PARP7 inhibitor and use thereof

Abstract

A PARP7 inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof. The present application also relates to the use of the PARP7 inhibitor in the selective inhibition of PARP7 activity, or in the treatment or prevention of diseases, disorders or conditions regulated or affected by PARP7 activity or in which PARP7 activity or overexpression is involved.

Description

PARP7 inhibitors and uses thereof Technical Field

[0001] The present invention belongs to the field of pharmaceuticals, and specifically relates to compounds having multiple nitrogen heterocycles and nitrogen heteroaryl structures such as 2-pyridone, and methods for preparing the compounds, as well as methods and uses thereof for treating and / or preventing diseases. Background Art

[0002] PARP (poly ADP-ribose polymerase) is a protein family composed of 17 enzymes that use nicotinamide adenine dinucleotide (NAD+) as a substrate to transfer ADP-ribose (ADPR) groups to target proteins. It is a multifunctional protein post-translational modification enzyme present in most eukaryotic cells. It is activated by recognizing structurally damaged DNA fragments and is considered a sensor of DNA damage, participating in a series of cellular processes such as DNA repair and genome stability. The PARP family is divided into two categories: polyPARPs and monoPARPs. PolyPARPs catalyze the sequential transfer of multiple ADPR molecules to substrate proteins, and the poly-ADPR chain can reach hundreds of units, while monoPARPs catalyze the transfer of a single ADPR group to the substrate. Therefore, polyPARPs and monoPARPs have different ADP-ribosylation modification substrates, play different roles in cell signal transduction and protein function regulation, and represent two different types of therapeutic targets.

[0003] PARP7 (TIPARP), a monoPARP, is a key regulator of innate immunity, transcription factor activity, and cellular stress responses. Multiple studies have demonstrated that PARP7 plays a key role in innate immune signaling pathways, particularly as a negative regulator of the type I interferon antiviral response. Knockout of PARP7 enhances interferon-β (IFN-β) expression induced by nucleic acid sensor agonists or viruses in various cell types. PARP7, as a suppressor of aryl hydrocarbon receptor (AHR) activity, is upregulated in response to cellular stress activated by the AHR following viral infection or exposure to cigarette smoke. Furthermore, PARP7 is regulated by liver X receptors (LXRs) and hypoxia-inducible factor 1 (HIF-1).

[0004] When infected by cancer cells or viruses, free intracellular nucleic acid fragments trigger innate immune perception through the TBK1-mediated type I interferon (IFN) pathway. This phosphorylation of the cytoplasmic interferon regulatory factor (IRF-3) leads to translocation to the nucleus and binding to transcriptional coactivators, promoting the transcription of type I IFNs. The transcription factor STAT1 is a key downstream effector of the IFN signaling pathway. Once IFN binds to its receptor, STAT1 is phosphorylated by the kinase JAK1, forming a dimer that translocates to the nucleus, regulating the transcription of interferon-stimulated genes (ISGs), thereby recruiting immune cells such as dendritic cells, macrophages, and lymphocytes to recognize and kill cancer cells. PARP7, while not expressed at high levels in normal cells, is overactive in many tumor types. High levels of PARP7 act as a brake in cancer cells, modifying the key kinase TBK1 through mono-ADP-ribosylation, thereby preventing the phosphorylation of IRF-3 and, consequently, the production of type I IFNs, thereby evading recognition and killing by immune cells. Therefore, inhibiting PARP7 can restore the response of the type I interferon signaling pathway to nucleic acids, directly inhibit tumor cell proliferation, and activate the immune system, effectively preventing tumor immune escape, thereby making tumor elimination possible.

[0005] At the same time, PARP7 may also be a target for the treatment of inflammation. PARP7 negatively regulates aryl hydrocarbon receptor (AHR) and type I interferon (IFN-I) signal transduction, both of which are related to intestinal homeostasis and immunity. Since the loss of PARP7 expression increases the AHR and IFN-I signaling pathways, in the mouse dextran sodium sulfate (DSS)-induced colitis model, the loss of PARP7 expression reduces the expression of inflammatory genes including interleukin IL-6, CXCL1, and lipocalin-2. Experimental results indicate that PARP7 may be involved in the recruitment of immune cells to inflammatory sites. Therefore, inhibiting PARP7 can reduce the severity of DSS-induced colitis in mice and inhibit the production of proinflammatory cytokines in tissues of patients with inflammatory bowel disease.

[0006] Because PARP7 is an extremely attractive therapeutic target. But so far, only one PARP7 selective inhibitor, RBN-2397, is in Phase I clinical trials for the treatment of solid tumors. Preclinical studies have shown that the trifluoropyridazinone compound RBN-2397 can selectively inhibit the enzymatic activity of PARP7, and can inhibit the growth and proliferation of a variety of cancer cells, and can cause tumor regression in mouse xenograft tumor models and homologous gene tumor models (Gozgit JMet al. Cancer Cell 2021, 39, 1-13). Phase I clinical trial data showed that RBN-2397 can induce IFN pathway activation and increase the infiltration of immune cells in tumors, indicating that patients have adaptive immune induction after treatment with RBN-2397. However, RBN-2397 has poor in vivo pharmacokinetic properties, such as low in vivo plasma exposure, short plasma half-life, and low oral bioavailability.

[0007] Therefore, it is necessary to develop PARP7 inhibitors with higher selectivity, improved in vivo pharmacokinetic properties, better biological activity and therapeutic effects, reduced clinical side effects, and the ability to be expanded to more indications such as tumors, autoimmune or inflammatory diseases.

[0008] Summary of the Invention

[0009] The present invention aims to provide a compound that can selectively inhibit the enzymatic activity of PARP7.

[0010] According to one aspect of the present invention, a PARP7 inhibitor is provided, which is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,

[0011] in,

[0012] R1 is selected from halogen, C1-6 haloalkyl, and C2-6 alkanoyl;

[0013] R2 is selected from hydrogen and deuterium;

[0014] R3 is selected from hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl and C1-6 haloalkyl; or,

[0015] R2 and R3 together with adjacent carbon atoms form a C3-6 cycloalkyl group;

[0016] Z is selected from a direct bond or a methylene group;

[0017] X is selected from carbon and nitrogen, represents a double bond or a single bond, provided that when X is nitrogen, the bond to X is a single bond, and when X is carbon, the bond to X is a double bond or a single bond, and that at most one double bond is attached to any one atom;

[0018] m is 0, 1 or 2, and when m is 1, R4 is selected from C1-6 alkyl, when m is 2, the two R4 are located on different ring atoms, and the two R4 together form a bridge bond of an alkylene group containing 1 to 3 carbon atoms;

[0019] Ring A is a 5-6 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group having 1-3 nitrogen atoms;

[0020] n is 0, 1 or 2, and each R5 is independently selected from nitrile, halogen, C3-6 cycloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C2-6 alkanoyl, C1-4 alkylsulfinylamide, C1-4 alkylsulfonyl, and phenyl optionally substituted with 1 or 2 halogens.

[0021] In another embodiment, Ring A is selected from pyrimidinyl, pyridinyl, pyrrolopyridinyl, imidazopyridinyl, and quinazolinyl; Ring A is more preferably selected from pyrimidin-2-yl, pyridin-2-yl, pyrrolo[2,3-c]pyridin-7-yl, imidazo[4,5-c]pyridin-4-yl, and quinazolin-2-yl; Ring A is most preferably pyrimidin-2-yl or imidazo[4,5-c]pyridin-4-yl.

[0022] In a preferred embodiment, n is 1.

[0023] In another preferred embodiment, R5 is selected from halogen, C3-6 cycloalkyl, C1-3 haloalkyl, and phenyl optionally substituted with 1 halogen; and, R5 is more preferably selected from trifluoromethyl or cyclopropyl.

[0024] In another preferred embodiment, the substitution position of R5 on ring A is para relative to the connection position between ring A and the nitrogen-containing six-membered heterocyclic group.

[0025] In another embodiment, X is N, and All are single bonds.

[0026] In this embodiment, preferably, m is 0, 1, or 2, more preferably 0 or 1. When m is 1, R4 is a C1-3 alkyl group, more preferably a methyl group; optionally or preferably, R4 is located in an ortho position relative to the X atom of the nitrogen-containing six-membered heterocyclic group. When m is 2, two R4 groups on different ring atoms together form a bridge selected from a methylene group or an ethylene group; optionally or preferably, the two R4 groups are each located in an ortho position relative to the X atom of the nitrogen-containing six-membered heterocyclic group or in a meta position relative to the X atom of the nitrogen-containing six-membered heterocyclic group.

[0027] In other embodiments, X is C or CH, and both One of them is a double bond and the other is a single bond; more preferably, X is C, and both The one connected to the X atom is a double bond, and the other is a single bond.

[0028] In this embodiment, preferably, m is 0 or 1, more preferably 0. When m is 1, R4 is a C1-3 alkyl group, more preferably a methyl group.

[0029] In a preferred aspect of the present invention, Z is a direct bond.

[0030] In another preferred embodiment, R2 is hydrogen.

[0031] In another preferred embodiment, R3 is selected from hydrogen, C1-3 alkyl, and C1-3 hydroxyalkyl; R3 is more preferably methyl or ethyl.

[0032] In other preferred embodiments, R1 is a C1-3 haloalkyl group, more preferably a trifluoromethyl group.

[0033] In another aspect of the present invention, a pharmaceutical composition is provided, which includes a compound of the present invention, or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.

[0034] Other aspects of the present invention also relate to methods or uses of the compounds of the present invention, or pharmaceutically acceptable salts, solvates, esters, acids, metabolites or prodrugs thereof, for selectively inhibiting PARP7 activity, or uses of the compounds of the present invention, or pharmaceutically acceptable salts, solvates, esters, acids, metabolites or prodrugs thereof, in the preparation of drugs for selectively inhibiting PARP7 activity.

[0035] In a further aspect, the present invention also relates to a method or use of the compound of the invention, or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, for treating or preventing a disease, disorder or condition that is regulated or affected by PARP7 activity or in which PARP7 activity or overexpression is involved, or the use of the compound of the invention, or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, in the preparation of a medicament for treating or preventing a disease, disorder or condition that is regulated or affected by PARP7 activity or in which PARP7 activity or overexpression is involved.

[0036] Preferably, the disease, disorder or condition modulated by or affected by PARP7 activity or in which PARP7 activity or overexpression is involved is a hyperproliferative disease, in particular cancer, an autoimmune or inflammatory disease.

[0037] In a more preferred aspect, the disease, disorder or condition is selected from cancer, including but not limited to squamous cell carcinoma of the lung, adenocarcinoma of the lung, large cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, breast cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, colorectal cancer, melanoma, ovarian cancer, esophageal squamous cell carcinoma, gastric cancer, liver cancer, oral cancer, urothelial carcinoma, prostate cancer, bladder cancer, renal cell carcinoma, gastrointestinal stromal tumor, cervical cancer, endometrial cancer, rhabdomyosarcoma, fibrosarcoma, neuroendocrine tumor, mesothelioma, brain cancer, and malignant glioma, etc.

[0038] In other preferred aspects, the disease, disorder or condition is selected from autoimmune or inflammatory diseases, including but not limited to ulcerative colitis, Crohn's disease, multiple sclerosis, autoimmune liver disease, type I diabetes, bronchial asthma, systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, psoriasis, polymyositis, and dermatomyositis. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] FIG1 is a graph showing that preferred compounds dose-dependently restore type I interferon signaling in CT26 cells. DETAILED DESCRIPTION

[0040] definition

[0041] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs. In the specification, unless the context clearly indicates otherwise, the singular also includes the plural. All publications, patent applications, patents or other references mentioned herein are incorporated herein by reference. In the event of a conflict, the present specification (including definitions) shall prevail. In addition, materials, methods and examples are illustrative only and are not intended to limit the scope of the present invention.

[0042] Unless otherwise indicated, the present invention employs conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the skill of the art. Unless specific definitions are provided, the nomenclature and laboratory procedures and techniques associated with analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are those known to those skilled in the art. In general, the aforementioned techniques and steps can be implemented by conventional methods well known in the art and described in various general and more specific literature, which are cited and discussed in this specification.

[0043] The term "alkyl" refers to an aliphatic hydrocarbon group, which can be a branched or straight chain alkyl group. Depending on the structure, the alkyl group can be a monovalent group or a divalent group (i.e., an alkylidene group). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a "low alkyl group" having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, amyl, hexyl, etc. It should be understood that "alkyl" mentioned herein includes all possible configurations and conformations of the alkyl group, for example, "propyl" mentioned herein includes n-propyl and isopropyl, "butyl" includes n-butyl, isobutyl and tert-butyl, and "pentyl" includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and penta-3-yl, etc.

[0044] The term "alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.

[0045] The term "alkoxyalkyl" refers to an alkyl group, as defined herein, substituted by an alkoxy group, as defined herein.

[0046] The term "cycloalkyl" refers to a monocyclic or polycyclic radical containing only carbon and hydrogen. Cycloalkyl includes a group having 3-12 ring atoms. According to structure, cycloalkyl can be a monovalent group or a divalent group (e.g., cycloalkylidene). In the present invention, cycloalkyl is preferably a cycloalkyl having 3-8 carbon atoms, more preferably a "low cycloalkyl" having 3-6 carbon atoms. The example of cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and adamantyl.

[0047] The term "alkyl (cycloalkyl)" or "cycloalkylalkyl" refers to an alkyl group as defined herein substituted with a cycloalkyl group as defined herein. Non-limiting examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0048] The term "aromatic" refers to a planar ring having a delocalized π electron system and containing 4n+2 π electrons, where n is an integer. The aromatic ring can be composed of five, six, seven, eight, nine, or more than nine atoms. The aromatic group can be optionally substituted. The term "aromatic" includes carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

[0049] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. The aryl ring can be composed of five, six, seven, eight, nine, or more than nine atoms. An aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl. Depending on the structure, an aryl group can be a monovalent group or a divalent group (i.e., an arylene group).

[0050] The term "aryloxy" refers to an -O-aryl group, wherein aryl is as defined herein.

[0051] The term "heteroaryl" refers to an aromatic group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The N-containing "heteroaryl" portion refers to an aromatic group in which at least one skeletal atom on the ring is a nitrogen atom. Depending on the structure, a heteroaryl group can be a monovalent group or a divalent group (i.e., a heteroarylidene group). Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindole, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, and furopyridinyl.

[0052] The term "alkyl (aryl)" or "aralkyl" refers to an alkyl group as defined herein substituted with an aryl group as defined herein. Non-limiting examples of alkyl (aryl) groups include benzyl, phenethyl, and the like.

[0053] The term "alkyl(heteroaryl)" or "heteroarylalkyl" means an alkyl group, as defined herein, substituted with a heteroaryl group, as defined herein.

[0054] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein where one or more of the backbone chain atoms is a heteroatom, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or a combination thereof. The heteroatom(s) may be located at any position within the heteroalkyl group or at the position where the heteroalkyl group is attached to the rest of the molecule.

[0055] As used herein, the term "heterocycloalkyl" or "heterocyclyl" refers to a non-aromatic ring in which one or more of the atoms forming the ring are heteroatoms selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring can be a monocyclic or polycyclic ring consisting of three, four, five, six, seven, eight, nine, or more than nine atoms. The heterocycloalkyl ring can be optionally substituted. Examples of heterocycloalkyls include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiinane, 1,4-oxathiinane, 1,4-oxathiinane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbital Acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazolidine, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1,3-oxathiolane. Depending on the structure, the heterocycloalkyl group can be a monovalent group or a divalent group (i.e., a heterocycloalkylene group).

[0056] The term "alkyl(heterocycloalkyl)" or "heterocycloalkylalkyl" means an alkyl group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0057] The term "alkoxy(heterocycloalkyl)" or "heterocycloalkylalkoxy" means an alkoxy group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0058] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0059] The terms "haloalkyl," "haloalkoxy," and "haloheteroalkyl" include structures of alkyl, alkoxy, or heteroalkyl groups in which at least one hydrogen atom is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from one another.

[0060] The term "hydroxy" refers to an -OH group.

[0061] The term "cyano" refers to a -CN group.

[0062] The term "ester group" refers to a chemical moiety having the formula -COOR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon), and heterocyclyl (attached through a ring carbon).

[0063] The term "amino" refers to a -NH2 group.

[0064] The term "aminoacyl" refers to a -CO-NH2 group.

[0065] The term "alkylaminoacyl" means a -CO-NH-R group, wherein R is alkyl as defined herein.

[0066] The term "amido" or "amido" refers to a -NR-CO-R' group, wherein R and R' are each independently hydrogen or alkyl.

[0067] The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups, and specifically refers to the group -NRR', wherein R and R' are each independently selected from hydrogen or lower alkyl, with the proviso that -NRR' is not -NH2. "Alkylamino" includes radicals of compounds wherein the nitrogen of -NH2 is attached to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like. "Dialkylamino" includes radicals wherein the nitrogen of -NH2 is attached to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.

[0068] The terms "arylamino" and "diarylamino" refer to amino substituents further substituted with one or two aryl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen, lower alkyl, or aryl, wherein N is attached to at least one or two aryl groups, respectively.

[0069] The term "cycloalkylamino" refers to an amino substituent further substituted with one or two cycloalkyl groups as defined herein.

[0070] The term "heteroalkylamino" refers to an amino substituent further substituted with one or two heteroalkyl groups as defined herein.

[0071] The term "aralkylamino" herein refers to the group -NRR' wherein R is lower aralkyl and R' is hydrogen, lower alkyl, aryl or lower aralkyl.

[0072] The term "heteroarylamino" refers to an amino substituent further substituted with one or two heteroaryl groups as defined herein.

[0073] The term "heterocycloalkylamino" refers to an amino group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0074] The term "alkylaminoalkyl" means an alkyl group, as defined herein, substituted with an alkylamino group, as defined herein.

[0075] The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups.

[0076] The term "aminoalkoxy" refers to an alkoxy substituent further substituted with one or more amino groups.

[0077] The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further substituted with one or more hydroxy groups.

[0078] The term "cyanoalkyl" refers to an alkyl substituent further substituted with one or more cyano groups.

[0079] The term "acyl" refers to a monovalent atomic group remaining after removing a hydroxyl group from an organic or inorganic oxygen-containing acid, and has the general formula RM(O)-, where M is usually C.

[0080] The term "carbonyl" refers to an organic functional group composed of two atoms, carbon and oxygen, connected by a double bond (C=O).

[0081] The term "alkanoyl" or "alkylcarbonyl" refers to a carbonyl group further substituted with an alkyl group. Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, hexanoyl, and the like.

[0082] The term "arylcarbonyl" means a carbonyl group, as defined herein, substituted with an aryl group, as defined herein.

[0083] The term "alkoxycarbonyl" refers to a carbonyl group further substituted with an alkoxy group.

[0084] The term "heterocycloalkylcarbonyl" refers to a carbonyl group further substituted with a heterocycloalkyl group.

[0085] The terms "alkylaminocarbonyl," "cycloalkylaminocarbonyl," "arylaminocarbonyl," "aralkylaminocarbonyl," and "heteroarylaminocarbonyl" refer to a carbonyl group, as defined herein, substituted with an alkylamino group, a cycloalkylamino group, an arylamino group, an aralkylamino group, or a heteroarylamino group, as defined herein, respectively.

[0086] The term "alkylcarbonylalkyl" or "alkanoylalkyl" refers to an alkyl group further substituted with an alkylcarbonyl group.

[0087] The term "alkylcarbonylalkoxy" or "alkanoylalkoxy" refers to an alkoxy group further substituted with an alkylcarbonyl group.

[0088] The term "heterocycloalkylcarbonylalkyl" refers to an alkyl group further substituted with a heterocycloalkylcarbonyl group.

[0089] The term "mercapto" refers to a -SH group. The term "alkylthio" refers to a mercapto group, as defined herein, substituted with an alkyl group, as defined herein.

[0090] The term "sulfone" or "sulfonyl" refers to the functional group of sulfonic acid after losing the hydroxyl group, specifically refers to the -S(=O)2- group.

[0091] The term "sulfoxide" or "sulfinyl" refers to -S(=O)-.

[0092] The term "aminosulfonyl" or "aminosulfonyl" refers to the -S(=O)2-NH2 group.

[0093] The term "alkylsulfoxide" or "alkylsulfinyl" refers to an alkyl-S(=O)- group.

[0094] The term "alkylsulfonyl" or "alkylsulfonyl" refers to -S(=O)2-R, where R is alkyl.

[0095] The term "alkylaminosulfonyl" refers to a sulfone group, as defined herein, substituted with an alkylamino group, as defined herein.

[0096] The term "alkylsulfonylamino(amine) group" or "alkylsulfonylamino(amine) group", and "cycloalkylsulfonylamino(amine) group" or "cycloalkylsulfonylamino(amine) group" means that an amino group as defined herein is substituted by an alkylsulfonyl or cycloalkylsulfonyl group as defined herein, i.e. -NH-S(=O)2-R, wherein R is an alkyl group and a cycloalkyl group, respectively.

[0097] The terms "cycloalkylsulfonyl" and "cycloalkylsulfonyl" refer to -S(=O)2-R, where R is cycloalkyl.

[0098] The term "quaternary ammonium group" refers to -N + RR'R", wherein R, R' and R" are each independently selected from an alkyl group having 1 to 8 carbon atoms.

[0099] The term "optionally" refers to one or more events described later that may or may not occur, and includes both events that occur and events that do not occur. The term "optionally substituted" or "substituted" refers to that the group mentioned can be substituted by one or more additional groups, each of which is independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methylsulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc. Among them, the amino protecting group is preferably selected from pivaloyl, tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl, etc.

[0100] As used herein, "pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, esters, acids, isomers, metabolites, prodrugs, and isotopically labeled derivatives of the disclosed compounds.

[0101] The term "pharmaceutically acceptable salts" herein refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesirable toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the free acid or free base form of the purified compound with a suitable base or acid, respectively.

[0102] "Solvate" or "solvate" refers to a solvent addition form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap fixed molar ratios of solvent molecules in their crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the association of one or more water molecules with one molecule of the substance, where the water remains in its molecular form as HO.

[0103] A "metabolite" of a compound disclosed herein is a derivative of the compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. The term "metabolized," as used herein, refers to the sum of processes by which a particular substance is altered by an organism (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Thus, an enzyme can produce a specific structural transformation into a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while diphosphoglucosyltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be obtained from "The Pharmacological Basis of Therapeutics," 9th edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds. Both methods are known in the art. In some embodiments, metabolites of the compound are formed by an oxidation process and correspond to the corresponding hydroxyl-containing compound. In some embodiments, the compound is metabolized to a pharmaceutically active metabolite.

[0104] As used herein, the term "modulate" refers to interacting directly or indirectly with a target to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0105] The term "prodrug" or "prodrug" refers to a derivative that may not be pharmacologically active but, in certain circumstances, can be administered orally or parenterally and thereafter metabolized in vivo to form a pharmacologically active compound of the present invention. Non-limiting examples of prodrugs include esters, carbonates, half-esters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, nitrogen-containing compounds, phosphoramides, glycosides, ethers, acetals, and ketals, among others.

[0106] An "effective amount" refers to an amount of a drug or pharmaceutical formulation that will elicit the biological or medical response of a tissue, system, animal, or human being, for example, that is being studied by a researcher or physician. Furthermore, the term "therapeutically effective amount" refers to any amount that results in treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject that has not received that amount. Also included within the scope of the term is an amount effective to enhance normal physiological function.

[0107] As used herein, the term "treating" refers to alleviating at least one symptom of a disease, disorder, or condition. The term includes administering and / or applying one or more compounds described herein to a subject to provide management or treatment of a condition. "Treatment" for the purposes of this disclosure may, but does not necessarily, provide a cure; rather, it is meant that "treatment" can be a form of management of a condition. When the compounds described herein are used to treat harmful proliferating cells (including cancer), "treatment" includes partial or complete destruction of the harmful proliferating cells with minimal damage to normal cells. The desired treatment mechanism for harmful rapidly proliferating cells (including cancer cells) at the cellular level is apoptosis.

[0108] As used herein, the term "prevention" includes both preventing or slowing the onset of clinically significant disease development or preventing or slowing the onset of a preclinically significant disease stage in an at-risk individual. This includes prophylactic treatment of individuals at risk of developing disease.

[0109] The term "subject" or "patient" includes organisms that can suffer from a disorder or a disorder associated with reduced or insufficient programmed cell death (apoptosis) or that can otherwise benefit from the administration of the compounds of the invention, such as humans and non-human animals. Preferred humans include human patients suffering from or prone to suffering from a disorder or related condition as described herein. The term "non-human animal" includes vertebrates, such as mammals, such as non-human primates, sheep, cattle, dogs, cats, and rodents such as mice, as well as non-mammals, such as chickens, amphibians, reptiles, etc.

[0110] The GI used in this paper 50 It refers to the drug concentration required to inhibit 50% of cell growth, that is, the drug concentration when the growth of 50% of cells (such as cancer cells) is inhibited or controlled.

[0111] IC used in this article 50 It refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition of the maximal effect in the assay in which the effect is measured.

[0112] The EC used in this paper 50 It refers to the dose, concentration or amount of a test compound that elicits a dose-dependent response that elicits 50% of the maximal expression of a specific response induced, stimulated or potentiated by the particular test compound.

[0113] PARP7 inhibitors of the present invention

[0114] The present invention relates to a PARP7 inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof.

[0115] in,

[0116] R1 is selected from halogen, C1-6 haloalkyl, and C2-6 alkanoyl;

[0117] R2 is selected from hydrogen and deuterium;

[0118] R3 is selected from hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl and C1-6 haloalkyl; or,

[0119] R2 and R3 together with adjacent carbon atoms form a C3-6 cycloalkyl group;

[0120] Z is selected from a direct bond or a methylene group;

[0121] X is selected from carbon and nitrogen, represents a double bond or a single bond, provided that when X is nitrogen, the bond to X is a single bond, and when X is carbon, the bond to X is a double bond or a single bond, and that at most one double bond is attached to any one atom;

[0122] m is 0, 1 or 2, and when m is 1, R4 is selected from C1-6 alkyl, when m is 2, the two R4 are located on different ring atoms, and the two R4 together form a bridge bond of an alkylene group containing 1 to 3 carbon atoms;

[0123] Ring A is a 5-6 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group having 1-3 nitrogen atoms;

[0124] n is 0, 1 or 2, and each R5 is independently selected from nitrile, halogen, C3-6 cycloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C2-6 alkanoyl, C1-4 alkylsulfinylamide, C1-4 alkylsulfonyl, and phenyl optionally substituted with 1 or 2 halogens.

