CN113321640B - Indole compound and application thereof - Google Patents

Indole compound and application thereof Download PDF

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CN113321640B
CN113321640B CN202110124967.0A CN202110124967A CN113321640B CN 113321640 B CN113321640 B CN 113321640B CN 202110124967 A CN202110124967 A CN 202110124967A CN 113321640 B CN113321640 B CN 113321640B
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acetyl
indole
synthesis
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delta
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CN113321640A (en
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许�永
向秋萍
张岩
薛晓纤
王超
宋明
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Guangzhou Zhiyao Biotechnology Co ltd
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Guangzhou Institute of Biomedicine and Health of CAS
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/4164—1,3-Diazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
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    • C07D243/30—Preparation including building-up the benzodiazepine skeleton from compounds already containing hetero rings
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Abstract

The invention provides an indole compound and application thereof, wherein the compound can effectively inhibit CBP/EP300Bromodomain receptor and can be used as a medicament for cancers, inflammatory diseases, autoimmune diseases, septicemia and virus infection.

Description

Indole compound and application thereof
The invention discloses an indole compound and application thereof, which are classified application numbers of 201710480445.8, application dates of 2017, 6 and 22.
Technical Field
The invention relates to the technical field of chemical medicines, in particular to an indole compound and application thereof.
Background
Bromodomain is a class of evolutionarily conserved modules that can mediate protein-protein interactions. Bromodomain is a histone acetylated reader, can specifically recognize histone acetylated lysine residues, and thus affects transcription and translation of target genes, and protein complex dysfunction is related to occurrence of various diseases, so that the Bromodomain protein becomes a novel target. Inhibitors of the Bromodomain protein are of great biological significance, for example, a number of compounds have been reported to have therapeutic efficacy in cancer, inflammatory diseases, autoimmune diseases, sepsis, viral infections, and the like.
Bromodomain proteins were named as first found in Drosophila genes, from which Bromodomain proteins are found in many nucleoproteins, such as Histone Acetyltransferases (HATs), ATP-dependent chromatin remodeling complexes, methyltransferases, and transcriptional coactivators, among others. The 61 bromodomains encoded by the human proteome are currently present in 46 different nuclear and cytoplasmic proteins. The Bromodomain protein family can be divided into 8 subfamilies according to its function. Among them, histone acetyltransferase is one type, which includes: CBP, EP300, P/CAF, GCN5, etc. CBP and EP300 are homologous proteins.
CBP/EP300 is a multifunctional transcriptional co-activator of the cAMP response element binding protein CREB, which is involved in a variety of physiological processes: cell cycle regulation, cell differentiation, apoptosis, and the like. The CBP/EP300 protein plays a bridge role between the transcription factor and the target DNA through the HAT of the CBP/EP300 protein; can inhibit cell replication and make cells stay in G1 phase; the CBP/EP300 protein has the function of a cancer suppressing factor and also participates in a plurality of cancer suppressing information conduction paths. CBP/EP300 is associated with various diseases such as prostate cancer, inflammatory therapy (pulmonary inflammation and asthma) in addition to recurrent acute lymphoblastic leukemia, RTS and neurodegenerative diseases. Targeting CBP/EP300 protein helps to provide new therapeutic strategies for cancer, neurodegenerative diseases and inflammatory diseases.
Zhou Mingming and its team found in the study that CBP Bromodomain interacted with tumor suppressor gene KAc382 in the p53 protein. To inhibit CBP-p53 interactions, zhou Mingming and colleagues have discovered CBP/EP300 Bromodomain small molecule inhibitors MS2126 and MS7972 using nuclear magnetic resonance techniques. Subsequently, through the use of epigenetic screening and targeted biochemistry, some small molecule compounds have been discovered, but no compounds are currently entering clinical studies.
Disclosure of Invention
Aiming at the technical problems in the prior art, the invention provides an indole compound and application thereof, wherein the compound can effectively inhibit CBP/EP300 Bromodomain receptor and can be used as a medicament for cancer, inflammatory diseases, autoimmune diseases, septicemia and virus infection.
In order to achieve the above purpose, the invention adopts the following technical scheme:
it is an object of the present invention to provide an indole compound having the following structures of formula I and formula II:
Figure GDA0004204982040000011
in the formula I, R 1 Is C 1 ～C 4 Alkyl, R 2 H, C of a shape of H, C 1 ～C 7 Alkyl, -R-X 1 or-X 2 ，R 3 H, C of a shape of H, C 1 ～C 5 Alkyl, C 3 ～C 5 Cycloalkyl, -OX 3 、-NHX 3 or-N (X) 3 ) 2 ；
Wherein R is C 1 ～C 4 Alkylene, X 1 is-OX 3 、-COOX 4 、-CONHX 4 Cycloalkyl, heterocyclyl, -COX 5 or-S (O) m X 5 ，X 2 Is C 3 ～C 7 Cycloalkyl, phenyl, naphthyl, heterocyclyl, -COX 5 or-S (O) m X 5 ；
Wherein m is 0 or 2, X 4 And X 5 H, C independently 1 ～C 4 Alkyl, C 3 ～C 7 Cycloalkyl, phenyl, naphthyl or heterocyclyl;
in formula II, R 4 Is C 1 ～C 4 Alkyl, R 5 Is C 1 ～C 7 Alkyl, -R' -Y 1 、Y 1 ′-(C 1 -C 4 Alkylene) -Y 1 Or Y 2 ，R 6 H, C of a shape of H, C 1 ～C 5 Alkyl, C 3 ～C 5 Cycloalkyl, -OY 3 、-NHY 3 or-N (Y) 3 ) 2 ；
Wherein R' is C 1 ～C 4 Alkylene group, Y 1 is-NHCOO t Bu、C 3 ～C 7 Cycloalkyl, phenyl, naphthyl, -OY 4 、-COY 4 、-COOY 4 、-NHCOY 4 or-S (O) m Y 4 ，Y 1 ' is-NHCOO t Bu、C 3 ～C 7 Cycloalkyl, phenyl, naphthyl, -OY 4 、-COY 4 、-COOY 4 、-NHCOY 4 or-S (O) m Y 4 ，Y 2 Is C 3 ～C 7 Cycloalkyl, phenyl, naphthyl or heterocyclyl;
wherein m is 0 or 2, Y 4 H, C of a shape of H, C 1 ～C 4 Alkyl, C 3 ～C 7 Cycloalkyl, phenyl, naphthyl or heterocyclyl.
Wherein in formula I, R 1 May be C 1 、C 2 、C 3 Or C 4 Alkyl, R 2 May be C 1 、C 2 、C 3 、C 4 、C 5 、C 6 Or C 7 Alkyl, R 3 May be C 1 、C 2 、C 3 、C 4 Or C 5 Alkyl, R 3 May be C 3 、C 4 Or C 5 Cycloalkyl, R can be C 1 、C 2 、C 3 Or C 4 Alkylene, X 2 May be C 3 、C 4 、C 5 、C 6 Or C 7 Cycloalkyl, X 4 And X 5 Independently can be C 1 、C 2 、C 3 Or C 4 Alkyl, X 4 And X 5 Independently can be C 3 、C 4 、C 5 、C 6 Or C 7 Cycloalkyl groups.
Wherein in formula II, R 4 May be C 1 、C 2 、C 3 Or C 4 Alkyl, R 5 May be C 1 、C 2 、C 3 、C 4 、C 5 、C 6 Or C 7 Alkyl, Y 1 ′-(C 1 -C 4 Alkylene) -Y 1 The medium alkyl group may be C 1 Alkylene, C 2 Alkylene, C 3 Alkylene or C 4 Alkylene group, R 6 May be C 1 、C 2 、C 3 、C 4 Or C 5 Alkyl, R 6 May be C 3 、C 4 Or C 5 Cycloalkyl, R' may be C 1 、C 2 、C 3 Or C 4 Alkylene group, Y 1 May be C 3 、C 4 、C 5 、C 6 Or C 7 Cycloalkyl, Y 1 ' may be C 3 、C 4 、C 5 、C 6 Or C 7 Cycloalkyl, Y 2 May be C 3 、C 4 、C 5 、C 6 Or C 7 Cycloalkyl, Y 4 May be C 1 、C 2 、C 3 Or C 4 Alkyl, Y 4 May be C 3 、C 4 、C 5 、C 6 Or C 7 Cycloalkyl groups.
As a preferred technical scheme of the invention, R in the formula I 1 Comprises methyl, ethyl and n-propylA radical, isopropyl or tert-butyl.
Preferably, R in formula I 2 comprises-R-X 1 or-X 2 Wherein R is C 1 ～C 2 Alkylene, X 1 is-COOX 4 、-CONHX 4 Cycloalkyl or heterocyclyl, X 2 is-COX 5 or-S (O) 2 X 5 Wherein X is 5 Is C 1 ～C 3 Alkyl, C 3 ～C 7 Cycloalkyl, phenyl, naphthyl or heterocyclyl.
Preferably, R in formula I 3 Including H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenolic hydroxyl, methoxy, ethoxy, propoxy, butoxy, aminomethyl, aminoethyl, aziropyl, or azetidinyl.
Preferably, R in formula II 4 Including methyl, ethyl, n-propyl, isopropyl or tert-butyl.
Preferably, R in formula II 5 comprising-R' -Y 1 Or Y 2 Wherein R' is C 1 ～C 4 Alkylene group, Y 1 Is C 3 ～C 7 Cycloalkyl, phenyl, naphthyl, -OY 4 、-COY 4 、-COOY 4 、-NHCOY 4 or-S (O) 2 Y 4 ，Y 2 Is C 3 ～C 7 Cycloalkyl, phenyl, naphthyl or heterocyclyl, wherein Y 4 H, C of a shape of H, C 1 ～C 4 Alkyl, C 3 ～C 7 Cycloalkyl, phenyl, naphthyl or heterocyclyl.
Preferably, R in formula II 6 Including H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenolic hydroxyl, methoxy, ethoxy, propoxy, butoxy, aminomethyl, aminoethyl, aziropyl, or azetidinyl.
As a preferred embodiment of the present invention, the compound of formula I is C 3 ～C 7 Cycloalkyl, phenyl and naphthyl contain 0 to 3 substituents, and the number of substituents may be 0, 1, 2 or 3.
Preferably, a pair ofThe substituent is halogen, C 1 ～C 4 Alkyl, trifluoromethyl, cyano, nitro, amino, amide, -COOX 6 、-COX 6 、-OX 6 、-NHCOX 6 、-C 6 H 5 X 7 Morpholinyl, piperidinyl, furyl, tetrahydrofuranyl or pyridyl wherein X 6 H, C of a shape of H, C 1 ～C 4 Alkyl, phenyl, X 7 Is C 1 ～C 4 Alkyl, halogen, trifluoromethyl, cyano, nitro, amino, amide, acetyl, methoxy or ethoxy.
Wherein the substituents may be C 1 、C 2 、C 3 Or C 4 Alkyl, X 6 May be C 1 、C 2 、C 3 Or C 4 Alkyl, X 7 May be C 1 、C 2 、C 3 Or C 4 An alkyl group.
As a preferred embodiment of the present invention, the heterocyclic group in formula I is an azetidinyl, oxetanyl, azetidinyl, oxolanyl, azacyclohexyl, oxolanyl, imidazol-2-onyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrrolyl, piperazinyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, 1, 3-dioxolanyl or benzo [ d ] thiazolyl group.
Preferably, the heterocyclic group in formula I contains 0 to 3 substituents, and the number of substituents may be 0, 1, 2 or 3.
Preferably, the substituents are halogen, C 1 ～C 4 Alkyl, trifluoromethyl, cyano, nitro, amino, amide, -COOX 6 、-COX 6 、-OX 6 、-NHCOX 6 、-C 6 H 5 X 7 Morpholinyl, piperidinyl, furyl, tetrahydrofuranyl or pyridyl wherein X 6 H, C of a shape of H, C 1 ～C 4 Alkyl, phenyl, X 7 Is C 1 ～C 4 Alkyl, halogen, trifluoromethyl, cyano, nitro, amino, amide, acetyl, methoxy or ethoxy.
Wherein the substituents may be C 1 、C 2 、C 3 Or C 4 Alkyl, X 6 May be C 1 、C 2 、C 3 Or C 4 Alkyl, X 7 May be C 1 、C 2 、C 3 Or C 4 An alkyl group.
As a preferred embodiment of the present invention, the compound of formula II C 3 ～C 7 Cycloalkyl, phenyl and naphthyl contain 0 to 3 substituents, and the number of substituents may be 0, 1, 2 or 3.
Preferably, the substituents are halogen, C 1 ～C 4 Alkyl, trifluoromethyl, cyano, nitro, amino, 1, 3-dioxolanyl, -COOY 5 、-COY 5 、-OY 5 、-NHCOY 5 、-C 6 H 5 Y 6 、-(CH 2 ) n NHY 7 、-NHCOO t Bu、-CH 2 OCOO t Bu, 1-methylpiperazine, morpholinyl, isoxazolyl, 3, 5-dimethylisoxazolyl, quinolinyl, isoquinolinyl, piperidinyl, thienyl, furyl, tetrahydrofuranyl, pyridyl, pyrimidinyl, 2-morpholinylpyridinyl, indolyl, 1, 4-benzodioxanyl, benzofuranyl, benzothienyl, 1-methyl-1H-indazolyl, pyrrolyl, 1H-pyrazolyl, 1-methyl-1H-pyrazolyl or tetrahydropyranyl, wherein n is 0 to 2, Y 5 Is from hydrogen, C 1 ～C 4 Alkyl or phenyl, Y 6 Is hydrogen, C 1 ～C 4 Alkyl, halogen, formyl, acetyl, methoxy, ethoxy, trifluoromethyl, cyano or methylsulfonyl, Y 7 Is C 1 ～C 5 Alkyl, C 0 ～C 2 Alkylene-phenyl, C 0 ～C 2 Alkylene-naphthyl or C 0 ～C 2 Alkylene-heterocyclyl, wherein Y 7 Wherein the phenyl, naphthyl or heterocyclyl is substituted with 0 to 3 halogens, C 1 ～C 4 Alkyl, trifluoromethyl, cyano, nitro or amino substitution.
Wherein the substituents may be C 1 、C 2 、C 3 Or C 4 Alkyl, Y 6 May be C 1 、C 2 、C 3 Or C 4 Alkyl, Y 7 May be C 1 、C 2 、C 3 、C 4 Or C 5 Alkyl, Y 7 Can be phenyl, C 1 Alkylene-phenyl or C 2 Alkylene-phenyl, Y 7 Can be naphthyl, C 1 Alkylene-naphthyl or C 2 Alkylene-naphthalenyl, Y 7 May be heterocyclic, C 1 Alkylene-heterocyclyl or C 2 Alkylene-heterocyclyl, Y 7 Wherein said phenyl, naphthyl or heterocyclyl is substituted with 0, 1, 2 or 3 substituents, Y 7 The substituents in (a) may be C 1 、C 2 、C 3 Or C 4 An alkyl group.
As a preferred embodiment of the present invention, the heterocyclic group in formula II is an azetidinyl, oxetanyl, azetidinyl, furanyl, thienyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrrolyl, tetrahydropyrrolyl, morpholinyl, 1, 3-dioxolanyl, benzo [ d ] thiazolyl, pyridinyl, 1, 4-benzodioxanyl, indazolyl, N-methylbenzimidazolyl, indolyl, indolinyl or 2-imidazolidinonyl group;
Preferably, the heterocyclic group in formula II contains 0 to 3 substituents, and the number of substituents may be 0, 1, 2 or 3.
Preferably, the substituents are halogen, C 1 ～C 4 Alkyl, trifluoromethyl, cyano, carboxyl, nitro, amino, 1, 3-dioxolanyl, -COOY 5 、-COY 5 、-OY 5 、-NHCOY 5 、-NHCOO t Bu or-C 6 H 5 Y 6 Wherein Y is 5 Is hydrogen, C 1 ～C 4 Alkyl or phenyl, Y 6 Is C 1 ～C 4 Alkyl, halogen, acetyl, methoxy or ethoxy.
Wherein the substituents may be C 1 、C 2 、C 3 Or C 4 Alkyl, Y 5 May be C 1 、C 2 、C 3 Or C 4 Alkyl, Y 6 May be C 1 、C 2 、C 3 Or C 4 An alkyl group.
