WO2021213521A1 - Cbp/ep300抑制剂及其用途 - Google Patents

Cbp/ep300抑制剂及其用途 Download PDF

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WO2021213521A1
WO2021213521A1 PCT/CN2021/089486 CN2021089486W WO2021213521A1 WO 2021213521 A1 WO2021213521 A1 WO 2021213521A1 CN 2021089486 W CN2021089486 W CN 2021089486W WO 2021213521 A1 WO2021213521 A1 WO 2021213521A1
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alkyl
hydrogen
dihydro
atoms
methyl
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PCT/CN2021/089486
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English (en)
French (fr)
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王利莎
张恩歌
李进
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南京药石科技股份有限公司
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Priority to CA3176493A priority Critical patent/CA3176493A1/en
Priority to EP21793622.8A priority patent/EP4140996A4/en
Priority to KR1020227041454A priority patent/KR20230005913A/ko
Priority to US17/920,890 priority patent/US20230159497A1/en
Priority to JP2022564523A priority patent/JP7462071B2/ja
Priority to CN202180028445.9A priority patent/CN115397822B/zh
Priority to AU2021259814A priority patent/AU2021259814B2/en
Publication of WO2021213521A1 publication Critical patent/WO2021213521A1/zh

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    • A—HUMAN NECESSITIES
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A—HUMAN NECESSITIES
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This application belongs to the field of chemistry and medicine, and specifically relates to a CBP/EP300 inhibitor and its use.
  • Chromatin refers to a linear composite structure composed of DNA, histones, non-histone proteins and a small amount of RNA in the interphase cell nucleus. Histones are the main protein components of chromatin. Cell activities directly related to the genome are carried out at the chromatin level, such as DNA replication, gene transcription, homologous recombination, DNA repair, including transcription-coupled repair, and various modifications of DNA and histones. These modifications include methylation, acetylation, phosphorylation, nitrosylation, and ubiquitination.
  • Histones are the most prone to post-translational modification. Histone modifications are dynamic because they can be added or removed in response to specific stimuli and these modifications lead to structural changes in chromatin and changes in gene transcription. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) acetylate or deacetylate specific histone lysine residues.
  • HAT histone acetyltransferase
  • HDAC histone deacetylase
  • CBP/EP300 is a lysine acetyltransferase that catalyzes the attachment of acetyl groups to the lysine side chains of histones and other protein substrates.
  • CBP and EP300 have extensive sequence identity and functional similarity, and are often referred to as CBP/EP300.
  • the acetylation of histones and other proteins catalyzed by CBP/EP300 is essential for gene activation.
  • the CBP/EP300 protein also has a specific functional domain called the bromodomain.
  • the bromodomain which is about 110 amino acids in length, is found in a large number of chromatin-related proteins and has been identified in about 70 human proteins that are often adjacent to other protein motifs.
  • the interaction between the bromodomain and modified histones may be an important mechanism that causes changes in chromatin structure and regulation of gene expression.
  • Cell type specificity and proper tissue functionality require strict control of the transcription program of different genes, which is closely affected by its structural environment.
  • the bromodomain is located in a key chromatin modification complex that controls the transcription pathways of unique disease-related disease-causing genes.
  • novel compounds with CBP/EP300 bromine domain inhibitory activity provide the possibility to treat cancer, inflammation, autoimmune diseases, infectious diseases, and cardiovascular diseases.
  • R 1 is selected from hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogen, cyano, -C(O)NR 5 R 6 , -C(O)R 5 ,- C(O)OR 5 , -OR 5 , -OC(O)R 5 , -OC(O)OR 5 , -OC(O)NR 5 R 6 , -NR 5 R 6 , -SR 5 , -S( O) R 5 , -S(O) 2 R 5 , -(CH 2 )nOH or a 5-6 membered saturated or unsaturated ring containing 0-3 N, O or S atoms; wherein, said containing 0- The 5-6 membered saturated or unsaturated ring of 3 N, O or S atoms is optionally substituted by 1-3 R 5;
  • R 2 is selected from hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogen, cyano, -C(O)NR 5 R 6 , -C(O)R 5 , -C( O)OR 5 , -OR 5 , -OC(O)R 5 , -OC(O)OR 5 , -OC(O)NR 5 R 6 , -NR 5 R 6 , -SR 5 , -S(O) R 5 , -S(O) 2 R 5 or -(CH 2 )nOH;
  • R 3 is selected from hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogen, cyano, -C(O)NR 5 R 6 , -C(O)R 5 , -C( O)OR 5 , -OR 5 , -OC(O)R 5 , -OC(O)OR 5 , -OC(O)NR 5 R 6 , -NR 5 R 6 , -SR 5 , -S(O) R 5 , -S(O) 2 R 5 , -(CH 2 )nOH or a 5-6 membered saturated or unsaturated ring containing 0-3 N, O or S atoms; wherein, said containing 0-3 The 5-6 membered saturated or unsaturated ring of N, O or S atoms is optionally substituted by 1-3 R 5;
  • R 4 is selected from hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogen, cyano, -C(O)NR 5 R 6 , -C(O)R 5 , -C( O)OR 5 , -OR 5 , -OC(O)R 5 , -OC(O)OR 5 , -OC(O)NR 5 R 6 , -NR 5 R 6 , -SR 5 , -S(O) R 5 , -S(O) 2 R 5 , -(CH 2 )nOH or a 5-6 membered saturated or unsaturated ring containing 0-3 N, O or S atoms; wherein, said containing 0-3 The 5-6 membered saturated or unsaturated ring of N, O or S atoms is optionally substituted by 1-3 R 5;
  • R 7 and R 8 are independently selected from hydrogen or C 1 -C 6 alkyl
  • Z 1 is -CH 2 -or -O-;
  • Ring A is a 5-6 membered saturated or unsaturated ring containing 0-3 N, O or S atoms;
  • Each m, n is independently selected from 0, 1, 2 or 3, respectively.
  • Formula (I) is Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), or Formula (Ie):
  • Formula (I) is Formula (If), Formula (Ig), or Formula (Ih):
  • R 1 is selected from hydrogen, halogen, methoxy,
  • R 2 is selected from -OH or -NHCH 3 .
  • R 3 is selected from hydrogen, halogen, or halo C 1 -C 6 alkyl.
  • R 3 is -CHF 2 .
  • R 4 is selected from hydrogen, -CH 2 OH, -C(O)NHCH 3 ,
  • this application also provides a compound having the following structure, an isomer thereof, or a pharmaceutically acceptable salt thereof:
  • this application also provides the use of the aforementioned compound, its isomers or pharmaceutically acceptable salts thereof in the preparation of drugs for diseases mediated by CBP and/or EP300.
  • the CBP and/or EP300-mediated disease is cancer, inflammatory disorder, autoimmune disease, viral infection or cardiovascular disease.
  • the cancer is leukemia, lymphoma, multiple myeloma, lung cancer, prostate cancer, head and neck cancer, breast cancer, pancreatic cancer, colorectal cancer or melanoma.
  • this application also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the aforementioned compound, its isomer or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition may also contain one or more other anti-cancer drugs.
  • the anticancer drug may be a chemotherapeutic drug.
  • isomeric forms as used in this application includes enantiomeric forms, diastereomeric forms, and geometric (or conformational) isomeric forms of a given structure.
  • this application includes the R and S configurations of each asymmetric center, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers and enantiomers, diastereomers Isomers and geometric (or conformational) isomer mixtures. Unless otherwise stated, this application includes all tautomeric forms of the structures described in this application.
  • pharmaceutically acceptable salt includes acid and base addition salts.
  • halo and halogen used in this application refer to an atom selected from fluorine (-F), chlorine (-C1), bromine (-Br), and iodine (-I).
  • C 1 -C 6 alkyl used in the present application is a saturated linear or branched hydrocarbon group having 1 to 6 carbon atoms.
  • C 1 -C 6 haloalkyl refers to one or more (e.g. three or four) halogen substituted as defined herein “C 1 -C 6 alkyl.”
  • C 3 -C 6 cycloalkyl refers to a saturated or unsaturated carbocyclic ring containing 3 to 6 carbon atoms.
  • heterocyclyl refers to a saturated or unsaturated carbocyclic ring in which one or more (for example, 1, 2, 3, or 4) carbon atoms have been replaced by heteroatoms (for example, O, N, or S).
  • terapéuticaally effective amount refers to the following amount of the compound of the present application, which (i) treats a specific disease, disorder or disorder; (ii) reduces, alleviates or eliminates a specific disease, disorder or disorder Or multiple symptoms; or (iii) prevent or delay the onset of one or more symptoms of the specific disease, disorder or disorder described in this application.
  • pharmaceutically acceptable carrier or excipient refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated with it.
  • Step 1 Preparation of 3-bromo-3H-isobenzofuran-1-one.
  • Dissolve phthalide (20.0g, 149.1mmol, 1.0eq.) in 1,2-dichloroethane (100mL)
  • AIBN 2.5g, 14.9mmol, 0.1eq.
  • NBS 31.9 g, 178.9mmol, 1.2eq.
  • Step 2 Preparation of 2-formylbenzoic acid .
  • 3-Bromo-3H-isobenzofuran-1-one (31.0g, 145.5mmol, 1.0eq.) was dissolved in 100mL of water and reacted at 100°C for 2h. After cooling to room temperature, it was extracted with EtOAc, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain the title compound as an off-white solid (21.0g, yield 96%). This compound can be used directly without further purification. .
  • MS (m/z) 151.04 [M+H] + .
  • Step 3 Preparation of methyl 2-formylbenzoate .
  • Dissolve 2-formylbenzoic acid (21.0g, 140.0mmol, 1.0eq.) in acetone (150mL) add potassium carbonate (19.3g, 140.0mmol, 1.0eq.) and methyl iodide (39.7g) under stirring. , 280.0mmol, 2.0eq.), the reaction mixture was continued to react at 70°C for 15h. After cooling to room temperature, the mixture was filtered and concentrated directly in vacuo to obtain the title compound as an off-white solid (22.0 g, yield 96%), which was used directly without further purification.
  • MS (m/z) 165.05 [M+H] + .
  • Step 4 Preparation of 1-oxo-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester .
  • Methyl 2-formylbenzoate (22.0g, 134.0mmol, 1.0eq.) and DBU (20.4g, 134.0mmol, 1.0eq.) were dissolved in dichloromethane (120mL) and added ( ⁇ )-BOC-A-phosphonoglycine trimethyl ester (39.8 g, 134.0 mmol, 1.0 eq.), and the reaction mixture was stirred at room temperature for 5 hours. Dilute with 100 mL of water.
  • Step 5 Preparation of 1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester .
  • Dissolve 1-oxo-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (30.0g, 100.0mmol, 1.0eq.) in 100mL hydrochloric acid dioxane solution (4.0M), the reaction mixture was continuously stirred at room temperature for 12h. After the reaction, it was directly concentrated in vacuo to obtain the title compound as an off-white solid (20.0 g, quantitative yield). MS (m/z) 204.07 [M+H] + .
  • Step 6 Preparation of methyl 1-chloroisoquinoline-3-carboxylate .
  • a mixture of methyl 1-oxo-1,2-dihydroisoquinoline-3-carboxylate (14.4 g, 70.9 mmol, 1.0 eq.) and POCl 3 (50 mL) was heated at 110° C. for 2 h.
  • the reaction solution was cooled to room temperature, and then a large amount of solids precipitated out, filtered, and the filtered solids were completely dissolved in 100 mL of dichloromethane.
  • Step 1 Preparation of N-(tert-butyl)-3-methylpyridine amide .
  • 2-cyano-3-methylpyridine (15.0g, 127.0mmol, 1.0eq.)
  • tert-butanol 40mL
  • concentrated sulfuric acid (15.0mL, 281.4mmol) was slowly added dropwise while stirring , 2.2eq.).
  • the reaction mixture was stirred and reacted at 75°C for 30 minutes, and then diluted by adding 200 mL of water, the pH of the reaction mixture was adjusted to 8 with ammonia water, and the reaction mixture was concentrated in vacuo.
  • Step 2 Preparation of ethyl 3-(2-(tert-butylamino)pyridin-3-yl)-2-oxopropanoate .
  • N-(tert-butyl)-3-methylpyridine amide (10.0 g, 52.0 mmol, 1.0 eq.) was dissolved in dry THF (200 mL) under stirring, and under stirring N-BuLi (6.7g, 104.0mmol, 2.0eq.) and tetramethylethylenediamine (6.0g, 52.0mmol, 1.0eq.) were added dropwise respectively, and the reaction mixture was stirred and reacted at -78°C for 30min.
  • Step 3 Preparation of ethyl 8-oxo-7,8-dihydro-1,7-naphthyridine-6-carboxylate. While stirring, ethyl 3-(2-(tert-butylamino)pyridin-3-yl)-2-oxopropaneate (4.5g, 15.4mmol, 1.0eq.) and acetic acid (45mL) were added to the acetic acid (45mL). Ammonium (2.4g, 30.8mmol, 2.0eq.), then heated at 110°C for 12h.
  • Step 4 Preparation of ethyl 8-chloro-1,7-naphthyridine-6-carboxylate.
  • a mixture of ethyl 8-oxo-7,8-dihydro-1,7-naphthyridine-6-carboxylate (1.0 g, 4.6 mmol, 1.0 eq.) and POCl 3 (8 mL) was heated at 110° C. for 2 h.
  • Step 1 Preparation of quinoline-7-formaldehyde.
  • the 7-methylquinoline (100.0g, 698.4mmol, 1.0eq.) was heated to 160°C, and then selenium dioxide (77.5g, 698.4mmol, 1.0eq.) was added in portions within 30min, and the reaction mixture continued at 160°C. React at °C for 8h. After cooling to room temperature, 1000mL of dichloromethane was added, a large amount of solids precipitated, the solids were filtered out and the filtrate was concentrated.
  • Step 2 Preparation of 7-difluoromethylquinoline.
  • Quinoline-7-carbaldehyde (63.3g, 402.9mmol, 1.0eq.) was dissolved in 600mL of dichloromethane, DAST (324.7g, 2.0mol, 5.0eq.) was added dropwise at 0°C, and the reaction mixture was reacted at 20°C 16 h.
  • the reaction mixture was poured into 1000 mL of saturated sodium bicarbonate solution, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated.
  • MS (m/z) 180.06 [M+H] + .
  • Step 4 Preparation of 6-bromo-7-difluoromethyl-1,2,3,4-tetrahydroquinoline .
  • Dissolve 7-difluoromethyl-1,2,3,4-tetrahydroquinoline (12.0g, 65.5mmol, 1.0eq.) in dichloromethane (120mL) add NBS (12.8g, 72.0mmol, 1.1eq.) and react at room temperature for 16h.
  • the reaction mixture was diluted with 100 mL of water, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated.
  • MS(m/z) 264.02 [M+H] + .
  • Step 5 Preparation of 7-difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline .
  • 1-methylpyrazole-4-boronic acid pinacol ester (4.8g, 22.9mmol, 1.2eq.)
  • 6-bromo-7-difluoromethyl-1,2,3,4-tetrahydroquinoline ( 5.0g, 19.1mmol, 1.0eq.)
  • Pd(dppf)Cl 2 1.4g, 1.9mmol, 0.1eq.
  • K 2 CO 3 (7.9g, 57.2mmol, 3.0eq.) were dissolved in 1, 4 -Dioxane (50mL) and water (10mL), react at 110°C for 18h under nitrogen protection.
  • Step 1 Preparation of 6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline .
  • 1-methylpyrazole-4-boronic acid pinacol ester 1.2g, 5.7mmol, 1.2eq.
  • 6-bromo-1,2,3,4-tetrahydroquinoline 1.0g, 4.7mmol, 1.0 eq.
  • Pd(dppf)Cl 2 345.0mg, 471.5 ⁇ mol, 0.1eq.
  • K 2 CO 3 2.0g, 14.1mmol, 3.0eq.
  • Step 2 1-[6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-isoquinoline-3-carboxylic acid methyl
  • Methyl 1-chloroisoquinoline-3-carboxylate (Intermediate I) (200.0mg, 902.4 ⁇ mol, 1.0eq.), 6-(1-methyl-1H-pyrazol-4-yl)-1, 2,3,4-Tetrahydroquinoline (288.7mg, 1.4mmol, 1.5eq.), Pd(OAc) 2 (20.3mg, 90.2 ⁇ mol, 0.1eq.), BINAP (112.4mg, 180.5 ⁇ mol, 0.2eq.) ), Cs 2 CO 3 (352.8 mg, 1.08 mmol, 1.2 eq.) were respectively dissolved in toluene (20 mL), and reacted at 90° C.
  • Step 3 1-[6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-isoquinoline-3-carboxylic acid methyl Preparation of amides.
  • Step 1 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-isoquine morpholine-3-carboxylic acid methyl ester.
  • Step 2 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-isoquine morpholine carboxamide-3-carboxylic acid.
  • Examples 3-15 were prepared in a similar manner to Example 2.
  • Example 16 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-7 - (3,6-dihydro -2H- pyrazol pyran-4-yl) - isoquinoline-3-carboxylic acid-carboxamide
  • Step 1 7-(3,6-Dihydro-2H-pyran-4-yl)-1-oxo-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl Preparation of base ester.
  • Step 2 Preparation of 7-(3,6-dihydro-2H-pyran-4-yl)-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid methyl ester.
  • Step 3 Preparation of 1-chloro-7-(3,6-dihydro-2H-pyran-4-yl)-isoquinoline-3-carboxylic acid methyl ester .
  • 7-(3,6-Dihydro-2H-pyran-4-yl)-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid methyl ester (0.2g, 778.1 ⁇ mol, 1.0 A mixture of eq.) and POCl 3 (10 mL) was heated at 110° C. for 2 h.
  • Step 4 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-7- Preparation of (3,6-Dihydro-2H- pyran-4-yl)-isoquinoline-3-carboxylic acid methyl ester.
  • Step 5 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-7- Preparation of (3,6-Dihydro-2H- pyran-4-yl)-isoquinoline-3-carboxylic acid carboxamide.
  • Example 17 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-7 - (tetrahydro-4-yl) - isoquinoline-3-carboxylic acid-carboxamide
  • Step 1 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-7- Preparation of (tetrahydro-4-yl) -isoquinoline-3-carboxylic acid carboxamide.
  • Examples 18-23 were prepared in a similar manner with reference to Example 17.
  • Example 24 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-7 -(2-oxo-oxazolidine- 3-yl)-isoquinoline-3-carboxylic acid carboxamide
  • Step 1 1-oxo-7-(2-oxo-oxazolidin-3-yl)-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester preparation.
  • the 2-oxazolidinone (150.4mg, 1.7mmol, 1.1eq.), 7-bromo-1-oxo-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (0.6g, 1.6mmol, 1.0eq.), Pd 2 (dba) 3 (143.8mg, 157.0 ⁇ mol, 0.1eq.), Xantphos (150.0mg, 314.0 ⁇ mol, 0.2eq.), Cs 2 CO 3 (1.0g , 3.1mmol, 2.0eq.) were dissolved in 1,4-dioxane (15mL), and reacted at 95°C for 14h under nitrogen protection.
  • Step 2 Preparation of 1-oxo-7-(2-oxo-oxazolidin-3-yl)-1,2-dihydro-isoquinoline-3-carboxylic acid methyl ester .
  • 1-oxo-7-(2-oxo-oxazolidin-3-yl)-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester 550.0mg , 1.4mmol, 1.0eq.
  • was dissolved in 20mL hydrochloric acid dioxane solution (4.0M) was stirred at room temperature for 12h. After the reaction, it was directly concentrated in vacuo to obtain the title compound as a white solid (350.0 mg, 86%).
  • MS (m/z) 289.08 [M+H] + .
  • Step 3 Preparation of 1-chloro-7-(2-oxo-oxazolidin-3-yl)-isoquinoline-3-carboxylic acid methyl ester .
  • Step 4 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-7- preparation of isoquinoline-3-carboxylate - (2-oxo - oxazolidin-3-yl).
