(s, 1H), 7.34(d, J =8.3Hz, 1H), 7.24(d, J =4.9Hz, 2H), 7.13(d, J =7.7Hz, 1H), 7.02-7.09(m, 1H), 6.94-7.01(m, 1H), 5.16(br.s., 1H), 4.64(br.s., 1H), 3.57(q, J =6.1Hz, 2H), 3.33(q, J =5.9Hz, 2H), 3.07-3.24(m, 10H), 2.37(s, 3H), 1.72-1.82(m, 2H), 2.25H = 3.92 (t = 3.52H), 7.7H, 3H (t = 3.2H), 3.25H, 3H).
Furan-2-carboxylic acid [5 ]-[3- (3-allyl-ureido) -propylcarbamoyl]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS(M+H)545；1HNMR (chloroform-d) ppm9.48(s, 1H), 8.89(d, J =1.7Hz, 1H), 7.74(dd, J =8.2,1.9Hz, 1H), 7.58(s, 1H), 7.35(s, 1H), 7.24(d, J =4.6Hz, 2H), 7.13(d, J =7.8Hz, 1H), 7.01-7.09(m, 1H), 6.93(br.s., 1H), 6.52-6.67(m, 1H), 5.77-5.96(m, 1H), 5.15-5.33(m, 2H), 5.10(d, J =10.2Hz, 1H), 4.84(br.s., 1H), 3.83(t, J =5.6Hz, 2H), 3.57 = 3.9H, 3.7H = 3.7H, 3.3.7H, 3H = 3H, 3H.
2-cyclopropyl-oxazole-4-carboxylic acid [5 ]-[3- (1H-tetrazol-5-yl)-Propylcarbamoyl radical]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]-amides of。
LCMS(M+H)556；1HNMR (chloroform-d) ppm10.01(br.s., 1H), 8.93(s, 1H), 8.16(s, 1H), 7.83(d, J =8.4Hz, 1H), 7.36(d, J =8.3Hz, 1H), 7.21-7.26(m, 2H), 7.14-7.20(m, 1H), 7.02-7.10(m, 1H), 3.55(d, J =5.6Hz, 2H), 3.21(d, J =4.0Hz, 4H), 3.15(d, J =3.8Hz, 4H), 3.07-3.12(m, 2H), 2.38(s, 3H), 2.08-2.18(m, 1H), 2.02(br.s., 2H), 1.10-1.24(m, 4H).
Furan-2-carboxylic acid [5 ]-[ (6-dimethylamino-methyl-pyridin-2-ylmethyl) -carbamoyl]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS(M+H)553；1HNMR (400MHz, methanol-d)4)ppm：2.35(s，3H)2.97(s，6H)3.17(s，8H)3.34-3.39(m，1H)4.46(s，2H)4.76(s，2H)6.64-6.74(m，1H)6.94-7.04(m，1H)7.12-7.23(m，3H)7.29-7.33(m，1H)7.35-7.40(m，1H)7.43-7.51(m，2H)7.69-7.77(m，1H)7.81-7.85(m，1H)7.86-7.93(m，1H)8.75-8.85(m，1H)。
Furan-2-carboxylic acid [5 ]-[3-((1R,4S) -5, 6-dihydroxy-3-oxo-2-aza-bicyclo [ 2.2.1)]Hept-2-yl) -propylcarbamoyl]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS(M+H)588；1HNMR (400MHz, methanol-d)4)ppm1.77-1.91(m，2H)1.91-1.99(m，1H)2.06-2.14(m，1H)2.35(s，3H)2.54-2.62(m，1H)2.99-3.10(m，1H)3.33-3.39(m，1H)3.40-3.51(m，2H)3.65-3.81(m，1H)3.97(d，J=1.61Hz，2H)6.63-6.75(m，1H)6.92-7.07(m，1H)7.09-7.24(m，3H)7.27-7.35(m，1H)7.37-7.51(m，1H)7.61-7.71(m，1H)7.74-7.94(m，1H)8.65-8.77(m，1H)。
2-cyclopropyl-oxazole-4-carboxylic acid [5- [3- (2-hydroxy-ethylcarbamoyl) -propylcarbamoyl]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS(M+H)575；1HNMR (400MHz, dichloromethane-d)2)ppm0.99-1.22(m，4H)1.94(d，J=8.88Hz，2H)2.05-2.17(m，1H)2.22-2.31(m，2H)2.35(s，3H)3.06-3.22(m，8H)3.38(d，J=4.34Hz，2H)3.48(d，J=6.25Hz，2H)3.60-3.72(m，1H)6.53-6.64(m，1H)6.81-6.94(m，1H)6.97-7.05(m，1H)7.13-7.24(m，3H)7.31(d，J=8.30Hz，1H)7.60(d，J=2.15Hz，1H)8.13(s，1H)8.82(d，J=2.10Hz，1H)9.86-10.05(m，1H)。
2-cyclopropyl-oxazole-4-carboxylic acid [5- [3- (3-methyl-2-oxo-imidazolidin-1-yl) -propylcarbamoyl]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS(M+H)586；1HNMR (400MHz, methanol-d)4)ppm1.12(d，J=6.59Hz，4H)1.71-1.88(m，2H)2.06-2.20(m，1H)2.35(s，3H)2.73(s，3H)3.06-3.15(m，4H)3.17-3.26(m，5H)3.30-3.44(m，6H)6.90-7.06(m，1H)7.09-7.25(m，3H)7.33-7.45(m，1H)7.53-7.67(m，1H)8.16-8.39(m，1H)8.63-8.96(m，1H)。
2-cyclopropyl-oxazole-4-carboxylic acid [5- [3- (acetyl-methyl-amino) -propylcarbamoyl]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS(M+H)559；1HNMR(400MHz，DMSO-d6)ppm9.92(1H，s)8.81(1H，d，J=1.81Hz)8.68(1H，s)8.35-8.50(1H，m)7.56-7.63(1H，m)7.42(1H，d，J=8.25Hz)7.18-7.25(2H，m)7.11-7.16(1H，m)7.01(1H，t，J=7.27Hz)3.34(2H，br.s.)3.19-3.29(2H，m)3.11(4H，d，J=4.59Hz)3.05(4H，br.s.)2.96(2H，s)2.79(1H，s)2.31(3H，s)2.15-2.24(1H，m)1.98(3H，d，J=3.51Hz)1.75-1.84(1H，m)1.69(1H，quin，J=6.97Hz)1.10-1.17(2H，m)1.03-1.09(2H，m)。
N- (5- ((3- ((ethyl (methyl) amino) methyl) benzyl) -carbamoyl) -2- (4- (o-tolyl) piperazin-1-yl) phenyl) furan-2-carboxamide.
LC/MS-ESI：[M+1]566.33, respectively; NMR (DMSO-d6)9.44(s, 1, NH-CO), 9.03(t, 1, CON-H), 8.64(d, 1, furan-H), 8.01(dd, 1, Ar-H), 7.70(dd, 1, Ar-H), 7.36-7.44(m, 5,5 × Ar-H), 7.31(d, 1, furan-H), 7.18(t, 2,2 × Ar-H), 7.11(d, 1, Ar-H), 6.98(t, 1, furan-H), 6.72(dd, 1, Ar-H), 4.50(d, 2, CON-CH)2)，4.35(dd，1，NC-H)，4.19(dd，1，NC-H)，3.00-3.16(m，10，2×CH2CH2，NCH2)，2.64(d，3，NCH3)，2.28(s，3，Ar-CH3)，1.19(t，3,3×CH2CH2-H)。
N- (5- ((3-sulfamoylbenzyl) carbamoyl) -2- (4- (o-tolyl) piperazin-1-yl) phenyl) furan-2-carboxamide.
LC/MS-ESI：[M+1]574.36, respectively; NMR (DMSO-d6)9.48(s, 1, CON-H), 9.15(t, 1, CON-H), 8.68(s, 1, furan-H), 8.04(s, 1, Ar-H), 7.81(s, 1, Ar-H), 7.74(m, 2,2 × Ar-H), 7.55(m, 2,2 × Ar-H), 7.43(d, 1, Ar-H), 7.33-7.39(m, 3,2 × Ar-H, furan-H), 7.14(d, 1Ar-H), 7.01(t, 1, furan-H), 6.75(m, 1, Ar-H), 4.57(d, 2, CON-CH2), 3.10(m, 8,8 × CH2CH2)，2.31(s，3，Ar-CH3)
(R) -N- (5- ((2-hydroxy-2-phenylethyl) carbamoyl) -2- (4)-(o-tolyl) piperazin-1-yl) phenyl) furan-2-carboxamide.
LC/MS-ESI：[M+1]525.3；NMR(DMSO-d6)9.45(s, 1, CON-H), 8.62(d, 1, furan-H), 8.43(t, 1, CON-H), 8.03(d, 1, Ar-H), 7.66(dd, 1, Ar-H), 7.31-7.43(m, 6, furan-H, 5 × Ar-H), 7.17-7.30(m, 3,3 × Ar-H), 7.14(d, 1, Ar-H)6.98(t, 1, furan-H), 6.75(dd, 1, Ar-H), 5.51(d, 1, HO-CH), 4.80(m, 1, O-H), 3.42-3.56(m, 1, CONC-H), 3.22-3.42(m, 1, CONC-H), 3.09(s, 8,2 × CH-H)2CH2)，2.92(s，3，Ar-CH3)。
N- (5- ((2- (2, 5-dioxopyrrolidin-1-yl) ethyl) carbamoyl) -2- (4- (o-tolyl) piperazin-1-yl) phenyl) furan-2-carboxamide.
LC/MS-ESI：[M+1]530.20；NMR(DMSO-d6)9.43(s, 1, CON-H), 8.54(d, 1, furan-H), 8.46(t, 1, CON-H), 8.01(m, 1, Ar-H), 7.53(dd, 1, Ar-H), 7.37(d, 1, Ar-H), 7.32(d, 1, furan-H), 7.18(d, 2,2 × Ar-H), 7.12(d, 1, Ar-H), 6.98(t, 1, furan-H), 6.72(dd, 1, Ar-H), 3.53(t, 2, CON-CH)2)，3.39(m，2，CON-CH2)，3.07(s，8,2×CH2CH2)，2.58(s，4,2×COCH2)，2.29(s，3，Ar-CH3)。
3- ((furan-2-ylmethyl) amino) -N- (3- (2-oxopyrrolidin-1-yl) propyl) -4- (4- (o-tolyl) piperazin-1-yl) benzamide.
LC/MS-ESI：[M+1]516.00；NMR(DMSO-d6)8.21(t, 1, CON-H), 7.59(s, 1, furan-H), 7.05-7.25(m,6, Ar-H)7.02(t, 1, Ar-H), 6.39(t, 1, furan-H), 6.29(d, 1, furan-H), 4.43(s, 2, furan-CH)2)，3.35(t，2，CON-CH2)，3.14-3.28(m，4，CON-CH2，CON-CH2)，3.08(s，4，CH2CH2)，3.02(s，4，CH2CH2)，2.31(s，3，Ar-CH3)，2.24(t，2，CO-CH2)，1.91(m，2，CH2)，1.69(m，2，CH2)。
N- (5- ((3-carbamoylbenzyl) carbamoyl) -2- (4- (o-tolyl) piperazin-1-yl) phenyl) -2-cyclopropyloxazole-4-carboxamide.
LC/MS-ESI：[M+1]579.37, respectively; NMR (DMSO-d6)9.91(s, 1, CON-H), 9.04(t, 1, CON-H), 8.85(d, 1, Ar-H), 8.67(d, 1, oxazole-H), 7.95(s, 1, CON-H), 7.82(s, 1, Ar-H), 7.73(d, 1, Ar-H), 7.68(dd, 1, Ar-H), 7.37-7.46(ddd, 3,3 xAr-H), 7.32(s, 1, CON-H), 7.16-7.24(m, 2,2 xAr-H), 7.13(d, 1, Ar-H), 7.00(t, 1, Ar-H), 4.50(d, 2, CON-CH)2)，3.10-3.04(m，8,2×CH2CH2)，2.30(s，3，Ar-CH3)，2.18(m，1，CH)，1.01-1.14(m，4,2×CH2)。
2-cyclopropyl-N- (5- (((1R,2S,3R,4R) -2, 3-dihydroxy-4)-(hydroxymethyl) cyclopentyl) carbamoyl) -2- (4- (o-tolyl) piperazin-1-yl) phenyl) oxazole-4-carboxamide.
LC/MS-ESI：[M+1]576.02；NMR(DMSO-d6)9.85(s, 1, CON-H), 8.73(d, 1, CO-NH), 8.60(s, 1, oxazole-H), 8.18(d, 1, Ar-H), 7.53(d, 1, Ar-H), 7.34(t, 1, Ar-H), 7.12(m, 2,2 xAr-H), 7.09(d, 1, Ar-H)6.93(t, 1, Ar-H), 4.09(t, 1, OC-H), 3.69(dq, 2, OC-H), 3.37(m, 2, OCH-H)2)，2.96-3.05(m，8,2×CH2CH2)，2.25(s，3，Ar-CH3)，1.75-2.13(m，4，OC-H，CH，CH2)，0.7-1.09(m，5，CH2，CH2，CH-H)。
2-cyclopropyl-N- (5- (((1R,2S,3R) -2, 3-dihydroxycyclohexyl) -carbamoyl) -2- (4- (o-tolyl) piperazin-1-yl) phenyl) oxazole-4-carboxamide trifluoroacetate salt.
LC/MS-ESI：[M+1]560.21, respectively; NMR (DMSO-d6)9.86(s, 1, CON-H), 8.72(s, 1, CON-H), 8.60(s, 1, oxazole-H), 7.94(d, 1, Ar-H), 7.56(d, 1, Ar-H), 7.34(s, 1, Ar-H), 7.15(d, 2,2 × Ar-H), 7.09(d, 1, Ar-H), 6.93(t, 1, Ar-H), 4.00(dd, 1, OC-H), 3.80(s, 1, CON-CH), 3.37(d, 1, OC-H), 3.04(s, 4, CH-H)2CH2)，2.99(s，4，CH2CH2)，2.25(s，3，Ar-CH3)，2.13(m，1，OC-H，CH，CH2)，1.01-1.71(m，11,5×CH2,5×CH2，C-H)。
2-cyclopropyl-N- (5- (((1R2S3R) -23-dihydroxy-cyclohexyl) -carbamoyl) -2- (4- (o-tolyl) piperazin-1-yl) phenyl) oxazole-4-carboxamide hydrochloride.
LC/MS-ESI：[M+1]560.21, respectively; NMR (DMSO-d6)9.93(s, 1, CON-H), 8.79(s, 1, CON-H), 8.68(s, 1, oxazole-H), 8.02(d, 1, Ar-H), 7.66(d, 1, Ar-H), 7.41(d, 1, Ar-H), 7.10-7.30(m, 3,3 × Ar-H), 7.03(t, 1, Ar-H), 4.06(tq, 1, OC-H), 3.87(s, 1, CON-CH), 3.44(dd, 1, OC-H), 3.14(s, 4, CH-H)2CH2)，3.08(s，4，CH2CH2)，2.51(s，3，Ar-CH3)，2.20(m，1，CH)，1.19-1.89(m，6,6×CH2)，1.00-1.19(m，4，CH2CH2)。
2-cyclopropyl-N- (5- (((1S,2R,3S) -2, 3-dihydroxycyclohexyl) carbamoyl) -2- (4- (o-tolyl) piperazin-1-yl) phenyl) oxazole-4-carboxamide.
LC/MS-ESI：[M+1]560.07, respectively; NMR (DMSO-d6)9.93(s, 1, CON-H), 8.79(s, 1, CON-H), 8.68(s, 1, oxazole-H), 8.02(d, 1, Ar-H), 7.66(d, 1, Ar-H), 7.41(d, 1, Ar-H), 7.10-7.30(m, 3,3 × Ar-H), 7.03(t, 1, Ar-H), 4.06(tq, 1, OC-H), 3.87(s, 1, CON-CH), 3.44(dd, 1, OC-H), 3.14(s, 4, CH-H)2CH2)，3.08(s，4，CH2CH2)，2.51(s，3，Ar-CH3)，2.20(m，1，CH)，1.19-1.89(m，6,6×CH2)，1.00-1.19(m，4，CH2CH2)。
2-cyclopropyl-N- (5- (((1R,3S) -3-hydroxycyclohexyl) carbamoyl) -2- (4- (o-tolyl) piperazin-1-yl) phenyl) oxazole-4-carboxamide.
