WO2024109688A1 - Pyrrole fused ring derivative and pharmaceutical use thereof - Google Patents

Pyrrole fused ring derivative and pharmaceutical use thereof Download PDF

Info

Publication number
WO2024109688A1
WO2024109688A1 PCT/CN2023/132607 CN2023132607W WO2024109688A1 WO 2024109688 A1 WO2024109688 A1 WO 2024109688A1 CN 2023132607 W CN2023132607 W CN 2023132607W WO 2024109688 A1 WO2024109688 A1 WO 2024109688A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
mmol
pyrrole
compound
tolyl
Prior art date
Application number
PCT/CN2023/132607
Other languages
French (fr)
Chinese (zh)
Inventor
袁永海
贾志龙
魏用刚
许学珍
孙毅
Original Assignee
成都百裕制药股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 成都百裕制药股份有限公司 filed Critical 成都百裕制药股份有限公司
Publication of WO2024109688A1 publication Critical patent/WO2024109688A1/en

Links

Classifications

    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/535—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D401/02—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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

Definitions

  • the present invention relates to a pyrrolocyclic derivative, a pharmaceutical composition thereof and a medical application thereof.
  • Mammalian cells mainly repair DNA double-strand breaks (DSBs) through non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ or alt-EJ) pathways to ensure genome stability.
  • DNA polymerase theta (Pol ⁇ or POLQ) is a key component of the MMEJ pathway and is involved in DNA double-strand break repair.
  • Pol ⁇ is one of 15 DNA polymerases in the human genome, consisting of a C-terminal family A DNA polymerase and an N-terminal superfamily 2 (SF2) type DNA helicase separated by a long and poorly conserved central domain of unknown function.
  • SF2 N-terminal superfamily 2
  • Pol ⁇ is barely expressed in normal tissues but is highly expressed in a variety of tumor types, such as breast cancer, ovarian cancer, HNSCC, and lung cancer.
  • BRCA2 When DNA end resection occurs, in the presence of BRCA2, BRCA2 not only recruits the recombinase RAD51 to DSB to promote HR, but also inhibits repair pathways such as MMEJ.
  • HR deficiency such as BRCA1 or BRCA2 mutations
  • Pol ⁇ is highly expressed and guides DSB repair toward alt-EJ, turning on the DNA repair process of MMEJ.
  • Pol ⁇ is therefore an attractive novel synthetic lethal therapeutic target in cancers with defects in DNA repair.
  • the purpose of the present invention is to provide a new pyrrolocyclic derivative having an inhibitory effect on Pol ⁇ , or a stereoisomer thereof, and a pharmaceutical composition thereof.
  • One or more embodiments of the present application provide a compound represented by general formula (I) or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:
  • A is a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O and S;
  • B is a 5-12 membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S;
  • C is a 5-12 membered aromatic group
  • X is N
  • Ra may be the same or different, and each Ra is independently H, C1-6 alkyl or OH, wherein the C1-6 alkyl is optionally substituted with 1 or more halogens; for example, 1, 2 or 3 halogens;
  • R b may be the same or different, and each R b is independently H, C 1-6 alkyl, CN or CONH 2 , wherein the C 1-6 alkyl is optionally substituted with 1 or more halogens; for example, 1, 2 or 3 halogens;
  • R1 is C1-3 alkyl
  • R c may be the same or different, R c is H or C 1-6 alkyl;
  • a 0, 1, 2 or 3;
  • b is 2 or 3;
  • the halogen is F.
  • One or more embodiments of the present application provide a compound represented by general formula (I), or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:
  • A is a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl contains 1 to 4 O;
  • B is a 5-8 membered heteroaryl group, wherein the 5-8 membered heteroaryl group contains 1-3 N, such as 1, 2 or 3 N;
  • C is a 5-8 membered aromatic group
  • Ra may be the same or different, and each Ra is independently H, C 1-3 alkyl or OH, and the C 1-3 alkyl is optionally further substituted by one or more halogens;
  • R b may be the same or different, R b is H, C 1-3 alkyl, CN or CONH 2 , and the C 1-3 alkyl is optionally substituted by one or more halogens;
  • R c may be the same or different, and each R c is independently H or C 1-3 alkyl;
  • a 0, 1, or 2;
  • b 2 or 3.
  • One or more embodiments of the present application provide a compound of formula (I), or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:
  • A is a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl contains 1 O;
  • B is a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group contains 1-3 N; for example, 1 N;
  • C is a 6-membered aryl group.
  • One or more embodiments of the present application provide a compound or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:
  • One or more embodiments of the present application provide a pharmaceutical composition, which comprises the above-mentioned compound of the present application or its stereoisomer or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, and one or more pharmaceutically acceptable carriers and/or excipients, and optionally one or more other active ingredients.
  • One or more embodiments of the present application provide the use of the pharmaceutical composition of the present application or the compound of the present application or its stereoisomer or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal in the preparation of a medicament for preventing and/or treating cancer or tumor.
  • the cancer is breast cancer, ovarian cancer, head and neck squamous cell carcinoma (HNSCC), and lung cancer.
  • HNSCC head and neck squamous cell carcinoma
  • One or more embodiments of the present application provide a pharmaceutical composition of the present application or a compound of the present application.
  • One or more embodiments of the present application provide a compound or composition of the present application for preventing and/or treating a disease.
  • One or more embodiments of the present application provide a compound or composition of the present application for preventing and/or treating cancer or tumor.
  • One or more embodiments of the present application provide a compound or composition of the present application for preventing and/or treating breast cancer, ovarian cancer, head and neck squamous cell carcinoma (HNSCC) and lung cancer.
  • HNSCC head and neck squamous cell carcinoma
  • One or more embodiments of the present application provide a compound or composition of the present application for preventing and/or treating a disease associated with Pol ⁇ enzyme.
  • One or more embodiments of the present application provide a method for preventing and/or treating a disease, comprising administering a compound or composition of the present application to an object in need thereof.
  • One or more embodiments of the present application provide a method for preventing and/or treating a cancer or tumor, comprising administering a compound or composition of the present application to an object in need thereof.
  • One or more embodiments of the present application provide a method for preventing and/or treating breast cancer, ovarian cancer, head and neck squamous cell carcinoma (HNSCC) and lung cancer, which comprises administering the compound or composition of the present application to a subject in need thereof.
  • HNSCC head and neck squamous cell carcinoma
  • One or more embodiments of the present application provide a method for preventing and/or treating a disease associated with Pol ⁇ enzyme, which comprises administering the compound or composition of the present application to a subject in need thereof.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include pro
  • Alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms, More preferably, the alkyl group has 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.
  • Cycloalkyl refers to a saturated cyclic hydrocarbon group, which can be a 3-10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4-12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10-20-membered polycyclic ring system (e.g., 11, 12, 13, 14, 15, 16, 17, 18, 19-membered) ring carbon atom preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, and further preferably 3 to 8 carbon atoms.
  • Non-limiting examples of "cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cycloheptatrienyl. When substituted, it may be optionally further substituted with zero or more substituents.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated non-aromatic cyclic group, which may be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1, 2 or 3 heteroatoms selected from N, O and S, preferably a 3-8 membered heterocyclic ring.
  • heterocycloalkyl may be oxidized to various oxidation states; “heterocycloalkyl” may be attached to a heteroatom or a carbon atom; “heterocycloalkyl” may be a bridged ring or a spiro ring.
  • heterocycloalkyl include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptanyl.
  • Heterocycle or “heterocyclic group” refers to a saturated or unsaturated aromatic heterocycle or non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the above “heteroaryl”; when it is a non-aromatic heterocycle, it can be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O and S, preferably a 3-8 membered heterocyclic group.
  • 1 to 4 e.g., 1, 2, 3, 4
  • heteroatoms selected from N, O and S, preferably a 3-8 membered heterocyclic group.
  • the 1 to 4 (e.g., 1, 2, 3, 4) N and S optionally substituted in the ring of the "heterocyclic group” or “heterocycle” can be oxidized to various oxidation states; the "heterocyclic group” or “heterocycle” can be attached to the heteroatom or on a carbon atom; “heterocyclic group” or “heterocycle” may be a cyclic, bridged or spirocyclic ring.
  • the “heterocyclic group” or “heterocycle” may be further substituted by one or more substituents.
  • Aryl refers to a substituted or unsubstituted aromatic ring, which can be a 5-8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, a 5-12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10-15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, which can be a bridged ring or a spirocyclic ring, non-limiting examples include phenyl and naphthyl.
  • the aryl group can be optionally further substituted by one or more substituents.
  • Heteroaryl refers to a substituted or unsubstituted aromatic ring, which can be a monocyclic ring of 3 to 12 members (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 members), and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O and S, preferably 5 to 8 heteroaryls.
  • the heteroaryl group can be attached to a heteroatom or a carbon atom, and the heteroaryl group can be a bridged ring or a spirocyclic ring, and non-limiting examples include cyclopyridyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl.
  • the heteroaryl group is optionally further substituted by one or more substituents.
  • “Pharmaceutical composition” refers to a mixture of one or more compounds described herein, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
  • Carrier refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.
  • Steps refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.
  • heterocyclyl optionally substituted with alkyl means that the alkyl group may but need not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl group and instances where the heterocyclyl group is not substituted with alkyl group.
  • reaction temperature is room temperature, and the most suitable reaction temperature is 20°C-30°C;
  • the raw material 3-azabicyclo[3.3.0]octane hydrochloride 1a (10 g) was added in batches to 10% sodium hypochlorite aqueous solution (60 mL) and 25 mL MTBE, and the reaction was continued for 2 h. TLC plate confirmed that the reaction was complete. After standing, the mixture was extracted with MTBT (20 mL ⁇ 2), and the obtained organic phase was directly used in the next reaction.
  • LiAlH4 (10.1 g, 263 mmol) was slowly added to 300 mL of tetrahydrofuran. After completion, the mixture was heated at 0 °C. Slowly add 2b (41g in 100mL THF) dropwise. After the reaction is complete as detected by LC-MS, add water to quench the reaction, filter through celite, and concentrate the filtrate under reduced pressure to obtain the target product 2c. (Crude product, 44g)
  • N-methyl-N-(m-tolyl)hexahydro-1H-furan[3,4-c]pyrrole-4-carboxamide 3a (254 mg, 1.0 mmol) was dissolved in N-methylpyrrolidone (3 mL), followed by the addition of N,N-diisopropylethylamine (387 mg, 3.0 mmol) and 2-bromo-6-methyl-4-trifluoromethylpyridine (288 mg, 1.2 mmol), and the mixture was heated to 140°C for 4 h.
  • Tetrahydrocyclopentadienyl[c]pyrrole-1,3(2H,3aH)-dione 5a (10.0 g, 71.86 mmol) was dissolved in anhydrous ethanol (100 ml), then cooled to -10°C, sodium borohydride (8.16 g, 215.59 mmol) was added, and the mixture was stirred for 30 minutes. Then, 1M sulfuric acid ethanol solution (14 mL) was added dropwise. After the addition was complete, the mixture was returned to room temperature for reaction for 1 hour. The temperature was then lowered to -10°C, and the pH was adjusted to 2 with 6N sulfuric acid ethanol solution.
  • reaction solution was directly quenched by adding water (30 mL), extracted with ethyl acetate (50 mL ⁇ 3), and the organic phases were combined, dried, and concentrated to obtain an oily crude product.
  • the crude product was prepared by reverse phase liquid phase to obtain compound 5 (white solid, 78 mg, 12% yield).
  • trimethyl sulfoxide iodide (3.5 g, 15.8 mmol) was dissolved in 10 mL of dimethyl sulfoxide, and a dimethyl sulfoxide solution (5 mL) of sodium hydride (633.6 mg, 15.8 mmol) was added in batches under an ice bath, and stirred at room temperature for 30 minutes. Then a dimethyl sulfoxide solution (5 mL) of 7c (4.3 g, 14.4 mmol) was added dropwise, and the mixture was reacted at 60 ° C for 5 h.
  • 3-Azabicyclo[3.1.0]hex-2-ene 9c (6.0 g, 73.97 mmol) was dissolved in anhydrous dichloromethane (100 mL) and methanol (10 mL), then cooled to 0 degrees, trimethylsilyl cyanide (11.01 g, 110.95 mmol) was added dropwise, and then the temperature was maintained for 2 hours.
  • 3-Azabicyclo[3.1.0]hexane-2-carbonitrile 9d (2.5 g, 23.12 mmol) was dissolved in 6N hydrochloric acid solution (40 mL), and the temperature was heated to 90°C for 2 h. The reaction solution was then directly concentrated to dryness, and then sodium hydroxide solution was added to adjust the pH to 8, and re-concentrated to dryness to obtain 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (light yellow solid 10.0 g), which was directly used in the next step.
  • 3-Azabicyclo[3.1.0]hexane-2-carboxylic acid 9e (666 mg, 1.57 mmol, content 30%), 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (416 mg, 1.89 mmol), diisopropylethylamine (609 mg, 4.72 mmol) were dissolved in N-methylpyrrolidone (2 mL), and then the reaction solution was heated to 100 degrees for 1 hour. After cooling to room temperature, ethyl acetate (50 mL) was added, followed by water (25 mL) and saturated brine (25 mL), and the organic phase was dried and concentrated to obtain an oily crude product.
  • the raw material octahydro-1H-isoindole (5.0 g, 40.0 mmol) was dissolved in methyl tert-butyl ether (50 mL), and sodium hypochlorite solution (10% aqueous solution) (38.5 ml, 51.8 mmol) was added, and the reaction solution was reacted at 0°C for 4 hours. After the reaction was completed, the reaction mixture was extracted, and the aqueous phase was extracted three times with methyl tert-butyl ether (20 ml ⁇ 3). The organic phases were combined, and then a prepared sodium hydroxide solution (5.4 g of sodium hydroxide in 16.2 ml of aqueous solution) was added.
  • reaction mixture was heated to 50° C. for 5 hours, and then the reaction mixture was extracted.
  • the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 10b (light yellow liquid, 4.0 g, 81.3% yield).
  • reaction solution was cooled to about 10°C, and the pH value was adjusted to about 5 with 1N hydrochloric acid, and then extracted with ethyl acetate (40 ml ⁇ 3), the organic phases were combined, and then washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by column chromatography to obtain 10e (white solid crude product, 2.5 g, 74.9% yield).
  • the raw material 7-(methyl(m-tolyl)carbamoyl)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (1.0 g, 2.7 mmol) was added to dichloromethane (10 ml), and then trifluoroacetic acid (10 ml) was added.
  • the reaction mixture was reacted at room temperature for 4 hours. After the reaction was completed, it was concentrated under reduced pressure to a solid. Then 1 mL of N-methylpyrrolidone and 5 mL of N, N-diisopropylethylamine were added.
  • the raw material 2-cyano-2-((trimethylsilyl)oxy)cyclopentane-1-carboxylic acid methyl ester (30 g, 12.4 mmol) was added to the reaction bottle, and then methanol (1.2 L) was added to dissolve.
  • Nickel chloride (32.1 g, 24.8 mmol) was added, the reaction mixture was cooled to below 10°C, sodium borohydride (46.9 g, 124.0 mmol) was slowly added, and the reaction temperature was controlled below 10°C, and the reaction was exothermic. After the addition was completed, the temperature was slowly raised to room temperature for 4 hours.
  • 2-Chlorocyclopent-1-ene-1-carboxaldehyde 12b (3.0 g, 23 mmol) and trimethylsilyl cyanide (3.42 g, 34.5 mmol) were mixed and zinc iodide (733 mg, 2.3 mmol) was added and the mixture was reacted in an ice bath for 1 hour.
  • ammonia methanol solution 120 mL, 7 M was added, the mixture was ice bathed to 0 degrees, and then the previous reaction solution was added dropwise, and the reaction was maintained for 1 hour, and then the temperature was raised to 50 degrees for 1 hour.
  • 2-Amino-2-(2-chlorocyclopent-1-ene-1-yl)acetonitrile 12c (3.0 g, 19.2 mmol) was dissolved in 6N hydrochloric acid solution (40 mL), heated to 100 degrees and reacted for 2 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness to obtain 2-amino-2-(2-chlorocyclopent-1-ene-1-yl)acetic acid 12d (3.0 g, gray solid), which was directly used for the next step reaction.
  • 2-Amino-2-(2-chlorocyclopent-1-ene-1-yl)acetic acid 12d (3.0 g, 19.09 mmol) was dissolved in tetrahydrofuran (20 mL) and water (20 mL), followed by the addition of sodium bicarbonate (4.81 g, 52.27 mmol), followed by the addition of di-tert-butyl carbonate (4.17 g, 19.09 mmol) in an ice bath. After 30 minutes, the mixture was heated to 40 degrees and reacted for 2 hours.
  • reaction solution was poured into water (50 mL), extracted with ethyl acetate (50X 3), the organic phases were combined, dried, and concentrated to obtain a crude product.
  • the compound was prepared into a 10 mM stock solution with DMSO, and the stock solution was serially diluted with 1% DMSO (v/v) (initial concentration 10 ⁇ M, 1:3 dilution, 10 gradients). 0.1 ⁇ L of each diluted compound was transferred to a 384-well plate (PerkinElmer, 6008260); 2 replicates were performed for each concentration.
  • DLD1 BRCA-/- cells in the logarithmic growth phase were digested with trypsin, resuspended and counted.
  • Cells 200 cells/well were seeded in a transparent 12-well plate (Corning, 3460) and cultured overnight in a 37°C incubator (5% CO 2 ).
  • the compound was prepared into a 10 mM stock solution with DMSO, and the stock solution was serially diluted in 1640 medium (containing 10% FBS, 1% Penicillin-Streptomycin) with 0.1% DMSO (v/v) (initial concentration 10 ⁇ M, 1:3 dilution, 5 gradients).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a pyrrole fused ring derivative or a stereoisomer thereof, a pharmaceutical composition thereof, and the pharmaceutical use thereof; and specifically relates to a pyrrole fused ring derivative as shown in general formula (I), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt or a co-crystal thereof, a pharmaceutical composition comprising same, and the use of the compound or composition of the present application in the preparation of a drug for treating cancer. The compound of the present invention has therapeutic effects on Polθ-mediated cancers or tumors, and also has a good selectivity and low side effects.

Description

一种吡咯并环类衍生物及其在医药上的应用A pyrrolocyclic derivative and its application in medicine 技术领域Technical Field
本发明涉及一种吡咯并环类衍生物，其药物组合物以及其在医药上的用途。The present invention relates to a pyrrolocyclic derivative, a pharmaceutical composition thereof and a medical application thereof.
背景技术Background technique
哺乳动物细胞主要通过非同源末端连接(NHEJ)、同源重组(HR)和微同源介导的末端连接(MMEJ或alt-EJ)途径来修复DNA双链断裂(DSB)以确保基因组稳定性。DNA聚合酶theta(Polθ或POLQ)是MMEJ通路的关键组成部分，参与DNA双链断裂修复。Mammalian cells mainly repair DNA double-strand breaks (DSBs) through non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ or alt-EJ) pathways to ensure genome stability. DNA polymerase theta (Polθ or POLQ) is a key component of the MMEJ pathway and is involved in DNA double-strand break repair.
Polθ是人类基因组中15种DNA聚合酶之一，包含一个C-末端A家族DNA聚合酶和N末端超家族2(SF2)型DNA解旋酶，中间由长且保守程度较低的未知功能中心域隔开。Polθ is one of 15 DNA polymerases in the human genome, consisting of a C-terminal family A DNA polymerase and an N-terminal superfamily 2 (SF2) type DNA helicase separated by a long and poorly conserved central domain of unknown function.
Polθ在正常组织中的几乎不表达，但在多种肿瘤类型(如乳腺癌、卵巢癌、HNSCC和肺癌)中高表达。当发生DNA末端切除时，在存在BRCA2的情况下，BRCA2不仅将重组酶RAD51募集到DSB以促进HR，而且还抑制MMEJ等修复途径。当同源重组介导的修复受到损害时(HR缺陷)，如BRCA1或BRCA2突变，Polθ高度表达并引导DSB修复朝向alt-EJ，开启MMEJ的DNA修复过程。在HR缺陷的情况下，Polθ的抑制通过毒性RAD51中间体的积累和alt-EJ修复途径的抑制，导致细胞死亡(Jia Zhou，et al.A first-in-class polymerase theta inhibitor selectively targets homologous-recombinationdeficient tumors.Nature Cancer，2021：598-610)。Polθ is barely expressed in normal tissues but is highly expressed in a variety of tumor types, such as breast cancer, ovarian cancer, HNSCC, and lung cancer. When DNA end resection occurs, in the presence of BRCA2, BRCA2 not only recruits the recombinase RAD51 to DSB to promote HR, but also inhibits repair pathways such as MMEJ. When homologous recombination-mediated repair is impaired (HR deficiency), such as BRCA1 or BRCA2 mutations, Polθ is highly expressed and guides DSB repair toward alt-EJ, turning on the DNA repair process of MMEJ. In the case of HR deficiency, inhibition of Polθ leads to cell death through the accumulation of toxic RAD51 intermediates and inhibition of the alt-EJ repair pathway (Jia Zhou, et al. A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. Nature Cancer, 2021: 598-610).
因此，在DNA修复缺陷的癌症中，Polθ是一种具有吸引力的新型合成致死治疗靶点。Polθ is therefore an attractive novel synthetic lethal therapeutic target in cancers with defects in DNA repair.
发明内容Summary of the invention
本发明的目的是提供一种对Polθ具有抑制作用的新的吡咯并环类衍生物，或者其立体异构体，其药物组合物。The purpose of the present invention is to provide a new pyrrolocyclic derivative having an inhibitory effect on Polθ, or a stereoisomer thereof, and a pharmaceutical composition thereof.
本申请的一个或多个实施方式提供一种通式(I)所示化合物或者其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶：
One or more embodiments of the present application provide a compound represented by general formula (I) or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:
其中：in:
A为3-8元环烷基或3-8元杂环烷基，所述3-8元杂环烷基包含1至4个选自N、O和S的杂原子；A is a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O and S;
B为5-12元杂芳基，所述5-12元杂芳基包含1至4个选自N、O和S的杂原子；B is a 5-12 membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S;
C为5-12元芳基；C is a 5-12 membered aromatic group;
X为N；X is N;
Ra可以相同或者不同，Ra各自独立地为H、C1-6烷基或OH，，所述C1-6烷基任选地被1个或者多个卤素取代；例如，1、2或3个卤素； Ra may be the same or different, and each Ra is independently H, C1-6 alkyl or OH, wherein the C1-6 alkyl is optionally substituted with 1 or more halogens; for example, 1, 2 or 3 halogens;
R2、R3为H，或者R2、R3与相连的碳原子形成＝O；R 2 and R 3 are H, or R 2 and R 3 form ＝O with the carbon atom to which they are connected;
Rb可以相同或者不同，Rb各自独立地为H、C1-6烷基、CN或CONH2，所述C1-6烷基任选地被1个或者多个卤素取代；例如，1、2或3个卤素；R b may be the same or different, and each R b is independently H, C 1-6 alkyl, CN or CONH 2 , wherein the C 1-6 alkyl is optionally substituted with 1 or more halogens; for example, 1, 2 or 3 halogens;
R1为C1-3烷基； R1 is C1-3 alkyl;
Rc可以相同或者不同，Rc为H或C1-6烷基；R c may be the same or different, R c is H or C 1-6 alkyl;
a为0、1、2或3；a is 0, 1, 2 or 3;
b为2或3；b is 2 or 3;
c为1。c is 1.
在一个或多个实施方式中，所述卤素为F。In one or more embodiments, the halogen is F.
本申请的一个或多个实施方式提供一种通式(I)所示化合物，或者其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶：One or more embodiments of the present application provide a compound represented by general formula (I), or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:
其中：in:
A为3-6元环烷基或3-6元杂环烷基，所述3-6元杂环烷基包含1至4个O；A is a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl contains 1 to 4 O;
B为5-8元杂芳基，所述5-8元杂芳基含有1-3个N；例如1、2或3个N；B is a 5-8 membered heteroaryl group, wherein the 5-8 membered heteroaryl group contains 1-3 N, such as 1, 2 or 3 N;
C为5-8元芳基；C is a 5-8 membered aromatic group;
Ra可以相同或者不同，Ra各自独立地为H、C1-3烷基或OH，所述C1-3烷基任选地进一步被1个或者多个卤素取代； Ra may be the same or different, and each Ra is independently H, C 1-3 alkyl or OH, and the C 1-3 alkyl is optionally further substituted by one or more halogens;
R2、R3为H，或者R2、R3与相连的碳原子形成＝O；R 2 and R 3 are H, or R 2 and R 3 form ＝O with the carbon atom to which they are connected;
Rb可以相同或者不同，Rb为H、C1-3烷基、CN或CONH2，所述C1-3烷基任选地被1个或者多个卤素取代；R b may be the same or different, R b is H, C 1-3 alkyl, CN or CONH 2 , and the C 1-3 alkyl is optionally substituted by one or more halogens;
Rc可以相同或者不同，Rc各自独立地为H或C1-3烷基；R c may be the same or different, and each R c is independently H or C 1-3 alkyl;
a为0、1或2；a is 0, 1, or 2;
b为2或3。b is 2 or 3.
本申请的一个或多个实施方式提供一种通式(I)化合物，或者其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶：One or more embodiments of the present application provide a compound of formula (I), or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:
其中：in:
A为3-6元环烷基或3-6元杂环烷基，所述3-6元杂环烷基包含1个O；A is a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl contains 1 O;
B为6元杂芳基，所述6元杂芳基含有1-3个N；例如，1个N；B is a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group contains 1-3 N; for example, 1 N;
C为6元芳基。C is a 6-membered aryl group.
本申请的一个或多个实施方式提供一种化合物或者其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶：

