CN113896673B - Amide derivatives as prostaglandin EP4 receptor antagonists and uses thereof - Google Patents

Amide derivatives as prostaglandin EP4 receptor antagonists and uses thereof Download PDF

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CN113896673B
CN113896673B CN202111276464.1A CN202111276464A CN113896673B CN 113896673 B CN113896673 B CN 113896673B CN 202111276464 A CN202111276464 A CN 202111276464A CN 113896673 B CN113896673 B CN 113896673B
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洪健
D.达斯
王景炳
乔丹丹
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Abstract

The present invention discloses a series of amide derivatives of formula I or pharmaceutically acceptable salts thereof and their use as prostaglandin E2 receptor 4 (EP 4) antagonists. The preparation of amide derivatives of formula I is described herein, wherein G, X, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 And ring a is as defined herein, and uses thereof are disclosed.
Figure DDA0003329505860000011
The invention also relates to pharmaceutically acceptable salts of formula I or as EP4 antagonists and their use in cancer and immune related diseases including, but not limited to, the reduction of pain, inflammation and other inflammation related diseases such as arthritis, and the treatment of cancers such as breast, colorectal, pancreatic and prostate cancer.

Description

Amide derivatives as prostaglandin EP4 receptor antagonists and uses thereof
Technical Field
The invention relates to the technical field of biological medicine, in particular to an amide derivative serving as a prostaglandin EP4 receptor antagonist and application thereof.
Background
Prostaglandins are a group of bioactive lipid compounds that are mediators of pain, fever and other symptoms associated with inflammation or cell membrane damage.
Prostaglandin E2 (PGE 2) is the major eicosanoid derivative in inflammation and is involved in a variety of biological processes including inflammation, pain, fever, renal function, mucosal integrity, hyperalgesia, uterine contractions, bone metabolism, platelet function, angiogenesis and tumor growth and cancer (Trends in Molecular Medicine 2012; 18:233-43). Cyclooxygenase (COX) is an important enzyme for synthesizing prostaglandins PGD2, PGE2, PGF2a, prostaglandin PGl2 and thromboxane TXA2 from arachidonic acid. Prostaglandins act by activating 7G protein-coupled receptors (GPCRs), EP1, EP2, EP3 and EP4 being PGE2 mediated activating receptors. The EP4 receptor is one of seven membrane receptors, whose activation is usually associated with an increase in intracellular cyclic adenosine monophosphate (cAMP) levels, thereby triggering multiple downstream events. PGE2 contributes to a pro-inflammatory immune response; PGE2, however, is believed to be an important component of the immunosuppressive environment of many solid neoplasias (Whiteside, expert Opinion in Biological Therapy,2010.10,1019-1035), and sustained levels in the tumor microenvironment promote tumor accumulation enhancing the activity of a variety of immunosuppressive cells, including tumor-associated macrophages (TAMs), treg cells, and myeloid-derived suppressor cells (MDSCs), thereby promoting tumor immune escape. There is increasing evidence that elevation of cAMP levels by EP4 is the primary signaling pathway leading to immune cell immunosuppression.
Prostaglandin E receptor subtypes EP2 and EP4 promote differentiation and expansion of Thl and Thl7 lymphocytes through different signaling modules (Nature Medicine,2009,15,633-640;Eur.J.Immunol 2009,39,1301-1312). The synergistic action of prostaglandin E2 with interleukin 23 has been reported in the literature to be beneficial for the expansion of human Thl7 (Blood, 2008, 112, 3696-3703), prostaglandin E2 regulating the differentiation and function of Thl7 cells via cyclic adenylate and EP2/EP4 receptor signaling (J.Exp. Med.2009,206, 535-548), prostaglandin E2 (PGE 2) acting as a cytokine amplification system via activated EP4 receptor, such as interleukin-6 (IL-6), and inducing the differentiation and expansion of pro-inflammatory T-helper lymphocytes (Th 1) (Yokoyama et al, pharmacol. Rev.2013,65:1 0-52).
High levels of COX2 and PGE2 expression are associated with tumor transformation, cell growth, angiogenesis, invasiveness, metastasis, and immune evasion. It is clear that COX2 promotes tumor growth, upregulation in colorectal, gastric, esophageal, pancreatic, breast and ovarian cancers primarily through PGE 2. Functional PGE2 antagonists have potential therapeutic use in a variety of diseases. EP4 antagonism brings beneficial results in the preclinical system of humans and mice as a therapeutic strategy for Abdominal Aortic Aneurysms (AAA) (Yokoyama et al, 2012,PLoS One 7,e36724). The mouse EP4 gene knockout showed a delay in tumorigenesis, indicating tumor promoting activity of PGE2-EP4 signaling in the host immune cells (Mutoh et al 2002,Cancer Res 62,28-32). In various preclinical tumor models, selective EP4 receptor antagonists can slow tumor progression and metastasis (Yang et al, 2006,. Cancer Research 66,9665-9672; mao et al, 2014,Clin Cancer Res 20,4096-4106). EP4 has been identified as a target for preventing the development of atherosclerosis by the lack of macrophages EP4 and inhibits atherosclerosis (Babaev et al 2008,Cell Metabolism 8,492-501).
EP4 receptors are involved in a variety of anti-inflammatory, osteogenic and hemostatic actions; EP4 agonists increase bone deposition, promote bone resorption; EP4 antagonist treatment inhibits the immunosuppressive and tumorigenic effects of PGE2 in tumors:
colorectal cancer: increased EP4 receptor expression in colorectal cancer has been reported to promote cell growth and anchorage (Chell et al, 2006,Cancer Research 66,3106-3113);
prostate cancer: EP4 was identified as a potential target for animal model treatment of castration resistant prostate Cancer (Terda et al, 2010 Cancer Research 70, 1606-1615);
breast cancer: EP4 antagonists protect natural killer cells from PGE 2-mediated immunosuppression and inhibit breast cancer metastasis (Ma et al, 2013,OncoImmunology 2,e22647). EP4 is a therapeutic target of breast cancer cells with stem cell-like properties (Kundu et al, 2014,Breast Cancer Research and Treatment 143,19-31);
ovarian cancer: (e.g., ovarian epithelial cancer: PGE2 synthesis and signaling in malignant transformation and progression, mol cancer, 2006,5,62);
pain and inflammation: the role of EP4 neuropathic pain in the chronic contraction injury model of rats (Murase et al, 2008,European Journal of Pharmacology 580,116-121) and inflammatory pain (Lin et al, 2006,Journal of Pharmacology and Experimental Therapeutics 319,1096-1103) was demonstrated.
There is growing evidence that EP4 antagonism, especially in combination with chemotherapy, endocrine therapy or immunotherapy, should be further investigated as a promising approach to cancer therapy. The EP4 receptor is a promising new therapeutic target for the treatment of breast cancer. Several EP4 antagonists are in early clinical trial stages of cancer treatment. The various biological functions of the EP4 receptor may explain the activation of EP4 and the opening of various signaling pathways.
EP4 antagonist E7046 reduces myeloid immunosuppression and reduces IL-2-diphtheria toxin fusion protein in synergy with tregs to restore anti-tumor immunity (album et al, 2017,OncoImmunology 6,e1338239). Targeting COX-2 and EP4 are known to control tumor growth, angiogenesis, lymphangiogenesis and lung and lymph node metastasis in breast cancer models (Xin et al 2012,Laboratory Investigation 92,1115-1128). EP4 antagonist CR6086 is reported to be an antirheumatic drug (Caselli et al, 2018,Pharmacological characterisation of CR6086). In WO-2018084230, EP4 receptor antagonists are reported to be useful in the treatment of NASH-related liver cancer. EP4 receptor agonists show promising results for Ulcerative Colitis (UC). KAG-308 with high oral bioavailability inhibits the development of colitis and promotes mucosal healing in a mouse model (Watanabe et al, 2015,European Journal of Pharmacology 754,179-189). EP4 is associated with diabetic nephropathy, ASP7657 is a selective EP4 receptor antagonist that dose-dependently reduces proteinuria in type 2 diabetic mice (Mizukami et al, 2018,Naunyn Schmiedebergs Arch Pharmacol 391,1319-1326). The EP4 antagonist ONO-AE3-208 inhibits cell invasion and metastasis of prostate cancer (Xu et al 2014,Cell Biochemistry and Biophysics 70,521-527). MF-766 is reported as a selective EP4 antagonist for the treatment of inflammatory pain (Colucci et al 2010,Bioorganic&Medicinal Chemistry Letters 20,3760-3763). The EP4 receptor antagonist CJ-042794 proved to be effective in a model of pain and inflammation in rats. EP4 agonists are used to control bone loss and arthritis, tha 0085Cr6086 has immunomodulatory properties, and is reported to reduce bone loss in a rat collagen-induced arthritis (CIA) model (Lanza et al, 2018,BMJ Publishing Group Ltd and European League Against Rheumatism,265-265).
Published patents WO2020012305, WO20190255013, WO2019149286, WO2019152982, WO2019038156, WO2018216640, WO2018162562, WO2017085198, WO2013004290, WO201207063, WO2012039972, WO2010019796, WO2009139373, EP-3632898, EP 2649061 disclose certain compounds as EP4 antagonists and for use in the treatment of prostaglandin mediated diseases.
Inhibition of PGE2/EP4 signaling is reported to be potentially of therapeutic value for inflammatory autoimmune diseases. Antagonists of the EP4 subtype of PGE receptors may be useful and useful in the treatment of diseases or conditions mediated by the EP4 receptor, for example cancer and inflammatory diseases or conditions such as acute and chronic pain, osteoarthritis, rheumatoid arthritis and multiple sclerosis.
Disclosure of Invention
To solve the above-mentioned problems, an object of the present invention is to provide an amide derivative as a prostaglandin EP4 receptor antagonist and use thereof. The present disclosure relates to the synthesis of novel compounds or pharmaceutically acceptable salts thereof and their use as prostaglandin EP4 antagonists. The compounds described herein are useful for the treatment or prevention of diseases in which EP4 receptors are involved. The compounds of the invention may be used as monotherapy or in combination with one or more other therapeutic methods.
The first object of the present invention is to provide a compound having the structural formula shown in formula I:
Figure BDA0003329505840000031
wherein:
ring A is selected from
Figure BDA0003329505840000032
Wherein W is 1 And 2 independently selected from C or N satisfying valence state;
R 1 selected from substituted or unsubstituted C 1-10 Straight-chain or branched alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 1-3 Deuterated alkyl, substituted or unsubstituted C 7-12 Alkylaryl or substituted or unsubstituted C 6-10 Alkyl heteroaryl;
when X is selected from NH, O, S or CH 2 When in use, R is 2 Selected from hydrogen, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted C 5-10 Heteroaryl, substituted or unsubstituted C 3-7 Saturated carbocycles or substituted or unsubstituted C 1-10 Linear or branched alkyl;
when X is selected from halogen, CN, CONH 2 Substituted or unsubstituted C 1-3 In the case of chain or cyclic alkyl, vinyl or ethynyl, R 2 Absence of;
R 3 and R is 4 Independently selected from hydrogen, halogen, CN, substituted or unsubstituted C 1-3 Alkyl, or substituted or unsubstituted C 1-3 An alkoxy group;
R 5 and R is 6 Independently selected from hydrogen, C 1-3 Linear or branched alkyl; or R is 5 And R is 6 Composition C 3-4 Cycloalkyl or C 3-4 A heterocycloalkyl group;
g is selected from hydrogen, alkyl alcohol group, tetrazolyl, -CONHSO 2 R 7 、-CO 2 R 7 、-CONHR 7 、-SO 2 NHR 7 Or NHSO 2 R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 7 Selected from hydrogen, substituted or unsubstituted C 1-5 Alkyl, aryl or heteroaryl.
Further, the structural formula of the compound is shown as formula I:
Figure BDA0003329505840000041
wherein: />
Ring A is selected from
Figure BDA0003329505840000042
Wherein W is 3 、W 4 Independently selected from C or N, W in a satisfactory valence state 5 、W 6 、W 7 And W is 8 Independently selected from CH 2 NH, O or S;
R 1 selected from substituted or unsubstituted C 1-10 Straight-chain or branched alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 1-3 Deuterated alkyl, substituted or unsubstituted C 7-12 Alkylaryl or substituted or unsubstituted C 6-10 Alkyl heteroaryl;
when X is selected from NH, O, S or CH 2 When in use, R is 2 Selected from hydrogen, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstitutedSubstituted C 5-10 Heteroaryl, substituted or unsubstituted C 3-7 Saturated carbocycles or substituted or unsubstituted C 1-10 Linear or branched alkyl;
when X is selected from halogen, CN, CONH 2 Substituted or unsubstituted C 1-3 In the case of chain or cyclic alkyl, vinyl or ethynyl, R 2 Absence of;
R 3 and R is 4 Independently selected from hydrogen, halogen, CN, substituted or unsubstituted C 1-3 Alkyl, or substituted or unsubstituted C 1-3 An alkoxy group;
R 5 and R is 6 Independently selected from hydrogen, C 1-3 Linear or branched alkyl; or R is 5 And R is 6 Composition C 3-4 Cycloalkyl or C 3-4 A heterocycloalkyl group;
g is selected from hydrogen, alkyl alcohol group, tetrazolyl, -CONHSO 2 R 7 、-CO 2 R 7 、-CONHR 7 、-SO 2 NHR 7 Or NHSO 2 R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 7 Selected from hydrogen, substituted or unsubstituted C 1-5 Alkyl, aryl or heteroaryl.
In the compounds of formula I above, A is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, alicyclic and 4-7 membered heterocarbocyclic containing one or more N, O heteroatoms.
