Condensed ring CBL-B inhibitor

Abstract

The present disclosure provides a novel class of compounds having CBL-B inhibitory activity, pharmaceutical compositions containing the compounds, intermediates for preparing the compounds, and methods of treating cancer using the compounds of the disclosure.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and relates to novel compounds having E3 ligase Casitas b-linege lymphoma B (CBL-B) inhibitory activity, pharmaceutical compositions containing the compounds, useful intermediates for preparing the compounds, and methods for treating CBL-B-mediated diseases using drugs prepared from the compounds of the present invention. Background Art

[0002] BL-B is a RING E3 ligase and a member of the highly conserved CBL protein family, which consists of three CBL genes in mammals: CBL, CBL-B, and CBL-C. CBL proteins interact with target proteins through their protein-protein interaction domains, thereby regulating multiple signaling pathways, including tyrosine kinase (TK) signaling in multiple cell types. The structure of CBL proteins includes an amino-terminal tyrosine kinase binding domain (TKBD), a linker helix region (LHR), and a very interesting novel gene (RING) domain, followed by a carboxyl-terminal region containing SRC homology 2 (SH2) and SRC homology binding sites (SH3) domain. The CBL TKBD consists of a four-helix bundle (4H), EF-hand, and a variant SH2 domain, which binds substrates, such as activated TKS, in a phosphotyrosine-dependent manner. Ubiquitination of activated receptor TKs by CBL-B regulates the assembly of endocytic proteins on membranes and sorting endosomes to promote lysosomal targeting, degradation, and signal termination. CBL-B is also important for reducing signaling from antigen and cytokine receptors by ubiquitinating receptor chains and associated cytosolic TKSs, leading to inactivation and / or proteasomal degradation. CBL-B is expressed in the immune cell lineage and functions as a master regulator of immune cell activation and maintenance of peripheral tolerance. CBL-B inhibitors may enhance the activity of cancer vaccines. In addition, mutations in the RING domain of the CBL protein and the CBL-B linker sequence have been found in a variety of diseases and cancers, including luvenile myelocytic leukemia (IMMF), Pleukemia chronic myeloid leukemia (CMMF), myeloid membrane leukemia, and acute myeloid leukemia (AMF). Therefore, CBL-B inhibition represents an opportunity for both tumor-intrinsic and extra-tumor toxic therapies.

[0003] Currently, there are many studies based on this mechanism of action, but no CBL-B inhibitor drugs have been found on the market. Therefore, there is an urgent need to develop effective CBL-B inhibitors for clinical patients. Summary of the invention

[0004] The present disclosure provides compounds of formula (I), isomers and pharmaceutically acceptable salts thereof,

[0005]

[0006] Ring A is selected from phenyl, 5-6 membered heteroaryl;

[0007] X1 is selected from CRa, wherein Ra is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl;

[0008] X2 Selected from CR b , the R b Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, substituted or unsubstituted C 3-6 Cycloalkyl;

[0009] X3 Selected from CR g , N;

[0010] Rg is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, CN;

[0011] R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl;

[0012] L1 is selected from C 1-4 Alkylene, C 1-4 deuterated alkylene;

[0013] R4 is selected from NR 11 R 12 ;

[0014] Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group;

[0015] R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy;

[0016] R 11 , R 12 are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, wherein C 3-6 The cycloalkyl group is optionally substituted with halogen, C1-4 Alkyl substitution;

[0017] m is selected from 0, 1, 2, 3, 4;

[0018] Y1 is independently selected from N, CR c , the R c Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl;

[0019] Y2 is selected from CR d , the R d are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, -NR e1 R e2 、-OR f 、-CN、-SO2-C 1-4 alkyl;

[0020] R e1 , R e2 are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, -CO-NH-C 1-4 Alkyl-CN, -SO2-C 1-4 Alkyl, where C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 The cycloalkyl group is optionally substituted by n atoms each independently selected from hydrogen, halogen, C 1-4 Alkyl, CN, -C 1-4 Alkyl-CN substituted;

[0021] n is selected from 0, 1, 2, 3;

[0022] R f are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, wherein C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 The cycloalkyl group is optionally substituted by r each independently selected from hydrogen, halogen, C 1-4 Alkyl, CN, -C 1-4 Alkyl-CN substituted;

[0023] r is selected from 0, 1, 2, 3;

[0024] R 13 , R 14are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, wherein C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 The cycloalkyl group is optionally substituted by t each independently selected from hydrogen, halogen, C 1-4 Alkyl substituted;

[0025] or R 13 , R 14 The carbon atom to which it is attached forms

[0026] t is selected from 0, 1, 2, 3;

[0027] Z is selected from CR k1 R k2 , the R k1 , R k2 are independently hydrogen, halogen, C 1-4 Alkyl, -C 2-4 Alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene -CN, -CN;

[0028] or R k1 , R k2 The carbon atoms connected to it form C 3-6 Cycloalkyl;

[0029] R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy.

[0030] The present disclosure provides compounds of formula (I), isomers and pharmaceutically acceptable salts thereof,

[0031]

[0032] Ring A is selected from phenyl, 5-6 membered heteroaryl;

[0033] X1 is selected from CRa, wherein Ra is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl; X2 is selected from CR b, the R b Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, substituted or unsubstituted C 3-6 Cycloalkyl;

[0034] X3 Selected from CR g , N;

[0035] Rg is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, CN;

[0036] R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl;

[0037] L1 is selected from C 1-4 Alkylene, C 1-4 deuterated alkylene;

[0038] Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group;

[0039] R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy;

[0040] m is selected from 0, 1, 2, 3, 4;

[0041] Y1 is independently selected from N, CR c , the R c Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl;

[0042] Y2 is selected from CR d , the R d are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, -NR e1 R e2 、-OR f ;

[0043] R e1 , R e2 are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, substituted or unsubstituted C 3-6 Cycloalkyl;

[0044] R f are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, substituted or unsubstituted C 3-6 Cycloalkyl;

[0045] Z is selected from CR k1 R k2 , the R k1 , R k2 are independently hydrogen, halogen, C 1-4 Alkyl, -C 2-4 Alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene -CN, -CN;

[0046] R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy.

[0047] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts, characterized in that ring A is selected from

[0048] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts are characterized in that Ra is selected from Cl, Br, CH3, C2H5, CF3, OCH3, OCHF2, OCF3,

[0049] In some embodiments of the present disclosure, the compound of the above formula (I), its isomers and pharmaceutically acceptable salts are characterized in that Rg is selected from F, Cl, and CN.

[0050] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts are characterized in that R1 is selected from H, F, Cl, CH3, C2H5,

[0051] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts are characterized by the structural unit Selected from

[0052] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts are characterized by the structural unit Selected from

[0053] In some embodiments of the present disclosure, the compound of the above formula (I), its isomers and pharmaceutically acceptable salts are characterized in that L1 is selected from -CH2-.

[0054] In some embodiments of the present disclosure, the compound of the above formula (I), its isomers and pharmaceutically acceptable salts are characterized in that L1 is selected from -CH(CH3)-.

[0055] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts, characterized in that ring B is selected from

[0056] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts, characterized in that ring B is selected from

[0057] In some embodiments of the present disclosure, the compound of the above formula (I), its isomers and pharmaceutically acceptable salts are characterized in that R2 is selected from -CH3.

[0058] In some embodiments of the present disclosure, the compound of the above formula (I), its isomers and pharmaceutically acceptable salts are characterized in that R2 is selected from H, -F, and -C(CH3)2.

[0059] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts are characterized by the structural unit Selected from

[0060] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts are characterized by the structural unit Selected from

[0061] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts, characterized in that R 11 , R 12 Each independently selected from H, -CH3, -CH2CH3, -C(CH3)2,

[0062] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts, characterized in that R e1, R e2 Each independently selected from

[0063] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts, characterized in that R e1 , R e2 Each independently selected from

[0064] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts are characterized in that R f Selected from

[0065] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts, characterized in that R f Selected from

[0066] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts are characterized in that R d Selected from

[0067] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts, characterized in that R d Selected from H, -CN,

[0068] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts are characterized in that R 13 , R 14 Each independently selected from H,

[0069] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts are characterized by the structural unit Selected from

[0070] In some embodiments of the present disclosure, the compound of formula (I), its isomers and pharmaceutically acceptable salts are characterized by the structural unit Selected from

[0071] In some embodiments of the present disclosure, the compound of the above formula (I), its isomers and pharmaceutically acceptable salts are characterized in that R3 is selected from -CH3.

[0072] The present disclosure also provides the following compounds, isomers thereof and pharmaceutically acceptable salts,

[0073]

[0074]

[0075]

[0076]

[0077] The present disclosure also provides a pharmaceutical composition, which contains a therapeutically effective amount of the above compound, its isomers and pharmaceutically acceptable salts and a pharmaceutically acceptable carrier.

[0078] In certain embodiments of the present disclosure, in the pharmaceutical composition, the content of the compound, stereoisomer or pharmaceutically acceptable salt thereof is selected from 0.1 mg to 1000 mg.

[0079] In certain embodiments of the present disclosure, in the pharmaceutical composition, the pharmaceutically acceptable carrier includes one or more of a filler, a disintegrant, a binder, a glidant, and a lubricant.

[0080] The present disclosure also provides use of the above-mentioned compound, its isomers and pharmaceutically acceptable salts or the above-mentioned pharmaceutical composition in the preparation of drugs for treating CBL-B target-mediated related diseases.

[0081] The present disclosure also provides use of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in preparing a drug for treating a disease mediated by CBL-B, wherein the CBL-B-mediated related disease includes cancer.

[0082] In the present disclosure, CBL-B-mediated cancers include urogenital tract cancers (e.g., bladder cancer, kidney cancer, renal cell carcinoma, penile cancer, prostate cancer, testicular cancer, Von Hippel-Lindau disease, etc.), uterine cancer, cervical cancer, ovarian cancer, breast cancer, gastrointestinal cancer (e.g., esophageal cancer, oropharyngeal cancer, gastric cancer, small intestine cancer or large intestine cancer, colon cancer or rectal cancer), bone tumors, myeloma, skin cancer (e.g., melanoma), head and neck cancer, liver cancer, gallbladder cancer, bile duct cancer, heart cancer, lung cancer, pancreatic cancer, salivary gland cancer, adrenal cancer, thyroid cancer, brain tumors (e.g., gliomas), ganglion cancers, central nervous system (CNS) tumors, peripheral nervous system (PNS) tumors, hematopoietic system tumors (i.e., blood malignancies), and immune system tumors (e.g., spleen tumors or thymomas).

[0083] Technical Effects

[0084] The disclosed compounds have significant CBL-B enzyme inhibitory activity and can be used for the treatment of cancer.

[0085] Description and Definition

[0086] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as being ambiguous or unclear without a special definition, but should be understood according to the ordinary meaning.

[0087] The compounds disclosed herein exist in geometric isomers and stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, and racemic mixtures and other mixtures thereof, and all such mixtures are within the scope of the present disclosure.

[0088] The term "enantiomer" refers to stereoisomers that are mirror images of each other.

[0089] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and are selected from molecules that are not mirror images of each other.

[0090] The term "cis-trans isomers" refers to configurations in which double bonds or single bonds of ring carbon atoms in a molecule cannot rotate freely.

[0091] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key Indicates the relative configuration of a stereocenter. For example The methyl group and the amino group are located on the same side of the cyclopentane. The stereoisomers of the compounds disclosed herein can be prepared by chiral synthesis or chiral reagents or other conventional techniques. For example, an enantiomer of a compound disclosed herein can be prepared by asymmetric catalysis technology or chiral auxiliary derivatization technology. Alternatively, a compound of a single stereo configuration can be obtained from a mixture by chiral resolution technology. Alternatively, it can be directly prepared using chiral starting materials. The separation of optically pure compounds disclosed herein is usually accomplished using preparative chromatography, using a chiral chromatographic column to achieve the purpose of separating chiral compounds.

[0092] The absolute stereo configuration of the compound can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction, the absolute configuration of the compound can also be confirmed by the chiral structure of the raw material and the reaction mechanism of asymmetric synthesis. The compounds marked as "absolute configuration not determined" herein are usually selected from a single isomer by chiral preparative SFC separation of the racemic compound, and then characterized and tested.

[0093] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0094] The term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound prepared with a relatively non-toxic acid or base. These salts can be prepared during the synthesis, separation, and purification of the compound, or the purified free form of the compound can be used alone to react with a suitable acid or base. When the compound contains a relatively acidic functional group, it reacts with an alkali metal, alkaline earth metal hydroxide or an organic amine to obtain a base addition salt, including cations based on alkali metals and alkaline earth metals and non-toxic ammonium, quaternary ammonium and amine cations, and also covers amino acid salts. When the compound contains a relatively basic functional group, it reacts with an organic acid or an inorganic acid to obtain an acid addition salt.

[0095] The term "pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering biologically active agents to animals, particularly mammals, including, for example, adjuvants, excipients or excipients, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the nature of the mode of administration and dosage form. Pharmaceutically acceptable carriers are formulated within the scope of ordinary technicians in the field according to a large number of factors. They include, but are not limited to: the type and nature of the active agent to be formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media and a variety of solid and semi-solid dosage forms. In addition to the active agent, such carriers include many different ingredients and additives, and such additional ingredients included in the prescription for various reasons (e.g., stabilizing the active agent, adhesives, etc.) are well known to ordinary technicians in the field.

[0096] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0097] Unless otherwise stated, structural units Links to other groups are

[0098] Unless otherwise specified, "substituted or unsubstituted" means that it may be substituted or unsubstituted. The types of substituents include but are not limited to halogen, alkyl, alkoxy, etc. The "substituted or unsubstituted C 3-6 Examples of "cycloalkyl" include, but are not limited to

[0099] The term "5-6 membered heteroaryl" refers to a monocyclic group having a conjugated π electron system consisting of 5-6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1 , 2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl), pyridyl, pyrimidinyl, etc.

[0100] The term "halogen" denotes a fluorine, chlorine, bromine or iodine atom.

[0101] The term "C 1-4 "Alkyl" is used to represent C 1-4 A straight or branched saturated hydrocarbon group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, and the like.

[0102] The term "C 1-4 "Haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. Examples include but are not limited to monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc.

[0103] The term "C 1-4 The term "deuterated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a deuterium atom, examples of which include but are not limited to monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, 2,2,2-trideuterioethyl, and the like.

[0104] The term "C 1-4 "Alkoxy" refers to a C 1-4 Alkyl. 1-4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy.

[0105] The term "C 1-4 "Alkylene" is used to represent C1-4 Straight or branched chain saturated alkylene. 1-4 Examples of alkylene include, but are not limited to, -CH2-, -(CH2)2-, -(CH2)3, -(CH2)4-, -CH(CH3)-, -C(CH3)2-.

[0106] The term "C 1-4 "Deuterated alkylene" is used to represent C 1-4 The hydrogen atoms in the straight or branched saturated alkylene group are replaced by D atoms. 1-4 Examples of deuterated alkylene groups include, but are not limited to, -CD2-, -CH(CD3)-.

[0107] The term "C 3-6 "Cycloalkyl" refers to a 3-6 membered monocyclic alkyl group. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0108] The term "5-10 membered heterocyclyl" refers to a substituted or unsubstituted 5-10 membered saturated or unsaturated non-aromatic ring containing 1-3 heteroatoms selected from N, O or S. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The "heterocyclic group" described in the present disclosure refers to a non-aromatic cyclic group derived from removing a hydrogen atom and containing at least one heteroatom as a ring atom; including saturated or partially saturated monocyclic heterocyclic groups and bicyclic heterocyclic groups; wherein the bicyclic heterocyclic group may be a fused ring heterocyclic group, a 3-4-membered cycloalkyl and a 3-4-membered heterocyclic group, or a 3-4-membered cycloalkyl and a 5-6-membered heterocyclic group. The heterocyclic group is independent of the connection position (i.e., it can be bonded through a carbon atom or a heteroatom). Examples of "heterocyclic groups" include, but are not limited to

[0109] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0110] The solvents used in the present disclosure are commercially available.

[0111] The structures of the compounds disclosed herein are determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS), or ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR is measured using a Bruker Neo 400M or Bruker Ascend 400 nuclear magnetic instrument, and the measuring solvent is selected from deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), heavy water (D2O), and the internal standard is selected from tetramethylsilane (TMS).

[0112] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260-6125B single quadrupole massspectrometer (the ion source was selected from electrospray ionization).

[0113] Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was performed using a Waters UPLC H-class SQD mass spectrometer (the ion source was selected from electrospray ionization).

[0114] HPLC determination was performed using Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

[0115] Preparative HPLC used Waters 2555-2489 (10 μm, ODS 250 cm×5 cm) or GILSON Trilution LC.

[0116] Chiral HPLC determination used waters acquity UPC2; the column was selected from Daicel chi ring Clpak AD-H (5um, 4.6*250mm).

[0117] Supercritical fluid chromatography (SFC) was performed using waters SFC 80Q.

[0118] The starting materials in the embodiments of the present disclosure are known and commercially available, or can be synthesized using or according to methods known in the art.

[0119] Unless otherwise specified, all reactions disclosed herein are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is selected from a dry solvent, and the reaction temperature unit is selected from degrees Celsius. DETAILED DESCRIPTION

[0120] Example 1

[0121] 4-Chloro-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0122]

[0123] Reaction route:

[0124]

[0125] Steps:

[0126] Step A: Under nitrogen protection at 0°C, dissolve the compound 6-bromo-4-chloro-7-fluoro-1H-indole-2-carboxylic acid methyl ester (500 mg, 1.63 mmol) in N,N-dimethylformamide (8 mL). Then, add sodium hydride (78 mg, 1.96 mmol) to the above solution and stir for 10 minutes. Then add 2-(trimethylsilyl)ethoxymethyl chloride (327 mg, 1.96 mmol) dropwise and continue stirring for 30 minutes.

[0127] After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into a saturated aqueous ammonium chloride solution (25 mL) for quenching, the mixed solution was extracted with ethyl acetate (10 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 700 mg of 6-bromo-4-chloro-7-fluoro-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid methyl ester.

[0128] 1 H NMR(400MHz,DMSO-d6)δ7.62(d,J=4.8Hz,1H),7.35(d,J=1.6Hz,1H),6.01(s, 2H),3.90(s,3H),3.46(t,J=7.6Hz,2H),0.77(t,J=7.6Hz,2H),-0.15(s,9H).