One or more embodiments of the present application provide a compound or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:

本申请的一个或多个实施方式提供了药物组合物，所述药物组合物包含上述本申请的化合物或其立体异构体或其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶，和一种或者多种药学上可接受的载体和/或赋形剂，以及任选的一种或者多种其他活性成分。One or more embodiments of the present application provide a pharmaceutical composition, which comprises the above-mentioned compound of the present application or its stereoisomer or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, and one or more pharmaceutically acceptable carriers and/or excipients, and optionally one or more other active ingredients.
本申请一个或多个实施方式提供了本申请的药物组合物或者本申请的化合物或其立体异构体或其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶在制备用于预防和/或治疗癌症或肿瘤的药物中的用途。One or more embodiments of the present application provide the use of the pharmaceutical composition of the present application or the compound of the present application or its stereoisomer or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal in the preparation of a medicament for preventing and/or treating cancer or tumor.
在一个或多个实施方式中，所述癌症为乳腺癌、卵巢癌、头颈部鳞状细胞癌(HNSCC)和肺癌。In one or more embodiments, the cancer is breast cancer, ovarian cancer, head and neck squamous cell carcinoma (HNSCC), and lung cancer.
本申请一个或多个实施方式提供了本申请的药物组合物或者本申请的化合 物或其立体异构体或其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶在制备用于治疗和/或预防与Polθ酶相关的疾病的药物中的用途。One or more embodiments of the present application provide a pharmaceutical composition of the present application or a compound of the present application. Use of a compound or a stereoisomer thereof or a stereoisomer thereof, a solvate, a prodrug, a metabolite, a deuterated compound, a pharmaceutically acceptable salt or a co-crystal in the preparation of a medicament for treating and/or preventing a disease associated with the Pol θ enzyme.
本申请的一个或多个实施方式提供了本申请的化合物或组合物，其用于预防和/或治疗疾病。One or more embodiments of the present application provide a compound or composition of the present application for preventing and/or treating a disease.
本申请的一个或多个实施方式提供了本申请的化合物或组合物，其用于预防和/或治疗癌症或肿瘤。One or more embodiments of the present application provide a compound or composition of the present application for preventing and/or treating cancer or tumor.
本申请的一个或多个实施方式提供了本申请的化合物或组合物，其用于预防和/或治疗乳腺癌、卵巢癌、头颈部鳞状细胞癌(HNSCC)和肺癌。One or more embodiments of the present application provide a compound or composition of the present application for preventing and/or treating breast cancer, ovarian cancer, head and neck squamous cell carcinoma (HNSCC) and lung cancer.
本申请的一个或多个实施方式提供了本申请的化合物或组合物，其用于预防和/或治疗与Polθ酶相关的疾病。One or more embodiments of the present application provide a compound or composition of the present application for preventing and/or treating a disease associated with Pol θ enzyme.
本申请的一个或多个实施方式提供了预防和/或治疗疾病的方法，其包括将本申请的化合物或组合物施用于有此需要的对象。本申请的一个或多个实施方式提供了预防和/或治疗癌症或肿瘤的方法，其包括将本申请的化合物或组合物施用于有此需要的对象。One or more embodiments of the present application provide a method for preventing and/or treating a disease, comprising administering a compound or composition of the present application to an object in need thereof. One or more embodiments of the present application provide a method for preventing and/or treating a cancer or tumor, comprising administering a compound or composition of the present application to an object in need thereof.
本申请的一个或多个实施方式提供了预防和/或治疗乳腺癌、卵巢癌、头颈部鳞状细胞癌(HNSCC)和肺癌的方法，其包括将本申请的化合物或组合物施用于有此需要的对象。One or more embodiments of the present application provide a method for preventing and/or treating breast cancer, ovarian cancer, head and neck squamous cell carcinoma (HNSCC) and lung cancer, which comprises administering the compound or composition of the present application to a subject in need thereof.
本申请的一个或多个实施方式提供了预防和/或治疗与Polθ酶相关的疾病的方法，其包括将本申请的化合物或组合物施用于有此需要的对象。One or more embodiments of the present application provide a method for preventing and/or treating a disease associated with Pol θ enzyme, which comprises administering the compound or composition of the present application to a subject in need thereof.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated otherwise, the terms used in the specification and claims have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基，优选为1至8个碳原子的烷基，更优选为1至6个(例如1、2、3、4、5、6个)碳原子的烷基， 进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；当烷基被取代基时，可以任选进一步被1个或者多个取代基所取代。"Alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms, More preferably, the alkyl group has 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.
“环烷基”是指饱和的环烃基，其环可以为3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至20元多环体系(例如11、12、13、14、15、16、17、18、19元)，环碳原子优选3至10个(例如3、4、5、6、7、8、9、10个)碳原子，进一步优选3至8个碳原子。“环烷基”非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1，5-环辛二烯基、1，4-环己二烯基和环庚三烯基等。当被取代时，可以任选进一步被0个或者多个取代基所取代。"Cycloalkyl" refers to a saturated cyclic hydrocarbon group, which can be a 3-10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4-12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10-20-membered polycyclic ring system (e.g., 11, 12, 13, 14, 15, 16, 17, 18, 19-membered) ring carbon atom preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, and further preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cycloheptatrienyl. When substituted, it may be optionally further substituted with zero or more substituents.
“杂环烷基”是指取代的或未取代的饱和非芳香环基，其可以是3至8元(例如3、4、5、6、7、8元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如11、12、13、14、15元)三环体系，且包含1、2或3个选自N、O和S的杂原子，优选3至8元杂环基。“杂环烷基”的环中选择性取代的N、S可被氧化成各种氧化态；“杂环烷基”可以连接在杂原子或者碳原子上；“杂环烷基”可以为桥环或者螺环。“杂环烷基”非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1，3-二氧戊环基、1，4-二氧戊环基、1，3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1，3-二噻烷基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。"Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group, which may be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1, 2 or 3 heteroatoms selected from N, O and S, preferably a 3-8 membered heterocyclic ring. The N and S optionally substituted in the ring of "heterocycloalkyl" may be oxidized to various oxidation states; "heterocycloalkyl" may be attached to a heteroatom or a carbon atom; "heterocycloalkyl" may be a bridged ring or a spiro ring. Non-limiting examples of “heterocycloalkyl” include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptanyl.
“杂环”或“杂环基”是指饱和或不饱和的芳香性杂环或者非芳香性杂环，当为芳香性杂环时，其定义与上文“杂芳基”定义相同；当为非芳香性杂环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至4个(例如1、2、3、4个)选自N、O和S的杂原子，优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态；“杂环基”或“杂环”可以连接在杂原子 或者碳原子上；“杂环基”或“杂环”可以为并环、桥环或者螺环。所述的“杂环基”或“杂环”可以任选进一步被1个或者多个取代基所取代。"Heterocycle" or "heterocyclic group" refers to a saturated or unsaturated aromatic heterocycle or non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the above "heteroaryl"; when it is a non-aromatic heterocycle, it can be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O and S, preferably a 3-8 membered heterocyclic group. The 1 to 4 (e.g., 1, 2, 3, 4) N and S optionally substituted in the ring of the "heterocyclic group" or "heterocycle" can be oxidized to various oxidation states; the "heterocyclic group" or "heterocycle" can be attached to the heteroatom or on a carbon atom; "heterocyclic group" or "heterocycle" may be a cyclic, bridged or spirocyclic ring. The "heterocyclic group" or "heterocycle" may be further substituted by one or more substituents.
“芳基”是指是指取代的或未取代的芳香环，其可以是5至8元(例如5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，其可以是桥环或者螺环，非限制性实例包括苯基、萘基。所述的芳基可以任选进一步被1个或者多个取代基所取代。"Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5-8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, a 5-12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10-15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, which can be a bridged ring or a spirocyclic ring, non-limiting examples include phenyl and naphthyl. The aryl group can be optionally further substituted by one or more substituents.
“杂芳基”是指取代的或未取代的芳香环，其可以是3至12元(例如3、4、5、6、7、8、9、10、11、12元)的单环，且包含1至6个(例如1、2、3、4、5、6个)选自N、O和S的杂原子，优选5至8元杂芳基。杂芳基可以连接在杂原子或者碳原子上，杂芳基可以是桥环或者螺环，非限制性实例包括环吡啶基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基。杂芳基任选进一步被1个或多个取代基所取代。"Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a monocyclic ring of 3 to 12 members (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 members), and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O and S, preferably 5 to 8 heteroaryls. The heteroaryl group can be attached to a heteroatom or a carbon atom, and the heteroaryl group can be a bridged ring or a spirocyclic ring, and non-limiting examples include cyclopyridyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl. The heteroaryl group is optionally further substituted by one or more substituents.
当上文所述的“烷基”、“杂环”、“杂环基”、“环烷基”、“杂环烷基”、“芳基”或者“杂芳基”被取代时，可以任选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C1-6烷基氨基、＝O、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-NRq4Rq5、＝NRq6、-C(＝O)OC1-6烷基、-OC(＝O)C1-6烷基、-C(＝O)NRq4Rq5、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-C(＝O)OC6-10芳基、-OC(＝O)C6-10芳基、-OC(＝O)C5-10杂芳基、-C(＝O)OC5-10杂芳基、-OC(＝O)C3-8杂环烷基、-C(＝O)OC3-8杂环烷基、-OC(＝O)C3-8环烷基、-C(＝O)OC3-8环烷基、-NHC(＝O)C3-8杂环烷基、-NHC(＝O)C6-10芳基、-NHC(＝O)C5-10杂芳基、-NHC(＝O)C3-8环烷基、-NHC(＝O)C3-8杂环烷基、-NHC(＝O)C2-6烯基和-NHC(＝O)C2-6炔基的取代基所取代，且其中所述的取代基C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-NHC(＝O)C6-10芳基、-NHC(＝O)C5-10杂芳基、-NHC(＝O)C3-8杂环烷基或者-NHC(＝O)C3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、-NRq4Rq5和＝O的取代基所取代；Rq1选自C1-6烷基、C1-6烷氧基和C6-10芳基；Rq2、Rq3选自H和C1-6烷基；Rq4、Rq5选自H、C1-6烷基、-NH(C＝NRq1)NRq2Rq3、-S(＝O)2NRq2Rq3、-C(＝O)Rq1和-C(＝O)NRq2Rq3，其中所述的C1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C1-6烷基、 C1-6烷氧基、C6-10芳基、C5-10杂芳基、C3-8环烷基和C3-8杂环烷基的取代基所取代；或者Rq4与Rq5及N原子形成一个3至8元杂环，所述的环可以含有1个或者多个选自N、O和S的杂原子。When the above-mentioned “alkyl”, “heterocycle”, “heterocyclyl”, “cycloalkyl”, “heterocycloalkyl”, “aryl” or “heteroaryl” is substituted, it may be further optionally substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 groups selected from F, Cl, Br, I, hydroxyl, thiol, nitro, cyano, amino, C 1-6 alkylamino, =O, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -NR q4 R q5 , =NR q6 , -C(=O)OC 1-6 alkyl, -OC(=O)C 1-6 alkyl, -C(=O)NR q4 R q5 , C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -C(=O)OC 6-10 aryl, -OC(=O)C The alkylene groups are C 6-10 aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 3-8 heterocycloalkyl, -C(=O)OC 3-8 heterocycloalkyl, -OC(=O)C 3-8 cycloalkyl, -C(=O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 2-6 alkenyl and -NHC(=O)C 2-6 alkynyl, and the alkylene groups are C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C wherein the cycloalkyl is optionally further substituted with 1 to 3 substituents selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy , -NR q4 R q5 and ＝O; R q1 is selected from C 1-6 alkyl, C 1-6 alkoxy and C 6-10 aryl; R q2 , R q3 is selected from H and C 1-6 alkyl; R q4 , R q5 is selected from H, C 1-6 alkyl , -NH(C ＝ NR q1 )NR q2 R q3 , -S ( ＝ O ) 2 NR q2 R q3 , -C(=O)R q1 and -C(=O)NR q2 R q3 , wherein the C 1-6 alkyl group is optionally further substituted by one or more selected from OH, F, Cl, Br, I, C 1-6 alkyl, R q4 is substituted with a C 1-6 alkoxy, C 6-10 aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl and C 3-8 heterocycloalkyl substituent; or R q4 , R q5 and the N atom form a 3 to 8 membered heterocyclic ring, and the ring may contain one or more heteroatoms selected from N, O and S.
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。"Pharmaceutical composition" refers to a mixture of one or more compounds described herein, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。"Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“任选地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。"Optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl group and instances where the heterocyclyl group is not substituted with alkyl group.
具体实施方式Detailed ways
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.
实施例中无特殊说明，反应的温度为室温，室温最适宜的反应温度，为20℃-30℃；Unless otherwise specified in the examples, the reaction temperature is room temperature, and the most suitable reaction temperature is 20°C-30°C;
MTBE：甲基叔丁基醚。MTBE: methyl tert-butyl ether.
实施例1Example 1
2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)八氢环戊烷[c]吡咯-1-甲酰胺化合物12-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopentane[c]pyrrole-1-carboxamide compound 1
2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
(1S)-2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)八氢环 戊烷[c]吡咯-1-甲酰胺化合物1-A(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopentadienyl Pentane[c]pyrrole-1-carboxamide compound 1-A
(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
(1R)-2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)八氢环戊烷[c]吡咯-1-甲酰胺化合物1-B(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide Compound 1-B
(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
第一步：first step:
2-氯八氢环戊并[c]吡咯1b2-Chlorooctahydrocyclopenta[c]pyrrole 1b
2-chlorooctahydrocyclopenta[c]pyrrole2-chlorooctahydrocyclopenta[c]pyrrole
在0℃下，将原料3-氮杂双环[3.3.0]辛烷盐酸盐1a(10g)分批加入到10％次氯酸钠水溶液中(60mL)和25mL MTBE中，继续反应2h。TLC板确认反应完全 后，静置，MTBT(20mL×2)萃取，所得有机相直接用于下一步反应。At 0°C, the raw material 3-azabicyclo[3.3.0]octane hydrochloride 1a (10 g) was added in batches to 10% sodium hypochlorite aqueous solution (60 mL) and 25 mL MTBE, and the reaction was continued for 2 h. TLC plate confirmed that the reaction was complete. After standing, the mixture was extracted with MTBT (20 mL×2), and the obtained organic phase was directly used in the next reaction.
LCMS m/z(ESI)＝146.1[M+1].LCMS m/z(ESI)＝146.1[M+1].
第二步：Step 2:
1，3a，4，5，6，6a-六氢环戊[c]吡咯1c1,3a,4,5,6,6a-Hexahydrocyclopenta[c]pyrrole 1c
1，3a，4，5，6，6a-hexahydrocyclopenta[c]pyrrole1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole
将25％氢氧化钠水溶液(40mL)以及四丁基溴化铵(1.4g)加入到上述有机溶液中，50℃反应。TLC板确认反应完全后，静置，分层，萃取，浓缩有机相后得到物1c。(油状物，3.0g，40.5％产率)25% sodium hydroxide aqueous solution (40 mL) and tetrabutylammonium bromide (1.4 g) were added to the above organic solution and reacted at 50°C. After TLC plate confirmed that the reaction was complete, the mixture was allowed to stand, separated, extracted, and the organic phase was concentrated to obtain product 1c. (Oil, 3.0 g, 40.5% yield)
第三步：third step:
八氢环戊二烯[c]吡咯-1-甲腈1dOctahydrocyclopentadienyl[c]pyrrole-1-carbonitrile 1d
octahydrocyclopenta[c]pyrrole-1-carbonitrileoctahydrocyclopenta[c]pyrrole-1-carbonitrile
将原料1c(3.0g，27.5mmol)溶解于40mL二氯甲烷中，接着加入5mL甲醇，冷至0℃，滴加三甲基氰硅烷(6.9mL，55mmol)，继续反应3h。LC-MS确认反应完全后，减压浓缩，粗品经柱层析分离纯化(石油醚/乙酸乙酯＝1/1)得到目标产物1d。(无色液体，3.0g，80％产率)The raw material 1c (3.0 g, 27.5 mmol) was dissolved in 40 mL of dichloromethane, and then 5 mL of methanol was added, cooled to 0°C, and trimethylsilyl cyanide (6.9 mL, 55 mmol) was added dropwise, and the reaction was continued for 3 h. After LC-MS confirmed that the reaction was complete, it was concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain the target product 1d. (Colorless liquid, 3.0 g, 80% yield)
LC-MS m/z(ESI)＝137.1[M+1].LC-MS m/z(ESI)＝137.1[M+1].
第四步：the fourth step:
八氢环戊并[c]吡咯-1-羧酸1eOctahydrocyclopenta[c]pyrrole-1-carboxylic acid 1e
octahydrocyclopenta[c]pyrrole-1-carboxylic acidoctahydrocyclopenta[c]pyrrole-1-carboxylic acid
依次加入原料1d(1.0g，7.3mmol)，氢氧化钾(825mg，14.7mmol)以及10mL乙醇/水(1/1)，加热回流5h。LC-MS确认反应完全后，加入10mL纯水，乙酸乙酯(10mL×3)萃取，水相调节pH至中性，减压浓缩后用甲醇打浆，有机相浓缩后得到目标产品1e。(类白色固体，800mg)Add raw material 1d (1.0 g, 7.3 mmol), potassium hydroxide (825 mg, 14.7 mmol) and 10 mL ethanol/water (1/1) in sequence, and heat to reflux for 5 h. After LC-MS confirmed that the reaction was complete, add 10 mL pure water, extract with ethyl acetate (10 mL×3), adjust the pH of the aqueous phase to neutral, concentrate under reduced pressure, and then slurry with methanol. After the organic phase is concentrated, the target product 1e is obtained. (Off-white solid, 800 mg)
LC-MS m/z(ESI)＝156.1[M+1].LC-MS m/z(ESI)＝156.1[M+1].
第五步：the fifth step:
2-(叔丁氧基羰基)八氢环戊二烯[c]吡咯-1-羧酸1f2-(tert-Butoxycarbonyl)octahydrocyclopentadienyl[c]pyrrole-1-carboxylic acid 1f
2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid
将1e(800g，5.1mmol)溶于10mL二氯甲烷中，接着加入N，N-二异丙基乙胺(1.3g，10.2mmol)以及二碳酸二叔丁酯(1.3g，6.2mmol)，室温反应2h。TLC板 确认反应完全后，加入10mL纯水，二氯甲烷(10mL×3)萃取，无水硫酸钠干燥，减压浓缩后得到目标产物1f。(粗品，1.5g)1e (800 g, 5.1 mmol) was dissolved in 10 mL of dichloromethane, and then N,N-diisopropylethylamine (1.3 g, 10.2 mmol) and di-tert-butyl dicarbonate (1.3 g, 6.2 mmol) were added and reacted at room temperature for 2 h. TLC plate After confirming that the reaction was complete, 10 mL of pure water was added, extracted with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product 1f. (Crude product, 1.5 g)
LCMS m/z(ESI)＝156.1[M-99].LCMS m/z(ESI)＝156.1[M-99].
第六步：Step 6:
1-(甲基(间甲苯基)氨基甲酰基)六氢环戊烷[c]吡咯-2(1H)-羧酸叔丁酯1g1-(Methyl(m-tolyl)carbamoyl)hexahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 1g
tert-butyl 1-(methyl(m-tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylatetert-butyl 1-(methyl(m-tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
将原料1f(1.5g，5.9mmol)溶于20mL四氢呋喃中，接着加入N，N-二异丙基乙胺(2.2g，11.8mmol)，HATU(4.4g，11.8mmol)以及N-甲基间甲苯胺(1.4g，11.8mmol)，50℃反应4h。LC-MS确认反应完全后，加入50mL纯水，乙酸乙酯(30mL×3)萃取，浓缩，粗品经柱层析分离纯化(石油醚/乙酸乙酯＝5/1)得到目标产物1g。(黄色液体；800mg，36％产率)The raw material 1f (1.5 g, 5.9 mmol) was dissolved in 20 mL of tetrahydrofuran, and then N, N-diisopropylethylamine (2.2 g, 11.8 mmol), HATU (4.4 g, 11.8 mmol) and N-methyl-m-toluidine (1.4 g, 11.8 mmol) were added, and the mixture was reacted at 50°C for 4 h. After LC-MS confirmed that the reaction was complete, 50 mL of pure water was added, and ethyl acetate (30 mL × 3) was used for extraction and concentration. The crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the target product 1 g. (Yellow liquid; 800 mg, 36% yield)
LC-MS m/z(ESI)＝259.1[M-99].LC-MS m/z(ESI)＝259.1[M-99].
第七步：Step 7:
N-甲基-N-(间甲苯基)八氢环戊二烯[c]吡咯-1-甲酰胺1hN-Methyl-N-(m-tolyl)octahydrocyclopentadienyl[c]pyrrole-1-carboxamide 1h
N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamideN-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
将1g(800mg；2.2mmol)溶于10mL盐酸二氧六环中，室温反应2h后，减压浓缩后得到目标产物1h。1 g (800 mg; 2.2 mmol) was dissolved in 10 mL of dioxane hydrochloride, reacted at room temperature for 2 h, and concentrated under reduced pressure to obtain the target product 1h.
LC-MS m/z(ESI)＝259.1[M+1].LC-MS m/z(ESI)＝259.1[M+1].
第八步：Step 8:
2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)八氢环戊烷[c]吡咯-1-甲酰胺化合物12-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopentane[c]pyrrole-1-carboxamide compound 1
2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
将1h(251mg，1.0mmol)溶于N-甲基吡咯烷酮(3mL)中，接着加入N，N-二异丙基乙胺(387mg，3.0mmol)以及2-氯-6-甲基-4-三氟甲基烟腈(264mg，1.2mmol)，加热至100℃反应2h。TLC板确认反应完全后，加入10mL纯水，乙酸乙酯(10mL×3)萃取，无水硫酸钠干燥后旋干，粗品柱层析分离纯化(石油醚/乙酸乙酯＝5/1)，得到化合物1(白色固体，262mg，61％产率)。 1h (251 mg, 1.0 mmol) was dissolved in N-methylpyrrolidone (3 mL), followed by the addition of N, N-diisopropylethylamine (387 mg, 3.0 mmol) and 2-chloro-6-methyl-4-trifluoromethylnicotinonitrile (264 mg, 1.2 mmol), and the mixture was heated to 100°C for 2 h. After the TLC plate confirmed that the reaction was complete, 10 mL of pure water was added, and the mixture was extracted with ethyl acetate (10 mL×3), dried over anhydrous sodium sulfate, and then spin-dried. The crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain compound 1 (white solid, 262 mg, 61% yield).
第九步Step 9
(1S)-2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)八氢环戊烷[c]吡咯-1-甲酰胺化合物1-A(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopentane[c]pyrrole-1-carboxamide Compound 1-A
(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
(1R)-2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)八氢环戊烷[c]吡咯-1-甲酰胺化合物1-B(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide Compound 1-B
(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
通过手性制备高效液相色谱(chiral pre-HPLC)拆分化合物1制备得到化合物1-A(白色粉末，32mg，35％产率)和化合物1-B(白色粉末，35mg，38％产率)。分析方法：手性柱AD-3，正己烷∶异丙醇＝95∶5为流动相，流速1mL/min。Compound 1-A (white powder, 32 mg, 35% yield) and compound 1-B (white powder, 35 mg, 38% yield) were prepared by chiral preparative high performance liquid chromatography (chiral pre-HPLC). Analysis method: chiral column AD-3, n-hexane: isopropanol = 95:5 as mobile phase, flow rate 1 mL/min.
化合物1-A：LC-MS m/z(ESI)＝443.1[M+1].Compound 1-A: LC-MS m/z(ESI)=443.1[M+1].
化合物1-ACompound 1-A
1H NMR(400MHz，Chloroform-d)87.35(t，1H)，7.25-7.15(m，3H)，6.74(s，1H)，4.68(s，1H)，4.35-4.31(m，1H)，4.02-3.98(m，1H)，3.27(s，3H)，3.00-2.95(m，1H)，2.59(d，1H)，2.51(s，3H)，2.41(s，3H)，1.92-1.75(m，1H)，1.63-1.36(m，4H)，1.03-0.81(m，1H). 1 H NMR (400 MHz, Chloroform-d) 87.35 (t, 1H), 7.25-7.15 (m, 3H), 6.74 (s, 1H), 4.68 (s, 1H), 4.35-4.31 (m, 1H), 4.02-3.98 (m, 1H), 3.27 (s, 3H), 3.00-2.95 (m, 1H), 2.59 (d, 1H), 2.51 (s, 3H), 2.41 (s, 3H), 1.92-1.75 (m, 1H), 1.63-1.36 (m, 4H), 1.03-0.81 (m, 1H).
化合物1-B：LC-MS m/z(ESI)＝443.1[M+1].Compound 1-B: LC-MS m/z(ESI)=443.1[M+1].
化合物1-BCompound 1-B
1H NMR(400MHz，Chloroform-d)δ7.35(t，1H)，7.26-7.14(m，3H)，6.74(s，1H)，4.68(s，1H)，4.35-4.31(m，1H)，4.02-3.98(m，1H)，3.26(s，3H)，3.00-2.95(m，1H)，2.59(d，1H)，2.51(s，3H)，2.41(s，3H)，1.85-1.79(m，1H)，1.62-1.36(m，4H)，0.94-0.88(m，1H). 1 H NMR (400 MHz, Chloroform-d) δ 7.35 (t, 1H), 7.26-7.14 (m, 3H), 6.74 (s, 1H), 4.68 (s, 1H), 4.35-4.31 (m, 1H), 4.02-3.98 (m, 1H), 3.26 (s, 3H), 3.00-2.95 (m, 1H), 2.59 (d, 1H), 2.51 (s, 3H), 2.41 (s, 3H), 1.85-1.79 (m, 1H), 1.62-1.36 (m, 4H), 0.94-0.88 (m, 1H).
实施例2Example 2
5-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)六氢-1H-呋喃[3，4-c]吡咯-4-甲酰胺化合物25-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)hexahydro-1H-furano[3,4-c]pyrrole-4-carboxamide compound 2
5-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)hexahydro-1H-furo[3，4-c]pyrrole-4-carboxamide
5-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)hexahydro-1H-furo[3，4-c]pyrrole-4-carboxamide
第一步：first step:
1-苄基吡咯烷-3，4-二羧酸二甲酯2b1-Benzylpyrrolidine-3,4-dicarboxylic acid dimethyl ester 2b
dimethyl 1-benzylpyrrolidine-3，4-dicarboxylatedimethyl 1-benzylpyrrolidine-3,4-dicarboxylate
将原料顺丁烯二酸二甲酯(30g，0.2mol)溶于二氯甲烷(300mL)中，接着加入三氟乙酸(15mL)，冰浴冷至0℃，滴加N-(甲氧甲基)-N-(三甲基硅甲基)苄胺(65mL，0.25mmol)，完成后室温继续反应。LC-MS检测反应完全后，减压浓缩，粗品经柱层析分离纯化(石油醚/乙酸乙酯＝3/1)得到目标产物2b。(粗品，41g)The raw material dimethyl maleate (30g, 0.2mol) was dissolved in dichloromethane (300mL), followed by the addition of trifluoroacetic acid (15mL), cooled to 0°C in an ice bath, and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (65mL, 0.25mmol) was added dropwise. After completion, the reaction was continued at room temperature. After the reaction was complete as detected by LC-MS, the reaction was concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain the target product 2b. (Crude product, 41g)
LC-MS m/z(ESI)＝278.1[M+1].LC-MS m/z(ESI)＝278.1[M+1].
第二步：Step 2:
1-苄基吡咯烷-3，4-二甲醇2c1-Benzylpyrrolidine-3,4-dimethanol 2c
(1-benzylpyrrolidine-3，4-diyl)dimethanol(1-benzylpyrrolidine-3，4-diyl)dimethanol
在300mL四氢呋喃中缓慢加入LiAlH4(10.1g，263mmol)，完成后在0℃下 缓慢滴加2b(41g in 100mL THF)。LC-MS检测反应完全后，加水淬灭反应，硅藻土过滤，滤液减压浓缩后得到目标产物2c。(粗品，44g)LiAlH4 (10.1 g, 263 mmol) was slowly added to 300 mL of tetrahydrofuran. After completion, the mixture was heated at 0 °C. Slowly add 2b (41g in 100mL THF) dropwise. After the reaction is complete as detected by LC-MS, add water to quench the reaction, filter through celite, and concentrate the filtrate under reduced pressure to obtain the target product 2c. (Crude product, 44g)
LC-MS m/z(ESI)＝222.1[M+1].LC-MS m/z(ESI)＝222.1[M+1].
第三步：third step:
5-苄基六氢-1H-呋喃[3，4-c]吡咯2d5-Benzylhexahydro-1H-furo[3,4-c]pyrrole 2d
5-benzylhexahydro-1H-furo[3，4-c]pyrrole5-benzylhexahydro-1H-furo[3,4-c]pyrrole
将2c(44g，0.2mol)溶于400mL甲苯中，接着分别加入N，N-二异丙基乙胺(38.7g，0.3mol)，对甲苯磺酰氯(57g，0.3mol)以及4-二甲氨基吡啶(2.4g，0.02mol)，室温反应12h。加入200mL纯水萃取，有机相继续加入N，N-二异丙基乙胺(25.8g，0.2mol)，加热回流反应4h。LC-MS检测反应完全后，加水淬灭反应，乙酸乙酯(100mL×3)萃取，无水硫酸钠干燥、减压浓缩后得到2d(粗品，40g)。2c (44 g, 0.2 mol) was dissolved in 400 mL of toluene, and then N, N-diisopropylethylamine (38.7 g, 0.3 mol), p-toluenesulfonyl chloride (57 g, 0.3 mol) and 4-dimethylaminopyridine (2.4 g, 0.02 mol) were added respectively, and the mixture was reacted at room temperature for 12 h. 200 mL of pure water was added for extraction, and N, N-diisopropylethylamine (25.8 g, 0.2 mol) was added to the organic phase, and the mixture was heated under reflux for 4 h. After the reaction was complete as detected by LC-MS, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2d (crude product, 40 g).
LC-MS m/z(ESI)＝204.1[M+1].LC-MS m/z(ESI)＝204.1[M+1].
第四步：the fourth step:
六氢-1H-呋喃并[3，4-c]吡咯2eHexahydro-1H-furo[3,4-c]pyrrole 2e
hexahydro-1H-furo[3，4-c]pyrrolehexahydro-1H-furo[3，4-c]pyrrole
将2d(40g，0.2mol)溶于400mL二氯乙烷中，接着1-氯乙基氯甲酸酯(42g，0.3mol)，50℃反应3h。减压浓缩，接着加入400mL甲醇，加热回流反应4h。LC-MS检测反应完全后，减压浓缩，粗品经柱层析分离纯化(石油醚/乙酸乙酯＝3/1)得到2e(黄色固体，12.5g，50％产率)。2d (40 g, 0.2 mol) was dissolved in 400 mL of dichloroethane, followed by 1-chloroethyl chloroformate (42 g, 0.3 mol), and reacted at 50°C for 3 h. The mixture was concentrated under reduced pressure, and then 400 mL of methanol was added, and the mixture was heated under reflux for 4 h. After the reaction was complete as detected by LC-MS, the mixture was concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain 2e (yellow solid, 12.5 g, 50% yield).
LC-MS m/z(ESI)＝114.1[M+1].LC-MS m/z(ESI)＝114.1[M+1].
第五步：the fifth step:
5-氯六氢-1H-呋喃[3，4-c]吡咯2f5-Chlorohexahydro-1H-furo[3,4-c]pyrrole 2f
5-chlorohexahydro-1H-furo[3，4-c]pyrrole5-chlorohexahydro-1H-furo[3，4-c]pyrrole
在0℃下，将2e(12.5g in 20mL MTBE)滴加到10％次氯酸钠水溶液中(60mL)和20mL MTBE中，继续反应4h。TLC板确认反应完全后，静置，MTBT(20mL×2)萃取，所得有机相直接用于下一步反应。2e (12.5 g in 20 mL MTBE) was added dropwise to 10% sodium hypochlorite aqueous solution (60 mL) and 20 mL MTBE at 0°C and the reaction was continued for 4 h. After the TLC plate confirmed that the reaction was complete, the mixture was allowed to stand and extracted with MTBT (20 mL × 2). The resulting organic phase was directly used for the next step.
LC-MS m/z(ESI)＝148.1[M+1].LC-MS m/z(ESI)＝148.1[M+1].
第六步：Step 6:
3，3a，4，6a-四氢-1H-呋喃[3，4-c]吡咯2g3,3a,4,6a-Tetrahydro-1H-furan[3,4-c]pyrrole 2g
3，3a，4，6a-tetrahydro-1H-furo[3，4-c]pyrrole 3,3a,4,6a-tetrahydro-1H-furo[3,4-c]pyrrole
将25％氢氧化钠水溶液(45mL)以及四丁基溴化铵(1.4g)加入到上述有机溶液中，50℃反应。TLC板确认反应完全后，静置，分层，萃取，浓缩有机相后得到2g。(油状物，4.7g)Add 25% sodium hydroxide aqueous solution (45 mL) and tetrabutylammonium bromide (1.4 g) to the above organic solution and react at 50°C. After TLC plate confirms that the reaction is complete, stand, separate, extract, and concentrate the organic phase to obtain 2 g. (Oil, 4.7 g)
第七步：Step 7:
六氢-1H-呋喃[3，4-c]吡咯-4-甲腈2hHexahydro-1H-furano[3,4-c]pyrrole-4-carbonitrile 2h
hexahydro-1H-furo[3，4-c]pyrrole-4-carbonitrilehexahydro-1H-furo[3，4-c]pyrrole-4-carbonitrile
将2g(4.7g，42mmol)溶解于40mL二氯甲烷中，接着加入5mL甲醇，冷至0℃，滴加三甲基氰硅烷(10.1mL，0.1mol)，继续反应3h。LC-MS确认反应完全后，减压浓缩，粗品经柱层析分离纯化(石油醚/乙酸乙酯＝1/1)得到目标产物2h。(黄色液体，2.7g，46％产率)2g (4.7g, 42mmol) was dissolved in 40mL dichloromethane, followed by addition of 5mL methanol, cooled to 0°C, and trimethylsilyl cyanide (10.1mL, 0.1mol) was added dropwise, and the reaction was continued for 3h. After LC-MS confirmed that the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain the target product 2h. (Yellow liquid, 2.7g, 46% yield)
LC-MS m/z(ESI)＝139.1[M+1].LC-MS m/z(ESI)＝139.1[M+1].
第八步：Step 8:
六氢-1H-呋喃[3，4-c]吡咯-4-羧酸2iHexahydro-1H-furano[3,4-c]pyrrole-4-carboxylic acid 2i
hexahydro-1H-furo[3，4-c]pyrrole-4-carboxylic acidhexahydro-1H-furo[3，4-c]pyrrole-4-carboxylic acid
依次加入2h(676mg，4.9mmol)，氢氧化钾(850mg，150mmol)以及10mL乙醇/水(1/1)，加热回流5h。LC-MS确认反应完全后，加入10mL纯水，乙酸乙酯(10×3)萃取，水相调节pH至中性，减压浓缩后用甲醇打浆，有机相浓缩后得到目标产品2i(类白色固体，630mg)。2h (676 mg, 4.9 mmol), potassium hydroxide (850 mg, 150 mmol) and 10 mL of ethanol/water (1/1) were added in sequence and heated to reflux for 5 h. After LC-MS confirmed that the reaction was complete, 10 mL of pure water was added, and ethyl acetate (10×3) was used for extraction. The pH of the aqueous phase was adjusted to neutral, and the mixture was concentrated under reduced pressure and then slurried with methanol. The organic phase was concentrated to obtain the target product 2i (off-white solid, 630 mg).
LC-MS m/z(ESI)＝158.1[M+1].LC-MS m/z(ESI)＝158.1[M+1].
第九步：Step 9:
5-(叔丁氧基羰基)六氢-1H-呋喃[3，4-c]吡咯-4-羧酸2j5-(tert-Butyloxycarbonyl)hexahydro-1H-furano[3,4-c]pyrrole-4-carboxylic acid 2j
5-(tert-butoxycarbonyl)hexahydro-1H-furo[3，4-c]pyrrole-4-carboxylic acid5-(tert-butoxycarbonyl)hexahydro-1H-furo[3，4-c]pyrrole-4-carboxylic acid
将2i(500mg，3.2mmol)溶于10mL二氯甲烷中，接着加入N，N-二异丙基乙胺(619.2mg，4.8mmol)以及二碳酸二叔丁酯(1.0g，4.8mmol)，室温反应2h。TLC板确认反应完全后，加入10mL纯水，二氯甲烷(10mL×3)萃取，无水硫酸钠干燥，减压浓缩后得到目标产物2j(白色固体，630mg)。2i (500 mg, 3.2 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of N, N-diisopropylethylamine (619.2 mg, 4.8 mmol) and di-tert-butyl dicarbonate (1.0 g, 4.8 mmol), and the reaction was carried out at room temperature for 2 h. After TLC confirmed that the reaction was complete, 10 mL of pure water was added, and the mixture was extracted with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product 2j (white solid, 630 mg).
LC-MS m/z(ESI)＝158.1[M-99].LC-MS m/z(ESI)＝158.1[M-99].
第十步：Step 10:
4-(甲基(间甲苯基)氨基甲酰基)四氢-1H-呋喃[3，4-c]吡咯-5(3H)-羧酸叔丁酯2k tert-Butyl 4-(methyl(m-tolyl)carbamoyl)tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-carboxylate 2k
tert-butyltert-butyl
4-(methyl(m-tolyl)carbamoyl)tetrahydro-1H-furo[3，4-c]pyrrole-5(3H)-carboxylate4-(methyl(m-tolyl)carbamoyl)tetrahydro-1H-furo[3，4-c]pyrrole-5(3H)-carboxylate
将原料2j(630mg，4.0mmol)溶于20mL四氢呋喃中，接着加入N，N-二异丙基乙胺(1.0g，8.0mmol)，HATU(3.0g，8.0mmol)以及N-甲基间甲苯胺(968mg，8.0mmol)，50℃反应4h。LC-MS确认反应完全后，加入50mL纯水，乙酸乙酯(30mL×3)萃取，浓缩，粗品经柱层析分离纯化(石油醚/乙酸乙酯＝5/1)得到目标产物2k。(黄色液体，800mg，57％产率)The raw material 2j (630 mg, 4.0 mmol) was dissolved in 20 mL of tetrahydrofuran, and then N, N-diisopropylethylamine (1.0 g, 8.0 mmol), HATU (3.0 g, 8.0 mmol) and N-methyl-m-toluidine (968 mg, 8.0 mmol) were added, and the mixture was reacted at 50°C for 4 h. After LC-MS confirmed that the reaction was complete, 50 mL of pure water was added, and ethyl acetate (30 mL×3) was used for extraction and concentration. The crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the target product 2k. (Yellow liquid, 800 mg, 57% yield)
LC-MS m/z(ESI)＝261.1[M-99].LC-MS m/z(ESI)＝261.1[M-99].
第十一步：Step 11:
N-甲基-N-(间甲苯基)六氢-1H-呋喃[3，4-c]吡咯-4-甲酰胺2lN-Methyl-N-(m-tolyl)hexahydro-1H-furan[3,4-c]pyrrole-4-carboxamide 2l
N-methyl-N-(m-tolyl)hexahydro-1H-furo[3，4-c]pyrrole-4-carboxamideN-methyl-N-(m-tolyl)hexahydro-1H-furo[3，4-c]pyrrole-4-carboxamide
将2k(800mg；2.2mmol)溶于10mL盐酸二氧六环中，室温反应2h后，减压浓缩后得到目标产物2l(粗品，251mg)。2k (800 mg; 2.2 mmol) was dissolved in 10 mL of dioxane hydrochloride, reacted at room temperature for 2 h, and then concentrated under reduced pressure to obtain the target product 2l (crude product, 251 mg).
LC-MS m/z(ESI)＝261.1[M+1].LC-MS m/z(ESI)＝261.1[M+1].
第十二步：Step 12:
5-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)六氢-1H-呋喃[3，4-c]吡咯-4-甲酰胺化合物25-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)hexahydro-1H-furano[3,4-c]pyrrole-4-carboxamide compound 2
5-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)hexahydro-1H-furo[3，4-c]pyrrole-4-carboxamide5-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)hexahydro-1H-furo[3，4-c]pyrrole-4-carboxamide
将2l(251mg，1.0mmol)溶于N-甲基吡咯烷酮(3mL)中，接着加入N，N-二异丙基乙胺(387mg，3.0mmol)以及2-氯-6-甲基-4-三氟甲基烟腈(264mg，1.2mmol)，加热至100℃反应2h。TLC板确认反应完全后，加入10mL纯水，乙酸乙酯(10mL×3)萃取，无水硫酸钠干燥后旋干，粗品经柱层析分离纯化(石油醚/乙酸乙酯＝5/1)得到目标产物化合物2(橙黄色固体，89mg，20％产率)。21 (251 mg, 1.0 mmol) was dissolved in N-methylpyrrolidone (3 mL), followed by the addition of N, N-diisopropylethylamine (387 mg, 3.0 mmol) and 2-chloro-6-methyl-4-trifluoromethylnicotinonitrile (264 mg, 1.2 mmol), and the mixture was heated to 100°C for 2 h. After the TLC plate confirmed that the reaction was complete, 10 mL of pure water was added, and the mixture was extracted with ethyl acetate (10 mL×3), dried over anhydrous sodium sulfate, and then spin-dried. The crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the target product, compound 2 (orange-yellow solid, 89 mg, 20% yield).
LC-MS m/z(ESI)＝445.1[M+1].LC-MS m/z(ESI)＝445.1[M+1].
1H NMR(400MHz，Chloroform-d)δ7.36(t，J＝7.9Hz，1H)，7.22(d，J＝7.0Hz，3H)，6.79(s，1H)，4.86(s，1H)，4.38-4.34(m，1H)，4.27-4.24(m，1H)，3.94-3.90(m，1H)，3.70-3.50(m，2H)，3.27(s，3H)，3.19-3.10(m，1H)，2.95-2.87(m，2H)，2.52(s，3H)，2.41(s，3H). 1 H NMR (400 MHz, Chloroform-d) δ 7.36 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 7.0 Hz, 3H), 6.79 (s, 1H), 4.86 (s, 1H), 4.38-4.34 (m, 1H), 4.27-4.24 (m, 1H), 3.94-3.90 (m, 1H), 3.70-3.50 (m, 2H), 3.27 (s, 3H), 3.19-3.10 (m, 1H), 2.95-2.87 (m, 2H), 2.52 (s, 3H), 2.41 (s, 3H).
实施例3Example 3
N-甲基-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(间甲苯基)六氢-1H-呋喃[3，4-c]吡咯-4-甲酰胺化合物3N-methyl-5-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)hexahydro-1H-furano[3,4-c]pyrrole-4-carboxamide Compound 3
N-methyl-5-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)hexahydro-1H-furo[3，4-c]pyrrole-4-carboxamide
N-methyl-5-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)hexahydro-1H-furo[3，4-c]pyrrole-4-carboxamide
将原料N-甲基-N-(间甲苯基)六氢-1H-呋喃[3，4-c]吡咯-4-甲酰胺3a(254mg，1.0mmol)溶于N-甲基吡咯烷酮(3mL)中，接着加入N，N-二异丙基乙胺(387mg，3.0mmol)以及2-溴-6-甲基-4-三氟甲基吡啶(288mg，1.2mmol)，加热至140℃反应4h。TLC板确认反应完全后，加入10mL纯水，乙酸乙酯(10mL×3)萃取，无水硫酸钠干燥后旋干，粗品经柱层析分离纯化(石油醚/乙酸乙酯＝3/1)得到目标产物化合物3(橙黄色固体，87mg，20％产率)。The raw material N-methyl-N-(m-tolyl)hexahydro-1H-furan[3,4-c]pyrrole-4-carboxamide 3a (254 mg, 1.0 mmol) was dissolved in N-methylpyrrolidone (3 mL), followed by the addition of N,N-diisopropylethylamine (387 mg, 3.0 mmol) and 2-bromo-6-methyl-4-trifluoromethylpyridine (288 mg, 1.2 mmol), and the mixture was heated to 140°C for 4 h. After the TLC plate confirmed that the reaction was complete, 10 mL of pure water was added, and the mixture was extracted with ethyl acetate (10 mL×3), dried over anhydrous sodium sulfate, and then spin-dried. The crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate=3/1) to obtain the target product compound 3 (orange-yellow solid, 87 mg, 20% yield).
LC-MS m/z(ESI)＝420.1[M+1].LC-MS m/z(ESI)＝420.1[M+1].
1H NMR(400MHz，Chloroform-d)87.37(t，J＝7.7Hz，1H)，7.30-7.15(m，3H)，6.63(s，1H)，6.37(s，1H)，4.58(s，1H)，4.06-3.85(m，2H)，3.77-3.73(m，1H)，3.56-3.53(m，1H)，3.45-3.43(m，1H)，3.26(s，3H)，3.22-3.14(m，1H)，3.05-3.00(m，1H)，2.98-2.90(m，1H)，2.48(s，3H)，2.42(s，3H). 1 H NMR (400 MHz, Chloroform-d) δ 7.37 (t, J = 7.7 Hz, 1H), 7.30-7.15 (m, 3H), 6.63 (s, 1H), 6.37 (s, 1H), 4.58 (s, 1H), 4.06-3.85 (m, 2H), 3.77-3.73 (m, 1H), 3.56-3.53 (m, 1H), 3.45-3.43 (m, 1H), 3.26 (s, 3H), 3.22-3.14 (m, 1H), 3.05-3.00 (m, 1H), 2.98-2.90 (m, 1H), 2.48 (s, 3H), 2.42 (s, 3H).
实施例4Example 4
2-(3-胺甲酰基-6-甲基-4-(三氟甲基)-2-吡啶)-N-甲基-N-(间甲苯基)八氢环戊烷[c]吡咯-1-甲酰胺化合物4 2-(3-carbamoyl-6-methyl-4-(trifluoromethyl)-2-pyridine)-N-methyl-N-(m-tolyl)octahydrocyclopentane[c]pyrrole-1-carboxamide compound 4
2-(3-carbamoyl-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
2-(3-carbamoyl-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
将原料2-(3-氰基-6-甲基-4-(三氟甲基)-2-吡啶)-N-甲基-N-(间甲苯基)八氢环戊烷[c]吡咯-1-甲酰胺4a(100mg，0.2mmol)溶于二甲亚砜(3mL)中，接着加入氢氧化钠(8mg，0.2mmol)，加热至45℃，滴加30％双氧水(68mg，0.6mmol)，完成后继续反应0.5h。LC-MS检测反应完全后，加入10mL纯水，二氯甲烷(10mL×3)萃取，无水硫酸钠干燥后浓缩，粗品经柱层析分离纯化(石油醚/乙酸乙酯＝3/1)得到目标产物化合物4(类白色固体，50mg，54％产率)。The raw material 2-(3-cyano-6-methyl-4-(trifluoromethyl)-2-pyridine)-N-methyl-N-(m-tolyl)octahydrocyclopentane[c]pyrrole-1-carboxamide 4a (100 mg, 0.2 mmol) was dissolved in dimethyl sulfoxide (3 mL), followed by the addition of sodium hydroxide (8 mg, 0.2 mmol), heating to 45°C, and dropwise addition of 30% hydrogen peroxide (68 mg, 0.6 mmol), followed by the reaction for 0.5 h. After the reaction was complete as detected by LC-MS, 10 mL of pure water was added, and the mixture was extracted with dichloromethane (10 mL×3), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate=3/1) to obtain the target product compound 4 (off-white solid, 50 mg, 54% yield).
LC-MS m/z(ESI)＝461.1[M+1].LC-MS m/z(ESI)＝461.1[M+1].
1H NMR(400MHz，Chloroform-d)δ7.36(t，J＝7.7Hz，1H)，7.25-7.19(m，3H)，6.74(s，1H)，5.88(s，1H)，4.91(d，J＝3.2Hz，1H)，4.11-4.07(m，1H)，3.44-3.41(m，1H)，3.25(s，3H)，2.99(s，1H)，2.85-2.67(m，1H)，2.53-2.49(m，4H)，2.43(s，3H)，1.88-1.57(m，2H)，1.55-1.13(m，3H)，0.79-0.74(m，1H). 1 H NMR (400 MHz, Chloroform-d) δ 7.36 (t, J = 7.7 Hz, 1H), 7.25-7.19 (m, 3H), 6.74 (s, 1H), 5.88 (s, 1H), 4.91 (d, J = 3.2 Hz, 1H), 4.11-4.07 (m, 1H), 3.44-3.41 (m, 1H), 3.25 (s, 3H), 2.99 (s, 1H), 2.85-2.67 (m, 1H), 2.53-2.49 (m, 4H), 2.43 (s, 3H), 1.88-1.57 (m, 2H), 1.55-1.13 (m, 3H), 0.79-0.74 (m, 1H).
实施例5Example 5
2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-3-氧代-N-(间甲苯基)八氢环戊二烯[c]吡咯-1-羧酰胺化合物52-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopentadienyl[c]pyrrole-1-carboxamide compound 5
2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
(1S)-2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-3-氧代-N-(间甲苯基) 八氢环戊二烯[c]吡咯-1-羧酰胺化合物5-A(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl) Octahydrocyclopentadienyl[c]pyrrole-1-carboxamide compound 5-A
(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
(1R)-2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-3-氧代-N-(间甲苯基)八氢环戊二烯[c]吡咯-1-羧酰胺化合物5-B(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopentadienyl[c]pyrrole-1-carboxamide compound 5-B
(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
第一步：first step:
3-乙氧基六氢环戊二烯[c]吡咯-1(2H)-酮5b3-Ethoxyhexahydrocyclopentadienyl[c]pyrrol-1(2H)-one 5b
3-ethoxyhexahydrocyclopenta[c]pyrrol-1(2H)-one3-ethoxyhexahydrocyclopenta[c]pyrrol-1(2H)-one
将四氢环戊二烯[c]吡咯-1，3(2H，3aH)-二酮5a(10.0g，71.86mmol)溶解于无水乙醇(100毫升)，随后降温至-10℃，加入硼氢化钠(8.16g，215.59mmol)，30分钟 后滴加入1M硫酸乙醇溶液(14mL)，滴加完毕，恢复室温反应1小时。随后降温至-10℃，用6N硫酸乙醇溶液调节pH＝2，搅拌1小时后恢复至室温，用1N氢氧化钾乙醇溶液调节pH＝8，搅拌30分钟后直接浓缩至干，加入水和氯仿各200mL，分液，收集有机相，干燥，浓缩得粗品。粗品经柱层析(二氯甲烷/甲醇(v/v)＝20/1)分离得5b(9.6g，无色油状物，78.9％产率)。Tetrahydrocyclopentadienyl[c]pyrrole-1,3(2H,3aH)-dione 5a (10.0 g, 71.86 mmol) was dissolved in anhydrous ethanol (100 ml), then cooled to -10°C, sodium borohydride (8.16 g, 215.59 mmol) was added, and the mixture was stirred for 30 minutes. Then, 1M sulfuric acid ethanol solution (14 mL) was added dropwise. After the addition was complete, the mixture was returned to room temperature for reaction for 1 hour. The temperature was then lowered to -10°C, and the pH was adjusted to 2 with 6N sulfuric acid ethanol solution. After stirring for 1 hour, the mixture was returned to room temperature, and the pH was adjusted to 8 with 1N potassium hydroxide ethanol solution. After stirring for 30 minutes, the mixture was directly concentrated to dryness, and 200 mL of water and chloroform were added, respectively. The organic phase was collected, dried, and concentrated to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol (v/v) = 20/1) to obtain 5b (9.6 g, colorless oil, 78.9% yield).
LCMS m/z(ESI)＝170.1[M+1].LCMS m/z(ESI)＝170.1[M+1].
第二步：Step 2:
3-氧代八氢环戊二烯[c]吡咯-1-甲腈5c3-Oxooctahydrocyclopentadienyl[c]pyrrole-1-carbonitrile 5c
3-oxooctahydrocyclopenta[c]pyrrole-1-carbonitrile3-oxooctahydrocyclopenta[c]pyrrole-1-carbonitrile
将5b(9.6g，56.73mmol)溶于无水二氯甲烷(100mL)，随后加入三甲基氰硅烷(8.44g，85.09mmol)，冷却至0℃，随后滴加入三氟化硼***(16.10g，113.46mmol)，保持此温度反应2小时。随后将反应液直接浓缩至干，经柱层析分离(二氯甲烷/甲醇(v/v)＝20/1)后得目标产物5c(7.6g，无色油状物，89.2％产率)。5b (9.6 g, 56.73 mmol) was dissolved in anhydrous dichloromethane (100 mL), followed by the addition of trimethylsilyl cyanide (8.44 g, 85.09 mmol), cooled to 0°C, followed by the dropwise addition of boron trifluoride etherate (16.10 g, 113.46 mmol), and the reaction was maintained at this temperature for 2 hours. The reaction solution was then directly concentrated to dryness, and the target product 5c (7.6 g, colorless oil, 89.2% yield) was obtained after column chromatography separation (dichloromethane/methanol (v/v) = 20/1).
LCMS m/z(ESI)＝151.1[M+1].LCMS m/z(ESI)＝151.1[M+1].
第三步：third step:
3-氧代八氢环戊二烯[c]吡咯-1-羧酸5d3-Oxooctahydrocyclopentadienyl[c]pyrrole-1-carboxylic acid 5d
3-oxooctahydrocyclopenta[c]pyrrole-1-carboxylic acid3-oxooctahydrocyclopenta[c]pyrrole-1-carboxylic acid
将5c(7.6g，50.61mmol)、溶于6N盐酸水溶液(100mL)，随后加热至100℃反应3小时。随后将反应液直接浓缩至干，加入二氯甲烷100mL，过滤，滤液直接浓缩至干得到化合物5d(无色油状物，3.0g)，直接用于下一步反应。5c (7.6 g, 50.61 mmol) was dissolved in 6N hydrochloric acid aqueous solution (100 mL), and then heated to 100°C for 3 hours. The reaction solution was then directly concentrated to dryness, 100 mL of dichloromethane was added, filtered, and the filtrate was directly concentrated to dryness to obtain compound 5d (colorless oil, 3.0 g), which was directly used in the next step.
LCMS m/z(ESI)＝170.1[M+1].LCMS m/z(ESI)＝170.1[M+1].
第四步：the fourth step:
N-甲基-3-氧代-N-(间甲苯基)八氢环戊[c]吡咯-1-甲酰胺5eN-Methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide 5e
N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamideN-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
将5d(2.0g，11.82mmol)、N，3-二甲基苯胺(1.58mg，13.00mmol)、溶解于无水吡啶(20mL)，随后冷却至0℃，滴加入1-丙基磷酸环酐(7.52g，23.64mmol)，随后恢复至室温反应2小时。直接反应液浓缩至干，将粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝20/1)，得到化合物5e(1.2g，无色油状物，37％产率)。5d (2.0 g, 11.82 mmol) and N, 3-dimethylaniline (1.58 mg, 13.00 mmol) were dissolved in anhydrous pyridine (20 mL), then cooled to 0°C, 1-propylphosphoric acid cyclic anhydride (7.52 g, 23.64 mmol) was added dropwise, and then returned to room temperature for 2 hours. The direct reaction solution was concentrated to dryness, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to obtain compound 5e (1.2 g, colorless oil, 37% yield).
LCMS m/z(ESI)＝273.1[M+1]. LCMS m/z (ESI) = 273.1 [M+1].
第五步：the fifth step:
2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-3-氧代-N-(间甲苯基)八氢环戊二烯[c]吡咯-1-羧酰胺化合物52-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopentadienyl[c]pyrrole-1-carboxamide compound 5
2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
将5e(400mg，1.47mmol)溶解于环戊基甲醚(10mL)，冷却到0℃，随后加入***(117.5mg，2.94mmol，60％含量)，于0℃反应30分钟，再次加入2-氯-6-甲基-4-(三氟甲基)烟腈(485.9mg，2.2mmol)，恢复至室温反应1小时，再加热至60℃继续反应3小时。将反应液加水(30mL)直接淬灭，用乙酸乙酯(50mL×3)萃取，合并有机相，干燥，浓缩，得油状粗品。粗品经反相液相制备得到化合物5(白色固体，78mg，12％产率)。5e (400 mg, 1.47 mmol) was dissolved in cyclopentyl methyl ether (10 mL), cooled to 0°C, and then sodium cyanide (117.5 mg, 2.94 mmol, 60% content) was added, and the mixture was reacted at 0°C for 30 minutes. 2-Chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (485.9 mg, 2.2 mmol) was added again, and the mixture was returned to room temperature for reaction for 1 hour, and then heated to 60°C for further reaction for 3 hours. The reaction solution was directly quenched by adding water (30 mL), extracted with ethyl acetate (50 mL×3), and the organic phases were combined, dried, and concentrated to obtain an oily crude product. The crude product was prepared by reverse phase liquid phase to obtain compound 5 (white solid, 78 mg, 12% yield).
第六步：Step 6:
(1S)-2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-3-氧代-N-(间甲苯基)八氢环戊二烯[c]吡咯-1-羧酰胺化合物5-A(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopentadienyl[c]pyrrole-1-carboxamide compound 5-A
(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
(1R)-2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-3-氧代-N-(间甲苯基)八氢环戊二烯[c]吡咯-1-羧酰胺化合物5-B(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopentadienyl[c]pyrrole-1-carboxamide compound 5-B
(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-l-carboxamide(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-l-carboxamide
通过手性制备高效液相色谱(chiral pre-HPLC)拆分化合物5制备得到化合物5-A(白色粉末，28mg，36％产率)和化合物5-B(白色粉末，27mg，35％产率)。分析方法：手性柱AD-3，正己烷∶乙醇＝95∶5为流动相，流速1mL/min。Compound 5-A (white powder, 28 mg, 36% yield) and compound 5-B (white powder, 27 mg, 35% yield) were prepared by chiral preparative high performance liquid chromatography (chiral pre-HPLC). Analysis method: chiral column AD-3, n-hexane: ethanol = 95: 5 as mobile phase, flow rate 1 mL/min.
化合物5-A：m/z(ESI)＝457.20[M+1]Compound 5-A: m/z (ESI) = 457.20 [M+1]
化合物5-ACompound 5-A
1H NMR(401MHz，CDCl3)δ7.33(t，1H)，7.31(s，1H)，7.20(d，1H)，7.09(d，2H)，4.56-4.57(d，1H)，3.32(m，4H)，2.68(m，4H)，2.40(s，3H)，2.12(m，1H)，1.88(m，1H)，1.69(m，1H)，1.53(m，1H)，1.06(m，1H). 1 H NMR (401 MHz, CDCl 3 ) δ 7.33 (t, 1H), 7.31 (s, 1H), 7.20 (d, 1H), 7.09 (d, 2H), 4.56-4.57 (d, 1H), 3.32 (m, 4H), 2.68 (m, 4H), 2.40 (s, 3H), 2.12 (m, 1H), 1.88 (m, 1H), 1.69 (m, 1H), 1.53 (m, 1H), 1.06 (m, 1H).
化合物5-B：m/z(ESI)＝457.20[M+1] Compound 5-B: m/z (ESI) = 457.20 [M+1]
化合物5-BCompound 5-B
1H NMR(400MHz，CDCl3)δ7.33(t，1H)，7.31(s，1H)，7.20(d，1H)，7.09(d，2H)，4.569(s，1H)，3.33(m，4H)，2.68(m，4H)，2.40(s，3H)，2.13(m，1H)，1.88(m，1H)，1.69(m，1H)，1.53(m，1H)，1.08(m，1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.33 (t, 1H), 7.31 (s, 1H), 7.20 (d, 1H), 7.09 (d, 2H), 4.569 (s, 1H), 3.33 (m, 4H), 2.68 (m, 4H), 2.40 (s, 3H), 2.13 (m, 1H), 1.88 (m, 1H), 1.69 (m, 1H), 1.53 (m, 1H), 1.08 (m, 1H).
实施例6Example 6
2-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-3-氧代-N-(间甲苯基)八氢环戊二烯[c]吡咯-1-羧酰胺化合物62-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopentadienyl[c]pyrrole-1-carboxamide compound 6
2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
(1S)-2-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-3-氧代-N-(间甲苯基)八氢环戊二烯[c]吡咯-1-羧酰胺化合物6-A(1S)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopentadienyl[c]pyrrole-1-carboxamide compound 6-A
(1S)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide(1S)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
(1R)-2-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-3-氧代-N-(间甲苯基)八氢环戊二烯[c]吡咯-1-羧酰胺化合物6-B(1R)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopentadienyl[c]pyrrole-1-carboxamide compound 6-B
(1R)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide

(1R)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide

第一步：first step:
3-乙氧基六氢环戊二烯[c]吡咯-1(2H)-酮6b3-Ethoxyhexahydrocyclopentadienyl[c]pyrrol-1(2H)-one 6b
3-ethoxyhexahydrocyclopenta[c]pyrrol-1(2H)-one3-ethoxyhexahydrocyclopenta[c]pyrrol-1(2H)-one
将6a(10.0g，71.86mmol)溶解于无水乙醇(100毫升)，随后降温至-10℃，加入硼氢化钠(8.16g，215.59mmol)，30分钟后滴加入1M硫酸乙醇溶液(14mL)，滴加完毕，恢复室温反应1小时。随后降温至-10℃，用6N硫酸乙醇溶液调节pH＝2，搅拌1小时后恢复至室温，用1N氢氧化钾乙醇溶液调节pH＝8，搅拌30分钟后直接浓缩至干，加入水和氯仿各200mL，分液，收集有机相，干燥，浓缩得粗品。粗品经柱层析(二氯甲烷/甲醇(v/v)＝20/1)分离得6b(9.6g，无色油状物78.9％产率)。6a (10.0 g, 71.86 mmol) was dissolved in anhydrous ethanol (100 ml), then cooled to -10 °C, sodium borohydride (8.16 g, 215.59 mmol) was added, and 1 M sulfuric acid ethanol solution (14 mL) was added dropwise after 30 minutes. After the addition was complete, the mixture was returned to room temperature for reaction for 1 hour. Then the mixture was cooled to -10 °C, pH was adjusted to 2 with 6N sulfuric acid ethanol solution, and the mixture was returned to room temperature after stirring for 1 hour. pH was adjusted to 8 with 1N potassium hydroxide ethanol solution, and the mixture was directly concentrated to dryness after stirring for 30 minutes. 200 mL of water and chloroform were added, the liquids were separated, the organic phase was collected, dried, and concentrated to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol (v/v) = 20/1) to obtain 6b (9.6 g, colorless oil, 78.9% yield).
LCMS m/z(ESI)＝170.1[M+1].LCMS m/z(ESI)＝170.1[M+1].
第二步：Step 2:
3-氧代八氢环戊二烯[c]吡咯-1-甲腈6c3-Oxooctahydrocyclopentadienyl[c]pyrrole-1-carbonitrile 6c
3-oxooctahydrocyclopenta[c]pyrrole-1-carbonitrile3-oxooctahydrocyclopenta[c]pyrrole-1-carbonitrile
将6b(9.6g，56.73mmol)溶于无水二氯甲烷(100mL)，随后加入三甲基氰硅烷(8.44g，85.09mmol)，冷却至0℃，随后滴加入三氟化硼***(16.10g，113.46mmol)，保持此温度反应2小时。随后将反应液直接浓缩至干，经柱层析分离后得目标产物6c(7.6g，无色油状物，89％产率)。6b (9.6 g, 56.73 mmol) was dissolved in anhydrous dichloromethane (100 mL), followed by the addition of trimethylsilyl cyanide (8.44 g, 85.09 mmol), cooled to 0°C, followed by the dropwise addition of boron trifluoride etherate (16.10 g, 113.46 mmol), and the reaction was maintained at this temperature for 2 hours. The reaction solution was then directly concentrated to dryness, and the target product 6c (7.6 g, colorless oil, 89% yield) was obtained after column chromatography separation.
LCMS m/z(ESI)＝151.1[M+1].LCMS m/z(ESI)＝151.1[M+1].
第三步：third step:
3-氧代八氢环戊二烯[c]吡咯-1-羧酸6d3-Oxooctahydrocyclopentadienyl[c]pyrrole-1-carboxylic acid 6d
3-oxooctahydrocyclopenta[c]pyrrole-1-carboxylic acid 3-oxooctahydrocyclopenta[c]pyrrole-1-carboxylic acid
将6c(7.6g，50.61mmol)、溶于6N盐酸水溶液(100mL)，随后加热至100℃反应3小时。随后将反应液直接浓缩至干，加入二氯甲烷100mL，过滤，滤液直接浓缩至干得到化合物6d(无色油状物，3.0g)，直接用于下一步反应。6c (7.6 g, 50.61 mmol) was dissolved in 6N hydrochloric acid aqueous solution (100 mL), and then heated to 100°C for 3 hours. The reaction solution was then directly concentrated to dryness, 100 mL of dichloromethane was added, filtered, and the filtrate was directly concentrated to dryness to obtain compound 6d (colorless oil, 3.0 g), which was directly used in the next step.
LCMS m/z(ESI)＝170.1[M+1].LCMS m/z(ESI)＝170.1[M+1].
第四步：the fourth step:
N-甲基-3-氧代-N-(间甲苯基)八氢环戊[c]吡咯-1-甲酰胺6eN-Methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide 6e
N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamideN-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
将6d(2.0g，11.82mmol)、N，3-二甲基苯胺(1.58mg，13.00mmol)、溶解于无水吡啶(20mL)，随后冷却至0℃，滴加入1-丙基磷酸环酐(7.52g，23.64mmol)，随后恢复至室温反应2小时。直接反应液浓缩至干，将粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝20/1)，得到化合物6e(1.2g，无色油状物，37％产率)。6d (2.0 g, 11.82 mmol) and N, 3-dimethylaniline (1.58 mg, 13.00 mmol) were dissolved in anhydrous pyridine (20 mL), then cooled to 0°C, 1-propylphosphoric acid cyclic anhydride (7.52 g, 23.64 mmol) was added dropwise, and then returned to room temperature for 2 hours. The direct reaction solution was concentrated to dryness, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to obtain compound 6e (1.2 g, colorless oil, 37% yield).
LCMS m/z(ESI)＝273.1[M+1].LCMS m/z(ESI)＝273.1[M+1].
第五步：the fifth step:
2-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-3-氧代-N-(间甲苯基)八氢环戊二烯[c]吡咯-1-羧酰胺化合物62-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopentadienyl[c]pyrrole-1-carboxamide compound 6
2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
将6e(400mg，1.47mmol)，2-溴-6-甲基-4-(三氟甲基)吡啶(423mg，1.76mmol)，碳酸铯(957mg，2.94mmol)，甲磺酸(2-二环己基膦基-2′，6′-二异丙氧基-1，1′-联苯基)(2-氨基-1，1′-联苯-2-基)钯(II)(122mg，0.14mmol)溶解于无水二氧六环(10mL)，随后氮气保护，加热至100℃反应6小时。将反应液冷却至室温加入乙酸乙酯(50mL)稀释，过滤，滤液直接浓缩至干，经柱层析分离(二氯甲烷/甲醇(v/v)＝20/1)得到纯品化合物6(白色固体，161mg，17％产率)。6e (400 mg, 1.47 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (423 mg, 1.76 mmol), cesium carbonate (957 mg, 2.94 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2′, 6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl) palladium (II) (122 mg, 0.14 mmol) were dissolved in anhydrous dioxane (10 mL), then nitrogen was protected and heated to 100° C. for 6 hours. The reaction solution was cooled to room temperature and diluted with ethyl acetate (50 mL), filtered, and the filtrate was directly concentrated to dryness. Pure compound 6 (white solid, 161 mg, 17% yield) was obtained by column chromatography separation (dichloromethane/methanol (v/v) = 20/1).
第六步：Step 6:
(1S)-2-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-3-氧代-N-(间甲苯基)八氢环戊二烯[c]吡咯-1-羧酰胺化合物6-A(1S)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopentadienyl[c]pyrrole-1-carboxamide compound 6-A
(1S)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide(1S)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
(1R)-2-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-3-氧代-N-(间甲苯基)八氢环 戊二烯[c]吡咯-1-羧酰胺化合物6-B(1R)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopentane Pentadienyl[c]pyrrole-1-carboxamide compound 6-B
(1R)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide(1R)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
通过手性制备高效液相色谱(chiral pre-HPLC)拆分化合物6制备得到化合物6-A(白色粉末，61mg，38％产率)和化合物6-B(白色粉末，58mg，36％产率)。分析方法：手性柱AD-3，正己烷∶异丙醇＝95∶5为流动相，流速1mL/min。Compound 6-A (white powder, 61 mg, 38% yield) and compound 6-B (white powder, 58 mg, 36% yield) were prepared by chiral preparative high performance liquid chromatography (chiral pre-HPLC). Analysis method: chiral column AD-3, n-hexane: isopropanol = 95:5 as mobile phase, flow rate 1 mL/min.
化合物6-A：m/z(ESI)＝432.20[M+1]Compound 6-A: m/z (ESI) = 432.20 [M+1]
化合物6-ACompound 6-A
1H NMR(400MHz，CDCl3)δ8.650(s，1H)，7.373-7.412(t，1H)，7.228-7.300(m，3H)，7.066(s，1H)，4.795-4.799(d，1H)，3.272-3.324(m，4H)，2.582-2.643(m，4H)，2.441(s，3H)，2.054-2.123(m，1H)，1.820-1.915(m，1H)，1.651-1.700(m，1H)，1.485-1.563(m，1H)，1.322-1.469(m，1H)，0.942-1.020(m，1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.650 (s, 1H), 7.373-7.412 (t, 1H), 7.228-7.300 (m, 3H), 7.066 (s, 1H), 4.795-4.799 (d, 1H), 3.272-3.324 (m, 4H), 2.582-2.643 (m, 4H), 2.441 (s, 3H), 2.054-2.123 (m, 1H), 1.820-1.915 (m, 1H), 1.651-1.700 (m, 1H), 1.485-1.563 (m, 1H), 1.322-1.469 (m, 1H), 0.942-1.020 (m, 1H).
化合物6-B：m/z(ESI)＝432.20[M+1]Compound 6-B: m/z (ESI) = 432.20 [M+1]
化合物6-BCompound 6-B
1H NMR(400MHz，CDCl3)δ8.651(s，1H)，7.373-7.411(t，1H)，7.227-7.299(m，3H)，7.062(s，1H)，4.779(s，1H)，3.274-3.326(m，4H)，2.584-2.616(m，4H)，2.440(s，3H)，2.055-2.124(m，1H)，1.820-1.915(m，1H)，1.634-1.725(m，1H)，1.470-1.583(m，1H)，1.321-1.430(m，1H)，0.939-1.018(m，1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.651 (s, 1H), 7.373-7.411 (t, 1H), 7.227-7.299 (m, 3H), 7.062 (s, 1H), 4.779 (s, 1H), 3.274-3.326 (m, 4H), 2.584-2.616 (m, 4H), 2.440 (s, 3H), 2.055-2.124 (m, 1H), 1.820-1.915 (m, 1H), 1.634-1.725 (m, 1H), 1.470-1.583 (m, 1H), 1.321-1.430 (m, 1H), 0.939-1.018 (m, 1H).
实施例7Example 7
3-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物73-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 7
3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