Further, in the compound shown in the formula I, halogen is selected from fluorine, chlorine or bromine atoms; substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 1-3 Alkyl or substituted or unsubstituted C 1-5 Including C in alkyl groups 1-3 A fluoroalkyl group; the fluoroalkyl is selected from trifluoromethyl, difluoromethyl, difluorodeuteromethyl or monofluoromethyl; substituted or unsubstituted C 1-3 Deuterated alkyl is selected from tri-deuterated methyl, difluoro-deuterated methyl or penta-deuterated ethyl.
Further, in the above compound of formula I, the hydrocarbylalcohol group comprises a methylene alcohol group (-CH) 2 OH) or ethylene alcohol groups (-CH) 2 CH 2 OH)。
Further, the compound represented by the above formula IWherein X is selected from NH, O, S or CH 2 ，R 2 Selected from hydrogen, substituted C 6-14 Aryl, substituted C 5-10 Heteroaryl, substituted C 5-6 A saturated carbocycle; or alternatively
X is selected from Cl, br, F, CF 3 CN or CONH 2 ，R 2 Is not present.
Further, of the compounds of formula I above, -XR 2 A group selected from the following structural formulae:
Figure BDA0003329505840000051
further, in the compound shown in the formula I, G is selected from a group shown in the following structural formula:
Figure BDA0003329505840000052
Preferably, in the compound of formula I, R 1 Selected from methyl, ethyl, propyl, fluoromethyl, trifluoromethyl or deuterated methyl.
Preferably, in the compound of formula I, R 3 And R is 4 Independently selected from hydrogen, methyl, trifluoromethyl, halogen (chlorine, bromine, fluorine), nitrile (-CN), or methoxy (-OMe).
Further, in the compound shown in the formula I, the structural formula is shown as one of formulas Ia-Ic:
Figure BDA0003329505840000061
further, in the compound shown in the formula I, the structural formula is shown as one of the formulas Id-If:
Figure BDA0003329505840000062
further, in the compound shown in the formula I, the structural formula is shown as the formula Ig-Ih:
Figure BDA0003329505840000063
wherein W is 5 、W 6 、W 7 And W is 8 Independently selected from CH 2 NH, O or S.
In formulas Ia to Ih, G, X, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 And ring a is as defined herein above.
Further, in the compound shown in the formula I, the structural formula is shown as one of the following formulas:
Figure BDA0003329505840000064
/>
Figure BDA0003329505840000071
/>
Figure BDA0003329505840000081
/>
Figure BDA0003329505840000091
further, in the compound shown in the formula I, the structural formula is shown as one of the following formulas:
Figure BDA0003329505840000092
/>
Figure BDA0003329505840000101
/>
Figure BDA0003329505840000111
taking G as carboxyl as an example, the invention further provides a preparation method of the compound shown in the formula I, wherein the reaction route is as follows:
Figure BDA0003329505840000112
halogenating the ester-containing functional group of the compound of formula 1 to obtain an ester-containing halide of formula 2 substituted at the 3-position; alkylation reaction is carried out on the compound of the formula 2 to obtain a compound of the formula 3; converting the compound of formula 3 to a compound of formula 4 under SNAr, suzuki or Buchwald reaction conditions; hydrolyzing the methyl ester derivative of formula 4 under alkaline conditions to obtain an acid derivative of formula 5; coupling the acid derivative of formula 5 with a compound of formula 6 in the presence of suitable coupling reaction conditions and reagents to give a derivative of formula I (wherein g=esters, alcohols, sulfonamides, amides, tetrazoles); hydrolyzing the ester group of formula I under basic reaction conditions to give the acid structure of formula I (wherein G= -CO 2 H)。
A second object of the present invention is to protect the use of the above-mentioned compounds, or pharmaceutically acceptable salts, stereoisomers, deuterium-substituted derivatives, hydrates or solvates thereof, for the manufacture of a medicament for the treatment of a disorder caused by EP 4 Conditions in which antagonism of the receptor is reduced or proliferation of cells or enzymes is inhibited, i.e. the medicament acts as an EP 4 Receptor antagonists.
Further, the EP4 receptor is a prostaglandin E2 (PGE 2) receptor.
The compounds of formula I described above may be prepared as preparations for inhibiting proliferation of cells and enzymes, and when such preparations are used, the cells are contacted with an effective amount of a compound of formula I or a deuterated derivative thereof, a stereoisomeric derivative thereof or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
Further, the condition is selected from one or more of cancer, inflammatory disease and pain.
Further, the condition is selected from one or more of lymphoma, renal cancer, skin cancer, colorectal cancer, prostate cancer, breast cancer, urothelial cancer, lung cancer, non-small cell lung cancer (NSCLC), triple Negative Breast Cancer (TNBC), ovarian cancer (e.g., ovarian epithelial cancer), cervical cancer, liver cancer, COX-associated pain, neuropathic pain, multiple sclerosis, endometriosis, inflammation, inflammatory pain, and migraine.
Further, the inflammation is rheumatoid arthritis.
The active compounds of the present invention are administered to a patient or subject to treat a variety of different conditions, particularly in "patient" or "subject" refers to an animal subject, preferably a rat, mouse, dog, cat, horse, cow, sheep, goat, monkey, etc., particularly a human subject. Any or part of the subject's condition may be treated from the list of:
further, the medicament is administered orally, parenterally, intravenously or transdermally.
The active compound may be administered to the subject by any suitable route, including orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or by an implanted reservoir. The term "parenteral injection" as used herein includes subcutaneous injections, intravenous injections, intramuscular injections, intra-articular injections, intrasynovial injections, intrasternal injections, intrathecal injections, intrahepatic injections, intra-traumatic injections or infusion techniques.
In the present invention, unless otherwise specified, terms are explained as follows:
"R" and "S" are terms describing isomers and are descriptors of stereochemical configuration of asymmetrically substituted carbon atoms. The designation of asymmetrically substituted carbon atoms as "R" or "S" is accomplished by application of the Cahn-Ingold Prelog priority rules well known to those skilled in the art and described in the International Union of pure and applied chemistry (lUPAC) organic chemistry naming rules.
The term C as used herein i-j Meaning that the moiety has i-j carbon atoms. For example, C 1-10 Alkyl means that the alkyl unit has any number of carbon atoms between 1 and 10. "alkyl" as used herein refers to a straight, branched, or cyclic hydrocarbon chain that is fully saturated.
"Ar" or "aryl" refers to an aromatic carbocyclic moiety having one or more closed rings. Including but not limited to phenyl, naphthyl, anthryl, benzanthraceyl, biphenyl, and pyrenyl.
"heteroaryl" refers to a cyclic moiety having one or more closed rings, wherein at least one ring has one or more heteroatoms (e.g., oxygen, nitrogen, or sulfur), wherein at least one ring is aromatic, and wherein one or more rings may be independently fused and/or bridged. Including but not limited to pyridyl, pyrrolyl, pyrazolinyl, quinolinyl, isoquinolinyl, indolyl, furanyl, thienyl, quinoxalinyl, indazolyl, thieno [2,3-c ] pyrazolinyl, benzofuranyl, thienyl, benzothiazolyl.
By "pharmaceutically acceptable salt" is meant an acid or base salt of a compound of the invention, which salt has the desired pharmacological activity and is biologically or otherwise non-detrimental. Including, but not limited to, acetate, adipate, benzoate, citrate, camphorester, camphorsulfonate, digluconate, dodecyl sulfate, ethyl ethane sulfonate, fumarate, glucose heptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, lactate, maleate, oxalate.
By means of the scheme, the invention has at least the following advantages:
the invention discloses a compound shown in formula I, which can be used for preparing EP of PGE2 4 Receptor antagonists or preparation of preparations for inhibiting cell and enzyme proliferation, for therapeutic use and EP 4 Receptor-related diseases offer new directions.
The foregoing description is only an overview of the present invention, and is presented in terms of preferred embodiments of the present invention and the following detailed description of the invention in conjunction with the accompanying drawings.
Drawings
FIG. 1 is the results of the effect of different compounds on tumor growth in colorectal cancer CT-26 cell tumor-bearing mice.
Detailed Description
The following describes the embodiments of the present invention in further detail with reference to examples. The following examples are illustrative of the invention and are not intended to limit the scope of the invention.
In the following examples, biotage SP4 was used for column chromatography unless otherwise specified; solvent removal was performed using a buchi rotary evaporator or a Genevac centrifugal evaporator; LC/MS was prepared under acidic mobile phase conditions using a Waters auto purifier and a 19x100mmxterra 5 micron MS CI8 column; nuclear magnetic resonance spectra were recorded with a warrior 400MHz spectrometer. When the term "inert" is used to describe a reactor (e.g., reaction vessel, flask, glass reactor, etc.), it is meant that the air in the reactor has been replaced with an inert gas (e.g., nitrogen, argon, etc.) that is substantially free of water or dry.
The following abbreviations have the indicated meanings:
HATU 2- (7-azobenzotriazole) -N, N' -tetramethylurea hexafluorophosphate; DPCI, N' -diisopropylcarbodiimide; DIEA: N, N-diisopropylethylamine; TEA, triethylamine; DMAP 4-dimethylaminopyridine; DMF is N, N-dimethylformamide; NMP N-methylpyrrolidone; THF: tetrahydrofuran; DCM: dichloromethane; TFA, trifluoroacetic acid; TLC, thin layer chromatography; structure is shown in the structural formula.
The compounds shown in table 1 are commercially available or prepared according to known literature methods:
the compounds A-1, A-2, A-3, A-5, A-21 are commercially available; reference to methods for the preparation of Compound A-4 Journal of Medicinal Chemistry,57 (7), 3040-3052;2014,Tetrahedron Letters,55 (13), 2056-2060;2014; methods for the preparation of Compound A-6 reference European Journal of Medicinal Chemistry,49,379-396;2012, wo2014073627; reference to methods for the preparation of Compound A-7 Journal of the American Chemical Society,140 (27), 8429-8433;2018, synthesis, (16), 2751-2757;2005, a step of detecting a defect; reference to methods for the preparation of compound a-8 WO 2012080450, WO 2011107884; WO2017100594 as a reference for the preparation of compound A-9; reference is made to the preparation of compound A-10 by ChemSusChem,12 (13), 3144-3151,2019; reference to methods of preparation of compound a-11 CN 102675311,Tetrahedron Letters 53 (15), 2005-2008,2012; WO 2003044014 A1,EP1314733A1 as a reference for the preparation of compound A-12; reference is made to the preparation of the compound A-13 from EP1479680A1, WO 2004031188; WO2003022856 as a reference for the preparation of compound A-14; reference is made to the preparation of compound A-15, WO9940913, JP 2004339176; reference is made to the preparation of compounds A-16 and A-17, WO2011013752, WO 2018119395; reference to the preparation of Compounds A-18, A-19 and A-20 WO2009037001
TABLE 1 Structure of different Compounds
Figure BDA0003329505840000141
Starting materials B-1 to B-42 (Table 2) are commercially available in addition to compound B-24; b-24 is according to WO2013092979 or RSC Advances,3 (24), 9391-9401; 2013.
TABLE 2 Structure of different Compounds
Figure BDA0003329505840000151
Compounds C-1 to C-10 (Table 3) are commercially available or are prepared in accordance with the literature. In particular, compounds C-1, C-2, C-3 and C-5 are commercially available; c-4 preparation methods reference WO2017156179, WO2006057845; ACS Catalysis,10 (1), 405-411;2020, wo 201110678; c-7 preparation methods reference Bioorganic & Medicinal Chemistry Letters,29 (17), 2503-2510;2019, wo2017156165; c-8 preparation methods reference WO2018214980, WO2009012375; reference is made to the preparation of C-9 from WO2018189340, US20080103182; reference is made to the preparation of C-10 from EP3101009 and WO2016193461.
TABLE 3 Structure of different Compounds
Figure BDA0003329505840000152
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Example 1: methyl (S) -4- (1- (3-chloro-1- (3- (trifluoromethyl) benzyl) -1H-indole-2-carboxamide) ethyl) benzoate (I-1)
Figure BDA0003329505840000161
The first step: preparation of 3-chloro-1H-indole-2-carboxylic acid methyl ester (7)
To a solution of methyl 1H-indole-2-carboxylate (A-1, 3.0g,17.1 mmol) in anhydrous DMF (30 mL) was added NCS (3.4 g,25.7 mmol) at room temperature. After stirring for 2 hours, the reaction mixture was poured onto crushed ice, the precipitate was filtered off and dried to obtain a crude product. The crude product was purified by column chromatography on silica gel, petroleum ether-ethyl acetate (10:1) to give intermediate 7 (2.6 g,75% yield).
1 H NMR(400MHz,CDCl3)δ7.70(d,J＝8.1Hz,1H),7.42–7.31(m,2H),7.20(ddd,J＝7.9,6.5,1.2Hz,1H),3.97(s,3H),LCMS:m/z 210.1[M+H] + 。
And a second step of: preparation of 3-chloro-1- (3- (trifluoromethyl) benzyl) -1H-indole-2-carboxylic acid methyl ester (8)
To a solution of methyl 3-chloro-1H-indole-2-carboxylate (7, 3.3g,15.7 mmol) in anhydrous DMF (33 mL) was added potassium carbonate (2.6 g,18.9mol,1.2 eq) and 1- (bromomethyl) -3- (trifluoromethyl) benzene (B-1, 4.12g,17.2mmol,1.1 eq), and after stirring at room temperature for 2 hours, the reaction mixture was poured into crushed ice, the solid filtered off and the filtrate dried to give an oil. The crude product was purified by silica gel column chromatography, petroleum ether-ethyl acetate (10:1) to give intermediate 8 (4.5 g, yield 77.3%).