LC/MS-ESI：[M+1]544.09；NMR(DMSO-d6)9.93(s, 1, CON-H), 8.79(d, 1, CON-H), 8.67(s, 1, oxazole-H), 8.24(d, 1, Ar-H), 7.60(dd, 1, Ar-H), 7.41(d, 1, Ar-H), 7.10-7.30(m, 3,3 × Ar-H), 7.02(m, 1, Ar-H), 4.06(tq, 1, OC-H), 3.24-4.11(broad, 3)3.12(d, 4, CH-H)2CH2)，3.06(d，4，CH2CH2)，2.32(s，3，Ar-CH3)，2.21(m，1，CH)，2.03(m，1，CH)，1.63-1.89(m，3,3×CH2)，1.00-1.37(m，8,2×CH2CH2)。
2-cyclopropyl-N- (5)-((1R,3R) -3-hydroxycyclohexyl) carbamoyl) -2- (4- (o-tolyl) piperazin-1-yl) phenyl) oxazole-4-carboxamide.
LC/MS-ESI：[M+1]544.19, respectively; NMR (DMSO-d6)9.93(s, 1, CON-H), 8.77(d, 1, CON-H), 8.67(s, 1, oxazole-H), 8.06(d, 1, Ar-H), 7.59(dd, 1, Ar-H), 7.40(d, 1, Ar-H), 7.10-7.30(m, 3,3 × Ar-H), 7.02(m, 1, Ar-H), 4.19(m, 1), 3.93(d, 1, OC-H), 3.23-3.84(broad), 3.12(d, 4, CH-H)2CH2)，3.05(d，4，CH2CH2)，2.32(s，3，Ar-CH3)，2.21(m，1，CH)，1.19-1.83(m，8,2×CH2CH2)，1.00-1.19(m，4，CH2CH2)。
2-cyclopropyl-N- (5- ((3-hydroxycyclohexyl) carbamoyl) -2- (4- (o-tolyl) piperazin-1-yl) phenyl) oxazole-4-carboxamide.
LC/MS-ESI：[M+1]544.40, respectively; NMR (DMSO-d6)9.85(s, 1, CON-H), 8.71(d, 1, CO-NH), 8.60(s, 1, oxazole-H), 8.16(dd, 0.46, Ar-H), 7.98(dd, 0.68, Ar-H), 7.47-7.56(m, 1, Ar-H), 7.28-7.37(m, 1, Ar-H), 7.04-7.20(m, 3,3 xAr-H), 6.93(m, 1, Ar-H), 4.06(tq, 1, OC-H), 3.24-4.11(broad, 3)3.12(d, 4, CH-H)2CH2)，3.06(d，4，CH2CH2)，2.25(s，3，Ar-CH3)，2.13(m，1，CH)，0.91-1.98(m，12,3×CH2CH2)。
Furan-2-carboxylic acid [5- [3- (4-hydroxy-phenyl) -propylcarbamic acid esterxBase of]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS: (method A)539.2(M + H), Rt4.8min, 96.7% (Max), 97.4% (254 nm).
1HNMR400MHz，CDCl3：9.48(s，1H)，8.68(s，1H)，7.78(d，J=4.00Hz，1H)，7.60(s，1H)，7.33(d，J=8.00Hz，1H)，7.30(t，J=4.00Hz，1H)，7.24(d，J=8.00Hz，2H)，7.13(d，J=8.00Hz，1H)，7.04-7.06(m，3H)，6.80(d，J=8.00Hz，2H)，6.61-6.62(m，1H)，6.53(s，1H)，5.83(s，1H)，3.46-3.51(m，2H)，3.12-3.18(m，8H)，2.67(t，J=4.00Hz，2H)，2.37(s，3H)，1.91-1.94(m，2H)。
Furan-2-carboxylic acid [5- [ 2-hydroxy-3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS: (method A)546.3(M + H), Rt3.8min, 97.3% (Max), 98.8% (254 nm).
1HNMR400MHz，CDCl3：9.42(s，1H)，8.98(d，J=4.00Hz，1H)，7.73(d，J=12.00Hz，1H)，7.53-7.57(m，2H)，7.32(d，J=8.00Hz，1H)，7.28(s，1H)，7.23-7.26(m，2H)，7.13(d，J=8.00Hz，1H)，7.06-7.08(m，1H)，6.60(d，J=4.00Hz，1H)，4.30(d，J=8.00Hz，1H)，4.01-4.02(m，1H)，3.73-3.79(m，1H)，3.50-3.60(m，3H)，3.33-3.43(m，2H)，3.17-3.18(m，4H)，3.12-3.14(m，4H)，2.46(t，J=8.00Hz，2H)，2.37(s，3H)，2.05-2.12(m，2H)。
Furan-2-carboxylic acid [5- [3- (2-oxo-imidazolidin-1-yl) -propylcarbamoyl]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS: (method A)531.2(M + H), Rt3.9min, 95.0% (Max). 93.5% (254 nm);
1HNMR400MHz，CDCl3：9.46(s，1H)，8.88(s，1H)，7.76(d，J=8.00Hz，1H)，7.57(s，1H)，7.53(t，J=4.00Hz，1H)，7.31(d，J=8.00Hz，2H)，7.23-7.34(m，2H)，7.13(d，J=8.00Hz，1H)，7.04-7.07(m，1H)，6.59(s，1H)，3.47-3.50(m，6H)，3.34-3.37(m，2H)，3.17-3.18(m，4H)，3.11-3.13(m，4H)，2.37(s，3H)，1.80-1.83(m，2H)。
2-cyclopropyl-oxazole-4-carboxylic acid {2- [4- (3-chloro-pyridin-2-yl) -piperazin-1-yl]-5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl]-phenyl } -amide.
LCMS: (method A)592.3(M + H), Rt4.4min, 95.4% (Max). 96.4% (254 nm);
1HNMR400MHz，CDCl3：9.94(s，1H)，8.97(d，J=4.00Hz，1H)，8.23-8.25(m，1H)，8.13(s，1H)，7.73(d，J=8.00Hz，1H)，7.65(s，1H)，7.58-7.63(m，1H)，7.26(s，1H)，6.88-6.91(m，1H)，3.65-3.67(m，4H)，3.40-3.45(m，6H)，3.11-3.13(m，4H)，2.44-2.48(m，2H)，2.03-2.11(m，3H)，1.81-1.84(m，2H)，1.14-1.18(m，2H)，1.08-1.09(m，2H)。
the compounds listed in table 2 were prepared according to scheme 1.
Example 2: synthetic route to (R) -3- [3- [ (furan-2-carbonyl) -amino ] -4- (4-o-tolyl-piperazin-1-yl) -benzoylamino ] -piperidine-1-carboxylic acid ethylamide (Compound No. 48)
Scheme 2
Step 1
Compound was prepared from 3- [ (furan-2-carbonyl) -amino ] -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid following a similar procedure as compound No. 11.
Step 2
(R) -3- [3- [ (furan-2-carbonyl) -amino ] -4- (4-o-tolyl-piperazin-1-yl) -benzoylamino ] -piperidine-1-carboxylic acid tert-butyl ester (0.12g, 0.204mmol) was stirred with a mixture of DCM (1.0mL) and TFA (1.0mL) for 4 h. LC-MS showed deprotection complete. The mixture was concentrated and dissolved in pyridine (5.0 mL). Ethyl isocyanate (EtNCO) (29mg, 0.41mmol) was added and the reaction mixture was stirred at 45 ℃ for 6 h. Pyridine was rotary evaporated and the crude product was dissolved in methanol and purified by preparative HPLC using water/methanol as eluent to give the desired product (0.02g, 18%).
LCMS(ESI)559(M+H)；1HNMR (400MHz, methanol-d 4) ppm1.05-1.13(m, 3H)1.50-1.68(m, 2H)1.73-1.81(m, 1H)1.96-2.08(m, 1H)2.32(s, 3H)2.78-2.96(m, 2H)3.12(s, 9H)3.17(q, J =7.19Hz, 3H)3.77-4.00(m, 3H)6.66(dd, J =3.51,1.76Hz, 1H)6.96(td, J =7.11,1.73Hz, 1H)7.08-7.19(m, 3H)7.28(d, J =3.47Hz, 1H)7.38(d, J =8.35Hz, 1H) 7.61.61 (dd = 8.63, 1H)7.79(d, 1H = 3H) 7.9 (d, 1H) 7.9 Hz, 1H).
The following compounds were prepared according to scheme 2:
following the same procedure as Compound No. 11, starting from 3-[ (furan-2-carbonyl) -amino group]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid {2- [3- [ (furan-2-carbonyl) -amino]-4- (4-o-tolyl-piperazin-1-yl) -benzoylamino]-ethyl } -methyl-carbamic acid tert-butyl ester (compound No. 64).
LCMS(ESI)562(M+H)；1HNMR (400MHz, dichloromethane-d 2) ppm1.40(s, 9H)1.54-1.64(m, 1H)2.36(s, 3H)2.89(brs, 3H)3.15(dd, J =17.01,5.59Hz, 8H)3.48(brs, 2H)3.52-3.60(m, 2H)6.60(dd, J =3.39,1.73Hz, 1H)6.97-7.05(m, 1H)7.12-7.25(m, 4H)7.31(brs, 1H)7.56(brs., 1H)7.60(s, 1H)8.83(d, J =2.00Hz, 1H)9.24-9.52(m, 1H).
Furan-2-carboxylic acid [5 ] was prepared according to the following procedure-(2-methylamino-ethylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl]-amide (compound No. 132): {2- [3- [ (furan-2-carbonyl) -amino group]-4- (4-o-tolyl-piperazin-1-yl) -benzoylamino]Tert-butyl-ethyl } -methyl-carbamate (0.1g, 0.17mmol) was stirred with a mixture of DCM (2.0mL) and TFA (2.0mL) for 2 hours. The reaction was concentrated to give 0.07g of TFA salt.
LCMS(ESI)462(M+H)；1HNMR (400MHz, methanol-d)4)ppm2.33(s，3H)2.74(s，3H)3.12-3.19(m，8H)3.23(t，J=5.66Hz，2H)3.68(t，J=5.66Hz，2H)6.67(dd，J=3.54,1.78Hz，1H)6.94-7.02(m，1H)7.12-7.20(m，3H)7.29(d，J=2.98Hz，1H)7.41(d，J=8.35Hz，1H)7.68(dd，J=8.35,2.15Hz，1H)7.80(d，J=1.02Hz，1H)8.72(d，J=2.10Hz，1H)。
Furan-2-carboxylic acid [5- {2 ] was prepared according to the following procedure-[ (2, 2-dimethyl-butyryl) -methyl-amino]-ethylcarbamoyl } -2- (4-o-tolyl-piperazin-1-yl) -phenyl]-amide (compound No. 133): to furan-2-carboxylic acid [5- (2-methylamino-ethylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl at 0 deg.C]Amide (0.04g, 0.086mmol) and diisopropylethylamine (0.5mL) in CH2Cl2(2.0mL) was added 2, 2-dimethylbutyrylchloride (0.173mmol) and the reaction mixture was stirred at 0-25 ℃ for 4 hours. CH for reactant2Cl2Diluted and saturated NaHCO3And (4) washing the solution. The organic layer was concentrated and dissolved in ACN and purified by preparative HPLC using water/methanol (0.1% TFA) as eluent to give the product (0.01g, 21% yield).
LCMS(ESI)560(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm0.81(t，J=7.49Hz，3H)1.22(s，6H)1.59-1.69(m，2H)2.34(s，3H)3.06-3.19(m，11H)3.54-3.67(m，4H)6.59(dd，J=3.47,1.76Hz，1H)7.00(td，J=7.33,1.24Hz，1H)7.11-7.15(m，1H)7.17-7.25(m，3H)7.29(s，1H)7.35(brs，1H)7.51(dd，J=8.27,2.07Hz，1H)7.57-7.64(m，1H)8.81(d，J=2.05Hz，1H)9.38(s，1H)。
Following the general procedure for the preparation of furan-2-carboxylic acid [5- {2- [ (2, 2-dimethyl-butyryl) -methyl-amino ] -methyl-amino]-ethylcarbamoyl } -2- (4-o-tolyl-piperazin-1-yl) -phenyl]Preparation of benzo [1,3 ] s from piperonyl chloride in the same procedure as for the amides]Dioxo le-5-carboxylic acid {2- [3- [ (furan-2-carbonyl) -amino ]]-4- (4-o-tolyl-piperazin-1-yl) -benzoylamino]-ethyl } -methyl-amide (compound No. 134).
LCMS(ESI)610(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm2.34(s，3H)3.06(s，3H)3.09-3.19(m，8H)3.68(brs，4H)5.98(s，2H)6.60(dd，J=3.47,1.76Hz，1H)6.80(d，J=7.91Hz，1H)6.89-6.96(m，1H)6.97-7.04(m，2H)7.08-7.15(m，1H)7.20(dd，J=6.83,5.26Hz，2H)7.25(d，J=3.42Hz，1H)7.33(d，J=8.30Hz，1H)7.48-7.56(m，1H)7.57-7.62(m，2H)8.70-8.97(m，1H)9.41(s，1H)。
Example 3: synthesis route of 4- [3- [ (5-methyl-furan-2-carbonyl) -amino ] -4- (4-o-tolyl-piperazin-1-yl) -benzoylamino ] -piperidine-1-carboxylic acid tert-butyl ester (Compound No. 175)
Scheme 3
Step 1
3-Nitro-4- (4-o-tolyl-piperazin-1-yl) -benzoic acid (1.0g, 2.9mmol) was dissolved with sulfuric acid (1.0mL) in methanol (100mL) and refluxed for 16 h. Concentrated, dissolved in ethyl acetate (300mL) and the organic layer washed with saturated NaHCO3The solution was washed, dried and concentrated to give 0.37g of 3-nitro-4- (4-o-tolyl-piperazine-1-yl) -benzoic acid methyl ester.
Step 2
The same procedure applies to the preparation of 3-amino-4- (4-o-tolyl-piperazin-1-yl) -benzoic acid
Step 3 and step 4
Triethylamine (1.7mL, 12.3mmol) was added to methyl 3-amino-4- (4-o-tolyl-piperazin-1-yl) -benzoate (2.0g, 6.15mmol) in CH2Cl2(50mL) and cooled to 0 ℃. Is added dropwise to CH2Cl25-Methylfuroyl chloride (1.06g, 7.38mmol) in (5.0mL) and the reaction mixture was stirred at 0-25 ℃ for 6 hours. Reaction mixture with CH2Cl2(100mL) diluted and saturated NaHCO3The solution was washed and dried to give the crude product, which was dissolved in a mixture of methanol (60mL) and THF (60mL), with lioh2A solution of O (2.17g, 53mmol) in water (20mL) was stirred together for 6 hours. The solvent was removed and the contents dissolved in water and acidified to ph5.0 with 2n hcl. Filtering and drying to obtain 3- [ (5-methyl-furan-2-carbonyl) -amino group]-4- (4-o-tolyl-piperazin-1-yl) -benzoic acid (1.37g, 64%).
Step 5
The compound was prepared from the acid intermediate 3- [ (5-methyl-furan-2-carbonyl) -amino ] -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid and 4-amino-piperidine-1-carboxylic acid tert-butyl ester following the EDC amidation procedure described in preparation No. 11.
LCMS(ESI)602(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm1.41-1.46(m，9H)1.94-2.03(m，2H)2.36(s，3H)2.43(s，3H)2.81-2.96(m，2H)3.15(dd，J=15.89,5.74Hz，8H)4.01-4.16(m，3H)6.07-6.26(m，2H)6.94-7.06(m，1H)7.09-7.14(m，2H)7.16-7.25(m，2H)7.32(d，J=8.25Hz，1H)7.58(dd，J=8.25,2.15Hz，1H)8.78(d，J=2.10Hz，1H)9.46(s，1H)。
The following compounds were prepared according to scheme 3:
following the same procedure as compound No. 11 starting from the intermediate acid 3- [ (5-methyl-furan-2-carbonyl) -amino]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid 5-methyl-furan-2-carboxylic acid [5- [2- (1H-imidazol-4-yl) -ethylcarbamoyl]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide (compound No. 185).
LCMS(ESI)513(M+H)；1HNMR (400MHz, dichloromethane-d 2) ppm1.76(t, J =6.03Hz, 2H)1.99-2.09(m, 2H)2.36-2.43(m, 5H)3.10-3.15(m, 4H)3.25-3.44(m, 10H)3.87(s, 3H)6.20(dd, J =3.37, 0.98Hz, 1H)6.89-7.05(m, 4H)7.11(d, J =3.32Hz, 1H)7.33(d, J =8.25Hz, 1H)7.64(dd, J =8.25Hz, 2H)8.87(d, J =2.10Hz, 1H)9.46(s, 1H).
