WO2024260408A1 - Pyrrolidine derivative and use thereof in medicine - Google Patents

Abstract

The present invention relates to a pyrrolidine derivative and a use thereof in medicine, and in particular to a pyrrolidine derivative as represented by general formula (I) or a stereoisomer, solvate, prodrug, metabolite, deuterated compound, pharmaceutically acceptable salt or eutectic crystal thereof, a pharmaceutical composition containing the pyrrolidine derivative, a use of the pyrrolidine derivative or the pharmaceutical composition in the present invention in preparation of an anti-tumor drug.

Description

A pyrrolidine derivative and its application in medicine Technical Field

The present invention relates to a pyrrolidine derivative and its application in medicine.

Background Art

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 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 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 directs 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).

Polθ is therefore an attractive novel synthetic lethal therapeutic target in cancers with defects in DNA repair.

Summary of the invention

The purpose of the present invention is to provide a new pyrrolidine derivative having an inhibitory effect on Polθ and its application in preparing antitumor drugs.

One or more embodiments of the present invention provide a compound represented by general formula (I) or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:

in:

_X1 is O, NH or _CH2 ;

X ₂ , X ₃ , and X ₄ are each independently N or CH;

R ₁ and R ₂ are H, or R ₁ and R ₂ form C=O or C=S with the carbon atom to which they are connected;

R ₃ may be the same or different, and are each independently H, CN, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl or C _1-6 alkoxy;

R ₄ may be the same or different and are each independently H, halogen, hydroxyl, mercapto, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, 3-9 membered carbocyclic ring or 3-9 membered heterocyclic ring, wherein the 3-9 membered carbocyclic ring or 3-9 membered heterocyclic ring is optionally substituted with one or more substituents selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _3-8 cycloalkyl;

n is selected from 1, 2 or 3;

m is selected from 1, 2 or 3.

In one or more embodiments of the present invention, wherein:

_R4 may be the same or different and each independently represents H, halogen, hydroxyl, mercapto, _NH2 , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, phenyl, 5-6 membered heteroaryl or The 5-6 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S, and the phenyl group, the 5-6 membered heteroaryl group or Optionally substituted with 1 or more substituents selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _3-8 cycloalkyl;

A is a C _3-6 cycloalkyl group or a C _3-6 heterocyclic group, wherein the C _3-6 heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

Z is N or CH.

One or more embodiments of the present invention provide a compound, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from:

One or more embodiments of the present invention provide a pharmaceutical composition, comprising:

(1) a compound of the present invention or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof;

(2) optionally one or more other active ingredients; and

(3) Pharmaceutically acceptable carriers and/or excipients.

One or more embodiments of the present invention provide the use of the compound of the present invention or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition of the present invention as a drug (i.e., for use in treatment).

One or more embodiments of the present invention provide use of the compound of the present invention or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition of the present invention in the preparation of anti-tumor drugs.

One or more embodiments of the present invention provide use of the compound of the present invention or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition of the present invention in the preparation of Polθ inhibitors.

One or more embodiments of the present invention provide a method for preventing and/or treating tumors, comprising administering to a patient a therapeutically effective dose of a compound of the present invention or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal, or a pharmaceutical composition of the present invention.

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, the isotopes of hydrogen include 12 C, 13 C and 14 C, the isotopes of hydrogen include 12 C, 13 C and 14 C, the isotopes of hydrogen include 12 C, 13 C and 14 C, the isotopes of hydrogen include 12 C, 13 C and 14 C, the isotopes of hydrogen include 12 C, 13 C and 14 C, the isotopes of carbon ... carbon include ¹² C, ¹³ C and ¹⁴ C, Including 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, bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"Alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 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.

"Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy and cyclobutyloxy. The definition of alkyl is the same as that of "alkyl" described above.

"Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 3-8 membered (e.g., 3, 4, 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, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably a 5-8 membered heteroaryl. The 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the heteroaryl ring can be oxidized to various oxidation states. Heteroaryl can be connected to a heteroatom or a carbon atom, and can be a bridged ring or a spiro ring, and non-limiting examples include cyclopyridyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridinyl, pyrrolopyridinyl. Heteroaryl is optionally further substituted by one or more substituents.

"Carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When it is an aromatic ring, its definition is the same as the definition of "aryl"above; when it is a non-aromatic ring, it can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10-membered) bicyclic ring, or a 10- to 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 cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, The "carbocyclic group" or "carbocycle" is optionally further substituted by one or more substituents.

"Heterocyclyl" or "heterocycle" 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 or S, preferably a 3-8 membered heterocyclyl. The 1 to 4 (e.g., 1, 2, 3, 4) N and S optionally substituted in the ring of "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states. "Ring" can be attached to a heteroatom or a carbon atom; "heterocyclyl" or "heterocycle" can be a bridged ring or a spirocycle. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxirane, glycidyl, aziridine, oxetanyl, azetidinyl, thiinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxetanyl, thiinyl, oxazepinyl, diazepinyl, thiopheneyl, oxazepinyl, thiopheneyl, oxetan ... Azepine, pyridinyl, piperidinyl, homopiperidinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzene imidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothiophenyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4 .1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolizinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl. The "heterocyclyl" or "heterocycle" may be optionally further substituted by one or more substituents.

"Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of 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 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20-membered) polycyclic ring system, and the ring carbon atoms are preferably 3 to 10 carbon atoms, and more 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, etc. When a cycloalkyl group is substituted, it may be optionally further substituted with one or more substituents.

When the above-mentioned “alkyl”, “alkoxy”, “heteroaryl”, “carbocyclyl”, “carbocycle”, “heterocyclyl”, “heterocycle” or “cycloalkyl” is substituted, it may be further substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 groups selected from F, Cl, Br, I, hydroxy, 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 group is preferably substituted with a substituent selected _{from the group consisting of: -OC(＝O)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 or -NHC(＝O)C _2-6 alkynyl, and the substituent selected from the group consisting of: C _1-6 alkyl, C _1-6 alkoxy, C 2-6 alkenyl, C _1-6 alkoxyl, C _2-6 alkenyl, C 2-6 alkynyl wherein the alkylene group is selected _{from C 2-6} alkynyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _6-10 aryl, C _5-10 heteroaryl, -NHC(=O)C _6-10 aryl, -NHC(=O)C _5-10 heteroaryl, -NHC(=O)C _3-8 heterocycloalkyl or -NHC(=O)C _3-8 cycloalkyl, 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 or ＝O; R ^q1 is selected from C _1-6 alkyl, C _1-6 alkoxy or C _6-10 aryl; R ^q2 and R ^q3 are selected from H or C 1-6 alkyl; Wherein, R ^q4 and R ^q5 are 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 or -C(＝O)NR ^q2 R ^q3 , wherein the C _1-6 alkyl is optionally further substituted by one or more substituents selected from OH, F, Cl, Br, I, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, C _5-10 heteroaryl, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl; or R ^q4 , R ^q5 and the N atom form a 3- to 8-membered heterocyclic ring, which may contain one or more heteroatoms selected from N, O or S.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

"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.

"Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

"Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

"Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

"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.

DETAILED DESCRIPTION

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.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) were measured in 10- The unit of 6 (ppm) is given. NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers, the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS);

For MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));

HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier;

The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, and Jiangsu Aikon Biomedicine Research and Development.

Example 1

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 1

2-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrol -1(2H)-one

first step:

3-Ethoxyhexahydrocyclopenta[c]pyrrol-1(2H)-one 1-2

3-ethoxyhexahydrocyclopenta[c]pyrrol-1(2H)-one

Dissolve tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione 1-1 (15.0 g, 109 mmol) in anhydrous ethanol (150 mL), then cool to -10°C, add sodium borohydride (12.24 g, 327 mmol), and dropwise add 1M sulfuric acid ethanol solution (21 mL) 30 minutes later. After the addition is complete, return to room temperature for reaction for 1 hour. Then cool to -10°C, adjust pH to 2 with 6N sulfuric acid ethanol solution, stir for 1 hour and return to room temperature, adjust pH to 8 with 1N potassium hydroxide ethanol solution, stir for 30 minutes and directly concentrate to dryness, add 200 mL of water and dichloromethane, separate the liquids, collect the organic phase, dry, and concentrate to obtain a crude product. The crude product is separated by column chromatography to obtain 3-ethoxyhexahydrocyclopenta[c]pyrrole-1(2H)-one 1-2 (13.5 g, colorless oil, yield 73%).