1 H NMR(400MHz,DMSO-d6)δ13.63(s,1H),7.69(dd,J＝8.2,5.2Hz,2H),7.60(d,J＝7.8Hz,1H),7.56(s,1H),7.51(t,J＝7.8Hz,1H),7.42(ddd,J＝8.4,7.1,0.9Hz,1H),7.31–7.20(m,2H),5.97(s,2H),3.99(s,3H)，LCMS:m/z368.1[M+H] + 。
And a third step of: preparation of 3-chloro-1- (3- (trifluoromethyl) benzyl) -1H-indole-2-carboxylic acid (9)
To a mixture of 3-chloro-1- (3- (trifluoromethyl) benzyl) -1H-indole-2-carboxylic acid methyl ester (8, 5.6g,15.2mol,1 eq) in THF (112 mL) and water (28 mL) was added sodium hydroxide (1.92 g,45.7mol,3 eq). The reaction mixture was heated to 50 ℃ -60 ℃. Monitored by thin layer chromatography until complete consumption of starting material 8. The reaction mixture was concentrated under reduced pressure, and the pH was adjusted to 5-6 with dilute hydrochloric acid, followed by extraction with ethyl acetate (20 ml. Times.3). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The product was purified by column chromatography on silica gel with methylene chloride-methanol (10:1) to give intermediate 9 (4.0 g, 75% yield).
1 HNMR(400MHz,DMSO-d6)δ13.63(s,1H),7.69(dd,J＝8.2,5.2Hz,2H),7.60(d,J＝7.8Hz,1H),7.56(s,1H),7.51(t,J＝7.8Hz,1H),7.42(ddd,J＝8.4,7.1,0.9Hz,1H),7.31–7.20(m,2H),5.97(s,2H)，LCMS:m/z 354.1[M+H] + 。
Fourth step: (S) -methyl 4- (1- (3-chloro-1- (3- (trifluoromethyl) benzyl) -1H-indole-2-carboxamide) ethyl) benzoate (I-1)
To a mixture of intermediate 9 (0.35 g,1mmol,1 eq) in DIPEA (0.4 mL,2.0mmol,2 eq) in DMF (5 mL) was added HATU (0.45 g,1.2mmol,1.2 eq) under nitrogen. After stirring the reaction mixture at room temperature for 30 min, methyl (S) -4- (1-aminoethyl) benzoate (C-1, 0.22g,1.2mmol,1.2 eq) was added to the solution and stirred until intermediate 9 completely disappeared on TLC. The reaction mixture was poured onto crushed ice and the precipitate was filtered off to give a crude mixture. The crude product was purified by silica gel column chromatography, petroleum ether-ethyl acetate (10:1) to give compound I-1 (0.33 g, yield 65%).
1 H NMR(400MHz,DMSO)δ9.26(d,J＝7.8Hz,1H),7.85(d,J＝8.3Hz,2H),7.69–7.57(m,3H),7.55(s,1H),7.46(dd,J＝7.9,4.1Hz,3H),7.39–7.30(m,1H),7.25(t,J＝7.5Hz,2H),5.74-5.53(m,2H),5.18(p,J＝7.0Hz,1H),3.84(s,3H),1.44(d,J＝7.0Hz,3H)，LCMS:m/z515.1[M+H] + 。
Example 2: (S) -4- (1- (3- ((3-chlorophenyl) amino) -1-methyl-1H-indole-2-carboxamide) ethyl) benzoate (I-2)
1. Synthetic intermediate 11
Figure BDA0003329505840000171
The first step: preparation of 3-bromo-1H-indole-2-carboxylic acid methyl ester (10)
This reaction procedure was similar to the first step of example 1, substituting NCS for NBS, to afford intermediate 10 (69.2% yield).
1 HNMR(400MHz,CDCl3)δ7.70(d,J＝8.1Hz,1H),7.42–7.31(m,2H),7.20(ddd,J＝7.9,6.5,1.2Hz,1H),3.97(s,3H),LCMS:m/z253.9[M+H] + 。
And a second step of: preparation of 3-bromo-1-methyl-1H-indole-2-carboxylic acid methyl ester (11)
To a solution of intermediate 10 (5.7 g,22.4mmol,1 eq) in anhydrous DMF (57 mL) was added potassium carbonate (6.0 g,44.89mmol,2 eq) and methyl iodide (B-2, 3.18g,22.4mmol,1 eq) and after stirring at room temperature for 2 hours the reaction mixture was poured onto crushed ice and the solid filtered and dried. Intermediate 11 was purified by silica gel column chromatography to give intermediate 11 (4.6 g, yield 76.8%).
1 HNMR(400MHz,CDCl3)δ7.70(d,J＝8.1Hz,1H),7.42–7.31(m,2H),7.20(ddd,J＝7.9,6.5,1.2Hz,1H),3.99(s,3H),3.92(s,3H),LCMS:m/z267.9[M+H] + 。
2. Synthesis of intermediate 13
Figure BDA0003329505840000172
The first step: general procedure for Buchwald reaction conditions:
to intermediate 11 (1.0 mmol) and raw RNH under nitrogen atmosphere 2 (1.2 mmol) to a mixture solution of toluene (5 mL) was added Pd (OAc) 2 (0.1 mmol), BINAP (0.15 mmol) and t-Buona (2 eq). The reaction mixture was stirred at 65-80 for about 2h, monitored by thin layer chromatography, and then diluted with water. The organic layer was separated, washed with brine, and dried Na 2 SO 4 Drying, concentrating under reduced pressure to obtain crude mixture, and purifying with petroleum ether-ethyl acetate (10:1) silica gel column chromatography to obtain intermediate 12.
And a second step of: general procedure for methyl ester hydrolysis
To a mixture of intermediate 12 (1 mmol) in THF (10 mL) and water (2.5 mL) was added sodium hydroxide (2 mmol) and the reaction mixture was heated to 50 ℃ to 60 ℃ until intermediate 12 completely disappeared on TLC. The reaction mixture was concentrated under reduced pressure, and after adjusting pH to 5-6 with dilute hydrochloric acid, extracted with ethyl acetate (10 ml. Times.3), anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure to obtain crude product, and purifying with petroleum ether-ethyl acetate (10:1) silica gel column chromatography to obtain intermediate 13.
Synthesis of intermediates 12a-12u and 13a-13u (Table 4) was prepared as per the protocol described above
TABLE 4 Structure and molecular weight of different Compounds
Figure BDA0003329505840000181
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Figure BDA0003329505840000191
3. Synthetic intermediate 14
Figure BDA0003329505840000192
HATU (1.5 mmol) was added to a mixture of intermediate 13 (1 mmol) and DIPEA (3 mmol) in DMF (8 mL) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 30min before adding starting material C-1 (1.0 mmol) to the above solution. After the reaction mixture was stirred for about 2 hours and the completion of the reaction was monitored by thin layer chromatography, the reaction mixture was poured onto crushed ice, and the precipitate was filtered to obtain a crude product, which was purified by silica gel column chromatography using petroleum ether-ethyl acetate (10:1) to obtain intermediate 14.
Compound I-2 was prepared in a similar manner to intermediate 14 using intermediate 13a and methyl (S) -4- (1-aminoethyl) benzoate (C-1).
1 HNMR(400MHz,DMSO-d6)δ8.64(d,J＝7.6Hz,1H),7.97(s,1H),7.84(d,J＝8.2Hz,2H),7.64(d,J＝8.4Hz,1H),7.40(td,J＝16.3,7.8Hz,4H),7.16(dt,J＝11.8,7.7Hz,2H),6.75(d,J＝7.7Hz,1H),6.67–6.52(m,2H),5.19(p,J＝6.9Hz,1H),3.99(s,3H),3.88(s,3H),1.40(d,J＝7.0Hz,3H)，LCMS:m/z462.1[M+H] + . Example 3: (S) -methyl 4- (1- (1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoate (I-3)
Compound I-3 was prepared in a similar manner to intermediate 14 using intermediate 13b and methyl (S) -4- (1-aminoethyl) benzoate (C-1).
1 HNMR(400MHz,DMSO-6)δ8.62(d,J＝7.7Hz,1H),8.09(s,1H),7.77(d,J＝8.3Hz,2H),7.60(d,J＝8.4Hz,1H),7.41(d,J＝8.0Hz,1H),7.37-7.25(m,4H),7.10(t,J＝7.5Hz,1H),6.99(d,J＝7.7Hz,1H),6.90(s,1H),6.82(d,J＝8.2Hz,1H),5.15(t,J＝7.2Hz,1H),3.95(s,3H),3.83(s,3H),1.35(d,J＝7.0Hz,3H)，LCMS:m/z496.1[M+H] + 。
Example 4 methyl (S) -4- (1- (1-methyl-3- ((3-nitrophenyl) amino) -1H-indole 2-carboxamide) ethyl) benzoate (I-4)
Compound I-4 was prepared in a similar manner to intermediate 14 using intermediate 13C and methyl (S) -4- (1-aminoethyl) benzoate (C-1).
1 HNMR(400MHz,DMSO)δ8.71(d,J＝7.8Hz,1H),8.33(s,1H),7.84(d,J＝8.2Hz,2H),7.71(d,J＝8.4Hz,1H),7.58(dd,J＝8.0,1.5Hz,1H),7.45(ddd,J＝15.3,13.2,5.1Hz,6H),7.20(t,J＝7.5Hz,1H),7.08(dd,J＝8.0,1.2Hz,1H),5.25(p,J＝6.9Hz,1H),4.03(s,3H),3.93(s,3H),1.46(d,J＝7.0Hz,3H)，LCMS:m/z473.2[M+H] + 。
Similarly, intermediates 14d-14u (Table 5) were prepared according to the preparation method of intermediate 14, starting with intermediates 13d-13u, respectively.
TABLE 5 Structure and molecular weight of different Compounds
Figure BDA0003329505840000211
Example 5 (S) -4- (1- (3-chloro-1- (3- (trifluoromethyl) benzyl) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-5)
Figure BDA0003329505840000221
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To a mixture of compound I-1 (0.47 gm,1 mol) in THF (10 mL) and water (2.5 mL) at room temperature was added sodium hydroxide (0.11 g,3.1 mmol). The reaction mixture was heated to 50 ℃ -60 ℃ until compound I-1 completely disappeared on TLC. The reaction mixture was then concentrated under reduced pressure, adjusted to pH 5-6 with dilute HCl, then extracted with ethyl acetate, anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure to obtain a crude product. The product was purified by column chromatography on silica gel (dichloromethane-methanol 10:1) to give compound I-5 (0.32 g, 65%).
1 HNMR(400MHz,DMSO)δ9.25(d,J＝7.9Hz,1H),7.85(d,J＝8.3Hz,2H),7.69–7.57(m,3H),7.55(s,1H),7.47(dd,J＝11.1,8.1Hz,3H),7.39–7.30(m,1H),7.30–7.19(m,2H),5.72–5.56(m,2H),5.18(p,J＝7.0Hz,1H),1.44(d,J＝7.0Hz,3H)，LCMS:m/z501.1[M+H] + 。
Example 6 (S) -4- (1- (1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-6)
Figure BDA0003329505840000222
To a mixture of compound I-3 (0.49 g,1 mmol) in THF (10 mL) and water (2.5 mL) at room temperature was added sodium hydroxide (0.11 g,3.1 mmol). The reaction mixture was heated to 50 ℃ -60 ℃ until compound I-3 completely disappeared on TLC. The reaction mixture was then concentrated under reduced pressure, adjusted to pH 5-6 with dilute HCl, then extracted with ethyl acetate (10 mL. Times.3), and concentrated over anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure to obtain crude product. The crude product was purified by column chromatography on silica gel (dichloromethane-methanol 10:1) to give compound I-6 (0.65 g, 70%).
1 H NMR(400MHz,DMSO-d6)δ12.82(s,1H),8.58(d,J＝7.7Hz,1H),8.07(s,1H),7.73(d,J＝8.2Hz,2H),7.60(d,J＝8.4Hz,1H),7.38(d,J＝8.0Hz,1H),7.31(dd,J＝13.7,8.4Hz,4H),7.09(t,J＝7.5Hz,1H),6.98(d,J＝7.6Hz,1H),6.86(s,1H),6.81(d,J＝8.2Hz,1H),5.18–5.04(m,1H),3.94(s,3H),1.32(d,J＝6.9Hz,3H)，LCMS:m/z482.2[M+H] + ，[α] 20 ＝+159.6(C＝1,CH 3 OH)。
Example 7 (S) -4- (1- (3- ((3, 5-dimethylphenyl) amino) -1-methyl-1H-indole-2-carboxamide) ethyl) benzoic acid (I-7)
Compound I-7 was prepared in a similar manner to that for compound I-6 in example 6 using intermediate 14d and sodium hydroxide.
LCMS:m/z442.2[M+H] + 。
Example 8 (S) -4- (1- (3- ((3-fluorophenyl) amino) -1-methyl-1H-indole-2-carboxamide) ethyl) benzoic acid (I-8)
Compound I-8 was prepared in a similar manner to that for compound I-6 in example 6 using intermediate 14e and sodium hydroxide.
1 HNMR(400MHz,DMSO-d6)δ12.84(s,1H),8.58(d,J＝7.6Hz,1H),7.93(s,1H),7.75(d,J＝8.3Hz,2H),7.59(d,J＝8.4Hz,1H),7.38(d,J＝8.0Hz,1H),7.35–7.27(m,3H),7.11(dt,J＝23.7,7.8Hz,2H),6.46(ddd,J＝10.1,6.4,2.0Hz,2H),6.27(dt,J＝11.8,2.2Hz,1H),5.19–5.05(m,1H),3.93(s,3H),1.34(d,J＝7.0Hz,3H)，LCMS:m/z432.2[M+H] + ，[α] 20 ＝+105.3(C＝1,CH 3 OH)。
Example 9 (S) -4- (1- (3- ((3-chlorophenyl) amino) -1-methyl-1H-indole-2-carboxamide) ethyl) benzoic acid (I-9)
Compound I-9 was prepared in a similar manner to that for compound I-6 in example 6 using compound I-2 and sodium hydroxide.