  • Step 5 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-7- preparation of isoquinoline-3-carboxylic acid-carboxamide - (2-oxo - oxazolidin-3-yl).
  • Examples 25-28 were prepared in a similar manner with reference to Example 24.
  • Example 29 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6 -(Tetrahydrofuran-2-yl) -isoquinoline-3-carboxylic acid carboxamide
  • Step 1 Preparation of 6-(4,5-dihydrofuran-2-yl)-1-oxo-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester .
  • 2,3-Dihydrofuran 1.0g, 2.6mmol, 1.0eq.
  • 6-bromo-1-oxy-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl Ester (366.8mg, 5.2mmol, 2.0eq.), (o-MePh) 3 P (159.1mg, 523.3 ⁇ mol, 0.2eq.) and Pd(OAc) 2 (58.6mg, 261.6 ⁇ mol, 0.1eq.) were dissolved in In DMF (20 mL), react at 80°C for 1 h under nitrogen protection.
  • Step 2 Preparation of 1-oxo-6-(tetrahydrofuran-2-yl)-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester .
  • Step 3 Preparation of 1-oxo-6-(tetrahydrofuran-2-yl)-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester .
  • Step 4 Preparation of 1-chloro-6-(tetrahydrofuran-2-yl)-isoquinoline-3-carboxylic acid methyl ester .
  • Mixture of 1-oxo-6-(tetrahydrofuran-2-yl)-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (0.5g, 1.8mmol, 1.0eq.) and POCl 3 (10mL) Heat at 110°C for 2h.
  • Step 5 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6- Preparation of (tetrahydrofuran-2- yl)-isoquinoline-3-carboxylic acid methyl ester.
  • Step 6 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6- Preparation of (tetrahydrofuran-2- yl)-isoquinoline-3-carboxylic acid carboxamide.
  • Step 1 Preparation of 7-difluoromethyl-6-pyrimidin-5-yl-1,2,3,4-tetrahydroquinoline.
  • 5-pyrimidine boronic acid pinacol ester (283.0mg, 1.4mmol, 1.2eq.)
  • 6-bromo-7-difluoromethyl-1,2,3,4-tetrahydroquinoline third of intermediate IX Step) (300.0mg, 1.1mmol, 1.0eq.)
  • Pd(dppf)Cl 2 (83.7mg, 114.5 ⁇ mol, 0.1eq.)
  • K 2 CO 3 474.6mg, 3.43mmol, 3.0eq.
  • Step 2 Preparation of 1-(7-difluoromethyl-6-pyrimidin-5-yl-3,4-dihydro-2H-quinolin-1-yl)-isoquinoline-3-carboxylic acid methyl ester .
  • Methyl 1-chloroisoquinoline-3-carboxylate (Intermediate I) (205.0mg, 925.0 ⁇ mol, 1.0eq.), 7-difluoromethyl-6-pyrimidin-5-yl-1,2,3 , 4-Tetrahydroquinoline (290.0mg, 1.1mmol, 1.2eq.), Pd(OAc) 2 (20.8mg, 92.5 ⁇ mol, 0.1eq.), BINAP (115.2mg, 185.0 ⁇ mol, 0.2eq.) Cs 2 CO 3 (361.6 mg, 1.1 mmol, 1.2 eq.) was dissolved in toluene (20 mL), and reacted at 90° C.
  • Step 3 Preparation of 1-(7-Difluoromethyl-6-pyrimidin-5-yl-3,4-dihydro-2H-quinolin-1-yl)-isoquinoline-3-carboxylic acid carboxamide .
  • 1-(7-Difluoromethyl-6-pyrimidin-5-yl-3,4-dihydro-2H-quinolin-1-yl)-isoquinoline-3-carboxylic acid methyl ester (0.3g, 672.0 ⁇ mol, 1.0eq.) was dissolved in methylamine ethanol solution (10mL) and reacted at 80°C for 2h.
  • Examples 31-39 were prepared in a similar manner to Example 30.
  • Example 40 1-[4-Methylamino-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-isoquine carboxamide-3-carboxylic acid
  • Step 1 Preparation of 6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-quinolin-4-one .
  • the 1-methylpyrazole-4-boronic acid pinacol ester (552.2mg, 2.6mmol, 1.2eq.), 6-bromo-2,3-dihydroquinoline-4(1H)-one (0.5g, 2.2mmol, 1.0eq.), Pd(dppf)Cl 2 (161.8mg, 221.2 ⁇ mol, 0.1eq.), K 2 CO 3 (917.0mg, 6.6mmol, 3.0eq.) respectively dissolved in 1,4-diox
  • the hexacyclic ring (50mL) and water (10mL) were reacted at 110°C for 18h under nitrogen protection.
  • Step 2 1-[6-(1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydro-2H-quinolin-1-yl]-isoquinoline- Preparation of methyl 3-carboxylate.
  • Methyl 1-chloroisoquinoline-3-carboxylate (Intermediate I) (292.6mg, 1.3mmol, 1.0eq.), 6-(1-methyl-1H-pyrazol-4-yl)-2, 3-Dihydro-1H-quinolin-4-one (300.0mg, 1.3mmol, 1.2eq.), Pd(OAc) 2 (29.6mg, 132.0 ⁇ mol, 0.1eq.), BINAP (164.4mg, 264.0 ⁇ mol, 0.2eq.) Cs 2 CO 3 (516.1mg, 1.6mmol, 1.2eq.) was dissolved in toluene (20mL), and reacted at 90°C for 15h under nitrogen protection.
  • Step 3 1-[4-Methylimino-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-isoquine morpholine carboxamide-3-carboxylic acid.
  • Step 4 1-[4-Methylamino-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-isoquinoline -3-carboxylic acid methylamide.
  • Step 1 1-[4-Hydroxy-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-isoquinoline-3 -Preparation of methyl carboxylate.
  • the acid methyl ester was dissolved in methanol (10 mL), and NaBH 4 (12.8 mg, 339.4 ⁇ mol, 1.0 eq.) was added in batches at room temperature to continue the reaction for 14 h.
  • Step 2 1-[4-Hydroxy-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-isoquinoline-3 -Preparation of carboxylic acid formamide.
  • Methyl ester (90.0mg, 217.1 ⁇ mol, 1.0eq.) was dissolved in methylamine ethanol solution (6mL) and reacted at 80°C for 2h.
  • Step 1 4-(7-Difluoromethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester preparation.
  • N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (3.3g, 10.8mmol, 2.8eq.)
  • 6-bromo-7-difluoromethyl-1,2, 3,4-Tetrahydroquinoline (the third step of Intermediate IX) (300.0mg, 1.1mmol, 1.0eq.), Pd(dppf)Cl 2 (279.2mg, 381.5 ⁇ mol, 0.1eq.), K 2 CO 3 (1.6g, 11.5mmol, 3.0eq.) were dissolved in 1,4-dioxane (20mL) and water (4mL) respectively, and reacted at 110°C for 14h under nitrogen protection.
  • Step 2 8-[6-(1-tert-Butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-7-difluoromethyl-3,4-dihydro-2H-quine Preparation of ethyl lin-1 -yl]-[1,7]naphthyridine-6-carboxylate.
  • Step 3 Add 8-[6-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-7-difluoromethyl-3,4-dihydro-2H- Quinolin-1-yl]-[1,7]naphthyridine-6-carboxylic acid ethyl ester (1.1g, 1.9mmol, 1.0eq.) was dissolved in 20mL hydrochloric acid dioxane solution (4.0M), the reaction mixture Continue to stir at room temperature for 12h.
  • Step 4 8-[7-Difluoromethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydro-2H-quinolin-1-yl]- [1,7] naphthyridin-6-carboxylic acid was prepared carboxamide. 8-[7-Difluoromethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-[1, 7] Ethyl naphthyridine-6-carboxylate (100 mg, 215.0 ⁇ mol, 1.0 eq.) was dissolved in methylamine ethanol solution (10 mL) and reacted at 80° C.
  • Example 43 8-[6-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7-difluoromethyl-3,4-dihydro-2H-quinoline 1-yl] - [1,7] naphthyridine-carboxamide-carboxylic acid
  • Step 1 8-[6-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7-difluoromethyl-3,4-dihydro-2H-quinoline- Preparation of 1-yl]-[1,7] naphthyridine-6-carboxylic acid ethyl ester .
  • Step 2 8-[6-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7-difluoromethyl-3,4-dihydro-2H-quinoline- Preparation of 1-yl]-[1,7] naphthyridine-6-carboxylic acid carboxamide .
  • Example 44 8-[7-Difluoromethyl-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydro-2H-quinoline -1-yl]-[1,7]naphthyridine -6-carboxylic acid carboxamide
  • Step 1 8-[7-Difluoromethyl-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydro-2H-quinoline- yl] 1--- preparation of [1,7] naphthyridin-6-carboxylate.
  • Step 2 8-[7-Difluoromethyl-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydro-2H-quinoline- 1- yl] - preparation of naphthalene-carboxamide-carboxylic acid [1,7].
  • Example 45 8-[7-Difluoromethyl-6-(1-methanesulfonyl-1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydro-2H-quine Lin-1-yl]-[1,7] naphthyridine-6-carboxylic acid carboxamide
  • Step 1 8-[7-Difluoromethyl-6-(1-methylsulfonyl-1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydro-2H-quinoline Preparation of ethyl -1-yl]-[1,7] naphthyridine-6-carboxylate.
  • Step 2 8-[7-Difluoromethyl-6-(1-methylsulfonyl-1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydro-2H-quinoline Preparation of -1-yl]-[1,7] naphthyridine-6-carboxylic acid carboxamide.
  • Step 1 Preparation of 4-(7-difluoromethyl-1,2,3,4-tetrahydroquinolin-6-yl)-piperidine-1-carboxylic acid tert-butyl ester.
  • Step 2 8-[6-(1-tert-butoxycarbonylpiperidin-4-yl)-7-difluoromethyl-3,4-dihydro-2H-quinolin-1-yl]-[1, 7] Preparation of ethyl naphthyridine-6-carboxylate.
  • Step 3 8-(7-Difluoromethyl-6-piperidin-4-yl-3,4-dihydro-2H-quinolin-1-yl)-[1,7]naphthyridine-6-carboxy Preparation of Ethyl Acid.
  • Ethyl naphthyridine-6-carboxylate (150.0 mg, 264.7 ⁇ mol, 1.0 eq.) was dissolved in 20 mL of dioxane hydrochloride solution (4.0 M), and the reaction mixture was stirred at room temperature for 12 hours.
  • Step 4 8-[6-(1-Acetylpiperidin-4-yl)-7-difluoromethyl-3,4-dihydro-2H-quinolin-1-yl]-[1,7] naphthyridine preparation of 6-carboxylate.
  • Step 5 8-[6-(1-Acetylpiperidin-4-yl)-7-difluoromethyl-3,4-dihydro-2H-quinolin-1-yl]-[1,7]naphthalene preparation of carboxamide-carboxylic acid.
  • Ethyl 6-carboxylate (50.0mg, 98.3 ⁇ mol, 1.0eq.) was dissolved in methylamine ethanol solution (10mL) and reacted at 80°C for 2h.
  • Examples 47-52 were prepared in a similar manner to Example 46.
  • Example 53 8-[6-(1-Azelaic acid-3-yl-1H-pyrazol-4-yl)-7-difluoromethyl-3,4-dihydro-2H-quinoline-1 -Yl]-[1,7]naphthyridine -6-carboxylic acid carboxamide
  • Step 1 3-[4-(7-Difluoromethyl-1,2,3,4-tetrahydroquinolin-6-yl)-pyrazol-1-yl]-azelaic acid-1-carboxylic acid Preparation of tert-butyl ester.
  • 1-(1-BOC-3-azetidinyl)pyrazole-4-boronic acid pinacol ester (799.5mg, 2.3mmol, 1.2eq.), 6-bromo-7-difluoromethyl-1 ,2,3,4-Tetrahydroquinoline (0.5g, 1.9mmol, 1.0eq.), Pd(dppf)Cl 2 (139.6mg, 190.8 ⁇ mol, 0.1eq.), K 2 CO 3 (791.0mg, 5.7 mmol, 3.0eq.) were dissolved in 1,4-dioxane (20mL) and water (4mL), and reacted at 110°C for 14h under the protection of nitrogen.
  • Step 2 8- ⁇ 6-[1-(1-tert-Butoxycarbonyl-azidine-3-yl)-1H-pyrazol-4-yl]-7-difluoromethyl-3,4-bis preparation of [7] naphthyridin-6-carboxylate - a] quinolin-1-yl -2H- hydrogen.
  • Step 3 8-[6-(1-Azepin-3-yl-1H-pyrazol-4-yl)-7-difluoromethyl-3,4-dihydro-2H-quinoline-1- Preparation of ethyl]-[1,7]naphthyridine -6-carboxylate.
  • Step 4 8-[6-(1-Azelaic acid-3-yl-1H-pyrazol-4-yl)-7-difluoromethyl-3,4-dihydro-2H-quinoline-1-
  • Example 54 8- ⁇ 7-Difluoromethyl-6-[1-(1-methyl-azidine-3-yl)-1H-pyrazol-4-yl]-3,4-dihydro -2H-quinolin-1 -yl ⁇ -[1,7]naphthyridine-6-carboxylic acid carboxamide
  • Step 1 8- ⁇ 7-Difluoromethyl-6-[1-(1-methyl-azidine-3-yl)-1H-pyrazol-4-yl]-3,4-dihydro- Preparation of ethyl 2H-quinolin-1 -yl ⁇ -[1,7]naphthyridine-6-carboxylate.
  • Naphthyridine-6-carboxylic acid ethyl ester (0.3g, 594.6 ⁇ mol, 1.0eq.) was dissolved in dichloromethane (50mL), and aqueous formaldehyde solution (2mL, 594.6 ⁇ mol, 1.0eq.) was added at room temperature After reacting for 1 h, STAB (376.4 mg, 1.2 mmol, 2.0 eq.) was added and the reaction was continued at room temperature for 20 h.
  • Step 2 8- ⁇ 7-Difluoromethyl-6-[1-(1-methyl-azidine-3-yl)-1H-pyrazol-4-yl]-3,4-dihydro- Preparation of 2H-quinolin-1 -yl ⁇ -[1,7]naphthyridine-6-carboxylic acid carboxamide.
  • Step 1 Preparation of [4-(7-Difluoromethyl-1,2,3,4-tetrahydroquinolin-6-yl)-pyrazol-1-yl]-acetonitrile.
  • [4-(4,4,5,5-Tetramethyl-[1,3,2]dioxin-2-yl)-pyrazol-1-yl]-acetonitrile 533.6mg, 2.3mmol, 2.8eq .
  • 6-bromo-7-difluoromethyl-1,2,3,4-tetrahydroquinoline 0.5g, 1.9mmol, 1.0eq.
  • Pd(dppf)Cl 2 139.6mg, 190.8 ⁇ mol , 0.1eq.
  • K 2 CO 3 791.0mg, 5.7mmol, 3.0eq.
  • Step 2 8-[6-(1-cyanomethyl-1H-pyrazol-4-yl)-7-difluoromethyl-3,4-dihydro-2H-quinolin-1-yl]- [1,7] Preparation of ethyl naphthyridine-6-carboxylate.
  • Step 3 8-[6-(1-cyanomethyl-1H-pyrazol-4-yl)-7-difluoromethyl-3,4-dihydro-2H-quinolin-1-yl]- [1,7] Preparation of Naphthyridine-6-Carboxamide. 8-[6-(1-cyanomethyl-1H-pyrazol-4-yl)-7-difluoromethyl-3,4-dihydro-2H-quinolin-1-yl]-[1, 7] Ethyl naphthyridine-6-carboxylate (0.3g, 614.1 ⁇ mol, 1.0eq.) was dissolved in methylamine ethanol solution (10mL) and reacted at room temperature for 2h.
  • Example 56 1-[7-Difluoromethyl-6-(1-methylcarbamoylmethyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinoline-1 -Yl]-isoquinoline- 3-carboxylic acid carboxamide
  • Step 1 1-[7-Difluoromethyl-6-(1-methylcarbamoylmethyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinoline-1- yl] - isobutyl -3-quinoline-carboxylic acid methylamide.
  • Ethyl naphthyridine-6-carboxylate (0.1 g, 614.1 ⁇ mol, 1.0 eq.) was dissolved in methylamine ethanol solution (10 mL) and reacted at 110° C.
  • Step 1 Preparation of 6-bromo-7-chloro-1,2,3,4-tetrahydro-quinine .
  • 7-Chloro-1,2,3,4-tetrahydroquinoline (2.0g, 12.1mmol, 1.0eq.) was dissolved in DMF (30mL), and NBS (2.2g, 12.5mmol, 1.0eq.), the reaction mixture continued to react at 0°C for 2h.
  • the reaction solution was poured into 100 mL of ice water, stirred to precipitate a white solid, filtered with suction and dried to obtain the title compound as a white solid (2.9 g, quantitative yield).
  • MS (m/z) 245.97 [M+H] + .
  • Step 2 Preparation of 7-chloro-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline .
  • 1-methylpyrazole-4-boronic acid pinacol ester (2.8g, 13.3mmol, 1.1eq.)
  • 6-bromo-7-chloro-1,2,3,4-tetrahydro-quinine (2.9g , 12.1mmol, 1.0eq.)
  • Pd(dppf)Cl 2 (887.4mg, 1.2mmol, 0.1eq.
  • K 2 CO 3 5.0g, 36.4mmol, 3.0eq.
  • Step 3 1-[7-chloro-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-isoquinoline-3 -Preparation of methyl carboxylate.
  • Methyl 1-chloroisoquinoline-3-carboxylate (Intermediate I) (280.0mg, 1.3mmol, 1.0eq.), 7-chloro-6-(1-methyl-1H-pyrazol-4-yl) )-1,2,3,4-tetrahydroquinoline (344.2mg, 1.4mmol, 1.1eq.), Pd(OAc) 2 (56.7mg, 252.7 ⁇ mol, 0.2eq.), BINAP (157.3mg, 252.7 ⁇ mol , 0.2 eq.) Cs 2 CO 3 (493.9 mg, 1.5 mmol, 1.2 eq.) was dissolved in toluene (20 mL), and reacted at 90° C. for 3 h under nitrogen protection.
  • Step 4 1-[7-chloro-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-isoquinoline-3 -Preparation of carboxylic acid formamide.
  • Example 58 1-(3-Methylcarbamoylisoquinolin-1-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid carboxamide
  • Step 1 Preparation of 1-(3-methoxycarbonylisoquinolin-1-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid ethyl ester .
  • 1-chloroisoquinoline-3-carboxylic acid methyl ester (Intermediate I) (180.0mg, 812.1 ⁇ mol, 1.0eq.), 1,2,3,4-tetrahydroquinoline-6-carboxylic acid ethyl ester ( 183.4mg, 893.3 ⁇ mol, 1.1eq.), Pd(OAc) 2 (36.5mg, 162.4 ⁇ mol, 0.2eq.), BINAP (101.1mg, 162.4 ⁇ mol, 0.2eq.) Cs 2 CO 3 (317.5mg, 974.6 ⁇ mol , 1.2eq.) were dissolved in toluene (20mL), and reacted at 90°C for 15h under nitrogen protection.
  • Step 2 Preparation of 1-(3-methylcarbamoylisoquinolin-1-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid carboxamide .
  • 1-(3-Methoxycarbonylisoquinolin-1-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid ethyl ester (88.0mg, 225.4 ⁇ mol, 1.0eq.) was added to methylamine In the ethanol solution (10 mL) at 80°C for 2h. The reaction solution was spin-dried to obtain the title compound as a pale yellow solid (15.0 mg, yield 18%).
  • Step 1 Preparation of 1-(6-hydroxymethyl-3,4-dihydro-2H-quinolin-1-yl)-isoquinoline-3-carboxylic acid carboxamide .
  • Ethyl 1-(3-methylcarbamoylisoquinolin-1-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (65.0mg, 166.9 ⁇ mol, 1.0eq.) Dissolved in THF (10 mL) , LiAlH 4 (25.3 mg, 667.6 ⁇ mol, 4.0 eq.) was added in batches at room temperature, and the reaction mixture continued to react at room temperature for 2 hours.