[0125] In another embodiment, Ring A is selected from pyrimidinyl, pyridinyl, pyrrolopyridinyl, imidazopyridinyl, and quinazolinyl; Ring A is more preferably selected from pyrimidin-2-yl, pyridin-2-yl, pyrrolo[2,3-c]pyridin-7-yl, imidazo[4,5-c]pyridin-4-yl, and quinazolin-2-yl; Ring A is most preferably pyrimidin-2-yl or imidazo[4,5-c]pyridin-4-yl.

[0126] In a preferred aspect of the present invention, Z is a direct bond.

[0127] In a preferred embodiment, n is 1.

[0128] In another preferred embodiment, R5 is selected from halogen, C3-6 cycloalkyl, C1-3 haloalkyl, and phenyl optionally substituted with 1 halogen; and, R5 is more preferably selected from trifluoromethyl or cyclopropyl.

[0129] In another preferred embodiment, the substitution position of R5 on ring A is para relative to the connection position between ring A and the nitrogen-containing six-membered heterocyclic group.

[0130] In another embodiment, X is N, and All are single bonds.

[0131] In this embodiment, preferably, m is 0, 1, or 2, more preferably 0 or 1. When m is 1, R4 is a C1-3 alkyl group, more preferably a methyl group; optionally or preferably, R4 is located in an ortho position relative to the X atom of the nitrogen-containing six-membered heterocyclic group. When m is 2, two R4 groups on different ring atoms together form a bridge selected from a methylene group or an ethylene group; optionally or preferably, the two R4 groups are each located in an ortho position relative to the X atom of the nitrogen-containing six-membered heterocyclic group or in a meta position relative to the X atom of the nitrogen-containing six-membered heterocyclic group.

[0132] In one aspect, the present invention relates to a PARP7 inhibitor, which is a compound of Formula (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,

[0133] wherein R1, R2, R3, R4, R5 and m are as defined above.

[0134] More preferred are compounds of formula (Ia) and (Ib), and most preferred is the compound of formula (Ia).

[0135] In other embodiments, X is C or CH, and both One of them is a double bond and the other is a single bond; more preferably, X is C, and both The one connected to the X atom is a double bond, and the other is a single bond.

[0136] In this embodiment, preferably, m is 0 or 1, more preferably 0. When m is 1, R4 is a C1-3 alkyl group, more preferably a methyl group.

[0137] In another aspect, the present invention relates to a PARP7 inhibitor, which is a compound of Formula (Id), (Ie), (If), (Ig) or (Ih) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,

[0138] wherein R1, R2, R3, R4, and R5 are as defined above.

[0139] More preferred are compounds of formula (Id) and (If), and most preferred is the compound of formula (Id).

[0140] In another preferred embodiment, R2 is hydrogen.

[0141] In another preferred embodiment, R3 is selected from hydrogen, C1-3 alkyl, and C1-3 hydroxyalkyl; R3 is more preferably methyl or ethyl.

[0142] In other preferred embodiments, R1 is a C1-3 haloalkyl group, more preferably a trifluoromethyl group.

[0143] More preferably, the compound of formula (I) of the present invention is selected from:

[0144] Described herein are novel PARP7 inhibitors. Also described herein are pharmaceutically acceptable salts, solvates, esters, acids, metabolites, and prodrugs of the compounds.

[0145] The compounds of the present invention may exist in free form, such as free base, free acid or zwitterion form, or in the form of a salt. The salt may be any salt, an organic or inorganic addition salt, in particular any physiologically acceptable organic or inorganic addition salt commonly used in pharmacy.

[0146] Salts which are preferred for the purposes of the present invention are physiologically acceptable salts of the compounds according to the invention. However, salts which are themselves unsuitable for pharmaceutical applications but which can be used, for example, for isolating or purifying the compounds according to the invention are also included.

[0147] The term "pharmaceutically acceptable salt" refers to the relatively non-toxic inorganic or organic acid addition salts of compounds of the present invention. See, for example, SM Berge et al., "Pharmaceutical Salts, J. Pharm. Sci. 1977, 66, 1-19."

[0148] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, such as salts of the following acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid; or salts with organic acids, such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, gallic acid, nicotinic acid, pamoic acid, Salts of pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, p-pentanoic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.

[0149] Pharmaceutically acceptable salts of the compounds of the invention also include salts of customary bases, such as, for example and preferably, alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, N-methylglucamine, dimethylglucamine, ethylglucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, tris(hydroxymethyl)aminomethane, aminopropylene glycol, Sovak's base, and 1-amino-2,3,4-butanetriol.

[0150] The present invention includes all possible salts of the compounds according to the invention, either as a single salt or as any mixture of said salts in any ratio.

[0151] The present invention includes all possible deuterated compounds of the present invention, wherein the deuterium atom may be substituted on any carbon atom or nitrogen atom.

[0152] For the purposes of the present invention, solvate is the term used for those forms of the compounds of the invention which form complexes with solvent molecules by coordination in the solid or liquid state. Hydrates are a special form of solvates in which coordination occurs with water. Hydrates are preferred as solvates within the scope of the present invention.

[0153] Furthermore, the present invention also includes prodrugs of the compounds of the present invention. The term "prodrug" includes compounds which themselves may be biologically active or inert but which are converted (eg by metabolism or hydrolysis) into compounds of the present invention during their residence time in the body.

[0154] Furthermore, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as individual polymorphs or as mixtures of more than one polymorph in any ratio.

[0155] In the present specification, the structural formula of the compound represents a specific isomer for convenience in some cases, but the present invention includes all isomers such as geometric isomers, optical isomers based on asymmetric carbon atoms, stereoisomers, tautomers and the like.

[0156] The present invention relates to compounds with chirality, which may be in any configuration or as mixed racemates. When the compounds used according to the present invention contain more than one chiral center, they may exist in diastereomeric forms. The diastereomeric compounds may be separated by methods known to those skilled in the art (e.g., chromatography or crystallization), and the individual enantiomers may be separated as described above. The present invention includes the use of a variety of diastereomeric compounds used according to the present invention and mixtures thereof. The compounds used according to the present invention may exist in different tautomeric forms or in different geometric isomer forms, and the present invention includes the use of individual tautomers and / or geometric isomers of the compounds used according to the present invention and mixtures thereof. The compounds used according to the present invention may exist in zwitterionic form. The present invention includes the use of individual zwitterionic forms of the compounds used according to the present invention and mixtures thereof.

[0157] Screening and characterizing pharmaceutically acceptable salts, polymorphs and / or solvates can be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, microscopy, elemental analysis. The various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state). Various microscopic techniques include, but are not limited to, IR microscopy and Raman microscopy.

[0158] Therefore, the present invention includes all possible salts, polymorphs, metabolites, hydrates, deuterated compounds, solvates, or prodrugs (e.g., esters) of the compounds of the present invention, as individual salts, polymorphs, metabolites, hydrates, deuterated compounds, solvates, or prodrugs, or as mixtures of more than one salt, polymorph, metabolite, hydrate, deuterated compound, solvate, prodrug in any ratio.

[0159] Pharmaceutical uses of the present invention

[0160] The compounds of the present invention, or pharmaceutically acceptable salts, solvates, esters, acids, metabolites or prodrugs thereof, can selectively inhibit the enzymatic activity of PARP7 and are therefore useful in treating or preventing diseases, disorders or conditions that are regulated or affected by PARP7 activity or in which PARP7 activity or overexpression is involved.

[0161] In a preferred aspect, the disease, disorder or condition regulated or affected by PARP7 activity or in which PARP7 activity or overexpression is involved is a hyperproliferative disease, particularly cancer, including but not limited to squamous cell carcinoma of the lung, lung adenocarcinoma, large cell lung cancer, small cell lung cancer, head and neck squamous cell carcinoma, breast cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, colorectal cancer, melanoma, ovarian cancer, esophageal squamous cell carcinoma, gastric cancer, liver cancer, oral cancer, urothelial carcinoma, prostate cancer, bladder cancer, renal cell carcinoma, gastrointestinal stromal tumor, cervical cancer, endometrial cancer, rhabdomyosarcoma, mesothelioma, neuroendocrine tumor, fibrosarcoma, brain cancer and malignant glioma, etc.

[0162] In another preferred aspect, the disease, disorder or condition regulated or affected by PARP7 activity or in which PARP7 activity or overexpression is involved is an autoimmune or inflammatory disease, including but not limited to ulcerative colitis, Crohn's disease, multiple sclerosis, autoimmune liver disease, type I diabetes, bronchial asthma, systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, psoriasis, polymyositis and dermatomyositis, etc.

[0163] The compounds of the present invention can act systemically and / or locally. For this purpose, they can be administered in an appropriate manner, for example, by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic routes, or in the form of an implant or stent.

[0164] Preferably, in an embodiment of the present invention, the medicament comprising the compound of the present invention may be administered to a patient by at least one of injection, oral administration, inhalation, rectal administration, and transdermal administration.

[0165] Regardless of the selected administration route, the PARP7 inhibitor of the present invention and / or the pharmaceutical composition of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0166] When treating the patient according to the present invention, the amount of a given drug depends on many factors, such as specific dosage regimen, disease or disease type and severity thereof, the uniqueness (such as body weight) of the patient or host for treatment, but, according to specific surrounding circumstances, including for example the specific drug, route of administration, the disease for treatment and the patient or host for treatment adopted, dosage can be determined conventionally by methods known in the art. Usually, with regard to the dosage used for adult treatment, dosage is typically at 0.02-5000mg / days, such as the scope of about 1-1500mg / days. The required dose can be easily expressed as a dose or (or in a short time) administered simultaneously or in a divided dose at appropriate intervals, such as two, three, four doses or more divided doses every day. It will be appreciated by those skilled in the art that, although above-mentioned dosage range has been provided, specific effective dose can be suitably adjusted according to the patient's situation and in conjunction with physician's diagnosis.

[0167] Actual dosage levels and time courses of administration of the compounds of the invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response in a particular patient and is not toxic to the patient.

[0168] Pharmaceutical composition

[0169] Another aspect of the present invention relates to pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, and a pharmaceutically acceptable diluent, carrier or excipient, and optionally one or more other therapeutic agents.

[0170] The compounds of the present invention can be administered as a single agent or in combination with one or more other therapeutic agents, wherein the combination does not induce unacceptable side effects. The pharmaceutical composition includes administering a single pharmaceutical dosage formulation comprising the compound of the present invention and one or more other therapeutic agents, as well as administering the compound of the present invention and various other therapeutic agents in their own separate pharmaceutical dosage formulations. For example, the compound of formula (I) and the other therapeutic agents can be administered to a patient together in a single oral dosage composition such as a tablet or capsule, or each agent can be administered in a separate dosage formulation.

[0171] When separate dosage formulations are used, the compound of the invention and one or more other therapeutic agents may be administered at essentially the same time (eg, simultaneously) or at separately staggered times (eg, sequentially).

[0172] In particular, the compounds of the present invention may be used in fixed combinations or alone with other antineoplastic agents, such as alkylating agents, antimetabolites, plant-derived antineoplastic agents, hormonal therapeutics, topoisomerase inhibitors, camptothecin derivatives, kinase inhibitors, targeted drugs, antibodies, interferons and / or biological response modifiers, anti-angiogenic compounds and other antineoplastic drugs.

[0173] The compounds of the present invention may also be used in conjunction with radiation therapy and / or surgical intervention for the treatment of cancer.

[0174] Preparation of compounds

[0175] The compounds of the present invention can be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. In addition, the solvents, temperatures, and other reaction conditions given herein can be varied according to the skill in the art. As further guidance, the following synthetic methods can also be utilized.

[0176] The reactions can be used sequentially to provide the compounds described herein; or they can be used to synthesize fragments that are subsequently added by methods described herein and / or known in the art.

[0177] The starting materials for synthesizing the compounds described herein can be synthesized or obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using techniques and raw materials known to those skilled in the art. General methods for preparing the compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties into the molecules provided herein.

[0178] If desired, the reaction products can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. These products can be characterized using conventional methods, including physical constants and spectral data.

[0179] Non-limiting examples of synthetic schemes for preparing compounds of formula (I) are described below.

[0180] Example

[0181] The following specific non-limiting examples are to be interpreted as merely illustrative and not limiting in any way. Although no further detailed description is required, it is believed that one skilled in the art can fully utilize the present disclosure based on the description herein.

[0182] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The solvent for NMR determination was deuterated dimethyl sulfoxide (DMSO-d6 ), deuterated chloroform (CDCl3) or deuterated methanol (CD3OD).

[0183] Unless otherwise specified in the examples, solution refers to aqueous solution.

[0184] Unless otherwise specified in the examples, the reaction temperature is room temperature, for example, 20°C to 30°C.

[0185] In the examples, reaction progress was monitored using thin-layer chromatography (TLC) and LCMS. The developing solvents used in the reactions, the eluents used for column chromatography, and the developing solvent systems used for TLC purification included: A: dichloromethane / methanol, B: n-hexane / ethyl acetate, and C: petroleum ether / ethyl acetate. The volume ratio of the solvents was adjusted based on the polarity of the compound and could also be adjusted by adding a small amount of a basic or acidic reagent such as triethylamine or acetic acid.

[0186] Common abbreviations meanings:

[0187] CAN acetonitrile;

[0188] CDI N,N'-carbonyldiimidazole;

[0189] DCM dichloromethane;

[0190] DIAD diisopropyl azodicarboxylate;

[0191] DIPEA N,N-diisopropylethylamine;

[0192] DMAP 4-dimethylaminopyridine;

[0193] DMF N,N-dimethylformamide;

[0194] DMT-MM 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride;

[0195] DPPA diphenylphosphoryl azide;

[0196] HATU 2-(7-azabenzotriazole)-N,N,N,N'-tetramethyluronium hexafluorophosphate;

[0197] LDA lithium diisopropylamide;

[0198] mCPBA meta-chloroperbenzoic acid;

[0199] NBS N-bromosuccinimide;

[0200] NMM N-methylmorpholine;

[0201] NMP N-methylpyrrolidone;

[0202] PyBrOP Trispyrrolidinylphosphonium bromide hexafluorophosphate

[0203] SEMCl 2-(trimethylsilyl)ethoxymethyl chloride;

[0204] SFC supercritical fluid chromatography;

[0205] TBAF tetrabutylammonium fluoride;

[0206] TBSCl tert-butyldimethylsilyl chloride;

[0207] TEA triethylamine;

[0208] TFA trifluoroacetic acid;

[0209] THF tetrahydrofuran;

[0210] TMSI trimethylsilyl iodide;

[0211] (R)-RUCY XylBINAP Chloro{(R)-(+)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl}[(2R)-(-)-1-(4-methoxyphenyl)-1-(4-methoxyphenyl-KC)-3-methyl-1,2-butanediamine]ruthenium(II).

[0212] Example 1: Synthesis of intermediates

[0213] 1.1 Synthesis of Intermediate A

[0214] 5-((Aminooxy)methyl)-3-(trifluoromethyl)pyridin-2(1H)-one

[0215] Step A: Preparation of (6-methoxy-5-(trifluoromethyl)pyridin-3-yl)methanol

[0216] 5-Bromo-2-methoxy-3-(trifluoromethyl)pyridine (3.05 g, 11.91 mmol, 1.0 eq.) was dissolved in toluene (80 ml), and tetrakis(triphenylphosphine)palladium (277 mg, 0.24 mmol, 0.02 eq.) and (tributyltin)methanol (5.74 g, 17.87 mmol, 1.5 eq.) were added sequentially. The reaction mixture was allowed to react at 110°C for 4 hours. The reaction mixture was cooled to room temperature and quenched with water (200 ml). The mixture was then extracted with ethyl acetate (3 x 150 ml). The organic phases were combined, washed with saturated brine (500 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 4; v / v) to afford (6-methoxy-5-(trifluoromethyl)pyridin-3-yl)methanol (620 mg, white solid) in a yield of 25.1%.

[0217] LCMS:(ESI)[M+H] + =208.0.

[0218] 1 H NMR: (400MHz, CDCl3) δ8.30-8.25(m,1H),7.90(d,J=1.6Hz,1H),4.68(d,J=3.2Hz,2H),4.03(s,3H),1.97-1.89(m,1H).

[0219] Step B: Preparation of 2-((6-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)isoindoline-1,3-dione

[0220] (6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)methanol (570 mg, 2.75 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (18 ml). N-hydroxyphthalimide (449 mg, 2.75 mmol, 1.0 eq.) and triphenylphosphine (795 mg, 3.03 mmol, 1.1 eq.) were added sequentially. Finally, diisopropyl azodicarboxylate (613 mg, 3.03 mmol, 1.1 eq.) was added dropwise. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was quenched with water (100 ml) and extracted with ethyl acetate (3 x 80 ml). The organic phases were combined, washed with saturated brine (300 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1; V / V) to give 2-((6-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)isoindoline-1,3-dione (950 mg, white solid) in a yield of 98.0%.

[0221] LCMS:(ESI)[M+H] + =353.2.

[0222] 1 H NMR: (400MHz, CDCl3) δ8.33 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.80-7.74 (m, 2H), 7.72-7.66 (m, 2H), 5.11 (s, 2H), 3.98 (s, 3H).

[0223] Step C: Preparation of 2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)methoxy)isoindoline-1,3-dione

[0224] 2-((6-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)isoindoline-1,3-dione (1.05 g, 2.98 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (40 mL), and iodotrimethylsilane (543 mg, 3.87 mmol, 1.3 eq.) was added dropwise. The reaction mixture was allowed to react at 90°C for 4 hours. The reaction mixture was cooled to room temperature and quenched with water (200 mL). The mixture was then extracted with ethyl acetate (3 x 150 mL). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2; V / V) to give 2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)methoxy)isoindoline-1,3-dione (420 mg, white solid) in a yield of 41.7%.

[0225] LCMS:(ESI)[M+H] + =339.0.

[0226] 1 H NMR: (400MHz, DMSO-d6) δ12.37(s,1H),8.16-8.10(m,1H),7.92-7.88(m,1H),7.87-7.83(m,4H),4.99(s,2H).

[0227] Step D: Preparation of 5-((aminooxy)methyl)-3-(trifluoromethyl)pyridin-2(1H)-one (Intermediate A)

[0228] 2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)methoxy)isoindoline-1,3-dione (310 mg, 0.92 mmol, 1.0 eq.) was dissolved in a mixture of dichloromethane (10 mL) and methanol (5 mL). Hydrazine hydrate (85%, 325 mg, 5.52 mmol, 6.0 eq.) was added. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was concentrated, and dichloromethane (20 mL) was added to the residue, which was filtered and concentrated again. The crude product was isolated and purified by column chromatography (dichloromethane / methanol = 10 / 1; V / V) to afford Intermediate A, 5-((aminooxy)methyl)-3-(trifluoromethyl)pyridin-2(1H)-one (150 mg, white solid) in a yield of 78.6%.

[0229] LCMS:(ESI)[M+H] + =209.0.

[0230] 1 H NMR: (400MHz, DMSO-d6) δ12.22 (br s, 1H), 7.94-7.86 (m, 1H), 7.67 (d, J = 1.6Hz, 1H), 6.00 (s, 2H), 4.34 (s, 2H).

[0231] 1.2 Synthesis of intermediate B

[0232] 5-(1-(Aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one

[0233] Step A: Preparation of 1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanone

[0234] 5-Bromo-2-methoxy-3-(trifluoromethyl)pyridine (5.00 g, 19.53 mmol, 1.0 eq.) was dissolved in toluene (80 ml), and tetrakis(triphenylphosphine)palladium (451 mg, 0.39 mmol, 0.02 eq.) and tributyl(1-ethoxyethylene)tin (10.58 g, 29.30 mmol, 1.5 eq.) were added. Under nitrogen, the reaction mixture was allowed to react at 110°C for 4 hours. The reaction mixture was cooled to room temperature and quenched with water (200 ml). The mixture was then extracted with ethyl acetate (3 x 150 ml). The organic phases were combined, washed with saturated brine (500 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; V / V) to give 1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanone (4.75 g, white solid) in a yield of 100%.

[0235] LCMS:(ESI)[M+H] + =220.0.

[0236] 1 H NMR: (400MHz, DMSO-d6) δ9.06 (d, J = 2.0Hz, 1H), 8.45-8.39 (m, 1H), 4.09 (s, 3H), 2.63 (s, 3H).

[0237] Step B: Preparation of 1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanol

[0238] 1-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanone (3.70 g, 16.88 mmol, 1.0 eq.) was dissolved in methanol (50 ml), and sodium borohydride (1.53 g, 40.51 mmol, 2.4 eq.) was added. The reaction mixture was reacted at 25°C for 1 hour. The reaction mixture was quenched with water (200 ml) and adjusted to pH 7 with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (3 x 150 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1; v / v) to give 1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanol (1.86 g, colorless oil) in a yield of 49.8%.

[0239] LCMS:(ESI)[M+H] + =222.0.

[0240] 1 H NMR: (400MHz, DMSO-d6) δ 8.39 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 5.39 (d, J = 4.4 Hz, 1H), 4.90-4.75 (m, 1H), 3.97 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H).

[0241] Step C: Preparation of 2-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethoxy)isoindoline-1,3-dione

[0242] 1-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanol (2.72 g, 12.30 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (80 ml). N-hydroxyphthalimide (2.00 g, 12.30 mmol, 1.0 eq.) and triphenylphosphine (3.55 g, 13.53 mmol, 1.1 eq.) were added sequentially. Diisopropyl azodicarboxylate (2.74 g, 13.53 mmol, 1.1 eq.) was then added dropwise to the reaction mixture. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was quenched with water (200 ml) and extracted with ethyl acetate (3 x 150 ml). The organic phases were combined, washed with saturated brine (500 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1; V / V) to give 2-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethoxy)isoindoline-1,3-dione (4.50 g, white solid) in a yield of 99.9%.

[0243] LCMS:(ESI)[M+H] + =367.0.

[0244] 1 H NMR: (400MHz, DMSO-d6) δ 8.53 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.85-7.81 (m, 4H), 5.48-5.38 (m, 1H), 3.98 (s, 3H), 1.69 (d, J = 6.8Hz, 3H).

[0245] Step D: Preparation of 2-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione

[0246] 2-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethoxy)isoindoline-1,3-dione (4.30 g, 11.74 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (50 mL) and iodotrimethylsilane (6.10 g, 30.52 mmol, 2.60 eq.) was added. The reaction mixture was reacted at 90°C for 4 hours. The reaction mixture was cooled to room temperature and quenched with water (200 mL). The mixture was then extracted with ethyl acetate (3 x 150 mL). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2; V / V) to give 2-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione (2.86 g, white solid) in a yield of 69.2%.

[0247] LCMS:(ESI)[M+H] + =353.0.

[0248] 1 H NMR: (400MHz, DMSO-d6) δ 12.32 (s, 1H), 8.15 (d, J = 2.0Hz, 1H), 7.85 (s, 4H), 7.80 (d, J = 2.8Hz, 1H), 5.17 (q, J = 6.8Hz, 1H), 1.61 (d, J = 6.8Hz, 3H).

[0249] Step E: Preparation of 5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (Intermediate B)

[0250] 2-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione (2.80 g, 7.95 mmol, 1.0 eq.) was dissolved in a mixture of dichloromethane (40 mL) and methanol (20 mL). Hydrazine hydrate (85%, 2.81 g, 47.70 mmol, 6.0 eq.) was added. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was concentrated, and dichloromethane (20 mL) was added to the residue. The insoluble matter was removed by filtration, and the filtrate was concentrated. The crude product was isolated and purified by column chromatography (dichloromethane / methanol = 10 / 1; v / v) to afford Intermediate B, 5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (940 mg, white solid) in a yield of 53.2%.

[0251] LCMS:(ESI)[M+H] + =223.2.

[0252] 1.3 Synthesis of Intermediate C

[0253] O-(1-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)propyl)hydroxylamine

[0254] Step A: Preparation of 6-methoxy-5-(trifluoromethyl)nicotinaldehyde

[0255] n-Butyllithium (2.5 M, 1.97 ml, 4.92 mmol, 2.5 eq.) was dissolved in tetrahydrofuran (5 ml). Under nitrogen, the temperature was lowered to -78°C in a dry ice / ethanol bath. 5-Bromo-2-methoxy-3-(trifluoromethyl)pyridine (500 mg, 1.97 mmol, 1.0 eq.) was added dropwise. The reaction mixture was allowed to react at -78°C for 1 hour. N,N-Dimethylformamide (286 mg, 3.92 mmol, 2.0 eq.) was added to the reaction mixture. The reaction mixture was allowed to react at room temperature for another 2 hours. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (35 ml) and extracted with ethyl acetate (2 x 20 ml). The organic phase was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 85 / 15; V / V) to give 6-methoxy-5-(trifluoromethyl)nicotinaldehyde (170 mg, yellow oil) in a yield of 42.1%.

[0256] LCMS:(ESI)[M+H] + =222.2.

[0257] 1 H NMR (400MHz, DMSO-d6) δ10.07(s,1H),9.03(s,1H),8.48(s,1H),4.13(s,3H).

[0258] Step B: Preparation of 1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propan-1-ol

[0259] 6-Methoxy-5-(trifluoromethyl)nicotinaldehyde (170 mg, 0.83 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (3 mL), and ethylmagnesium bromide (1.25 mL, 1.25 mmol, 1.5 eq.) was added at 0°C. The reaction mixture was allowed to react at 0°C for 2 hours. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 85 / 15; v / v) to afford 1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propan-1-ol (80 mg, colorless oil) in a yield of 41.0%.

[0260] LCMS:(ESI)[M+H] + =236.2.

[0261] 1H NMR (400MHz, DMSO-d6) δ8.51-8.37(m,1H),8.06(d,J=2.2Hz,1H),5.43(d,J=4.7H z,1H),4.74-4.48(m,1H),4.05(s,3H),1.79-1.63(m,2H),0.90(t,J=7.4Hz,3H).

[0262] Step C: Preparation of 2-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)isoindoline-1,3-dione

[0263] 1-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)propan-1-ol (80 mg, 0.341 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (2 mL). N-hydroxyphthalimide (59 mg, 0.36 mmol, 1.05 eq.) and triphenylphosphine (100 mg, 0.38 mmol, 1.1 eq.) were added sequentially. Finally, diisopropyl azodicarboxylate (76 mg, 0.38 mmol, 1.1 eq.) was added dropwise at 0°C. The reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 x 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1; V / V) to give 2-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)isoindoline-1,3-dione (30 mg, colorless oil) in a yield of 23.2%.