1 HNMR(400MHz,DMSO-d6)δ12.85(s,1H),8.59(d,J＝7.6Hz,1H),7.93(s,1H),7.77(d,J＝8.2Hz,2H),7.59(d,J＝8.4Hz,1H),7.39(d,J＝8.0Hz,1H),7.32(d,J＝8.2Hz,3H),7.18–7.05(m,2H),6.71(dd,J＝7.8,1.1Hz,1H),6.62–6.55(m,1H),6.53(d,J＝1.8Hz,1H),5.14(p,J＝6.9Hz,1H),3.94(s,3H),1.35(d,J＝7.0Hz,3H),LCMS:m/z448.1[M+H] + ，[α] 20 ＝+182.3(C＝1,CH 3 OH)。
Example 10 (S) -4- (1- (3- ((3-bromophenyl) amino) -1-methyl-1H-indole-2-carboxamide) ethyl) benzoic acid (I-10)
Compound I-10 was prepared in a similar manner to that used to prepare Compound I-6 in example 6 using intermediate 14f and sodium hydroxide.
LCMS:m/z492.1[M+H] + 。
Example 11 (S) -4- (1- (1-methyl-3- (m-toluidinyl) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-11)
Compound I-11 was prepared in a similar manner to that for compound I-6 in example 6 using intermediate 14g and sodium hydroxide.
1 HNMR(400MHz,DMSO-d6)δ12.84(s,1H),8.78(d,J＝7.6Hz,1H),7.81(d,J＝8.2Hz,2H),7.69(s,1H),7.63(d,J＝8.4Hz,1H),7.43(d,J＝7.9Hz,1H),7.35(dd,J＝13.5,7.9Hz,3H),7.09(dt,J＝21.6,7.6Hz,2H),6.60(d,J＝7.4Hz,1H),6.48(d,J＝7.7Hz,2H),5.17(p,J＝6.9Hz,1H),4.03(s,3H),2.21(s,3H),1.38(d,J＝6.9Hz,3H)，LCMS:m/z428.2[M+H] + ，[α] 20 ＝+373.9(C＝1,CH 3 OH)。
Example 12 (S) -4- (1- (3- ((3-methoxyphenyl) amino) -1-methyl-1H-indole-2-carboxamide) ethyl) benzoic acid (I-12)
Compound I-12 was prepared in a similar manner to that for compound I-6 in example 6 using intermediate 14h and sodium hydroxide.
LCMS:m/z444.2[M+H] + 。
Example 13 (S) -4- (1- (1-methyl-3- ((4- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-13)
Compound I-13 was prepared in a similar manner to that for compound I-6 in example 6 using intermediate 14I and sodium hydroxide.
1 HNMR(400MHz,DMSO-d6)δ12.76(s,1H),8.52(d,J＝7.7Hz,1H),8.19(s,1H),7.73(d,J＝8.3Hz,2H),7.59(d,J＝8.4Hz,1H),7.42(d,J＝8.6Hz,2H),7.37(d,J＝8.0Hz,1H),7.30(dd,J＝16.2,7.8Hz,3H),7.09(t,J＝7.5Hz,1H),6.68(d,J＝8.5Hz,2H),5.12(p,J＝6.9Hz,1H),3.92(s,3H),1.34(d,J＝7.0Hz,3H)，LCMS:m/z482.2[M+H] + 。
Example 14 (S) -4- (1- (3- ((3, 5-bis (trifluoromethyl) phenyl) amino) -1-methyl-1H-indole-2-carboxamide) ethyl) benzoic acid (I-14)
Compound I-14 was prepared in a similar manner to that used to prepare Compound I-6 in example 6 using intermediate 14j and sodium hydroxide.
LCMS:m/z550.1[M+H] + 。
Example 15 (S) -4- (1- (3- ((4-chloro-3- (trifluoromethyl) phenyl) amino) -1-methyl-1H-indole-2-carboxamide) ethyl) benzoic acid (I-15)
Compound I-15 was prepared in a similar manner to that used to prepare Compound I-6 in example 6 using intermediate 14k and sodium hydroxide.
LCMS:m/z516.1[M+H] + 。
EXAMPLE 16 (S) -4- (1- (1-methyl-3- ((3- (pyrrolidin-1-yl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-16)
Compound I-16 was prepared in a similar manner to that for compound I-6 in example 6 using intermediate 14l and sodium hydroxide.
LCMS:m/z483.2[M+H] + 。
EXAMPLE 17 (S) -4- (1- (1-methyl-3- ((3-morpholinophenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-17)
Compound I-17 was prepared in a similar manner to that used to prepare Compound I-6 in example 6 using intermediate 14m and sodium hydroxide.
LCMS:m/z499.2[M+H] + 。
Example 18 (S) -4- (1- (5-fluoro-1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-18)
1. Preparation of intermediate 19 and intermediate 20
Figure BDA0003329505840000241
Intermediates 19a-19e and 20a-20e (Table 6) were prepared according to the procedure above:
step 1: intermediates 19a-19e were prepared in a similar manner to that of intermediate 10 starting from A-2, A-3, A-4, A-5, A-6 and NBS, respectively.
Step 2: intermediates 20a-20e were prepared in a similar manner to intermediate 11 starting from intermediates 19a-19d and methyl iodide (B-2), respectively.
TABLE 6 Structure and molecular weight of different Compounds
Figure BDA0003329505840000242
2. Preparation of intermediate 21 and intermediate 22
Figure BDA0003329505840000251
Intermediates 21a-21e and 22a-22e were prepared by the routes above:
step 1: intermediates 21a-21e were prepared in a similar manner to intermediate 12 using intermediates 20a-20e and 3- (trifluoromethyl) aniline (B-4) as starting materials, respectively.
Step 2: intermediates 22a-22e were prepared in a similar manner to intermediate 13 using intermediates 21a-21e and sodium hydroxide, respectively, as starting materials.
TABLE 7 Structure and molecular weight of different Compounds
Figure BDA0003329505840000252
3. Preparation of intermediate 23
Figure BDA0003329505840000253
Intermediate 23 was prepared in a similar manner to that for intermediate 14 using intermediate 22 and methyl (S) -4- (1-aminoethyl) benzoate (C-1) as starting materials. Intermediates 23a-23e (Table 8) were prepared according to the routes described above.
TABLE 8 Structure and molecular weight of different Compounds
Figure BDA0003329505840000261
I-18 was prepared in a similar manner to that for compound I-6 using intermediate 23a and sodium hydroxide as starting materials.
LCMS:m/z500.1[M+H] + 。
Example 19 (S) -4- (1- (5-chloro-1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-19)
Compound I-19 was prepared in a similar manner to that for compound I-6 using intermediate 23b and sodium hydroxide as starting materials.
LCMS:m/z516.1[M+H] + 。
Example 20 (S) -4- (1- (6-chloro-1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-20)
Compound I-20 was prepared in a similar manner to that for compound I-6 using intermediate 23c and sodium hydroxide as starting materials.
LCMS:m/z516.1[M+H] + 。
Example 21 (S) -4- (1, 5-dimethyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-21)
Compound I-21 was prepared in a similar manner to that for compound I-6 using intermediate 23d and sodium hydroxide as starting materials.
LCMS:m/z496.2[M+H] + 。
EXAMPLE 22 (S) -4- (1- (1- (methyl-d 3) -3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-22)
1. Synthesis of intermediate 24
Figure BDA0003329505840000262
Intermediates 24a-24f were prepared in a similar manner to intermediate 11 using intermediates 10 and B-1, B-15, B-16, B-17, B-18 and B-19, respectively, as starting materials (Table 9).
TABLE 9 Structure and molecular weight of different Compounds
Figure BDA0003329505840000271
2. Synthetic intermediate 26
Figure BDA0003329505840000272
Intermediates 25a-25f and 26a-26f (Table 10) were prepared according to the above routes:
step 1: intermediate 25 was prepared in a similar manner to intermediate 12 using intermediate 24 and 3- (trifluoromethyl) aniline (B-4) as starting materials.
Step 2: intermediate 26 was prepared in a similar manner to intermediate 13 using intermediate 25 and sodium hydroxide as starting materials.
TABLE 10 Structure and molecular weight of different Compounds
Figure BDA0003329505840000273
3. Synthesis of intermediate 27
Figure BDA0003329505840000281
Intermediates 27a-27f (Table 11) were prepared according to the route above: intermediate 27 was prepared in a similar manner to that for intermediate 14 using intermediate 26 and methyl (S) -4- (1-aminoethyl) benzoate (C-1) as starting materials.
TABLE 11 Structure and molecular weight of different Compounds
Figure BDA0003329505840000282
Compound I-22 was prepared in a similar manner to that of compound I-6 in scheme 7 using intermediate 27a and sodium hydroxide as starting materials. LCMS (liquid Crystal Module):m/z485.2[M+H] + 。
Example 23 (S) -4- (1- (1-ethyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-23)
Compound I-23 was prepared in a similar manner to that for compound I-6 using intermediate 27b and sodium hydroxide as starting materials. LCMS: M/z496.2[ M+H ]] + 。
Example 24 (S) -4- (1- (1- (2-hydroxyethyl) -3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-24)
Compound I-24 was prepared in a similar manner to that for compound I-6 using intermediate 27c and sodium hydroxide as starting materials.
LCMS:m/z512.2[M+H] + 。
Example 25 (S) -4- (1- (1-isobutyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-25)
Compound I-25 was prepared in a similar manner to that for compound I-6 using intermediate 27d and sodium hydroxide as starting materials.
LCMS:m/z524.2[M+H] + 。
EXAMPLE 26 (S) -4- (1- (1-benzyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-26)
Compound I-26 was prepared in a similar manner to that for compound I-6 using intermediate 27e and sodium hydroxide as starting materials.
LCMS:m/z558.2[M+H] + 。
EXAMPLE 27 (R) -4- (1- (1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-27)
Figure BDA0003329505840000291
Step 1: intermediate 28 was prepared in a similar manner to intermediate 14 using intermediate 13b and methyl (R) -4- (1-aminoethyl) benzoate (C-2) as starting materials.
Step 2: i-27 was prepared in a similar manner to that for compound I-6 using intermediate 28 and sodium hydroxide as starting materials.
1 HNMR(400MHz,DMSO-d6)δ12.82(s,1H),8.62(d,J＝7.7Hz,1H),8.11(s,1H),7.78(d,J＝8.3Hz,2H),7.64(d,J＝8.4Hz,1H),7.43(d,J＝8.0Hz,1H),7.40–7.29(m,4H),7.13(t,J＝7.4Hz,1H),7.03(d,J＝7.6Hz,1H),6.92(s,1H),6.86(d,J＝8.2Hz,1H),5.17(p,J＝7.0Hz,1H),3.98(s,3H),1.37(d,J＝7.0Hz,3H)，LCMS:m/z496.2[M+H] + ，[α] 20 ＝-177.2(C＝1,CH 3 OH)。
EXAMPLE 28 (S) -4- (1- (1-methyl-3- (pyridin-2-ylamino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-28)
Compound I-28 was prepared in a similar manner to that for compound I-6 using intermediate 14n and sodium hydroxide as starting materials.
LCMS:m/z415.2[M+H] + 。
Example 29 (S) -4- (1- (1-methyl-3- ((6-methylpyridin-2-yl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-29)
Compound I-29 was prepared in a similar manner to that for compound I-6 using intermediate 14o and sodium hydroxide as starting materials.
LCMS:m/z429.2[M+H] + 。
EXAMPLE 30 (S) -4- (1- (1-methyl-3- (3- (trifluoromethyl) phenoxy) -1H-indole 2-carboxamide) ethyl) benzoic acid (I-30)
1. Synthetic intermediate 31
Figure BDA0003329505840000301
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Intermediates 29a, 29B can be prepared from intermediate 11 and intermediate 3 to prepare- (trifluoromethyl) phenol (B-22) and 3- (trifluoromethyl) benzenethiol (B-23) respectively following a similar procedure as in WO 2019199979. Intermediate 29c was prepared in a similar manner to WO2007068621 using intermediate 11 and 4, 5-tetramethyl-2- (3- (trifluoromethyl) benzyl) -1,3, 2-dioxolane (B-24). Intermediate 30a-C was obtained in a similar manner to intermediate 12 starting from intermediate 29a-C methyl ester, which was coupled to methyl (S) -4- (1-aminoethyl) benzoate (C-1) (step 2) to prepare intermediate 31a-C, respectively, in a similar manner to intermediate 14.
31a：LCMS:m/z497.2[M+H] + 。
31b： 1 H NMR(400MHz,DMSO-d 6 )δ9.29(d,J＝7.7Hz,1H),7.83(d,J＝8.3Hz,2H),7.67(d,J＝8.3Hz,1H),7.52(dd,J＝13.2,8.1Hz,3H),7.45–7.30(m,4H),7.26–7.08(m,2H),5.20(p,J＝7.1Hz,1H),3.85(s,3H),3.83(s,3H),1.46(d,J＝7.0Hz,3H)，LCMS:m/z513.2[M+H] + 。
31c： 1 H NMR(400MHz,DMSO-d 6 )δ9.18(d,J＝7.9Hz,1H),7.91(d,J＝8.1Hz,2H),7.59(d,J＝7.8Hz,1H),7.53(d,J＝7.8Hz,3H),7.48(t,J＝7.3Hz,2H),7.45–7.36(m,2H),7.24(t,J＝7.6Hz,1H),7.05(t,J＝7.5Hz,1H),5.30–5.15(m,1H),4.35–4.16(m,2H),3.84(s,3H),3.74(s,3H),1.48(d,J＝7.0Hz,3H),LCMS:m/z495.2[M+H] + 。
2. Synthesis of I-30
Compound I-30 was prepared in a similar manner to that for compound I-6 using intermediate 31a and sodium hydroxide as starting materials.