  • reaction solution was quenched by adding 0.1 mL of water dropwise under ice bath conditions, filtered, and the filter cake was washed with THF.
  • the filter cake was dried to obtain the title compound as Off-white solid (46.0 mg, 79% yield).
  • Example 60 1-[7-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-isoquinoline -3-carboxylic acid formamide
  • Step 1 Preparation of 7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine .
  • 1-Methylpyrazole-4-boronic acid pinacol ester (1.2g, 5.6mmol, 1.2eq.), 7-bromo-3,4-dihydro-2H-benzo[1,4]oxazine (1.0 g, 4.7mmol, 1.0eq.), Pd(dppf)Cl 2 (341.8mg, 467.2 ⁇ mol, 0.1eq.), K 2 CO 3 (1.9g, 14.0mmol, 3.0eq.) were dissolved in 1,4- In dioxane (25mL) and water (5mL), the reaction was carried out at 110°C for 14h under the protection of nitrogen.
  • Step 2 1-[7-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-isoquinoline- Preparation of methyl 3-carboxylate.
  • Methyl 1-chloroisoquinoline-3-carboxylate (Intermediate I) (205.9mg, 929.1 ⁇ mol, 1.0eq.), 7-(1-methyl-1H-pyrazol-4-yl)-3, 4-Dihydro-2H-benzo[1,4]oxazine (200.0mg, 929.1 ⁇ mol, 1.0eq.), Pd(OAc) 2 (20.9mg, 92.9 ⁇ mol, 0.2eq.), BINAP (115.7mg, 185.8 ⁇ mol, 0.2 eq.) Cs 2 CO 3 (363.3 mg, 111.0 ⁇ mol, 1.2 eq.) were dissolved in toluene (10 mL), and reacted at 95° C.
  • Step 3 1-[7-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-isoquinoline- Preparation of 3-carboxylic acid formamide.
  • Example 61 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6 , 7-dihydro -5H- [2] pyrazole-3-carboxylic acid methylamide
  • Step 1 Preparation of ethyl 6,7-dihydro-5H-[2]pyridine-3-carboxylate.
  • 1,6-Heptadiyne (3.7g, 40.2mmol, 1.0eq.) was dissolved in 1,2-dichloromethane (50mL), and then ethyl cyanoformate (6.0g, 60.2mmol, 1.5eq.) was added.
  • ethyl cyanoformate 6.0g, 60.2mmol, 1.5eq.
  • (1,5-cyclooctadiene) penentamethylcyclopentadienyl
  • ruthenium chloride (305.1mg, 803.1 ⁇ mol, 0.02eq.)
  • Step 2 Preparation of ethyl 2-oxy-6,7-dihydro-5H-[2]pyridine-3-carboxylate .
  • 6,7-Dihydro-5H-[2]pyridine-3-carboxylic acid ethyl ester (730.0mg, 3.8mmol, 1.0eq.) was dissolved in dichloromethane (15mL), and then m-CPBA (1.3g, 7.6mmol, 2.0eq.) and react at room temperature for 12h.
  • Step 3 Preparation of 1-chloro-6,7-dihydro-5H-[2]pyridine-3-carboxylic acid ethyl ester. 2-oxo-6,7-dihydro -5H- [2] pyridine-3-carboxylic acid ethyl ester (750.0mg, 3.6mmol, 1.0eq.) And a mixture of POCl 3 (8mL) was heated 12h at 50 °C.
  • Step 4 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6, Preparation of ethyl 7-dihydro-5H-[2] pyrazine-3-carboxylate.
  • Step 5 1-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6, Preparation of 7-dihydro-5H-[2] pyrazine-3-carboxylic acid carboxamide.
  • Example 62 was prepared in a similar manner to Example 61.
  • Step 1 Preparation of 7-chloro-furan[2,3-c]pyridine-5-carboxylic acid methyl ester.
  • 7-Chloro-furan[2,3-c]pyridine-5-carboxylic acid (500.0 mg, 2.5 mmol, 1.0 eq.) was dissolved in SOCl 2 (301.1 mg, 2.5 mmol, 1.0 eq.), and the reaction mixture was at room temperature Stir for 12h.
  • Step 2 7-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-furan[ 2,3-c] Preparation of pyridine-5-carboxylic acid methyl ester.
  • Step 3 7-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-furan[ 2,3-c]
  • pyridine-5-carboxylic acid carboxamide 7-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-furan[2,3 -c]
  • Methyl pyridine-5-carboxylate (290.0 mg, 641.0 ⁇ mol, 1.0 eq.) was added to the ethanol solution of methylamine (10 mL) and reacted at 80° C.
  • Step 1 Preparation of methyl 2-formylnicotinate .
  • Methyl 2-methylnicotinate (100.0g, 698.4mmol, 1.0eq.) was dissolved in 1,4-dioxane (50mL), and then selenium dioxide (77.5g, 698.4mmol, 1.0eq.) was added in batches .), the reaction mixture was reacted at 120°C for 15 hours. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated. The resulting crude product was added with 50 mL of water and EtOAc, extracted with EtOAc, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated.
  • Step 2 Preparation of 5-oxo-5H-[1,6]naphthyridine-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester .
  • Methyl 2-formylnicotinate (1.7g, 10.3mmol, 1.0eq.) and DBU (1.6g, 10.3mmol, 1.0eq.) were dissolved in dichloromethane (20mL) and added ( ⁇ ) at 0°C -BOC-A-phosphonoglycine trimethyl ester (3.1 g, 10.3 mmol, 1.0 eq.), and the reaction mixture was stirred at room temperature for 5 h.
  • Step 3 Preparation of 5-oxo-5,6-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester .
  • Dissolve 5-oxo-5H-[1,6]naphthyridine-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester (1.3g, 4.3mmol, 1.0eq.) in 10mL of hydrochloric acid In the oxane solution (4.0M), the reaction mixture was continuously stirred at room temperature for 12h. After the reaction, it was directly concentrated in vacuo to obtain the title compound as a yellow solid (0.8 g, 92%). MS (m/z) 205.06 [M+H] + .
  • Step 4 Preparation of methyl 5-chloro-[1,6]naphthyridine-7-carboxylate .
  • Step 5 5-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-[1 , preparation 6] naphthyridine-7-carboxylate.
  • Step 6 5-[7-Difluoromethyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-[1 , preparation 6] naphthyridine-7-carboxylic acid methylamide.
  • Methyl naphthyridine-7-carboxylate (80.0 mg, 172.6 ⁇ mol, 1.0 eq.) was added to the ethanol solution of methylamine (10 mL) and reacted at 80° C. for 2 hours.
  • Example 65 8-[6-Difluoromethyl-7-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-benzo[1,4]oxazine-4 -Yl]-[1,7]naphthyridine-6- carboxylic acid carboxamide
  • Step 1 Preparation of 2-bromo-4-fluoro-5-nitrobenzaldehyde .
  • 2-Bromo-4fluorobenzaldehyde 1.0g, 4.9mmol, 1.0eq.
  • concentrated sulfuric acid 6mL
  • concentrated nitric acid 6mL
  • 0°C room temperature Reaction for 2h.
  • Step 2 Preparation of 1-bromo-2-difluoromethyl-5-fluoro-4-nitrobenzene .
  • 2-Bromo-4-fluoro-5-nitrobenzaldehyde (1.2g, 4.8mmol, 1.0eq.) was dissolved in 100mL of dichloromethane, and DAST (3.1g, 19.3mmol, 4.0eq.) was added dropwise at 0°C The reaction mixture was reacted at room temperature for 16 hours. The reaction mixture was poured into 50 mL of saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated.
  • Step 3 Preparation of 1-bromo-5-(2-bromo-ethoxy)-2-difluoromethyl-4-nitrobenzene .
  • MS (m/z) 373.88 [
  • Step 4 Preparation of 4-bromo-2-(2-bromoethoxy)-5-difluoromethylaniline .
  • 1-bromo-5-(2-bromo-ethoxy)-2-difluoromethyl-4-nitrobenzene 1.g, 3.7mmol, 1.0eq.
  • HOAc 1-bromo-5-(2-bromo-ethoxy)-2-difluoromethyl-4-nitrobenzene
  • iron Powder 1.0g, 17.9mmol, 4.8eq.
  • Step 5 Preparation of 7-bromo-6-difluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine.
  • 4-Bromo-2-(2-bromoethoxy)-5-difluoromethylaniline (1.0g, 2.9mmol, 1.0eq.) was dissolved in DMF (20mL), and then K 2 CO 3 (801.3 mg, 5.8mmol, 2.0eq.), NaI (434.5mg, 2.9mmol, 1.0eq.) was reacted at 80°C for 12h.
  • Step 6 Preparation of 6-difluoromethyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine .
  • 1-methylpyrazole-4-boronic acid pinacol ester 425.5mg, 2.0mmol, 1.2eq.
  • 7-bromo-6-difluoromethyl-3,4-dihydro-2H-benzo[1 , 4] oxazine 450.0mg, 1.7mmol, 1.0eq.
  • Pd (dppf) Cl 2 (124.7mg, 170.4 ⁇ mol, 0.1eq.
  • K 2 CO 3 706.6mg, 5.1mmol, 3.0eq.
  • Step 7 8-[6-Difluoromethyl-7-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-benzo[1,4]oxazine-4- Preparation of ethyl]-[1,7]naphthyridine -6-carboxylate.
  • Step 8 8-[6-Difluoromethyl-7-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-benzo[1,4]oxazine-4- The preparation of the base]-[1,7]naphthyridine -6-carboxylic acid carboxamide.
  • Step 1 Preparation of 5-bromo-3-iodo-1-methyl-1H-indazole .
  • 5-Bromo-3-iodo-1H-indazole (2.0g, 6.2mmol, 1.0eq.) was dissolved in acetonitrile (30mL), and then CH 3 I (1.3g, 9.3mmol, 1.5eq.) and Cs were added 2 CO 3 (3.0 g, 9.3 mmol, 1.5 eq.), and the reaction mixture was stirred at room temperature for 1 h.
  • Step 2 Preparation of 5-bromo-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole .
  • 1-methylpyrazole-4-boronic acid pinacol ester (1.2g, 5.6mmol, 1.1eq.)
  • 5-bromo-3-iodo-1-methyl-1H-indazole (1.7g, 5.1mmol, 1.0eq.)
  • Pd(dppf) Cl 2 (368.8mg, 504.5 ⁇ mol, 0.1eq.)
  • K 2 CO 3 2.1g, 15.1mmol, 3.0eq.
  • Step 3 1-Methyl-3-(1-methyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]diox (In-2-yl)-1H-indazole preparation.
  • Pinacol diboronic acid ester (1.1g, 4.1mmol, 1.5eq.)
  • 5-bromo-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole 0.8g, 2.8mmol, 1.0eq.
  • Pd(dppf)Cl 2 (200.9mg, 274.8 ⁇ mol, 0.1eq.)
  • KOAc (809.0mg, 8.2mmol, 3.0eq.) respectively dissolved in 1,4-diox
  • the hexacyclic ring (20mL) was reacted at 110°C for 18h under nitrogen protection.
  • Step 4 8-[1-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl]-[1,7]naphthyridine-6-carboxy Preparation of Ethyl Acid.
  • Step 5 8-[1-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl]-[1,7]naphthyridine-6-carboxy Preparation of acid formamide. 8-[1-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl]-[1,7]naphthyridine-6-carboxylic acid ethyl ester (200.0mg, 484.9 ⁇ mol, 1.0eq.) was added to the ethanol solution of methylamine (10mL) and reacted at 80°C for 2h.
  • the affinity between the compound synthesized in this patent and the CBP recombinant protein is determined by the competitive HTRF method.
  • the His tag-labeled cyclic adenosine monophosphate response element binding protein (CREB binding protein, CBP) was expressed in the E. coli system and further purified.
  • Biotin-labeled CBP ligands (CBP biotinylated ligand) are all homemade.
  • the supernatant of the cell lysate was purified by Ni ion affinity column and Superdex75 molecular sieve column in sequence. The purity of the final CBP protein is 95%.
  • the fluorescence donor reagent MAb Anti 6HIS-Eu cryptate Gold (Cisbio#61HI2KLA), the acceptor reagent Streptavidin-XL665 (#610SAXLA) and the detection buffer (#62SDBRDD) required for HTRF were obtained from Cisbio Bioassays (Codolet, France).
  • CBP recombinant protein affinity-competitive HTRF assay method General procedure: add 0.05% Tween-20 and 1mM TCEP just before the assay, perform the assay in a buffer composed of 0.1mg/ml BSA, 50mM HEPES, pH 7.5, 5mM NaCl . Add 2.5 ⁇ L of the compound solution in the assay buffer with 4% DMSO and 5 ⁇ L of the CBP solution in the assay buffer to a white low-volume 384-well microtiter plate, incubate at room temperature for 20 minutes, and then add 2.5 ⁇ L to the assay buffer. ⁇ L of biotin-labeled ligand solution was incubated at room temperature for 40 minutes.
  • the final concentrations of CBP, biotin-labeled ligand and DMSO were 5nM, 50nM and 1%, respectively. Then, 5 ⁇ L of MAb Anti 6HIS-Eu cryptate Gold and 5 ⁇ L of Streptavidin-XL665 in the detection buffer from the manufacturer were added to the mixture, followed by incubation for 60 minutes. The final Streptavidin-XL665 concentration is 12.5nM, and MAb Anti 6HIS-Eu cryptate Gold is diluted according to the final concentration provided by the supplier.
  • Use Tecan( Switzerland) Multi-function microplate reader Spark reads the plate and detects two sets of homogeneous time-resolved fluorescence intensity.
  • the excitation wavelength is 320nm
  • the emission wavelength is 665nm and 620nm.