LCMS m/z(ESI)＝170.10[M+1].

Step 2:

3-Oxooctahydrocyclopentadienyl[c]pyrrole-1-carbonitrile 1-3

3-oxooctahydrocyclopenta[c]pyrrole-1-carbonitrile

3-Ethoxyhexahydrocyclopentadien[c]pyrrole-1(2H)-one 1-2 (13.5 g, 80 mmol) was dissolved in anhydrous dichloromethane (130 mL), followed by the addition of trimethylsilyl cyanide (11.88 g, 120 mmol), cooled to 0°C, followed by the dropwise addition of boron trifluoride etherate (23 g, 160 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 3-oxooctahydrocyclopentadien[c]pyrrole-1-carbonitrile 1-3 (9.4 g, colorless oil, yield 78%) was obtained after column chromatography separation.

LCMS m/z(ESI)＝151.10[M+1].

Step 3:

3-Oxooctahydrocyclopentadienyl[c]pyrrole-1-carboxylic acid 1-4

3-oxooctahydrocyclopenta[c]pyrrole-1-carboxylic acid

3-Oxooctahydrocyclopentadien[c]pyrrole-1-carbonitrile 1-3 (9.4 g, 62.66 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 3-oxooctahydrocyclopentadien[c]pyrrole-1-carboxylic acid 1-4 (10.2 g, colorless oil), which was directly used in the next step reaction.

LCMS m/z＝170.10[M+1].

Step 4:

3-Oxooctahydrocyclopenta[c]pyrrole-1-carboxylic acid methyl ester 1-5

methyl 3-oxooctahydrocyclopenta[c]pyrrole-1-carboxylate

3-Oxooctahydrocyclopenta[c]pyrrole-1-carboxylic acid 1-4 (10.2 g, 55.73 mmol) was dissolved in methanol (100 mL) and cooled to 0° C. Then SOCl ₂ (35.37 g) was added dropwise, and then the temperature was raised to 60° C. for reaction for 2 hours. The reaction solution was then directly concentrated to dryness to obtain 3-oxooctahydrocyclopenta[c]pyrrole-1-carboxylic acid methyl ester 1-5 (8.0 g, yellow oil), which was directly used in the next step reaction.

LCMS m/z＝184.10[M+1].

Step 5:

Methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carboxylic acid methyl ester 1-7

Methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carboxylate

3-Oxooctahydocyclopenta[c]pyrrole-1-carboxylic acid methyl ester 1-5 (7.50 g, 17.36 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine 1-6 (10.08 g, 20.4 mmol), cesium carbonate (33.75 g, 52.08 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (II) (3.00 g, 0.17 mmol) were dissolved in anhydrous dioxane (80 mL), then protected by nitrogen and heated to 100 ° C for 6 hours. The reaction solution was cooled to room temperature, ethyl acetate (100 mL) was added to dilute it, and the filtrate was directly concentrated to dryness. The pure compound methyl 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctanoic acid methyl ester 1-7 (9.0 g, 60% yield) was separated by column chromatography.

LCMS m/z＝343.10[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.44(s,1H),7.43(s,1H),4.72(d,1H),3.70(s,3H),3.21(m,1H),2.70( s,1H),2.46(s,3H),1.43–2.03(m,6H).

Step 6:

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbohydrazide 1-8

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbohydrazide

The pure compound methyl 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carboxylate 1-7 (1.0 g, 2.90 mmol) obtained by column chromatography was dissolved in MeOH (10 mL) and cooled to 0°C. Hydrazine hydrate (780 mg, 7.25 mmol) was then added dropwise, and then the temperature was raised to 35°C for reaction for 12 hours. The reaction solution was then directly concentrated to dryness to obtain 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbohydrazide 1-8 (900 mg, yellow color) Oily product) was directly used in the next reaction.

LCMS m/z＝343.10[M+1].

Step 7:

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(5-(m-tolyl)-1,3,4-oxadiazol-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 1

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(5-(m-tolyl)-1,3,4-oxadiazol-2-yl)hexahydrocyclopenta[c]pyrrol-1( 2H)-one

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbohydrazide 1-8 (90 mg, yellow oil) was dissolved in dichloromethane (1 mL), followed by addition of DIPEA (113 mg, 0.87 mmol) and HATU (134 mg, 0.35 mmol), and then stirred at room temperature for 15 minutes before adding 3-methylbenzoic acid 1-9 (39 mg, 0.28 mmol). After reacting at room temperature for 2 hours, Burgess reagent (145 mg, 0.52 mmol) was added to continue reacting at room temperature for 2 hours. The reaction solution was directly spin-dried and then reverse-phase purified to obtain 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(5-(m-tolyl)-1,3,4-oxadiazol-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 1 (8 mg).

LCMS m/z(ESI)＝443.20[M+1].

¹ H NMR (400MHz, DMSO-d ₆ )δ8.48(s,1H),7.76–7.80(m,2H),7.40–7.49(m,3H),5.74(d,1H),3.44(m,1H),2.94(m,1H),2.40 (s,3H),2.33(s,3H),1.06–2.13(m,6H).

Example 2

(3S,3aS,6aR)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one compound 2a

(3S,3aS,6aR)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3- yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

(3R,3aR,6aS)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 2b

(3R,3aR,6aS)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3- yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

first step:

N,N-dimethyl-N'-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)carboxylic acid hydrazide 2-1

N,N-dimethyl-N'-(2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)formohydrazonamide

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbohydrazide 1-8 (500 mg, 1.46 mmol) was dissolved in acetonitrile (5.0 mL), and then DMF-DMA (170 mg, 0.87 mmol) was added. After stirring at 60° C. for 30 minutes, the reaction solution was directly spin-dried to obtain N,N-dimethyl-N’-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)carbohydrazide 2-1, which was directly used in the next step reaction.

LCMS m/z(ESI)＝398.10[M+1].

Step 2:

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 2

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrol- 1(2H)-one

The crude N,N-dimethyl-N'-(2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)formylhydrazide 2-1 obtained in the previous step was dissolved in acetic acid (2 mL), and then m-toluidine 2-2 (220 mg, 2.056 mmol) was added. After reacting at 120°C for 2 hours, the reaction solution was directly spin-dried and purified by column chromatography to obtain 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 2 (60 mg, white solid, 10% yield).

LCMS m/z(ESI)＝442.10[M+1].

Step 3:

(3S,3aS,6aR)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one compound 2a

(3S,3aS,6aR)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3- yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

(3R,3aR,6aS)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 2b

(3R,3aR,6aS)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3- yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

Compound 2a and compound 2b were separated by chiral prep-HPLC. Analysis method: C4 IC MB 25% 1mL 10min 1cm, ethanol as mobile phase, flow rate 1mL/min, retention time of compound 2a was 2.778min, and retention time of compound 2b was 3.998min.

Compound 2a (white solid, 25 mg):

LCMS m/z(ESI)＝442.10[M+1].

¹ H NMR (400MHz, DMSO-d ₆ )δ8.71(s,1H),8.48(s,1H),7.56(t,1H),7.47–7.37(m,3H),7.33(s,1H),5.34(d,1H),3.41 (td,1H),2.91–2.80(m,1H),2.43(s,3H),2.29(s,3H),2.01–1.90(m,3H),1.63–1.37(m,3H).

Compound 2b (white solid, 25 mg):

LCMS m/z(ESI)＝442.10[M+1].

¹ H NMR (400MHz, DMSO-d ₆ )δ8.71(s,1H),8.48(s,1H),7.56(t,1H),7.47–7.37(m,3H),7.33(s,1H),5.34(d,1H),3.41 (td,1H),2.91–2.80(m,1H),2.43(s,3H),2.29(s,3H),2.01–1.90(m,3H),1.63–1.37(m,3H).