LCMS:m/z483.2[M+H] + 。
Example 31 (S) -4- (1- (1-methyl-3- ((3- (trifluoromethyl) phenyl) thio) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-31)
Compound I-31 was prepared in a similar manner to that for compound I-6 using intermediate 31b and sodium hydroxide as starting materials.
1 H NMR(400MHz,DMSO-d 6 )δ12.85(s,1H),9.27(d,J＝7.6Hz,1H),7.81(d,J＝8.2Hz,2H),7.75–7.62(m,2H),7.50(dd,J＝8.1,3.7Hz,2H),7.46–7.31(m,4H),7.20(t,J＝7.7Hz,2H),5.28–5.09(m,1H),3.85(s,3H),1.45(d,J＝7.0Hz,3H).
LCMS:m/z499.1[M+H] + 。
EXAMPLE 32 (S) -4- (1- (1-methyl-3- (3- (trifluoromethyl) benzyl) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-32)
Compound I-32 was prepared in a similar manner to that for compound I-6 using intermediate 31c and sodium hydroxide as starting materials.
1 H NMR(400MHz,DMSO)δ12.87(s,1H),9.16(d,J＝7.9Hz,1H),7.89(d,J＝8.2Hz,2H),7.59(d,J＝8.0Hz,1H),7.56–7.35(m,7H),7.24(t,J＝7.6Hz,1H),7.05(t,J＝7.5Hz,1H),5.24(p,J＝7.0Hz,1H),4.34–4.16(m,2H),3.74(s,3H),1.47(d,J＝7.0Hz,3H).
LCMS:m/z481.2[M+H] + 。
Example 33 (S) -4- (1- (3- (cyclohexylamino) -1-methyl-1H-indole-2-carboxamide) ethyl) benzoic acid (I-33)
Compound I-33 was prepared in a similar manner to that for compound I-6 using intermediate 14p and sodium hydroxide as starting materials.
LCMS:m/z420.2[M+H] + 。
Example 34 (S) -4- (1- (3- (tert-butylamino) -1-methyl-1H-indole-2-carboxamide) ethyl) benzoic acid (I-34)
Compound I-34 was prepared in a similar manner to that for compound I-6 using intermediate 14q and sodium hydroxide as starting materials.
LCMS:m/z394.2[M+H] + 。
Example 35 (S) -4- (1- (1-methyl-3- (naphthalen-1-ylamino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-35)
Compound I-35 was prepared in a similar manner to that for compound I-6 using intermediate 14r and sodium hydroxide as starting materials.
LCMS:m/z464.2[M+H] + 。
EXAMPLE 36 (S) -4- (1- (1-methyl-3- (pyridin-4-amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-36)
Compound I-36 was prepared in a similar manner to that for Compound I-6 using intermediate 14s and sodium hydroxide as starting materials.
LCMS:m/z415.2[M+H] + 。
Example 37 (S) -4- (1- (1- (3- (trifluoromethyl) benzyl) -3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-37)
Compound I-37 was prepared in a similar manner to that for compound I-6 using intermediate 27f and sodium hydroxide as starting materials.
LCMS:m/z626.2[M+H] + 。
EXAMPLE 38 (S) -4- (1- (1-methyl-5- (trifluoromethyl) -3- ((3- (trifluoro-methyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-38)
Compound I-38 was prepared in a similar manner to that for compound I-6 using intermediate 23e and sodium hydroxide as starting materials.
LCMS:m/z550.2[M+H] + 。
Example 39 (S) -4- (1- (1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-pyrrole [2,3-b ] pyridine-2-carboxamide) ethyl) benzoic acid (I-39)
1. Synthetic intermediates 36a-c
Figure BDA0003329505840000321
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Intermediates 36a-c were prepared following the above route using A-7, A-8 and A-9 as starting materials (Table 12). Specifically, the bromination step (step 1) was prepared using NBS in a similar manner to that for preparing intermediate 10. Alkylation step (step 2) was prepared using methyl iodide (B-2) in a similar manner to the preparation of intermediate 11. Buchwald reaction step (step 3) was prepared using 3- (trifluoromethyl) aniline (B-4) in a similar manner to that for intermediate 12. The hydrolysis step (step 4) was prepared in a similar manner to the preparation of intermediate 13 using sodium hydroxide to obtain intermediates 35a-c. Intermediate 36a-c was prepared by a coupling reaction using intermediate 35a-c and methyl (S) -4- (1-aminoethyl) benzoate (c-1) as starting materials in a manner analogous to that for intermediate 14.
TABLE 12 Structure and molecular weight of different Compounds
Figure BDA0003329505840000322
2. Synthesis of Compound I-39
Compound I-39 was prepared in a similar manner to that for compound I-6 using intermediate 36a and sodium hydroxide as starting materials.
1 H NMR(400MHz,DMSO)δ12.78(s,1H),8.67(d,J＝7.7Hz,1H),8.44(dd,J＝4.5,1.2Hz,1H),8.13(s,1H),7.83(dd,J＝7.9,1.1Hz,1H),7.74(d,J＝8.2Hz,2H),7.38–7.26(m,3H),7.16(dd,J＝7.9,4.6Hz,1H),7.00(d,J＝7.7Hz,1H),6.91(s,1H),6.83(d,J＝8.2Hz,1H),5.13(p,J＝7.1Hz,1H),3.97(s,3H),1.33(d,J＝7.0Hz,3H).
LCMS:m/z483.2[M+H] + 。
Example 40 (S) -4- (1- (1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-pyrrole [3,2-c ] pyridine-2-carboxamide) ethyl) benzoic acid (I-40)
Compound I-40 was prepared in a similar manner to that for compound I-6 using intermediate 36b and sodium hydroxide as starting materials.
LCMS:m/z483.2[M+H] + 。
EXAMPLE 41 (S) -4- (1- (7-methyl-5- ((3- (trifluoromethyl) phenyl) amino) -7H-pyrrole [2,3-d ] pyrimidine-6-carboxamide) ethyl) benzoic acid (I-41)
Compound I-41 was prepared in a similar manner to that for compound I-6 using intermediate 36c and sodium hydroxide as starting materials.
LCMS:m/z484.2[M+H] + 。
Example 42 (S) -4- (1- (5-chloro-7- ((3- ((difluoro-l 3-methyl) -l 2-fluoroacyl) phenyl) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic oxime) ethyl) benzoic acid (I-42)
Figure BDA0003329505840000331
Intermediate 37 was prepared by the method of synthesis I-1 starting from compound A9. Compound I-42 was prepared in a similar manner to that for compound I-6 using intermediate 37 and sodium hydroxide as starting materials. LCMS: M/z503.1[ M+H ]] + .
Example 43 (S) -4- (1- (1-methyl-3- ((3-nitrophenyl) amino) -1H indole-2-carboxamide) ethyl) benzoic acid (I-43)
Compound I-43 was prepared in a similar manner to that for Compound I-6 using product I-4 and sodium hydroxide as starting materials.
1 HNMR(400MHz,DMSO-d6)δ12.78(s,1H),8.59(d,J＝7.8Hz,1H),8.24(s,1H),7.73(d,J＝8.3Hz,2H),7.61(d,J＝8.4Hz,1H),7.49(dd,J＝8.0,1.5Hz,1H),7.39(d,J＝8.2Hz,2H),7.33(dd,J＝12.0,4.6Hz,4H),7.10(t,J＝7.4Hz,1H),7.01(dd,J＝8.1,1.7Hz,1H),5.23-5.05(m,1H),3.94(s,3H),1.35(d,J＝7.0Hz,4H)，LCMS:m/z459.2[M+H] + ，[α] 20 ＝+104.4(C＝1,CH 3 OH)。
EXAMPLE 44 (S) -4- (1- (3- ((3-cyanophenyl) amino) -1-methyl-1H-indole-2-carboxamide) ethyl) benzoic acid (I-44)
Compound I-44 was prepared in a similar manner to that for Compound I-6 using intermediate 14t and sodium hydroxide as starting materials.
LCMS:m/z439.2[M+H] + 。
EXAMPLE 45 (S) -4- (1- (3- ([ 1,1' -biphenyl ] -3-amino) -1-methyl-1H-indole-2-carboxamide) ethyl) benzoic acid (I-45)
Compound I-45 was prepared in a similar manner to that for Compound I-6 using intermediate 14u and sodium hydroxide as starting materials.
LCMS:m/z490.2[M+H] + 。
EXAMPLE 46 (S) -4- (1- (3- (trifluoromethyl) -1- (3- (trifluoromethyl) benzyl) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-46)
Figure BDA0003329505840000341
Intermediate 38 was prepared following the procedure for preparation I-1 starting from compound A-11; compound I-46 was prepared in a similar manner to that for compound I-5, starting from intermediate 38 and sodium hydroxide. LCMS: M/z535.1[ M+H ]] + 。
Example 47 (S) -4- (1- (3-cyano-1- (3- (trifluoromethyl) benzyl) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-47)
Figure BDA0003329505840000342
Starting from compounds a-12 and B-1, the intermediate methyl 3-cyano-1- (3-trifluoromethyl) benzyl) -1H-indole-2-carboxylate is obtained in a similar manner to intermediate 8, and the subsequent step of methyl ester hydrolysis is prepared in a similar manner to intermediate 9, condensation of the product with methyl (S) -4- (1-aminoethyl) benzoate (C-1) to prepare compound 64, i.e. (S) -methyl 4- (1- (3-cyano-1- (3-trifluoromethyl) benzyl) -1H-indole-2-carboxamide) ethyl) benzoate 39 in a similar manner to I-1; compound I-47 was prepared in a similar manner to that for compound I-5 starting from intermediate 39 and sodium hydroxide.
1 H NMR(400MHz,DMSO-d 6 )δ12.78(s,1H),9.78(d,J＝7.8Hz,1H),7.84(d,J＝8.3Hz,2H),7.80–7.73(m,2H),7.63(d,J＝7.9Hz,1H),7.59(s,1H),7.53–7.34(m,5H),7.30(d,J＝7.8Hz,1H),5.80–5.66(m,2H),5.18(p,J＝7.0Hz,1H),1.44(d,J＝7.0Hz,3H).
LCMS:m/z492.2[M+H] + 。
EXAMPLE 48 (S) -4- (1- (3-carbamoyl) -1- (3- (trifluoromethyl) benzyl) -1H indole-2-carboxamide) ethyl) benzoic acid (I-48)
Figure BDA0003329505840000343
To dilute sulfuric acid (100 mg, 84%) was added 50mg of product I-47, the reaction mixture was stirred at 20 ℃ -30 ℃, the reaction was monitored by TLC, after completion of the reaction, a series of workup and dried in vacuo to give the crude product, which was purified by silica gel column chromatography with ethyl acetate to give compound I-48 (15 mg, 32%). LCMS M/z510.2[ M+H ]] + 。
EXAMPLE 49 (S) -4- (1- (3-chloro-1-neopentyl-1H-indole-2-carboxamide) ethyl) benzoic acid (I-49)
Figure BDA0003329505840000351
Methyl (S) -methyl (4- (1- (3-chloro-1-neopentyl-1H-indole-2-carboxamide) ethyl) benzoate (40) was prepared in a similar manner to I-1 by condensation of the product with methyl (S) -4- (1-aminoethyl) benzoate (C-1) using intermediate 7 and compound 1-bromo-2, 2-dimethylpropane (B-40) as starting materials in a similar manner to compound 8 by hydrolysis of methyl ester in a subsequent step in a similar manner to intermediate 9. The method comprises the steps of carrying out a first treatment on the surface of the
Compound I-49 was prepared in a similar manner to that for compound I-5 using intermediate 40 and sodium hydroxide as starting materials. LCMS: M/z413.2[ M+H ] ] + 。
EXAMPLE 50 4- ((1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole 2-carboxamide) methyl) benzoic acid (I-50)
1. Synthesis of intermediates 41a-41f
Figure BDA0003329505840000353
Using intermediate 13b and amines (C-3, C-4, C-5, C-6, C-7, and C-8) as starting materials, intermediates 41a-41f were prepared in a similar manner to that of intermediate 14 (Table 13).
TABLE 13 Structure and molecular weight of different Compounds
Figure BDA0003329505840000352
2. Synthesis of I-50
Compound I-50 was prepared in a similar manner to that for compound I-6 using intermediate 41a and sodium hydroxide as starting materials.
LCMS:m/z468.2[M+H] + 。
EXAMPLE 51 4- (2- (1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) propan-2-yl) benzoic acid (I-51)
Compound I-51 was prepared in a similar manner to that for compound I-6 using intermediate 41b and sodium hydroxide as starting materials.
LCMS:m/z468.2[M+H] + 。
EXAMPLE 52 4- (1- (1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) cyclopropyl) benzoic acid (I-52)
Compound I-52 was prepared in a similar manner to that for compound I-6 using intermediate 41c and sodium hydroxide as starting materials.
LCMS:m/z494.2[M+H] + 。
EXAMPLE 53 4- (1- (1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) cyclobutyl) benzoic acid (I-53)
Compound I-53 was prepared in a similar manner to that for compound I-6 using intermediate 41d and sodium hydroxide as starting materials.