  • Prism 7 La Jolla, 15CA
  • Example IC 50 (nM) Example IC 50 (nM) Example IC 50 (nM) Example IC 50 (nM) 1 72 2 19 3 245 4 >1000 5 >1000 6 >1000 7 >1000 8 >1000 9 >1000 10 N/A 11 >1000 12 >1000 13 twenty one 14 15 15 7.5 16 13 17 12 18 19 19 6.9 20 18 twenty one 38 twenty two twenty two twenty three 18 twenty four 7.8 25 4.2 26 11 27 3.3 28 5.3 29 16 30 twenty two 31 49 32 36 33 44 34 32 35 16 36 12 37 16 38 14 39 13 40 62 41 57 42 50 43 6.7 44 64 45 8.5 46 5.4 47 31 48 13 49 12 50 54 51 twenty two 52 27 53 14 54 11 55 15 56 twenty four 57 36

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Abstract

本申请提供一种式(I)化合物、其立体异构体或其药学上可接受的盐，以及其用于制备由CBP和/或EP300介导的疾病药物中的用途。

Description

CBP/EP300抑制剂及其用途 技术领域
本申请属于化学医药领域，具体涉及一种CBP/EP300抑制剂及其用途。
背景技术
染色质是指间期细胞核内由DNA、组蛋白、非组蛋白及少量RNA组成的线性复合结构。组蛋白是染色质的主要蛋白质组分。与基因组直接相关的细胞活动都是在染色质水平进行的，如DNA复制、基因转录、同源重组、DNA修复，包括转录耦联的修复以及DNA和组蛋白的各种修饰。这些修饰包括甲基化、乙酰化、磷酸化、亚硝基化和泛素化等。
在所有类别的蛋白质中，组蛋白是最易于发生翻译后修饰的。组蛋白修饰是动态的，这是因为其可响应于特定的刺激而被添加或去除且这些修饰既引导染色质发生结构变化，又引导基因转录发生改变。组蛋白乙酰基转移酶(HAT)和组蛋白去乙酰基酶(HDAC)使特定的组蛋白赖氨酸残基发生乙酰化或去乙酰化。
CBP/EP300是赖氨酸乙酰基转移酶，可催化乙酰基与组蛋白和其他蛋白质底物的赖氨酸侧链连接。CBP和EP300具有广泛的序列同一性和功能相似性，通常被称为CBP/EP300。CBP/EP300催化的组蛋白和其他蛋白质的乙酰化对于基因激活至关重要。与此同时CBP/EP300蛋白还具有一类称为溴结构域的特定功能域。
长度为约110个氨基酸的溴结构域在大量染色质相关蛋白质中被发现且已在约70种常常与其它蛋白质基序相邻的人类蛋白质中被鉴定。溴结构域与经修饰的组蛋白之间的相互作用可能是引起染色质结构变化和基因表达调节的重要机制。细胞型特异性和适当的组织功能性需要对不同基因的转录程序进行严格的控制，这个转录程序受到其结构环境的密切影响。溴结构域位于对独特的疾病相关致病基因转录途径进行控制的关键染色质修饰复合物中。在特异性家族中选择性抑制溴结构域例如选择性抑制CBP/EP300的溴结构域，该转录稳态的改变与多种致病基因调控直接相关，最明显为癌症、免疫性炎症、感染性疾病，神经病症和心血管，代谢疾病。进而对下游多种致病蛋白的表达进行调控。
因此，具有CBP/EP300溴结构域抑制活性的新颖化合物为治疗癌症，炎症，自身免疫性疾病，感染性疾病，以及心血管系统疾病等提供可能。
发明内容
本申请一方面提供式(I)化合物、其异构体或其药学上可接受的盐：
Figure PCTCN2021089486-appb-000001
其中，R 1选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5、-(CH 2)nOH或含有0-3个N、O或S原子的5-6元饱和或非饱和环；其中，所述含有0-3个N、O或S原子的5-6元饱和或非饱和环可选地被1-3个R 5取代；
R 2选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5或-(CH 2)nOH；
R 3选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5、-(CH 2)nOH或含有0-3个N、O或S原子的5-6元饱和或非饱和环；其中，所述含有0-3个N、O或S原子的5-6元饱和或非饱和环可选地被1-3个R 5取代；
R 4选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5、-(CH 2)nOH或含有0-3个N、O或S原子的5-6元饱和或非饱和环；其中，所述含有0-3个N、O或S原子的5-6元饱和或非饱和环可选地被1-3个R 5取代；
每个R 5、R 6分别独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、可选被R 7取代的3-6元杂环基、卤代C 1-C 6烷基、卤素、＝O、-(CH 2)nC(O)NR 7R 8、-C(O)R 7、-C(O)OR 7、-OR 7、-OC(O)R 7、-OC(O)OR 7、-OC(O)NR 7R 8、-(CH 2)nNR 7R 8、-SR 7、-S(O)R 7、-(CH 2)nS(O) 2R 7、-(CH 2)nOH或-(CH 2)nCN；
每个R 7、R 8分别独立地选自氢或C 1-C 6烷基；
Z 1为-CH 2-或-O-；
环A为含有0-3个N、O或S原子的5-6元饱和或非饱和环；并且
每个m、n分别独立地选自0、1、2或3。
在一些实施方案中，式(I)为式(Ia)、式(Ib)、式(Ic)、式(Id)或式(Ie)：
Figure PCTCN2021089486-appb-000002
在另一些实施方案中，式(I)为式(If)、式(Ig)、或式(Ih)：
Figure PCTCN2021089486-appb-000003
在另一些实施方案中，R 1选自氢、卤素、甲氧基、
Figure PCTCN2021089486-appb-000004
Figure PCTCN2021089486-appb-000005
在另一些实施方案中，R 2选自-OH或-NHCH 3。
在另一些实施方案中，R 3选自氢、卤素或卤代C 1-C 6烷基。
在另一些实施方案中，R 3为-CHF 2。
在另一些实施方案中，R 4选自氢、-CH 2OH、-C(O)NHCH 3、
Figure PCTCN2021089486-appb-000006
Figure PCTCN2021089486-appb-000007
另一方面，本申请还提供具有如下结构的化合物、其异构体或其药学上可接受的盐：
Figure PCTCN2021089486-appb-000008
Figure PCTCN2021089486-appb-000009
Figure PCTCN2021089486-appb-000010
Figure PCTCN2021089486-appb-000011
Figure PCTCN2021089486-appb-000012
另一方面，本申请还提供前述化合物、其异构体或其药学上可接受的盐用于制备由CBP和/或EP300介导的疾病药物中的用途。
在一些实施方案中，所述CBP和/或EP300介导的疾病为癌症，炎性病症，自身免疫性疾病，病毒感染或心血管系统疾病。特别的，所述癌症为白血病，淋巴瘤，多发性骨髓瘤，肺癌，前列腺癌，头颈癌，乳腺癌，胰腺癌，结直肠癌或黑色素瘤。
另一方面，本申请还提供一种药物组合物，其包含治疗有效量的前述的化合物、其异构体或其药学上可接受的盐；以及药学上可接受的载体或赋形剂。所述的药物组合物还可包含其它一种或多种抗癌药物。所述抗癌药物可以为化疗药物。
本申请使用的术语“异构体”包括给定结构的对映异构形式、非对映异构形式和几何(或构象)异构形式。例如，本申请包括每个不对称中心的R和S构型、Z和E双键异构体、Z和E构象异构体、单一立体化学异构体及对映异构体、非对映异构体和几何(或构象)异构体混合物。除非另有说明，本申请包括本申请所述结构的所有互变异构形式。
本申请使用的术语“药学上可接受的盐”包括酸和碱加成盐。
本申请使用的术语“非饱和”是指基团具有一个或多个不饱和单元。
本申请使用的术语“卤代”和“卤素”是指选自氟(-F)、氯(-C1)、溴(-Br)和碘(-I)的原子。
本申请使用的术语“氧代”是指“＝O”。
本申请使用的术语“C 1-C 6烷基”是具有1-6个碳原子的饱和的直链或支链的烃基。
本申请使用的术语“C 1-C 6卤代烷基”是指被一个或多个(例如1、2、3或4个)卤素取代的本申请定义的“C 1-C 6烷基”。
本申请使用的术语“C 3-C 6环烷基”指包含3-6个碳原子的饱和或非饱和的碳环。
本申请使用的术语“杂环基”指一个或多个(例如1、2、3或4个)碳原子已被杂原子(例如O、N或S)代替的饱和或非饱和的碳环。
本申请使用的术语“治疗有效量”是指本申请化合物的以下量，其(i)治疗具体的疾病、病症或障碍；(ii)减轻、缓解或消除具体的疾病、病症或障碍的一种或多种症状；或(iii)预防或延迟本申请所述具体的疾病、病症或障碍的一种或多种症状的发作。
本申请使用的术语“药学上可接受的载体或赋形剂”是指不破坏用其配制的化合物的药理活性的无毒载体、辅料或媒介物。
具体实施方式
中间体Ⅰ的合成： 1-氯异喹啉-3-羧酸甲酯
Figure PCTCN2021089486-appb-000013
步骤一： 3-溴-3H-异苯并呋喃-1-酮的制备。将苯酞(20.0g，149.1mmol，1.0eq.)溶于 1，2-二氯乙烷(100mL)中，在搅拌下分别加入AIBN(2.5g，14.9mmol，0.1eq.)和NBS(31.9g，178.9mmol，1.2eq.)，氮气保护下在80℃反应12h。冷却至室温后，将反应混合物用50mL水稀释，分液后有机相再用水(50mL)洗一次，最后饱和食盐水洗，无水硫酸镁干燥，过滤并浓缩即得到标题化合物为淡黄色固体(31.0g，收率98％)，该化合物无需进一步纯化可以直接使用。MS(m/z)＝212.95[M+H] +。
步骤二： 2-甲酰基苯甲酸的制备。将3-溴-3H-异苯并呋喃-1-酮(31.0g，145.5mmol，1.0eq.)溶于100mL水中于100℃反应2h。冷却至室温后，用EtOAc萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩即得到标题化合物为灰白色固体(21.0g，收率96％)，该化合物无需进一步纯化可以直接使用。MS(m/z)＝151.04[M+H] +。
步骤三： 2-甲酰苯甲酸甲酯的制备。将2-甲酰基苯甲酸(21.0g，140.0mmol，1.0eq.)溶于丙酮(150mL)中，在搅拌下分别加入碳酸钾(19.3g，140.0mmol，1.0eq.)和碘甲烷(39.7g，280.0mmol，2.0eq.)，反应混合物继续在70℃反应15h。冷却至室温，将混合物过滤后真空直接浓缩即得到标题化合物为灰白色固体(22.0g，收率96％)，该化合物无需进一步纯化可以直接使用。MS(m/z)＝165.05[M+H] +。
步骤四： 1-氧代-1H-异喹啉-2,3-二羧酸2-叔丁基酯3-甲基酯的制备。将2-甲酰苯甲酸甲酯(22.0g，134.0mmol，1.0eq.)和DBU(20.4g，134.0mmol，1.0eq.)溶于二氯甲烷(120mL)中，在0℃下加入(±)-BOC-A-膦酰基甘氨酸三甲酯(39.8g，134.0mmol，1.0eq.)，反应混合物继续在室温搅拌5h。加入100mL水稀释，分液后有机相分别用饱和食盐水洗，无水硫酸镁干燥，过滤并浓缩即得到标题化合物为灰白色固体(30.0g，收率74％)，该化合物无需进一步纯化可以直接使用。MS(m/z)＝304.12[M+H] +。
步骤五： 1-氧代-1,2-二氢异喹啉-3-羧酸甲酯的制备。将1-氧代-1H-异喹啉-2,3-二羧酸2-叔丁基酯3-甲基酯(30.0g，100.0mmol，1.0eq.)溶于100mL盐酸二氧六环溶液(4.0M)中，反应混合物继续在室温搅拌12h。反应结束后真空直接浓缩得到标题化合物为灰白色固体(20.0g，定量收率)。MS(m/z)＝204.07[M+H] +。
步骤六： 1-氯异喹啉-3-羧酸甲酯的制备。1-氧代-1,2-二氢异喹啉-3-羧酸甲酯(14.4g，70.9mmol，1.0eq.)和POCl 3(50mL)的混合物在110℃加热2h。将反应液冷却至室温，随后大量固体析出，过滤，滤出的固体用100mL二氯甲烷完全溶解，搅拌下依次加入冰水和NaHCO 3固体，直至无剧烈气泡冒出同时保证混合物的PH＝8左右，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为灰白色固体(13.0g，83％)，其不经进一步纯化即用于下一步骤中。MS(m/z)＝222.03[M+H] +。
中间体Ⅱ、Ⅲ根据中间体Ⅰ类似的方法制得。
Figure PCTCN2021089486-appb-000014
Figure PCTCN2021089486-appb-000015
中间体Ⅳ的合成： 8-氯-1,7-萘啶-6-羧酸乙酯
Figure PCTCN2021089486-appb-000016
步骤一： N-(叔丁基)-3-甲基吡啶酰胺的制备。向70℃的2-氰基-3-甲基吡啶(15.0g，127.0mmol，1.0eq.)和叔丁醇(40mL)的混合物中，在搅拌同时缓慢滴加浓硫酸(15.0mL，281.4mmol，2.2eq.)。反应混合物继续在75℃搅拌反应30min，随后加入200mL水稀释后，用氨水将反应混合物的PH调节至8，并真空浓缩。浓缩后的混合物用EtOAc萃取，合并有机相用饱和食盐水洗，无水硫酸镁干燥，过滤并浓缩。将粗产品通过柱层析纯化(PE/EtOAc＝10:1)得到标题化合物，最初为淡黄色油状物，其静置一段时间后为白色固体(20.0g，收率82％)。MS(m/z)＝193.13[M+H] +。
步骤二： 3-(2-(叔丁基氨基)吡啶-3-基)-2-氧丙烷酸乙酯的制备。在-78℃和N 2保护下，搅拌下将N-(叔丁基)-3-甲基吡啶酰胺(10.0g，52.0mmol，1.0eq.)溶于干燥的THF(200mL)中，搅拌下分别滴加n-BuLi(6.7g，104.0mmol，2.0eq.)和四甲基乙二胺(6.0g，52.0mmol，1.0eq.),反应混合物继续在-78℃搅拌反应30min。在相同条件下滴加草酸二乙酯(15.2g，104.0mmol，2.0eq.)的THF(200mL)溶液，并将所得的混合物继续搅拌反应3h，随后用饱和的氯化铵水溶液淬灭反应，EtOAc萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩。将粗产品通过柱层析纯化(PE/EtOAc＝3:1)得到标题化合物为无色油状物(9.6g，收率63％)。MS(m/z)＝293.15[M+H] +。
步骤三： 8-氧代-7,8-二氢-1,7-萘啶-6-羧酸乙酯的制备。在搅拌同时，向醋酸(45mL)中分别加入3-(2-(叔丁基氨基)吡啶-3-基)-2-氧丙烷酸乙酯(4.5g，15.4mmol，1.0eq.)和醋酸铵(2.4g，30.8mmol，2.0eq.)，随后在110℃加热12h。真空直接浓缩得粗品，通过柱层析纯化(CH 2Cl 2/MeOH＝10:1)得到标题化合物为灰白色固体(3.0g，收率88％)。MS(m/z)＝219.08[M+H] +。
步骤四： 8-氯-1,7-萘啶-6-羧酸乙酯的制备。8-氧代-7,8-二氢-1,7-萘啶-6-羧酸乙酯(1.0g， 4.6mmol，1.0eq.)和POCl 3(8mL)的混合物在110℃加热2h。将反应混合物置于冰浴中，搅拌下依次加入冰水和NaHCO 3固体，直至无剧烈气泡冒出同时保证混合物的PH＝8左右，CH 2Cl 2萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为灰白色固体(1.1g，定量收率)，其不经进一步纯化即用于下一步骤中。MS(m/z)＝237.04[M+H] +。
中间体V、Ⅵ、Ⅶ、Ⅷ根据中间体Ⅳ类似的方法制得。
Figure PCTCN2021089486-appb-000017
中间体Ⅸ的合成： 7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉
Figure PCTCN2021089486-appb-000018
步骤一： 喹啉-7-甲醛的制备。将7-甲基喹啉(100.0g，698.4mmol，1.0eq.)升温至160℃，随后在30min内分批加入二氧化硒(77.5g，698.4mmol，1.0eq.)，反应混合物继续在160℃反应8h。冷却至室温后，加入1000mL二氯甲烷，有大量的固体析出，滤除固体后滤液浓缩，所得粗品用500mL正庚烷打浆30min，过滤，得滤饼烘干，即得到标题化合物为灰白色固体(63.3g,收率58％)。MS(m/z)＝158.06[M+H] +。
步骤二： 7-二氟甲基喹啉的制备。将喹啉-7-甲醛(63.3g，402.9mmol，1.0eq.)溶于600mL二氯甲烷中，0℃下滴加DAST(324.7g，2.0mol，5.0eq.)，反应混合物在20℃反应16 h。将反应混合物倒入到1000mL饱和碳酸氢钠溶液中，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩。即得到标题化合物为黄色固体(23.8g，收率33％)。MS(m/z)＝180.06[M+H] +。
步骤三： 7-二氟甲基-1,2,3,4-四氢喹啉的制备。将7-二氟甲基喹啉(23.8g，132.8mmol，1.0eq.)和NaBH 3CN(41.7g，664.2mmol，5.0eq.)溶于甲醇中(250mL)，于0℃滴加三氟化硼乙醚(34mL)，反应混合物在65℃反应16h。将反应混合物倒入到1000mL饱和碳酸氢钠溶液中，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩。将粗产品通过柱层析纯化(PE/EtOAc＝10:1)得到标题化合物为棕色油状物(12.0g，收率49％)。MS(m/z)＝186.11[M+H] +。
步骤四： 6-溴-7-二氟甲基-1,2,3,4-四氢喹啉的制备。将7-二氟甲基-1,2,3,4-四氢喹啉(12.0g，65.5mmol，1.0eq.)溶于二氯甲烷中(120mL)，加入NBS(12.8g，72.0mmol，1.1eq.)并在室温反应16h。反应混合物用100mL水稀释，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩。将粗产品通过柱层析纯化(PE/EtOAc＝10:1)得到标题化合物为灰白色固体(15.0g，收率87％)。MS(m/z)＝264.02[M+H] +。
步骤五： 7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉的制备。1-甲基吡唑-4-硼酸频哪醇酯(4.8g，22.9mmol，1.2eq.)，6-溴-7-二氟甲基-1,2,3,4-四氢喹啉(5.0g，19.1mmol，1.0eq.)，Pd(dppf)Cl 2(1.4g，1.9mmol，0.1eq.)，K 2CO 3(7.9g，57.2mmol，3.0eq.)分别溶于1，4-二氧六环(50mL)和水(10mL)中，氮气保护下在110℃反应18h。将反应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝10:1-3:1梯度洗脱)得到标题化合物为灰白色固体(0.3g，收率99％)。MS(m/z)＝266.15[M+H] +。
实施例1： 1-[6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酰胺
Figure PCTCN2021089486-appb-000019
步骤一： 6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉的制备。1-甲基吡唑-4-硼酸频哪醇酯(1.2g，5.7mmol，1.2eq.)，6-溴-1,2,3,4-四氢喹啉(1.0g，4.7mmol，1.0eq.)，Pd(dppf)Cl 2(345.0mg，471.5μmol，0.1eq.)，K 2CO 3(2.0g，14.1mmol，3.0eq.)分别溶于1,4-二氧六环(50mL)和水(10mL)中，氮气保护下在80℃反应14h。将反应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝10:1-3:1梯度洗脱)得到标题化合物为黄色固体(0.5g，收率50％)。MS(m/z)＝214.13[M+H] +。
步骤二： 1-[6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酯的制备。 1-氯异喹啉-3-羧酸甲酯(中间体Ⅰ)(200.0mg，902.4μmol，1.0eq.)，6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(288.7mg，1.4mmol，1.5eq.)，Pd(OAc) 2(20.3mg，90.2μmol，0.1eq.)，BINAP(112.4mg，180.5μmol，0.2eq.)，Cs 2CO 3(352.8mg，1.08mmol，1.2eq.)分别溶于甲苯(20mL)中，氮气保护下在90℃反应3h。将反应液直接旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色固体(200.0mg，收率56％)。MS(m/z)＝399.18[M+H] +。
步骤三： 1-[6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酰胺的制备。1-[6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酯(100.0mg，251.0μmol，1.0eq.)加入甲胺的乙醇溶液中(8mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(50.0mg，收率50％)。 1H NMR(400MHz,DMSO)δ8.60(d,1H),8.31(s,1H),8.17(d,1H),7.95(s,1H),7.85–7.73(m,2H),7.71(s,1H),7.61–7.48(m,1H),7.37(d,1H),6.98(dd,1H),6.06(d,1H),3.96(t,2H),3.82(s,3H),2.96(t,2H),2.88(d,3H),2.16(dd,2H).MS(m/z)＝398.20[M+H] +。
实施例2： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酰 胺
Figure PCTCN2021089486-appb-000020
步骤一： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲 酯的制备。将1-氯异喹啉-3-羧酸甲酯(中间体Ⅰ)(300.0mg，1.4mmol，1.0eq.)，7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体Ⅸ)(427.6mg，1.6mmol，1.2eq.)，Pd(OAc) 2(30.4mg，135.3μmol，0.1eq.)，BINAP(168.6mg，270.7μmol，0.2eq.)Cs 2CO 3(529.2mg，1.6μmol，1.2eq.)分别溶于甲苯(20mL)中，氮气保护下在90℃反应3h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色固体(0.1g，收率20％)。MS(m/z)＝449.18[M+H] +。
步骤二： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲 酰胺的制备。1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酯(102.6mg，228.9μmol，1.0eq.)溶于甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(30.0mg，收率29％)。 1H NMR(400MHz,DMSO)δ8.59(d,1H),8.41(s,1H),8.23(d,1H),8.04–7.74 (m,3H),7.70–7.59(t,1H),7.54(s,1H),7.28(s,1H),6.66(t,1H),6.27(s,1H),3.97(t,2H),3.87(s,3H),3.01(t,2H),2.88(d,3H),2.26–2.11(m,2H)。MS(m/z)＝448.19[M+H] +。
实施例3-15参考实施例2类似方法制得。
Figure PCTCN2021089486-appb-000021
Figure PCTCN2021089486-appb-000022
Figure PCTCN2021089486-appb-000023
Figure PCTCN2021089486-appb-000024
Figure PCTCN2021089486-appb-000025
实施例16： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-7-(3,6-二氢-2H-吡 喃-4-基)-异喹啉-3-羧酸甲酰胺
Figure PCTCN2021089486-appb-000026