[0129] Step B: Under nitrogen protection at -70°C, compound 6-bromo-4-chloro-7-fluoro-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid methyl ester (500 mg, 1.14 mmol) was dissolved in tetrahydrofuran (8 mL). Subsequently, 2.5 M lithium aluminum hydride tetrahydrofuran solution (0.4 mL, 1.03 mmol) was added dropwise to the above solution. The reaction system was then stirred at -60°C for 0.5 hours.

[0130] After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into a mixed solution of water (20 mL) and ethyl acetate (10 mL) to quench. The mixed solution was extracted with ethyl acetate (10 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 460 mg (6-bromo-4-chloro-7-fluoro-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol.

[0131] MS (ESI) M / Z: 407.9 [M+H] + .

[0132] Step C: Dissolve the compound (6-bromo-4-chloro-7-fluoro-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol (460 mg, 1.12 mmol) in dichloromethane (8 mL) at room temperature. Then, slowly add thionyl chloride (268 mg, 2.25 mmol) dropwise to the solution. Then, stir the reaction system at room temperature for 1 hour.

[0133] After LCMS monitoring showed that the starting material disappeared, the reaction solution was added dropwise into ice water (20 mL) to quench the mixture, and the mixed solution was extracted with dichloromethane (20 mL×2 times). The organic phases were combined and then washed with saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 450 mg of a crude product of 6-bromo-4-chloro-2-(chloromethyl)-7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole.

[0134] MS (ESI) M / Z: 426.0 [M+H] + .

[0135] Step D: Dissolve 6-bromo-4-chloro-2-(chloromethyl)-7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (450 mg, 1.06 mmol) in acetonitrile (4 mL) at room temperature. Then, potassium carbonate (439 mg, 3.18 mmol) and potassium iodide (178 mg, 1.06 mmol) were added to the solution in sequence and stirred for 5 minutes. Then (S)-3-methylpiperidine hydrochloride (187 mg, 1.38 mmol) was added and stirring was continued for 3 hours.

[0136] After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (15 mL×2 times), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 380 mg of (S)-6-bromo-4-chloro-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0137] MS (ESI) M / Z: 489.1 [M+H] + .

[0138] Step E: Under nitrogen protection at room temperature, compound (S)-6-bromo-4-chloro-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole (380 mg, 0.77 mmol), bis-pinacol borate (314 mg, 1.23 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (65 mg, 0.08 mmol) and potassium acetate (230 mg, 2.3 mmol) were dissolved in 1,4-dioxane (3.5 mL). The reaction system was then stirred at 90° C. for 16 hours.

[0139] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of 600 mg (S)-4-chloro-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0140] MS (ESI) M / Z: 537.3 [M+H] + .

[0141] Step F: At room temperature, under nitrogen protection, compound (S)-4-chloro-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (600 mg, 0.77 mmol), 3-((1S,3S)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (235 mg, 0.77 mmol), sodium carbonate (163 mg, 1.54 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (93 mg, 0.11 mmol) were dissolved in 1,4-dioxane (3.5 mL) and water (0.35 mL). Then the reaction system was stirred at 90°C for 2 hours.

[0142] After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (15 mL×2 times), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 300 mg of 4-chloro-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0143] MS (ESI) M / Z: 636.4 [M+H] + .

[0144] Step G: Compound 4-chloro-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (300 mg, 0.47 mmol) was dissolved in dichloromethane (3 mL) at room temperature. Subsequently, trifluoroacetic acid (3 mL) was added dropwise to the above solution and stirring was continued for 2 hours. After LCMS monitoring showed that the starting material disappeared, ammonia water was added to the reaction solution until it was alkaline and stirring was continued for 16 hours.

[0145] After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution, and the mixed solution was extracted with dichloromethane (15 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 35 mg of 4-chloro-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0146] MS (ESI) M / Z: 506.2 [M+H] + .

[0147] 1 H NMR(400MHz,DMSO-d6)δ11.96(s,1H),8.28(s,1H),7.53-7.43(m,3H),7.38-7.31(m, 1H),7.10(d,J=5.6Hz,1H),6.38(s,1H),3.64(d,J=14.0Hz,1H),3.60(d,J=14.4Hz,1H ),3.21(s,3H),2.94-2.86(m,2H),2.84-2.73(m,2H),2.61-2.54(m,3H),1.95-1.86(m ,1H),1.70-1.54(m,4H),1.52-1.41(m,1H),1.09(d,J=5.2Hz,3H),0.89-0.74(m,4H).

[0148] Example 2

[0149] 2-((1R,3S)-3-(3-(4-chloro-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile

[0150]

[0151] Reaction route:

[0152]

[0153] Steps:

[0154] Step A: At room temperature, under nitrogen protection, the crude product of compound (S)-4-chloro-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (300 mg, 0.56 mmol), 2-((1S,3S)-3-( 3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (45 mg, 0.14 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (17 mg, 0.021 mmol) and sodium carbonate (30 mg, 0.28 mmol) were dissolved in 1,4-dioxane (0.8 mL) and water (0.1 mL). The reaction system was then stirred at 90 ° C for 4 hours.

[0155] After LCMS monitoring showed that the starting material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 33 mg of 2-((1R,3S)-3-(3-(4-chloro-7-fluoro-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxymethyl)-1H-indol-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile.

[0156] MS (ESI) M / Z: 661.3 [M+H] + .

[0157] Step B: At room temperature, compound 2-((1R,3S)-3-(3-(4-chloro-7-fluoro-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxymethyl)-1H-indol-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (33 mg, 0.05 mmol) was dissolved in dichloromethane (0.5 mL). Subsequently, trifluoroacetic acid (0.5 mL) was added dropwise to the above solution and stirred for 2 hours. Then the temperature was lowered to 0°C, and ammonia (4.0 mL) was slowly added dropwise to adjust to pH = 8, and the temperature was raised to room temperature and stirred for 2 hours.

[0158] After LCMS monitoring showed that the raw material disappeared, water (15 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 2.56 mg of 2-((1R,3S)-3-(3-(4-chloro-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile.

[0159] MS (ESI) M / Z: 531.3 [M+H] + .

[0160] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),8.31(s,1H),7.53(s,1H),7.50-7.45(m,2H),7.40-7.33(m,1H),7.14(d,J=5.6Hz,1H),6.40(d,J=2.0Hz,1 H),3.63(s,2H),3.23(s,3H),3.00-2.88(m,2H),2.85-2.66(m,7H),1.9 7-1.85(m,1H),1.71-1.55(m,4H),1.53-1.40(m,1H),0.87-0.75(m,4H).

[0161] Example 3

[0162] 2-((1S,3R)-3-(3-(4-chloro-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile

[0163]

[0164] Reaction route:

[0165]

[0166] Steps:

[0167] Step A: At room temperature, under nitrogen protection, compound (S)-4-chloro-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (322 mg, 0.60 mmol), 2-((1R,3R)-3-(3 -bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (50 mg, 0.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (19 mg, 0.023 mmol) and sodium carbonate (32 mg, 0.30 mmol) were dissolved in 1,4-dioxane (0.8 mL) and water (0.1 mL). The reaction system was then stirred at 90 ° C for 4 hours.

[0168] After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 35 mg of 2-((1S,3R)-3-(3-(4-chloro-7-fluoro-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxymethyl)-1H-indol-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile.

[0169] MS (ESI) M / Z: 661.3 [M+H] + .

[0170] Step B: Dissolve the compound 2-((1S,3R)-3-(3-(4-chloro-7-fluoro-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxymethyl)-1H-indol-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (35 mg, 0.05 mmol) in dichloromethane (0.7 mL) at room temperature. Then, trifluoroacetic acid (0.7 mL) was added dropwise to the above solution and stirred for 2 hours. Then, the temperature was lowered to 0°C, and ammonia (5.0 mL) was slowly added dropwise to adjust to pH = 8, and the temperature was raised to room temperature and stirred for 2 hours.

[0171] After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 7.04 mg of 2-((1S,3R)-3-(3-(4-chloro-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile.

[0172] MS (ESI) M / Z: 531.3 [M+H] + .

[0173] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.40(s,1H),7.52-7.42(m,2H),7.37(s,1H),7 .21-7.16(m,1H),7.11(d,J=5.6Hz,1H),6.39(d,J=2.8Hz,1H),3.64(d,J=14.4Hz,1H) ,3.60(d,J=14.4Hz,1H),3.26(s,3H),3.20-3.10(m,2H),2.85-2.70(m,4H),2.63-2.5 1(m,3H),1.95-1.85(m,1H),1.71-1.54(m,4H),1.53-1.40(m,1H),0.87-0.74(m,4H).

[0174] Example 4

[0175] 4-Chloro-7-fluoro-6-(3-((1S,3R)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0176]

[0177] Reaction route:

[0178]

[0179] Steps:

[0180] Step A: At room temperature, under nitrogen protection, the crude compound (S)-4-chloro-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (550 mg, crude), 3-((1S,3S)-1-(3-bromophenyl)-3-methoxycyclobutyl)-4-methyl-4H-1,2,4-triazole (80 mg, 0.25 mmol), sodium carbonate (53 mg, 0.50 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (41 mg, 0.05 mmol) were dissolved in dioxane / water (2 mL / 0.2 mL). Then the reaction system was stirred at 90°C for 3 hours.

[0181] After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered, the filter cake was washed with ethyl acetate (8 mL×2 times), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 100 mg of 4-chloro-7-fluoro-6-(3-((1S,3R)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0182] MS (ESI) M / Z: 652.4 [M+H] + .

[0183] Step B: At room temperature, compound 4-chloro-7-fluoro-6-(3-((1S,3R)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (100 mg, 0.15 mmol) was dissolved in dichloromethane (1 mL). Subsequently, trifluoroacetic acid (2 mL) was slowly added dropwise to the above solution and stirring was continued for 2 hours. After LCMS monitoring showed that the starting material disappeared, aqueous ammonia was added to the reaction solution to adjust it to alkaline and stirring was continued for 2 hours.

[0184] After LCMS monitoring showed that the intermediate disappeared, water (8 mL) was added to the reaction solution, and the mixed solution was extracted with dichloromethane (15 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 6.5 mg of 4-chloro-7-fluoro-6-(3-((1S,3R)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0185] MS (ESI) M / Z: 522.3 [M+H] + .

[0186] 1 H NMR(400MHz,DMSO-d6)δ11.97(s,1H),8.30(s,1H),7.51-7.42(m,3H),7.3 6-7.30(m,1H),7.12(d,J=5.6Hz,1H),6.39(s,1H),4.12-4.04(m,1H),3.62 (s,2H),3.23(s,3H),3.17(s,3H),3.14-3.06(m,2H),2.85-2.72(m,4H),1 .97-1.86(m,1H),1.68-1.54(m,4H),1.53-1.40(m,1H),0.89-0.75(m,4H).

[0187] Example 5

[0188] 7-Fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1H-indole

[0189]

[0190] Reaction route:

[0191]

[0192] Steps:

[0193] Step A: Under nitrogen protection at 0°C, compound 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (15 g, 71.77 mmol) was dissolved in concentrated sulfuric acid (71 mL). Subsequently, N-bromosuccinimide (61.4 g, 273 mmol) was added to the above solution. The reaction system was then stirred at room temperature for 12 hours.

[0194] After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into ice water (200 mL) for quenching, the mixed solution was extracted with ethyl acetate (100 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (150 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 11.5 g of 1-bromo-2-fluoro-3-nitro-5-(trifluoromethyl)benzene.

[0195] 1 H NMR (400MHz, DMSO-d6) δ8.68 (dd, J=5.2, 2.0Hz, 1H), 8.53 (dd, J=6.0, 2.0Hz, 1H).

[0196] Step B: Dissolve the compound 1-bromo-2-fluoro-3-nitro-5-(trifluoromethyl)benzene (11.5 g, 39.79 mmol) in ethanol / water (132 / 66 mL) at room temperature. Then, add iron powder (11.14 g, 198.96 mmol) and ammonium chloride (10.5 g, 198.96 mmol) to the solution. Then stir the reaction system at 70°C for 2 hours.

[0197] After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered and concentrated under reduced pressure. The mixture was dissolved in ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL × 2 times). It was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 7 g of 3-bromo-2-fluoro-5-(trifluoromethyl)aniline.

[0198] MS (ESI) M / Z: 258.0 [M+H] + .

[0199] Step C: Dissolve the compound 3-bromo-2-fluoro-5-(trifluoromethyl)aniline (7 g, 27.13 mmol) in concentrated hydrochloric acid (30 mL) at -10 °C. Then, slowly drop a solution of sodium nitrite (1.93 g, 28.49 mmol) in water (3.9 mL) and stir for 2 hours. Then cool the reaction solution to -30 °C, slowly drop the solution into a solution of stannous chloride (10.26 g, 54.26 mmol) in concentrated hydrochloric acid (13 mL), heat to -20 °C, and continue stirring for 1 hour.

[0200] After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered, and the filter cake was rinsed with water (50 mL×2 times) and petroleum ether (50 mL) in sequence and dried in vacuo to obtain 7 g of a crude product (3-bromo-2-fluoro-5-(trifluoromethyl)phenyl)hydrazine.

[0201] MS (ESI) M / Z: 273.0 [M+H] + .

[0202] Step D: Dissolve the compound (3-bromo-2-fluoro-5-(trifluoromethyl)phenyl)hydrazine (7 g, 25.73 mmol) in ethanol (36 mL) at room temperature. Then, add ethyl pyruvate (3.28 g, 28.31 mmol) to the solution. Then, continue to stir the reaction system at room temperature for 2 minutes.

[0203] After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered, and the filter cake was rinsed with petroleum ether (30 mL×2 times) and dried to obtain 7 g of ethyl (Z)-2-(2-(3-bromo-2-fluoro-5-(trifluoromethyl)phenyl)hydrazino)propanoate.

[0204] MS (ESI) M / Z: 371.0 [M+H] + .

[0205] Step E: Dissolve compound (Z)-ethyl 2-(2-(3-bromo-2-fluoro-5-(trifluoromethyl)phenyl)hydrazino)propanoate (7 g, 18.87 mmol) in polyphosphoric acid (84 g) at room temperature, and then stir the reaction system at 80°C for 3 hours.

[0206] After LCMS monitoring showed that the raw material disappeared, water (100 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (100 mL × 2 times), and the organic phases were combined and washed with saturated brine (150 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.2 g of 6-bromo-7-fluoro-4-(trifluoromethyl)-1H-indole-2-carboxylic acid ethyl ester.

[0207] Step F: Under nitrogen protection at 0°C, the compound 6-bromo-7-fluoro-4-(trifluoromethyl)-1H-indole-2-carboxylic acid ethyl ester (2.2g, 6.23mmol) was dissolved in N,N-dimethylformamide (30mL). Subsequently, 60%wt sodium hydride (374mg, 9.35mmol) was added to the above solution and stirred for 10 minutes. Then 2-(trimethylsilyl)ethoxymethyl chloride (1.34g, 8.10mmol) was added dropwise at 0°C and stirred for 30 minutes. After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into a saturated aqueous ammonium chloride solution (90mL) to quench, the mixed solution was extracted with ethyl acetate (50mL×2 times), the organic phases were combined, and the organic phases were washed with saturated brine (100mL×2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 728 mg of ethyl 6-bromo-7-fluoro-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate.

[0208] Step G: Dissolve 6-bromo-7-fluoro-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid ethyl ester (728 mg, 1.51 mmol) in tetrahydrofuran (6 mL) at 0°C. Then, lithium hydroxide (316 mg, 7.54 mmol) was dissolved in water (3 mL) and added to the solution. The reaction system was then stirred at room temperature for 2 hours.

[0209] After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure, ethyl acetate / water (20 / 20 mL) was added to the obtained concentrate, and the pH was adjusted to 4 with 1M dilute hydrochloric acid. The mixed solution was extracted with ethyl acetate (40 mL×2 times), and the organic phases were combined. Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 600 mg of 6-bromo-7-fluoro-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid.

[0210] MS (ESI) M / Z: 477.8 [M+23].

[0211] Step H: Dissolve 6-bromo-7-fluoro-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid (600 mg, 1.32 mmol) in borane tetrahydrofuran solution (3 mL) at room temperature. Then stir the reaction system at 50°C for 2 hours.

[0212] After LCMS monitoring showed that the raw material disappeared, the above reaction solution was added dropwise to ice water (50 mL) to quench, the mixed solution was extracted with dichloromethane (50 mL × 2 times), the organic phases were combined, and then washed with saturated sodium bicarbonate solution (80 mL × 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 380 mg (6-bromo-7-fluoro-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol.

[0213] Step I: Dissolve the compound (6-bromo-7-fluoro-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol (380 mg, 0.86 mmol) in dichloromethane (4 mL) at room temperature. Then, slowly add thionyl chloride (203 mg, 1.72 mmol) dropwise to the solution. Then, stir the reaction system at room temperature for 2 hours.

[0214] After LCMS monitoring showed that the raw material disappeared, the above reaction solution was added dropwise to ice water (20 mL) to quench, the mixed solution was extracted with dichloromethane (20 mL × 2 times), the organic phases were combined, then washed with saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 350 mg of 6-bromo-2-(chloromethyl)-7-fluoro-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole.

[0215] Step J: Dissolve 6-bromo-2-(chloromethyl)-7-fluoro-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (300 mg, 0.65 mmol) in acetonitrile (3 mL) at room temperature. Then, potassium carbonate (269 mg, 1.95 mmol) and potassium iodide (162 mg, 0.98 mmol) were added to the solution in sequence and stirred for 5 minutes. Then (S)-3-methylpiperidine hydrochloride (133 mg, 0.98 mmol) was added and stirred for 3 hours.

[0216] After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (15 mL×2 times), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 213 mg of (S)-6-bromo-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0217] MS (ESI) M / Z: 523.2 [M+H] + .

[0218] Step K: At room temperature, under nitrogen protection, compound (S)-6-bromo-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole (50 mg, 0.10 mmol), 4-methyl-3-((1S,3S)-3-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4H-12,4-triazole (42 mg, 0.12 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (12 mg, 0.02 mmol) and sodium carbonate (32 mg, 0.30 mmol) were dissolved in 1,4-dioxane / water (0.9 / 0.1 mL). The reaction system was then stirred at 90°C for 7 hours.

[0219] After LCMS monitoring showed that the starting material disappeared, water (3 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (5 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (2 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 60 mg of 7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole.