When the structural type is formula I, the compound may be prepared by the following reaction:
Figure GDA0004204982040000031
when R in formula I 2 is-R-COX 5 In this case, the compound may be prepared by the following reaction:
Figure GDA0004204982040000032
when R in formula I 2 is-S (O) m X 5 (m=2), the compound may be prepared by the following reaction:
Figure GDA0004204982040000033
when the structural type is formula II, the preparation method can be prepared by the following 2 steps of reactions:
Figure GDA0004204982040000041
the above-described preparation methods are for illustrative purposes and are not intended to be limited to the listed compounds or any particular substituents. The number of substituents shown in the schemes does not necessarily correspond to the number used in the claims and for clarity the single substituents are shown attached to compounds which allow multiple substituents under the definition of Wen Zhongshi I and formula II above.
The second object of the present invention is to provide an application of the indole compound, wherein the indole compound is used for preparing a CBP/EP300Bromodomain receptor inhibitor.
As a preferred technical scheme of the invention, the CBP/EP300Bromodomain receptor inhibitor is used for preparing medicines for treating cancers, cell proliferation disorder diseases, inflammatory diseases, autoimmune diseases, septicemia, virus infection and neurogenic recession diseases.
The invention also provides a pharmaceutical composition containing the indole compound.
As a preferred embodiment of the present invention, the pharmaceutical composition is used for treating, preventing or ameliorating cancer, cell proliferative disorders, inflammation, autoimmune diseases, sepsis, viral infections or neurodegenerative diseases.
Medicaments prepared from CBP/EP300Bromodomain receptor inhibitors, and cancers treatable by the pharmaceutical composition include adrenal tumor, acoustic neuroma, acromelama, acrosweat adenoma, acute eosinophilic leukemia, acute red leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adipose tissue tumors, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aids-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, undifferentiated thyroid carcinoma, vascular myolipoma, angiosarcoma, astrocytoma, atypical malformed rod-shaped tumors, B-cell chronic lymphocytic leukemia, B-cell pre-lymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract carcinoma, bladder carcinoma, blastoma, bone tumor, brown tumor, burkitt lymphoma breast cancer, brain cancer, carcinoma in situ, chondrioma, cementoma, myeloid sarcoma, chondrioma, chordoma, choriocarcinoma, chorioallantoic papilloma, renal clear cell sarcoma, craniopharyngeal tumor, cutaneous T-cell lymphoma, cervical cancer, colon cancer, small round cell tumor, diffuse B-cell lymphoma, neuroepithelial tumor, asexual cell tumor, embryonal carcinoma endocrine gland tumor, endodermal sinus tumor, esophageal cancer, fibroma, fibrosarcoma, follicular lymphoma, follicular astrocytoma, thyroid cancer gastrointestinal cancer, germ cell tumor, pregnancy choriocarcinoma, giant cell fibroblast tumor, bone giant cell tumor, glioma, glioblastoma multiforme, glioma, granulocytoma, male cytoma, gall bladder cancer, stomach cancer, angioblastoma, head and neck cancer, angioderm tumor malignancy, hepatoblastoma, cell lymphoma, hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, renal cancer, laryngeal cancer, fatal midline carcinoma, leukemia, testicular stromal cytoma, liposarcoma, lung cancer, lymphangioma, lymphoepithelioma, lymphoma, acute lymphangiosarcoma, lymphocytic leukemia, chronic lymphoblastic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, malt lymphoma, malignant fibrous histiocytoma, malignant peripheral schwannoma, marginal zone b cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, breast medullary carcinoma, medullary thyroid carcinoma, medulloblastoma, melanoma, meningioma, merck cell carcinoma, mesothelioma, metastatic cell carcinoma, mixed muller tumor, myxoma, multiple myeloma, muscle tissue tumor, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neuroblastoma, neurofibroma, neuroma, ocular cancer, eosinophilic, optic nerve sheath meningioma, tumor, oral cancer, osteosarcoma, ovarian cancer, papillary thyroid carcinoma, tumor paraganglioma, pineal tumor, pituitary cell tumor, precursor T-lymphoblastoma, primary central nervous system lymphoma, peritoneal carcinoma, prostate carcinoma, pancreatic carcinoma, pharyngeal carcinoma, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, rectal cancer, sarcoma, seminoma, trophoblastoma, skin carcinoma, small round cell tumor, and tumor, small cell carcinoma, soft tissue sarcoma, somatostatin tumor, spinal cord tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, small intestine cancer, squamous cell carcinoma, gastric cancer, T cell lymphoma, testicular cancer, thyroid cancer, transitional cell carcinoma, laryngeal carcinoma, umbilical duct cancer, genitourinary cancer, uterine cancer, warty cancer, visual pathway glioma, vulval cancer, or vaginal cancer, etc.
Medicaments prepared from CBP/EP300 Bromodomain receptor inhibitors, and cell proliferative disorders treatable by the pharmaceutical compositions include benign soft tissue tumors, brain and spinal cord tumors, eyelid and orbital tumors, granulomas, lipomas, meningiomas, multiple endocrine tumors, nasal polyps, pituitary tumors, lactating tumors, seborrheic keratins, gastric polyps, thyroid nodules, hepatic hemangiomas, vocal cord nodules, polyps, cysts, tibetan hair diseases, cutaneous fibromas, pears cysts, suppurative granulomas, and the like.
The CBP/EP300 Bromodomain receptor inhibitor and the inflammatory diseases which can be treated by the pharmaceutical composition comprise inflammatory pelvic diseases, urethritis, skin sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, pancreatitis, psoriasis, allergy, crohn's disease, intestinal syndrome, ulcerative colitis, tissue graft rejection, organ transplant rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease, autoimmune diseases, autoimmune alopecia, anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolysis and thrombocytopenia, pulmonary hemorrhagic nephritis syndrome, atherosclerosis, addison's disease, parkinson's disease, alzheimer's disease, diabetes, infectious shock, systemic lupus erythematosus, rheumatoid arthritis, psoriasis arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, severe myasthenia, thyroiditis, acute lymphocytic joint degeneration, mycosis, or acute mycosis.
Medicaments prepared from CBP/EP300 Bromodomain receptor inhibitors, and viral infections treatable by the pharmaceutical compositions include human papilloma virus, herpes virus, barl virus, human immunodeficiency virus, hepatitis B virus or hepatitis C virus infections, and the like.
Medicaments prepared from CBP/EP300 Bromodomain receptor inhibitors, and neurodegenerative diseases treatable by the pharmaceutical compositions include alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, creutzfeldt-jakob disease, huntington's disease, cerebellar atrophy, multiple sclerosis, parkinson's disease, primary lateral sclerosis or spinal muscular atrophy, and the like.
The pharmaceutical prepared from CBP/EP300 Bromodomain receptor inhibitors, and the pharmaceutical compositions, may be adapted for use in a variety of routes of administration, typical but non-limiting examples of which are: oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal, by lumbar puncture, transurethral, transdermal or parenteral (including intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathecal, surgical implantation), and the like.
The pharmaceutical compositions of the present invention may be in liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration used. The compositions of the present invention may be administered in the following manner: oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposomal and the like.
The pharmaceutical compositions for oral administration may be solid, gel or liquid. Examples of solid formulations include, but are not limited to, tablets, capsules, granules, and bulk powders. These formulations may optionally contain binders, diluents, disintegrants, lubricants, glidants, sweeteners, flavoring agents and the like. Examples of binders include, but are not limited to, microcrystalline cellulose, dextrose solution, acacia syrup, gelatin solution, sucrose, and starch paste; examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, stearic acid; examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, dicalcium phosphate; examples of glidants include, but are not limited to, silicon dioxide; examples of disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, and carboxymethylcellulose.
Parenteral administration of the pharmaceutical compositions of the present invention is typically based on injection, including subcutaneous, intramuscular or intravenous injection. The injection may be formulated in any conventional form, such as a liquid solution or suspension, a solid form suitable for dissolution or suspension in a liquid prior to injection, or an emulsion. Examples of pharmaceutically acceptable carriers that can be used in the injection formulations of the present invention include, but are not limited to, aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifying agents, chelating agents and other pharmaceutically acceptable substances. Examples of aqueous carriers include sodium chloride injection, ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated ringer's injection; examples of non-aqueous carriers include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil; examples of antimicrobial agents include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, and the like; examples of isotonic agents include sodium chloride and glucose; buffers include phosphates and citrates.
The pharmaceutical composition of the invention can also be prepared into sterile freeze-dried powder injection, the compound is dissolved in sodium phosphate buffer solution containing glucose or other suitable excipients, and then the solution is subjected to sterile filtration under standard conditions known to those skilled in the art, followed by freeze-drying, so as to obtain the required preparation.
In the compounds of the present invention, when any variable (e.g., R1, R2, etc.) occurs more than once in any component, the definition of each occurrence is independent of the definition of each other occurrence. Also, combinations of substituents and variables are permissible provided that such combinations stabilize the compounds. The lines drawn from the substituents into the ring system indicate that the bond referred to may be attached to any substitutable ring atom. If the ring system is polycyclic, it means that such bonds are only attached to any suitable carbon atom adjacent to the ring. It is to be understood that substituents and substitution patterns of the compounds of this invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that may be readily synthesized by techniques in the art and from readily available starting materials. If the substituent itself is substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, as long as the structure is stabilized. The phrase "optionally substituted with one or more substituents" is considered to be equivalent to the phrase "optionally substituted with at least one substituent" and in this case preferred embodiments will have from 0 to 3 substituents.
The terms "alkyl" and "alkylene" as used herein are meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, the definition of "C1-C4" in "C1-C4" alkyl includes groups having 1, 2, 3, 4, carbon atoms arranged in a straight or branched chain. For example, "C1-C4" alkyl "specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, methyl-cyclopropyl, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, and the like.
Unless otherwise defined, alkyl, phenyl, naphthyl, cycloalkyl, and heterocyclyl substituents may be unsubstituted or substituted. For example, the C1-C4 alkyl group may be substituted with one, two or three substituents selected from halogen, alkoxy, methyl, ethyl, propyl, isopropyl, t-butyl, trifluoromethyl, cyano, carboxyl, nitro, amino, methylsulfonyl, phenyldiazenyl or heterocyclyl, such as morpholinyl, piperidinyl, quinolinyl, furyl, tetrahydrofuranyl, pyridyl and the like.
The present invention includes the free forms of the compounds of formula I and formula II, as well as pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to an amine compound in a non-salt form. Included are pharmaceutically acceptable salts including not only the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the compounds of formula I and formula II in free form. The free form of the particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention such acid and base salts are otherwise pharmaceutically comparable to their respective free forms.
Pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess of an inorganic or organic acid in the form of the desired salt in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.
Thus, pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention formed by the reaction of a basic compound of the invention with an inorganic or organic acid. For example, conventional nontoxic salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, and also salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.
If the compounds of the present invention are acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases, salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, and the like. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, guava, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Since under physiological conditions the deprotonated acidic moiety, e.g. carboxyl, in the compound may be anionic, and this charge may then be balanced out by the protonated or alkylated basic moiety, e.g. tetravalent nitrogen atom, which is internally cationic, it should be noted that the compounds of the present invention are potentially internal salts or zwitterions.
Compared with the prior art, the invention has at least the following beneficial effects:
the invention provides an indole compound which can effectively inhibit a CBP/EP300 Bromodomain receptor and can be used as a therapeutic drug for treating cancers, cell proliferation disorders, inflammatory diseases, autoimmune diseases, septicemia, viral infection or neurogenic degenerative diseases.
Detailed Description
For a better illustration of the present invention, which is convenient for understanding the technical solution of the present invention, exemplary but non-limiting examples of the present invention are as follows:
example 1
Synthesis of methyl 1- (2- (3-acetyl-1H-indol-1-yl) acetyl) piperidine-4-carboxylate:
(1) Synthesis of methyl 1- (2-chloroacetyl) piperidine-4-carboxylate
Methyl piperidine-4-carboxylic acid ethyl ester (2 g,14 mmol) was dissolved in 20mL of DCM and then 2-chloroacetyl chloride (1.16 mL,15.4 mmol) and K2CO3 (5.8 g,42 mmol) were added. The reaction system was stirred at room temperature for 5h. After completion of the reaction, 30mL of water was added and extracted with DCM (3X 20 mL), and the organic phase was washed once with saturated brine and dried over anhydrous sodium sulfate. The organic phase was dried by spin-drying under vacuum to give 2.072g (67.4% yield) of yellow oil. 1H NMR (400 MHz, CDCl 3) delta 4.32 (m, 1H), 4.10 (m, 1H), 4.02-3.76 (s, 3H), 3.70 (s, 2H), 3.30-3.14 (m, 1H), 2.94 (td, J=13.4, 2.9Hz, 1H), 2.70-2.50 (m, 1H), 2.08-1.90 (m, 2H), 1.90-1.61 (m, 2H).
(2) Synthesis of QP19 1- (2- (3-acetyl-1H-indol-1-yl) acetyl) piperidine-4-carboxylic acid methyl ester
Intermediate 1- (2-chloroacetyl) piperidine-4-carboxylic acid methyl ester (437.48 mg,2 mmol) was dissolved in 50mL acetone, 1-acetylindole (264 mg,1.66 mmol) was added, K2CO3 (688 mg,4.98mmol, KI (42 mg,0.252 mmol) the reaction system was stirred at 56℃for 5H after the reaction was completed, cooled to room temperature, 20mL water was added, extracted with EA (3X 30 mL), the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, the organic phase was dried in vacuo and the crude product was isolated via a silica gel column (MeOH: dcm=1:10), white solid 397mg (yield 70%). 1H NMR (400 mhz, dmso-d 6) δ8.24 (s, 1H), 8.18 (d, j=6.9 hz, 1H), 7.44 (d, j=7.2 hz, 1H), 7.20 (s, 2H), 5.29 (m, 2H), 4.17 (d, j=12.5 hz, 1H), 3.94 (d, j=12.9 hz, 1H), 3.64 (s, 3H), 3.24 (t, j=12.1 hz, 1H), 2.80 (t, j=11.7 hz, 1H), 2.69 (t, j=10.7 hz, 1H), 2.42 (s, 3H), 1.94 (d, j=11.6 hz, 1H), 1.86 (d, j=12.6 hz, 1H), 1.71 (d, j=10.5 hz, 1.44, 1H).
Example 2
Synthesis of ethyl 2- (3-acetyl-1H-indol-1-yl) acetate was performed as in example 1.1H NMR (400 MHz, CDCl 3) δ8.39 (dd, J=6.4, 2.6Hz, 1H), 7.76 (s, 1H), 7.31 (dt, J=6.9, 3.5Hz, 2H), 7.26 (s, 1H), 4.88 (s, 2H), 4.25 (q, J=7.1 Hz, 2H), 1.60 (s, 3H), 1.28 (d, J=7.1 Hz, 3H).
Example 3
Synthesis of 2- (3-acetyl-1H-indol-1-yl) acetic acid is carried out as in example 8.1H NMR (400 MHz, DMSO). Delta.8.32 (s, 1H), 8.22-8.16 (m, 1H), 7.49 (d, J=7.4 Hz, 1H), 7.28-7.18 (m, 2H), 5.12 (s, 2H), 2.44 (s, 3H).
Example 4
Synthesis of (3-acetyl-1H-indol-1-yl) -N-isobutylacetamide was carried out as in example 1.1H NMR (400 MHz, CDCl 3) delta 8.47-8.34 (m, 1H), 7.74 (s, 1H), 7.42-7.29 (m, 3H), 5.46 (s, 1H), 4.85 (s, 2H), 3.03 (t, J=6.5 Hz, 2H), 2.51 (s, 3H), 0.74 (d, J=6.7 Hz, 6H).
Example 5
Synthesis of (3-acetyl-1H-indol-1-yl) acetamide is carried out as in example 1.1H NMR (400 MHz, CDCl 3) δ8.29 (s, 1H), 8.18 (d, J=7.9 Hz, 1H), 7.71 (s, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.34 (s, 1H), 7.31-7.15 (m, 2H), 4.89 (s, 2H), 2.44 (s, 3H).
Example 6
Synthesis of ethyl 3- (3-acetyl-1H-indol-1-yl) propionate is performed as in example 1.1H NMR (400 MHz, CDCl 3) delta 8.46-8.32 (m, 1H), 7.83 (s, 1H), 7.35 (dd, J=10.0, 5.2Hz, 1H), 7.33-7.27 (m, 2H), 4.50 (t, J=6.5 Hz, 2H), 4.13 (q, J=7.1 Hz, 2H), 2.87 (t, J=6.5 Hz, 2H), 2.52 (s, 3H), 1.21 (t, J=7.1 Hz, 3H).