Example 3

(3S,3aS,6aR)-3-(4-(3-chloro-4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 3a

(3S,3aS,6aR)-3-(4-(3-chloro-4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl) pyridin-2-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

(3R,3aR,6aS)-3-(4-(3-chloro-4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 3b

(3R,3aR,6aS)-3-(4-(3-chloro-4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl) pyridin-2-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

first step:

3-(4-(3-chloro-4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-one compound 3

3-(4-(3-chloro-4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoro methyl)pyridin-2-yl)hexahydrocyclopenta [c]pyrrol-1(2H)-one

The compound N,N-dimethyl-N'-(2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)carboxylic acid hydrazide 2-1 (500 mg, 1.2 mmol) was dissolved in acetic acid (10 mL), and then 3-chloro-4-fluoroaniline 3-1 (440 mg, 3.0 mmol) was added. The mixture was reacted at 120°C for 2 hours under nitrogen protection. The reaction solution was directly spin-dried and purified by column chromatography to obtain 3-(4-(3-chloro-4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 3 (220 mg, white solid, 46% yield).

LC-MS m/z(ESI)=442.31[M+1].

Step 2:

(3S,3aS,6aR)-3-(4-(3-chloro-4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 3a

(3S,3aS,6aR)-3-(4-(3-chloro-4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl) pyridin-2-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

(3R,3aR,6aS)-3-(4-(3-chloro-4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 3b

(3R,3aR,6aS)-3-(4-(3-chloro-4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl) pyridin-2-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

Compound 3a and compound 3b were separated by chiral prep-HPLC. Analysis method: C4 IC MB 20% 1mL 10min 1cm, ethanol as mobile phase, flow rate 1mL/min, retention time of compound 3a was 3.291min, and retention time of compound 3b was 5.026min.

Compound 3a (white solid, 108 mg):

LC-MS m/z＝432.46[M+1].

¹ H NMR (400MHz, Chloroform-d) δ = 8.60 (s, 1H), 8.28 (s, 1H), 7.48 (t, 1H), 7.43 (d, 1H), 7.21 (s, 1H), 7.02 (s, 1H) ),5.56(s,1H) ,3.46–3.44(m,1H),2.74–2.68(m,1H),2.48(s,3H),2.34(s,3H),2.21–2.13(m,1H),2.11–1.87(m,2H) ,1.70–1.44(m,3H).

Compound 3b (white solid, 102 mg):

LC-MS m/z＝432.46[M+1].

¹ H NMR (400MHz, Chloroform-d) δ = 8.60 (s, 1H), 8.28 (s, 1H), 7.48 (t, 1H), 7.43 (d, 1H), 7.21 (s, 1H), 7.02 (s, 1H) ),5.56(s,1H) ,3.46–3.44(m,1H),2.74–2.68(m,1H),2.48(s,3H),2.34(s,3H),2.21–2.13(m,1H),2.11–1.87(m,2H) ,1.70–1.44(m,3H).

Example 4

3-(4-(Bicyclo[4.2.0]oct-1,3,5-3-en-3-yl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-one compound 4

3-(4-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4 -(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

N, N-dimethyl-N'-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)carboxylic acid hydrazide 2-1 (500 mg, 1.2 mmol) was dissolved in acetic acid (5 mL), and then 4-aminobenzocyclobutene 4-1 (200 mg, 1.5 mmol) was added. After nitrogen protection and reaction at 120 °C for 2 h, the reaction solution was directly spin-dried and purified by column chromatography to obtain the target compound. Compound 3-(4-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one Compound 4 (240 mg, white solid, 53% yield).

LC-MS m/z(ESI)＝454.28[M+1].

¹ H NMR (400MHz, Chloroform-d) δ = 8.61 (s, 1H), 8.15 (s, 1H), 7.26–7.22 (m, 2H), 7.12 (s, 1H), 7.01 (s, 1H), 5.52 (s ,1H),3.51–3.46( m,1H),3.30(s,4H),2.70–2.64(m,1H),2.35(s,3H),2.19–2.14(m,1H),1.98–1.91(m,2H),1.71–1.51( m,2H),1.51–1.39(m,1H).

Example 5

(5-methyl-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 5

3-(5-methyl-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[ c]pyrrol-1(2H)-one

first step:

N,N-dimethyl-N'-(2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopentyl[c]pyrrole-1-carbonyl)acetylhydrazideamide 5-1

N,N-dimethyl-N'-(2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydro cyclopenta[c]pyrrole-1-carbonyl)acetohydrazonamide

The compound 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbohydrazide 1-8 (500 mg, 1.25 mmol) was dissolved in acetonitrile (5.0 mL), and then 1,1-dimethoxy-N,N-dimethylethane-1-amine (200 mg, 1.5 mmol) was added. After stirring at 60°C for 2 h, the reaction solution was directly spin-dried and purified by column chromatography to obtain N,N-dimethyl-N'-(2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)acethydrazide amide 5-1 (500 mg, white solid, 97% yield).

LC-MS m/z(ESI)＝412.09[M+1].

Step 2:

(5-methyl-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 5

3-(5-methyl-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoro methyl)pyridin-2-yl)hexahydrocyclopenta [c]pyrrol-1(2H)-one

N,N-dimethyl-N'-(2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopentyl[c]pyrrole-1-carbonyl)acetylhydrazideamide 5-1 (500 mg, 1.22 mmol) was dissolved in acetic acid (10.0 mL), and then m-toluidine 2-2 (160 mg, 1.45 mmol) was added. After reacting at 100°C for 2 h, the reaction solution was directly spin-dried and then purified by reverse phase column chromatography to obtain (5-methyl-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-one compound 5 (400 mg, white solid, 72% yield).

LC-MS m/z(ESI)＝456.10[M+1].

¹ H NMR (400MHz, Chloroform-d) δ = 8.57 (s, 1H), 7.49 (t, 1H), 7.41 (d, 1H), 7.07–7.03 (m, 3H), 5.38 (s, 1H), 3.33 (t ,1H),2.66–2.6 1(m,1H),2.48(s,3H),2.42(s,3H),2.26(s,3H),2.15–2.08(m,1H),1.93–1.82(m,2H),1.62–1.50( m,2H),1.43–1.34(m,1H).

Example 6

(3S,3aS,6aR)-3-(5-bromo-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-one compound 6

(3S,3aS,6aR)-3-(5-bromo-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-

(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

The (3S,3aS,6aR)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 2a (50 mg, 0.1 mmol) was dissolved in acetonitrile (0.5 mL), and then NBS (16 mg, 0.12 mmol) was added under nitrogen protection. After reacting at 25°C for 12 h, the reaction solution was directly spin-dried and purified by reverse phase column chromatography to obtain (3S,3aS,6aR)-3-(5-bromo-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one. -2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 6 (25 mg, white solid, 48% yield).

LC-MS m/z(ESI)＝521.09[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.57(s,1H),7.52–7.49(m,1H),7.44(d,1H),7.05(s,1H),7.01–6.87(m,1H),5.40 (s,1H),3.40–3.24(m,1 H),2.67–2.66(m,1H),2.48(s,3H),2.43(s,3H),2.18–2.06(m,1H),1.99–1.78(m,2H),1.72–1.46(m, 2H),1.45–1.37(d,J=24.9Hz,1H).

Example 7

(3S,3aS,6aR)-3-(5-chloro-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-one compound 7

(3S,3aS,6aR)-3-(5-chloro-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl) pyridin-2-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

(3S,3aS,6aR)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 2a (50 mg, 0.1 mmol) was dissolved in acetonitrile (0.5 mL), followed by the addition of NCS (16 mg, 0.12 mmol) and the mixture was stirred for 3 hours under nitrogen atmosphere. After the reaction was allowed to stand for 12 h at 25 °C, the reaction solution was directly spin-dried and then purified by reverse phase column chromatography to obtain (3S,3aS,6aR)-3-(5-chloro-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-one compound 7 (20 mg, white solid, 42% yield).