[0264] LCMS:(ESI)[M+H] + =381.2.

[0265] Step D: Preparation of O-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propyl)hydroxylamine (Intermediate C)

[0266] 2-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)isoindoline-1,3-dione (250 mg, 0.66 mmol, 1.0 eq.) was dissolved in a mixture of dichloromethane (2 mL) and methanol (1 mL). Hydrazine hydrate (85%, 200 mg, 3.95 mmol, 6.0 eq.) was added. The reaction mixture was allowed to react at room temperature for 1 hour. The reaction mixture was concentrated, and dichloromethane (10 mL) was added to the residue, stirred, and filtered. The filtrate was concentrated again. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; v / v) to afford Intermediate C, O-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propyl)hydroxylamine (80 mg, white solid) in a yield of 48.7%.

[0267] LCMS:(ESI)[M+H] + =251.2.

[0268] 1 H NMR (400MHz, DMSO-d6) δ8.35(d,J=2.0Hz,1H),7.93(d,J=2.1Hz,1H),5.96(s,2H),4.43(t ,J=6.7Hz,1H),3.99(s,3H),1.88-1.70(m,1H),1.67-1.54(m,1H),0.81(t,J=7.4Hz,3H).

[0269] 1.4 Synthesis of Intermediate D

[0270] (R)-5-(1-(Aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one

[0271] Step A: Preparation of 1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanone

[0272] 5-Bromo-2-methoxy-3-(trifluoromethyl)pyridine (10.00 g, 39.06 mmol, 1.0 eq.) was dissolved in toluene (150 ml), and tetrakis(triphenylphosphine)palladium (1.80 g, 1.56 mmol, 0.04 eq.) and tributyl(1-ethoxyethylene)tin (21.16 g, 58.59 mmol, 1.5 eq.) were added. Under nitrogen, the reaction mixture was allowed to react at 110°C for 4 hours. The reaction mixture was cooled to room temperature and quenched with water (400 ml). The mixture was then extracted with ethyl acetate (3 x 350 ml). The organic phases were combined, washed with saturated brine (1.2 L), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; V / V) to give 1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanone (6.28 g, white solid) in a yield of 73.4%.

[0273] LCMS:(ESI)[M+H] + =220.0.

[0274] 1 H NMR: (400MHz, DMSO-d6) δ9.07 (d, J = 1.6 Hz, 1H), 8.43 (d, J = 1.6 Hz, 1H), 4.09 (s, 3H), 2.63 (s, 3H).

[0275] Step B: Preparation of (S)-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanol

[0276] 1-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanone (8.00 g, 36.36 mmol, 1.0 eq.) was dissolved in a mixed solvent of ethanol (75 mL) and propanol (63 mL). Potassium tert-butoxide (204 mg, 1.82 mmol, 0.05 eq.) and (R)-RUCY XylBINAP (213 mg, 0.18 mmol, 0.005 eq.) were added. The reaction mixture was allowed to react at 25°C under a hydrogen atmosphere for 18 hours. The reaction mixture was concentrated, the residue diluted with water (300 mL), and extracted with ethyl acetate (2 x 280 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1; V / V) to give (S)-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanol (6.85 g, colorless oil) in a yield of 85.2%.

[0277] LCMS:(ESI)[M+H] + =222.3.

[0278] 1H NMR: (400MHz, DMSO-d6) δ8.33(d,J=2.4Hz,1H),7.96(d,J=2.4Hz,1H),5.34(d,J=4.4Hz,1H),4.81-4.72(m,1H),3.91(s,3H),1.30(d,J=6.4Hz,3H).

[0279] Step C: Preparation of (R)-2-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethoxy)isoindoline-1,3-dione

[0280] (S)-1-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanol (11.00 g, 52.09 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (200 ml). N-hydroxyphthalimide (8.50 g, 52.09 mmol, 1.0 eq.) and triphenylphosphine (28.69 g, 109.39 mmol, 2.1 eq.) were added sequentially, followed by the dropwise addition of diisopropyl azodicarboxylate (21.07 g, 104.18 mmol, 2.0 eq.). The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was quenched with water (400 ml) and extracted with ethyl acetate (3 x 350 ml). The organic phases were combined, washed with saturated brine (1.2 L), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1; V / V) to give (R)-2-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethoxy)isoindoline-1,3-dione (7.20 g, white solid) in a yield of 37.7%.

[0281] LCMS:(ESI)[M+H] + =367.0.

[0282] 1 H NMR: (400MHz, CDCl3) δ8.35(d,J=2.0Hz,1H),8.17(d,J=2.0Hz,1H),7.85-7.78(m, 2H),7.77-7.72(m,2H),5.46(q,J=6.4Hz,1H),4.04(s,3H),1.75(d,J=6.8Hz,3H).

[0283] Step D: Preparation of (R)-2-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione

[0284] (R)-2-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethoxy)isoindoline-1,3-dione (7.20 g, 19.66 mmol, 1.0 eq.) was dissolved in dichloromethane (100 mL), and trimethylsilyl iodide (10.23 g, 51.12 mmol, 2.60 eq.) was added dropwise. The reaction mixture was allowed to react at 25°C for 18 hours. The reaction mixture was quenched with water (200 mL) and extracted with dichloromethane (3 x 150 mL). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2; V / V) to give (R)-2-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione (5.60 g, white solid) in a yield of 80.8%.

[0285] LCMS:(ESI)[M+H] + =353.3.

[0286] 1 H NMR: (400MHz, DMSO-d6) δ 12.37 (s, 1H), 8.21 (d, J = 2.0Hz, 1H), 7.90 (s, 4H), 7.86 (d, J = 2.4Hz, 1H), 5.23 (q, J = 6.4Hz, 1H), 1.67 (d, J = 6.8Hz, 3H).

[0287] Step E: Preparation of (R)-5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (Intermediate D)

[0288] (R)-2-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione (5.60 g, 15.89 mmol, 1.0 eq.) was dissolved in a mixture of dichloromethane (100 ml) and methanol (50 ml). Hydrazine hydrate (85%, 5.61 g, 95.34 mmol, 6.0 eq.) was added. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was concentrated, and dichloromethane (20 ml) was added to the residue. The insoluble matter was removed by filtration, and the filtrate was concentrated. The crude product was separated and purified by column chromatography (dichloromethane / methanol = 10 / 1; V / V) to give intermediate D, (R)-5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (3.30 g, white solid), yield: 93.5%.

[0289] LCMS:(ESI)[M+H] + =223.2.

[0290] 1 H NMR: (400MHz, DMSO-d6) δ 12.14 (s, 1H), 7.85 (d, J = 2.0Hz, 1H), 7.59 (d, J = 2.4Hz, 1H), 5.88 (s, 2H), 4.40 (q, J = 6.4Hz, 1H), 1.28 (d, J = 6.4Hz, 3H).

[0291] 1.5 Synthesis of Intermediate E

[0292] 2-(Piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride

[0293] Step A: Preparation of tert-butyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate

[0294] 2-Chloro-5-(trifluoromethyl)pyrimidine (4.00 g, 21.92 mmol, 1.05 eq.) and tert-butyl piperazine-1-carboxylate (3.89 g, 20.87 mmol, 1.0 eq.) were dissolved in N-methylpyrrolidone (40 ml), and potassium carbonate (3.46 g, 25.04 mmol, 1.2 eq.) was added. The reaction solution was heated to 80°C for 5 hours. The reaction solution was cooled to room temperature, and water (150 ml) was added to the reaction solution to precipitate a solid. The solid was collected by filtration and dissolved in ethyl acetate (150 ml), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (6.4 g, white solid) in a yield of 87.9%.

[0295] LCMS:(ESI)[M+H-56] + =276.8.

[0296] 1 H NMR: (400MHz, DMSO-d6) δ8.74(s,2H),3.89-3.79(m,4H),3.49-3.42(m,4H),1.44(s,9H).

[0297] Step B: Preparation of 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (Intermediate E)

[0298] Tert-butyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (3.00 g, 9.03 mmol, 1.0 eq.) was dissolved in dichloromethane (10 ml), and a 4 M dioxane hydrochloride solution (10 ml) was added. The reaction mixture was reacted at 25°C for 1 hour. The reaction mixture was concentrated to afford Intermediate E (2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine, 2.90 g, as a white solid) in a 100% yield.

[0299] LCMS:(ESI)[M+H] + =233.0.

[0300] 1.6 Synthesis of Intermediate F

[0301] 1-(5-(Trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid

[0302] Step A: Preparation of 1,2,3,6-tetrahydropyridine-4-carboxylic acid hydrochloride

[0303] Dissolve 1-(tert-Butyloxycarbonyl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (4.00 g, 17.60 mmol, 1.0 eq.) in dichloromethane (50 mL) and add a 4 M dioxane hydrochloride solution (20 mL). The reaction mixture is allowed to react at 25°C for 2 hours. The reaction mixture is concentrated to provide 1,2,3,6-tetrahydropyridine-4-carboxylic acid hydrochloride (2.87 g, white solid) in a 99.6% yield.

[0304] LCMS:(ESI)[M+H] + =128.4.

[0305] Step B: Preparation of 1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (Intermediate F)

[0306] 1,2,3,6-Tetrahydropyridine-4-carboxylic acid hydrochloride (2.87 g, 17.54 mmol, 1.0 eq.) was dissolved in dichloromethane (50 mL). N,N-diisopropylethylamine (10.20 g, 78.94 mmol, 4.5 eq.) and 2-chloro-5-trifluoromethylpyrimidine (3.20 g, 17.54 mmol, 1.0 eq.) were added sequentially. The reaction mixture was allowed to react at 25°C for 16 hours. The reaction mixture was diluted with water (80 mL), adjusted to pH 5 with dilute hydrochloric acid (1 M), and extracted with dichloromethane (2 x 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford Intermediate F, 1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (4.20 g, yellow solid) in an 87.7% yield.

[0307] LCMS:(ESI)[M+H] + =274.2.

[0308] 1 H NMR: (400MHz, DMSO-d6) δ 12.47 (s, 1H), 8.74 (s, 2H), 6.98-6.84 (m, 1H), 4.47-4.38 (m, 2H), 3.96 (t, J = 5.6Hz, 2H), 2.42-2.32 (m, 2H).

[0309] 1.7 Synthesis of Intermediate G

[0310] 7-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridine 5-oxide

[0311] Step A: Preparation of 7-bromo-1H-imidazo[4.5-c]pyridine

[0312] 5-Bromo-3,4-diaminopyridine (8.80 g, 46.80 mmol, 1.0 eq.) was dissolved in ethanol (70 ml), and triethyl orthoformate (110 ml) and L-camphorsulfonic acid (109 mg, 0.47 mmol, 0.01 eq.) were added. The reaction mixture was allowed to react at 80°C for 2 hours. The reaction mixture was concentrated to yield 7-bromo-1H-imidazo[4,5-c]pyridine (9.40 g, crude, white solid).

[0313] LCMS:(ESI)[M+H] + =198.0.

[0314] 1H NMR: (400MHz, DMSO-d6) δ8.92(s,1H),8.55(s,1H),8.46(s,1H).

[0315] Step B: Preparation of 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridine

[0316] 7-Bromo-1H-imidazo[4.5-c]pyridine (9.90 g, 50.00 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (150 mL) and cooled to 0°C under nitrogen. Sodium hydride (60%, 3.00 g, 75.00 mmol, 1.0 eq.) was added. The reaction mixture was allowed to react at 0°C for 0.5 hours. 2-(Trimethylsilyl)ethoxymethyl chloride (8.34 g, 50.00 mmol, 1.0 eq.) was added dropwise to the reaction mixture. The reaction mixture was continued at 30°C for 2 hours. The reaction mixture was cooled to 0°C in an ice bath, quenched with water (500 mL), and extracted with ethyl acetate (3 x 400 mL). The organic phases were combined, washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1; V / V) to give 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridine (9.60 g, colorless oil) in a yield of 58.5%.

[0317] LCMS:(ESI)[M+H] + =328.0.

[0318] 1 H NMR: (400MHz, CDCl3) δ9.02(s,1H),8.53(s,1H),8.06(s,1H),5.83(s,2H),3.62-3.56(m,2H),0.95-0.88(m,2H),0.05(s,6H).

[0319] Step C: Preparation of 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridine 5-oxide (Intermediate G)

[0320] 7-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridine (3.28 g, 10.00 mmol, 1.0 eq.) was dissolved in dichloromethane (50 mL), and m-chloroperbenzoic acid (85%, 4.06 g, 20.00 mmol, 2.0 eq.) was added. The reaction mixture was reacted at 30°C for 2 hours. The reaction mixture was quenched by the addition of aqueous sodium thiosulfate (0.5 M, 80 mL) and extracted with dichloromethane (2 x 100 mL). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (dichloromethane / methanol = 10 / 1; V / V) to give intermediate G, 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridine 5-oxide (3.40 g, yellow solid) in a yield of 98.8%.

[0321] LCMS:(ESI)[M+H] + =344.2.

[0322] 1.8 Synthesis of Intermediate H

[0323] 2-(1-(5-bromo-6-methoxypyridin-3-yl)ethoxy)isoindoline-1,3-dione

[0324] Step A: Preparation of 5-bromo-6-methoxynicotinic acid

[0325] Methyl 5-bromo-6-methoxynicotinate (1.5 g, 6.09 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (15 ml), and water (10 ml) and lithium hydroxide (292 mg, 12.19 mmol, 2.0 eq.) were added. The reaction mixture was reacted at 25°C for 16 hours. Water (10 ml) was added to the reaction mixture, and the pH was adjusted to 5 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 15 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford 5-bromo-6-methoxynicotinic acid (1.3 g, white solid) in a yield of 91.9%.

[0326] LCMS:(ESI)[M+H] + =232.0.

[0327] Step B: Preparation of 5-bromo-N,6-dimethoxy-N-methylnicotinamide

[0328] 5-Bromo-6-methoxynicotinic acid (1.3 g, 5.62 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (15 ml), and N,N-diisopropylethylamine (2.2 g, 16.88 mmol, 3.0 eq.), 2-(7-azabenzotriazole)-N,N,N,N'-tetramethyluronium hexafluorophosphate (2.5 g, 6.75 mmol, 1.2 eq.), and N,O-dimethylhydroxylamine hydrochloride (818 mg, 8.44 mmol, 1.5 eq.) were added. The reaction mixture was reacted at 25°C for 2 hours. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (3 x 30 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1; V / V) to give 5-bromo-N,6-dimethoxy-N-methylnicotinamide (1.5 g, yellow solid) in a yield of 96.9%.

[0329] LCMS:(ESI)[M+H] + =275.0.

[0330] 1 H NMR: (400MHz, CDCl3) δ 8.58 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 4.07 (s, 3H), 3.59 (s, 3H), 3.38 (s, 3H).

[0331] Step C: Preparation of 1-(5-bromo-6-methoxypyridin-3-yl)ethan-1-one

[0332] 5-Bromo-N,6-dimethoxy-N-methylnicotinamide (1.5 g, 5.45 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (20 mL), and methylmagnesium bromide (3 M, 2.7 mL, 8.18 mmol, 1.5 eq.) was added at 0°C. The reaction mixture was allowed to react at 0°C for 2 hours. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1; v / v) to afford 1-(5-bromo-6-methoxypyridin-3-yl)ethan-1-one (1 g, white solid) in an 80.0% yield.

[0333] LCMS:(ESI)[M+H] + =230.0.

[0334] Step D: Preparation of 1-(5-bromo-6-methoxypyridin-3-yl)ethan-1-ol

[0335] 1-(5-bromo-6-methoxypyridin-3-yl)ethan-1-one (1 g, 4.36 mmol, 1.0 eq.) was dissolved in methanol (10 ml), and sodium borohydride (414 mg, 10.91 mmol, 1.5 eq.) was added. The reaction mixture was reacted at 25°C for 1 hour. The reaction mixture was quenched with water (20 ml) and extracted with dichloromethane (3 x 20 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; v / v) to obtain 1-(5-bromo-6-methoxypyridin-3-yl)ethan-1-ol (900 mg, colorless oil) in a yield of 36.5%.

[0336] LCMS:(ESI)[M+H] + =232.2.

[0337] 1 H NMR: (400MHz, CDCl3) δ 8.00-7.96 (m, 1H), 7.84-7.79 (m, 1H), 4.81 (q, J = 6.5Hz, 1H), 3.93 (s, 3H), 1.43 (d, J = 6.5Hz, 3H).

[0338] Step E: Preparation of 2-(1-(5-bromo-6-methoxypyridin-3-yl)ethoxy)isoindoline-1,3-dione (Intermediate H)

[0339] 1-(5-Bromo-6-methoxypyridin-3-yl)ethan-1-ol (900 mg, 3.87 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (15 ml). N-hydroxyphthalimide (698 mg, 4.28 mmol, 1.3 eq.) and triphenylphosphine (1.5 g, 5.84 mmol, 1.5 eq.) were added sequentially, followed by the dropwise addition of diisopropyl azodicarboxylate (1.5 g, 7.79 mmol, 2.0 eq.). The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was quenched with water (20 ml) and extracted with ethyl acetate (3 x 20 ml). The organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1; V / V) to give intermediate H, 2-(1-(5-bromo-6-methoxypyridin-3-yl)ethoxy)isoindoline-1,3-dione (1 g, white solid) in a yield of 68.4%.

[0340] LCMS:(ESI)[M+H] + =377.0.

[0341] Example 2: Synthesis of Compound 2

[0342] N-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)methoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0343] Step A: Preparation of N-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)methoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0344] 5-((Aminooxy)methyl)-3-(trifluoromethyl)pyridin-2(1H)-one (100 mg, 0.48 mmol, 1.0 eq.) and 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (129 mg, 0.48 mmol, 1.0 eq.) were dissolved in tetrahydrofuran (20 ml). N,N-diisopropylethylamine (248 mg, 1.92 mmol, 4.0 eq.) and N,N'-carbonyldiimidazole (94 mg, 0.58 mmol, 1.2 eq.) were added sequentially. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was quenched with water (100 ml) and extracted with ethyl acetate (3 x 80 ml). The organic phases were combined, washed with saturated brine (300 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (dichloromethane / methanol = 10 / 1; V / V), and the crude product was further purified by prep-HPLC to give compound 2, N-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)methoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (74.58 mg, white solid), yield: 33.3%.

[0345] LCMS:(ESI)[M+H] + =467.2.

[0346] 1 H NMR: (400MHz, DMSO-d6) δ12.33(s,1H),9.83(s,1H),8.73(s,2H),8.06-8.00( m,1H),7.79-7.73(m,1H),4.56(s,2H),3.84-3.76(m,4H),3.43-3.35(m,4H).

[0347] Embodiment 3, 4, 5:

[0348] Synthesis of compound 3

[0349] N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0350] Synthesis of compound 4

[0351] (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0352] Synthesis of compound 5

[0353] (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0354] Step A: Preparation of N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0355] 5-(1-(Aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (660 mg, 2.97 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (30 mL). 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (400 mg, 1.49 mmol, 0.5 eq.), N,N-diisopropylethylamine (690 mg, 5.34 mmol, 2.0 eq.), and N,N'-carbonyldiimidazole (289 mg, 1.78 mmol, 0.6 eq.) were added sequentially. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 80 mL). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (dichloromethane / methanol = 10 / 1; V / V) to give a racemic crude product (410 mg, white solid) in a yield of 57.1%.

[0356] The crude racemic product (150 mg) was further purified by prep-HPLC (formic acid) to give compound 3, N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (125 mg, white solid).

[0357] LCMS:(ESI)[M+H] + =481.0.

[0358] 1 H NMR: (400MHz, DMSO-d6) δ12.30(s,1H),9.69(s,1H),8.72(s,2H),8.03(d,J=2.0Hz,1H),7.68(d, J=2.0Hz, 1H), 4.66 (q, J=6.4Hz, 1H), 3.85-3.71 (m, 4H), 3.38-3.33 (m, 4H), 1.39 (d, J= 6.8Hz, 3H).

[0359] Step B: Preparation of the isomers (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide and (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0360] The obtained racemic product compound 3, N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (95.0 mg, 0.198 mmol) was resolved by SFC to give:

[0361] Compound 4, (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (36.59 mg, white solid), yield: 38.5%;

[0362] LCMS:(ESI)[M+H] + =481.2.

[0363] 1 H NMR: (400MHz, DMSO-d6) δ12.35(s,1H),9.77(s,1H),8.79(s,2H),8.10(d,J=2.0Hz,1H),7.75(d, J=2.0Hz, 1H), 4.73 (q, J=6.4Hz, 1H), 3.93-3.79 (m, 4H), 3.48-3.41 (m, 4H), 1.46 (d, J= 6.4Hz, 3H).

[0364] Compound 5, (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (25.55 mg, white solid), yield: 26.9%.

[0365] LCMS:(ESI)[M+H] + =481.2.

[0366] 1 H NMR: (400MHz, DMSO-d6) δ12.31(s,1H),9.71(s,1H),8.74(s,2H),8.08-8.02(m,1H),7.73-7. 65(m,1H),4.68(q,J=6.4Hz,1H),3.86-3.74(m,4H),3.43-3.35(m,4H),1.41(d,J=6.4Hz,3H).

[0367] Embodiment 6, 7, 8:

[0368] Synthesis of compound 6

[0369] N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0370] Synthesis of compound 7

[0371] (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0372] Synthesis of compound 8

[0373] (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0374] Step A: Preparation of N-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0375] O-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propyl)hydroxylamine (200 mg, 0.8 mmol, 1.0 eq.), N,N'-carbonyldiimidazole (155 mg, 0.96 mmol, 1.2 eq.), and N,N-diisopropylethylamine (413 mg, 3.2 mmol, 4.0 eq.) were dissolved in tetrahydrofuran (7 ml), and the reaction mixture was reacted at 25°C for 1 hour. Finally, 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (215 mg, 0.8 mmol, 1.0 eq.) was added to the reaction mixture. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was quenched with water (20 ml) and extracted with ethyl acetate (3 x 20 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 4; V / V) to give N-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (330 mg, colorless oil) in a yield of 73.3%.

[0376] LCMS:(ESI)[M+H] + =531.2.

[0377] 1 H NMR (400MHz, DMSO-d6) δ9.69(s,1H),8.71(d,J=0.6Hz,2H),8.41(d,J=1.9Hz,1H),8.08(d,J=2.0Hz,1H),4.70(t,J=6.8 Hz,1H),3.98(s,3H),3.80-3.68(m,4H),3.32-3.28(m,4H),1.93-1.84(m,1H),1.78-1.66(m,1H),0.88(t,J=7.4Hz,3H).

[0378] Step B: Preparation of N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0379] N-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (330 mg, 0.65 mmol, 1.0 eq.) was dissolved in dichloromethane (6 ml) and trimethylsilyl iodide (0.3 ml) was added. The reaction mixture was allowed to react at room temperature for 3 hours. The reaction mixture was quenched with water (10 ml) and extracted with ethyl acetate (3 x 10 ml). The organic phases were combined, washed with saturated brine (2 x 10 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to give racemic compound 6, N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (35 mg, white solid), yield: 10.9%.

[0380] LCMS:(ESI)[M+H] + =495.2.

[0381] 1 H NMR (400MHz, DMSO-d6) δ12.30(s,1H),9.64(s,1H),8.72(d,J=0.7Hz,2H),7.92(d,J=2.0Hz,1H),7.67(d,J=2.0Hz,1H),4 .44(t,J=6.9Hz,1H),3.82-3.69(m,4H),3.32-3.27(m,4H),1.95-1.75(m,1H),1.71-1.53(m,1H),0.86(t,J=7.4Hz,3H).

[0382] Step C: Preparation of (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide and (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0383] Racemic compound 6, N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (35 mg, 0.07 mmol, 1.0 eq.) was resolved by SFC to give:

[0384] Isomer 7, (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (10.8 mg, white solid), yield: 30.8%;

[0385] LCMS:(ESI)[M+H] + =495.2.

[0386] 1 H NMR (400MHz, DMSO-d6) δ12.29(s,1H),9.63(s,1H),8.71(s,2H),7.92(s,1H),7.66(s,1H),4.44(t,1H),3.80-3. 72(m,4H),3.32-3.28(m,4H),1.84(dt,J=14.2,7.2Hz,1H),1.63(dt,J=14.1,7.2Hz,1H),0.86(t,J=7.3Hz,3H).

[0387] Isomer 8, (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (11.83 mg, white solid), yield: 33.7%.

[0388] LCMS:(ESI)[M+H] + =495.2.

[0389] 1 H NMR (400MHz, DMSO-d6) δ12.29(s,1H),9.63(s,1H),8.71(s,2H),7.92(s,1H),7.67(s,1H),4.44(t,J=6.9H z,1H),3.81-3.70(m,4H),3.31-3.28(m,4H),1.89-1.77(m,1H),1.69-1.58(m,1H),0.86(t,J=7.4Hz,3H).

[0390] Embodiment 9, 10, 11:

[0391] Synthesis of compound 9

[0392] 2-Methyl-N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0393] Synthesis of compound 10

[0394] (S)-2-Methyl-N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0395] Synthesis of compound 11

[0396] (R)-2-Methyl-N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0397] Step A: Preparation of tert-butyl 2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate

[0398] 2-Chloro-5-(trifluoromethyl)pyrimidine (1 g, 5.49 mmol, 1.0 eq.) was dissolved in dichloromethane (15 ml), and triethylamine (1.1 g, 10.98 mmol, 4.0 eq.) and tert-butyl 2-methylpiperazine-1-carboxylate (1.2 g, 6.04 mmol, 1.1 eq.) were added sequentially. The reaction mixture was allowed to react at 25°C for 16 hours. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (2 x 20 ml). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1; v / v) to afford tert-butyl 2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (1.8 g, white solid) in a yield of 94.7%.

[0399] LCMS:(ESI)[M+H-100] + =247.4.

[0400] 1 H NMR: (400MHz, DMSO-d6) δ8.71(s,2H),4.58-4.43(m,2H),4.32-4.19(m,1H),3.88-3. 77(m,1H),3.33-3.25(m,1H),3.15-3.04(m,2H),1.43(s,9H),1.04(d,J=6.7Hz,3H).

[0401] Step B: Preparation of 2-(3-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride

[0402] Tert-butyl 2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (1.8 g, 5.20 mmol, 1.0 eq.) was dissolved in a 4M hydrochloric acid solution in dioxane (15 ml). The reaction mixture was allowed to react at 25°C for 2 hours. The reaction mixture was concentrated to yield 2-(3-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (1.6 g, crude product, white solid).

