PARP7 inhibitors and uses thereof

Abstract

The present invention discloses, including but not limited to, PARP7 inhibitors and uses thereof.

Description

[0001] Cross-references to related applications This application claims the benefit of PCT application No. PCT / CN2023 / 071671, filed January 10, 2023, and U.S. Provisional Application No. 63 / 445,227, filed February 13, 2023, the entire contents of which are incorporated herein by reference for all purposes. Background Technology

[0002] Enzymes of the poly(ADP-ribose) polymerase (PARP) family, which use nicotinamide adenine dinucleotide (NAD) as their precursor, are called poly(ADP-ribose) polymerases. + PARP enzymes catalyze post-translational modifications of proteins, adding ADP-ribose to target proteins. The PARP family comprises 17 enzymes that regulate cellular processes, including gene expression, protein degradation, DNA damage repair, and cellular stress responses. Based on their catalytic activity, the PARP family can be divided into three categories: poly-PARPs catalyze the transfer of poly-ADP-ribose units to their substrates (PARP1, PARP2, PARP5A, and PARP5b); single PARPs catalyze the transfer of single ADP-ribose units to substrates (most in the PARP family, including PARP7); and PARP13, whose catalytic activity has not yet been confirmed. PARP7 has been identified as a negative regulator of nucleic acid sensing, and its expression is upregulated in cancer, thereby downregulating type I interferon (IFN) signaling. Inhibition of PARP7 can restore IFN signaling, preventing cancer cells from escaping the immune system and thus effectively inhibiting cancer cell growth. This article specifically discloses solutions to these and other problems in this field. Summary of the Invention

[0003] On the one hand, compounds having the following general formula or pharmaceutically acceptable salts thereof are provided: (I).

[0004] Ring A is a substituted or unsubstituted heterocyclic alkene or a substituted or unsubstituted heteroaryl group. In the examples, ring A is not substituted or unsubstituted piperidinene or substituted or unsubstituted pyrrolidineene.

[0005] Cycle B is a substituted or unsubstituted heterocyclic alkene.

[0006] The ring C is a substituted or unsubstituted heteroaryl group.

[0007] L 1 It is a heteroalkylene group with 2 to 10 members, substituted or unsubstituted.

[0008] R 1is hydrogen, halogen, -CN, -NH2, -OH, -COOH, -CONH2, -C(O)H, -CHX 1 2, -CX 1 3, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted 2 to 6 membered heterocycloalkyl.

[0009] each X 1 is independently -F, -CI, -Br, or -I.

[0010] In an aspect is provided a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] In an aspect is provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0012] In an aspect is provided a method of inhibiting PARP7 activity, the method comprising contacting a PARP7 protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION

[0013] I. DEFINITIONS The abbreviations used herein have their normal chemical and biological meanings. The chemical structures and formulas listed herein are constructed according to standard valence rules known in the chemical arts.

[0014] When substituent groups are named with chemical formulas from left to right, they are also meant to encompass the chemically identical substituent groups that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0015] Unless otherwise indicated, the term “alkyl,” by itself or as part of another substituent group, means a straight (i.e., unbranched) or branched carbon chain (or carbons), or a combination thereof, which can be fully saturated, mono-unsaturated, or poly-unsaturated, and can include monovalent, divalent, and multivalent radicals. Alkoxy is an alkyl group attached to the rest of the molecule by an oxygen linking group (-O-). The alkyl group can be an alkenyl group. The alkyl group can be an alkynyl group. Alkenyl groups include one or more double bonds. Alkynyl groups include one or more triple bonds.

[0016] The term “alkene,” by itself or as part of another substituent group, unless otherwise indicated, means a divalent radical derived from an alkyl group, such as, but not limited to, the following: -CH2CH2CH2CH 2-The term "alkene," by itself or as part of another substituent, means, unless otherwise specified, a divalent radical derived from an alkene. The term "alkyne," by itself or as part of another substituent, means, unless otherwise specified, a divalent radical derived from an alkyne.

[0017] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise specified, a stable straight chain or branched chain, or combination thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatom(s) (e.g., N, S, Si, or P) can be placed at any interior position of the heteroalkyl group or at the position on the heteroalkyl group that is attached to the remainder of the molecule. The heteroalkyl is unsubstituted or substituted with one or more of the same or different substituents. Unless otherwise specified, the term "heteroalkenyl," by itself or in combination with another term, means a heteroalkyl group, as defined herein, including at least one double bond. The term "heteroalkynyl," by itself or in combination with another term, means, unless otherwise specified, a heteroalkyl group, as defined herein, including at least one triple bond.

[0018] Likewise, the term "heteroalkylene," by itself or as part of another substituent means, unless otherwise specified, a divalent radical derived from heteroalkyl, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. The term "heteroalkene," by itself or as part of another substituent, means, unless otherwise specified, a divalent radical derived from heteroalkene. The term "heteroalkyne," by itself or as part of another substituent, means, unless otherwise specified, a divalent radical derived from heteroalkyne.

[0019] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise specified, a cyclic version of "alkyl" and "heteroalkyl," respectively. The cycloalkyl and heterocycloalkyl groups are not aromatic. Also, for heterocycloalkyl, one of the heteroatoms can occupy the position at which the heterocycle is attached to the remainder of the molecule. "Cycloalkylene" and "heterocycloalkylene," by themselves or as part of another substituent, mean a divalent radical derived from cycloalkyl and heterocycloalkyl, respectively.

[0020] The term "halo" or "halogen," by itself or as part of another substituent, means, unless otherwise specified, a fluorine, chlorine, bromine, or iodine atom. Additionally, the terms "haloalkyl" and the like include monohaloalkyl and polyhaloalkyl.

[0021] The term "acyl," unless otherwise specified, means -C(O)R, where R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0022] The term "aryl" means a polyunsaturated, aromatic hydrocarbon substituent group that can be a single ring or multiple rings (preferably from 1 to 3 rings) fused together (i.e., fused rings aryl) or covalently linked (i.e., joined rings aryl). Fused ring aryl means multiple rings fused together wherein at least one of the fused rings is an aryl ring and the multiple rings are attached to the remainder of the molecule through any of the carbon atoms contained in the aryl ring of the multiple rings. The term "heteroaryl" means an aryl group (or ring) that contains at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. The term "heteroaryl" therefore includes fused ring heteroaryl (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring and the multiple rings are attached to the remainder of the molecule through any of the atoms contained in the heteroaromatic ring of the multiple rings). The heteroaryl group can be attached to the remainder of the molecule through a carbon atom or a heteroatom. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. "Aryl" and "heteroaryl", alone or as part of another substituent, mean, respectively, divalent groups derived from aryl and heteroaryl. A heteroaryl substituent can be -O- bonded to a ring heteroatom nitrogen.

[0023] The symbol "— " represents the point of attachment of a chemical moiety to the remainder of the molecule or chemical formula.

[0024] The term "carbonyl" as used herein means a carbon atom double bonded to an oxygen atom.

[0025] Each of the above noted terms (e.g., "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl" and "heteroaryl") include substituted and unsubstituted versions of the indicated radical. Preferred substituents for each type of radical are provided below.

[0026] The terms "heteroatom" or "ring heteroatom" as used herein include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In embodiments, the terms "heteroatom" or "ring heteroatom" mean include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0027] ​Certain compounds disclosed herein possess asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers (R)- or (S)- in absolute stereochemistry, or (D)- or (L)- in the case of amino acids, and single isomers are all included within the scope of this disclosure. The compounds disclosed herein do not include those known in the art to be unstable and impossible to synthesize and / or isolate. This disclosure includes compounds in racemic and optically pure forms. Optically active (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral syntheses or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other geometrically asymmetric centers, unless otherwise stated, the compounds should include both E and Z geometric isomers.

[0028] As used in this article, "isomers" refers to compounds that have the same number and type of atoms and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms.

[0029] The term "tautomer" as used in this paper refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomer to another.

[0030] It will be apparent to those skilled in the art that some of the compounds disclosed herein may exist in isomeric forms, and all such isomeric forms are within the scope of this disclosure.

[0031] Unless otherwise stated, the structure described herein also includes all stereochemical forms of the structure, i.e., the R and S configurations of each asymmetric center. Therefore, single stereochemical isomers of this compound, as well as mixtures of enantiomers and diastereomers, are within the scope of this disclosure.

[0032] Unless otherwise stated, the structures described herein also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium, or using atoms rich in deuterium or tritium... 13 C or 14 Compounds having this structure, except those in which carbon is substituted for carbon in C, are all within the scope of this disclosure.

[0033] The term "pharmaceutically acceptable salt" means a salt of a compound that is produced with a relatively nontoxic acid or base, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Certain specific compounds of the present disclosure contain both basic and acidic functionalities, allowing the compounds to be converted into either base or acid addition salts.

[0034] Accordingly, the compounds of the present disclosure can exist in salt form, for example, with pharmaceutically acceptable acids. The present disclosure includes such salts. These salts can be prepared by methods known to those skilled in the art.

[0035] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical conversion by metabolic processes to provide the compounds of the present disclosure in vivo. The prodrugs of the compounds described herein can be converted by metabolic processes into the compounds of the present disclosure after administration. In addition, prodrugs can be converted into the compounds of the present disclosure by chemical or biochemical processes in in vitro

[0036] Certain compounds of the present disclosure can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are included in the scope of the present disclosure. Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent and are intended to be within the scope of the present disclosure.

[0037] The term "treatment" means any successful indication of treating or ameliorating an injury, disease, pathology, or condition, including any objective or subjective parameters, such as alleviation; relief from; lessening of symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the end point of degeneration less debilitating; or improving the patient's physical or mental well-being. Treatment or amelioration of symptoms can be based on objective or subjective parameters including results of physical examination, neurologic examination, and / or psychiatric evaluations. In various embodiments, treatment is prophylactic. In various embodiments, treatment does not include prophylactic treatment. In various embodiments, treatment does not include prophylactic treatment.

[0038] An "effective amount" refers to an amount of a compound sufficient to achieve a desired purpose relative to the absence of the compound (e.g., to achieve an effect of administration, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce a signal pathway, to reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to treat, prevent or reduce one or more symptoms of a disease, which can also be referred to herein as a "therapeutically effective amount." To "reduce" a symptom (and grammatical equivalents of this phrase) means to lessen the severity or frequency of the symptom, or to eliminate the symptom. A "prophylactically effective amount" of a drug is an amount that, when administered to a subject, precludes or delays the onset of, or reduces the likelihood of, or reduces the symptoms of, a damage, disease, pathology or condition (or recurrence thereof) as intended. A single administration need not preclude a complete prophylactic effect, which can be achieved through multiple administrations. Thus, an effective prophylactic amount can be achieved through one or more administrations. As used herein, an "activity reducing amount" refers to an amount of an antagonist required to reduce enzyme activity relative to the absence of the antagonist. As used herein, a "function disrupting amount" refers to an amount of an antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. As used herein, an "activity increasing amount" refers to an amount of an agonist required to increase the activity of an enzyme relative to the absence of the agonist. The exact amount will depend on the purpose of the treatment, and those skilled in the art will be able to determine appropriate amounts using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy , 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0039] "Control" or "control experiment" is used in its ordinary sense to refer to an experiment in which the subject or reagent is treated the same as in a parallel experiment except that a certain procedure, reagent or variable of the experiment is omitted. In some cases, a control is used as a comparison standard to assess the effect of an experiment. In some embodiments, a control is measuring the activity of a protein (e.g., a signal pathway) in the absence of a compound described herein (including embodiments, examples, figures or tables).

[0040] As defined herein, the term "inhibit" and like terms, when referring to a cellular component-inhibitor interaction, means to negatively affect the activity or function of a cellular component (e.g., to reduce a signaling pathway stimulated by a cellular component such as a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microbe, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). Thus, inhibition at least in part includes partially or completely blocking stimulation, reducing, preventing or delaying activation, or inactivating, desensitizing, or down-regulating a signaling pathway or enzymatic activity or amount of cellular component.

[0041] The terms "inhibitor," "inhibitory factor," "antagonist," or "down-regulatory factor" are used interchangeably to refer to a substance that is capable of detecting a decrease in expression or activity of a particular gene or protein. The antagonist can decrease the expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% compared to a control without the antagonist. In some cases, the expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more lower than the expression or activity without the antagonist.

[0042] A "patient," "patient in need of treatment," "subject," or "subject in need of treatment" refers to an organism that is suffering from or susceptible to suffering from a disease or disorder that can be treated by administering a pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammalian animals. In embodiments, the patient is a human. In embodiments, the patient in need is a human. In embodiments, the subject is a human. In embodiments, the subject in need is a human.

[0043] A "disease" or "disorder" refers to a state of being or health of a patient or subject that can be treated with a compound or method provided herein. In some embodiments, the disease is a disease associated with (e.g., caused by) a cellular component such as a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microbe, vesicle, small molecule, protein complex, protein aggregate, or macromolecule. In embodiments, the disease is a cancer.

[0044] The term "cancer" as used herein refers to various cancers, tumors, or malignant tumors found in mammals such as humans.

[0045] The term "drug" is used according to its ordinary meaning to refer to a substance that has a physiological effect (e.g., a beneficial effect that helps treat the subject) when it enters the body of a subject or is on the body of a subject (e.g., in or on the body of a subject or patient). A drug molecule is a moiety of a drug.

[0046] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids in the administration of an active agent to a subject and its absorption, which can be included in the compositions of the present application without

[0047] In treating a disease, the initial dose of a compound used in the pharmaceutical compositions of the present application is from about 0.001 mg / kg to about 1000 mg / kg per day. The daily dose can range from about 0.01 mg / kg to about 500 mg / kg, or from about 0.1 mg / kg to about 200 mg / kg, or from about 1 mg / kg to about 100 mg / kg, or from about 10 mg / kg to about 50 mg / kg. However, the dose can vary depending on the requirements of the patient, the severity of the condition being treated, and the compound or drug used.

[0048] The term “PARP7” or “Poly (ADP-ribose) polymerase 7” or “TIPARP” or “TCDD- inducible poly [ADP-ribose] polymerase” refers to a protein that mediates mono-ADP- ribosylation of glutamate, aspartate, and cysteine residues (including homologs, isoforms, and functional fragments thereof). The term includes any recombinant form or naturally occurring variant of PARP7 that retains PARP7 activity (e.g., at least in the range of 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% of its activity compared to wild-type PARP7). In embodiments, PARP7 is encoded by TIPARP or PARP7 Gene. In embodiments, PARP7 has the amino acid sequence set forth in or corresponding to Entrez 25976, UniProt Q7Z3E1, RefSeq (protein) NP_001171646.1, RefSeq (protein) NP_001171647.1, or RefSeq (protein) NP_056323.2.

[0049] II. Compounds In one aspect, provided are compounds of the following formula, or pharmaceutically acceptable salts thereof: (I).

[0050] Ring A is a substituted or unsubstituted heterocyclenyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In embodiments, Ring A is not a substituted or unsubstituted piperidinylidene or a substituted or unsubstituted pyrrolidinylidene.

[0051] Ring B is a substituted or unsubstituted heterocycloalkenyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered).

[0052] Ring C is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0053] L 1 is a substituted or unsubstituted 2- to 10-membered ring heteroalkylene.

[0054] R 1 is hydrogen, halogen, -CN, -NH2, -OH, -COOH, -CONH2, -C(O)H, -CHX 1 2, -CX 1 3, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted 2- to 6-membered heterocycloalkyl.

[0055] each X 1 is independently -F, -Cl, -Br, or -I.

[0056] In embodiments, substituted Ring A (e.g., substituted heterocyclenyl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein, if substituted Ring A is substituted with multiple groups selected from substituent, size-limited substituent, and lower substituent, each substituent, size-limited substituent, and / or lower substituent can optionally be different. In embodiments, when Ring A is substituted, it is substituted with at least one substituent. In embodiments, when Ring A is substituted, it is substituted with at least one size-limited substituent. In embodiments, when Ring A is substituted, it is substituted with at least one lower substituent.

[0057] In embodiments, Ring A is a substituted or unsubstituted piperazinylidene, a substituted or unsubstituted imidazolidinylidene, a substituted or unsubstituted oxadiazolidinylidene, or a substituted or unsubstituted triazolidinylidene.

[0058] In embodiments, Ring A is a substituted or unsubstituted piperazinyl enone, a substituted or unsubstituted imidazolidinyl enone, a substituted or unsubstituted 1,2,4-oxadiazolyl enone, a substituted or unsubstituted 1,3,4-oxadiazolyl enone, or a substituted or unsubstituted 1,2,3-triazolyl enone.

[0059] In embodiments, Ring A is an unsubstituted piperazinyl enone, an unsubstituted imidazolidinyl enone, an unsubstituted 1,2,4-oxadiazolyl enone, an unsubstituted 1,3,4-oxadiazolyl enone, or an unsubstituted 1,2,3-triazolyl enone.

[0060] In embodiments, Ring A is , , , , In embodiments, Ring A is In embodiments, Ring A is In embodiments, Ring A is In embodiments, Ring A is In embodiments, Ring A is

[0061] In embodiments, substituted Ring B (e.g., substituted heterocycloalkenyl) is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein if substituted Ring B is substituted with multiple groups selected from substituent, size-limited substituent, and lower substituent, each substituent, size-limited substituent, and / or lower substituent can optionally be different. In embodiments, when Ring B is substituted, it is substituted with at least one substituent group. In embodiments, when Ring B is substituted, it is substituted with at least one size-limited substituent. In embodiments, when Ring B is substituted, it is substituted with at least one lower substituent group.

[0062] In embodiments, Ring B is a substituted or unsubstituted piperidinyl ene, a substituted or unsubstituted 8-azabicyclooctane, a substituted or unsubstituted pyrrolidinyl ene, or a substituted or unsubstituted azetidinyl ene. In embodiments, Ring B is an unsubstituted piperidinyl ene, an unsubstituted pyrrolidinyl ene, or an unsubstituted azetidinyl ene.

[0063] In embodiments, Ring B is , , In embodiments, Ring B is In embodiments, Ring B is In embodiments, Ring B is .

[0064] In embodiments, substituted ring C (e.g., substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein if substituted ring C is substituted with multiple groups selected from substituent, size-limited substituent, and lower substituent, each substituent, size-limited substituent, and / or lower substituent can optionally be different. In embodiments, when ring C is substituted, it is substituted with at least one substituent group. In embodiments, when ring C is substituted, it is substituted with at least one size-limited substituent. In embodiments, when ring C is substituted, it is substituted with at least one lower substituent group.

[0065] In embodiments, ring C is substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted thiadiazolyl, or substituted or unsubstituted pyridazinyl. In embodiments, ring C is substituted or unsubstituted 1,3,4-thiadiazolyl.

[0066] In embodiments, ring C is R 2 substituted or unsubstituted heteroaryl.

[0067] R 2 is independently halogen, -CN, -NH2, -OH, -COOH, -CONH2, -C(O)H, -CX 2 3, -CHX 2 2, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted 2 to 6 membered heterocycloalkyl, or substituted or unsubstituted C3-C8cycloalkyl.

[0068] each X 2 is independently -F, -Cl, -Br, or -I.

[0069] In embodiments, substituted R 2 (e.g., substituted C1-C6alkyl, substituted 2 to 6 membered heteroalkyl, and / or substituted C3-C8cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein if substituted R 2 is substituted with multiple groups selected from substituent, size-limited substituent, and lower substituent, each substituent, size-limited substituent, and / or lower substituent can optionally be different. In embodiments, when R 2 is substituted, it is substituted with at least one substituent group. In embodiments, when R 2 is substituted, it is substituted with at least one size-limited substituent. In embodiments, when R 2When substituted, it is substituted with at least one lower substituent.

[0070] R is independently -F. In embodiments, R 2 is independently halogen. In embodiments, R 2 is independently -F. In embodiments, R 2 is independently -Cl. In embodiments, R 2 is independently -Br. In embodiments, R 2 is independently -I. In embodiments, R 2 is independently -CN. In embodiments, R 2 is independently -NH2. In embodiments, R 2 is independently -OH. In embodiments, R 2 is independently -COOH. In embodiments, R 2 is independently -CONH2. In embodiments, R 2 is independently -C(O)H. In embodiments, R 2 is independently -CX 2 3. In embodiments, R 2 is independently -CF3. In embodiments, R 2 is independently -CCl3. In embodiments, R 2 is independently -CBr3. In embodiments, R 2 is independently -CI3. In embodiments, R 2 is independently -CHX 2 2. In embodiments, R 2 is independently -CHF2. In embodiments, R 2 is independently -CHCl2. In embodiments, R 2 is independently -CHBr2. In embodiments, R 2 is independently -CHI2. In embodiments, R 2 is independently substituted or unsubstituted C1-C6alkyl. In embodiments, R 2 is independently unsubstituted C1-C6alkyl. In embodiments, R 2 is independently unsubstituted methyl. In embodiments, R 2 is independently unsubstituted ethyl. In embodiments, R 2 is independently unsubstituted propyl. In embodiments, R 2 is independently unsubstituted n-propyl. In embodiments, R 2 is independently unsubstituted isopropyl. In embodiments, R 2 is independently unsubstituted butyl. In embodiments, R 2Independently, it is an unsubstituted n-butyl group. In the implementation scheme, R 2 Independently, it is an unsubstituted isobutyl group. In the implementation, R 2 Independently, it is unsubstituted tert-butyl. In the implementation, R 2 Independently, it is a substituted or unsubstituted heteroalkyl group at the 2 to 6 positions. In the embodiments, R 2 Independently, it is an unsubstituted heteroalkyl group at positions 2 to 6. In the embodiments, R 2 Independently, it is an unsubstituted methoxy group. In the embodiments, R 2 Independently, it is an unsubstituted ethoxy group. In the embodiments, R 2 Independently, it is an unsubstituted propoxy group. In the embodiments, R 2 Independently, it is an unsubstituted propoxy group. In the embodiments, R 2 Independently, it is an unsubstituted isopropoxy group. In the embodiments, R 2 It is independently an unsubstituted butoxy group. In the embodiments, R 2 Independently, it is a substituted or unsubstituted C3-C8 cycloalkyl group. In the embodiments, R 2 Independently, it is an unsubstituted C3-C8 cycloalkyl group. In the embodiments, R 2 Independent of the unsubstituted cyclopropyl group. In the embodiments, R 2 Independently, it is an unsubstituted cyclobutyl group. In the implementation, R 2 Independent of the unsubstituted cyclopentyl group. In the implementation scheme, R 2 Independently, it is an unsubstituted cyclohexyl group. In the implementation scheme, R 2 Independently, it is an unsubstituted cycloheptanyl group. In the embodiment, R 2 Independent of unsubstituted cyclooctyl.

[0071] In the implementation plan, R 2 Independently -F, -Cl, -CF (3) 、- CN, -CH3, -CF (2) H -Br, -C(O)H or substituted or unsubstituted C3-C8 cycloalkyl groups.

[0072] In the implementation plan, ring C is R 2 -Substituted or unsubstituted pyrimidinyl group, R 2 -Substituted or unsubstituted pyridinyl, R 2 -Substituted or unsubstituted thiazolyl group, R 2 -Substituted or unsubstituted thiadiazole group, or R 2 -Substituted or unsubstituted pyridazinyl group.

[0073] In embodiments, Ring C is 5-(trifluoromethyl)pyrimidinyl, 5-(difluoromethyl)pyrimidinyl, 5-fluoropyrimidinyl, 5-bromopyrimidinyl, 5-chloropyrimidinyl, 5-methylpyrimidinyl, pyrimidine-5-carbonitrile, or 5-cyclopropylpyrimidinyl. In embodiments, Ring C is 3-(trifluoromethyl)pyridinyl, 3-(difluoromethyl)pyridinyl, 3-fluoropyridinyl, 3-fluoropyridinyl, 3-methylpyridinyl, nicotinonitrile, or nicotinaldehyde. In embodiments, Ring C is 5-(trifluoromethyl)pyridazinyl.

[0074] In embodiments, Ring C is , , , , , , , , , , , , , , , , , , , , , , , , or In particular embodiments, Ring C is In particular embodiments, Ring C is In particular embodiments, Ring C is In particular embodiments, Ring C is In particular embodiments, Ring C is In particular embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is In embodiments, Ring C is .

[0075] In embodiments, substituted R 1 (e.g., substituted alkyl and / or substituted heteroalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein if substituted R 1 is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents; each substituent, size-limited substituent, and / or lower substituent can optionally be different. In embodiments, when R 1 is substituted, it is substituted with at least one substituent. In embodiments, when R 1 is substituted, it is substituted with at least one size-limited substituent. In embodiments, when R 1 is substituted, it is substituted with at least one lower substituent.

[0076] In embodiments, R 1 is hydrogen. In embodiments, R 1 is halogen. In embodiments, R 1 is -F. In embodiments, R 1 is -Cl. In embodiments, R 1 is -Br. In embodiments, R 1 is -I. In embodiments, R 1 is -CN. In embodiments, R 1 is -NH2. In embodiments, R 1 is -OH. In embodiments, R 1 is -COOH. In embodiments, R 1 is -CONH2. In embodiments, R 1 is -C(O)H. In embodiments, R 1 is -CHX 1 2. In embodiments, R 1 is -CHF2. In embodiments, R 1 is -CHCl2. In embodiments, R 1is -CHBr2. In embodiments, R 1 is -CHI2. In embodiments, R 1 is -CX 1 3. In embodiments, R 1 is -CF3. In embodiments, R 1 is -CCl3. In embodiments, R 1 is -CBr3. In embodiments, R 1 is -CI3. In embodiments, R1is substituted or unsubstituted C1-C6alkyl. In embodiments, R 1 is substituted C1-C6alkyl. In embodiments, substituted C1-C6alkyl is -C(O)R 1A , wherein R 1A is unsubstituted C1-C5alkyl. In embodiments, R 1 is -C(O)R 1A , wherein R 1A is unsubstituted C1-C5alkyl. In embodiments, R 1 is unsubstituted C1-C6alkyl. In embodiments, R 1 is unsubstituted methyl. In embodiments, R 1 is unsubstituted ethyl. In embodiments, R 1 is unsubstituted propyl. In embodiments, R 1 is unsubstituted n-propyl. In embodiments, R 1 is unsubstituted isopropyl. In embodiments, R 1 is unsubstituted butyl. In embodiments, R 1 is unsubstituted n-butyl. In embodiments, R 1 is unsubstituted isobutyl. In embodiments, R 1 is unsubstituted t-butyl. In embodiments, R 1 is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 1 is unsubstituted methoxy. In embodiments, R 1 is unsubstituted ethoxy. In embodiments, R 1 is unsubstituted propoxy. In embodiments, R 1 is unsubstituted n-propoxy. In embodiments, R 1 is unsubstituted isopropoxy. In embodiments, R 1 is unsubstituted butoxy.

[0077] In embodiments, R 1A is unsubstituted methyl. In embodiments, R 1Ais unsubstituted ethyl. In embodiments, R 1A is unsubstituted propyl. In embodiments, R 1A is unsubstituted n-propyl. In embodiments, R 1A is unsubstituted isopropyl. In embodiments, R 1A is unsubstituted butyl. In embodiments, R 1A is unsubstituted n-butyl. In embodiments, R 1A is unsubstituted isobutyl. In embodiments, R 1A is unsubstituted t-butyl. In embodiments, R 1A is unsubstituted pentyl.

[0078] In embodiments, substituted L 1 (e.g., substituted C1-C4 alkylene) is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein if substituted L 1 is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents, each substituent, size-limited substituent, and / or lower substituent can optionally be different. In embodiments, when L 1 is substituted, it is substituted with at least one substituent. In embodiments, when L 1 is substituted, it is substituted with at least one size-limited substituent. In embodiments, when L 1 is substituted, it is substituted with at least one lower substituent.

[0079] In embodiments, L 1 is -N(R 3 )-L 2 -O-L 3 -, wherein the nitrogen atom is attached to the pyridazinone, L 3 is attached to ring A, L 2 and L 3 are independently substituted or unsubstituted C1-C4 alkylene. R 3 is hydrogen or unsubstituted C1-C4 alkyl.

[0080] In embodiments, substituted L 2 (e.g., substituted C1-C4 alkylene) is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein if substituted L 2 is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents, each substituent, size-limited substituent, and / or lower substituent can optionally be different. In embodiments, when L 2 is substituted, it is substituted with at least one substituent. In embodiments, when L2 When substituted, it is substituted with at least one size-limited substituent. In embodiments, when L 2 When substituted, it is substituted with at least one lower substituent.

[0081] In embodiments, L 2 is unsubstituted C1-C4 alkylene. In embodiments, L 2 is unsubstituted methylene. In embodiments, L 2 is unsubstituted ethylene. In embodiments, L 2 is unsubstituted propylene. In embodiments, L 2 is unsubstituted n-propylene. In embodiments, L 2 is unsubstituted iso-propylene. In embodiments, L 2 is unsubstituted butylene. In embodiments, L 2 is unsubstituted n-butylene. In embodiments, L 2 is unsubstituted iso-butylene. In embodiments, L 2 is unsubstituted t-butylene. In embodiments, L 2 is -CH(CH3)-CH2-.

[0082] In embodiments, substituted L 3 (e.g., substituted C1-C4 alkylene) is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein each substituent, size-limited substituent, and / or lower substituent can optionally be different if substituted L 3 is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents. In embodiments, when L 3 is substituted, it is substituted with at least one substituent. In embodiments, when L 3 is substituted, it is substituted with at least one size-limited substituent. In embodiments, when L 3 is substituted, it is substituted with at least one lower substituent.

[0083] In embodiments, L 3 is unsubstituted C1-C4 alkylene. In embodiments, L 3 is unsubstituted methylene. In embodiments, L 3 is unsubstituted ethylene. In embodiments, L 3 is unsubstituted propylene. In embodiments, L 3 is unsubstituted n-propylene. In embodiments, L 3 is unsubstituted iso-propylene. In embodiments, L 3 is unsubstituted butylene. In embodiments, L 3is unsubstituted n-butenylene. In embodiments, L 3 is unsubstituted iso-butenylene. In embodiments, L 3 is unsubstituted t-butenylene. In embodiments, L 3 is unsubstituted methylene, unsubstituted ethylene, or unsubstituted propylene.

[0084] In embodiments, L 2 and L 3 are independently R 4 -substituted or unsubstituted C1-C4 alkylene. R 4 is independently unsubstituted C1-C4 alkyl.

[0085] In embodiments, L 2 is R 4 -substituted C1-C4 alkylene. In embodiments, L 2 is R 4 -substituted methylene. In embodiments, L 2 is R 4 -substituted ethylene. In embodiments, L 2 is R 4 -substituted propylene. In embodiments, L 2 is R 4 -substituted n-butenylene. In embodiments, L 2 is R 4 -substituted iso-butenylene. In embodiments, L 2 is R 4 -substituted butenylene. In embodiments, L 2 is R 4 -substituted n-butenylene. In embodiments, L 2 is R 4 -substituted iso-butenylene. In embodiments, L 2 is R 4 -substituted t-butenylene.

[0086] In embodiments, L 3 is R 4 -substituted C1-C4 alkylene. In embodiments, L 3 is R 4 -substituted methylene. In embodiments, L 3 is R 4 -substituted ethylene. In embodiments, L 3 is R 4 -substituted propylene. In embodiments, L 3 is R 4 -substituted n-butenylene. In embodiments, L 3 is R4 substituted isopropene. In embodiments, L 3 is R 4 substituted butene. In embodiments, L 3 is R 4 substituted n-butene. In embodiments, L 3 is R 4 substituted iso-butene. In embodiments, L 3 is R 4 substituted tert-butene.

[0087] In embodiments, R 3 is hydrogen. In embodiments, R 3 is unsubstituted C1-C4 alkyl. In embodiments, R 3 is unsubstituted methyl. In embodiments, R 3 is unsubstituted ethyl. In embodiments, R 3 is unsubstituted propyl. In embodiments, R 3 is unsubstituted n-propyl. In embodiments, R 3 is unsubstituted iso-propyl. In embodiments, R 3 is unsubstituted butyl. In embodiments, R 3 is unsubstituted n-butyl. In embodiments, R 3 is unsubstituted iso-butyl. In embodiments, R 3 is unsubstituted tert-butyl.

[0088] In embodiments, R 4 is independently unsubstituted methyl. In embodiments, R 4 is independently unsubstituted ethyl. In embodiments, R 4 is independently unsubstituted propyl. In embodiments, R 4 is independently unsubstituted n-propyl. In embodiments, R 4 is independently unsubstituted iso-propyl. In embodiments, R 4 is independently unsubstituted butyl. In embodiments, R 4 is independently unsubstituted n-butyl. In embodiments, R 4 is independently unsubstituted iso-butyl. In embodiments, R 4 is independently unsubstituted tert-butyl.

[0089] In embodiments, L 1 is or In embodiments, L 1 is In embodiments, L1 is In embodiments, L 1 is In embodiments, L 1 is In embodiments, L 1 is In embodiments, L 1 is .

[0090] In embodiments, when ring A is substituted, ring A is substituted with one or more first substituents denoted by R A .1 , as described in the definition section above under "first substituents". In embodiments, when a R A.1 substituent is substituted, the R A.1 substituent is substituted with one or more second substituents denoted by R A.2 , as described in the definition section above under "first substituents". In embodiments, when a R A.2 substituent group is substituted, the R A.2 substituent group is substituted with one or more third substituent groups denoted by R A.3 , as described in the definition section above under "first substituent groups". In the above embodiments, the values of ring A, R A.1 , R A.2 , and R A.3 correspond to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively. Where R WW , R WW.1 , R WW.2) , and R WW.3 correspond to ring A, R A.1 , R A.2 , and R A.3 , respectively.

[0091] In embodiments, when ring B is substituted, ring B is substituted with one or more first substituents denoted by R B.1 , as described in the definition section above under "first substituents". In embodiments, when a R B.1 substituent is substituted, the R B.1 substituent is substituted with one or more second substituents denoted by R B.2 , as described in the definition section above under "first substituents". In embodiments, when a R B.2 substituent group is substituted, the R B.2 substituent group is substituted with one or more third substituent groups denoted by R B.3the third substituent group is represented by RWW, as defined above in the definition section under "first substituent group". In the above embodiments, the values of ring C, R B.1 , R B.2 , and R B.3 correspond to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as defined above in the definition section under "first substituent". Where RWW, R WW.1 , R WW.2) , and R WW.3 correspond to ring C, R B.1 , R B.2 , and R B.3 , respectively.

[0092] In embodiments, when ring C is substituted, ring C is substituted with one or more first substituents represented by R C.1 , as defined above in the definition section under "first substituent". In embodiments, when the R C.1 substituent is substituted, the R C.1 substituent is substituted with one or more second substituents represented by R C.2 , as defined above in the definition section under "first substituent". In embodiments, when the R C.2 substituent is substituted, the R C.2 substituent is substituted with one or more third substituents represented by R C.3 , as defined above in the definition section under "first substituent". In the above embodiments, the values of ring C, R C.1 , R C.2 , and R C.3 correspond to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively. Where R WW , R WW.1 , R WW.2) , and R WW.3 correspond to ring C, R C.1 , R C.2 , and R C.3 , respectively.

[0093] In embodiments, when R 1 is substituted, R 1 is substituted with one or more first substituents represented by R 1.1 , as defined above in the definition section under "first substituent". In embodiments, when R 1.1R 1.1 is substituted with one or more second substituents represented by R 1.2 , as described above in the description of "first substituents". In embodiments, when R 1.2 is substituted, R 1.2 is substituted with one or more third substituents, as described above in the description of "first substituents", represented by R 1.3 . In the above embodiments, the values of R 1 , R 1.1 , R 1.2 , and R 1.3 correspond to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as described above in the description of "first substituents". Where R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1 , R 1.1 , R 1.2 , and R 1.3 , respectively.