LC-MS m/z(ESI)=476.32[M+1].

Example 8

3-(4-(2,5-dimethylphenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 8

3-(4-(2,5-dimethylphenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2- yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

N,N-dimethyl-N'-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)formamide 2-1 (250 mg, 0.6 mmol) was dissolved in acetic acid (5.0 mL), and then 2,5-dimethylaniline 8-1 (200 mg, 1.5 mmol) was added. The mixture was reacted at 120°C for 2 h under nitrogen protection. The reaction solution was directly spin-dried and purified by column chromatography to obtain the target compound 3-(4-(2,5-dimethylphenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 8 (30 mg, white solid, 11% yield).

LC-MS m/z(ESI)＝456.18[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.57(s,1H),8.26(s,1H),7.33(s,2H),7.26–7.24(m,1H),7.07(s,1H),5.51(d ,1H),3.24(d,1H), 2.63–2.55(m,1H),2.42–2.35(s,6H),2.24–2.11(d,3H),2.02–1.74(m,2H),2.02(d,1H),1.94–1.74(m,1H ),1.64–1.23(m,2H).

Example 9

-3-(4-(2-fluoro-5-methylphenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 9

3-(4-(2-fluoro-5-methylphenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[ c]pyrrol-1(2H)-one

N,N-dimethyl-N'-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)formamide 2-1 (250 mg, 0.6 mmol) was dissolved in acetic acid (5.0 mL), and then 2-fluoro-5-methylaniline 9-1 (117 mg, 0.9 mmol) was added. The mixture was reacted at 120°C for 2 h under nitrogen protection. The reaction solution was directly spin-dried and purified by column chromatography to obtain the target compound 3-(4-(2-fluoro-5-methylphenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 9 (34 mg, white solid, 8% yield).

LC-MS m/z(ESI)＝458.43[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.55(s,1H),8.27(s,1H),7.39(m,1H),7.29–7.24(m,1H),7.12(s,1H),7.02(s ,1H),5.47(s,1 H),3.48–3.43(m,1H),2.81–2.75(m,1H),2.42(s,3H),2.31(s,3H),2.20–2.13(m,1H),2.07–1.92(m, 2H),1.72–1.51(m,3H).

Example 10

3-(4-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 10

3-(4-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrol- 1(2H)-one

N,N-dimethyl-N'-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl) Methylhydrazine 2-1 (250 mg, 0.6 mmol) was dissolved in acetic acid (5.0 mL), and then 3-fluoroaniline 10-1 (104 mg, 0.9 mmol) was added. The mixture was reacted at 120 ° C for 2 h under nitrogen protection. The reaction solution was directly spin-dried and purified by column chromatography to obtain the target compound 3-(4-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-one compound 10 (60 mg, white solid, 22% yield).

LC-MS m/z(ESI)=446.23[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.62(s,1H),8.35(s,1H),7.60–7.67(m,1H),7.39–7.27(m,3H),7.05(s,1H),5.54 (d,1H),3.4 5–3.45(m,1H),2.66–2.68(m,1H),2.36(s,3H),2.14–2.23(m,1H),2.07–1.92(m,2H),1.55–1.70(m,2H ).1.52–1.42(m,1H).

Embodiment 11

3-(4-(3-chlorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 11

3-(4-(3-chlorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrol- 1(2H)-one

N,N-dimethyl-N'-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)formamide 2-1 (250 mg, 0.6 mmol) was dissolved in acetic acid (5.0 mL), and then 3-chloroaniline 11-1 (118 mg, 0.9 mmol) was added. The mixture was reacted at 120°C for 2 h under nitrogen protection. The reaction solution was directly spin-dried and purified by column chromatography to obtain the target compound 3-(4-(3-chlorophenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 11 (70 mg, white solid, 25% yield).

LC-MS m/z(ESI)=462.20[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.61(s,1H),8.38(s,1H),7.67–7.56(m,2H),7.55(s,1H),7.39(d,1H),7.05(s ,1H),5.5 1(s,1H),3.50–3.45(m,1H),2.75–2.63(m,1H),2.37(s,3H),2.21–2.14(m,1H),2.01–1.92(m,2H), 1.74–1.42(m,3H).

Example 12

3-(4-(3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-one compound 12

3-(4-(3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoro methyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrol -1(2H)-one

N,N-dimethyl-N'-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)formamide 2-1 (250 mg, 0.6 mmol) was dissolved in acetic acid (5.0 mL), and then 3-methoxyaniline 12-1 (111 mg, 0.9 mmol) was added. The mixture was reacted at 120°C for 2 h under nitrogen protection. The reaction solution was directly spin-dried and purified by column chromatography to obtain the target compound 3-(4-(3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 12 (70 mg, white solid, 21% yield).

LC-MS m/z(ESI)=446.23[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.62(s,1H),8.20(s,1H),7.51(t,1H),7.11(dd,1H),7.04(dd,1H),7.01(s,1H ),6.97(t,1H),5.58(d,1H),3 .89(s,3H),3.52–3.47(m,1H),2.71–2.62(m,1H),2.34(s,3H),2.22– 2.13(m,1H),2.01–1.89(m,2H),1.69–1.55(m,2H),1.52–1.44(m,1H).

Embodiment 13

(3S,3aS,6aR)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-thione compound 13

(3S,3aS,6aR)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3- yl)hexahydrocyclopenta[c]pyrrole-1(2H)-thione

(3S,3aS,6aR)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one compound 2a (100 mg, 0.2 mmol) was dissolved in toluene (1.0 mL), and then Lawesson's reagent (137 mg, 1.5 mmol) was added. Under nitrogen protection, the reaction was carried out at 100° C. for 4 h, and the reaction solution was directly spin-dried and purified by column chromatography to obtain the target compound (3S, 3aS, 6aR)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-thione compound 13 (75 mg, bright yellow solid, 75% yield).

LC-MS m/z(ESI)＝458.15[M+1].

¹ H NMR (400MHz, CDCl ₃ )δ9.05(s,1H),8.39(s,1H),7.48(t,J＝7.3Hz,1H),7.40(d,J＝7.6Hz,1H),7.17(d,J＝15.6Hz, 3H),5.98(s,1H),3.68 (s,1H),2.84(s,1H),2.47(s,3H),2.40(s,4H),2.14–2.01(m,1H),1.95(s,1H),1.49–1.69(dd,J =20.4,9.9Hz,3H).

Embodiment 14

3-(4-(3-ethylphenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-one compound 14

3-(4-(3-ethylphenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrol- 1(2H)-one

N,N-dimethyl-N'-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)formamide 2-1 (250 mg, 0.6 mmol) was dissolved in acetic acid (5.0 mL), and then 3-ethylaniline 14-1 (73 mg, 0.9 mmol) was added. The mixture was reacted at 100°C for 1 h under nitrogen protection. The reaction solution was directly spin-dried and purified by column chromatography to obtain the target compound 3-(4-(3-ethylbenzene)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 14 (60 mg, white solid, 22% yield).

LC-MS m/z(ESI)＝456.10[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.59(s,1H),8.34(s,1H),7.53(t,1H),7.45(d,1H),7.25(d,1H),7.22(s,1H ),7.03(s,1H),5.55(d,1H),3. 44–3.39(m,1H),2.80–2.77(m,2H),2.74–2.66(m,1H),2.35(s,3H),2 .19–2.13(m,1H),1.99–1.90(m,2H),1.70–1.43(m,3H),1.31(t,3H).

Embodiment 15

3-(4-(3-cyclopropylphenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-one compound 15

3-(4-(3-cyclopropylphenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoro methyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrol -1(2H)-one

N,N-dimethyl-N'-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)formamide 2-1 (250 mg, 0.6 mmol) was dissolved in acetic acid (5.0 mL), and then 3-cyclopropylaniline 15-1 (110 mg, 0.9 mmol) was added. The mixture was reacted at 100°C for 1 h under nitrogen protection. The reaction solution was directly spin-dried and purified by column chromatography to obtain the target compound 3-(4-(3-cyclopropylphenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 15 (60 mg, white solid, 22% yield).