Following the same procedure as compound No. 11 starting from 3- [ (5-methyl-furan-2-carbonyl) -amino]Preparation of 4- (4-o-tolyl-piperazin-1-yl) -benzoic acid 5-methyl-furan-2-carboxylic acid [5- (3, 4-dimethoxy-benzylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide (compound No. 171).
LCMS(ESI)569(M+H)；1HNMR (400MHz, methanol-d 4) ppm2.35(s, 3H)2.45(s, 3H)3.08-3.21(m, 8H)3.82(d, J =8.25Hz, 6H)4.52(s, 2H)6.31(dd, J =3.42, 0.93Hz, 1H)6.91-6.93(m, 2H)6.97-7.02(m, 2H)7.12-7.21(m, 4H)7.41(d, J =8.30Hz, 1H)7.65(dd, J =8.30, 2.15Hz, 1H)8.74(d, J =2.10Hz, 1H).
Following the same procedure as compound No. 11 starting from 3- [ (5-methyl-furan-2-carbonyl) -amino]Preparation of 5-methyl-furan-2-carboxylic acid [5- [2- (1, 1-dioxo-1. lamda. 6. times. -thiomorpholin-4-yl) ethylcarbamoyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid]-2- (4-o-tolyl-piperazine-1-Phenyl radical]Amide (compound No. 174).
LCMS(ESI)580(M+H)；1HNMR (400MHz, methanol-d 4) ppm2.35(s, 3H)2.45(s, 3H)2.77(t, J =6.35Hz, 2H)3.05-3.20(m, 16H)3.52(t, J =6.30Hz, 2H)6.31(dd, J =3.42, 0.98Hz, 1H)6.96-7.01(m, 1H)7.12-7.21(m, 4H)7.42(d, J =8.30Hz, 1H)7.61(d, J =2.15Hz, 1H)8.74(d, J =2.10Hz, 1H).
Following the same procedure as compound No. 11 starting from 3- [ (5-methyl-furan-2-carbonyl) -amino]Preparation of 4- (4-o-tolyl-piperazin-1-yl) -benzoic acid 5-methyl-furan-2-carboxylic acid [5- { [4- (4-methoxy-phenyl) -1H-pyrazol-3-ylmethyl]-carbamoyl } -2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide (compound No. 172).
LCMS(ESI)605(M+H)；1HNMR (400MHz, methanol-d 4) ppm2.32-2.37(m, 3H)2.45(s, 3H)3.15(q, J =5.81Hz, 8H)3.79-3.84(m, 3H)4.58(s, 2H)6.31(dd, J =3.42, 0.93Hz, 1H)6.94-7.06(m, 4H)7.12-7.21(m, 4H)7.38(d, J =8.30Hz, 1H)7.51-7.60(m, 3H)8.62(d, J =2.05Hz, 1H).
Following the same procedure as compound No. 11 starting from 3- [ (5-methyl-furan-2-carbonyl) -amino]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid 5-methyl-furan-2-carboxylic acid [ 5-cyclopropylcarbamoyl-2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide (compound No. 195).
LCMS(ESI)459(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm0.55-0.64(m，2H)0.77-0.86(m，2H)2.41(d，J=12.30Hz，6H)2.79-2.91(m，1H)3.09-3.27(m，8H)6.21(dd，J=3.37，0.98Hz，1H)6.35(s，1H)7.01-7.07(m，1H)7.10-7.26(m，4H)7.33(d，J=8.30Hz，1H)7.57(dd，J=8.25,2.10Hz，1H)8.74(d，J=2.05Hz，1H)9.45(brs，1H)。
Following the same procedure as compound No. 11 starting from the intermediate acid 3- [ (5-methyl-furan-2-carbonyl) -amino]Preparation of (R) -3- [3- [ (5-methyl-furan-2-carbonyl) -amino ] -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid]-4- (4-o-tolyl-piperazin-1-yl) -benzoylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (compound No. 142).
LCMS(ESI)588(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm1.44(s，9H)1.81-2.00(m，1H)2.23(dq，J=13.47,6.54Hz，1H)2.35(s，3H)2.43(s，3H)3.07-3.17(m，8H)3.18-3.32(m，1H)3.37-3.51(m，2H)3.64-3.77(m，1H)4.49-4.70(m，1H)6.20(dd，J=3.37，0.98Hz，1H)6.46(d，J=11.37Hz，1H)6.93-7.04(m，1H)7.07-7.13(m，2H)7.14-7.25(m，2H)7.31(d，J=8.25Hz，1H)7.57(dd，J=8.22,2.12Hz，1H)8.78(d，J=1.90Hz，1H)9.45(s，1H)。
Following the same procedure as compound No. 11 starting from 3- [ (5-methyl-furan-2-carbonyl) -amino]Preparation of 4- (4-o-tolyl-piperazin-1-yl) -benzoic acid 5-methyl-furan-2-carboxylic acid [5- [ (pyridin-3-ylmethyl) -carbamoyl]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide (compound No. 218).
LCMS(ESI)510(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm2.36(s，3H)2.44(s，3H)3.09-3.20(m，8H)4.70(d，J=5.86Hz，2H)6.21(d，J=2.68Hz，1H)6.95-7.06(m，2H)7.11(d，J=3.66Hz，2H)7.20(t，J=8.35Hz，2H)7.35(d，J=8.30Hz，1H)7.51(brs，1H)7.67(dd，J=8.25,2.00Hz，1H)8.01(d，J=7.91Hz，1H)8.52-8.75(m，2H)8.88(d，J=1.95Hz，1H)9.46(brs，1H)。
Following the same procedure as compound No. 11 starting from 3- [ (5-methyl-furan-2-carbonyl) -amino]Preparation of (4-o-tolyl-piperazin-1-yl) -benzoic acid 5-methyl-furan-2-carboxylic acid [5- (3-imidazol-1-yl-propylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide (compound No. 210).
LCMS(ESI)527(M+H)；1HNMR (400MHz, chloroform-d) ppm2.14(quin, J =6.80Hz, 2H)2.38(s, 3H)2.45(s, 3H)3.16(dd, J =16.08,4.95Hz, 8H)3.50(q, J =6.52Hz, 2H)4.07(t, J =7.05Hz, 2H)6.22(d, J =2.64Hz, 1H)6.59(t, J =5.30Hz, 1H)6.96-7.13(m, 5H)7.15-7.22(m, 2H)7.35(d, J =8.25Hz, 1H)7.52-7.58(m, 1H)7.76(dd, J =8.27,1.73Hz, 1H)8.81(d, J =1.61, 1H)9.51 Hz, 1H).
Following the same procedure as compound No. 11 starting from 3- [ (5-methyl-furan-2-carbonyl) -amino]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid 5-methyl-furan-2-carboxylic acid [5- (3-hydroxy-propylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS(ESI)477(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm1.69-1.81(m，2H)2.35(s，3H)2.43(s，3H)3.08-3.21(m，8H)3.52-3.69(m，4H)6.21(d，J=2.59Hz，1H)6.71-6.83(m，1H)6.91-7.04(m，1H)7.07-7.13(m，2H)7.16-7.25(m，2H)7.33(d，J=8.30Hz，1H)7.64(dd，J=8.27,2.07Hz，1H)8.83(d，J=1.66Hz，1H)9.26-9.58(m，1H)。
Following the same procedure as compound No. 11 starting from 3- [ (5-methyl-furan-2-carbonyl) -amino]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid 5-methyl-furan-2-carboxylic acid [5- (4-hydroxy-butylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide (compound No. 241).
LCMS(ESI)491(M+H)；1HNMR (400MHz, chloroform-d) ppm1.72-1.85(m, 4H)2.38(s, 3H)2.45(s, 3H)3.00(brs, 1H)3.15(dd, J =17.16,5.49Hz, 8H)3.50(q, J =5.63Hz, 2H)3.81-3.88(m, 2H)6.21(d, J =2.64Hz, 1H)7.02-7.12(m, 2H)7.16(d, J =3.32Hz, 1H)7.20-7.26(m, 2H)7.33(d, J =8.25Hz, 1H)7.74(t, J =4.15Hz, 1H)7.81(dd, J =8.27,1.98Hz, 1H)8.81(d = 8.90, 1H) 1.52 (d, J =4.15Hz, 1H).
Following the same procedure as compound No. 11 starting from 3- [ (5-methyl-furan-2-carbonyl) -amino]Preparation of 4- [3- [ (5-methyl-furan-2-carbonyl) -amino ] -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid]-4- (4-o-tolyl-piperazin-1-yl) -benzoylamino]-ethyl butyrate.
LCMS(ESI)533(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm1.19-1.29(m，3H)1.93(quin，J=7.05Hz，3H)2.33-2.48(m，6H)3.15(dd，J=15.25,5.64Hz，8H)3.40-3.52(m，3H)4.11(q，J=7.13Hz，2H)6.22(d，J=2.64Hz，1H)6.50(t，J=5.08Hz，1H)6.98-7.05(m，1H)7.09-7.15(m，2H)7.16-7.25(m，2H)7.33(d，J=8.25Hz，1H)7.60(dd，J=8.25,2.05Hz，1H)8.81(s，1H)9.47(brs，1H)。
Example 4: synthetic route to 5-methyl-furan-2-carboxylic acid [5- (3-amino-propylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
Scheme 4
The following compounds were prepared according to scheme 4:
following the same procedure as compound No. 11 starting from 3- [ (5-methyl-furan-2-carbonyl) -amino]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid {3- [3- [ (5-methyl-furan-2-carbonyl) -amino]-4- (4-o-tolyl-piperazin-1-yl) -benzoylamino]-propyl } -carbamic acid tert-butyl ester (compound No. 258).
LCMS(ESI)576(M+H)；1HNMR (400MHz, dichloromethane-d 2) ppm0.81-0.90(m, 1H)1.08-1.17(m, 1H)1.23-1.31(m, 1H)1.43(s, 9H)1.65-1.82(m, 5H)2.37(s, 2H)2.43(s, 2H)3.12-3.22(m, 8H)3.41(s, 2H)6.09-6.25(m, 1H)6.97-7.06(m, 1H)7.13(d, J =3.47Hz, 2H)7.17-7.24(m, 1H)7.35(s, 1H)7.52-7.69(m, 1H)8.68-8.92(m, 1H)9.38-9.59(m, 1H).
Preparation of 5-methyl-furan-2-carboxylic acid [5- (3-acetylaminopropylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] according to the following procedure]-amide (compound No. 259): the {3- [3- [ (5-methyl-furan-2-carbonyl) -amino group prepared above is reacted with]-4- (4-o-tolyl-piperazin-1-yl) -benzoylamino]-propyl } -carbamic acid tert-butyl ester (0.20g, 0.347mmol) and CH-2Cl2A mixture of/TFA (5.0mL/5.0mL) was stirred together for 3 hours. The reaction mixture was concentrated to give the intermediate amine, which was dissolved in CH (0.070g, 0.147mmol)2Cl2(2.0 mL). DIPEA (0.371g, 2.87mmol) was added, followed by acetic anhydride (0.32g, 3.13 mmol). The reaction mixture was stirred at room temperature for 3 hours, concentrated and the crude product was purified by preparative HPLC using water/methanol as eluent.
LCMS(ESI)518(M+H)；1HNMR (400MHz, methanol-d 4) ppm1.78(quin, J =6.81Hz, 2H)1.93(s, 3H)2.34(s, 3H)2.43(s, 3H)3.12-3.21(m, 8H)3.21-3.26(m, 2H)3.26-3.26(m, 1H)3.40(t, J =6.88Hz, 2H)6.29(dd, J =3.39, 0.85Hz, 1H)6.96-7.01(m, 1H)7.12-7.21(m, 4H)7.39(d, J =8.30Hz, 1H)7.61(dd, J =8.30, 2.15Hz, 1H)8.69(d, J =2.05Hz, 1H).
Preparation of 5-methyl-furan-2-carboxylic acid [5- [3- (3-ethyl-ureido) -propylcarbamoyl ] amide according to a procedure similar to Compound No. 48]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS(ESI)547(M+H)；1HNMR (400MHz, methanol-d 4) ppm1.07(t, J =7.22Hz, 3H)1.74(t, J =6.69Hz, 2H)2.35(s, 3H)2.42(s, 3H)3.08-3.23(m, 12H)3.41(t, J =6.74Hz, 2H)6.28(dd, J =3.32, 0.78Hz, 1H)6.93-7.06(m, 1H)7.01(s, 1H)7.11-7.23(m, 4H)7.39(d, J =8.35Hz, 1H)7.61(dd, J =8.30, 2.10Hz, 1H)8.69(d, J =2.10Hz, 1H).
The same procedure as compound No. 133 was followed from 5-methyl-furan-2-carboxylic acid [5- (3-amino-propylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl]Preparation of {3- [3- [ (5-methyl-furan-2-carbonyl) -amino ] -amide]-4- (4-o-tolyl-piperazin-1-yl) -benzoylamino]-propyl } -carbamic acid methyl ester.
LCMS(ESI)534(M+H)；1HNMR (400MHz, methanol-d 4) ppm1.77(t, J =6.76Hz, 2H)2.34(s, 3H)2.42(s, 3H)3.09-3.22(m, 10H)3.40(t, J =6.86Hz, 2H)3.61(s, 3H)6.28(d, J =3.32Hz, 1H)7.00(dd, J =6.44,2.10Hz, 1H)7.11-7.23(m, 4H)7.38(d, J =8.30Hz, 1H)7.60(dd, J =8.27,2.07Hz, 1H)8.68(d, J =2.00Hz, 1H).
Example 5: synthetic route for thiophene-2-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide (compound No. 40)
Scheme 5
Step 1
To 4-fluoro-3-nitro-benzoic acid (5.0g, 27.02mmol) in CH2Cl2(150mL) was added HOBt (6.5g, 48.63mmol) and EDC.HCl (6.2g, 40.53mmol), followed by DIPEA (6.12mL, 35.12 mmol). The reaction mixture was stirred at room temperature for 6 hours. Water (50.0mL) was added and the two layers were separated. The organic layer was washed with brine and concentrated to give the crude 4-fluoro-3-nitro-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl product]Benzamide (7.5g, 90%). The product was used in the next step without further purification.
Step 2
To 4-fluoro-3-nitro-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]-benzamide (2.0g, 6.47mmol) in DMF (10mL) was added K2CO3(1.7g, 12.94mmol), 1-o-tolyl-piperazine (1.7g, 9.7mmol) was further added, and the reaction mixture was stirred at room temperature for 16 hours. DMF (2.0mL) was added and filtered. The solid was washed with methanol (300mL) and the methanol layer was evaporated off, which yielded an acid: 3-nitro-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]-4- (4-o-tolyl-piperazin-1-yl) -benzamide (1.8g, 62%).
Step 3
3-Nitro-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide (1.5g, 3.2mmol) was dissolved in a mixture of ethanol/methanol (50.0mL/20.0 mL). The solution was charged to a flask containing Pd/C (5wt%) (0.15 g). The solution was evacuated, purged with nitrogen, and stirred under a hydrogen balloon for 8 hours. LC-MS showed the reaction was complete. The reaction was terminated, the reaction mixture evacuated, purged with nitrogen, and filtered through celite. The solvent was removed by rotary evaporation to give 3-amino-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide (0.7g, 47%).
Step 4
In a 20mL scintillation vial, the 3-amino group was reacted in the presence of nitrogen-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]-4- (4-o-tolyl-piperazin-1-yl) -benzamide (0.06g, 0.137mmol) was dissolved in CH2Cl2(2.0mL) followed by DIPEA (0.12mL, 0.685mmol) and DMAP (0.0016g, 0.0137mmol) and the mixture cooled to 0 ℃. Then added dropwise to CH2Cl22-thiophene chloride (0.206mmol, 0.03g) in (1.0 mL). After 40 minutes, the reaction was complete. Adding 10.0mLCH2Cl2The mixture was then washed with 4.0mL of water followed by 3.0mL of saturated sodium bicarbonate solution and 3.0mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was dissolved in methanol and purified by preparative HPLC using methanol/water (0.1% TFA) as eluent to give the desired product (0.06g, 81%).
LCMS(ESI)546(M+H)；1HNMR (400MHz, methanol-d)4)ppm1.84(quin，J=6.87Hz，2H)2.04(quin，J=7.60Hz，2H)2.34(s，3H)2.35-2.40(m，2H)3.18(s，7H)3.33-3.40(m，4H)3.44-3.53(m，2H)6.97-7.04(m，1H)7.14-7.24(m，4H)7.38(d，J=8.40Hz，1H)7.67(dd，J=8.32,2.12Hz，1H)7.75(dd，J=4.98,1.07Hz，1H)7.86(dd，J=3.73,1.05Hz，1H)8.48(d，J=2.15Hz，1H)。
The following compounds were prepared according to scheme 5:
prepared by the same procedure as Compound No. 133 using 3-amino-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzamide 3- (2, 2-dimethyl-propionylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]-4- (4-o-tolyl-piperazin-1-yl) -benzamide (compound No. 177).