[0403] LCMS:(ESI)[M+H] + =274.4.

[0404] Step C: Preparation of 2-methyl-N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0405] (R)-5-(1-(Aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (200 mg, 0.900 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (5 mL), and N,N'-carbonyldiimidazole (160 mg, 0.990 mmol, 1.1 eq.) was added, followed by stirring at 25°C for 20 minutes. N,N-diisopropylethylamine (464 mg, 3.603 mmol, 4.0 eq.) and 2-(3-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (279 mg, 0.990 mmol, 1.0 eq.) were added to the reaction solution. The reaction was continued at 25°C for 2 hours. The reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to give compound 9, 2-methyl-N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (210 mg, white solid), yield: 47.2%.

[0406] LCMS:(ESI)[M+H] + =495.2.

[0407] 1H NMR: (400MHz, DMSO-d6) δ12.28(s,1H),9.67-9.60(m,1H),8.70(s,2H),8.02(s,1H),7.67(d,J=2.2Hz,1H),4.69-4.62(m,1H),4.57-4.49(m, 1H),4.48-4.41(m,1H),4.22-4.13(m,1H),3.72-3.63(m,1H),3.25-3. 18(m,1H),3.08-2.95(m,2H),1.39(d,J=6.6Hz,3H),1.01-0.93(m,3H).

[0408] Step D: Preparation of (S)-2-methyl-N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide and (R)-2-methyl-N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0409] 2-Methyl-N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (120 mg, 0.242 mmol, 1.0 eq.) was resolved by SFC to give:

[0410] Isomer 10, (S)-2-methyl-N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (25 mg, white solid), yield: 20.8%;

[0411] LCMS:(ESI)[M+H] + =495.2.

[0412] 1H NMR: (400MHz, DMSO-d6) δ12.28(s,1H),9.65(s,1H),8.70(s,2H),8.02(d, J=2.0Hz,1H),7.67(d,J=2.1Hz,1H),4.70-4.62(m,1H),4.52(d,J=9.9Hz,1 H),4.46(d,J=13.2Hz,1H),4.23-4.11(m,1H),3.73-3.59(m,1H),3.21(dd, J=13.3,3.7Hz,1H),3.07-2.94(m,2H),1.39(d,3H),0.98(d,J=6.7Hz,3H).

[0413] Isomer 11, (R)-2-methyl-N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (20 mg, white solid), yield: 16.6%.

[0414] LCMS:(ESI)[M+H] + =495.2.

[0415] 1 H NMR: (400MHz, DMSO-d6) δ12.28(s,1H),9.63(s,1H),8.71(s,2H),8.01(d, J=1.8Hz,1H),7.67(d,J=2.0Hz,1H),4.69-4.60(m,1H),4.52(d,J=9.8Hz,1 H),4.45(d,J=13.2Hz,1H),4.22-4.11(m,1H),3.73-3.63(m,1H),3.22(dd, J=13.3,3.8Hz,1H),3.09-2.95(m,2H),1.39(d,3H),0.96(d,J=6.6Hz,3H).

[0416] Embodiment 12, 13, 14:

[0417] Synthesis of compound 12

[0418] N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxamide

[0419] Synthesis of compound 13

[0420] (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxamide

[0421] Synthesis of compound 14

[0422] (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxamide

[0423] Step A: Preparation of 7-chloro-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine

[0424] 5-(Trifluoromethyl)-3-nitro-2-chloropyridine (4.00 g, 17.66 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (80 mL). Under nitrogen, the temperature was lowered to -78°C, and vinylmagnesium bromide (1 M, 106 mL, 106.00 mmol, 6.0 eq.) was added dropwise. The reaction mixture was allowed to react at -20°C for 1 hour. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; v / v) to afford 7-chloro-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine (900 mg, yellow solid) in a yield of 23.1%.

[0425] LCMS:(ESI)[M+H] + =221.0.

[0426] 1 H NMR: (400MHz, CDCl3) δ9.00 (s, 1H), 8.33 (d, J = 1.2Hz, 1H), 7.58-7.56 (m, 1H), 6.84-6.81 (m, 1H).

[0427] Step B: Preparation of tert-butyl 4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylate

[0428] 7-Chloro-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine (300 mg, 1.36 mmol, 1.0 eq.) was dissolved in N-methylpyrrolidone (5 mL). N,N-diisopropylethylamine (704 mg, 5.44 mmol, 4.0 eq.) and 1-Boc-piperazine (760 mg, 4.08 mmol, 3.0 eq.) were added sequentially. The reaction mixture was reacted at 135°C for 18 hours. The reaction mixture was cooled to room temperature and diluted with water (80 mL). The mixture was extracted with ethyl acetate (2 x 80 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1; V / V) to give tert-butyl 4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylate (500 mg, yellow solid) in a yield of 99.3%.

[0429] LCMS:(ESI)[M+H] + =371.0.

[0430] 1 H NMR: (400MHz, CDCl3) δ10.90 (s, 1H), 8.09 (d, J = 1.2Hz, 1H), 7.32 (t, J = 2.8Hz ,1H),6.62-6.56(m,1H),3.62-3.57(m,4H),3.54-3.50(m,4H),1.46(s,9H).

[0431] Step C: Preparation of 7-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride

[0432] Tert-butyl 4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxylate (300 mg, 0.81 mmol, 1.0 eq.) was dissolved in dichloromethane (2 mL), and a 4M solution of dioxane hydrochloride (4 mL) was added. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was concentrated to yield 7-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (300 mg, crude product, yellow solid).

[0433] LCMS:(ESI)[M+H] + =271.0.

[0434] Step D: Preparation of N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxamide

[0435] 5-(1-(Aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (71 mg, 0.32 mmol, 1.1 eq.) was dissolved in tetrahydrofuran (5 mL), and N,N'-carbonyldiimidazole (52 mg, 0.32 mmol, 1.1 eq.) was added. The reaction mixture was allowed to react at 25°C for 20 minutes. N,N-diisopropylethylamine (150 mg, 1.16 mmol, 4.0 eq.) and 7-(piperazin-1-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (90 mg, 0.29 mmol, 1.0 eq.) were added to the reaction mixture. The reaction mixture was continued at 25°C for 2 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, washed with saturated brine (120 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to give racemic compound 12, N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxamide (47 mg, white solid), in a yield of 30.9%.

[0436] LCMS:(ESI)[M+H] + =519.2.

[0437] 1 H NMR: (400MHz, DMSO-d6) δ12.30(s,1H),11.83(s,1H),9.70(s,1H),8.09-7.99(m,2H),7. 71-7.62(m,2H),6.52(s,1H),4.67(q,J=6.4Hz,1H),3.45(s,8H),1.40(d,J=6.8Hz,3H).

[0438] Step E: Preparation of (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxamide and (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxamide

[0439] N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxamide (40 mg, 0.08 mmol, 1.0 eq.) was resolved by SFC to give:

[0440] Isomer 13, (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxamide (9.84 mg, white solid), yield: 24.6%;

[0441] LCMS:(ESI)[M+H] + =519.2.

[0442] 1 H NMR: (400MHz, DMSO-d6) δ12.30(s,1H),11.82(s,1H),9.69(s,1H),8.08-8.00(m,2H),7. 69-7.62(m,2H),6.52(s,1H),4.67(q,J=6.4Hz,1H),3.45(s,8H),1.40(d,J=6.4Hz,3H).

[0443] And isomer 14, (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperazine-1-carboxamide (5.51 mg, white solid), yield: 13.8%.

[0444] LCMS:(ESI)[M+H] + =519.2.

[0445] 1 H NMR: (400MHz, DMSO-d6) δ12.30(s,1H),11.83(s,1H),9.70(s,1H),8.07-8.02(m,2H),7.69(s,1H), 7.65(t,J=2.8Hz,1H),6.56-6.50(m,1H),4.68(q,J=6.4Hz,1H),3.46(s,8H),1.40(d,J=6.8Hz,3H).

[0446] Example 15: Synthesis of Compound 15

[0447] (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(7-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazine-1-carboxamide

[0448] Step A: Preparation of tert-butyl 4-(7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazine-1-carboxylate

[0449] 7-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridine 5-oxide (3.00 g, 8.71 mmol, 1.0 eq.) was dissolved in dichloromethane (30 mL). 1-Boc-piperazine (16.23 g, 87.14 mmol, 10.0 eq.), tripyrrolidinylphosphonium bromide hexafluorophosphate (5.28 g, 11.32 mmol, 1.3 eq.), and potassium carbonate (3.61 g, 26.13 mmol, 3.0 eq.) were added sequentially. The reaction mixture was allowed to react at 30°C for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; V / V) to give tert-butyl 4-(7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazine-1-carboxylate (4.10 g, yellow solid) in a yield of 91.8%.

[0450] LCMS:(ESI)[M+H] + =512.2.

[0451] 1 H NMR: (400MHz, CDCl3) δ8.03(s,1H),7.86(s,1H),5.83(s,2H),4.16-4.05(m,4H),3.65-3.56(m,6H),1.52(s,9H),1.00-0.91(m,2H),0.00(s,9H).

[0452] Step B: Preparation of tert-butyl 4-(7-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazine-1-carboxylate

[0453] Tert-butyl 4-(7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazine-1-carboxylate (1.60 g, 3.12 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (20 ml), and cuprous iodide (297 mg, 1.56 mmol, 0.5 eq.) and methyl fluorosulfonyldifluoroacetate (2.40 g, 12.48 mmol, 4.0 eq.) were added. Under nitrogen, the reaction mixture was allowed to react at 100°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (80 ml), and extracted with ethyl acetate (2 x 100 ml). The organic phases were combined, washed with saturated brine (300 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; V / V) to give tert-butyl 4-(7-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazine-1-carboxylate (400 mg, yellow solid) in a yield of 25.5%.

[0454] LCMS:(ESI)[M+H] + =502.2.

[0455] 1 H NMR: (400MHz, DMSO-d6)δ8.55(s,1H),8.28(s,1H),5.67(s,2H),4.40-4.22(m,4H), 3.64-3.57(m,2H),3.56-3.48(m,4H),1.50(s,9H),0.92-0.87(m,2H),0.00(s,9H).

[0456] Step C: Preparation of 4-(piperazin-1-yl)-7-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine hydrochloride

[0457] Tert-butyl 4-(7-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazine-1-carboxylate (400 mg, 0.80 mmol, 1.0 eq.) was dissolved in dichloromethane (5 mL), and a 4M solution of dioxane hydrochloride (20 mL) was added. The reaction mixture was allowed to react at 30°C for 2 hours. The reaction mixture was concentrated to give 4-(piperazin-1-yl)-7-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine hydrochloride (280 mg, crude product, white solid).

[0458] LCMS:(ESI)[M+H] + =272.4.

[0459] Step D: Preparation of (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(7-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazine-1-carboxamide

[0460] (R)-5-(1-(Aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (70 mg, 0.32 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (10 mL), and N,N'-carbonyldiimidazole (57 mg, 0.35 mmol, 1.1 eq.) was added. The reaction mixture was reacted at 30°C for 20 minutes. N,N-diisopropylethylamine (165 mg, 1.28 mmol, 4.0 eq.) and 4-(piperazin-1-yl)-7-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine hydrochloride (98 mg, 0.32 mmol, 1.0 eq.) were added to the reaction mixture. The reaction mixture was reacted at 30°C for 2 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, washed with saturated brine (120 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to give Compound 15, (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-4-(7-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazine-1-carboxamide (49.22 mg, white solid), in a yield of 33.1%.

[0461] LCMS:(ESI)[M+H] + =520.2.

[0462] 1 H NMR: (400MHz, DMSO-d6) δ13.21(s,1H),12.30(s,1H),9.68(s,1H),8.26(s,1H),8.12(d,J=1.2Hz,1H),8.04(d,J= 2.0Hz,1H),7.72-7.66(m,1H),4.67(q,J=6.8Hz,1H),4.32-4.12(m,4H),3.41-3.35(m,4H),1.40(d,J=6.8Hz,3H).

[0463] Example 16: Synthesis of Compound 16

[0464] N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

[0465] Step A: Preparation of tert-butyl 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0466] 2-Chloro-5-(trifluoromethyl)pyrimidine (819 mg, 4.49 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL). Triethylamine (908 mg, 8.97 mmol, 2.0 eq.) and 8-BOC-3,8-diazabicyclo[3.2.1]octane (1.00 g, 4.71 mmol, 1.05 eq.) were added sequentially. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was diluted with saturated aqueous ammonium chloride (50 mL) and extracted with dichloromethane (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1; V / V) to give tert-butyl 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.45 g, white solid) in a yield of 90.2%.

[0467] LCMS:(ESI)[M+H-56] + =303.2.

[0468] 1 H NMR: (400MHz, CDCl3) δ8.48(s,2H),4.53-4.45(m,2H),4.45-4.22(m,2H),3.26-3.11(m,2H),1.99-1.87(m,2H),1.69-1.62(m,2H),1.49(s,9H).

[0469] Step B: Preparation of 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane hydrochloride

[0470] Tert-butyl 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 1.95 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL), and a 4M dioxane hydrochloride solution (5 mL) was added. The reaction mixture was allowed to react at 25°C for 1 hour. A solid precipitated, which was filtered and vacuum-dried to yield 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (500 mg, white solid) in a yield of 86.9%.

[0471] LCMS:(ESI)[M+H] + =259.2.

[0472] Step C: Preparation of N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

[0473] (R)-5-(1-(Aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (50 mg, 0.22 mmol, 1.1 eq.) was dissolved in tetrahydrofuran (0.5 ml), and N,N'-carbonyldiimidazole (36 mg, 0.22 mmol, 1.1 eq.) was added. The reaction mixture was allowed to react at 25°C for 0.5 hours. A solution of 3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (60 mg, 0.20 mmol, 1.0 eq.) and N,N-diisopropylethylamine (105 mg, 0.81 mmol, 4.0 eq.) in tetrahydrofuran (0.5 ml) was added to the reaction mixture. The reaction mixture was continued at 25°C for 1 hour. The reaction solution was quenched with water (50 ml) and extracted with ethyl acetate (3×30 ml). The organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate and concentrated. The crude product was separated and purified by prep-HPLC to give compound 16, N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide (5.31 mg, white solid), yield: 5.2%.

[0474] LCMS:(ESI)[M+H] + =507.0.

[0475] 1H NMR: (400MHz, DMSO-d6) δ12.27(s,1H),9.81(s,1H),8.70(d,J=0.4Hz,2H),8.00(d,J=2.0Hz,1H),7.68(d,J=2.0Hz,1H),4.69(q,J=6.4H z,1H),4.39-4.31(m,2H),4.27-4.21(m,2H),3.03(dd,J=12.0,8.8Hz,2H),1.77-1.70(m,2H),1.54-1.47(m,2H),1.39(d,J=6.4Hz,3H).

[0476] According to the same method for synthesizing compound 16, the following compounds 17 and 18 were prepared using (R)-5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (Intermediate D) and appropriate amine compounds.

[0477] Example 17: Compound 17

[0478] N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-8-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxamide

[0479] LCMS:(ESI)[M+H] + =507.2.

[0480] 1 H NMR: (400MHz, DMSO-d6) δ12.30(s,1H),9.55(s,1H),8.72(d,J=0.8Hz,2H),8.01(d,J=2.0Hz,1H),7.67(d,J=2.0Hz,1H),4.73(s,2H),4. 65(q,J=6.4Hz,1H),3.65(dd,J=24.4,12.0Hz,2H),2.92(t,J=12.0Hz,2H),1.93-1.80(m,2H),1.71-1.60(m,2H),1.38(d,J=6.8Hz,3H).

[0481] Example 18: Compound 18

[0482] N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide

[0483] LCMS:(ESI)[M+H] + =493.2.

[0484] 1 H NMR: (400MHz, DMSO-d6) δ12.18(s,1H),9.75(s,1H),8.74(s,2H),7.90(d,J=2.4Hz,1H),7.54(d,J=2.0Hz,1H),4.56(q,J=6.4Hz,1H),4 .32-4.21(m,2H),4.01(t,J=12.0Hz,2H),3.55(dd,J=12.4,8.4Hz,2H),2.62-2.54(m,1H),1.49(d,J=8.8Hz,1H),1.30(d,J=6.8Hz,3H).

[0485] Example 19: Synthesis of Compound 19

[0486] (R)-4-(5-acetylaminopyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)piperazine-1-carboxamide

[0487] Step A: Preparation of tert-butyl 4-(5-nitropyrimidin-2-yl)piperazine-1-carboxylate

[0488] 1-Boc-piperazine (583 mg, 3.31 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (1.21 g, 9.39 mmol, 3.0 eq.) and 2-chloro-5-nitropyrimidine (500 mg, 3.31 mmol, 1.0 eq.) were added sequentially. The reaction mixture was allowed to react at 25°C for 18 hours. The reaction mixture was quenched with water (80 mL), adjusted to pH 6 with dilute hydrochloric acid (1 M), and extracted with ethyl acetate (2 x 70 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford tert-butyl 4-(5-nitropyrimidin-2-yl)piperazine-1-carboxylate (960 mg, light yellow solid) in a yield of 93.8%.

[0489] LCMS:(ESI)[M+H-56] + =254.0.

[0490] 1 H NMR: (400MHz, DMSO-d6) δ9.13(s,2H),3.94-3.90(m,4H),3.48-3.44(m,4H),1.43(s,9H).

[0491] Step B: Preparation of tert-butyl 4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylate

[0492] tert-Butyl 4-(5-nitropyrimidin-2-yl)piperazine-1-carboxylate (460 mg, 1.49 mmol, 1.0 eq.) was dissolved in methanol (10 ml) and palladium on carbon (46 mg) was added under nitrogen. The reaction solution was degassed with a hydrogen balloon and allowed to react at 25°C under a hydrogen atmosphere for 3 hours. The reaction solution was filtered to remove the palladium on carbon, and the filtrate was concentrated to give tert-butyl 4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylate (400 mg, yellow solid) in a yield of 96.2%.

[0493] LCMS:(ESI)[M+H] + =280.2.

[0494] 1 H NMR: (400MHz, CDCl3) δ8.00 (s, 2H), 3.70-3.65 (m, 4H), 3.55-3.46 (m, 4H), 3.20 (s, 2H), 1.50 (s, 9H).

[0495] Step C: Preparation of tert-butyl 4-(5-acetylaminopyrimidin-2-yl)piperazine-1-carboxylate

[0496] tert-Butyl 4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylate (370 mg, 1.32 mmol, 1.0 eq.) was dissolved in dichloromethane (20 mL). 4-Dimethylaminopyridine (9 mg, 0.07 mmol, 0.05 eq.), pyridine (157 mg, 1.98 mmol, 1.5 eq.), and acetic anhydride (202 mg, 1.98 mmol, 1.5 eq.) were added sequentially. The reaction mixture was allowed to react at 25°C for 18 hours. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (2 x 45 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford tert-butyl 4-(5-acetamidopyrimidin-2-yl)piperazine-1-carboxylate (370 mg, white solid) in a yield of 87.3%.

[0497] LCMS:(ESI)[M+H] + =322.2.

[0498] 1 H NMR: (400MHz, CDCl3) δ8.42(s,2H),7.12(s,1H),3.80-3.73(m,4H),3.51-3.44(m,4H),2.17(s,3H),1.48(s,9H).

[0499] Step D: Preparation of N-(2-(piperazin-1-yl)pyrimidin-5-yl)acetamide hydrochloride

[0500] Tert-butyl 4-(5-acetamidopyrimidin-2-yl)piperazine-1-carboxylate (370 mg, 1.15 mmol, 1.0 eq.) was dissolved in dioxane (2 ml), and a 4 M solution of hydrochloric acid in dioxane (6 ml) was added. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was concentrated to yield N-(2-(piperazin-1-yl)pyrimidin-5-yl)acetamide hydrochloride (330 mg, crude product, white solid).

[0501] LCMS:(ESI)[M+H] + =222.4.

[0502] Step E: Preparation of (R)-4-(5-acetylaminopyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)piperazine-1-carboxamide

[0503] (R)-5-(1-(Aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (389 mg, 1.75 mmol, 1.5 eq.) was dissolved in tetrahydrofuran (10 ml), and N,N'-carbonyldiimidazole (227 mg, 1.40 mmol, 1.2 eq.) was added. The reaction mixture was allowed to react at 25°C for 0.5 h. N-(2-(piperazin-1-yl)pyrimidin-5-yl)acetamide hydrochloride (300 mg, 1.17 mmol, 1.0 eq.) and N,N-diisopropylethylamine (605 mg, 4.68 mmol, 4.0 eq.) were added to the reaction mixture. The reaction mixture was continued at 25°C for 1 h. The reaction mixture was quenched with water (60 ml) and extracted with ethyl acetate (2 x 50 ml). The organic phases were combined, washed with saturated brine (2 x 100 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to yield compound 19, (R)-4-(5-acetamidopyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)piperazine-1-carboxamide (11.49 mg, white solid), in a yield of 2.1%.

[0504] LCMS:(ESI)[M+H] + =470.2.

[0505] 1H NMR: (400MHz, DMSO-d6) δ9.87(s,1H),9.65(s,1H),8.51(s,2H),8.01-7.94(m,1H),7.72-7.65(m,1 H), 4.64 (q, J = 6.4Hz, 1H), 3.66-3.58 (m, 4H), 3.31-3.28 (m, 4H), 2.01 (s, 3H), 1.38 (d, J = 6.8Hz, 3H).

[0506] Example 20: Synthesis of Compound 20

[0507] (R)-4-(5-cyclopropylpyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)piperazine-1-carboxamide

[0508] Step A: Preparation of tert-butyl 4-(5-cyclopropylpyrimidin-2-yl)piperazine-1-carboxylate

[0509] 2-Chloro-5-cyclopropylpyrimidine (75 mg, 0.488 mmol, 1.0 eq.) was dissolved in ethanol (3 mL), and N,N-diisopropylethylamine (190 mg, 1.47 mmol, 3.0 eq.) and tert-butyl piperazine-1-carboxylate (100 mg, 0.54 mmol, 1.1 eq.) were added sequentially. The reaction mixture was reacted at 80°C for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 88 / 12; v / v) to obtain tert-butyl 4-(5-cyclopropylpyrimidin-2-yl)piperazine-1-carboxylate (100 mg, white solid) in a yield of 68.3%.

[0510] LCMS:(ESI)[M+H] + =249.2.

[0511] Step B: Preparation of 5-cyclopropyl-2-(piperazin-1-yl)pyrimidine hydrochloride

[0512] Dissolve tert-butyl 4-(5-cyclopropylpyrimidin-2-yl)piperazine-1-carboxylate (100 mg, 0.329 mmol, 1.0 eq.) in dichloromethane (2 ml), and add a dioxane hydrochloride solution (2 ml). The reaction mixture is allowed to react at 25°C for 1 hour. The reaction mixture is concentrated to yield 5-cyclopropyl-2-(piperazin-1-yl)pyrimidine hydrochloride (90 mg, crude, white solid).

[0513] LCMS:(ESI)[M+H]+ =205.3.

[0514] Step C: (R)-4-(5-cyclopropylpyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl ...

[0515] Preparation of (ethoxy)piperazine-1-carboxamide

[0516] (R)-5-(1-(Aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (108 mg, 0.49 mmol, 1.1 eq.) was dissolved in tetrahydrofuran (3 ml), and N,N'-carbonyldiimidazole (80 mg, 0.49 mmol, 1.1 eq.) was added. The reaction mixture was allowed to react at 25°C for 20 minutes. N,N-diisopropylethylamine (232 mg, 1.8 mmol, 4.0 eq.) and 5-cyclopropyl-2-(piperazin-1-yl)pyrimidine hydrochloride (90 mg, 0.45 mmol, 1.0 eq.) were added to the reaction mixture. The reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (2 x 30 ml). The organic phases were combined, washed with saturated brine (40 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to give compound 20, (R)-4-(5-cyclopropylpyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)piperazine-1-carboxamide (78.58 mg, white solid), yield: 87.3%.

[0517] LCMS:(ESI)[M+H] + =453.2.

[0518] 1 H NMR (400MHz, DMSO-d6) δ12.29(s,1H),9.65(s,1H),8.18(s,2H),8.03(d,J=2.1Hz,1H),7.68(s,1H),4.66(q,J=6.5Hz,1H ),3.69-3.56(m,4H),3.31-3.24(m,4H),1.83-1.69(m,1H),1.39(d,J=6.6Hz,3H),0.95-0.81(m,2H),0.70-0.51(m,2H).

[0519] Example 21: Synthesis of Compound 21

[0520] (R)-4-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)piperazine-1-carboxamide

[0521] Step A: Preparation of 2-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)-5-(trifluoromethyl)isonicotinic acid

[0522] 2-Chloro-5-(trifluoromethyl)isonicotinic acid (2.4 g, 10.6 mmol, 1.0 eq.) was dissolved in ethanol (25 ml), and tert-butyl piperazine-1-carboxylate (2.97 g, 16.0 mmol, 1.5 eq.) and N,N-diisopropylethylamine (4.1 g, 31.8 mmol, 3.0 eq.) were added. The reaction mixture was reacted at 70°C for 16 hours. The reaction mixture was concentrated, and the resulting crude product was separated and purified by column chromatography (dichloromethane / methanol = 9 / 1; v / v) to obtain 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-(trifluoromethyl)isonicotinic acid (3.2 g, white solid) in a yield of 80.0%.

[0523] LCMS:(ESI)[M+H] + =320.2.

[0524] Step B: Preparation of tert-butyl 4-(4-((methoxycarbonyl)amino)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate

[0525] 2-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)-5-(trifluoromethyl)isonicotinic acid (3.2 g, 8.54 mmol, 1.0 eq.) was dissolved in toluene (40 ml), and triethylamine (1.72 g, 17.07 mmol, 2.0 eq.) was added. Diphenylphosphoryl azide (9.3 g, 34.16 mmol, 4.0 eq.) was added at 0°C, and the reaction solution was reacted at 100°C for 30 minutes. The reaction solution was cooled to room temperature, and methanol (10 ml) was added. The reaction solution was reacted at 100°C for 16 hours. The reaction solution was cooled to room temperature and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 75 / 25; V / V) to give tert-butyl 4-(4-((methoxycarbonyl)amino)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (1.5 g, yellow oil) in a yield of 44.1%.

[0526] LCMS:(ESI)[M+H] + =405.4.