LC-MS m/z(ESI)＝468.10[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.59(s,1H),8.33(s,1H),7.48(t,1H),7.29(s,1H),7.21(d,1H),7.09(s,1H ),7.03(s,1H),5.55(d,1H),3.44– 3.40(m,1H),2.73–2.67(m,1H),2.35(s,3H),2.23–2.12(m,2H),1.99– 1.92(m,2H),1.69–1.45(m,3H),1.15–1.09(m,2H),0.79–0.75(m,2H).

Example 16

3-(4-(1-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 16

3-(4-(1-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2- yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

N,N-dimethyl-N'-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)formamide 2-1 (250 mg, 0.6 mmol) was dissolved in acetic acid (5.0 mL), and then 1-methyl-1H-pyrazol-3-amine 16-1 (110 mg, 0.9 mmol) was added. The mixture was reacted at 100°C for 1 h under nitrogen protection. The reaction solution was directly spin-dried and purified by column chromatography to obtain the target compound 3-(4-(1-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 16 (80 mg, white solid, 31% yield).

LC-MS m/z(ESI)=432.10[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.58(s,1H),8.54(s,1H),7.76(s,1H),7.74(s,1H),7.07(s,1H),5.54(s,1H ),4.05( s,3H),3.40–3.30(m,1H),2.70–2.68(d,1H),2.36(s,3H),2.17–2.15(d,1H),2.02–1.90(m,2H),1.70– 1.53(m,3H).

Embodiment 17

3-(4-(3-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 17

3-(4-(3-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c ]pyrrol-1(2H)-one

N,N-dimethyl-N'-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)formamide 2-1 (250 mg, 0.6 mmol) was dissolved in acetic acid (5.0 mL), and then 3-(trifluoromethyl)aniline 17-1 (110 mg, 0.9 mmol) was added. The mixture was reacted at 100°C for 1 h under nitrogen protection. The reaction solution was directly spin-dried and purified by column chromatography to obtain the target compound 3-(4-(3-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 17 (80 mg, white solid, 31% yield).

LC-MS m/z(ESI)＝496.10[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.59(s,1H),8.56(s,1H),7.94(d,1H),7.83(t,1H),7.7 9(s,1H),7.74(d,1H),7.05(s,1H),5.46(d,1H),3.49–3.44(m,1H),2.79–2.73(m,1H), 2.34(s,3H),2.23–2.15(m,1H),2.03–1.92(m,2H),1.74–1.40(m,3H).

Embodiment 18

3-(4-(Benzo[d]thiazol-6-yl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-1-one Compound 18

3-(4-(benzo[d]thiazol-6-yl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoro methyl)pyridin-2-yl )hexahydrocyclopenta[c]pyrrol-1(2H)-one

N,N-dimethyl-N'-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)formamide 2-1 (200 mg, 0.5 mmol) was dissolved in acetic acid (4.0 mL), and then benzo[d]thiazol-6-amine 18-1 (90 mg, 0.6 mmol) was added. The mixture was reacted at 100°C for 1 h under nitrogen protection. The reaction solution was directly spin-dried and purified by reverse phase C18 column chromatography to obtain the target compound 3-(4-(benzo[d]thiazol-6-yl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-1-one compound 18 (65 mg, white solid, 27% yield).

LC-MS m/z(ESI)＝485.10[M+1].

¹ H NMR (400MHz, DMSO-d ₆ )δ9.59(s,1H),8.84(s,1H),8.49(d,1H),8.46(s,1H),8.37(d,1H),7.79(m,1H),7.32(d,1H ),5.38(s ,1H),3.49–3.39(m,1H),2.91(d,1H),2.29(s,3H),2.01–1.91(m,3H),1.60–1.46(m,2H),1.39(m,1H ).

Embodiment 19

3-(4-(Benzo[d]thiazol-5-yl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-1-one Compound 19

3-(4-(benzo[d]thiazol-5-yl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoro methyl)pyridin-2-yl )hexahydrocyclopenta[c]pyrrol-1(2H)-one

N,N-dimethyl-N'-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbonyl)formamide 2-1 (200 mg, 0.5 mmol) was dissolved in acetic acid (4.0 mL), and then benzo[d]thiazol-5-amine 19-1 (90 mg, 0.6 mmol) was added. The mixture was reacted at 100°C for 1 h under nitrogen protection. The reaction solution was directly spin-dried and purified by reverse phase C18 column chromatography to obtain the target compound 3-(4-(benzo[d]thiazol-5-yl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-1-one compound 19 (90 mg, white solid, 37% yield).

LC-MS m/z(ESI)＝485.10[M+1].

¹ H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.56(d,2H),8.31(s,1H),8.25(d,1H),7.57(s,1H),7.05(s,1H ),5.57(s,1H), 3.46(t,1H),2.81–2.71(m,1H),2.40(s,3H),2.16–2.11(m,1H),2.01–1.89(m,2H),1.63(m,1H),1.55( m,1H),1.43(m,1H).

Embodiment 20

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(1-(m-methylphenyl)-1H-1,2,4-triazol-5-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-1-one compound 20

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(1-(m-tolyl)-1H-1,2,4-triazol-5-yl)hexahydrocyclopenta[c]pyrrol- 1(2H)-one

first step:

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopentyl[c]pyrrole-1-carboxylic acid 20-1

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carboxylic acid

Methyl 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carboxylic acid methyl ester 1-7 (10 g, 30.0 mmol) was dissolved in methanol (100 mL), followed by the addition of lithium hydroxide monohydrate (2.40 g, 58 mmol). After stirring at 25°C for 5 h, the reaction of the raw materials was completed as monitored by LCMS. The reaction solution was adjusted to pH = 6, extracted with ethyl acetate, dried, and concentrated to obtain the target compound 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carboxylic acid 20-1 (9.5 g, yellow solid, 96% yield).

LCMS m/z(ESI)＝329.10[M+1].

Step 2:

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxoctylcarbamate [c] pyrrole-1-carboxamide 20-2

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carboxamide

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctane-hydrogen cyclopenta[c]pyrrole-1-carboxylic acid 20-1 (300 mg, 0.9 mmol) was dissolved in 10 mL DMF, followed by the addition of ammonium chloride (96 mg, 1.8 mmol), HOBt (182 mg, 1.35 mmol), EDCI (260 mg, 1.35 mmol), and DIEA (233 mg, 1.8 mmol). The mixture was stirred at room temperature for 3 hours. The reaction was completed after monitoring by LCMS. The mixture was purified by reverse phase C18 column chromatography (alkaline method) to obtain the target compound 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctane-hydrogen cyclopenta[c]pyrrole-1-carboxamide 20-2 (white solid, 200 mg, 68% yield).

LC-MS m/z(ESI)=328.10[M+H] ⁺ .

Step 3:

N-(dimethylamino)methylene)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctane-hydrogencyclopenta[c]pyrrole-1-carboxamide 20-3

N-(dimethylamino)methylene)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carboxamide

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctane-hydrogen cyclopenta[c]pyrrole-1-carboxamide 20-2 (200 mg, 0.6 mmol) was dissolved in 2 mL 1,4-dioxane, and then DMF-DMA (90 mg, 0.72 mmol) was added and stirred at 100 °C for 2 hours under _N2 protection. The reaction was completed after LCMS monitoring, and normal phase purification was performed to obtain the target compound N-(dimethylamino)methylene)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctane-hydrogen cyclopenta[c]pyrrole-1-carboxamide 20-3 (white solid, 210 mg, 76% yield).

LC-MS m/z(ESI)=383.10[M+H] ⁺ .