LCMS(ESI)520(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm1.34(s，9H)1.83(quin，J=6.32Hz，2H)2.08(quin，J=7.65Hz，2H)2.38(s，3H)2.51(t，J=8.13Hz，2H)3.09-3.26(m，8H)3.35-3.52(m，6H)7.03-7.09(m，1H)7.12-7.17(m，1H)7.19-7.25(m，2H)7.36(d，J=8.35Hz，1H)7.46-7.58(m，1H)7.65(dd，J=8.30，2.15Hz，1H)8.74(d，J=2.10Hz，1H)8.91(s，1H)。
Prepared by the same procedure as Compound No. 133 using 3-amino-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzamide 3- (2-cyclopropyl-acetylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]-4- (4-o-tolyl-piperazin-1-yl) -benzamide (compound No. 219).
LCMS(ESI)518(M+H)；1HNMR (400MHz, dichloromethane-d 2) ppm0.04-0.05(m, 2H)0.38-0.47(m, 2H)0.51-0.59(m, 1H)0.79(dddt, J =12.59,7.56,5.05,2.51,2.51Hz, 1H)0.94-1.00(m, 1H)1.44(quin, J =6.15Hz, 2H)1.68-1.77(m, 2H)2.01-2.11(m, 7H)2.78(s, 8H)3.01-3.12(m, 6H)6.66-6.73(m, 1H)6.76(d, J =7.27Hz, 1H)6.84-6.91(m, 2H)7.02(d, J = 8.30H) 7.24.35H (m, 2H) 1H = 1H 1Hz, 62 brh 1H)1 Hz.
Prepared by the same procedure as Compound No. 133 using 3-amino-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]Preparation of 4- (4-o-tolyl-piperazin-1-yl) -benzamide 6-methyl-pyridine-2-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide (compound No. 186).
LCMS(ESI)555(M+H)；1HNMR (400MHz, methanol-d)4)ppm1.76-1.91(m，2H)2.05(quin，J=7.59Hz，2H)2.33(s，3H)2.35-2.41(m，2H)2.68(s，3H)3.10-3.16(m，4H)3.20-3.25(m，4H)3.38(td，J=6.91,2.05Hz，4H)3.49(t，J=7.08Hz，2H)6.91-7.00(m，1H)7.10-7.21(m，3H)7.39(d，J=8.35Hz，1H)7.46(d，J=7.76Hz，1H)7.62(dd，J=8.25,2.10Hz，1H)7.88(t，J=7.74Hz，1H)8.04(d，J=7.66Hz，1H)8.93(d，J=2.05Hz，1H)。
Preparation of N- [3- (2-oxo-pyrrolidin-1-yl)-Propyl radical]-3- (pyrimidin-2-ylamino) -4- (4-o-tolyl-piperazin-1-yl) -benzamide (compound No. 242): in a microwave glass tube, Pd (OAc)2(0.0025g, 0.0115mmol) and X-PHOS (5.4mg, 0.0115mmol) were dissolved in tert-butanol: a mixture (2.0mL) of toluene (1: 5) was stirred. The solution was evacuated for 5 minutes and purged with nitrogen. Adding 3-amino-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]-4- (4-o-tolyl-piperazin-1-yl) -benzamide (0.05g, 0.115mmol) and 2-bromo-pyrimidine (2.7mg, 0.172mmol), evacuated and purged with nitrogen. The mixture was stirred at 140 ℃ for 30 minutes under microwave conditions. LC-MS showed product formation with some other by-products. The reaction mixture was concentrated, dissolved in methanol and purified by preparative HPLC using water/methanol as eluent to give the desired product (10.0mg, 17%).
LCMS(ESI)514(M+H)；1HNMR (400MHz, methanol-d)4)ppm1.15(t，J=7.03Hz，1H)1.84(t，J=6.81Hz，2H)1.96-2.10(m，2H)2.27-2.34(m，3H)2.34-2.42(m，2H)3.05-3.14(m，8H)3.37(q，J=6.74Hz，4H)3.43-3.54(m，3H)6.80-6.99(m，2H)7.04-7.19(m，3H)7.33(d，J=8.25Hz，1H)7.50(dd，J=8.25,2.10Hz，1H)8.49(d，J=4.83Hz，1H)8.85(d，J=2.10Hz，1H)。
Prepared by the same procedure as Compound No. 133 using 3-amino-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]Preparation of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzamide 5-bromo-furan-2-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide (compound No. 143).
LCMS(ESI)608(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm1.76(dt，J=11.99,6.13Hz，4H)1.95-2.12(m，2H)2.26-2.46(m，5H)2.98-3.25(m，8H)3.27-3.49(m，6H)6.55(d，J=3.56Hz，1H)7.01(dd，J=6.52,2.27Hz，1H)7.12-7.26(m，3H)7.33(d，J=8.25Hz，1H)7.67(dd，J=8.18,1.93Hz，2H)8.85(d，J=1.90Hz，1H)9.55(s，1H)。
Example 6: synthetic route to 5-ethynyl-furan-2-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide (compound No. 176)
Scheme 6
In a 20mL scintillation vial, 5-bromo-furan-2-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide (0.1g, 0.231mmol) was dissolved in acetonitrile (5.0 mL). Trimethylsilylacetylene (0.045g, 0.462mmol), CuI (0.009g, 0.046mmol), triethylamine (0.116g, 1.155mmol) and PdCl were then added2(Ph3P) (0.032g, 0.046mmol), the solution was evacuated for 5 minutes, purged with nitrogen and stirred at 80 ℃ for 4 hours. LC-MS showed the reaction was complete. Dilute with acetonitrile, filter through celite, and concentrate. The crude product was dissolved in THF and stirred with TBAF (2.0mL of a solution of 2M in THF) for 16h at room temperature. The reaction was concentrated, dissolved in methanol and purified by preparative HPLC using water/methanol as eluent to give the desired product (0.018g, 14% yield).
LCMS(ESI)554(M+H)；1HNMR (400MHz, methanol-d)4)ppm1.28-1.37(m，2H)1.84(quin，J=6.87Hz，2H)2.04(quin，J=7.59Hz，2H)2.31-2.44(m，5H)3.11-3.21(m，4H)3.36(td，J=6.83,3.17Hz，4H)3.48(t，J=7.05Hz，2H)4.18(s，1H)6.88(d，J=3.61Hz，1H)6.99-7.08(m，1H)7.17-7.31(m，4H)7.39(d，J=8.30Hz，1H)7.63(dd，J=8.27,2.07Hz，1H)8.71(d，J=2.00Hz，1H)。
The following compounds were prepared according to scheme 6:
furan-2, 5-dicarboxylic acid 2-amide 5- { [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -amide was prepared according to the following procedure]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]-amide } (compound No. 216): 5-bromo-furan-2-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amides (0.1g, 0.164mmol), Zn (CN)2(0.038g, 0.33mmol) and Zn (2.1mg, 0.033mmol) were dissolved in DMA (5.0mL) and the solution degassed for 5 minutes. Adding Pd (t-Bu)3P)2(8.0mg, 0.016mmol), the solution is degassed again and purged with nitrogen. The reaction mixture was stirred for 5 hours at 85 ℃ in the presence of nitrogen. Cooled and dissolved in methanol and purified by preparative HPLC using water/methanol as eluent to give intermediate nitrile (0.07g, 79%). The nitrile (0.05g, 0.09mmol) was dissolved in DMSO (2.0mL), and K was added2CO3(0.074mg, 0.54mmol) and H was added2O2(0.031g, 0.27mmol) and the reaction mixture stirred at room temperature for 4 hours. LC-MS showed the reaction was complete. Water (2.0mL) was added to yield the product. Filtration and drying gave the desired product (0.025g, 47%).
LCMS(ESI)573(M+H)；1HNMR(400MHz，DMSO-d6)ppm1.66(quin，J=6.97Hz，2H)1.88(quin，J=7.53Hz，2H)2.15-2.21(m，2H)2.25(s，3H)3.04(s，8H)3.15-3.22(m，4H)3.31(t，J=6.98Hz，2H)6.84-6.97(m，1H)7.07-7.16(m，3H)7.23(d，J=3.61Hz，1H)7.29-7.34(m，2H)7.64(dd，J=8.42,1.98Hz，2H)8.09(brs，1H)8.36(t，J=5.64Hz，1H)8.42(d，J=2.00Hz，1H)9.68(s，1H)。
Example 7: synthetic route to furan-2-carboxylic acid {2- [4- (2-methyl-benzyl) -piperazin-1-yl ] -5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -phenyl } -amide
Scheme 7
Steps 1,2,3 and 4
The reaction was carried out according to a procedure similar to compound No. 11.
Step 5 and step 6
To furan-2-carboxylic acid {5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl]-2-piperazin-1-yl-phenyl } -amide (0.1g, 0.23mmol) in acetonitrile (3.0mL) and DMF (0.5mL) K was added2CO3(0.094g, 0.68mmol) and 1-bromomethyl-2-methyl-benzene (0.05g, 0.3mmol), the reaction mixture was stirred at room temperature for 4 hours. Water was added, extracted with DCM, concentrated and the crude product was purified on silica gel using DCM/methanol (10%) as eluent to give the product (0.027g, 22% yield).
LCMS(ESI)544(M+H)；1HNMR (400MHz, methanol-d 4) ppm1.85(t, J =6.88Hz, 2H)2.00-2.11(m, 2H)2.38(d, J =8.25Hz, 2H)2.42(s, 3H)2.73(brs, 4H)2.98(t, J =4.73Hz, 4H)3.34-3.41(m, 4H)3.50(t, J =7.10Hz, 2H)3.62(s, 2H)6.71(dd, J =3.56,1.76Hz, 1H)7.10-7.19(m, 4H)7.26-7.31(m, 2H)7.32(d, J =8.35Hz, 1H)7.61(dd, J =8.32,2.12Hz, 1H)7.82 (J = 8.68, 1H)7.68 (dd, 2H) 1.71Hz, 1H).
The following compounds were prepared according to scheme 7:
preparation of 4- {2- [ (furan-2-carbonyl) -amino ] -amino-acid following the same procedure as in Compound No. 11]-4- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl]-phenyl } -piperazine-1-carboxylic acid ethyl ester (compound No. 62).
LCMS(ESI)512(M+H)；1HNMR (400MHz, methanol-d 4) ppm1.28(t, J =7.10Hz, 3H)1.85(t, J =6.91Hz, 2H)2.01-2.11(m, 2H)2.36-2.43 (H) ((m, 2H))m，2H)2.91-2.99(m，4H)3.34-3.41(m，4H)3.50(t，J=7.08Hz，2H)3.71(brs，4H)4.16(q，J=7.08Hz，2H)6.68(dd，J=3.54,1.78Hz，1H)7.29(dd，J=3.56，0.68Hz，1H)7.33(d，J=8.35Hz，1H)7.63(dd，J=8.32,2.12Hz，1H)7.81(dd，J=1.73，0.71Hz，1H)8.69(d，J=2.05Hz，1H)。
The reaction sequence described for Synthesis of Compound No. 175 was followed from 4-o-tolyl-piperidine and 4-fluoro-3-nitro-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]Preparation of 5-methyl-furan-2-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl group by reaction with benzamide]-2- (4-o-tolyl-piperidin-1-yl) -phenyl]Amide (compound No. 165).
LCMS(ESI)543(M+H)；1HNMR (400MHz, methanol-d)4)ppm1.83(quin，J=6.91Hz，2H)1.88-1.95(m，2H)1.99-2.09(m，4H)2.13(s，1H)2.34-2.40(m，5H)2.42(s，3H)2.92-3.02(m，3H)3.18(d，J=11.18Hz，2H)3.32(s，1H)3.36(td，J=6.87,3.88Hz，4H)3.48(t，J=7.08Hz，2H)6.28(dd，J=3.37，0.68Hz，1H)7.01-7.20(m，4H)7.34(d，J=8.35Hz，2H)7.59(dd，J=8.30，2.10Hz，1H)8.73(d，J=2.05Hz，1H)。
Synthesis of Compound No. 175 from 1- (2-fluoro-phenyl) -piperazine and-fluoro-3-nitro-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]-benzamide reaction to produce 5-methyl-furan-2-carboxylic acid {2- [4- (2-fluoro-phenyl) -piperazin-1-yl]-5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl]-phenyl } -amide (compound No. 130).
LCMS(ESI)548(M+H)；1HNMR (400MHz, methanol-d 4) ppm1.84(t, J =6.91Hz, 2H)2.00-2.09(m, 2H)2.35(s, 1H)2.37-2.41(m, 4H)3.11-3.16(m, 4H)3.30-3.40(m, 8H)3.48(t, J =7.08Hz, 2H)6.28(dd, J =3.39, 0.95Hz, 1H)6.94-7.09(m, 2H)7.09-7 (m, 2H).12(m，2H)7.15(d，J=3.47Hz，1H)7.38(d，J=8.30Hz，1H)7.61(dd，J=8.30，2.10Hz，1H)8.70(d，J=2.10Hz，1H)。
Synthesis of Compound No. 175 from 1- (2-methoxy-phenyl) -piperazine and 4-fluoro-3-nitro-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]-benzamide reaction to produce 5-methyl-furan-2-carboxylic acid {2- [4- (2-methoxy-phenyl) -piperazin-1-yl]-5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl]Phenyl } -amide (compound No. 173).
LCMS(ESI)560(M+H)；1HNMR (400MHz, dichloromethane-d 2) ppm1.76(t, J =6.03Hz, 2H)1.99-2.09(m, 2H)2.36-2.43(m, 5H)3.10-3.15(m, 4H)3.25-3.44(m, 10H)3.87(s, 3H)6.20(dd, J =3.37, 0.98Hz, 1H)6.89-7.05(m, 4H)7.11(d, J =3.32Hz, 1H)7.33(d, J =8.25Hz, 1H)7.64(dd, J =8.25Hz, 2H)8.87(d, J =2.10Hz, 1H)9.46(s, 1H).
The reaction sequence described for synthetic compound No. 175 was followed from 1-phenyl-piperazine, 1- (2-fluoro-phenyl) -piperazine and 4-fluoro-3-nitro-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]Preparation of 5-methyl-furan-2-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl group by reaction with benzamide]-2- (4-phenyl-piperazin-1-yl) -phenyl]Amide (compound No. 167).
LCMS(ESI)530(M+H)；1HNMR (400MHz, methanol-d 4) ppm1.89(t, J =6.96Hz, 2H)2.05-2.14(m, 2H)2.39(s, 3H)2.40-2.45(m, 2H)3.15-3.20(m, 4H)3.38-3.48(m, 8H)3.54(t, J =7.08Hz, 2H)6.32(dd, J =3.42, 0.98Hz, 1H)6.91(t, J =7.35Hz, 1H)7.08(d, J =7.91Hz, 2H)7.20(d, J =3.12Hz, 1H)7.27-7.33(m, 2H)7.41(d, J =8.30Hz, 1H)7.66(dd, J =8.10, 1H) 8.05 (d, 1H).
Preparation of 5-methyl-furan-2-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] methyl ester according to the following procedure]-2- (4-o-tolyl- [1, 4)]Diazepan-1-yl) -phenyl]-amide (compound No. 194): in a microwave glass tube, Pd (OAc)2(33.6mg, 0.15mmol) and X-PHOS (71.4mg, 0.15mmol) were dissolved in t-butanol: a mixture (4.0mL) of toluene (1: 5) was stirred. The solution was evacuated for 5 minutes and purged with nitrogen. Adding [1,4 ]]Diazepan-1-carboxylic acid tert-butyl ester (0.2g, 1.0mmol) and 1-bromo-2-methyl-benzene (0.255mg, 1.5mmol), evacuated and purged with nitrogen. The mixture was stirred at 140 ℃ for 30 minutes under microwave conditions. The reaction was cooled, concentrated on celite, purified on silica gel using CH2Cl2Methanol (10%) as eluent to obtain intermediate product 4-o-tolyl- [1, 4%]Diazepan-1-carboxylic acid tert-butyl ester (0.15g, 51%). The intermediate product is dissolved in CH2Cl2(2.0mL) was stirred with trifluoroacetic acid (1.0mL) for 16 hours. The reaction mixture was concentrated, and the crude product, 1-o-tolyl- [1,4, was used in the same manner as in Compound No. 11]Diazepane.