[0527] Step C: Preparation of tert-butyl 4-(4-amino-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate

[0528] Tert-butyl 4-(4-((methoxycarbonyl)amino)-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (1.3 g, 3.22 mmol, 1.0 eq.) was dissolved in a mixed solvent of methanol (10 ml) and water (10 ml), and potassium hydroxide (720 mg, 12.8 mmol, 4.0 eq.) was added. The reaction mixture was reacted at 65°C for 4 hours. The reaction mixture was quenched with water (40 ml) and extracted with ethyl acetate (2 x 35 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 75 / 25; v / v) to give tert-butyl 4-(4-amino-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (430 mg, colorless oil) in a yield of 39%.

[0529] LCMS:(ESI)[M+H] + =347.2.

[0530] 1 H NMR (400MHz, DMSO-d6) δ7.97(s,1H),6.07(s,2H),5.99(s,1H),3.46-3.36(m,8H),1.42(s,9H).

[0531] Step D: Preparation of tert-butyl 4-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate

[0532] tert-Butyl 4-(4-amino-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (215 mg, 0.63 mmol, 1.0 eq.) was dissolved in acetonitrile (3 ml), and tert-butyl nitrite (128 mg, 1.24 mmol, 2.0 eq.) and cuprous chloride (123 mg, 1.24 mmol, 2.0 eq.) were added sequentially. The reaction mixture was reacted at 60°C for 2 hours. The reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (3 x 25 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; v / v) to afford tert-butyl 4-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (110 mg, colorless oil) in a yield of 48.6%.

[0533] LCMS:(ESI)[M+H-56] + =310.2.

[0534] 1H NMR (400MHz, DMSO-d6) δ8.42(s,1H),7.15(s,1H),3.71-3.62(m,4H),3.47-3.36(m,4H),1.42(s,9H).

[0535] Step E: Preparation of 1-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine trifluoroacetate

[0536] tert-Butyl 4-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (220 mg, 0.61 mmol, 1.0 eq.) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was added. The reaction mixture was reacted at 25°C for 1 hour. The reaction mixture was concentrated to provide 1-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine trifluoroacetate (160 mg, white solid) in a 100% yield.

[0537] LCMS:(ESI)[M+H] + =266.2.

[0538] Step F: Preparation of (R)-4-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)piperazine-1-carboxamide

[0539] (R)-5-(1-(Aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (110 mg, 0.49 mmol, 1.1 eq.) and N,N'-carbonyldiimidazole (80 mg, 0.49 mmol, 1.1 eq.) were dissolved in tetrahydrofuran (3 ml), and the reaction mixture was allowed to react at 25°C for 20 minutes. N,N-Diisopropylethylamine (232 mg, 1.8 mmol, 4.0 eq.) and 1-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazine trifluoroacetate (120 mg, 0.45 mmol, 1.0 eq.) were then added to the reaction mixture. The reaction mixture was allowed to react at 25°C for 2 hours. The reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (2 x 30 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to give compound 21, (R)-4-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)piperazine-1-carboxamide (80 mg, colorless oil), yield: 34.3%.

[0540] LCMS:(ESI)[M+H] + =514.0.

[0541] 1 H NMR (400MHz, DMSO-d6) δ12.30(s,1H),9.72-9.67(m,1H),8.43(s,1H),8.03(d,J=2.0Hz,1H),7.68(s, 1H), 7.16 (s, 1H), 4.66 (q, J = 6.5Hz, 1H), 3.69-3.57 (m, 4H), 3.37-3.33 (m, 4H), 1.39 (d, J = 6.6Hz, 3H).

[0542] Example 22: Synthesis of Compound 22

[0543] N-(1-(5-bromo-6-oxo-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0544] Step A: Preparation of 2-(1-(5-bromo-6-oxo-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione

[0545] 2-(1-(5-bromo-6-methoxypyridin-3-yl)ethoxy)isoindoline-1,3-dione (1 g, 2.65 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL), and trimethylsilyl iodide (1 mL) was added. The reaction mixture was reacted at 25°C for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1; v / v) to obtain 2-(1-(5-bromo-6-oxo-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione (700 mg, yellow solid) in a yield of 72.7%.

[0546] LCMS:(ESI)[M+H] + =363.0.

[0547] Step B: Preparation of 5-(1-(aminooxy)ethyl)-3-bromopyridin-2(1H)-one

[0548] 2-(1-(5-bromo-6-oxo-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione (700 mg, 1.92 mmol, 1.0 eq.) was dissolved in ethanol (10 ml), and hydrazine hydrate (85%, 576 mg, 11.52 mmol, 6.0 eq.) was added. The reaction mixture was reacted at 80°C for 2 hours. The reaction mixture was concentrated, and dichloromethane (10 ml) was added to the residue. The insoluble matter was removed by filtration, and the filtrate was concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1; v / v) to obtain 5-(1-(aminooxy)ethyl)-3-bromopyridin-2(1H)-one (250 mg, white solid) in a yield of 55.8%.

[0549] LCMS:(ESI)[M+H] + =233.2.

[0550] 1 H NMR: (400MHz, DMSO-d6) δ12.00 (s, 1H), 7.87 (d, J = 2.3Hz, 1H), 7.33 (d, J = 2.2Hz, 1H), 7.26-7.10 (m, 2H), 4.34 (q, J = 6.5Hz, 1H), 1.26 (d, J = 6.5Hz, 3H).

[0551] Step C: Preparation of N-(1-(5-bromo-6-oxo-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0552] 5-(1-(Aminooxy)ethyl)-3-bromopyridin-2(1H)-one (150 mg, 0.64 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (4 ml), and N,N'-carbonyldiimidazole (124 mg, 0.76 mmol, 1.2 eq.) was added. The reaction mixture was allowed to react at 25°C for 0.5 h. 2-(Piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (188 mg, 0.70 mmol, 1.1 eq.) and N,N-diisopropylethylamine (330 mg, 2.56 mmol, 4.0 eq.) were added to the reaction mixture. The reaction mixture was continued at 25°C for 2 h. The reaction mixture was quenched with water (10 ml) and extracted with ethyl acetate (3 x 10 ml). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by prep-HPLC to give compound 22, N-(1-(5-bromo-6-oxo-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (13.44 mg, white solid), with a recovery rate of 4.2%.

[0553] LCMS:(ESI)[M+H] + =491.2.

[0554] 1 H NMR: (400MHz, DMSO-d6) δ12.05(s,1H),9.66(s,1H),8.72(s,2H),8.03(d,J=2.3Hz,1H),7.41(d, J=2.2Hz, 1H), 4.59 (q, J=6.5Hz, 1H), 3.83-3.72 (m, 4H), 3.40-3.33 (m, 4H), 1.37 (d, J= 6.5Hz, 3H).

[0555] Example 23: Synthesis of Compound 23

[0556] N-(1-(5-acetyl-6-oxo-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0557] Step A: Preparation of 2-(1-(5-acetyl-6-methoxypyridin-3-yl)ethoxy)isoindoline-1,3-dione

[0558] 2-(1-(5-bromo-6-methoxypyridin-3-yl)ethoxy)isoindoline-1,3-dione (Intermediate H, 3 g, 7.97 mmol, 1.0 eq.) was added to toluene (30 ml), followed by tributyl(1-ethoxyvinyl)stannane (4 g, 11.17 mmol, 1.4 eq.) and tetrakis(triphenylphosphine)palladium (460 mg, 0.38 mmol, 0.05 eq.). The reaction mixture was reacted at 110°C for 5 hours. Aqueous potassium fluoride solution (30 ml) was added and stirred for 1 hour. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (3 x 30 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1; V / V) to give 2-(1-(5-acetyl-6-methoxypyridin-3-yl)ethoxy)isoindoline-1,3-dione (1.5 g, white solid) in a yield of 55.3%.

[0559] LCMS:(ESI)[M+H] + =341.2,t R =0.731.

[0560] 1H NMR: N02-09193-1 (400MHz, DMSO-d6) δ8.47 (d, J=2.5Hz, 1H), 8.22 (d, J=2.5Hz, 1H), 7.8 7-7.78(m,4H),5.40(q,J=6.5Hz,1H),3.98(s,3H),2.57(s,3H),1.66(d,J=6.6Hz,3H).

[0561] Step B: Preparation of 2-(1-(5-acetyl-6-oxo-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione

[0562] 2-(1-(5-acetyl-6-methoxypyridin-3-yl)ethoxy)isoindoline-1,3-dione (1 g, 2.94 mmol, 1.0 eq.) was added to acetonitrile (15 mL), followed by aluminum chloride (977 mg, 7.35 mmol, 2.5 eq.) and sodium iodide (882 mg, 5.88 mmol, 2.0 eq.). The reaction mixture was allowed to react at 40°C for 1 hour. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1; v / v) to afford 2-(1-(5-acetyl-6-oxo-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione (900 mg, yellow solid) in a yield of 93.9%.

[0563] LCMS:(ESI)[M+H] + =327.2.

[0564] Step C: Preparation of 3-acetyl-5-(1-(aminooxy)ethyl)pyridin-2(1H)-one hydrochloride

[0565] 2-(1-(5-acetyl-6-oxo-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione (500 mg, 1.53 mmol, 1.0 eq.) was added to ethanol (8 mL), followed by the addition of hydrazine hydrate (85%, 230 mg, 4.60 mmol, 3.0 eq.). The reaction mixture was allowed to react at 25°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. Dilute hydrochloric acid (1 M, 10 mL) was added and stirred at 25°C for an additional 2 hours. The reaction mixture was concentrated, and the resulting crude product was isolated and purified by reverse-phase column chromatography (acetonitrile / water = 2 / 1; v / v) to afford 3-acetyl-5-(1-(aminooxy)ethyl)pyridin-2(1H)-one hydrochloride (50 mg, white solid) in a yield of 16.6%.

[0566] LCMS:(ESI)[M+H] + =197.0.

[0567] Step D: Preparation of N-(1-(5-acetyl-6-oxo-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide

[0568] 3-Acetyl-5-(1-(aminooxy)ethyl)pyridin-2(1H)-one (35 mg, 0.17 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (3 mL), and N,N'-carbonyldiimidazole (31 mg, 0.19 mmol, 1.1 eq.) was added. The reaction mixture was allowed to react at 30°C for 20 minutes. N,N-diisopropylethylamine (98 mg, 0.76 mmol, 4.0 eq.) and 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (51 mg, 0.19 mmol, 1.1 eq.) were added to the reaction mixture. The reaction mixture was continued at 30°C for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to give compound 23, N-(1-(5-acetyl-6-oxo-1,6-dihydropyridin-3-yl)ethoxy)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxamide (13.38 mg, white solid), yield: 16.8%.

[0569] LCMS:(ESI)[M+H] + =455.2.

[0570] 1 H NMR: (400MHz, DMSO-d6) δ11.84(s,1H),8.77-8.72(s,2H),7.61(d,J=2.6Hz,1H),7.40(d,J=2.4Hz,1H),5.16( d,J=4.3Hz,1H),4.60-4.51(m,1H),3.98-3.87(m,4H),3.66-3.47(m,4H),2.27(s,3H),1.28(d,J=6.4Hz,3H).

[0571] Embodiment 24, 25:

[0572] Synthesis of compound 24

[0573] N-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)methoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0574] Synthesis of compound 25

[0575] N-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)methoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyridine-4-carboxamide

[0576] Step A: Preparation of N-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)methoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide and N-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)methoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyridine-4-carboxamide

[0577] 1-(5-(Trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (79 mg, 0.29 mmol, 1.2 eq.) was dissolved in N,N-dimethylformamide (5 mL). 5-((aminooxy)methyl)-3-(trifluoromethyl)pyridin-2(1H)-one (50 mg, 0.24 mmol, 1.0 eq.), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (119 mg, 0.31 mmol, 1.3 eq.), and N,N-diisopropylethylamine (93 mg, 0.72 mmol, 3.0 eq.) were added sequentially. The reaction mixture was reacted at 20°C for 2 hours. The reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, washed with saturated brine (2 × 60 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to give compound 24, N-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)methoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (2.10 mg, white solid), yield: 1.9%;

[0578] LCMS:(ESI)[M+H] + =464.0.

[0579] 1H NMR:(400MHz,DMSO-d6)δ12.32(br s,1H),11.17(s,1H),8.74(s,2H),8.04-8.00(m,1H),7.79-7.74(m,1H),6.56-6.4 9(m,1H),4.64(s,2H),4.42-4.33(m,2H),3.95(t,J=5.6Hz,2H),2.35-2.31(m,2H).

[0580] And compound 25, N-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)methoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyridine-4-carboxamide (7.47 mg, white solid), yield: 6.7%.

[0581] LCMS:(ESI)[M+H] + =464.0.

[0582] 1 H NMR:(400MHz,DMSO-d6)δ12.36(br s,1H),11.05(s,1H),8.85(s,2H),8.01-7.96(m,1H),7.79-7.73(m,1H),7.56(dd,J=8.4,1.6Hz,1H), 4.99(dd,J=8.4,3.6Hz,1H),4.61(s,2H),3.95(t,J=5.6Hz,2H),3.00-2.92(m,1H),2.07-1.84(m,2H).

[0583] Examples 26, 27, and 28:

[0584] Synthesis of compound 26

[0585] N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0586] Synthesis of compound 27

[0587] (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0588] Synthesis of compound 28

[0589] (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0590] Step A: Preparation of N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0591] 1-(5-(Trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (55 mg, 0.20 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (3.5 mL) and cooled to 0°C in an ice bath. 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (77 mg, 0.26 mmol, 1.3 eq.) was added. The reaction mixture was allowed to react at 0°C for 5 minutes. N-methylmorpholine (61 mg, 0.60 mmol, 3.0 eq.) and 5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (667 mg, 0.30 mmol, 1.5 eq.) were added to the reaction mixture. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC (formic acid) to give racemic compound 26, N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (42 mg, white solid), in a yield of 44.0%.

[0592] LCMS:(ESI)[M+H] + =478.0.

[0593] 1 H NMR: (400MHz, DMSO-d6) δ12.30(s,1H),11.01(s,1H),8.73(d,J=0.8Hz,2H),8.01(d,J=2.0Hz,1H),7.68(d,J=2.0Hz,1H),6 .51-6.42(m,1H),4.77(q,J=6.4Hz,1H),4.39-4.29(m,2H),3.93(t,J=5.6Hz,2H),2.35-2.26(m,2H),1.42(d,J=6.8Hz,3H).

[0594] Step B: Preparation of (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide and (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0595] Racemic compound 26, N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (85 mg, 0.18 mmol, 1.0 eq.) was dissolved in methanol (4 ml) and resolved by SFC to give:

[0596] Isomer 27, (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (19.06 mg, white solid), yield: 22.4%;

[0597] LCMS:(ESI)[M+H] + =478.0.

[0598] 1 H NMR: (400MHz, DMSO-d6) δ12.30(s,1H),11.02(s,1H),8.73(d,J=0.4Hz,2H),8.01(d,J=2.0Hz,1H),7.68(d,J=1.6Hz,1H),6 .50-6.43(m,1H),4.77(q,J=6.4Hz,1H),4.39-4.29(m,2H),3.93(t,J=5.6Hz,2H),2.36-2.26(m,2H),1.42(d,J=6.8Hz,3H).

[0599] Isomer 28, (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (20.27 mg, white solid), yield: 23.8%.

[0600] LCMS:(ESI)[M+H] + =478.2.

[0601] 1 H NMR: (400MHz, DMSO-d6) δ12.29(s,1H),11.02(s,1H),8.73(s,2H),8.01(d,J=2.0Hz,1H),7.68(d,J=2.0Hz,1H),6.51- 6.42(m,1H),4.77(q,J=6.4Hz,1H),4.39-4.30(m,2H),3.93(t,J=5.6Hz,2H),2.36-2.26(m,2H),1.43(d,J=6.4Hz,3H).

[0602] Embodiment 29, 30:

[0603] Synthesis of compound 29

[0604] (R)-N-(1-deuterio-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0605] Synthesis of compound 30

[0606] (S)-N-(1-deuterio-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0607] Step A: Preparation of 1-deuterio-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanol

[0608] 1-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanone (2.09 g, 9.54 mmol, 1.0 eq.) was dissolved in methanol (50 mL) and cooled to 0°C in an ice bath. Sodium borodeuteride (959 mg, 22.90 mmol, 2.4 eq.) was added. The reaction mixture was allowed to react at 25°C for 18 hours. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (2 x 180 mL). The organic phases were combined, washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1; v / v) to afford 1-deuterated-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanol (1.90 g, yellow oil) in a yield of 89.7%.

[0609] LCMS:(ESI)[M+H] + =223.4.

[0610] 1 H NMR: (400MHz, DMSO-d6) δ 8.40 (d, J = 1.6 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 5.38 (s, 1H), 3.98 (s, 3H), 1.36 (s, 3H).

[0611] Step B: Preparation of 2-(1-deuterio-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethoxy)isoindoline-1,3-dione

[0612] 1-Deuterium-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethanol (1.80 g, 8.10 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (40 ml) and cooled to 0°C in an ice bath. N-hydroxyphthalimide (1.32 g, 8.10 mmol, 1.0 eq.) and triphenylphosphine (4.46 g, 17.01 mmol, 2.1 eq.) were added sequentially, followed by the dropwise addition of diisopropyl azodicarboxylate (3.28 g, 16.20 mmol, 2.0 eq.). The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was quenched with water (300 ml) and extracted with ethyl acetate (3 x 280 ml). The organic phases were combined, washed with saturated brine (800 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1; V / V) to give 2-(1-deuterio-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethoxy)isoindoline-1,3-dione (2.20 g, white solid) in a yield of 73.9%.

[0613] LCMS:(ESI)[M+H] + =368.2.

[0614] 1 H NMR: (400MHz, CDCl3) δ8.21 (d, J = 2.0 Hz, 1H), 8.02 (dd, J = 2.4, 0.4 Hz, 1H), 7.68-7.64 (m, 2H), 7.63-7.58 (m, 2H), 3.90 (s, 3H), 1.60 (s, 3H).

[0615] Step C: Preparation of 2-(1-deuterio-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione

[0616] 2-(1-deuterio-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethoxy)isoindoline-1,3-dione (1.00 g, 2.72 mmol, 1.0 eq.) was dissolved in dichloromethane (20 mL), and iodotrimethylsilane (1 M, 2 mL, 5.44 mmol, 2.0 eq.) was added. The reaction mixture was incubated at 25°C for 18 hours. The reaction mixture was quenched with water (100 mL) and extracted with dichloromethane (2 x 80 mL). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2; V / V) to give 2-(1-deuterio-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione (810 mg, yellow solid) in a yield of 84.2%.

[0617] LCMS:(ESI)[M+H] + =354.0.

[0618] 1 H NMR: (400MHz, CDCl3) δ8.12 (d, J = 2.0 Hz, 1H), 7.79-7.71 (m, 2H), 7.71-7.66 (m, 2H), 7.57 (d, J = 2.4 Hz, 1H), 1.61 (s, 3H).

[0619] Step D: Preparation of 5-(1-(aminooxy)-1-deuteroethyl)-3-(trifluoromethyl)pyridin-2(1H)-one

[0620] 2-(1-deuterio-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione (760 mg, 2.15 mmol, 1.0 eq.) was dissolved in dichloromethane (6 mL) and methanol (3 mL), and hydrazine hydrate (80%, 2 mL) was added. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated. The residue was diluted with dichloromethane (20 mL), the insoluble matter was filtered off, and the filtrate was concentrated. The crude product was isolated and purified by column chromatography (dichloromethane / methanol = 10 / 1; v / v) to give 5-(1-(aminooxy)-1-deuterioethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (360 mg, white solid) in a yield of 75.0%.

[0621] LCMS:(ESI)[M+H] + =224.0.

[0622] 1H NMR: (400MHz, DMSO-d6) δ12.26 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 5.86 (s, 2H), 1.27 (s, 3H).

[0623] Step E: Preparation of N-(1-deuterio-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0624] 1-(5-(Trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (Intermediate F, 330 mg, 1.21 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (10 ml) and cooled to 0°C in an ice bath. 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (435 mg, 1.57 mmol, 1.3 eq.) was added. The reaction mixture was allowed to react at 0°C for 20 minutes. N-methylmorpholine (367 mg, 3.63 mmol, 3.0 eq.) and 5-(1-(aminooxy)-1-deuteroethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (270 mg, 1.21 mmol, 1.0 eq.) were added to the reaction mixture. The reaction mixture was allowed to react at 25°C for 5 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (2 × 80 mL). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1; v / v) to afford the crude racemic compound (N-(1-deuterio-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide) (578 mg, white solid).

[0625] Step F: Preparation of (R)-N-(1-deuterio-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide and (S)-N-(1-deuterio-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0626] The racemic compound N-(1-deuterium-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (578 mg, white solid) was resolved by SFC to give:

[0627] Isomer 29, (R)-N-(1-deuterio-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (61.20 mg, white solid), yield: 10.6%;

[0628] LCMS:(ESI)[M+H] + =479.0.

[0629] 1 H NMR: (400MHz, DMSO-d6) δ12.29(s,1H),11.01(s,1H),8.74(s,2H),8.01(d,J=2.0Hz,1H),7.69(d,J=2. 0Hz, 1H), 6.51-6.45 (m, 1H), 4.40-4.32 (m, 2H), 3.94 (t, J = 5.6Hz, 2H), 2.34-2.28 (s, 2H), 1.42 (s, 3H).

[0630] And isomer 30, (S)-N-(1-deuterio-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (61.94 mg, white solid), yield 10.7%.

[0631] LCMS: [M+H] + =479.2.

[0632] 1 H NMR: (400MHz, DMSO-d6) δ12.31(s,1H),11.01(s,1H),8.74(s,2H),8.01(d,J=2.0Hz,1H),7.69(d,J=2.0Hz, 1H), 6.51-6.45 (m, 1H), 4.39-4.32 (m, 2H), 3.94 (t, J = 5.6Hz, 2H), 2.36-2.27 (d, J = 1.7Hz, 2H), 1.42 (s, 3H).

[0633] Embodiment 31, 32, 33:

[0634] Synthesis of compound 31

[0635] N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0636] Synthesis of compound 32

[0637] (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0638] Synthesis of compound 33

[0639] (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0640] Step A: Preparation of N-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0641] 1-(5-(Trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (230 mg, 0.84 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (5 mL). O-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propyl)hydroxylamine (210 mg, 0.84 mmol, 1.0 eq.), 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (320 mg, 0.93 mmol, 1.1 eq.), and N-methylmorpholine (255 mg, 2.52 mmol, 3.0 eq.) were added sequentially. The reaction mixture was allowed to react at 20°C for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated brine (2 x 30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 7 / 3; V / V) to give N-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (260 mg, colorless oil) in a yield of 67.1%.

[0642] LCMS:(ESI)[M+H] + =506.2.

[0643] 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.72(s,2H),8.41(d,J=1.9Hz,1H),8.09(d,J=2.0Hz,1H),6.41(s,1H),4.81(t,J=6.9Hz,1H),4. 32(d,J=2.8Hz,2H),3.98(s,3H),3.92(t,J=5.7Hz,2H),2.33-2.21(m,2H),2.04-1.87(m,1H),1.85-1.66(m,1H),0.88(t,J=7.4Hz,3H).

[0644] Step B: Preparation of N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0645] N-(1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (260 mg, 0.52 mmol, 1.0 eq.) was dissolved in dichloromethane (3 ml) and iodotrimethylsilane (0.3 ml) was added. The reaction mixture was reacted at 25°C for 2 hours. The reaction mixture was quenched with water (10 ml) and extracted with ethyl acetate (3 x 10 ml). The organic phases were combined, washed with saturated brine (2 x 10 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to give racemic compound 31, N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (21.68 mg, white solid), yield: 8.3%.

[0646] LCMS:(ESI)[M+H] + =492.2.

[0647] 1H NMR (400MHz, DMSO-d6) δ12.32(s,1H),10.97(s,1H),8.75(s,2H),7.94(s,1H),7.69(s,1H),6.45(s,1H),4.56(t,J=7.0Hz ,1H),4.38-4.31(m,2H),3.94(t,J=5.7Hz,2H),2.31(s,2H),1.98-1.81(m,1H),1.77-1.58(m,1H),0.88(t,J=7.4Hz,3H).

[0648] Step C: Preparation of (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide and (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0649] Racemic compound 31, N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (95 mg, 0.193 mmol, 1.0 eq.) was resolved by SFC to give:

[0650] Isomer 32, (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (30.34 mg, white solid), yield: 31.93%.

[0651] LCMS:(ESI)[M+H] + =492.2.

[0652] 1H NMR (400MHz, DMSO-d6) δ12.31(s,1H),10.96(s,1H),8.74(d,J=0.6Hz,2H),7.93(d,J=1.9Hz,1H),7.68(s,1H),6.45(s,1H),4.56(t,J =7.0Hz,1H),4.42-4.30(m,2H),3.94(t,J=5.8Hz,2H),2.34-2.25(m,2H),1.95-1.83(m,1H),1.78-1.60(m,1H),0.88(t,J=7.4Hz,3H).

[0653] And isomer 33, (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (34.96 mg, white solid), yield: 36.8%.

[0654] LCMS:(ESI)[M+H] + =492.2.

[0655] 1 H NMR (400MHz, DMSO-d6) δ12.30(s,1H),10.95(s,1H),8.73(s,2H),7.92(s,1H),7.67(s,1H),6.43(s,1H),4.54(t,J=7.0Hz,1 H), 4.43-4.26 (m, 2H), 3.92 (t, J = 5.8Hz, 2H), 2.32-2.24 (m, 2H), 1.93-1.81 (m, 1H), 1.74-1.59 (m, 1H), 0.86 (t, J = 7.4Hz, 3H).

[0656] Embodiment 34, 35:

[0657] Synthesis of compound 34

[0658] (R)-1-(5-cyclopropylpyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0659] Synthesis of compound 35

[0660] (S)-1-(5-cyclopropylpyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0661] Step A: Preparation of 1-(5-cyclopropylpyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid

[0662] 1,2,3,6-Tetrahydropyridine-4-carboxylic acid hydrochloride (100 mg, 0.614 mmol, 1.0 eq.) was dissolved in a mixture of ethanol (6 mL) and water (1 mL). N,N-diisopropylethylamine (314 mg, 2.47 mmol, 4.0 eq.) and 2-chloro-5-cyclopropylpyrimidine (95 mg, 0.614 mmol, 1.0 eq.) were added sequentially. The reaction mixture was allowed to react at 80°C for 16 hours. The reaction mixture was diluted with water (30 mL), adjusted to pH 6 with dilute hydrochloric acid (1 M), and extracted with ethyl acetate (2 x 25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford 1-(5-cyclopropylpyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (110 mg, white solid) in a yield of 57.3%.