[0220] MS (ESI) M / Z: 670.3 [M+H] + .

[0221] Step L: Compound 7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (60 mg, 0.09 mmol) was dissolved in dichloromethane (0.4 mL) at room temperature. Trifluoroacetic acid (0.4 mL) was then added dropwise to the solution and stirring continued for 2 hours. After LCMS monitoring showed the disappearance of the starting material, ammonia was added to the reaction solution until pH = 8 and stirring continued for 3 hours.

[0222] After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (15 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 20.93 mg of 7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1H-indole.

[0223] MS (ESI) M / Z: 540.2 [M+H] + .

[0224] 1 H NMR(400MHz,DMSO-d6)δ12.18(s,1H),8.29(s,1H),7.58-7.46(m,3H),7.42-7.34(m,2H),6.48(s,1H),3.66(s,2H),3.22(s,3H),2.9 7-2.73(m,4H),2.61-2.53(m,3H),2.03-1.83(m,1H),1.72-1.56(m,4H),1.54-1.40(m,1H),1.09(d,J=5.2Hz,3H),0.89-0.75(m,4H).

[0225] Example 6

[0226] 4-Cyclopropyl-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0227]

[0228] Reaction route:

[0229]

[0230] Steps:

[0231] Step A: Under nitrogen protection at room temperature, compound 4-bromo-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (50 mg, 0.07 mmol), cyclopropylboronic acid (19 mg, 0.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (5.7 mg, 0.007 mmol) and potassium carbonate (19 mg, 0.14 mmol) were dissolved in 1,4-dioxane (0.9 mL). The reaction system was then stirred at 90°C for 12 hours.

[0232] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (5 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 20 mg of 4-cyclopropyl-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0233] MS (ESI) M / Z: 642.3 [M+H] + .

[0234] Step B: At room temperature, the compound 4-cyclopropyl-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (20 mg, 0.03 mmol) was dissolved in dichloromethane (1 mL). Subsequently, trifluoroacetic acid (0.5 mL) was added dropwise to the above solution and stirring was continued for 2 hours. After LCMS monitoring showed that the raw material disappeared, ammonia water was added to the reaction solution to adjust the pH to 8 and stirring was continued for 16 hours.

[0235] After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (5 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 1.12 mg of 4-cyclopropyl-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0236] MS (ESI) M / Z: 512.3 [M+H] + .

[0237] 1 H NMR(400MHz,DMSO-d6)δ11.49(s,1H),8.28(s,1H),7.50-7.38(m,3H),7.33(d ,J=7.2Hz,1H),6.59-6.41(m,2H),3.62(s,2H),3.25(s,3H),2.95-2.71(m,4H) ,2.64-2.51(m,3H),2.19-2.13(m,1H),1.99-1.83(m,1H),1.70-1.42(m,5H),1 .09(d,J=5.2Hz,3H),0.99-0.91(m,2H),0.88-0.79(m,4H),0.78-0.72(m,2H).

[0238] Example 7

[0239] 4-Bromo-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0240]

[0241] Reaction route:

[0242]

[0243] Steps:

[0244] Step A: Under nitrogen protection at 0°C, compound 4-bromo-1-fluoro-2-nitrobenzene (40 g, 182 mmol) was dissolved in trifluoromethanesulfonic acid (182 mL). Then, N-iodosuccinimide (61.4 g, 273 mmol) was added to the above solution. The reaction system was then stirred at room temperature for 12 hours.

[0245] After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into ice water (200 mL) for quenching, the mixed solution was extracted with ethyl acetate (100 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (150 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 53 g of 5-bromo-2-fluoro-1-iodo-3-nitrobenzene.

[0246] Step B: Under nitrogen protection at 0°C, compound 5-bromo-2-fluoro-1-iodo-3-nitrobenzene (48 g, 139 mmol) was dissolved in ethanol / water (347 / 173 mL). Subsequently, iron powder (38.8 g, 695 mmol) and ammonium chloride (37 g, 695 mmol) were added to the above solution in sequence. The reaction system was then stirred at 70°C for 2 hours.

[0247] After LCMS monitoring showed that the raw material disappeared, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 35 g of 5-bromo-2-fluoro-3-iodoaniline.

[0248] MS (ESI) M / Z: 315.9 [M+H] + .

[0249] Step C: Dissolve the compound 5-bromo-2-fluoro-3-iodoaniline (16.6 g, 52.9 mmol) in concentrated hydrochloric acid (56 mL) at -10°C. Then, slowly drop a mixed solution of sodium nitrite (3.8 g, 55.5 mmol) / water (7.4 mL) into the above solution and stir for 2 hours. Then cool to -30°C, slowly drop a mixed solution of stannous chloride (20 g, 105.8 mmol) / concentrated hydrochloric acid (25 mL), heat to -20°C, and continue stirring for 1 hour.

[0250] After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered, and the filter cake was rinsed with water (50 mL×2 times) and petroleum ether (50 mL) in turn, and dried to obtain 17.5 g of a crude product (5-bromo-2-fluoro-3-iodophenyl)hydrazine.

[0251] MS (ESI) M / Z: 330.9 [M+H] + .

[0252] Step D: Dissolve the compound (5-bromo-2-fluoro-3-iodophenyl)hydrazine (17.5 g, 53.2 mmol) in ethanol (80 mL) at room temperature. Then, add ethyl pyruvate (6.8 g, 58.5 mmol) dropwise to the solution. Then, continue stirring the reaction system for 2 minutes.

[0253] After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered and the filter cake was rinsed with petroleum ether (30 mL×2 times) to obtain 7 g of (5-bromo-2-fluoro-3-iodophenyl)amino)alanine ethyl ester.

[0254] MS (ESI) M / Z: 428.9 [M+H] + .

[0255] Step E: Dissolve (5-bromo-2-fluoro-3-iodophenyl)amino)alanine ethyl ester (7 g, 16.3 mmol) in polyphosphoric acid (116 g) at room temperature, and then stir the reaction system at 80°C for 3 hours.

[0256] After LCMS monitoring showed that the raw material disappeared, ice water (150 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (100 mL × 2 times), and the organic phases were combined and washed with saturated brine (150 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.6 g of 4-bromo-7-fluoro-6-iodo-1H-indole-2-carboxylic acid ethyl ester.

[0257] Step F: Under nitrogen protection at 0°C, dissolve the compound 4-bromo-7-fluoro-6-iodo-1H-indole-2-carboxylic acid ethyl ester (3.6 g, 8.7 mmol) in N,N-dimethylformamide (44 mL). Then, add 60% wt sodium hydride (452 ​​mg, 13 mmol) to the above solution and stir for 10 minutes. Then add 2-(trimethylsilyl)ethoxymethyl chloride (1.9 g, 13 mmol) dropwise and continue stirring for 30 minutes.

[0258] After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into a saturated aqueous ammonium chloride solution (80 mL) for quenching, the mixed solution was extracted with ethyl acetate (20 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (50 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.7 g of 4-bromo-7-fluoro-6-iodo-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid ethyl ester.

[0259] Step G: Under nitrogen protection at 0°C, the compound 4-bromo-7-fluoro-6-iodo-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid ethyl ester (3.7 g, 6.8 mmol) was dissolved in tetrahydrofuran / methanol (34 / 17 mL). Subsequently, a solution of lithium hydroxide (1.4 g, 34.2 mmol) in water (8.5 mL) was added to the above solution. The reaction system was then stirred at room temperature for 2 hours.

[0260] After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure. Ethyl acetate / water (20 / 20 mL) was added to the resulting mixture for dilution, and 1M dilute hydrochloric acid was added dropwise to adjust the pH to 4. The mixed solution was extracted with ethyl acetate (40 mL × 2 times), and the organic phases were combined. Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3.4 g of 4-bromo-7-fluoro-6-iodo-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid.

[0261] MS (ESI) M / Z: 536.0 [M+Na] + .

[0262] Step H: Dissolve the compound 4-bromo-7-fluoro-6-iodo-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid (3.4 g, 7.0 mmol) in tetrahydrofuran (14 mL) at room temperature. Then, slowly add 1 M borane tetrahydrofuran solution (21 mL, 21 mmol) to the above solution. Then continue to stir the reaction system for 2 hours.

[0263] After LCMS monitoring showed that the raw material disappeared, the above reaction solution was added dropwise to ice water (50 mL) to quench, and the mixed solution was extracted with dichloromethane (50 mL × 2 times), and the organic phases were combined. Then it was washed with saturated sodium bicarbonate solution (80 mL × 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.7 g (4-bromo-7-fluoro-6-iodo-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol.

[0264] MS (ESI) M / Z: 482.0 [M-OH].

[0265] Step I: Dissolve the compound (4-bromo-7-fluoro-6-iodo-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol (1.7 g, 3.4 mmol) in dichloromethane (17 mL) at room temperature. Then, slowly add thionyl chloride (802 mg, 6.8 mmol) dropwise to the solution. Then, continue stirring the reaction system for 2 hours.

[0266] After LCMS monitoring showed that the raw material disappeared, the above reaction solution was added dropwise to ice water (20 mL) to quench, the mixed solution was extracted with dichloromethane (20 mL × 2 times), the organic phases were combined, then washed with saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 940 mg of 4-bromo-2-(chloromethyl)-7-fluoro-6-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole.

[0267] Step J: Dissolve 4-bromo-2-(chloromethyl)-7-fluoro-6-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (940 mg, 1.82 mmol) in acetonitrile (9 mL) at room temperature. Then, potassium carbonate (502 mg, 3.64 mmol) and potassium iodide (604 mg, 3.64 mmol) were added to the solution in sequence and stirred for 5 minutes. Then (S)-3-methylpiperidine hydrochloride (319 mg, 2.36 mmol) was added and stirring was continued for 3 hours.

[0268] After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (15 mL×2 times), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 870 mg of (S)-4-bromo-7-fluoro-6-iodo-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0269] MS (ESI) M / Z: 581.0 [M+H] + .

[0270] Step K: At room temperature, under nitrogen protection, (S)-4-bromo-7-fluoro-6-iodo-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole (870 mg, 2.1 mmol), 4-methyl-3-((1S,3S)-3-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4H-12,4-triazole (741 mg, 1.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (183 mg, 0.23 mmol) and sodium carbonate (477 mg, 4.5 mmol) were dissolved in 1,4-dioxane / water (7.5 / 0.8 mL). The reaction system was then stirred at 90°C for 7 hours.

[0271] After LCMS monitoring showed that the starting material disappeared, water (30 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (15 mL × 2 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of 940 mg 4-bromo-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0272] MS (ESI) M / Z: 680.2 [M+H] + .

[0273] Step L: At room temperature, compound 4-bromo-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (50 mg, 0.07 mmol) was dissolved in dichloromethane (0.5 mL). Subsequently, trifluoroacetic acid (0.5 mL) was added dropwise to the above solution and stirring was continued for 16 hours. After LCMS monitoring showed that the starting material disappeared, ammonia water was added to the reaction solution to adjust the pH to 8 and stirring was continued for 16 hours.

[0274] After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (15 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 4.92 mg of 4-bromo-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0275] MS (ESI) M / Z: 550.3 [M+H] + .

[0276] 1H NMR (400MHz, DMSO-d6) δ12.00(s,1H),8.28(s,1H),7.52-7.42(m,3H),7.39-7.31(m,1H),7.23(d,J=5 .6Hz,1H),6.32(s,1H),3.62(s,2H),3.20(s,3H),2.95-2.73(m,4H),2.63-2.50(m,3H),2.00-1.83(m,

[0277] 1H),1.70-1.41(m,5H),1.08(d,J=5.2Hz,3H),0.89-0.73(m,4H).

[0278] Example 8

[0279] 7-Fluoro-4-methyl-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0280]

[0281] Reaction route:

[0282]

[0283] Steps:

[0284] Step A: Under nitrogen protection at room temperature, compound 4-bromo-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (120 mg, 0.18 mmol), methylboronic acid (32 mg, 0.55 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (15 mg, 0.02 mmol) and potassium carbonate (50 mg, 0.36 mmol) were dissolved in 1,4-dioxane (0.9 mL). The reaction system was then stirred at 90° C. for 12 hours.

[0285] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (5 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 40 mg of 7-fluoro-4-methyl-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0286] MS (ESI) M / Z: 308.9 [M / 2+H] + .

[0287] Step B: Compound 7-fluoro-4-methyl-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (40 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL) at room temperature. Subsequently, trifluoroacetic acid (0.5 mL) was added dropwise to the above solution and stirring was continued for 2 hours. After LCMS monitoring showed that the starting material disappeared, ammonia water was added to the reaction solution to adjust the pH to 8 and stirring was continued for 16 hours.

[0288] After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (5 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 1.07 mg of 7-fluoro-4-methyl-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0289] MS (ESI) M / Z: 486.3 [M+H] + .

[0290] 1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),8.28(s,1H),7.62-7.38(m,3H),7.38 -7.25(m,1H),6.80(d,J=5.6Hz,1H),6.36(s,1H),3.59(s,2H),3.20(s,3H) ,2.93-2.74(m,4H),2.66-2.55(m,3H),2.43(s,3H),1.97-1.84(m,1H),1.7 6-1.54(m,4H),1.54-1.40(m,1H),1.09(d,J=2.8Hz,3H),0.96-0.73(m,4H).

[0291] Example 9

[0292] 3-Bromo-4-chloro-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0293]

[0294] Reaction route:

[0295]

[0296] Steps:

[0297] Step A: Under nitrogen protection at room temperature, compound 4-chloro-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (250 mg, 0.39 mmol) was dissolved in acetonitrile (2 mL). Subsequently, the solution was cooled to 0°C and N-bromosuccinimide (70 mg, 0.39 mmol) was added. The reaction system was then stirred at room temperature for 3 hours.

[0298] After LCMS monitoring showed that the starting material disappeared, water (15 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 200 mg of 3-bromo-4-chloro-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole.

[0299] MS (ESI) M / Z: 714.2 [M+H] + .

[0300] Step B: Dissolve the compound 3-bromo-4-chloro-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (38 mg, 0.05 mmol) in dichloromethane (0.5 mL) at room temperature. Then, trifluoroacetic acid (0.5 mL) was added dropwise to the solution and stirred for 2 hours. Ammonia was then added dropwise to adjust the pH to 8 and stirring was continued for 1 hour.

[0301] After LCMS monitoring showed that the raw material disappeared, water (15 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (15 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude product. The resulting crude product was purified by preparative high performance liquid chromatography to obtain 11.10 mg of 3-bromo-4-chloro-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0302] MS (ESI) M / Z: 585.2 [M+H] + .

[0303] 1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),δ8.29(s,1H),7.54-7.45(m,3H),7. 40-7.33(m,1H),7.16(d,J=6.0Hz,1H),3.64(s,2H),3.21(s,3H),2.96-2. 87(m,2H),2.82-2.72(m,2H),2.62-2.52(m,3H),2.04-1.92(m,1H),1.75- 1.52(m,4H),1.50-1.39(m,1H),1.09(d,J=5.2Hz,3H),0.89-0.76(m,4H).

[0304] Example 10

[0305] 6-(4-chloro-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)-N-ethyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine

[0306]

[0307] Reaction route:

[0308]

[0309] Steps:

[0310] Step A: Under nitrogen protection at room temperature, 2,6-dichloro-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (100.0 mg, 0.34 mmol) and ethylamine hydrochloride (275.4 mg, 3.4 mmol) were dissolved in dimethyl sulfoxide (4.0 mL). Subsequently, N,N-diisopropylethylamine (877.2 mg, 6.8 mmol) was added to the above solution. The reaction system was then stirred at 150°C for 2 hours.

[0311] After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (5 mL × 3 times), and the organic phases were combined and washed with saturated brine (15 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 75 mg of 6-chloro-N-ethyl-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine.

[0312] MS (ESI) M / Z: 306.2 [M+H] + .

[0313] Step B: At room temperature, under nitrogen protection, 6-chloro-N-ethyl-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine (61.0 mg, 0.2 mmol) and (S)-4-chloro-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole (160.5 mg, 0.3 mmol) were dissolved in toluene (2.0 mL) and water (0.2 mL). Subsequently, cesium carbonate (195.0 mg, 0.6 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (24.5 mg, 0.03 mmol) were added to the above solution in sequence, and the reaction system was stirred at 100° C. for 3 hours.

[0314] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50 mg of 6-(4-chloro-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indol-6-yl)-N-ethyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine.

[0315] MS (ESI) M / Z: 680.3 [M+H] + .

[0316] Step C: Under nitrogen protection at room temperature, compound 6-(4-chloro-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indol-6-yl)-N-ethyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine (50 mg, 0.07 mmol) was dissolved in dichloromethane (1.0 mL). Subsequently, trifluoroacetic acid (0.5 mL) was added dropwise to the above solution and stirred for 2 hours. Then, ammonia water (1.0 mL) was added dropwise at 0°C, and the mixture was allowed to stand for 1 hour from room temperature to room temperature.

[0317] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (15 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and then by chiral separation column purification to obtain 10.5 mg of 6-(4-chloro-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)-N-ethyl-4-((1S, 3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine.

[0318] MS (ESI) M / Z: 550.2 [M+H] + .

[0319] 1H NMR (400MHz, DMSO-d6) δ11.93(s,1H),8.33(s,1H),7.60(d,J=5.6Hz,1H),6.84( s,1H),6.65(t,J=5.0Hz,1H),6.39(s,1H),6.36(s,1H),3.62(s,2H),3.39-3.27( m,2H),3.24(s,3H),2.87-2.71(m,4H),2.62-2.53(m,3H),1.99-1.82(m,1H),1. 70-1.41(m,5H),1.17(t,J=7.0Hz,3H),1.09(d,J=6.0Hz,3H),0.90-0.74(m,4H).

[0320] Embodiment 11

[0321] 6-(4-chloro-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)-N-ethyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine

[0322]

[0323] Reaction route:

[0324]

[0325] Steps:

[0326] Step A: At room temperature, under nitrogen protection, compound 6-chloro-N-ethyl-4-((1R,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine (70 mg, 0.23 mmol) and (S)-4-chloro-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole (188 mg, 0.35 mmol) were dissolved in toluene (2.3 mL) and water (0.3 mL). Subsequently, cesium carbonate (150 mg, 0.46 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (37 mg, 0.046 mmol) were added to the above solution in sequence, and the reaction system was stirred at 120° C. for 16 hours.