第一步：first step:
1-苄基-4-(三氟甲基)-2，5-二氢-1H-]咯-3-羧酸乙酯7c1-Benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-]pyrrole-3-carboxylic acid ethyl ester 7c
ethyl 1-benzyl-4-(trifluoromethyl)-2，5-dihydro-1H-pyrrole-3-carboxylateethyl 1-benzyl-4-(trifluoromethyl)-2，5-dihydro-1H-pyrrole-3-carboxylate
氮气氛围下，将7a(10g，60mmol)溶于30mL二氯甲烷(DCM)中，冰浴下滴加7b(14.4g，60mmol)的二氯甲烷溶液(10mL)，随后缓慢滴加三氟乙酸(684mg，6mmol)的二氯甲烷溶液(10mL)，室温搅拌2h。将反应液加入30mL水中，DCM萃取三次，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，硅胶柱层析纯化(乙酸乙酯/石油醚＝1/10)，得到目标产物7c(黄色油状液体，15.5g，86％产率)，直接用于下一步反应。Under nitrogen atmosphere, 7a (10 g, 60 mmol) was dissolved in 30 mL of dichloromethane (DCM), and a dichloromethane solution (10 mL) of 7b (14.4 g, 60 mmol) was added dropwise under ice bath, followed by a dichloromethane solution (10 mL) of trifluoroacetic acid (684 mg, 6 mmol) was slowly added dropwise, and stirred at room temperature for 2 h. The reaction solution was added into 30 mL of water, extracted with DCM three times, washed with 30 mL of saturated brine, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/10) to obtain the target product 7c (yellow oily liquid, 15.5 g, 86% yield), which was directly used for the next step reaction.
LC-MS m/z(ESI)＝300.1[M+1]LC-MS m/z(ESI)＝300.1[M+1]
第二步：Step 2:
3-苄基-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯7d3-Benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 7d
ethyl-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylateethyl-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate
氮气氛围下，将三甲基碘化亚砜(3.5g，15.8mmol)溶于10mL二甲亚砜中，冰浴下分批次加入氢化钠(633.6mg，15.8mmol)的二甲亚砜溶液(5mL)，室温搅拌30分钟。随后滴加7c(4.3g，14.4mmol)的二甲亚砜溶液(5mL)，60℃反应5h。饱和氯化铵淬灭反应，DCM 30mL萃取，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，硅胶柱层析纯化(乙酸乙酯/石油醚＝1/10)，得到目标产物7d(无色油状液体，3.5g，78％产率)，直接用于下一步反应。Under nitrogen atmosphere, trimethyl sulfoxide iodide (3.5 g, 15.8 mmol) was dissolved in 10 mL of dimethyl sulfoxide, and a dimethyl sulfoxide solution (5 mL) of sodium hydride (633.6 mg, 15.8 mmol) was added in batches under an ice bath, and stirred at room temperature for 30 minutes. Then a dimethyl sulfoxide solution (5 mL) of 7c (4.3 g, 14.4 mmol) was added dropwise, and the mixture was reacted at 60 ° C for 5 h. The reaction was quenched with saturated ammonium chloride, extracted with 30 mL of DCM, washed with 30 mL of saturated brine, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/10) to obtain the target product 7d (colorless oily liquid, 3.5 g, 78% yield), which was directly used in the next step.
1H NMR(400MHz，DMSO-d6)δ7.34-7.24(m，5H)，4.11(q，2H)，3.66(s，2H)，3.08-3.01(m，2H)，2.86-2.82(m，1H)，2.65-2.62(m，1H)，1.82-1.79(m，2H)，1.15(t，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.34-7.24 (m, 5H), 4.11 (q, 2H), 3.66 (s, 2H), 3.08-3.01 (m, 2H), 2.86-2.82 (m, 1H), 2.65-2.62 (m, 1H), 1.82-1.79 (m, 2H), 1.15 (t, 3H).
LC-MS m/z(ESI)＝314.1[M+1]LC-MS m/z(ESI)＝314.1[M+1]
第三步：third step:
3-苄基-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸7e3-Benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 7e
3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid
将化合物7d(3.5g，1.1mol)用四氢呋喃(6ml)、水(6ml)和甲醇(0.6ml)混匀，然后加入一水合氢氧化锂(1.9g，44mmol)，在60℃下反应1h。LC-MS监测反应完全后，冷却到室温，减压除去有机溶剂，再用二氯甲烷(10mL)萃取水相，有机相再用水(5ml)反萃一次，合并水相，用浓盐酸调节pH至3～4，然后用乙酸乙酯萃取水相(10mL×6次)，合并有机相，用无水硫酸钠干燥，减压浓缩，得到化合物7e(粗品245g，棕色液体)，直接投下一步。Compound 7d (3.5 g, 1.1 mol) was mixed with tetrahydrofuran (6 ml), water (6 ml) and methanol (0.6 ml), and then lithium hydroxide monohydrate (1.9 g, 44 mmol) was added and reacted at 60°C for 1 h. After the reaction was completed as monitored by LC-MS, the mixture was cooled to room temperature, the organic solvent was removed under reduced pressure, the aqueous phase was extracted with dichloromethane (10 mL), the organic phase was back-extracted with water (5 ml) once, the aqueous phases were combined, the pH was adjusted to 3-4 with concentrated hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (10 mL×6 times), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 7e (crude product 245 g, brown liquid), which was directly used for the next step.
LC-MS m/z(ESI)＝286.20[M+1]LC-MS m/z(ESI)＝286.20[M+1]
第四步：the fourth step:
3-苄基-N-甲基-N-(间甲苯基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺7f3-Benzyl-N-methyl-N-(m-tolyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 7f
3-benzyl-N-methyl-N-(m-tolyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-benzyl-N-methyl-N-(m-tolyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
将化合物7e(4.0g，14.0mmol)用N，N-二甲基甲酰胺(40mL)溶解，然后加入HATU(8.0g，21.0mmol)，DIPEA(3.66mL，21.0mmol)常温搅拌反应0.5h后再加入3-(甲氨基)甲苯(3.55mL，28.0mmol)于85℃下反应5h。LC-MS监测反应完全后，冷却到室温，加入乙酸乙酯和水萃取(100mL*3)，合并有机相，经柱层析(石油醚/乙酸乙酯＝10∶1-3∶1)得到化合物7f(5.1g，淡黄色液体，93.6％产率)Compound 7e (4.0 g, 14.0 mmol) was dissolved in N, N-dimethylformamide (40 mL), and then HATU (8.0 g, 21.0 mmol) and DIPEA (3.66 mL, 21.0 mmol) were added. The mixture was stirred at room temperature for 0.5 h, and then 3-(methylamino)toluene (3.55 mL, 28.0 mmol) was added and reacted at 85°C for 5 h. After the reaction was completed by LC-MS monitoring, the mixture was cooled to room temperature, and ethyl acetate and water were added for extraction (100 mL*3). The organic phases were combined and subjected to column chromatography (petroleum ether/ethyl acetate = 10:1-3:1) to obtain compound 7f (5.1 g, light yellow liquid, 93.6% yield).
LC-MS m/z(ESI)＝389.20[M+1]LC-MS m/z(ESI)＝389.20[M+1]
第五步：the fifth step:
N-甲基-N-(间甲苯基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺7gN-methyl-N-(m-tolyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 7 g
N-methyl-N-(m-tolyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamideN-methyl-N-(m-tolyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
将化合物7f(5.1g，13.1mmol)用1，2-二氯乙烷(50mL)溶解，常温搅拌下加入1-氯乙基氯甲酸酯(2.1mL，19.7mmol)后升温至50℃下反应4h，旋干1，2-二氯乙烷，向反应中加入甲醇(50mL)升温至回流反应3h。LC-MS监测反应完全 后，旋干甲醇得到化合物7g(572mg，淡黄色液体，粗品)Compound 7f (5.1 g, 13.1 mmol) was dissolved in 1,2-dichloroethane (50 mL), 1-chloroethyl chloroformate (2.1 mL, 19.7 mmol) was added under stirring at room temperature, and the temperature was raised to 50°C for reaction for 4 h. 1,2-dichloroethane was dried by spin drying, and methanol (50 mL) was added to the reaction and the temperature was raised to reflux for reaction for 3 h. LC-MS monitored the reaction to be complete. After that, methanol was dried by spin drying to obtain compound 7g (572 mg, light yellow liquid, crude product)
LC-MS m/z(ESI)＝299.10[M+1]LC-MS m/z(ESI)＝299.10[M+1]
第六步：Step 6:
3-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物73-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 7
3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
将化合物7g(572mg，1.92mmol)用N-甲基吡咯烷酮(20mL)溶解，常温搅拌下加入N，N-二异丙基乙胺(1.34mL，7.67mmol)和2-氯-6-甲基-4-三氟甲基烟腈(486mg，2.21mmol)后升温至100℃反应4h。LC-MS监测反应完全后，冷却到室温，加入乙酸乙酯和水萃取(30mLx3)，合并有机相，经柱层析(石油醚/乙酸乙酯＝10∶1-2∶1)得到化合物7(480mg，淡黄色液体，51.9％产率)Compound 7g (572 mg, 1.92 mmol) was dissolved in N-methylpyrrolidone (20 mL), N, N-diisopropylethylamine (1.34 mL, 7.67 mmol) and 2-chloro-6-methyl-4-trifluoromethylnicotinonitrile (486 mg, 2.21 mmol) were added under stirring at room temperature, and the temperature was raised to 100°C for reaction for 4 h. After the reaction was complete as monitored by LC-MS, the mixture was cooled to room temperature, ethyl acetate and water were added for extraction (30 mL x 3), the organic phases were combined, and compound 7 (480 mg, light yellow liquid, 51.9% yield) was obtained by column chromatography (petroleum ether/ethyl acetate = 10:1-2:1).
LC-MS m/z(ESI)＝483.20[M+1]LC-MS m/z(ESI)＝483.20[M+1]
1H NMR(400MHz，DMSO-d6)δ7.38-7.32(m，1H)，7.32-7.21(m，1H)，7.17s，2H)，7.14(s，1H)，4.28-4.14(m，2H)，4.08-4.01(m，1H)，4.00-3.95(m，1H)，3.20(s，3H)，2.46(s，3H)，2.35(s，3H)，1.24-1.15(m，1H)，0.85-0.72(m，1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.38-7.32 (m, 1H), 7.32-7.21 (m, 1H), 7.17s, 2H), 7.14 (s, 1H), 4.28-4.14 (m, 2H), 4.08-4.01 (m, 1H), 4.00-3.95 (m, 1H), 3.20 (s, 3H), 2.46 (s, 3H), 2.35 (s, 3H), 1.24-1.15 (m, 1H), 0.85-0.72 (m, 1H).
实施例8Example 8
3-(3-氨甲酰-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物83-(3-carbamoyl-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 8
3-(3-carbamoyl-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

3-(3-carbamoyl-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物8a(280mg，0.58mmol)用DMSO(3mL)溶解后加入碳酸钾(24mg，0.17mmol)，搅拌下再缓慢加入30％双氧水(1.74mL，1.74mmol)。LC-MS监测反应完全，向反应中加入水(20mL)，析出大量白色固体，过滤经重结晶得到化合物8(白色固体，113mg，38.9％产率)。Compound 8a (280 mg, 0.58 mmol) was dissolved in DMSO (3 mL), potassium carbonate (24 mg, 0.17 mmol) was added, and 30% hydrogen peroxide (1.74 mL, 1.74 mmol) was slowly added under stirring. The reaction was complete after LC-MS monitoring, and water (20 mL) was added to the reaction to precipitate a large amount of white solid, which was filtered and recrystallized to obtain compound 8 (white solid, 113 mg, 38.9% yield).
LC-MS m/z(ESI)＝501.20[M+1]LC-MS m/z(ESI)＝501.20[M+1]
1H NMR(400MHz，DMSO-d6)δ8.03(s，1H)，7.87(s，1H)，7.40-7.33(m，1H)，7.20-7.16(m，1H)，7.15-7.08(m，2H)，6.90(s，1H)，4.09-4.01(m，2H)，3.92-3.86(m，1H)，3.76-3.69(m，1H)，3.35(s，3H)，2.39(s，3H)，2.36(s，3H)，1.11-1.02(m，1H)，0.68-0.59(m，1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.03 (s, 1H), 7.87 (s, 1H), 7.40-7.33 (m, 1H), 7.20-7.16 (m, 1H), 7.15-7.08 (m, 2H), 6.90 (s, 1H), 4.09-4.01 (m, 2H), 3.92-3.86 (m, 1H), 3.76-3.69 (m, 1H), 3.35 (s, 3H), 2.39 (s, 3H), 2.36 (s, 3H), 1.11-1.02 (m, 1H), 0.68-0.59 (m, 1H).
实施例9Example 9
3-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)-3-氮杂双环[3.1.0]己烷-2-甲酰胺化合物93-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide compound 9
3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide化合物9