[0663] LCMS:(ESI)[M+H] + =246.0.

[0664] Step B: Preparation of 1-(5-cyclopropylpyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0665] 1-(5-Cyclopropylpyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (100 mg, 0.41 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (3 mL). 5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (108 mg, 0.49 mmol, 1.2 eq.), 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (156 mg, 0.54 mmol, 1.3 eq.), and N-methylmorpholine (124 mg, 1.23 mmol, 3.0 eq.) were added sequentially. The reaction mixture was allowed to react at 20°C for 6 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated brine (2 x 30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to give the racemic compound 1-(5-cyclopropylpyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide (40 mg, white solid) in a yield of 21.7%.

[0666] Step C: Preparation of (R)-1-(5-cyclopropylpyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide and (S)-1-(5-cyclopropylpyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0667] The racemic compound 1-(5-cyclopropylpyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide (40 mg, 0.09 mmol, white solid) was separated and purified by SFC to give:

[0668] Isomer 34, (R)-1-(5-cyclopropylpyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide (17.65 mg, white solid), yield: 44.2%;

[0669] LCMS:(ESI)[M+H] + =450.2.

[0670] 1 H NMR (400MHz, DMSO-d6) δ12.29(s,1H),10.97(s,1H),8.19(s,2H),8.00(s,1H),7.68(s,1H),6.45(s,1H),4.76(q,J=6.4Hz,1H),4.20 (d,J=2.8Hz,2H),3.79(t,J=5.6Hz,2H),2.25(t,2H),1.81-1.70(m,1H),1.42(d,J=6.6Hz,3H),0.93-0.80(m,2H),0.68-0.58(m,2H).

[0671] And isomer 35, (S)-1-(5-cyclopropylpyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide (1.57 mg, white solid), yield: 3.9%.

[0672] LCMS:(ESI)[M+H] + =450.2.

[0673] 1 H NMR(400MHz,DMSO-d6)δ12.28(s,1H),10.96(s,1H),8.19(s,2H),7.97(s, 1H),7.69(s,1H),6.45(s,1H),4.76(q,J=6.4Hz,1H),4.20(d,J=2.9Hz,2H),3.79(t,J=5.6Hz,2 H), 2.25 (t, 2H), 1.81-1.71 (m, 1H), 1.41 (d, J = 6.6Hz, 3H), 0.88-0.83 (m, 2H), 0.66-0.60 (m, 2H).

[0674] Example 36: Synthesis of Compound 36

[0675] (R)-1-(5-acetylaminopyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0676] Step A: Preparation of 1,2,3,6-tetrahydropyridine-4-carboxylic acid methyl ester hydrochloride

[0677] 1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (2.00 g, 8.80 mmol, 1.0 eq.) was dissolved in methanol (50 ml), and thionyl chloride (5.23 g, 44.00 mmol, 5.0 eq.) was added. The reaction mixture was reacted at 50°C for 2 hours. The reaction mixture was concentrated to provide methyl 1,2,3,6-tetrahydropyridine-4-carboxylate hydrochloride (1.30 g, white solid) in a yield of 83.1%.

[0678] LCMS:(ESI)[M+H] + =142.2.

[0679] Step B: Preparation of methyl 1-(5-nitropyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate

[0680] Methyl 1,2,3,6-tetrahydropyridine-4-carboxylate hydrochloride (500 mg, 2.82 mmol, 1.0 eq.) and 2-chloro-5-nitropyrimidine (472 mg, 2.96 mmol, 1.05 eq.) were dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (1.09 g, 8.46 mmol, 3.0 eq.) was added. The reaction mixture was allowed to react at 25°C for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (3 x 40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1; v / v) to afford methyl 1-(5-nitropyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (0.43 g, yellow solid) in a yield of 58.1%.

[0681] LCMS:(ESI)[M+H] + =265.2.

[0682] 1 H NMR: (400MHz, CDCl3) δ9.03 (s, 2H), 6.96-6.90 (m, 1H), 4.48 (q, J = 3.2Hz, 2H), 4.05 (t, J = 6.0Hz, 2H), 3.72 (s, 3H), 2.51-2.45 (m, 2H).

[0683] Step C: Preparation of methyl 1-(5-aminopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate

[0684] Methyl 1-(5-nitropyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (400 mg, 1.51 mmol, 1.0 eq.) was dissolved in ethanol (30 mL), and stannous chloride (1.43 g, 7.56 mmol, 5.0 eq.) was added. The reaction mixture was allowed to react at 70°C for 6 hours. The reaction mixture was cooled to room temperature and diluted with water (80 mL) and dichloromethane (60 mL). The aqueous phase was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane (3 x 60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1; v / v) to afford methyl 1-(5-aminopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (260 mg, pale yellow solid) in a yield of 74.3%.

[0685] LCMS:(ESI)[M+H] + =235.4.

[0686] 1H NMR: (400MHz, MeOD) δ8.28 (s, 2H), 7.02-7.00 (m, 1H), 4.40-4.34 (m, 2H), 3.94 (t, J = 5.6Hz, 2H), 3.75 (s, 3H), 2.50-2.42 (m, 2H).

[0687] Step D: Preparation of methyl 1-(5-acetylaminopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate

[0688] Methyl 1-(5-aminopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (220 mg, 0.94 mmol, 1.0 eq.) was dissolved in dichloromethane (6 mL). Pyridine (111 mg, 1.41 mmol, 1.5 eq.), 4-dimethylaminopyridine (11 mg, 0.09 mmol, 0.05 eq.), and acetic anhydride (144 mg, 1.41 mmol, 1.5 eq.) were added sequentially. The reaction mixture was allowed to react at 25°C for 12 hours. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (3 x 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1; V / V) to give methyl 1-(5-acetamidopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (95 mg, yellow solid) in a yield of 36.5%.

[0689] LCMS:(ESI)[M+H] + =277.2.

[0690] 1 H NMR: (400MHz, CDCl3) δ8.43(s,2H),7.08(s,1H),7.03-6.99(m,1H),4.38-4.3 3(m,2H),3.92(t,J=5.6Hz,2H),3.77(s,3H),2.54-2.45(m,2H),2.17(s,3H).

[0691] Step E: Preparation of 1-(5-acetylaminopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid

[0692] Methyl 1-(5-acetamidopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (90 mg, 0.33 mmol, 1.0 eq.) was dissolved in a mixture of methanol (6 mL) and water (2 mL). Lithium hydroxide (23 mg, 0.97 mmol, 3.0 eq.) was added. The reaction mixture was allowed to react at 25°C for 4 hours. The reaction mixture was diluted with water (10 mL), adjusted to pH 6 with dilute hydrochloric acid (1 M), and extracted with a mixture of dichloromethane and methanol (5 x 20 mL, dichloromethane / methanol = 10 / 1, v / v). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford 1-(5-acetamidopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (45 mg, white solid) in a yield of 50.0%.

[0693] LCMS:(ESI)[M+H] + =263.2.

[0694] Step F: Preparation of (R)-1-(5-acetylaminopyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0695] 1-(5-Acetylaminopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (39 mg, 0.15 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (3 mL) and cooled to 0°C in an ice bath. 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (57 mg, 0.19 mmol, 1.3 eq.) was added. The reaction mixture was allowed to react at 0°C for 5 minutes. N-methylmorpholine (45 mg, 0.45 mmol, 3.0 eq.) and (R)-5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (50 mg, 0.22 mmol, 1.5 eq.) were added to the reaction mixture. The reaction mixture was allowed to react at 25°C for 6 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to give compound 36, (R)-1-(5-acetamidopyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide (1.40 mg, white solid), in a yield of 2.0%.

[0696] LCMS:(ESI)[M+H] + =467.2.

[0697] 1H NMR: (400MHz, MeOD) δ8.49 (s, 2H), 8.11 (d, J = 2.0Hz, 1H), 7.68 (d, J = 2.4Hz, 1H), 6.56-6.47 (m, 1H), 4.84-4. 80(m,1H),4.31-4.26(m,2H),3.90(t,J=5.6Hz,2H),2.40-2.31(m,2H),2.11(s,3H),1.54(d,J=6.8Hz,3H).

[0698] Embodiment 37, 38:

[0699] Synthesis of compound 37

[0700] (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-5'-(trifluoromethyl)-3,6-dihydro-2H-[1,2'-bipyridine]-4-carboxamide

[0701] Synthesis of compound 38

[0702] (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-5'-(trifluoromethyl)-3,6-dihydro-2H-[1,2'-bipyridine]-4-carboxamide

[0703] Step A: Preparation of 5'-(trifluoromethyl)-3,6-dihydro-2H-[1,2'-bipyridine]-4-carboxylic acid

[0704] 1,2,3,6-Tetrahydropyridine-4-carboxylic acid hydrochloride (80 mg, 0.491 mmol, 1.0 eq.) was dissolved in a mixture of ethanol (1 mL) and water (0.5 mL). N,N-diisopropylethylamine (254 mg, 1.97 mmol, 4.0 eq.) and 2-chloro-5-(trifluoromethyl)pyridine (94 mg, 0.52 mmol, 1.05 eq.) were added sequentially. The reaction mixture was allowed to react at 70°C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford 5'-(trifluoromethyl)-3,6-dihydro-2H-[1,2'-bipyridine]-4-carboxylic acid (70 mg, white solid) in a yield of 58.3%.

[0705] LCMS:(ESI)[M+H] + =273.2.

[0706] 1H NMR (400MHz, DMSO-d6) δ8.49-8.38(m,1H),7.82(dd,J=9.1,2.4Hz,1H),6.95(d,J=9.2H z,1H),6.93-6.90(m,1H),4.29-4.19(m,2H),3.80(t,J=5.7Hz,2H),2.40-2.33(m,2H).

[0707] Step B: Preparation of N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-5'-(trifluoromethyl)-3,6-dihydro-2H-[1,2'-bipyridine]-4-carboxamide

[0708] 5'-(Trifluoromethyl)-3,6-dihydro-2H-[1,2'-bipyridine]-4-carboxylic acid (70 mg, 0.258 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (2 mL). 5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (69 mg, 0.31 mmol, 1.2 eq.), 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (99 mg, 0.336 mmol, 1.3 eq.), and N-methylmorpholine (79 mg, 0.78 mmol, 3.0 eq.) were added sequentially. The reaction mixture was allowed to react at 20°C for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated brine (2 x 30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to give N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-5'-(trifluoromethyl)-3,6-dihydro-2H-[1,2'-bipyridine]-4-carboxamide (90 mg, white solid) in a yield of 73.8%.

[0709] Step C: Preparation of (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-5'-(trifluoromethyl)-3,6-dihydro-2H-[1,2'-bipyridine]-4-carboxamide and (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-5'-(trifluoromethyl)-3,6-dihydro-2H-[1,2'-bipyridine]-4-carboxamide

[0710] N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-5'-(trifluoromethyl)-3,6-dihydro-2H-[1,2'-bipyridine]-4-carboxamide (90 mg, white solid) was separated and purified by SFC to give:

[0711] Isomer 37, (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-5'-(trifluoromethyl)-3,6-dihydro-2H-[1,2'-bipyridine]-4-carboxamide (18.43 mg, white solid), yield: 20.4%.

[0712] LCMS:(ESI)[M+H] + =477.2.

[0713] 1 H NMR (400MHz, DMSO-d6) δ12.31(s,1H),11.02(s,1H),8.42(s,1H),8.01(d,1H),7.82(dd,J=9.1,2.3Hz,1H),7.69(s,1H),6.95(d,J=9. 1Hz, 1H), 6.47 (s, 1H), 4.82-4.72 (m, 1H), 4.16 (d, J = 2.8Hz, 2H), 3.77 (t, J = 5.6Hz, 2H), 2.32 (t, J = 10.1Hz, 2H), 1.42 (d, J = 6.6Hz, 3H).

[0714] And isomer 38, (S)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-5'-(trifluoromethyl)-3,6-dihydro-2H-[1,2'-bipyridine]-4-carboxamide (0.9 mg, white solid), yield: 1.0%.

[0715] LCMS:(ESI)[M+H] + =477.2.

[0716] 1H NMR (400MHz, DMSO-d6) δ12.31(s,1H),11.02(s,1H),8.43(s,1H),8.00(d,1H),7.82(dd,J=9.1,2.5Hz,1H),7.69(s,1H),6.95(d,J =9.1Hz,1H),6.47(s,1H),4.77(q,J=6.7Hz,1H),4.15(d,J=2.6Hz,2H),3.77(t,J=5.6Hz,2H),2.30(t,2H),1.42(d,J=6.5Hz,3H).

[0717] Embodiment 39, 40:

[0718] Synthesis of compound 39

[0719] (R)-5-Methyl-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0720] Synthesis of compound 40

[0721] 5-Methyl-N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyridine-4-carboxamide

[0722] Step A: Preparation of ethyl 3-oxo-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-4-carboxylate

[0723] Ethyl 3-oxopiperidine-4-carboxylate hydrochloride (4.00 g, 19.26 mmol, 1.0 eq.) was dissolved in dichloromethane (20 ml), and 2-chloro-5-trifluoromethylpyrimidine (3.52 g, 19.26 mmol, 1.0 eq.) and N,N-diisopropylethylamine (12.45 g, 96.30 mmol, 5.0 eq.) were added sequentially. The reaction mixture was allowed to react at 25°C for 20 hours. The reaction mixture was diluted with water (400 ml) and extracted with ethyl acetate (2 x 350 ml). The mixture was washed with saturated brine (800 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1; v / v) to afford ethyl 3-oxo-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-4-carboxylate (5.30 g, white solid) in a yield of 86.7%.

[0724] LCMS:(ESI)[M+H] + =318.0.

[0725] 1 H NMR: (400MHz, DMSO-d6) δ11.97 (s, 1H), 8.76 (d, J = 0.4Hz, 2H), 4.44-4.39 (m, 2H), 4. 22(q,J=7.2Hz,2H),3.97(t,J=5.6Hz,2H),2.39-2.32(m,2H),1.25(t,J=7.2Hz,3H).

[0726] Step B: Preparation of ethyl 1-(5-(trifluoromethyl)pyrimidin-2-yl)-5-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,6-tetrahydropyridine-4-carboxylate

[0727] Ethyl 3-oxo-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-4-carboxylate (3.00 g, 9.46 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (90 ml) and cooled to 0°C in an ice bath under nitrogen. Sodium hydride (60%, 454 mg, 11.35 mmol, 1.2 eq.) was added. The reaction mixture was reacted at 0°C for 1 hour. N-phenylbis(trifluoromethanesulfonyl)imide (3.72 g, 10.41 mmol, 1.1 eq.) was added to the reaction mixture. The reaction mixture was reacted at 25°C for 18 hours. The reaction mixture was quenched with water (400 ml) and extracted with ethyl acetate (2 x 350 ml). The organic phases were combined, washed with saturated brine (800 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1; V / V) to give 1-(5-(trifluoromethyl)pyrimidin-2-yl)-5-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,6-tetrahydropyridine-4-carboxylic acid ethyl ester (3.50 g, yellow oil) in a yield of 82.4%.

[0728] LCMS:(ESI)[M+H] + =450.0.

[0729] 1 H NMR: (400MHz, CDCl3) δ8.48 (d, J = 0.4Hz, 2H), 4.48 (t, J = 2.8Hz, 2H), 4.25 (q, J =7.2Hz, 2H), 3.98 (t, J = 5.6Hz, 2H), 2.67-2.59 (m, 2H), 1.27 (t, J = 7.2Hz, 3H).

[0730] Step C: Preparation of ethyl 5-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate

[0731] Ethyl 1-(5-(trifluoromethyl)pyrimidin-2-yl)-5-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,6-tetrahydropyridine-4-carboxylate (3.50 g, 7.79 mmol, 1.0 eq.) was dissolved in a mixture of dioxane (80 mL) and water (20 mL). Potassium phosphate (4.96 g, 23.37 mmol, 3.0 eq.), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (570 mg, 0.78 mmol, 0.1 eq.), and trimethylboroxine (1.08 g, 8.57 mmol, 1.1 eq.) were added sequentially. The reaction mixture was reacted at 100°C for 3 hours. The reaction mixture was cooled to room temperature and quenched with water (300 mL). The mixture was then extracted with ethyl acetate (2 x 240 mL). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1; v / v) to afford ethyl 5-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (1.60 g, yellow solid) in a yield of 65.2%.

[0732] LCMS:(ESI)[M+H] + =316.0.

[0733] 1 H NMR: (400MHz, DMSO-d6)δ8.73(d,J=0.8Hz,2H),4.34-4.27(m,2H),4.15(q,J=7.2Hz ,2H),3.93(t,J=5.6Hz,2H),2.45-2.37(m,2H),2.05(s,3H),1.23(t,J=7.2Hz,3H).

[0734] Step D: Preparation of 5-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid

[0735] Ethyl 5-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (400 mg, 1.27 mmol, 1.0 eq.) was dissolved in water (4 mL) and concentrated hydrochloric acid (6 M, 4 mL) was added. The reaction mixture was reacted at 100°C for 2 hours. The reaction mixture was cooled to room temperature and diluted with water (40 mL). Extraction was performed with ethyl acetate (2 x 35 mL). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated to afford 5-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (360 mg, yellow solid) in a yield of 98.8%.

[0736] LCMS:(ESI)[M+H] + =288.0.

[0737] 1 H NMR: (400MHz, DMSO-d6) δ 12.44 (s, 1H), 8.73 (d, J = 0.8Hz, 2H), 4.28 (s, 2H), 3.92 (t, J = 5.6Hz, 2H), 2.43-2.34 (m, 2H), 2.05 (s, 3H).

[0738] Step E: (R)-5-methyl-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0739] 5-Methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (259 mg, 0.90 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (10 ml) and cooled to 0°C in an ice bath. 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (324 mg, 1.17 mmol, 1.3 eq.) was added. The reaction mixture was allowed to react at 0°C for 20 minutes. N-methylmorpholine (273 mg, 2.70 mmol, 3.0 eq.) and (R)-5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (200 mg, 0.90 mmol, 1.0 eq.) were added to the reaction mixture. The reaction mixture was allowed to react at 25°C for 5 hours. The reaction solution was quenched with water (80 ml) and extracted with ethyl acetate (2×70 ml). The organic phases were combined, washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 1 / 1; V / V) and further separated and purified by prep-HPLC to give compound 39, (R)-5-methyl-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (50.84 mg, white solid), yield: 11.5%.

[0740] LCMS:(ESI)[M+H] + =492.2.

[0741] 1 H NMR: (400MHz, DMSO-d6) δ12.32(s,1H),10.88(s,1H),8.72(s,2H),7.98(d,J=1.6Hz,1H),7.68(d,J=2.0Hz,1H) ,4.82(q,J=6.4Hz,1H),4.17(s,2H),3.97-3.85(m,2H),2.28-2.16(m,2H),1.65(s,3H),1.41(d,J=6.8Hz,3H).

[0742] Step F: Preparation of 5-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyridine-4-carboxylic acid

[0743] Ethyl 5-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (800 mg, 2.54 mmol, 1.0 eq.) was dissolved in a mixture of tetrahydrofuran (4 mL), water (4 mL), and ethanol (2 mL). Lithium hydroxide (533 mg, 12.70 mmol, 5.0 eq.) and sodium hydroxide (254 mg, 6.35 mmol, 2.5 eq.) were added. The reaction mixture was reacted at 30°C for 18 hours. Dilute hydrochloric acid (1 M, 30 mL) was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 28 mL). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated to give 5-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyridine-4-carboxylic acid (702 mg, yellow solid). Yield: 96.3%.

[0744] LCMS:(ESI)[M+H] + =288.0.

[0745] 1 H NMR: (400MHz, DMSO-d6) δ12.51(s,1H),8.81(s,2H),7.42(s,1H),4.19(dt,J=13.2,4.4Hz,1H) ,3.69-3.55(m,1H),3.06(t,J=4.4Hz,1H),2.22-2.11(m,1H),2.02-1.88(m,1H),1.84(s,3H).

[0746] Step G: Preparation of 5-methyl-N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyridine-4-carboxamide

[0747] 5-Methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyridine-4-carboxylic acid (388 mg, 1.35 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (15 ml) and cooled to 0°C in an ice bath. 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (487 mg, 1.76 mmol, 1.3 eq.) was added. The reaction mixture was allowed to react at 0°C for 20 minutes. N-methylmorpholine (410 mg, 4.05 mmol, 3.0 eq.) and (R)-5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (300 mg, 1.35 mmol, 1.0 eq.) were added to the reaction mixture. The reaction mixture was allowed to react at 25°C for 5 hours. The reaction solution was quenched with water (80 ml) and extracted with ethyl acetate (2×70 ml). The organic phases were combined, washed with saturated brine (150 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 1 / 1; V / V) and further separated and purified by prep-HPLC to give compound 40, 5-methyl-N-((R)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyridine-4-carboxamide (52.13 mg, white solid), yield: 7.9%.

[0748] LCMS:(ESI)[M+H] + =492.2.

[0749] 1 H NMR: (400MHz, DMSO-d6) δ12.35 (s, 1H), 11.01 (d, J = 3.2Hz, 1H), 8.79 (s, 2H) ,7.99(dd,J=6.4,2.0Hz,1H),7.70(dd,J=7.2,2.0Hz,1H),7.42-7.34(m,1H) ,4.80(q,J=6.4Hz,1H),4.04-3.92(m,1H),3.92-3.75(m,1H),2.78-2.69(m, 1H), 1.95-1.78 (m, 2H), 1.60 (d, J = 24.0Hz, 3H), 1.42 (dd, J = 6.4, 1.6Hz, 3H).

[0750] Example 41: Synthesis of Compound 41

[0751] (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(7-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0752] Step A: Preparation of methyl 1-(7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate

[0753] 7-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridine 5-oxide (800 mg, 2.32 mmol, 1.0 eq.) was dissolved in dichloromethane (20 mL). 1,2,3,6-tetrahydropyridine-4-carboxylic acid methyl ester hydrochloride (655 mg, 4.64 mmol, 2.0 eq.), tripyrrolidinylphosphonium bromide hexafluorophosphate (1.41 g, 3.02 mmol, 1.3 eq.), and potassium carbonate (962 mg, 6.96 mmol, 3.0 eq.) were added sequentially. The reaction mixture was allowed to react at 30°C for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; V / V) to give 1-(7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid methyl ester (390 mg, yellow solid) in a yield of 35.9%.

[0754] LCMS:(ESI)[M+H] + =467.0.

[0755] 1 H NMR: (400MHz, DMSO-d6) δ8.49(s,1H),8.03(s,1H),7.17-7.07(m,1H),5.86(s,2H),4.76-4.70(m,2H),4 .32(t,J=5.6Hz,2H),3.77(s,3H),3.64-3.59(m,2H),2.53-2.47(m,2H),0.94-0.89(m,2H),0.00(s,9H).

[0756] Step B: Preparation of methyl 1-(7-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate

[0757] Methyl 1-(7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (340 mg, 0.73 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (70 mg, 0.37 mmol, 0.5 eq.) and methyl fluorosulfonyldifluoroacetate (561 mg, 2.92 mmol, 4.0 eq.) were added. Under nitrogen, the reaction mixture was allowed to react at 100°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (2 x 40 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; V / V) to give methyl 1-(7-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (75 mg, yellow solid) in a yield of 22.6%.

[0758] LCMS:(ESI)[M+H] + =457.0.

[0759] 1 H NMR: (400MHz, DMSO-d6) δ8.57(s,1H),8.30(s,1H),7.14-7.09(m,1H),5.69(s,2H),4.96-4.86(m,2H),4 .47(t,J=5.6Hz,2H),3.77(s,3H),3.62-3.57(m,2H),2.55-2.50(m,2H),0.92-0.87(m,2H),0.00(s,9H).

[0760] Step C: Preparation of 1-(7-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid

[0761] Methyl 1-(7-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (70 mg, 0.15 mmol, 1.0 eq.) was dissolved in a mixture of tetrahydrofuran (6 mL) and water (3 mL). Lithium hydroxide (38 mg, 0.90 mmol, 6.0 eq.) was added. The reaction mixture was reacted at 30°C for 2 hours. The reaction mixture was diluted with water (30 mL), adjusted to pH 6 with dilute hydrochloric acid (1 M), and extracted with ethyl acetate (2 x 30 mL). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and concentrated to give 1-(7-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (75 mg, crude, yellow solid).

[0762] LCMS:(ESI)[M+H] + =443.0.

[0763] Step D: Preparation of (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(7-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxymethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0764] 1-(7-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (70 mg, 0.16 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (5 mL) and cooled to 0°C in an ice bath. 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (58 mg, 0.21 mmol, 1.3 eq.) was added. The reaction mixture was allowed to react at 0°C for 20 minutes. N-methylmorpholine (49 mg, 0.48 mmol, 3.0 eq.) and (R)-5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (36 mg, 0.16 mmol, 1.0 eq.) were then added to the reaction mixture. The reaction mixture was reacted at 30°C for 5 hours. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (2×50 ml). The organic phases were combined, washed with saturated brine (120 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1; V / V) to give (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(7-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxymethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (55 mg, white solid) in a yield of 53.5%.

[0765] LCMS:(ESI)[M+H] + =647.2.

[0766] 1 H NMR: (400MHz, DMSO-d6) δ12.37(s,1H),11.04(s,1H),8.54(s,1H),8.28(s,1H),8.08(s,1H),7.75(s,1H),6.62-6.54(m,1H),5.67(s,2H), 4.91-4.75(m,3H),4.49-4.39(m,2H),3.59(t,J=8.0Hz,2H),2.47-2.39(m,2H),1.49(d,J=6.4Hz,3H),0.90(t,J=8.0Hz,2H),0.00(s,9H).

[0767] Step E: Preparation of (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(7-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0768] (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(7-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxymethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (64 mg, 0.10 mmol, 1.0 eq.) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (2 ml) was added. The reaction mixture was reacted at 30°C for 2 hours. The reaction was quenched by adding saturated sodium carbonate solution (50 ml) and extracted with dichloromethane (2×50 ml). . The organic phases were combined, washed with saturated brine (120 ml), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1; V / V), and further separated and purified by prep-HPLC to give compound 41, (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(7-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (10.38 mg, white solid), yield: 20.3%.