Example 7
Synthesis of (3-acetyl-1H-indol-1-yl) -1- (piperidin-1-yl) ethanone was performed as in example 1.1H NMR (400 MHz, DMSO). Delta.8.24 (s, 1H), 8.19-8.15 (m, 1H), 7.42 (dd, J=6.7, 1.7Hz, 1H), 7.25-7.16 (m, 2H), 5.26 (s, 2H), 3.53 (s, 2H), 3.48-3.39 (m, 2H), 2.43 (s, 3H), 1.63 (s, 4H), 1.47 (s, 2H).
Example 8
Synthesis of 1- (2- (3-acetyl-1H-indol-1-yl) acetyl) piperidine-4-carboxylic acid methyl ester Synthesis of 1- (2- (3-acetyl-1H-indol-1-yl) acetyl) piperidine-4-carboxylic acid was as in example 1.
The compound methyl 1- (2- (3-acetyl-1H-indol-1-yl) acetyl) piperidine-4-carboxylate (284 mg,0.83 mmol) was dissolved in 8mL MeOH and 1M NaOH (4 mL,4.15 mmol) was added to the reaction system. The reaction was stirred at room temperature for 2h and monitored by TLC. After the reaction, most of the solvent was removed by vacuum spinning, the remaining solution was adjusted to a slightly acidic pH with 1M hydrochloric acid solution, a large amount of white solid was precipitated, suction filtration was performed under reduced pressure, the cake was washed with 20mL of water, and 156mg of white solid was obtained by vacuum drying (yield 57.2%). The synthesis was as in example 1.1H NMR (400 MHz, DMSO). Delta.12.32 (s, 1H), 8.23 (s, 1H), 8.20-8.09 (m, 1H), 7.44 (d, J=7.2 Hz, 1H), 7.27-7.14 (m, 2H), 5.28 (d, J=3.9 Hz, 2H), 4.16 (d, J=13.0 Hz, 1H), 3.94 (d, J=13.4 Hz, 1H), 3.27-3.19 (m, 1H), 2.81 (t, J=11.1 Hz, 1H), 2.61-2.55 (m, 1H), 2.43 (s, 3H), 1.98-1.89 (m, 1H), 1.85 (d, J=11.2 Hz, 1H), 1.69 (d, J=10.6 Hz, 1H), 1.43 (d, J=9.9 Hz, 1H), 1.24 (s, 1H).
Example 9
Synthesis of methyl 1- (2- (3-acetyl-1H-indol-1-yl) acetyl) piperidine-3-carboxylate was performed as in example 1.1H NMR (400 MHz, DMSO). Delta.8.21 (d, J=6.4 Hz, 1H), 8.18 (d, J=6.8 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.21 (m, 2H), 5.33 (d, J=7.8 Hz, 1H), 5.27 (s, 1H), 3.86 (t, J=11.7 Hz, 1H), 3.76 (s, 1H), 3.64 (s, 3H), 3.57-3.48 (m, 1H), 3.16 (dt, J=19.7, 10.4Hz, 1H), 2.77 (s, 1H), 2.43 (s, 3H), 1.99 (s, 1H), 1.79 (d, J=9.9 Hz, 1H), 1.72-1.52 (m, 1H), 1.43 (d, J=9.2 Hz, 1H).
Example 10
Synthesis of 1- (2- (3-acetyl-1H-indol-1-yl) acetyl) piperidine-3-carboxylic acid was performed as in example 8.1H NMR (400 MHz, DMSO). Delta.8.21 (d, J=12.3 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H), 7.44 (d, J=5.7 Hz, 1H), 7.25-7.16 (m, 2H), 5.44-5.24 (m, 2H), 3.83 (dd, J=12, 11.9Hz, 1H), 3.66-3.55 (m, 1H), 2.89-2.78 (m, 1H), 2.66 (s, 1H), 2.43 (s, 3H), 2.34 (s, 1H), 2.00 (d, J=8.3 Hz, 1H), 1.78 (s, 1H), 1.69-1.49 (m, 1H), 1.44 (s, 1H).
Example 11
Synthesis of 1- (1- (thiophene-2-carbonyl) -1H-indol-3-yl) ethanone 1- (1H-indol-3-yl) ethan-1-one (100 mg, 0.6278 mmol) was dissolved in 30mL tetrahydrofuran, followed by addition of methyl tert-butoxide (281.87 mg,2.512 mmol), stirring at room temperature for 15min, and thiophene-2-carbonyl chloride (184.1 mg,1.256 mmol) was added to the reaction system and stirred at room temperature. After completion of the reaction, water was added and extracted with DCM (3X 20 mL), and the organic phase was washed once with saturated brine and dried over anhydrous sodium sulfate. The organic phase was dried in vacuo and the crude product was isolated by column chromatography on silica gel (PE: ea=10:1, 4:1) to give 152mg (90% yield) of product. 1H NMR (400 MHz, DMSO). Delta.8.71 (s, 1H), 8.28 (dd, J=6.3, 2.4Hz, 1H), 8.23 (dd, J=5.0, 1.0Hz, 1H), 8.19 (dd, J=6.7, 2.1Hz, 1H), 8.03 (dd, J=3.8, 1.0Hz, 1H), 7.45-7.41 (m, 2H), 7.39 (dd, J=4.9, 3.9Hz, 1H), 2.57 (s, 3H).
Example 12
Synthesis of 1- (1- (propylsulfonyl) -1H-indol-3-yl) ethanone 1- (1H-indol-3-yl) ethan-1-one (100 mg, 0.6278 mmol) is dissolved in 30mL tetrahydrofuran, the reaction system is brought to 0℃and NaH (75.2 mg,1.88 mmol) is added thereto, and stirring is carried out at room temperature for 1H, propane-1-sulfonyl chloride (98.325 mg,0.7 mmol) is added to the system. After completion of the reaction, water was added thereto and extracted with EA (3X 20 mL), and the organic phase was washed once with saturated brine and dried over anhydrous sodium sulfate. The organic phase was dried in vacuo and the crude product was isolated by column chromatography on silica gel (PE: ea=4:1) to give 117mg (70.27% yield) of product. 1H NMR (400 MHz, CDCl 3) delta 8.46-8.34 (m, 1H), 8.06 (s, 1H), 7.87 (dt, J=4.8, 3.0Hz, 1H), 7.48-7.36 (m, 2H), 3.42-3.26 (m, 2H), 2.57 (s, 3H), 1.83-1.68 (m, 2H), 0.99 (t, J=7.4 Hz, 3H).
Example 13
Synthesis of 1- (1- (phenylsulfonyl) -1H-indol-3-yl) ethanone is carried out as in example 12.1H NMR (400 MHz, CDCl 3) delta 8.38-8.29 (m, 1H), 8.21 (s, 1H), 7.95 (t, J=7.8 Hz, 3H), 7.60 (t, J=7.5 Hz, 1H), 7.50 (t, J=7.8 Hz, 2H), 7.44-7.30 (m, 2H), 2.58 (s, 3H).
Example 14
Synthesis of 1- (1- (thiophen-2-ylsulfonyl) -1H-indol-3-yl) ethanone is carried out as in example 12.1H NMR (400 MHz, DMSO). Delta.8.75 (s, 1H), 8.21 (d, J=7.7 Hz, 1H), 8.14 (s, 1H), 8.13 (q, J=1.4 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.50-7.43 (m, 1H), 7.43-7.36 (m, 1H), 7.24 (dd, J=4.7, 4.2Hz, 1H), 2.59 (s, 3H).
Example 15
Synthesis of methyl 1- (2- (3-acetyl-6-methoxy-1H-indol-1-yl) acetyl) piperidine-4-carboxylate was performed as in example 1.1H NMR (400 MHz, DMSO). Delta.8.10 (s, 1H), 8.02 (d, J=8.7 Hz, 1H), 6.99 (d, J=2.0 Hz, 1H), 6.83 (dd, J=8.7, 2.2Hz, 1H), 5.23 (d, J=3.0 Hz, 2H), 4.18 (d, J=13.4 Hz, 1H), 3.94 (d, J=13.6 Hz, 1H), 3.78 (s, 3H), 3.64 (s, 3H), 2.81 (t, J=11.5 Hz, 1H), 2.69 (dd, J=12.9, 9.1Hz, 1H), 2.39 (s, 3H), 2.03-1.82 (m, 2H), 1.71 (d, J=9.4 Hz, 1H), 1.52-1.37 (m, 1H), 1.20 (d, J=23.7 Hz, 1H).
Example 16
Synthesis of 1- (2- (3-acetyl-6-methoxy-1H-indol-1-yl) acetyl) piperidine-4-carboxylic acid was performed as in example 8.1H NMR (400 MHz, DMSO). Delta.8.10 (s, 1H), 8.02 (d, J=8.7 Hz, 1H), 6.99 (d, J=1.9 Hz, 1H), 6.83 (dd, J=8.7, 2.1Hz, 1H), 5.29-5.14 (m, 2H), 4.17 (d, J=13.1 Hz, 1H), 3.93 (d, J=13.6 Hz, 1H), 3.78 (s, 3H), 2.81 (t, J=11.2 Hz, 1H), 2.56 (m, 1H), 2.39 (s, 3H), 1.89 (m, 2H), 1.69 (m, 1H), 1.50-1.34 (m, 1H).
Example 17
Synthesis of methyl 1- (2- (3-acetyl-6-hydroxy-1H-indol-1-yl) acetyl) piperidine-4-carboxylate:
1- (2- (3-acetyl-6-methoxy-1H-indol-1-yl) acetyl) piperidine-4-carboxylic acid methyl ester synthesis method is as in example 1.
1- (2- (3-acetyl-6-methoxy-1H-indol-1-yl) acetyl) piperidine-4-carboxylic acid methyl ester (100 mg,0.27 mmol) was dissolved in 15mL of dichloromethane, BBr3 (167 mg,0.68 mmol) was taken and dissolved in 10mL of DCM, and the mixture was added dropwise to the reaction system under ice-bath conditions, followed by reaction at room temperature and TLC monitoring. At the end of the reaction, the mixture was quenched by slowly dropping methanol and aqueous NH4Cl, extracted with water, EA (3X 30 mL), washed with saturated brine, dried over anhydrous sodium sulfate, dried by spin-drying, and recrystallized to give 76.86mg of a white solid (yield 57.2%). 1H NMR (400 MHz, DMSO). Delta.9.34 (s, 1H), 8.04 (s, 1H), 7.90 (d, J=8.7 Hz, 1H), 6.72 (d, J=8.1 Hz, 2H), 5.23-5.06 (m, 2H), 4.15 (d, J=13.4 Hz, 1H), 3.93 (d, J=12.7 Hz, 1H), 3.63 (s, 1H), 3.21 (s, 2H), 2.80 (t, J=11.9 Hz, 1H), 2.36 (s, 3H), 2.02-1.76 (m, 2H), 1.64 (d, J=9.9 Hz, 1H), 1.42 (s, 1H), 1.22 (s, 2H).
Example 18
Synthesis of 1- (2- (3-acetyl-6-hydroxy-1H-indol-1-yl) acetyl) piperidine-4-carboxylic acid was performed as in example 8.1H NMR (400 MHz, DMSO). Delta.9.22 (s, 1H), 8.02 (s, 1H), 7.98-7.85 (m, 1H), 6.70 (s, 2H), 5.25-5.04 (m, 2H), 4.16 (d, J=12.9 Hz, 1H), 3.93 (d, J=12.9 Hz, 1H), 2.80 (t, J=11.8 Hz, 1H), 2.37 (s, 3H), 1.89 (dd, J=29.8, 11.7Hz, 2H), 1.65 (d, J=10.9 Hz, 1H), 1.41 (d, J=10.8 Hz, 1H), 1.23 (s, 1H).
Example 19
Synthesis of 1- (6-methoxy-1- (phenylsulfonyl) -1H-indol-3-yl) ethanone is carried out as in example 12.1H NMR (400 MHz, CDCl 3) δ8.19 (d, J=8.8 Hz, 1H), 8.09 (s, 1H), 7.98-7.85 (m, 2H), 7.62 (t, J=7.5 Hz, 1H), 7.51 (t, J=7.8 Hz, 2H), 7.44 (d, J=2.2 Hz, 1H), 6.96 (dd, J=8.8, 2.3Hz, 1H), 3.87 (s, 3H), 2.55 (s, 3H).
When the structural type is II:
example 20
Synthesis of 3- (1-acetyl-1H-indole-3-carboxamide) pyrrolidine-1-carboxylic acid tert-butyl ester:
(1) Synthesis of 1-acetyl-1H-indole-3-carboxylic acid
3-Indolecarboxylic acid (1.5 g,9.3 mmol) was added to 12mL of DCE, followed by Et3N (4 mL,27.9 mmol), DMAP (0.114 g,0.93 mmol), acetic anhydride (2.8 mL,27.9 mmol). The reaction was allowed to react at 60℃for 3h, followed by TLC. At the end of the reaction, most of the solvent was spun off in vacuo, redissolved in EA, washed with saturated NaHCO3, the organic phase was discarded, the aqueous layer was acidified with 1M HCl solution to give a large amount of white precipitate, filtered in vacuo, the filter cake was washed three times with water and dried in vacuo to give 1.20g of a white solid (63%). 1H NMR (400 MHz, DMSO). Delta.8.42 (s, 1H), 8.35 (dd, J=6.9, 1.8Hz, 1H), 8.08 (dd, J=6.5, 2.1Hz, 1H), 7.44-7.28 (m, 2H), 2.73 (s, 3H).
(2) Synthesis of tert-butyl 3- (1-acetyl-1H-indole-3-carboxamido) pyrrolidine-1-carboxylate
30mL of DCM was added to intermediate 1-acetyl-1H-indole-3-carboxylic acid (100 mg,0.49 mmol) followed by HATU (218 mg,0.74 mmol) and DIPEA (191 mg,1.48 mmol). After stirring at room temperature for 30min, 3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (111.9 mg,0.74 mmol) was added. The reaction was stirred at room temperature overnight. After completion of the reaction, 20mL of water was added, and the mixture was extracted with EA (3X 30 mL), washed once with saturated brine, and finally dried over anhydrous sodium sulfate. The organic phase was dried in vacuo and the crude product was separated on a silica gel column (PE: ea=2:1). 130mg (71.5% yield) of white solid was obtained. 1H NMR (400 MHz, DMSO). Delta.8.56 (s, 1H), 8.32 (d, J=7.4 Hz, 2H), 8.23-8.15 (m, 1H), 7.35 (tt, J=7.3, 6.0Hz, 2H), 4.46 (s, 1H), 3.60 (s, 1H), 3.44 (dt, J=14.1, 5.8Hz, 2H), 3.21 (d, J=7.8 Hz, 1H), 2.70 (s, 3H), 2.14 (dt, J=13.4, 6.6Hz, 1H), 1.91 (s, 1H), 1.41 (s, 9H).
Example 21
Synthesis of N- (2-acetamidoethyl) -1-acetyl-1H-indole-3-carboxamide was performed as in example 20.1H NMR (400 MHz, CDCl 3) delta 8.51-8.43 (m, 1H), 8.12-8.05 (m, 1H), 8.02 (s, 1H), 7.46-7.37 (m, 2H), 7.17 (s, 1H), 6.34 (s, 1H), 3.64 (dd, J=10.7, 5.0Hz, 2H), 3.55 (dd, J=10.9, 5.5Hz, 2H), 2.70 (s, 3H), 2.03 (s, 3H).
Example 22
Synthesis of tert-butyl 4- (1-acetyl-1H-indole-3-carboxamide) butyl carbamate by the method of example 20.1H NMR (400 MHz, DMSO). Delta.8.50 (s, 1H), 8.32 (d, J=7.8 Hz, 1H), 8.30-8.14 (m, 2H), 7.34 (dq, J=7.3, 6.2Hz, 2H), 6.80 (s, 1H), 3.29-3.15 (m, 2H), 2.95 (dd, J=12.6, 6.4Hz, 2H), 2.69 (s, 3H), 1.62-1.41 (m, 4H), 1.38 (d, J=11.5 Hz, 9H), 1.23 (s, 1H).
Example 23
Synthesis of 1-acetyl-N- (2- (2-oxoimidazolidin-1-yl) ethyl) -1H-indole-3-carboxamide was performed as in example 20.1H NMR (400 MHz, DMSO). Delta.8.48 (s, 1H), 8.33 (d, J=8.2 Hz, 2H), 8.19 (d, J=7.4 Hz, 1H), 7.43-7.25 (m, 2H), 6.29 (s, 1H), 3.51-3.37 (m, 4H), 3.23 (dd, J=13.8, 6.9Hz, 4H), 2.69 (s, 3H).