[0327] After LCMS monitoring showed that the raw material disappeared, ice water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 43 mg of 6-(4-chloro-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indol-6-yl)-N-ethyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine.

[0328] MS (ESI) M / Z: 680.3 [M+H] + .

[0329] Step B: Compound 6-(4-chloro-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-6-yl)-N-ethyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine (43 mg, 0.06 mmol) was dissolved in dichloromethane (0.6 mL) at room temperature. Subsequently, trifluoroacetic acid (0.6 mL) was added dropwise to the above solution. The reaction system was then stirred for 2 hours.

[0330] After LCMS monitoring showed that the raw material disappeared, ammonia water was added dropwise to the reaction solution to adjust the pH to 8, and stirring was continued for 2 hours. Subsequently, water (25 mL) was added to dilute the above solution, the mixed solution was extracted with dichloromethane (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 9.62 mg of 6-(4-chloro-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)-N-ethyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine.

[0331] MS (ESI) M / Z: 550.2 [M+H] + .

[0332] 1 H NMR (400MHz, DMSO-d6) δ11.94(s,1H),8.40(s,1H),7.60(d,J=5.6Hz,1H),6.74(s,1H),6.64(t,J =5.2Hz,1H),6.36(s,1H),6.22(d,J=1.2Hz,1H),3.62(s,2H),3.32-3.31(m,2H),3.29(s,3H),3.1 1-3.02(m,2H),2.83-2.72(m,2H),2.41-2.29(m,1H),2.26-2.16(m,2H),1.96-1.85(m,1H),1.68 -1.55(m,4H),1.54-1.42(m,1H),1.16(t,J=7.2Hz,3H),1.11(d,J=6.4Hz,3H),0.87-0.77(m,4H).

[0333] Example 12

[0334] 7-Fluoro-4-methoxy-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0335]

[0336] Reaction route:

[0337]

[0338] Steps:

[0339] Step A: Under nitrogen protection at room temperature, compound 4-bromo-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole (80 mg, 0.12 mmol) was dissolved in methanol (0.6 mL). Subsequently, sodium methoxide (32 mg, 0.59 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (14 mg, 0.017 mmol) were added to the above solution. The reaction system was then stirred at 85°C for 3 hours.

[0340] After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (5 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 38 mg of 7-fluoro-4-methoxy-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0341] MS (ESI) M / Z: 316.3 [M / 2+H] + .

[0342] Step B: At room temperature, compound 7-fluoro-4-methoxy-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (38 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL). Subsequently, trifluoroacetic acid (0.5 mL) was added dropwise to the above solution and stirring was continued for 2 hours. After LCMS monitoring showed that the starting material disappeared, ammonia water was added to the reaction solution to adjust the pH to 8 and stirring was continued for 16 hours.

[0343] After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution for dilution, and the mixed solution was extracted with dichloromethane (5 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 0.57 mg of 7-fluoro-4-methoxy-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0344] MS (ESI) M / Z: 502.3 [M+H] + .

[0345] 1 H NMR(400MHz,DMSO-d6)δ11.55(s,1H),8.29(s,1H),7.55-7.43(m,3H),7.3 4(s,1H),6.43(d,J=4.4Hz,1H),6.33(s,1H),3.88(s,3H),3.58(s,2H),3. 22(s,3H),2.95-2.70(m,4H),2.63-2.52(m,3H),1.95-1.81(m,1H),1.73- 1.52(m,4H),1.52-1.41(m,1H),1.09(d,J=5.2Hz,3H),0.88-0.73(m,4H).

[0346] Embodiment 13

[0347] 4-Chloro-6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0348]

[0349] Reaction route:

[0350]

[0351] Steps:

[0352] Step A: At room temperature, under nitrogen protection, compound (S)-4-chloro-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (175 mg, 0.32 mmol), 2-chloro-6-cyclopropyl-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (50 mg, 0.16 mmol), cesium carbonate (104 mg, 0.32 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (13 mg, 0.016 mmol) were dissolved in toluene / water (1 mL / 0.2 mL). The reaction system was then stirred at 120°C for 16 hours.

[0353] After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (8 mL×2 times), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 40 mg of 4-chloro-6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0354] MS (ESI) M / Z: 677.4 [M+H] + .

[0355] Step B: At room temperature, compound 4-chloro-6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (40 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL). Subsequently, trifluoroacetic acid (2 mL) was added dropwise to the above solution and stirred for 4 hours. After LCMS monitoring showed that the starting material disappeared, ammonia water was added dropwise to the reaction solution to adjust it to alkalinity and stirring was continued for 16 hours.

[0356] After LCMS monitoring showed that the intermediate disappeared, water (4 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 11.4 mg of 4-chloro-6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0357] MS (ESI) M / Z: 547.3 [M+H] + .

[0358] 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.34(s,1H),7.51(d,J=5.6Hz,1H),7.38(s,1H) ,7.31(d,J=1.6Hz,1H),6.38(s,1H),3.62(s,2H),3.23(s,3H),2.95-2.84(m,2H),2.8 3-2.72(m,2H),2.65-2.54(m,3H),2.24-2.15(m,1H),1.95-1.86(m,1H),1.70-1.54(m ,4H),1.54-1.40(m,1H),1.09(d,J=5.6Hz,3H),1.05-0.93(m,4H),0.89-0.73(m,4H).

[0359] Embodiment 14

[0360] 4-Chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0361]

[0362] Reaction route:

[0363]

[0364] Steps:

[0365] Step A: At room temperature, under nitrogen protection, compound (S)-4-chloro-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (140 mg, 0.26 mmol), 2-chloro-6-cyclopropyl-4-(( 1R,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (40 mg, 0.13 mmol), cesium carbonate (85 mg, 0.26 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (11 mg, 0.013 mmol) were dissolved in toluene / water (0.8 mL / 0.18 mL). The reaction system was then stirred at 120°C for 16 hours.

[0366] After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (8 mL×2 times), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 32 mg of 4-chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0367] MS (ESI) M / Z: 677.4 [M+H] + .

[0368] Step B: At room temperature, compound 4-chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (40 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL). Subsequently, trifluoroacetic acid (2 mL) was added dropwise to the above solution and stirred for 4 hours. After LCMS monitoring showed that the starting material disappeared, ammonia water was added dropwise to the reaction solution to adjust the pH to 8, and stirring was continued for 16 hours.

[0369] After LCMS monitoring showed that the intermediate disappeared, water (4 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 11 mg of 4-chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0370] MS (ESI) M / Z: 547.3 [M+H] + .

[0371] 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.41(s,1H),7.50(d,J=5.6Hz,1H),7.26(s,1H) ,7.15(d,J=1.2Hz,1H),6.38(s,1H),3.62(s,2H),3.27(s,3H),3.16-3.07(m,2H),2.8 3-2.71(m,2H),2.40-2.28(m,3H),2.21-2.15(m,1H),1.95-1.85(m,1H),1.69-1.54(m ,4H),1.53-1.41(m,1H),1.11(d,J=6.0Hz,3H),1.05-0.94(m,4H),0.87-0.75(m,4H).

[0372] Embodiment 15

[0373] 4-Chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0374]

[0375] Reaction route:

[0376]

[0377] Steps:

[0378] Step A: At room temperature, under nitrogen protection, compound 2,6-dichloro-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (312.0 mg, 1.0 mmol) and (S)-4-chloro-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (536.0 mg, 1.0 mmol) were dissolved in 1,4-dioxane (9.0 mL) and water (1.0 mL). Subsequently, sodium carbonate (320.0 mg, 3.0 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (120.0 mg, 0.15 mmol) were added to the above solution in sequence, and the reaction system was stirred at 100° C. for 2 hours.

[0379] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (15 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 110 mg of (S)-4-chloro-6-(6-chloro-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl.

[0380] MS (ESI) M / Z: 687.3 [M+H] + .

[0381] Step B: Compound (S)-4-chloro-6-(6-chloro-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl (110.0 mg, 0.16 mmol) and cyclopropylboronic acid (55.1 mg, 0.64 mmol) were dissolved in toluene (1.4 mL) and water (0.14 mL) at room temperature under nitrogen protection. Subsequently, cesium carbonate (104.0 mg, 0.32 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (13.1 mg, 0.016 mmol) were added to the above solution in sequence. The reaction system was then stirred at 100° C. for 3 hours.

[0382] After LCMS monitoring showed that the raw material disappeared, water (8 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (5 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 70 mg of (S)-4-chloro-6-(6-cyclopropyl-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0383] MS (ESI) M / Z: 693.3 [M+H] + .

[0384] Step C: Under nitrogen protection at room temperature, compound (S)-4-chloro-6-(6-cyclopropyl-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (70 mg, 0.10 mmol) was dissolved in dichloromethane (1.0 mL). Subsequently, trifluoroacetic acid (0.5 mL) was added dropwise to the above solution and stirred for 2 hours. Then the temperature was lowered to 0°C, and aqueous ammonia (1.0 mL) was slowly added dropwise to adjust to pH = 8, and the temperature was raised to room temperature and stirred for 2 hours.

[0385] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (15 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography and then purified by chiral separation column to obtain 4.1 mg of 4-chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0386] MS (ESI) M / Z: 563.2 [M+H] + .

[0387] 1H NMR(400MHz,DMSO-d6)δ12.02(s,1H),8.36(s,1H),7.51(d,J=5.6Hz,1H),7.34(s,1H) ,7.31(d,J=1.2Hz,1H),6.38(d,J=2.4Hz,1H),4.20-4.09(m,1H),3.62(s,2H),3.26(s ,3H),3.18(s,3H),3.15-3.07(m,2H),2.87-2.72(m,4H),2.24-2.16(m,1H),1.96-1.8 5(m,1H),1.69-1.54(m,4H),1.53-1.42(m,1H),1.07-0.95(m,4H),0.88-0.76(m,4H).

[0388] Example 16

[0389] 4-Chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0390]

[0391] Reaction route:

[0392]

[0393] Steps:

[0394] Step A: At room temperature, under nitrogen protection, compound 2,6-dichloro-4-((1R,3R)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (62.0 mg, 0.20 mmol) and (S)-4-chloro-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (128.0 mg, 0.24 mmol) were dissolved in 1,4-dioxane (9.0 mL) and water (1.0 mL). Subsequently, sodium carbonate (63.6 mg, 0.6 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (244.5 mg, 0.03 mmol) were added to the above solution, and the reaction system was stirred at 100° C. for 2 hours.

[0395] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (15 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 110 mg of 4-chloro-6-(6-chloro-4-((1R,3S)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl.

[0396] MS (ESI) M / Z: 687.2 [M+H] + .

[0397] Step B: Compound 4-chloro-6-(6-chloro-4-((1R,3S)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl (55.0 mg, 0.08 mmol) and cyclopropylboronic acid (27.5 mg, 0.32 mmol) were dissolved in toluene (0.7 mL) and water (0.07 mL) at room temperature under nitrogen protection. Subsequently, cesium carbonate (52.0 mg, 0.16 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (6.5 mg, 0.008 mmol) were added to the above solution. The reaction system was then stirred at 100° C. for 3 hours.

[0398] After LCMS monitoring showed that the raw material disappeared, water (5 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (5 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 70 mg of 4-chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl.

[0399] MS (ESI) M / Z: 693.2 [M+H] + .

[0400] Step C: Under nitrogen protection at room temperature, compound 4-chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl (22 mg, 0.03 mmol) was dissolved in dichloromethane (0.5 mL). Subsequently, trifluoroacetic acid (0.3 mL) was added dropwise to the above solution and stirred for 2 hours. Then the temperature was lowered to 0°C, aqueous ammonia was added dropwise to adjust the pH to 8, the temperature was raised to room temperature, and stirring was continued for 1 hour.

[0401] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (15 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 5.2 mg of 4-chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0402] MS (ESI) M / Z: 563.2 [M+H] + .

[0403] 1H NMR (400MHz, DMSO-d6) δ12.02(s,1H),8.43(s,1H),7.52(d,J=5.6Hz,1H),7.25(s,1 H),7.17(d,J=1.6Hz,1H),6.39(s,1H),3.92-3.85(m,1H),3.64(s,2H),3.32-3.29( m,2H),3.27(s,3H),3.19(s,3H),2.86-2.71(m,2H),2.60-2.51(m,2H),2.24-2.13( m,1H),2.00-1.85(m,1H),1.71-1.42(m,5H),1.06-0.94(m,4H),0.88-0.77(m,4H).

[0404] Embodiment 17

[0405] 4-Chloro-7-fluoro-6-(3-((1S,3R)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0406]

[0407] Reaction route:

[0408]

[0409] Steps:

[0410] Step A: Under nitrogen protection at -78°C, compound (1R,3R)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-ol (600 mg, 1.95 mmol) was dissolved in dichloromethane (19.5 mL). Subsequently, diethylaminosulfur trifluoride (945 mg, 5.86 mmol) was added dropwise to the above solution. The reaction system was then stirred at 0°C for 2 hours.

[0411] After LCMS monitoring showed that the raw material disappeared, water (30 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (50 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 140 mg of 3-((1S, 3S)-1-(3-bromophenyl)-3-fluorocyclobutyl)-4-methyl-4H-1,2,4-triazole.

[0412] MS (ESI) M / Z: 310.0 [M+H] + .

[0413] Step B: Under nitrogen protection at room temperature, compound 3-((1S,3S)-1-(3-bromophenyl)-3-fluorocyclobutyl)-4-methyl-4H-1,2,4-triazole (60 mg, 0.19 mmol) was dissolved in 1,4-dioxane (1.9 mL) and water (0.2 mL). Subsequently, (S)-4-chloro-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (208 mg, 0.39 mmol), sodium carbonate (62 mg, 0.58 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (24 mg, 0.03 mmol) were added to the above solution in sequence. The reaction system was then stirred at 100° C. for 2 hours.

[0414] After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 80 mg of 4-chloro-7-fluoro-6-(3-((1S,3R)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl.

[0415] MS (ESI) M / Z: 640.2 [M+H] + .

[0416] Step C: At room temperature, the compound 4-chloro-7-fluoro-6-(3-((1S,3R)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl (80 mg, 0.13 mmol) was dissolved in dichloromethane (0.6 mL). Subsequently, trifluoroacetic acid (0.6 mL) was added dropwise to the above solution and stirred for 2 hours. Then, ammonia water (1 mL) was added dropwise at 0°C to adjust the pH to 8, the temperature was raised to room temperature, and stirring was continued for 2 hours.

[0417] After LCMS monitoring showed that the raw material disappeared, water (15 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 6.99 mg of 4-chloro-7-fluoro-6-(3-((1S,3R)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0418] MS (ESI) M / Z: 510.2 [M+H] + .

[0419] 1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),8.34(s,1H),7.53-7.41(m,3H),7.36- 7.26(m,1H),7.14(d,J=5.6Hz,1H),6.39(d,J=2.4Hz,1H),5.45-5.33(m,0.5 H),5.31-5.20(m,0.5H),3.62(s,2H),3.30-3.22(m,5H),3.21-3.05(m,2H), 2.86-2.71(m,2H),1.98-1.83(m,1H),1.69-1.40(m,5H),0.91-0.71(m,4H).

[0420] Embodiment 18

[0421] 4-Chloro-7-fluoro-6-(3-((1R,3S)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0422]

[0423] Reaction route:

[0424]

[0425] Steps:

[0426] Step A: Under nitrogen protection at room temperature, compound (S)-4-chloro-7-fluoro-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (104 mg, 0.2 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.1 mL). Subsequently, 3-((1R,3R)-1-(3-bromophenyl)-3-fluorocyclobutyl)-4-methyl-4H-1,2,4-triazole (30 mg, 0.1 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (12 mg, 0.01 mmol), and sodium carbonate (31 mg, 0.3 mmol) were added to the above solution in sequence. Then the reaction system was stirred at 100°C for 3 hours.

[0427] After LCMS monitoring showed that the raw material disappeared, ice water (15 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 2 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 22 mg of 4-chloro-7-fluoro-6-(3-((1R,3S)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl.

[0428] MS (ESI) M / Z: 640.2 [M+H] + .

[0429] Step B: At room temperature, the compound 4-chloro-7-fluoro-6-(3-((1R,3S)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl (22 mg, 0.03 mmol) was dissolved in dichloromethane (0.3 mL). Subsequently, trifluoroacetic acid (0.3 mL) was added dropwise to the above solution and stirred for 2 hours. Then the temperature was lowered to 0°C, aqueous ammonia was added dropwise to adjust the pH to 8, the temperature was raised to room temperature, and stirring was continued for 2 hours.

[0430] After LCMS monitoring showed that the raw material disappeared, water (15 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 2.82 mg of 4-chloro-7-fluoro-6-(3-((1R,3S)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0431] MS (ESI) M / Z: 510.3 [M+H] + .

[0432] 1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),8.40(s,1H),7.52-7.46(m,2H),7.38(s,1 H),7.24-7.18(m,1H),7.13(d,J=5.6Hz,1H),6.39(s,1H),5.20-5.10(m,0.5H),5 .05-4.96(m,0.5H),3.63(s,2H),3.55-3.43(m,2H),3.24(s,3H),2.96-2.72(m, 4H),1.98-1.86(m,1H),1.70-1.55(m,4H),1.54-1.41(m,1H),0.89-0.75(m,4H).

[0433] Embodiment 19

[0434] 4-(Difluoromethyl)-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0435]

[0436] Reaction route:

[0437]

[0438] Steps:

[0439] Step A: Under nitrogen protection, ethyl 4-bromo-6-chloro-7-fluoro-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate (700 mg, 1.56 mmol), 3-oxobenzo[d]isothiazole-2(3H)-carbaldehyde 1,1-dioxide (822 mg, 3.90 mmol), 1,4-(bis(diphenylphosphino)butane) (133 mg, 0.31 mmol), palladium acetate (71 mg, 0.31 mmol), sodium carbonate (496 mg, 4.68 mmol) and triethylsilane (362 mg, 3.12 mmol) were dissolved in N,N-dimethylformamide (7.8 mL) at room temperature. The reaction system was then stirred at 75°C for 3 hours.

[0440] After LCMS monitoring showed that the raw material disappeared, water (30 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 2 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 80 mg of 6-chloro-7-fluoro-4-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid ethyl ester.