[0769] LCMS:(ESI)[M+H] + =517.2.

[0770] 1 H NMR: (400MHz, DMSO-d6) δ13.20(s,1H),12.30(s,1H),10.98(s,1H),8.28-8.25(m,1H),8.15-8.11(m,1H),8.01(d,J=2.0H z,1H),7.69(s,1H),6.55-6.48(m,1H),4.90-4.70(m,3H),4.38(t,J=5.6Hz,2H),2.39-2.33(m,2H),1.43(d,J=6.4Hz,3H).

[0771] Example 42: Synthesis of Compound 42

[0772] (R)-1-(5-cyanopyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0773] Step A: Preparation of 1-(5-cyanopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid

[0774] 1,2,3,6-Tetrahydropyridine-4-carboxylic acid hydrochloride (55 mg, 0.34 mmol, 1.0 eq.) was dissolved in dichloromethane (5 mL). 2-Chloro-5-cyanopyrimidine (47 mg, 0.34 mmol, 1.0 eq.) and N,N-diisopropylethylamine (200 mg, 1.55 mmol, 5.0 eq.) were added sequentially. The reaction mixture was allowed to react at 25°C for 16 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by column chromatography (dichloromethane / methanol = 10 / 1; v / v) to afford 1-(5-cyanopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (75 mg, yellow solid) in a yield of 96.9%.

[0775] LCMS:(ESI)[M+H] + =231.0.

[0776] 1 H NMR: (400MHz, DMSO-d6) δ8.86 (s, 2H), 7.00-6.95 (m, 1H), 4.51-4.46 (m, 2H), 4.03 (t, J = 5.6Hz, 2H), 2.44-2.40 (m, 2H).

[0777] Step B: Preparation of (R)-1-(5-cyanopyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0778] 1-(5-Cyanopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (75 mg, 0.33 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (5 mL) and cooled to 0°C in an ice bath. 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (119 mg, 0.43 mmol, 1.3 eq.) was added. The reaction mixture was allowed to react at 0°C for 20 minutes. N-methylmorpholine (100 mg, 0.99 mmol, 3.0 eq.) and (R)-5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (73 mg, 0.33 mmol, 1.0 eq.) were added to the reaction mixture. The reaction mixture was allowed to react at 25°C for 5 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 x 45 mL). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 2 / 1; V / V) and further separated and purified by prep-HPLC to give compound 42, (R)-1-(5-cyanopyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide (5.30 mg, white solid), in a yield of 3.7%.

[0779] LCMS:(ESI)[M+H] + =435.0.

[0780] 1 H NMR: (400MHz, DMSO-d6) δ12.31(s,1H),11.02(s,1H),8.79(s,2H),8.01(d,J=2.0Hz,1H),7.72-7.65(m,1H),6.49-6. 43(m,1H),4.77(q,J=6.4Hz,1H),4.40-4.33(m,2H),3.94(t,J=6.0Hz,2H),2.35-2.27(m,2H),1.43(d,J=6.4Hz,3H).

[0781] Example 43: Synthesis of Compound 43

[0782] (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(quinazolin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0783] Step A: Preparation of 1-(quinazolin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid

[0784] 1,2,3,6-Tetrahydropyridine-4-carboxylic acid (150 mg, 0.92 mmol, 1.0 eq.) was dissolved in a mixture of ethanol (3 mL) and water (1.5 mL). N,N-diisopropylethylamine (475 mg, 3.68 mmol, 4.0 eq.) and 2-chloroquinazoline (150 mg, 0.92 mmol, 1.0 eq.) were added sequentially. The reaction mixture was reacted at 70°C for 2 hours. The reaction mixture was diluted with water (30 mL), adjusted to pH 6 with dilute hydrochloric acid (1 M), and extracted with ethyl acetate (5 x 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford 1-(quinazolin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (140 mg, yellow solid) in a yield of 60.1%.

[0785] LCMS:(ESI)[M+H] + =256.2.

[0786] 1 H NMR (400MHz, DMSO-d6) δ12.41(s,1H),9.24(s,1H),7.85(dd,1H),7.78-7.69(m,1H),7.54(d,J=8.5Hz, 1H),7.33-7.25(m,1H),7.03-6.93(m,1H),4.55-4.37(m,2H),4.02(t,J=5.7Hz,2H),2.43-2.35(m,2H).

[0787] Step B: Preparation of (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(quinazolin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0788] 1-(Quinazolin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (130 mg, 0.51 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (3 mL). (R)-5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (115 mg, 0.51 mmol, 1.0 eq.), 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (180 mg, 0.61 mmol, 1.2 eq.), and N-methylmorpholine (178 mg, 1.53 mmol, 3.0 eq.) were added sequentially. The reaction mixture was allowed to react at 20°C for 2 hours. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated brine (2 x 30 mL), dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was separated and purified by prep-HPLC to obtain compound 43.

[0789] (R)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(quinazolin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (97.65 mg, white solid), yield: 44.9%.

[0790] LCMS:(ESI)[M+H] + =460.0.

[0791] 1 H NMR(400MHz,DMSO-d6)δ12.30(s,1H),11.00(s,1H),9.24(s,1H),8.02(d,J =2.0Hz,1H),7.86(d,J=8.0Hz,1H),7.78-7.72(m,1H),7.69(s,1H),7.53(d ,J=8.5Hz,1H),7.29(t,J=7.4Hz,1H),6.52(s,1H),4.84-4.72(m,1H),4.41 (d, J = 2.8 Hz, 2H), 4.00 (t, J = 5.6 Hz, 2H), 2.33 (s, 2H), 1.43 (d, J = 6.6 Hz, 3H).

[0792] Example 44: Synthesis of Compound 44

[0793] (R)-1-(5-bromopyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0794] Step A: Preparation of methyl 1-(5-bromopyrimidin-2-yl)piperidine-4-carboxylate

[0795] 5-Bromo-2-chloropyrimidine (11.61 g, 60.00 mmol, 1.0 eq.) was dissolved in N-methylpyrrolidone (100 ml), and N,N-diisopropylethylamine (19.39 g, 150.00 mmol, 2.5 eq.) and methyl 4-piperidinate (9.45 g, 66.00 mmol, 1.1 eq.) were added sequentially. The reaction mixture was allowed to react at 80°C for 1 hour. The reaction mixture was cooled to room temperature and diluted with water (500 ml), and extracted with ethyl acetate (2 x 200 ml). The organic phases were combined, washed with saturated brine (2 x 300 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 15 / 1; v / v) to afford methyl 1-(5-bromopyrimidin-2-yl)piperidine-4-carboxylate (15.63 g, white solid) in a yield of 86.8%.

[0796] LCMS:(ESI)[M+H] + =300.0.

[0797] 1 H NMR: (400MHz, CDCl3) δ8.27 (s, 2H), 4.56 (dt, J = 13.6, 3.6Hz, 2H), 3.69 (s, 3H) ,3.10-2.99(m,2H),2.63-2.53(m,1H),2.01-1.92(m,2H),1.74-1.64(m,2H).

[0798] Step B: Preparation of methyl 1-(5-bromopyrimidin-2-yl)-4-(phenylseleno)piperidine-4-carboxylate

[0799] Methyl 1-(5-bromopyrimidin-2-yl)piperidine-4-carboxylate (1.80 g, 6.00 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (40 ml) and cooled to -78°C under nitrogen. Lithium diisopropylamide (2 M, 3.30 ml, 6.60 mmol, 1.1 eq.) was added dropwise. The reaction mixture was allowed to react at -78°C for 0.5 h. A solution of phenylselenium chloride (1.26 g, 6.60 mmol, 1.1 eq.) in tetrahydrofuran (5 ml) was added dropwise. The reaction mixture was heated to 20°C and reacted for 3 h. The reaction mixture was quenched by addition of saturated ammonium chloride (100 ml) and extracted with ethyl acetate (2 x 100 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 25 / 1; V / V) to give methyl 1-(5-bromopyrimidin-2-yl)-4-(phenylseleno)piperidine-4-carboxylate (0.83 g, light yellow solid) in a yield of 30.4%.

[0800] LCMS:(ESI)[M+H] + =456.0.

[0801] 1 H NMR: (400MHz, CDCl3) δ8.27(s,2H),7.58-7.53(m,2H),7.44-7.38(m,1H),7.35-7.29(m,2H ),4.25-4.15(m,2H),3.66(s,3H),3.46-3.35(m,2H),2.24-2.13(m,2H),1.97-1.87(m,2H).

[0802] Step C: Preparation of methyl 1-(5-bromopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate

[0803] Methyl 1-(5-bromopyrimidin-2-yl)-4-(phenylseleno)piperidine-4-carboxylate (400 mg, 0.88 mmol, 1.0 eq.) was dissolved in dichloromethane (10 ml). Under nitrogen, the temperature was cooled to -78°C, and m-chloroperbenzoic acid (80%, 190 mg, 0.88 mmol, 1.0 eq.) was added. The reaction solution was reacted at -78°C for 1 hour. Triethylamine (267 mg, 2.64 mmol, 3.0 eq.) was added to the reaction solution. The reaction solution was continued at -78°C for 1 hour. The reaction solution was quenched by adding saturated aqueous sodium bicarbonate (50 ml) and extracted with ethyl acetate (2 x 70 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1; V / V) to give methyl 1-(5-bromopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (230 mg, light yellow solid) in a yield of 87.8%.

[0804] LCMS:(ESI)[M+H] + =298.0.

[0805] 1 H NMR: (400MHz, CDCl3) δ8.32 (s, 2H), 7.03-6.97 (m, 1H), 4.34 (q, J = 3.2Hz, 2H), 3.92 (t, J = 5.6Hz, 2H), 3.77 (s, 3H), 2.53-2.44 (m, 2H).

[0806] Step D: Preparation of 1-(5-bromopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid

[0807] Methyl 1-(5-bromopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (119 mg, 0.40 mmol, 1.0 eq.) was dissolved in a mixture of tetrahydrofuran (3 mL) and water (1.5 mL). Lithium hydroxide (67 mg, 1.60 mmol, 4.0 eq.) was added. The reaction mixture was allowed to react at 20°C for 6 hours. The reaction mixture was diluted with water (50 mL) and washed with ethyl acetate (20 mL). The aqueous phase was collected, adjusted to pH 6 with dilute hydrochloric acid (1 M), and extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford 1-(5-bromopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (91 mg, pale yellow solid) in a yield of 80.1%.

[0808] LCMS:(ESI)[M+H] + =284.0.

[0809] 1 H NMR: (400MHz, CDCl3) δ8.33 (s, 2H), 7.16-7.10 (m, 1H), 4.43-4.33 (m, 2H), 3.94 (t, J = 5.6Hz, 2H), 2.55-2.45 (m, 2H).

[0810] Step E: Preparation of (R)-1-(5-bromopyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0811] 1-(5-Bromopyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (71 mg, 0.25 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (3.5 mL) and cooled to 0°C in an ice bath. 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (96 mg, 0.33 mmol, 1.3 eq.) was added. The reaction mixture was allowed to react at 0°C for 5 minutes. N-methylmorpholine (76 mg, 0.75 mmol, 3.0 eq.) and (R)-5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (58 mg, 0.26 mmol, 1.05 eq.) were added to the reaction mixture. The reaction mixture was allowed to react at 20°C for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to yield compound 44, (R)-1-(5-bromopyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide (20.53 mg, white solid), in a yield of 16.8%.

[0812] LCMS:(ESI)[M+H] + =488.0.

[0813] 1 H NMR: (400MHz, DMSO-d6) δ12.15(s,1H),11.01(s,1H),8.48(s,2H),8.01(d,J=1.6Hz,1H),7.68(d,J=2.0Hz,1H),6.50- 6.41(m,1H),4.78(q,J=6.4Hz,1H),4.27-4.18(m,2H),3.82(t,J=5.6Hz,2H),2.32-2.22(m,2H),1.43(d,J=6.4Hz,3H).

[0814] Example 45: Synthesis of Compound 45

[0815] (R)-1-(5-(4-fluorophenyl)pyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0816] Step A: Preparation of methyl 1-(5-bromopyrimidin-2-yl)piperidine-4-carboxylate

[0817] 5-Bromo-2-chloropyrimidine (11.61 g, 60.00 mmol, 1.0 eq.) was dissolved in N-methylpyrrolidone (100 ml), and N,N-diisopropylethylamine (19.39 g, 150.00 mmol, 2.5 eq.) and methyl 4-piperidinate (9.45 g, 66.00 mmol, 1.1 eq.) were added sequentially. The reaction mixture was allowed to react at 80°C for 1 hour. The reaction mixture was cooled to room temperature and diluted with water (500 ml), and extracted with ethyl acetate (2 x 200 ml). The organic phases were combined, washed with saturated brine (2 x 300 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 15 / 1; v / v) to afford methyl 1-(5-bromopyrimidin-2-yl)piperidine-4-carboxylate (15.63 g, white solid) in a yield of 86.8%.

[0818] LCMS:(ESI)[M+H] + =300.0.

[0819] 1 H NMR: (400MHz, CDCl3) δ8.27 (s, 2H), 4.56 (dt, J = 13.6, 3.6Hz, 2H), 3.69 (s, 3H) ,3.10-2.99(m,2H),2.63-2.53(m,1H),2.01-1.92(m,2H),1.74-1.64(m,2H).

[0820] Step B: Preparation of methyl 1-(5-(4-fluorophenyl)pyrimidin-2-yl)piperidine-4-carboxylate

[0821] Methyl 1-(5-bromopyrimidin-2-yl)piperidine-4-carboxylate (2.50 g, 8.36 mmol, 1.0 eq.) was added to anhydrous 1,4-dioxane (25 mL). (4-Fluorophenyl)boronic acid (1.28 g, 9.19 mmol, 1.1 eq.), potassium carbonate (3.46 g, 25.08 mmol, 3.0 eq.), water (3 mL), and tetrakistriphenylphosphine palladium (0.482 g, 0.42 mmol, 0.05 eq.) were also added. The reaction mixture was reacted at 100°C under nitrogen for 5 hours. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (2 x 30 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; V / V) to give methyl 1-(5-(4-fluorophenyl)pyrimidin-2-yl)piperidine-4-carboxylate (2.1 g, yellow solid) in a yield of 81.9%.

[0822] LCMS:(ESI)[M+H] +=316.2.

[0823] Step C: Preparation of methyl 1-(5-(4-fluorophenyl)pyrimidin-2-yl)-4-(phenylseleno)piperidine-4-carboxylate

[0824] Methyl 1-(5-(4-fluorophenyl)pyrimidin-2-yl)piperidine-4-carboxylate (1.9 g, 6.03 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (20 ml). Under nitrogen, the mixture was cooled to -78°C and lithium diisopropylamide (2 M, 6 ml, 12.06 mmol, 6.0 eq.) was added dropwise. After a half-hour reaction, phenylselenium chloride (1.4 g, 7.23 mmol, 1.2 eq.) was added to the reaction mixture and allowed to react at -78°C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 ml) and extracted with ethyl acetate (3 x 20 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; V / V) to give methyl 1-(5-(4-fluorophenyl)pyrimidin-2-yl)-4-(phenylseleno)piperidine-4-carboxylate (1.4 g, white solid) in a yield of 49.2%.

[0825] LCMS:(ESI)[M+H] + =472.2.

[0826] 1 H NMR: (400MHz, CDCl3) δ8.41(s,2H),7.53-7.48(m,2H),7.38-7.31(m,3H),7.29-7.23(m,2H),7.10-7 .02(m,2H),4.30-4.17(m,2H),3.60(s,3H),3.47-3.34(m,2H),2.22-2.10(m,2H),1.97-1.84(m,2H).

[0827] Step D: Preparation of methyl 1-(5-(4-fluorophenyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate

[0828] Methyl 1-(5-(4-fluorophenyl)pyrimidin-2-yl)-4-(phenylseleno)piperidine-4-carboxylate (1.4 g, 2.97 mmol, 1.0 eq.) was dissolved in dichloromethane (15 ml), cooled to -78°C, and m-chloroperbenzoic acid (1.0 g, 5.94 mmol, 2.0 eq.) was added. The reaction mixture was reacted at -78°C for 30 minutes. Triethylamine (3.0 g, 29.7 mmol, 10.0 eq.) was added to the reaction mixture. The reaction mixture was reacted at -78°C for 2 hours. The reaction mixture was quenched with aqueous ammonium chloride (30 ml) and extracted with ethyl acetate (3 x 30 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; V / V) to give methyl 1-(5-(4-fluorophenyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (800 mg, white solid) in a yield of 86.0%.

[0829] LCMS:(ESI)[M+H] + =314.2.

[0830] 1 H NMR: (400MHz, DMSO-d6)δ8.72(s,2H),7.75-7.65(m,2H),7.29(t,J=8.5Hz, 2H),7.02(s,1H),4.41(s,2H),3.99-3.91(m,2H),3.70(s,3H),2.40(s,2H).

[0831] Step E: Preparation of 1-(5-(4-fluorophenyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid

[0832] Methyl 1-(5-(4-fluorophenyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (200 mg, 0.63 mmol, 1.0 eq.) was dissolved in a mixture of tetrahydrofuran (8 mL) and water (4 mL), and lithium hydroxide (30 mg, 1.27 mmol, 2.0 eq.) was added. The reaction mixture was allowed to react at 25°C for 2 hours. The reaction mixture was diluted with water (10 mL), adjusted to pH 6 with dilute hydrochloric acid (1 M), and extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford 1-(5-(4-fluorophenyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (170 mg, white solid) in a yield of 89.1%.

[0833] 1H NMR: (400MHz, DMSO-d6) δ12.46(s,1H),8.72(s,2H),7.72-7.67(m,2H),7.31-7.26(m ,2H),6.99-6.93(m,1H),4.43-4.34(m,2H),3.93(t,J=5.7Hz,2H),2.42-2.30(m,2H).

[0834] Step F: Preparation of (R)-1-(5-(4-fluorophenyl)pyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0835] 1-(5-(4-Fluorophenyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (80 mg, 0.26 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (3 mL) and cooled to 0°C in an ice bath. 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (88 mg, 0.32 mmol, 1.2 eq.) was added. The reaction mixture was allowed to react at 0°C for 5 minutes. N-methylmorpholine (81 mg, 0.80 mmol, 3.0 eq.) and (R)-5-(1-(aminooxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (60 mg, 0.26 mmol, 1.0 eq.) were added to the reaction mixture. The reaction mixture was allowed to react at 25°C for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to give compound 45, (R)-1-(5-(4-fluorophenyl)pyrimidin-2-yl)-N-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1,2,3,6-tetrahydropyridine-4-carboxamide (36.38 mg, white solid), in a yield of 27.0%.

[0836] LCMS:(ESI)[M+H] + =504.2.

[0837] 1H NMR: (400MHz, DMSO-d6) δ12.30(s,1H),11.00(s,1H),8.71(s,2H),8.01(d,J=2.0Hz,1H),7.73-7.65(m,3H),7.33-7.23(m ,2H),6.49(s,1H),4.78(d,J=6.4Hz,1H),4.31(d,J=2.9Hz,2H),3.90(t,J=5.7Hz,2H),2.30(s,2H),1.43(d,J=6.6Hz,3H).

[0838] Example 46: Synthesis of Compound 46

[0839] N-(2-Hydroxy-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0840] Step A: Preparation of 2-methoxy-3-(trifluoromethyl)-5-vinylpyridine

[0841] 5-Bromo-2-methoxy-3-(trifluoromethyl)pyridine (5 g, 19.6 mmol, 1.0 eq.) was dissolved in tert-butanol (50 ml). Potassium ethylene trifluoroborate (3.9 g, 29.3 mmol, 1.5 eq.), 1,1-bis(diphenylphosphino)diphenylferric palladium(II) chloride (731 mg, 1.0 mmol, 0.05 eq.), and triethylamine (2 g, 19.6 mmol, 1.0 eq.) were added. The reaction mixture was reacted at 100°C for 16 hours. The reaction mixture was cooled to room temperature and quenched with water (60 ml). The mixture was then extracted with ethyl acetate (2 x 50 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 95 / 5; V / V) to give 2-methoxy-3-(trifluoromethyl)-5-vinylpyridine (1.3 g, yellow oil) in a yield of 33.3%.

[0842] LCMS:(ESI)[M+H] + =204.2.

[0843] Step B: Preparation of 2-methoxy-5-(oxiran-2-yl)-3-(trifluoromethyl)pyridine

[0844] 2-Methoxy-3-(trifluoromethyl)-5-vinylpyridine (800 mg, 3.95 mmol, 1.0 eq.) was dissolved in a mixture of tert-butanol (8 mL) and water (8 mL). N-bromosuccinimide (698 mg, 3.95 mmol, 1.0 eq.) was added, and the reaction mixture was reacted at 40°C for 16 hours. The reaction mixture was cooled to 0°C, and sodium hydroxide solution (2.37 mL, 11.85 mmol, 5 M, 3.0 eq.) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 x 25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 98 / 2; V / V) to give 2-methoxy-5-(oxiran-2-yl)-3-(trifluoromethyl)pyridine (590 mg, yellow oil) in a yield of 77.5%.

[0845] LCMS:(ESI)[M+H] + =220.2.

[0846] 1 H NMR (400MHz, CDCl3) δ8.22 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 3.97 (s, 3H), 3.84-3.78 (m, 1H), 3.13-3.11 (m, 1H), 2.79-2.70 (m, 1H).

[0847] Step C: Preparation of 1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethane-1,2-diol

[0848] 2-Methoxy-5-(oxiran-2-yl)-3-(trifluoromethyl)pyridine (590 mg, 2.53 mmol, 1.0 eq.) was dissolved in a mixture of tetrahydrofuran (4 mL) and water (2 mL). Sulfuric acid (2 mL) was added at 0°C. The reaction mixture was reacted at 60°C for 2 hours. The pH of the reaction mixture was adjusted to 7 with aqueous sodium bicarbonate solution and extracted with ethyl acetate (2 x 35 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to yield 1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethane-1,2-diol (660 mg, yellow oil) in a 100% yield.

[0849] LCMS:(ESI)[M+H] + =238.2.

[0850] Step D: Preparation of 2-(tert-butyldimethylsilyloxy)-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethan-1-ol

[0851] 1-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)ethane-1,2-diol (660 mg, 2.79 mmol, 1.0 eq.) was dissolved in dichloromethane (8 mL). t-Butyldimethylsilyl chloride (627 mg, 4.18 mmol, 1.5 eq.), triethylamine (705 mg, 6.98 mmol, 2.5 eq.), and 4-dimethylaminopyridine (66 mg, 0.54 mmol, 0.2 eq.) were added sequentially. The reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; V / V) to give 2-(tert-butyldimethylsilyloxy)-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethan-1-ol (560 mg, colorless oil) in a yield of 57.3%.

[0852] LCMS:(ESI)[M+H] + =352.2.

[0853] 1 H NMR (400MHz, CDCl3) δ8.21(d,J=2.2Hz,1H),7.84(d,J=2.2Hz,1H),4.74-4.60(m,1H),3.96(s,3H) ,3.77-3.62(m,1H),3.51-3.44(m,1H),2.90(d,J=2.8Hz,1H),0.84(s,9H),0.00(d,J=2.6Hz,6H).

[0854] Step E: Preparation of 2-(2-(tert-butyldimethylsilyloxy)-1-(6-methoxy-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione

[0855] 2-(tert-Butyldimethylsilyloxy)-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethan-1-ol (560 mg, 1.6 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (8 mL). 2-Hydroxyisoindoline-1,3-dione (274 mg, 1.68 mmol, 1.05 eq.) and triphenylphosphine (462 mg, 1.76 mmol, 1.1 eq.) were added sequentially. Finally, diisopropyl azodicarboxylate (356 mg, 1.76 mmol, 1.1 eq.) was added dropwise at 0°C. The reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 7 / 3; V / V) to give 2-(2-(tert-butyldimethylsilyloxy)-1-(6-methoxy-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione (760 mg, colorless oil) in a yield of 100%.

[0856] LCMS:(ESI)[M+H] + =497.2.

[0857] Step F: Preparation of 2-(2-(tert-butyldimethylsilyloxy)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione

[0858] Dissolve 2-(2-(tert-Butyldimethylsilyloxy)-1-(6-methoxy-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione (760 mg, 1.52 mmol, 1.0 eq.) in dichloromethane (7 mL) and add trimethylsilyl iodide (0.7 mL). The reaction mixture is allowed to react at room temperature for 2 hours. The reaction mixture is quenched with water (40 mL) and extracted with dichloromethane (2 x 30 mL). The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (dichloromethane / methanol = 94 / 6; V / V) to give 2-(2-(tert-butyldimethylsilyloxy)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione (240 mg, colorless oil) in a yield of 32.6%.

[0859] LCMS:(ESI)[M+H] + =483.0.

[0860] 1H NMR (400MHz, DMSO-d6) δ12.32 (s, 1H), 8.19 (d, J = 2.0Hz, 1H), 7.83 (s, 4H), 7.80 (s, 1H), 5.13 (t, J = 4.4Hz, 1H), 4.18-3.91 (m, 2H), 0.82 (s, 9H), 0.01 (d, J = 4.0Hz, 6H).

[0861] Step G: Preparation of 5-(1-(aminooxy)-2-(tert-butyldimethylsilyloxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one

[0862] 2-(2-(tert-Butyldimethylsilyloxy)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)isoindoline-1,3-dione (220 mg, 0.576 mmol, 1.0 eq.) was dissolved in a mixture of dichloromethane (2 mL) and methanol (1 mL). Hydrazine hydrate (85%, 173 mg, 3.46 mmol, 6.0 eq.) was added. The reaction mixture was allowed to react at room temperature for 16 hours. The reaction mixture was concentrated, and dichloromethane (20 mL) was added to the residue, which was then filtered. The filtrate was concentrated again. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 9; V / V) to give 5-(1-(aminooxy)-2-(tert-butyldimethylsilyloxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (100 mg, white solid) in a yield of 62.5%.

[0863] LCMS:(ESI)[M+H] + =353.2.

[0864] 1 H NMR (400MHz, DMSO-d6) δ12.27(s,1H),7.89(d,J=2.0Hz,1H),7.63(d,J=2.2Hz,1H) ,6.07(s,2H),4.39(t,J=4.7Hz,1H),3.81-3.75(m,2H),0.84(s,9H),-0.00(s,6H).