步骤一： 7-(3,6-二氢-2H-吡喃-4-基)-1-氧代-1H-异喹啉-2,3-二羧酸2-叔丁基酯3-甲基酯的制备。将3,6-二氢-2H-吡喃-4-硼酸频哪醇酯(164.9mg，784.9μmol，1.0eq.)，7-溴-1-氧-1H-异喹啉-2,3-二羧酸2-叔丁基酯3-甲基酯(300.0mg，784.9μmol，1.0eq.)，Pd(dppf)Cl 2(57.4mg，78.5μmol，0.1eq.)，K 2CO 3(108.5mg，784.9μmol，3.0eq.)分别溶于1，4-二氧六环(40mL)和水(8mL)中，氮气保护下在110℃反应18h。将反应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝10:1-3:1梯度洗脱)得到标题化合物为灰白色固体(0.3g，收率99％)。MS(m/z)＝386.16[M+H] +。
步骤二： 7-(3,6-二氢-2H-吡喃-4-基)-1-氧代-1,2-二氢-异喹啉-3-羧酸甲酯的制备。将7-(3,6-二氢-2H-吡喃-4-基)-1-氧代-1H-异喹啉-2,3-二羧酸2-叔丁基酯3-甲基酯(0.3g，778.4μmol，1.0eq.)溶于20mL盐酸二氧六环溶液(4.0M)中，反应混合物继续在室温搅拌12h。反应结束后真空直接浓缩得到标题化合物为灰白色固体(0.2g，定量收率)。MS(m/z)＝286.11[M+H] +。
步骤三： 1-氯-7-(3,6-二氢-2H-吡喃-4-基)-异喹啉-3-羧酸甲酯的制备。7-(3,6-二氢-2H-吡喃-4-基)-1-氧代-1,2-二氢-异喹啉-3-羧酸甲酯(0.2g，778.1μmol，1.0eq.)和POCl 3(10mL)的混合物在110℃加热2h。将反应混合物置于冰浴中，搅拌下依次加入冰水和NaHCO 3固体，直至无剧烈气泡冒出同时保证混合物的PH＝8左右，CH 2Cl 2萃取，饱和食盐水洗涤有机相， 无水硫酸镁干燥，过滤并浓缩得到标题化合物为灰白色固体(0.2g，定量收率)，其不经进一步纯化即用于下一步骤中。MS(m/z)＝304.07[M+H] +。
步骤四： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-7-(3,6-二氢-2H- 吡喃-4-基)-异喹啉-3-羧酸甲酯的制备。将1-氯-7-(3,6-二氢-2H-吡喃-4-基)-异喹啉-3-羧酸甲酯(230.0mg，757.2μmol，1.2eq.)，7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体Ⅸ)(299.0mg，1.14mmol，1.5eq.)，Pd(OAc) 2(17.0mg，75.7μmol，0.1eq.)，BINAP(94.3mg，151.5μmol，0.2eq.)Cs 2CO 3(296.1mg，908.7μmol，1.2eq.)分别溶于甲苯(20mL)中，氮气保护下在90℃反应3h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色固体(0.23g，收率63％)。MS(m/z)＝531.22[M+H] +。
步骤五： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-7-(3,6-二氢-2H- 吡喃-4-基)-异喹啉-3-羧酸甲酰胺的制备。1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-7-(3,6-二氢-2H-吡喃-4-基)-异喹啉-3-羧酸甲酯(0.23g，433.5μmol，1.0eq.)溶于甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(0.2g，收率87％)。 1H NMR(400MHz,DMSO)δ8.61–8.51(m,1H),8.33(s,1H),8.17(d,1H),8.00(dd,1H),7.78(s,1H),7.66(s,1H),7.53(s,1H),7.31(s,1H),6.68(t,1H),6.41(s,1H),6.35(s,1H),4.20(d,2H),4.01(t,2H),3.88(s,3H),3.73(t,2H),3.00(t,2H),2.88(d,J＝4.9Hz,3H),2.17(m,4H)。MS(m/z)＝530.24[M+H] +。
实施例17： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-7-(四氢-4-基)-异喹 啉-3-羧酸甲酰胺
Figure PCTCN2021089486-appb-000027
步骤一： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-7-(四氢-4-基)- 异喹啉-3-羧酸甲酰胺的制备。1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-7-(3,6-二氢-2H-吡喃-4-基)-异喹啉-3-羧酸甲酰胺(197.0mg，548.8μmol，1.0eq.)溶于THF(20mL)中，接着加入10％的Pd/C(4.5mg，37.2μmol，0.1eq.)，H 2抽换气3次，室温下反应12h。将反应液抽滤，滤液旋干得到标题化合物为灰白色固体(150.0mg，76％)。 1H NMR(400MHz,DMSO)δ8.57(d,1H),8.34(s,1H),8.15(d,1H),7.77(d,2H),7.55(d,2H),7.31(s,1H),6.66(t,1H),6.34(s,1H),4.03(dd,2H),3.92–3.74(m,5H),3.39(d,2H),3.01(t,2H),2.92–2.77(m,4H),2.24–2.06(m,2H),1.68–1.41(m,4H)。MS(m/z)＝532.25[M+H] +。
实施例18-23参考实施例17类似方法制得。
Figure PCTCN2021089486-appb-000028
Figure PCTCN2021089486-appb-000029
实施例24： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-7-(2-氧代-噁唑烷 -3-基)-异喹啉-3-羧酸甲酰胺
Figure PCTCN2021089486-appb-000030
步骤一： 1-氧代-7-(2-氧代-噁唑烷-3-基)-1H-异喹啉-2,3-二羧酸2-叔丁基酯3-甲基酯的制备。将2-唑烷酮(150.4mg，1.7mmol，1.1eq.)，7-溴-1-氧-1H-异喹啉-2,3-二羧酸2-叔丁基酯3-甲基酯(0.6g，1.6mmol，1.0eq.)，Pd  2(dba) 3(143.8mg，157.0μmol，0.1eq.)，Xantphos(150.0mg，314.0μmol，0.2eq.)，Cs 2CO 3(1.0g，3.1mmol，2.0eq.)分别溶于1，4-二氧六环(15mL)中，氮气保护下在95℃反应14h。将反应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色固体(550.0mg，收率90％)。MS(m/z)＝389.13[M+H] +。
步骤二： 1-氧代-7-(2-氧代-噁唑烷-3-基)-1,2-二氢-异喹啉-3-羧酸甲酯的制备。将1-氧代-7-(2-氧代-噁唑烷-3-基)-1H-异喹啉-2,3-二羧酸2-叔丁基酯3-甲基酯(550.0mg，1.4mmol，1.0eq.)溶于20mL盐酸二氧六环溶液(4.0M)中，反应混合物继续在室温搅拌12h。反应结束后真空直接浓缩得到标题化合物为白色固体(350.0mg，86％)。MS(m/z)＝289.08[M+H] +。
步骤三： 1-氯-7-(2-氧代-噁唑烷-3-基)-异喹啉-3-羧酸甲酯的制备。将1-氧代-7-(2-氧代-噁唑烷-3-基)-1,2-二氢-异喹啉-3-羧酸甲酯(350.0mg，1.2mmol，1.0eq.)和POCl 3(10mL)的混合物在110℃加热2h。将反应混合物置于冰浴中，搅拌下依次加入冰水和NaHCO 3固体，直至无剧烈气泡冒出同时保证混合物的PH＝8左右，CH 2Cl 2萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为白色固体(300.0mg，80％)，其不经进一步纯化即用于下一步骤中。MS(m/z)＝307.05[M+H] +。
步骤四： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-7-(2-氧代-噁唑 烷-3-基)-异喹啉-3-羧酸甲酯的制备。1-氯-7-(2-氧代-噁唑烷-3-基)-异喹啉-3-羧酸甲酯(200.0mg，652.1μmol，1.0eq.)，6-溴-7-二氟甲基-1,2,3,4-四氢喹啉(中间体Ⅸ)(188.9mg，717.3μmol，1.1eq.)，Pd(OAc) 2(14.6mg，65.2μmol，0.1eq.)，BINAP(81.2mg，130.4μmol，0.2eq.)Cs 2CO 3(255.0mg，782.5μmol，1.2eq.)分别溶于甲苯(20mL)中，氮气保护下在90℃反应15h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色固体(100.0mg，收率29％)。MS(m/z)＝534.19[M+H] +。
步骤五： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-7-(2-氧代-噁唑 烷-3-基)-异喹啉-3-羧酸甲酰胺的制备。1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-7-(2-氧代-噁唑烷-3-基)-异喹啉-3-羧酸甲酯(100.0mg，187.4μmol，1.0eq.)溶于甲胺的乙醇溶液中(8mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(50.0mg，收率50％)。 1H NMR(400MHz,DMSO)δ8.49(d,1H),8.40(s,1H),8.24(dt,2H),7.88(s,1H),7.78(s,1H),7.54(s,1H),7.27(s,1H),6.69(t,1H),6.35(s,1H),4.43(t,2H),4.03–3.79(m,7H),3.00(t,2H),2.87(d,3H),2.23–2.06(m,2H)。MS(m/z)＝533.21[M+H] +。
实施例25-28参考实施例24类似方法制得。
Figure PCTCN2021089486-appb-000031
Figure PCTCN2021089486-appb-000032
实施例29： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-6-(四氢呋喃-2-基)- 异喹啉-3-羧酸甲酰胺
Figure PCTCN2021089486-appb-000033
步骤一： 6-(4,5-二氢呋喃-2-基)-1-氧代-1H-异喹啉-2,3-二羧酸2-叔丁基酯3-甲基酯的制备。将2,3-二氢呋喃(1.0g，2.6mmol，1.0eq.)6-溴-1-氧-1H-异喹啉-2,3-二羧酸2-叔丁基酯3-甲基酯(366.8mg，5.2mmol，2.0eq.)，(o-MePh) 3P(159.1mg，523.3μmol，0.2eq.)和Pd(OAc) 2(58.6mg，261.6μmol，0.1eq.)溶于DMF中(20mL)，氮气保护下在80℃反应1h。将反 应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝10:1-3:1梯度洗脱)得到标题化合物为灰白色固体(0.8g，收率82％)。MS(m/z)＝372.14[M+H] +。
步骤二： 1-氧代-6-(四氢呋喃-2-基)-1H-异喹啉-2,3-二羧酸2-叔丁基酯3-甲酯的制备。将6-(4,5-二氢呋喃-2-基)-1-氧代-1H-异喹啉-2,3-二羧酸2-叔丁基酯3-甲基酯(0.8g，2.2mmol，1.0eq.)和Pd/C(261.6mg，2.2mmol，1.0eq.)溶于甲醇中(50mL)并于室温反应16h。将反应液小心抽滤，滤液旋干，得到标题化合物为灰白色固体(0.8g，定量收率)。MS(m/z)＝374.16[M+H] +。
步骤三： 1-氧代-6-(四氢呋喃-2-基)-1,2-二氢异喹啉-3-羧酸甲酯的制备。将1-氧代-6-(四氢呋喃-2-基)-1H-异喹啉-2,3-二羧酸2-叔丁基酯3-甲酯(0.8g，2.1mmol，1.0eq.)溶于20mL盐酸二氧六环溶液(4.0M)中，反应混合物继续在室温下搅拌12h。反应结束后真空直接浓缩得到标题化合物为灰白色固体(0.5g，85％)。MS(m/z)＝274.11[M+H] +。
步骤四： 1-氯-6-(四氢呋喃-2-基)-异喹啉-3-羧酸甲酯的制备。1-氧代-6-(四氢呋喃-2-基)-1,2-二氢异喹啉-3-羧酸甲酯(0.5g，1.8mmol，1.0eq.)和POCl 3(10mL)的混合物在110℃加热2h。将反应混合物置于冰浴中，搅拌下依次加入冰水和NaHCO 3固体，直至无剧烈气泡冒出同时保证混合物的PH＝8左右，CH 2Cl 2萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为灰白色固体(0.4g，75％)，其不经进一步纯化即用于下一步骤中。MS(m/z)＝292.07[M+H] +。
步骤五： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-6-(四氢呋喃-2- 基)-异喹啉-3-羧酸甲酯的制备。1-氯-6-(四氢呋喃-2-基)-异喹啉-3-羧酸甲酯(0.4g，1.4mmol，1.0eq.)，7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体Ⅸ)(541.5mg，2.1mmol，1.5eq.)，Pd(OAc) 2(30.8mg，137.1μmol，0.1eq.)，BINAP(170.7mg，274.2μmol，0.2eq.)Cs 2CO 3(536.1mg，1.6mmol，1.2eq.)分别溶于甲苯(20mL)中，氮气保护下在90℃反应3h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色固体(0.23g，收率36％)。MS(m/z)＝519.22[M+H] +。
步骤六： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-6-(四氢呋喃-2- 基)-异喹啉-3-羧酸甲酰胺的制备。1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-6-(四氢呋喃-2-基)-异喹啉-3-羧酸甲酯(0.23g，433.5μmol，1.0eq.)溶于甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(0.1g，收率44％)。 1H NMR(400MHz,DMSO)δ8.58(q,1H),8.37(s,1H),8.12(s,1H),7.84(d,1H),7.78(s,1H),7.62–7.53(m,1H),7.54(s,1H),7.27(s,1H),6.67(t,1H),6.28(s,1H),5.02(t,1H),4.07(dd,1H),4.00–3.80(m,6H),3.00(t,2H),2.87(d,3H),2.40(td,1H),2.22–2.09(m,2H),2.03–1.91(m,2H),1.72(ddd,1H)。MS(m/z)＝518.24[M+H] +。
实施例30： 1-(7-二氟甲基-6-嘧啶-5-基-3,4-二氢-2H-喹啉-1-基)-异喹啉-3-羧酸甲酰胺
Figure PCTCN2021089486-appb-000034
步骤一： 7-二氟甲基-6-嘧啶-5-基-1,2,3,4-四氢喹啉的制备。5-嘧啶硼酸频哪醇酯(283.0mg，1.4mmol，1.2eq.)，6-溴-7-二氟甲基-1,2,3,4-四氢喹啉(中间体Ⅸ的第三步)(300.0mg，1.1mmol，1.0eq.)，Pd(dppf)Cl 2(83.7mg，114.5μmol，0.1eq.)，K 2CO 3(474.6mg，3.43mmol，3.0eq.)分别溶于1，4-二氧六环(50mL)和水(10mL)中，氮气保护下在110℃反应18h。将反应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝5:1-1:1梯度洗脱)得到标题化合物为灰白色固体(290.0mg，收率97％)。MS(m/z)＝262.12[M+H] +。
步骤二： 1-(7-二氟甲基-6-嘧啶-5-基-3,4-二氢-2H-喹啉-1-基)-异喹啉-3-羧酸甲酯的制备。1-氯异喹啉-3-羧酸甲酯(中间体Ⅰ)(205.0mg，925.0μmol，1.0eq.)，7-二氟甲基-6-嘧啶-5-基-1,2,3,4-四氢喹啉(290.0mg，1.1mmol，1.2eq.)，Pd(OAc) 2(20.8mg，92.5μmol，0.1eq.)，BINAP(115.2mg，185.0μmol，0.2eq.)Cs 2CO 3(361.6mg，1.1mmol，1.2eq.)分别溶于甲苯(20mL)中，氮气保护下在90℃反应3h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色固体(0.3g，收率73％)。MS(m/z)＝447.16[M+H] +。
步骤三： 1-(7-二氟甲基-6-嘧啶-5-基-3,4-二氢-2H-喹啉-1-基)-异喹啉-3-羧酸甲酰胺的制备。1-(7-二氟甲基-6-嘧啶-5-基-3,4-二氢-2H-喹啉-1-基)-异喹啉-3-羧酸甲酯(0.3g，672.0μmol，1.0eq.)溶于甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(0.1g，收率33％)。 1H NMR(400MHz,DMSO)δ9.19(s,1H),8.77(s,2H),8.62(d,1H),8.49(s,1H),8.28(d,1H),7.95(d,1H),7.87(t,1H),7.77–7.66(m,1H),7.29(s,1H),6.64(t,1H),6.30(s,1H),3.96(s,2H),3.05(t,2H),2.88(d,3H),2.27–2.10(m,2H)。MS(m/z)＝446.18[M+H] +。
实施例31-39参考实施例30类似方法制得。
Figure PCTCN2021089486-appb-000035
Figure PCTCN2021089486-appb-000036
Figure PCTCN2021089486-appb-000037
Figure PCTCN2021089486-appb-000038
实施例40: 1-[4-甲基氨基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲 酰胺
Figure PCTCN2021089486-appb-000039
步骤一： 6-(1-甲基-1H-吡唑-4-基)-2,3-二氢-1H-喹啉-4-酮的制备。将1-甲基吡唑-4-硼酸频哪醇酯(552.2mg，2.6mmol，1.2eq.)，6-溴-2,3-二氢喹啉-4(1H)-酮(0.5g，2.2mmol，1.0eq.)，Pd(dppf)Cl 2(161.8mg，221.2μmol，0.1eq.)，K 2CO 3(917.0mg，6.6mmol，3.0eq.)分别溶于1，4-二氧六环(50mL)和水(10mL)中，氮气保护下在110℃反应18h。将反应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝5:1-1:1梯度洗脱)得到标题化合物为灰白色固体(0.3g，收率60％)。MS(m/z)＝228.11[M+H] +。
步骤二： 1-[6-(1-甲基-1H-吡唑-4-基)-4-氧代-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酯的制备。1-氯异喹啉-3-羧酸甲酯(中间体Ⅰ)(292.6mg，1.3mmol，1.0eq.)，6-(1-甲基-1H-吡唑-4-基)-2,3-二氢-1H-喹啉-4-酮(300.0mg，1.3mmol，1.2eq.)，Pd(OAc) 2(29.6mg，132.0μmol，0.1eq.)，BINAP(164.4mg，264.0μmol，0.2eq.)Cs 2CO 3(516.1mg，1.6mmol，1.2eq.)分别溶于甲苯(20mL)中，氮气保护下在90℃反应15h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色固体(0.3g，收率55％)。MS(m/z)＝413.16[M+H] +。
步骤三： 1-[4-甲基亚氨基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸 甲酰胺的制备。1-[6-(1-甲基-1H-吡唑-4-基)-4-氧代-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酯(0.3g，727.4μmol，1.0eq.)溶于甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(0.1g，收率32％)。MS(m/z)＝425.21[M+H] +。
步骤四： 1-[4-甲基氨基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲 酰胺的制备。将1-[4-甲基亚氨基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酰胺(0.1g，235.6μmol，1.0eq.)溶于甲醇(20mL)中，室温下分批加入NaBH 4(8.9mg，235.6μmol，1.0eq.)继续反应14h。向反应液中加入水和EtOAc各20mL，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为无色油状物(50.0mg，收率50％)。 1H NMR(400MHz,DMSO)δ8.61(d,1H),8.34(s,1H),8.18(d,1H),7.96(s,1H),7.86–7.73(m,2H),7.71(s,1H),7.61–7.50(m,1H),7.01(dd,1H),6.03(d,1H),4.03(dd,1H),3.92(s,1H),3.83(s,4H),2.88(d,3H),2.48(s,3H),2.19(s,1H),2.10(s,1H)。
MS(m/z)＝427.22[M+H] +。
实施例41: 1-[4-羟基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酰胺
Figure PCTCN2021089486-appb-000040
步骤一： 1-[4-羟基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酯的制备。1-[6-(1-甲基-1H-吡唑-4-基)-4-氧代-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酯溶于甲醇(10mL)中，室温下分批加入NaBH 4(12.8mg，339.4μmol，1.0eq.)继续反应14h。向反应液中加入水和EtOAc各20mL，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩，粗产品通过柱层析纯化(PE/EtOAc＝1:1-0:1梯度洗脱)得到标题化合物为黄色固体(90.0mg，收率64％)。MS(m/z)＝415.18[M+H] +。
步骤二： 1-[4-羟基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酰胺的制备。1-[4-羟基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酯(90.0mg，217.1μmol，1.0eq.)溶于甲胺的乙醇溶液中(6mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(65.0mg，收率72％)。 1H NMR(400MHz,DMSO)δ8.60(q,1H),8.36(s,1H),8.19(d,1H),7.95(s,1H),7.84(d,1H),7.81–7.74(m,1H),7.69(d,1H),7.59(dt,2H),7.03(dd,1H),6.03(d,1H),5.45(d,1H),4.83(dd,1H),4.06(s,1H),3.83(s,4H),2.88(d,3H),2.35–2.20(m,1H),2.15–2.01(m,1H).MS(m/z)＝414.19[M+H] +。
实施例42： 8-[7-二氟甲基-6-(1,2,3,6-四氢吡啶-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸 甲酰胺
Figure PCTCN2021089486-appb-000041
步骤一： 4-(7-二氟甲基-1,2,3,4-四氢喹啉-6-基)-3,6-二氢-2H-吡啶-1-羧酸叔丁酯的制备。N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(3.3g，10.8mmol，2.8eq.)，6-溴-7-二氟甲基-1,2,3,4-四氢喹啉(中间体Ⅸ的第三步)(300.0mg，1.1mmol，1.0eq.)，Pd(dppf)Cl 2(279.2mg，381.5μmol，0.1eq.)，K 2CO 3(1.6g，11.5mmol，3.0eq.)分别溶于1，4-二氧六环(20mL)和水(4mL)中，氮气保护下在110℃反应14h。将反应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝3:1-1:1梯度洗脱)得到标题化合物为黄色固体(1.0g，收率75％)。MS(m/z) ＝365.20[M+H] +。