LCMS(ESI)558(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm1.67-1.81(m，3H)1.96-2.17(m，4H)2.30-2.41(m，8H)3.22-3.44(m，13H)6.19(d，J=2.64Hz，1H)6.94(s，1H)7.06-7.21(m，4H)7.31(d，J=8.30Hz，1H)7.51-7.65(m，2H)8.87(d，J=2.05Hz，1H)9.55(s，1H)。
Starting from 2- (1-methyl-1H-imidazol-4-yl) -ethylamine and 3- [ (2-cyclopropyl-oxazole-4-carbonyl) -amino]Preparation of 2-cyclopropyl-oxazole-4-carboxylic acid [5- [2- (1-methyl-1H-imidazol-4-yl) -ethylcarbamoyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amides of the above starting materials 3- [ (2-cyclopropyl-oxazole-4-carbonyl) -amino group mediated by LiOH]-4- (4-o-tolyl-piperazine-1-yl) -benzoic acid methyl ester and HATU amide coupling using the desired amine.
LCMS(ESI)554(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm1.06-1.19(m，4H)2.10(s，1H)2.35(s，3H)2.80(t，J=6.22Hz，2H)3.06-3.20(m，8H)3.59-3.69(m，5H)6.75(s，1H)7.01(dd，J=7.27,1.66Hz，1H)7.14-7.23(m，3H)7.29(d，J=8.25Hz，1H)7.43(s，1H)7.61(dd，J=8.22,2.12Hz，1H)7.66-7.77(m，1H)8.13(s，1H)8.87(d，J=2.05Hz，1H)9.94(brs，1H)。
Starting from N- (4-amino-butyl) -acetamide and 3- [ (2-cyclopropyl-oxazole-4-carbonyl) -amino]Preparation of 2-cyclopropyl-oxazole-4-carboxylic acid [5- [2- (1-methyl-1H-imidazol-4-yl) -ethylcarbamoyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amides of the above starting materials 3- [ (2-cyclopropyl-oxazole-4-carbonyl) -amino group mediated by LiOH]-4- (4-o-tolyl-piperazin-1-yl) -benzoic acid methyl ester hydrolysis and HATU amide coupling using the desired amine.
LCMS(ESI)559(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm1.07-1.18(m，4H)1.53-1.70(m，4H)2.00(s，3H)2.05-2.15(m，1H)2.37(s，3H)3.09-3.24(m，8H)3.30(q，J=6.36Hz，2H)3.43-3.51(m，2H)6.22-6.47(m，1H)6.68(brs，1H)6.97-7.35(m，5H)7.61(dd，J=8.22,2.07Hz，1H)8.12(s，1H)8.82(d，J=2.05Hz，1H)9.94(s，1H)。
Example 8: synthetic route to 2-cyclopropyl-oxazole-4-carboxylic acid [5- [3- (2-methyl-5-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
Scheme 8
Step 1
To a frozen solution of NaH (0.505g, 12.6mmol) in DMF (20mL) was slowly added 5-methyl-pyrrolidin-2-one (1.0g, 10.1mmol) in DMF (10.0 mL). Stirring at 0-25 deg.C for 30 min. 2- (3-bromo-propyl) -isoindole-1, 3-dione (2.47g, 9.0mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Adding saturated NH4Cl solution (10.0mL) was extracted with ethyl acetate. The organic layer was washed with LiCl solution and concentrated. The crude product was purified on silica gel using CH2Cl2Methanol (10%) as eluent to give 2- [3- (3-methyl-2-oxo-pyrrolidin-1-yl) -propyl]-isoindole-1, 3-dione (1.2g, 41%).
Step 2
2- [3- (3-methyl-2-oxo-pyrrolidin-1-yl) -propyl]-isoindole-1, 3-dione (0.5g, 1.74mmol) was dissolved in a mixture of THF/methanol (3.0mL/3.0 mL). Adding hydrazine hydrate (0.44)g8.7mmol) and the reaction stirred at 50 ℃ for 16 h. The precipitate is filtered off and the filtrate is concentrated to give the product 1- (3-amino-propyl) -5-methyl-pyrrolidin-2-one (0.12)g，45%)。
Step 3
1- (3-amino-propyl) -5-methyl-pyrrolidin-2-one was coupled with 3- [ (2-cyclopropyl-oxazole-4-carbonyl) -amino ] -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid following HATU coupling procedure.
LCMS(ESI)585(M+H)；1HNMR (400MHz, dichloromethane-d)2)ppm1.06-1.17(m，4H)1.25(d，J=6.30Hz，3H)1.56-1.69(m，1H)1.72-1.83(m，2H)2.09(s，1H)2.18-2.30(m，1H)2.39(s，3H)2.42(d，J=8.05Hz，2H)3.11-3.29(m，10H)3.49-3.63(m，2H)3.73(d，J=6.78Hz，1H)7.01-7.10(m，1H)7.16-7.27(m，3H)7.31(d，J=8.30Hz，1H)7.64-7.78(m，2H)8.15(s，1H)8.87(d，J=2.00Hz，1H)9.94(brs，1H)。
General procedure for HATU coupling:
the following compounds were prepared according to scheme 8:
following the same procedure as compound No. 258 from 3- [ (furan-2-carbonyl) -methyl-amino]Preparation of furan-2-carboxylic acid methyl- [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -4- (4-o-tolyl-piperazin-1-yl) benzoic acid]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]Amide (compound No. 169).
LCMS(ESI)544(M+H)；1HNMR (400MHz, methanol-d 4) ppm1.84(t, J =6.81Hz, 2H)2.08(d, J =7.52Hz, 2H)2.41(t, J =8.10Hz, 2H)2.79-2.98(m, 4H)3.06-3.18(m, 2H)3.37(q, J =7.08Hz, 4H)3.49(t, J =7.08Hz, 4H)6.03-6.18(m, 1H)6.24-6.34(m, 1H)6.94(d, J =0.78Hz, 1H)7.04(d, J =0.73Hz, 1H)7.15(t, J =7.88Hz, 3H)7.42(s, 1H)7.77(d, J =2.20, 1H)7.84(d, J =8.44 Hz, 8H).
Following the same procedure as compound No. 258 from 3- [ (furan-2-carbonyl) -methyl-amino]Preparation of 2-cyclopropyl-oxazole-4-carboxylic acid [5- [2- (3H-imidazol-4-yl) ethylcarbamoyl ] -4- (4-o-tolyl-piperazin-1-yl) benzoic acid]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS(ESI)540(M+H)；1HNMR(400MHz，DMSO-d6)ppm1.06(s，2H)1.14(s2H)2.20(s，1H)2.32(s，3H)2.84(s，2H)3.05(brs，4H)3.08-3.21(m，4H)3.51(s，2H)7.0(s，1H)7.16(s，2H)7.18-7.29(m，2H)7.42(s，1H)7.56(s，1H)8.29(s，1H)8.54(s，1H8.67(s，1H)8.79(s，1H)9.92(s，1H)
Following the same procedure as compound No. 258 from 3- [ (furan-2-carbonyl) -methyl-amino]Preparation of 2-methyl-thiazole-4-carboxylic acid [5- [2- (3H-imidazol-4-yl) -ethylcarbamoyl ] -4- (4-o-tolyl-piperazin-1-yl) benzoic acid]-2- (4-o-tolyl-piperazin-1-yl) -phenyl]-an amide.
LCMS(ESI)530(M+H)；1HNMR(400MHz，DMSO-d6)ppm2.31(s，3H)2.77(s，3H)2.80-2.90(m，2H)3.08(brs，4H)3.11-3.23(m，4H)3.47-3.61(m，2H)6.93-7.07(m，1H)7.12(s，2H)7.18-7.27(m，2H)7.36-7.48(m，1H)7.53-7.64(m，1H)8.15-8.24(m，1H)8.33(s，1H)8.47-8.60(m，1H)8.84(d，J=2.00Hz，1H)10.37-10.48(m，1H)。
Following the same procedure as compound No. 258 from 3- [ (furan-2-carbonyl) -methyl-amino]Preparation of 3- (cyclopropanecarbonyl-amino) -N- [2- (3H-imidazol-4-yl) -ethyl 44-o-tolylpiperazin-1-yl-benzamide from (4-o-tolyl-piperazin-1-yl) benzoic acid
LCMS(ESI)473(M+H)；1HNMR(400MHz，DMSO-d6)ppm0.70-0.88(m，4H)1.96-2.12(m，1H)2.30(s，3H)2.69-2.80(m，2H)3.07(d，J=7.42Hz，8H)3.37-3.56(m，2H)6.94-7.02(m，1H)7.07-7.14(m，1H)7.15-7.21(m，2H)7.21-7.27(m，1H)7.49-7.56(m，1H)7.55-7.64(m，1H)8.20-8.32(m，1H)8.38-8.52(m，1H)9.17-9.29(m，1H)。
Preparation of 3- [ (5-methyl-furan-2-carbonyl) -amino ] amino following the same procedure as the intermediate aniline of compound No. 40]-4- (4-m-tolyl-piperazin-1-yl) -benzoic acid 3- (2-oxo-pyrrolidin-1-yl) -propyl ester (compound No. 243).
LCMS(ESI)544(M+H)；1HNMR (400MHz, chloroform-d) ppm1.82(s，2H)2.08(d，J=7.56Hz，2H)2.36(d，J=1.90Hz，6H)2.45(t，J=8.10Hz，2H)3.05-3.18(m，4H)3.30-3.48(m，10H)6.17(dd，J=3.34，0.95Hz，1H)6.84(brs，2H)7.11-7.30(m，4H)7.45-7.59(m，1H)7.71(d，J=2.10Hz，1H)8.96(d，J=2.05Hz，1H)9.38(s，1H)。
Preparation of 3- [ (5-methyl-furan-2-carbonyl) -amino ] amino following the same procedure as the intermediate aniline of compound No. 40]-4- [4- (2-trifluoromethyl-phenyl) -piperazin-1-yl]-benzoic acid 3- (2-oxo-pyrrolidin-1-yl) -propyl ester (compound No. 246).
LCMS(ESI)598(M+H)；1HNMR (400MHz, chloroform-d) ppm1.82(t, J =6.25Hz, 2H)1.98-2.15(m, 2H)2.35-2.52(m, 5H)3.04-3.14(m, 4H)3.15-3.25(m, 4H)3.28-3.51(m, 6H)6.21(dd, J =3.37, 0.88Hz, 1H)7.17(d, J =3.37Hz, 1H)7.28-7.34(m, 2H)7.44(d, J =7.96Hz, 2H)7.58(s, 1H)7.64-7.78(m, 2H)8.96(d, J =2.05Hz, 1H)9.46(s, 1H)19FNMR (376MHz, chloroform-d) ppm-60.77(s, 3F).
Preparation of 4- [4- (2, 6-dimethyl-phenyl) -piperazin-1-yl following the same procedure as for the intermediate aniline of compound No. 40]-3- [ (5-methyl-furan-2-carbonyl) -amino]-benzoic acid 3- (2-oxo-pyrrolidin-1-yl) -propyl ester.
LCMS(ESI)558(M+H)；1HNMR (400MHz, chloroform-d) ppm1.81-1.88(m, 2H)2.07(quin, J =7.58Hz, 2H)2.33-2.51(m, 12H)3.05(t, J =4.54Hz, 4H)3.36(brs, 4H)3.40-3.53(m, 6H)6.20(dd, J =3.37, 0.93Hz, 1H)6.94-7.09(m, 2H)7.18(d, J =3.37Hz, 1H)7.31(d, J =8.30Hz, 1H)7.53(t, J =6.10Hz, 1H)7.73(dd, J =8.25,2.10Hz, 1H)8.99(d, J =2.05Hz, 1H)9.48(s, 1H).
Preparation of 3- [ (2-cyclopropyl-oxazole-4-carbonyl) -amino ] according to the same procedure as intermediate aniline of compound No. 40 (HATU coupling of 2-cyclopropyl-1, 3-oxazole-4-carboxylic acid substituted acid chloride)]-4- (4-m-tolyl-piperazin-1-yl) -benzoic acid 3- (2-oxo-pyrrolidin-1-yl) -propyl ester (compound No. 249).
LCMS(ESI)571(M+H)；1HNMR (400MHz, chloroform-d) ppm0.94-1.14(m, 4H)1.81(quin, J =6.21Hz, 2H)1.95-2.15(m, 3H)2.36(s, 3H)2.45(t, J =8.10Hz, 2H)2.96-3.20(m, 4H)3.27-3.53(m, 10H)6.75(d, J =7.32Hz, 1H)6.80-6.92(m, 2H)7.11-7.26(m, 2H)7.61(t, J =6.05Hz, 1H)7.73(dd, J =8.25,2.00Hz, 1H)8.13(s, 1H)8.97(d, J =1.95, 1H)9.88(s, 1H).
Preparation of 3- [ (2-cyclopropyl-oxazole-4-carbonyl) -amino ] according to the same procedure as intermediate aniline of compound No. 40 (HATU coupling of 2-cyclopropyl-1, 3-oxazole-4-carboxylic acid substituted acid chloride)]-4- [4- (2-trifluoromethyl-phenyl) -piperazin-1-yl]-benzoic acid-3- (2-oxo-pyrrolidin-1-yl) -propyl ester (compound No. 250).
LCMS(ESI)625(M+H)；1HNMR (400MHz, chloroform-d) ppm1.05-1.29(m, 4H)1.82(s, 2H)2.07(s, 3H)2.38-2.52(m, 2H)3.02-3.12(m, 4H)3.21(d, J =3.95Hz, 4H)3.43(t, J =6.20Hz, 6H)7.29(d, J =8.35Hz, 2H)7.54(s, 3H)7.64-7.78(m, 2H)8.15(s, 1H)8.99(d, J =2.00Hz, 1H)9.85-9.97(m, 1H)19FNMR (376MHz, chloroform-d) ppm-60.76(s, 3F).
Preparation of 3- [ (2-cyclopropyl-oxazole-4-carbonyl) -amino ] according to the same procedure as intermediate aniline of compound No. 40 (HATU coupling of 2-cyclopropyl-1, 3-oxazole-4-carboxylic acid substituted acid chloride)]-4- [4- (2, 6-dimethyl-phenyl) -piperazin-1-yl]-benzoic acid 3- (2-oxo-pyrrolidin-1-yl) -propaneAnd (3) an ester.
LCMS(ESI)585(M+H)；1HNMR (400MHz, chloroform-d) ppm1.02-1.24(m, 4H)1.74-1.88(m, 2H)2.07(s, 3H)2.31-2.52(m, 8H)3.04(t, J =4.54Hz, 4H)3.29-3.51(m, 10H)6.93-7.10(m, 3H)7.30(s, 1H)7.48-7.59(m, 1H)7.68-7.80(m, 1H)8.14(s, 1H)9.01(d, J =2.10Hz, 1H)9.82-9.94(m, 1H).
Preparation of 3- [ (2-cyclopropyl-oxazole-4-carbonyl) -amino ] according to the same procedure as intermediate aniline of compound No. 40 (HATU coupling of 2-cyclopropyl-1, 3-oxazole-4-carboxylic acid substituted acid chloride)]-4- [4- (4-fluoro-2-methyl-phenyl) -piperazin-1-yl]-benzoic acid-3- (2-oxo-pyrrolidin-1-yl) -propyl ester.
LCMS(ESI)589(M+H)；1HNMR (400MHz, chloroform-d) ppm1.00-1.23(m, 4H)1.81(quin, J =6.22Hz, 2H)1.96-2.17(m, 3H)2.36(s, 3H)2.40-2.49(m, 2H)2.95-3.20(m, 8H)3.31-3.49(m, 6H)6.80-6.99(m, 2H)7.12(dd, J =8.71,5.30Hz, 1H)7.28(s, 1H)7.64(t, J =6.05Hz, 1H)7.73(dd, J =8.27,2.07Hz, 1H)8.13(s, 1H)8.97(d, J =2.05Hz, 1H)9.94(s, 1H)19FNMR (376MHz, chloroform-d) ppm-120.69(td, J =8.74,5.28Hz, 1F).
Preparation of 4- [4- (2-bromo-phenyl) -piperazin-1-yl following the same procedure as the intermediate aniline of compound No. 40 (HATU coupling of 2-cyclopropyl-1, 3-oxazole-4-carboxylic acid instead of acid chloride)]-3- [ (2-cyclopropyl-oxazole-4-carbonyl) -amino]-benzoic acid 3- (2-oxo-pyrrolidin-1-yl) -propyl ester.