[0441] Step B: Under nitrogen protection at 0°C, compound 6-chloro-7-fluoro-4-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid ethyl ester (80 mg, 0.2 mmol) was dissolved in dichloromethane (1 mL), and then diethylaminosulfur trifluoride (97 mg, 0.6 mmol) was slowly added dropwise to the above solution. The reaction system was then stirred at room temperature for 12 hours.

[0442] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (5 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 55 mg of 6-chloro-4-(difluoromethyl)-7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid ethyl ester.

[0443] Step C: At 0°C, under nitrogen protection, compound 6-chloro-4-(difluoromethyl)-7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid ethyl ester (55 mg, 0.13 mmol), 4-methyl-3-(1S,3S)-3-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl )-4H-12,4-triazole (69 mg, 0.20 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (15 mg, 0.02 mmol) and cesium carbonate (85 mg, 0.26 mmol) were dissolved in 1,4-dioxane / water (0.86 / 0.09 mL). The reaction system was then stirred at 90°C for 2 hours.

[0444] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (5 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 80 mg of 4-(difluoromethyl)-7-fluoro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid ethyl ester.

[0445] MS (ESI) M / Z: 613.2 [M+H] + .

[0446] Step D: At 0°C, the compound 4-(difluoromethyl)-7-fluoro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid ethyl ester (80 mg, 0.13 mmol) was dissolved in tetrahydrofuran (1 mL). Subsequently, a 2.5 M solution of lithium aluminum hydride in tetrahydrofuran (0.1 mL) was slowly added dropwise to the above solution. The reaction system was then stirred for 1 hour.

[0447] After LCMS monitoring showed that the raw material disappeared, the reaction solution was added dropwise to ice water (5 mL) to quench. The mixed solution was extracted with dichloromethane (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 40 mg (4-(difluoromethyl)-7-fluoro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol.

[0448] MS (ESI) M / Z: 571.2 [M+H] + .

[0449] Step E: Compound (4-(difluoromethyl)-7-fluoro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol (40 mg, 0.07 mmol) was dissolved in dichloromethane (0.35 mL) at room temperature. Subsequently, thionyl chloride (17 mg, 0.14 mmol) was added dropwise to the solution. The reaction system was then stirred for 2 hours.

[0450] After LCMS monitoring showed that the starting material disappeared, the reaction solution was added dropwise to ice water (10 mL) to quench. The mixed solution was extracted with dichloromethane (5 mL × 2 times), the organic phases were combined, then washed with saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 50 mg of 2-(chloromethyl)-4-(difluoromethyl)-7-fluoro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole.

[0451] MS (ESI) M / Z: 589.2 [M+H] + .

[0452] Step F: Dissolve 2-(chloromethyl)-4-(difluoromethyl)-7-fluoro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (50 mg, 0.09 mmol) in acetonitrile (0.9 mL) at room temperature. Then, potassium carbonate (25 mg, 0.18 mmol) and potassium iodide (30 mg, 0.18 mmol) were added to the solution in sequence and stirred for 5 minutes. Then, (S)-3-methylpiperidine hydrochloride (15 mg, 0.11 mmol) was added and stirring was continued for 3 hours.

[0453] After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (15 mL×2 times), the filtrate was collected and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 32 mg of 4-(difluoromethyl)-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl.

[0454] MS (ESI) M / Z: 652.3 [M+H] + .

[0455] Step G: At room temperature, compound 4-(difluoromethyl)-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl (32 mg, 0.05 mmol) was dissolved in dichloromethane (1 mL). Subsequently, trifluoroacetic acid (1 mL) was added dropwise to the above solution and stirred for 2 hours. After LCMS monitoring showed that the starting material disappeared, aqueous ammonia was added to the reaction solution to adjust the pH to 8, and stirring was continued for 16 hours.

[0456] After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (15 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 0.74 mg of 4-(difluoromethyl)-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0457] MS (ESI) M / Z: 522.2 [M+H] + .

[0458] 1 H NMR(400MHz,DMSO)δ11.93(s,1H),8.29(s,1H),7.54-7.44(m,3H),7.39-7.33(m ,1H),7.29(d,J=6.0Hz,1H),7.23-7.09(m,1H),6.52(s,1H),3.63(s,2H),3.21(s ,3H),2.94-2.85(m,2H),2.84-2.73(m,2H),2.63-2.55(m,3H),1.96-1.86(m,1H) ,1.70-1.54(m,4H),1.53-1.41(m,1H),1.09(d,J=5.6Hz,3H),0.87-0.76(m,4H).

[0459] Embodiment 20

[0460] 7-Fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0461]

[0462] Reaction route:

[0463]

[0464] Steps:

[0465] Step A: At room temperature, under nitrogen protection, compound 6-chloro-7-fluoro-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid ethyl ester (265 mg, 0.71 mmol), 4-methyl-3-(1S,3S)-3-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4H -1,2,4-triazole (378 mg, 1.07 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (84 mg, 0.11 mmol) and cesium carbonate (463 mg, 1.42 mmol) were dissolved in 1,4-dioxane / water (4.7 / 0.5 mL). The reaction system was then stirred at 90 ° C for 2 hours.

[0466] After LCMS monitoring showed that the raw material disappeared, water (30 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (15 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 480 mg of 7-fluoro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid ethyl ester.

[0467] MS (ESI) M / Z: 563.2 [M+H] + .

[0468] Step B: Dissolve the compound 7-fluoro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid ethyl ester (480 mg, 0.85 mmol) in tetrahydrofuran (7 mL) at 0°C. Then, slowly add 3M lithium aluminum hydride tetrahydrofuran solution (0.68 mL) to the above solution. Then, stir the reaction system at room temperature for 1 hour.

[0469] After LCMS monitoring showed that the starting material disappeared, the reaction solution was added dropwise to ice water (50 mL) to quench, and the mixed solution was extracted with dichloromethane (50 mL × 2 times), and the organic phases were combined. Then, the mixture was washed with saturated sodium bicarbonate aqueous solution (80 mL × 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 400 mg of (7-fluoro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol.

[0470] MS (ESI) M / Z: 521.2 [M+H] + .

[0471] Step C: Compound (7-fluoro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol (400 mg, 0.77 mmol) was dissolved in dichloromethane (4 mL) at room temperature. Subsequently, thionyl chloride (0.11 mL) was added dropwise to the solution. The reaction system was then stirred for 2 hours.

[0472] After LCMS monitoring showed that the starting material disappeared, the reaction solution was added dropwise to ice water (20 mL) to quench, and the mixed solution was extracted with dichloromethane (20 mL × 2 times), and the organic phases were combined. Then it was washed with saturated sodium bicarbonate aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 63 mg of 2-(chloromethyl)-7-fluoro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole.

[0473] MS (ESI) M / Z: 539.2 [M+H] + .

[0474] Step D: Dissolve 2-(chloromethyl)-7-fluoro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (63 mg, 0.12 mmol) in acetonitrile (0.6 mL) at room temperature. Then, potassium carbonate (33 mg, 0.24 mmol) and potassium iodide (40 mg, 0.24 mmol) were added to the solution in sequence and stirred for 5 minutes. Then, (S)-3-methylpiperidine hydrochloride (17 mg, 0.13 mmol) was added and stirring was continued for 3 hours.

[0475] After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (15 mL×2 times), the filtrate was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 20 mg of 7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl.

[0476] MS (ESI) M / Z: 602.3 [M+H] + .

[0477] Step E: Compound 7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl (20 mg, 0.04 mmol) was dissolved in dichloromethane (1 mL) at room temperature. Subsequently, trifluoroacetic acid (1 mL) was added dropwise to the above solution and stirring was continued for 2 hours. After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added to the reaction solution until pH = 8 and stirring was continued for 16 hours.

[0478] After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution for dilution, and the mixed solution was extracted with dichloromethane (15 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 1.05 mg of 7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0479] MS (ESI) M / Z: 472.4 [M+H]+ .

[0480] 1 H NMR (400 MHz, DMSO) δ 11.54 (s, 1H), 8.29 (s, 1H), 7.51-7.42 (m, 3H), 7.38-7.30 (m, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.36 (s, 1H), 3.63-3.55 (m, 2H), 3.21 (s, 3H), 2.92-2.84 (m, 2H), 2.84-2.73 (m, 2H), 2.61-2.54 (m, 3H), 1.94-1.83 (m, 1H), 1.69-1.54 (m, 4H), 1.52-1.41 (m, 1H), 1.09 (d, J = 5.6 Hz, 3H), 0.88-0.75 (m, 4H). Example 21

[0481] 7-Fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole-4-carbonitrile

[0482]

[0483] Reaction route:

[0484]

[0485] Steps:

[0486] Step A: Under nitrogen protection at room temperature, compound 4-bromo-7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole (40 mg, 0.06 mmol) was dissolved in N-methylpyrrolidone (0.6 mL). Subsequently, cuprous cyanide (16 mg, 0.18 mmol) was added to the above solution. The reaction system was then stirred at 170°C for 2 hours.

[0487] After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into a mixed solution of ice water (30 mL) and ethyl acetate (10 mL) to quench. The mixed solution was extracted with ethyl acetate (15 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 10 mg (7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole-4-carbonitrile.

[0488] MS (ESI) M / Z: 627.3 [M+H] + .

[0489] Step B: Compound (7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole-4-carbonitrile (10 mg, 0.02 mmol) was dissolved in dichloromethane (0.2 mL) at room temperature. Subsequently, trifluoroacetic acid (0.2 mL) was added dropwise to the above solution and stirred for 2 hours. After LCMS monitoring showed that the starting material disappeared, aqueous ammonia was added to the reaction solution to adjust the pH to 8 and stirring was continued for 2 hours.

[0490] After LCMS monitoring showed that the intermediate disappeared, water (20 mL) was added to the reaction solution, and the mixed solution was extracted with dichloromethane (10 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 1.71 mg of 7-fluoro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole-4-carbonitrile.

[0491] MS (ESI) M / Z: 497.3 [M+H] + .

[0492] 1H NMR (400MHz, DMSO-d6) δ12.29(s,1H),8.28(s,1H),7.69(d,J=6.0Hz,1H),7.57(s, 1H),7.53-7.45(m,2H),7.35-7.29(m,1H),6.52(d,J=3.2Hz,1H),3.67(s,2H),3.2 1(s,3H),2.96-2.85(m,2H),2.84-2.73(m,2H),2.62-2.53(m,3H),1.99-1.87(m,1 H),1.72-1.55(m,4H),1.54-1.43(m,1H),1.08(d,J=5.6Hz,3H),0.91-0.75(m,4H).

[0493] Embodiment 22

[0494] N-((4-chloro-7-fluoro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1H-indol-2-yl)methyl)-1-methylcyclobutane-1-amine

[0495]

[0496] Reaction route:

[0497]

[0498] Steps:

[0499] Step A: At room temperature, the compound 1-methylcyclobutane-1-amine hydrochloride (115 mg, 0.94 mmol) was dissolved in acetonitrile (2.5 mL). Subsequently, potassium iodide (117 mg, 0.71 mmol), potassium carbonate (195 mg, 1.41 mmol) and the compound 6-bromo-4-chloro-2-(chloromethyl)-7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (200 mg, 0.47 mmol) were added to the above solution in sequence. The reaction system was then stirred at room temperature for 18 hours.

[0500] After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 150 mg of N-((6-bromo-4-chloro-7-fluoro-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl-1-methylcyclobutane-1-amine.

[0501] MS (ESI) M / Z: 475.0 [M+H] + .

[0502] Step B: Under nitrogen protection at room temperature, compound N-((6-bromo-4-chloro-7-fluoro-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl-1-methylcyclobutane-1-amine (70 mg, 0.15 mmol), 4-methyl-3-((1S,3S)-3-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4H-12,4-triazole (63 mg, 0.18 mmol), sodium carbonate (47 mg, 0.45 mmol) and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (18 mg, 0.02 mmol) were dissolved in 1,4-dioxane (1.4 mL) and water (0.17 mL). The reaction system was then stirred at 95° C. for 6 hours.

[0503] After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 80 mg of N-((4-chloro-7-fluoro-6-(3-((1s, 3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl ester)-1-methylcyclobutane-1-amine.

[0504] MS (ESI) M / Z: 622.3 [M+H] + .

[0505] Step C: Compound N-((4-chloro-7-fluoro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl ester)-1-methylcyclobutane-1-amine (80 mg, 0.13 mmol) was dissolved in dichloromethane (0.6 mL) at room temperature. Subsequently, trifluoroacetic acid (0.6 mL) was added dropwise to the above solution. The reaction system was then stirred at room temperature for 2 hours.

[0506] After LCMS monitoring showed that the raw material disappeared, ammonia water was added to the reaction solution to adjust the pH to 8, the mixed solution was extracted with dichloromethane (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 19 mg of N-((4-chloro-7-fluoro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1H-indol-2-yl)methyl)-1-methylcyclobutane-1-amine.

[0507] MS (ESI) M / Z: 492.3 [M+H] + .

[0508] 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),8.29(s,1H),7.53-7.44(m,3H),7.38-7.31(m,1H),7.09(d,J=5.6Hz,1H),6.43(d,J=3.2Hz,1H),3 .79(s,2H),3.21(s,3H),2.96-2.83(m,2H),2.63-2.54(m,4H),2.03-1.88(m,2H),1.76-1.60(m,4H),1.25(s,3H),1.09(d,J=5.2Hz,3H).

[0509] Embodiment 23

[0510] 7-Fluoro-6-(3-((1R,3S)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole-4-carbonitrile

[0511]

[0512] Reaction route:

[0513]

[0514] Steps:

[0515] Step A: Under nitrogen protection at room temperature, the compound 4-bromo-6-chloro-7-fluoro-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid ethyl ester (185.0 mg, 0.41 mmol) was dissolved in N-methylpyrrolidone (2.0 mL). Subsequently, cuprous cyanide (110.6 mg, 1.23 mmol) was added to the above solution. The reaction system was then stirred at 180°C for 5 hours.

[0516] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (3 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 55.0 mg of 6-chloro-4-cyano-7-fluoro-1H-indole-2-carboxylic acid ethyl ester.

[0517] 1 H NMR (400MHz, DMSO-d6) δ13.41(s,1H),8.01(d,J=6.0Hz,1H),7.26(t,J=2.4Hz,1H),4.39(q,J=7.2Hz,2H),1.37(t,J=7.2Hz,3H).

[0518] Step B: Under nitrogen protection at 0°C, compound 6-chloro-4-cyano-7-fluoro-1H-indole-2-carboxylic acid ethyl ester (55.0 mg, 0.21 mmol) was dissolved in anhydrous tetrahydrofuran (1.7 mL). Subsequently, 2.5 M lithium aluminum hydride tetrahydrofuran solution (0.13 mL) was slowly added dropwise to the above solution. The reaction system was then stirred at 0°C for 0.5 hours.

[0519] After LCMS monitoring showed that the raw material disappeared, ice water (5 mL) was slowly added dropwise to the reaction solution to quench, the mixed solution was filtered and extracted with dichloromethane (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (5 mL × 2 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 35.0 mg of 6-chloro-7-fluoro-2-(hydroxymethyl)-1H-indole-4-carbonitrile.

[0520] 1 H NMR (400MHz, DMSO-d6) δ12.46(s,1H),7.79(d,J=6.0Hz,1H),6.56(d,J=3.6Hz,1H),5.50(t,J=5.8,Hz,1H),4.66(d,J=5.2Hz,2H).

[0521] Step C: Under nitrogen protection at 0°C, compound 6-chloro-7-fluoro-2-(hydroxymethyl)-1H-indole-4-carbonitrile (35 mg, 0.15 mmol) was dissolved in dichloromethane (1.5 mL). Subsequently, thionyl chloride (53.1 mg, 0.45 mmol) was added dropwise to the above solution. The reaction system was then stirred at room temperature for 1 hour.

[0522] After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure to obtain 37.0 mg of crude 6-chloro-2-(chloromethyl)-7-fluoro-1H-indole-4-carbonitrile.

[0523] Step D: Compound (S)-3-methylpiperidine hydrochloride (30.0 mg, 0.29 mmol) was dissolved in acetonitrile (1.0 mL) at room temperature. Potassium carbonate (84.0 mg, 0.60 mmol), 6-chloro-2-(chloromethyl)-7-fluoro-1H-indole-4-carbonitrile (37.0 mg, 0.19 mmol) and potassium iodide (50.0 mg, 0.30 mmol) were then added to the solution in sequence. The reaction system was then stirred for 6 hours.

[0524] After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (5 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 25.0 mg (S)-6-chloro-7-fluoro-2-(3-methylpiperidin-1-yl)methyl)-1H-indole-4-carbonitrile.

[0525] MS (ESI) M / Z: 306.1 [M+H] +.

[0526] Step E: At room temperature, under nitrogen protection, compound (S)-6-chloro-7-fluoro-2-(3-methylpiperidin-1-yl)methyl)-1H-indole-4-carbonitrile (22.0 mg, 0.07 mmol) and 3-((1R,3R)-3-fluoro-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4-methyl-4H-1,2,4-triazole (36.0 mg, 0.10 mmol) were dissolved in 1,4-dioxane (0.7 mL) and water (0.07 mL). Subsequently, cesium carbonate (45.0 mg, 0.14 mmol) and chloro[(4,5-bis(diphenylphosphine)-9,9-dimethylxanthene)-2-(2-aminobiphenyl)]palladium (8.0 mg, 0.01 mmol) were added to the above solution in sequence, and the reaction system was stirred at 90° C. for 6 hours.

[0527] After LCMS monitoring showed that the starting material disappeared, water (5 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (5 mL × 3 times), and the organic phases were combined and washed with saturated brine (5 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 3.4 mg of 7-fluoro-6-(3-((1R,3S)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole-4-carbonitrile.

[0528] MS (ESI) M / Z: 501.3 [M+H] + .

[0529] 1 H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.40 (s, 1H), 7.72 (d, J = 6.0 Hz, 1H), 7.56-7.44 (m, 3H), 7.24-7.17 (m, 1H), 6.53 (s, 1H), 5.20-5.10 (m, 0.5H), 5.06-4.97 (m, 0.5H), 3.68 (s, 2H), 3.54-3.43 (m, 2H), 3.25 (s, 3H), 2.95-2.71 (m, 4H), 2.02-1.86 (m, 1H), 1.72-1.56 (m, 4H), 1.56-1.41 (m, 1H), 0.92-0.75 (m, 4H). Example 24

[0530] 6-(3-((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl ester)-1H-indole

[0531]

[0532] Reaction route:

[0533]

[0534] Steps:

[0535] Step A: Under nitrogen protection at -10°C, 5.0M sodium methoxide methanol solution (80.0mL) was dissolved in anhydrous methanol (200.0mL). Subsequently, a methanol (100.0mL) solution of compound 4-bromo-5-fluoro-2-methylbenzaldehyde (21.6g, 100.0mmol) and methyl 2-azidoacetate (46.0g, 500.0mmol) was added to the above solution. The reaction system was then stirred at room temperature for 16 hours.