步骤二： 8-[6-(1-叔丁氧羰基-1,2,3,6-四氢吡啶-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1- 基]-[1,7]萘啶-6-羧酸乙酯的制备。8-氯-1,7-萘啶-6-羧酸乙酯(中间体Ⅳ)(762.4mg，3.4mmol，1.2eq.)，4-(7-二氟甲基-1,2,3,4-四氢喹啉-6-基)-3,6-二氢-2H-吡啶-1-羧酸叔丁酯(1.0g，2.8mmol，1.0eq.)，Pd(OAc) 2(64.1mg，285.4μmol，0.1eq.)，BINAP(355.4mg，570.8μmol，0.2eq.)Cs 2CO 3(1.1g，3.4mmol，1.2eq.)分别溶于甲苯(20mL)中，氮气保护下在90℃反应3h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色固体(1.1g，收率67％)。MS(m/z)＝565.26[M+H] +。
步骤三：将8-[6-(1-叔丁氧羰基-1,2,3,6-四氢吡啶-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙酯(1.1g，1.9mmol，1.0eq.)溶于20mL盐酸二氧六环溶液(4.0M)中，反应混合物继续在室温搅拌12h。反应结束后反应液直接浓缩，加入饱和碳酸氢钠和二氯甲烷各30mL，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为黄色固体(0.8g，92％)。MS(m/z)＝465.21[M+H] +
步骤四： 8-[7-二氟甲基-6-(1,2,3,6-四氢吡啶-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧 酸甲酰胺的制备。8-[7-二氟甲基-6-(1,2,3,6-四氢吡啶-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙酯(100mg，215.0μmol，1.0eq.)溶于甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(50.0mg，收率50％)。 1H NMR(400MHz,DMSO)δ8.56(d,1H),8.44(s,1H),8.25(d,1H),7.86(dd,2H),7.71–7.61(m,1H),7.10(s,1H),6.74(t,1H),6.19(s,1H),5.51(s,1H),3.94(s,2H),3.66(s,2H),3.28(d,2H),2.99(d,2H),2.88(d,3H),2.50(s,2H),2.22–2.08(m,2H).MS(m/z)＝449.21[M+H] +。
实施例43： 8-[6-(1-乙酰基-1,2,3,6-四氢吡啶-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘 啶-6-羧酸甲酰胺
Figure PCTCN2021089486-appb-000042
步骤一： 8-[6-(1-乙酰基-1,2,3,6-四氢吡啶-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7] 萘啶-6-羧酸乙酯的制备。将8-[7-二氟甲基-6-(1,2,3,6-四氢吡啶-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙酯(0.4g，887.9μmol，1.0eq.)和三乙胺(89.8mg，887.9μmol，1.0eq.)分别溶于二氯甲烷(20mL)中，随后向反应混合物中加入乙酰氯(69.7mg，887.9μmol，1.0eq.)的二氯甲烷溶液，室温反应1h。向反应体系中加入50mL水稀释，二氯甲烷萃取，饱 和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为黄色固体(230.0mg，53％)。MS(m/z)＝507.22[M+H] +。
步骤二： 8-[6-(1-乙酰基-1,2,3,6-四氢吡啶-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7] 萘啶-6-羧酸甲酰胺的制备。8-[6-(1-乙酰基-1,2,3,6-四氢吡啶-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙酯(230.0mg，467.0μmol，1.0eq.)溶于甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(200.0mg，收率87％)。 1H NMR(400MHz,DMSO)δ8.83(dd,1H),8.59(dd,1H),8.44(d,1H),8.29(s,1H),7.78(dd,1H),7.10(d,1H),6.77(dt,1H),6.59(s,1H),5.56(s,1H),4.19–3.98(m,4H),3.64(dt,2H),2.92(t,2H),2.87(d,3H),2.41(s,1H),2.32(s,1H),2.11–1.99(m,5H).MS(m/z)＝492.22[M+H] +。
实施例44： 8-[7-二氟甲基-6-(1-甲基-1,2,3,6-四氢吡啶-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶 -6-羧酸甲酰胺
Figure PCTCN2021089486-appb-000043
步骤一： 8-[7-二氟甲基-6-(1-甲基-1,2,3,6-四氢吡啶-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,7]萘 啶-6-羧酸乙酯的制备。将8-[7-二氟甲基-6-(1,2,3,6-四氢吡啶-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙酯(0.4g，887.9μmol，1.0eq.)溶于二氯甲烷中(50mL)，室温下加入甲醛水溶液(2mL，887.9μmol，1.0eq.)反应1h，接着加入STAB(376.4mg，1.8mmol，2.0eq.)继续室温反应20h。向反应体系中加入50mL饱和碳酸钠水溶液稀释，二氯甲烷萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为黄色固体(0.4g，97％)。MS(m/z)＝479.23[M+H] +。
步骤二： 8-[7-二氟甲基-6-(1-甲基-1,2,3,6-四氢吡啶-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,7]萘 啶-6-羧酸甲酰胺的制备。将8-[7-二氟甲基-6-(1-甲基-1,2,3,6-四氢吡啶-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙酯(216.9mg，467.0μmol，1.0eq.)溶于甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(200.0mg，收率92％)。 1H NMR(400MHz,DMSO)δ8.83(dd,1H),8.58(dd,1H),8.42(d,1H),8.28(s,1H),7.78(dd,1H),7.07(s,1H),6.74(t,1H),6.58(s,1H),5.58(s,1H),4.14–4.11(m,2H),3.00–2.90(m,7H),2.58–2.53(m,2H),2.35(s,2H),2.30(s,3H),2.12–2.01(m,2H)..MS(m/z)＝464.23[M+H] +。
实施例45： 8-[7-二氟甲基-6-(1-甲磺酰基-1,2,3,6-四氢吡啶-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,7] 萘啶-6-羧酸甲酰胺
Figure PCTCN2021089486-appb-000044
步骤一： 8-[7-二氟甲基-6-(1-甲磺酰基-1,2,3,6-四氢吡啶-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,7] 萘啶-6-羧酸乙酯的制备。将8-[7-二氟甲基-6-(1,2,3,6-四氢吡啶-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙酯(PB24-079-01的第三步)(0.2g，430.6μmol，1.0eq.)和三乙胺(43.6mg，430.6μmol，1.0eq.)分别溶于二氯甲烷(20mL)中，随后向反应混合物中加入甲磺酰氯(49.3mg，430.6μmol，1.0eq.)的二氯甲烷溶液，室温反应1h。向反应体系中加入50mL水稀释，二氯甲烷萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为黄色固体(150.0mg，64％)。MS(m/z)＝543.19[M+H] +。
步骤二： 8-[7-二氟甲基-6-(1-甲磺酰基-1,2,3,6-四氢吡啶-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,7] 萘啶-6-羧酸甲酰胺的制备。8-[7-二氟甲基-6-(1-甲磺酰基-1,2,3,6-四氢吡啶-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙酯(150.0mg，276.5μmol，1.0eq.)溶于甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(130.0mg，收率89％)。 1H NMR(400MHz,DMSO)δ8.83(dd,1H),8.60(dd,1H),8.45(d,1H),8.29(s,1H),7.78(dd,1H),7.12(s,1H),6.74(t,1H),6.58(s,1H),5.58(s,1H),4.16–4.07(m,2H),3.83(d,2H),3.39(t,2H),3.00–2.90(m,5H),2.89–2.82(m,3H),2.47(s,1H),2.12–2.01(m,2H).MS(m/z)＝528.19[M+H] +。
实施例46： 8-[6-(1-乙酰哌啶-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸甲酰 胺
Figure PCTCN2021089486-appb-000045
步骤一： 4-(7-二氟甲基-1,2,3,4-四氢喹啉-6-基)-哌啶-1-羧酸叔丁酯的制备。
4-(7-二氟甲基-1,2,3,4-四氢喹啉-6-基)-3,6-二氢-2H-吡啶-1-羧酸叔丁酯(200.0mg，548.8μmol，1.0eq.)溶于甲醇(20mL)中，接着加入5％的Pd/C(10.0mg)，H 2抽换气3次，室 温下反应16h。将反应液抽滤，滤液旋干得到标题化合物为灰白色固体(0.2g，定量收率)。MS(m/z)＝367.22[M+H] +。
步骤二： 8-[6-(1-叔丁氧羰基哌啶-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6- 羧酸乙酯的制备。8-氯-1,7-萘啶-6-羧酸乙酯(中间体Ⅳ)(129.2mg，545.8μmol，1.0eq.)，4-(7-二氟甲基-1,2,3,4-四氢喹啉-6-基)-哌啶-1-羧酸叔丁酯(0.2g，545.8μmol，1.0eq.)，Pd(OAc) 2(12.2mg，54.6μmol，0.1eq.)，BINAP(68.0mg，109.2μmol，0.2eq.)Cs 2CO 3(213.4mg，3.4mmol，1.2eq.)分别溶于甲苯(20mL)中，氮气保护下在90℃反应3h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色固体(150.0mg，收率50％)。MS(m/z)＝567.28[M+H] +。
步骤三： 8-(7-二氟甲基-6-哌啶-4-基-3,4-二氢-2H-喹啉-1-基)-[1,7]萘啶-6-羧酸乙酯的制备。将8-[6-(1-叔丁氧羰基哌啶-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙酯(150.0mg，264.7μmol，1.0eq.)溶于20mL盐酸二氧六环溶液(4.0M)中，反应混合物继续在室温搅拌12h。反应结束后反应液直接浓缩，加入饱和碳酸氢钠和二氯甲烷各30mL，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为黄色固体(0.1g，81％)。MS(m/z)＝467.23[M+H] +。
步骤四： 8-[6-(1-乙酰基哌啶-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙 酯的制备。将8-(7-二氟甲基-6-哌啶-4-基-3,4-二氢-2H-喹啉-1-基)-[1,7]萘啶-6-羧酸乙酯(100.4mg，215.3μmol，1.0eq.)和三乙胺(21.2mg，215.3μmol，1.0eq.)分别溶于二氯甲烷(20mL)中，随后向反应混合物中加入乙酰氯(16.9mg，215.3μmol，1.0eq.)的二氯甲烷溶液，室温反应1h。向反应体系中加入50mL水稀释，二氯甲烷萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为黄色固体(50.0mg，46％)。MS(m/z)＝509.24[M+H] +。
步骤五： 8-[6-(1-乙酰哌啶-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸甲酰 胺的制备。8-[6-(1-乙酰基哌啶-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙酯(50.0mg，98.3μmol，1.0eq.)溶于甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(20.0mg，收率41％)。 1H NMR(400MHz,DMSO)δ8.81(dd,1H),8.58(dd,1H),8.40(d,1H),8.25(s,1H),7.77(dd,1H),7.20(s,1H),6.93(t,1H),6.57(s,1H),4.54(d,1H),4.16–4.04(m,2H),3.93(d,1H),3.15–2.96(m,2H),2.91(t,2H),2.86(d,3H),2.62–2.53(m,1H),2.09–1.98(m,4H),1.68(m,3H),1.51(dt,1H).MS(m/z)＝494.24[M+H] +。
实施例47-52以实施例46类似的方法制得。
Figure PCTCN2021089486-appb-000046
Figure PCTCN2021089486-appb-000047
Figure PCTCN2021089486-appb-000048
实施例53: 8-[6-(1-壬二酸-3-基-1H-吡唑-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶 -6-羧酸甲酰胺
Figure PCTCN2021089486-appb-000049
步骤一： 3-[4-(7-二氟甲基-1,2,3,4-四氢喹啉-6-基)-吡唑-1-基]-壬二酸-1-羧酸叔丁酯的制备。1-(1-BOC-3-氮杂环丁烷基)吡唑-4-硼酸频哪醇酯(799.5mg，2.3mmol，1.2eq.)，6-溴-7-二氟甲基-1,2,3,4-四氢喹啉(0.5g，1.9mmol，1.0eq.)，Pd(dppf)Cl 2(139.6mg，190.8μmol，0.1eq.)，K 2CO 3(791.0mg，5.7mmol，3.0eq.)分别溶于1，4-二氧六环(20mL)和水(4mL)中，氮气保护下在110℃反应14h。将反应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝3:1-1:1梯度洗脱)得到标题化合物为黄色固体(0.7g，收率91％)。MS(m/z)＝405.21[M+H] +。
步骤二： 8-{6-[1-(1-叔丁氧羰基-氮杂苷-3-基)-1H-吡唑-4-基]-7-二氟甲基-3,4-二氢-2H-喹 啉-1-基]-[1,7]萘啶-6-羧酸乙酯的制备。8-氯-1,7-萘啶-6-羧酸乙酯(中间体Ⅳ)(409.6mg，1.7mmol，1.2eq.)，3-[4-(7-二氟甲基-1,2,3,4-四氢喹啉-6-基)-吡唑-1-基]-壬二酸-1-羧酸叔丁酯(0.7g，1.7mmol，1.0eq.)，Pd(OAc) 2(38.9mg，173.1μmol，0.1eq.)，BINAP(215.5mg，346.1μmol，0.2eq.)和Cs 2CO 3(676.7mg，2.1mmol，1.2eq.)分别溶于甲苯(20mL)中，氮气保护下在90℃反应3h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色固体(0.8g，收率76％)。MS(m/z)＝605.27[M+H] +。
步骤三： 8-[6-(1-氮杂苷-3-基-1H-吡唑-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶 -6-羧酸乙酯的制备。8-{6-[1-(1-叔丁氧羰基-氮杂苷-3-基)-1H-吡唑-4-基]-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙酯(0.8g，1.3mmol，1.0eq.)溶于20mL盐酸二氧六环溶液(4.0M)中，反应混合物继续在室温搅拌12h。反应结束后反应液直接浓缩，加入饱和碳酸氢钠和二氯甲烷各30mL，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为黄色固体(0.6g，90％)。MS(m/z)＝505.22[M+H] +。
步骤四： 8-[6-(1-壬二酸-3-基-1H-吡唑-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶 -6-羧酸甲酰胺的制备。8-[6-(1-氮杂苷-3-基-1H-吡唑-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙酯(0.3g，594.6μmol，1.0eq.)溶于甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(50.0mg，收率17％)。 1H NMR(400MHz,DMSO)δ8.89–8.77(m,1H),8.65 –8.55(m,1H),8.48(d,1H),8.30(s,1H),8.00(s,1H),7.78(t,2H),7.27(s,1H),6.91–6.55(m,2H),5.48–5.33(m,1H),4.35–3.96(m,6H),2.91(dd,5H),2.18–2.02(m,2H).MS(m/z)＝490.22[M+H] +。
实施例54: 8-{7-二氟甲基-6-[1-(1-甲基-氮杂苷-3-基)-1H-吡唑-4-基]-3,4-二氢-2H-喹啉-1- 基}-[1,7]萘啶-6-羧酸甲酰胺
Figure PCTCN2021089486-appb-000050
步骤一: 8-{7-二氟甲基-6-[1-(1-甲基-氮杂苷-3-基)-1H-吡唑-4-基]-3,4-二氢-2H-喹啉-1- 基}-[1,7]萘啶-6-羧酸乙酯的制备。8-[6-(1-氮杂苷-3-基-1H-吡唑-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙酯(0.3g，594.6μmol，1.0eq.)溶于二氯甲烷中(50mL)，室温下加入甲醛水溶液(2mL，594.6μmol，1.0eq.)反应1h，接着加入STAB(376.4mg，1.2mmol，2.0eq.)继续室温反应20h。向反应体系中加入50mL饱和碳酸钠水溶液稀释，二氯甲烷萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为黄色固体(0.3g，97％)。MS(m/z)＝519.23[M+H] +。
步骤二： 8-{7-二氟甲基-6-[1-(1-甲基-氮杂苷-3-基)-1H-吡唑-4-基]-3,4-二氢-2H-喹啉-1- 基}-[1,7]萘啶-6-羧酸甲酰胺的制备。8-{7-二氟甲基-6-[1-(1-甲基-氮杂苷-3-基)-1H-吡唑-4-基]-3,4-二氢-2H-喹啉-1-基}-[1,7]萘啶-6-羧酸乙酯(0.3g，578.5μmol，1.0eq.)溶于甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(0.2g，收率69％)。 1H NMR(400MHz,DMSO)δ8.83(dd,1H),8.59(dd,1H),8.48(q,1H),8.29(s,1H),7.99(s,1H),7.78(dd,1H),7.65(s,1H),7.28(s,1H),6.90–6.56(m,2H),5.00(p,1H),4.20–4.10(m,2H),3.79–3.67(m,2H),3.42(td,2H),2.95(t,2H),2.88(d,3H),2.34(s,3H),2.14–2.03(m,2H).MS(m/z)＝504.23[M+H] +。
实施例55: 8-[6-(1-氰基甲基-1H-吡唑-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧 酸甲酰胺
Figure PCTCN2021089486-appb-000051
步骤一: [4-(7-二氟甲基-1,2,3,4-四氢喹啉-6-基)-吡唑-1-基]-乙腈的制备。[4-(4,4,5,5-四甲基-[1,3,2]二噁英-2-基)-吡唑-1-基]-乙腈(533.6mg，2.3mmol，2.8eq.)，6-溴-7-二氟甲基-1,2,3,4-四氢喹啉(0.5g，1.9mmol，1.0eq.)，Pd(dppf)Cl 2(139.6mg，190.8μmol，0.1eq.)，K 2CO 3(791.0mg，5.7mmol，3.0eq.)分别溶于1，4-二氧六环(20mL)和水(4mL)中，氮气保护下在110℃反应14h。将反应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝3:1-1:1梯度洗脱)得到标题化合物为黄色固体(0.5g，收率91％)。MS(m/z)＝289.13[M+H] +。
步骤二： 8-[6-(1-氰基甲基-1H-吡唑-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6- 羧酸乙酯的制备。8-氯-1,7-萘啶-6-羧酸乙酯(中间体Ⅳ)(410.4mg，1.7mmol，1.0eq.)，[4-(7-二氟甲基-1,2,3,4-四氢喹啉-6-基)-吡唑-1-基]-乙腈(0.5g，1.7mmol，1.0eq.)，Pd(OAc) 2(38.9mg，173.4μmol，0.1eq.)，BINAP(215.5mg，346.9μmol，0.2eq.)Cs 2CO 3(678.1mg，2.1mmol，1.2eq.)分别溶于甲苯(20mL)中，氮气保护下在90℃反应3h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色固体(0.3g，收率35％)。MS(m/z)＝489.18[M+H] +。
步骤三： 8-[6-(1-氰基甲基-1H-吡唑-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6- 羧酸甲酰胺的制备。8-[6-(1-氰基甲基-1H-吡唑-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙酯(0.3g，614.1μmol，1.0eq.)溶于甲胺的乙醇溶液中(10mL)于室温反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(0.1g，收率34％)。 1H NMR(400MHz,DMSO)δ8.84(dd,1H),8.60(dd,1H),8.49(d,1H),8.30(s,1H),7.97(s,1H),7.82–7.72(m,2H),7.29(s,1H),6.89–6.52(m,2H),5.54(s,2H),4.21–4.08(m,2H),2.96(t,2H),2.88(d,3H),2.16–2.02(m,2H).MS(m/z)＝478.18[M+H] +。
实施例56: 1-[7-二氟甲基-6-(1-甲基氨甲酰甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉 -3-羧酸甲酰胺
Figure PCTCN2021089486-appb-000052
步骤一： 1-[7-二氟甲基-6-(1-甲基氨甲酰甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异 喹啉-3-羧酸甲酰胺的制备。8-[6-(1-氰基甲基-1H-吡唑-4-基)-7-二氟甲基-3,4-二氢-2H-喹啉-1-基]-[1,7]萘啶-6-羧酸乙酯(0.1g，614.1μmol，1.0eq.)溶于甲胺的乙醇溶液中(10mL)于110℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(0.05g，收率50％)。 1H NMR(400MHz,DMSO)δ8.60(d,1H),8.41(s,1H),8.24(d,1H),7.95(d,1H),7.90–7.78(m,3H),7.69–7.61(m,1H),7.59(s,1H),7.31(s,1H),6.67(t,1H),6.29(s,1H),4.80(s,2H),3.98(t,2H),3.02(t,2H),2.88(d,3H),2.63(d,2H),2.24–2.10(m,2H).MS(m/z)＝505.22[M+H] +。