Example 24
Synthesis of 1-acetyl-N- (2- (pyridin-2-yl) ethyl) -1H-indole-3-carboxamide was performed as in example 20.1H NMR (400 MHz, DMSO). Delta.8.53 (d, J=3.9 Hz, 1H), 8.48 (s, 1H), 8.38 (t, J=5.5 Hz, 1H), 8.32 (d, J=7.4 Hz, 1H), 8.21-8.15 (m, 1H), 7.72 (td, J=7.6, 1.8Hz, 1H), 7.40-7.29 (m, 3H), 7.23 (dd, J=7.0, 5.3Hz, 1H), 3.72-3.61 (m, 2H), 3.03 (t, J=7.4 Hz, 2H), 2.68 (s, 3H).
Example 25
Synthesis of 1-acetyl-N- (2-chlorophenyl ethyl) -1H-indole-3-carboxamide was performed as in example 20.1H NMR (400 MHz, DMSO). Delta.8.48 (s, 1H), 8.41 (t, J=5.6 Hz, 1H), 8.32 (d, J=7.9 Hz, 1H), 8.18 (d, J=7.0 Hz, 1H), 7.44 (dd, J=7.4, 1.7Hz, 1H), 7.42-7.20 (m, 5H), 3.53 (dd, J=14.1, 6.3Hz, 2H), 3.00 (t, J=7.4 Hz, 2H), 2.68 (s, 3H).
Example 26
Synthesis of tert-butyl 3- (1-acetyl-1H-indole-3-carboxamide) azetidine-1-carboxylate was carried out as in example 20.1H NMR (400 MHz, DMSO). Delta.8.80 (d, J=7.3 Hz, 1H), 8.56 (s, 1H), 8.33 (d, J=7.8 Hz, 1H), 8.18 (d, J=7.2 Hz, 1H), 7.35 (m, 2H), 4.81-4.59 (m, 1H), 4.18 (t, J=8.1 Hz, 2H), 3.95-3.74 (m, 2H), 2.71 (s, 3H), 1.40 (s, 9H).
Example 27
Synthesis of 1-acetyl-N- (3-chlorobenzyl) -1H-indole-3-carboxamide was performed as in example 20.1H NMR (400 MHz, CDCl 3) δ8.45 (d, J=7.8 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J=7.3 Hz, 1H), 7.40 (dd, J=19.7, 7.6Hz, 3H), 7.27 (s, 4H), 6.44 (s, 1H), 4.66 (d, J=5.6 Hz, 2H), 2.66 (s, 3H).
Example 28
Synthesis of 1-acetyl-N- ((6-chloropyridin-3-yl) methyl) -1H-indole-3-carboxamide was performed as in example 20.1H NMR (400 MHz, CDCl 3) δ8.46 (d, J=8.1 Hz, 1H), 8.41 (d, J=2.2 Hz, 1H), 8.02 (s, 1H), 7.88 (d, J=7.4 Hz, 1H), 7.74 (dd, J=8.2, 2.5Hz, 1H), 7.48-7.30 (m, 3H), 6.47 (s, 1H), 4.69 (d, J=6.0 Hz, 2H), 2.69 (s, 3H).
Example 29
Synthesis of 1-acetyl-N- (3, 5-bis (trifluoromethyl) benzyl) -1H-indole-3-carboxamide was performed as in example 20.1H NMR (400 MHz, DMSO). Delta.9.00 (t, J=5.9 Hz, 1H), 8.58 (s, 1H), 8.34 (d, J=7.8 Hz, 1H), 8.19 (d, J=7.3 Hz, 1H), 8.06 (s, 2H), 8.01 (s, 1H), 7.36 (ddd, J=13.6, 10.5,6.1Hz, 2H), 4.69 (d, J=5.9 Hz, 2H), 2.70 (s, 3H).
Example 30
Synthesis of 1-acetyl-N- (4-methoxybenzyl) -1H-indole-3-carboxamide was performed as in example 20.1H NMR (400 MHz, DMSO). Delta.8.70 (t, J=5.8 Hz, 1H), 8.58 (s, 1H), 8.33 (d, J=7.6 Hz, 1H), 8.27-8.19 (m, 1H), 7.40-7.32 (m, 2H), 7.30 (s, 1H), 7.28 (s, 1H), 6.92 (s, 1H), 6.90 (s, 1H), 4.44 (d, J=5.8 Hz, 2H), 3.73 (s, 3H), 2.68 (s, 3H).
Example 31
Synthesis of 1-acetyl-N- (3, 4, 5-trifluorobenzyl) -1H-indole-3-carboxamide was performed as in example 20.1H NMR (400 MHz, DMSO). Delta.8.88 (t, J=5.9 Hz, 1H), 8.59 (s, 1H), 8.34 (d, J=7.7 Hz, 1H), 8.22-8.15 (m, 1H), 7.42-7.35 (m, 1H), 7.35-7.24 (m, 3H), 4.49 (d, J=5.9 Hz, 2H), 2.70 (s, 3H).
Example 32
Synthesis of 1-acetyl-N- (pyridin-4-ylmethyl) -1H-indole-3-carboxamide was performed as example 20.1H NMR (400 MHz, DMSO). Delta.8.91 (s, 1H), 8.62 (s, 1H), 8.53 (d, J=4.6 Hz, 3H), 8.35 (d, J=7.8 Hz, 1H), 8.21 (d, J=7.5 Hz, 1H), 8.17-8.03 (m, 1H), 7.51-7.21 (m, 5H), 7.13 (dd, J=14.3, 7.5Hz, 1H), 4.52 (dd, J=16.4, 5.6Hz, 3H), 2.71 (s, 3H).
Example 33
Synthesis of 1-acetyl-N- (2-chloro-4-fluorobenzyl) -1H-indole-3-carboxamide was performed as in example 20.1H NMR (400 MHz, DMSO). Delta.8.56 (s, 1H), 8.48 (t, J=4.5 Hz, 1H), 8.32 (d, J=7.5 Hz, 1H), 8.23 (d, J=7.1 Hz, 1H), 7.47-7.24 (m, 5H), 4.63 (d, J=3.6 Hz, 2H), 2.66 (s, 3H).
Example 34
Synthesis of 1-acetyl-N- ((5-methyl-1H-indazol-3-yl) methyl) -1H-indole-3-carboxamide was performed as in example 20.1H NMR (400 MHz, DMSO). Delta.12.75 (s, 1H), 8.76 (t, J=5.5 Hz, 1H), 8.57 (s, 1H), 8.37-8.23 (m, 2H), 7.60 (s, 1H), 7.44-7.30 (m, 3H), 7.17 (d, J=8.4 Hz, 1H), 4.82 (d, J=5.7 Hz, 2H), 2.64 (s, 3H), 2.36 (s, 3H).
Example 35
Synthesis of 1-acetyl-N- ((4-methyl-6- (trifluoromethyl) pyrimidin-2-yl) methyl) -1H-indole-3-carboxamide was performed as in example 20.1H NMR (400 MHz, CDCl 3) delta 8.57-8.44 (m, 1H), 8.23-8.08 (m, 2H), 7.54 (s, 1H), 7.49-7.37 (m, 3H), 5.01 (d, J=4.6 Hz, 2H), 2.70 (s, 6H).
Example 36
Synthesis of 1-acetyl-N- (4-fluoro-3- (trifluoromethyl) benzyl) -1H-indole-3-carboxamide was performed as in example 20.1H NMR (400 MHz, DMSO). Delta.8.90 (t, J=5.6 Hz, 1H), 8.57 (s, 1H), 8.34 (d, J=7.9 Hz, 1H), 8.20 (d, J=7.2 Hz, 1H), 7.77 (d, J=6.9 Hz, 2H), 7.57-7.45 (m, 1H), 7.45-7.28 (m, 2H), 4.57 (d, J=5.8 Hz, 2H), 2.69 (s, 3H).
Example 37
Synthesis of 1-acetyl-N- ((1-methyl-5- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) methyl) -1H-indole-3-carboxamide was performed as in example 20.1H NMR (400 MHz, DMSO). Delta.8.98 (t, J=5.4 Hz, 1H), 8.66 (s, 1H), 8.34 (d, J=7.7 Hz, 1H), 8.24 (d, J=7.2 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.43-7.28 (m, 2H), 4.86 (d, J=5.5 Hz, 2H), 3.92 (s, 3H), 2.68 (s, 3H).
Example 38
Synthesis of 1-acetyl-N- ((5-fluoro-1H-indol-2-yl) methyl) -1H-indole-3-carboxamide is performed as in example 20.1H NMR (400 MHz, DMSO). Delta.11.11 (s, 1H), 8.78 (t, J=5.5 Hz, 1H), 8.62 (s, 1H), 8.34 (d, J=7.2 Hz, 1H), 8.29-8.19 (m, 1H), 7.35 (ddt, J=11.0, 8.9,5.3Hz, 3H), 7.22 (dd, J=10.0, 2.5Hz, 1H), 6.87 (td, J=9.4, 2.6Hz, 1H), 6.36 (s, 1H), 4.64 (d, J=5.5 Hz, 2H), 2.68 (s, 3H).
Example 39
Synthesis of 1-acetyl-N- ((5-methoxy-1H-indol-2-yl) methyl) -1H-indole-3-carboxamide is performed as in example 20.1HNMR (400 MHz, DMSO). Delta.10.82 (s, 1H), 8.73 (t, J=5.4 Hz, 1H), 8.62 (s, 1H), 8.42-8.30 (m, 1H), 8.30-8.21 (m, 1H), 7.36 (dq, J=7.3, 5.8Hz, 2H), 7.23 (d, J=8.7 Hz, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.68 (dd, J=8.7, 2.4Hz, 1H), 6.28 (s, 1H), 4.62 (d, J=5.5 Hz, 2H), 3.72 (s, 3H), 2.68 (d, J=4.9 Hz, 4H).
Example 40
Synthesis of methyl 3- (1-acetyl-1H-indole-3-carboxamide) -3- (3, 5-dimethylphenyl) propionate was performed as in example 20.1H NMR (400 MHz, CDCl 3) delta 8.46 (dd, J=5.9, 3.1Hz, 1H), 8.00 (t, J=4.3 Hz, 2H), 7.45-7.36 (m, 2H), 7.26-7.18 (m, 2H), 6.99 (d, J=9.9 Hz, 2H), 5.81 (dd, J=13.9, 6.2Hz, 1H), 3.65 (s, 3H), 2.96 (dd, J=6.2, 2.4Hz, 2H), 2.64 (s, 3H), 2.45 (s, 3H), 2.28 (s, 3H).
Example 41
Synthesis of methyl 2- ((1-acetyl-1H-indole-3-carboxamide) methyl) benzoate was performed as in example 20.1H NMR (400 MHz, DMSO). Delta.8.71 (s, 1H), 8.38 (d, J=8.0 Hz, 1H), 7.92 (d, J=7.4 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.79 (t, J=7.3 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.59 (t, J=7.2 Hz, 1H), 7.39 (dt, J=20.9, 6.9Hz, 2H), 5.10 (s, 2H), 3.83 (s, 3H), 2.71 (s, 3H).
Example 42
Synthesis of methyl 2- (1-acetyl-1H-indole-3-carboxamide) -3- (furan-2-yl) propanoate was performed as in example 20.1H NMR (400 MHz, DMSO). Delta.8.70 (d, J=7.8 Hz, 1H), 8.62 (s, 1H), 8.33 (d, J=8.1 Hz, 1H), 8.15 (d, J=7.4 Hz, 1H), 7.55 (d, J=0.8 Hz, 1H), 7.35 (dt, J=14.3, 6.9Hz, 2H), 6.39-6.30 (m, 1H), 6.23 (d, J=2.9 Hz, 1H), 4.81 (dd, J=14.1, 8.4Hz, 1H), 3.67 (s, 3H), 3.20 (m, 2H), 2.71 (s, 3H).
Example 43
Ethyl 3- (1-acetyl-1H-indole-3-carboxamido) -4- (5-methylfuran-2-yl) butanoate was synthesized as described in example 20.1H NMR (400 MHz, DMSO). Delta.8.62 (d, J=8.4 Hz, 1H), 8.58 (s, 1H), 8.33 (d, J=7.6 Hz, 1H), 8.22 (d, J=7.0 Hz, 1H), 7.42-7.28 (m, 2H), 6.21 (d, J=3.0 Hz, 1H), 6.01 (d, J=2.2 Hz, 1H), 5.58 (q, J=7.8 Hz, 1H), 4.12-4.00 (m, 2H), 2.98-2.84 (m, 2H), 2.69 (s, 3H), 2.24 (s, 3H), 1.23 (s, 2H), 1.13 (t, J=7.1 Hz, 3H).
Example 44
Synthesis of methyl 4- ((1-acetyl-1H-indole-3-carboxamide) methyl) thiophene-2-carboxylate was performed as in example 20.1H NMR (400 MHz, DMSO). Delta.9.04 (t, J=5.9 Hz, 1H), 8.58 (s, 1H), 8.34 (d, J=7.6 Hz, 1H), 8.22 (d, J=7.2 Hz, 1H), 7.68 (d, J=3.8 Hz, 1H), 7.46-7.28 (m, 2H), 7.15 (d, J=3.8 Hz, 1H), 4.70 (d, J=5.8 Hz, 2H), 3.79 (s, 3H), 2.69 (s, 3H).
Example 45
Synthesis of 4- ((1-acetyl-1H-indole-3-carboxamide) methyl) thiophene-2-carboxylic acid was performed as in example 8.1H NMR (400 MHz, DMSO). Delta.9.03 (t, J=5.8 Hz, 1H), 8.59 (s, 1H), 8.40-8.30 (m, 1H), 8.22 (dd, J=6.9, 1.7Hz, 1H), 7.59 (d, J=3.7 Hz, 1H), 7.36 (pd, J=7.2, 1.4Hz, 2H), 7.12 (d, J=3.7 Hz, 1H), 4.68 (d, J=5.8 Hz, 2H), 2.69 (s, 3H).
Example 46
Synthesis of 3- (1-acetyl-1H-indole-3-carboxamide) -3- (3, 5-dimethylphenyl) propionic acid was performed as in example 8.1H NMR (400 MHz, DMSO). Delta.12.25 (s, 1H), 8.61 (s, 1H), 8.59 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.17 (d, J=7.1 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H), 7.32 (d, J=4.0 Hz, 1H), 7.29 (d, J=7.3 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H), 6.97 (s, 1H), 5.70-5.56 (m, 1H), 2.86-2.73 (m, 2H), 2.71 (s, 3H), 2.40 (s, 3H), 2.23 (s, 3H).
Example 47
Synthesis of 1-acetyl-N- (3-acetylphenyl) -1H-indole-3-carboxamide
When the structural type is II:
the synthesis of 1-acetyl-1H-indole-3-carboxylic acid is the same as the above-described method. 1- (3-aminophenyl) ethan-1-one (110 mg,0.82 mmol) was dissolved in 30mL of toluene, followed by the addition of intermediate 1-acetyl-1H-indole-3-carboxylic acid (200 mg,0.98 mmol), 2-chloro-1-methylpyridine iodide (502 mg,1.96 mmol) and N-Bu3N (729 mg,3.93 mmol). The reaction was stirred overnight at 90℃under nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, 30mL of water was added, the mixture was extracted with EA (3X 30 mL), and the organic phase was washed once with saturated brine and dried over anhydrous sodium sulfate. The organic phase was dried in vacuo and the crude product was separated on a silica gel column (PE: ea=4:1). 105mg (33.4% yield) of white solid was obtained. 1H NMR (400 MHz, DMSO). Delta.10.27 (s, 1H), 8.81 (s, 1H), 8.36 (d, J=7.4 Hz, 1H), 8.29 (s, 1H), 8.26 (d, J=7.1 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.48-7.30 (m, 2H), 2.76 (s, 3H), 2.50 (s, 3H).
Example 48
Synthesis of methyl 3- (1-acetyl-1H-indole-3-carboxamido) benzoate was performed as in example 47.1H NMR (400 MHz, CDCl 3) delta 8.45 (d, J=7.6 Hz, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 8.08-8.04 (m, 1H), 8.03 (s, 1H), 8.02 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.48-7.44 (m, 1H), 7.42 (d, J=1.7 Hz, 1H), 7.42-7.38 (m, 1H), 3.91 (s, 3H), 2.68 (s, 3H).
Example 49
Synthesis of 1-acetyl-N- (3, 5-dinitrophenyl) -1H-indole-3-carboxamide was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.10.88 (s, 1H), 9.17-9.02 (m, 2H), 8.87 (s, 1H), 8.51 (d, J=26.7 Hz, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.28 (d, J=7.4 Hz, 1H), 7.58-7.33 (m, 2H), 2.79 (s, 3H).