Step 4:

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(1-(m-methylphenyl)-1H-1,2,4-triazol-5-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-1-one compound 20

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(1-(m-tolyl)-1H-1,2,4-triazol-5-yl)hexahydrocyclopenta[c]pyrrol- 1(2H)-one

N-(dimethylamino)methylene)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctane-hydrocyclopenta[c]pyrrole-1-carboxamide 20-3 (210 mg, 0.55 mmol) was dissolved in 4 mL of acetic acid, and then m-toluhydrazine (100 mg, 0.825 mmol) was added and stirred at 100°C for 1 hour. The reaction was completed after monitoring by LCMS, and the mixture was purified by reverse phase C18 column chromatography (alkaline method) to obtain the target compound 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(1-(m-tolyl)-1H-1,2,4-triazol-5-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-1-one compound 20 (light yellow solid, 80 mg, 33% yield).

LC-MS m/z(ESI)=441.10[M+H] ⁺ .

¹ H NMR(400MHz,Chloroform-d)δ8.58(s,1H),7.97(s,1H),7.48(d,1H),7.41–7.34(m,3H),7.01(s,1H),5.60(d ,1H),3.4 7(m,1H),2.74(m,1H),2.48(s,3H),2.28(s,3H),2.24–2.14(m,1H),2.08–1.92(m,2H),1.69(m, 1H),1.63–1.52(m,2H).

Embodiment 21

(3S,3aS,6aR)-3-(5-(difluoromethyl)-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-1-one Compound 21

(3S,3aS,6aR)-3-(5-(difluoromethyl)-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-( trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

first step:

5-((1S,3aR,6aS)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrol-1-yl)-4-(m-methyl)-4H-1,2,4-triazole-3-carbaldehyde 21-1

5-((1S,3aR,6aS)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrol-1-yl)-4-(m-tolyl) -4H-1,2,4-triazole-3-carbaldehyde

10 mL of DMF was added to a three-necked flask, nitrogen was replaced, POCl ₃ (870 mg, 5.66 mmol) was slowly added dropwise at 0°C, and stirred at 0°C for 2 hours. Then, (3S, 3aS, 6aR)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-1-one compound 2 (500 mg, 1.13 mmol) was dissolved in 3 mL of DMF, and the above reaction solution was slowly added dropwise at 0°C. After stirring at 0°C for 2 hours, the mixture was reacted at room temperature for 16 hours. The reaction was completed by LCMS monitoring, and the mixture was extracted with dichloromethane and the organic phase was concentrated to obtain the target compound (1S,3aR,6aS)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctanecarbonyl cyclopenta[c]pyrrole-1-carboxamide 21-1 (pink oil, 600 mg crude product), which was used directly in the next step.

LC-MS m/z(ESI)=470.10[M+H] ⁺ .

Step 2:

(3S,3aS,6aR)-3-(5-(difluoromethyl)-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 21

(3S,3aS,6aR)-3-(5-(difluoromethyl)-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-( trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

The (1S,3aR,6aS)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctanecarbonylcyclopenta[c]pyrrole-1-carboxamide 21-1 (600 mg crude product) obtained in the previous step was dissolved in 10 mL DCM, and DAST (364 mg, 2.26 mmol) was slowly added dropwise at -10°C under _N2 protection. The reaction was completed after LCMS monitoring, and the reaction was purified by reverse phase to obtain the target compound (3S,3aS,6aR)-3-(5-(difluoromethyl)-4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 21 (white solid, 10 mg, two-step yield 2%).

LC-MS m/z(ESI)=492.10[M+H] ⁺ .

¹ H NMR(400MHz,Chloroform)δ8.60(s,1H),7.49(t,1H),7.43(d,1H),7.26(s,1H),7.04(s,1H),6.82(t,1H), 5.31(s,1H),3 .38(s,1H),2.66(m,1H),2.47(s,3H),2.42(s,3H),2.22–2.11(m,1H),1.99–1.79(m,1H),1.60–1.49 (m,2H),1.36(m,2H).

Embodiment 22

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(1-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 22

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(1-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)hexahydrocyclopenta[c]pyrrol-1( 2H)-one

first step:

3-(Hydroxymethyl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one 22-1

3-(hydroxymethyl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydro cyclopenta[c]pyrrol-1(2H)-one

Methyl 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctanoic acid methyl ester 1-7 (1.5 g, 4.3 mmol) was dissolved in methanol (15 mL), cooled to 0°C, and then sodium borohydride (833 mg, 20 mmol) was added. The mixture was protected by nitrogen and reacted at 25°C for 4 h. The reaction solution was then spin-dried, separated by adding water and ethyl acetate, and the organic phase was dried and concentrated to obtain the target compound 3-(hydroxymethyl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-one 22-1 (0.9 g, yellow solid, 65% yield).

LC-MS m/z(ESI)＝315.12[M+1].

Step 2:

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbaldehyde 22-2

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbaldehyde

Oxalyl chloride (720 mg, 5.6 mmol) was dissolved in dichloromethane (10 mL), cooled to -78 °C, and DMSO (2 mL, 3.0 mmol) of dichloromethane solution. Then 3-(hydroxymethyl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-one 22-1 (0.9 g, 2.8 mmol) was added, and after reacting at -78°C for 1 hour, triethylamine (930 mg, 8.4 mmol) was added, and stirred at -78°C for 1 hour, and the temperature was slowly raised to 0°C, and water was added to quench the reaction, and the liquid was separated, and the dichloromethane phase was dried and concentrated to obtain the target compound 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carboxaldehyde 22-2 (500 mg, white solid, 57% yield).

LC-MS m/z(ESI)＝313.10[M+1].

Step 3:

3-(1H-imidazol-2-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one 22-3

3-(1H-imidazol-2-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydro cyclopenta[c]pyrrol-1(2H)-one

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-oxooctahydrocyclopenta[c]pyrrole-1-carbaldehyde 22-2 (500 mg, 1.6 mmol) was dissolved in methanol (5 mL), and NH ₃ ·H ₂ O (346 mg, 9.6 mmol) was added, followed by glyoxal (464 mg, 8.0 mmol). The mixture was reacted at 50° C. for 3 h under nitrogen protection. The reaction solution was directly spin-dried and purified by column chromatography to obtain the target compound 3-(1H-imidazole-2-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one 22-3 (300 mg, white solid, 53% yield).

LC-MS m/z(ESI)＝351.10[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.62(s,1H),7.14(s,1H),6.98(s,2H),5.56(s ,1H),3.55–3.45(m,2H),2.63(s,3H),2.22–2.05(m,4H),1.73–1.67(m,2H).

Step 4:

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(1-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 22

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(1-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)hexahydrocyclopenta[c]pyrrol-1( 2H)-one

3-(1H-imidazol-2-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one 22-3 (150 mg, 0.4 mmol) was dissolved in DMF (2.0 mL), followed by the addition of 2-bromo-6-methylpyridine (147 mg, 0.8 mmol) and Cs ₂ CO ₃ (280 mg, 0.8 mmol) under nitrogen protection. The reaction was carried out at 100° C. for 8 h, and then the reaction solution was added with water and ethyl acetate for separation. The organic phase was dried and concentrated, and then purified by reverse phase column chromatography to obtain the target compound 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(1-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 22 (50 mg, white solid, 31% yield).

LC-MS m/z(ESI)=442.10[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.61(s,1H),7.79(t,1H),7.22(dd,2H),7.14(d,1H),6.99(d,1H),6.89(s,1H ),5.91(d,1H),3 .59(td,1H),3.03–2.93(m,1H),2.65(s,3H),2.22(dt,2H),2.09(s,3H),2.05–1.96(m,1H),1.80(dq ,1H),1.71–1.64(m,2H).