实施例57: 1-[7-氯-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酰胺
Figure PCTCN2021089486-appb-000053
步骤一： 6-溴-7-氯-1,2,3,4-四氢-奎宁的制备。7-氯-1,2,3,4-四氢喹啉(2.0g，12.1mmol，1.0eq.)溶于DMF中(30mL)，0℃条件下在20min内分批加入NBS(2.2g，12.5mmol，1.0eq.)，反应混合物继续在0℃反应2h。将反应液倒入100mL冰水中，搅拌析出白色固体，抽滤并烘干得到标题化合物为白色固体(2.9g，定量收率)。MS(m/z)＝245.97[M+H] +。
步骤二： 7-氯-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉的制备。1-甲基吡唑-4-硼酸频哪醇酯(2.8g，13.3mmol，1.1eq.)，6-溴-7-氯-1,2,3,4-四氢-奎宁(2.9g，12.1mmol，1.0eq.)，Pd(dppf)Cl 2(887.4mg，1.2mmol，0.1eq.)，K 2CO 3(5.0g，36.4mmol，3.0eq.)分别溶于1，4-二氧六环(50mL)和水(10mL)中，氮气保护下在110℃反应14h。将反应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝10:1-3:1梯度洗脱)得到标题化合物为灰白色固体(2.8g，收率92％)。MS(m/z)＝248.09[M+H] +。
步骤三： 1-[7-氯-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酯的制备。1-氯异喹啉-3-羧酸甲酯(中间体Ⅰ)(280.0mg，1.3mmol，1.0eq.)，7-氯-6-(1-甲基-1H- 吡唑-4-基)-1,2,3,4-四氢喹啉(344.2mg，1.4mmol，1.1eq.)，Pd(OAc) 2(56.7mg，252.7μmol，0.2eq.)，BINAP(157.3mg，252.7μmol，0.2eq.)Cs 2CO 3(493.9mg，1.5mmol，1.2eq.)分别溶于甲苯(20mL)中，氮气保护下在90℃反应3h。将反应液旋干，粗产品用PE/EtOAc＝1:1(15mL)超声并过滤，滤饼烘干得到标题化合物为黄色固体(230.0mg，收率42％)。MS(m/z)＝433.14[M+H] +。
步骤四： 1-[7-氯-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酰胺的制备。将1-[7-氯-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-异喹啉-3-羧酸甲酯(230.0mg，528.8μmol，1.0eq.)加入甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品用EtOAc(10mL)超声并过滤，滤饼烘干得到标题化合物为淡黄色固体(180.0mg，收率79％)。 1H NMR(400MHz,DMSO)δ8.62(s,1H),8.42(s,1H),8.23(d,1H),8.00(s,1H),7.88(d,2H),7.85–7.82(m,2H),7.71-7.66(m,2H),7.37(s,1H),6.06(s,1H),3.92-3.86(m,5H),2.97-2.88(m,5H),2.15(t,2H).MS(m/z)＝432.16[M+H] +。
实施例58: 1-(3-甲基氨甲酰异喹啉-1-基)-1,2,3,4-四氢喹啉-6-羧酸甲酰胺
Figure PCTCN2021089486-appb-000054
步骤一： 1-(3-甲氧羰基异喹啉-1-基)-1,2,3,4-四氢喹啉-6-羧酸乙酯的制备。1-氯异喹啉-3-羧酸甲酯(中间体Ⅰ)(180.0mg，812.1μmol，1.0eq.)，1,2,3,4-四氢喹啉-6-羧酸乙酯(183.4mg，893.3μmol，1.1eq.)，Pd(OAc) 2(36.5mg，162.4μmol，0.2eq.)，BINAP(101.1mg，162.4μmol，0.2eq.)Cs 2CO 3(317.5mg，974.6μmol，1.2eq.)分别溶于甲苯(20mL)中，氮气保护下在90℃反应15h。将反应液旋干，粗产品用PE/EtOAc＝1:1(15mL)超声并过滤，滤饼烘干得到标题化合物为淡黄色固体(88.0mg，收率28％)。MS(m/z)＝391.17[M+H] +。
步骤二： 1-(3-甲基氨甲酰异喹啉-1-基)-1,2,3,4-四氢喹啉-6-羧酸甲酰胺的制备。1-(3-甲氧羰基异喹啉-1-基)-1,2,3,4-四氢喹啉-6-羧酸乙酯(88.0mg，225.4μmol，1.0eq.)加入甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干得到标题化合物为淡黄色固体(15.0mg，收率18％)。 1H NMR(400MHz,DMSO)δ8.64(s,1H),8.43(s,1H),8.23(d,1H),8.11(s,1H),7.81(d,2H),7.70–7.48(m,2H),7.25(d,1H),5.97(d,1H),3.95(s,2H),2.98(s,2H),2.87(d,3H),2.72(d,3H),2.16(s,2H).MS(m/z)＝375.18[M+H] +。
实施例59: 1-(6-羟甲基-3,4-二氢-2H-喹啉-1-基)-异喹啉-3-羧酸甲酰胺
Figure PCTCN2021089486-appb-000055
步骤一： 1-(6-羟甲基-3,4-二氢-2H-喹啉-1-基)-异喹啉-3-羧酸甲酰胺的制备。将1-(3-甲基氨甲酰异喹啉-1-基)-1,2,3,4-四氢喹啉-6-羧酸乙酯(65.0mg，166.9μmol，1.0eq.)溶于THF(10mL)中，室温下分批加入LiAlH 4(25.3mg，667.6μmol，4.0eq.)，反应混合物继续室温反应2h。反应液在冰浴条件下滴加0.1mL水淬灭，过滤，THF洗涤滤饼，滤液旋干所得粗品用PE/EtOAc＝5:1(5mL)超声并过滤，滤饼烘干得标题化合物为灰白色固体(46.0mg，收率79％)。 1H NMR(400MHz,DMSO)δ8.59(d,1H),8.30(s,1H),8.16(d,1H),7.76(d,2H),7.54(t,1H),7.12(s,1H),6.73(d,1H),6.02(d,1H),4.98(t,1H),4.35(d,2H),3.94(t,2H),2.92(t,2H),2.88(d,3H),2.23–2.03(m,2H).MS(m/z)＝348.17[M+H] +。
实施例60: 1-[7-(1-甲基-1H-吡唑-4-基)-2,3-二氢-苯并[1,4]噁嗪-4-基]-异喹啉-3-羧酸甲酰胺
Figure PCTCN2021089486-appb-000056
步骤一： 7-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-苯并[1,4]噁嗪的制备。1-甲基吡唑-4-硼酸频哪醇酯(1.2g，5.6mmol，1.2eq.)，7-溴-3,4-二氢-2H-苯并[1,4]噁嗪(1.0g，4.7mmol，1.0eq.)，Pd(dppf)Cl 2(341.8mg，467.2μmol，0.1eq.)，K 2CO 3(1.9g，14.0mmol，3.0eq.)分别溶于1，4-二氧六环(25mL)和水(5mL)中，氮气保护下在110℃反应14h。将反应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝5:1-2:1梯度洗脱)得到标题化合物为淡黄色固体(0.8g，收率80％)。MS(m/z)＝216.11[M+H] +。
步骤二： 1-[7-(1-甲基-1H-吡唑-4-基)-2,3-二氢-苯并[1,4]噁嗪-4-基]-异喹啉-3-羧酸甲酯的制备。1-氯异喹啉-3-羧酸甲酯(中间体Ⅰ)(205.9mg，929.1μmol，1.0eq.)，7-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-苯并[1,4]噁嗪(200.0mg，929.1μmol，1.0eq.)，Pd(OAc) 2(20.9mg，92.9μmol，0.2eq.)，BINAP(115.7mg，185.8μmol，0.2eq.)Cs 2CO 3(363.3mg，111.0μmol，1.2eq.)分别溶于甲苯(10mL)中，氮气保护下在95℃反应15h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝1:5-1:9梯度洗脱)得到标题化合物为黄色固体(320.0mg，收率86％)。MS(m/z)＝401.16[M+H] +。
步骤三： 1-[7-(1-甲基-1H-吡唑-4-基)-2,3-二氢-苯并[1,4]噁嗪-4-基]-异喹啉-3-羧酸甲酰胺 的制备。1-[7-(1-甲基-1H-吡唑-4-基)-2,3-二氢-苯并[1,4]噁嗪-4-基]-异喹啉-3-羧酸甲酯(320.0mg，799.1μmol，1.0eq.)加入甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(210.0mg，收率66％)。 1H NMR(400MHz,DMSO)δ8.59(q,1H),8.34(s,1H),8.21(d,1H),8.07(d,1H),7.99(s,1H),7.87–7.77(m,1H),7.73(d,1H),7.69–7.61(m,1H),7.11(d,1H),6.76(dd,1H),6.20(d,1H),4.58–4.50(m,2H),4.05(dd,2H),3.82(s,3H),2.88(d,\3H).MS(m/z)＝400.18[M+H] +。
实施例61: 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-6,7-二氢-5H-[2]吡 嗪-3-羧酸甲酰胺
Figure PCTCN2021089486-appb-000057
步骤一： 6,7-二氢-5H-[2]吡啶-3-羧酸乙酯的制备。将1，6-庚二炔(3.7g，40.2mmol，1.0eq.)溶于1，2-二氯甲烷(50mL)中，随后加入氰基甲酸乙酯(6.0g，60.2mmol，1.5eq.)和(1,5-环辛二烯)(五甲基环戊二烯)氯化钌(305.1mg，803.1μmol，0.02eq.)，N 2保护下反应混合物在60℃继续反应2h。旋出溶剂，残留物中加入水和EtOAc各50mL，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩，将粗产品通过柱层析纯化(PE/EtOAc＝5:1-1:1梯度洗脱)得到标题化合物为黄色油状物(730.0mg，10％)。MS(m/z)＝192.10[M+H] +。
步骤二： 2-氧基-6,7-二氢-5H-[2]吡啶-3-羧酸乙酯的制备。6,7-二氢-5H-[2]吡啶-3-羧酸乙酯(730.0mg，3.8mmol，1.0eq.)溶于二氯甲烷(15mL)中，随后加入m-CPBA(1.3g，7.6mmol，2.0eq.)并在室温反应12h。反应体系中加入饱和的Na 2S 2O 3(50mL)，二氯甲烷萃取，饱和的Na 2CO 3洗，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为棕色油状物(750.0mg，95％)。MS(m/z)＝208.10[M+H] +。
步骤三：1-氯-6,7-二氢-5H-[2]吡啶-3-羧酸乙酯的制备。 2-氧基-6,7-二氢-5H-[2]吡啶-3-羧 酸乙酯(750.0mg，3.6mmol，1.0eq.)和POCl 3(8mL)的混合物在50℃加热12h。将反应混合物置于冰浴中，搅拌下依次加入冰水和NaHCO 3固体，直至无剧烈气泡冒出同时保证混合物的PH＝8左右，CH 2Cl 2萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为灰白色固体(140.0mg，17％)，其不经进一步纯化即用于下一步骤中。MS(m/z)＝226.06[M+H] +。
步骤四： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-6,7-二氢-5H-[2] 吡嗪-3-羧酸乙酯的制备。1-氯-6,7-二氢-5H-[2]吡啶-3-羧酸乙酯(140.0mg，620.4μmol，1.0eq.)，7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体Ⅸ)(163.3mg，620.4μmol， 1.0eq.)，Pd(OAc) 2(13.9mg，62.0μmol，0.1eq.)，BINAP(77.3mg，124.1μmol，0.2eq.)Cs 2CO 3(242.6mg，744.5μmol，1.2eq.)分别溶于甲苯(15mL)中，氮气保护下在95℃反应15h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝1:5-1:9梯度洗脱)得到标题化合物为黄色固体(160.0mg，收率57％)。MS(m/z)＝453.21[M+H] +。
步骤五： 1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-6,7-二氢-5H-[2] 吡嗪-3-羧酸甲酰胺的制备。1-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-6,7-二氢-5H-[2]吡嗪-3-羧酸乙酯(160.0mg，353.6μmol，1.0eq.)加入甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(100.0mg，收率65％)。 1H NMR(400MHz,DMSO)δ8.44(q,1H),7.82(s,1H),7.71(s,1H),7.56(s,1H),7.23(s,1H),6.85(t,1H),6.57(s,1H),3.97–3.77(m,5H),2.95(t,2H),2.89–2.73(m,5H),2.39(t,2H),2.08–1.86(m,4H).MS(m/z)＝438.21[M+H] +。
实施例62以实施例61类似的方法制得。
Figure PCTCN2021089486-appb-000058
实施例63： 7-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-呋喃[2,3-c]吡啶-5- 羧酸甲酰胺
Figure PCTCN2021089486-appb-000059
步骤一: 7-氯-呋喃[2,3-c]吡啶-5-羧酸甲酯的制备。7-氯-呋喃[2,3-c]吡啶-5-羧酸(500.0mg，2.5mmol，1.0eq.)溶于SOCl 2(301.1mg，2.5mmol，1.0eq.)中，反应混合物在室温搅拌 12h。反应体系中加入0.1M NaOH水溶液(10mL)调节PH＝8左右，CH 2Cl 2萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩，粗产品通过柱层析纯化(PE/EtOAc＝3:1-0:1梯度洗脱)得到标题化合物为白色固体(500.0mg，93％)。MS(m/z)＝212.01[M+H] +。
步骤二： 7-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-呋喃[2,3-c]吡啶 -5-羧酸甲酯的制备。7-氯-呋喃[2,3-c]吡啶-5-羧酸甲酯(167.3mg，790.7μmol，1.0eq.)，7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体Ⅸ)(208.2mg，790.7μmol，1.0eq.)，Pd(OAc) 2(17.8mg，79.1μmol，0.1eq.)，BINAP(98.5mg，158.1μmol，0.2eq.)Cs 2CO 3(309.1mg，948.8μmol，1.2eq.)分别溶于甲苯(15mL)中，氮气保护下在95℃反应15h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色固体(290.0mg，收率84％)。MS(m/z)＝439.16[M+H] +。
步骤三： 7-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-呋喃[2,3-c]吡啶 -5-羧酸甲酰胺的制备。7-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-呋喃[2,3-c]吡啶-5-羧酸甲酯(290.0mg，641.0μmol，1.0eq.)加入甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(220.0mg，收率78％)。 1H NMR(400MHz,DMSO)δ8.39(q,1H),8.13(d,1H),8.05(s,1H),7.85(s,1H),7.60(s,1H),7.29(s,1H),7.15(d,1H),7.01–6.64(m,2H),4.16–4.09(m,2H),3.90(s,3H),2.91(t,2H),2.85(d,3H),2.11–2.01(m,2H).MS(m/z)＝438.17[M+H] +。
实施例64： 5-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,6]萘啶-7-羧酸 甲酰胺
Figure PCTCN2021089486-appb-000060
步骤一： 2-甲酰烟酸甲酯的制备。2-甲基烟酸甲酯(100.0g，698.4mmol，1.0eq.)溶于1，4-二氧六环(50mL)中，随后分批加入二氧化硒(77.5g，698.4mmol，1.0eq.)，反应混合物在120℃反应15h。冷却至室温后，滤除固体后滤液浓缩，所得粗品加入水和EtOAc各50mL，EtOAc萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩，粗产品通过柱层析纯化(PE/EtOAc＝5:1-1:1梯度洗脱)得到标题化合物为棕色油状物(1.7g，31％)。MS(m/z)＝166.05[M+H] +。
步骤二： 5-氧代-5H-[1,6]萘啶-6,7-二羧酸6-叔丁基酯7-甲基酯的制备。2-甲酰烟酸甲酯(1.7g，10.3mmol，1.0eq.)和DBU(1.6g，10.3mmol，1.0eq.)溶于二氯甲烷(20mL)中，在0℃下加入(±)-BOC-A-膦酰基甘氨酸三甲酯(3.1g，10.3mmol，1.0eq.)，反应混合物继续在 室温搅拌5h。加入50mL水稀释，二氯甲烷萃取，分液后有机相分别用饱和食盐水洗，无水硫酸镁干燥，过滤并浓缩，粗产品通过柱层析纯化(PE/EtOAc＝3:1-1:1梯度洗脱)得到标题化合物为淡黄色液体(1.3g，收率41％)。MS(m/z)＝305.11[M+H] +。
步骤三： 5-氧代-5,6-二氢-[1,6]萘啶-7-羧酸甲酯的制备。将5-氧代-5H-[1,6]萘啶-6,7-二羧酸6-叔丁基酯7-甲基酯(1.3g，4.3mmol，1.0eq.)溶于10mL盐酸二氧六环溶液(4.0M)中，反应混合物继续在室温搅拌12h。反应结束后真空直接浓缩得到标题化合物为黄色固体(0.8g，92％)。MS(m/z)＝205.06[M+H] +。
步骤四： 5-氯-[1,6]萘啶-7-羧酸甲酯的制备。5-氧代-5,6-二氢-[1,6]萘啶-7-羧酸甲酯(0.8g，3.8mmol，1.0eq.)和POCl 3(20mL)的混合物在50℃加热12h。将反应混合物置于冰浴中，搅拌下依次加入冰水和NaHCO 3固体，直至无剧烈气泡冒出同时保证混合物的PH＝8左右，CH 2Cl 2萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为棕色固体(750.0mg，86％)，其不经进一步纯化即用于下一步骤中。MS(m/z)＝223.03[M+H] +。
步骤五： 5-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,6]萘啶-7-羧酸 甲酯的制备。5-氯-[1,6]萘啶-7-羧酸甲酯(180.0mg，760.6μmol，1.0eq.)，7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体Ⅸ)(200.3mg，760.6μmol，1.0eq.)，Pd(OAc) 2(17.1mg，76.1μmol，0.1eq.)，BINAP(94.7mg，152.1μmol，0.2eq.)Cs 2CO 3(297.4mg，912.7μmol，1.2eq.)分别溶于甲苯(15mL)中，氮气保护下在95℃反应15h。将反应液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色固体(80.0mg，收率23％)。MS(m/z)＝450.17[M+H] +。
步骤六： 5-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,6]萘啶-7-羧酸 甲酰胺的制备。5-[7-二氟甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-[1,6]萘啶-7-羧酸甲酯(80.0mg，172.6μmol，1.0eq.)加入甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(60.0mg，收率77％)。 1H NMR(400MHz,DMSO)δ9.14(dd,1H),8.66(q,1H),8.25(d,1H),8.20–8.12(m,1H),7.81(s,1H),7.59(dd,1H),7.56(s,1H),7.32(s,1H),6.69(t,1H),6.45(s,1H),4.03(dd,2H),3.88(s,3H),3.00(t,2H),2.89(d,3H),2.23–2.07(m,2H).MS(m/z)＝449.19[M+H] +。
实施例65： 8-[6-二氟甲基-7-(1-甲基-1H-吡唑-4-基)-2,3-二氢-苯并[1,4]噁嗪-4-基]-[1,7]萘啶-6- 羧酸甲酰胺
Figure PCTCN2021089486-appb-000061
步骤一： 2-溴-4-氟-5-硝基苯甲醛的制备。2-溴-4氟苯甲醛(1.0g，4.9mmol，1.0eq.)溶于浓硫酸(6mL)中，随后在0℃下滴加浓硝酸(0.6mL，4.9mmol，1.0eq.)于室温反应2h。反应体系中加入50mL水，EtOAc萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩，粗产品通过柱层析纯化(PE/EtOAc＝10:1-2:1梯度洗脱)得到标题化合物为白色固体(1.2g，定量收率)。MS(m/z)＝247.94[M+H] +。
步骤二： 1-溴-2-二氟甲基-5-氟-4-硝基苯的制备。2-溴-4-氟-5-硝基苯甲醛(1.2g，4.8mmol，1.0eq.)溶于100mL二氯甲烷中，0℃下滴加DAST(3.1g，19.3mmol，4.0eq.)，反应混合物在室温反应16h。将反应混合物倒入到50mL饱和碳酸氢钠溶液中，二氯甲烷萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩。粗产品通过柱层析纯化(PE/EtOAc＝10:1-2:1梯度洗脱)得到标题化合物为无色油状物(1.3g，收率85％)。MS(m/z)＝269.94[M+H] +。
步骤三： 1-溴-5-(2-溴-乙氧基)-2-二氟甲基-4-硝基苯的制备。将1-溴-2-二氟甲基-5-氟-4-硝基苯(1.0g，3.7mmol，1.0eq.)溶于THF(10mL)中，0℃下滴加LDA(0.6mL，4.4mmol，1.2eq.)，搅拌30min后加入2-溴乙醇(555.4mg，4.4mmol，1.2eq.)的THF(10mL)溶液，反应体系中加入50mL水，EtOAc萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩，粗产品通过柱层析纯化(PE/EtOAc＝5:1-1:1梯度洗脱)得到标题化合物为淡黄色油状物(1.4g，定量收率)。MS(m/z)＝373.88[M+H] +。
步骤四： 4-溴-2-(2-溴乙氧基)-5-二氟甲基苯胺的制备。往1-溴-5-(2-溴-乙氧基)-2-二氟甲基-4-硝基苯(1.4g，3.7mmol，1.0eq.)中加入HOAc(10mL)，接着加入铁粉(1.0g，17.9mmol，4.8eq.)，反应混合物在室温反应1h。滤除固体，先后加入10mL水和1.0M NaOH水溶液调节PH＝8，EtOAc萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩得到标题化合物为淡黄色油状物(1.0g，78％)。MS(m/z)＝343.91[M+H] +。
步骤五： 7-溴-6-二氟甲基-3,4-二氢-2H-苯并[1,4]噁嗪的制备。将4-溴-2-(2-溴乙氧基)-5-二氟甲基苯胺(1.0g，2.9mmol，1.0eq.)溶于DMF(20mL)中，随后加入K 2CO 3(801.3mg，5.8mmol，2.0eq.)，NaI(434.5mg，2.9mmol，1.0eq.)于80℃反应12h。减压旋去溶剂，残留物中加入50mL水，EtOAc萃取，饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤并浓缩，粗产品通过柱层析纯化(PE/EtOAc＝5:1-1:1梯度洗脱)得到标题化合物为黄色油状物(450.0mg，59％)。MS(m/z)＝263.98[M+H] +。