[0536] After LCMS monitoring showed that the raw material disappeared, the reaction solution was filtered and concentrated, diluted with water (100 mL), and the mixed solution was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined and washed with saturated brine (100 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 4.9 g of methyl 2-azido-3-(4-bromo-5-fluoro-2-methylphenyl)acrylate.

[0537] Step B: Under nitrogen protection at room temperature, methyl 2-azido-3-(4-bromo-5-fluoro-2-methylphenyl)acrylate (4.9 g, 15.7 mmol) was dissolved in xylene (58.3 mL), and the reaction system was stirred at 170° C. for 4 hours.

[0538] After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated and filtered, and the obtained solid was purified by silica gel column chromatography to obtain 3.5 g of methyl 6-bromo-7-fluoro-4-methyl-1H-indole-2-carboxylate.

[0539] 1H NMR (400MHz, DMSO-d6) δ12.63 (s, 1H), 7.31-7.26 (m, 1H), 7.08 (d, J = 5.6Hz, 1H), 3.89 (s, 3H), 2.46 (s, 3H).

[0540] Step C: Under nitrogen protection at 0°C, dissolve the compound 6-bromo-7-fluoro-4-methyl-1H-indole-2-carboxylic acid methyl ester (3.5 g, 12.3 mmol) in N,N-dimethylformamide (61.0 mL). Then, add 60% wt sodium hydride (639.6 mg, 16.0 mmol) to the above solution and stir for 0.5 hours. Then cool the above solution to 0°C, slowly add 2-(trimethylsilyl)ethoxymethyl chloride (2.53 g, 14.8 mmol) and continue stirring for 1 hour.

[0541] After LCMS monitoring showed that the raw material disappeared, ice water (180.0 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (45 mL × 3 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 4.5 g of 6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid methyl ester.

[0542] MS (ESI) M / Z: 438.0 [M+Na] + .

[0543] Step D: Dissolve 6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid methyl ester (4.9 g, 11.8 mmol) in tetrahydrofuran (80.0 mL) and water (40.0 mL) at 0°C. Then, lithium hydroxide monohydrate (1.52 g, 35.4 mmol) was added to the solution. The reaction system was then stirred at room temperature for 16 hours.

[0544] After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated and adjusted to pH = 4 with 2M dilute hydrochloric acid. The mixed solution was extracted with dichloromethane (50 mL × 3 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.9 g of 6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid.

[0545] MS (ESI) M / Z: 424.0 [M+Na] + .

[0546] Step E: Under nitrogen protection at 0°C, compound 6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylic acid (3.9 g, 10.1 mmol) was dissolved in anhydrous tetrahydrofuran (50.0 mL). Subsequently, 1.0 M borane tetrahydrofuran complex solution (30.0 mL) was added dropwise to the above solution. The reaction system was then stirred at 50°C for 2 hours.

[0547] After LCMS monitoring showed that the raw material disappeared, methanol (20.0 mL) and water (40.0 mL) were added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (45 mL × 3 times), and the organic phases were combined and washed with saturated brine (40 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 3.2 g of 6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol.

[0548] MS (ESI) M / Z: 410.0 [M+Na] + .

[0549] Step F: Under nitrogen protection at 0°C, compound 6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol (3.2 g, 8.3 mmol) was dissolved in anhydrous dichloromethane (41.0 mL). Subsequently, triphenylphosphine (4.3 g, 16.6 mmol) and carbon tetrabromide (5.5 g, 16.6 mmol) were added to the above solution in sequence. The reaction system was then stirred at room temperature for 4 hours.

[0550] After LCMS monitoring showed that the raw material disappeared, the reaction solution was filtered and ice water (30 mL) was added to the filtrate to quench. The mixed solution was extracted with dichloromethane (50 mL × 3 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.1 g of 6-bromo-2-(bromomethyl)-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole.

[0551] Step G: Compound 6-bromo-2-(bromomethyl)-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (1.1 g, 2.45 mmol) and (S)-3-methylpiperidine hydrochloride (400.0 mg, 2.94 mmol) were dissolved in acetonitrile (12.0 mL) at 0°C. Potassium carbonate (1.0 g, 7.35 mmol) and potassium iodide (614.2 mg, 3.7 mmol) were then added to the solution. The reaction system was then stirred at room temperature for 16 hours.

[0552] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.0 g of (S)-6-bromo-7-fluoro-4-methyl-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0553] MS (ESI) M / Z: 469.2 [M+H] + .

[0554] Step H: Under nitrogen protection at 0°C, compound (S)-6-bromo-7-fluoro-4-methyl-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (300.0 mg, 0.64 mmol) and biboronic acid pinacol ester (487.7 mg, 1.92 mmol) were dissolved in 1,4-dioxane (3.0 mL) and water (0.3 mL). Subsequently, potassium acetate (188.3 mg, 1.92 mmol) and 1,1-bis(diphenylphosphine)diphenylferric palladium dichloride dichloromethane complex (49.0 mg, 0.06 mmol) were added to the above solution in sequence. The reaction system was then stirred at 95°C for 16 hours.

[0555] After LCMS monitoring showed that the raw material disappeared, water (5 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (5 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 250.0 mg of (S)-7-fluoro-4-methyl-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0556] MS (ESI) M / Z: 517.4 [M+H] + .

[0557] Step I: At 0°C under nitrogen protection, compound (S)-7-fluoro-4-methyl-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (51.0 mg, 0.10 mmol) and (R)-3-((3-bromophenyl)(cyclobutyl)methyl)-4-methyl-4H-1,2,4-triazole (25.0 mg, 0.08 mmol) were dissolved in 1,4-dioxane (1.0 mL) and water (0.1 mL). Subsequently, sodium carbonate (16.0 mg, 0.15 mmol) and 1,1-bis(diphenylphosphine)dichloropalladium iron dichloromethane complex (8.0 mg, 0.01 mmol) were added to the above solution in sequence, and the reaction system was stirred at 100° C. for 2.5 hours.

[0558] After LCMS monitoring showed that the raw material disappeared, water (5 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (5 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 40.0 mg of 6-(3-((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl.

[0559] MS (ESI) M / Z: 616.4 [M+H] + .

[0560] Step J: Compound 6-(3-((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl (40.0 mg, 0.06 mmol) was dissolved in dichloromethane (1.0 mL) at 0°C. Trifluoroacetic acid (0.5 mL) was then added dropwise to the solution. The reaction system was then stirred at room temperature for 3 hours.

[0561] After LCMS monitoring showed that the starting material disappeared, aqueous ammonia was added dropwise to the reaction solution to adjust the pH to 8, and then the reaction system was stirred at 50°C for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 3.5 mg of 6-(3-((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl ester)-1H-indole.

[0562] MS (ESI) M / Z: 486.4 [M+H] + .

[0563] 1 H NMR (400MHz, DMSO-d6) δ11.49(s,1H),8.32(s,1H),7.47-7.35(m,3H),7.18(d,J= 7.2Hz,1H),6.79(d,J=6.4Hz,1H),6.36(s,1H),4.25(d,J=10.4Hz,1H),3.60(s,2H ),3.42(s,3H),3.23-3.17(m,1H),2.87-2.75(m,1H),2.44(s,3H),2.14-2.06(m, 1H),2.03-1.95(m,2H),1.88-1.76(m,4H),1.72-1.41(m,6H),0.89-0.78(m,4H)).

[0564] Embodiment 25

[0565] 6-(6-ethoxy-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole

[0566]

[0567] Reaction route:

[0568]

[0569] Steps:

[0570] Step A: Dissolve the compound 2,6-dichloro-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (80 mg, 0.27 mmol) in ethanol (2.7 mL) at room temperature. Then, add sodium ethoxide (184 mg, 2.70 mmol) to the above solution, heat to 140°C, and stir for 24 hours. Then cool to room temperature, add sodium ethoxide (184 mg, 2.70 mmol), heat to 140°C, and continue stirring for 24 hours.

[0571] After LCMS monitoring showed that the starting material disappeared, water (15 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (5 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50.0 mg of 2-chloro-6-ethoxy-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine.

[0572] MS (ESI) M / Z: 307.2 [M+H] + .

[0573] Step B: At 0°C under nitrogen protection, compound (S)-7-fluoro-4-methyl-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (51.0 mg, 0.10 mmol) and 2-chloro-6-ethoxy-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (25.0 mg, 0.08 mmol) were dissolved in 1,4-dioxane (1.0 mL). Subsequently, cesium carbonate (48.8 mg, 0.15 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (15.7 mg, 0.02 mmol) were added to the above solution in sequence, and the reaction system was stirred at 100° C. for 2 hours.

[0574] After LCMS monitoring showed that the starting material disappeared, water (5 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (5 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 20.0 mg of 6-(6-ethoxy-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl.

[0575] MS (ESI) M / Z: 331.2 [M / 2+H] + .

[0576] Step C: Compound 6-(6-ethoxy-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl (18.0 mg, 0.03 mmol) was dissolved in dichloromethane (0.5 mL) at 0°C. Trifluoroacetic acid (0.2 mL) was then added dropwise to the solution. The reaction system was then stirred at room temperature for 3 hours.

[0577] After LCMS monitoring showed that the starting material disappeared, aqueous ammonia was added dropwise to the reaction solution to adjust the pH to 8. The reaction system was then stirred at 50°C for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 2.4 mg of 6-(6-ethoxy-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0578] MS (ESI) M / Z: 531.4 [M+H] + .

[0579] 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),8.33(s,1H),7.31(d,J=6.4Hz,1H),7.15(s,1H) ,6.74(d,J=1.2Hz,1H),6.38(s,1H),4.41(q,J=6.8Hz,2H),3.65(s,2H),3.23(s,3H), 2.91-2.77(m,4H),2.64-2.53(m,3H),2.44(s,3H),1.99-1.88(m,1H),1.74-1.55(m,4 H),1.53-1.42(m,1H),1.37(t,J=7.0Hz,3H),1.08(d,J=6.0Hz,3H),0.89-0.77(m,4H).

[0580] Embodiment 26

[0581] N-(3-(7-Fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)methanesulfonamide

[0582]

[0583] Reaction route:

[0584]

[0585] Steps:

[0586] Step A: Under nitrogen protection at room temperature, compound 3-(1-(3-bromo-5-iodophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (300 mg, 0.70 mmol) was dissolved in 1,4-dioxane (3.5 mL). Subsequently, tert-butyl carbamate (107 mg, 0.91 mmol), tris(dibenzylideneacetone)palladium (64 mg, 0.07 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (40 mg, 0.07 mmol) and cesium carbonate (460 mg, 1.40 mmol) were added to the above solution in sequence. The reaction system was then stirred at 90°C for 3 hours.

[0587] After LCMS monitoring showed that the raw material disappeared, ice water (40 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (30 mL × 2 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 228 mg of tert-butyl (3-bromo-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamate.

[0588] MS (ESI) M / Z: 421.3 [M+H] + .

[0589] Step B: Under nitrogen protection at 0°C, dissolve the compound tert-butyl (3-bromo-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamate (160 mg, 0.38 mmol) in N,N-dimethylformamide (1.9 mL). Then, add 60% wt sodium hydride (30 mg, 0.76 mmol) to the above solution and stir for 0.5 hour. Then, add methylsulfonyl chloride (65 mg, 0.57 mmol) dropwise, warm to room temperature, and continue stirring for 0.5 hour.

[0590] After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (16 mL × 2 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 120 mg of tert-butyl (3-bromo-5-((1S, 3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)(methylsulfonyl)carbamate.

[0591] 1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.56(s,1H),7.29(s,1H),7.10(s,1H),3.38(s,3H) ,3.20(s,3H),2.87-2.76(m,2H),2.73-2.56(m,3H),1.46(s,9H),1.14(d,J=5.6Hz,3H).

[0592] Step C: At 0°C under nitrogen protection, compound (S)-7-fluoro-4-methyl-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (51.0 mg, 0.10 mmol) and tert-butyl (3-bromo-5-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)(methylsulfonyl)carbamate (39.0 mg, 0.08 mmol) were dissolved in 1,4-dioxane (1.0 mL) and water (0.1 mL). Subsequently, sodium carbonate (16.0 mg, 0.15 mmol) and 1,1-bis(diphenylphosphine)dichloropalladium iron dichloromethane complex (8.0 mg, 0.01 mmol) were added to the above solution in sequence, and the reaction system was stirred at 100° C. for 2.5 hours.

[0593] After LCMS monitoring showed that the starting material disappeared, water (5 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (5 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 38.0 mg of tert-butyl (3-(7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indol-6-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)(methylsulfonyl)carbamate.

[0594] MS (ESI) M / Z: 405.3 [M / 2+H] + .

[0595] Step D: At 0°C, the compound tert-butyl (3-(7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-6-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)(methylsulfonyl)carbamate (38.0 mg, 0.05 mmol) was dissolved in dichloromethane (1.0 mL). Subsequently, trifluoroacetic acid (0.5 mL) was added dropwise to the above solution. The reaction system was then stirred at room temperature for 3 hours.

[0596] After LCMS monitoring showed that the starting material disappeared, aqueous ammonia was added dropwise to the reaction solution to adjust the pH to 8, and then the reaction system was stirred at 50°C for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 2.9 mg of N-(3-(7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)methanesulfonamide.

[0597] MS (ESI) M / Z: 579.4 [M+H] + .

[0598] 1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),9.81(s,1H),8.31(s,1H),7.31(s,1H),7.21 (s,1H),7.15(s,1H),6.78(d,J=6.4Hz,1H),6.37(s,1H),3.60(s,2H),3.23(s,3H) ,3.01(s,3H),2.90-2.75(m,4H),2.64-2.55(m,3H),2.44(s,3H),1.96-1.84(m,1H ),1.68-1.54(m,4H),1.53-1.41(m,1H),1.09(d,J=4.8Hz,3H),0.88-0.77(m,4H).

[0599] Embodiment 27

[0600] 2-((1R,3S)-3-(3-(7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile

[0601]

[0602] Reaction route:

[0603]

[0604] Steps:

[0605] Step A: At 0°C under nitrogen protection, compound (S)-7-fluoro-4-methyl-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (51.0 mg, 0.10 mmol) and 2-((1S,3S)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (26.4 mg, 0.08 mmol) were dissolved in 1,4-dioxane (1.0 mL) and water (0.1 mL). Subsequently, sodium carbonate (16.0 mg, 0.15 mmol) and 1,1-bis(diphenylphosphine)dichloropalladium iron dichloromethane complex (8.0 mg, 0.01 mmol) were added to the above solution in sequence, and the reaction system was stirred at 100° C. for 2.5 hours.

[0606] After LCMS monitoring showed that the starting material disappeared, water (5 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (5 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 35.0 mg of 2-((1R,3S)-3-(3-(7-fluoro-4-methyl-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl-1H-indol-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile.

[0607] MS (ESI) M / Z: 641.3 [M+H] + .

[0608] Step B: Compound 2-((1R,3S)-3-(3-(7-fluoro-4-methyl-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl-1H-indol-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (35.0 mg, 0.05 mmol) was dissolved in dichloromethane (1.0 mL) at 0°C. Subsequently, trifluoroacetic acid (0.5 mL) was added dropwise to the solution. The reaction system was then stirred at room temperature for 3 hours.

[0609] After LCMS monitoring showed that the starting material disappeared, aqueous ammonia was added dropwise to the reaction solution to adjust the pH to 8, and then the reaction system was stirred at 50°C for 12 hours. After the reaction was complete, it was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 3.5 mg of 2-((1R,3S)-3-(3-(7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile.

[0610] MS (ESI) M / Z: 511.4 [M+H] + .

[0611] 1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),8.31(s,1H),7.52-7.44(m,3H),7.3 6-7.34(m,1H),6.81(d,J=6.0Hz,1H),6.36(s,1H),3.60(s,2H),3.23(s,3H ),2.97-2.87(m,2H),2.86-2.73(m,5H),2.72-2.66(m,2H),2.44(s,3H),1. 95-1.85(m,1H),1.70-1.54(m,4H),1.53-1.41(m,1H),0.89-0.76(m,4H)..

[0612] Embodiment 28

[0613] N-(6-(7-Fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)-4-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)methanesulfonamide

[0614]

[0615] Reaction route:

[0616]

[0617] Steps:

[0618] Step A: Under nitrogen protection at room temperature, compound 2,6-dichloro-4-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)oxazol-3-yl)cyclobutyl)pyridine (50 mg, 0.17 mmol) was dissolved in 1,4-dioxane (2.0 mL) and N,N-dimethylformamide (0.1 mL). Subsequently, methanesulfonamide (24 mg, 0.25 mmol), cesium carbonate (165 mg, 0.51 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg, 0.02 mmol) and palladium acetate (5 mg, 0.02 mmol) were added to the above solution in sequence. The reaction system was then stirred at 140 ° C in a microwave for 1 hour.

[0619] After LCMS monitoring showed that the raw material disappeared, water (5 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (5 mL × 3 times), and the organic phases were combined and washed with saturated brine (5 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 25 mg of N-(6-chloro-4-((1s, 3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)methanesulfonamide.

[0620] MS (ESI) M / Z: 356.2 [M+H] + .

[0621] Step B: At room temperature, under nitrogen protection, compound N-(6-chloro-4-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)methanesulfonamide (25 mg, 0.07 mmol) was dissolved in 1,4-dioxane (1.0 mL) and water (0.1 mL). Subsequently, (S)-7-fluoro-4-methyl-2-((3-methylpiperidin-1-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (36 mg, 0.07 mmol), potassium carbonate (28 mg, 0.21 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (8 mg, 0.01 mmol) were added to the above solution in sequence. The reaction system was then stirred at 90° C. for 5 hours.

[0622] After LCMS monitoring showed that the starting material disappeared, water (5 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (5 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (5 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 15 mg of N-(6-(7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-6-yl)-4-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)methanesulfonamide.

[0623] MS (ESI) M / Z: 710.3 [M+H] + .