[0094] In embodiments, when R 2 is substituted, R 2 is substituted with one or more first substituents, as described above in the description of "first substituents", represented by R 2.1 . In specific embodiments, when R 2.1 is substituted, R 2.1 is substituted with one or more second substituents, as described above in the description of "first substituents", represented by R 2.2 . In embodiments, when R 2.2 is substituted, R 2.2 is substituted with one or more third substituents, as described above in the description of "first substituents", represented by R 2.3 . In the above embodiments, the values of R 2 , R 2.1 , R 2.2 , and R 2.3 correspond to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as described above in the description of "first substituents". Where R WW , R WW.1R WW.2 and R WW.3 Corresponding to R respectively 2 R 2.1 R 2.2 and R 2.3 .

[0095] In the implementation plan, when L 1 When replaced, L 1 Replaced by one or more first substituents, as described in the "First Substituents" section of the definition above, R L1.1 In the implementation plan, when R... L1.1 When the substituent is substituted, R L1.1 Substituents are replaced by one or more R L1.2 The second substituent is indicated by substitution, as described in the "First Substituent" section above. In an embodiment, when R... L1.2 When the substituent group is substituted, R L1.2 Substituents are replaced by one or more R L1.3 The third substituent group is substituted, as described in the "First Substituent Group" section above. In the above embodiments, L 1 R L1.1 R L1.2 and R L1.3 The values ​​of L are respectively WW R LWW.1 R LWW.2 and R LWW.3 The value corresponds to L. WW R LWW.1 R LWW.2 and R LWW.3 L respectively 1 R L1.1 R L1.2 and R L1.3 .

[0096] In the implementation plan, when L 2 When replaced, L 2 Used by one or more R L2.1 The first substituent substitution is indicated as described in the "First Substituent" section above. In the embodiment, when R L2.1 When the substituent group is substituted, R L2.1 Substituents are replaced by one or more R L2.2 The second substituent group indicates substitution, as defined above in the description of the "first substituent group". In an embodiment, when R... L2.2 When the substituent group is substituted, R L2.2 The substituent group is replaced by one or more third substituent groups, the third substituent groups being represented by R.L2.3 As described in the description of "first substituent" in the Definitions section above. In the above embodiments, the values of L 2 , R L2.1 , R L2.2 and R L2.3 correspond to the values of L WW , R LWW.1 , R LWW.2 and R LWW.3 , respectively, as described in the description of "first substituent" in the Definitions section above. Where L WW , R LWW.1 , R LWW.2 and R LWW.3 are L 2 , R L2.1 , R L2.2 and R L2.3 , respectively.

[0097] In embodiments, when L 3 is substituted, L 3 is substituted with one or more first substituents, as described in the description of "first substituent" in the Definitions section above, and R L3.1 represents. In embodiments, when R L3.1 is substituted, R L3.1 is substituted with one or more second substituents, as described in the description of "first substituent" in the Definitions section above, and R L3.2 represents. In embodiments, when R L3.2 is substituted, R L3.2 is substituted with one or more third substituents, as described in the description of "first substituent" in the Definitions section above, and R L3.3 represents. In the above embodiments, the values of L 3 , R L3.1 , R L3.2 and R L3.3 correspond to the values of L WW , R LWW.1 , R LWW.2 and R LWW.3 , respectively, as described in the description of "first substituent" in the Definitions section above. Where L WW , R LWW.1 , R LWW.2) and R LWW.3 are L 3 , R L3.1 , R L3.2 and R L3.3 , respectively.

[0098] In embodiments, the compound is 5-((1-(3-(2-oxo-4-(1-(5-(trifluoromethyl)pyrimidin-2- yl)piperidin-4-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazine- 3(2H)-one.

[0099] In embodiments, the compound is 5-((1-(3-(2-oxo-3-(1-(5-(trifluoromethyl)pyrimidin-2- yl)piperidin-3-yl)imidazolidin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazine- 3(2H)-one.

[0100] In embodiments, the compound is 5-((1-(3-(2-oxo-3-(1-(5-(trifluoromethyl)pyrimidin-2- yl)piperidin-3-yl)imidazolidin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazine- 3(2H)-one.

[0101] In embodiments, the compound is 5-((1-(3-(2-oxo-3-(1-(5-(trifluoromethyl)pyrimidin-2- yl)piperidin-3-yl)imidazolidin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazine- 3(2H)-one.

[0102] In embodiments, the compound is 4-(trifluoromethyl)-5-(1-((3-(1-(5- (trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2- yl amino)pyridazine-3(2H)-one.

[0103] In embodiments, the compound is 6-(4-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)nicotinonitrile.

[0104] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((3-(1-(5- (trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2- yl)amino)pyridazine-3(2H)-one.

[0105] In embodiments, the compound is 5-((1-((3-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)- 1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one.

[0106] In embodiments, the compound is 5-((1-((3-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)- 1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0107] In embodiments, the compound is 2-(4-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)thiazole- 5-carbonitrile.

[0108] In embodiments, the compound is 5-((1-((3-(1-(thiazol-2-yl)piperidin-4-yl)-1,2,4- oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0109] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((3-(1-(5- (trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one.

[0110] In embodiments, the compound is 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)pyrimidine- 5-carbonitrile.

[0111] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((3-(1-(5- (trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one.

[0112] In embodiments, the compound is 6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)nicotinic acid.

[0113] In embodiments, the compound is 5-((1-((3-(1-(5-fluoropyridin-2-yl)azetidin-3-yl)- 1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0114] In embodiments, the compound is 5-((1-((3-(1-(5-chloropyridin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0115] In embodiments, the compound is 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)thiazole-5-carbonitrile.

[0116] In embodiments, the compound is (S) 4-(trifluoromethyl)-5-(1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)pyridazin-3(2H)-one.

[0117] In embodiments, the compound is (R) 4-(trifluoromethyl)-5-(1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)pyridazin-3(2H)-one.

[0118] In embodiments, the compound is 5-((1-((3-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0119] In embodiments, the compound is 5-((1-((3-(1-(5-chlorothiazol-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0120] In embodiments, the compound is 5-((1-((3-(1-(5-methylpyrimidin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0121] In embodiments, the compound is 5-((1-((3-((1-(5-(difluoromethyl)pyrimidin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0122] In embodiments, the compound is 5-((1-((3-(1-(5-methylthiazol-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0123] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one.

[0124] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one.

[0125] In embodiments, the compound is 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1-yl)thiazole-5-carbonitrile.

[0126] In embodiments, the compound is 5-((1-((3-(1-(5-fluoropyrimidin-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0127] In embodiments, the compound is 5-((1-((3-(1-(5-chloropyrimidin-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0128] In embodiments, the compound is 6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1-yl)nicotinonitrile.

[0129] In embodiments, the compound is 5-((1-((3-(1-(5-methylpyridin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0130] In embodiments, the compound is 5-((1-((3-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)- 1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0131] In embodiments, the compound is 5-((1-((3-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)- 1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0132] In embodiments, the compound is 5-((1-((3-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)- 1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0133] In embodiments, the compound is 5-((1-((3-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)- 1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0134] In embodiments, the compound is 6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)nicotinaldehyde.

[0135] In embodiments, the compound is 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)thiazole- 5-carbaldehyde.

[0136] In embodiments, the compound is 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)thiazole- 5-carbaldehyde.

[0137] In embodiments, the compound is 6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)nicotinaldehyde.

[0138] In embodiments, the compound is 5-((1-((3-(1-(5-chloropyridin-2-yl)pyrrolidin-3-yl)- 1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0139] In embodiments, the compound is 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1- yl)thiazole-5-carbaldehyde.

[0140] In embodiments, the compound is 5-((1-((3-(1-(5-chloropyridin-2-yl)pyrrolidin-3-yl)- 1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0141] In embodiments, the compound is 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1- yl)thiazole-5-carbaldehyde.

[0142] In embodiments, the compound is 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1- yl)thiazole-5-carbaldehyde.

[0143] In embodiments, the compound is 5-((1-((3-(1-(5-chloropyridin-2-yl)pyrrolidin-3-yl)- 1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0144] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((3-(1-(6- (trifluoromethyl)pyridazin-3-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one.

[0145] In embodiments, the compound is 5-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1- yl)picolinonitrile.

[0146] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((1-(5- (trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one.

[0147] In embodiments, the compound is 5-((1-((1-(1-(5-fluoropyrimidin-2-yl)piperidin-4- yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)- one.

[0148] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((1-(5- (trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one.

[0149] In embodiments, the compound is 6-(4-(4-((2-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)piperidin- 1-yl)nicotinonitrile.

[0150] In embodiments, the compound is 5-((1-((3-(1-(5-fluoropyrimidin-2-yl)azetidin-3- yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)- one.

[0151] In embodiments, the compound is 5-((1-((1-(1-(5-methylthiazol-2-yl)piperidin-4- yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)- one.

[0152] In embodiments, the compound is 5-((1-((1-(1-(thiazol-2-yl)piperidin-4-yl)-1H-1,2,3- triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0153] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((1-(5- (trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one.

[0154] In embodiments, the compound is 5-((1-((1-(1-(5-chloropyrimidin-2-yl)azetidin-3-yl)- 1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0155] In embodiments, the compound is 5-((1-((1-(1-(5-chloropyrimidin-2-yl)azetidin-3-yl)- 1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0156] In embodiments, the compound is 6-(3-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)azetidin-1-yl)nicotinonitrile.

[0157] In embodiments, the compound is 2-(4-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)pyrimidine- 5-carbonitrile.

[0158] In embodiments, the compound is 5-((1-((1-(1-(5-chloropyrimidin-2-yl)azetidin-3-yl)- 1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0159] In embodiments, the compound is 5-((1-((1-(1-(5-chloropyrimidin-2-yl)azetidin-3-yl)- 1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0160] In embodiments, the compound is 5-((1-((1-(1-(5-chloropyrimidin-2-yl)azetidin-3-yl)- 1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0161] In embodiments, the compound is 5-((1-((1-(1-(5-chloropyrimidin-2-yl)azetidin-3-yl)- 1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0162] In embodiments, the compound is 5-((1-((1-(1-(5-chloropyridin-2-yl)piperidin-4-yl)- 1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0163] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((1-(5- (trifluoromethyl)pyrimidin-2-yl)piperidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one.

[0164] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((1-(5- (trifluoromethyl)pyrimidin-2-yl)piperidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one.

[0165] In embodiments, the compound is 6-(3-(4-((2-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1- yl)piperidin-1-yl)nicotinonitrile.

[0166] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((1-(5- (trifluoromethyl)pyrimidin-2-yl)piperidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one.

[0167] In embodiments, the compound is 2-(3-(4-((2-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1- yl)piperidin-1-yl)thiazole-5-carbonitrile.

[0168] In embodiments, the compound is 5-((1-((1-(1-(5-chloropyridin-2-yl)piperidin-4-yl)- 1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0169] In embodiments, the compound is 5-((1-((1-(1-(5-chloropyridin-2-yl)piperidin-4-yl)- 1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0170] In embodiments, the compound is 5-((1-((1-(1-(5-fluoropyridin-2-yl)piperidin-4- yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazine- 3(2H)-one.

[0171] In embodiments, the compound is 2-(3-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1- yl)pyrimidine-5-carbonitrile.

[0172] In embodiments, the compound is 5-((1-((1-(1-(5-fluoropyridin-2-yl)piperidin-4- yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazine- 3(2H)-one.

[0173] In embodiments, the compound is 5-((1-((1-(1-(5-fluoropyridin-2-yl)piperidin-4- yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazine- 3(2H)-one.

[0174] In embodiments, the compound is 5-((1-((1-(1-(5-fluoropyridin-2-yl)piperidin-4- yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazine- 3(2H)-one.

[0175] In embodiments, the compound is 5-((1-((1-(1-(5-fluoropyridin-2-yl)piperidin-4- yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazine- 3(2H)-one.

[0176] In embodiments, the compound is 5-((1-((1-(1-(5-fluoropyridin-2-yl)piperidin-4- yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazine- 3(2H)-one.

[0177] In embodiments, the compound is 2-(3-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1- yl)pyrimidine-5-carbonitrile.

[0178] In embodiments, the compound is 2-(3-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)thiazole- 4-carbaldehyde.

[0179] In embodiments, the compound is 2-(4-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)thiazole-5- carbaldehyde.

[0180] In embodiments, the compound is 5-((1-((1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-1H- 1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0181] In embodiments, the compound is 5-((1-((1-(1-(5-methylpyrimidin-2-yl)pyrrolidin-3-yl)- 1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0182] In embodiments, the compound is 5-((1-((1-(1-(5-(difluoromethyl)pyridin-2-yl)pyrrolidin-3- yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0183] In embodiments, the compound is (R)-4-(trifluoromethyl)-5-((1-((1-(5- (trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino) pyridazin-3(2H)-one.

[0184] In embodiments, the compound is (S)-4-(trifluoromethyl)-5-((1-((1-(1-(5- (trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino) pyridazin-3(2H)-one.

[0185] In embodiments, the compound is 5-((1-((1-(1-(5-chloropyrimidin-2-yl)pyrrolidin-3-yl)- 1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0186] In embodiments, the compound is 5-((1-((1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4- (trifluoromethyl)pyridazin-3(2H)-one.

[0187] In embodiments, the compound is 5-((1-((1-(1-(5-methylpyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4- (trifluoromethyl)pyridazin-3(2H)-one.

[0188] In embodiments, the compound is 5-((1-((1-(1-(5-cyclopropylpyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4- (trifluoromethyl)pyridazin-3(2H)-one.

[0189] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((1-(1-(6-(trifluoromethyl)pyridazin-3-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one.

[0190] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((5-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one.

[0191] In embodiments, the compound is 5-((1-((5-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4- (trifluoromethyl)pyridazin-3(2H)-one.

[0192] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((5-(1-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one.

[0193] In embodiments, the compound is 2-(4-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,3,4-oxadiazol-2-yl)piperidin-1- yl)pyrimidine-5-carbonitrile.

[0194] In embodiments, the compound is 5-((1-((5-(1-(5-bromopyrimidin-2-yl)piperidin-4- yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)- one.

[0195] In embodiments, the compound is 2-(4-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)pyrimidine- 4-carbonitrile.

[0196] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((5-(1-(5- (trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino) pyridazin-3(2H)-one.

[0197] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((5-(1-(5- (trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino) pyridazin-3(2H)-one.

[0198] In embodiments, the compound is 6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,3,4-oxadiazol-2-yl)azetidin-1-yl)nicotinonitrile.

[0199] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((5-(1-(5- (trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino) pyridazin-3(2H)-one.

[0200] In embodiments, the compound is 5-((1-((5-(1-(5-chloropyrimidin-2-yl)azetidin-3-yl)- 1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0201] In embodiments, the compound is 5-((1-((5-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)- 1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0202] In embodiments, the compound is 5-((1-((5-(1-(5-(difluoromethyl)pyrimidin-2-yl)azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4- (trifluoromethyl)pyridazin-3(2H)-one.

[0203] In embodiments, the compound is 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,3,4-oxadiazol-2-yl)azetidin-1-yl)pyrimidine-5- carbonitrile.

[0204] In embodiments, the compound is 5-((1-((5-(1-(5-chloropyridin-2-yl)azetidin-3-yl)-1,3,4- oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0205] In embodiments, the compound is (6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,3,4-oxadiazol-2-yl)azetidin-1-yl)nicotinaldehyde.

[0206] In embodiments, the compound is 5-((1-((5-(1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yl)-1,3,4- oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0207] In embodiments, the compound is 5-((1-((5-(1-(5-methylpyrimidin-2-yl)azetidin-3-yl)-1,3,4- oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0208] In embodiments, the compound is 5-((1-((5-(1-(5-(difluoromethyl)pyridin-2-yl)azetidin-3-yl)-1,3,4- oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0209] In embodiments, the compound is 5-((1-((5-(1-(5-fluoropyridin-2-yl)azetidin-3-yl)-1,3,4- oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0210] In embodiments, the compound is 5-(3-(5-((2-((6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,3,4-oxadiazol-2-yl)azetidin-1- yl)pyridinecarbonitrile.

[0211] In embodiments, the compound is 5-((1-((5-(1-(5-chloropyrimidin-2-yl)piperidin-4- yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin- 3(2H)-one.

[0212] In embodiments, the compound is 6-(4-(5-((2-((6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1- yl)nicotinaldehyde.

[0213] In embodiments, the compound is 2-(4-(5-((2-((6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1- yl)pyrimidine-5-carbaldehyde.

[0214] In embodiments, the compound is 5-((1-((3-(1-(5-(difluoromethyl)pyrimidin-2- yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4- (trifluoromethyl)pyridazin-3(2H)-one.

[0215] In embodiments, the compound is 5-((1-((3-(1-(5-(difluoromethyl)pyrimidin-2- yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4- (trifluoromethyl)pyridazin-3(2H)-one.

[0216] In embodiments, the compound is 5-((1-((3-(2-methyl-1-(5- (trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan- 2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0217] In embodiments, the compound is 5-((1-((3-(2-methyl-1-(5- (trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan- 2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0218] In embodiments, the compound is 5-((1-((3-(1-(5-fluoropyrimidin-2-yl)-2- methylpiperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4- (trifluoromethyl)pyridazin-3(2H)-one.

[0219] In embodiments, the compound is 2-(2-methyl-4-(5-((2-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4- oxadiazol-3-yl)piperidin-1-yl)pyrimidine-5-carbonitrile.

[0220] In embodiments, the compound is 6-(2-methyl-4-(5-((2-((6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4- oxadiazol-3-yl)piperidin-1-yl)nicotinonitrile.

[0221] In embodiments, the compound is 5-((1-((3-(2,2-dimethyl-1-(5- (trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan- 2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0222] In embodiments, the compound is 5-((1-((5-(1-(3-methyl-5- (trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2- yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0223] In embodiments, the compound is 5-((1-((5-(1-(3-ethyl-5- (trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2- yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0224] In embodiments, the compound is 5-((1-((5-(2-methyl-1-(5- (trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2- yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0225] In embodiments, the compound is 5-((1-((5-(2,2-dimethyl-1-(5- (trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2- yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0226] In embodiments, the compound is 5-((1-((1-(2-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0227] In embodiments, the compound is 4-(trifluoromethyl)-5-((1-((8-(5-(trifluoromethyl)pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one.

[0228] In embodiments, the compound is 5-((1-((1-(8-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0229] In embodiments, the compound is useful as a comparator compound. In embodiments, the comparator compound is useful to assess the activity of a test compound in a detection method described herein (e.g., in the Examples section, Figures, or Tables).

[0230] In embodiments, the compound is a compound described herein, including in embodiments. In embodiments, the compound is a compound described herein (e.g., in the embodiments section, Figures, Tables, or claims).

[0231] III. Pharmaceutical Ingredients In one aspect, a pharmaceutical composition is provided, comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0232] In embodiments, the pharmaceutical composition comprises an effective amount of the compound. In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound.

[0233] In embodiments, the compound is a compound of Formula (I), including all embodiments thereof.

[0234] IV. Methods of Use A method of treating cancer in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0235] In embodiments, the compound is a compound of Formula (I), including all embodiments thereof.

[0236] In embodiments, the cancer is breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, large intestine cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, upper gastrointestinal cancer, colorectal cancer, urethral cancer, or colon cancer. In embodiments, the cancer is adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, or undifferentiated carcinoma. In embodiments, the ovarian cancer is high-grade ovarian serous adenocarcinoma, ovarian mucinous cystadenocarcinoma, or malignant ovarian Brenner tumor. In embodiments, the kidney cancer is clear cell renal cell carcinoma. In embodiments, the tongue cancer is squamous cell carcinoma of the tongue. In embodiments, the lung cancer is lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung carcinoma, large cell lung carcinoma, small cell lung carcinoma, lung papillary adenocarcinoma, or non-small cell lung carcinoma. In embodiments, the pancreatic cancer is pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma. In embodiments, the esophageal cancer is esophageal squamous cell carcinoma. In embodiments, the mesothelioma is biphasic mesothelioma. In embodiments, the central nervous system cancer is neuroglioma, glioblastoma, or glioblastoma multiforme. In embodiments, the stomach cancer is gastric adenocarcinoma. In embodiments, the breast cancer is breast ductal carcinoma, breast adenocarcinoma, or HR+ breast cancer. In embodiments, the bladder cancer is bladder squamous cell carcinoma. In embodiments, the melanoma is malignant melanoma. In embodiments, the colon cancer is colon adenocarcinoma. In embodiments, the head and neck cancer is small squamous cell carcinoma of the head and neck.

[0237] A method of inhibiting PARP7 activity is provided, the method comprising contacting a PARP7 protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0238] A method of reducing the level of PARP7 protein activity in a cell is provided, the method comprising contacting the cell with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0239] In embodiments, the level of activity of the PARP7 protein is reduced by about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, 1,000-, 10,000-, 100,000-, 1,000,000-, 10,000,000-, 100,000,000-, or 1,000,000,000-fold relative to a control. In embodiments, the level of activity of the PARP7 protein is reduced by at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, 1,000-, 10,000-, 100,000-, 1,000,000-, 10,000,000-, 100,000,000-, or 1,000,000,000-fold relative to a control.

[0240] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be obvious to persons skilled in the art and are to be included within the purview of this application and the scope of the appended claims. The entire contents of all publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety.

[0241] EMBODIMENTS Synthetic methods and characterization data Abbreviations: ACN: MeCN r.t. or rt: room temperature TEA: triethylamine TFA: trifluoroacetic acid THF: tetrahydrofuran Intermediate A: synthesis of 5-chloro-2-(4-methoxybenzyl)-4- (trifluoromethyl)pyridazin-3(2H)-one

[0242] Step 1: To a solution of 4,5-dibromopyridazin-3(2H)-one (10 g, 39.39 mmol) in DMF (100 mL), NaH (2.36 g, 59.08 mmol, 60% purity) was added portionwise at 0-10 °C, then 1-(bromomethyl)-4-methoxybenzene (11.88 g, 59.08 mmol, 8.61 mL) was added at 0 °C. The resulting solution was stirred at 25 °C for 4 h. The mixture was quenched with H2O (100 mL) and extracted with EtOAc (150 mL*2). The combined organic phase was washed with saturated brine (80 mL*3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by FCC (PE:EA = 20:1 to 1:1) to give 4,5-dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one (8.2 g, 21.92 mmol, 55.66% yield) as a yellow solid. LCMS ESI: 372.6 [M + H] + . 1 H NMR (400 MHz, DMSO) δ 8.17 (s, 1H), 7.27 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.19 (s, 2H), 3.73 (s, 3H).

[0243] Step 2: To a solution of 4,5-dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one (9.1 g, 24.33 mmol) in methanol (90.00 mL), potassium hydroxide (4.10 g, 72.99 mmol, 2.00 mL) was added, and the reaction was stirred at 25 °C for 3 h. The reaction was concentrated, and the solid was collected by filtration. The filter cake was stirred in water (40 mL) for 1 h to give 4-bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one (6.7 g, 20.61 mmol, 84.69% yield) as a yellow solid. LCMS ESI: 324.8 [M + 23] + .

[0244] Step 3: To a solution of 4-bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one (3 g, 9.23 mmol) in NMP (20 mL) was added copper iodide (878.57 mg, 4.61 mmol, 156.33 μL) followed by dropwise addition of 2,2-difluoro-2-fluorosulfonylacetate (5.32 g, 27.68 mmol, 3.50 mL). The resulting solution was stirred at 100 °C for 3 h. The reaction was then quenched by the addition of 30 mL of water and extracted with EtOAc (3 x 50 mL). The organic layers were combined and washed with 20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc / PE, 1 / 1, v / v) to give 5-methoxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (2 g, 6.36 mmol, 68.98% yield) as a yellow solid. LCMS ESI: 314.9 [M + H] + .

[0245] Step 4: To a solution of 5-methoxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (2 g, 6.36 mmol) in DMF (15 mL) was added iodotrimethylsilane (1.64 g, 8.21 mmol, 1.14 mL) dropwise at 25 °C. The resulting solution was stirred at 85 °C for 12 h. The reaction was then quenched by the addition of 30 mL of water and the reaction was extracted with dichloromethane (3 x 50 mL), the organic layers were combined and dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum to give the crude product which was purified by column chromatography (EtOAc / PE, 0 / 1, v / v) to give 5-hydroxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1.9 g, 5.95 mmol, 93.47% yield, 94% purity) as a yellow oil. LCMS ESI: 300.8 [M + H] + .

[0246] Step 5: To a solution of 5-hydroxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1.8 g, 6.00 mmol) in DMF (10 mL) was added oxalyl chloride (1.52 g, 11.99 mmol, 1.05 mL) dropwise at 0-5 °C. The reaction was stirred at 25 °C for 12 h. Then the reaction was quenched by adding 20 mL water and extracted with EA (2*20 mL). The organic layer was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (EtOAc / PE, 4 / 1, v / v) to give 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (950 mg, 2.98 mmol, 9.72% yield). 1 H NMR (400 MHz, DMSO) δ 8.20 (d, J = 0.6 Hz, 1H), 7.25 (d, J = 8.7 Hz,2H), 6.88 (d, J = 8.7 Hz, 2H), 5.16 (s, 2H), 3.70 (s, 3H).

[0247] Synthesis of Intermediate B: 5-{[1-({[1-(hexahydropyridin-4-yl)-1,2,3-triazol-4- yl]methyl}oxy)propan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one

[0248] Step 1: To a solution of 4-hydroxypiperidine-1-carboxylic acid benzyl ester (2.5 g, 10.60 mmol) in THF (5 ml) was added triphenylphosphine (1.95 g, 7.45 mmol) and diisopropyl azodicarboxylate (1.51 g, 7.45 mmol, 1.46 ml) at 0 °C, after stirring for 5 minutes, [azooxy(phenoxy)phosphino]oxybenzene (2.05 g, 7.45 mmol, 1.62 ml) was added. The reaction was warmed to room temperature and stirred for 17 h. The reaction was diluted with water (10 ml) and extracted with EA (30 ml*2). The organic layers were combined, washed with brine, dried over Na2SO4, concentrated to give the crude product. The crude product was purified by column chromatography (PE:EA=0~25%) to give 4-azidopiperidine-1-carboxylic acid benzyl ester (2.1 g, 8.07 mmol, 76.11%) as colorless oil.

[0249] Step 2: To a solution of 2-methylprop-2-yl [(1-hydroxypropan-2-yl)amino]carbamate (1 g, 5.71 mmol) in dry DMF (15 ml) was added KOH (1.60 g, 28.53 mmol) followed by dropwise addition of 3-bromoprop-1-yne (1.36 g, 11.41 mmol) dropwise over 5 minutes. After 18 hours the reaction mixture was poured into water (30 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic phases were concentrated in vacuo and the remaining liquid was extracted with diethyl ether (15 ml), washed with water (2 x 10 ml) and then brine (1 x 10 ml) and dried over Na2S04. Purification by column chromatography (PE / EA) gave tert-butyl (1-(prop-2-yn-1-yloxy)propan-2-yl)carbamate (900 mg, 4.22 mmol, 73.94%). 1 H NMR (400 MHz, CDCl3) δ 4.70 (s, 1H), 4.16 (d, J = 2.3 Hz, 2H), 3.84 (s,1H), 3.48 (qd, J = 9.2, 4.5 Hz, 2H), 2.43 (t, J = 2.3 Hz, 1H), 1.44 (s, 9H),1.18 (d, J = 6.8 Hz, 3H).

[0250] Step 3: tert-Butyl (1-(prop-2-yn-1-yloxy)propan-2-yl)carbamate (800 mg, 3.75 mmol), benzyl 4-azidopiperidine-1-carboxylate (976.33 mg, 3.75 mmol), sodium ascorbate (445.86 mg, 2.25 mmol) and copper sulfate pentahydrate (280.96 mg, 1.13 mmol) were added to a 1:1 mixture of H20 (2 mL) and EtOH (2 mL) in a sealed microwave reaction vessel. After microwave irradiation at 80 °C for 30 minutes, the mixture was concentrated under reduced pressure. The residue was extracted with CH2Cl2, washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. Purification by column chromatography (PE / EA = 3:7 then CH2Cl2 / MeOH = 96:4) gave benzyl (S)-4-(4-((2-(tert-butoxycarbonylamino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (1500 mg, 3.17 mmol, 84.44%) as a yellow oil. LCMS ESI: 473.9 [M + H] + . 1H NMR (400 MHz, CDC13) δ 7.54 (s, 1H), 7.43 - 7.29 (m, 5H), 5.30 (s, 2H), 5.16 (s, 2H), 4.72 - 4.57 (m, 4H), 4.35 (s, 2H), 3.84 (s, 1H), 3.53 - 3.43 (m, 2H), 3.03 (s, 2H), 2.21 (d, J = 11.7 Hz, 2H), 1.98 (dt, J = 12.0, 8.2 Hz, 2H), 1.43 (s, 9H), 1.16 (d, J = 6.7 Hz, 3H).

[0251] Step 4: To a solution of 4-[4-(4,8,8-trimethyl-6-oxo-5-aza-2,7-dioxa- bicyclo[3.2.1]oct-1-yl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylic acid benzyl ester (1.5 g, 3.17 mmol) in 4N HCI / EtOAc (5 mL) and EtOAc (5 mL) was added and stirred at room temperature for 3 hours. The reaction was concentrated to give 4-(4-{[(2-aminopropyl)oxy]methyl}-1,2,3-triazol-1-yl)hexahydropyridine-1-carboxylic acid benzyl ester hydrochloride (1.2 g, 2.93 mmol, 92.35%) as yellow oil. LCMS ESI: 374.0 [M + H] + .

[0252] Step 5: To a solution of 4-(4-((2-aminopropoxy)methyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid benzyl ester hydrochloride (1.2 g, 2.93 mmol) in EtOH (15 mL) was added triethylamine (1.22 ml, 8.78 mmol). The mixture was stirred at room temperature for 5 minutes. To the mixture was then added 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (0.93 g, 2.93 mmol). The mixture was stirred at 60 oThe mixture was stirred overnight at C. After the reaction was complete, the reactants were concentrated, and the residue was purified by column chromatography (PE / EtOAc = 100 / 0 ~ 10 / 90) to give benzyl 4-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-thiazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylate (1.8 g, 2.75 mmol, 93.75%) as a yellow oil. LCMS ESI: 655.8 [M+H] + .

[0253] Step 6: In 0 o At C, 33% HBr / HOAc (3 ml) was added to a DCM (10 ml) solution of 4-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]hexahydropyridine-1-carboxylic acid benzyl ester (1.9 g, 2.90 mmol). o The reaction mixture was stirred at C for 30 minutes, then stirred at room temperature for 30 minutes. After the reaction was complete, the volatiles were removed by concentration under reduced pressure. The residue was purified by reversed-phase HPLC (5% H2O: 95% CH3CN + 0.1% TFA solution) to give 5-{[1-({[1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]methyl}oxy)propyl-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (900 mg, 1.73 mmol, 59.55%) as a colorless oil. LCMS ESI: 521.8 [M+H] + .

[0254] Intermediate C: Synthesis of 2-[(4-methoxyphenyl)methyl]-5-{[1-({[1-(tetrahydro-1H-pyrrolo-3-yl)-1,2,3-triazol-4-yl]methyl}oxy)propyl-2-yl]amino}-4-(trifluoromethyl)-2H,3H-1,2-diazine-3-one

[0255] Step 1: To a solution of 2-methylprop-2-yl [(1-hydroxypropan-2-yl)amino]carbamate (5 g, 28.53 mmol) in N,N-dimethylformamide (50 mL) was added 3-bromoprop-1-yn (6.79 g, 57.07 mmol) and potassium hydroxide (8.01 g, 142.67 mmol) and the reaction was stirred at room temperature for 17 h. The reaction was diluted with H2O and extracted with dichloromethane. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 10:1) to give 2-methylprop-2-yl{[1-(prop-2-ynyloxy)propan-2-yl]amino}carbamate (5 g, 23.44 mmol, 82.16%). 1 H NMR (300 MHz, DMSO-d6) δ 7.70-7.66 (m, 2H),7.48-7.34 (m, 1H), 7.32-7.24 (m, 3H), 6.96-6.92 (m, 2H), 1.29 (s, 12H).

[0256] Step 2: To a solution of benzyl 3-azidopyrrolidine-1-carboxylate (2.5 g, 10.15 mmol) in EtOH (5 mL) and H2O (5 mL) was added sodium ascorbate (1.21 g, 6.09 mmol), copper sulfate pentahydrate (0.76 g, 3.05 mmol) and 2-methylprop-2-yl{[1-(prop-2-ynyloxy)propan-2-yl]amino}carbamate (2.17 g, 10.15 mmol). The mixture was microwave irradiated at 80 °C for 30 min and then concentrated under reduced pressure. The residue was extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (PE / AcOEt = 3:7 then CH2Cl2 / MeOH = 96:4) gave benzyl 3-(4-((2-((tert-butoxycarbonyl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidine-1-carboxylate (2.5 g, 5.44 mmol, 53.60%) as a white oil. ESI-MS m / z: 459.8 [M+H] + .

[0257] Step 3: To the HCl / EA solution (5 mL) was added 3-(4-((2-((tert- butyloxycarbonyl)amino)propoxy)methyl)-lH-l,2,3-triazol-l-yl)pyrrolidine- 1 -carboxylate benzyl ester (1.5 g, 3.26 mmol), the mixture was stirred at room temperature for 4 hours. The mixture was concentrated under vacuum to give 3-(4-((2- aminopropoxy)methyl)-lH-l,2,3-triazol-l-yl)pyrrolidine-l-carboxylate benzyl ester (2 g, 5.56 mmol, 69.20%) yellow solid. ESI-MS m / z: 359.9 [M+H] + .

[0258] Step 4: To a solution of 3-(4-((2-aminopropoxy)methyl)-lH-l,2,3-triazol-l- yl)pyrrolidine-l-carboxylate benzyl ester (1.2 g, 3.34 mmol) in EtOH (10 mL) was added TEA (1.01 g, 10.02 mmol) and 5-chloro-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-l,2-diazin-3-one (1.06 g, 3.34 mmol), the mixture was stirred at 80 °C. After the reaction was completed, the reaction was concentrated under reduced pressure. The residue was extracted with CH2Cl2, washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 0: 1) to give 3-(4-((2-((l-(4- methoxybenzyl)-6-oxo-5-(trifluoromethyl)-l,6-dihydropyridazin-4-yl)amino)propoxy)methyl)- lH-l,2,3-triazol-l-yl)pyrrolidine-l-carboxylate benzyl ester (1.5 g, 2.34 mmol, 70.09%). ESI-MS m / z: 641.7 [M+H] + .

[0259] Step 5: To a solution of 3-(4-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidine-1- carboxylate benzyl ester (1.5 g, 2.34 mmol) in EtOAC (20 ml) was added Pd / C (150 g, mmol), the mixture was stirred at room temperature for 3 hours under H2protection. The mixture was filtered and concentrated under reduced pressure to give 2-[(4- methoxyphenyl)methyl]-5-{[1-({[1-(tetrahydro-1H-pyrrol-3-yl)-1,2,3-triazol-4-yl]methyl}oxy)propan- 2-yl]amino}-4-(trifluoromethyl)-2H,3H-1,2-dioxazin-3-one (1 g, 1.97 mmol, 84.29%) white oil. ESI-MS m / z: 508 [M+H] + .