LCMS:m/z508.2[M+H] + 。
EXAMPLE 54 4- (3- (1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) oxetan-3-yl) benzoic acid (I-54)
Compound I-54 was prepared in a similar manner to that for compound I-6 using intermediate 41e and sodium hydroxide as starting materials.
LCMS:m/z510.2[M+H] + 。
EXAMPLE 55 3- (1- (1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-55)
Compound I-55 was prepared in a similar manner to that for compound I-6 using intermediate 41f and sodium hydroxide as starting materials.
LCMS:m/z482.2[M+H] + 。
EXAMPLE 56N- (4- (1H-tetrazol-5-yl) benzyl) -1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide (I-56)
Figure BDA0003329505840000361
Using intermediate 13b and (4- (1H-tetrazol-5-yl) phenyl) methanamine (C-9) as starting materials, compound I-56 was prepared in a similar manner to intermediate 14, and the reaction scheme was as above. Product LCMS: m/z492.2[ M+H ]] + 。
EXAMPLE 57N- (4- (N-cyclopropylsulfamoyl) benzyl) -1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide (I-57)
Compound I-57 was prepared in a similar manner to that for compound I-56 using intermediate 13b and 4- (aminomethyl) -N-cyclopropylbenzenesulfonamide (C-10) as starting materials. Product LCMS: m/z543.2[ M+H ] ] + 。
Example 58 (S) -N- (1- (4- (hydroxymethyl) phenyl) ethyl) -1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide (I-58)
Figure BDA0003329505840000371
To a solution of product I-3 (50 mg,0.1 mmol) in THF (5 ml) was added sodium borohydride (11.4 mg,0.3 mmol) in portions. The mixture was cooled to 0℃and boron trifluoride etherate (0.5 mL,133 mmol) was added dropwise over about 10 minutes. After the reaction was heated to 20-30 ℃ and monitored by TLC to completion, the reaction was cooled to 0 ℃ and carefully quenched with sodium hydroxide water. The contents were stirred for 3h, THF was removed under vacuum, the resulting aqueous suspension was cooled to 0 ℃ and the product was filtered and the crude product was purified by column chromatography on silica gel using n-hexane-ethyl acetate (1:1) to give compound I-58 (20 mg, 43%). Product LCMS M/z468.2[ M+H ]] + 。
EXAMPLE 59 (S) -N- (1- (4-carbamoylphenyl) ethyl) -1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-indole-2-carboxamide (I-59)
Figure BDA0003329505840000372
To the flask was added product I-6 (300 mg,0.62 mmol), silica-supported ammonium chloride (50 mg,0.93mmol,1.5 eq.) and TsCl (178 mg,0.93mmol,1.5 eq.) TEA (93 mg,0.93mmol,1.5 eq.) under nitrogen and mixed thoroughly. After completion of the TLC detection reaction, ethyl acetate (50 mL) was added, followed by filtration, and the filtrate was washed with 0.02NHCl solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by silica gel column chromatography, n-hexane-ethyl acetate (1:1) to give compound I-59 (149 mg, 50%).
1 HNMR(400MHz,DMSO)δ8.54(d,J＝7.7Hz,1H),8.07(s,1H),7.86(s,1H),7.69(d,J＝8.3Hz,2H),7.59(d,J＝8.5Hz,1H),7.37(d,J＝7.9Hz,1H),7.32(ddd,J＝8.3,3.1,1.7Hz,2H),7.26(d,J＝8.2Hz,3H),7.09(t,J＝7.3Hz,1H),6.99(d,J＝7.8Hz,1H),6.90–6.80(m,2H),5.18–4.99(m,1H),3.94(s,3H),1.29(d,J＝7.0Hz,3H)，LCMS:m/z481.2[M+H] + 。
Example 60 (S) -4- (1- (-1 (-3 (trifluoromethyl) benzyl) -3-vinyl-1H-indole-2-carboxamide) ethyl) benzoic acid (I-60)
1. Synthesis of intermediates 45a-d
Figure BDA0003329505840000381
Intermediate 42 can be prepared from compound A-1 and N-iodosuccinimide (NIS) in a manner analogous to that of intermediate 8, intermediate 43a, 43c can be prepared from intermediate 42 and the analogous methods of vinyl boronic acid pinacol ester (B-32), cyclopropyl boronic acid (B-34) with reference to WO2020016453, intermediate 43B can be prepared from intermediate 42 and trimethylethynyl silicon (B-33) with reference to WO2016154434, and intermediate 43d can be prepared from intermediate 42 and (difluoromethyl) trimethylsilane (B-35) with reference to J.Am.chem. Soc.134:5524-5527, respectively. Starting from intermediate 43a-d methyl ester, intermediate 44a-d was obtained in a similar manner to intermediate 12, which was coupled to methyl (S) -4- (1-aminoethyl) benzoate (C-1) (step 2) to prepare intermediate 45a-d, respectively, in a similar manner to intermediate 14.
TABLE 14 Structure and molecular weight of different Compounds
Figure BDA0003329505840000382
2. Synthesis of Compound I-60
Compound I-60 was prepared in a similar manner to that for compound I-6 using intermediate 45a and sodium hydroxide as starting materials.
Product LCMS: m/z493.2[M+H] + 。
Example 61 (S) -4- (1- (3-ethynyl-1- (3- (trifluoromethyl) benzyl) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-61)
Compound I-61 was prepared in a similar manner to that for compound I-6 using intermediate 45b and sodium hydroxide as starting materials.
Product LCMS: m/z491.1[ M+H ]] + 。
Example 62 (S) -4- (1- (3-cyclopropyl-1- (3- (trifluoromethyl) benzyl) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-62)
Compound I-62 was prepared in a similar manner to that for compound I-6 using intermediate 45c and sodium hydroxide as starting materials.
Product LCMS: m/z507.2[ M+H ]] + 。
EXAMPLE 63 (S) -4- (1- (3- (difluoromethyl) -1- (3 (trifluoromethyl) benzyl) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-63)
Compound I-63 was prepared in a similar manner to that for compound I-6 using intermediate 45d and sodium hydroxide as starting materials.
Product LCMS: m/z517.2[ M+H ]] + 。
EXAMPLE 64 (S) -4- (1- (3-chloro-1- (cyclopropylmethyl) -1H-indole-2-carboxamide) ethyl) benzoic acid (I-64)
Using intermediate 7 and compound B-36 as starting materials, methyl 3-chloro-1- (cyclopropylmethylene) -1H-indole-2-carboxylate was prepared in a similar manner to compound 8, the hydrolysis of the methyl ester in the subsequent step was prepared in a similar manner to the synthesis of intermediate 9, condensation of the product with methyl (S) -4- (1-aminoethyl) benzoate (C-1) and the preparation of methyl (S) -4- (1- (3-chloro-1- (cyclopropylmethyl) -1H-indole-2-carboxamide) ethyl) benzoate in a similar manner to the synthesis of I-1.
Compound I-64 was prepared in a similar manner to compound I-5 using the intermediate methyl (S) -4- (1- (3-chloro-1- (cyclopropylmethyl) -1H-indole-2-carboxamide) ethyl) benzoate and sodium hydroxide as starting materials.
Product LCMS: m/z397.1[ M+H ]] + 。
Example 65 (S) -4- (1- (3-cyano-1- (3- (trifluoromethyl) benzyl) -4,5,6, 7-tetrahydro-1H-indole-2-carboxamide (ethyl) benzoic acid (I-65)
1. Synthesis of intermediates 50a-g
Figure BDA0003329505840000391
Intermediate 46a-g can be prepared from compound A-15,16,17,18,19,20, and bromine, respectively, in sequence, in a similar manner to that of document "organic chemistry" 2006:23 (7) 798-802. Intermediate 47a-g can be prepared from intermediate 46a-g and CuCN, respectively, in a similar manner to that of WO2003044014 under palladium catalysis, intermediate 48a-g can be obtained from intermediate 47a-g as starting material in a similar manner to that of intermediate 8, intermediate 49a-g can be obtained from intermediate 48a-g as starting material in a similar manner to that of intermediate 9, and finally the intermediate 50a-g can be prepared from the intermediate by condensation reaction with methyl (S) -4- (1-aminoethyl) benzoate (C-1) in a similar manner to that of intermediate I-1, respectively. The results of the products are shown in tables 15-19.
TABLE 15 Structure and molecular weight of different Compounds
Figure BDA0003329505840000401
TABLE 16 Structure and molecular weight of different Compounds
Figure BDA0003329505840000402
TABLE 17 Structure and molecular weight of different Compounds
Figure BDA0003329505840000411
TABLE 18 Structure and molecular weight of different Compounds
Figure BDA0003329505840000412
TABLE 19 Structure and molecular weight of different Compounds
Figure BDA0003329505840000421
2. Compound I-65 was prepared in a similar manner to that for compound I-6 using intermediate 50a and sodium hydroxide as starting materials.
Product LCMS: m/z496.2[ M+H ]] + 。
Example 66 (S) -4- (1- (3-bromo-1- (3- (trifluoromethyl) benzyl) -4,5,6, 7-tetrahydro-1H-indole-2-carboxamide (ethyl) benzoic acid (I-66)
Using intermediate 46a and 1- (bromomethyl) -3- (trifluoromethyl) benzene (B-1) as starting materials, methyl 3-bromo-1- (3- (trifluoromethyl) benzyl) -4,5,6, 7-4-tetrahydro-1H-indole-2-carboxylate was prepared in a similar manner to compound 8, and methyl ester hydrolysis in the subsequent step was prepared in a similar manner to synthetic intermediate 9, condensation of the product with methyl (S) -4- (1-aminoethyl) benzoate (C-1) to prepare (S) -4- (1- (3-bromo-1- (3- (trifluoromethyl) benzyl) -4,5,6, 7-tetrahydro-1H-indole-2-carboxamido (ethyl) benzoic acid in a similar manner to synthetic I-1.
Compound I-66 was prepared in a similar manner to that of compound I-6 using the intermediate (S) -4- (1- (3-bromo-1- (3- (trifluoromethyl) benzyl) -4,5,6, 7-tetrahydro-1H-indole-2-carboxamido (ethyl) benzoic acid and sodium hydroxide as starting materials.
Product LCMS: m/z549.1[ M+H ]] + 。
EXAMPLE 67 (S) -4- (1- (3-cyano-1- (3- (trifluoromethyl) benzyl) -1,5,6, 7-tetrahydropyran [3,2-b ] pyrrole-2-carboxamide) ethyl) benzoic acid (I-67)
Compound I-67 was prepared in a similar manner to that for compound I-6 using intermediate 50b and sodium hydroxide as starting materials.
Product LCMS: m/z498.2[ M+H ]] + 。
Example 68 (S) -4- (1- (3-cyano-1- (3- (trifluoromethyl) benzyl) -1,4,6, 7-tetrahydropyran [4,3-b ] pyrrole-2-carboxamide) ethyl) benzoic acid (I-68)
Compound I-68 was prepared in a similar manner to that for compound I-6 using intermediate 50c and sodium hydroxide as starting materials.
Product LCMS: m/z498.2[ M+H ]] + 。
Example 69 (S) -4-1- (3-cyano-1- (3- (trifluoromethyl) benzyl) -4,5,6, 7-tetrahydro-1H-pyrrolo [2,3-b ] pyridine-2-carboxamide (ethyl) benzoic acid (I-69)
The intermediate 50d was used to remove Boc from trifluoroacetic acid and dichloromethane to give methyl (S) -4- (1- (3-cyano-1- (3- (trifluoromethyl) benzyl) -4,5,6, 7-tetrahydro-1H-pyrrolo [2,3-b ] pyridine-2-carboxamide) ethyl) benzoate, which was used as starting material with sodium hydroxide, in a similar manner to the preparation of compound I-6.
Product LCMS: m/z497.2[ M+H ]] + 。
Example 70 (S) -4- (1- (3-cyano-1- (3- (trifluoromethyl) benzyl) -4,5,6, 7-tetrahydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide (ethyl) benzoic acid (I-70)
The intermediate 50e was used to remove Boc in a trifluoroacetic acid and dichloromethane system to give methyl (S) -4- (1- (3-cyano-1- (3- (trifluoromethyl) benzyl) -4,5,6, 7-tetrahydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide) ethyl) benzoate, which was used as starting material with sodium hydroxide, in a similar manner to prepare compound I-6.
Product LCMS: m/z497.2[ M+H ]] + 。
Example 71 (S) -4- (1- (3-cyano-1- (3- (trifluoromethyl) benzyl) -4,5,6, 7-tetrahydro-1H-pyrrolo [3,2-b ] pyridine-2-carboxamide (ethyl) benzoic acid (I-71)
The intermediate 50f was used to remove Boc in a trifluoroacetic acid and dichloromethane system to give the intermediate methyl (S) -4- (1- (3-cyano-1- (3- (trifluoromethyl) benzyl) -4,5,6, 7-tetrahydro-1H-pyrrolo [3,2-b ] pyridine-2-carboxamide) ethyl) benzoate, which was used as starting material with sodium hydroxide, in a similar manner to prepare Compound I-6.