步骤六： 6-二氟甲基-7-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-苯并[1,4]噁嗪的制备。1-甲基 吡唑-4-硼酸频哪醇酯(425.5mg，2.0mmol，1.2eq.)，7-溴-6-二氟甲基-3,4-二氢-2H-苯并[1,4]噁嗪(450.0mg，1.7mmol，1.0eq.)，Pd(dppf)Cl 2(124.7mg，170.4μmol，0.1eq.)，K 2CO 3(706.6mg，5.1mmol，3.0eq.)分别溶于1，4-二氧六环(25mL)和水(5mL)中，氮气保护下在110℃反应18h。将反应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝10:1-3:1梯度洗脱)得到标题化合物为黄色固体(400.0mg，收率88％)。MS(m/z)＝266.11[M+H] +。
步骤七： 8-[6-二氟甲基-7-(1-甲基-1H-吡唑-4-基)-2,3-二氢-苯并[1,4]噁嗪-4-基]-[1,7]萘啶 -6-羧酸乙酯的制备。8-氯-1,7-萘啶-6-羧酸乙酯(中间体Ⅳ)(177.9mg，799.2μmol，1.0eq.)，6-二氟甲基-7-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-苯并[1,4]噁嗪(212.0mg，799.2μmol，1.0eq.)，Pd(OAc) 2(17.9mg，79.9μmol，0.1eq.)，BINAP(99.5mg，159.8μmol，0.2eq.)，Cs 2CO 3(312.5mg，959.1μmol，1.2eq.)分别溶于甲苯(20mL)中，氮气保护下在90℃反应3h。将反应液直接旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色固体(43.0mg，收率12％)。MS(m/z)＝466.17[M+H] +。
步骤八： 8-[6-二氟甲基-7-(1-甲基-1H-吡唑-4-基)-2,3-二氢-苯并[1,4]噁嗪-4-基]-[1,7]萘啶 -6-羧酸甲酰胺的制备。8-[6-二氟甲基-7-(1-甲基-1H-吡唑-4-基)-2,3-二氢-苯并[1,4]噁嗪-4-基]-[1,7]萘啶-6-羧酸乙酯(43.0mg，92.4μmol，1.0eq.)加入甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(20.0mg，收率48％)。 1H NMR(400MHz,DMSO)δ8.95(dd,1H),8.62(dd,1H),8.34(d,1H),8.29(s,1H),7.84(dd,2H),7.59(s,1H),7.00(d,2H),6.76(t,1H),4.50–4.40(m,2H),4.37–4.24(m,2H),3.89(s,3H),2.87(d,3H).MS(m/z)＝451.17[M+H] +。
实施例66： 8-[1-甲基-3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-5-基]-[1,7]萘啶-6-羧酸甲酰胺
Figure PCTCN2021089486-appb-000062
步骤一： 5-溴-3-碘-1-甲基-1H-吲唑的制备。将5-溴-3-碘-1H-吲唑(2.0g，6.2mmol，1.0eq.)溶于乙腈(30mL)中，随后加入CH 3I(1.3g，9.3mmol，1.5eq.)和Cs 2CO 3(3.0g，9.3mmol，1.5eq.)，反应混合物室温搅拌1h。滤除固体，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝5:1-2:1梯度洗脱)得到标题化合物为白色固体(1.7g，收率81％)。MS(m/z)＝336.88[M+H] +。
步骤二： 5-溴-1-甲基-3-(1-甲基-1H-吡唑-4-基)-1H-吲唑的制备。1-甲基吡唑-4-硼酸频哪醇酯(1.2g，5.6mmol，1.1eq.)，5-溴-3-碘-1-甲基-1H-吲唑(1.7g，5.1mmol，1.0eq.)，Pd(dppf) Cl 2(368.8mg，504.5μmol，0.1eq.)，K 2CO 3(2.1g，15.1mmol，3.0eq.)分别溶于1，4-二氧六环(25mL)和水(5mL)中，氮气保护下在110℃反应18h。将反应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为白色固体(1.2g，收率82％)。MS(m/z)＝291.02[M+H] +。
步骤三： 1-甲基-3-(1-甲基-1H-吡唑-4-基)-5-(4,4,5,5-四甲基-[1,3,2]二噁英-2-基)-1H-吲唑的制备。联硼酸频哪醇酯(1.1g，4.1mmol，1.5eq.)，5-溴-1-甲基-3-(1-甲基-1H-吡唑-4-基)-1H-吲唑(0.8g，2.8mmol，1.0eq.)，Pd(dppf)Cl 2(200.9mg，274.8μmol，0.1eq.)，KOAc(809.0mg，8.2mmol，3.0eq.)分别溶于1，4-二氧六环(20mL)中，氮气保护下在110℃反应18h。将反应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝2:1-0:1梯度洗脱)得到标题化合物为黄色油状物(0.8g，收率86％)。MS(m/z)＝339.20[M+H] +。
步骤四： 8-[1-甲基-3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-5-基]-[1,7]萘啶-6-羧酸乙酯的制备。8-氯-1,7-萘啶-6-羧酸乙酯(中间体Ⅳ)(223.9mg，946.2μmol，0.8eq.)，1-甲基-3-(1-甲基-1H-吡唑-4-基)-5-(4,4,5,5-四甲基-[1,3,2]二噁英-2-基)-1H-吲唑(0.4g，1.2mmol，1.0eq.)，Pd(dppf)Cl 2(86.5mg，118.3μmol，0.1eq.)，K 2CO 3(490.4mg，3.6mmol，3.0eq.)分别溶于1，4-二氧六环(25mL)和水(5mL)中，氮气保护下在100℃反应2h。将反应液抽滤，滤液旋干，粗产品通过柱层析纯化(PE/EtOAc＝1:1-0:1梯度洗脱)得到标题化合物为黄色固体(0.2g，收率41％)。MS(m/z)＝413.17[M+H] +。
步骤五： 8-[1-甲基-3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-5-基]-[1,7]萘啶-6-羧酸甲酰胺的制备。8-[1-甲基-3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-5-基]-[1,7]萘啶-6-羧酸乙酯(200.0mg，484.9μmol，1.0eq.)加入甲胺的乙醇溶液中(10mL)于80℃反应2h。将反应液旋干，粗产品通过厚制备板纯化(CH 2Cl 2/MeOH＝20:1)得到标题化合物为黄色固体(100.0mg，收率52％)。 1H NMR(400MHz,DMSO)δ9.17(dd,1H),8.94(d,1H),8.82(s,1H),8.71(dd,1H),8.60(s,1H),8.38(s,1H),8.28(dd,1H),8.02(d,1H),7.89(dd,1H),7.76(d,1H),4.13(s,3H),3.93(s,3H),2.94(d,3H).MS(m/z)＝398.17[M+H] +。
实验例1 CBP蛋白亲和力测定
本专利所合成化合物和CBP重组蛋白的亲和力通过竞争性HTRF方法来测定。His标签标记的环磷酸腺苷反应元件结合蛋白的结合蛋白(CREBbinding protein，CBP)在大肠杆菌系统中进行表达并进一步提纯。生物素标记的CBP配体(CBP biotinylated ligand)均为自制。转染N端His标签标记CBP蛋白基因的BL21 star(DE3)感受态细胞，37度条件下培养16小时至OD值在0.6-0.8之间，0.5mM IPTG诱导并培养过夜。细胞裂解液上清依次采用Ni离子亲和柱和Superdex75分子筛柱进行提纯。最终所得CBP蛋白纯度为95％。HTRF所需荧光供体试剂MAb Anti 6HIS-Eu cryptate Gold(Cisbio#61HI2KLA)、受体试剂Streptavidin-XL665(#610SAXLA)和检测缓冲液Detection buffer(#62SDBRDD)从Cisbio Bioassays(Codolet,France)获得。三(2-羧乙基)膦(TCEP)、氯化钠、三磷酸腺苷(ATP)、Tween-20、二甲 基亚砜(DMSO)、bovine serum albumin(BSA)和HEPES缓冲液以可获得的最高纯度水平从Sigma获得。
CBP重组蛋白亲和力竞争性HTRF测定方法一般程序：在即将进行测定之前添加0.05％Tween-20和1mM TCEP，在由0.1mg/ml BSA，50mM HEPES、pH 7.5，5mM NaCl组成的缓冲液中执行测定。将具有4％DMSO的测定缓冲液中的2.5μL化合物溶液和测定缓冲液中的5μL CBP溶液添加到白色低体积384孔微量滴定板中，室温孵育20分钟，再通过在测定缓冲液中添加2.5μL生物素标记配体溶液室温孵育40分钟。CBP、生物素标记配体和DMSO的最终浓度分别为5nM、50nM和1％。之后将来自制造商的在检测缓冲液中的5μL MAb Anti 6HIS-Eu cryptate Gold以及5μL Streptavidin-XL665，加到混合物中，接着孵育60分钟。最终Streptavidin-XL665浓度为12.5nM，MAb Anti 6HIS-Eu cryptate Gold按照供应商提供的最终浓度稀释。使用Tecan(
Figure PCTCN2021089486-appb-000063
Switzerland)多功能酶标仪Spark进行读板，检测两组均相时间分辨荧光强度，其中激发波长为320nm，并且发射波长为665nm和620nm。通过使用Prism 7(La Jolla,15CA)在S形剂量反应曲线中拟合665nm/620nm荧光强度比值相对于抑制剂浓度来获得抑制剂的IC 50值。
本申请代表性化合物的上述IC 50数据见表1。
表1
实施例 IC 50(nM) 实施例 IC 50(nM) 实施例 IC 50(nM)
1 72 2 19 3 245
4 ＞1000 5 ＞1000 6 ＞1000
7 ＞1000 8 ＞1000 9 ＞1000
10 N/A 11 ＞1000 12 ＞1000
13 21 14 15 15 7.5
16 13 17 12 18 19
19 6.9 20 18 21 38
22 22 23 18 24 7.8
25 4.2 26 11 27 3.3
28 5.3 29 16 30 22
31 49 32 36 33 44
34 32 35 16 36 12
37 16 38 14 39 13
40 62 41 57 42 50
43 6.7 44 64 45 8.5
46 5.4 47 31 48 13
49 12 50 54 51 22
52 27 53 14 54 11
55 15 56 24 57 36
58 100 59 402 60 58
61 70 62 287 63 136
64 14 65 12 66 49
“N/A”表示未测。

Claims (15)

  1. 式(I)化合物、其异构体或其药学上可接受的盐：
    Figure PCTCN2021089486-appb-100001
    其中，R 1选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5、-(CH 2)nOH或含有0-3个N、O或S原子的5-6元饱和或非饱和环；其中，所述含有0-3个N、O或S原子的5-6元饱和或非饱和环可选地被1-3个R 5取代；
    R 2选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5或-(CH 2)nOH；
    R 3选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5、-(CH 2)nOH或含有0-3个N、O或S原子的5-6元饱和或非饱和环；其中，所述含有0-3个N、O或S原子的5-6元饱和或非饱和环可选地被1-3个R 5取代；
    R 4选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5、-(CH 2)nOH或含有0-3个N、O或S原子的5-6元饱和或非饱和环；其中，所述含有0-3个N、O或S原子的5-6元饱和或非饱和环可选地被1-3个R 5取代；
    每个R 5、R 6分别独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、可选被R 7取代的3-6元杂环基、卤代C 1-C 6烷基、卤素、＝O、-(CH 2)nC(O)NR 7R 8、-C(O)R 7、-C(O)OR 7、-OR 7、-OC(O)R 7、-OC(O)OR 7、-OC(O)NR 7R 8、-(CH 2)nNR 7R 8、-SR 7、-S(O)R 7、-(CH 2)nS(O) 2R 7、-(CH 2)nOH或-(CH 2)nCN；
    每个R 7、R 8分别独立地选自氢或C 1-C 6烷基；
    Z 1为-CH 2-或-O-；
    环A为含有0-3个N、O或S原子的5-6元饱和或非饱和环；并且
    每个m、n分别独立地选自0、1、2或3。
  2. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，式(I)为式(Ia)、式(Ib)、式(Ic)、式(Id)或式(Ie)：
    Figure PCTCN2021089486-appb-100002
    其中
    R 1选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5、-(CH 2)nOH或含有0-3个N、O或S原子的5-6元饱和或非饱和环；其中，所述含有0-3个N、O或S原子的5-6元饱和或非饱和环可选地被1-3个R 5取代；
    R 2选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5或-(CH 2)nOH；
    R 3选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5、-(CH 2)nOH或含有0-3个N、O或S原子的5-6元饱和或非饱和环；其中，所述含有0-3个N、O或S原子的5-6元饱和或非饱和环可选地被1-3个R 5取代；
    R 4选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5、-(CH 2)nOH或含有0-3个N、O或S原子的5-6元饱和或非饱和环；其中，所述含有0-3个N、O或S原子的5-6元饱和或非饱和环可选地被1-3个R 5取代；
    每个R 5、R 6分别独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、可选被R 7取代的3-6元杂环基、卤代C 1-C 6烷基、卤素、＝O、-(CH 2)nC(O)NR 7R 8、-C(O)R 7、-C(O)OR 7、-OR 7、-OC(O)R 7、-OC(O)OR 7、-OC(O)NR 7R 8、-(CH 2)nNR 7R 8、-SR 7、-S(O)R 7、-(CH 2)nS(O) 2R 7、-(CH 2)nOH或-(CH 2)nCN；
    每个R 7、R 8分别独立地选自氢或C 1-C 6烷基；
    Z 1为-CH 2-或-O-；并且
    m、n分别独立地选自0、1、2或3。
  3. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，式(I)为式(If)、式(Ig)、或式(Ih)：
    Figure PCTCN2021089486-appb-100003
    Figure PCTCN2021089486-appb-100004
    其中
    R 1选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5、-(CH 2)nOH或含有0-3个N、O或S原子的5-6元饱和或非饱和环；其中，所述含有0-3个N、O或S原子的5-6元饱和或非饱和环可选地被1-3个R 5取代；
    R 2选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5或-(CH 2)nOH；
    R 3选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5、-(CH 2)nOH或含有0-3个N、O或S原子的5-6元饱和或非饱和环；其中，所述含有0-3个N、O或S原子的5-6元饱和或非饱和环可选地被1-3个R 5取代；
    R 4选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氰基、-C(O)NR 5R 6、-C(O)R 5、-C(O)OR 5、-OR 5、-OC(O)R 5、-OC(O)OR 5、-OC(O)NR 5R 6、-NR 5R 6、-SR 5、-S(O)R 5、-S(O) 2R 5、-(CH 2)nOH或含有0-3个N、O或S原子的5-6元饱和或非饱和环；其中，所述含有0-3个N、O或S原子的5-6元饱和或非饱和环可选地被1-3个R 5取代；
    每个R 5、R 6分别独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、可选被R 7取代的3-6元杂环基、卤代C 1-C 6烷基、卤素、＝O、-(CH 2)nC(O)NR 7R 8、-C(O)R 7、-C(O)OR 7、-OR 7、-OC(O)R 7、-OC(O)OR 7、-OC(O)NR 7R 8、-(CH 2)nNR 7R 8、-SR 7、-S(O)R 7、-(CH 2)nS(O) 2R 7、-(CH 2)nOH或-(CH 2)nCN；
    每个R 7、R 8分别独立地选自氢或C 1-C 6烷基；
    Z 1为-CH 2-或-O-；并且
    m、n分别独立地选自0、1、2或3。
  4. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，R 1选自氢、卤素、甲氧基、
    Figure PCTCN2021089486-appb-100005
    Figure PCTCN2021089486-appb-100006
  5. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，R 2选自-OH或-NHCH 3。
  6. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，R 3选自氢、 卤素或卤代C 1-C 6烷基。
  7. 根据权利要求6所述的化合物、其异构体或其药学上可接受的盐，其中，R 3为-CHF 2。
  8. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，R 4选自氢、-CH 2OH、-C(O)NHCH 3、
    Figure PCTCN2021089486-appb-100007
    Figure PCTCN2021089486-appb-100008
  9. 具有如下结构的化合物、其异构体或其药学上可接受的盐：
    Figure PCTCN2021089486-appb-100009
    Figure PCTCN2021089486-appb-100010
    Figure PCTCN2021089486-appb-100011
    Figure PCTCN2021089486-appb-100012
    Figure PCTCN2021089486-appb-100013
  10. 权利要求1-9任一项化合物、其异构体或其药学上可接受的盐用于制备由CBP和/或EP300介导的疾病药物中的用途。
  11. 根据权利要求10所述的用途，其中，所述CBP和/或EP300介导的疾病为癌症，炎性病症，自身免疫性疾病，病毒感染或心血管系统疾病。
  12. 根据权利要求11所述的用途，其中，所述癌症为白血病，淋巴瘤，多发性骨髓瘤，肺癌，前列腺癌，头颈癌，乳腺癌，胰腺癌，结直肠癌或黑色素瘤。
  13. 一种药物组合物，其包含治疗有效量的权利要求1-9任一项所述的化合物、其异构体或其药学上可接受的盐；以及药学上可接受的载体或赋形剂。
  14. 根据权利要求13所述的药物组合物，其还包含其它一种或多种抗癌药物。
  15. 根据权利要求14所述的药物组合物，所述抗癌药物为化疗药物。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115448919A (zh) * 2022-10-31 2022-12-09 滨州医学院附属医院 一种海洋来源的萘啶类抗炎活性化合物及其制备方法
WO2024046504A1 (zh) * 2022-08-29 2024-03-07 北京沐华生物科技有限责任公司 一种ep300/cbp调节剂及其制备方法和用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012072068A (ja) * 2010-09-28 2012-04-12 Astellas Pharma Inc 二環式へテロ環化合物
CN107108512A (zh) * 2014-10-10 2017-08-29 基因泰克公司 治疗性化合物及其用途
CN109476641A (zh) * 2016-05-24 2019-03-15 基因泰克公司 Cbp/ep300的杂环抑制剂及其在治疗癌症中的用途
WO2019204781A1 (en) * 2018-04-20 2019-10-24 Design Therapeutics Inc. Methods and compounds for the treatment of genetic disease

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016086200A1 (en) 2014-11-27 2016-06-02 Genentech, Inc. 4,5,6,7-tetrahydro-1 h-pyrazolo[4,3-c]pyridin-3-amine compounds as cbp and/or ep300 inhibitors
CN112165944B (zh) 2018-03-29 2024-04-09 德州大学系统董事会 转录激活蛋白的咪唑并哌嗪抑制剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012072068A (ja) * 2010-09-28 2012-04-12 Astellas Pharma Inc 二環式へテロ環化合物
CN107108512A (zh) * 2014-10-10 2017-08-29 基因泰克公司 治疗性化合物及其用途
CN109476641A (zh) * 2016-05-24 2019-03-15 基因泰克公司 Cbp/ep300的杂环抑制剂及其在治疗癌症中的用途
WO2019204781A1 (en) * 2018-04-20 2019-10-24 Design Therapeutics Inc. Methods and compounds for the treatment of genetic disease

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SARAH M. BRONNER, JEREMY MURRAY, F. ANTHONY ROMERO, KWONG WAH LAI, VICKIE TSUI, PATRICK CYR, MAUREEN H. BERESINI, GLADYS DE LEON B: "A Unique Approach to Design Potent and Selective Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP) Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 60, no. 24, 28 December 2017 (2017-12-28), US , pages 10151 - 10171, XP055450236, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.7b01372 *
See also references of EP4140996A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024046504A1 (zh) * 2022-08-29 2024-03-07 北京沐华生物科技有限责任公司 一种ep300/cbp调节剂及其制备方法和用途
CN115448919A (zh) * 2022-10-31 2022-12-09 滨州医学院附属医院 一种海洋来源的萘啶类抗炎活性化合物及其制备方法
CN115448919B (zh) * 2022-10-31 2024-01-26 滨州医学院附属医院 一种海洋来源的萘啶类抗炎活性化合物及其制备方法

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