[0260] 3-azidopyrrolidine-1-carboxylate benzyl ester

[0261] To a solution of 3-hydroxypyrrolidine-1-carboxylate benzyl ester (3 g, 13.56 mmol) in THF (5 mL) was added triphenylphosphine (5.33 g, 20.34 mmol) and DIAD (4.11 g, 20.34 mmol) at 0 °C and stirred for 5 minutes. [azido(phenoxy)phosphoryl]oxybenzene (5.60 g, 20.34 mmol, 1.62 ml) was added. The reaction was warmed to room temperature and stirred for 3 hours. The reaction was diluted with water (10 mL) and extracted with EA (30 mL *2). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by column chromatography (PE:EA=0~25%) and concentrated to give 3-azidopyrrolidine-1-carboxylate benzyl ester (2.5 g, 10.16 mmol, 74.91%) colorless oil. 1 H NMR (400 MHz, DMSO) δ 7.42 - 7.27 (m, 5H), 5.08 (s, 2H), 4.36 (s, 1H), 3.57 - 3.48 (m, 1H), 3.34 - 3.29 (m, 1H), 2.21 - 1.81 (m, 2H).

[0262] Synthesis of Intermediate D: 5-{[l-({[l-(azetidin-3-yl)-l,2,3-triazol-4-yl]methyl}oxy)propan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-l,2-dioxin-3-one

[0263] Step 1: 2-methylpropan-2-yl {[l-(prop-2-ynyloxy)propan-2-yl]amino}carbamate (1 g, 4.69 mmol), 3-azidazetidine-l-carboxylate benzyl ester (1.09 g, 4.69 mmol), Cu2SO4.5 H2O (0.35 g, 1.41 mmol) and sodium ascorbate (0.56 g, 2.81 mmol) were added to a 1:1 mixture of H2O (10 mL) and EtOH (10 mL) in a sealed microwave reactor. After microwave irradiation at 80 °C for 30 minutes, the mixture was concentrated under reduced pressure. Purification by column chromatography (PE / AcOEt = 1:7) gave 3-(4-((2-((tert-butoxycarbonyl)amino)propoxy)methyl)-lH-l,2,3-triazol-l-yl)azetidine-l-carboxylate benzyl ester (1.2 g, 2.69 mmol, 57.43%) as a white oil. ESI-MS m / z: 445.8 [M+H] + .

[0264] Step 2: 3-(4-((2-((tert-butoxycarbonyl)amino)propoxy)methyl)-lH-l,2,3-triazol-l-yl)azetidine-l-carboxylate benzyl ester (1.2 g, 2.63 mmol) and TFA (1 mL) were added to DCM (2 mL) and the reaction was stirred at 25 °C for 2 hours. The reaction was diluted with DCM and saturated NaHCO3solution. The organic layer was separated and washed with saturated sodium chloride solution. The reaction was concentrated in vacuo to give 3-(4-((2-aminopropoxy)methyl)-lH-l,2,3-triazol-l-yl)azetidine-l-carboxylate benzyl ester (600 mg, 1.69 mmol, 63.83%) as a white oil. ESI-MS m / z: 359.8 [M+H] + .

[0265] Step 3: To a solution of 3-(4-((2-amino-propoxy)-methyl)-1H-1,2,3-triazol-1-yl)- azetidine-1-carboxylate benzyl ester (800 mg, 2.32 mmol) in EtOH (3 mL) was added TEA (0.96 ml, 6.95 mmol), 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H- 1,2-diazin-3-one (738.11 mg, 2.32 mmol), the mixture was stirred at 60 °C for 17 h. The residue was purified by column chromatography (PE:EA = 100:1-1:100) to give 3-(4-((2-((1-(4- methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)- 1H-1,2,3-triazol-1-yl)azetidine-1-carboxylate benzyl ester (800 mg, 1.27 mmol, 55.03%) white oil. ESI-MS m / z: 627.7 [M+H] + .

[0266] Step 4: To a solution of 3-(4-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)azetidine-1-carboxylate benzyl ester (100 mg, 0.16 mmol) in MeOH (3 mL) was added Pd / C (10 mg, 0.09 mmol), the mixture was stirred under H2at room temperature for 17 hours, the reaction was concentrated in vacuum to give 5-{[1-({[1-(azetidin-3-yl)-1,2,3-triazol-4-yl]methyl}oxy)propan-2-yl]amino}-2-[(4- methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (60 mg, 0.12 mmol, 76.31%). ESI-MS m / z: 493.8 [M+H] + .

[0267] 3-azidotetrahydro-2H-pyran-4-carboxylic acid benzyl ester:

[0268] To a solution of 3-hydroxyazetidine-1-carboxylic acid benzyl ester (2 g, 9.65 mmol) in tetrahydrofuran (20 mL) was added triphenylphosphine (3.80 g, 14.48 mmol), DPPA (3.98 g, 14.48 mmol), DIAD (2.93 g, 14.48 mmol), the mixture was stirred at 25 °C for 17 hours, the reaction was concentrated in vacuo. The residue was purified by column chromatography (PE:EA=100:1-1:100) to give 3-azidoazetidine-1-carboxylic acid benzyl ester (1.2 g, 5.17 mmol, 53.54%) as white oil. 1 H NMR (400 MHz, DMSO) δ 7.45 – 7.25 (m, 5H), 5.04 (d, J = 5.4Hz, 2H), 4.46 (tt, J = 7.3, 4.5 Hz, 1H), 4.22 (t, J = 8.0 Hz, 2H), 3.81 (d, J= 4.7 Hz, 2H).

[0269] Synthesis of Intermediate E: 5-((1-((3-(azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride

[0270] Step 1: A solution of 2-amino-1-propanol (15 g, 199.71 mmol), 2-benzofuran-1,3-dione (29.58 g, 199.71 mmol) and triethylamine (8.30 ml, 59.91 mmol) in toluene (100 mL) was heated at reflux for 20 hours with a Dean-Stark trap to remove H2O azeotropically. To the resulting residue was added 5 mL of ethyl ether. After crystallization was complete, the solid was collected, washed with 5 mL of hexane and dried in vacuum to give 2-(1-hydroxypropan-2-yl)isoindole-1,3-dione (36 g, 175.43 mmol, 87.85%). ESI-MS m / z: 206.1 [M+H] + .

[0271] Step 2: To a solution of 2-(1-hydroxypropan-2-yl)isoindole-1,3-dione (36 g, 175.43 mmol) in dichloromethane (200 mL) was added 3-bromopropan-1-ol (20.00 g, 140.34 mmol) and potassium carbonate (48.00 g, 350.34 mmol) at 0 oC, to a solution of NaH (3.86 g, 160.81 mmol) in DMF (80 ml) was added a solution of 2-(1-hydroxypropan-2-yl)isoindole-1,3-dione (33 g, 160.81 mmol) in DMF (80 ml), stirred for 0.5 h, then 0 o C, a solution of 2-methylpropan-2-yl bromoacetate (90.92 ml, 643.24 mmol) in DMF (80 ml) was added. The reaction was stirred at 0 o C for 1 h, then stirred at room temperature for 3 h. The reaction was quenched with water, extracted with EA, the organic layers were combined and concentrated, purified by column chromatography to give 2-methylpropan-2-yl{[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propyl]oxy}acetate (16 g, 50.10 mmol, 31.15%). ESI-MS m / z: 264.1 [M+H-t-Bu] + .

[0272] Step 3: To a solution of 2-methylpropan-2-yl{[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2- yl)propyl]oxy}acetate (16 g, 50.10 mmol) in DCM (20 mL) was added TFA (5 ml, 65.34 mmol), then stirred at room temperature overnight. The solvent was removed in vacuo, the crude product was used directly in the next step. ESI-MS m / z: 264.1 [M+H] + .

[0273] Step 4: {[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propyl]oxy}acetic acid (13 g, 49.38 mmol) was added to thionyl chloride (30 ml, 49.38 mmol), stirred at 75 °C for 2 h, after the reaction was completed, the reaction was concentrated to give {[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propyl]oxy}acetyl chloride (13 g, 46.15 mmol, 93.46%) as yellow oil. Used directly in the next step. ESI-MS m / z: 278.1 [M+H+CH3] + .

[0274] Step 5: To a solution of 2-methylprop-2-yl 3-[(Z)-amino(hydroxyimino)methyl]azetidine-1- carboxylate (11.92 g, 55.38 mmol) and triethylamine (12.79 ml, 92.30 mmol) in DCM (150 ml) was added {[2-(l,3-dioxo-2,3-dihydro-lH-isoindol-2-yl)propyl]oxy}acetyl chloride (13 g, 46.15 mmol) slowly at 0 °C. The reaction was stirred at room temperature for 2 h. The solvent was removed under vacuum and the mixture was refluxed in 1,4-dioxane for 3 h. The mixture was purified by column chromatography to give 3-[5-({[2-(l,3-dioxo-2,3-dihydro-lH-isoindol-2-yl)propyl]oxy}methyl)-l,2,4-oxadiazol-3-yl]azetidine-l- carboxylic acid 2-methylprop-2-yl ester (9.5 g, 21.47 mmol, 46.52%). ESI-MS m / z: 442.90 [M+H] o C for 2 h. The solvent was removed under vacuum and the mixture was refluxed in 1,4-dioxane for 3 h. The mixture was purified by column chromatography to give 3-[5-({[2-(l,3-dioxo-2,3-dihydro-lH-isoindol-2-yl)propyl]oxy}methyl)-l,2,4-oxadiazol-3-yl]azetidine-l- carboxylic acid 2-methylprop-2-yl ester (9.5 g, 21.47 mmol, 46.52%). ESI-MS m / z: 442.90 [M+H] + .

[0275] Step 6: To a solution of 2-methylprop-2-yl 3-[5-({[2-(l,3-dioxo-2,3-dihydro-lH-isoindol-2-yl)propyl]oxy}methyl)-l,2,4-oxadiazol-3-yl]azetidine-l-carboxylate (9 g, 20.34 mmol) in EtOH (50 mL) was added hydrazine hydrate (3.05 g, 61.02 mmol). The reaction was stirred at 90 °C overnight. The solvent was removed under vacuum and the mixture was purified by column chromatography to give tert-butyl 3-(5-((2-aminopropoxy)methyl)-l,2,4-oxadiazol-3-yl)azetidine-l-carboxylate (5.5 g, 17.63 mmol, 86.67%). ESI-MS m / z: 312.90 [M+H] o C for 2 h. The solvent was removed under vacuum and the mixture was refluxed in 1,4-dioxane for 3 h. The mixture was purified by column chromatography to give 3-[5-({[2-(l,3-dioxo-2,3-dihydro-lH-isoindol-2-yl)propyl]oxy}methyl)-l,2,4-oxadiazol-3-yl]azetidine-l- carboxylic acid 2-methylprop-2-yl ester (9.5 g, 21.47 mmol, 46.52%). ESI-MS m / z: 442.90 [M+H] + .

[0276] Step 7: To a solution of 2-methylprop-2-yl 3-(5-{[(2-aminopropyl)oxy]methyl}-l,2,4-oxadiazol-3-yl)azetidine-l-carboxylate (5 g, 16.01 mmol) in EtOH (80 mL) was added 5-chloro-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-l,2-diazin-3-one (5.10 g, 16.01 mmol) and triethylamine (6.66 ml, 48.03 mmol). The reaction was stirred at 50 °C for 2 h. The solvent was removed under vacuum and the mixture was purified by column chromatography to give 2-methylprop-2-yl 3-(5-{[(2-aminopropyl)oxy]methyl}-l,2,4-oxadiazol-3-yl)azetidine-l-carboxylate (5 g, 13.01 mmol, 81.01%). ESI-MS m / z: 402.90 [M+H] oC stirred overnight. The solvent was removed under vacuum and purified by column chromatography to obtain 2-methylprop-2-yl 3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]azetidine- 1 -carboxylate (7 g, 11.77 mmol, 73.55%). ESI-MS m / z: 594.90 [M+H] + .

[0277] Step 8: A solution of 2-methylprop-2-yl 3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]azetidine- 1 -carboxylate (7 g, 11.77 mmol) in HC1-EA (40 ml) was stirred at room temperature for 3 hours. The solution was then removed under vacuum and the crude was used directly for the next reaction. ESI-MS m / z: 494.90 [M+H] + .

[0278] Intermediate F: Synthesis of 2-[(4-methoxyphenyl)methyl]-5-{[1-({[3-(tetrahydro-1H-pyrrol-3- yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)prop-2-yl]amino}-4-(trifluoromethyl)-2H,3H-1,2-diazon-3- one

[0279] Step 1 : 2-Amino-1-propanol (22 g, 292.90 mmol), 2-benzofuran-1,3-dione (43.38 g, 292.90 mmol) and triethylamine (12.18 ml 87.87 mmol) were added to toluene (100 mL) and refluxed for 20 hours with Dean-Stark trap to remove H20 azeotropically. To the obtained residue, 5 mL of ether was added. After completion of crystallization, the solid was collected, washed with 5 mL of hexane and dried under vacuum to obtain 2-(1 -hydroxyprop-2-yl)isoindole-1,3-dione (45 g, 219.29 mmol, 74.87%). ESI-MS m / z: 206.1 [M+H] + .

[0280] Step 2: To a solution of 2-(1-hydroxypropan-2-yl)isoindoline-1,3-dione (45 g, 219.29 mmol) in THF (1000 mL) was added NaH (17.54 g, 448.32 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h, then 2-methylprop-2-yl bromoacetate (213.87 g, 1096.45 mmol) was added at 0 °C. After 1 h at -10 °C and 3 h at room temperature, the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate and concentrated. Purification by column chromatography (PE: EA = 10: 1 to 0: 1) gave tert-butyl 2-(2-(1,3-dioxoisoindolin-2-yl)propoxy)acetate (28 g, 87.68 mmol, 39.11%) as yellow oil. ESI-MS m / z: 264.1 [M+H-tBu] + .

[0281] Step 3: To a solution of tert-butyl 2-(2-(1,3-dioxoisoindolin-2-yl)propoxy)acetate (28 g, 87.68 mmol) in DCM (64 mL) was added TFA (16 ml, 209.09 mmol) and the reaction was stirred at 25 °C. The solvent was removed under reduced pressure to give {[2-(1,3-dioxo-2,3-dihydro-1H- isoindol-2-yl)propyl]oxy}acetic acid (23 g, 87.37 mmol, 99.65%). ESI-MS m / z: 264.1 [M+H] + .

[0282] Step 4: To {[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propyl]oxy}acetic acid (23 g, 87.37 mmol) was added dichlorosulfoxide (50 mL) and stirred at 75 °C for 2 h. After the reaction was completed, the reaction was concentrated to give {[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propyl]oxy}acetyl chloride (23 g, 81.65 mmol, 93.45%) as yellow oil. It was used directly in the next step. ESI-MS m / z: 278.1 [M+H+CH3] + .

[0283] Step 5: Dissolve 3-[(Z)-amino(hydroxyimino)methyl]tetrahydropyrrole-1- carboxylate benzyl ester (13.46 g, 51.12 mmol) in dichloromethane (25 mL), add triethylamine (11.81 ml, 85.20 mmol) and stir under N2protection at 0 °C for ten minutes. Then add dropwise a solution of {[2-(1,3-dioxo-2,3-dihydro-1H- isoindol-2-yl)propyl]oxy}acetyl chloride (12 g, 42.60 mmol) in dichloromethane (5 mL) over 20 minutes. After dropwise addition is complete, the reaction is allowed to warm to room temperature naturally and stirred for one hour. Concentrate the reaction mixture to give an intermediate, then dissolve the intermediate in 1,4-dioxane (50 mL) and stir at 100 °C for 3 hours. After 3 hours, concentrate the reaction mixture to give a crude product, which is purified by column chromatography (EA: PE = 0~50%) to give 3-[5-({[2-(1,3-dioxo-2,3-dihydro-1H- isoindol-2-yl)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]tetrahydropyrrole-1- carboxylate benzyl ester (8.5 g, 17.33 mmol, 40.68%). ESI-MS m / z: 490.7 [M+H] + .

[0284] Step 6: To a solution of 3-(5-((2-(1,3-dioxoisoindolin-2-yl)propoxy)methyl)-1,2,4- oxadiazol-3-yl)pyrrolidine-1-carboxylate benzyl ester (6.5 g, 13.25 mmol) in EtOH (60 mL) is added hydrazine hydrate (2.65 g, 53.01 mmol). The mixture is stirred at 80 o C overnight. The resulting mixture is filtered. The filtrate is concentrated under reduced pressure, quenched with water, then extracted with DCM (100 mL *2). The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated to give 3-(5-((2- aminopropoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidine-1-carboxylate benzyl ester (4.7 g, 13.04 mmol, 98.41%) as an orange oil. Used directly in the next step. ESI-MS m / z: 361.2 [M+H] + .

[0285] Step 7: To a solution of 5-chloro-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (4.57 g, 14.34 mmol) in MeCN (40 mL) is added triethylamine (3.62 ml, 26.08 mmol). The mixture is stirred at 60 oC under stirring for 3 hours. The mixture was concentrated in vacuum and purified by silica gel column chromatography (PE:EA = 100 / 0 ~ 0 / 100) to give 3-(5-((2-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidine-1 -carboxylate (8 g, 12.45 mmol, 95.46%) as orange oil. ESI-MS m / z: 643.3 [M+H] + .

[0286] Step 8: 3-(5-((2-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidine-1 -carboxylate (4 g, 6.22 mmol) was added into a solution of 4N EA / HCI (15 mL). The mixture was stirred at 80 o C overnight. The reaction was quenched with saturated Na2C03, adjusted pH = 7-8, then extracted with DCM (100 mL*2). The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by FCC (PE:EA = 10:1 ~ 0:1) to give 2-[(4-methoxyphenyl)methyl]-5-{[1-({[3-(tetrahydro-1H-pyrrol-3-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (1.6 g, 3.15 mmol, 50.55%) as orange oil. ESI-MS m / z: 509.2 [M+H] + .

[0287] Intermediate G: Synthesis of 2-(4-methoxybenzyl)-5-((1-((5-(1-(2,2,2-trifluoroacetyl)-1H-azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0288] Step 1: A solution of 2-amino-1-propanol (22 g, 292.90 mmol), 2-benzofuran-1,3-dione (43.38 g, 292.90 mmol) and triethylamine (12.18 ml, 87.87 mmol) in toluene (100 ml) was heated at reflux for 20 hours with a Dean-Stark trap to remove H2O azeotropically. To the residue obtained, 5 ml of ethyl ether was added. After crystallization was completed, the solid was collected, washed with 5 ml of hexane and dried under vacuum to give 2-(1-hydroxypropan-2-yl)isoindole-1,3-dione (46 g, 224.16 mmol, 76.53%). ESI-MS m / z: 206.1 [M+H] + .

[0289] Step 2: To a solution of 2-[(2S)-1-hydroxypropan-2-yl]isoindole-1,3-dione (46 g, 224.16 mmol) in THF (1000 ml) was added NaH (17.93 g, 448.32 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, then 2-methylprop-2-yl bromoacetate (218.62 g, 1120.80 mmol) was added at 0 °C. After being kept at -10 °C for 1 hour and at room temperature for 3 hours, the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate and concentrated. Purification by column chromatography (PE:EA = 10:1 to 0:1) gave 2-methylprop-2-yl{[(2S)-2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propyl]oxy}acetate (28 g, 87.68 mmol, 39.11%) as yellow oil. ESI-MS m / z: 264.1 [M+H-tBu] + .

[0290] Step 3: To a solution of 2-methylprop-2-yl{[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propyl]oxy}acetate (28 g, 87.68 mmol) in DCM (64 ml) was added TFA (16 ml, 209.09 mmol) and the reaction was stirred at 25 °C. The solvent was removed under reduced pressure to give {[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propyl]oxy}acetic acid (23 g, 87.37 mmol, 99.65%). ESI-MS m / z: 264.1 [M+H] + .

[0291] Step 4: Add {[2-(l,3-dioxo-2,3-dihydro-lH-isoindol-2-yl)propyl]oxy}acetic acid (23 g, 87.37 mmol) into dichlorosulfoxide (50 mL) and stir at 75 °C for 2 hours. After the reaction is complete, concentrate the reaction to get {[2-(l,3-dioxo-2,3-dihydro-lH-isoindol-2-yl)propyl]oxy}acetyl chloride (23 g, 81.65 mmol, 93.45%) as yellow oil. Use directly for the next step. ESI-MS m / z: 278.1 [M+H+CH3] + .

[0292] Step 5: Add 2-methylprop-2-yl 3-(diazaacylcarbonyl)azetidine- 1-carboxylate (9.17 g, 42.60 mmol) and triethylamine (11.81 ml, 85.20 mmol) into DCM (200 mL) and stir at 0 °C under N2for ten minutes. Then add a solution of {[2-(l,3-dioxo-2,3-dihydro-lH-isoindol-2-yl)propyl]oxy}acetyl chloride (12 g, 42.60 mmol) in dichloromethane (20 mL) dropwise over 20 minutes. After the dropwise addition is complete, allow the reaction to warm to room temperature naturally and stir for 2 hours. Quench the reaction with water and extract with DCM (100 mL * 2). Dry the combined organic layers over anhydrous Na2S04, filter and concentrate. Dissolve the crude product in THF (150 mL) and add Burgess reagent (19.64 g, 82.52 mmol). Stir the reaction at room temperature under N2for two hours. After the addition of the Burgess reagent, the reaction mixture changes from a cloudy suspension to a clear solution. Purify the residue by column chromatography (EA: PE = 0~50%) to get 2-methylprop-2-yl 3-[5-({[2-(l,3-dioxo-2,3-dihydro-lH-isoindol-2-yl)propyl]oxy}methyl)-l,3,4-oxadiazol-2-yl]azetidine-l-carboxylate (12 g, 27.12 mmol, 65.73%). ESI-MS m / z: 442.7 [M+H] + .

[0293] Step 6: A solution of 3-[5-({[2-(l,3-dioxo-2,3-dihydro-lH-isoindol-2-yl)propyl]oxy}methyl)- l,3,4-oxadiazol-2-yl]azetidine-l-carboxylic acid 2-methylprop-2-yl ester (5 g, 11.30 mmol) and hydrazine hydrate (6.66 g, 113.00 mmol) in EtOH (100 mL) was stirred at room temperature overnight. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure, quenched with water, and then extracted with DCM (100 mL * 2). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated to give 2-methylprop-2-yl 3-(5-{[(2-aminopropyl)oxy]methyl}-l,3,4-oxadiazol-2-yl)azetidine-l-carboxylate (3.5 g, 11.20 mmol, 99.15%) which was used directly in the next step. ESI-MS m / z: 312.7 [M+H] + .

[0294] Step 7: To a solution of 2-methylprop-2-yl 3-(5-{[(2-aminopropyl)oxy]methyl}-l,3,4-oxadiazol-2- yl)azetidine-l-carboxylate (3.5 g, 11.20 mmol) in MeCN (50 mL) was added triethylamine (3.11 mL, 22.41 mmol) and 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-l,2-diazin-3-one (3.57 g, 11.20 mmol), and the reaction was stirred at 60 °C for 6 hours. The mixture was purified by column chromatography (PE:EA = 10: 1 to 0: 1) to give 2-methylprop-2-yl 3-[5-[{[2-[{l-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-l,2-diazin-4-yl}amino]propyl]oxy}methyl]-l,3,4-oxadiazol-2-yl]azetidine-l-carboxylate (3 g, 5.05 mmol, 45.03%). ESI-MS m / z: 594.7 [M+H] + .

[0295] Step 8: 2-methylpropan-2-yl 3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,3,4-oxadiazol-2-yl]azetidine- 1-carboxylate (3 g, 5.05 mmol) and TFA (3 ml) were added into DCM (12 ml). The mixture was stirred at room temperature for 1 hour, the reaction was concentrated, the residue was washed with Et2O (2 ml) to give 2-(4-methoxybenzyl)-5-(1-(5-(1-(2,2,2-trifluoroacetyl)-1H-4-azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4- (trifluoromethyl)pyridazin-3(2H)-one (2.7 g, 4.65 mmol, 92.19%). ESI-MS m / z: 494.7 [M+H] + .

[0296] Intermediate G: Synthesis of 5-{[1-({[3-(hexahydropyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one

[0297] Step 1: NH2OH.HC1 (5.1 g, 73 mmol) was added to a solution of Na2C03(4.9 g, 46 mmol) in water (60 ml), then a solution of 4-cyanobenzyl hexahydropyridine-1-carboxylate (15 g, 61.40 mmol) in EtOH (120 ml) was added. The mixture was heated at reflux overnight. The mixture was cooled and evaporated, the solid product was filtered, washed with water and dried to give 4-[diazenyl(hydroxyamino)methyl]benzyl hexahydropyridine-1-carboxylate (16 g, 57.70 mmol, 93.96%) as a white solid. ESI-MS m / z: 278.90 [M+H] + .

[0298] Step 2: To a solution of 4-[diazenyl(hydroxyamino)methyl]benzyl hexahydropyridine-1- carboxylate (16 g, 57.70 mmol) in DCM (100 ml) was added triethylamine (16.00 ml, 115.40 mmol), the mixture was stirred at 0 o C, dichlorosulfoxide (6.52 g, 57.70 mmol) was added slowly dropwise over 20 minutes. The reaction was stirred at 0 oC The mixture was stirred for 10 minutes at room temperature, then stirred for 2 hours at room temperature. The solution was removed under vacuum, 1,4-dioxane (100 mL) was added and heated to reflux for 2 hours. Purification by column chromatography (PE:EA=5:1) to give 4-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate benzyl ester (14 g, 41.79 mmol, 72.43%). ESI-MS m / z: 335.90 [M+H] + .

[0299] Step 3: To a mixture of 4-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate benzyl ester (5.00 g, 14.89 mmol), tetrabutylammonium hydrogen sulfate (1.01 g, 2.99 mmol) and NaOH (23.89 g, 597.20 mmol) was added water (25 mL). The mixture was stirred for 5 minutes at room temperature. Then 2-methylprop-2-yl[(1-hydroxypropan-2-yl)amino]carbamate (2.62 g, 14.93 mmol) in dichloromethane (120 mL) was added slowly to the reaction, the mixture was stirred for 2 hours at room temperature, then quenched with water and extracted with dichloromethane. The organic layer was concentrated and finally purified by column chromatography to give 4-(5-((2-((tert-butoxycarbonyl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate benzyl ester (3.8 g, 5.61 mmol, 37.59%) (70% purity). ESI-MS m / z: 374.90 [M+H] + .

[0300] Step 4: A solution of 4-(5-((2-((tert-butoxycarbonyl)-l2-azacyclopentyl)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate benzyl ester (5.0 g, 10.57 mmol) in HCl-EA (40 mL) was stirred for 3 hours at room temperature. Then the solution was concentrated, the crude product was used directly for the next reaction. ESI-MS m / z: 374.90 [M+H] + .

[0301] Step 5: Add 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-yl)piperidin-1-carboxylic acid benzyl ester (2.5 g, 6.68 mmol) and triethylamine (1.85 ml, 13.38 mmol) to a solution of 4-(5-((2-aminopropoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-carboxylic acid benzyl ester (2.5 g, 6.68 mmol) in EtOH (50 mL) and triethylamine (1.85 mL, 13.38 mmol). The reaction is carried out at 50 °C. o Stirred overnight at C. The solvent was removed under vacuum, followed by purification by column chromatography to give benzyl 4-(5-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (2.0 g, 3.05 mmol, 45.66%). ESI-MS m / z: 656.90 [M+H] + .

[0302] Step 6: Add a solution of hydrobromic acid in acetic acid (5 mL) to a DCM solution of 4-(5-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-carboxylic acid benzyl ester (2 g, 3.05 mmol). Stir at room temperature for 2 hours, then purify by PRE-HPLC to obtain 5-{[1-({[3-(hexahydropyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)prop-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (1 g, 1.91 mmol, 62.77%). ESI-MS m / z: 522.90 [M+H] + .

[0303] Example 1: 5-((1-(3-(2-oxo-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)piperazin-1-yl)propoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0304] Step 1: 1-[5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridin-4-one (730 mg, 3.0 mmol), piperidin-2-one (387.5 mg, 3.9 mmol) and 2 drops of AcOH were added into MeOH (20 mL), the mixture was stirred at rt for 0.5 h. To the reaction mixture was added NaCNBH3(562.7 mg, 9.0 mmol) and stirred at rt for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3 x 30 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (DCM / MeOH = 10 / 1) to give 4-{1-[5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridin-4-yl}piperidin-2-one (480 mg, 49.0% yield) as a white solid. LCMS: m / z 330.1 [M+H] + .

[0305] Step 2: 4-{1-[5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridin-4-yl}piperidin-2-one (480 mg, 1.5 mmol), 2-methylprop-2-yl({1-[(3-chloropropyl)oxy]propan-2-yl}amino)carbamate (753 mg, 3.0 mmol), TBAB (96 mg, 0.3 mmol) and KOH (168 mg, 3 mmol) were added into THF (10 mL) and stirred under N2atmosphere for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 x 20 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE / EA = 1 / 1) to give [(1-{[3-(2-oxo-4-{1-[5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridin-4-yl}piperidin-1-yl)propyl]oxy}propan-2-yl)amino]carbamic acid 2-methylprop-2-yl ester (150 mg, 18.0% yield) as a colorless oil. LCMS: m / z 545.2 [M+H] + .

[0306] Step 3: [(l-{[3-(2-oxo-4-{l-[5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridin-4- yl}piperazin-l-yl)propyl]oxy}propan-2-yl)amino]acetic acid (150 mg, 0.28 mmol) was added into hydrochloric acid dioxane (4 M, 7 ml), the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated to give l-{3-[(2-aminopropyl)oxy]propyl}-4-{l-[5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridin-4-yl}piperazin-2-one (122 mg, 100% yield) as a white solid. LCMS: m / z 445.2 [M+H] + .

[0307] Step 4: l-{3-[(2-aminopropyl)oxy]propyl}-4-{l-[5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridazin-4-yl}piperazin-2-one (122 mg, 0.27 mmol), 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-l,2-diazin-3-one (96.21 mg, 0.30 mmol), TEA (83 mg, 0.82 mmol) were added into EtOH (10 ml), 70 o C for 5 h. The reaction mixture was concentrated. The residue was purified by column chromatography (DCM / MeOH = 10 / 1) to give 2-[(4-methoxyphenyl)methyl]-5-[(l-{[3-(2-oxo-4-{l-[5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridin-4-yl}piperazin-l-yl)propyl]oxy}propan-2-yl)amino]-4-(trifluoromethyl)-2H,3H-l,2-diazin-3-one (80 mg, 40.1%) as a white solid. LCMS: m / z 727.3 [M+H] + .

[0308] Step 5: 2-[(4-methoxyphenyl)methyl]-5-[(l-{[3-(2-oxo-4-{l-[5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridin-4-yl}piperazin-l-yl)propyl]oxy}propan-2-yl)amino]-4-(trifluoromethyl)-2H,3H-l,2-diazin-3-one (80 mg, 0.11 mmol) was added into CF3SO3H (0.5 ml) / CF3COOH (3 ml), the reaction was stirred at -15 oC stirred for 0.5 h. The reaction mixture was concentrated and the pH was adjusted to 8 with saturated aqueous NaHC03solution. The resulting solution was extracted with DCM (3 x 30 ml). The combined organic phase was washed with brine (10 ml), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography (PE / EA = 1 / 1) to give 5-[(1-{[3-(2-oxo-4-{1-[5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridin-4- yl}piperazin-1-yl)propyl]oxy}prop-2-yl)amino]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3- one (20 mg, 30.0%) white solid. LCMS: 607.2 m / z [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 12.42 (s, 1H), 8.67 (s, 2H), 7.93 (s, 1H), 6.24 (s, 1H),4.68 (d, J = 12.0 Hz, 2H), 4.16 (s, 1H), 3.38 - 3.47 (m, 4H), 3.24 (t, J = 8.0Hz, 2H), 3.17 (t, J = 4.0 Hz, 2H), 3.09 (s, 2H), 3.03 (t, J = 12.0 Hz, 2H), 2.69(t, J = 4.0 Hz, 2H), 2.55 - 2.60 (m, 1H), 1.85 – 1.87 (m, 2H), 1.59 – 1.72 (m,2H), 1.30- 1.39 (m, 2H), 1.16 (d, J = 8.0 Hz, 3H)。

[0309] Example 2: Synthesis of 5-((1-(3-(2-oxo-3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)imidazolidin-1-yl)propoxy)prop-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0310] Step 1 : To a solution of 2-chloro-5-(trifluoromethyl)pyrimidine (1 g, 5.47 mmol) and potassium carbonate (2.27 g, 16.41 mmol) in N,N-dimethylformamide (10 mL) was added l-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-amine hydrochloride (1.02 g, 5.47 mmol). The mixture was stirred at 50 °C overnight. The reaction was poured into water (100 mL) and extracted with DCM (100 mL*2). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated to give (l-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (2 g, 6.02 mmol) as a white solid. Used directly for next step. o C under stirring overnight. The reaction was poured into water (100 mL) and extracted with DCM (100 mL*2). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated to give (l-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (2 g, 6.02 mmol) as a white solid. Used directly for next step.

[0311] Step 2: (l-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (2 g, 6.02 mmol) was added into 4N HC1 / EtOAc (10 ml). Stirred at room temperature overnight. The reaction was concentrated to give l-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-amine hydrochloride (1.8 g, 6.70 mmol, 90 %) as a white solid.

[0312] Step 3: To a solution of l-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-amine hydrochloride (900 mg, 3.35 mmol) in DCM (15 mL) was added triethylamine (0.93 ml, 6.70 mmol) and l-chloro-2-isocyanatoethane (600.71 mg, 5.02 mmol) and stirred at 0 °C for 15 min. Then the reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched with water (15 mL) and extracted with dichloromethane (100 mL*2), the organic layers were combined, washed with brine and dried over anhydrous Na2S04. Finally the organic layer was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (PE:EtOAc = 5:1 ~ 1 : 1) to give l-(2-chloroethyl)-3-(l-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)urea (980 mg, 2.90 mmol, 86.64 %) as a white solid. LCMS ESI: 337.8 [M+H] + .

[0313] Step 4: To a solution of l-(2-chloroethyl)-3-(l-(5-(trifluoromethyl)pyrimidin-2- yl)pyrrolidin-3-yl)urea (980 mg, 2.90 mmol) in THF (10 mL) was added dropwise lithium bis(trimethylsilyl)amide (1 M in THF, 4.26 mL) at 0 °C. After the reaction was completed, the reaction was quenched with saturated NH4CI (pH = 7) and then extracted with EtOAc (5 mL x 2). The organic layer was washed with brine, dried over anhydrous Na2S04, and concentrated to give l-(l-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)imidazolidin-2-one (720 mg, 2.39 mmol, 82.4%) as a white solid. LCMS ESI: 301.9 [M+H] + .

[0314] Step 5: To a solution of 2-[3-(2-oxotetrahydro-lH-imidazol-l-yl)tetrahydro-lH-pyrrol-l- yl]-5-(trifluoromethyl)pyrimidine (200 mg, 0.66 mmol) in dry DMF (5 mL) was added NaH (132.77 mg, 3.32 mmol) under N2condition. The mixture was then stirred at 50 o C for 30 minutes. The reaction was cooled to 0 o C in an ice bath, 2-methylprop-2-yl ({l-[(3-iodopropyl)oxy]propan-2-yl}amino)carbamic acid pinacol ester (683.53 mg, 1.99 mmol) in DMF (5 mL) was added dropwise and stirred at 0 °C for 1.5 hours. The reaction was quenched with water (2 mL) and then extracted with DCM (50 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography (PE / EtOAc = 100 / 0 to 0 / 100) to give 2-methylprop-2-yl[(l-{[3-(2-oxo-l-{l-[5-(trifluoromethyl)pyrimidin-2-yl]tetrahydro-lH-pyrrol-3-yl}tetrahydro-lH-imidazol-3-yl)propyl]oxy}propan-2-yl)amino]carbamic acid pinacol ester (103 mg, 0.20 mmol, 30.04%) as a colorless liquid. LCMS ESI: 517.3 [M+H] + .