Product LCMS: m/z497.2[ M+H ]] + 。
Example 72 (S) -4- (1- (3-bromo-1- (3- (trifluoromethyl) benzyl) -4,5,6, 7-tetrahydro-1H-pyrrolo [3,2-b ] pyridine-2-carboxamide (ethyl) benzoic acid (I-72)
The compound 4- (tert-butyl) 2-methyl 3-bromo-1- (3- (trifluoromethyl) benzyl) -1,5,6, 7-tetrahydro-4H-pyrrolo [3,2-B ] pyridine-2, 4-dicarboxylic acid ester was prepared in a similar manner to the synthesis of intermediate 9 using intermediate 46f and 1- (bromomethyl) -3- (trifluoromethyl) benzene (B-1) as starting materials, and the condensation of the product with methyl (S) -4- (1-aminoethyl) benzoate (C-1) was prepared in a similar manner to the synthesis of I-1 to methyl (S) -4- (1- (3-bromo-1- (3- (trifluoromethyl) benzyl) -4,5,6, 7-tetrahydro-1H-pyrrolo [3,2-B ] pyridine-2-carboxamido (ethyl) benzoate.
Compound I-72 was prepared in a similar manner to compound I-6 using the intermediate (S) -methyl 4- (1- (3-bromo-1- (3- (trifluoromethyl) benzyl) -4,5,6, 7-tetrahydro-1H-pyrrolo [3,2-b ] pyridine-2-carboxamido (ethyl) benzoate and sodium hydroxide as starting materials.
Product I-72LCMS: m/z550.1[ M+H ]] + 。
EXAMPLE 73 (S) -4- (1- (3- (trifluoromethyl) -1- (3- (trifluoromethyl) benzyl) -1H-pyrrolo [3,2-b ] pyridine-2-carboxamide (ethyl) benzoic acid (I-73)
1. Synthesis of intermediates 54a-b
Figure BDA0003329505840000441
Intermediates 51a-B can be prepared from intermediates A-7, A-13 and trifluoroiodomethane (B-42) in sequence, respectively, as described in references Tetrahedr on Letters,53 (15), 2005-2008;2012, then intermediate 52a-b was obtained in a similar manner to intermediate 8, intermediate 52a-b was obtained in a similar manner to intermediate 9, intermediate 53a-b was obtained in a similar manner to intermediate 9, and finally intermediate 54a-b was prepared separately in a similar manner to intermediate I-1 by a condensation reaction of the intermediate with methyl (S) -4- (1-aminoethyl) benzoate (C-1). The results of the products are shown in Table 20.
TABLE 20 Structure and molecular weight of different Compounds
Figure BDA0003329505840000451
2. Compound I-73 was prepared in a similar manner to that for compound I-6 using intermediate 54a and sodium hydroxide as starting materials.
Product I-73LCMS: m/z536.2[ M+H ]] + 。
Example 74 (S) -4- (1- (3-cyano-1- (3- (trifluoromethyl) benzyl) -1H-pyrrole [3,2-b ] pyridine-2-carboxamide) ethyl) benzoic acid (I-74)
1. Synthesis of intermediates 59a-d
Figure BDA0003329505840000452
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Intermediate 55a-d can be prepared from compound A-13,14,8,7 and N-bromosuccinimide (NBS) in sequence, respectively, in a similar manner to intermediate 8, intermediate 56a-d can be prepared from intermediate 55a-d and CuCN, respectively, under palladium catalysis, in a similar manner to WO2003044014, intermediate 57a-d can be obtained from intermediate 56a-d as starting material in a similar manner to intermediate 8, intermediate 58a-d can be obtained from intermediate 57a-d as starting material in a similar manner to intermediate 9, and finally the intermediate can be prepared from intermediate 59a-d by condensation with methyl (S) -4- (1-aminoethyl) benzoate (C-1) in a similar manner to intermediate I-1, respectively. The results of the products are shown in Table 21.
TABLE 21 Structure and molecular weight of different Compounds
Figure BDA0003329505840000461
Compound I-74 was prepared in a similar manner to that for compound I-6 using intermediate 59a and sodium hydroxide as starting materials. The I-74 characterization results are as follows:
1 H NMR(400MHz,DMSO)δ12.54(s,1H),8.92(d,J＝8.5Hz,1H),8.71(d,J＝5.7Hz,1H),8.58(dd,J＝8.0,0.7Hz,1H),7.86(d,J＝8.2Hz,2H),7.73(d,J＝8.8Hz,2H),7.66–7.52(m,2H),7.49–7.36(m,3H),6.18(s,2H),5.18(p,J＝7.0Hz,1H),1.52(d,J＝7.0Hz,3H).
product LCMS: m/z493.2[ M+H ]] + 。
Example 75 (S) -4- (1- (1-methyl-3- ((3- (trifluoromethyl) phenyl) amino) -1H-pyrrolo [2,3-c ] pyridine-2-carboxamide (ethyl) benzoic acid (I-75)
Compound I-75 was prepared in a similar manner to that for Compound I-6, starting with Compound A-14 (with A-14 replacing starting material A-1).
1 H NMR(400MHz,DMSO-d 6 )δ13.04(s,1H),9.03(s,1H),8.83(d,J＝7.6Hz,1H),8.18(d,J＝5.5Hz,1H),8.08(s,1H),7.74(d,J＝8.2Hz,2H),7.39–7.24(m,4H),6.98(d,J＝7.5Hz,1H),6.88(s,1H),6.80(d,J＝8.0Hz,1H),5.22–5.04(m,1H),4.00(s,3H),1.34(d,J＝7.0Hz,3H).
Product LCMS: m/z483.2[ M+H ]] + 。
Example 76 (S) -4- (1- (3-ethynyl-1- (3- (trifluoromethyl) benzyl) -1H-pyrrole [3,2-b ] pyridine-2-carboxamide) ethyl) benzoic acid (I-76)
1. Synthesis of intermediates 63a-d
Figure BDA0003329505840000471
Intermediate 60a-d can be prepared from intermediate 55a or 55d and B-33 or B-39, respectively, under palladium catalysis in a similar manner as described with reference to 43B,43e, respectively, followed by intermediate 60a-d as starting material, intermediate 61a-d being obtained in a similar manner to intermediate 8, followed by intermediate 61a-d as starting material, intermediate 62a-d being obtained in a similar manner to intermediate 9, and finally the condensation of intermediate with methyl (S) -4- (1-aminoethyl) benzoate (C-1) to prepare intermediate 63a-d, respectively, in a similar manner to intermediate I-1. The results of the products are shown in Table 22.
TABLE 22 Structure and molecular weight of different Compounds
Figure BDA0003329505840000481
Compound I-76 was prepared in a similar manner to that for compound I-6 using intermediate 63a and sodium hydroxide as starting materials.
1 H NMR(400MHz,DMSO)δ12.84(s,1H),9.32(d,J＝7.8Hz,1H),8.51(dd,J＝4.5,1.2Hz,1H),8.09(dd,J＝8.5,1.2Hz,1H),7.86(d,J＝8.3Hz,2H),7.62(d,J＝7.8Hz,1H),7.57(s,1H),7.49(t,J＝8.4Hz,3H),7.37–7.25(m,2H),5.75(s,2H),5.25–5.08(m,1H),4.51(s,1H),1.42(d,J＝7.0Hz,3H).
Product LCMS: m/z492.2[ M+H ]] + 。
EXAMPLE 77 (S) -4- (1- (3-cyano-1- (3- (trifluoromethoxy) benzyl) -1H-indole-2-carboxamide (ethyl) benzoic acid (I-77)
Figure BDA0003329505840000482
Starting from compound a-12 and 3-trifluoromethoxybenzyl bromide (B-37), intermediate 3-cyano-1- (3-trifluoromethoxy) benzyl) -1H-indole-2-carboxylic acid methyl ester was obtained in a similar manner to intermediate 8, methyl ester hydrolysis in the subsequent step was prepared in a similar manner to intermediate 9, condensation of the product with (S) -4- (1-aminoethyl) benzoic acid methyl ester (C-1) to prepare compound 64, i.e. (S) -4- (1- (3-cyano-1- (3-trifluoromethoxy) benzyl) -1H-indole-2-carboxamide) ethyl) benzoic acid methyl ester in a similar manner to I-1;
compound I-63 was prepared in a similar manner to that for compound I-6 using intermediate 64 and sodium hydroxide as starting materials.
Product LCMS: m/z517.2[ M+H ]] + 。
EXAMPLE 78 (S) -4- (1- (1- (2-chloro-3-fluorobenzyl) -3-cyano-1H-indole-2-carboxamide (ethyl) benzoic acid (trifluoromethyl) benzyl-1H-indole-2-carboxamide (ethyl) benzoic acid (I-78)
Figure BDA0003329505840000491
Starting from compound a-12 and 2-chloro-3-fluorobenzyl bromide (B-38), in a manner analogous to that for intermediate 8, intermediate 1- (2-chloro-3-fluorobenzyl) -3-cyano-1H-indole-2-carboxylic acid methyl ester, the subsequent step of methyl ester hydrolysis being prepared in a manner analogous to that for intermediate 9, condensation of the product with methyl (S) -4- (1-aminoethyl) benzoate (C-1) to prepare compound 65, i.e. (S) -methyl 4- (1- (1- (2-chloro-3-fluorobenzyl) -3-cyano-1H-indole-2-carboxamide) ethyl) benzoate, in a manner analogous to that for I-1;
Compound I-78 was prepared in a similar manner to that for compound I-6 using intermediate 65 and sodium hydroxide as starting materials.
Product LCMS: m/z517.2[ M+H ]] + 。
Example 79 (S, E) -4- (1- (3- (propyl-1-en-1-yl) -1- (3- (trifluoromethyl) benzyl) -1H-indole-2-carboxamide (ethyl) benzoic acid (I-79)
Compound I-79 was prepared in a similar manner to that for compound I-6 using intermediate 45e and sodium hydroxide as starting materials.
Product LCMS: m/z507.2[ M+H ]] + 。
EXAMPLE 80 (S) -4- (1- (3- (trifluoromethyl) -1- (3- (trifluoromethyl) benzyl) -1H-pyrrolo [2,3-b ] pyridine-2-carboxamide (ethyl) benzoic acid (I-80)
Compound I-80 was prepared in a similar manner to that for compound I-6 using intermediate 54b and sodium hydroxide as starting materials.
Product LCMS: m/z536.2[ M+H ]] + 。
Example 81 (S) -4- (1- (1-neopentyl-3- (trifluoromethyl) -1H-pyrrole [2,3-b ] pyridine-2-carboxamide) ethyl) benzoic acid (I-81)
Methyl (S) -methyl 4- (1- (1-neopentyl-3- (trifluoromethyl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxamide) benzoate was prepared in a similar manner to synthesis of I-1 by using intermediate 51B and 1-bromo-2, 2-dimethylpropane (B-40) as starting materials, obtaining methyl 1-neopentyl-3- (trifluoromethyl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxylate as intermediate, hydrolysis of the methyl in the subsequent step was prepared in a similar manner to synthesis of intermediate 9, condensation of the product with methyl (S) -4- (1-aminoethyl) benzoate (C-1).
Compound I-81 was prepared in a similar manner to that of compound I-6 using the intermediate (S) -methyl 4- (1- (1-neopentyl-3- (trifluoromethyl) -1H-pyrrolo [2,3-b ] pyridine-2-carboxamide) ethyl) benzoate and sodium hydroxide as starting materials.
Product LCMS: m/z448.2[ M+H ]] + 。
EXAMPLE 82 (S) -4- (1- (3-cyano-1- (3- (trifluoromethyl) benzyl) -1H-pyrrole [3,2-c ] pyridine-2-carboxamide) ethyl) benzoic acid (I-82)
Compound I-82 was prepared in a similar manner to that for compound I-6 using intermediate 59b and sodium hydroxide as starting materials.
Product LCMS: m/z493.2[ M+H ]] + 。
EXAMPLE 83 (S) -4- (1- (3-cyano-1- (3- (trifluoromethyl) benzyl) -1H-pyrrole [3,2-b ] pyridine-2-carboxamide (ethyl) benzoic acid (I-83)
Compound I-83 was prepared in a similar manner to that for compound I-6 using intermediate 59c and sodium hydroxide as starting materials.
Product LCMS: m/z493.2[ M+H ]] + 。
Example 84 (S) -4- (1-) (3-bromo-1- (3- (trifluoromethyl) benzyl) -1H-pyrrole [3,2-b ] pyridine-2-carboxamido ethyl) benzoic acid (I-84)
Starting from intermediate 55a and 1- (bromomethyl) -3- (trifluoromethyl) benzene (B-1), the compound methyl 3-bromo-1- (3- (trifluoromethyl) benzyl) -1H-pyrrolo [3,2-B ] pyridine-2-carboxylate was prepared in a similar manner to compound 8, and the subsequent hydrolysis of the methyl ester in the step was prepared in a similar manner to the synthesis of intermediate 9, and condensation of the product with methyl (S) -4- (1-aminoethyl) benzoate (C-1) prepared in a similar manner to the synthesis of I-1 (S) -4- (1-) (3-bromo-1- (3- (trifluoromethyl) benzyl) -1H-pyrrolo [3,2-B ] pyridine-2-carboxamidoethyl) benzoate.
Compound I-84 was prepared in a similar manner to compound I-6 using the intermediate (S) -methyl 4- (1-) (3-bromo-1- (3- (trifluoromethyl) benzyl) -1H-pyrrolo [3,2-b ] pyridine-2-carboxamidoethyl) benzoate and sodium hydroxide as starting materials.
Product LCMS：m/z546.1[M+H] + 。
Example 85 (S) -4- (1- (3-ethynyl-1- (3- (trifluoromethyl) benzyl) -1H-pyrrole [2,3-b ] pyridine-2-carboxamide ethyl) benzyl (I-85)
Compound I-85 was prepared in a similar manner to that for compound I-6 using intermediate 63b and sodium hydroxide as starting materials.