3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide Compound 9

第一步：first step:
3-氯-3-氮杂双环[3.1.0]己烷9b3-Chloro-3-azabicyclo[3.1.0]hexane 9b
3-chloro-3-azabicyclo[3.1.0]hexane3-chloro-3-azabicyclo[3.1.0]hexane
将次氯酸钠(71.58g，96.16mmol，10％w/t)，甲丁基叔丁基醚(50mL)，冷却至0度，随后加入3-氮杂双环[3.1.0]己烷盐酸盐(10.0g，83.62mmol)保持温度反应1小时。静置，分液，收集有机相，水相加入50mL甲丁基叔丁基萃取，合并有机相，直接用于下一步反应。Sodium hypochlorite (71.58 g, 96.16 mmol, 10% w/t) and methyl butyl tert-butyl ether (50 mL) were cooled to 0 degrees, and then 3-azabicyclo[3.1.0]hexane hydrochloride (10.0 g, 83.62 mmol) was added to maintain the temperature for 1 hour. The mixture was allowed to stand for separation, and the organic phase was collected. 50 mL of methyl butyl tert-butyl ether was added to the aqueous phase for extraction, and the organic phases were combined and directly used for the next step reaction.
第二步：Step 2:
3-氮杂双环[3.1.0]己-2-烯9c3-Azabicyclo[3.1.0]hex-2-ene 9c
3-azabicyclo[3.1.0]hex-2-ene3-azabicyclo[3.1.0]hex-2-ene
取250mL三口瓶，加入25％氢氧化钠溶液(100mL)，随后在0度下滴加步骤一所得9b有机相100mL，随后将反应液加热至60度，反应2小时。分液，收集有机相，用20％氯化钠溶液100mL清洗有机相，干燥，浓缩，得6g(粗品，无色液体)。直接用于下一步。Take a 250mL three-necked flask, add 25% sodium hydroxide solution (100mL), then add 100mL of the organic phase 9b obtained in step 1 dropwise at 0 degrees, then heat the reaction solution to 60 degrees and react for 2 hours. Separate the liquid, collect the organic phase, wash the organic phase with 100mL of 20% sodium chloride solution, dry, and concentrate to obtain 6g (crude product, colorless liquid). Use it directly in the next step.
第三步：third step:
3-氮杂双环[3.1.0]己烷-2-甲腈9d3-Azabicyclo[3.1.0]hexane-2-carbonitrile 9d
3-azabicyclo[3.1.0]hexane-2-carbonitrile3-azabicyclo[3.1.0]hexane-2-carbonitrile
将3-氮杂双环[3.1.0]己-2-烯9c(6.0g，73.97mmol)溶于无水二氯甲烷(100mL)，甲醇(10mL)，随后冷却至0度，滴加入三甲基氰硅烷(11.01g，110.95mmol)，随后保持温度反应2小时。将反应液直接浓缩，后经硅胶柱层析(二氯甲烷/甲醇(v/v)＝20/1)分离得3-氮杂双环[3.1.0]己烷-2-甲腈(4.3g，无色液体，54％，产率)。 3-Azabicyclo[3.1.0]hex-2-ene 9c (6.0 g, 73.97 mmol) was dissolved in anhydrous dichloromethane (100 mL) and methanol (10 mL), then cooled to 0 degrees, trimethylsilyl cyanide (11.01 g, 110.95 mmol) was added dropwise, and then the temperature was maintained for 2 hours. The reaction solution was directly concentrated and then separated by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to obtain 3-azabicyclo[3.1.0]hexane-2-carbonitrile (4.3 g, colorless liquid, 54%, yield).
LC-MS m/z(ESI)＝109.20[M+1]LC-MS m/z(ESI)＝109.20[M+1]
第四步：the fourth step:
3-氮杂双环[3.1.0]己烷-2-羧酸9e3-Azabicyclo[3.1.0]hexane-2-carboxylic acid 9e
3-azabicyclo[3.1.0]hexane-2-carboxylic acid3-azabicyclo[3.1.0]hexane-2-carboxylic acid
将3-氮杂双环[3.1.0]己烷-2-甲腈9d(2.5g，23.12mmol)溶于6N盐酸溶液(40mL)，将温度加热至90℃反应2h。随后将反应液直接浓缩至干，随后加入氢氧化钠溶液调节pH＝8，重新浓缩至干，得3-氮杂双环[3.1.0]己烷-2-羧酸(浅黄色固体10.0g)，直接用于下一步。3-Azabicyclo[3.1.0]hexane-2-carbonitrile 9d (2.5 g, 23.12 mmol) was dissolved in 6N hydrochloric acid solution (40 mL), and the temperature was heated to 90°C for 2 h. The reaction solution was then directly concentrated to dryness, and then sodium hydroxide solution was added to adjust the pH to 8, and re-concentrated to dryness to obtain 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (light yellow solid 10.0 g), which was directly used in the next step.
LC-MS m/z(ESI)＝128.10[M+1]LC-MS m/z(ESI)＝128.10[M+1]
第五步：the fifth step:
3-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-3-氮杂双环[3.1.0]己烷-2-羧酸9g3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid 9 g
3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid
将3-氮杂双环[3.1.0]己烷-2-羧酸9e(666mg，1.57mmol，含量为30％)，2-氯-6-甲基-4-(三氟甲基)烟腈(416mg，1.89mmol)，二异丙基乙胺(609mg，4.72mmol)，溶于N-甲基吡咯烷酮(2mL)，随后将反应液升温至100度反应1小时。冷却至室温后加入乙酸乙酯(50mL)，随后加入水(25mL)，饱和食盐水(25mL)，干燥有机相，浓缩得油状粗品。粗品经硅胶柱层析(二氯甲烷/甲醇(v/v)＝20/1)分离得3-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-3-氮杂双环[3.1.0]己烷-2-羧酸(200mg，无色油状物，12％产率)。3-Azabicyclo[3.1.0]hexane-2-carboxylic acid 9e (666 mg, 1.57 mmol, content 30%), 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (416 mg, 1.89 mmol), diisopropylethylamine (609 mg, 4.72 mmol) were dissolved in N-methylpyrrolidone (2 mL), and then the reaction solution was heated to 100 degrees for 1 hour. After cooling to room temperature, ethyl acetate (50 mL) was added, followed by water (25 mL) and saturated brine (25 mL), and the organic phase was dried and concentrated to obtain an oily crude product. The crude product was separated by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give 3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, colorless oil, 12% yield).
LC-MS m/z(ESI)＝312.10[M+1]LC-MS m/z(ESI)＝312.10[M+1]
第六步：Step 6:
3-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)-3-氮杂双环[3.1.0]己烷-2-甲酰胺化合物93-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide compound 9
3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
3-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-3-氮杂双环[3.1.0]己烷-2-羧酸9g(200mg，0.64mmol)，N，3-二甲基苯胺(85.65mg，0.7mmol)溶于吡啶(5mL)，随后冷却至0度，滴加入丙基磷酸酐(817mg，1.29mmol)，30分钟后直接加入乙酸乙 酯(50mL)，再加入水25mL，分液，有机相用饱和食盐水25mL清洗，干燥，浓缩得粗品。粗品经柱层析(二氯甲烷/甲醇(v/v)＝20/1)分离得到化合物9(83mg，白色固体，31％产率)3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid 9g (200mg, 0.64mmol), N, 3-dimethylaniline (85.65mg, 0.7mmol) were dissolved in pyridine (5mL), then cooled to 0 degrees, propylphosphoric anhydride (817mg, 1.29mmol) was added dropwise, and ethyl acetate was added directly after 30 minutes. Ester (50 mL), then add 25 mL of water, separate the liquids, wash the organic phase with 25 mL of saturated brine, dry, and concentrate to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol (v/v) = 20/1) to obtain compound 9 (83 mg, white solid, 31% yield)
LC-MS m/z(ESI)＝415.10[M+1]LC-MS m/z(ESI)＝415.10[M+1]
1H NMR(400MHz，Chloroform-d)δ7.37(t，1H)，7.26-7.18(m，3H)，6.75(s，1H)，4.98(s，1H)，4.38(d，1H)，4.25(dd，1H)，3.28(s，3H)，2.49(s，3H)，2.42(s，3H)，1.78(tt，1H)，1.57(td，1H)，0.66(td，1H)，0.14(q，1H). 1 H NMR (400 MHz, Chloroform-d) δ 7.37 (t, 1H), 7.26-7.18 (m, 3H), 6.75 (s, 1H), 4.98 (s, 1H), 4.38 (d, 1H), 4.25 (dd, 1H), 3.28 (s, 3H), 2.49 (s, 3H), 2.42 (s, 3H), 1.78 (tt, 1H), 1.57 (td, 1H), 0.66 (td, 1H), 0.14 (q, 1H).
实施例10Example 10
2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)八氢-1H-异吲哚-1-甲酰胺化合物102-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydro-1H-isoindole-1-carboxamide compound 10
2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahvdro-1H-isoindole-1-carboxamide
2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahvdro-1H-isoindole-1-carboxamide
第一步：first step:
3a，4，5，6，7，7a-六氢-1H-异吲哚10b3a,4,5,6,7,7a-Hexahydro-1H-isoindole 10b
3a，4，5，6，7，7a-hexahydro-1H-isoindole3a,4,5,6,7,7a-hexahydro-1H-isoindole
将原料八氢-1H-异吲哚(5.0g，40.0mmol)溶于甲基叔丁基醚(50mL)中，再加入次氯酸钠溶液(10％的水溶液)(38.5ml，51.8mmol)，反应液于0℃反应4小时， 反应完成后，萃取，水相再用甲基叔丁基醚(20ml×3)萃取3次，有机相合并，然后再加入配制好的氢氧化钠溶液(5.4g氢氧化钠的16.2ml水溶液)，升温至50℃反应5小时后，反应液萃取，有机相用饱和食盐水洗涤，再用无水硫酸钠干燥，减压浓缩得到10b(浅黄色液体，4.0g，81.3％产率)The raw material octahydro-1H-isoindole (5.0 g, 40.0 mmol) was dissolved in methyl tert-butyl ether (50 mL), and sodium hypochlorite solution (10% aqueous solution) (38.5 ml, 51.8 mmol) was added, and the reaction solution was reacted at 0°C for 4 hours. After the reaction was completed, the reaction mixture was extracted, and the aqueous phase was extracted three times with methyl tert-butyl ether (20 ml × 3). The organic phases were combined, and then a prepared sodium hydroxide solution (5.4 g of sodium hydroxide in 16.2 ml of aqueous solution) was added. The reaction mixture was heated to 50° C. for 5 hours, and then the reaction mixture was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 10b (light yellow liquid, 4.0 g, 81.3% yield).
第二步：Step 2:
八氢-1H-异吲哚-1-碳腈10cOctahydro-1H-isoindole-1-carbonitrile 10c
octahydro-1H-isoindole-1-carbonitrileoctahydro-1H-isoindole-1-carbonitrile
将3a，4，5，6，7，7a-六氢-1H-异吲哚(4.0g，32.5mmol)溶于甲醇(5ml)和二氯甲烷(50ml)混合溶液中，降温至0℃后，缓慢滴加三甲基氰硅烷(9.68g，97.5mmol)，滴加完成后，于10℃左右反应2小时，反应完成后，直接经柱层析(二氯甲烷/甲醇(v/v)＝20/1)纯化，得到10c(黄色固体，3.0g，61.4％产率)。3a,4,5,6,7,7a-Hexahydro-1H-isoindole (4.0 g, 32.5 mmol) was dissolved in a mixed solution of methanol (5 ml) and dichloromethane (50 ml). After cooling to 0°C, trimethylsilyl cyanide (9.68 g, 97.5 mmol) was slowly added dropwise. After the addition was completed, the mixture was reacted at about 10°C for 2 hours. After the reaction was completed, it was directly purified by column chromatography (dichloromethane/methanol (v/v) = 20/1) to obtain 10c (yellow solid, 3.0 g, 61.4% yield).
LCMS m/z(ESI)＝151.1[M+1].LCMS m/z(ESI)＝151.1[M+1].
第三步：third step:
八氢-1H-异吲哚-1-羧酸10dOctahydro-1H-isoindole-1-carboxylic acid 10d
octahydro-1H-isoindole-1-carboxylic acidoctahydro-1H-isoindole-1-carboxylic acid
将原料八氢-1H-异吲哚-1-碳腈(3.0g，20.0mmol)加入到反应瓶中，再加入30ml浓盐酸，回流反应5小时，反应完成后，直接浓缩，得到的固体用乙酸乙酯(30ml)打浆，然后过滤，旋干，得到10d(白色固体粗品，2.1g，62.0％产率)。第四步：The raw material octahydro-1H-isoindole-1-carbonitrile (3.0 g, 20.0 mmol) was added to the reaction bottle, and then 30 ml of concentrated hydrochloric acid was added, and the reaction was refluxed for 5 hours. After the reaction was completed, it was directly concentrated, and the obtained solid was slurried with ethyl acetate (30 ml), then filtered and spin-dried to obtain 10d (white solid crude product, 2.1 g, 62.0% yield). Step 4:
2-(叔丁氧基羰基)八氢-1H-异吲哚-1-羧酸10e2-(tert-Butoxycarbonyl)octahydro-1H-isoindole-1-carboxylic acid 10e
2-(tert-butoxycarbonyl)octahydro-1H-isoindole-1-carboxylic acid2-(tert-butoxycarbonyl)octahydro-1H-isoindole-1-carboxylic acid
将上一步粗品6-氮杂螺环[3.4]辛烷-7-羧酸(2.1g，12.4mmol)加入纯化水(5ml)和四氢呋喃(20ml)，反应液降温至10℃附近，缓慢滴加饱和的氢氧化钠水溶液，调节pH值至13，然后再加入二碳酸二叔丁酯(5.4g，24.8mmol)，室温反应4小时后，反应液降温至10℃附近，用1N的盐酸，调节pH值至5左右，然后用乙酸乙酯萃取(40ml×3)，合并有机相，然后用饱和食盐水洗涤，无水硫酸钠干燥后，过滤旋干，粗品经柱层析纯化，得到10e(白色固体粗品，2.5g，74.9％产率)。The crude product 6-azaspiro[3.4]octane-7-carboxylic acid (2.1 g, 12.4 mmol) of the previous step was added with purified water (5 ml) and tetrahydrofuran (20 ml), the reaction solution was cooled to about 10°C, saturated aqueous sodium hydroxide solution was slowly added dropwise to adjust the pH value to 13, and then di-tert-butyl dicarbonate (5.4 g, 24.8 mmol) was added. After reacting at room temperature for 4 hours, the reaction solution was cooled to about 10°C, and the pH value was adjusted to about 5 with 1N hydrochloric acid, and then extracted with ethyl acetate (40 ml×3), the organic phases were combined, and then washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by column chromatography to obtain 10e (white solid crude product, 2.5 g, 74.9% yield).
LCMS m/z(ESI)＝270.2[M+1].LCMS m/z(ESI)＝270.2[M+1].
第五步： the fifth step:
1-(甲基(间甲苯基)氨甲酰基)八氢-2H-异吲哚-2-羧酸叔丁酯10f1-(Methyl(m-tolyl)carbamoyl)octahydro-2H-isoindole-2-carboxylic acid tert-butyl ester 10f
tert-butyl1-(methyl(m-tolyl)carbamoyl)octahydro-2H-isoindole-2-carboxylatetert-butyl1-(methyl(m-tolyl)carbamoyl)octahydro-2H-isoindole-2-carboxylate
将原料2-(叔丁氧基羰基)八氢-1H-异吲哚-1-羧酸(2.5g，9.3mmol)、3-(甲氨基)甲苯(1.15g，9.5mmol)、2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(6.54g，17.2mmol)和N，N-二异丙基乙胺(3.3g，25.8mmol)加入到二氯甲烷(25ml)中，反应混合液于室温反应6小时，反应完成后，再用水萃取，水相再用二氯甲烷(50ml×3)萃取，合并有机相，然后用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，然后经柱层析过柱(石油醚/乙酸乙酯＝5/1)纯化，得到10f(无色液体，1.5g，43.3％产率)。The raw materials 2-(tert-butoxycarbonyl)octahydro-1H-isoindole-1-carboxylic acid (2.5 g, 9.3 mmol), 3-(methylamino)toluene (1.15 g, 9.5 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (6.54 g, 17.2 mmol) and N,N-diisopropylethylamine (3.3 g, 25.8 mmol) were added to dichloromethane (25 ml), and the reaction mixture was reacted at room temperature for 6 hours. After the reaction was completed, it was extracted with water, and the aqueous phase was extracted with dichloromethane (50 ml×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain 10f (colorless liquid, 1.5 g, 43.3% yield).
LCMS m/z(ESI)＝373.4[M+1].LCMS m/z(ESI)＝373.4[M+1].
第六步：Step 6:
2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)八氢-1H-异吲哚-1-甲酰胺化合物102-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydro-1H-isoindole-1-carboxamide compound 10
2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydro-1H-isoindole-1-carboxamide2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)octahydro-1H-isoindole-1-carboxamide
将原料7-(甲基(间甲苯基)氨甲酰)-6-氮杂螺环[3.4]辛烷-6-羧酸叔丁酯(1.0g，2.7mmol)加入到二氯甲烷(10ml)，然后再加入三氟乙酸(10ml)，反应混合液于室温反应4小时，反应完成后减压浓缩成固体。然后再加入1mL N-甲基吡咯烷酮和5mL N，N-二异丙基乙胺，室温搅拌0.5h后，再加入2-氯-6-甲基-4-三氟甲基烟腈(696mg，3.2mmol)，加热至100℃反应2小时。TLC检测反应完成后，降至室温，反应混合液直接经柱层析纯化(石油醚/乙酸乙酯＝5/1)，得到化合物10(白色固体，150mg，15.0％产率)。The raw material 7-(methyl(m-tolyl)carbamoyl)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (1.0 g, 2.7 mmol) was added to dichloromethane (10 ml), and then trifluoroacetic acid (10 ml) was added. The reaction mixture was reacted at room temperature for 4 hours. After the reaction was completed, it was concentrated under reduced pressure to a solid. Then 1 mL of N-methylpyrrolidone and 5 mL of N, N-diisopropylethylamine were added. After stirring at room temperature for 0.5 h, 2-chloro-6-methyl-4-trifluoromethylnicotinonitrile (696 mg, 3.2 mmol) was added and heated to 100 ° C for 2 hours. After the reaction was completed by TLC detection, it was cooled to room temperature, and the reaction mixture was directly purified by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 10 (white solid, 150 mg, 15.0% yield).
LCMS m/z(ESI)＝457.2[M+1].LCMS m/z(ESI)＝457.2[M+1].
1H NMR(400MHz，DMSO-d6)7.42-7.33(m，3H)，7.1(d，J＝7.6Hz，1H)，7.04(d，J＝6.8Hz，1H)，4.35(d，J＝2.4Hz，1H)，4.00-3.96(m，1H)，3.76(t，J＝9.6Hz，1H)，3.15(s，3H)，2.67-2.65(m，1H)，2.54(s，3H)，2.34(s，3H)，2.23-2.17(m，1H)，1.53-1.49(m，2H)，1.39-1.21(m，3H)，1.09-1.00(m，3H). 1 H NMR (400 MHz, DMSO-d6) 7.42-7.33 (m, 3H), 7.1 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 6.8 Hz, 1H), 4.35 (d, J = 2.4 Hz, 1H), 4.00-3.96 (m, 1H), 3.76 (t, J = 9.6 Hz, 1H), 3.15 (s, 3H), 2.67-2.65 (m, 1H), 2.54 (s, 3H), 2.34 (s, 3H), 2.23-2.17 (m, 1H), 1.53-1.49 (m, 2H), 1.39-1.21 (m, 3H), 1.09-1.00 (m, 3H).
实施例11 Embodiment 11
2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-3a-羟基-N-甲基-N-(间甲苯基)八氢环戊[c]吡咯-1-甲酰胺化合物112-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide compound 11
2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
(1S)-2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-3a-羟基-N-甲基-N-(间甲苯基)八氢环戊[c]吡咯-1-甲酰胺化合物11-A(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide Compound 11-A
(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-l-carboxamide(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-l-carboxamide
(1R)-2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-3a-羟基-N-甲基-N-(间甲苯基)八氢环戊[c]吡咯-l-甲酰胺化合物11-B(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-l-carboxamide Compound 11-B
(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
第一步： first step:
2-氰基-2-((三甲基甲硅基)氧基)环戊烷-1-羧酸甲酯11b2-Cyano-2-((trimethylsilyl)oxy)cyclopentane-1-carboxylic acid methyl ester 11b
methyl 2-cyano-2-((trimethylsilyl)oxy)cyclopentane-1-carboxylatemethyl 2-cyano-2-((trimethylsilyl)oxy)cyclopentane-1-carboxylate
将原料2-氧代环戊烷-1-羧酸甲酯(20g，14.1mmol)加入到反应瓶中，再加入碘化锌(2.2g，7.05mmol)，然后于室温缓慢滴加三甲基氰硅烷(1.4g，14.1mmol)。反应放热，升温至40℃反应4h。完成后，加入二氯甲烷(200ml)和纯化水(200ml)，萃取有机相，干燥后过滤，浓缩得到化合物11b(粗品，30.1g)。The raw material 2-oxocyclopentane-1-carboxylic acid methyl ester (20 g, 14.1 mmol) was added to the reaction bottle, and zinc iodide (2.2 g, 7.05 mmol) was added, and then trimethylsilyl cyanide (1.4 g, 14.1 mmol) was slowly added dropwise at room temperature. The reaction was exothermic, and the temperature was raised to 40 ° C for 4 hours. After completion, dichloromethane (200 ml) and purified water (200 ml) were added, the organic phase was extracted, dried, filtered, and concentrated to obtain compound 11b (crude product, 30.1 g).
LCMS m/z(ESI)＝242.1[M+1].LCMS m/z(ESI)＝242.1[M+1].
第二步：Step 2:
2-(氨基甲基)-2-羟基环戊烷-1-羧酸甲酯11c2-(Aminomethyl)-2-hydroxycyclopentane-1-carboxylic acid methyl ester 11c
methyl 2-(aminomethyl)-2-hydroxycyclopentane-1-carboxylatemethyl 2-(aminomethyl)-2-hydroxycyclopentane-1-carboxylate
将原料2-氰基-2-((三甲基甲硅基)氧基)环戊烷-1-羧酸甲酯(30g，12.4mmol)加入到反应瓶中，然后再加入甲醇(1.2L)溶解。再加入氯化镍(32.1g，24.8mmol)，反应混合液降温至10℃以下，缓慢加入硼氢化钠(46.9g，124.0mmol)，控制反应温度于10℃以下，反应放气放热。加入完毕后，缓慢升温至室温反应4h，反应完成后，缓慢滴加氨水(100ml)淬灭反应，然后反应混合液经硅藻土过滤，滤液浓缩，经硅胶柱过柱(二氯甲烷/甲醇(v/v)＝20/1)纯化，得到目标化合物11c(无色油状物，12.5g，57.7％产率)。The raw material 2-cyano-2-((trimethylsilyl)oxy)cyclopentane-1-carboxylic acid methyl ester (30 g, 12.4 mmol) was added to the reaction bottle, and then methanol (1.2 L) was added to dissolve. Nickel chloride (32.1 g, 24.8 mmol) was added, the reaction mixture was cooled to below 10°C, sodium borohydride (46.9 g, 124.0 mmol) was slowly added, and the reaction temperature was controlled below 10°C, and the reaction was exothermic. After the addition was completed, the temperature was slowly raised to room temperature for 4 hours. After the reaction was completed, ammonia water (100 ml) was slowly added dropwise to quench the reaction, and then the reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated, and purified through a silica gel column (dichloromethane/methanol (v/v) = 20/1) to obtain the target compound 11c (colorless oil, 12.5 g, 57.7% yield).
LCMS m/z(ESI)＝174.1[M+1].LCMS m/z(ESI)＝174.1[M+1].
第三步：third step:
3a-羟基六氢环戊[c]吡咯-1(2H)-酮11d3a-Hydroxyhexahydrocyclopenta[c]pyrrol-1(2H)-one 11d
3a-hydroxyhexahydrocyclopenta[c]pyrrol-1(2H)-one3a-hydroxyhexahydrocyclopenta[c]pyrrol-1(2H)-one
将原料2-(氨基甲基)-2-羟基环戊烷-1-羧酸甲酯(12.5g，72.2mmol)溶于甲醇(200ml)中，再将氢氧化钠(1.44g，36.1mmol)溶于纯化水(20ml)中，反应液降温至0℃，再将配置好的氢氧化钠溶液加入到反应液中，反应液缓慢升温至室温，反应3小时后，反应完成，缓慢滴加1N的盐酸溶液，调节pH值至5，然后浓缩除去溶剂，过柱纯化(二氯甲烷/甲醇(v/v)＝20/1)得到目标产物11d(无色油状，7.8g，76.5％产率)。The raw material 2-(aminomethyl)-2-hydroxycyclopentane-1-carboxylic acid methyl ester (12.5 g, 72.2 mmol) was dissolved in methanol (200 ml), and then sodium hydroxide (1.44 g, 36.1 mmol) was dissolved in purified water (20 ml). The reaction solution was cooled to 0°C, and then the prepared sodium hydroxide solution was added to the reaction solution. The reaction solution was slowly heated to room temperature. After 3 hours of reaction, the reaction was completed, and 1N hydrochloric acid solution was slowly added dropwise to adjust the pH value to 5. Then, the solvent was removed by concentration, and the target product 11d (colorless oil, 7.8 g, 76.5% yield) was obtained after column purification (dichloromethane/methanol (v/v) = 20/1).
LCMS m/z(ESI)＝142.1[M+1].LCMS m/z(ESI)＝142.1[M+1].
第四步： the fourth step:
3a-羟基八氢环戊[c]吡咯-1-腈11e3a-Hydroxyoctahydrocyclopenta[c]pyrrole-1-carbonitrile 11e
3a-hydroxyoctahydrocyclopenta[c]pyrrole-1-carbonitrile3a-hydroxyoctahydrocyclopenta[c]pyrrole-1-carbonitrile
将原料3a-羟基六氢环戊[c]吡咯-1(2H)-酮(6.0g，42.5mmol)溶于二氯甲烷中(40ml)中，降温至0℃，再加入氢氯二茂锆(16.4g，63.8mmol)，于氮气氛围下，反应1小时，然后缓慢升温至室温反应2h，然后再加入三甲基硅氰(6.3g，63.8mmol)反应液于室温反应4h，反应完成后，直接浓缩至干，得到粗品化合物11e(浅黄色固体，3.0g)。The raw material 3a-hydroxyhexahydrocyclopenta[c]pyrrole-1(2H)-one (6.0 g, 42.5 mmol) was dissolved in dichloromethane (40 ml), cooled to 0°C, and then zirconocene hydrochloride (16.4 g, 63.8 mmol) was added. The mixture was reacted for 1 hour under a nitrogen atmosphere, and then the temperature was slowly raised to room temperature for 2 hours. Then, trimethylsilyl cyanide (6.3 g, 63.8 mmol) was added to the reaction solution and reacted at room temperature for 4 hours. After the reaction was completed, it was directly concentrated to dryness to obtain a crude compound 11e (light yellow solid, 3.0 g).
LCMS m/z(ESI)＝153.1[M+1].LCMS m/z(ESI)＝153.1[M+1].
第五步：the fifth step:
2-(叔丁氧羰基)-3a-羟基八氢环戊[c]吡咯-1-羧酸11f2-(tert-Butyloxycarbonyl)-3a-hydroxyoctahydrocyclopenta[c]pyrrole-1-carboxylic acid 11f
2-(tert-butoxycarbonyl)-3a-hydroxyoctahydrocyclopenta[c]pyrrole-1-carboxylicacid2-(tert-butoxycarbonyl)-3a-hydroxyoctahydrocyclopenta[c]pyrrole-1-carboxylic acid
将上一步粗品3a-羟基八氢环戊[c]吡咯-1-腈(3.0g，19.7mmol)加入6N的浓盐酸(50ml)，反应混合液升温至回流反应6小时，反应完成后，减压浓缩除去溶剂，再加入纯化水(10ml)，反应混合液降温至0℃，缓慢滴加15％的氢氧化钠溶液，调节pH值至13，再加入15ml四氢呋喃，然后再加入二碳酸二叔丁酯(10.8g，49.6mmol)，反应混合液于室温反应4小时，反应完成后，用饱和的硫酸氢钾溶液调节pH至4，然后再加入乙酸乙酯(100ml×3)萃取，合并有机相后，浓缩，过柱纯化(二氯甲烷/甲醇(v/v)＝20/1)得到化合物11f(白色固体，1.2g，22.5％产率)。The crude product 3a-hydroxyoctahydrocyclopenta[c]pyrrole-1-carbonitrile (3.0 g, 19.7 mmol) of the previous step was added with 6N concentrated hydrochloric acid (50 ml), and the reaction mixture was heated to reflux for reaction for 6 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and purified water (10 ml) was added. The reaction mixture was cooled to 0°C, and 15% sodium hydroxide solution was slowly added dropwise to adjust the pH value to 13. 15 ml of tetrahydrofuran was added, and then di-tert-butyl dicarbonate (10.8 g, 49.6 mmol) was added. The reaction mixture was reacted at room temperature for 4 hours. After the reaction was completed, the pH was adjusted to 4 with a saturated potassium hydrogen sulfate solution, and then ethyl acetate (100 ml×3) was added for extraction. The organic phases were combined, concentrated, and purified by column chromatography (dichloromethane/methanol (v/v)=20/1) to obtain compound 11f (white solid, 1.2 g, 22.5% yield).
LCMS m/z(ESI)＝272.1[M+1].LCMS m/z(ESI)＝272.1[M+1].
第六步：Step 6:
3a-羟基-1-(甲基(间甲苯基)氨基甲酰基)六氢环戊[c]吡咯-2(1H)-羧酸叔丁酯11g3a-Hydroxy-1-(methyl(m-tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 11g
tert-butyltert-butyl
3a-hydroxy-1-(methyl(m-tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate3a-hydroxy-1-(methyl(m-tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