[0315] Step 6: A solution of 2-methylprop-2-yl [(1-{[3-(2-oxo-1-{1-[5-(trifluoromethyl)pyrimidin-2-yl]tetrahydro-1H-pyrrol-3-yl}tetrahydro-1H-imidazol-3-yl)propyl]oxy}propan-2-yl)amino]carbamate (103 mg, 0.20 mmol) in 4N HC1 / EtOAc (5 ml) was stirred at room temperature for 2 hours. The reaction was concentrated to give 1-{[3-(2-oxo-1-{1-[5-(trifluoromethyl)pyrimidin-2-yl]tetrahydro-1H-pyrrol-3-yl}tetrahydro-1H-imidazol-3-yl)propyl]oxy}propan-2-amine HC1 salt (90 mg, 0.20 mmol, 99.66%) as colorless oil. LCMS ESI: 417.2 [M+H] + .

[0316] Step 7: To a solution of 1-(3-(2-aminopropoxy)propyl)-3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)imidazolidin-2-one HC1 salt (85 mg, 0.19 mmol) in EtOH (5 ml) was added triethylamine (0.08 ml, 0.56 mmol). The mixture was stirred at room temperature for 5 minutes. Then to the mixture was added 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (59.81 mg, 0.19 mmol). The mixture was stirred at 60 o C overnight. The reaction was concentrated and purified by column chromatography (PE / EtOAc = 100 / 0 to 10 / 90) to give 2-[(4-(4-methoxyphenyl)methyl]-5-[(1-{[3-(2-oxo-1-{1-[5-(trifluoromethyl)pyrimidin-2-yl]tetrahydro-1H-pyrrol-3-yl}tetrahydro-1H-imidazol-3-yl)propyl]oxy}propan-2-yl)amino]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (67 mg, 0.10 mmol, 51.09%) as oil. LCMS ESI: 698.7 [M+H] + .

[0317] Step 8: To a solution of 2-[(4-methoxyphenyl)methyl]-5-[(1-{[3-(2-oxo-1-{1-[5- (trifluoromethyl)pyrimidin-2-yl]tetrahydro-1H-pyrrol-3-yl}tetrahydro-1H-imidazol-3- yl)propyl]oxy}propan-2-yl)amino]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (67 mg, 0.10 mmol) in trifluoroacetic acid (2 mL) was added trifluoromethanesulfonic acid (0.5 mL) and the reaction mixture turned red in color. The mixture was stirred at room temperature for 10 min. The reaction was quenched with saturated NaHCO3pH = 7-8 and then extracted with DCM (100 mL*2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-[(1-{[3-(2-oxo-3-{1-[5-(trifluoromethyl)pyrimidin-2-yl]tetrahydro-1H-pyrrol-3- yl}tetrahydro-1H-imidazol-1-yl)propyl]oxy}propan-2-yl)amino]-4-(trifluoromethyl)-3H,2H- 1,2-diazin-3-one (20 mg, 0.03 mmol, 36.05%) as a white solid. LCMS ESI 578.7 [M+H] + . 1 HNMR (400 MHz, CDCl3) δ 10.45 (d, J = 19.0 Hz, 1H), 8.51 (d, J = 0.6 Hz, 2H),7.70 (s, 1H), 5.84 (d, J = 7.2 Hz, 1H), 4.78 – 4.56 (m, 1H), 3.94 (s, 1H),3.84 (ddd, J = 18.7, 7.4, 4.5 Hz, 2H), 3.65 –3.54 (m, 3H), 3.51 (tt, J = 6.2,3.1 Hz, 2H), 3.42 (ddd, J = 9.4, 5.4, 2.0 Hz, 1H), 3.38 – 3.17 (m, 5H), 2.24(dt, J = 7.3, 4.9 Hz, 1H), 2.18– 2.07 (m, 1H), 1.84 – 1.72 (m, 2H), 1.32 (d,J = 6.6 Hz, 3H)。

[0318] Example 3: Synthesis of 5-((1-(3-(2-oxo-3-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4- yl)imidazolidin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0319] Step 1: Add tert-butyl piperidine-4-ylcarbamate (4.00 g, 20 mmol) to a solution of 2-fluoro-5-(trifluoromethyl)pyridine (3.00 g, 18.18 mmol) and K₂CO₃ (5.00 g, 36.36 mmol) in ACN (30 ml), and mix at 50 °C. o The mixture was stirred overnight at C. The reaction solution was quenched with water, extracted with DCM, and the organic layer was dried over Na2SO4 and concentrated to give tert-butyl 1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-ylcarbamate (6.17 g, 17.88 mmol, 98.36%). LCMS ESI: 346.0 [M + H] + .

[0320] Step 2: 1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-ylcarbamate tert-butyl ester (6.17 g, 17.88 mmol) was added to HCl / EA (4 M, 30 mL), stirred at room temperature for 3 hours, then filtered. The solid was washed with MTBE and dried to give a white solid 1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-amine hydrochloride (4.4 g, 18.1 mmol, 101.23%). LCMS ESI: 245.8 [M + H] + .

[0321] Step 3: Triethylamine (5.00 g, 50 mmol) and 1-chloro-2-isocyanate ethane (2.4 g, 22 mmol) were added to a DCM (30 mL) solution of 1-(5-(trifluoromethyl)pyridin-2-yl)piperidine-4-amine hydrochloride (4.4 g, 18.1 mmol). The mixture was stirred at 0°C for 15 min, then at room temperature for 1 h. The crude product was purified by column chromatography (PE:EtOAc = 1:1) to give 1-[(2-chloroethyl)amino]-N-{1-[5-(trifluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}carboxamide (3.4 g, 9.7 mmol, 54%). LCMS ESI: 350.8 [M + H] + .

[0322] Step 4: Add LiHMDS (7.98 mL, 1 M) to a THF (30 mL) solution of 1-[(2-chloroethyl)amino]-N-{1-[5-(trifluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}carboxamide (1.4 g, 3.99 mmol), and heat at 0°C.o C Stirring under nitrogen atmosphere. The mixture was then stirred at room temperature for 4 hours. The reaction was then quenched with water and extracted with EA, the organic layer was concentrated and washed with MTBE to get 2-[4-(2-oxotetrahydro-lH-imidazol-l-yl)hexahydropyridin-l-yl]-5- (trifluoromethyl)pyridine (550 mg, 1.75 mmol, 43.84%) as white solid. LCMS ESI: 314.8 [M + H] + .

[0323] Step 5: To dry DMF (5 mL) of 2-[4-(2-oxotetrahydro-lH-imidazol-l-yl)hexahydropyridin-l-yl]-5- (trifluoromethyl)pyridine (200 mg, 0.64 mmol) was added NaH (127.26 mg, 3.18 mmol) and stirred under N2. The mixture was then stirred at 50 o C for 30 minutes. The reaction was cooled to 0 o C under ice bath. To the mixture was added dropwise a solution of 2-methylprop-2-yl({l-[(3- iodopropyl)oxy]propan-2-yl}amino)carbamate (655.17 mg, 1.91 mmol) in DMF (5 mL) and stirred under ice bath for 1.5 hours. The reaction was quenched with water (2 mL) and then extracted with DCM (50 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography (PE / EtOAc = 100 / 0 to 0 / 100) to give 2-methylprop-2-yl[(l-{[3-(2-oxo-l-{l-[5-(trifluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}tetrahydro-lH-imidazol-3-yl)propyl]oxy}propan-2-yl)amino]carbamate (150 mg, 0.28 mmol, 44.51%) as colorless liquid. LCMS ESI: 529.9 [M + H] + .

[0324] Step 6: 2-Methylpropyl-2-yl[(1-{[3-(2-oxo-1-{1-[5-(trifluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}tetrahydro-1H-imidazol-3-yl)propyl]oxy}propyl-2-yl)amino]carbamate (150 mg, 0.28 mmol) was added to 4N HCl / EtOAc (5 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give 1-{[3-(2-oxo-1-{1-[5-(trifluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}tetrahydro-1H-imidazol-3-yl)propyl]oxy}propyl-2-amine (130 mg, 0.28 mmol, 98.51%), a colorless oil. LCMS ESI: 429.9 [M+H] + .

[0325] Step 7: Triethylamine (0.19 mL, 1.40 mmol) was added to a solution of 1-(3-(2-aminopropoxy)propyl)-3-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)imidazolidine-2-one hydrochloride (150 mg, 0.32 mmol) in EtOH (5 mL). The mixture was stirred at room temperature for 5 minutes. Then, 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (177.83 mg, 0.56 mmol) was added to the mixture. The mixture was stirred at 60 °C. o The mixture was stirred at C for 3 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography (PE / EtOAc = 100 / 0 to 10 / 90) to give 2-[(4-methoxyphenyl)methyl]-2-[(4-methoxyphenyl)(4-methoxyphenyl)methyl]-5-[(1-{[3-(2-oxo-1-{1-[5-(trifluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}tetrahydro-1H-imidazol-3-yl)propyl]oxy}propyl-2-yl)amino]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (80 mg, 0.11 mmol, 40.29%) as a white solid. LCMS ESI: 711.7 [M+H] + .

[0326] Step 8: To a solution of 2-[(4-methoxyphenyl)methyl]-5-[(1-{[3-(2-oxo-1-{1-[5- (trifluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}tetrahydro-1H-imidazol-3- yl)propyl]oxy}propan-2-yl)amino]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (80 mg, 0.11 mmol) in trifluoroacetic acid (3 ml) was added trifluoromethanesulfonic acid (1 ml) and the reaction mixture turned red in color. The mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous NaHC03solution, pH was adjusted to 7-8 and then extracted with DCM (100 ml *2). The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-[(1-{[3-(2-oxo-1-{1-[5-(trifluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}tetrahydro-1H-imidazol-3-yl)propyl]oxy}propan-2-yl)amino]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (10 mg, 0.02 mmol, 15.04%) as a white solid. LCMS ESI: 591.7 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 8.38 (s, 1H), 7.69(s,1H), 7.61 (dd, J = 9.0, 2.4 Hz, 1H), 6.66 (d, J = 9.0 Hz, 1H),5.86 (s, 1H),4.51 (d, J = 12.4 Hz, 2H), 4.08 – 3.88 (m, 2H), 3.60 – 3.47 (m, 3H), 3.42(dd, J = 9.4, 5.4 Hz, 1H), 3.31 – 3.19 (m,5H), 2.97 (dd, J = 18.5, 7.4 Hz,2H), 1.85 – 1.72 (m, 4H), 1.69 – 1.60 (m, 3H), 1.32 (d, J = 6.6 Hz, 3H)。

[0327] Example 4: Synthesis of 5-((1-(3-(2-oxo-3-(1-(5-(trifluoromethyl)pyrimidin-2- yl)azetidin-3-yl)imidazolidin-1-yl)propoxy)propan-2-yl)amino)-4- (trifluoromethyl)pyridazin-3(2H)-one

[0328] Step 1: To a solution of 2-chloro-5-(trifluoromethyl)pyrimidine (1 g, 5.48 mmol) in DMF (15 ml) was added 2-methylprop-2-yl(azetidin-3-ylamino)carbamate (0.94 g, 5.48 mmol) and potassium carbonate (1.89 g, 13.70 mmol), the reaction was stirred at 50 °C for 12 h. The reaction was diluted with H2O (20 ml) and extracted with EA (30 ml*2). The organic layer was dried over Na2SO4, filtered and concentrated to give 2-methylprop-2-yl({1-[5-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-yl}amino)carbamate (1.5 g, 4.71 mmol) as yellow solid. LCMS ESI: 318.9 [M + H] + .

[0329] Step 2: 2-methylprop-2-yl({1-[5-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-yl}amino)carbamate (1.5 g, 4.71 mmol) was added to EA (15 ml), then HCl / EA (10 ml) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated to give 1-[5-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-amine (1.1 g) as yellow solid. LCMS ESI: 218.9 [M + H] + .

[0330] Step 3: To a solution of 1-[5-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-amine (650 mg, 2.55 mmol) in dichloromethane (20 ml) was added triethylamine (0.88 ml, 6.38 mmol) and N-(2-chloroethyl)-1-oxoformamidine (0.24 ml, 2.81 mmol), the reaction was stirred at room temperature for 2 hours. The reaction was diluted with DCM and water, the organic layer was separated, washed with saturated NaCl solution, concentrated in vacuum, dried to give 1-(2-chloroethyl)-3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)urea (700 mg, 2.16 mmol, 84.72%) as yellow solid. LCMS ESI: 323.9 [M + H] + .

[0331] Step 4: To a solution of 1-(2-chloroethyl)-3-(1-(5-(trifluoromethyl)pyrimidin-2- yl)azetidin-3-yl)urea (800 mg, 2.47 mmol) in DMF (5 mL) was added sodium hydride (148.29 mg, 3.71 mmol) at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with EA (10 mL), washed with water (10 mL) and saturated sodium chloride solution. The EA layer was dried over Na2S04, filtered and concentrated to get the crude product which was triturated with MTBE (10 mL). The resulting solid was filtered using a separating funnel and collected to get 2-[3-(2-oxotetrahydro-1H-imidazol-1-yl)azetidin-1-yl]-5- (trifluoromethyl)pyrimidine (300 mg, 1.04 mmol, 42.26%) as a yellow solid. LCMS ESI: 287.9 [M + H] + .

[0332] Step 5: To a solution of 2-[3-(2-oxotetrahydro-1H-imidazol-1-yl)azetidin-1-yl]-5- (trifluoroethyl)pyrimidine (200 mg, 0.70 mmol) in dry DMF (5 mL) was added NaH (83.55 mg, 2.09 mmol) at room temperature under N2. The mixture was then stirred at 50 o C for 30 min. The reaction was cooled to 0 o C in an ice bath. To the mixture was added dropwise a solution of 2-methylprop-2-yl ({1-[(3- iodopropyl)oxy]propan-2-yl}amino)carbamate (716.89 mg, 2.09 mmol) in DMF (5 mL) and stirred at the ice bath for 1.5 h. The reaction was quenched with water (2 mL) and extracted with dichloromethane (50 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography (PE / EtOAc = 100 / 0 to 0 / 100) to get 2-methylprop-2-yl [(1-{[3-(2-oxo-1-{1-[5-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-yl} tetrahydro-1H-imidazol-3-yl)propyl]oxy}propan-2-yl)amino]carbamate (200 mg, 0.40 mmol, 57.16%) as a colorless liquid. LCMS ESI: 502.8 [M + H] + .

[0333] Step 6: 2-Methylpropyl-2-yl[(1-{[3-(2-oxo-1-{1-[5-(trifluoromethyl)pyrimidin-2-yl]azacyclobutane-3-yl}tetrahydro-1H-imidazol-3-yl)propyl]oxy}propyl-2-yl)amino]carbamate (200 mg, 0.40 mmol) was added to 4N HCl / EtOAc (8 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to give 1-{[3-(2-oxo-1-{1-[5-(trifluoromethyl)pyrimidin-2-yl]azacyclobutane-3-yl}tetrahydro-1H-imidazol-3-yl)propyl]oxy}propyl-2-amine hydrochloride (200 mg, 0.46 mmol, 114.51%), a yellow oil. LCMS ESI: 402.8 [M + H] + .

[0334] Step 7: Triethylamine (0.32 ml, 2.28 mmol) was added to a solution of 1-(3-(2-aminopropoxy)propyl)-3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutan-3-yl)imidazolidine-2-one hydrochloride (200 mg, 0.46 mmol) in 15 mL of EtOH. The mixture was stirred at room temperature for 5 minutes. Then, 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (217.84 mg, 0.68 mmol) was added to the mixture. The mixture was stirred at 60 °C. o The mixture was stirred overnight at C. The reactants were concentrated and purified by column chromatography (PE / EtOAc = 100 / 0 ~ 10 / 90) to give a yellow oily substance of 2-[(4-(4-methoxyphenyl)methyl]-5-[(1-{[3-(2-oxo-1-{1-[5-(trifluoromethyl)pyrimidin-2-yl]azacyclobutane-3-yl}tetrahydro-1H-imidazol-3-yl)propyl]oxy}propyl-2-yl)amino]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (70 mg, 0.10 mmol, 22.44%). LCMS ESI: 684.7 [M + H] + .

[0335] Step 8: To a solution of 2-[(4-methoxyphenyl)methyl]-5-[(1-{[3-(2-oxo-1-{1-[5- (trifluoromethyl)pyrimidin-2-yl]azetidin-3-yl}tetrahydro-1H-imidazol-3-yl)propyl]oxy}propan- 2-yl)amino]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (70 mg, 0.10 mmol) in trifluoroacetic acid (2 mL) was added trifluoromethanesulfonic acid (0.5 mL) and the reaction mixture turned red in color. The mixture was stirred at room temperature for 10 min. The reaction was quenched with saturated aqueous NaHC03solution, pH was adjusted to 7-8 and then extracted with dichloromethane (100 mL*2). The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-[(1-{[3-(2-oxo-1-{1-[5-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-yl}tetrahydro-1H- imidazol-3-yl)propyl]oxy}propan-2-yl)amino]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (15 mg, 0.03 mmol, 25.99%) as a white solid. LCMS ESI: 564.7 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.50 (d, J = 0.6Hz, 2H), 7.69 (s, 1H), 5.90 – 5.79 (m, 1H), 4.97 (tt, J = 8.0, 5.6 Hz, 1H),4.44 – 4.36 (m, 2H), 4.27 (dd, J = 10.3, 5.7 Hz, 2H), 3.94 (s, 1H), 3.60 –3.46 (m, 5H), 3.45 – 3.35 (m, 3H), 3.27 (t, J = 7.0 Hz, 2H), 1.79 (s, 2H),1.32 (d, J = 6.6 Hz, 3H)。

[0336] Example 5: 4-(trifluoromethyl)-5-(1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4- yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)pyridazin-3(2H)-one

[0337] Step 1: To a solution of 5-{[1-({[3-(hexahydropyridin-4-yl)-1,2,4-oxadiazol-5- yl]methyl}oxy)propan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-2H,3H-1,2-diazin-3-one (130 mg, 0.25 mmol) and potassium carbonate (103.15 mg, 0.75 mmol) in MeCN (5 ml) was added 2-chloro-5- (trifluoromethyl)pyrimidine (45.41 mg, 0.25 mmol). The reaction was stirred at room temperature for 2 h. The reaction was concentrated and purified by column chromatography (PE / EtOAc = 100 / 0 ~ 50 / 50) to give 2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-5-[(1-{[(3-{1-[5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridin- 4-yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}propan-2-yl)amino]-3H,2H-1,2-diazin-3-one (150 mg, 0.22 mmol, 90.18%) as a yellowish oil. LCMS ESI: 668.8 [M+H] + .

[0338] Step 2: To a solution of 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(3-{1- [5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridin-4-yl}-1,2,4-oxadiazol-5-yl)methyl] oxy}propan-2-yl)amino]-3H,2H-1,2-diazin-3-one (150 mg, 0.22 mmol) in trifluoromethanesulfonic acid (0.5 ml) was added trifluoroacetic acid (2 ml) and the reaction mixture turned red in color. The mixture was stirred at room temperature for 30 min. It was quenched with saturated NaHC03solution and extracted with DCM (100 ml*2). The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by Prep-HPLC to give 4-(trifluoromethyl)-5-[(1-{[(3-{1-[5- (trifluoromethyl)pyrimidin-2-yl]hexahydropyridin-4-yl}-1,2,4-oxadiazol-5-yl)methyl]oxy} propan-2-yl)amino]-3H,2H-1,2-diazin-3-one (33 mg, 0.06 mmol, 26.82%) as a white solid. LCMS ESI: 549.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 10.86 (d, J =19.2 Hz, 1H), 8.49 (d, J = 0.5 Hz, 2H), 7.68 (s, 1H), 5.85 – 5.74 (m, 1H),4.86 – 4.79 (m, 2H), 4.78 (d, J = 1.7 Hz, 2H), 4.00 (d, J = 5.1 Hz, 1H), 3.78(dd, J = 9.2, 4.0 Hz, 1H), 3.66 (dd, J = 9.2, 5.3 Hz, 1H), 3.27 – 3.09 (m,3H), 2.13 (d, J = 13.4 Hz, 2H), 1.90 – 1.76 (m, 2H), 1.36 (d, J = 6.6 Hz,3H)。

[0339] Example 6: Synthesis of 6-(4-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4- yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)nicotinonitrile

[0340] Step 1: To a solution of 5-{[1-({[3-(hexahydropyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propan- 2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (100 mg, 0.19 mmol) and K2CO3(52.52 mg, 0.38 mmol) in ACN (2 ml), 6-fluoropyridine-3-carbonitrile (46.40 mg, 0.38 mmol) was added and the reaction was stirred at 50 o C for 35 minutes. The reaction was concentrated to give 4-{4-[5-({[2-[{1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]hexahydropyridin-1- yl}benzene-1-carbonitrile (100 mg, 0.16 mmol, 83.79%). ESI-MS m / z: 624.80 [M+H] + .

[0341] Step 2: 6-{4-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)- 1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]hexahydropyridin-1- yl}pyridine-3-carbonitrile (100 mg, 0.16 mmol) was taken in TFA (4 ml) and TfOH (1 ml), stirred at room temperature for 30 minutes and then purified by Prep-HPLC to get 6-[4-(5-{[(2-{[6-oxo-5-(trifluoromethyl)-1H-1,2-diazin-4-yl]amino}propyl)oxy]methyl}- 1,2,4-oxadiazol-3-yl)hexahydropyridin-1-yl]pyridine-3-carbonitrile (28.25 mg, 0.06 mmol, 34.98%). ESI-MS m / z: 505.20 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.07 (s,1H), 8.41 (d, J = 1.9 Hz, 1H), 7.69 (s, 1H), 7.61 (dd, J = 9.0, 2.2 Hz, 1H),6.65 (d, J = 9.1 Hz, 1H), 5.80 (s, 1H), 4.78 (d, J = 2.5 Hz, 2H), 4.43 (d, J= 13.4 Hz, 2H), 4.01 (s, 1H), 3.79 (dd, J = 9.2, 3.9 Hz, 1H), 3.66 (dd, J =9.2, 5.3 Hz, 1H), 3.25 – 3.08 (m, 3H), 2.14 (d, J = 13.4 Hz, 2H), 1.92 – 1.80(m, 2H), 1.36 (d, J = 6.6 Hz, 3H)。

[0342] Example 7: Synthesis of 4-(trifluoromethyl)-5-((1-((3-(1-(5-(trifluoromethyl)pyridin-2- yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0343] Step 1 : To a solution of 5-{[1-({[3-(hexahydropyridin-4-yl)-1,2,4-oxadiazol-5- yl]methyl}oxy)propan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-2H,3H-1,2-diazin-3-one (100 mg, 0.19 mmol) and K2CO3(79.34 mg, 0.57 mmol) in ACN (2 ml), was added 2-fluoro-5-trifluoromethylpyridine (63.19 mg, 0.38 mmol). The reaction was stirred at 60 °C overnight, concentrated and purified by column chromatography to give 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(3-{1-[5- (trifluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}-1,2,4-oxadiazol-5-yl)methyl)oxy}propan- 2-yl)amino]-3H,2H-1,2-diazin-3-one (100 mg, 0.15 mmol, 78.27%). ESI-MS m / z: 668.20 [M+H] o C under microwave overnight, concentrated and purified by column chromatography to give 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(3-{1-[5- (trifluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}-1,2,4-oxadiazol-5-yl)methyl)oxy}propan- 2-yl)amino]-3H,2H-1,2-diazin-3-one (100 mg, 0.15 mmol, 78.27%). ESI-MS m / z: 668.20 [M+H] + .

[0344] Step 2: To a solution of 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(3-{1-[5- (trifluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}propan- 2-yl)amino]-3H,2H-1,2-diazin-3-one (100 mg, 0.15 mmol) was added TFA (2 ml) and TfOH (0.5 ml) and stirred at room temperature for 30 min. Concentrated and purified by Prep-HPLC to give 4-(trifluoromethyl)-5-[(1-{[(3-{1-[5-(trifluoromethyl)pyridin-2-yl]hexahydropyridin-4- yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}propan-2-yl)amino]-3H,2H-1,2-diazin-3-one (33 mg, 0.06 mmol, 40.24%). ESI-MS m / z: 548.20 [M+H] + . 1H NMR (400 MHz, CDC13) δ 11.36 (s, 1H), 8.39 (s, 1H), 7.69 (s, 1H), 7.62 (dd, J = 9.0, 2.4Hz, 1H), 6.69 (d, J = 9.0 Hz, 1H), 5.79 (s, 1H), 4.78 (d, J = 2.0 Hz, 2H),4.42 (d, J = 13.5 Hz, 2H), 4.00 (s, 1H), 3.78 (dd, J = 9.2, 4.0 Hz, 1H), 3.66(dd, J = 9.2, 5.3 Hz, 1H), 3.23 - 3.03 (m, 3H), 2.13 (d, J = 13.3 Hz, 2H),1.93 - 1.79 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H).

[0345] Example 8: Synthesis of 5-((1-((3-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)-1,2,4- oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0346] Step 1: To a solution of 5-{[1-({[3-(hexahydropyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (100 mg, 0.19 mmol) and K2CO3 (79.34 mg, 0.57 mmol) in MeCN (2 ml) was added 2-chloro-5-fluoropyrimidine (50.72 mg, 0.38 mmol) and stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 20 ml). The combined organic layer was washed with water (2 x 20 ml), brine (1 x 20 ml), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography to give 5-({1-[({3-[1-(5-fluoropyrimidin-2-yl)hexahydropyridin-4-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (70 mg, 0.11 mmol, 59.13 %). ESI-MS m / z: 618.20 [M+H] o C overnight. Finally, the crude product was purified by column chromatography to give 5-({1-[({3-[1-(5-fluoropyrimidin-2-yl)hexahydropyridin-4-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (70 mg, 0.11 mmol, 59.13 %). ESI-MS m / z: 618.20 [M+H] + .

[0347] Step 2: 5-({1-[({3-[1-(5-fluoropyrimidin-2-yl)hexahydropyridin-4-yl]-1,2,4- oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (100 mg, 0.16 mmol) was taken in TFA (2 ml) and TfOH (0.5 ml), stirred at room temperature for 30 min, concentrated and purified by Prep-HPLC to get 5-({1-[({3-[1-(5-fluoropyrimidin-2-yl)hexahydropyridin-4-yl]-1,2,4- oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3- one (13 mg, 0.03 mmol, 16.13%). ESI-MS m / z: 499.20 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 10.46(s, 1H), 8.20 (s, 2H), 7.68 (s, 1H), 5.79 (s, 1H), 4.78 (d, J = 1.4 Hz, 2H),4.68 (d, J = 13.5 Hz, 2H), 4.00 (s, 1H), 3.77 (dd, J = 9.2, 4.0 Hz, 1H), 3.65(dd, J = 9.2, 5.4 Hz, 1H), 3.11 (ddd, J = 11.2, 6.9, 3.7 Hz, 3H), 2.09 (d, J= 12.7 Hz, 2H), 1.90 – 1.75 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H)。

[0348] Example 9: 5-((1-((3-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5- yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0349] Step 1 : To a solution of 5-{[1-({[3-(hexahydropyridin-4-yl)-1,2,4-oxadiazol-5- yl]methyl}oxy)propan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-2H,3H-1,2-diazin-3-one (100 mg, 0.19 mmol) and K2CO3(52.90 mg, 0.38 mmol) in ACN (2 ml), was added 2-chloro-5-methylpyrimidine (49.21 mg, 0.38 mmol) and the reaction was stirred at 80 °C for 2 h in a microwave. Finally, the reaction mixture was concentrated and purified by column chromatography to give 2-[(4-methoxyphenyl)methyl]-5-({1 -[({3-[1 -(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (80 mg, 0.13 mmol, 68.01 %). ESI-MS m / z: 615.20 [M+H] o C under stirring for 2 h. Finally, the reaction mixture was concentrated and purified by column chromatography to give 2-[(4-methoxyphenyl)methyl]-5-({1 -[({3-[1 -(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (80 mg, 0.13 mmol, 68.01 %). ESI-MS m / z: 615.20 [M+H] + .

[0350] Step 2: To a solution of 2-[(4-methoxyphenyl)methyl]-5-({1 -[({3-[1 -(5-methylpyrimidin-2- yl)hexahydropyridin-4-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (80 mg, 0.13 mmol) was added TFA (2 ml) and TfOH (0.5 ml) and stirred at room temperature for 30 min. After concentration, purification by Prep-HPLC gave 5-({1 -[({3-[1 -(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (10.86 mg, 0.02 mmol, 16.87 %). ESI-MS m / z: 495.20 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 10.92 (s, 1H), 8.17 (s, 2H), 7.68 (s, 1H), 5.83 – 5.71 (m, 1H), 4.78 (s, 2H), 4.74 – 4.64 (m, 2H), 4.00 (s, 1H), 3.77 (dd, J = 9.2, 4.0 Hz, 1H), 3.65 (dd, J = 9.2, 5.3 Hz, 1H), 3.16 – 3.01 (m, 3H), 2.17 – 2.03 (m, 5H), 1.83 (ddd, J = 21.2, 11.6, 2.4 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H).

[0351] Example 10: Synthesis of 2-(4-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)thiazolyl-5-carboxynitrile

[0352] Step 1: To a mixture of 5-{[1-({[3-(hexahydropyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propyl-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (100 mg, 0.19 mmol) and K₂CO₃ (52.52 mg, 0.38 mmol) in ACN (2 ml), 2-chloro-1,3-thiazolyl-5-carboxynitrile (54.94 mg, 0.38 mmol) was added. The reaction was carried out at 50 °C. o The solution was stirred in a microwave oven for 35 minutes and concentrated to obtain 2-{4-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-thiazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]hexahydropyridin-1-yl}-1,3-thiazolyl-5-carboxynitrile (80 mg, 0.13 mmol, 66.29%). ESI-MS m / z: 631.20 [M+H] + .

[0353] Step 2: 2-{4-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)- 1,2-thiazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]hexahydropyridin-1-yl}- 1,3-thiazole-5-carbonitrile (80 mg, 0.13 mmol) was taken in TFA (2 ml) and TfOH (0.5 ml), stirred at room temperature for 30 minutes, concentrated and purified by Prep- HPLC to get 2-[4-(5-{[(2-{[6-oxo-5-(trifluoromethyl)-1H-1,2-diazin-4-yl]amino}propyl)oxy]methyl}- 1,2,4-oxadiazol-3-yl)hexahydropyridin-1-yl]-1,3-thiazole-5-carbonitrile (27 mg, 0.05 mmol, 40.04%). ESI-MS m / z: 511.1 [M+H]+. 1 H NMR (400 MHz, CDCl3) δ 11.37(s, 1H), 7.69 (d, J = 5.2 Hz, 2H), 5.86 – 5.72 (m, 1H), 4.87 – 4.71 (m, 2H),4.12 – 3.95 (m, 3H), 3.80 (dd, J = 9.2, 3.9 Hz, 1H), 3.66 (dd, J = 9.2, 5.3Hz, 1H), 3.42 – 3.28 (m, 2H), 3.13 (ddd, J = 10.8, 7.0, 3.8 Hz, 1H), 2.24 –2.10 (m, 2H), 1.97 (tdd, J = 20.4, 7.6, 5.5 Hz, 2H), 1.37 (d, J = 6.6 Hz,3H)。

[0354] Example 11: Synthesis of 5-((1-((3-(1-(thiazol-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5- yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0355] Step 1 : 5-{[1-({[3-(hexahydropyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}- 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (150 mg, 0.29 mmol), Xantphos (33.22 mg, 0.06 mmol), tris[(1 E,4E)-1,5-diphenylpenta-1,4-dien-3-yl]palladium(0) (26.29 mg, 0.03 mmol), Cs2CO3(283.46 mg, 0.87 mmol), 2-bromo-5-methyl-1,3-thiazole (102.22 mg, 0.57 mmol) were added in dioxane (3 ml) and the reaction was stirred at 80 °C overnight. The reaction was concentrated and purified by column chromatography to give 2-(4-methoxybenzyl)-5-((1-((3-(1-(thiazol-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (80 mg, 0.13 mmol, 44.97%). ESI-MS m / z: 605.90 [M+H] o C under stirring overnight. The reaction was concentrated and purified by column chromatography to give 2-(4-methoxybenzyl)-5-((1-((3-(1-(thiazol-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (80 mg, 0.13 mmol, 44.97%). ESI-MS m / z: 605.90 [M+H] + .

[0356] Step 2: 2-[(4-methoxyphenyl)methyl]-5-({1-[({3-[1-(1,3-thiazol-2-yl)hexahydropyridin-4-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (80 mg, 0.13 mmol) was added in TFA (2 ml) and TfOH (0.5 ml) and stirred at room temperature for 30 minutes. After concentration, it was purified by Prep-HPLC to give 5-({1-[({3-[1-(1,3-thiazol-2-yl)hexahydropyridin-4-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (12 mg, 0.02 mmol, 18.71%). ESI-MS m / z: 486.10 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 11.26 (s,1H), 7.69 (s, 1H), 7.19 (d, J = 3.6 Hz, 1H), 6.57 (d, J = 3.6 Hz, 1H), 5.86 –5.72 (m, 1H), 4.87 – 4.72 (m, 2H), 4.04 (ddd, J = 12.4, 8.0, 4.4 Hz, 3H),3.78 (dd, J = 9.2, 4.0 Hz, 1H), 3.66 (dd, J = 9.2, 5.3 Hz, 1H), 3.25 – 3.14(m, 2H), 3.07 (tt, J = 11.1, 3.7 Hz, 1H), 2.20 – 2.09 (m, 2H), 2.04 – 1.91(m, 2H), 1.36 (d, J = 6.6 Hz, 3H)。

[0357] Example 12: Synthesis of 4-(trifluoromethyl)-5-((1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0358] Step 1: To 5-{[1-({[3-(azetidin-3-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (150 mg, 0.30 mmol) and K2CO3 (104.81 mg, 0.76 mmol) in ACN (3 ml) was added 2-chloro-5-(trifluoromethyl)pyrimidine (83.06 mg, 0.46 mmol). The reaction was stirred at 80 °C for overnight. After concentration, purification by column chromatography gave 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(3-{1-[5-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}propan-2-yl)amino]-2H,3H-1,2-diazin-3-one (160 mg, 0.25 mmol, 82.34%). ESI-MS m / z: 640.9 [M+H] o C under stirring for overnight. After concentration, purification by column chromatography gave 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(3-{1-[5-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}propan-2-yl)amino]-2H,3H-1,2-diazin-3-one (160 mg, 0.25 mmol, 82.34%). ESI-MS m / z: 640.9 [M+H] + .

[0359] Step 2: 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(3-{1-[5- (trifluoromethyl)pyridin-2-yl]azetidin-3-yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}propan-2- yl)amino]-2H,3H-1,2-dioxazin-3-one (160 mg, 0.25 mmol) was taken in TFA (2 ml) and TfOH (0.5 ml) and stirred at room temperature for 30 min. After concentration, purification by Prep- HPLC gave 4-(trifluoromethyl)-5-[(1-{[(3-{1-[5-(trifluoromethyl)pyrimidin-2-yl]azetidin-3- yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}propan-2-yl)amino]-2H,3H-1,2-dioxazin-3-one (30 mg, 0.06 mmol, 23.04%). ESI-MS m / z: 521.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 10.73 (s, 1H), 8.52 (s, 2H), 7.67 (s, 1H), 5.81 - 5.68 (m, 1H), 4.82 (s, 2H), 4.61 (t, J = 9.0 Hz, 2H), 4.48 - 4.39 (m, 2H), 4.25 - 4.11 (m, 1H), 4.01 (s, 1H), 3.79 (dd, J = 9.2, 4.0 Hz, 1H), 3.66 (dd, J = 9.2, 5.5 Hz, 1H), 1.36 (d, J = 6.6 Hz, 3H).