[0624] Step C: At room temperature, compound N-(6-(7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-6-yl)-4-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)methanesulfonamide (15 mg, 0.02 mmol) was dissolved in dichloromethane (2.5 mL). Subsequently, trifluoroacetic acid (0.25 mL) was added dropwise to the above solution and stirred for 3 hours. Then the temperature was lowered to 0°C, ammonia water was added dropwise to adjust the pH to 8, the temperature was raised to 50°C, and stirring was continued for 16 hours.

[0625] After LCMS monitoring showed that the raw material disappeared, water (3 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (5 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (3 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 3 mg of N-(6-(7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)-4-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)methanesulfonamide.

[0626] MS (ESI) M / Z: 580.2 [M+H] + .

[0627] 1 H NMR(400MHz,DMSO-d6)δ11.59(s,1H),10.66–10.32(m,1H),8.36(s,1H),7.33(s,1H), 7.26(d,J=6.3Hz,1H),6.80(d,J=1.4Hz,1H),6.42–6.34(m,1H),3.67–3.55(m,2H),3.4 2(s,3H),3.26(s,3H),2.84–2.76(m,3H),2.63–2.58(m,2H),2.55–2.52(m,3H),2.44( s,3H),1.96–1.88(m,1H),1.69–1.55(m,4H),1.11(d,J=5.3Hz,3H),0.90–0.75(m,4H).

[0628] Embodiment 29

[0629] N-(6-(7-Fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)-4-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)acetamide

[0630]

[0631] Reaction route:

[0632]

[0633] Steps:

[0634] Step A: At room temperature, under nitrogen protection, compound 6-(6-chloro-4-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (0.13 g, 0.2 mmol), ammonium acetate) 0.048 g, 0.8 mmol), tris(dibenzylideneacetone)dipalladium (0.0184 g, 0.02 mmol), dimethylbis(diphenylphosphinothrene)oxanthene (0.032 g, 0.004 mmol) and cesium carbonate (0.13 g, 0.4 mmol) were dissolved in 1,4-dioxane solution (2 mL). Subsequently, the reaction system was heated to 100°C and stirred for 2 hours.

[0635] After LCMS monitoring showed that the raw material was converted into the product, the product was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 80 mg of the compound N-(6-(7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-6-yl)-4-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)acetamide.

[0636] MS (ESI) M / Z: 674.4 [M+H] + .

[0637] Step B: Under nitrogen protection, at room temperature, compound N-(6-(7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-6-yl)-4-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)acetamide (0.08 g, 0.12 mmol) was dissolved in dichloromethane (1 mL) at 0°C. Subsequently, trifluoroacetic acid (0.41 g, 3.60 mmol) was added dropwise to the reaction solution. The reaction system was warmed to room temperature and stirred for 12 hours.

[0638] After LCMS monitoring showed that the raw material was converted into the product, the solvent was concentrated under reduced pressure, ammonia methanol (6M) solution was added and stirred for 2 hours, and then concentrated under reduced pressure. The resulting residue was purified by preparative chromatography to obtain 22 mg of compound N-(6-(7-fluoro-4-methyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)-4-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)acetamide.

[0639] MS (ESI) M / Z: 544.2 [M+H] +.

[0640] 1 H NMR (400MHz, DMSO-d6) δ11.68(s,1H),10.58(s,1H),8.35(s,1H),8.13(d,J=12.0Hz,1H) ,7.34(d,J=6.3Hz,1H),7.29(d,J=1.7Hz,1H),6.49(s,1H),3.84(s,2H),3.23(s,3H),3. 09–2.88(m,2H),2.87–2.74(m,2H),2.69–2.56(m,3H),2.45(s,3H),2.12(s,4H),2.02–1 .79(m,1H),1.74–1.59(m,3H),1.60–1.47(m,1H),1.15–1.04(m,3H),0.96–0.75(m,4H).

[0641] Embodiment 30

[0642] 2-(Azetidin-1-ylmethyl)-7-fluoro-4-methyl-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1H-indole

[0643]

[0644] Reaction route:

[0645]

[0646] Steps:

[0647] Step A: Dissolve 6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carbaldehyde (110.0 mg, 0.29 mmol) in dichloromethane (3.0 mL) at 0°C. Then, add azetidine (34.2 mg, 0.60 mmol) and sodium cyanoborohydride (75.6 mg, 1.20 mmol) to the solution. Then, stir the reaction system at room temperature for 16 hours.

[0648] After LCMS monitoring showed that the raw material disappeared, water (15 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 3 times), the organic phase was combined, and the organic phase was washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 70.0 mg 2-(azetidin-1-ylmethyl)-6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole.

[0649] MS (ESI) M / Z: 427.0 [M+H] + .

[0650] Step B: Under nitrogen protection at 0°C, compound 2-(azetidin-1-ylmethyl)-6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (70.0 mg, 0.16 mmol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.15 mL). Subsequently, 4-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4H-12,4-triazole (57.6 mg, 0.17 mmol), 1,1-bis(diphenylphosphino)diferroni palladium dichloride (16.3 mg, 0.02 mmol) and sodium carbonate (50.9 mg, 0.48 mmol) were added to the above solution. The reaction system was then stirred at 100°C for 16 hours.

[0651] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (5 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 61.0 mg of 2-(azetidin-1-ylmethyl)-7-fluoro-4-methyl-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole.

[0652] MS (ESI) M / Z: 287.7 [M / 2+H] + .

[0653] Step C: Compound 2-(azetidin-1-ylmethyl)-7-fluoro-4-methyl-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (60.0 mg, 0.11 mmol) was dissolved in dichloromethane (1.1 mL) at 0°C. Subsequently, trifluoroacetic acid (0.55 mL) was added dropwise to the solution. The reaction system was then stirred at room temperature for 4 hours.

[0654] After LCMS monitoring showed that the raw material disappeared, ammonia water was added dropwise to the reaction solution to adjust the pH to 8. The mixed solution was extracted with dichloromethane (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 12.0 mg of 2-(azetidin-1-ylmethyl)-7-fluoro-4-methyl-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1H-indole.

[0655] MS (ESI) M / Z: 444.3 [M+H] + .

[0656] 1H NMR (400MHz, DMSO-d6) δ11.47(s,1H),8.28(s,1H),7.48-7.40(m,3H),7.35-7.29(m,1H),6.79(d,J=6.4Hz,1H),6.33(s,1H), 3.65(s,2H),3.22-3.14(m,7H),2.93-2.82(m,2H),2.60-2.52(m,3H),2.43(s,3H),2.03-1.95(m,2H),1.09(d,J=5.2Hz,3H).

[0657] Embodiment 31

[0658] (R)-N-((6-(3-((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-1H-indol-2-yl)methyl)tetrahydrofuran-3-amine

[0659]

[0660] Reaction route:

[0661]

[0662] Steps:

[0663] Step A: Under nitrogen protection at room temperature, compound (R)-3-((3-bromophenyl)(cyclobutyl)methyl)-4-methyl-4H-1,2,4-triazole (300 mg, 0.98 mmol) was dissolved in 1,4-dioxane (9.8 mL). Subsequently, diboric acid pinacol ester (375 mg, 1.47 mmol), 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (80 mg, 0.10 mmol) and potassium acetate (192 mg, 1.96 mmol) were added to the above solution in sequence. The reaction system was then stirred at 90°C for 6 hours.

[0664] After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 310 mg of (R)-3-(cyclobutyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)-4-methyl-4H-1,2,4-triazole.

[0665] MS (ESI) M / Z: 354.2 [M+H] + .

[0666] Step B: Dissolve the compound 6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carbaldehyde (100 mg, 0.26 mmol) in dichloromethane (1.3 mL) at room temperature. Then, add the compound (R)-tetrahydrofuran-3-amine (45 mg, 0.52 mmol) and acetic acid (23 mg, 0.39 mmol) to the above solution in sequence and stir for 2 hours. Then, cool the above solution to 0°C, add sodium cyanoborocyanide (66 mg, 1.04 mmol), warm to room temperature, and continue stirring for 1 hour.

[0667] After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 90 mg of (R)-N-((6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-ylmethyl)tetrahydrofuran-3-amine.

[0668] MS (ESI) M / Z: 457.2 [M+H] + .

[0669] Step C: Under nitrogen protection at room temperature, compound (R)-N-((6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-ylmethyl)tetrahydrofuran-3-amine (50 mg, 0.11 mmol), (R)-3-(cyclobutyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)-4-methyl-4H-1,2,4-triazole (47 mg, 0.13 mmol), sodium carbonate (23 mg, 0.22 mmol) and 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (9 mg, 0.01 mmol) were dissolved in 1,4-dioxane (1.1 mL) and water (0.12 mL). The reaction system was then stirred at 100° C. for 18 hours.

[0670] After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (20 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50 mg of (R)-N-((6-(3-((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)tetrahydrofuran-3-amine.

[0671] MS (ESI) M / Z: 604.4 [M+H] + .

[0672] Step D: Compound (R)-N-((6-(3-((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)tetrahydrofuran-3-amine (50 mg, 0.08 mmol) was dissolved in dichloromethane (1.7 mL) at room temperature. Subsequently, trifluoroacetic acid (0.17 mL) was added dropwise to the solution. The reaction system was then stirred at room temperature for 2 hours.

[0673] After LCMS monitoring showed that the raw material disappeared, ammonia water was added dropwise to the reaction solution to adjust the pH to 8, and then the mixture was stirred at 50°C for 48 hours, then cooled to room temperature, extracted with dichloromethane (15 mL×3 times), and the organic phases were combined and washed with saturated brine (25 mL×2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 10 mg of (R)-N-((6-(3-((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-1H-indol-2-yl)methyl)tetrahydrofuran-3-amine.

[0674] MS (ESI) M / Z: 474.3 [M+H] + .

[0675] 1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),8.32(s,1H),7.47-7.34(m,3H),7.18(d ,J=7.2Hz,1H),6.78(d,J=6.0Hz,1H),6.38(s,1H),4.25(d,J=10.4Hz,1H),3.8 3(s,2H),3.77-3.61(m,2H),3.48-3.40(m,7H),3.29-3.26(m,1H),2.43(s,3H ),2.13-2.06(m,1H),1.96-1.89(m,1H),1.86-1.75(m,4H),1.73-1.63(m,2H).

[0676] Embodiment 32

[0677] 6-(3-((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-2-(((S)-3-fluoropyrrolidin-1-yl)methyl]-4-methyl-1H-indole

[0678]

[0679] Reaction route:

[0680]

[0681] Steps:

[0682] Step A: Dissolve 6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carbaldehyde (100 mg, 0.26 mmol) in dichloromethane (1.3 mL) at room temperature. Then, add (3S)-3-fluoropyrrolidine hydrochloride (65 mg, 0.52 mmol), triethylamine (92 mg, 0.91 mmol) and acetic acid (23 mg, 0.39 mmol) to the solution and stir for 2 hours. Then add sodium cyanoborohydride (65 mg, 1.04 mmol) and continue stirring for 3 hours.

[0683] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (15 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 110 mg of (S)-6-bromo-7-fluoro-2-((3-fluoropyrrolidin-1-yl)methyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-indole.

[0684] MS (ESI) M / Z: 459.2 [M+H] + .

[0685] Step B: Under nitrogen protection at room temperature, compound (S)-6-bromo-7-fluoro-2-((3-fluoropyrrolidin-1-yl)methyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (100 mg, 0.22 mmol) was dissolved in 1,4-dioxane (1.1 mL) and water (0.12 mL). Subsequently, (R)-3-(cyclobutyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)-4-methyl-4H-1,2,4-triazole (100 mg, 0.28 mmol), sodium carbonate (46 mg, 0.44 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (18 mg, 0.02 mmol) were added to the above solution in sequence. Then the reaction system was stirred at 100°C for 2 hours.

[0686] After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 90 mg of 6-(3-((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-2-(((S)-3-fluoropyrrolidin-1-yl)methyl.

[0687] MS (ESI) M / Z: 606.4 [M+H] + .

[0688] Step C: At room temperature, compound 6-(3-((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-2-(((S)-3-fluoropyrrolidin-1-yl)methyl (90 mg, 0.15 mmol) was dissolved in dichloromethane (1.4 mL). Subsequently, trifluoroacetic acid (0.74 mL) was added dropwise to the above solution and stirred for 3 hours. Then the temperature was lowered to 0°C, aqueous ammonia was added dropwise to adjust the pH to 8, the temperature was raised to room temperature, and stirring was continued for 16 hours.

[0689] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (15 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 4.94 mg of 6-(3-((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-2-(((S)-3-fluoropyrrolidin-1-yl)methyl]-4-methyl-1H-indole.

[0690] MS (ESI) M / Z: 476.2 [M+H] + .

[0691] 1 H NMR (400MHz, DMSO-d6) δ11.68(d,J=1.6Hz,1H),8.44(s,1H),7.58-7.46(m,3H),7.30(d,J= 7.2Hz,1H),6.91(d,J=6.0Hz,1H),6.51(s,1H),5.40(t,J=5.6Hz,0.5H),5.26(t,J=5.6Hz,0 .5H),4.37(d,J=10.4Hz,1H),3.89(s,2H),3.55(s,3H),3.38-3.27(m,1H),3.04-2.90(m,2H ),2.87-2.72(m,1H),2.56(s,3H),2.53-2.47(m,1H),2.35-2.17(m,2H),2.09-1.75(m,6H).

[0692] Embodiment 33

[0693] 6-(3-(((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-2-((((R)-3-methylpiperidin-1-yl)methyl ester)-1H-indole

[0694]

[0695] Reaction route:

[0696]

[0697] Steps:

[0698] Step A: Under nitrogen protection at room temperature, compound (R)-6-bromo-7-fluoro-4-methyl-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (40 mg, 0.09 mmol), (R)-3-(cyclobutyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)-4-methyl-4H-1,2,4-triazole (36 mg, 0.10 mmol), sodium carbonate (19 mg, 0.18 mmol) and 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (9 mg, 0.01 mmol) were dissolved in 1,4-dioxane (0.9 mL) and water (0.1 mL). The reaction system was then stirred at 100° C. for 18 hours.

[0699] After LCMS monitoring showed that the starting material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 40 mg of 6-(3-(((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-2-((((R)-3-methylpiperidin-1-yl)methyl.

[0700] MS (ESI) M / Z: 616.4 [M+H] + .

[0701] Step B: At room temperature, compound 6-(3-(((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-2-((((R)-3-methylpiperidin-1-yl)methyl (40 mg, 0.07 mmol) was dissolved in dichloromethane (1.6 mL). Subsequently, 6 M dilute hydrochloric acid (0.8 mL) was added dropwise to the above solution and stirred for 4 hours. Then the temperature was lowered to 0°C, aqueous ammonia was added dropwise to adjust the pH to 8, the temperature was raised to room temperature, and stirring was continued for 3 hours.

[0702] After LCMS monitoring showed that the raw material disappeared, water (15 mL) was added to the reaction solution to dilute it, and the mixed solution was extracted with dichloromethane (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 8 mg of 6-(3-(((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-2-((((R)-3-methylpiperidin-1-yl)methyl ester)-1H-indole.

[0703] MS (ESI) M / Z: 486.4 [M+H] + .

[0704] 1 H NMR(400MHz,DMSO-d6)δ11.48(s,1H),8.32(s,1H),7.48-7.34(m,3H),7.22-7.14(m,1H) ,6.79(d,J=6.0Hz,1H),6.35(s,1H),4.25(d,J=10.4Hz,1H),3.62(d,J=13.6Hz,1H),3.57 (d,J=14.0Hz,1H),3.42(s,3H),3.25-3.14(m,1H),2.85-2.73(m,2H),2.44(s,3H),2.15- 2.05(m,1H),1.94-1.74(m,5H),1.74-1.54(m,5H),1.54-1.41(m,1H),0.89-0.75(m,4H).

[0705] Embodiment 34

[0706] 2-(Azetidin-1-ylmethyl)-7-fluoro-4-methyl-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1H-indole

[0707]

[0708] Reaction route:

[0709]

[0710] Steps:

[0711] Step A: Dissolve 6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carbaldehyde (110.0 mg, 0.29 mmol) in dichloromethane (3.0 mL) at 0°C. Then, add (R)-3-methylpiperidine hydrochloride (39 mg, 0.60 mmol) and sodium cyanoborohydride (75.6 mg, 1.20 mmol) to the solution. Then, stir the reaction system at room temperature for 16 hours.

[0712] After LCMS monitoring showed that the raw material disappeared, water (15 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 70.0 mg of (R)-6-bromo-7-fluoro-4-methyl-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole.

[0713] MS (ESI) M / Z: 469.9 [M+H] + .

[0714] Step B: Compound (R)-6-bromo-7-fluoro-4-methyl-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (70.0 mg, 0.14 mmol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.15 mL) at 0°C under nitrogen protection. Subsequently, 4-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4H-12,4-triazole (57.6 mg, 0.17 mmol), 1,1-bis(diphenylphosphino)diferronichloridopalladium (16.3 mg, 0.02 mmol) and sodium carbonate (50.9 mg, 0.48 mmol) were added to the above solution. Then the reaction system was stirred at 100°C for 16 hours.

[0715] After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (5 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 61.0 mg of 7-fluoro-4-methyl-6-(3-((1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((R)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole.

[0716] MS (ESI) M / Z: 616.4 [M+H] + .

[0717] Step C: Compound 7-fluoro-4-methyl-6-(3-((1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((R)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (60.0 mg, 0.11 mmol) was dissolved in dichloromethane (1.1 mL) at 0°C. Trifluoroacetic acid (0.55 mL) was then added dropwise to the solution. The reaction system was then stirred at room temperature for 4 hours.

[0718] After LCMS monitoring showed that the starting material disappeared, aqueous ammonia was added dropwise to the reaction solution to adjust the pH to 8. The mixed solution was extracted with dichloromethane (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 12.0 mg of 7-fluoro-4-methyl-6-(3-((1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((R)-3-methylpiperidin-1-yl)methyl)-1H-indole.

[0719] MS (ESI) M / Z: 486.2 [M+H] + .

[0720] 1 H NMR(400MHz,DMSO-d6)δ11.48(s,1H),8.29–8.26(m,1H),7.49–7.41(m,3H) ),7.32(d,J=7.0Hz,1H),6.79(d,J=6.4Hz,1H),6.35(s,1H),3.62–3.55(m, 2H),3.20(s,3H),2.94–2.72(m,4H),2.60–2.53(m,3H),2.43(s,3H),1.94 –1.86(m,1H),1.69–1.44(m,5H),1.09(d,J=4.8Hz,3H),0.88–0.69(m,4H).