[0865] Step H: Preparation of N-(2-(tert-butyldimethylsilyloxy)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0866] 1-(5-(Trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (65 mg, 0.228 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (2 mL). 5-(1-(aminooxy)-2-(tert-butyldimethylsilyloxy)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (80 mg, 0.228 mmol, 1.0 eq.), 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (80 mg, 0.274 mmol, 1.2 eq.), and N-methylmorpholine (70 mg, 0.684 mmol, 3.0 eq.) were added sequentially. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 x 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give N-(2-(tert-butyldimethylsilyloxy)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (160 mg, yellow solid), yield: 100%.

[0867] LCMS:(ESI)[M+H] + =608.1.

[0868] Step I: Preparation of N-(2-hydroxy-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0869] N-(2-(tert-Butyldimethylsilyloxy)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (120 mg, 0.198 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (1 ml), and tetrabutylammonium fluoride (0.4 ml, 0.396 mmol, 2.0 eq.) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was quenched with water (10 ml) and extracted with ethyl acetate (2 x 10 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to give compound 46, N-(2-hydroxy-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (37.37 mg, white solid), yield: 38.1%.

[0870] LCMS:(ESI)[M+H]+ =494.2.

[0871] 1 H NMR(400MHz,DMSO-d6)δ12.33(s,1H),11.19(s,1H),8.74(s,2H),8.02(s,1H),7.71(s,1H),6.55-6.48(m ,1H),4.67(t,J=5.1Hz,1H),4.36(d,J=2.8Hz,2H),3.95(t,J=5.7Hz,2H),3.76-3.62(m,2H),2.32(s,2H).

[0872] Example 47: Synthesis of Compound 47

[0873] N-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0874] Step A: Preparation of 2-methoxy-5-(isopropenyl)-3-(trifluoromethyl)pyridine

[0875] 5-Bromo-2-methoxy-3-(trifluoromethyl)pyridine (300 mg, 1.18 mmol, 1.0 eq.) was dissolved in a mixture of N,N-dimethylformamide (6 ml) and water (2 ml). Isopropenylboronic acid pinacol ester (296 mg, 1.76 mmol, 1.5 eq.), tetrakistriphenylphosphine palladium (138 mg, 0.12 mmol, 0.1 eq.), and cesium carbonate (770 mg, 2.36 mmol, 2.0 eq.) were added. The reaction mixture was reacted at 100°C for 16 hours. The reaction mixture was cooled to room temperature and quenched with water (30 ml). The mixture was then extracted with ethyl acetate (2 x 25 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 99 / 1; V / V) to give 2-methoxy-5-(isopropenyl)-3-(trifluoromethyl)pyridine (160 mg, colorless oil) in a yield of 62.5%.

[0876] LCMS:(ESI)[M+H] + =218.2.

[0877] 1H NMR (400MHz, CDCl3) δ8.32 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 2.4, 0.5 Hz, 1H), 5.27 (s, 1H), 5.10-5.00 (m, 1H), 3.97 (s, 3H), 2.15-1.95 (m, 3H).

[0878] Step B: Preparation of 2-methoxy-5-(2-methyloxiran-2-yl)-3-(trifluoromethyl)pyridine

[0879] 2-Methoxy-5-(isopropenyl)-3-(trifluoromethyl)pyridine (320 mg, 1.48 mmol, 1.0 eq.) was dissolved in a mixture of tert-butanol (5 mL) and water (3 mL). N-bromosuccinimide (262 mg, 1.48 mmol, 1.0 eq.) was added, and the reaction mixture was allowed to react at 40°C for 2 hours. The reaction mixture was cooled to 0°C, and aqueous sodium hydroxide solution (0.89 mL, 4.44 mmol, 5 M, 3.0 eq.) was added. The reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 x 25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 97 / 3; V / V) to give 2-methoxy-5-(2-methyloxiran-2-yl)-3-(trifluoromethyl)pyridine (240 mg, yellow oil) in a yield of 68.5%.

[0880] LCMS:(ESI)[M+H] + =234.2.

[0881] 1 H NMR (400MHz, CDCl3) δ8.26 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 2.3, 0.5 Hz, 1H), 3.96 (s, 3H), 2.94 (d, J = 5.1 Hz, 1H), 2.73 (dd, J = 5.1, 0.5 Hz, 1H), 1.66 (s, 3H).

[0882] Step C: Preparation of 2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propan-1-ol

[0883] 2-Methoxy-5-(2-methyloxiran-2-yl)-3-(trifluoromethyl)pyridine (160 mg, 0.69 mmol, 1.0 eq.) was dissolved in methanol (3 ml), and palladium on carbon (16 mg) and triethylamine (346 mg, 3.44 mmol, 5.0 eq.) were added. The reaction solution was degassed with a hydrogen balloon and reacted at 50°C under a hydrogen atmosphere for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; v / v) to give 2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propan-1-ol (160 mg, colorless oil) in a yield of 99.3%.

[0884] LCMS:(ESI)[M+H] + =236.2.

[0885] 1 H NMR (400MHz, CDCl3) δ8.12(d,J=2.1Hz,1H),7.66(d,J=2.3Hz,1H),3.95(s,3 H), 3.73-3.51 (m, 2H), 2.98-2.75 (m, 1H), 1.56 (s, 1H), 1.22 (d, J = 7.1Hz, 3H).

[0886] Step D: Preparation of 2-(2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)isoindoline-1,3-dione

[0887] 2-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)propan-1-ol (160 mg, 0.68 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (3 mL). 2-Hydroxyisoindoline-1,3-dione (117 mg, 0.72 mmol, 1.05 eq.) and triphenylphosphine (197 mg, 0.75 mmol, 1.1 eq.) were added sequentially. Finally, diisopropyl azodicarboxylate (152 mg, 0.75 mmol, 1.1 eq.) was added dropwise at 0°C. The reaction mixture was allowed to react at room temperature for 16 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 78 / 22; V / V) to give 2-(2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)isoindoline-1,3-dione (240 mg, colorless oil) in a yield of 93%.

[0888] LCMS:(ESI)[M+H] + =381.2.

[0889] Step E: Preparation of O-(2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propyl)hydroxylamine

[0890] 2-(2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)isoindoline-1,3-dione (240 mg, 0.64 mmol, 1.0 eq.) was dissolved in a mixture of dichloromethane (2 mL) and methanol (1 mL). Hydrazine hydrate (85%, 190 mg, 3.79 mmol, 6.0 eq.) was added. The reaction mixture was allowed to react at room temperature for 2 hours, then concentrated. Dichloromethane (20 mL) was added to the residue, stirred, filtered, and the filtrate was concentrated again. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate = 7 / 3; v / v) to afford O-(2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propyl)hydroxylamine (150 mg, colorless oil) in a yield of 95.5%.

[0891] LCMS:(ESI)[M+H] + =251.2.

[0892] 1 H NMR (400MHz, CDCl3) δ8.11(d,J=2.0Hz,1H),7.64(d,J=2.1Hz,1H),3.95(s,3H),3.70-3.58(m,2H),3.15-2.93(m,1H),1.18(d,J=1.9Hz,3H).

[0893] Step F: Preparation of N-(2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0894] 1-(5-(Trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (140 mg, 0.52 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (3 mL). O-(2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propyl)hydroxylamine (120 mg, 0.52 mmol, 1.0 eq.), 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (184 mg, 0.63 mmol, 1.2 eq.), and N-methylmorpholine (158 mg, 1.56 mmol, 3.0 eq.) were added sequentially. The reaction mixture was reacted at 20°C for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 x 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated, and the crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 4; V / V) to give N-(2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (70 mg, yellow oil) in a yield of 26.7%.

[0895] LCMS:(ESI)[M+H] + =506.2.

[0896] Step G: Preparation of N-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

[0897] Step G

[0898] N-(2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (50 mg, 0.1 mmol, 1.0 eq.) was dissolved in acetonitrile (1 ml), and aluminum chloride (33 mg, 0.25 mmol, 2.5 eq.) and sodium iodide (30 mg, 0.2 mmol, 2.0 eq.) were added. The reaction mixture was reacted at 40°C for 2 hours. The reaction mixture was quenched with water (10 ml) and extracted with ethyl acetate (2 x 10 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by prep-HPLC to give compound 47, N-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)propoxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide (8.86 mg, white solid), yield: 17.9%.

[0899] LCMS:(ESI)[M+H] + =492.0.

[0900] 1 H NMR (400MHz, DMSO-d6) δ12.25(s,1H),11.19(s,1H),8.74(d,J=0.6Hz,2H),7.95(d,1H),7.65(s,1H),6.54(s,1H ), 4.37 (d, J = 2.8Hz, 2H), 3.95 (t, 2H), 3.90-3.82 (m, 2H), 3.03-2.90 (m, 1H), 2.34 (s, 2H), 1.16 (d, J = 7.1Hz, 3H).

[0901] Example 48

[0902] Biological testing

[0903] Determination of compound inhibition of PARP7 enzyme activity

[0904] Recombinant human PARP7 (Abcam, catalog number ab271651) was used for the assay. A 384-well reaction plate was first coated with 30 μL of histone coating buffer (1.5 μg / mL, purchased from Active Motif, catalog number 81167) at 37°C for 2 hours. The histone coating buffer was then washed away, and 30 μL of blocking buffer (PBS containing 0.05% Tween-20 and 5% BSA) was added to each well. The plates were incubated at 25°C for 60 minutes, after which the blocking buffer was washed away. Prepare the compound (1000×), dilute it threefold from 1 mM to 0.05 μM, and transfer the prepared compound to a 384-well plate using Echo, with 25 nL per well, so that the final concentration of the compound in the reaction system is 1000 nM, 333.33 nM, 111.11 nM, 37.03 nM, 12.34 nM, 4.11 nM, 1.37 nM, 0.45 nM, 0.15 nM, and 0.05 nM, which are used as test wells; at the same time, add 25 nL DMSO to the max control well. Prepare PARP7 enzyme solution (1.67×) and add 15 μL of this solution to the wells. Simultaneously, add 15 μL of reaction buffer (20 mM HEPES, pH 7.5, containing 100 mM NaCl, 0.002% Tween-20, 2 mM DTT, and 0.1% BSA) to the min control wells. Incubate at 25°C for 15 minutes. Next, add 10 μL of Biotin-NAD+ substrate solution (2.5×, purchased from R&D, Cat. No. 6573) and incubate at 25°C for 60 minutes. Wash the reaction mixture, and add 30 μL of horseradish peroxidase (HRP)-conjugated streptavidin (Thermo Pierce, Cat. No. 21127) diluted 1:5000 in blocking buffer to each well. Incubate at 25°C for 30 minutes. After washing away the HRP buffer, 50 μL of HRP chemiluminescent substrate mixture (purchased from Thermo Pierce, Cat. No. 15159) was added to each well, and the luminescent signal (RLU) of each well was detected using a microplate reader (Multi-Mode Detection Plaform, manufacturer MOLECULAR DEVICES, model Paradigm).

[0905] Calculation formula: Inhibition rate % = (max control average - RLU compound) / (max control average - min control average)) × 100%. The dose-response curve of each compound was fitted by GraphPad Prism 8 and the IC 50 value.

[0906] The experimental results are shown in Table 1.

[0907] Table 1. Determination of the inhibition of PARP7 enzyme activity by each compound ("-", indicates not tested)

[0908] Determination of the inhibition of PARP1 and PARP12 enzyme activities by compounds 4 and 27

[0909] In this example, compound 4 and compound 27 were tested for their inhibitory activity against other PARP enzymes (PARP1 and PARP12), and compound RBN-2397 (Cat. No: HY-136174, MedChemEcpress, Shanghai, China) was tested for its inhibitory activity against PARP7, PARP1, and PARP12 enzymes to detect their selectivity in inhibiting PARP7.

[0910] The inhibition of PARP12 activity by the compounds was tested using recombinant human PARP12 (BPS, catalog number 80513). Except for the addition of a different enzyme, the remaining steps were consistent with the PARP7 activity test method. For details, see the PARP7 activity test method above.

[0911] The inhibition of PARP1 enzyme activity by the compound was determined using recombinant human PARP1 protein (BPS, catalog number 80501). First, a 384-well reaction plate was coated with 25 μL of histone coating solution (1.5 μg / mL) at 4°C overnight. The histone coating solution was washed away, and 50 μL of blocking buffer was added to each well. After incubation at 25°C for 60 minutes, the blocking buffer was washed away. The compound stock solution (2000×) was prepared and diluted threefold from 2 mM to 0.1 μM, so that the final concentration of the compound in the reaction system was 1000 nM, 333.33 nM, 111.11 nM, 37.03 nM, 12.34 nM, 4.11 nM, 1.37 nM, 0.45 nM, 0.15 nM, and 0.05 nM. Add 50 nL of the prepared compound stock solution to 20 μL of reaction buffer, shake and mix thoroughly, then aliquot 5 μL into a 384-well plate as a test well. Simultaneously, add an equal amount of DMSO to the max control wells. Incubate the mixture of PARP1 and activated DNA (purchased from Genscript, Cat. No. L05182-01&02&03) at 25°C for 10 minutes. Then, aliquot 10 μL of this mixture into the test wells and the max control wells. Add 10 μL of DNA to the min control wells and incubate at 25°C for 10 minutes. Then, add 10 μL of Biotin-NAD+ substrate solution (2.5×) and incubate at 25°C for 60 minutes. Wash the reaction mixture, add 20 μL of rabbit monoclonal antibody against poly / mono-ADP Ribose (purchased from CST, Cat. No. 83732S), incubate at 25°C for 90 minutes, and then wash three times with PBST (PBS containing 0.05% Tween-20). After diluting HRP-labeled anti-rabbit secondary antibody (purchased from CST, Cat. No. 7074P2) at a ratio of 1:2000 in blocking buffer, 20 μL was added to each well and incubated at 25°C for 60 minutes. After washing away the HRP buffer, 25 μL of HRP chemiluminescent substrate mixture (purchased from Thermo Pierce, Cat. No. 15159) was added to each well, and the luminescent signal (RLU) of each well was measured using a microplate reader (Multi-Mode Detection Platform, manufacturer: MOLECULAR DEVICES, model: Paradigm).

[0912] Calculation formula: Inhibition rate % = (max control average - RLU compound) / (max control average - min control average)) × 100%. The dose-response curve of each compound was fitted by GraphPad Prism 8 and the IC 50 value.

[0913] The experimental results are shown in Table 2.

[0914] Table 2. Inhibitory activity of compounds RBN-2397, 4, and 27 against PARP1 and PARP12 and their selectivity against PARP7

[0915] As shown in Table 2, the selectivity of compounds 4 and 27 for PARP1 over PARP7 was 300.7 and 421.6 times, respectively, significantly higher than the 64.4-fold selectivity of the reference compound RBN-2397. Compounds 4 and 27 also exhibited 53.3 and 120.5-fold selectivity for PARP12 over PARP7, significantly higher than the 35.6-fold selectivity of the reference compound RBN-2397. These results demonstrate that compounds 4 and 27 exhibit highly selective inhibitory activity against the PARP7 enzyme.

[0916] Assays for compound restoration of type I interferon signaling pathway in cells

[0917] In the Examples, whether Compound 4 and Compound 27 can increase the expression of STAT1 protein and p-STAT1 protein in CT26 mouse colon cancer cells was determined to demonstrate whether the compounds can restore the type I interferon signaling pathway in the cells.

[0918] CT26 cells in the exponential growth phase (purchased from Wuhan Punosai Life Science Technology Co., Ltd., catalog number CL-0071) were digested with trypsin (purchased from Thermo Fisher, catalog number 25300120) to form a single cell suspension and counted and seeded in 12-well plates at 2 × 10 cells per well. 5 Cells were plated and cultured overnight at 37°C. The day after seeding, stock solutions of compounds 4 and 27 (1000×) were prepared in DMSO (Sigma, catalog number D4540) and diluted threefold starting from 10 mM to 0.1 mM. The prepared stock solutions were added to a 12-well plate to achieve final concentrations of 0.1, 0.3, 1, 3, and 10 μM for compounds 4 and 27, respectively. The same amount of DMSO as used in the drug-treated wells was added to the negative control wells (final concentration 1‰), and RBN-2397 (prepared with a 1000× stock solution in DMSO, final concentration 1 μM) was added to the positive control wells. After 24 hours of treatment, proteins were extracted using SDS lysis buffer (Beyotime, catalog number P0013G) supplemented with protease inhibitors (Roche, catalog number 11836170001). Protein quantification was performed using a BCA kit (purchased from Thermo Fisher, catalog number 23227). After adjusting the protein concentration, conventional western blot experiments were performed (p-STAT1 antibody: Santa Cruz, catalog number sc-136229; STAT1 antibody: Cell Signaling, catalog number 9172; β-actin antibody: Beyotime, catalog number AF2811).

[0919] The experimental results are shown in FIG1 . Both compound 4 and compound 27 can dose-dependently cause an increase in the expression of STAT1 protein and p-STAT1 protein, indicating that both compounds can restore the type I interferon signaling pathway in cells.

[0920] Compound pharmacokinetic testing

[0921] In this example, pharmacokinetic tests were performed on compound RBN-2397, compound 4, and compound 27 in mice to illustrate their pharmacokinetic properties in mice.

[0922] Preparation method of test compound solution:

[0923] Preparation of intravenous and oral administration solutions: the test compound was dissolved in a solution prepared by 5% DMSO, 50% PEG300, and 45% saline.

[0924] Dosage (calculated as the amount of compound in the dosing solution (mg) / mouse body weight (kg)): 3 mg / kg for intravenous injection (IV), 10 mg / kg for oral gavage (PO).

[0925] Experimental methods for pharmacokinetic studies in mice:

[0926] Eighteen male CD-1 mice (Shanghai Jihui Laboratory Animal Breeding Co., Ltd.), weighing 28-31 g, were fasted for 12 hours and randomly divided into two groups (Group A and Group B), with nine mice in each group. Group A animals were administered a 10 mg / kg dose of the test compound solution via gavage; Group B animals were administered a 3 mg / kg dose of the test compound solution via tail vein injection. Blank blood was drawn before dosing. Approximately 110 μL of venous blood was collected from Group A animals at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after dosing; and approximately 110 μL of venous blood was collected from Group B animals at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after dosing. All blood samples were placed in heparinized tubes, centrifuged, and plasma was collected and stored at -70°C for testing.

[0927] The experimental results are shown in Table 3.

[0928] Table 3: Comparison of pharmacokinetic data of compound RBN-2397, compound 4 and compound 27

[0929] AUC last It represents the area under the drug-time curve from the start of drug administration to the last point, that is, the area enclosed by the blood drug concentration curve on the time axis; CL(iv) represents the drug clearance rate of intravenous administration; T 1 / 2The plasma half-life of a drug refers to the time required for half of the drug to be eliminated from the body; C max It represents the maximum drug concentration reached in plasma after administration; F% represents the oral bioavailability of the drug.

[0930] As shown in Table 3, after injection of 3 mg / kg into the tail vein, the area under the concentration-time curve (AUC last ), that is, the plasma exposure is about 8.2 times that of RBN-2397, and the plasma exposure of compound 27 is about 4.4 times that of RBN-2397; the drug clearance rate (CL(iv)) of RBN-2397 after intravenous administration is 8.4 and 4.5 times that of compound 4 and 27, respectively; the drug plasma half-life (T 1 / 2 ) were 8.2 times and 5.4 times that of RBN-2397, respectively. After oral administration (gavage) of 10 mg / kg, the plasma exposure of compounds 4 and 27 was approximately 33.3 times and 16.1 times that of RBN-2397, respectively; the maximum blood concentration (C max ) were 11.0-fold and 7.6-fold higher than RBN-2397, respectively; and their oral bioavailability (F%) were 3.9-fold and 3.7-fold higher than RBN-2397, respectively. These experimental results demonstrate that compounds 4 and 27 possess superior pharmacokinetic properties compared to RBN-2397, overcoming the shortcomings of RBN-2397, such as its short half-life and poor oral bioavailability. This is expected to translate into superior clinical efficacy. Their superior target inhibitory activity and pharmacokinetic properties offer the potential for expanding their clinical indications.

[0931] Industrial Applicability

[0932] The present invention provides a PARP7 inhibitor and its use, which can selectively inhibit the enzymatic activity of PARP7 and can be used to treat or prevent diseases, disorders or conditions regulated by or affected by PARP7 activity or in which PARP7 activity or overexpression is involved, and is therefore suitable for industrial application.

Claims

1. A PARP7 inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, Wherein, R1 is selected from halogen, C1-6 haloalkyl, and C2-6 alkanoyl; R2 is selected from hydrogen and deuterium; R3 is selected from hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl; or, R2 and R3 together with the adjacent carbon atoms form a C3-6 cycloalkyl; Z is selected from a direct bond or methylene; X is selected from carbon and nitrogen, represents a double bond or a single bond, provided that when X is nitrogen, the bond connected to X is a single bond, and when X is carbon, the bond connected to X is a double bond or a single bond, and at most one double bond is connected to any one atom; m is 0, 1 or 2, and when m is 1, R4 is selected from C1-6 alkyl, and when m is 2, two R4 are located on different ring atoms, and two R4 together form a bridging bond of an alkylene containing 1-3 carbon atoms; Ring A is a 5-6 membered monocyclic heteroaryl or 9-10 membered bicyclic heteroaryl having 1-3 nitrogen atoms; n is 0, 1 or 2, and each R5 is independently selected from cyano, halogen, C3-6 cycloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C2-6 alkoxycarbonylamino, C1-4 alkylsulfinylamino, C1-4 alkylsulfonylamino, and phenyl optionally substituted by 1 or 2 halogens.

2. The PARP7 inhibitor according to claim 1, wherein, Ring A is selected from pyrimidinyl, pyridinyl, pyrrolo[2,3-c]pyridinyl, imidazo[4,5-c]pyridinyl, and quinazolinyl; Ring A is more preferably selected from pyrimidin-2-yl, pyridin-2-yl, pyrrolo[2,3-c]pyridin-7-yl, imidazo[4,5-c]pyridin-4-yl, and quinazolin-2-yl; Ring A is most preferably pyrimidin-2-yl or imidazo[4,5-c]pyridin-4-yl.

3. The PARP7 inhibitor according to claim 1 or 2, wherein, n is 1; and / or, R5 is selected from halogen, C3-6 cycloalkyl, C1-3 haloalkyl, and phenyl optionally substituted by 1 halogen; R5 is more preferably selected from trifluoromethyl or cyclopropyl; and / or, Relative to the connection position of Ring A and the nitrogen-containing six-membered heterocyclic group, the substitution position of R5 on Ring A is the para position.

4. The PARP7 inhibitor according to any one of claims 1-3, wherein, X is N, and are both single bonds; and / or, m is 0, 1 or 2, more preferably 0 or 1; When m is 1, R4 is C1-3 alkyl, more preferably methyl; and / or, R4 is located at the ortho position of the X atom of the nitrogen-containing six-membered heterocyclic group; When m is 2, two R4 on different ring atoms together form a bridging bond selected from methylene or ethylene; and / or, two R4 are respectively located at the ortho position or the meta position of the X atom of the nitrogen-containing six-membered heterocyclic group.

5. The PARP7 inhibitor according to any one of claims 1-3, wherein, X is C or CH, and two One of them is a double bond and the other is a single bond; more preferably, X is C, and both the one connected to the X atom is a double bond and the other is a single bond; and / or, m is 0 or 1, more preferably 0; When m is 1, R4 is C1-3 alkyl, more preferably methyl.

6. The PARP7 inhibitor according to any one of claims 1-5, wherein, Z is a direct bond.

7. The PARP7 inhibitor according to any one of claims 1-6, wherein, R2 is hydrogen; and / or, R3 is selected from hydrogen, C1-3 alkyl, and C1-3 hydroxyalkyl; R3 is more preferably methyl or ethyl.

8. The PARP7 inhibitor according to any one of claims 1-7, wherein R1 is C1-3 haloalkyl, more preferably trifluoromethyl.

9. The PARP7 inhibitor according to claim 1, wherein, The compounds of formula (I) are selected from:

10. A pharmaceutical composition comprising the PARP7 inhibitor according to any one of claims 1-9, and a pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.

11. Use of the PARP7 inhibitor according to any one of claims 1-9 in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition regulated by or affected by PARP7 activity or in which PARP7 activity or overexpression is involved.

12. The use according to claim 11, wherein the disease, disorder or condition is a hyperproliferative disease, an autoimmune or inflammatory disease.

13. The use according to claim 11 or 12, wherein the disease, disorder or condition is a cancer selected from squamous cell lung cancer, adenocarcinoma of the lung, large cell lung cancer, small cell lung cancer, head and neck squamous cell carcinoma, breast cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, colorectal cancer, melanoma, ovarian cancer, esophageal squamous cell carcinoma, gastric cancer, liver cancer, oral cancer, urothelial carcinoma, prostate cancer, bladder cancer, renal cell carcinoma, gastrointestinal stromal tumor, cervical cancer, endometrial cancer, rhabdomyosarcoma, fibrosarcoma, neuroendocrine tumor, mesothelioma, brain cancer, or malignant glioma, or the disease, disorder or condition is an autoimmune or inflammatory disease selected from ulcerative colitis, Crohn's disease, multiple sclerosis, autoimmune liver disease, type I diabetes, bronchial asthma, systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, psoriasis, polymyositis, or dermatomyositis.

14. The PARP7 inhibitor according to any one of claims 1-9 for the treatment or prevention of a disease, disorder or condition regulated by or affected by PARP7 activity or in which PARP7 activity or overexpression is involved.

15. The use of the PARP7 inhibitor according to claim 14, wherein the disease, disorder or condition is a hyperproliferative disease, an autoimmune or inflammatory disease.

16. The use of the PARP7 inhibitor according to claim 14 or 15, wherein the disease, disorder or condition is a cancer selected from squamous cell lung cancer, adenocarcinoma of the lung, large cell lung cancer, small cell lung cancer, head and neck squamous cell carcinoma, breast cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, colorectal cancer, melanoma, ovarian cancer, esophageal squamous cell carcinoma, gastric cancer, liver cancer, oral cancer, urothelial carcinoma, prostate cancer, bladder cancer, renal cell carcinoma, gastrointestinal stromal tumor, cervical cancer, endometrial cancer, rhabdomyosarcoma, fibrosarcoma, neuroendocrine tumor, mesothelioma, brain cancer, or malignant glioma, or The disease, disorder or condition is an autoimmune or inflammatory disease selected from ulcerative colitis, Crohn's disease, multiple sclerosis, autoimmune liver disease, type I diabetes, bronchial asthma, systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, psoriasis, polymyositis, or dermatomyositis.

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