将原料2-(叔丁氧羰基)-3a-羟基八氢环戊[c]吡咯-1-羧酸(300mg，1.11mmol)加入到50ml烧瓶中，再加入5ml吡啶，降温至0℃，再加入1-丙基磷酸酐(1.41g， 2.22mmol，50％的乙酸乙酯溶液)，然后缓慢滴加3-(甲氨基)甲苯(184mg，1.52mmol)。滴加完成后缓慢升温至室温反应1小时，反应完成后，加入水和乙酸乙酯(各50ml)萃取，然后有机相经用饱和食盐水萃取，再经无水硫酸钠干燥，过滤后旋干溶剂，经硅胶过柱(二氯甲烷/甲醇(v/v)＝20/1)纯化得到化合物11g：3a-羟基-1-(甲基(间甲苯基)氨基甲酰基)六氢环戊[c]吡咯-2(1H)-羧酸叔丁酯(304mg，73.1％产率)。The raw material 2-(tert-butyloxycarbonyl)-3a-hydroxyoctahydrocyclopenta[c]pyrrole-1-carboxylic acid (300 mg, 1.11 mmol) was added to a 50 ml flask, and then 5 ml of pyridine was added, and the temperature was lowered to 0°C, and then 1-propylphosphoric anhydride (1.41 g, 2.22mmol, 50% ethyl acetate solution), and then slowly drop 3-(methylamino)toluene (184mg, 1.52mmol). After the dropwise addition, slowly heat to room temperature to react for 1 hour. After the reaction is completed, add water and ethyl acetate (50ml each) for extraction, and then the organic phase is extracted with saturated brine, dried over anhydrous sodium sulfate, filtered and the solvent is dried, and purified by silica gel column (dichloromethane/methanol (v/v) = 20/1) to obtain compound 11g: tert-butyl 3a-hydroxy-1-(methyl(m-tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (304mg, 73.1% yield).
LCMS m/z(ESI)＝375.2[M+1].LCMS m/z(ESI)＝375.2[M+1].
第七步：Step 7:
3a-羟基-N-甲基-N-(间甲苯基)八氢环戊[c]吡咯-1-甲酰胺11h3a-Hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide 11h
3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
将原料3a-羟基-1-(甲基(间甲苯基)氨基甲酰基)六氢环戊[c]吡咯-2(1H)-羧酸叔丁酯(304mg，0.81mmol)加入到反应瓶中，再加入盐酸溶液(4mol/L的HCl/1，4-二氧六环溶液)(10ml)，反应混合液于室温反应3h，然后减压浓缩除去溶剂，得到化合物11h(无色液体，210mg，94.6％产率)。The raw material tert-butyl 3a-hydroxy-1-(methyl(m-tolyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (304 mg, 0.81 mmol) was added to a reaction bottle, and then a hydrochloric acid solution (4 mol/L HCl/1,4-dioxane solution) (10 ml) was added. The reaction mixture was reacted at room temperature for 3 h, and then concentrated under reduced pressure to remove the solvent to obtain compound 11h (colorless liquid, 210 mg, 94.6% yield).
LCMS m/z(ESI)＝275.2[M+1].LCMS m/z(ESI)＝275.2[M+1].
第八步：Step 8:
2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-3a-羟基-N-甲基-N-(间甲苯基)八氢环戊[c]吡咯-1-甲酰胺化合物112-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide compound 11
2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
将原料3a-羟基-N-甲基-N-(间甲苯基)八氢环戊[c]吡咯-1-甲酰胺(210mg，0.77mmol)、2-氯-6-甲基-4-三氟甲基烟腈(170mg，0.77mmol)和N，N-二异丙基乙胺(199mg，1.54mmol)加入到50mL烧瓶中，再加入5mLN-甲基吡咯烷酮，加热至80℃反应3小时。TLC检测反应完成后，反应液用二氯甲烷稀释，然后经过柱纯化，得到化合物11(浅黄色固体，160mg，45.3％产率)。The raw material 3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (210 mg, 0.77 mmol), 2-chloro-6-methyl-4-trifluoromethylnicotinonitrile (170 mg, 0.77 mmol) and N, N-diisopropylethylamine (199 mg, 1.54 mmol) were added to a 50 mL flask, and then 5 mL of N-methylpyrrolidone was added, and the mixture was heated to 80° C. and reacted for 3 hours. After the reaction was completed by TLC detection, the reaction solution was diluted with dichloromethane and then purified by column to obtain compound 11 (light yellow solid, 160 mg, 45.3% yield).
LCMS m/z(ESI)＝459.2[M+1].LCMS m/z(ESI)＝459.2[M+1].
第九步：Step 9:
(1S)-2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-3a-羟基-N-甲基-N-(间甲苯基)八氢环戊[c]吡咯-1-甲酰胺化合物11-A (1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide Compound 11-A
(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydroeyclopenta[c]pyrrole-1-carboxamide(1S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydroeyclopenta[c]pyrrole-1-carboxamide
(1R)-2-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-3a-羟基-N-甲基-N-(间甲苯基)八氢环戊[c]吡咯-1-甲酰胺化合物11-B(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide Compound 11-B
(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydroeyclopenta[c]pyrrole-1-carboxamide(1R)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3a-hydroxy-N-methyl-N-(m-tolyl)octahydroeyclopenta[c]pyrrole-1-carboxamide
通过手性制备高效液相色谱(chiral pre-HPLC)拆分化合物11制备得到化合物11-A(65mg)和化合物11-B(70mg)。分析方法：手性柱AD-1，正己烷∶异丙醇＝90∶10为流动相，流速1mL/min。Compound 11-A (65 mg) and compound 11-B (70 mg) were prepared by chiral preparative high performance liquid chromatography (chiral pre-HPLC) to separate compound 11. Analysis method: chiral column AD-1, n-hexane: isopropanol = 90:10 as mobile phase, flow rate 1 mL/min.
化合物11-A：LCMS m/z(ESI)＝459.2[M+1].Compound 11-A: LCMS m/z(ESI)＝459.2[M+1].
化合物11-ACompound 11-A
1H NMR(400MHz，DMSO-d6)δ7.40-7.20(m，4H)，7.06(s，1H)，5.18(s，1H)，4.60(d，J＝3.6Hz，1H)，4.20(d，J＝10.4Hz，1H)，3.92(d，J＝10.4Hz，1H)，3.31-3.30(m，1H)，3.13(s，3H)，2.50(s，3H)，2.33(s，3H)，2.31-2.05(m，1H)，1.71-1.49(m，4H)，1.36-1.27(m，1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.40-7.20 (m, 4H), 7.06 (s, 1H), 5.18 (s, 1H), 4.60 (d, J=3.6 Hz, 1H), 4.20 (d, J=10.4 Hz, 1H), 3.92 (d, J=10.4 Hz, 1H), 3.31-3.30 (m, 1H), 3.13 (s, 3H), 2.50 (s, 3H), 2.33 (s, 3H), 2.31-2.05 (m, 1H), 1.71-1.49 (m, 4H), 1.36-1.27 (m, 1H).
化合物11-B：LCMS m/z(ESI)＝459.2[M+1].Compound 11-B: LCMS m/z(ESI)＝459.2[M+1].
化合物11-BCompound 11-B
1H NMR(400MHz，DMSO-d6)δ7.42-7.22(m，4H)，7.07(s，1H)，5.19(s，1H)，4.61(d，J＝3.6Hz，1H)，4.21(d，J＝10.4Hz，1H)，3.92(d，J＝10.4Hz，1H)，3.31-3.30(m，1H)，3.13(s，3H)，2.50(s，3H)，2.33(s，3H)，2.31-2.05(m，1H)，1.71-1.49(m，4H)，1.36-1.27(m，1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.42-7.22 (m, 4H), 7.07 (s, 1H), 5.19 (s, 1H), 4.61 (d, J=3.6 Hz, 1H), 4.21 (d, J=10.4 Hz, 1H), 3.92 (d, J=10.4 Hz, 1H), 3.31-3.30 (m, 1H), 3.13 (s, 3H), 2.50 (s, 3H), 2.33 (s, 3H), 2.31-2.05 (m, 1H), 1.71-1.49 (m, 4H), 1.36-1.27 (m, 1H).
实施例12Example 12
3aS，6aS-3a，6a-二羟基-N-甲基-2-(6-甲基-4-三氟甲基吡啶-2-基)-3-氧代-N-间甲苯基八氢环戊基吡咯-1-甲酰胺化合物123aS, 6aS-3a, 6a-dihydroxy-N-methyl-2-(6-methyl-4-trifluoromethylpyridin-2-yl)-3-oxo-N-m-tolyloctahydrocyclopentylpyrrole-1-carboxamide compound 12
(3aS，6aS)-3a，6a-dihydroxy-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxo-N-(m-tolyl)octahydroeyclopenta[c]pyrrole-1-carboxamide
(3aS, 6aS)-3a, 6a-dihydroxy-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxo-N-(m-tolyl)octahydroeyclopenta[c]pyrrole-1-carboxamide
第一步：first step:
2-氯环戊-1-烯-1-甲醛2-Chlorocyclopent-1-ene-1-carbaldehyde
2-chlorocyclopent-1-ene-1-carbaldehyde 12b
2-chlorocyclopent-1-ene-1-carbaldehyde 12b
将环戊酮12a(10.0g，119mmol)溶于二氯甲烷(100mL)，随后冷却至0℃，再次加入(氯亚甲基)二甲基氯化铵(25.0g，195mmol)，恢复至室温反应1h。反应完毕，将反应液直接倒入冰水(200mL)中，用碳酸钠固体调节pH为7，分液，有机相干燥，浓缩得粗品。粗品经过硅胶柱层析(石油醚/乙酸乙酯＝5/1)分离得12b(7.0g，无色油状物，45％产率)。Cyclopentanone 12a (10.0 g, 119 mmol) was dissolved in dichloromethane (100 mL), then cooled to 0°C, (chloromethylene) dimethylammonium chloride (25.0 g, 195 mmol) was added again, and the mixture was returned to room temperature for 1 h. After the reaction was completed, the reaction solution was directly poured into ice water (200 mL), and the pH was adjusted to 7 with solid sodium carbonate. The liquid was separated, the organic phase was dried, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain 12b (7.0 g, colorless oil, 45% yield).
第二步：Step 2:
2-氨基-2-(2-氯环戊-1-烯-1-基)乙腈2-Amino-2-(2-chlorocyclopent-1-en-1-yl)acetonitrile
2-amino-2-(2-chlorocyclopent-1-eh-1-yl)acetonitrile 12c
2-amino-2-(2-chlorocyclopent-1-eh-1-yl)acetonitrile 12c
将2-氯环戊-1-烯-1-甲醛12b(3.0g，23mmol)，三甲基氰硅烷(3.42g，34.5mmol)，混合后加入碘化锌(733mg，2.3mmol)，冰浴反应1小时。另起一反应瓶，加入氨甲醇溶液(120mL，7M)，冰浴至0度，随后滴加入前反应液，保持反应1小时，随后升温至50度反应1小时。反应完毕，减压除去大部分甲醇后加入二氯甲烷(200mL)，分液，有机相用饱和食盐水(100mL)清洗，干燥，浓缩得粗品。粗品经过硅胶柱层析分离得12c(3.0g，浅黄色油状物)。2-Chlorocyclopent-1-ene-1-carboxaldehyde 12b (3.0 g, 23 mmol) and trimethylsilyl cyanide (3.42 g, 34.5 mmol) were mixed and zinc iodide (733 mg, 2.3 mmol) was added and the mixture was reacted in an ice bath for 1 hour. In another reaction bottle, ammonia methanol solution (120 mL, 7 M) was added, the mixture was ice bathed to 0 degrees, and then the previous reaction solution was added dropwise, and the reaction was maintained for 1 hour, and then the temperature was raised to 50 degrees for 1 hour. After the reaction was completed, most of the methanol was removed under reduced pressure and dichloromethane (200 mL) was added, the liquid was separated, and the organic phase was washed with saturated brine (100 mL), dried, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain 12c (3.0 g, light yellow oil).
LCMS m/z(ESI)＝157.20[M+1]LCMS m/z(ESI)＝157.20[M+1]
第三步：third step:
2-氨基-2-(2-氯环戊-1-烯-1-基)乙酸2-Amino-2-(2-chlorocyclopent-1-en-1-yl)acetic acid
2-amino-2-(2-chlorocyclopent-1-eh-1-yl)acetic acid 12d
2-amino-2-(2-chlorocyclopent-1-eh-1-yl)acetic acid 12d
将2-氨基-2-(2-氯环戊-1-烯-1-基)乙腈12c(3.0g，19.2mmol)溶于6N盐酸溶液(40mL)，加热到100度反应2小时。反应完毕，直接将反应液浓缩至干得2-氨基-2-(2-氯环戊-1-烯-1-基)乙酸12d(3.0g，灰色固体)。直接用于下一步反应。2-Amino-2-(2-chlorocyclopent-1-ene-1-yl)acetonitrile 12c (3.0 g, 19.2 mmol) was dissolved in 6N hydrochloric acid solution (40 mL), heated to 100 degrees and reacted for 2 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness to obtain 2-amino-2-(2-chlorocyclopent-1-ene-1-yl)acetic acid 12d (3.0 g, gray solid), which was directly used for the next step reaction.
LCMS m/z(ESI)＝176.20[M+1]LCMS m/z(ESI)＝176.20[M+1]
第四步： the fourth step:
2-(叔丁氧羰基)氨基)-2-(2-氯环戊-1-烯-1-基)乙酸12e2-(tert-Butyloxycarbonyl)amino)-2-(2-chlorocyclopent-1-en-1-yl)acetic acid 12e
2-((tert-butoxycarbonyl)amino)-2-(2-chlorocyclopent-1-en-1-yl)acetic acid
2-((tert-butoxycarbonyl)amino)-2-(2-chlorocyclopent-1-en-1-yl)acetic acid
将2-氨基-2-(2-氯环戊-1-烯-1-基)乙酸12d(3.0g，19.09mmol)溶于四氢呋喃(20mL)，水(20mL)，随后加入碳酸氢钠(4.81g，52.27mmol)，冰浴加入碳酸二叔丁酯(4.17g，19.09mmol).30分钟后加热至40度反应2小时。反应完毕，直接向反应液中加入水(20mL)，随后用硫酸氢钾(1N)调节pH为3～4，再用乙酸乙酯(100mL)萃取水相，有机相经过干燥，浓缩得粗品12e(7.0g，黑色油状物)，直接用于下一步。2-Amino-2-(2-chlorocyclopent-1-ene-1-yl)acetic acid 12d (3.0 g, 19.09 mmol) was dissolved in tetrahydrofuran (20 mL) and water (20 mL), followed by the addition of sodium bicarbonate (4.81 g, 52.27 mmol), followed by the addition of di-tert-butyl carbonate (4.17 g, 19.09 mmol) in an ice bath. After 30 minutes, the mixture was heated to 40 degrees and reacted for 2 hours. After the reaction was completed, water (20 mL) was directly added to the reaction solution, followed by the pH being adjusted to 3-4 with potassium bisulfate (1 N), and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was dried and concentrated to obtain a crude product 12e (7.0 g, black oil), which was directly used in the next step.
LCMS m/z(ESI)＝176.20[M-99]LCMS m/z(ESI)＝176.20[M-99]
第五步：the fifth step:
(2-氯环戊-1-烯-1-基)-2-(甲基(间甲苯基)氨基)-2-氧代乙基氨基甲酸叔丁酯12fTert-butyl (2-chlorocyclopent-1-en-1-yl)-2-(methyl(m-tolyl)amino)-2-oxoethylcarbamate 12f
tert-butyltert-butyl
(1-(2-chlorocyclopent-1-en-1-yl)-2-(methyl(m-tolyl)amino)-2-oxoethyl)carbamate
(1-(2-chlorocyclopent-1-en-1-yl)-2-(methyl(m-tolyl)amino)-2-oxoethyl)carbamate
将2-(叔丁氧羰基)氨基)-2-(2-氯环戊-1-烯-1-基)乙酸12e(7.0g，25.39mmol)，3-(甲氨基)甲苯(3.08g，25.39mmol)，二异丙基乙胺(13mL，76mmol)溶于乙酸乙酯(100mL)，随后冰浴滴加入T3P(24.25g，50％wt乙酸乙酯溶液)，恢复室温反应1小时。反应完毕，加入乙酸乙酯(20mL)稀释反应液，随后加入饱和碳酸氢钠溶液(100mL)，分液，有机相再依次用1N盐酸溶液(100mL)，饱和食盐水(100mL)清洗，干燥，浓缩得粗品。粗品经过硅胶柱层析(石油醚/乙酸乙酯＝5/1)分离得12f(黄色固体，5.0g，52％产率)。2-(tert-Butyloxycarbonyl)amino)-2-(2-chlorocyclopent-1-ene-1-yl)acetic acid 12e (7.0 g, 25.39 mmol), 3-(methylamino)toluene (3.08 g, 25.39 mmol), diisopropylethylamine (13 mL, 76 mmol) were dissolved in ethyl acetate (100 mL), and then T3P (24.25 g, 50% wt ethyl acetate solution) was added dropwise in an ice bath, and the mixture was returned to room temperature for reaction for 1 hour. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, and then saturated sodium bicarbonate solution (100 mL) was added, and the liquid was separated. The organic phase was then washed with 1N hydrochloric acid solution (100 mL) and saturated brine (100 mL) in turn, dried, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain 12f (yellow solid, 5.0 g, 52% yield).
LCMS m/z(ESI)＝279.20[M-99] LCMS m/z(ESI)＝279.20[M-99]
1H NMR(400MHz，Chloroform-d)δ7.30(d，1H)，7.14(d，1H)，7.01-6.92(m，2H)，5.62(s，1H)，5.21(d，1H)，3.26(s，3H)，2.45-2.38(m，2H)，2.37(s，3H)，2.29-2.17(m，1H)，2.07-2.16(m，1H)，1.74-1.92(m，2H)，1.42(s，9H). 1 H NMR (400 MHz, Chloroform-d) δ 7.30 (d, 1H), 7.14 (d, 1H), 7.01-6.92 (m, 2H), 5.62 (s, 1H), 5.21 (d, 1H), 3.26 (s, 3H), 2.45-2.38 (m, 2H), 2.37 (s, 3H), 2.29-2.17 (m, 1H), 2.07-2.16 (m, 1H), 1.74-1.92 (m, 2H), 1.42 (s, 9H).
第六步：Step 6:
3-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)-3-氮杂双环[3.1.0]己烷-2-甲酰胺12g3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide 12 g
3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide
将(2-氯环戊-1-烯-1-基)-2-(甲基(间甲苯基)氨基)-2-氧代乙基氨基甲酸叔丁酯12f(1.2g，3.17mmol)，铁***(834mg，2.51mmol)，2-二-叔丁膦基-2′，4′，6′-三异丙基联苯(134mg，0.3mmol)，甲烷磺酸(2-二叔丁基膦基-2′，4′，6′-三异丙基-1，1′-联苯基)(2′-氨基-1，1′-联苯-2-基)钯(II)(251mg，0.3mmol)，乙酸钾(932mg，9.5mmol)，溶于二氧六环(10mL)，水(5mL)，排气后氮气保护，微波120度反应4h。反应完毕，将反应液倒入水(50mL)中，用乙酸乙酯萃取(50X 3)，合并有机相，干燥，浓缩得粗品。粗品经过硅胶柱层析分离纯化(石油醚/乙酸乙酯＝5/1)得12g(1.2g，无色油状物，100％产率)。Dissolve tert-butyl (2-chlorocyclopent-1-en-1-yl)-2-(methyl(m-tolyl)amino)-2-oxoethylcarbamate 12f (1.2 g, 3.17 mmol), potassium ferrocyanide (834 mg, 2.51 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (134 mg, 0.3 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium (II) (251 mg, 0.3 mmol), and potassium acetate (932 mg, 9.5 mmol) in dioxane (10 mL) and water (5 mL), exhaust the air, protect with nitrogen, and react at 120 degrees in a microwave for 4 h. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (50X 3), the organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain 12 g (1.2 g, colorless oil, 100% yield).
LCMS m/z(ESI)＝314.20[M-55]LCMS m/z(ESI)＝314.20[M-55]
第七步：Step 7:
(1-(2-氰基环戊-1-烯-1-基)-2-(甲基(间甲苯基)氨基)-2-氧代乙基)氨基甲酸叔丁酯12hTert-butyl (1-(2-cyanocyclopent-1-en-1-yl)-2-(methyl(m-tolyl)amino)-2-oxoethyl)carbamate 12h
tert-butyl(1-(2-cyanocyclopent-1-en-1-yl)-2-(methyl(m-tolyl)amino)-2-oxoethyl)carhamate
tert-butyl(1-(2-cyanocyclopent-1-en-1-yl)-2-(methyl(m-tolyl)amino)-2-oxoethyl)carhamate
3-(3-氰基-6-甲基-4-(三氟甲基)吡啶-2-基)-N-甲基-N-(间甲苯基)-3-氮杂双环[3.1.0]己烷-2-甲酰胺12g(1.2g，3.25mmol)和碳酸钾(134mg，0.9mmol)溶于二甲亚砜(20mL)，将双氧水(662mg，19mmol)滴加入溶液中，加热至40℃，反应4h。反应完毕，将反应液直接倒入水(50mL)中，加入乙酸乙酯萃取(50mL×3)，合并有机相，干燥，浓缩得粗品。粗品经过硅胶柱层析(二氯甲烷/甲醇(v/v)＝20/1)分离得12h(445mg，无色油状物，35％产率)。3-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide 12g (1.2g, 3.25mmol) and potassium carbonate (134mg, 0.9mmol) were dissolved in dimethyl sulfoxide (20mL), and hydrogen peroxide (662mg, 19mmol) was added dropwise to the solution, heated to 40°C, and reacted for 4h. After the reaction was completed, the reaction solution was directly poured into water (50mL), and ethyl acetate was added for extraction (50mL×3), the organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) to obtain 12h (445mg, colorless oil, 35% yield).
LCMS m/z(ESI)＝388.20[M+1]LCMS m/z(ESI)＝388.20[M+1]
第八步：Step 8:
1-(甲基间甲苯基)氨基甲酰基)-3-氧代-3，4，5，6-四氢环戊基吡咯-2(1H)-羧酸叔丁酯12i1-(Methyl-m-tolyl)carbamoyl)-3-oxo-3,4,5,6-tetrahydrocyclopentylpyrrole-2(1H)-carboxylic acid tert-butyl ester 12i
tert-butyltert-butyl
1-(methyl(m-tolyl)carbamoyl)-3-oxo-3，4，5，6-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
1-(methyl(m-tolyl)carbamoyl)-3-oxo-3，4，5，6-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
(1-(2-氰基环戊-1-烯-1-基)-2-(甲基(间甲苯基)氨基)-2-氧代乙基)氨基甲酸叔丁酯12h(445mg，1mmol)溶于四氢呋喃(5mL)，加入碳酸二叔丁酯(2.51g，11.4mmol)，4-二甲氨基吡啶(841mg，6.8mmol)，将反应液加热至45h反应4h。反应完毕，直接将反应液浓缩至干，经硅胶柱层析(二氯甲烷/甲醇(v/v)＝20/1)分离得12i(170mg，无色油状物，40％产率)。Tert-butyl (1-(2-cyanocyclopent-1-en-1-yl)-2-(methyl(m-tolyl)amino)-2-oxoethyl)carbamate 12h (445 mg, 1 mmol) was dissolved in tetrahydrofuran (5 mL), and di-tert-butyl carbonate (2.51 g, 11.4 mmol) and 4-dimethylaminopyridine (841 mg, 6.8 mmol) were added. The reaction solution was heated to 45 h and reacted for 4 h. After the reaction was completed, the reaction solution was directly concentrated to dryness and separated by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to obtain 12i (170 mg, colorless oil, 40% yield).
LCMS m/z(ESI)＝271.20[M-99] LCMS m/z(ESI)＝271.20[M-99]
第九步：Step 9:
叔丁基(3a，6a-二羟基-1-(甲基(间甲苯基)氨基甲酰基)-3-氧代六氢环戊[c]吡咯-2(1H)-羧酸酯12jTert-butyl (3a, 6a-dihydroxy-1-(methyl(m-tolyl)carbamoyl)-3-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 12j
tert-butyl3a，6a-dihydroxy-1-(methyl(m-tolyl)carbamoyl)-3-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
tert-butyl3a，6a-dihydroxy-1-(methyl(m-tolyl)carbamoyl)-3-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
1-(甲基间甲苯基)氨基甲酰基)-3-氧代-3，4，5，6-四氢环戊基吡咯-2(1H)-羧酸叔丁酯12i(170mg，0.45mmol)溶于水(1mL)，乙腈(3mL)，乙酸乙酯(3mL)，随后加入三氯化钌(9.52mg，0.045mmol)，高碘酸钠(147mg，0.68mmol)，室温反应1h。反应完毕，向反应液中加入饱和亚硫酸钠(50mL)，乙酸乙酯(50mL)，搅拌0.5h后分液，有机相干燥，浓缩，得粗品。粗品经过柱层析(二氯甲烷/甲醇(v/v)＝20/1)分离12j(无色油状物，180mg，97％产率)。Tert-butyl 1-(methyl-m-tolyl)carbamoyl)-3-oxo-3,4,5,6-tetrahydrocyclopentylpyrrole-2(1H)-carboxylate 12i (170 mg, 0.45 mmol) was dissolved in water (1 mL), acetonitrile (3 mL), and ethyl acetate (3 mL), followed by the addition of ruthenium trichloride (9.52 mg, 0.045 mmol) and sodium periodate (147 mg, 0.68 mmol), and the mixture was reacted at room temperature for 1 h. After the reaction was completed, saturated sodium sulfite (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was stirred for 0.5 h before separation. The organic phase was dried and concentrated to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol (v/v) = 20/1) to obtain 12j (colorless oil, 180 mg, 97% yield).
LCMS m/z(ESI)＝305.20[M-99]LCMS m/z(ESI)＝305.20[M-99]
第十步：Step 10:
3a，6a-二羟基-N-甲基-3-氧代-N-间甲苯基八氢环戊[c]吡咯-1-甲酰胺12k3a,6a-Dihydroxy-N-methyl-3-oxo-N-m-tolyloctahydrocyclopenta[c]pyrrole-1-carboxamide 12k
3a，6a-dihydroxy-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carhoxamide
3a,6a-dihydroxy-N-methyl-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carhoxamide
叔丁基3a，6a-二羟基-1-(甲基(间甲苯基)氨基甲酰基)-3-氧代六氢环戊[c]吡咯-2(1H)-羧酸酯12j(180mg)溶于盐酸二氧六环溶液(5mL，4N)，室温反应30分钟。直接将反应液浓缩至干得12k(130mg，无色油状物)，直接用于下一步反应。Tert-butyl 3a,6a-dihydroxy-1-(methyl(m-tolyl)carbamoyl)-3-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 12j (180 mg) was dissolved in dioxane hydrochloride solution (5 mL, 4N) and reacted at room temperature for 30 minutes. The reaction solution was directly concentrated to dryness to obtain 12k (130 mg, colorless oil), which was directly used in the next step.
LCMS m/z(ESI)＝305.20[M+1]LCMS m/z(ESI)＝305.20[M+1]
第十一步：Step 11:
化合物12： Compound 12:
3a，6a-二羟基-N-甲基-2-(6-甲基-4-三氟甲基吡啶-2-基)-3-氧代-N-间甲苯基八氢环戊基吡咯-1-甲酰胺3a,6a-Dihydroxy-N-methyl-2-(6-methyl-4-trifluoromethylpyridin-2-yl)-3-oxo-N-m-tolyloctahydrocyclopentylpyrrole-1-carboxamide
3a，6a-dihydroxy-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
3a,6a-dihydroxy-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
3a，6a-二羟基-N-甲基-3-氧代-N-间甲苯基八氢环戊[c]吡咯-1-甲酰胺(130mg，0.42mmol)，2-溴-6-甲基-4-三氟甲基吡啶(205mg，0.85mmol)，碳酸铯(417mg，1.28mmol)，甲磺酸(2-二环己基膦基-2′，6′-二异丙氧基-1，1′-联苯基)(2-氨基-1，1′-联苯-2-基)钯(II)(35mg，0.042mmol)溶于二氧六环(2mL)，氮气保护加热至110度反应4小时。反应完毕，将反应液冷却至室温，直接经过MPLC制备分离纯化得化合物12(白色固体，10mg，5％产率)。3a,6a-dihydroxy-N-methyl-3-oxo-N-m-tolyloctahydrocyclopenta[c]pyrrole-1-carboxamide (130 mg, 0.42 mmol), 2-bromo-6-methyl-4-trifluoromethylpyridine (205 mg, 0.85 mmol), cesium carbonate (417 mg, 1.28 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2′, 6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl) palladium (II) (35 mg, 0.042 mmol) were dissolved in dioxane (2 mL), heated to 110 degrees under nitrogen protection and reacted for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and directly subjected to MPLC preparative separation and purification to obtain compound 12 (white solid, 10 mg, 5% yield).
m/z(ESI)＝464.20[M+1]m/z(ESI)＝464.20[M+1]
1H NMR(400MHz，Chloroform-d)δ8.55(s，1H)，7.47(s，2H)，7.38(t，1H)，7.23(d，1H)，7.10(s，1H)，5.10(s，1H)，3.36(s，3H)，2.53(s，3H)，2.44(s，3H)，2.44-2.32(m，1H)，2.24-2.09(m，1H)，2.06-1.79(m，2H)，1.65-1.43(m，2H). 1 H NMR (400 MHz, Chloroform-d) δ 8.55 (s, 1H), 7.47 (s, 2H), 7.38 (t, 1H), 7.23 (d, 1H), 7.10 (s, 1H), 5.10 (s, 1H), 3.36 (s, 3H), 2.53 (s, 3H), 2.44 (s, 3H), 2.44-2.32 (m, 1H), 2.24-2.09 (m, 1H), 2.06-1.79 (m, 2H), 1.65-1.43 (m, 2H).
第十二步：Step 12:
1S-3a，6a-二羟基-N-甲基-2-(6-甲基-4-三氟甲基吡啶-2-基)-3-氧代-N-间甲苯基八氢环戊[c]吡咯-1-甲酰胺化合物12-A1S-3a,6a-dihydroxy-N-methyl-2-(6-methyl-4-trifluoromethylpyridin-2-yl)-3-oxo-N-m-tolyloctahydrocyclopenta[c]pyrrole-1-carboxamide compound 12-A
1S-3a，6a-dihydroxy-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide1S-3a,6a-dihydroxy-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
1R-3a，6a-二羟基-N-甲基-2-(6-甲基-4-三氟甲基吡啶-2-基)-3-氧代-N-间甲苯基八氢环戊[c]吡咯-1-甲酰胺化合物12-B1R-3a,6a-dihydroxy-N-methyl-2-(6-methyl-4-trifluoromethylpyridin-2-yl)-3-oxo-N-m-tolyloctahydrocyclopenta[c]pyrrole-1-carboxamide compound 12-B
1R-3a，6a-dihydroxy-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
1R-3a,6a-dihydroxy-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxo-N-(m-tolyl)octahydrocyclopenta[c]pyrrole-1-carboxamide
通过手性制备高效液相色谱(chiral pre-HPLC)拆分得到化合物12-A和化合物12-B拆分方法：手性柱：CHIRALPAK OX-H，30*250mm；流动相：A：CO2B：EtOH，流速1mL/min。Compound 12-A and compound 12-B were separated by chiral pre-HPLC. Separation method: chiral column: CHIRALPAK OX-H, 30*250 mm; mobile phase: A: CO 2 B: EtOH, flow rate 1 mL/min.
生物测试例Biological test cases
1、POLQ酶学活性测试1. POLQ enzyme activity test
本实验中，通过dsDNA染料(Thermo fisher，P7581)测定化合物对POLQ活性的抑制能力。具体操作过程如下：In this experiment, through The inhibitory ability of the compound on POLQ activity was determined by dsDNA dye (Thermo fisher, P7581). The specific operation process is as follows:
用DMSO将化合物配置成为10mM母液，使用1％DMSO(v/v)将母液进行连续倍比稀释(起始浓度10μM，1∶3稀释，10个梯度)。将稀释得到的各浓度化合物各取0.1μL转移至384孔板(PerkinElmer，6008260)；每个浓度2个重复。各孔加入5μL含4nM POLQ酶溶液(含25mM Tris-HCl(pH 7.5)，12.5mM NaCl，0.5mM MgCl2，5％glycerol，0.01％Triton X-100，0.01％BGG和1mM DTT)，4℃1000rpm离心1min；室温(25℃)孵育10min。加入5μL底物工作液(含40μM dNTP、100nM dsDNA)启动反应，室温(25℃)孵育60min。加入5μLPicoGreen染料，室温(25℃)孵育90min。使用酶标仪读取485nm和520nm荧光信号，计算各孔抑制率，并利用GraphPad Prism进行曲线拟合和IC50值计算。