[0360] Example 13: Synthesis of 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4- yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)pyrimidine-5-carbonitrile

[0361] Step 1 : To 5-{[l-({[3-(azetidin-3-yl)-l,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}- 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-l,2-diazin-3-one (150 mg, 0.30 mmol) and K2CO3 (125.77 mg, 0.91 mmol) in ACN (3 ml) was added 2-fluoro-5- (trifluoromethyl)pyridine (75.12 mg, 0.46 mmol). The reaction was stirred at 80 °C under microwave overnight. After concentration, the product was purified by silica gel column to give 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(l-{[(3-{l-[5- (trifluoromethyl)pyridin-2-yl]azetidin-3-yl}-l,2,4-oxadiazol-5-yl)methyl]oxy}propan-2- yl)amino]-2H,3H-l,2-diazin-3-one (100 mg, 0.16 mmol, 51.54%). ESI-MS m / z: 640.9 [M+H]+. o C under microwave overnight. After concentration, the product was purified by silica gel column to give 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(l-{[(3-{l-[5- (trifluoromethyl)pyridin-2-yl]azetidin-3-yl}-l,2,4-oxadiazol-5-yl)methyl]oxy}propan-2- yl)amino]-2H,3H-l,2-diazin-3-one (100 mg, 0.16 mmol, 51.54%). ESI-MS m / z: 640.9 [M+H]+. + .

[0362] Step 2: To 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(l-{[(3-{l-[5- (trifluoromethyl)pyridin-2-yl]azetidin-3-yl}-l,2,4-oxadiazol-5-yl)methyl]oxy}propan-2- yl)amino]-2H,3H-l,2-diazin-3-one (90 mg, 0.14 mmol) was added TFA (2 ml) and TfOH (0.5 ml) and stirred at room temperature for 30 min. After concentration, purification by Prep- HPLC gave 4-(trifluoromethyl)-5-[(l-{[(3-{l-[5-(trifluoromethyl)pyridin-2-yl]azetidin-3- yl}-l,2,4-oxadiazol-5-yl)methyl]oxy}propan-2-yl)amino]-2H,3H-l,2-diazin-3-one (32 mg, 0.06 mmol, 43.78%). ESI-MS m / z: 520.1 [M+H]+. 1HNMR (400 MHz, CDCl3) δ 10.95 (s, 1H), 8.32 (s, 1H), 7.61 (s, 1H), 7.57 (dd, J= 8.8, 2.4 Hz, 1H), 6.28 (d, J = 8.7 Hz, 1H), 5.75 – 5.63 (m, 1H), 4.74 (s,2H), 4.43 (t, J = 8.3 Hz, 2H), 4.30 – 4.20 (m, 2H), 4.12 (ddd, J = 8.6, 7.2,4.3 Hz, 1H), 3.94 (s, 1H), 3.72 (dd, J = 9.2, 4.0 Hz, 1H), 3.59 (dd, J = 9.2,5.5 Hz, 1H), 1.28 (d, J = 6.6 Hz, 3H).

[0363] Example 14: Synthesis of 4-(trifluoromethyl)-5-((1-((3-(1-(5-(trifluoromethyl)pyridin-2-yl)azacyclobutane-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propyl-2-yl)amino)pyridazine-3(2H)-one

[0364] Step 1: To a solution of 5-{[1-({[3-(azacyclobutan-3-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propyl-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (200 mg, 0.40 mmol) and K₂CO₃ (167.69 mg, 1.21 mmol) in ACN (3 ml), add 6-fluoropyridine-3-carboxynitrile (98.77 mg, 0.81 mmol). The reaction is carried out at 80 °C. o The mixture was stirred overnight at C. After concentration, the product was purified by silica gel column chromatography to give 6-{3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]azacyclobutane-1-yl}pyridine-3-carboxylonitrile (150 mg, 0.25 mmol, 62.17%). ESI-MS m / z: 596.9 [M+H] + .

[0365] Step 2: 5-({1-[({3-[1-(5-chloropyrimidin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (200 mg, 0.33 mmol) was taken in TFA (2 ml) and TfOH (0.5 ml), stirred at room temperature for 30 minutes, concentrated and purified by Prep-HPLC to get 6-[3-(5-{[(2-{[3-oxo-4-(trifluoromethyl)-2H-1,2-diazin-5-yl]amino}propyl)oxy]methyl}-1,2,4-oxadiazol-3-yl)azetidin-1-yl]pyridine-3-carbonitrile (58 mg, 0.12 mmol, 36.95%). ESI-MS m / z: 477.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 10.49 (s,1H), 8.41 (d, J = 1.8 Hz, 1H), 7.67 (s, 1H), 7.63 (dd, J = 8.7, 2.2 Hz, 1H),6.30 (d, J = 8.8 Hz, 1H), 5.77 (s, 1H), 4.81 (s, 2H), 4.53 (t, J = 8.7 Hz,2H), 4.43 – 4.31 (m, 2H), 4.20 (tt, J = 8.7, 5.8 Hz, 1H), 4.01 (s, 1H), 3.80(dd, J = 9.2, 3.9 Hz, 1H), 3.66 (dd, J = 9.2, 5.5 Hz, 1H), 1.36 (d, J = 6.6Hz, 3H)。

[0366] Example 15: Synthesis of 6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)nicotinonitrile

[0367] Step 1 : To a solution of 5-{[1-({[3-(azetidin-3-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}- 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (200 mg, 0.40 mmol) and K2CO3 (167.69 mg, 1.21 mmol) in ACN (3 ml), was added 6-fluoropyridine-3-carbonitrile (98.77 mg, 0.81 mmol). The reaction was stirred at 80 °C for overnight. After concentration, the product was purified by silica gel column to give 6-{3-[5-({[2-({1 -[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propan-2-yl]oxy}methyl)-1,2,4-oxadiazol-3-yl]azetidin-1 -yl}pyridine-3-carbonitrile (150 mg, 0.25 mmol, 62.17%). ESI-MS m / z: 596.9 [M+H] o C under stirring for overnight. After concentration, the product was purified by silica gel column to give 6-{3-[5-({[2-({1 -[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propan-2-yl]oxy}methyl)-1,2,4-oxadiazol-3-yl]azetidin-1 -yl}pyridine-3-carbonitrile (150 mg, 0.25 mmol, 62.17%). ESI-MS m / z: 596.9 [M+H] + .

[0368] Step 2: 5-({1 -[({3-[1 -(5-chloropyrimidin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (200 mg, 0.33 mmol) was added into TFA (2 ml) and TfOH (0.5 ml), stirred at room temperature for 30 min, concentrated and purified by Prep-HPLC to give 6-[3-(5-{[(2-{[3-oxo-4-(trifluoromethyl)-2H-1,2-diazin-5-yl]amino}propan-2-yl)oxy]methyl}-1,2,4-oxadiazol-3-yl)azetidin-1 -yl]pyridine-3-carbonitrile (58 mg, 0.12 mmol, 36.95%). ESI-MS m / z: 477.1 [M+H] + . 1H NMR (400 MHz, CDC13) δ 10.49 (s, 1H), 8.41 (d, J = 1.8 Hz, 1H), 7.67 (s, 1H), 7.63 (dd, J = 8.7, 2.2 Hz, 1H), 6.30 (d, J = 8.8 Hz, 1H), 5.77 (s, 1H), 4.81 (s, 2H), 4.53 (t, J = 8.7 Hz, 2H), 4.43 - 4.31 (m, 2H), 4.20 (tt, J = 8.7, 5.8 Hz, 1H), 4.01 (s, 1H), 3.80 (dd, J = 9.2, 3.9 Hz, 1H), 3.66 (dd, J = 9.2, 5.5 Hz, 1H), 1.36 (d, J = 6.6 Hz, 3H).

[0369] Example 16: Synthesis of 5-((l-((3-(l-(5-fluoropyridin-2-yl)azetidin-3-yl)-l,2,4- oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0370] Step 1: 5-(1-((3-(azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)- 2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride (350 mg, 0.66 mmol), cesium carbonate (429.57 mg, 1.32 mmol), [5-(diphenylphosphoryl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine (76.29 mg, 0.13 mmol), tris[(1E,4E)-1,5-diphenylpenta-1,4-dien-3-yl]bis[palladium(0)] (60.37 mg, 0.07 mmol), 2-bromo-5-fluoropyridine (174.02 mg, 0.99 mmol) and dioxane (6 mL) were added into a 20 mL microwave tube. The mixture was stirred at 100 °C overnight. The reaction mixture was diluted with H2O (10 mL) and washed with EA (10 mL*2). The EA layer was dried over Na2SO4, filtered and concentrated, purified by column chromatography (PE : EA = 10 : 1 to 0 : 1) to give 5-({1-[({3-[1-(5-fluoropyridin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (50 mg, 0.08 mmol, 12.87%) as yellow oil. ESI-MS m / z: 590.3 [M+H] + .

[0371] Step 2: To 5-({1-[({3-[1-(5-fluoropyridin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)- 3H,2H-1,2-diazin-3-one (50 mg, 0.08 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was added trifluoromethanesulfonic acid (0.5 mL) and the reaction turned red in color. The mixture was stirred at room temperature for 10 min. The reaction was quenched with saturated Na2CO3, pH was adjusted to 7-8 and then extracted with dichloromethane (100 mL*2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-({1-[({3-[1-(5-fluoropyridin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (12.39 mg, 0.03 mmol, 31.12%) as a white solid. ESI-MS m / z: 469.7 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 11.03 (s, 1H), 8.03 (d, J = 2.9 Hz, 1H), 7.68 (s, 1H), 7.31 –7.25 (m, 1H), 6.32 (dd, J = 9.0, 3.4 Hz, 1H), 5.81 – 5.71 (m, 1H), 4.80 (s,2H), 4.45 – 4.35 (m, 2H), 4.28 –4.19 (m, 2H), 4.14 (ddd, J = 8.4, 7.1, 4.2Hz, 1H), 4.00 (d, J = 4.9 Hz, 1H), 3.78 (dd, J = 9.2, 4.0 Hz, 1H), 3.66 (dd,J = 9.2, 5.5 Hz, 1H), 1.35 (d, J = 6.6 Hz, 3H).

[0372] Example 17: Synthesis of 5-((1-((3-(1-(5-chloropyridin-2-yl)azetidin-3-yl)-1,2,4- oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0373] Step 1 : To 5-(l-((3-(azetidin-3-yl)-l,2,4-oxadiazol-5-yl)methoxy)propan-2- ylamino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride (250 mg, 0.47 mmol) and potassium carbonate (195.22 mg, 1.41 mmol) in MeCN (10 mL) was added 5-chloro-2-fluoropyridine (92.90 mg, 0.71 mmol). The reaction was stirred at 80 °C overnight. The reaction was concentrated and purified by column chromatography (PE / EtOAc = 100 / 0 ~ 80 / 20) to give 5-({l-[({3-[l-(5-chloropyridin-2-yl)azetidin-3-yl]-l,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-l,2-diazin-3-one (130 mg, 0.21 mmol, 45.56%) as a light yellow oil. ESI-MS m / z: 605.7 [M+H] o C Under. + .

[0374] Step 2: To a solution of 5-({l-[({3-[l-(5-chloropyridin-2-yl)azetidin-3-yl]-l,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-l,2-diazin-3-one (130 mg, 0.21 mmol) in 2,2,2- trifluoroacetic acid (2 mL) was added trifluoromethanesulfonic acid (0.5 mL) and the reaction turned red. The mixture was stirred at room temperature for 10 min. The reaction was quenched with saturated Na2CO3, adjusted to pH = 7-8, and then extracted with dichloromethane (100 mL*2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC to give 5-({l-[({3-[l-(5-chloropyridin-2-yl)azetidin-3-yl]-l,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-l,2-diazin-3-one (25 mg, 0.05 mmol, 23.99%) as a white solid. ESI-MS m / z: 485.7 [M+H] + . 1H NMR (400 MHz, CDC13) δ 10.92 (s, 1H), 8.10 (d, J = 2.5 Hz, 1H), 7.67 (s, 1H), 7.43 (dd, J = 8.8, 2.5 Hz, 1H), 6.30 (d, J = 8.8 Hz, 1H), 5.81 - 5.70 (m, 1H), 4.81 (s, 2H), 4.46 - 4.37 (m, 2H), 4.25 (ddd, J = 7.8, 6.0, 1.7 Hz, 2H), 4.15 (ddd, J = 8.5, 7.1, 4.2 Hz, 1H), 4.00 (s, 1H), 3.78 (dd, J = 9.2, 4.0 Hz, 1H), 3.66 (dd, J = 9.2, 5.5 Hz, 1H), 1.35 (d, J = 6.6 Hz, 3H).

[0375] Example 18: Synthesis of 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4- yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)thiazole-5-carbonitrile

[0376] Step 1: To 5-{[l-({[3-(azetidin-3-yl)-l,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}- 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-l,2-dioxazin-3-one (200 mg, 0.40 mmol) and K2CO3 (167.69 mg, 1.21 mmol) in ACN (2 ml) was added 2-chloro-l,3-thiazole-5- carbonitrile (116.96 mg, 0.81 mmol). The reaction was stirred at 50 °C for 35 min and upon concentration gave 2-{3-[5-({[2-({l-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-l,2-thiazin-4-yl}amino)propyl]oxy}methyl)-l,2,4-oxadiazol-3-yl]azetidin-l- yl}-l,3-thiazole-5-carbonitrile (160 mg, 0.27 mmol, 65.65 %). ESI-MS m / z: 602.9 [M+H] o C under microwave for 35 min and upon concentration gave 2-{3-[5-({[2-({l-[(4- methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-l,2-thiazin-4-yl}amino)propyl]oxy}methyl)-l,2,4- oxadiazol-3-yl]azetidin-l-yl}-l,3-thiazole-5-carbonitrile (160 mg, 0.27 mmol, 65.65 %). ESI-MS m / z: 602.9 [M+H] + .

[0377] Step 2: 2-{3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)- 1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]azetidin-1-yl}-1,3- thiazole-5-carbonitrile (130 mg, 0.22 mmol) was taken in TFA (2 mL) and TfOH (0.5 ml) and stirred at room temperature for 30 min. After concentration, purification by Prep- HPLC gave 2-[3-(5-{[(2-{[6-oxo-5-(trifluoromethyl)-1H-1,2-diazin-4-yl]amino}propyl)oxy]methyl}-1,2,4-oxadiazol-3-yl)azetidin-1-yl]-1,3-thiazole-5-carbonitrile (54 mg, 0.11 mmol, 51.88%). ESI-MS m / z: 483.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ11.14 (s, 1H), 7.63 (d, J = 3.5 Hz, 2H), 5.68 (s, 1H), 4.75 (s, 2H), 4.49 (t,J = 8.6 Hz, 2H), 4.34 (t, J = 6.4 Hz, 2H), 4.22 (dd, J = 13.1, 7.1 Hz, 1H),3.95 (s, 1H), 3.73 (dd, J = 9.1, 3.6 Hz, 1H), 3.60 (dd, J = 9.0, 5.6 Hz, 1H),1.29 (d, J = 6.5 Hz, 3H)。

[0378] Example 19: Synthesis of (S) 4-(trifluoromethyl)-5-(1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)pyridazin-3(2H)-one

[0379] Step 1: Add NH2OH·HCl (5.1 g, 73 mmol) to a solution of Na2CO3 (4.9 g, 46 mmol) in water (60 mL), followed by a solution of 4-cyanohexahydropyridine-1-carboxylate (15 g, 61.40 mmol) in EtOH (120 mL). Heat the resulting mixture under reflux for 3 hours. Add Na2CO3 (4.9 g, 46 mmol) and NH2OH·HCl (5.1 g, 73 mmol), and reflux the mixture overnight. Cool and concentrate the mixture, filter, wash the solid product with water, and dry to give 4-[azomethylene(hydroxyamino)methyl]hexahydropyridine-1-carboxylate (16 g, 57.70 mmol, 93.96%) as a white solid. ESI-MS m / z: 278.90 [M+H] + .

[0380] Step 2: Add triethylamine (16.00 ml, 115.40 mmol) to a DCM (100 mL) solution of benzyl 4-[azodimethyl(hydroxyamino)methyl]hexahydropyridine-1-carboxylate (16 g, 57.70 mmol), and mix at 0°C. o Stirring at C, chloroacetyl chloride (6.52 g, 57.70 mmol) was slowly added dropwise over 20 minutes. The reactants were stirred at 0°C. o The mixture was stirred at C for 10 minutes, then stirred at room temperature for 2 hours. The solution was removed under vacuum, 1,4-dioxane (100 mL) was added, and the mixture was refluxed for 2 hours. After concentration, the product was purified by silica gel column chromatography (PE:EA = 5:1) to give benzyl 4-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (14 g, 41.79 mmol, 72.43%). ESI-MS m / z: 335.90 [M+H] + .

[0381] Step 3: To a mixture of 2-methylpropan-2-yl {[(2S)-1-hydroxypropan-2- yl]amino}carbamate (1 g, 2.99 mmol), tetrabutylammonium hydrogen sulfate (0.20 g, 0.60 mmol) and NaOH (4.78 g, 119.40 mmol) was added water (5 mL). The mixture was stirred at room temperature for 5 min. Then a solution of 4-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)piperidine-1- carboxylate benzyl ester (1 g, 2.99 mmol) in DCM (30 mL) was added slowly to the reaction and stirred for 2 h. Then the reaction was quenched with water and extracted with dichloromethane. The organic layer was concentrated and finally purified by silica gel column to give (S)-4-(5-((2-((tert-butoxycarbonyl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidine-1- carboxylate benzyl ester (1 g, 0.63 mmol, 21.20%). ESI-MS m / z: 374.90 [M+H] + .

[0382] Step 4: (S)-4-(5-((2-((tert-butoxycarbonyl)amino)propoxy)methyl)-1,2,4-oxadiazol-3- yl)piperidine-1-carboxylate benzyl ester (900 mg, 0.85 mmol) was added to HCl-EA (10 mL) and stirred at room temperature for 3 h. Then the solution was concentrated and the crude was used directly for the next step. ESI-MS m / z: 374.90 [M+H] + .

[0383] Step 5: To (S)-4-(5-((2-aminopropoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate benzyl ester hydrochloride (900 mg, 2.41 mmol) in EtOH (20 mL) was added 5-chloro-2-[(4- methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (460.13 mg, 1.44 mmol) and TEA (0.27 mL, 1.93 mmol). The reaction was stirred at 50 o C overnight. The solvent was removed under vacuum and then purified by silica gel column to give (S)-4-(5-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate benzyl ester (900 mg, 1.37 mmol, 57.1%). ESI-MS m / z: 656.90 [M+H] + .

[0384] Step 6: To a solution of (S)-4-(5-((2-((1-(4-methoxybenzyl)-6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3- yl)piperidine-1-carboxylate (900 mg, 1.37 mmol) in DCM (5 mL) was added 33% hydrobromic acid in acetic acid (5 mL) and stirred at room temperature for 2 h. It was then purified by Prep-HPLC to give (S)-2-(4-methoxybenzyl)-5-((1-((3-(piperidin-4-yl)-1,2,4-oxadiazol-5- yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (180 mg, 0.33 mmol, 21.9%). ESI-MS m / z: 523.90 [M+H] + .

[0385] Step 7: To a solution of (S)-2-(4-methoxybenzyl)-5-((1-((3-(piperidin-4-yl)-1,2,4- oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (140 mg, 0.27 mmol) and K2CO3 (79.34 mg, 0.57 mmol) in ACN (5 mL) was added 2-chloro-5- trifluoromethylpyrimidine (73.92 mg, 0.40 mmol) and stirred at room temperature for 2 h. The solvent was removed under vacuum and purified by silica gel column to give (S)-2-(4- methoxybenzyl)-4-(trifluoromethyl)-5-((1-((3-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin- 4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (120 mg, 0.18 mmol, 66.99%). ESI-MS m / z: 667.90 [M+H] + .

[0386] Step 8: (S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-((3-(1-(5- (trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan- 2-yl)amino)pyridazin-3(2H)-one (120 mg, 0.18 mmol) was taken in TFA (2 ml) and TfOH (0.5 ml), stirred at room temperature for 30 minutes and then purified by Prep- HPLC to get (S) 4-(trifluoromethyl)-5-(1-((3-(1-(5-(trifluoromethyl)pyrimidin-2- yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)pyridazin-3(2H)- one (40 mg, 0.07 mmol, 40.63%). ESI-MS m / z: 549.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.49(s, 2H), 7.70 (s, 1H), 5.82 (d, J = 5.8 Hz, 1H), 4.81 (d, J = 18.9 Hz, 4H),4.01 (s, 1H), 3.78 (dd, J = 9.1, 3.8 Hz, 1H), 3.67 (dd, J = 9.1, 5.2 Hz, 1H),3.18 (ddd, J = 17.0, 14.7, 9.5 Hz, 3H), 2.14 (d, J = 12.9 Hz, 2H), 1.84 (dd,J = 23.4, 12.8 Hz, 3H), 1.36 (d, J = 6.5 Hz, 3H)。

[0387] Example 20: Synthesis of (R) 4-(trifluoromethyl)-5-(1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)pyridazin- 3(2H)-one

[0388] Step 1: Add NH2OH·HCl (5.1 g, 73 mmol) to a solution of Na2CO3 (4.9 g, 46 mmol) in water (60 mL), followed by a solution of 4-cyanohexahydropyridine-1-carboxylate (15 g, 61.40 mmol) in EtOH (120 mL). The reaction mixture was heated under reflux for 3 hours. Then, Na2CO3 (4.9 g, 46 mmol) and NH2OH·HCl (5.1 g, 73 mmol) were added, and the mixture was refluxed overnight. The mixture was cooled and evaporated, filtered, and the solid product was washed with water and dried to give 4-[azomethylene(hydroxyamino)methyl]hexahydropyridine-1-carboxylate (16 g, 57.70 mmol, 93.96%) as a white solid. ESI-MS m / z: 278.90 [M+H] + .

[0389] Step 2: Add triethylamine (16.00 ml, 115.40 mmol) to a DCM (100 mL) solution of benzyl 4-[azodimethyl(hydroxyamino)methyl]hexahydropyridine-1-carboxylate (16 g, 57.70 mmol), and mix at 0°C. o Stirring at C, slowly add chloroacetyl chloride (6.52 g, 57.70 mmol) dropwise over 20 minutes. The reactants are at 0... o The solution was stirred at C for 10 minutes, then stirred at room temperature for 2 hours. The solution was removed under vacuum, 1,4-dioxane (100 mL) was added, and the mixture was refluxed for 2 hours. After concentration, the solution was purified by column chromatography (PE:EA = 5:1) to give benzyl 4-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (14 g, 41.79 mmol, 72.43%). ESI-MS m / z: 335.90 [M+H] + .

[0390] Step 3: To a mixture of 2-methylpropan-2-yl {[(2R)-1-hydroxypropan-2- yl]amino}carbamate (0.78 g, 4.48 mmol), tetrabutylammonium hydrogen sulfate (0.20 g, 0.60 mmol) and NaOH (4.78 g, 119.40 mmol) was added water (5 mL). The mixture was stirred at room temperature for 5 min. Then a solution of 4-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)piperidine-1- carboxylate benzyl ester (1 g, 2.99 mmol) in DCM (30 mL) was added slowly to the reaction. The mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with dichloromethane. The organic layer was concentrated and finally purified by silica gel column to give (R)-4-(5-((2-((tert-butoxycarbonyl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidine-1- carboxylate benzyl ester (1 g, 0.95 mmol, 31.80%). ESI-MS m / z: 374.90 [M+H] + .

[0391] Step 4: (R)-4-(5-((2-((tert-butoxycarbonyl)amino)propoxy)methyl)-1,2,4-oxadiazol-3- yl)piperidine-1-carboxylate benzyl ester (900 mg, 0.85 mmol) was added to HCl-EA (10 mL) and stirred at room temperature for 3 h. Then the reaction was concentrated and the crude was used directly for the next step. ESI-MS m / z: 374.90 [M+H] + .

[0392] Step 5: To (R)-4-(5-((2-aminopropoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate benzyl ester hydrochloride (900 mg, 2.41 mmol) in EtOH (20 mL) was added 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (460.13 mg, 1.44 mmol) and TEA (0.27 mL, 1.93 mmol). The reaction was stirred at 50 o C overnight. The solvent was removed under vacuum and then purified by silica gel column to give (R)-4-(5-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate benzyl ester (900 mg, 0.41 mmol, 42.76%). ESI-MS m / z: 656.90 [M+H] + .

[0393] Step 6: To a solution of (R)-4-(5-((2-((1-(4-methoxybenzyl)-6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4- oxadiazol-3-yl)piperidine-1-carboxylate (300 mg, 0.23 mmol) in DCM (5 mL) was added hydrobromic acid acetic acid (5 mL) and stirred at room temperature for 2 h. Then purified by Prep-HPLC to give (R)-2-(4-methoxybenzyl)-5-((1-((3-(piperidin-4-yl)-1,2,4-oxadiazol-5- yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (60 mg, 0.11 mmol, 50.22%). ESI-MS m / z: 523.90 [M+H] + .

[0394] Step 7: To a solution of 5-{[(2R)-1-({[3-(hexahydropyridin-4-yl)-1,2,4- oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-2H,3H-1,2-diazin-3-one (100 mg, 0.19 mmol) and K2CO3 (52.90 mg, 0.38 mmol) in ACN (5 mL) was added 2-chloro-5-trifluoromethylpyrimidine (52.40 mg, 0.29 mmol) and stirred at room temperature for 1.5 h. The solvent was removed under vacuum and then purified by silica gel column to give (R)-2-(4-methoxybenzyl)-4- (trifluoromethyl)-5-((1-((3-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4- oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (70 mg, 0.10 mmol, 54.71%). ESI-MS m / z: 667.90 [M+H] + .

[0395] Step 8: 5-{[[(2R)-1-{[(3-{1-[5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridin-4-yl}- 1,2,4-oxadiazol-5-yl)methyl]oxy}propan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-2H,3H-1,2-diazin-3-one (70 mg, 0.10 mmol) was taken in TFA (2 ml) and TfOH (0.5 ml) and stirred at room temperature for 30 minutes. It was then purified by Prep-HPLC to get (R)-4-(trifluoromethyl)-5-((1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)- 1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one (22 mg, 0.04 mmol, 38.31%). ESI-MS m / z: 549.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ10.99 (s, 1H), 8.49 (s, 2H), 7.68 (s, 1H), 7.26 (s, 1H), 5.87 – 5.71 (m, 1H),4.87 – 4.76 (m, 4H), 4.00 (s, 1H), 3.78 (dd, J = 9.2, 4.0 Hz, 1H), 3.66 (dd,J = 9.2, 5.3 Hz, 1H), 3.28 – 3.10 (m, 3H), 2.13 (d, J = 13.5 Hz, 2H), 1.92 –1.76 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H)。

[0396] Example 21: Synthesis of 5-((1-((3-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)-1,2,4- oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0397] Step 1 : To a solution of 5-{[1-({[3-(azetidin-3-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}- 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (200 mg, 0.40 mmol) and K2CO3(167.69 mg, 1.21 mmol) in ACN (2 ml), was added 2-chloro-5-fluoropyrimidine (107.20 mg, 0.81 mmol) and the reaction was stirred at 60 °C overnight. After completion of the reaction, the reaction was concentrated and purified by silica gel column to get 5-({1 -[({3-[1 -(5-fluoropyrimidin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (140 mg, 0.24 mmol, 58.61 %). ESI-MS m / z: 591.20 [M+H] o C under stirring overnight. After completion of the reaction, the reaction was concentrated and purified by silica gel column to get 5-({1 -[({3-[1 -(5-fluoropyrimidin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (140 mg, 0.24 mmol, 58.61 %). ESI-MS m / z: 591.20 [M+H] + .

[0398] Step 2: To 5-({1 -[({3-[1 -(5-fluoropyrimidin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (180 mg, 0.30 mmol) was added TFA (2.5 ml) and TfOH (0.5 ml) and stirred at room temperature for 30 min. After concentration of the reaction, it was purified by Prep-HPLC to get 5-({1 -[({3-[1 -(5-fluoropyrimidin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (53 mg, 0.11 mmol, 36.96 %). ESI-MS m / z: 471.1 [M+H] + . 1H NMR (400 MHz, CDC13) δ 11.26 (s, 1H), 8.18 (s, 2H), 7.62 (s, 1H), 5.70 (s, 1H), 4.74 (s, 2H), 4.45 (t, J = 8.6 Hz, 2H), 4.29 (t, J = 6.4 Hz, 2H), 4.06 (td, J = 8.2, 4.2 Hz, 1H), 3.94 (s, 1H), 3.71 (dd, J = 9.1, 3.8 Hz, 1H), 3.59 (dd, J = 9.1, 5.5 Hz, 1H), 1.28 (d, J = 6.5 Hz, 3H).

[0399] Example 22: Synthesis of 5-((1-((3-(1-(5-chlorothiazol-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0400] Step 1: 5-(1-((3-(azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)-2-(4- methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride (300 mg, 0.57 mmol), cesium carbonate (368.21 mg, 1.13 mmol), [[5-(diphenylphosphoryl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine (65.39 mg, 0.11 mmol), tris[(1E,4E)-1,5-diphenylpenta-1,4-dien-3-ylone]bis[palladium(0)] (51.74 mg, 0.06 mmol), 2-bromo-5-chloro-1,3-thiazole (168.21 mg, 0.85 mmol) and dioxane (8 ml) were added into a 20 ml microwave tube. The mixture was stirred at 100 °C overnight. The reaction mixture was diluted with H2O (10 ml), extracted with EA (10 ml*2). The EA layer was dried over Na2SO4, filtered and concentrated, purified by column chromatography (PE: EA = 10: 1 to 0: 1) to give 5-({1-[({3-[1-(5-chloro-1,3-thiazol-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (150 mg, 0.25 mmol, 43.37%). ESI-MS m / z: 611.6 [M+H] + .

[0401] Step 2: To a solution of 5-({1-[({3-[1-(5-chloro-1,3-thiazol-2-yl)azetidin-3-yl]-1,2,4- oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (150 mg, 0.25 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was added trifluoromethanesulfonic acid (0.5 mL) and the reaction mixture turned red in color. The mixture was stirred at room temperature for 10 min. The reaction was quenched with saturated Na2CO3, pH was adjusted to 7-8 and then extracted with dichloromethane (100 mL*2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-({1-[({3-[1-(5-chloro-1,3-thiazol-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (20 mg, 0.04 mmol, 16.59%) as a white solid. ESI-MS m / z: 491.6 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.28 (s, 1H), 7.69 (s, 1H), 7.00 (s, 1H), 5.83 - 5.68 (m, 1H), 4.82 (s, 2H), 4.44 (t, J = 8.1 Hz, 2H), 4.33 - 4.26 (m, 2H), 4.22 (ddd, J = 8.5, 7.1, 4.2 Hz, 1H), 4.02 (s, 1H), 3.79 (dd, J = 9.2, 4.0 Hz, 1H), 3.67 (dd, J = 9.2, 5.5 Hz, 1H), 1.36 (d, J = 6.6 Hz, 3H).

[0402] Example 23: Synthesis of 5-((1-((3-(1-(5-methylpyrimidin-2-yl)azetidin-3-yl)-1,2,4- oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0403] Step 1 : To a solution of 5-{[1-({[3-(azetidin-3-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}- 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (220 mg, 0.44 mmol) and K2CO3(184.46 mg, 1.33 mmol) in ACN (2 ml), 2-chloro-5-methylpyrimidine (110 mg, 0.89 mmol) was added and the reaction was stirred under microwave condition at 80 °C for 2 h. The reaction mixture was concentrated and purified by silica gel column to give 2-[(4-methoxyphenyl)methyl]-5-({1 -[({3-[1 -(5-methylpyrimidin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (150 mg, 0.26 mmol, 57.48%). ESI-MS m / z: 586.9 [M+H] o C under stirring for 2 h. The reaction mixture was concentrated and purified by silica gel column to give 2-[(4-methoxyphenyl)methyl]-5-({1 -[({3-[1 -(5-methylpyrimidin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (150 mg, 0.26 mmol, 57.48%). ESI-MS m / z: 586.9 [M+H] + .

[0404] Step 2: To a solution of 2-[(4-methoxyphenyl)methyl]-5-({1 -[({3-[1 -(5-methylpyrimidin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (50 mg, 0.09 mmol) in TFA (2 ml) and TfOH (0.5 ml) was added and stirred at room temperature for 30 min. The reaction mixture was concentrated and then purified by Prep-HPLC to give 5-({1 -[({3-[1 -(5-methylpyrimidin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (17 mg, 0.04 mmol, 42.76%). ESI-MS m / z: 466.7 [M+H] + . 1H NMR (400MHz, CDCl3) δ 10.98 (s, 1H), 8.13 (s, 2H), 7.61 (s, 1H), 5.68 (s, 1H), 4.74(s, 2H), 4.45 (t, J = 8.5 Hz, 2H), 4.37 – 4.23 (m, 2H), 4.06 (td, J = 8.5,4.3 Hz, 1H), 3.94 (s, 1H), 3.70 (dd, J = 9.2, 3.9 Hz, 1H), 3.58 (dd, J = 9.2,5.5 Hz, 1H), 2.08 (s, 3H), 1.28 (d, J = 6.6 Hz, 3H).

[0405] Example 24: Synthesis of 5-((1-((3-((1-(5-(difluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one

[0406] Step 1: Add 2-chloropyrimidine-5-carboxaldehyde (86.48 mg, 0.61 mmol) to a solution of 5-{[1-({[3-(azacyclobutan-3-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propyl-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (300 mg, 0.61 mmol) in ACN (3 mL), and react at 60 °C. o Stirred overnight at C. The solvent was removed under vacuum, followed by purification by silica gel column chromatography to give 2-{3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]azacyclobutane-1-yl}pyrimidin-5-carboxaldehyde (200 mg, 0.33 mmol, 54.89%). ESI-MS m / z: 600.9 [M+H] + .

[0407] Step 2: To a solution of 2-{3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]azetidin- 1-yl}pyrimidine-5-carbaldehyde (200 mg, 0.33 mmol) in THF (3 ml) was added DAST (265.96 mg, 1.65 mmol). The reaction was stirred at room temperature for 48 h. The reaction was concentrated and purified by silica gel column to give 5-[(1-{[(3-{1-[5-(difluoromethyl)pyrimidin-2-yl]azetidin-3-yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}prop-2-yl)amino]-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazonin-3-one (120 mg, 0.19 mmol, 57.88%). ESI-MS m / z: 622.9 [M+H] + .

[0408] Step 3: 4-((Difluoro-l3-methyl)-l2-fluoroalkyl)-5-((1-((3-((1-(5-(difluoromethyl)pyrimidin- 2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)prop-2-yl)amino)-2-(4-methoxybenzyl)pyridazin- 3(2H)-one (120 mg, 0.19 mmol) was added to TFA (2 ml) and TfOH (0.19 mmol) and stirred at room temperature for 30 min. The reaction was concentrated and purified by Prep-HPLC to give 4-((difluoro-l3-methyl)-l2-fluoroalkyl)-5-((1-((3-(1-(5-methylpyrimidin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)prop-2-yl)amino)pyridazin-3(2H)-one (40 mg, 0.08 mmol, 41.27%). ESI-MS m / z: 502.7 [M+H] + . 1H NMR (400 MHz, CDC13) δ 11.20 (s, 1H), 8.45 (s, 2H), 7.68 (s, 1H), 6.59 (t, J = 56.0 Hz, 1H), 5.85 - 5.66 (m, 1H), 4.82 (s, 2H), 4.60 (t, J = 8.9 Hz, 2H), 4.43 (dd, J = 10.4, 4.2 Hz, 2H), 4.24 - 4.10 (m, 1H), 4.01 (s, 1H), 3.78 (dd, J = 9.2, 3.9 Hz, 1H), 3.66 (dd, J = 9.2, 5.5 Hz, 1H), 1.35 (d, J = 6.6 Hz, 3H).