Example 50
Synthesis of 1-acetyl-N- (4-bromo-2-nitrophenyl) -1H-indole-3-carboxamide was performed as in example 47.1H NMR (400 MHz, CDCl 3) δ11.07 (s, 1H), 8.93 (d, J=9.1 Hz, 1H), 8.55-8.35 (m, 2H), 8.20 (dd, J=5.8, 3.0Hz, 1H), 8.12 (s, 1H), 7.81 (dd, J=9.1, 2.2Hz, 1H), 7.54-7.40 (m, 2H), 2.76 (s, 3H).
Example 51
Synthesis of 1-acetyl-N- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -1H-indole-3-carboxamide was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.9.91 (s, 1H), 8.72 (s, 1H), 8.36 (d, J=7.8 Hz, 1H), 8.23 (d, J=7.2 Hz, 1H), 7.45-7.29 (m, 3H), 7.16 (dd, J=8.7, 2.3Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 4.24 (dd, J=9.8, 5.1Hz, 4H), 2.72 (d, J=21.3 Hz, 3H).
Example 52
Synthesis of dimethyl (1-acetyl-1H-indole-3-carboxamide) isophthalate using the method described in example 47.1H NMR (400 MHz, CDCl 3) δ8.52 (s, 2H), 8.45 (d, J=8.8 Hz, 2H), 8.15 (s, 1H), 8.11 (s, 1H), 8.05 (d, J=7.1 Hz, 1H), 7.44 (m, 2H), 3.95 (s, 6H), 2.72 (s, 3H).
Example 53
Synthesis of N- (3- (1, 3-dioxolan-2-yl) phenyl) -1-acetyl-1H-indole-3-carboxamide was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.10.12 (s, 1H), 8.81 (s, 1H), 8.37 (d, J=7.7 Hz, 1H), 8.26 (d, J=7.0 Hz, 1H), 7.94-7.77 (m, 2H), 7.47-7.29 (m, 3H), 7.17 (d, J=7.6 Hz, 1H), 5.75 (s, 1H), 4.07 (dd, J=8.9, 4.8Hz, 2H), 4.04-4.01 (m, 1H), 3.98 (dd, J=9.0, 4.8Hz, 2H), 2.76 (s, 3H), 2.50 (s, 2H), 2.05-1.90 (m, 1H), 1.17 (t, J=7.Hz, 1H).
Example 54
Synthesis of 1-acetyl-N- (1-acetylindolin-5-yl) -1H-indole-3-carboxamide
The synthesis was as in example 47.1H NMR (400 MHz, DMSO). Delta.9.99 (s, 1H), 8.75 (s, 1H), 8.36 (d, J=8.0 Hz, 1H), 8.24 (d, J=7.3 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.74 (s, 1H), 7.52-7.29 (m, 3H), 4.11 (t, J=8.5 Hz, 2H), 3.17 (t, J=8.4 Hz, 2H), 2.75 (s, 3H), 2.15 (s, 3H).
Example 55
Synthesis of (1-acetyl-1H-indole-3-carboxamido) benzoic acid using the method described in example 8.1H NMR (400 MHz, DMSO). Delta.12.99 (s, 1H), 10.24 (s, 1H), 8.84 (s, 1H), 8.38 (d, J=1.1 Hz, 1H), 8.36 (d, J=1.9 Hz, 1H), 8.27 (dd, J=6.5, 1.3Hz, 1H), 8.11 (dd, J=8.1, 1.1Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.40 (pd, J=7.2, 1.4Hz, 2H), 2.76 (s, 3H).
Example 56
Synthesis of methyl 3- (1-acetyl-1H-indole-3-carboxamide) -5-bromobenzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.10.39 (s, 1H), 8.83 (s, 1H), 8.44 (s, 1H), 8.37 (s, 1H), 8.35 (s, 1H), 8.26 (d, J=7.1 Hz, 1H), 7.77 (s, 1H), 7.56-7.31 (m, 2H), 3.90 (s, 3H), 2.76 (s, 3H).
Example 57
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -5-bromobenzoic acid was performed as in example 8.1H NMR (400 MHz, DMSO). Delta.10.38 (s, 1H), 8.84 (s, 1H), 8.41 (t, J=1.9 Hz, 1H), 8.36 (d, J=7.3 Hz, 1H), 8.34-8.31 (m, 1H), 8.28-8.23 (m, 1H), 7.78-7.74 (m, 1H), 7.45-7.35 (m, 2H), 2.76 (s, 3H).
Example 58
Synthesis of methyl 3- (1-acetyl-1H-indole-3-carboxamide) -5- (furan-2-yl) benzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.10.35 (s, 1H), 8.87 (s, 1H), 8.47 (s, 1H), 8.37 (d, J=7.7 Hz, 1H), 8.34 (s, 1H), 8.30 (d, J=7.0 Hz, 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.54-7.28 (m, 2H), 7.07 (d, J=3.0 Hz, 1H), 6.66 (s, 1H), 3.92 (s, 3H), 2.77 (s, 3H).
Example 59
Synthesis of methyl 3- (1-acetyl-1H-indole-3-carboxamide) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) benzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.10.29 (s, 1H), 8.84 (s, 1H), 8.38 (s, 2H), 8.27 (d, J=7.2 Hz, 1H), 8.09 (s, 1H), 7.67 (s, 1H), 7.46-7.28 (m, 2H), 4.77 (s, 1H), 4.73 (d, J=6.7 Hz, 1H), 4.55 (d, J=12.4 Hz, 1H), 3.89 (s, 3H), 3.86-3.77 (m, 1H), 3.55-3.47 (m, 1H), 2.76 (s, 3H), 1.84-1.64 (m, 2H), 1.62-1.42 (m, 4H).
Example 60
Synthesis of methyl 3- (1-acetyl-1H-indole-3-carboxamide) -5- (4-methylpiperazin-1-yl) benzoate was carried out as in example 47.1H NMR (400 MHz, DMSO). Delta.10.34 (s, 1H), 8.97 (s, 1H), 8.37 (d, J=7.9 Hz, 1H), 8.27 (d, J=7.6 Hz, 1H), 7.93 (s, 2H), 7.46-7.33 (m, 2H), 7.31 (s, 1H), 3.87 (s, 4H), 3.50 (s, 3H), 3.18 (s, 4H), 2.85 (s, 3H), 2.77 (s, 3H).
Example 61
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) benzoic acid was performed as in example 7.1H NMR (400 MHz, DMSO). Delta.13.04 (s, 1H), 10.27 (s, 1H), 8.85 (s, 1H), 8.37 (d, J=7.8 Hz, 1H), 8.34 (s, 1H), 8.27 (d, J=7.1 Hz, 1H), 8.07 (s, 1H), 7.65 (s, 1H), 7.46-7.32 (m, 2H), 4.74 (t, J=7.9 Hz, 2H), 4.54 (d, J=12.4 Hz, 1H), 3.82 (m, 1H), 3.53-3.48 (m, 1H), 2.76 (s, 3H), 1.74 (m, 2H), 1.53 (m, 4H).
Example 62
Synthesis of methyl 3- (1-acetyl-1H-indole-3-carboxamide) -5- (hydroxymethyl) benzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.10.25 (s, 1H), 8.83 (s, 1H), 8.36 (dd, J=7.1, 1.3Hz, 1H), 8.31 (s, 1H), 8.29-8.24 (m, 1H), 8.08 (s, 1H), 7.66 (s, 1H), 7.39 (pd, J=7.2 Hz,1.4Hz, 2H), 5.45 (t, J=5.7 Hz, 1H), 4.59 (d, J=5.5 Hz, 2H), 3.88 (s, 3H), 2.75 (s, 3H).
Example 63
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -5- (furan-2-yl) benzoic acid was carried out as in example 8.1H NMR (400 MHz, DMSO). Delta.10.34 (s, 1H), 8.88 (s, 1H), 8.45 (s, 1H), 8.37 (d, J=7.4 Hz, 1H), 8.31 (s, 1H), 8.28 (d, J=1.5 Hz, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.47-7.34 (m, 2H), 7.05 (d, J=3.4 Hz, 1H), 6.65 (m, 1H), 2.77 (s, 3H).
Example 64
Synthesis of methyl (1-acetyl-1H-indole-3-carboxamide) -4- ((3-fluorophenyl) amino) benzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.9.74 (s, 1H), 8.73 (s, 1H), 8.37 (d, J=7.4 Hz, 1H), 8.28 (s, 1H), 8.23-8.17 (m, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.77 (dd, J=8.6, 2.0Hz, 1H), 7.43 (d, J=3.6 Hz, 1H), 7.41 (s, 1H), 7.39 (t, J=1.7 Hz, 1H), 7.30 (dd, J=15.2, 8.1Hz, 1H), 6.97 (dd, J=8.1, 1.4Hz, 1H), 6.90 (dt, J=11.5, 2.2Hz, 1H), 6.73 (td, J=8.4, 2.2Hz, 1H), 3.84 (t, J=1.7 Hz, 1H), 3.71 (s, 3H).
Example 65
Synthesis of methyl 3- (1-acetyl-1H-indole-3-carboxamide) -4- (benzylamino) benzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.9.67 (s, 1H), 8.80 (s, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.28-8.19 (m, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.63 (dd, J=8.6, 2.0Hz, 1H), 7.45-7.40 (m, 2H), 7.40-7.36 (m, 2H), 7.33 (t, J=7.5 Hz, 2H), 7.23 (t, J=7.2 Hz, 1H), 6.68 (t, J=6.1 Hz, 1H), 6.59 (d, J=8.7 Hz, 1H), 4.47 (d, J=6.0 Hz, 2H), 3.76 (s, 3H), 2.75 (s, 3H).
Example 66
Synthesis of methyl 3- (1-acetyl-1H-indole-3-carboxamido) -4- (cyclopentylamino) benzoate was performed as in example 47.1HNMR (400 MHz, DMSO). Delta.9.59 (s, 1H), 8.78 (s, 1H), 8.37 (d, J=7.6 Hz, 1H), 8.25-8.09 (m, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.73 (dd, J=8.6, 2.0Hz, 1H), 7.47-7.32 (m, 2H), 6.81 (d, J=8.8 Hz, 1H), 5.60 (d, J=6.4 Hz, 1H), 3.88 (dd, J=12.2, 6.5Hz, 1H), 3.78 (s, 3H), 2.74 (s, 3H), 2.10-1.95 (m, 2H), 1.67 (d, J=6.4 Hz, 2H), 1.57 (dd, J=9.8, 5.4Hz, 1H), 1.54-1.46 (m, 2H).
Example 67
Synthesis of methyl 3- (1-acetyl-1H-indole-3-carboxamido) -4- (cyclopropylamino) benzoate was performed as in example 47.1HNMR (400 MHz, DMSO). Delta.9.46 (s, 1H), 8.77 (s, 1H), 8.37 (d, J=7.6 Hz, 1H), 8.23-8.11 (m, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.77 (dd, J=8.6, 2.0Hz, 1H), 7.48-7.28 (m, 2H), 7.11 (d, J=8.6 Hz, 1H), 6.35 (s, 1H), 3.79 (s, 3H), 2.74 (s, 3H), 1.65-1.51 (m, 1H), 0.84-0.75 (m, 2H), 0.54-0.45 (m, 2H).
Example 68
Synthesis of (1-acetyl-1H-indole-3-carboxamido) -4- (cyclopentylamino) benzoic acid using the method described in example 7.1H NMR (400 MHz, DMSO). Delta.12.17 (s, 1H), 9.62 (s, 1H), 8.79 (s, 1H), 8.37 (d, J=7.7 Hz, 1H), 8.18 (d, J=7.0 Hz, 1H), 7.77 (d, J=1.9 Hz, 1H), 7.71 (dd, J=8.6, 1.9Hz, 1H), 7.46-7.32 (m, 2H), 6.79 (d, J=8.7 Hz, 1H), 5.51 (d, J=6.3 Hz, 1H), 3.87 (dd, J=12.5, 6.3Hz, 1H), 2.74 (s, 3H), 2.10-1.95 (m, 2H), 1.67 (d, J=6.6 Hz, 2H), 1.62-1.54 (m, 2H), 1.50 (dd, J=12.7 Hz, 1.7 Hz, 1H).
Example 69
Synthesis of methyl 3- (1-acetyl-1H-indole-3-carboxamido) -4- (isopropylamino) benzoate was performed as in example 47.1HNMR (400 MHz, DMSO). Delta.9.55 (s, 1H), 8.78 (s, 1H), 8.37 (d, J=7.9 Hz, 1H), 8.18 (d, J=7.6 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.51-7.27 (m, 2H), 6.79 (d, J=8.8 Hz, 1H), 5.46 (d, J=7.5 Hz, 1H), 3.77 (s, 3H), 2.74 (s, 3H), 1.20 (d, J=6.3 Hz, 6H).
Example 70
Synthesis of tert-butyl 3- (1-acetyl-1H-indole-3-carboxamido) -4- (butylamino) benzoate was performed as in example 47.1HNMR (400 MHz, DMSO). Delta.9.79 (s, 1H), 8.40 (s, 1H), 8.35 (d, J=8.2 Hz, 1H), 8.23 (d, J=8.3 Hz, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.91 (s, 1H), 7.79 (dd, J=12.6, 8.9Hz, 2H), 7.47 (d, J=8.3 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.31 (t, J=7.6 Hz, 2H), 7.19 (t, J=7.6 Hz, 1H), 2.63 (s, 3H), 2.32 (s, 3H), 1.54 (s, 9H), 0.86 (dd, J=14.6, 7.7, 6H).
Example 71
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -4- (butylamino) benzoic acid tert-butyl 3- (1-acetyl-1H-indole-3-carboxamide) -4- (butylamino) benzoate the procedure is as in example 45.
3- (1-acetyl-1H-indole-3-carboxamido) -4- (butylamino) benzoic acid tert-butyl ester (50 mg,0.112 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (0.5 mL) was added. The reaction was carried out at room temperature for 5h, washed with water, extracted with DCM (3X 20 mL), the organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, dried by spin, and recrystallized from ethyl acetate and petroleum ether to give 28.9mg (57.5%) of the product. 1H NMR (400 MHz, DMSO). Delta.9.77 (s, 1H), 8.39 (s, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.23 (d, J=8.3 Hz, 1H), 8.05-7.94 (m, 2H), 7.85 (d, J=8.2 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.39 (t, J=7.7 Hz, 1H), 7.30 (t, J=8.6 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 2.63 (s, 3H), 2.30 (s, 3H), 0.87 (m, 6H).
Example 72
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -4- (propylamino) benzoic acid using the method of example 71.1H NMR (400 MHz, DMSO). Delta.12.24 (s, 1H), 9.56 (s, 1H), 8.77 (s, 1H), 8.37 (d, J=7.9 Hz, 1H), 8.19 (d, J=7.4 Hz, 1H), 7.74 (s, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.51-7.27 (m, 2H), 6.74 (d, J=8.6 Hz, 1H), 5.80 (s, 1H), 3.14 (t, J=6.9 Hz, 3H), 2.74 (s, 3H), 1.59 (dd, J=14.4, 7.2Hz, 2H), 0.93 (t, J=7.3 Hz, 3H).
Example 73
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -4-fluorobenzoic acid using the method described in example 71.1H NMR (400 MHz, DMSO). Delta.10.11 (s, 1H), 8.84 (s, 1H), 8.37 (d, J=7.2 Hz, 2H), 8.21 (d, J=7.3 Hz, 1H), 7.83 (s, 1H), 7.50-7.33 (m, 3H), 2.75 (s, 3H).
Example 74
Synthesis of tert-butyl 3- (1-acetyl-1H-indole-3-carboxamido) -4- (benzylamino) benzoate was performed as in example 47.1HNMR (400 MHz, DMSO). Delta.9.69 (s, 1H), 8.80 (s, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.27-8.19 (m, 1H), 7.67 (d, J=1.9 Hz, 1H), 7.57 (dd, J=8.6, 1.9Hz, 1H), 7.39 (dd, J=7.1, 5.2Hz, 4H), 7.32 (t, J=7.5 Hz, 3H), 7.23 (d, J=7.2 Hz, 1H), 6.56 (d, J=8.8 Hz, 2H), 4.46 (d, J=6.0 Hz, 2H), 2.75 (s, 3H), 1.50 (s, 9H).
Example 75
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -4- (benzylamino) benzoic acid using the method of example 71.1H NMR (400 MHz, DMSO). Delta.12.46 (s, 1H), 9.66 (s, 1H), 8.80 (s, 1H), 8.38 (d, J=7.4 Hz, 1H), 8.23 (d, J=7.5 Hz, 1H), 7.75 (s, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.40 (d, J=7.3 Hz, 4H), 7.34 (d, J=7.5 Hz, 2H), 7.24 (d, J=7.0 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 4.47 (s, 2H), 2.75 (s, 3H).