Product LCMS: m/z491.2[ M+H ]] + 。
Example 86 (S, E) -4- (1- (3- (propyl-1-en-1-yl) -1- (3- (trifluoromethyl) benzyl) -1H-pyrrolo [3,2-b ] pyridine-2-carboxamide (ethyl) benzoic acid (I-86)
Compound I-86 was prepared in a similar manner to that for compound I-6 using intermediate 63c and sodium hydroxide as starting materials.
Product LCMS: m/z508.2[ M+H ]] + 。
Example 87 (S, E) -4- (1- (3- (propyl-1-en-1-yl) -1- (3- (trifluoromethyl) benzyl-1H-pyrrolo [2,3-b ] pyridine-2-carboxamide (ethyl) benzoic acid (I-87)
Compound I-87 was prepared in a similar manner to that for compound I-6 using intermediate 63d and sodium hydroxide as starting materials.
Product LCMS: m/z508.2[ M+H ]] + 。
Example 88 (S) -4- (1- (3-cyano-1- (3-fluorobenzyl) -1H-pyrrole [2,3-c ] pyridine-2-carboxamide) ethyl) benzoic acid (I-88)
Methyl 3-cyano-1- (3-fluorobenzyl) -1H-pyrrolo [2,3-C ] pyridine-2-carboxylate was prepared in a similar manner to compound 8 using intermediate 55B and trifluorobromobenzyl (B-41) as starting materials, and methyl ester hydrolysis in the subsequent step was prepared in a similar manner to intermediate 9, condensation of the product with methyl (S) -4- (1-aminoethyl) benzoate (C-1) was prepared in a similar manner to compound I-1 to methyl (S) -4- (1- (3-cyano-1- (3-fluorobenzyl) -1H-pyrrolo [2,3-C ] pyridine-2-carboxamide) ethyl) benzoate.
Compound I-88 was prepared in a similar manner to compound I-6 using the intermediate (S) -methyl 4- (1- (3-cyano-1- (3-fluorobenzyl) -1H-pyrrole [2,3-c ] pyridine-2-carboxamide) ethyl) benzoate and sodium hydroxide as starting materials.
Product LCMS: m/z443.2[ M+H ]] + 。
EXAMPLE 89 (S) -4- (1- (3-bromo-1- (3- (trifluoromethyl) benzyl) -1H-pyrrolo [2,3-b ] pyridine-2-carboxamido (ethyl) benzoic acid (I-89)
Starting from intermediate 55d and 1- (bromomethyl) -3- (trifluoromethyl) benzene (B-1), the compound methyl 3-bromo-1- (3- (trifluoromethyl) benzyl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxylate was prepared in a similar manner to compound 8, and the subsequent hydrolysis of the methyl ester in the step was prepared in a similar manner to the synthesis of intermediate 9, condensation of the product with methyl (S) -4- (1-aminoethyl) benzoate (C-1) to prepare methyl (S) -4- (1- (3-bromo-1- (3- (trifluoromethyl) benzyl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxamido (ethyl) benzoate in a similar manner to the synthesis of I-1.
Compound I-89 was prepared in a similar manner to compound I-6 using the intermediate (S) -4- (1- (3-bromo-1- (3- (trifluoromethyl) benzyl) -1H-pyrrolo [2,3-b ] pyridine-2-carboxamido (ethyl) benzoic acid methyl ester and sodium hydroxide as starting materials.
Product LCMS: m/z546.1[ M+H ]] + 。
EXAMPLE 90 (S) -4- (1- (3-cyano-1- (3- (trifluoromethyl) benzyl) -1,4,6, 7-tetrahydrothiopyrano [4,3-b ] pyrrole-2-carboxamide) ethyl) benzoic acid (I-90)
Compound I-90 was prepared in a similar manner to that for Compound I-6, using 50g of intermediate and sodium hydroxide as starting materials.
Product LCMS: m/z514.2[ M+H ]] + 。
EXAMPLE 91 (S) -4- (1- (3-cyano-1- (3- (trifluoromethyl) benzyl) -1H-pyrrolo [2,3-b ] pyridine-2-carboxamide (ethyl) benzoic acid (I-91)
Compound I-91 was prepared in a similar manner to that for compound I-6 using intermediate 59d and sodium hydroxide as starting materials.
1 H NMR(400MHz,DMSO-d 6 )δ12.74(s,1H),8.81(d,J＝8.5Hz,1H),8.65(d,J＝5.7Hz,1H),8.49(dd,J＝8.0,0.7Hz,1H),7.78(d,J＝8.2Hz,2H),7.67(d,J＝8.8Hz,2H),7.65–7.51(m,2H),7.51–7.35(m,3H),6.20(s,2H),5.21(p,J＝7.0Hz,1H),1.55(d,J＝7.0Hz,3H).
Product LCMS: m/z493.2[ M+H ]] + 。
EXAMPLE 92 biological Activity test
Some of the compounds prepared in the examples above were selected for the following tests with control compounds:
1. determination of EP1 and EP3 receptor inhibitory activity of different compounds-IP 1 assay:
1. preparing an activation buffer solution with the concentration of 1 time of working solution according to the instruction of the kit for later use;
2. performing gradient dilution on positive compounds and compounds to be tested by using DMSO (dimethyl sulfoxide), then respectively diluting the compounds with 10 concentrations to corresponding concentrations which are 10 times of the compounds with 1 time of working solution concentration activating buffer solution, and uniformly mixing by vibration for later use; the EP1 positive compound is AH6809, and the EP3 positive compound is L-798106; wherein, the corresponding concentrations of the compounds to be tested of the EP1 and the EP3 receptor are 200000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05 and 1.02nM respectively;
EP1-HEK and EP3-HEK cells were subjected to pancreatin digestion, centrifuged to remove the medium, the cells were resuspended in 1-fold working solution concentration of activation buffer, and after cell counting, inoculated in 384-well plates. The inoculation density was about 4500 cells/well/9.1. Mu.L for EP1 and about 5000 cells/well/9.1. Mu.L for EP3, respectively;
4. taking 1.4 mu L of 10-fold corresponding concentration diluted in the step 2, respectively adding into corresponding experimental holes (2 repeats), wherein a Max hole is added with 1.4 mu L of positive compound solution with the maximum concentration and 10-fold corresponding concentration, a Min hole is added with 1.4 mu L of DMSO buffer (2 v%) with the minimum concentration and 10-fold corresponding concentration, centrifuging, and then placing at 37 ℃ for incubation for 10Min;
5. preparing 120nM PGE2 buffer with 1-fold working solution concentration activation buffer, and adding 3.5 μl into each experimental well of EP1 receptor; preparing 60nM PGE2 buffer, adding 3.5 mu L to each experimental hole of the EP3 receptor; centrifuging, and then placing at 37 ℃ for incubation for 1h;
6. diluting the IP1 and Anti-IP1 to working concentrations with a test buffer;
7. after incubation was completed, 3 μl IP1 was added to all experimental wells;
8. then adding 3 mu L of Anti-IP1 into all experimental holes, centrifuging and standing at room temperature for 1h;
9. after incubation was completed, 665nm and 620nm reads were detected.
2. Determination of EP2 and EP4 receptor inhibitory activity by compounds-cAMP assay:
1. preparing an activation buffer solution with the concentration of 1 time of working solution according to the instruction of the kit for later use;
2. using DMSO to carry out gradient dilution on the positive compound and the compound to be tested for 10 or 11 concentrations, and then using an activation buffer solution with the concentration of 1 time of working solution to dilute the positive compound and the DMSO to corresponding concentrations of 10 times respectively; the initial concentrations of the compounds to be tested for the EP2 and the EP4 receptor are 20 mu M, and the 10 corresponding concentrations of the EP2 receptor are 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05 and 1.02nM respectively; the 11 corresponding concentrations of EP4 receptor were 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05, 1.02, 0.34nM, respectively;
the cells of EP2-HEK and EP4-HEK were subjected to pancreatin digestion, centrifuged to remove the medium, resuspended in 1-fold working solution in activation buffer, and counted and seeded in 384-well plates. The inoculation density is 1500 cells/hole/5 mu L;
4. adding 1 mu L of the compound with the concentration which is 10 times that diluted in the step 2 into corresponding experimental holes, respectively, wherein 1 mu L of the positive compound with the concentration which is 10 times that of the maximum Max hole is added, 1 mu L of the DMSO buffer with the concentration which is 10 times that of the minimum Min hole is added, centrifuging, and then placing the mixture at 37 ℃ for 15Min;
5. Preparing 0.125nM PGE2 buffer with 1-fold working solution concentration activation buffer, and adding 4 μL into each experimental hole of the EP2 receptor; preparing 100nM PGE2 buffer, and adding 4 mu L to each experimental hole of the EP4 receptor; centrifuging, and incubating at 37 ℃ for 30min;
6. diluting Eu-cAMP to the working concentration by using a test buffer solution, and adding 5 mu L/hole into a corresponding experimental hole;
7. will ULIght TM -anti-cAMP was diluted to working concentration with test buffer and then 5 μl/well was added to the corresponding experimental well; centrifuging, and then placing at room temperature for incubation for 1h;
8. after incubation was completed, 665nm and 620nm reads were detected.
Inhibition of human prostaglandin E2 receptor (EP 1, EP2, EP3, EP 4) activity by some examples in cAMP assays is shown in tables 23-24.
Concentration of compounds of Table 23 for inhibition of EP4 enzyme IC 50
Figure BDA0003329505840000531
Inhibitory concentration IC of compounds of Table 24 for human prostaglandin E2 receptor 50
Figure BDA0003329505840000532
Figure BDA0003329505840000541
Table 24 shows that the compound of example 6 (I-6) has better selectivity for the EP receptor subtype than E7046, has stronger inhibition of EP4 and no inhibition of EP1/EP2/EP 3.
3. Cell Activity test
The specific test scheme is as follows:
(1) Day 0, floor
Cells were digested with 0.25% Trypsin-EDTA and resuspended cells were counted using an automatic cell counter. Depending on the seeding density, the cell suspension is diluted to the desired density. mu.L of cells at 37℃and 5% CO were added to each well 2 Culturing overnight.
(2) Day 1 compound formulation
The compounds in Table 20 were formulated into 200-fold final solutions (compound final solution concentration 10 uM) with DMSO. mu.L of 200-fold final solution was added to 197. Mu.L of the medium to prepare a 3-fold final solution. mu.L of the 3-fold final solution was added to the well plate at 37℃with 5% CO 2 Culturing for 72 hours.
(3) Day 4 detection
Will test the balance of the orifice plateTo room temperature. Add 40. Mu.L per well
Figure BDA0003329505840000543
The reagent was shaken for 2 min and incubated at room temperature for 60 min. Detection was performed by Envision.
(4) After the detection is finished, data analysis is carried out
First calculate IC using GraphPad Prism 5 50 The calculation formula is as follows:
％Inh＝(Max signal-Compound signal)/(Max signal-Min signal)×100.
here, max signal is the result of the test in which no compound is added to the well plate in the above step (2) and only DMSO is added, and Min signal is the result of the test in which only medium is added to the whole well plate in the above step (2). The results are shown in Table 25.
Compounds of table 25 inhibit IC against tumor cell proliferation 50
Figure BDA0003329505840000542
4. In vivo testing
BALB/c mice were ordered from Shanghai Ji Hui laboratory animal feeding limited and distributed to the study at 5-6 weeks of age. Animal breeding, feeding and health conditions follow the animal welfare guidelines. Mouse colorectal cancer CT-26 cells were cultured in RPMI-1640 medium+10% FBS medium and passaged at least 3 times before inoculation. Each mouse was vaccinated with approximately 2X 10 5 Mouse colorectal cancer CT-26 cells were collected in sterile PBS solution and inoculated at a volume of about 100. Mu.L. BALB/c mice were previously anesthetized with 3-4% isoflurane. When the tumor grows to an average of about 100-200mm 3 When the number of mice was about, 24 mice with appropriate tumor sizes were randomly divided into 4 groups of 6 mice each according to tumor size and body weight, and each group was administered orally for 11 days, namely, vehicle (group G1), E7046 150mg/kg (group G2), 75mg/kg (group G3) of the compound of example 6 (I-6), and 150mg/kg (group G4) of the compound of example 6 (I-6). The results of tumor volume inhibition are shown in table 26.
The calculation method of the tumor volume (V) is as follows:v= (length x width 2 )/2。
Tumor inhibition rate (TGI) = [1- (TV) t -TV initial )/(CV t -CV initial )]*100%; wherein, the liquid crystal display device comprises a liquid crystal display device,
TV t tumor volume, TV, of Day11 treatment group initial : tumor volume CV of Day 0 treated group t : day11 control tumor volume, CV initial : tumor volume of Day 0 control.
Table 26 Effect of different Compounds on tumor proliferation Rate of colorectal cancer CT-26 cell tumor-bearing mice
Figure BDA0003329505840000551
Annotation: p.o.q.d. 11D represents oral/day, administration for 11 days; day11 represents Day11 post-administration.
As can be seen by combining FIG. 1 and Table 26, the compound of example 6 (I-6) and E7046 have a significant inhibitory effect on tumor growth in colorectal cancer CT-26 cell tumor-bearing mice, and the compound of example 6 (I-6) is significantly better than E7046 at the same dose.
The above is only a preferred embodiment of the present invention, and it should be noted that it should be understood by those skilled in the art that several improvements and modifications can be made without departing from the technical principle of the present invention, and these improvements and modifications should also be considered as the protection scope of the present invention.

Claims (3)

1. A compound characterized by one of the following structural formulas:
Figure FDA0004036752740000011
2. use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder caused by EP 4 Conditions in which receptor antagonism is reduced.
3. The use according to claim 2, wherein the condition is selected from one or more of cancer, inflammatory disease and pain.
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