Embodiment 23

3-(1-(5-fluoro-6-methylpyridin-2-yl)-1H-imidazol-2-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentane [c] pyrrol-1(2H)-one compound 23

3-(1-(5-fluoro-6-methylpyridin-2-yl)-1H-imidazol-2-yl)-2-(6-methyl-4(trifluoro methyl)pyridin-2-yl)hexahydrocyclopenta[c] pyrrol-1(2H)-one

3-(1H-imidazol-2-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one 22-3 (200 mg, 0.57 mmol) was dissolved in DMSO (2.0 mL), followed by the addition of 6-bromo-3-fluoro-2-methylpyridine (162 mg, 0.85 mmol), Cs ₂ CO ₃ (280 mg, 0.8 mmol), CuI (108 mg, 0.57 mmol), (1R, 2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (81 mg, 0.57 mmol), nitrogen protection, reaction at 120 ° C for 8 hours, the reaction solution was added with water and ethyl acetate for separation, the organic phase was dried and concentrated, and then purified by reverse phase column chromatography to obtain the target compound 3-(1-(5-fluoro-6-methylpyridin-2-yl)-1H-imidazole-2-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-one compound 23 (110 mg, brown solid, 47% yield).

LC-MS m/z(ESI)＝460.10[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.61(s,1H),7.55(t,J＝8.3Hz,1H),7.25–7.22(m,1H),7.10(d,1H),7.01(s,1H ),6.91(s,1H),5.79(d,1H),3 .61–3.56(m,1H),3.00–2.94(m,1H),2.62(d,3H),2.23–2.16(m,2H), 2.13(s,3H),2.04–1.95(m,1H),1.83–1.78(m,1H),1.69–1.60(m,2H).

Embodiment 24

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(1-(m-tolyl)-1H-imidazol-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 24

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(1-(m-tolyl)-1H-imidazol-2-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

3-(1H-imidazol-2-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one 22-3 (500 mg, 1.4 mmol) was dissolved in DMSO (10 mL), followed by the addition of 1-iodo-3-toluene (610 mg, 2.8 mmol), Cs ₂ CO ₃ (634 mg, 1.8 mmol), CuI (265 mg, 0.57 mmol), (1R, 2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (198 mg, 0.57 mmol), nitrogen protection, reaction at 120 ° C for 8 hours, the reaction solution was added with water and ethyl acetate for separation, the organic phase was dried and concentrated, and then purified by reverse phase column chromatography to obtain the target compound 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(1-(m-tolyl)-1H-imidazol-2-yl)hexahydrocyclopentyl[c]pyrrole-1(2H)-one compound 24 (220 mg, brown solid, 33% yield).

LC-MS m/z(ESI)＝441.10[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.48(s,1H),7.54–7.42(m,3H),7.15(m,1H),7.08(s,2H),7.00(s,1H),5.62(d ,1H),3.09–3.05(m ,1H),2.84–2.80(m,1H),2.43(s,3H),2.38(s,3H),2.11–2.05(m,1H),1.99–1.82(m,2H),1.71–1.61(m ,2H),1.51–1.39(m,1H).

Embodiment 25

3-(1-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-1H-imidazol-2-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 25

3-(1-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-1H-imidazol-2-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin- 2-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

3-(1H-imidazol-2-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one 22-3 (200 mg, 0.57 mmol) was dissolved in DMSO (2.0 mL), followed by the addition of 6-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine (117 mg, 0.85 mmol), Cs ₂ CO ₃ (280 mg, 0.8 mmol), CuI (108 mg, 0.57 mmol), (1R, 2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (81 mg, 0.57 mmol), nitrogen protection, reaction at 120 ° C for 8 hours, the reaction solution was added with water and ethyl acetate for separation, the organic phase was dried and concentrated, and then purified by reverse phase column chromatography to obtain the target compound 3-(1-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-1H-imidazole-2-yl)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)hexahydrocyclopentyl[c]pyrrol-1(2H)-one compound 25 (40 mg, brown solid, 47% yield).

LC-MS m/z(ESI)＝481.10[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.50(s,1H),8.06(d,1H),7.33(d,1H),7.20(s,1H),7.12–7.10(m,2H),6.92(s ,1H),6.59(d,1H),5.94(s,1H), 3.93(s,3H),3.64–3.59(m,1H),3.10–3.08(m,1H),2.14(s,3H),2.01– 1.96(m,1H),1.88–1.87(m,2H),1.73–1.67(m,2H),1.39–1.30(m,1H).

Embodiment 26

6-Methyl-2-1-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopentyl[c]pyrrol-2(1H)-yl)-4-(trifluoromethyl)nicotinonitrile compound 26

6-methyl-2-1-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(trifluoromethyl) nicotinonitrile

first step:

Ethyl-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carboxylic acid 26-3

ethyl-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxylate

Octahydrocyclopentyl[c]pyrrole-1-carboxylic acid ethyl ester 26-1 (1.0 g, 5.46 mmol) and 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile 26-2 (1.80 g, 8.19 mmol) were dissolved in NMP (10 mL), followed by the addition of DIPEA (2.13 g, 16.4 mmol). The mixture was reacted at 120°C for 3 h. After the reaction was complete, water and ethyl acetate were added, the liquids were separated, the organic phase was dried, and concentrated to obtain the target compound ethyl-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carboxylic acid 26-3 (1.6 g, red oil, 81% yield).

LC-MS m/z(ESI)＝368.10[M+1].

Step 2:

2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carbohydrazide 26-4

2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrole-1-carbohydrazide

Ethyl-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carboxylic acid 26-3 (1.60 g, 4.5 mmol) was dissolved in ethanol (10 mL), and N ₂ H ₄ ·HCl (764 mg, 13.5 mmol) was added, followed by DBU (2.7 g, 13.5 mmol) under nitrogen protection. After reacting at 70° C. for 4 h, the reaction solution was directly spin-dried to obtain the target compound 2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carbohydrazide 26-4 (2.0 g, crude product), which was directly used in the next step.

LC-MS m/z(ESI)＝354.10[M+1].

Step 3:

N'-(2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carbonyl)-N,N-dimethylformylhydrazideamide 26-5

N'-(2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrole-1-carbonyl)-N,N-dimethylformohydrazonamide

2-(3-Cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carbohydrazide 26-4 (2.0 g, crude product) was dissolved in acetonitrile (20 mL), and then DMF-DMA (1.01 g, 8.5 mmol) was added. Under nitrogen protection, the reaction was carried out at 60°C for 1 h, and then the reaction solution was added with water and ethyl acetate for separation. The organic phase was dried and concentrated, and then purified by reverse phase column chromatography to obtain the target compound N’-2-(3-Cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carbonyl)-N,N-dimethylformhydrazide amide 26-5 (1.3 g, white solid, 31% yield).

LC-MS m/z(ESI)=409.10[M+1].

Step 4:

6-Methyl-2-(1-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopentyl[c]pyrrol-2(1H)-yl)-4-(trifluoromethyl)nicotinonitrile compound 26

6-methyl-2-(1-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(trifluoromethyl )nicotinotrile

N'-(2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carbonyl)-N,N-dimethylformylhydrazideamide 26-5 (250 mg, 0.6 mmol) was dissolved in acetic acid (5 mL), and then m-toluidine (200 mg, 1.5 mmol) was added. The mixture was reacted at 120°C for 2 h under nitrogen protection. The reaction solution was directly spin-dried and purified by column chromatography to obtain the target compound 6-methyl-2-(1-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopentyl[c]pyrrole-2(1H)-yl)-4-(trifluoromethyl)nicotinonitrile compound 26 (76 mg, white solid, 20% yield).

LC-MS m/z(ESI)＝453.10[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.29(s,1H),7.43(t,1H),7.37–7.35(m,1H),7.16–7.15(m,1H),7.08(s,1H),6.75 (s,1H),5.52(d,1H),4.2 5–4.20(m,1H),3.85–3.82(m,1H),3.05–3.01(m,1H),2.80–2.73(m,1H),2.43(s,3H),2.30(s,3H), 1.96–1.76(m,3H),1.66–1.51(m,3H).

Embodiment 27

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)octahydrocyclopenta[c]pyrrole compound 27

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)octahydrocyclopenta[c]pyrrole

first step:

Ethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carboxylate 27-2

ethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxylate

Octahydrocyclopentyl[c]pyrrole-1-carboxylic acid ethyl ester 26-1 (1.1 g, 6.0 mmol), 2-bromo-6-methyl-4-trifluoromethylpyridine (1.58 g, 6.6 mmol), cesium carbonate (5.85 g, 18 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (II) (0.50 g, 0.6 mmol) were dissolved in anhydrous dioxane (10 mL), then protected by nitrogen and heated to 100°C for 6 h. The reaction solution was cooled to room temperature, ethyl acetate (100 mL) was added to dilute it, and the filtrate was directly concentrated to dryness. The pure compound ethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carboxylate 27-2 (2.0 g, yellow oil, 90% yield) was separated by column chromatography.