[0721] Embodiment 35

[0722] N-((7-Fluoro-4-methyl-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1H-indol-2-yl)methyl)-N-methylethylamine

[0723]

[0724] Reaction route:

[0725]

[0726] Steps:

[0727] Step A: At room temperature, under nitrogen protection, the compound N-((6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl]-N-methylethylamine (46 mg, 0.11 mmol) was dissolved in 1,4-dioxane (1.1 mL) and water (0.1 mL). Subsequently, 4-methyl-3-((1S,3S)-3- Methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4H-12,4-triazole (57 mg, 0.16 mmol), sodium carbonate (23 mg, 0.22 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (9 mg, 0.01 mmol). The reaction system was then stirred at 100°C for 16 hours.

[0728] After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 55 mg of N-((7-fluoro-4-methyl-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl.

[0729] MS (ESI) M / Z: 576.3 [M+H] + .

[0730] Step B: At room temperature, the compound N-((7-fluoro-4-methyl-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl (50 mg, 0.09 mmol) was dissolved in dichloromethane (2.2 mL). Subsequently, 6M aqueous hydrochloric acid solution (1.1 mL) was added dropwise to the above solution and stirred for 3 hours. Then the temperature was lowered to 0°C, aqueous ammonia was added dropwise to adjust the pH to 8, and then the temperature was raised to room temperature and stirring was continued for 2 hours.

[0731] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (15 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 4.33 mg of N-((7-fluoro-4-methyl-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1H-indol-2-yl)methyl)-N-methylethylamine.

[0732] MS (ESI) M / Z: 446.2 [M+H] + .

[0733] 1 H NMR (400MHz, DMSO-d6) δ11.48(s,1H),8.29(s,1H),7.52-7.44(m,3H),7.32(d,J=6.4Hz,1H),6.80(d,J=6.4Hz,1H),6.36(s,1H),3.64( s,2H),3.21(s,3H),2.95-2.80(m,2H),2.61-2.53(m,3H),2.47-2.38(m,5H),2.17(s,3H),1.09(d,J=4.8Hz,3H),1.04(t,J=7.0Hz,3H).

[0734] Embodiment 36

[0735] (R)-N-((6-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-1H-indol-2-yl)methyl]-N-methylethylamine

[0736]

[0737] Reaction route:

[0738]

[0739] Steps:

[0740] Step A: Dissolve 6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carbaldehyde (200 mg, 0.52 mmol) in dichloromethane (5 mL) at room temperature. Then, add N-ethylmethylamine (61 mg, 1.04 mmol) to the solution and stir for 2 hours. Then add sodium cyanoborohydride (65 mg, 1.04 mmol) and continue stirring for 18 hours.

[0741] After LCMS monitoring showed that the raw material disappeared, water (15 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (15 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 116 mg of N-((6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl]-N-methylethylamine.

[0742] MS (ESI) M / Z: 429.2 [M+H] + .

[0743] Step B: At room temperature, under nitrogen protection, the compound N-((6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl]-N-methylethylamine (50 mg, 0.12 mmol) was dissolved in 1,4-dioxane (1.2 mL) and water (0.1 mL). Subsequently, (R)-3-(cyclobutyl(3-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)-4-methyl-4H-1,2,4-triazole (50 mg, 0.14 mmol), sodium carbonate (25 mg, 0.23 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10 mg, 0.01 mmol). The reaction system was then stirred at 100°C for 16 hours.

[0744] After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50 mg of (R)-N-((6-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl]-1H-indol-2-yl)methyl]-N-methylethylamine.

[0745] MS (ESI) M / Z: 576.3 [M+H] + .

[0746] Step C: At room temperature, compound (R)-N-((6-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl]-1H-indol-2-yl)methyl]-N-methylethylamine (45 mg, 0.08 mmol) was dissolved in dichloromethane (1.6 mL). Subsequently, trifluoroacetic acid (0.16 mL) was added dropwise to the above solution and stirred for 3 hours. The temperature was then lowered to 0°C, aqueous ammonia was added dropwise to adjust the pH to 8, the temperature was then raised to room temperature, and stirring was continued for 16 hours.

[0747] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (15 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 7.69 mg (R)-N-((6-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-1H-indol-2-yl)methyl]-N-methylethylamine.

[0748] MS (ESI) M / Z: 446.1 [M+H] + .

[0749] 1 H NMR(400MHz,DMSO-d6)δ11.47(s,1H),8.32(s,1H),7.47-7.34(m,3H),7.18(d ,J=7.2Hz,1H),6.78(d,J=6.0Hz,1H),6.36(s,1H),4.25(d,J=10.4Hz,1H),3. 64(s,2H),3.42(s,3H),3.25-3.13(m,1H),2.47-2.38(m,5H),2.18(s,3H),2. 13-2.04(m,1H),1.89-1.77(m,4H),1.75-1.64(m,1H),1.04(t,J=7.2Hz,3H).

[0750] Embodiment 37

[0751] N-((7-Fluoro-4-methyl-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1H-indol-2-yl)methyl)-N-methylpropan-2-amine

[0752]

[0753] Reaction route:

[0754]

[0755] Steps:

[0756] Step A: Dissolve the compound 6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carbaldehyde (100 mg, 0.26 mmol) in dichloromethane (1.3 mL) at room temperature. Then, add the compound N-methylpropan-2-amine (57 mg, 0.78 mmol) to the above solution and stir for 2 hours. Then cool to 0°C, add sodium cyanoborohydride (82 mg, 1.30 mmol), then warm to room temperature and continue stirring for 18 hours.

[0757] After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50 mg of N-((6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-N-methylpropan-2-amine.

[0758] MS (ESI) M / Z: 443.2 [M+H] + .

[0759] Step B: Under nitrogen protection at room temperature, compound N-((6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-N-methylpropan-2-amine (50 mg, 0.11 mmol), 4-methyl-3-((1S,3S)-3-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4H-12,4-triazole (80 mg, 0.23 mmol), sodium carbonate (24 mg, 0.22 mmol) and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (9 mg, 0.01 mmol) were dissolved in 1,4-dioxane (1.1 mL) and water (0.12 mL). The reaction system was then stirred at 100° C. for 18 hours.

[0760] After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50 mg of N-((7-fluoro-4-methyl-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl ester)-N-methylpropan-2-amine.

[0761] MS (ESI) M / Z: 590.4 [M+H] + .

[0762] Step C: At room temperature, the compound N-((7-fluoro-4-methyl-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl ester)-N-methylpropan-2-amine (50 mg, 0.08 mmol) was dissolved in dichloromethane (2.1 mL). Subsequently, 6M dilute hydrochloric acid (1.06 mL) was added dropwise to the above solution and stirred for 4 hours. Then the temperature was lowered to 0°C, ammonia water was added dropwise to adjust to pH = 8, and then the temperature was raised to room temperature and stirring was continued for 48 hours.

[0763] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 10 mg of N-((7-fluoro-4-methyl-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1H-indol-2-yl)methyl)-N-methylpropan-2-amine.

[0764] MS (ESI) M / Z: 460.3 [M+H] + .

[0765] 1H NMR (400MHz, DMSO-d6) δ11.42(s,1H),8.28(s,1H),7.51-7.40(m,3H),7.36-7.28(m,1H),6.79(d,J=6.4Hz,1H),6.37(s,1H),3.66 (s,2H),3.21(s,3H),2.95-2.81(m,3H),2.63-2.51(m,3H),2.43(s,3H),2.14(s,3H),1.09(d,J=5.6Hz,3H),1.03(d,J=6.4Hz,6H).

[0766] Embodiment 38

[0767] (R)-N-((6-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-1H-indol-2-yl)methyl]-N-methylpropan-2-amine

[0768]

[0769] Reaction route:

[0770]

[0771] Steps:

[0772] Step A: Dissolve the compound 6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carbaldehyde (80 mg, 0.21 mmol) in dichloromethane (2 mL) at room temperature. Then, add N-isopropylmethylamine (30 mg, 0.42 mmol) to the above solution and stir for 2 hours. Then add sodium cyanoborohydride (52 mg, 0.83 mmol) and continue stirring for 18 hours.

[0773] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (15 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 53 mg of N-((6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl]-N-methylpropan-2-amine.

[0774] MS (ESI) M / Z: 443.2 [M+H] + .

[0775] Step B: At room temperature, under nitrogen protection, the compound N-((6-bromo-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl]-N-methylpropan-2-amine (43 mg, 0.10 mmol) was dissolved in 1,4-dioxane (1.0 mL) and water (0.1 mL). Subsequently, (R)-3-(cyclobutyl(3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)-4-methyl-4H-1,2,4-triazole (45 mg, 0.13 mmol), sodium carbonate (21 mg, 0.19 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (8 mg, 0.01 mmol). The reaction system was then stirred at 100°C for 16 hours.

[0776] After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50 mg of (R)-N-((6-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl]-1H-indol-2-yl)methyl]-N-methylpropan-2-amine.

[0777] MS (ESI) M / Z: 590.4 [M+H] + .

[0778] Step C: At room temperature, compound (R)-N-((6-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl]-1H-indol-2-yl)methyl]-N-methylpropan-2-amine (45 mg, 0.08 mmol) was dissolved in dichloromethane (2.5 mL). Subsequently, trifluoroacetic acid (0.25 mL) was added dropwise to the above solution and stirred for 3 hours. Then the temperature was lowered to 0°C, aqueous ammonia was added dropwise to adjust the pH to 8, the temperature was raised to 50°C, and stirring was continued for 16 hours.

[0779] After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (15 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 8.47 mg (R)-N-((6-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-7-fluoro-4-methyl-1H-indol-2-yl)methyl]-N-methylpropan-2-amine.

[0780] MS (ESI) M / Z: 460.3 [M+H] + .

[0781] 1 H NMR(400MHz,DMSO-d6)δ11.41(s,1H),8.32(s,1H),7.45-7.34(m,3H),7.20-7.1 5(m,1H),6.78(d,J=6.0Hz,1H),6.36(s,1H),4.25(d,J=10.8Hz,1H),3.65(s,2H ),3.42(s,3H),3.24-3.16(m,1H),2.92-2.82(m,1H),2.43(s,3H),2.13(s,3H), 2.11-2.04(m,1H),1.88-1.76(m,4H),1.74-1.64(m,1H),1.02(d,J=6.8Hz,6H).

[0782] Biological Activity

[0783] Test Example 1 Cbl-b Activity Experiment Experimental Purpose: To test the interaction between Cbl-b and fluorophore-labeled probe ligand in the presence of candidate compounds Experimental Method: 150nL 3-fold diluted compound (final concentration selected from 10μM-0.5nM, starting and ending concentration selected from 10μM, 3-fold dilution, 10 points, the 10th point is 0.5nM) was incubated with 5μL 72nM GST-Cbl-b protein (Bioduro) at room temperature for 1 hour, and the reaction buffer was selected from 50mM HEPES PH7.5 (Sigma), 50mM (Sigma) 50mM NaCl (Sigma), 0.01% Brij-35 (Sigma), 0.05mM DTT (Sigma), 100μg / mL BSA (Sigma). 5μL of fluorophore-labeled probe ligand (Bioduro) with a final concentration selected from 346.5nM was added to the reaction plate. 5 μL of 100-fold diluted Streptavidin-Tb antibody (Cisbio) was added to the reaction plate, incubated for 1 hour at room temperature on a shaker, and TR-FRET 520 / 615 was read on Envision (Perkin Elmer).

[0784] The compounds disclosed herein have a good inhibitory effect on Cbl-b, and their IC 50 The values ​​are generally less than 1 micromolar; the IC values ​​of some compounds disclosed herein are 50 The IC values ​​of the compounds disclosed herein are lower than 0.5 micromolar. 50The value is lower than 0.3 micromolar, even lower than 0.1 micromolar. The inhibition results of some compounds disclosed in the present invention on Cbl-b are shown in Table 1.

[0785] Table 1 Enzyme inhibition results

[0786]

[0787]

[0788] Conclusion: The disclosed compounds have a good inhibitory effect on Cbl-b.

[0789] Test Example 2: Jurkat T activation experiment

[0790] Experimental purpose: To test the effect of compounds on the activation of IL2 release from Jurkat T cells. Experimental method: 96-well cell plates (Corning) were coated with 100 μL 5ug / mL anti-human CD3 (BD) antibody diluent at 4°C overnight, washed once with PBS, the supernatant was removed, 100uL 4μg / mL anti-human CD28 (BD) antibody diluent was added, and mixed evenly. Compounds were diluted 5-fold (final concentration was selected from 1μM-0.32nM, starting concentration was selected from 1μM, 5-fold dilution, 6 points, the 6th point was 0.32nM), pre-mixed with 2x 106 / mL Jurkat T cell suspension (ATCC) at a ratio of 1:1, and incubated at 37°C for 1 hour. 100μL of the mixture of compounds and cells was transferred to the pre-treated plate wells, and the cells were cultured at 37°C for 24 hours. The supernatant was collected and the amount of IL2 released was detected using the IL2-TR FRET kit (bioauxilium). EC was analyzed using Prism 50 .

[0791]

[0792]

[0793] Conclusion: The disclosed compounds have good activity on the IL2 release and activation of Jurkat T cells.

Claims

1. A compound represented by formula (II), its isomers and pharmaceutically acceptable salts thereof, Ring A is selected from phenyl, 5-6 membered heteroaryl; X1 is selected from CRa, wherein Ra is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl; X2 Selected from CR b , the R b Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, substituted or unsubstituted C 3-6 Cycloalkyl; X3 Selected from CR g , N; Rg is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, CN; R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl; L1 is selected from C 1-4 Alkylene, C 1-4 deuterated alkylene; R4 is selected from NR 11 R 12 ; Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group; R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy; R 11 , R 12 are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, wherein C 3-6 The cycloalkyl group is optionally substituted with halogen, C 1-4 Alkyl substitution; m is selected from 0, 1, 2, 3, 4; Y1 is independently selected from N, CR c , the R c Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl; Y2 is selected from CR d , the R d are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, -NR e1 R e2 、-OR f 、-CN、-SO2-C 1-4 alkyl; R e1 , R e2 are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, -CO-NH-C 1-4 Alkyl-CN, -SO2-C 1-4 Alkyl, where C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 The cycloalkyl group is optionally substituted by n atoms each independently selected from hydrogen, halogen, C 1-4 Alkyl, CN, -C 1-4 Alkyl-CN substituted; n is selected from 0, 1, 2, 3; R f are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, wherein C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 The cycloalkyl group is optionally substituted by r each independently selected from hydrogen, halogen, C 1-4 Alkyl, CN, -C 1-4 Alkyl-CN substituted; r is selected from 0, 1, 2, 3; R 13 , R 14 are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, wherein C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 The cycloalkyl group is optionally substituted by t each independently selected from hydrogen, halogen, C 1-4 Alkyl substituted; or R 13 , R 14 The carbon atom to which it is attached forms t is selected from 0, 1, 2, 3; Z is selected from CR k1 R k2 , the R k1 , R k2 are independently hydrogen, halogen, C 1-4 Alkyl, -C 2-4 Alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene -CN, -CN; or R k1 , R k2 The carbon atoms connected to it form C 3-6 Cycloalkyl; R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy.

2. A compound represented by formula (I), its isomers and pharmaceutically acceptable salts thereof, in, Ring A is selected from phenyl, 5-6 membered heteroaryl; X1 is selected from CRa, wherein Ra is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, substituted or unsubstituted C 3-6 Cycloalkyl; X2 Selected from CR b , the R b Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, substituted or unsubstituted C 3-6 Cycloalkyl; X3 Selected from CR g , N; Rg is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, CN; R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl; L1 is selected from C 1-4 Alkylene, C 1-4 deuterated alkylene; Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group; R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy; m is selected from 0, 1, 2, 3, 4; Y1 is independently selected from N, CR c , the R c Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl; Y2 is selected from CR d , the R d are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, -NR e1 R e2 、-OR f ; R e1 , R e2 are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, substituted or unsubstituted C 3-6 Cycloalkyl; R f are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, substituted or unsubstituted C 3-6 Cycloalkyl; Z is selected from CR k1 R k2 , the R k1 , R k2 are independently hydrogen, halogen, C 1-4 Alkyl, -C 2-4 Alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene -CN, -CN; R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy.

3. The compound according to claim 1 or 2, its isomer and pharmaceutically acceptable salt thereof, characterized in that Ring A is selected from and / or Ra is selected from Cl, Br, CH3, C2H5, CF3, OCH3, OCHF2, OCF3, and / or Rg is selected from F, Cl, CN; and / or R1 is selected from H, F, Cl, CH3, C2H5, and / or structural units Selected from and / or structural units Selected from 4. The compound according to any one of claims 1 to 3, its isomers and pharmaceutically acceptable salts thereof, characterized in that L1 is selected from -CH2-, -CH(CH3)-.

5. The compound according to any one of claims 1 to 4, its isomers and pharmaceutically acceptable salts thereof, characterized in that Ring B is selected from and / or R2 is selected from H, -F, -CH3, -C(CH3)2; and / or structural units Selected from 6. The compound according to any one of claims 1 to 5, its isomers and pharmaceutically acceptable salts thereof, characterized in that R 11 , R 12 Each independently selected from H, -CH3, -CH2CH3, -C(CH3)2, 7. The compound according to any one of claims 1 to 6, its isomers and pharmaceutically acceptable salts thereof, characterized in that R e1 , R e2 Each independently selected from and / or R f Selected from and / or R d Selected from H, -CN, 8. The compound according to any one of claims 1 to 7, its isomers and pharmaceutically acceptable salts thereof, characterized in that R 13 , R 14 Each independently selected from H, 9. The compound according to any one of claims 1 to 7, its isomers and pharmaceutically acceptable salts thereof, characterized in that Structural unit Selected from 10. The compound according to any one of claims 1 to 9, its isomers and pharmaceutically acceptable salts thereof, characterized in that R3 is selected from -CH3.

11. A compound, an isomer thereof, and a pharmaceutically acceptable salt thereof, 12 . A pharmaceutical composition comprising the compound according to claim 1 , its isomers and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

13. Use of the compound according to any one of claims 1 to 11, its isomers and pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 12 in the preparation of drugs for treating diseases mediated by CBL-B target.

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