[0409] Example 25: Synthesis of 5-((l-((3-(l-(5-methylthiazol-2-yl)azetidin-3-yl)-l,2,4- oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0410] Step 1: 5-(1-((3-(azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)-2-(4- methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride (400 mg, 0.76 mmol), cesium carbonate (490.94 mg, 1.50 mmol), [[5-(diphenylphosphoryl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine (87.18 mg, 0.14 mmol), tris[(1E,4E)-1,5-diphenylpenta-1,4-dien-3-yl]bis[palladium(0)] (68.98 mg, 0.08 mmol), 2-bromo-5-methylthiazole (202.92 mg, 1.14 mmol) and dioxane (8 mL) were added into a 20 mL microwave tube. The mixture was stirred at 100 °C overnight. The reaction mixture was diluted with H2O (10 mL), extracted with EA (10 mL*2). The EA layer was dried over Na2SO4, filtered and concentrated, purified by column chromatography (PE : EA = 10 : 1~0 : 1) to give 2-(4-methoxybenzyl)-5-((1-((3-(1-(5-methylthiazol-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (100 mg, 0.17 mmol, 22.37%). ESI-MS m / z: 591.7 [M+H] + .

[0411] Step 2: To a stirred solution of 2-(4-methoxybenzyl)-5-((1-((3-(1-(5- methylthiazol-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4- (trifluoromethyl)pyridazin-3(2H)-one (100 mg, 0.17 mmol) in 2,2,2-trifluoroacetic acid (2.5 mL) was added trifluoromethanesulfonic acid (0.5 mL) and the reaction mixture turned red in color. The mixture was stirred at room temperature for 10 min. The reaction was quenched with saturated Na2CO3, pH was adjusted to 7-8 and then extracted with dichloromethane (100 mL*2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-((1-((3-(1-(5-methylthiazol-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (23.77 mg, 0.05 mmol, 29.66%) as a white solid. ESI-MS m / z: 471.7 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.67(d, J = 70.4 Hz, 1H), 7.70 (s,1H), 6.84 (s, 1H), 5.85 – 5.65 (m, 1H), 4.81(s, 2H), 4.42 (t, J = 8.0Hz, 2H), 4.27 (d, J = 5.2 Hz, 2H), 4.19 (dd, J =13.6, 7.0 Hz, 1H),4.02 (s, 1H), 3.78 (dd, J = 9.1, 3.7 Hz, 1H), 3.66 (dd, J =9.0, 5.4Hz, 1H), 2.31 (s, 3H), 1.35 (d, J = 6.4 Hz, 3H)。

[0412] Example 26: Synthesis of 4-(trifluoromethyl)-5-((1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0413] Step 1 : To a solution of 2-[(4-methoxyphenyl)methyl]-5-{[l-({[3-(tetrahydro-lH- pyrrol-3-yl)-l,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}-4- (trifluoromethyl)-2H,3H-l,2-dioxazin-3-one (150 mg, 0.29 mmol) in MeCN (3 ml) was added K2CO3(81.53 mg, 0.59 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (80.77 mg, 0.44 mmol), the mixture was stirred at 80 °C overnight. The mixture was concentrated in vacuum, purified by silica gel column chromatography (PE:EA = 100 / 0 ~ 0 / 100) to give 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(l-{[(3-{l-[5- (trifluoromethyl)pyrimidin-2-yl]tetrahydro-lH-pyrrol-3-yl}-l,2,4-oxadiazol-5- yl)methyl]oxy}propan-2-yl)amino]-2H,3H-l,2-dioxazin-3-one (180 mg, 0.27 mmol, 93.22%) as orange oil. ESI-MS m / z: 654.6 [M+H] o . + .

[0414] Step 2: To a solution of 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(l-{[(3-{l-[5- (trifluoromethyl)pyrimidin-2-yl]tetrahydro-lH-pyrrol-3-yl}-l,2,4-oxadiazol-5- yl)methyl]oxy}propan-2-yl)amino]-2H,3H-l,2-dioxazin-3-one (180 mg, 0.27 mmol) in TFA (2.5 ml, 32.67 mmol) was added TfOH (0.5 ml, 5.66 mmol), the reaction turned red in color, the mixture was stirred at room temperature for 10 minutes. Then the reaction was quenched with saturated Na2CO3, adjusted pH = 7-8, and extracted with DCM (50 ml*2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 4-(trifluoromethyl)-5-[(l-{[(3-{l-[5-(trifluoromethyl)pyrimidin-2-yl]tetrahydro-lH-pyrrol-3-yl}-l,2,4-oxadiazol-5-yl)methyl]oxy}propan-2-yl)amino]-2H,3H-l,2-dioxazin-3-one (54 mg, 0.10 mmol, 36.74%) as white solid. ESI-MS m / z: 535.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 11.02 (s, 1H), 8.52 (s, 2H), 7.69 (s,1H), 5.82 – 5.69 (m, 1H), 4.79 (s, 2H), 4.13 – 4.05 (m, 1H), 4.01 (d, J = 5.6Hz, 1H), 3.90 (ddd, J = 13.0, 7.5, 3.6 Hz, 2H), 3.82 – 3.70(m, 3H), 3.65 (dd,J = 9.2, 5.5 Hz, 1H), 2.55 – 2.34 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H)。

[0415] Example 27: Synthesis of 4-(trifluoromethyl)-5-((1-((3-(1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0416] Step 1: To a solution of 2-[(4-methoxyphenyl)methyl]-5-{[1-({[3-(tetrahydro-1H-pyrrol-3-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}-4- (trifluoromethyl)-2H,3H-1,2-dioxazin-3-one (150 mg, 0.29 mmol) in MeCN (3 ml) was added K2CO3(81.53 mg, 0.59 mmol) and 2-fluoro-5-(trifluoromethyl)pyridine (73.05 mg, 0.44 mmol), the mixture was stirred at 50 o C overnight. The mixture was concentrated in vacuum, purified by silica gel column chromatography (PE:EA =100 / 0 ~ 0 / 100) to give 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(3-{1-[5-(trifluoromethyl)pyridin-2-yl]tetrahydro-1H-pyrrol-3-yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}propan-2-yl)amino]-2H,3H-1,2-dioxazin-3-one (190 mg, 0.29 mmol, 98.55%) orange oil. ESI-MS m / z: 654.20 [M+H] + .

[0417] Step 2: To a solution of 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(3-{1-[5-(trifluoromethyl)pyridin-2-yl]tetrahydro-1H-pyrrol-3-yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}propan-2-yl)amino]-2H,3H-1,2-diazin-3-one (190 mg, 0.29 mmol) in TFA (2.5 ml, 32.67 mmol) was added TfOH (0.5 ml, 5.66 mmol) and the reaction mixture turned red in color. The mixture was stirred at room temperature for 10 min. The reaction was quenched with saturated Na2CO3, pH was adjusted to 7-8 and then extracted with DCM (50 ml*2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 4-(trifluoromethyl)-5-[(1-{[(3-{1-[5-(trifluoromethyl)pyridin-2-yl]tetrahydro-1H-pyrrol-3-yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}propan-2-yl)amino]-2H,3H-1,2-diazin-3-one (49 mg, 0.09 mmol, 31.60%) as a white solid. ESI-MS m / z: 534.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 12.09 (s, 1H), 8.39 (s, 1H), 7.70 (s,1H), 7.61 (dd, J = 8.9, 2.3 Hz, 1H), 6.41 (d, J = 8.9 Hz, 1H), 5.79 (dd, J =12.3, 5.7 Hz, 1H), 4.79 (s, 2H), 3.98 (dd, J = 18.3, 7.8 Hz, 2H), 3.77 (tt, J= 21.0, 6.6 Hz, 4H), 3.69 – 3.54 (m, 2H), 2.57 – 2.33 (m, 2H), 1.34 (d, J =6.6 Hz, 3H)。

[0418] Example 28: Synthesis of 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1-yl)thiazole-5-carbonitrile

[0419] Step 1 : To a solution of 2-[(4-methoxyphenyl)methyl]-5-{[l-({[3-(tetrahydro-lH- pyrrol-3-yl)-l,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}-4-(trifluoromethyl)- 2H,3H-l,2-dioxazin-3-one (150 mg, 0.29 mmol) in MeCN (3 ml) was added K2CO3(81.53 mg, 0.59 mmol) and 2-chloro-l,3-thiazole-5-carbonitrile (63.97 mg, 0.44 mmol) and the mixture was stirred in the microwave at 60 °C for 1 h. The mixture was concentrated in vacuo and purified by column chromatography on silica gel (PE:EA = 100 / 0 ~ 0 / 100) to give 2-{3-[5-({[2-({l-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-l,2-diazin-4-yl}amino)propan-2-yl]oxy}methyl)-l,2,4-oxadiazol-3-yl] tetrahydro-lH-pyrrol-l-yl}-l,3-thiazole-5-carbonitrile (130 mg, 0.21 mmol, 71.47%) as an orange oil. ESI-MS m / z: 617.2 [M+H] o C was stirred in the microwave at 60 °C for 1 h. The mixture was concentrated in vacuo and purified by column chromatography on silica gel (PE:EA = 100 / 0 ~ 0 / 100) to give 2-{3-[5-({[2-({l-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-l,2-diazin-4-yl}amino)propan-2-yl]oxy}methyl)-l,2,4-oxadiazol-3-yl] tetrahydro-lH-pyrrol-l-yl}-l,3-thiazole-5-carbonitrile (130 mg, 0.21 mmol, 71.47%) as an orange oil. ESI-MS m / z: 617.2 [M+H] + .

[0420] Step 2: To a solution of 2-{3-[5-({[2-({l-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-l,2-diazin-4-yl}amino)propan-2-yl]oxy}methyl)-l,2,4-oxadiazol-3-yl] tetrahydro-lH-pyrrol-l-yl}-l,3-thiazole-5-carbonitrile (130 mg, 0.21 mmol) in TFA (2.5 ml, 32.67 mmol) was added TfOH (0.5 ml, 5.66 mmol) and the reaction turned red in color. The mixture was stirred at room temperature for 10 min. The reaction was quenched with saturated Na2CO3and the pH was adjusted to 7-8 before extraction with DCM (50 ml*2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 2-[3-(5-{[(2-{[6-oxo-5- (trifluoromethyl)-lH-l,2-diazin-4-yl]amino}propan-2-yl)oxy]methyl}-l,2,4-oxadiazol-3-yl) tetrahydro-lH-pyrrol-l-yl]-l,3-thiazole-5-carbonitrile (32 mg, 0.06 mmol, 30.57%) as a white solid. ESI-MS m / z: 497.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 11.12 (s, 1H), 7.71 (d, J = 11.9 Hz,2H), 5.85 – 5.68 (m, 1H), 4.79 (s, 2H), 4.10 – 3.90 (m, 2H), 3.89 – 3.76 (m, 3H), 3.76 – 3.69 (m, 1H), 3.65 (dt, J = 16.1, 8.0 Hz, 2H), 2.61 – 2.40 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H).

[0421] Example 29: Synthesis of 5-((1-((3-(1-(5-fluoropyrimidin-2-yl)pyrrolidine-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one

[0422] Step 1: Add K₂CO₃ (108.71 mg, 0.79 mmol) and 2-chloro-5-fluoropyrimidine (78.18 mg, 0.59 mmol) to a MeCN (3 mL) solution of 2-[(4-methoxyphenyl)methyl]-5-{[1-({[3-(tetrahydro-1H-pyrrolo-3-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propyl-2-yl]amino}-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (200 mg, 0.39 mmol) and 2-chloro-5-fluoropyrimidine (78.18 mg, 0.59 mmol). The mixture is heated at 80 °C. o The mixture was stirred overnight at C. The mixture was concentrated under vacuum and purified by silica gel column chromatography (PE:EA = 100 / 0 ~ 0 / 100) to give an orange oil of 5-({1-[({3-[1-(5-fluoropyrimidin-2-yl)tetrahydro-1H-pyrrolo-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propyl-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (130 mg, 0.22 mmol, 54.67%). ESI-MS m / z: 605.2 [M+H] + .

[0423] Step 2: To a solution of 5-({1-[({3-[1-(5-fluoropyrimidin-2-yl)tetrahydro-1H-pyrrol-3-yl]- 1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-2H,3H-1,2-diazin-3-one (130 mg, 0.22 mmol) in TFA (2 ml, 26.14 mmol) was added TfOH (0.5 ml, 5.66 mmol) and the reaction mixture turned red in color. The mixture was stirred at room temperature for 10 min. The reaction was quenched with saturated Na2CO3, pH was adjusted to 7-8 and then extracted with DCM (100 ml*2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-({1-[({3-[1-(5-fluoropyrimidin-2-yl)tetrahydro-1H-pyrrol-3-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (43 mg, 0.09 mmol, 41.28%) as white solid. ESI-MS m / z: 485.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 11.25 (s, 1H), 8.23 (s, 2H), 7.69 (s,1H), 5.88 – 5.62 (m, 1H),4.78 (s, 2H), 4.02 (ddd, J = 11.0, 7.6, 3.3Hz, 2H), 3.89 – 3.59 (m, 6H), 2.51– 2.27 (m, 2H), 1.35 (d, J = 6.6Hz, 3H)。

[0424] Example 30: Synthesis of 5-((1-((3-(1-(5-chloropyrimidin-2-yl)pyrrolidin-3-yl)-1,2,4- oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0425] Step 1 : To a solution of 2-[(4-methoxyphenyl)methyl]-5-{[1-({[3-(tetrahydro-1H- pyrrol-3-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}-4-(trifluoromethyl)- 2H,3H-1,2-dioxazin-3-one (200 mg, 0.39 mmol) in MeCN (3 mL) was added K2CO3 (108.71 mg, 0.79 mmol) and 2,5-dichloropyrimidine (87.89 mg, 0.59 mmol, mixture in 80 o C overnight. The mixture was concentrated in vacuo and purified by silica gel column chromatography (PE:EA = 100 / 0 ~ 0 / 100) to give 5-({1-[({3-[1-(5-chloropyrimidin-2-yl)tetrahydro-1H-pyrrol-3-yl]- 1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-2H,3H-1,2-dioxazin-3-one (150 mg, 0.24 mmol, 61.41%) orange oil. ESI-MS m / z: 621.2 [M+H] + .

[0426] Step 2: To a solution of 5-({1-[({3-[1-(5-chloropyrimidin-2-yl)tetrahydro-1H-pyrrol-3-yl]- 1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-2H,3H-1,2-dioxazin-3-one (150 mg, 0.24 mmol) in TFA (2.5 ml) was added TfOH (0.5 ml, 5.66 mmol), the reaction turned red in color, the mixture was stirred at room temperature for 10 minutes. The reaction was quenched with saturated Na2CO3, adjusted pH = 7-8, then extracted with DCM (100 mL*2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-({1-[({3-[1-(5-chloropyrimidin-2-yl)tetrahydro-1H-pyrrol-3-yl]-1,2,4- oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-2H,3H-1,2-dioxazin-3- one (53 mg, 0.11 mmol, 43.81%) white solid. ESI-MS m / z: 500.7 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 11.37 (s, 1H), 8.26 (s, 2H), 7.69 (s,1H), 5.78 (dd, J = 13.1, 5.7Hz, 1H), 4.78 (s, 2H), 4.02 (ddd, J =11.1, 7.6, 3.4 Hz, 2H), 3.87 – 3.75 (m,3H), 3.75 – 3.69 (m, 1H), 3.69 – 3.62 (m, 2H), 2.53 – 2.29 (m, 2H), 1.35 (d, J= 6.6 Hz, 3H).

[0427] Example 31: Synthesis of 6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidine-1-yl)nicotinonitrile

[0428] Step 1: Add K₂CO₃ (108.71 mg, 0.79 mmol) and 6-fluoropyridine-3-carboxylonitrile (72.04 mg, 0.59 mmol) to a MeCN (3 ml) solution of 2-[(4-methoxyphenyl)methyl]-5-{[1-({[3-(tetrahydro-1H-pyrrolo-3-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propyl-2-yl]amino}-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (200 mg, 0.39 mmol) oxidized to 3 ml of MeCN. The mixture was microwaved at 80 °C. o The mixture was stirred at C for 2 hours. It was then concentrated under vacuum and purified by silica gel column chromatography (PE:EA = 100 / 0 ~ 0 / 100) to give 6-{3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]tetrahydro-1H-pyrrolo-1-yl}pyridine-3-carboxynitrile (200 mg, 0.33 mmol, 83.28%) as an orange oil. ESI-MS m / z: 611.2 [M+H] + .

[0429] Step 2: To a solution of 6-{3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl] tetrahydro-1H-pyrrol-1-yl}pyridine-3-carbonitrile (200 mg, 0.33 mmol) in TFA (2 ml, 26.14 mmol) was added TfOH (0.5 ml, 5.66 mmol) and the reaction mixture turned red in color. The mixture was stirred at room temperature for 10 min. The reaction was quenched with saturated Na2CO3, pH was adjusted to 7-8 and then extracted with DCM (20 ml*2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 6-[3-(5-{[(2-{[3-oxo-4- (trifluoromethyl)-2H-1,2-diazin-5-yl]amino}propyl)oxy]methyl}-1,2,4-oxadiazol-3-yl) tetrahydro-1H-pyrrol-1-yl]pyridine-3-carbonitrile (92 mg, 0.19 mmol, 57.27%) as a white solid. ESI-MS m / z: 491.2 [M+H] + . 1 H NMR (400 MHz, CDCl3)δ 11.02 (s, 1H), 8.42 (d, J = 2.1 Hz,1H), 7.69 (s, 1H), 7.61 (dd, J = 8.9,2.2 Hz, 1H), 6.39 (d, J = 8.9 Hz,1H), 5.84 – 5.69 (m, 1H), 4.79 (s, 2H), 4.06– 3.92 (m, 2H), 3.90 –3.70 (m, 4H), 3.66 (dd, J = 9.2, 5.5 Hz, 2H), 2.58 –2.31 (m, 2H),1.36 (d, J = 6.6 Hz, 3H)。

[0430] Example 32: Synthesis of 5-((1-((3-(1-(5-methylpyridin-2-yl)azetidin-3-yl)-1,2,4- oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0431] Step 1: 5-(1-((3-(azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)- 2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride (50 mg, 0.09 mmol), cesium carbonate (306.84 mg, 0.94 mmol), [5-(diphenylphosphoryl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine (54.49 mg, 0.09 mmol), tris[(1E,4E)-1,5-diphenylpenta-1,4-dien-3-yl]bis[palladium(0)] (43.12 mg, 0.05 mmol), 2-bromo-5-methylpyridine (121.51 mg, 0.71 mmol) and dioxane (8 mL) were added into a 20 mL microwave tube, the mixture was stirred at 105 °C overnight. The reaction mixture was diluted with H2O (10 mL), extracted with EA (10 mL*2). The EA layer was dried over Na2SO4, filtered and concentrated, purified by FCC (PE:EA = 10:1 to 0:1) to give 2-[(4-methoxyphenyl)methyl]-5-({1-[({3-[1-(5-methylpyridin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (45 mg, 0.08 mmol, 16.32%) yellow oil. ESI-MS m / z: 585.7 [M+H] + .

[0432] Step 2: To a solution of 2-[(4-methoxyphenyl)methyl]-5-({1-[({3-[1-(5- methylpyridin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)- 4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (45 mg, 0.08 mmol) in 2,2,2-trifluoroacetic acid (2 mL) was added trifluoromethanesulfonic acid (0.5 mL), the reaction turned red in color, the mixture was stirred at room temperature for 10 min. The reaction was quenched with saturated Na2CO3, adjusted pH = 7-8, then extracted with dichloromethane (100 mL*2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-({1-[({3-[1-(5-methylpyridin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (6.13 mg, 0.01 mmol, 17.14%) white solid. ESI-MS m / z: 465.8 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 10.96 (s, 1H), 8.01 - 7.85 (m, 1H), 7.61 (s, 1H), 7.26 (dd, J = 8.4, 2.1 Hz, 1H), 6.24 (d, J = 8.4 Hz, 1H), 5.76 - 5.61 (m, 1H), 4.73 (s, 2H), 4.39 - 4.29 (m, 2H), 4.20 - 4.12 (m, 2H), 4.07 (ddd, J = 8.4, 7.2, 4.2 Hz, 1H), 3.97 - 3.85 (m, 1H), 3.70 (dd, J = 9.2, 4.0 Hz, 1H), 3.58 (dd, J = 9.2, 5.5 Hz, 1H), 2.13 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H).

[0433] Example 33: Synthesis of 5-((1-((3-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-1,2,4- oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0434] Step 1 : To a solution of 5-{[1-({[3-(hexahydropyridin-4-yl)-1,2,4-oxadiazol-5- yl]methyl}oxy)propan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (150 mg, 0.29 mmol) and K2CO3(119.02 mg, 0.86 mmol) in ACN (3 mL) was added 2-chloro-5-fluoropyrimidine (50.72 mg, 0.38 mmol) and the reaction was stirred at 80 °C overnight. The reaction was concentrated and finally purified by silica gel column to give 5-({1 -[({3-[1 -(5-chloropyrimidin-2-yl)hexahydropyridin-4-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (150 mg, 0.24 mmol, 82.28%). ESI-MS m / z: 635.20 [M+H] o C overnight. The reaction was concentrated and finally purified by silica gel column to give 5-({1 -[({3-[1 -(5-chloropyrimidin-2-yl)hexahydropyridin-4-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (150 mg, 0.24 mmol, 82.28%). ESI-MS m / z: 635.20 [M+H] + .

[0435] Step 2: To a solution of 5-({1 -[({3-[1 -(5-chloropyrimidin-2-yl)hexahydropyridin-4-yl]- 1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]- 4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (150 mg, 0.24 mmol) was added TFA (2 ml) and TfOH (0.5 ml) and stirred at room temperature for 30 min, then purified by Prep-HPLC to give 5-({1 -[({3-[1 -(5-chloropyrimidin-2-yl)hexahydropyridin-4-yl]- 1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H- 1,2-diazin-3-one (30 mg, 0.06 mmol, 24.67%). ESI-MS m / z: 514.70 [M+H] + . 1H NMR (400 MHz, CDC13) δ 10.57 (s, 1H), 8.23 (s, 2H), 7.68 (s, 1H), 5.79 (s, 1H), 4.78 (d, J = 1.2 Hz, 2H), 4.70 (d, J = 13.5 Hz, 2H), 4.00 (s, 1H), 3.77 (dd, J = 9.2, 4.0 Hz, 1H), 3.65 (dd, J = 9.2, 5.4 Hz, 1H), 3.13 (dt, J = 19.6, 5.4 Hz, 3H), 2.10 (d, J = 13.0 Hz, 2H), 1.93 - 1.75 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H).

[0436] Example 34: Synthesis of 5-((1-((3-(1-(5-chloropyrimidin-2-yl)azetidin-3-yl)-1,2,4- oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0437] Step 1: To a solution of 5-{[1-({[3-(azetidin-3-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl] amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (200 mg, 0.40 mmol) and K2CO3 (167.69 mg, 1.21 mmol) in ACN (2 ml) was added 2,5-dichloropyrimidine (120.51 mg, 0.81 mmol) and the reaction was stirred at 80 °C overnight. The reaction was concentrated and the product was purified by silica gel column to give 5-({1-[({3-[1-(5-chloropyrimidin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (120 mg, 0.20 mmol, 48.88%). ESI-MS m / z: 606.9 [M+H] o C overnight. The reaction was concentrated and the product was purified by silica gel column to give 5-({1-[({3-[1-(5-chloropyrimidin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (120 mg, 0.20 mmol, 48.88%). ESI-MS m / z: 606.9 [M+H] + .

[0438] Step 2: 5-({1-[({3-[1-(5-chloropyrimidin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (200 mg, 0.33 mmol) was taken in TFA (2 mL) and TfOH (0.5 mL) and stirred at room temperature for 30 min. The reaction mixture was concentrated and purified by Prep-HPLC to give 5-({1-[({3-[1-(5-chloropyrimidin-2-yl)azetidin-3-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (30 mg, 0.06 mmol, 18.70%). ESI-MS m / z: 487.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.00 (d, J = 88.0 Hz, 1H), 8.27 (s, 2H), 7.68 (s, 1H), 5.85 - 5.66 (m, 1H), 4.81 (s, 2H), 4.53 (t, J = 8.8 Hz, 2H), 4.37 (ddd, J = 8.7, 6.0, 2.4 Hz, 2H), 4.14 (tt, J = 8.7, 5.9 Hz, 1H), 4.01 (s, 1H), 3.78 (dd, J = 9.2, 4.0 Hz, 1H), 3.66 (dd, J = 9.2, 5.5 Hz, 1H), 1.35 (d, J = 6.6 Hz, 3H).

[0439] Example 35: Synthesis of 5-((1-((3-(1-(5-(difluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)- 1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0440] Step 1: Add K₂CO₃ (108.71 mg, 0.79 mmol) and 2-chloropyrimidine-5-carboxaldehyde (84.09 mg, 0.59 mmol) to a MeCN (3 mL) solution of 2-[(4-methoxyphenyl)methyl]-5-{[1-({[3-(tetrahydro-1H-pyrrolo-3-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propyl-2-yl]amino}-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (200 mg, 0.39 mmol) and 2-chloropyrimidine-5-carboxaldehyde. The mixture is then heated at 80 °C. o The mixture was stirred overnight at C. The mixture was concentrated under vacuum and purified by silica gel column chromatography (PE: EA from 100 / 0 to 0 / 100) to give 2-{3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]tetrahydro-1H-pyrrolo-1-yl}pyrimidin-5-carboxaldehyde (200 mg, 0.33 mmol, 82.74%) as an orange oil. ESI-MS m / z: 615.2 [M+H] + .

[0441] Step 2: 0 o At C, DAST (786.82 mg, 4.88 mmol) was added to a DCM (20 ml) solution of 2-{3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]tetrahydro-1H-pyrrolo-1-yl}pyrimidine-5-carboxaldehyde (200 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 12 hours. After concentration, the product was purified by silica gel column chromatography to give 5-[(1-{[(3-{1-[5-(difluoromethyl)pyrimidin-2-yl]tetrahydro-1H-pyrrolo-3-yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}propyl-2-yl)amino]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (180 mg, 0.28 mmol, 86.89%). ESI-MS m / z: 637.2 [M+H] + .

[0442] Step 3: To a solution of 5-[(1-{[(3-{1-[5-(difluoromethyl)pyrimidin-2-yl]tetrahydro-1H-pyrrol-3-yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}propan-2-yl)amino]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (180 mg, 0.28 mmol) in TFA (2 ml, 26.14 mmol) was added TfOH (0.5 ml, 5.66 mmol) and the reaction mixture turned red in color and stirred at room temperature for 10 min. The reaction was quenched with saturated Na2CO3, pH was adjusted to 7-8 and then extracted with DCM (20 ml*2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-[(1-{[(3-{1-[5-(difluoromethyl)pyrimidin-2-yl]tetrahydro-1H-pyrrol-3-yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}propan-2-yl)amino]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (74 mg, 0.14 mmol, 50.68%) as a white solid. ESI-MS m / z: 516.7 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 10.51 (s, 1H), 8.44 (s, 2H), 7.68 (d, J= 1.8 Hz,1H), 6.58 (t, J = 56.1 Hz, 1H), 5.76 (s, 1H), 4.78 (s, 2H),4.15 – 4.05 (m,1H), 4.01 (s, 1H), 3.89 (dt, J = 12.4, 4.6 Hz, 2H),3.82 – 3.69 (m, 3H), 3.65(dd, J = 9.2, 5.6 Hz, 1H), 2.43 (tdd, J =12.5, 10.4, 5.2 Hz, 2H), 1.35 (d, J= 6.6 Hz, 3H)。

[0443] Example 36: Synthesis of 5-((1-((3-((1-(5-(difluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0444] Step 1: Add K₂CO₃ (108.71 mg, 0.79 mmol) and 6-fluoronicotinaldehyde (73.81 mg, 0.59 mmol) to a MeCN (3 mL) solution of 2-[(4-methoxyphenyl)methyl]-5-{[1-({[3-(tetrahydro-1H-pyrrolo-3-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propyl-2-yl]amino}-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (200 mg, 0.39 mmol) and 6-fluoronicotinaldehyde (73.81 mg, 0.59 mmol). The mixture is heated to 80 °C. o The mixture was stirred overnight at C. The mixture was concentrated under vacuum and purified by silica gel column chromatography (PE: EA from 100 / 0 to 0 / 100) to give 6-{3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]tetrahydro-1H-pyrrole-1-yl}pyridine-3-carboxaldehyde (180 mg, 0.29 mmol, 74.58%) as an orange oil. ESI-MS m / z: 614.2 [M+H] + .

[0445] Step 2: Add DAST (709.28 mg, 4.40 mmol) to a DCM (20 ml) solution of 6-{3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]tetrahydro-1H-pyrrole-1-yl}pyridine-3-carboxaldehyde (180 mg, 0.29 mmol). Stir overnight at room temperature. The reaction solution was concentrated and the product was purified by silica gel column chromatography to give 5-[(1-{[(3-{1-[5-(difluoromethyl)pyridin-2-yl]tetrahydro-1H-pyrrolo-3-yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}propyl-2-yl)amino]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (150 mg, 0.24 mmol, 80.45%). ESI-MS m / z: 635.7 [M+H] + .

[0446] Step 3: To a solution of 5-[(1-{[(3-{1-[5-(difluoromethyl)pyridin-2-yl]tetrahydro-1H- pyrrol-3-yl}-1,2,4-oxadiazol-5-yl)methyl]oxy}propan-2-yl)amino]-2-[(4- methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (150 mg, 0.24 mmol) in TFA (2 ml, 26.14 mmol) was added TfOH (0.5 ml, 5.66 mmol) and the reaction mixture turned red in color and stirred at room temperature for 10 min. The reaction was quenched with saturated Na2CO3, pH was adjusted to 7-8 and then extracted with DCM (100 ml*2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-[(1-{[(3-{1-[5-(difluoromethyl)pyridin-2-yl]tetrahydro-1H-pyrrol-3-yl}-1,2,4- oxadiazol-5-yl)methyl]oxy}propan-2-yl)amino]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (16 mg, 0.03 mmol, 13.15%) as white solid. ESI-MS m / z: 516.2 [M+H] + . 1 HNMR (400 MHz, CDCl3) δ 10.32 (d, J = 13.1 Hz, 1H), 8.24 (d, J= 1.6 Hz, 1H),7.67 (s, 1H), 7.60 (dd, J = 8.8, 2.2 Hz, 1H), 6.57 (s,1H), 6.43 (d, J = 8.7Hz, 1H), 5.75 (s, 1H), 4.78 (s, 2H), 4.05 – 3.92(m, 2H), 3.85 – 3.70 (m, 4H),3.68 – 3.56 (m, 2H), 2.55 – 2.37 (m,2H), 1.35 (d, J = 6.6 Hz, 3H)。

[0447] Example 37: Synthesis of 6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4- yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)nicotinaldehyde

[0448] To a solution of 6-(3-(5-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1- yl)nicotinaldehyde (100 mg, 0.17 mmol) in 2,2,2-trifluoroacetic acid (2.5 mL) was added trifluoromethanesulfonic acid (0.5 mL), the color of the reaction turned red, the mixture was stirred at room temperature for 10 minutes. The reaction was quenched with saturated Na2CO3, adjusted pH = 7-8, then extracted with dichloromethane (100 mL*2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4- yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)nicotinaldehyde (14.65 mg, 0.03 mmol, 17.65%) as a white solid. ESI-MS m / z: 480.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.06 (s, 1H),9.80 (s, 1H), 8.56 (s,1H), 7.94 (d, J = 8.6 Hz, 1H), 7.68 (s, 1H), 6.35 (d, J= 8.7 Hz, 1H),5.76 (s, 1H), 4.82 (s, 2H), 4.58 (t, J = 8.7 Hz, 2H), 4.48 –4.34 (m,2H), 4.31 – 4.14 (m, 1H), 4.01 (s, 1H), 3.80 (dd, J = 9.0, 3.7 Hz,1H), 3.67 (dd, J = 9.0, 5.6 Hz, 1H), 1.36 (d, J = 6.5 Hz, 3H)。

[0449] Example 38: Synthesis of 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1- yl)thiazole-5-carbaldehyde

[0450] Step 1: 5-(1-((3-(azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)-2-(4- methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride (200 mg, 0.38 mmol), K2CO3(103.66 mg, 0.75 mmol), 2-chlorothiazole-5-carbaldehyde (110.21 mg, 0.75 mmol) and MeCN (8 mL) were added into a 20 mL microwave tube, the resulting mixture was stirred at 80 °C overnight. The reaction mixture was concentrated and purified by column chromatography (PE: EA = 10:1 ~ 0:1) to give 2-(3-(5-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)thiazole-5- carbaldehyde (103 mg, 0.17 mmol, 44.74%). ESI-MS m / z: 605.7 [M+H] + .

[0451] Step 2: To a stirred solution of 2-(3-(5-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)thiazole-5- carbaldehyde (103 mg, 0.17 mmol) in 2,2,2-trifluoroacetic acid (2.5 mL) was added trifluoromethanesulfonic acid (0.5 mL), the reaction mixture turned red in color and was stirred at room temperature for 10 min. The reaction was quenched with saturated Na2CO3, the pH was adjusted to 7-8, then extracted with dichloromethane (10 mL*2). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)thiazole-5- carbaldehyde (9.97 mg, 0.02 mmol, 11.76%) as a white solid. ESI-MS m / z: 486.1 [M+H] + . 1H NMR (400 MHz, CDC13) δ 10.30 (s, 1H), 9.72 (s, 1H), 7.88 (s, 1H), 7.68 (s, 1H), 5.74 (s, 1H), 4.82(s, 2H), 4.60 (t, J = 8.8 Hz, 2H), 4.52 - 4.40 (m, 2H), 4.29 (ddd, J = 8.7, 7.3, 4.4 Hz, 1H), 4.02(s, 1H), 3.80 (dd, J = 9.2, 4.0 Hz, 1H), 3.67 (dd, J = 9.2, 5.6 Hz, 1H), 1.36 (d, J = 6.6 Hz, 3H).

[0452] Example 39: Synthesis of 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1- yl)pyrimidine-5-carbonitrile

[0453] Step 1: To a solution of 2-[(4-methoxyphenyl)methyl]-5-{[1-({[3-(tetrahydro-1H- pyrrol-3-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}-4- (trifluoromethyl)-2H,3H-1,2-diazin-3-one (200 mg, 0.39 mmol) in MeCN (3 mL) was added K2CO3 (108.71 mg, 0.79 mmol) and 5-bromo-2-chloropyrimidine (114.12 mg, 0.59 mmol). The mixture was stirred in a microwave oven at 60 o C for 1 hour. The mixture was concentrated in vacuo and purified by column chromatography on silica gel (PE:EA from 100 / 0 to 0 / 100) to give 5-({1-[({3-[1-(5-bromopyrimidin-2-yl)tetrahydro-1H-pyrrol-3-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (180 mg, 0.27 mmol, 68.77%) as an orange oil. ESI-MS m / z: 665.1 [M+H] + .