Example 76
Synthesis of tert-butyl 3- (1-acetyl-1H-indole-3-carboxamido) -4- (cyclopropylamino) benzoate using the method as in example 47.1H NMR (400 MHz, DMSO). Delta.9.48 (s, 1H), 8.76 (s, 1H), 8.37 (d, J=7.8 Hz, 1H), 8.19 (d, J=7.1 Hz, 1H), 7.77-7.66 (m, 2H), 7.44-7.30 (m, 2H), 7.08 (d, J=9.1 Hz, 1H), 6.24 (s, 1H), 2.73 (s, 3H), 1.52 (s, 9H), 1.17 (t, J=7.1 Hz, 1H), 0.85 (dd, J=7.2, 5.0Hz, 2H), 0.78 (d, J=4.7 Hz, 2H).
Example 77
Synthesis of tert-butyl 3- (1-acetyl-1H-indole-3-carboxamide) -4- ((cyclohexylmethyl) amino) benzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.9.59 (s, 1H), 8.76 (s, 1H), 8.37 (d, J=7.9 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H), 7.68 (s, 1H), 7.65 (d, J=4.2 Hz, 1H), 7.44-7.33 (m, 2H), 6.72 (d, J=8.7 Hz, 1H), 5.80 (t, J=5.7 Hz, 1H), 3.02 (t, J=6.2 Hz, 2H), 2.74 (s, 3H), 1.78 (d, J=12.5 Hz, 2H), 1.66 (s, 2H), 1.59 (s, 1H), 1.51 (s, 9H), 1.14 (d, J=8.2 Hz, 2H), 0.97-0.91 (m, 2H), 0.80 (m-0.80 (m, 2H).
Example 78
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -4- ((cyclohexylmethyl) amino) benzoic acid using the method as in example 71.1H NMR (400 MHz, DMSO). Delta.12.25 (s, 1H), 9.58 (s, 1H), 8.77 (s, 1H), 8.37 (d, J=7.9 Hz, 1H), 8.18 (d, J=7.4 Hz, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.43-7.32 (m, 2H), 6.72 (d, J=8.5 Hz, 1H), 3.03 (d, J=6.6 Hz, 2H), 2.74 (s, 3H), 1.79 (d, J=12.5 Hz, 2H), 1.67 (d, J=10.8 Hz, 2H), 1.61 (d, J=4.0 Hz, 2H), 1.23 (s, 1H), 1.16 (s, 2H), 0.94 (dd, J=22.5, 11.0Hz, 2H).
Example 79
Synthesis of tert-butyl 3- (1-acetyl-1H-indole-3-carboxamide) -4- ((3-fluorophenyl) amino) benzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.10.37 (s, 1H), 8.84 (s, 1H), 8.40 (s, 1H), 8.38 (d, J=7.6 Hz, 1H), 8.33 (s, 1H), 8.28 (d, J=7.3 Hz, 1H), 7.88 (s, 1H), 7.56 (m, 3H), 7.46-7.36 (m, 2H), 7.28 (t, J=8.3 Hz, 1H), 2.78 (s, 3H), 1.60 (s, 9H).
Example 80
Synthesis of methyl 3- (1-acetyl-1H-indole-3-carboxamido) -4- (phenylamino) benzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.9.73 (s, 1H), 8.75 (s, 1H), 8.37 (d, J=7.4 Hz, 1H), 8.26-8.17 (m, 1H), 8.08 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.73 (dd, J=8.6, 2.0Hz, 1H), 7.44-7.36 (m, 2H), 7.36-7.33 (m, 1H), 7.32 (d, J=2.5 Hz, 1H), 7.30 (d, J=1.3 Hz, 1H), 7.18 (s, 1H), 7.16 (s, 1H), 6.99 (t, J=7.3 Hz, 1H), 3.82 (s, 3H), 2.72 (s, 3H).
Example 81
Synthesis of tert-butyl 3- (1-acetyl-1H-indole-3-carboxamido) -4- (propylamino) benzoate was performed as in example 47.1HNMR (400 MHz, DMSO). Delta.9.58 (s, 1H), 8.77 (s, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.19 (d, J=7.4 Hz, 1H), 7.68 (s, 1H), 7.66 (s, 1H), 7.46-7.32 (m, 2H), 6.73 (d, J=9.2 Hz, 1H), 5.79 (t, J=5.4 Hz, 1H), 3.13 (dd, J=13.3, 6.5Hz, 2H), 2.74 (s, 3H), 1.58 (d, J=7.6 Hz, 2H), 1.51 (s, 9H), 0.93 (t, J=7.3 Hz, 3H).
Example 82
Synthesis of tert-butyl 3- (1-acetyl-1H-indole-3-carboxamido) -4- (cycloheptylamino) benzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.9.62 (s, 1H), 8.77 (s, 1H), 8.37 (d, J=7.7 Hz, 1H), 8.18 (d, J=6.9 Hz, 1H), 7.68 (dd, J=4.4, 2.5Hz, 2H), 7.48-7.33 (m, 2H), 6.69 (d, J=9.3 Hz, 1H), 5.34 (d, J=7.5 Hz, 1H), 3.55 (m, 1H), 2.74 (s, 3H), 1.91 (m, 2H), 1.64 (m, 3H), 1.56 (m, 3H), 1.51 (s, 9H).
Example 83
Synthesis of tert-butyl 3- (1-acetyl-1H-indole-3-carboxamide) -4- ((cyclopropylmethyl) amino) benzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.9.64 (s, 1H), 8.79 (s, 1H), 8.37 (d, J=7.6 Hz, 1H), 8.23-8.17 (m, 1H), 7.68 (s, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.45-7.33 (m, 2H), 6.77 (d, J=9.3 Hz, 1H), 5.81 (t, J=5.5 Hz, 1H), 3.07 (t, J=6.1 Hz, 2H), 2.74 (s, 3H), 1.52 (s, 9H), 1.13-1.04 (m, 1H), 0.51-0.42 (m, 2H), 0.30-0.21 (m, 2H).
Example 84
Synthesis of tert-butyl 3- (1-acetyl-1H-indole-3-carboxamido) -4- (isobutylamino) benzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.9.63 (s, 1H), 8.78 (s, 1H), 8.37 (d, J=7.9 Hz, 1H), 8.19 (d, J=7.2 Hz, 1H), 7.68 (s, 1H), 7.65 (d, J=2.7 Hz, 1H), 7.46-7.31 (m, 2H), 6.73 (d, J=8.6 Hz, 1H), 5.79 (t, J=5.7 Hz, 1H), 2.99 (t, J=6.3 Hz, 2H), 2.74 (s, 3H), 1.88 (dt, J=13.3, 6.7Hz, 1H), 1.52 (s, 9H), 0.92 (d, J=6.6 Hz, 6H).
Example 85
Synthesis of (1-acetyl-1H-indole-3-carboxamido) -4- (cycloheptylamino) benzoic acid using the method described in example 71.1H NMR (400 MHz, DMSO). Delta.12.18 (s, 1H), 9.62 (s, 1H), 8.78 (s, 1H), 8.37 (d, J=7.9 Hz, 1H), 8.18 (d, J=7.5 Hz, 1H), 7.75 (s, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.46-7.31 (m, 2H), 6.69 (d, J=8.7 Hz, 1H), 5.37 (d, J=7.1 Hz, 1H), 3.58 (m, 1H), 2.74 (s, 3H), 1.97-1.85 (m, 2H), 1.71-1.46 (m, 10H).
Example 86
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -4- ((cyclopropylmethyl) amino) benzoic acid using the method as in example 71.1H NMR (400 MHz, DMSO). Delta.12.22 (s, 1H), 9.63 (s, 1H), 8.79 (s, 1H), 8.37 (d, J=7.9 Hz, 1H), 8.20 (d, J=7.4 Hz, 1H), 7.75 (s, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.48-7.30 (m, 2H), 6.77 (d, J=8.6 Hz, 1H), 5.82 (s, 1H), 3.07 (d, J=4.9 Hz, 2H), 2.74 (s, 3H), 1.10 (m, 1H), 0.47 (m, 2H), 0.26 (m, 2H).
Example 87
Synthesis of (1-acetyl-1H-indole-3-carboxamido) -4- (isobutylamino) benzoic acid using the method as in example 71.1H NMR (400 MHz, DMSO). Delta.12.34 (s, 1H), 8.78 (s, 1H), 8.37 (d, J=7.9 Hz, 1H), 8.19 (d, J=7.7 Hz, 1H), 7.72 (d, J=2.2 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.45-7.32 (m, 2H), 6.74 (d, J=8.6 Hz, 1H), 3.00 (d, J=6.8 Hz, 2H), 2.74 (s, 3H), 1.89 (dt, J=13.3, 6.6Hz, 1H), 0.93 (d, J=6.6 Hz, 6H).
Example 88
Synthesis of tert-butyl 3- (1-acetyl-1H-indole-3-carboxamide) -4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) benzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.9.59 (s, 1H), 8.76 (s, 1H), 8.37 (d, J=7.7 Hz, 1H), 8.24-8.13 (m, 1H), 7.67 (dd, J=8.6, 1.9Hz, 1H), 7.64 (d, J=1.9 Hz, 1H), 7.43-7.31 (m, 2H), 6.76 (d, J=8.7 Hz, 1H), 5.87 (t, J=5.8 Hz, 1H), 3.84 (dd, J=11.1, 2.9Hz, 2H), 3.24 (t, J=10.9 Hz, 2H), 3.08 (t, J=6.3 Hz, 2H), 2.74 (s, 3H), 2.32 (t, J=6.9, 1H), 1.90-1.77 (m, 1H), 1.65 (t, J=5.8 Hz, 1H), 3.84 (dd, 2.9Hz, 2H), 3.24 (t, 3H), 3.9 Hz, 2.9Hz, 2H).
Example 89
Synthesis of 3- (1-acetyl-1H-indole-3-carboxamide) -4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) benzoic acid was performed as in example 71.1H NMR (400 MHz, DMSO). Delta.12.21 (s, 1H), 9.57 (s, 1H), 8.76 (s, 1H), 8.37 (d, J=7.9 Hz, 1H), 8.18 (d, J=7.3 Hz, 1H), 7.72 (s, 1H), 7.70 (d, J=1.9 Hz, 1H), 7.45-7.30 (m, 2H), 6.77 (d, J=8.4 Hz, 1H), 5.88 (s, 1H), 3.84 (dd, J=11.0, 2.9Hz, 2H), 3.27 (d, J=10.7 Hz, 2H), 3.09 (d, J=6.6 Hz, 2H), 2.74 (s, 3H), 1.92-1.78 (m, 1H), 1.67 (d, J=12.6 Hz, 2H), 1.24 (m, 2H).
Example 90
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -4- ((tetrahydro-2H-pyran-4-yl) amino) benzoic acid using the method described in example 71.1H NMR (400 MHz, DMSO). Delta.12.26 (s, 1H), 9.58 (s, 1H), 8.78 (s, 1H), 8.37 (d, J=7.8 Hz, 1H), 8.19 (d, J=7.4 Hz, 1H), 7.78 (s, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.46-7.32 (m, 2H), 6.87 (d, J=8.7 Hz, 1H), 5.49 (s, 1H), 3.87 (d, J=11.2 Hz, 2H), 3.67 (m, 1H), 3.46 (d, J=11.2 Hz, 2H), 2.74 (s, 3H), 1.92 (d, J=12.2 Hz, 2H), 1.49 (m, 2H).
Example 91
Synthesis of methyl (1-acetyl-1H-indole-3-carboxamide) -5- (((tert-butoxycarbonyl) oxy) methyl) benzoate was performed as in example 47.1H NMR (500 MHz, DMSO). Delta.10.32 (s, 1H), 8.84 (s, 1H), 8.41-8.34 (m, 2H), 8.27 (d, J=7.8 Hz, 1H), 8.13 (s, 1H), 7.68 (s, 1H), 7.48-7.33 (m, 2H), 5.17 (s, 2H), 3.90 (s, 3H), 2.76 (s, 3H), 1.45 (s, 9H).
Example 92
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -5-cyclopropylbenzoic acid using the method of example 71.1H NMR (400 MHz, DMSO). Delta.12.97 (s, 1H), 10.18 (s, 1H), 8.83 (d, J=4.0 Hz, 1H), 8.37 (d, J=7.7 Hz, 1H), 8.27 (d, J=5.4 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.52 (s, 1H), 7.45-7.34 (m, 2H), 2.76 (d, J=4.0 Hz, 3H), 2.66 (d, J=7.4 Hz, 2H), 1.65 (d, J=7.4 Hz, 1H), 0.93 (m, 2H).
Example 93
Methyl 3- (1-acetyl-1H-indole-3-carboxamide) -5- (((2-fluorophenyl) amino) methyl) benzoate was synthesized as in example 47.1H NMR (500 MHz, DMSO). Delta.10.27 (s, 1H), 8.82 (s, 1H), 8.36 (d, J=7.9 Hz, 1H), 8.31 (s, 1H), 8.26 (d, J=7.8 Hz, 1H), 8.10 (s, 1H), 7.72 (s, 1H), 7.38 (dq, J=13.7, 7.0Hz, 2H), 7.03 (dd, J=11.8, 8.0Hz, 1H), 6.87 (t, J=7.6 Hz, 1H), 6.53 (t, J=6.9 Hz, 2H), 6.35 (s, 1H), 4.42 (d, J=5.8 Hz, 2H), 3.87 (s, 3H), 2.75 (s, 3H).
Example 94
Methyl 3- (1-acetyl-1H-indole-3-carboxamide) -5- (((cyclopropylmethyl) amino) methyl) benzoate was synthesized as in example 47.1H NMR (400 MHz, DMSO). Delta.10.31 (s, 1H), 8.82 (s, 1H), 8.36 (dd, J=10.9, 4.0Hz, 2H), 8.28 (d, J=7.0 Hz, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.46-7.30 (m, 4H), 4.94 (s, 2H), 3.89 (s, 3H), 2.76 (s, 3H), 2.51-2.49 (m, 2H), 0.83 (dd, J=11.7, 5.9Hz, 1H), 0.43 (s, 2H), 0.13 (s, 2H).
Example 95
Synthesis of 5- (1-acetyl-1H-indole-3-carboxamide) - [1,1' -biphenyl ] -3-carboxylic acid was performed as in example 71.1H NMR (400 MHz, DMSO). Delta.13.07 (s, 1H), 10.33 (s, 1H), 8.86 (s, 1H), 8.42 (s, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 8.29 (d, J=7.2 Hz, 1H), 7.92 (s, 1H), 7.72 (s, 1H), 7.70 (s, 1H), 7.54 (t, J=7.6 Hz, 2H), 7.48-7.35 (m, 3H), 2.78 (s, 3H).
Example 96
Synthesis of 5- (1-acetyl-1H-indole-3-carboxamide) -3 '-fluoro- [1,1' -biphenyl ] -3-carboxylic acid was carried out as in example 71.1H NMR (400 MHz, DMSO). Delta.13.15 (s, 1H), 10.34 (s, 1H), 8.85 (s, 1H), 8.41 (d, J=0.9 Hz, 2H), 8.38 (d, J=7.8 Hz, 1H), 8.29 (d, J=7.1 Hz, 1H), 7.93 (s, 1H), 7.61-7.50 (m, 3H), 7.46-7.35 (m, 2H), 7.28 (t, J=7.8 Hz, 1H), 2.77 (s, 3H).
Example 97
Methyl 3- (1-acetyl-1H-indole-3-carboxamide) -5- (((3-fluorophenyl) amino) methyl) benzoate was synthesized as in example 47.1H NMR (400 MHz, DMSO). Delta.10.27 (s, 1H), 8.83 (s, 1H), 8.37 (d, J=7.8 Hz, 1H), 8.30 (s, 1H), 8.26 (d, J=7.3 Hz, 1H), 8.12 (s, 1H), 7.71 (s, 1H), 7.38 (m, 2H), 7.06 (m, 1H), 6.74 (s, 1H), 6.42 (d, J=7.8 Hz, 1H), 6.30 (m, 2H), 4.37 (d, J=5.5 Hz, 2H), 3.87 (s, 3H), 2.75 (s, 3H).
Example 98
Methyl 3- (1-acetyl-1H-indole-3-carboxamide) -5- ((cyclopentylamino) methyl) benzoate was synthesized as described in example 47.1H NMR (400 MHz, DMSO). Delta.10.31 (s, 1H), 8.84 (s, 1H), 8.37 (t, J=8.1 Hz, 2H), 8.30 (d, J=6.7 Hz, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.46-7.36 (m, 3H), 4.78 (s, 2H), 3.90 (s, 3H), 2.77 (s, 3H), 1.79 (s, 2H), 1.63 (s, 4H), 1.42 (s, 2H), 1.23 (s, 1H).