LCMS(ESI)635(M+H)；1HNMR (400MHz, chloroform-d) ppm1.00-1.23(m, 4H)1.81(quin, J =6.22Hz, 2H)1.92-2.15(m, 3H)2.45(t, J =8.10Hz, 2H)3.14(t, J =4.42Hz, 4H)3.32(brs, 4H)3.38-3.47(m, 6H)6.97(td, J =7.61,1.46Hz, 1H)7.19(dd, J =8.00, 1.32Hz, 1H)7.28-7.38(m, 2H)7.55-7.65(m，2H)7.74(dd，J=8.27,2.07Hz，1H)8.13(s，1H)8.97(d，J=1.95Hz，1H)9.95(s，1H)。
According to the reaction with furan-2-carboxylic acid {2- [4- (2-methyl-benzyl) -piperazin-1-yl]-5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl]Intermediate of phenyl } -amide piperazine same procedure was used to prepare 3- [ (5-methyl-furan-2-carbonyl) -amino]-4- [4- (2-nitro-phenyl) -piperazin-1-yl]-benzoic acid 3- (2-oxo-pyrrolidin-1-yl) -propyl ester.
LCMS(ESI)575(M+H)1HNMR (400MHz, chloroform-d) ppm1.81(quin, J =6.25Hz, 2H)2.03-2.13(m, 3H)2.29-2.49(m, 5H)3.05-3.17(m, 4H)3.25-3.36(m, 4H)3.37-3.49(m, 5H)6.11-6.25(m, 1H)7.05-7.28(m, 4H)7.46-7.60(m, 2H)7.71(dd, J =8.25,2.00Hz, 1H)7.81(dd, J =8.13,1.29Hz, 1H)8.95(d, J =1.95Hz, 1H)9.39(s, 1H).
Example 9: synthetic route for thiophene-3-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
To 3-amino-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl]A suspension of (E) -4- (4-o-tolyl-piperazin-1-yl) -benzamide (0.1g, 0.229mmol) in dichloromethane (5ml) was added triethylamine (0.069g, 0.489mmol), thiophene-3-carboxylic acid (0.044g, 0.344mmol) and 1-propylphosphoric anhydride (0.21g, 0.489 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and extracted with dichloromethane (10ml x 1). The organic layer was washed with water (10ml X2) and dried over anhydrous sodium sulfate. The organic layer was concentrated and the crude product obtained was purified by flash silica gel column chromatography to give (0.34g, 34%) the title compound as a brown solid.
LCMS: found (M + 546.3).
The method comprises the following steps: a-0.1% TFA in water, B-0.1% TFA in ACN at a flow rate of-2 ml/min.
Column: XBridgeC8(50x4.6mm, 3.5 μm), positive ion mode.
Rt (min): 4.17,% area: 97.91(Max), 98.87(254 nm).
1HNMR(400MHz，CDCl3)9.4(s，1H)，8.9(s，1H)，8.10(s，1H)，7.77(dd，J=1.52，6.68Hz，1H)，7.69(s，1H)，7.57(d，J=4.2Hz，1H)，7.44(dd，J=3.0，8.04Hz，1H)，7.37(d，J=8.28Hz，1H)，7.25(t，J=5.36Hz，2H)，7.22-7.13(m，1H)，7.07-7.03(m，1H)，3.45-3.40(m，6H)，3.16(m，8H)，2.47((t，J=7.92Hz，2H)，2.36(s，3H)，2.11-2.03(m，2H)，1.83(t，J=6.08Hz，2H)。
The following compounds were prepared in a similar manner, unless otherwise indicated. LCMS and HPLC analysis were performed as follows: the method comprises the following steps: a-aqueous 0.1% TFA, B-ACN 0.1% TFA at a flow rate of-2 ml/min; column: XBridgeC8(50x4.6mm, 3.5 μm), positive ion mode.
2-bromo-thiazole-5-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 25.1 percent.
Color and appearance: a white solid.
LCMS: found (M + 625.0).
Rt (min): 4.26,% area: 95.75(Max), 95.35(254 nm).
1HNMR(400MHz，CDCl3)9.38(s，1H)，8.83(s，1H)，8.17(s，1H)，7.81(d，J=8.08Hz，1H)7.74(s，1H)，7.41(d，J=8.36Hz，1H)，7.24(d，J=7.32Hz，2H)，7.16(d，J=7.68Hz，1H)，7.09(t，J=7.28Hz，1H)，3.45-3.40(m，6H)，3.21(m，8H)，2.49(t，J=7.88Hz，2H)，2.38(s，3H)，2.10(t，J=7.64Hz，2H)，1.82(t，J=5.4Hz，2H)。
3- (3-methyl-butyrylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 23.4 percent.
Color and appearance: a white solid.
LCMS: found (M + 520.3).
Rt (min): 4.26,% area: 97.85(Max), 98.03(254 nm).
1HNMR(400MHz，CDCl3)8.75(s，2H)，7.74(d，J=8.16Hz，1H)，7.58(s，1H)，7.34(d，J=8.16Hz，1H)7.25(t，J=7.32Hz，2H)，7.16(d，J=7.84Hz，1H)，7.09(t，J=7.64Hz，1H)，3.44-3.38(m，6H)，3.21(m，8H)，2.46(t，J=7.92Hz，2H)，2.38(s，3H)，2.35(t，J=6.8Hz，2H)，2.28-2.25(m，1H)，2.11-2.02(m，2H)，1.83-1.79(m，2H)，1.11(d，6H)。
3-benzoylamino-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 53.4 percent.
Color and appearance: a white solid.
LCMS: found (M + 540.3).
Rt (min): 4.35,% area: 95.75(Max), 98.12(254 nm).
1HNMR(400MHz，CDCL3)9.38(s，1H)，9.04(s，1H)，7.98(dd，J=1.12,7.84Hz，2H)，7.76(dd，J=2.04,8.24Hz，1H)7.58-7.51(m，4H)，7.36(d，J=8.28Hz，1H)，7.24(t，J=7.44Hz，2H)，7.09-7.02(m，2H)，3.45-3.41(m，6H)，3.12(m，8H)，2.47(t，J=7.92Hz，2H)，2.36(s，3H)，2.09(m，2H)，1.84(t，J=6.24Hz，2H)。
3- (3-chloro-benzoylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 34.1 percent.
Color and appearance: a white solid.
LCMS: found (M + 574.3).
Rt (min): 4.72,% area: 96.54(Max), 97.81(254 nm).
1HNMR(400MHz，CDCL3)9.46(s，1H)，9.00(s，1H)，8.00(s，1H)，7.86(d，J=7.52Hz，1H)7.77(d，J=8.12Hz，1H)，7.61(m，1H)，7.56(d，J=7.88Hz，1H)，7.49(t，J=7.8Hz，1H)，7.38(d，J=8.24Hz，1H)，7.24(t，J=7.0Hz，2H)，7.13(d，J=8.12Hz，1H)，7.07(t，J=7.36Hz，1H)，3.45-3.43(m，6H)，3.15(m，8H)，2.48-2.44(m，2H)，2.37(s，3H)，2.12-2.04(m，2H)，1.85-1.79(m，2H)。
3- (4-chloro-benzoylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 44.7 percent.
Color and appearance: a white solid.
LCMS: found (M + 574.3).
Rt (min): 4.75,% area: 98.33(Max), 98.98(254 nm).
1HNMR(400MHz，CDCL3)9.61(s，1H)，8.90(s，1H)，7.98(d，J=7.04Hz，2H)，7.81(d，J=7.72Hz，1H)7.73(s，1H)，7.52(d，J=8.28Hz，2H)，7.41(d，J=8.16Hz，1H)，7.23(d，J=5.16Hz，2H)，7.13(d，J=8.12Hz，1H)，7.08(t，J=7.32Hz，1H)，3.45-3.41(m，6H)，3.22(m，8H)，2.48(t，J=8.00Hz，2H)，2.37(s，3H)，2.12-2.04(m，2H)，1.85-1.79(m，2H)。
3- (3-fluoro-benzoylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 23.5 percent.
Color and appearance: a brown solid.
LCMS: found (M + 558.3).
Rt (min): 4.46,% area: 95.23(Max), 97.78(254 nm).
1HNMR(400MHz，CDCL3)9.5(s，1H)，8.97(s，1H)，7.79-7.68(m，4H)，7.54-7.48(m，1H)7.39(d，J=8.28Hz，1H)，7.30(d，J=1.84Hz，1H)，7.25(t，J=4.36Hz，2H)，7.13(d，J=7.84Hz，1H)，7.08(t，J=7.48Hz，1H)，3.46-3.41(m，6H)，3.17(m，8H)，2.48(t，J=7.92Hz，2H)，2.37(s，3H)，2.12-2.05(m，2H)，1.84(t，J=6.2Hz，2H)。
3- (4-fluoro-benzoylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 39.1 percent.
Color and appearance: a white solid.
LCMS: found (M + 558.3).
Rt (min): 4.45,% area: 94.80(Max), 96.67(254 nm).
1HNMR(400MHz，CDCl3)9.31(s，1H)，9.01(d，J=2.0Hz，1H)，7.99-7.96(m，2H)，7.76(dd，J=2.08,8.28Hz，1H)7.63(t，J=6.04Hz，1H)，7.36(d，J=8.28Hz，1H)，7.23-7.21(m，4H)，7.09-7.03(m，2H)，3.45-3.41(m，6H)，3.3.11(m，8H)，2.48(t，J=7.92Hz，2H)，2.36(s，3H)，2.11-2.06(m，2H)，1.85-1.80(m，2H)。
3- (3-cyano-benzoylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 23.8 percent.
Color and appearance: a brown solid.
LCMS: found (M + 565.3).
Rt (min): 4.16,% area: 97.43(Max), 98.93(254 nm).
1HNMR(400MHz，CDCL3)9.49(s，1H)，8.97(s，1H)，8.32(s，1H)，8.21(s，1H)7.87(d，J=7.68Hz，1H)，7.81(s，1H)，7.69(t，J=7.8Hz，1H)，7.41(d，J=8.32Hz，1H)，7.26-7.21(m，3H)，7.14(d，J=8.00Hz，1H)，7.07(t，J=7.24Hz，1H)，3.46-3.42(m，6H)，3.17(m，8H)，2.49(t，J=7.92Hz，2H)，2.36(s，3H)，2.13-2.07(m，2H)，1.83(t，J=5.68Hz，2H)。
3- (4-cyano-benzoylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 39.2 percent.
Color and appearance: a white solid.
LCMS: found (M + 565.3).
Rt (min): 4.20,% area: 96.63(Max), 96.91(254 nm).
1HNMR(400MHz，CDCL3)9.61(s，1H)，8.95(s，1H)，8.12(d，J=6.8Hz，2H)，7.85-7.81(m，4H)7.42(d，J=8.2Hz，1H)，7.25(d，J=5.04Hz，2H)，7.10(m，2H)，3.46-3.41(m，6H)，3.18(m，8H)，2.49(t，J=7.96Hz，2H)，2.36(s，3H)，2.11-2.07(m，2H)，1.83(t，J=5.36Hz，2H)。
3- (3-methyl-benzoylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 53.7 percent.
Color and appearance: a white solid.
LCMS: found (M + 554.3).
Rt (min): 4.66,% area: 95.87(Max), 97.22(254 nm).
1HNMR(400MHz，CDCL3)9.40(s，1H)，9.03(s，1H)，7.82(s，1H)，7.75(d，J=6.6Hz，2H)7.58(t，J=5.8Hz，1H)，7.43-7.34(m，3H)，7.24(t，J=7.36Hz，2H)，7.09-7.02(m，2H)，3.45-3.42(m，6H)，3.12(m，8H)，2.47-2.41(m，5H)，2.2.36(s，3H)，2.11-2.03(m，2H)，1.86-1.80(m，2H)。
3- (4-methyl-benzoylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 39.5 percent.
Color and appearance: a brown solid.
LCMS: found (M + 554.3).
Rt (min): 4.67, area%: 97.74(Max), 98.64(254 nm).
1HNMR(400MHz，CDCL3)9.38(s，1H)，8.99(s，1H)，7.89(d，J=8.08Hz，2H)，7.76(dd，J=1.92,8.24Hz，1H)7.55(s，1H)，7.36(t，J=8.4Hz，3H)，7.24-7.21(m，2H)，7.11(d，J=4.84Hz，1H)，7.09(t，J=11.2Hz，1H)，3.45-3.41(m，6H)，3.15(m，8H)，2.47-2.43(m，5H)，2.36(s，3H)，2.11-2.03(m，2H)，1.85-1.79(m，2H)。
Pyridine-2-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 69.4 percent.
Color and appearance: a brown solid.
LCMS: found (M + 541.3).
Rt (min): 4.23,% area: 96.20(Max), 96.53(254 nm).
1HNMR(400MHz，CDCL3)11.07(s，1H)，9.06(s，1H)，8.66(d，J=4.4Hz，1H)，8.35(d，J=4.4Hz，1H)，7.14(d，J=7.76Hz，1H)，7.94(d，J=6.32Hz，1H)，7.77(dd，J=1.92,6.36Hz，1H)，7.61(t，J=5.6Hz，1H)，7.50(t，J=4.76Hz，1H)，7.31-7.24(m，3H)，7.09(t，J=7.12Hz，1H)，3.46-3.43(m，6H)，3.28-3.21(m，8H)，2.48-2.41(m，5H)，2.09-2.04(m，2H)，1.86-1.80(m，2H)。
N- [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -nicotinamide
The yield is as follows: 42.0 percent.
Color and appearance: a white solid.
LCMS: found (M + 541.3).
Rt (min): 3.12,% area: 96.61(Max), 96.94(254 nm).
1HNMR(400MHz，CDCL3)9.52(s，1H)，9.21(s，1H)，9.00(s，1H)，8.81(d，J=3.68Hz，1H)，8.40(d，J=6.88Hz，1H)，7.81-7.75(m，2H)，7.80-7.75(m，1H)，7.55(d，J=4.68Hz，1H)，7.23-7.20(m，2H)，7.13(d，J=7.76Hz，1H)，7.06(t，J=7.92Hz，1H)，3.46-3.41(m，6H)，3.16(m，8H)，2.49(t，J=7.92Hz，2H)，2.36(s，3H)，2.10(t，J=7.52Hz，2H)，1.83(t，J=5.72Hz，2H)。
N- [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -isonicotinamide
The yield is as follows: 45.7 percent.
Color and appearance: a white solid.
LCMS: found (M + 541.3).
Rt (min): 3.02,% area: 97.96(Max), 98.48(254 nm).
1HNMR(400MHz，CDCL3)9.48(s，1H)，9.04(s，1H)，8.86(d，J=5.96Hz，2H)，7.81-7.77(m，3H)7.74(t，J=6.08Hz，1H)，7.39(d，J=8.32Hz，1H)，7.25-7.21(m，2H)，7.10-7.05(m，2H)，3.46-3.41(m，6H)，3.12(m，8H)，2.49(t，J=7.96Hz，2H)，2.36(s，3H)，2.12-2.07(m，2H)，1.83(t，J=6.04Hz，2H)。
N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -3- (3-trifluoromethyl-benzoylamino) -benzamide
The yield is as follows: 32.7 percent.
Color and appearance: a white solid.
LCMS: found (M + 608.3).
Rt (min): 4.98,% area: 98.14(Max), 99.10(254 nm).
1HNMR(400MHz，CDCL3)9.66(s，1H)，9.01(s，1H)，8.27-8.22(m，2H)，7.85-7.67(m，4H)7.41(d，J=8.24Hz，1H)，7.23(d，J=7.16Hz，2H)，7.12(d，J=8.0Hz，1H)，7.08(d，J=7.28Hz，1H)，3.46-3.43(m，6H)，317(m，8H)，2.49(t，J=8.0Hz，2H)，2.37(s，3H)，2.10(t，J=7.48Hz，2H)，1.84(t，J=6.08Hz，2H)。
N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -3- (4-trifluoromethyl-benzoylamino) -benzamide
The yield is as follows: 60.5 percent.
Color and appearance: a white solid.
LCMS: found (M + 608.3).
Rt (min): 5.00,% area: 99.07(Max), 98.92(254 nm).
1HNMR(400MHz，CDCL3)9.53(s，1H)，8.99(s，1H)，8.12(d，J=7.92Hz，2H)，7.81-7.78(m，3H)7.72(s，1H)，7.41(d，J=8.28Hz，1H)，7.25-7.22(m，2H)，7.11-7.03(m，2H)，3.46-3.41(m，6H)，3.17(m，8H)，2.48(t，J=7.92Hz，2H)，2.36(s，3H)，2.12-2.06(m，2H)，1.85-1.79(m，2H)。
3- (2-methoxy-benzoylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 60.5 percent.
Color and appearance: a white solid.
LCMS: found (M + 570.3).
Rt (min): 4.54,% area: 97.66(Max), 98.26(254 nm).