[0454] Step 2: To a solution of 5-({1-[({3-[1-(5-bromopyrimidin-2-yl)tetrahydro-1H-pyrrol-3-yl]- 1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-2H,3H-1,2-diazin-3-one (180 mg, 0.27 mmol) in DMF (3 ml) was added Zn(CN)2(127.04 mg, 1.08 mmol), XPHOS (25.79 mg, 0.05 mmol), Zn (5.31 mg, 0.08 mmol) and Pd2(dba)3(21.89 mg, 0.03 mmol). The reaction was stirred at 110 °C under N2atmosphere for 2 hours. The reaction was diluted with dichloromethane and water. The organic layer was separated and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE:EA=10:1-1:10) to give 2-{3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-1,2-diazin-4-yl}amino)propan-2-yl]oxy}methyl)-1,2,4-oxadiazol-3-yl] tetrahydro-1H-pyrrol-1-yl}pyrimidine-5-carbonitrile (80 mg, 0.13 mmol, 48.49%) orange oil. ESI-MS m / z: 612.2 [M+H] o Step 2: To a solution of 5-({1-[({3-[1-(5-bromopyrimidin-2-yl)tetrahydro-1H-pyrrol-3-yl]- 1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-2H,3H-1,2-diazin-3-one (180 mg, 0.27 mmol) in DMF (3 ml) was added Zn(CN)2(127.04 mg, 1.08 mmol), XPHOS (25.79 mg, 0.05 mmol), Zn (5.31 mg, 0.08 mmol) and Pd2(dba)3(21.89 mg, 0.03 mmol). The reaction was stirred at 110 °C under N2atmosphere for 2 hours. The reaction was diluted with dichloromethane and water. The organic layer was separated and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE:EA=10:1-1:10) to give 2-{3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-1,2-diazin-4-yl}amino)propan-2-yl]oxy}methyl)-1,2,4-oxadiazol-3-yl] tetrahydro-1H-pyrrol-1-yl}pyrimidine-5-carbonitrile (80 mg, 0.13 mmol, 48.49%) orange oil. ESI-MS m / z: 612.2 [M+H] + .

[0455] Step 3: To a solution of 2-{3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-1,2-diazin-4-yl}amino)propan-2-yl]oxy}methyl)-1,2,4-oxadiazol-3-yl] tetrahydro-1H-pyrrol-1-yl}pyrimidine-5-carbonitrile (80 mg, 0.13 mmol) in TFA (2.5 ml, 32.67 mmol) was added TfOH (0.5 ml, 5.66 mmol), the reaction turned red in color, the mixture was stirred at room temperature for 10 minutes. The reaction was quenched with saturated Na2CO3, adjusted pH = 7-8, then extracted with DCM (20 ml*2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 2-[3-(5-{[(2-{[3-oxo-4- (trifluoromethyl)-2H-1,2-diazin-5-yl]amino}propan-2-yl)oxy]methyl}-1,2,4-oxadiazol-3-yl) tetrahydro-1H-pyrrol-1-yl]pyrimidine-5-carbonitrile (13 mg, 0.03 mmol, 20.22%) white solid. ESI-MS m / z: 492.2 [M+H]+ . 1 H NMR (400 MHz, CDCl3) δ11.33 (s, 1H), 8.53 (s, 2H), 7.70 (s,1H), 5.84 – 5.72 (m, 1H), 4.77 (d, J =15.2 Hz, 2H), 4.13 – 3.98 (m,2H), 3.95 – 3.84 (m, 2H), 3.83 – 3.70 (m, 3H),3.66 (dd, J = 9.2, 5.4Hz, 1H), 2.54 – 2.33 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H)。

[0456] Example 40: Synthesis of 6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1- yl)nicotinaldehyde

[0457] To a solution of 5-(1-((3-(1-(5-(difluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-1,2,4- oxadiazol-5-yl)methoxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one (50 mg, 0.097 mmol) in H2O (5 mL) was added K2CO3(26.22 mg, 0.19 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and purified by silica gel column chromatography (PE:EA from 100 / 0 to 0 / 100) to give 6-(3-(5-((2-(6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-ylamino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1- yl)nicotinaldehyde (41 mg, 0.083 mmol, 85.67%) as a white solid. ESI-MS m / z: 494.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ 10.52 (s, 1H), 9.79 (s, 1H), 8.58 (d, J= 2.0 Hz, 1H), 7.94 (dd,J = 8.9, 2.2 Hz, 1H), 7.68 (s, 1H), 6.46 (d, J= 8.9 Hz, 1H), 5.76 (s, 1H),4.79 (s, 2H), 4.01 (s, 2H), 3.93 – 3.60(m, 6H), 2.61 – 2.37 (m, 2H), 1.36 (d,J = 6.6 Hz, 3H)。

[0458] Example 41: Synthesis of 5-((1-((3-(1-(5-chloropyridin-2-yl)pyrrolidin-3-yl)-1,2,4- oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0459] Step 1: To a solution of 2-[(4-methoxyphenyl)methyl]-5-{[1-({[3-(tetrahydro-1H-pyrrol-3- yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}-4-(trifluoromethyl)-2H,3H-1,2- diazin-3-one (400 mg, 0.78 mmol) in MeCN (5 ml) was added K2CO3(217.42 mg, 1.58 mmol) and 5-chloro-2-fluoropyridine (310.4 mg, 2.36 mmol). The mixture was stirred at 80 o C overnight. The mixture was concentrated in vacuo and purified by column chromatography on silica gel (PE:EA from 100 / 0 to 0 / 100) to give 5-({1-[({3-[1-(5-chloropyridin-2-yl)tetrahydro-1H-pyrrol-3-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2- diazin-3-one (100 mg, 0.10 mmol, 20.67%) orange oil. ESI-MS m / z: 621.2 [M+H] + .

[0460] Step 2: To a solution of 5-({1-[({3-[1-(5-chloropyridin-2-yl)tetrahydro-1H-pyrrol-3-yl]- 1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-2H,3H-1,2-dioxazin-3-one (100 mg, 0.16 mmol) in TFA (2.5 ml, 32.67 mmol) was added TfOH (0.5 ml, 5.66 mmol). The reaction turned red in color. The mixture was stirred under constant temperature for 10 minutes. The reaction was quenched with saturated Na2CO3, adjusted pH = 7 - 8, then extracted with DCM (100 ml*2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-({1-[({3-[1-(5-chloropyridin-2-yl)tetrahydro-1H-pyrrol-3-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-2H,3H-1,2-dioxazin-3-one (14 mg, 0.03 mmol, 17.37%) white solid. ESI-MS m / z: 500.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 11.68 (s, 1H), 8.09 (d, J = 2.4 Hz,1H), 7.69 (s, 1H), 7.39 (dd,J = 8.9, 2.5 Hz, 1H), 6.33 (d, J = 8.9 Hz,1H), 5.87 – 5.69 (m, 1H), 4.78 (s,2H), 4.01 (s, 1H), 3.94 – 3.85 (m,1H), 3.82 – 3.62 (m, 5H), 3.60 – 3.51 (m,1H), 2.54 – 2.32 (m, 2H),1.35 (d, J = 6.6 Hz, 3H)。

[0461] Example 42: Synthesis of 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4- yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1-yl)thiazole-5-carbaldehyde

[0462] Step 1 : To a solution of 2-[(4-methoxyphenyl)methyl]-5-{[l-({[3-(tetrahydro-lH- pyrrol-3-yl)-l,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}-4-(trifluoromethyl)- 2H,3H-l,2-dioxazin-3-one (200 mg, 0.39 mmol) in MeCN (3 mL) was added K2CO3 (108.71 mg, 0.79 mmol) and 2-chloro-l,3-thiazole-5-carbaldehyde (87.07 mg, 0.59 mmol). The mixture was stirred at 80 °C overnight. The mixture was concentrated in vacuo and purified by silica gel column chromatography (PE:EA from 100 / 0 to 0 / 100) to give 2-{3-[5-({[2-({l-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-l,2-dioxazin-4-yl}amino)propan-2-yl]oxy}methyl)-l,2,4-oxadiazol-3-yl]tetrahydro-lH-pyrrol-l-yl}-l,3- thiazole-5-carbaldehyde (150 mg, 0.24 mmol, 61.55%) as orange oil. ESI-MS m / z: 620.2 [M+H] o C Under stirring at room temperature for 10 minutes. The mixture was concentrated in vacuo and purified by silica gel column chromatography (PE:EA from 100 / 0 to 0 / 100) to give 2-{3-[5-({[2-({l-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-l,2-dioxazin-4-yl}amino)propan-2-yl]oxy}methyl)-l,2,4-oxadiazol-3-yl]tetrahydro-lH-pyrrol-l-yl}-l,3- thiazole-5-carbaldehyde (150 mg, 0.24 mmol, 61.55%) as orange oil. ESI-MS m / z: 620.2 [M+H] + .

[0463] Step 2: To a solution of 2-{3-[5-({[2-({l-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-l,2-dioxazin-4-yl}amino)propan-2-yl]oxy}methyl)-l,2,4-oxadiazol-3-yl]tetrahydro-lH-pyrrol-l-yl}-l,3-thiazole-5-carbaldehyde (150 mg, 0.24 mmol) in TFA (2 ml, 26.14 mmol) was added TfOH (0.5 ml, 5.66 mmol) and the reaction mixture turned red. The mixture was stirred at room temperature for 10 minutes. The reaction was quenched with saturated Na2CO3 and the pH was adjusted to 7-8, then extracted with DCM (100 mL*2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 2-[3-(5-{[(2-{[6-oxo-5-(trifluoromethyl)-lH-l,2-dioxazin-4-yl]amino}propan-2-yl)oxy]methyl}-l,2,4-oxadiazol-3-yl)tetrahydro-lH-pyrrol-l-yl]-l,3-thiazole-5-carbaldehyde (40 mg, 0.08 mmol, 33.08%) as a white solid. ESI-MS m / z: 500.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ 11.64 (s, 1H), 9.69 (s, 1H), 7.91 (s,1H), 7.70 (s, 1H), 5.88 –5.64 (m, 1H), 4.80 (s, 2H), 4.02 (d, J = 5.3Hz, 2H), 3.83 (ddd, J = 14.9, 13.0, 8.7 Hz, 4H), 3.67 (dd, J = 9.2,5.4 Hz, 2H), 2.64 – 2.39 (m, 2H), 1.36(d, J = 6.6 Hz, 3H)。

[0464] Example 43: Synthesis of 5-((1-((3-((1-(5-(difluoromethyl)pyridin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0465] Step 1: 5-(1-((3-(azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)-2-(4- methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride (400 mg, 0.76 mmol), K2CO3(207.32 mg, 1.50 mmol), 6-fluoronicotinaldehyde (187.65 mg, 1.50 mmol) and MeCN (8 mL) were added into a 20 mL microwave tube. The resulting mixture was stirred at 80 °C overnight. The reaction mixture was concentrated and purified by column chromatography (PE : EA = 10:1 to 0:1) to give 6-(3-(5-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)nicotinaldehyde (350 mg, 0.58 mmol, 76.32%) as orange oil. ESI-MS m / z: 599.7 [M+H] + .

[0466] Step 2: To a stirred solution of 6-(3-(5-((2-((1-(4-methoxybenzyl)-6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3- yl)azetidin-1-yl)nicotinaldehyde (250 mg, 0.42 mmol) in DCM (20 mL) was added DAST (1.02 g, 63 mmol). The resulting mixture was stirred at 25 °C overnight. The reaction was concentrated and purified by column chromatography (PE: EA = 10: 1 ~ 0: 1) to give 5-((1-((3-(1-(5-(difluoromethyl)pyridin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5- yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)- one (200 mg, 0.32 mmol, 76.19%) as orange oil. ESI-MS m / z: 621.7 [M+H] + .

[0467] Step 3: To a stirred solution of 5-((1-((3-((1-(5-(difluoromethyl)pyridin-2-yl)azetidin-3- yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4- (trifluoromethyl)pyridazin-3(2H)-one (200 mg, 0.32 mmol) in 2,2,2-trifluoroacetic acid (2.5 mL) was added trifluoromethanesulfonic acid (0.5 mL), the reaction mixture turned red in color. The mixture was stirred at constant temperature for 10 minutes. The reaction was quenched with saturated Na2CO3, adjusted pH = 7 - 8, then extracted with dichloromethane (10 mL*2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA = 10 : 1 to 0 : 1) to give 5-((1-((3-(1-(5-(difluoromethyl)pyridin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5- yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (65.58 mg, 0.13 mmol, 41.63%) as white solid. ESI-MS m / z: 501.7 [M+H] + . 1H NMR (400 MHz, CDC13) δ 10.65 (s, 1H), 8.25 (s, 1H), 7.67 (s, 1H), 7.62 (d, J = 8.7 Hz, 1H), 6.58 (t, J = 56.3 Hz, 1H), 6.37 (d, J = 8.6 Hz, 1H), 5.76 (s, 1H), 4.81 (s, 2H), 4.49 (t, J = 8.3 Hz, 2H), 4.31 (dd, J = 10.1, 3.9 Hz, 2H), 4.23 - 4.13 (m, 1H), 4.00 (s, 1H), 3.78 (dd, J = 9.2, 4.0 Hz, 1H), 3.66 (dd, J = 9.2, 5.5 Hz, 1H), 1.35 (d, J = 6.6 Hz, 3H).

[0468] Example 44: Synthesis of 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1- yl)thiazole-4-carbaldehyde

[0469] Step 1: 5-(1-((3-(azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)- 2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride (200 mg, 0.38 mmol), K2CO3(103.66 mg, 0.75 mmol), 2-chlorothiazole-4-carbaldehyde (110.21 mg, 0.75 mmol) and MeCN (8 mL) were added into a 20 mL microwave tube. The resulting mixture was stirred at 80 °C overnight. The reaction mixture was purified by column chromatography (PE:EA = 10:1 to 0:1) to give 2-(3-(5-((2-((1-(4-methoxybenzyl)-6-oxo-5- (trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3- yl)azetidin-1-yl)thiazole-4-carbaldehyde (103 mg, 0.17 mmol, 44.74%). ESI-MS m / z: 605.7 [M+H] + .

[0470] Step 2: To a solution of 2-(3-(5-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1- yl)thiazole-4-carbaldehyde (103 mg, 0.17 mmol) in 2,2,2-trifluoroacetic acid (2.5 mL) was added trifluoromethanesulfonic acid (0.5 mL). The reaction turned red in color. The mixture was stirred at room temperature for 10 min. The reaction was quenched with saturated Na2CO3, adjusted pH = 7-8, then extracted with dichloromethane (10 mL*2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-((1-((3-(1-(5-(difluoromethyl)pyridin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5- yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (5.19 mg, 0.01 mmol, 5.88%) white solid. ESI-MS m / z: 485.7 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 10.59(s, 1H), 9.72 (s, 1H), 7.68 (s,1H), 7.53 (s, 1H), 5.75 (s, 1H), 4.81 (s, 2H),4.55 (td, J = 8.4, 2.2Hz, 2H), 4.46 – 4.34 (m, 2H), 4.25 (ddd, J = 14.6, 8.5,6.1 Hz, 1H),4.01 (s, 1H), 3.79 (dd, J = 9.2, 3.9 Hz, 1H), 3.67 (dd, J = 9.2,5.5Hz, 1H), 1.36 (d, J = 6.6 Hz, 3H)。

[0471] Example 45: Synthesis of 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4- yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1-yl)thiazole-4-carbaldehyde

[0472] Step 1 : To a solution of 2-[(4-methoxyphenyl)methyl]-5-{[l-({[3-(tetrahydro-lH- pyrrol-3-yl)-l,2,4-oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}-4-(trifluoromethyl)- 2H,3H-l,2-dioxazin-3-one (200 mg, 0.39 mmol) in MeCN (3 ml) was added K2CO3(108.71 mg, 0.79 mmol) and 2-chloro-l,3-thiazole-4-carbaldehyde (87.07 mg, 0.59 mmol). The mixture was stirred at 80 °C overnight. The mixture was concentrated in vacuum and purified by silica gel column chromatography (PE:EA from 100 / 0 to 0 / 100) to give 2-{3-[5-({[2-({l-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-l,2-dioxazin-4-yl}amino)propan-2-yl]oxy}methyl)-l,2,4-oxadiazol-3-yl]tetrahydro-lH-pyrrol-l-yl}-l,3- thiazole-4-carbaldehyde (110 mg, 0.18 mmol, 45.14%) as orange oil. ESI-MS m / z: 620.2 [M+H] o C Under stirring at room temperature for 10 minutes. The mixture was concentrated in vacuum and purified by silica gel column chromatography (PE:EA from 100 / 0 to 0 / 100) to give 2-{3-[5-({[2-({l-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-l,2-dioxazin-4-yl}amino)propan-2-yl]oxy}methyl)-l,2,4-oxadiazol-3-yl]tetrahydro-lH-pyrrol-l-yl}-l,3- thiazole-4-carbaldehyde (110 mg, 0.18 mmol, 45.14%) as orange oil. ESI-MS m / z: 620.2 [M+H] + .

[0473] Step 2: To a solution of 2-{3-[5-({[2-({l-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-l,2-dioxazin-4-yl}amino)propan-2-yl]oxy}methyl)-l,2,4-oxadiazol-3-yl]tetrahydro-lH-pyrrol-l-yl}-l,3-thiazole-4-carbaldehyde (110 mg, 0.18 mmol) in TFA (2 ml, 26.14 mmol) was added TfOH (0.5 ml, 5.66 mmol) and the reaction mixture turned red in color. The mixture was stirred at room temperature for 10 minutes. The reaction was quenched with saturated Na2CO3and the pH was adjusted to 7-8, then extracted with DCM (100 ml*2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 2-[3-(5-{[(2-{[6-oxo-5-(trifluoromethyl)-lH-l,2-dioxazin-4-yl]amino}propan-2-yl)oxy]methyl}-l,2,4-oxadiazol-3-yl)tetrahydro-lH-pyrrol-l-yl]-l,3-thiazole-4-carbaldehyde (10 mg, 0.02 mmol, 11.28%) as white solid. ESI-MS m / z: 499.7 [M+H] + . 1H NMR (400MHz, CDCl3) δ 11.49 (s, 1H), 9.70 (s, 1H), 7.70 (d, J= 3.9 Hz, 1H), 7.44 (s,1H), 5.82 – 5.69 (m, 1H), 4.79 (d, J = 2.0Hz, 2H), 3.99 (dd, J = 10.1, 7.7Hz, 2H), 3.89 – 3.70 (m, 4H), 3.65(dt, J = 9.6, 7.1 Hz, 2H), 2.60 – 2.37 (m,2H), 1.36 (d, J = 6.6 Hz,3H)。

[0474] Example 46: Synthesis of 5-((1-((3-(1-(5-chlorothiazol-2-yl)pyrrolidin-3-yl)-1,2,4- oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0475] Step 1: 2-[(4-methoxyphenyl)methyl]-5-{[1-({[3-(tetrahydro-1H-pyrrol-3-yl)-1,2,4- oxadiazol-5-yl]methyl}oxy)propan-2-yl]amino}-4-(trifluoromethyl)-2H,3H-1,2-diazin-3- one (250 mg, 0.49 mmol), Cs2CO3(320.37 mg, 0.98 mmol), XANT PHOS (56.90 mg, 0.10 mmol), Pd2(dba)3(45.02 mg, 0.05 mmol), 2-bromo-4-chloro-1,3-thiazole (146.36 mg, 0.74 mmol) and 1,4-dioxane (3 mL) were added into a 20 mL microwave tube. The resulting mixture was stirred at 100 °C overnight. The reaction mixture was diluted with H2O (10 mL), washed with EA (10 mL*2). The EA layer was dried over Na2SO4, filtered and concentrated, purified by FCC (PE:EA = 10: 1 to 0:1) to give 5-({1-[({3-[1-(5-chloro-1,3-thiazol-2-yl)tetrahydro-1H-pyrrol-3-yl]-1,2,4- oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (120 mg, 0.04 mmol, 7.80%) yellow oil. ESI-MS m / z: 626.1 [M+H] +.

[0476] Step 2: To the stirred 5-({1-[({3-[1-(5-chloro-1,3-thiazol-2-yl)tetrahydro-1H-pyrrol-3-yl]- 1,2,4-oxadiazol-5-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (120 mg, 0.04 mmol) in TFA (2 ml, 26.14 mmol) was added TfOH (0.5 ml, 5.66 mmol) and the reaction color turned red. The mixture was stirred at room temperature for 10 min. The reaction was quenched with saturated Na2CO3, pH was adjusted to 7-8 and then extracted with DCM (20 ml*2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-({1-[({3-[1-(5-chloro-1,3-thiazol-2-yl)tetrahydro-1H-pyrrol-3-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (9.5 mg, 0.02 mmol, 48.98%) as white solid. ESI-MS m / z: 506.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.15 (s, 1H), 7.69 (s, 1H), 7.00 (s,1H), 5.85 –5.68 (m, 1H), 4.79 (s, 2H), 4.01 (s, 1H), 3.92 – 3.81 (m,1H), 3.76 (ddd, J =20.5, 9.1, 5.1 Hz, 3H), 3.69 – 3.60 (m, 2H), 3.55(dt, J = 9.7, 7.3 Hz, 1H),2.55 – 2.36 (m, 2H), 1.36 (d, J = 6.6 Hz,3H)。

[0477] Example 47: Synthesis of 4-(trifluoromethyl)-5-((1-((3-(1-(6-(trifluoromethyl)pyridazin-3- yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0478] Step 1: 5-(1-((3-(azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)- 2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride (150 mg, 0.28 mmol), K2CO3(77.40 mg, 0.56 mmol), 3-chloro-6-trifluoromethylpyridazine (187.65 mg, 1.50 mmol) and MeCN (8 mL) were added into a 20 mL microwave tube, the resulting mixture was stirred at 80 °C overnight. The reaction mixture was purified by column chromatography (PE : EA = 10 : 1 ~ 0 : 1) to give 2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-((3-(1-(6- (trifluoromethyl)pyridazin-3-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one (100 mg, 0.16 mmol, 57.14%). ESI-MS m / z: 640.7 [M+H] + .

[0479] Step 2: To a solution of 2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-((3-(1-(6- (trifluoromethyl)pyridazin-3-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one (100 mg, 0.16 mmol) in 2,2,2-trifluoroacetic acid (2.5 mL) was added trifluoromethanesulfonic acid (0.5 mL), the reaction mixture turned red in color. The mixture was stirred at room temperature for 10 minutes. The reaction was quenched with saturated Na2CO3, adjusted pH = 7 - 8, then extracted with dichloromethane (10 mL*2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-((1-((3-(1-(5-(difluoromethyl)pyridin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5- yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (50.13 mg, 0.10 mmol, 62.50%) as a white solid. ESI-MS m / z: 521.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ11.34 (s, 1H), 7.70 (s, 1H), 7.50 (d, J= 9.3 Hz, 1H), 6.66 (d, J = 9.3 Hz,1H), 5.84 – 5.65 (m, 1H), 4.82(s, 2H), 4.63 (td, J = 8.6, 4.2 Hz, 2H), 4.47(t, J = 7.0 Hz, 2H), 4.34– 4.21 (m, 1H), 4.02 (s, 1H), 3.80 (dd, J = 9.2, 3.9Hz, 1H), 3.67(dd, J = 9.2, 5.6 Hz, 1H), 1.36 (d, J = 6.6 Hz, 3H).

[0480] Example 48: Synthesis of 5-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azacyclobutane-1-yl)pyridinenitrile

[0481] Step 1: Add K₂CO₃ (52.06 mg, 0.38 mmol) and 5-fluoropyridine-2-carboxynitrile (45.99 mg, 0.38 mmol) to a MeCN (3 mL) solution of 5-(1-((3-(azacyclobutan-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propyl-2-ylamino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazine-3(2H)-one hydrochloride (100 mg, 0.19 mmol) and 5-fluoropyridine-2-carboxynitrile (45.99 mg, 0.38 mmol). The mixture was heated at 80 °C. o The mixture was stirred overnight at C. The mixture was concentrated under vacuum and purified by silica gel column chromatography (PE: EA from 100 / 0 to 0 / 100) to give 5-{3-[5-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,4-oxadiazol-3-yl]azacyclobutane-1-yl}pyridine-2-carboxynitrile (68 mg, 0.11 mmol, 60.52%) as an orange oil. ESI-MS m / z: 597.2 [M+H] + .

[0482] Step 2: To a solution of 5-(l-((3-(azetidin-3-yl)-l,2,4-oxadiazol-5-yl)methoxy)propan-2- ylamino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one hydrochloride (100 mg, 0.19 mmol) in MeCN (3 mL) was added K2CO3(52.06 mg, 0.38 mmol) and 5-fluoropyridine-2-carbonitrile (45.99 mg, 0.38 mmol). The mixture was stirred at 80 °C overnight. The mixture was concentrated in vacuo and purified by silica gel column chromatography eluting with (PE:EA from 100 / 0 to 0 / 100) to give 5-{3-[5-({[2-({l-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-l,2-diazin-4-yl}amino)propyl]oxy}methyl)-l,2,4-oxadiazol-3-yl]azetidin-l-yl}pyridine-2-carbonitrile (68 mg, 0.11 mmol, 60.52%) as orange oil. ESI-MS m / z: 476.7 [M+H] o C Under stirring at 80 °C overnight. The mixture was concentrated in vacuo and purified by silica gel column chromatography eluting with (PE:EA from 100 / 0 to 0 / 100) to give 5-{3-[5-({[2-({l-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-l,2-diazin-4-yl}amino)propyl]oxy}methyl)-l,2,4-oxadiazol-3-yl]azetidin-l-yl}pyridine-2-carbonitrile (68 mg, 0.11 mmol, 60.52%) as orange oil. ESI-MS m / z: 476.7 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.47 (s, 1H), 7.96 (d, J = 2.8 Hz,1H), 7.93(s, 1H), 7.74 (d, J = 8.6 Hz, 1H), 6.94 (dd, J = 8.6, 2.8 Hz,1H), 6.33 (dd, J= 8.3, 4.0 Hz, 1H), 4.88 (s, 2H), 4.46 (t, J = 8.2 Hz,2H), 4.25 (td, J = 8.3,5.2 Hz, 2H), 4.17 (dd, J = 7.8, 5.8 Hz, 2H),3.65 (d, J = 5.7 Hz, 2H), 1.17(d, J = 6.5 Hz, 3H)。

[0483] Example 49: Synthesis of 4-(trifluoromethyl)-5-((l-((l-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-lH-l,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0484] Step 1 : To a solution of 5-{[1-({[1-(hexahydropyridin-4-yl)-1,2,3-triazol-4- yl]methyl}oxy)propan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (100 mg, 0.19 mmol) and potassium carbonate (78.77 mg, 0.57 mmol) in MeCN (5 mL) was added 2-chloro-5- (trifluoromethyl)pyrimidine (69.36 mg, 0.38 mmol). The reaction was stirred at RT for 1 h. The reaction was concentrated and purified by silica gel column chromatography (PE / EtOAc from 100 / 0 to 50 / 50) to give 2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-5-[(1-{[(1-{1-[5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridin- 4-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-3H,2H-1,2-diazin-3-one (100 mg, 0.15 mmol, 78.12%) as a light yellow oil. LCMS ESI: 667.7 [M+H] + .

[0485] Step 2: To a solution of 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(1-{1- [5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridin-4-yl}-1,2,3-triazol-4-yl)methyl]oxy} propan-2-yl)amino]-3H,2H-1,2-diazin-3-one (140 mg, 0.21 mmol) in trifluoroacetic acid (2 mL) was added trifluoromethanesulfonic acid (0.5 mL) and the reaction mixture turned red in color. The mixture was stirred at RT for 10 min. The reaction was quenched with saturated aqueous NaHC03solution, pH was adjusted to 7-8 and then extracted with DCM (100 mL*2). The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by Prep-HPLC to give 4-(trifluoromethyl)-5-[(1-{[(1-{1-[5- (trifluoromethyl)pyrimidin-2-yl]hexahydropyridin-4-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan- 2-yl)amino]-3H,2H-1,2-diazin-3-one (47 mg, 0.09 mmol, 40.94%) as a white solid. LCMS ESI: 547.7 [M+H] + . 1H NMR (400MHz, CDCl3) δ 11.11 (s, 1H), 8.52 (s, 2H), 7.65 (s, 1H), 7.52 (s, 1H), 5.78 –5.66 (m, 1H), 5.01 (d, J = 13.7 Hz, 2H), 4.82 – 4.72 (m, 1H), 4.72 – 4.63 (m,2H), 3.94 (s, 1H), 3.71 (dd, J = 9.6, 3.8 Hz, 1H), 3.55 (dd, J = 9.6, 5.5 Hz,1H), 3.28 –3.13 (m, 2H), 2.32 (d, J = 9.9 Hz, 2H), 2.12 – 1.94 (m, 2H), 1.30 (d, J = 6.6 Hz, 3H).

[0486] Example 50: Synthesis of 5-((1-((1-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one

[0487] Step 1: Add 2-chloro-5-fluoropyrimidine (50.82 mg, 0.38 mmol) to a MeCN (5 ml) solution of 5-{[1-({[1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]methyl}oxy)propyl-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (100 mg, 0.19 mmol) and potassium carbonate (79.49 mg, 0.58 mmol), and react at 60 °C. o The mixture was stirred at C for 24 hours. The reaction mixture was concentrated and purified by column chromatography on silica gel (PE / EtOAc, concentrations from 100 / 0 to 80 / 20) to give 5-({1-[({1-[1-(5-fluoropyrimidin-2-yl)hexahydropyridin-4-yl]-1,2,3-triazol-4-yl}methyl)oxy]propyl-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (70 mg, 0.11 mmol, 59.11%), a pale yellow oil. LCMS ESI: 617.8 [M + H] + .

[0488] Step 2: To a stirred solution of 5-({1-[({1-[1-(5-fluoropyrimidin-2-yl)hexahydropyridin-4- yl]-1,2,3-triazol-4-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (70 mg, 0.11 mmol) in trifluoroacetic acid (2 mL) was added trifluoromethanesulfonic acid (0.5 mL) and the reaction mixture turned red in color. The mixture was stirred at RT for 10 min. The reaction was quenched with saturated aqueous NaHCO3solution, pH was adjusted to 7-8 and then extracted with DCM (100 mL*2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-({1-[({1-[1-(5-fluoropyrimidin-2-yl)hexahydropyridin-4-yl]-1,2,3-triazol-4- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (16 mg, 0.03 mmol, 28.38%) as a white solid. LCMS ESI: 497.7 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 10.60 (s, 1H), 8.22 (s, 2H), 7.64 (s, 1H), 7.51 (s, 1H), 5.84 - 5.63 (m, 1H), 4.84 (d, J = 13.6 Hz, 2H), 4.73 (ddd, J = 11.5, 7.8, 3.4 Hz, 1H), 4.70 - 4.63 (m, 2H), 3.93 (s, 1H), 3.70 (dd, J = 9.6, 3.9 Hz, 1H), 3.55 (dd, J = 9.6, 5.5 Hz, 1H), 3.21 - 3.05 (m, 2H), 2.35 - 2.23 (m, 2H), 2.11 - 1.94 (m, 2H), 1.30 (d, J = 6.6 Hz, 3H).

[0489] Example 51: Synthesis of 4-(trifluoromethyl)-5-((1-((1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4- yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0490] Step 1 : To a solution of 5-{[1-({[1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]methyl}oxy)propan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (100 mg, 0.19 mmol) and potassium carbonate (79.49 mg, 0.58 mmol) in MeCN (5 mL) was added 2-fluoro-5-(trifluoromethyl)pyridine (47.48 mg, 0.29 mmol). The reaction was stirred at 60 °C for 24 h. The reaction was concentrated and purified by column chromatography on silica gel (PE / EtOAc, concentration from 100 / 0 to 80 / 20) to give 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(1-{1-[5-(trifluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-3H,2H-1,2-diazin-3-one (66 mg, 0.10 mmol, 51.64%) as a yellowish oil. LCMS ESI: 666.7 [M + H] o . + .

[0491] Step 2: To a solution of 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(1-{1-[5-(trifluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-3H,2H-1,2-diazin-3-one (66 mg, 0.10 mmol) in trifluoroacetic acid (2 mL) was added trifluoromethanesulfonic acid (0.5 mL) and the reaction mixture turned red in color. The mixture was stirred at room temperature for 10 min. The reaction was quenched with saturated aqueous NaHC03solution, pH was adjusted to 7-8 and then extracted with dichloromethane (100 mL*2). The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by Prep-HPLC to give 4-(trifluoromethyl)-5-[(1-{[(1-{1-[5-(trifluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-3H,2H-1,2-diazin-3-one (16 mg, 0.03 mmol, 29.57%) as a white solid. LCMS ESI: 546.7 [M + H] + . 1H NMR(400 MHz, CDCl3) δ 10.87 (s, 1H), 8.42 (s, 1H), 7.66 (dd, J = 9.8, 3.2 Hz,2H), 7.51 (s, 1H), 6.73 (d, J = 9.0 Hz, 1H), 5.78 – 5.61 (m, 1H), 4.82 – 4.62(m, 3H), 4.57 (d, J = 13.7 Hz, 2H), 3.94 (s, 1H), 3.71 (dd, J = 9.6, 3.8 Hz,1H), 3.55 (dd, J = 9.6, 5.6 Hz, 1H), 3.25 – 3.08 (m, 2H), 2.32 (d, J = 9.6Hz, 2H), 2.07 (td, J = 11.7, 3.3 Hz, 2H), 1.30 (d, J = 6.6 Hz, 3H).

[0492] Example 52: Synthesis of 6-(4-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)nicotinonitrile

[0493] Step 1: To a solution of 5-{[1-({[1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]methyl}oxy)propyl-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (100 mg, 0.19 mmol) and potassium carbonate (78.77 mg, 0.57 mmol) in MeCN (5 mL), 6-fluoropyridin-3-carboxynitrile (35.12 mg, 0.29 mmol) was added. The reaction was carried out at 60 °C. o Stirred at C for 1 hour. The reaction mixture was concentrated and purified by column chromatography on silica gel (PE / EtOAc from 100 / 0 to 90 / 10) to give 6-{4-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]hexahydropyridin-1-yl}pyridine-3-carboxylonitrile (90 mg, 0.14 mmol, 75.27%), a pale yellow oil. LCMS ESI: 623.8 [M + H] + .

[0494] Step 2: To a solution of 6-{4-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]hexahydropyridin-1-yl}pyridine-3-carbonitrile (90 mg, 0.14 mmol) in trifluoroacetic acid (2 mL) was added trifluoromethanesulfonic acid (0.5 mL) and the reaction mixture turned red in color. The mixture was stirred at RT for 10 min. The reaction was quenched with saturated aqueous NaHCO3solution, pH was adjusted to 7-8 and then extracted with DCM (100 mL*2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 6-[4-(4-{[(2-{[6-oxo-5-(trifluoromethyl)-1H-1,2-diazin-4-yl]amino}propyl)oxy]methyl}-1,2,3-triazol-1-yl)hexahydropyridin-1-yl]pyridine-3-carbonitrile (22 mg, 0.04 mmol, 30.28%) as a white solid. LCMS ESI: 503.7 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.02 (s,1H), 8.43 (d, J = 2.2 Hz, 1H), 7.70 – 7.61 (m, 2H), 7.51 (s, 1H), 6.70 (d, J= 9.0 Hz, 1H), 5.79 – 5.61 (m, 1H), 4.75 (ddd, J = 11.3, 7.2, 4.2 Hz, 1H),4.71 – 4.63 (m, 2H), 4.58 (d, J = 13.7 Hz, 2H), 3.95 (s, 1H), 3.72 (dd, J =9.6, 3.8 Hz, 1H), 3.55 (dd, J = 9.6, 5.7 Hz, 1H), 3.28 – 3.14 (m, 2H), 2.33(d, J = 9.7 Hz, 2H), 2.06 (ddd, J = 23.6, 11.9, 3.9 Hz, 2H), 1.31 (d, J = 6.6Hz, 3H)。

[0495] Example 53: Synthesis of 5-((1-((3-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0496] Step 1: 5-{[1-({[1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]methyl}oxy)propan-2-yl]amino}- 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (110 mg, 0.21 mmol), 2-chloro-5-methyl-1,3-thiazole (38.4 mg, 0.3 mmol), potassium carbonate (87.44 mg, 0.63 mmol) and DMF (2 mL) were added into a 10 mL microwave tube. The mixture was reacted at 80 °C for 1 h. The reaction mixture was diluted with H2O (10 mL) and washed with EA (10 mL*2). The EA layer was dried over Na2SO4, filtered and concentrated, purified by FCC (PE:EA=10:1·0:1) to give 2-{4-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propan-2-yl]oxy}methyl)-1,2,3-triazol-1-yl]hexahydropyridin-1-yl}-1,3-thiazole-5-carbonitrile (100 mg, 0.14 mmol, 68.52%) yellow oil. LCMS ESI: 629.7 [M + H] + .