Example 99
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -5-isobutylbenzoic acid using the method of example 71.1H NMR (400 MHz, DMSO). Delta.12.87 (s, 1H), 10.17 (s, 1H), 8.83 (s, 1H), 8.37 (d, J=7.8 Hz, 1H), 8.27 (d, J=7.4 Hz, 1H), 8.22 (s, 1H), 7.91 (s, 1H), 7.49 (s, 1H), 7.45-7.34 (m, 2H), 2.76 (s, 3H), 2.54 (d, J=7.0 Hz, 2H), 1.87 (m, 1H), 0.91 (d, J=6.5 Hz, 6H).
Example 100
Synthesis of (1-acetyl-1H-indole-3-carboxamido) -5-cyclopentylbenzoic acid using the method described in example 71.1H NMR (400 MHz, DMSO). Delta.10.17 (s, 1H), 8.83 (s, 1H), 8.37 (d, J=7.9 Hz, 1H), 8.27 (d, J=7.1 Hz, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.57 (s, 1H), 7.46-7.33 (m, 2H), 3.10-3.04 (m, 1H), 2.76 (s, 3H), 2.07 (m, 2H), 1.81 (m, 2H), 1.70 (m, 2H), 1.64-1.51 (m, 2H).
Example 101
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -5-cyclohexylbenzoic acid Using the method of example 71.1H NMR (400 MHz, DMSO). Delta.12.97 (s, 1H), 10.16 (s, 1H), 8.82 (s, 1H), 8.37 (d, J=7.7 Hz, 1H), 8.27 (d, J=7.1 Hz, 1H), 8.20 (s, 1H), 7.97 (s, 1H), 7.55 (s, 1H), 7.45-7.35 (m, 2H), 2.76 (s, 3H), 2.60 (s, 1H), 1.84 (m, 4H), 1.73 (m, 1H), 1.51-1.34 (m, 5H).
Example 102
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -5- (2-methylpyridin-4-yl) benzoic acid was carried out as in example 71.1H NMR (500 MHz, DMSO). Delta.10.43 (s, 1H), 8.92 (s, 1H), 8.88 (s, 1H), 8.65 (s, 1H), 8.51 (s, 1H), 8.44 (s, 1H), 8.38 (d, J=7.9 Hz, 1H), 8.34 (s, 1H), 8.29 (d, J=7.7 Hz, 1H), 8.02 (s, 1H), 7.41 (m, 2H), 2.78 (s, 3H), 2.51 (s, 3H).
Example 103
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -5- (benzofuran-3-yl) benzoic acid using the method of example 71.1H NMR (400 MHz, DMSO). Delta.10.39 (s, 1H), 8.85 (s, 1H), 8.27 (d, J=7.5 Hz, 1H), 8.12 (d, J=7.7 Hz, 1H), 7.99 (s, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.56-7.45 (m, 2H), 7.45-7.34 (m, 2H), 2.77 (s, 3H).
Example 104
Synthesis of 3- (1-acetyl-1H-indole-3-carboxamide) -5-ethylbenzoic acid was carried out as in example 71.1H NMR (500 MHz, DMSO). Delta.12.95 (s, 1H), 10.17 (s, 1H), 8.83 (s, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.27 (d, J=7.2 Hz, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.54 (s, 1H), 7.39 (m, 2H), 2.76 (s, 3H), 2.70 (q, J=7.5 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H).
Example 105
Synthesis of (1-acetyl-1H-indole-3-carboxamide) -5-phenethyl benzoic acid using the method of example 71.1H NMR (500 MHz, DMSO). Delta.12.97 (s, 1H), 10.18 (d, J=5.1 Hz, 1H), 8.82 (d, J=14.8 Hz, 1H), 8.37 (d, J=7.6 Hz, 1H), 8.30-8.24 (m, 1H), 8.22 (s, 1H), 7.98 (d, J=12.1 Hz, 1H), 7.57 (s, 1H), 7.39 (dd, J=15.2, 7.9Hz, 2H), 7.35-7.26 (m, 4H), 7.19 (d, J=6.4 Hz, 1H), 2.95 (d, J=6.6 Hz, 3H), 2.76 (d, J=6.3 Hz, 3H), 1.63 (d, J=7.1 Hz, 1H).
Example 106
Synthesis of 5- (1-acetyl-1H-indole-3-carboxamide) -3'- (trifluoromethyl) - [1,1' -biphenyl ] -3-carboxylic acid was performed as in example 71.1H NMR (500 MHz, DMSO). Delta.10.37 (s, 1H), 8.85 (s, 1H), 8.48 (s, 1H), 8.41 (s, 1H), 8.37 (d, J=8.1 Hz, 1H), 8.29 (d, J=7.6 Hz, 1H), 8.03 (d, J=7.4 Hz, 1H), 7.99 (s, 1H), 7.96 (s, 1H), 7.79 (m, 2H), 7.47-7.33 (m, 2H), 2.77 (s, 3H).
Example 107
Synthesis of 5- (1-acetyl-1H-indole-3-carboxamide) -3 '-methoxy- [1,1' -biphenyl ] -3-carboxylic acid was performed as in example 71.1H NMR (500 MHz, DMSO). Delta.10.33 (s, 1H), 8.85 (s, 1H), 8.41 (s, 1H), 8.38 (d, J=7.9 Hz, 2H), 8.29 (d, J=7.7 Hz, 1H), 7.91 (s, 1H), 7.50-7.36 (m, 3H), 7.26 (d, J=7.6 Hz, 1H), 7.20 (s, 1H), 7.02 (d, J=8.2, 2.0Hz, 1H), 3.85 (s, 3H), 2.77 (s, 3H).
Example 108
Synthesis of 5- (1-acetyl-1H-indole-3-carboxamide) -3 '-chloro- [1,1' -biphenyl ] -3-carboxylic acid was performed as in example 71.1H NMR (500 MHz, DMSO). Delta.13.13 (s, 1H), 10.35 (s, 1H), 8.86 (s, 1H), 8.41 (s, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 8.29 (d, J=6.8 Hz, 1H), 7.92 (s, 1H), 7.71 (s, 1H), 7.70 (s, 1H), 7.54 (t, J=7.6 Hz, 2H), 7.48-7.35 (m, 3H), 2.77 (s, 3H).
Example 109
Synthesis of 3- (1-acetyl-1H-indole-3-carboxamide) -5- (1-methyl-1H-indazol-5-yl) benzoic acid was performed as in example 71.1H NMR (500 MHz, DMSO). Delta.10.34 (s, 1H), 8.87 (s, 1H), 8.46 (s, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 8.30 (d, J=7.6 Hz, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.77 (dd, J=18.6, 8.8Hz, 2H), 7.47-7.36 (m, 2H), 4.10 (s, 3H), 2.78 (s, 3H).
Example 110
Synthesis of 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamido) -5- (furan-2-yl) benzoic acid was performed as in example 71.1H NMR (400 MHz, DMSO). Delta.13.19 (s, 1H), 8.84 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 8.25 (d, J=9.0 Hz, 1H), 7.98 (s, 1H), 7.83 (d, J=1.2 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.06 (d, J=3.3 Hz, 1H), 7.01 (m, 1H), 6.65 (m, 1H), 3.84 (s, 3H), 2.74 (s, 3H).
Example 111
Synthesis of 3- (1-acetyl-5-hydroxy-1H-indole-3-carboxamide) -5- (furan-2-yl) benzoic acid was performed as in example 17.1H NMR (500 MHz, DMSO). Delta.13.15 (s, 1H), 10.25 (s, 1H), 9.40 (s, 1H), 8.78 (s, 1H), 8.45 (s, 1H), 8.29 (s, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 7.83 (s, 1H), 7.67 (s, 1H), 7.04 (s, 1H), 6.86 (s, 1H), 6.65 (s, 1H), 2.72 (s, 3H).
Example 112
Synthesis of (1-acetyl-5-ethoxy-1H-indole-3-carboxamido) -5- (furan-2-yl) benzoic acid Synthesis method of 3- (1-acetyl-5-hydroxy-1H-indole-3-carboxamido) -5- (furan-2-yl) benzoic acid is as in example 17.
3- (1-acetyl-5-hydroxy-1H-indole-3-carboxamido) -5- (furan-2-yl) benzoic acid (120 mg,0.26 mmol) was dissolved in 20mL acetone followed by K2CO3 (107.6 g,0.78 mmol) and iodoethane (0.037 mL,0.39 mmol) and stirred overnight at 70 ℃. After the completion of the reaction, acetone was dried in vacuo, water was added, ethyl acetate was extracted (3X 50 mL), and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to give a white solid (56 mg, 48.27%). 1H NMR (500 MHz, DMSO). Delta.11.89 (s, 1H), 10.06 (s, 1H), 8.50 (s, 1H), 8.42 (d, J=2.3 Hz, 1H), 8.31 (s, 1H), 7.92 (s, 2H), 7.83 (s, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.02 (d, J=3.0 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H), 6.65 (s, 1H), 4.29 (t, J=6.6 Hz, 2H), 2.29 (s, 3H), 1.77 (dd, J=14.1, 7.0Hz, 2H), 1.01 (t, J=7.4 Hz, 3H).
Example 113
Synthesis of 3- (1-acetyl-5-propoxy-1H-indole-3-carboxamide) -5- (furan-2-yl) benzoic acid using the method described in example 112.1H NMR (500 MHz, DMSO). Delta.11.89 (s, 1H), 10.06 (s, 1H), 8.50 (s, 1H), 8.42 (d, J=2.3 Hz, 1H), 8.31 (s, 1H), 7.92 (s, 2H), 7.83 (s, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.02 (d, J=3.0 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H), 6.65 (s, 1H), 4.29 (t, J=6.6 Hz, 2H), 2.29 (s, 3H), 1.77 (dd, J=14.1, 7.0Hz, 2H), 1.01 (t, J=7.4 Hz, 3H).
Example 114
Synthesis of 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamide) -5- (1-methyl-1H-pyrazol-4-yl) benzoic acid was carried out as in example 71.1H NMR (500 MHz, DMSO). Delta.13.07 (s, 1H), 10.22 (s, 1H), 8.83 (s, 1H), 8.25 (t, J=6.5 Hz, 3H), 8.19 (s, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.79 (d, J=2.3 Hz, 1H), 7.01 (dd, J=9.0, 2.5Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 2.74 (s, 3H).
Example 115
Synthesis of methyl 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamide) -5- (furan-2-yl) benzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.10.31 (s, 1H), 8.84 (s, 1H), 8.47 (t, J=1.7 Hz, 1H), 8.38-8.30 (m, 1H), 8.25 (d, J=9.1 Hz, 1H), 7.98 (s, 1H), 7.84 (d, J=1.3 Hz, 1H), 7.79 (d, J=2.6 Hz, 1H), 7.08 (d, J=3.3 Hz, 1H), 7.01 (m, 1H), 6.66 (dd, J=3.4, 1.8Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 2.74 (s, 3H).
Example 116
Synthesis of tert-butyl 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamido) -5- (1-methyl-1H-pyrazol-4-yl) benzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.10.24 (s, 1H), 8.81 (s, 1H), 8.29-8.23 (m, 2H), 8.22 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.78 (d, J=2.0 Hz, 2H), 7.02 (m, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 2.74 (s, 3H), 1.59 (s, 9H).
Example 117
Synthesis of methyl 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamide) -5- (1-methyl-1H-pyrazol-4-yl) benzoate was performed as in example 47.1H NMR (400 MHz, DMSO). Delta.10.31 (s, 1H), 8.89 (s, 1H), 8.26 (dd, J=12.2, 7.9Hz, 4H), 7.88 (s, 1H), 7.84 (s, 1H), 7.79 (d, J=2.3 Hz, 1H), 7.01 (dd, J=9.0, 2.2Hz, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 2.74 (s, 3H).
Example 118
Synthesis of tert-butyl 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamide) -5- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzoate using the method described in example 47.1H NMR (400 MHz, DMSO). Delta.10.28 (s, 1H), 8.81 (s, 1H), 8.33 (s, 1H), 8.28-8.20 (m, 2H), 7.78 (s, 2H), 7.19-7.13 (m, 2H), 7.02 (d, J=4.0 Hz, 1H), 7.00 (d, J=3.9 Hz, 1H), 4.30 (s, 4H), 3.83 (s, 3H), 2.74 (s, 3H), 1.59 (s, 9H).
Example 119
Synthesis of tert-butyl 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamide) -5- (1-methyl-1H-indazol-5-yl) benzoate using the method described in example 47.1H NMR (400 MHz, DMSO). Delta.10.33 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 8.07 (s, 1H), 7.91 (s, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.02 (dd, J=9.0, 2.5Hz, 1H), 4.10 (s, 3H), 3.83 (s, 3H), 2.75 (s, 3H), 1.61 (s, 9H).
Example 120
Synthesis of 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamide) -5- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzoic acid was carried out as in example 71.1H NMR (400 MHz, DMSO). Delta.13.05 (s, 1H), 8.82 (s, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 8.25 (d, J=9.0 Hz, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.17 (d, J=6.1 Hz, 2H), 7.00 (d, J=7.7 Hz, 2H), 4.30 (s, 4H), 3.83 (s, 3H), 2.74 (s, 3H).
Example 121
Synthesis of (1-acetyl-5-methoxy-1H-indole-3-carboxamide) -5- (1-methyl-1H-indazol-5-yl) benzoic acid using the method described in example 71.1H NMR (400 MHz, DMSO). Delta.13.19 (s, 1H), 10.30 (s, 1H), 8.85 (s, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 8.25 (d, J=8.2 Hz, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.79 (m, 3H), 7.02 (s, 1H), 4.10 (s, 3H), 3.83 (s, 3H), 2.75 (s, 3H).
Example 122
Synthesis of N- ([ 1,1' -biphenyl ] -3-yl) -1-acetyl-5-methoxy-1H-indole-3-carboxamide is performed as in example 47.1H NMR (500 MHz, DMSO). Delta.10.15 (s, 1H), 8.79 (s, 1H), 8.25 (d, J=9.1 Hz, 1H), 8.08 (s, 1H), 7.80 (s, 1H), 7.77 (d, J=2.7 Hz, 1H), 7.68 (s, 1H), 7.67 (s, 1H), 7.49 (m, 3H), 7.41 (s, 1H), 7.40 (s, 1H), 7.01 (m, 1H), 3.82 (s, 3H), 2.74 (s, 3H).
Example 123
Synthesis of 1-acetyl-5-methoxy-N- (3- (1-methyl-1H-indazol-5-yl) phenyl) -1H-indole-3-carboxamide is described in example 47.1H NMR (500 MHz, DMSO). Delta.10.14 (s, 1H), 8.80 (s, 1H), 8.25 (d, J=9.0 Hz, 1H), 8.13 (s, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.80-7.76 (m, 2H), 7.75 (s, 1H), 7.74 (d, J=1.4 Hz, 1H), 7.51-7.41 (m, 2H), 7.01 (m, 1H), 4.09 (s, 3H), 3.83 (s, 3H), 2.74 (s, 3H).
Example 124
Synthesis of N- ([ 1,1' -biphenyl ] -3-yl) -1-acetyl-5-hydroxy-1H-indole-3-carboxamide is performed as in example 17.1H NMR (500 MHz, DMSO). Delta.10.10 (s, 1H), 9.40 (s, 1H), 8.72 (s, 1H), 8.15 (d, J=8.7 Hz, 1H), 8.07 (s, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.67 (d, J=7.8 Hz, 3H), 7.57-7.43 (m, 3H), 7.40 (m, 2H), 6.84 (d, J=8.4 Hz, 1H), 2.72 (s, 3H).
Example 125
Synthesis of 1-acetyl-5-hydroxy-N- (3- (1-methyl-1H-indazol-5-yl) phenyl) -1H-indole-3-carboxamide is performed as in example 17.1H NMR (500 MHz, DMSO). Delta.10.09 (s, 1H), 9.40 (s, 1H), 8.73 (s, 1H), 8.14 (m, 3H), 8.03 (s, 1H), 7.76 (m, 3H), 7.67 (s, 1H), 7.46 (m, 2H), 6.84 (d, J=7.1 Hz, 1H), 4.09 (s, 3H), 2.72 (s, 3H).
Example 126
Synthesis of 1-acetyl-5-methoxy-N- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) -1H-indole-3-carboxamide is described in example 47.1H NMR (500 MHz, DMSO). Delta.10.06 (s, 1H), 8.78 (s, 1H), 8.25 (d, J=9.0 Hz, 1H), 8.11 (s, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 7.77 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.00 (d, J=9.0 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 2.73 (s, 3H).