The compound was prepared into a 10 mM stock solution with DMSO, and the stock solution was serially diluted with 1% DMSO (v/v) (initial concentration 10 μM, 1:3 dilution, 10 gradients). 0.1 μL of each diluted compound was transferred to a 384-well plate (PerkinElmer, 6008260); 2 replicates were performed for each concentration. 5 μL of 4 nM POLQ enzyme solution (containing 25 mM Tris-HCl (pH 7.5), 12.5 mM NaCl, 0.5 mM MgCl2, 5% glycerol, 0.01% Triton X-100, 0.01% BGG and 1 mM DTT) was added to each well, centrifuged at 1000 rpm at 4°C for 1 min; incubated at room temperature (25°C) for 10 min. 5 μL of substrate working solution (containing 40 μM dNTP, 100 nM dsDNA) was added to start the reaction, and incubated at room temperature (25°C) for 60 min. 5 μL PicoGreen dye was added and incubated at room temperature (25°C) for 90 min. The fluorescence signals at 485 nm and 520 nm were read using an ELISA reader, the inhibition rate of each well was calculated, and the curve fitting and IC 50 value calculation were performed using GraphPad Prism.

结果表明：本发明化合物对POLQ具有显著的生物抑制活性。The results showed that the compounds of the present invention had significant bioinhibitory activity against POLQ.
2、克隆形成实验2. Clone formation experiment
本实验中，通过细胞克隆形成数量评价化合物对DLD1BRCA-/-细胞(ATCC)的克隆形成抑制能力。具体操作过程如下：In this experiment, the ability of the compound to inhibit the cloning of DLD1 BRCA-/- cells (ATCC) was evaluated by the number of cell clones. The specific operation process is as follows:
处于对数生长期的DLD1BRCA-/-细胞，通过胰酶消化重悬并计数。将细胞(200个/孔)接种于透明12孔板(Coming，3460)中，置于37℃培养箱(5％CO2)内过夜培养。用DMSO将化合物配置成为10mM母液，使用0.1％DMSO(v/v)的1640培养基(含10％FBS，1％Penicillin-Streptomycin)将母液进行连续倍比稀释(起始浓度10μM，1∶3稀释，5个梯度)。随后各孔加入1mL稀释后的含待测化合物的培养基，置于37℃培养箱(5％CO2)内继续培养10天，每5天换一次液。弃掉培养基，使用PBS清洗细胞2遍；每孔加入500μL多聚甲醛溶液进行固定，室温放置30min；弃掉溶液，使用PBS清洗细胞2遍；每孔加入500μL结晶紫染液，室温染色30min；弃掉染料，使用PBS清洗细胞，5min/次，直至背景干净。室温晾干培养皿，随后对孔内克隆数量进行计数，计算各孔抑制率，并利用GraphPad Prism进行曲线拟合和IC50值计算。DLD1 BRCA-/- cells in the logarithmic growth phase were digested with trypsin, resuspended and counted. Cells (200 cells/well) were seeded in a transparent 12-well plate (Corning, 3460) and cultured overnight in a 37°C incubator (5% CO 2 ). The compound was prepared into a 10 mM stock solution with DMSO, and the stock solution was serially diluted in 1640 medium (containing 10% FBS, 1% Penicillin-Streptomycin) with 0.1% DMSO (v/v) (initial concentration 10 μM, 1:3 dilution, 5 gradients). Subsequently, 1 mL of the diluted medium containing the test compound was added to each well, and the plate was placed in a 37°C incubator (5% CO 2 ) and cultured for 10 days, with the medium changed every 5 days. Discard the culture medium and wash the cells twice with PBS; add 500 μL of paraformaldehyde solution to each well for fixation and place at room temperature for 30 min; discard the solution and wash the cells twice with PBS; add 500 μL of crystal violet stain to each well and stain at room temperature for 30 min; discard the dye and wash the cells with PBS for 5 min/time until the background is clear. Dry the culture dish at room temperature, then count the number of clones in the well, calculate the inhibition rate of each well, and use GraphPad Prism for curve fitting and IC 50 value calculation.
结果表明：本发明化合物对DLD1BRCA-/-细胞克隆形成具有显著的生物抑制作用。The results showed that the compounds of the present invention had a significant biological inhibitory effect on the clone formation of DLD1 BRCA-/- cells.
本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。 The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as limiting the present invention. For those skilled in the art, without departing from the principle of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims (7)

  1. 一种通式(I)所示的化合物或者其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶：
    A compound represented by general formula (I) or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:
    其中：in:
    A为3-8元环烷基或3-8元杂环烷基，所述3-8元杂环烷基包含1至4个选自N、O和S的杂原子；A is a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O and S;
    B为5-12元杂芳基，所述5-12元杂芳基包含1至4个选自N、O和S的杂原子；B is a 5-12 membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S;
    C为5-12元芳基；C is a 5-12 membered aromatic group;
    X为N；X is N;
    Ra可以相同或者不同，Ra各自独立地为H、C1-6烷基或OH，所述C1-6烷基任选地被1个或者多个卤素取代，优选地1-3个卤素； Ra may be the same or different, and each Ra is independently H, C1-6 alkyl or OH, wherein the C1-6 alkyl is optionally substituted by one or more halogens, preferably 1-3 halogens;
    R2、R3为H，或者R2、R3与相连的碳原子形成＝O；R 2 and R 3 are H, or R 2 and R 3 form ＝O with the carbon atom to which they are connected;
    Rb可以相同或者不同，Rb各自独立地为H、C1-6烷基、CN或CONH2，所述C1-6烷基任选地被1个或者多个卤素取代，优选地1-3个卤素；R b may be the same or different, and each R b is independently H, C 1-6 alkyl, CN or CONH 2 , wherein the C 1-6 alkyl is optionally substituted by 1 or more halogens, preferably 1 to 3 halogens;
    优选地，所述卤素为F；Preferably, the halogen is F;
    R1为C1-3烷基； R1 is C1-3 alkyl;
    Rc可以相同或者不同，Rc各自独立地为H或C1-6烷基；R c may be the same or different, and each R c is independently H or C 1-6 alkyl;
    a为0、1、2或3；a is 0, 1, 2 or 3;
    b为2或3；b is 2 or 3;
    c为1。c is 1.
  2. 根据权利要求1所述的化合物，或者其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶：The compound according to claim 1, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:
    其中：in:
    A为3-6元环烷基或3-6元杂环烷基，所述3-6元杂环烷基包含1至4个O；A is a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl contains 1 to 4 O;
    B为5-8元杂芳基，所述5-8元杂芳基含有1-3个N，优选地1个N； B is a 5-8 membered heteroaryl group, wherein the 5-8 membered heteroaryl group contains 1-3 N, preferably 1 N;
    C为5-8元芳基；C is a 5-8 membered aromatic group;
    Ra可以相同或者不同，Ra各自独立地为H、C1-3烷基或OH，所述C1-3烷基任选地进一步被1个或者多个卤素取代；Ra may be the same or different, and each Ra is independently H, C 1-3 alkyl or OH, and the C 1-3 alkyl is optionally further substituted by one or more halogens;
    R2、R3为H，或者R2、R3与相连的碳原子形成＝O；R 2 and R 3 are H, or R 2 and R 3 form ＝O with the carbon atom to which they are connected;
    Rb可以相同或者不同，Rb各自独立地为H、C1-3烷基、CN或CONH2，所述C1-3烷基任选地被1个或者多个卤素取代；R b may be the same or different, and each R b is independently H, C 1-3 alkyl, CN or CONH 2 , wherein the C 1-3 alkyl is optionally substituted by one or more halogens;
    Rc可以相同或者不同，Rc各自独立地为H或C1-3烷基；R c may be the same or different, and each R c is independently H or C 1-3 alkyl;
    a为0、1或2；a is 0, 1, or 2;
    b为2或3。b is 2 or 3.
  3. 根据权利要求2所述的化合物，或者其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶，其中：The compound according to claim 2, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein:
    A为3-6元环烷基或3-6元杂环烷基，所述3-6元杂环烷基包含1个O；A is a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl contains 1 O;
    B为6元杂芳基，所述6元杂芳基含有1-3个N，优选地1个N；B is a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group contains 1-3 N, preferably 1 N;
    C为6元芳基。C is a 6-membered aryl group.
  4. 根据权利要求1-3中任一项所述的化合物或者其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶，所述的化合物选自以下结构：

    The compound according to any one of claims 1 to 3 or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the following structures:

  5. 一种药物组合物，所述药物组合物包含：A pharmaceutical composition, comprising:
    (1)权利要求1-4中任一项所述的化合物或其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶；(1) The compound according to any one of claims 1 to 4, or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal;
    (2)任选的一种或者多种其他活性成分；以及(2) optionally one or more other active ingredients; and
    (3)药学上可接受的载体和/或赋形剂。(3) Pharmaceutically acceptable carriers and/or excipients.
  6. 权利要求1-4中任一项所述的化合物或其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶或者权利要求5所述的药物组合物在制备用于治疗和/预防癌症或肿瘤的药物中的用途；优选地，所述癌症为乳腺癌、卵巢癌、头颈部鳞状细胞癌(HNSCC)和肺癌。 Use of the compound or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal according to any one of claims 1 to 4, or the pharmaceutical composition according to claim 5, in the preparation of a medicament for treating and/or preventing cancer or tumors; preferably, the cancer is breast cancer, ovarian cancer, head and neck squamous cell carcinoma (HNSCC) and lung cancer.
  7. 权利要求1-4中任一项所述的化合物或其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶或者权利要求5所述的药物组合物在制备用于治疗和/或预防与Polθ酶相关的疾病的药物中的用途。 Use of the compound according to any one of claims 1 to 4 or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition according to claim 5 in the preparation of a medicament for treating and/or preventing a disease associated with the Polθ enzyme.
PCT/CN2023/132607 2022-11-21 2023-11-20 Pyrrole fused ring derivative and pharmaceutical use thereof WO2024109688A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202211451781.7 2022-11-21
CN202211451781 2022-11-21
CN202310180655 2023-02-28
CN202310180655.0 2023-02-28

Publications (1)

Publication Number Publication Date
WO2024109688A1 true WO2024109688A1 (en) 2024-05-30

Family

ID=91195257

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/132607 WO2024109688A1 (en) 2022-11-21 2023-11-20 Pyrrole fused ring derivative and pharmaceutical use thereof

Country Status (1)

Country Link
WO (1) WO2024109688A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101490002A (en) * 2006-07-12 2009-07-22 阿斯利康(瑞典)有限公司 3-oxoisoindoline-1-carboxamide derivatives as analgesic agents
WO2020160134A1 (en) * 2019-01-30 2020-08-06 Ideaya Biosciences, Inc. Acetamido derivatives as dna polymerase theta inhibitors
WO2022026565A1 (en) * 2020-07-29 2022-02-03 Ideaya Biosciences, Inc. Cyclized acetamido derivatives as dna polymerase theta inhibitors
CN116730979A (en) * 2022-03-11 2023-09-12 武汉人福创新药物研发中心有限公司 Pol theta inhibitor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101490002A (en) * 2006-07-12 2009-07-22 阿斯利康(瑞典)有限公司 3-oxoisoindoline-1-carboxamide derivatives as analgesic agents
WO2020160134A1 (en) * 2019-01-30 2020-08-06 Ideaya Biosciences, Inc. Acetamido derivatives as dna polymerase theta inhibitors
WO2022026565A1 (en) * 2020-07-29 2022-02-03 Ideaya Biosciences, Inc. Cyclized acetamido derivatives as dna polymerase theta inhibitors
CN116730979A (en) * 2022-03-11 2023-09-12 武汉人福创新药物研发中心有限公司 Pol theta inhibitor

Similar Documents

Publication Publication Date Title
CN105189488B (en) Carbazole compound as bromodomain inhibitor
WO2021073439A1 (en) Pyrazine derivative for inhibiting shp2 activity
CN106029659B (en) Glutaminase inhibitors
ES2808987T3 (en) Aryl and Heteroaryl Fused Lactams
US9738630B2 (en) Inhibitors of lysine methyl transferase
WO2023051716A1 (en) Heteroaryl derivative parp inhibitor and use thereof
CN105121443B (en) Certain protein kinase inhibitors
CN105601573B (en) 2-aminopyrimidine compound and pharmaceutical composition and application thereof
AU2018208231B2 (en) Imidazopyrazine compound, preparation method therefor and use thereof
WO2021088945A1 (en) Compound as shp2 inhibitor and use thereof
CN107344940B (en) BTK inhibitors and uses thereof
CN102388043A (en) Histamine h3 inverse agonists and antagonists and methods of use thereof
CN110036005A (en) Amide derivatives and its application in drug
CN112920183A (en) Compounds as KRAS-G12C inhibitors and uses thereof
CN115304623A (en) Pyrimido-cyclic derivative and application thereof in medicine
WO2016011979A1 (en) 2,4-disubstituted 7h-pyrrolo[2,3-d]pyrimidine derivative, preparation method and medicinal use thereof
WO2015004075A1 (en) Modified bet-protein-inhibiting dihydroquinoxalinones and dihydropyridopyrazinones
WO2023025116A1 (en) Heterocyclic derivative, preparation method therefor and use thereof in medicine
MX2014009180A (en) Isoquinoline and naphthyridine derivatives.
EP3617204A1 (en) Indoleamine 2,3-dioxygenase inhibitor and application
CN103664734B (en) Heterocycle hydroximic acid compound and medicinal compositions thereof and application
WO2021018173A1 (en) Adenosine receptor antagonist
CN109563033A (en) Aliphatic Prolinamide derivatives
WO2024109688A1 (en) Pyrrole fused ring derivative and pharmaceutical use thereof
WO2023169573A1 (en) POLθ INHIBITOR