LC-MS m/z(ESI)=343.10[M+1].

Step 2:

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carbohydrazide 27-3

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrole-1-carbohydrazide

Ethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carboxylate 27-2 (1.0 g, 3.0 mmol) was dissolved in ethanol (10 mL), and N ₂ H ₄ ·HCl (612 mg, 9 mmol) was added, followed by DBU (1.36 g, 10.5 mmol). The mixture was reacted at 70° C. for 4 h under nitrogen protection, and the reaction solution was directly spin-dried to obtain the target compound 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carbohydrazide 27-3 (700 mg, crude product), which was directly used in the next step.

LC-MS m/z(ESI)=329.10[M+1].

Step 3:

N,N-dimethyl-N'-(2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrole-1-carbonyl)carboxylic acid hydrazide 27-4

N,N-dimethyl-N'-(2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclo penta[c]pyrrole-1-carbonyl)formohydrazonamide

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carbohydrazide 27-3 (700 mg, 2.1 mmol) was dissolved in acetonitrile (7 mL), and then DMF-DMA (378 mg, 3.18 mmol) was added. After reacting at 60°C for 1 h under nitrogen protection, the reaction solution was added with water and ethyl acetate for separation. The organic phase was dried and concentrated, and then purified by reverse phase column chromatography to obtain the target compound N,N-dimethyl-N'-(2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopentyl[c]pyrrole-1-carbonyl)carbohydrazide 27-4 (780 mg, white solid, 90% yield).

LC-MS m/z(ESI)＝384.10[M+1].

Step 4:

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)octahydrocyclopentyl[c]pyrrole compound 27

2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)octahydrocyclopenta[c]pyrrole

N,N-dimethyl-N'-(2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrole-1-carbonyl)carboxylic acid hydrazide 27-4 (250 mg, 0.65 mmol) was dissolved in acetic acid (5 mL), and then m-toluidine (84 mg, 0.78 mmol) was added. The mixture was protected by nitrogen and reacted at 120°C for 2 h. The reaction solution was directly spin-dried and purified by column chromatography to obtain the target compound 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)octahydrocyclopenta[c]pyrrole compound 27 (76 mg, white solid, 20% yield).

LC-MS m/z(ESI)＝428.10[M+1].

¹ H NMR(400MHz,Chloroform-d)δ8.12(s,1H),7.44(t,1H),7.35–7.33(m,1H),7. 32–7.26(m,1H),6.54(s,1H),6.34(s,1H),5.19(d,1H),4.00–3.96(m,1H),3.3 1–3.27(m,1H),3.22–3.13(m,1H),2.74–2.68(m,1H),2.45(s,3H),2.27(s,3H ),1.96–1.84(m,2H),1.78–1.71(m,1H),1.63–1.55(m,2H),1.46–1.40(m,1H).

Biological test cases

1. Polθ enzyme activity test

In this experiment, through The inhibitory ability of the compound on Polθ activity was determined by dsDNA dye (Thermo fisher, P7581). The specific operation process is as follows:

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 Polθ enzyme solution (containing 25 mM Tris-HCl (pH 7.5), 12.5 mM NaCl, 0.5 mM MgCl ₂ , 5% glycerol, 0.01% Triton X-100, 0.01% BGG and 1 mM DTT) was added to each well, and centrifuged at 1000 rpm at 4°C for 1 min; incubated at room temperature (25°C) for 10 min. Add 5 μL substrate working solution (containing 40 μM dNTP, 100 nM dsDNA) to start the reaction and incubate at room temperature (25°C) for 60 min. Add 5 μL PicoGreen dye and incubate at room temperature (25°C) for 90 min. Use an ELISA reader to read the 485nm and 520nm fluorescence signals, calculate the inhibition rate of each well, and use GraphPad Prism to perform curve fitting and IC ₅₀ values. calculate.

Note: A represents IC ₅₀ ≤100nM; B represents 100nM＜IC ₅₀ ≤500nM; C represents 500nM＜
_IC50 ≤1000nM.

The results showed that the compounds of the present invention had significant biological inhibitory activity against Polθ.

2. Clone formation experiment

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:

DLD1 ^BRCA-/- cells in the logarithmic growth phase were digested with trypsin, resuspended and counted. Cells (200 cells/well) were inoculated 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 (initial concentration 10 μM, 1:3 dilution, 5 gradients) using 1% DMSO (v/v) 1640 medium (containing 10% FBS, 1% Penicillin-Streptomycin). Subsequently, 1 mL of the diluted medium containing the test compound was added to each well, and the culture was continued in a 37°C incubator (5% CO ₂ ) 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.

The results showed that the compounds of the present invention had a significant biological inhibitory effect on the clone formation of DLD1 ^BRCA -/- cells.

3. MMEJ pathway inhibition experiment

The test compound was diluted with DMSO and transferred to a 384-well plate. The final concentration of the compound in the reaction system was 10 μM, and the concentration was 9 times diluted 3 times. The final concentration of DMSO was 0.1%. MMEJ dsDNA substrate (ICE Bioscience) was transferred into HEK293T cells using the Neon transfection system, and the transfected cells were inoculated in a 384-well plate at a density of 4000 cells/well (25 μL/well). The compound and cells were placed in a 37°C, 5% CO ₂ incubator. After culturing for 24 hours, 40 μL/well Nano-Glo Luciferase Assay kit (Promega, N1120) was added, and the cells were incubated at 300 rpm in the dark for 3 minutes. The fluorescence value was detected using a BMG multifunctional microplate reader.

MMEJ = (fluorescence value of compound well - fluorescence value of Yangshen) / (fluorescence value of DMSO well - fluorescence value of Yangshen), and then the IC ₅₀ of the compound was obtained by fitting using Graphpad software with compound concentration as the abscissa and MMEJ as the ordinate.

The results show that the compounds of the present invention have a significant inhibitory effect on the cell MMEJ pathway.

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 (5)

A compound represented by general formula (I) or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof:
in: _X1 is O, NH or _CH2 ; X ₂ , X ₃ , and X ₄ are each independently N or CH; R ₁ and R ₂ are H, or R ₁ and R ₂ form C=O or C=S with the carbon atom to which they are connected; R ₃ may be the same or different, and are each independently H, CN, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl or C _1-6 alkoxy; R ₄ may be the same or different and are each independently H, halogen, hydroxyl, mercapto, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, 3-9 membered carbocyclic ring or 3-9 membered heterocyclic ring, wherein the 3-9 membered carbocyclic ring or 3-9 membered heterocyclic ring is optionally substituted with one or more substituents selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _3-8 cycloalkyl; n is selected from 1, 2 or 3; m is selected from 1, 2 or 3. The compound according to claim 1, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof: in: _R4 may be the same or different and each independently represents H, halogen, hydroxyl, mercapto, _NH2 , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, phenyl, 5-6 membered heteroaryl or The 5-6 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S, and the phenyl group, the 5-6 membered heteroaryl group or Optionally substituted with 1 or more substituents selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _3-8 cycloalkyl; A is a C _3-6 cycloalkyl group or a C _3-6 heterocyclic group, wherein the C _3-6 heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S; Z is N or CH. The compound according to claim 1 or 2, or a stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal thereof: Wherein, the compound is selected from:

A pharmaceutical composition, comprising: (1) The compound according to any one of claims 1 to 3, or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal; (2) optionally one or more other active ingredients; and (3) Pharmaceutically acceptable carriers and/or excipients. Use of the compound according to any one of claims 1 to 3 or its stereoisomer, solvate, prodrug, metabolite, deuterated substance, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 4 in the preparation of an anti-tumor drug.