Example 127
Synthesis of 1-acetyl-5-hydroxy-N- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) -1H-indole-3-carboxamide is described in example 17.1H NMR (500 MHz, DMSO). Delta.10.09 (s, 1H), 9.40 (s, 1H), 8.80 (s, 1H), 8.15 (d, J=8.9 Hz, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.65 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.29 (d, J=7.4 Hz, 1H), 6.89-6.79 (m, 1H), 3.89 (s, 3H), 2.72 (s, 3H).
Example 128
Synthesis of (furan-2-yl) -5- (1H-indole-3-carboxamido) benzoic acid the synthesis of (1-acetyl-1H-indole-3-carboxamido) -5- (furan-2-yl) benzoic acid was as in example 7.
(1-acetyl-1H-indole-3-carboxamido) -5- (furan-2-yl) benzoic acid (100 mg,0.25 mmol) was dissolved in 8mL MeOH and 1M NaOH (1.25 mL,1.25 mmol) was added to the reaction system. The reaction was stirred at room temperature and monitored by TLC tracking. After the reaction, most of the solvent was removed by vacuum spinning, the remaining solution was adjusted to a slightly acidic pH with 1M hydrochloric acid solution, a large amount of white solid was precipitated, suction filtration was performed under reduced pressure, the cake was washed with 20mL of water, and 49.52mg of white solid was obtained by vacuum drying (yield 57.20%). 1H NMR (400 MHz, DMSO). Delta.11.85 (s, 1H), 9.97 (s, 1H), 8.44 (s, 1H), 8.40 (d, J=2.8 Hz, 1H), 8.27 (s, 1H), 8.24 (d, J=7.4 Hz, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.25-7.10 (m, 2H), 6.96 (d, J=3.2 Hz, 1H), 6.63 (m, 1H).
Example 129
Synthesis of tert-butyl 3- (furan-2-yl) -5- (1-propionyl-1H-indole-3-carboxamido) benzoate using the method described in example 47.1H NMR (400 MHz, DMSO). Delta.10.32 (s, 1H), 8.90 (s, 1H), 8.47-8.43 (m, 1H), 8.40 (d, J=7.5 Hz, 1H), 8.33-8.26 (m, 1H), 8.22 (d, J=1.5 Hz, 1H), 7.92 (s, 1H), 7.84 (d, J=1.2 Hz, 1H), 7.40 (tt, J=7.2, 3.8Hz, 2H), 7.04 (d, J=3.3 Hz, 1H), 6.66 (dd, J=3.4, 1.8Hz, 1H), 3.18 (q, J=7.2 Hz, 2H), 1.60 (s, 9H), 1.24 (d, J=7.2 Hz, 3H).
Example 130
Synthesis of (furan-2-yl) -5- (1-propionyl-1H-indole-3-carboxamido) benzoic acid using the method described in example 71.1H NMR (400 MHz, DMSO). Delta.10.30 (s, 1H), 8.92 (s, 1H), 8.45 (s, 1H), 8.41 (d, J=7.6 Hz, 1H), 8.31 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.83 (d, J=1.2 Hz, 1H), 7.46-7.35 (m, 2H), 7.05 (d, J=3.3 Hz, 1H), 6.65 (dd, J=3.3, 1.8Hz, 1H), 3.21-3.16 (m, 2H), 1.25 (d, J=7.3 Hz, 3H).
Example 131
Synthesis of 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamide) -4-fluoro-5- (1-methyl-1H-pyrazol-4-yl) benzoic acid was carried out as in example 71.1H NMR (500 MHz, DMSO). Delta.13.16 (s, 1H), 10.10 (s, 1H), 8.85 (s, 1H), 8.29 (s, 1H), 8.26 (d, J=9.1 Hz, 1H), 8.19 (d, J=5.4 Hz, 1H), 8.07 (d, J=4.9 Hz, 1H), 7.96 (s, 1H), 7.74 (s, 1H), 7.01 (d, J=8.9 Hz, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 2.73 (s, 3H).
Example 132
Synthesis of 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamide) -4-fluoro-5- (1-methyl-1H-pyrazol-4-yl) benzoic acid tert-butyl ester was performed as in example 71.1HNMR (400 MHz, DMSO). Delta.10.13 (s, 1H), 8.83 (s, 1H), 8.31-8.24 (m, 2H), 8.06 (d, J=6.8 Hz, 1H), 8.03 (d, J=6.4 Hz, 1H), 7.96 (s, 1H), 7.72 (d, J=2.1 Hz, 1H), 7.01 (dd, J=9.0, 2.1Hz, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 2.73 (s, 3H), 1.58 (s, 9H).
Example 133
Synthesis of 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamide) -4-fluoro-5- (1-methyl-1H-indazol-6-yl) benzoic acid tert-butyl ester was performed as in example 47.1H NMR (500 MHz, DMSO). Delta.10.17 (s, 1H), 8.84 (s, 1H), 8.26 (d, J=9.1 Hz, 2H), 8.16 (s, 1H), 7.99 (s, 1H), 7.88 (d, J=6.6 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.73 (s, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.02 (d, J=9..1 Hz, 1H), 4.10 (s, 3H), 3.82 (s, 3H), 2.73 (s, 3H), 1.99 (d, J=1.6 Hz, 2H), 1.58 (s, 9H).
Example 134
Synthesis of 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamido) -4-fluoro-5- (1-methyl-1H-indazol-6-yl) benzoic acid was performed as in example 71.1H NMR (400 MHz, DMSO). Delta.10.15 (s, 1H), 8.86 (s, 1H), 8.38 (dd, J=6.8, 1.9Hz, 1H), 8.26 (d, J=9.1 Hz, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.93 (dd, J=6.8, 2.0Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.75 (d, J=2.6 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.02 (dd, J=9.1, 2.6Hz, 1H), 4.10 (s, 3H), 3.82 (s, 3H), 2.73 (s, 3H).
Example 135
Synthesis of 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamide) -5- (benzofuran-6-yl) -4-fluorobenzoic acid tert-butyl ester using the method of example 47.1H NMR (500 MHz, DMSO). Delta.10.18 (s, 1H), 8.84 (s, 1H), 8.26 (d, J=9.3 Hz, 2H), 8.09 (s, 1H), 7.92-7.85 (m, 2H), 7.79-7.70 (m, 2H), 7.52 (d, J=8.2 Hz, 1H), 7.07 (s, 1H), 7.02 (d, J=9.0 Hz, 1H), 3.81 (s, 3H), 2.73 (s, 3H), 1.58 (s, 9H).
Example 136
Synthesis of 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamide) -5- (benzofuran-6-yl) -4-fluorobenzoic acid was carried out as in example 71.1H NMR (400 MHz, DMSO). Delta.13.03 (s, 1H), 10.15 (s, 1H), 8.86 (s, 1H), 8.39 (d, J=5.0 Hz, 1H), 8.26 (d, J=9.1 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.76 (d, J=6.4 Hz, 1H), 7.74 (s, 1H), 7.06 (d, J=1.2 Hz, 1H), 7.01 (dd, J=9.1, 2.5Hz, 1H), 3.82 (s, 3H), 2.73 (s, 3H).
Example 137
Synthesis of 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamide) -5- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -4-fluorobenzoic acid tert-butyl ester was carried out as in example 47.1H NMR (400 MHz, DMSO). Delta.10.13 (s, 1H), 8.83 (s, 1H), 8.24 (dd, J=11.7, 7.7Hz, 2H), 7.77 (dd, J=6.7, 2.1Hz, 1H), 7.72 (d, J=2.6 Hz, 1H), 7.08 (s, 2H), 7.01 (d, J=7.9 Hz, 2H), 4.31 (s, 4H), 3.81 (s, 3H), 2.72 (s, 3H), 1.57 (s, 9H).
Example 138
Synthesis of 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamide) -5- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -4-fluorobenzoic acid was carried out as in example 71.1H NMR (400 MHz, DMSO). Delta.13.07 (s, 1H), 10.12 (s, 1H), 8.85 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 8.25 (d, J=9.1 Hz, 1H), 7.82 (d, J=5.1 Hz, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.08 (d, J=13.1 Hz, 2H), 7.05-6.93 (m, 2H), 4.31 (s, 4H), 3.81 (s, 3H), 2.73 (s, 3H).
Example 139
Synthesis of methyl 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamido) -5- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -4-fluorobenzoate was performed as in example 47.1HNMR (400 MHz, DMSO). Delta.10.14 (s, 1H), 8.85 (s, 1H), 8.38 (dd, J=6.7, 2.1Hz, 1H), 8.26 (d, J=9.1 Hz, 1H), 7.83 (dd, J=6.8, 2.2Hz, 1H), 7.73 (d, J=2.6 Hz, 1H), 7.13-7.05 (m, 2H), 7.01 (dd, J=8.7, 2.9Hz, 2H), 4.31 (s, 4H), 3.90 (s, 3H), 3.82 (s, 3H), 2.73 (s, 3H).
Example 140
Methyl 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamido) -5- (benzofuran-6-yl) -4-fluorobenzoic acid methyl ester was synthesized as in example 47.1H NMR (400 MHz, DMSO). Delta.10.17 (s, 1H), 8.86 (s, 1H), 8.43 (dd, J=6.7, 2.1Hz, 1H), 8.26 (d, J=9.1 Hz, 1H), 8.09 (d, J=2.1 Hz, 1H), 7.93 (dd, J=8.4, 3.7Hz, 2H), 7.75 (t, J=6.3 Hz, 2H), 7.56 (dd, J=12.8, 5.5Hz, 1H), 7.07 (d, J=2.1 Hz, 1H), 7.02 (dd, J=9.1, 2.6Hz, 1H).
Example 141
Methyl 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamido) -4-fluoro-5- (1-methyl-1H-indazol-6-yl) benzoate was synthesized as in example 47.1H NMR (400 MHz, DMSO). Delta.10.16 (s, 1H), 8.86 (s, 1H), 8.42 (dd, J=6.7, 2.0Hz, 1H), 8.26 (d, J=9.1 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.94 (dd, J=6.8, 2.1Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (d, J=2.6 Hz, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.02 (dd, J=9.0, 2.6Hz, 1H), 4.10 (s, 3H), 3.91 (s, 3H), 3.82 (s, 3H), 2.73 (s, 3H).
Example 142
Synthesis of tert-butyl 3- (1-acetyl-5-methoxy-1H-indole-3-carboxamido) -5- (furan-2-yl) benzoate using the method described in example 47.1H NMR (400 MHz, DMSO). Delta.10.31 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 8.25 (d, J=9.0 Hz, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.84 (d, J=1.2 Hz, 1H), 7.78 (d, J=2.6 Hz, 1H), 7.01 (m, 2H), 6.6. Delta (dd, J=3.3, 1.8Hz, 1H), 3.84 (s, 3H), 2.74 (s, 3H), 1.60 (s, 9H).
Comparative example 1
For SGC-CBP30 in vitro activity experiments, the inhibition capability of the compound to CBP/EP300 protein is verified by adopting an alpha screen detection technology.
The structures of the compounds of examples 1-142 and comparative example 1 are shown in Table 1.
Figure GDA0004204982040000231
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Figure GDA0004204982040000241
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Figure GDA0004204982040000251
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Figure GDA0004204982040000261
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Figure GDA0004204982040000271
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Figure GDA0004204982040000281
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Figure GDA0004204982040000291
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Figure GDA0004204982040000301
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Figure GDA0004204982040000311
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Figure GDA0004204982040000321
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Figure GDA0004204982040000331
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Figure GDA0004204982040000341
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Figure GDA0004204982040000351
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Figure GDA0004204982040000361
In vitro activity experiments were performed on indole compounds prepared in examples 1-142: the invention adopts an alpha screen detection technology to verify the CBP/EP300 protein inhibition capability of the compound.
The in vitro activity test material comprises: the target protein CBP; experiment buffer (10X) MOPS (500 mm), CHAPS (0.5 mm), naF (500 mm), BSA (1 mg/mL), pH7.4; donor microbeads 50. Mu.g/mL and acceptor microbeads 50. Mu.g/mL in the kit; CBP ligand, short peptide H4KAc 4-statin (SGRG { Lys-Ac } GG { Lys-Ac } GLG { Lys-Ac } GGA { Lys-Ac } RHR { Lys (biotin) }) 50nM; 150. Mu.L of the reaction system: CBP 15. Mu.L, assay buffer: 15 μl, deionized water: 15 μl, small molecule compound: 15 μl, donor microbeads: 15 μl, receptor microbeads: 15. Mu.L; positive inhibitors: SGC-CBP30.
The in vitro activity experiment method is to add the protein and the short peptide into the reaction solution, incubate for 1.5h at 20 ℃, add the donor and acceptor microbeads, incubate for 1h in the dark. Transfer to 384 well plates, transfer 40 μl of liquid per well, excite wavelength by PE Envison2104 multifunctional detection microplate reader: 680nM, emission wavelength 520-620 nM.
Comparative example 1 was validated using the AlphaScreen detection technique, and the validation results are shown in table 1:
TABLE 1
Figure GDA0004204982040000362
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Figure GDA0004204982040000371
Note that: the above activity data are for CBP/EP300 proteins of the Bromodomain family.
Some of the compounds in the table showed activity comparable to that of the positive control SGC-CBP30, although slightly lower than SGC-CBP30, but also showed stronger activity. Wherein examples 44, 46, 51, 63, 73, 109, 110, 111, 114,120, 121 and 131 have reached nanomolar levels, in particular examples 110, 111, 114 and 131 describe compounds which are comparable to positive compounds and which have the advantage of being structurally stable and easy to prepare. And most of the examples have good selectivity to CBP/EP 300. The molecular level activity data of table 1 indicate that these compounds can bind efficiently to proteins with the Bromodomain domain.
Indole compound cell activity assay: prostate cancer cells (LNCaP and 22Rv 1) were cultured with RPMI1640, and 10% FBS was added. Cells were grown in 5% CO2 incubator at 37 ℃. To test the viability of the cells, the cells were seeded at 1000 cells/well (optimal growth density) in 384 impermeable plates with a transparent bottom in a total volume of 20 μl of medium. After 12 hours, a total volume of 10. Mu.L of medium (three dilutions) of the compound was added to each well at a final concentration of 5nM to 100. Mu.M. For LNCaP cells, the medium is RPMI1640 with 10% FBS. For 22Rv1 cells, the medium was RPMI1640 with 10% cds-FBS. The assay was performed 96 hours after inoculation, 25. Mu.LCell-Titer GLO reagent (Promega) was added and luminescence was measured on a GLOMAX microplate photometer (Promega) according to manufacturer's instructions. The estimated in vitro maximal half-inhibitory concentration (IC 50) values were calculated using GraphPad Prism 6 software. Wherein examples 115, 132 and 142 have cell activities at levels within 5 μm.
For colony formation, 1000 22Rv1 cells and 2000C 4-2B cells were individually seeded in wells of a 6-well plate and incubated with vehicle or indicated concentrations of compound with 3mL of medium for 14 days. When cell clone growth was visible, the medium was removed and the plates were washed once with 2mL PBS. Cell colonies were stained with 2.5% crystal violet (in MeOH) for 2 hours. After washing 3 times with water, the colony count was counted. Example 115 shows levels within 5 μm in a cell clone formation experiment. Therefore, the compounds are fully shown to have the potential of becoming diseases such as cancers, inflammatory diseases, autoimmune diseases, septicemia, virus infection and the like.
The applicant states that the detailed structural features of the present invention are described by the above embodiments, but the present invention is not limited to the above detailed structural features, i.e. it does not mean that the present invention must be implemented depending on the above detailed structural features. It should be apparent to those skilled in the art that any modifications of the present invention, equivalent substitutions of selected components of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope of the present invention and the scope of the disclosure.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention. In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further. Moreover, any combination of the various embodiments of the invention can be made without departing from the spirit of the invention, which should also be considered as disclosed herein.

Claims (4)

1. An indole compound for inhibiting CBP/EP300Bromodomain receptor, characterized in that said compound is the following compound:
Figure FDA0004185526390000011
2. use of an indole compound according to claim 1 for the preparation of a CBP/EP300Bromodomain receptor inhibitor.
3. The use according to claim 2, wherein the CBP/EP300Bromodomain receptor inhibitor is used for the preparation of a medicament for the treatment of cancer, a medicament for the treatment of a cell proliferative disorder, a medicament for the treatment of inflammatory and autoimmune diseases, a medicament for the treatment of sepsis, a medicament for the treatment of viral infections or a medicament for the treatment of neurodegenerative diseases.
4. A pharmaceutical composition comprising an indole compound of claim 1.
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