1HNMR(400MHz，CDCL3)10.46(s，1H)，8.86(s，1H)，8.34(dd，J=1.64,7.84Hz，1H)，7.75(dd，J=2.0，8.28Hz，1H)7.54(m，1H)，7.44(t，J=5.48Hz，1H)，7.30-7.28(m，3H)，7.24-7.17(m，1H)，7.10-7.05(m，3H)，4.13(s，3H)，3.45-3.41(m，6H)，3.20-3.18(m，8H)，2.46-2.42(t，J=7.96Hz，2H)，2.40(s，3H)，2.09(t，J=7.56Hz，2H)，1.84(t，J=6.2Hz，2H)。
3- (4-methoxy-benzoylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 21.1 percent.
Color and appearance: a white solid.
LCMS: found (M + 570.3).
Rt (min): 4.36,% area: 94.07(Max), 94.05(254 nm).
1HNMR(400MHz，CDCL3)9.45(s，1H)，8.94(s，1H)，7.99(d，J=7.8Hz，2H)，7.77(d，J=7.96Hz，1H)7.56(s，1H)，7.38(d，J=8.32Hz，1H)，7.24-7.21(m，2H)，7.13(d，J=8.0Hz，1H)，7.08-7.00(m，3H)，3.89(s，3H)，3.45-3.42(m，6H)，3.20(m，8H)，2.47(d，J=8.04Hz，2H)，2.37(s，3H)，2.11-2.04(m，2H)，1.85-1.79(m，2H)。
Naphthalene-2-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 16.2 percent.
Color and appearance: a white solid.
LCMS: found (M + 590.3).
Rt (min): 4.86,% area: 98.40(Max), 97.81(254 nm).
1HNMR(400MHz，CDCL3)9.61(s，1H)，9.07(s，1H)，8.54(s，1H)，8.04-7.92(m，4H)7.79(d，J=8.12Hz，1H)，7.67-7.57(m，3H)，7.39(d，J=8.32Hz，1H)，7.22(t，J=6.68Hz，2H)，7.11-7.07(m，2H)，3.45-3.43(m，6H)，3.18(m，8H)，2.48((t，J=7.92Hz，2H)，2.37(s，3H)，2.10(t，J=7.48Hz，2H)，1.85(t，J=5.92Hz，2H)。
Quinoline-8-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 50.4 percent.
Color and appearance: a brown solid.
LCMS: found (M + 591.3).
Rt (min): 4.33,% area: 95.24(Max), 97.34(254 nm).
1HNMR(400MHz，CDCL3)13.54(s，1H)，9.20(dd，J=1.8,4.28Hz，1H)，9.03(dd，J=1.52,7.4Hz，1H)，8.98(s，1H)8.36(dd，J=1.76,8.28Hz，1H)，8.06(dd，J=1.48,8.12Hz，1H)，7.78-7.77(m，2H)，7.76-7.75(m，1H)，7.58-7.55(m，1H)，7.31(m，1H)，7.29(m，2H)，7.19(m，2H)，3.46-3.42(m，6H)，3.23-3.14(m，8H)，2.46-2.42(t，J=7.92Hz，2H)，2.35(s，3H)，2.09-2.07(m，2H)，1.84(m，2H)。
4-methyl-thiazole-5-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 78 percent.
Color and appearance: a brown solid.
LCMS: found (M + 561.3).
Rt (min): 3.80,% area: 92.03(Max), 95.82(254 nm).
1HNMR(400MHz，CDCl3)9.17(s，1H)，8.93(s，1H)，8.78(s，1H)，7.76(dd，J=2.04,8.32Hz，1H)，7.61(s，1H)，7.40(d，J=8.28Hz，1H)，7.25(t，J=7.52Hz，2H)，7.13(d，J=7.72Hz，1H)，7.08(t，J=7.96Hz，1H)，3.46-3.40(m，6H)，3.17-3.15(m，8H)，2.89(s，3H)，2.47(t，J=7.96Hz，2H)，2.39(s，3H)，2.12-2.04(m，2H)，1.85-1.79(m，2H)。
2-methyl-4-trifluoromethyl-thiazole-5-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 11.7 percent.
Color and appearance: a white solid.
LCMS: found (M + 629.3).
Rt (min): 4.30,% area: 95.39(Max), 98.27(254 nm).
1HNMR(400MHz，CDCL3)9.28(s，1H)，8.83(s，1H)，7.79(dd，J=1.76,8.32Hz，1H)，7.6(s，1H)，7.41(d，J=8.28Hz，1H)，7.22(d，J=7.6Hz，2H)，7.07-7.01(m，2H)，3.45.3.40(m，6H)，3.06(m，8H)，2.79(s3H)，2.47(t，J=8.0Hz，2H)，2.36(s，3H)，2.12-2.04(m，2H)，1.83-1.80(m，2H)。
2-bromo-4-methyl-thiazole-5-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 15.2 percent.
Color and appearance: a white solid.
LCMS: found (M + 639.0).
Rt (min): 4.54,% area: 94.07(Max), 94.89(254 nm).
1HNMR(400MHz，CDCl3)9.09(s，1H)，8.90(s，1H)，7.77(dd，J=1.96,8.28Hz，1H)，7.63(t，J=5.52Hz，1H)，7.40(d，J=8.32Hz，1H)，7.25(t，J=5.96Hz，2H)，7.12(d，J=7.76Hz，1H)，7.08-7.04(m，1H)，3.45-3.40(m，6H)，3.14-3.12(m，8H)，2.83(s，3H)，2.47((t，J=7.92Hz，2H)，2.37(s，3H)，2.12-2.04(m，2H)，1.84-1.78(m，2H)。
Thiazole-4-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 40.7 percent.
Color and appearance: a brown gum.
LCMS: found (M + 547.2).
Rt (min): 3.98,% area: 96.25(Max), 96.95(254 nm).
1HNMR(400MHz，CDCl3)10.37(s，1H)，9.03(s，1H)，8.84(s，1H)，9.32(d，J=2.04Hz，1H)，7.77-7.49(m，1H)，7.62(s，1H)，7.32(d，J=8.28Hz，1H)，7.24(m，3H)，7.08(s，1H)，3.45-3.42(m，6H)，3.29-3.21(m，8H)，2.48-2.43(m，5H)，2.11-2.04(m，2H)，1.85-1.79(m，2H)。
2-methyl-thiazole-4-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 35.4 percent.
Color and appearance: a brown solid.
LCMS: found (M + 561.3).
Rt (min): 4.32,% area: 96.08(Max), 98.00(254 nm).
1HNMR(400MHz，CDCl3)10.36(s，1H)，9.02(s，1H)，8.09(s，1H)，7.751(dd，J=2.04,8.24Hz，1H)，7.55(t，J=11.72Hz，1H)，7.34-7.22(m，4H)，7.17(t，J=7.88Hz，1H)，3.45-3.33(m，14H)，2.80(s，3H)，2.53(s，3H)，2.48(t，J=7.96Hz，2H)，2.11-2.05(m，2H)，1.83-1.79(m，2H)。
2-methyl-oxazole-4-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 54.7 percent.
Color and appearance: a brown gum.
LCMS: found (M + 545.3).
Rt (min): 4.02,% area: 96.73(Max), 97.79(254 nm).
1HNMR(400MHz，CDCl3)9.91(s，1H)，8.99(s，1H)，8.19(s，1H)，7.75(dd，J=2.04,8.32Hz，1H)，7.60(t，J=6.0Hz，1H)，7.31(d，J=8.28Hz，1H)，7.24(t，J=5.56Hz，3H)，7.06(t，J=4.72Hz，1H)，3.45-3.40(m，6H)，3.26-3.17(m，8H)，2.52(s，3H)，2.48(t，J=7.96Hz，2H)，2.42(s，3H)，2.11-2.03(m，2H)，1.84-1.78(m，2H)。
2-methyl-5-trifluoromethyl-oxazole-4-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 63.0 percent.
Color and appearance: a white solid.
LCMS: found (M + 613.3).
Rt (min): 4.81,% area: 98.99(Max), 99.59(254 nm).
1HNMR(400MHz，CDCl3)10.13(s，1H)，8.92(s，1H)，7.75(dd，J=1.96,8.28Hz，1H)，7.32(t，J=8.32Hz，2H)，7.25(t，J=7.64Hz，2H)，7.15(d，J=7.64Hz，1H)，7.08(t，J=7.4Hz，1H)，3.46-3.39(m，6H)，3.22-3.21(m，8H)，2.60(s，3H)，2.45(t，J=8.04Hz，2H)，2.39(s，3H)，2.11-2.0(m，2H)，1.86-1.79(m，2H)。
5-ethyl-oxazole-4-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 51.5 percent.
Color and appearance: a milky white solid.
LCMS: found (M + 559.3).
Rt (min): 4.38,% area: 93.67(Max), 97.04(254 nm).
1HNMR(400MHz，CDCl3)9.9(s，1H)，8.9(s，1H)，7.76(s，1H)，7.73-7.71(m，1H)，7.48(t，J=5.92Hz，1H)，7.29-7.21(m，3H)，7.16(d，J=7.64Hz，1H)，7.05(t，J=7.2Hz，1H)，3.45-3.3.40(m，6H)，3.24-3.18(m，10H)，2.46(t，J=7.96Hz，2H)，2.36(s，3H)，2.09-2.03(m，2H)，1.84(m，2H)，1.32(t，J=7.56Hz，3H)。
5-methyl-oxazole-4-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 27.7 percent.
Color and appearance: a white solid.
LCMS: found (M + 545.3).
Rt (min): 4.04,% area: 91.51(Max), 97.19(254 nm).
1HNMR(400MHz，CDCl3)9.90(s，1H)，8.92(s，1H)，7.75(s，1H)，7.74-7.72(m，2H)，7.59(t，J=6.0Hz，2H)，7.30(t，J=8.48Hz，2H)，7.08(t，J=7.2Hz，1H)，3.45-3.40(m，6H)，3.25-3.31(m，8H)，2.74(s，3H)，2.47-2.40(m，5H)，2.11-2.05(m，2H)，1.84-1.80(s，2H)。
2-ethyl-oxazole-4-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 39.2 percent.
Color and appearance: a white solid.
LCMS: found (M + 559.3).
Rt (min): 4.42,% area: 93.72(Max), 96.42(254 nm).
1HNMR(400MHz，CDCl3)10.00(s，1H)，9.00(s，1H)，8.20(s，1H)，7.75(dd，J=2.04,8.24Hz，1H)，7.60(s，1H)，7.24(d，J=2.72Hz，1H)，7.21-7.19(m，2H)，7.13(d，J=7.6Hz，1H)，7.06(t，J=7.32Hz，1H)，3.45-3.40(m，6H)，3.21-3.12(m，8H)，2.87-2.81(m，2H)，2.48(t，J=7.92Hz，2H)，2.38(s，3H)，2.09-2.05(m，2H)，1.83(t，J=6.44Hz，2H)，1.44(t，J=7.56Hz，3H)。
3-methyl-isoxazole-4-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 18.5 percent.
Color and appearance: a white solid.
LCMS: found (M + 545.3).
Rt (min): 3.78,% area: 96.87(Max), 98.58(254 nm).
1HNMR(400MHz，CDCl3)8.94(s，1H)，8.89(s，1H)，8.84(s，1H)，7.76(dd，J1.88,8.24Hz，1H)，7.66(s，1H)，7.38(d，J=8.32Hz，1H)，7.24(t，J=3.96Hz，2H)，.09-7.03(m，2H)，3.45-3.40(m，6H)，3.09(m，8H)，2.65(s，3H)，2.48(t，J=7.96Hz，2H)，2.36(s，3H)，2.12-2.04(m，2H)，1.84-1.78(m，2H)。
5-ethyl-3-methyl-isoxazole-4-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 13.8 percent.
Color and appearance: a white solid.
LCMS: found (M + 573.3).
Rt (min): 4.41,% area: 95.41(Max), 97.34(254 nm).
1HNMR(400MHz，CDCl3)9.00(s，1H)，8.90(s，1H)，7.75(dd，J=2.0，8.32Hz，1H)，7.68(s，1H)7.43(d，J=8.28Hz，1H)，7.23(t，J=7.2Hz，2H)，7.07t，J=7.92Hz，2H)，3.46-3.42(m，6H)，3.09(m，8H)，3.06-3.04(m，2H)，2.75(s，3H)，2.47(t，J=8.0Hz，2H)，2.36(s，3H)，2.08-2.04(m，2H)，1.85-1.81(m，2H)，1.42(t，J=4.56Hz，3H)。
3- (cyclohexanecarbonyl-amino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: and (4) 64.9%.
Color and appearance: a brown solid.
LCMS: found (M + 546.3).
Rt (min): 4.56,% area: 95.44(Max), 95.51(254 nm).
1HNMR(400MHz，CDCl3)8.8(s，1H)，8.6(s，1H)，7.70(dd，J=1.96,8.24Hz，1H)，7.43(s，1H)，7.24(m，1H)，7.22(t，J=6.16Hz，2H)，7.11(d，J=7.48Hz，1H)，7.06(t，J=7.36Hz，1H)，3.44-3.38(m，6H)，3.11-3.07(m，8H)，2.45(t，J=8.0Hz，2H)，2.36(s，3H)，2.34(m，1H)，2.08-2.06(m，4H)，2.04-2.00(m，1H)，1.88-1.80(m，3H)，1.57-1.53(m，2H)，1.38-1.25(m，4H)。
Tetrahydro-furan-2-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 75.8 percent.
Color and appearance: a white solid.
LCMS: found (M + 534.3).
Rt (min): 3.98,% area: 98.49(Max), 98.11(254 nm).
1HNMR(400MHz，CDCl3)9.6(s，1H)，8.91(s，1H)，7.72(dd，J=2.0，8.28Hz，1H)，7.55(s，1H)，7.26-7.20(m，3H)，7.13(d，J=7.12Hz，1H)，7.06(t，J=7.32Hz，1H)，4.55-4.51(m，1H)，4.10-4.08(m，1H)，4.00-3.98(m，1H)，3.44-3.41(m，6H)，3.18-3.04(m，8H)，2.46(m，3H)，2.37(s，3H)，2.08-2.05(m，1H)，1.97-1.94(m，2H)，1.83-1.82(m，2H)，1.80-1.79(m，2H)。
1-methyl-piperidine-4-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 19.7 percent.
Color and appearance: a brown gum.
LCMS: found (M + 561.3).
Rt (min): 2.85,% area: 95.09(Max), 97.27(254 nm).
1HNMR(400MHz，MeOD)8.31(s，1H)，7.66(dd，J=2.08,8.32Hz，1H)，7.33(d，J=8.4Hz，1H)，7.19-7.14(m，3H)，6.98(t，J=1.6Hz，1H)，3.52(t，J=7.08Hz，2H)，3.48-3.38(m，4H)，3.10(m，8H)，3.32-3.31(m，2H)，3.01-2.98(m，1H)，2.42-2.38(m，2H)，2.34-3.32(m，3H)，2.17(s，3H)，2.08-2.04(m，2H)，1.91-1.90(m，2H)，1.88-1.87(m，2H)，1.85-1.83(m，4H)。
3- (cyclopropanecarbonyl-amino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 67.4 percent.
Color and appearance: a white solid.
LCMS: found (M + 504.3).
Rt (min): 3.56,% area: 95.97(Max), 97.03(254 nm).
1HNMR(400MHz，CDCl3)8.77(s，1H)，8.63(s，1H)，7.70(dd，J=2.04,8.24Hz，1H)，7.42(s，1H)，7.29(s，1H)，7.23(t，J=7.68Hz，2H)，7.12(d，J=7.8Hz，1H)，7.05(t，J=7.36Hz，1H)，3.37(m，6H)，3.2(m，8H)，2.42(m，2H)，2.3(s，3H)，2.05-2.02(m，2H)，1.83-1.81(m，2H)，1.78-1.76(m，1H)，1.15-1.11(m，2H)，0.98-0.86(m，2H)。
3- (2-chloro-benzoylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 51.7 percent.
Color and appearance: a brown solid.
LCMS: found (M + 574.3).
Rt (min): 4.28,% area: 93.60(Max), 96.10(254 nm).
1HNMR(400MHz，CDCl3)9.35(s，1H)，9.06(s，1H)，7.84(d，J=6.96Hz，1H)，7.77(dd，J=1.68,8.24Hz，1H)，7.58(s，1H)，7.49-7.46(m，1H)，7.44-7.38(m，3H)，7.23(t，J=7.84Hz，2H)，7.19(m，2H)，3.46-3.42(m，6H)，3.19(m，8H)，2.47-2.42(m，5H)，2.10-2.06(m，2H)，1.84-1.79(m，2H)。
3- (2-fluoro-benzoylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 36.7 percent.
Color and appearance: a brown solid.
LCMS: found (M + 558.3).
Rt (min): 4.39,% area: 96.46(Max), 96.94(254 nm).
1HNMR(400MHz，CDCl3)9.96(s，1H)，9.09(s，1H)，8.29(t，J=6.4Hz，1H)，7.78(dd，J=2.08,8.28Hz，1H)，7.68(m，1H)，7.54-7.52(m，1H)，7.40(d，J=8.28Hz，1H)，7.36(t，J=6.92Hz，1H)，7.32(m，4H)，7.13(t，J=4.24Hz，1H)，3.46-3.42(m，6H)，3.28(m，8H)，2.48-2.43(m，5H)，2.10-2.06(m，2H)，1.85-1.82(m，2H)。
3- (3-dimethylamino-benzoylamino) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -benzamide
The yield is as follows: 45.3 percent.
Color and appearance: a brown gum.
LCMS: found (M + 583.3).
Rt (min): 3.73,% area: 92.47(Max), 94.61(254 nm).
1HNMR(400MHz，CDCl3)9.41(s，1H)，9.04(s，1H)，7.76(dd，J=1.84,8.24Hz，1H)，7.59(s，1H)，7.41-7.33(m，3H)，7.23(t，J=7.28Hz，3H)，7.07(m，2H)，6.92(s，1H)，3.46-3.42(m，6H)，3.12-3.05(m，8H)，3.01(s，6H)，2.47(t，J=7.88Hz，2H)，2.36(s，3H)，2.11-2.03(m，2H)，1.86-1.80(m，2H)。
N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -4- (4-o-tolyl-piperazin-1-yl) -3- (2-trifluoromethyl-benzoylamino) -benzamide
The yield is as follows: 32.3 percent.
Color and appearance: a brown solid.
LCMS: found (M + 608.3).
Rt (min): 4.49,% area: 95.91(Max), 97.61(254 nm).
1HNMR(400MHz，CDCl3)8.94(s，2H)，7.79(t，J=7.6Hz，2H)，7.69-7.62(m，3H)，7.53(s，1H)，7.39(d，J=8.28Hz，1H)，7.22-7.15(m，2H)，7.05(t，J=7.72Hz，2H)，3.46-3.42(m，6H)，3.13-3.04(m，8H)，2.46(t，J=8.0Hz，2H)，2.36(s，3H)，2.11-2.04(m，2H)，1.85-1.80(m，2H)。
Naphthalene-1-carboxylic acid [5- [3- (2-oxo-pyrrolidin-1-yl) -propylcarbamoyl ] -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 10.9 percent.
Color and appearance: a brown gum.
LCMS: found (M + 590.3).
Rt (min): 4.70,% area: 90.60(Max), 91.80(254 nm).
1HNMR(400MHz，CDCl3)9.1(s，2H)，8.52(d，J=8.92Hz，1H)，7.99(d，J=8.2Hz，1H)，7.94(d，J=7.28Hz，1H)，7.80(t，J=6.72Hz，2H)，7.60(s，1H)，7.59-7.55(m，3H)，7.38(d，J=8.28Hz，1H)，7.20-7.15(m，2H)，7.04(t，J=7.28Hz，1H)，6.96(d，J=8.08Hz，1H)，3.47-3.44(m，6H)，3.16-3.10(m，8H)，2.48(t，J=8.0Hz，2H)，2.35(s，3H)，2.10-2.06(m，2H)，1.87-1.84(m，2H)。
Furan-2-carboxylic acid [5- (3-phenyl-propylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
To a suspension of- [ (furan-2-carbonyl) -amino ] -4- (4-o-tolyl-piperazin-1-yl) -benzoic acid (0.1g, 0.246mmol) in dichloromethane (5ml) was added triethylamine (0.074g, 0.74mmol), (3-phenylpropyl) amine (0.044g, 0.370mmol) and 1-propylphosphoric anhydride (0.23g, 0.74 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and extracted with dichloromethane (10ml x 1). The organic layer was washed with water (10ml X2) and dried over anhydrous sodium sulfate. The organic layer was concentrated and the crude product obtained was purified by flash silica gel column chromatography to give (0.070g, 67.9%) the title compound as a brown solid.
LCMS: found (M + 523.3).
Rt (min): 5.42,% area: -90.74(Max), 92.59(254 nm).
1HNMR(400MHz，CDCl3)9.5(s，1H)，8.80(s，1H)，7.75(dd，J=2.08,8.28Hz，1H)，7.58(s，1H)，7.34(d，J=8.32Hz，2H)，7.30-7.25(m，7H)，7.14(d，J=8.08Hz，1H)，7.05(m，1H)，6.61(s，1H)，6.60(s，1H)，3.51(m，2H)，3.18-3.12(m，8H)，2.75(t，J=7.44Hz，2H)，2.37(s，3H)，1.99-96(m，2H)。
HPLC: rt (min)5.46, area%: 92.64(Max), 94.27(254 nm).
Furan-2-carboxylic acid [5- (3-pyrazol-1-yl-propylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: and (4) 64.4%.
Color and appearance: yellow solid.
LCMS: found (M + 513.3).
Rt (min): 4.49,% area: 99.33(Max), 99.86(254 nm).
1HNMR(400MHz，，CDCl3)9.5(s，1H)，8.85(s，1H)，7.76(dd，J=2.12,8.28Hz，1H)，7.58(s，2H)，7.57(s，1H)，7.34(d，J=8.28Hz，1H)，7.29-7.28(m，3H)，7.25-7.2481(m，2H)，7.23(m，1H)，6.60(s，1H)，6.27(s，1H)，4.30(t，J=6.4Hz，2H)，2.48-2.46(m，2H)，3.19-3.13(m，8H)，2.37(s，3H)，2.18-1.76(m，2H)。
Furan-2-carboxylic acid [5- (1-cyclopentylcarbamoyl-ethylcarbamoyl) -2- (4-o-tolyl-piperazin-1-yl) -phenyl ] -amide
The yield is as follows: 48.4 percent.
Color and appearance: a brown solid.
LCMS: found (M + 544.3).
Rt (min): 4.72,% area: 90.79(Max), 90.20(254 nm).
1HNMR(400MHz，CDCl3)95(s，1H)，8.88(s，1H)，7.69(dd，J=2.04,8.24Hz，1H)，7.57(s，1H)，7.34(d，J=8.28Hz，1H)，7.29-7.28(m，3H)，7.25(d，J=7.08Hz，1H)，7.18(m，1H)，7.09(d，J=7.36Hz，1H)，6.85(d，J=7.48Hz，1H)，6.61(m，1H)，4.64(m，1H)，4.20-4.18(m，1H)，3.21-3.18(m，8H)，2.40(s，3H)，1.98-1.97(m，2H)，1.69-1.67(m，2H)，1.65-1.58(m，2H)，1.49-1.48(m，3H)，1.44-1.40(m，2H)。
Example 10: in CHOFSHR cells and in EC20EC for Cyclic AMP production in the Presence of FSH50(test A)
2500 Cho-FSHR-LUC-1-1-43 cells were fixed in 5. mu.l phenol red free medium DMEM/F12+1% FBS per well. Cells were plated in 384-well white low-volume plates (Greiner784075) using a aliquotter. Mu.l (2X) of EC in DMEM/F12 and 0.1% BSA were assayed using a liquid separator20FSH/IBMX additionTo 2. mu.l of test compound fixed in 384 well plates (compound diluted to 1: 50). The final FSH concentration was 0.265pM and the final IBMX concentration was 200. mu.M. The layout of the compound culture plates is as follows: column 1: 2 μ l DMSO; column 2: 2 μ l DMSO; columns 3-12 and 13-24: 2 μ l of test compound, diluted with 100% DMSO to 1: 4, or 2 μ l fsh, diluted to 1: 4. the initial concentration of FSH was 50nM (final concentration was 0.5 nM). Furthermore, column 23 contains 2. mu. lEC100FSH reference (100X) (diluted with DMEM/F12+0.1% BSA) at a final concentration of 0.5nM, column 24 containing 2. mu.l of 1mMAS707664/2 reference compound, 2.5. mu.l of compound and EC20The mixture of FSH was transferred to a cell culture plate (5. mu.l of cell culture medium with 1: 2 dilution). The plates were incubated at 37 ℃ for 1 hour. Mu.l of mixed HTRF (CisBio #62AM4PEC) reagent was added to each well and incubated for 1 hour at room temperature. Plates were read by Envision using the cAMPHTRF-low volume 384-well protocol. The readings are calculated fluorescence ratios (665nm/620 nm). Values are given as percentages (%) and represent the percentage of the effect (response) at a given agonist concentration relative to the maximum response of the FSH standard. The results are shown in tables 1 and 2.
Example 11: rat granulosa cell EC50FSH (test B)
The test was carried out with reference to the teaching of the following documents: yanofsky et al (2006), allometric activity of a platelet-stimulating hormone (FSH) receptor by electrostatic charge, nonpatent activities. JBC281 (19): 13226-13233, which is incorporated herein by reference. The results are shown in tables 1 and 2.
Example 12: pharmaceutical preparation
(A) Injection bottle: a solution of 100g of the compound of the invention as active ingredient with 5g of sodium dihydrogenphosphate in 3L of redistilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile-filtered, transferred to an injection vial, sterile-lyophilized, and aseptically sealed. Each solution bottle contained 5mg of active ingredient.
(B) Suppository: 20g of the compound of the invention as active ingredient are mixed with 100g of soya lecithin and 1400g of cocoa butter, poured into moulds and cooled. Each suppository contains 20mg of active ingredient.
(C) Solution preparation: 1g of the compound of the present invention as an active ingredient, 9.38g of NaH2PO4·2H2O、28.48gNa2HPO4·12H2O and 0.1g benzalkonium chloride in 940mL redistilled water. The pH of the solution was adjusted to 6.8, the solution was made up to 1L and sterilized by radiation. The solution is used in the form of an eye drop.
(D) Ointment: 500mg of the compound of the invention as active ingredient are mixed under sterile conditions with 99.5g of vaseline.
(E) And (3) tablet preparation: 1kg of the compound of the invention as active ingredient, 4kg of lactose, 1.2kg of potato flour, 0.2kg of talc and 0.1kg of magnesium stearate are compressed into tablets according to the conventional method so that each tablet contains 10mg of active ingredient.
(F) Coating tablets: tablets were compressed analogously to example E and then coated in a conventional manner with a sucrose coating, potato starch, talc, tragacanth and dye.
(G) And (3) capsule preparation: 2kg of the compound of the present invention as an active ingredient was introduced into hard capsules according to a conventional method so that each capsule contained 20mg of the active ingredient.
(H) An ampoule agent: a solution of 1kg of the compound of the invention as active ingredient in 60L of redistilled water is sterile-filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10mg of active ingredient.
(I) Inhalation spray: 14g of the compound of the invention as active ingredient are dissolved in 10L of isotonic sodium chloride solution and the solution is transferred to a commercially available spray container with pump mechanism. The solution may be sprayed into the mouth or into the nose. One injection (about 0.1ml) corresponds to a dose of about 0.14 mg.

Claims (8)

1. A compound of the formula (I-A),
in the formula (I), the compound is shown in the specification,
R1is represented by- (CY)2)n-E-(CY2)n-Het3、-(CY2)n-Cyc-Het3、-(CY2)n-NHCO-Het3、-(CY2)n-C(Y)(OH)-(CY2)n-Het3、-(CY2)n-Het1、-(CY2)n-NHCO-Het1、-(CY2)n-Ar、-(CY2)n-C(Y)(OH)-(CY2)n-Ar、-(CY2)n-Cyc、-(CY2)n-CONH-Cyc、A、-(CYR8)n-OY、-(CY2)n-COOY、-(CYR8)n-CO-(CY2)n-N(R8)2、-(CY2)n-[C(Y)OH]]m-(CYR8)n-NY2、[-(CY2)n-O]m-(CYR8)n-NYCOY、-(CY2)n-NYCOOY、-(CY2)n-NYCON(R8)2、-(CY2)n-NHCO-CH＝CH2Or- (CY)2)n-NHCO-NH-(CY2)n＝CH2；
R3Represents Het1、Het3Ar, H, A or Cyc;
R5represents E-Ar or Het1；
R8Each Y independently represents H or A;
x represents CO or- (CY)2)m；
E represents- (CY)2)m-, CO or-COO-;
a represents a linear or branched alkyl group containing 1 to 10 carbon atoms, wherein 1 to 7 hydrogen atoms may each independently be substituted by Hal and/or OH;
cyc represents cycloalkyl having 3 to 7 carbon atoms, wherein 1 to 4 hydrogen atoms may each independently be replaced by Hal and/or OH;
ar represents an unsaturated or aromatic monocyclic or bicyclic carbocyclic ring containing 5 to 10 carbon atoms, which carbocyclic ring may be substituted by at least one substituent selected from the group consisting of: A. hal, OY, COOY, CONH2、NHCOY、-(CH2)n-NY2、SO2NH2、NO2CN and Het2；
Het1Represents an unsaturated or aromatic monocyclic or bicyclic heterocycle containing from 1 to 9 carbon atoms and from 1 to 3N, O and/or S atoms, which heterocycle may be mono-or disubstituted by at least one substituent selected from the group consisting of: hal, A, Cyc, OY, CONH2、NHCOY、-(CH2)n-NY2、SO2NY2、NHSO2Y, CN and Ar;
Het2represents imidazolyl, pyrazinyl, thiazolyl or tetrazolyl, which may be mono-substituted by methyl;
Het3represents a saturated monocyclic heterocycle containing 3 to 6 carbon atoms and 1 to 3N, O and/or S atoms, which heterocycle may be mono-, di-or tri-substituted by at least one substituent selected from the group consisting of: o, A, Hal, - (CY)2)n-Cyc、-(CY2)n-OY、COY、COOY、CONY2、NHCOY、NY2、CN、SO2Y and- (CY)2)n-Ar；
Hal represents F, Cl, Br or I; and
m, n each independently represent 0, 1,2 or 3;
or a physiologically acceptable salt.
2. The compound of claim 1, wherein the compound has the following sub-formula (I-B),
in the formula (I), the compound is shown in the specification,
R1is represented by- (CY)2)n-Het3、-(CY2)n-NHCO-Het3、-(CY2)n-C(Y)(OH)-(CY2)n-Het3、-(CY2)n-Het1、-(CY2)n-Ar、-(CY2)n-C(Y)(OH)-Ar、Cyc、-(CY2)n-CO-NY2、-(CY2)n-NYCOY、-(CY2)n-NYCONY2Or- (CY)2)n-NHCO-NH-(CY2)n＝CH2；
Y represents H or A;
a represents a linear or branched alkyl group containing 1 to 6 carbon atoms, wherein 1 to 4 hydrogen atoms may each independently be substituted by Hal and/or OH;
cyc represents a cycloalkyl group having 3 to 6 carbon atoms, wherein 1 to 4 hydrogen atoms may be substituted by OH;
ar represents an aromatic monocyclic carbocyclic ring containing 6 to 8 carbon atoms, which carbocyclic ring may be mono-or disubstituted by at least one substituent selected from the group consisting of: A. hal, OY, CONH2、-(CH2)n-NA2、SO2NH2And Het2；
Het1Represents an unsaturated or aromatic monocyclic heterocycle containing from 1 to 6 carbon atoms and from 1 to 3N, O and/or S atoms, which heterocycle may be mono-or disubstituted by at least one substituent selected from the group consisting of: hal, A, Cyc and- (CH)2)n-NA2；
Het2Represents a tetrazolyl group;
Het3represents a saturated monocyclic heterocycle containing 3 to 6 carbon atoms and 1 to 3N, O and/or S atoms, which heterocycle may be mono-, di-or tri-substituted by at least one substituent selected from the group consisting of: o, A and OY;
hal represents F, Cl or Br; and
n represents 0, 1,2 or 3;
or a physiologically acceptable salt.
3. The compound of claim 1, selected from the group consisting of,
or a physiologically acceptable salt thereof.
4. A medicament comprising at least one compound according to any one of claims 1 to 3 and/or a physiologically acceptable salt thereof.
5. A pharmaceutical composition for oral administration comprising as active ingredient at least one compound according to any one of claims 1 to 3 and/or a physiologically acceptable salt thereof and a pharmaceutically tolerable adjuvant, optionally in combination with at least one other active pharmaceutical ingredient.
6. Use of a compound according to any one of claims 1 to 3 and/or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment of fertility disorders.
7. Use of a compound according to any one of claims 1 to 3 and/or a physiologically acceptable salt thereof in the manufacture of a medicament for modulating the FSH receptor in the presence of FSH.
8. The compound of claim 1 which is
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