[0497] Step 2: 2-{4-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propan-2-yl]oxy}methyl)-1,2,3-triazol-1-yl]hexahydropyridin-1-yl}-1,3-thiazole-5-carbonitrile (100 mg, 0.16 mmol) was added into TFA (1 ml, 13.07 mmol) and TfOH (0.2 ml, 2.27 mmol). The resulting mixture was stirred at room temperature for 1 h. Purified by Prep-HPLC to give 2-[4-(4-{[(2-{[6-oxo-5-(trifluoromethyl)-1H-1,2-diazin-4-yl]amino}propan-2-yl)oxy]methyl}-1,2,3-triazol-1-yl)hexahydropyridin-1-yl]-1,3-thiazole-5-carbonitrile (18.6 mg, 0.03 mmol, 21.61%) white solid. LCMS ESI: 509.7 [M + H] + . 1HNMR (400 MHz, CDC13) δ 11.05 (s, 1H), 7.70 (s, 1H), 7.66 (s, 1H), 7.51 (s, 1H), 5.76 - 5.63 (m, 1H), 4.78 - 4.66 (m, 3H), 4.19 (d, J = 13.6 Hz, 2H), 3.96 (s, 1H), 3.73 (dd, J = 9.6, 3.7 Hz, 1H), 3.55 (dd, J = 9.6, 5.7 Hz, 1H), 3.44 - 3.34 (m, 2H), 2.41 - 2.30 (m, 2H), 2.19 (qd, J = 11.7, 4.4 Hz, 2H), 1.31 (d, J = 6.6 Hz, 3H).

[0498] Example 54: Synthesis of 5-((1-((1-(1-(5-methylthiazol-2-yl)piperidin-4-yl)-1H-1,2,3- triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0499] Step 1: { [1-({ [1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]methyl}oxy)propan-2-yl] amino}-2-[(4- methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-dioxin-3-one (100 mg, 0.19 mmol), 2-bromo-5- methyl-1,3-thiazole (51.21 mg, 0.29 mmol), tris[(1E,4E)-1,5-diphenylpenta-1,4-dien-3-yl]bis[palladium(0)] (17.56 mg, 0.02 mmol), [5-(diphenylphosphoroxy)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (22.19 mg, 0.04 mmol), Cs2CO3 (187.41 mg, 0.58 mmol) and dioxane (3 ml) were added into a 10 ml microwave tube. The resulting mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with H2O (10 ml), washed with EA (10 ml*2). The EA layer was dried over Na2SO4, filtered and concentrated, purified by FCC (PE : EA = 10 : 1 ~ 0 : 1) to give 2-[(4-methoxyphenyl)methyl]-5-({1-[({1-[1-(5-methyl-1,3-thiazol-2-yl)hexahydropyridin-4-yl]-1,2,3-triazol-4-yl}methyl)oxy]propan-2-yl}amino)-4- (trifluoromethyl)-3H,2H-1,2-dioxin-3-one (65 mg, 0.11 mmol, 54.80%) yellow oil. LCMS ESI: 618.7 [M + H] + .

[0500] Step 2: 2-[(4-methoxyphenyl)methyl]-5-({1-[({1-[1-(5-methyl-1,3-thiazol-2-yl)hexahydropyridin-4-yl]-1,2,3-triazol-4-yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-dioxin-3-one (60 mg, 0.10 mmol) was added into TFA (1 ml) and TfOH (0.2 ml, 2.61 mmol), the resulting mixture was stirred at room temperature for 1 h. Purified by Prep-HPLC to give 5-({1-[({1-[1-(5-methyl-1,3-thiazol-2-yl)hexahydropyridin-4-yl]-1,2,3-triazol-4-yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-dioxin-3-one (6 mg, 0.01 mmol, 12.41%) white solid. LCMS ESI: 498.7 [M + H]+ . 1 HNMR (400MHz, CDCl3)δ 10.18 (s, 1H), 7.64 (s, 1H), 7.51(s, 1H), 6.83 (d, J= 1.3 Hz, 1H),5.71 (s, 1H), 4.76 – 4.60 (m,3H), 4.09 (d, J = 13.3 Hz, 2H),3.94 (s, 1H), 3.71 (dd, J = 9.6, 3.9Hz, 1H), 3.54 (dd, J = 9.6, 5.6 Hz, 1H),3.23 – 3.11 (m, 2H), 2.35 – 2.07 (m, 7H), 1.31 (d, J = 6.6 Hz, 3H)。

[0501] Example 55: Synthesis of 5-((1-((1-(1-(thiazol-2-yl)piperidin-4-yl)-1H-1,2,3- triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0502] Step 1: 5-{[1-({[1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]methyl}oxy)propan-2-yl]amino}- 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (150 mg, 0.29 mmol), cesium carbonate (187.41 mg, 0.58 mmol), XANT PHOS (33.28 mg, 0.06 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (O) (26.34 mg, 0.03 mmol), 2-bromo-1,3-thiazole (94.35 mg, 0.58 mmol) were added in dioxane (8 ml) and the mixture was heated at 100 °C for 16 h. oC stirred overnight under N2 atmosphere. The reaction was concentrated and the residue was purified by silica gel column chromatography (PE / EtOAc from 100 / 0 to 0 / 100) to give 2-[(4-methoxyphenyl)methyl]-5-({1-[({1-[1-(1,3- thiazol-2-yl)hexahydropyridin-4-yl]-1,2,3-triazol-4-yl}methyl)oxy]propan-2-yl}amino)-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (85 mg, 0.14 mmol, 48.88%) yellow solid. LCMS ESI: 604.7 [M + H] + .

[0503] Step 2: To a stirred solution of 2-[(4-methoxyphenyl)methyl]-5-({1-[({1-[1-(1,3- thiazol-2-yl)hexahydropyridin-4-yl]-1,2,3-triazol-4-yl}methyl)oxy]propan-2-yl}amino)-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (85 mg, 0.14 mmol) in TFA (2 ml) was added triflic acid (0.5 ml) and the reaction mixture turned red in color. The mixture was stirred at RT for 10 min. The reaction was quenched with saturated aqueous NaHC03solution, pH was adjusted to 7-8 and then extracted with DCM (100 ml*2). The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by Prep-HPLC to give 5-({1-[({1-[1-(1,3-thiazol-2-yl)hexahydropyridin-4-yl]-1,2,3-triazol-4- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (6 mg, 0.01 mmol, 8.81%) white solid. LCMS ESI: 484.7 [M + H] + . 1H NMR (400 MHz, CDCl3) δ10.30 (s, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.21 (d, J = 3.6 Hz, 1H), 6.62 (d,J = 3.6 Hz, 1H), 5.71 (s, 1H), 4.75 – 4.60 (m, 3H), 4.18 (d, J = 13.3 Hz,2H), 3.94 (s, 1H), 3.71 (dd, J = 9.6, 3.8 Hz, 1H), 3.55 (dd, J = 9.6, 5.6 Hz,1H), 3.32 – 3.19 (m, 2H), 2.32 (dd, J = 14.4, 1.9 Hz, 2H), 2.25 – 2.10 (m,2H), 1.31 (d, J = 6.6 Hz, 3H).

[0504] Example 56: Synthesis of 4-(trifluoromethyl)-5-((1-((1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propyl-2-yl)amino)pyridazine-3(2H)-one

[0505] Step 1: Add 2-chloro-5-(trifluoromethyl)pyrimidine (55.48 mg, 0.30 mmol) and K2CO3 (83.89 mg, 0.61 mmol) to a solution of 5-{[1-({[1-(azacyclobutan-3-yl)-1,2,3-triazol-4-yl]methyl}oxy)propyl-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (100 mg, 0.20 mmol) in ACN (2 ml) and mix at 70 °C. o The mixture was stirred at C for 17 hours. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 100:1-1:100) to give 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(1-{1-[5-(trifluoromethyl)pyridin-2-yl]azacyclobutane-3-yl}-1,2,3-triazol-4-yl)methyl]oxy}propyl-2-yl)amino]-3H,2H-1,2-diazin-3-one (100 mg, 0.2 mmol, 77.2%). ESI-MS m / z: 639.6 [M+H] + .

[0506] Step 2: 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(1-{1-[5- (trifluoromethyl)pyridin-2-yl]azetidin-3-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2- yl)amino]-3H,2H-1,2-diazin-3-one (100 mg, 0.16 mmol) was taken in TFA (2 ml) and TfOH (0.5 ml) and the mixture was stirred at 25 °C for 17 h. To the mixture, saturated NaHCO3solution was added to adjust the pH to 7, the reaction was diluted with water and extracted with DCM. The combined organic layer was washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to get 4-(trifluoromethyl)-5-((1-((1-(5- (trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one (20 mg, 0.04 mmol, 24.64%) as white solid. ESI-MS m / z: 519.7 [M+H] o C under stirring for 17 h. To the mixture, saturated NaHCO3solution was added to adjust the pH to 7, the reaction was diluted with water and extracted with DCM. The combined organic layer was washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to get 4-(trifluoromethyl)-5-((1-((1-(5- (trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2- yl)amino)pyridazin-3(2H)-one (20 mg, 0.04 mmol, 24.64%) as white solid. ESI-MS m / z: 519.7 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.30 (s,1H), 8.56 (s, 2H), 7.72 (s, 1H), 7.67 (s, 1H), 5.69 (dd, J = 12.9, 5.5 Hz,1H), 5.55 (tt, J = 7.9, 5.1 Hz, 1H), 4.80 (t, J = 9.0 Hz, 2H), 4.72 (d, J =12.9 Hz, 2H), 4.62 (dt, J = 10.3, 5.2 Hz, 2H), 3.96 (s, 1H), 3.73 (dd, J =9.6, 3.7 Hz, 1H), 3.56 (dd, J = 9.6, 5.8 Hz, 1H), 1.31 (d, J = 6.6 Hz, 3H)。

[0507] Example 57: Synthesis of 5-((1-((1-(1-(5-chloropyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3- triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0508] Step 1 : To a solution of 5-{[1-({[1-(azetidin-3-yl)-1,2,3-triazol-4-yl]methyl}oxy)propan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (100 mg, 0.20 mmol) in ACN (2 ml) was added K2CO3 (84.01 mg, 0.61 mmol), 2,5-dichloropyrimidine (45.28 mg, 0.30 mmol), the mixture was stirred at 60 °C for 17 h. The residue was purified by column chromatography on silica gel (PE:EA=100:1-1 : 100) to give 5-({1-[({1-[1-(5-chloropyrimidin-2-yl)azetidin-3-yl]-1,2,3-triazol-4-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (50 mg, 0.08 mmol, 40.72%) white solid. ESI-MS m / z: 605.7 [M+H] o C for 17 h. The residue was purified by column chromatography on silica gel (PE:EA=100:1-1 : 100) to give 5-({1-[({1-[1-(5-chloropyrimidin-2-yl)azetidin-3-yl]-1,2,3-triazol-4-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (50 mg, 0.08 mmol, 40.72%) white solid. ESI-MS m / z: 605.7 [M+H] + .

[0509] Step 2: 5-({1-[({1-[1-(5-chloropyrimidin-2-yl)azetidin-3-yl]-1,2,3-triazol-4-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (100 mg, 0.17 mmol) was added into TFA (2 ml) and TfOH (0.5 ml), the mixture was stirred at 25 °C for 30 min. To the mixture was added saturated NaHC03 solution, the pH value was adjusted to 7. The reaction was diluted with H20 and extracted with dichloromethane. The combined organic layers were washed with water and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to give 5-({1-[({1-[1-(5-chloropyrimidin-2-yl)azetidin-3-yl]-1,2,3-triazol-4-yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (20 mg, 0.04 mmol, 24.95%) white solid. ESI-MS m / z: 485.7 [M+H] o C for 17 h. The residue was purified by column chromatography on silica gel (PE:EA=100:1-1 : 100) to give 5-({1-[({1-[1-(5-chloropyrimidin-2-yl)azetidin-3-yl]-1,2,3-triazol-4-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (50 mg, 0.08 mmol, 40.72%) white solid. ESI-MS m / z: 605.7 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 11.36(s, 1H), 8.31 (s, 2H), 7.75 (s,1H), 7.67 (s, 1H), 5.69 (dd, J = 12.8, 5.6 Hz,1H), 5.52 (dq, J = 7.9, 5.0 Hz, 1H), 4.77 – 4.63 (m, 4H), 4.58 – 4.42 (m,2H), 3.96 (s, 1H), 3.72 (dd, J = 9.6, 3.7 Hz, 1H), 3.55 (dd, J = 9.5, 5.7 Hz,1H), 1.31 (d, J = 6.6 Hz, 3H).

[0510] Example 58: Synthesis of 5-((1-((1-(1-(5-(difluoromethyl)pyridin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one

[0511] Step 1: Add 6-fluoropyridin-3-carboxaldehyde (71.96 mg, 0.58 mmol) and K2CO3 (53.00 mg, 0.38 mmol) to a solution of 5-{[1-({[1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]methyl}oxy)propyl-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (200 mg, 0.38 mmol) in ACN (5 ml) and mix at 60 °C. o The mixture was stirred at C for 18 hours. The residue was purified by silica gel column chromatography (PE:EA = 100:1-1:100) to give 6-(4-(4-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)nicotinaldehyde (150 mg, 0.25 mmol, 49.38%), a white oil. ESI-MS m / z: 626.8 [M+H] + .

[0512] Step 2: To a solution of 6-(4-(4-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)- 1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)nicotinaldehyde (160 mg, 0.26 mmol) in THF (5 ml) was added DAST (823.13 mg, 5.11 mmol), the mixture was stirred at 25 o C for 17 h. The mixture was diluted with DCM and saturated NaHC03solution. The organic layer was separated, washed with saturated NaCl solution, and the reaction was concentrated in vacuum. The residue was purified by silica gel column chromatography (PE:EA = 100:1-1:100) to give 5-[(1-{[(1-{1-[5-(fluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (60 mg, 0.09 mmol, 36.23%) white oil. ESI-MS m / z: 648.7 [M+H] + .

[0513] Step 3: 5-[(1-{[(1-{1-[5-(fluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (50 mg, 0.08 mmol) was added into TFA (2 ml) and TfOH (0.5 ml), the mixture was stirred at 25 o C for 1 h. Saturated NaHC03solution was added to adjust the pH to 7, the reaction was diluted with water and extracted with DCM. The combined organic layer was washed with water and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to give 5-[(1-{[(1-{1-[5-(difluoromethyl)pyridin-2-yl]hexahydropyridin-4-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (10 mg, 0.02 mmol, 23.87%). ESI-MS m / z: 528.7 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 10.96 (s, 1H), 8.27 (d, J = 1.4 Hz,1H), 7.69 – 7.58 (m, 2H), 7.51 (s, 1H), 6.76 (d, J = 8.9 Hz,1H), 6.59 (t, J = 56.3 Hz, 1H), 5.78 – 5.64 (m, 1H), 4.83 – 4.62 (m, 3H), 4.54 (d, J = 13.6 Hz, 2H), 3.94 (s, 1H), 3.71 (dd, J = 9.6, 3.8 Hz, 1H), 3.54 (dd,J = 9.6, 5.6 Hz, 1H), 3.19 – 3.08 (m, 2H), 2.31 (d, J =12.1 Hz, 2H), 2.05 (dt, J = 14.4, 10.0 Hz, 2H), 1.30 (d, J = 6.6 Hz, 3H).

[0514] Example 59: Synthesis of 6-(3-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)azacyclobutane-1-yl)nicotinonitrile

[0515] Step 1: Add 6-fluoropyridine-3-carboxynitrile (55.67 mg, 0.46 mmol) and K2CO3 (126.02 mg, 0.91 mmol) to a MeCN (5 ml) solution of 5-{[1-({[1-(azacyclobutan-3-yl)-1,2,3-triazol-4-yl]methyl}oxy)propyl-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (150 mg, 0.30 mmol) and K2CO3 (126.02 mg, 0.91 mmol). The mixture is then heated at 60 °C. o The mixture was stirred in a microwave at C for 1 hour. The mixture was concentrated under vacuum and purified by silica gel column chromatography (PE:EA = 1:10) to give a white oily substance of 6-{3-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]azacyclobutane-1-yl}pyridine-3-carboxynitrile (120 mg, 0.20 mmol, 66.29%). ESI-MS m / z: 595.7 [M+H] + .

[0516] Step 2: 6-{3-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)- 1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]azetidin-1-yl}pyridine-3- carbonitrile (110 mg, 0.18 mmol) was added to TFA (2 ml) and TfOH (0.5 ml) and the mixture was stirred at 25 °C for 10 min. The mixture was diluted with DCM and saturated NaHCO3solution. The organic layer was separated and washed with saturated sodium chloride solution and then concentrated in vacuo. The mixture was purified by Prep-HPLC to give 6-(3-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy) methyl)-1H-1,2,3-triazol-1-yl)azetidin-1-yl)nicotinonitrile (22 mg, 0.05 mmol, 25.05%) as a white solid. ESI-MS m / z: 475.7. [M+H] o C under stirring for 10 min. The mixture was diluted with DCM and saturated NaHCO3solution. The organic layer was separated and washed with saturated sodium chloride solution and then concentrated in vacuo. The mixture was purified by Prep-HPLC to give 6-(3-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy) methyl)-1H-1,2,3-triazol-1-yl)azetidin-1-yl)nicotinonitrile (22 mg, 0.05 mmol, 25.05%) as a white solid. ESI-MS m / z: 475.7. [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.30 (s, 1H), 8.50 - 8.38 (m, 1H), 7.71 (s, 1H), 7.69 - 7.64 (m, 2H), 6.40 (d, J = 8.7 Hz, 1H), 5.66 (dd, J = 7.5, 5.7 Hz, 1H), 5.56 (tt, J = 7.8, 5.0 Hz, 1H), 4.75 - 4.65 (m, 4H), 4.52 (dt, J = 8.8, 4.2 Hz, 2H), 3.96 (d, J = 5.3 Hz, 1H), 3.74 (dd, J = 9.6, 3.7 Hz, 1H), 3.56 (dd, J = 9.6, 5.9 Hz, 1H), 1.31 (d, J = 6.6 Hz, 3H).

[0517] Example 60: Synthesis of 2-(4-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4- yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)pyrimidine-5-carbonitrile

[0518] Step 1: Add K2CO3 (53.00 mg, 0.38 mmol) and 5-bromo-2-chloropyrimidine (166.89 mg, 0.86 mmol) to a solution of 5-{[1-({[1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]methyl}oxy)propyl-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (300 mg, 0.58 mmol) in ACN (10 ml), and stir the mixture at 60°C for 18 hours. The residue was purified by silica gel column chromatography (PE:EA = 100:1-1:100) to give 2-{3-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]azacyclobutane-1-yl}pyrimidin-5-carboxaldehyde (150 mg, 0.25 mmol, 49.38%), a white oil. ESI-MS m / z: 677.5 [M+H] + .

[0519] Step 2: Add Zn(CN)₂ (83.07 mg, 0.71 mmol), Pd₂(dba)₃ (161.95 mg, 0.18 mmol), X-PHOS (16.86 mg, 0.04 mmol), and Zn (34.69 mg, 0.53 mmol) to a DMF (3 mL) solution of 5-({1-[({1-[1-(5-bromopyrimidin-2-yl)hexahydropyridin-4-yl]-1,2,3-triazol-4-yl}methyl)oxy]propyl-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (120 mg, 0.18 mmol) and 1 mL of 2-(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (120 mg, 0.18 mmol), 2-(4-(5-bromopyrimidin-2-yl)hexahydropyridin-4-yl]-1,2,3-triazol-4-yl}methyl)oxy]propyl-2-yl}amino)-2-[ ... o The mixture was stirred in a microwave at C under N2 conditions for 1 hour. The reactants were diluted with dichloromethane and water. The organic layer was separated and concentrated by air separation. The residue was purified by silica gel column chromatography (PE:EA = 10:1 to 1:10) to give 2-{4-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]hexahydropyridin-1-yl}pyrimidin-5-carboxylonitrile (100 mg, 0.16 mmol, 90.52%). ESI-MS m / z: 624.7 [M+H]+ .

[0520] Step 3: 2-{4-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)- 1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]hexahydropyridin-1- yl}pyrimidine-5-carbonitrile (70 mg, 0.11 mmol) was added to TFA (2 ml) and TfOH (0.5 ml) and the mixture was stirred at 25 °C for 30 minutes. The mixture was diluted with DCM and saturated NaHCO3solution. The organic layer was separated and washed with saturated sodium chloride solution and then concentrated in vacuo. The mixture was purified with Prep-HPLC to give 2,2-[4-(4-{[(2-{[6-oxo-5-(trifluoromethyl)-1H-1,2-diazin-4-yl]amino}propyl)oxy]methyl}- 1,2,3-triazol-1-yl)hexahydropyridin-1-yl]pyrimidine-5-carbonitrile (10 mg, 0.02 mmol, 17.69%) as a white solid. ESI-MS m / z: 504.7 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.45 (s, 1H), 8.79 (s, 2H), 8.14 (s, 1H), 7.89 (s, 1H), 6.26 (dd, J = 8.3, 4.0 Hz, 1H), 4.96 - 4.85 (m, 1H), 4.81 (d, J = 13.6 Hz, 2H), 4.60 - 4.47 (m, 2H), 4.23 - 4.09 (m, 1H), 3.53 (d, J = 5.6 Hz, 2H), 3.28 - 3.22 (m, 2H), 2.23 - 2.12 (m, 2H), 1.93 (tt, J = 12.0, 6.1 Hz, 2H), 1.15 (d, J = 6.5 Hz, 3H).

[0521] Example 61: Synthesis of 5-((1-((1-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)-1H- 1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0522] Step 1: To a solution of 5-{[1-({[1-(azetidin-3-yl)-1,2,3-triazol-4-yl]methyl}oxy)propan-2- yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (200 mg, 0.41 mmol) in ACN (5 mL) was added 2-chloro-5-fluoropyrimidine (80.56 mg, 0.61 mmol) and K2CO3 (168.03 mg, 1.22 mmol), the mixture was stirred at 60 °C for 17 h. The reaction was concentrated in vacuo and purified by silica gel column chromatography (PE:EA = 1:10) to give 5-({1-[({1-[1-(5-fluoropyrimidin-2-yl)azetidin-3-yl]-1,2,3-triazol-4- yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3- one (50 mg, 0.08 mmol, 20.93%) as white oil. ESI-MS m / z: 589.7 [M+H] + .

[0523] Step 2: 5-({1-[({1-[1-(5-fluoropyrimidin-2-yl)azetidin-3-yl]-1,2,3-triazol-4-yl}methyl)oxy]propan-2- yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (70 mg, 0.11 mmol) was added to TFA (2 ml) and TfOH (0.5 ml), the mixture was stirred at 25 °C for 30 min, the mixture was diluted with DCM and saturated NaHCO3 solution. The organic layer was separated, washed with saturated sodium chloride solution, and concentrated in vacuo. The mixture was purified by Prep-HPLC to give 5-({1-[({1-[1-(5-fluoropyrimidin-2-yl)azetidin-3-yl]-1,2,3-triazol-4- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (10 mg, 0.02 mmol, 20.93%) as white solid. ESI-MS m / z: 469.7 [M+H] o C under stirring for 30 min, the mixture was diluted with DCM and saturated NaHCO3 solution. The organic layer was separated, washed with saturated sodium chloride solution, and concentrated in vacuo. The mixture was purified by Prep-HPLC to give 5-({1-[({1-[1-(5-fluoropyrimidin-2-yl)azetidin-3-yl]-1,2,3-triazol-4- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (10 mg, 0.02 mmol, 20.93%) as white solid. ESI-MS m / z: 469.7 [M+H] + . 1H NMR (400MHz, CDCl3) δ 10.79 (s, 1H), 8.28 (d, J = 0.5 Hz, 2H), 7.74 (s, 1H), 7.65 (s,1H), 5.74 – 5.59 (m, 1H), 5.50 (ddd, J = 12.7, 6.3, 3.9 Hz, 1H), 4.76 – 4.63(m, 4H), 4.47 (td, J = 9.1, 5.0 Hz, 2H), 3.95 (d, J = 5.5 Hz, 1H), 3.72 (dd,J = 9.6, 3.8 Hz, 1H), 3.55 (dd, J = 9.6, 5.8 Hz, 1H), 1.30 (d, J = 6.6 Hz, 3H).

[0524] Example 62: Synthesis of 5-((1-((1-(1-(5-(difluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one

[0525] Step 1: Add 2-chloropyrimidine-5-carboxaldehyde (72.21 mg, 0.51 mmol) and K2CO3 (210.03 mg, 1.52 mmol) to a THF (5 mL) solution of 5-{[1-({[1-(azacyclobutan-3-yl)-1,2,3-triazol-4-yl]methyl}oxy)propyl-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (250 mg, 0.51 mmol) and K2CO3 (210.03 mg, 1.52 mmol). The reaction is carried out at 60 °C. o The mixture was stirred at C for 18 hours. The residue was purified by silica gel column chromatography (PE:EA = 100:1-1:100) to give 2-{3-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]azacyclobutane-1-yl}pyrimidin-5-carboxaldehyde (150 mg, 0.25 mmol, 49.38%), a white oil. ESI-MS m / z: 599.7 [M+H] + .

[0526] Step 2: To a solution of 2-{3-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]azetidin- 1-yl}pyrimidine-5-carbaldehyde (150 mg, 0.25 mmol) in THF (5 ml) was added DAST (806.51 mg, 5.00 mmol) and the mixture was stirred at 25 °C for 17 h. The mixture was diluted with DCM and saturated NaHC03solution. The organic layer was separated and washed with saturated NaCl solution, and the reaction was concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE:EA = 100:1-1:100) to give 5-[(1-{[(1-{1-[5-(difluoromethyl)pyrimidin-2-yl]azetidin-3-yl}-1,2,3- triazol-4-yl)methyl]oxy}propan-2-yl)amino]-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (60 mg, 0.10 mmol, 38.58%) as a white oil. ESI-MS m / z: 621.7 [M+H] o C was stirred for 17 h. The mixture was diluted with DCM and saturated NaHC03solution. The organic layer was separated and washed with saturated NaCl solution, and the reaction was concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE:EA = 100:1-1:100) to give 5-[(1-{[(1-{1-[5-(difluoromethyl)pyrimidin-2-yl]azetidin-3-yl}-1,2,3- triazol-4-yl)methyl]oxy}propan-2-yl)amino]-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (60 mg, 0.10 mmol, 38.58%) as a white oil. ESI-MS m / z: 621.7 [M+H] + .

[0527] Step 3: 5-[(1-{[(1-{1-[5-(difluoromethyl)pyrimidin-2-yl]azetidin-3-yl}-1,2,3-triazol-4- yl)methyl]oxy}propan-2-yl)amino]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)- 3H,2H-1,2-diazin-3-one (70 mg, 0.11 mmol) was added to TFA (2 ml) and TfOH (0.5 ml) and the reaction was stirred at room temperature for 30 min. The PH was adjusted to 7 with saturated sodium bicarbonate solution, the reaction was diluted with water and extracted with dichloromethane. The combined organic layer was washed with water and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to give 5-[(1-{[(1-{1-[5-(difluoromethyl)pyrimidin-2-yl]azetidin-3-yl}-1,2,3- triazol-4-yl)methyl]oxy}propan-2-yl)amino]-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (10 mg, 0.02 mmol, 14.29%) as a white solid. ESI-MS m / z: 501.7 [M+H] + . 1H NMR (400 MHz, CDC13) δ 10.50 (s, 1H), 8.49 (s, 2H), 7.68 (d, J = 24.9 Hz, 2H), 6.62 (t, J = 56.0 Hz, 1H), 5.74 - 5.62 (m, 1H), 5.54 (tt, J = 7.8, 5.0 Hz, 1H), 4.86 - 4.64 (m, 4H), 4.57 (td, J = 9.3, 5.0 Hz, 2H), 3.96 (s, 1H), 3.73 (dd, J = 9.6, 3.8 Hz, 1H), 3.55 (dd, J = 9.6, 5.8 Hz, 1H), 1.31 (d, J = 6.6 Hz, 3H).

[0528] Example 63: Synthesis of 5-((1-((1-(5-(difluoromethyl)pyrimidin-2-yl)azetidin-3-yl)-1H- 1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0529] Step 1: 2-[(4-methoxyphenyl)methyl]-5-{[1-({[1-(tetrahydro-1H-pyrrol-3-yl)-1,2,3- triazol-4-yl]methyl}oxy)propan-2-yl]amino}-4-(trifluoromethyl)-3H,2H-1,2-diazin-3- one (200 mg, 0.39 mmol), Pd2(dba)3 (36.09 mg, 0.04 mmol), Cs2CO3 (254.14 mg, 0.78 mmol) and xantphos (37.57 mg, 0.08 mmol) were added into dioxane (4 ml), the reaction was bubbled with N2for 30 seconds. The reaction was heated at 100 o C for 16 hours. The reaction was purified by silica gel column (EA: PE = 0~100%) to give 5-({1-[({1-[1-(5-fluoropyridin-2-yl)tetrahydro-1H-pyrrol-3-yl]-1,2,3-triazol-4-yl}methyl)oxy]propan- 2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (41 mg, 0.07 mmol, 17.27%). ESI-MS m / z: 602.7 [M+H] + .

[0530] Step 2: To a solution of 5-({1-[({1-[1-(5-fluoropyridin-2-yl)tetrahydro-1H-pyrrol-3-yl]- 1,2,3-triazol-4-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (41 mg, 0.07 mmol) in TFA (2 ml) was added CF3SO3H (0.5 ml). The reaction was then stirred at 25 °C for 10 minutes. The reaction was quenched with Na2CO3 and extracted with DCM (20 ml*2). The organic layers were combined, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by Prep-HPLC to give 5-({1-[({1-[1-(5-fluoropyridin-2-yl)tetrahydro-1H-pyrrol-3-yl]-1,2,3-triazol-4- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (3.88 mg, 0.01 mmol, 11.82%). ESI-MS m / z: 482.7 [M+H] o C was stirred for 10 minutes. The reaction was quenched with Na2CO3 and extracted with DCM (20 ml*2). The organic layers were combined, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by Prep-HPLC to give 5-({1-[({1-[1-(5-fluoropyridin-2-yl)tetrahydro-1H-pyrrol-3-yl]-1,2,3-triazol-4- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (3.88 mg, 0.01 mmol, 11.82%). ESI-MS m / z: 482.7 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.06 (d, J = 2.9 Hz, 1H), 7.64 (s,1H), 7.50 (d, J = 4.8 Hz, 1H), 7.33 – 7.27 (m, 1H), 6.39 (dd, J = 9.1, 3.3Hz, 1H), 5.67 (s, 1H), 5.35 (dd, J = 6.2, 3.8 Hz, 1H), 4.65 (s, 2H), 3.96(ddd, J = 14.7, 11.6, 4.9 Hz, 3H), 3.76 –3.59 (m, 3H), 3.58 – 3.46 (m, 1H),2.76 – 2.47 (m, 2H), 1.29 (d, J = 6.6 Hz, 3H)。

[0531] Example 64: Synthesis of 5-((1-((1-(1-(5-fluoropyridin-2-yl)pyrrolidin-3-yl)-1H-1,2,3- triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0532] Step 1: 5-{[1-({[1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]methyl}oxy)propan-2-yl]amino}- 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (350 mg, 0.67 mmol), 2-bromo-5-chloro-1,3-thiazole (199.77 mg, 1.01 mmol), XANT PHOS (77.66 mg, 0.13 mmol), Pd2(dba)3 (61.45 mg, 0.07 mmol) were added into dioxane (5 ml), the mixture was stirred at 100 °C for 17 h. The reaction was concentrated in vacuum. The residue was purified by column chromatography on silica gel (PE:EA=100:1-1:100) to give 5-({1-[({1-[1-(5-chloro-1,3-thiazol-2-yl)hexahydropyridin-4-yl]-1,2,3-triazol-4-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (200 mg, 0.31 mmol, 46.63%) white solid. ESI-MS m / z: 638.6 [M+H] o . + .

[0533] Step 2: 5-({1-[({1-[1-(5-chloro-1,3-thiazol-2-yl)hexahydropyridin-4-yl]-1,2,3-triazol-4-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (100 mg, 0.16 mmol) was added into TFA (2 ml) and TfOH (0.5 ml), the mixture was stirred at 25 °C for 30 min, saturated NaHCO3 solution was added to adjust the PH to 7, the reaction was diluted with water and extracted with DCM. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to give 5-((1-((1-((5-(difluoromethyl)thiazol-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (10 mg, 0.02 mmol, 11.70%) white solid. ESI-MS m / z: 518.9 [M+H] + . 1H NMR (400 MHz, CDC13) δ 10.69 (s, 1H), 7.65 (s, 1H), 7.51 (s, 1H), 7.00 (s, 1H), 5.76 - 5.59 (m, 1H), 4.77 - 4.60 (m, 3H), 4.06 (dd, J = 10.4, 3.0 Hz, 2H), 3.94 (s, 1H), 3.72 (dd, J = 9.6, 3.8 Hz, 1H), 3.55 (dd, J = 9.6, 5.6 Hz, 1H), 3.32 - 3.12 (m, 2H), 2.38 - 2.27 (m, 2H), 2.24 - 2.06 (m, 2H), 1.31 (d, J = 6.6 Hz, 3H).

[0534] Example 65: Synthesis of 5-((1-((1-(1-(5-chloropyridin-2-yl)piperidin-4-yl)-1H-1,2,3- triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0535] Step 1: To a solution of 5-{[1-({[1-(hexahydropyridin-4-yl)-1,2,3-triazol-4-yl]methyl}oxy)propan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (200 mg, 0.38 mmol) in ACN (1 mL) was added 5-chloro-2-fluoropyridine (75.66 mg, 0.58 mmol) and K2CO3 (158.76 mg, 1.15 mmol), the mixture was stirred at 80 °C for 17 hours. The residue was purified by column chromatography on silica gel (PE:EA = 100:1-1:100) to give 5-({1-[({1-[1-(5-chloropyridin-2-yl)hexahydropyridin-4-yl]-1,2,3-triazol-4-yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (20 mg, 0.03 mmol, 8.24%) white solid. ESI-MS m / z: 632.7 [M+H] + .

[0536] Step 2: 5-({1-[({1-[1-(5-chloropyridin-2-yl)hexahydropyridin-4-yl]-1,2,3-triazol-4- yl}methyl)oxy]propan-2-yl}amino)-2-[(4-methoxyphenyl)methyl]-4- (trifluoromethyl)-3H,2H-1,2-diazin-3-one (80 mg, 0.13 mmol) was taken in a solution of TFA (2 ml) and TfOH (0.5 ml) and stirred at 25 °C for 30 min, then the pH was adjusted to 7 by adding saturated NaHCO3solution. The reaction was diluted with H2O and extracted with dichloromethane. The combined organic layer was washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to get 5-({1-[({1-[1-(5-chloropyridin-2-yl)hexahydropyridin-4-yl]-1,2,3-triazol-4- yl}methyl)oxy]propan-2-yl}amino)-4-(trifluoromethyl)-3H,2H-1,2-diazin-3-one (10 mg, 0.02 mmol, 15.43%) as white solid. ESI-MS m / z: 512.7 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.57 (s,1H), 8.12 (d, J = 2.5 Hz,1H), 7.66 (s, 1H), 7.52 (s, 1H), 7.44 (dd, J = 9.0,2.6 Hz, 1H), 6.67(d, J = 9.0 Hz, 1H), 5.78 – 5.65 (m, 1H), 4.75 – 4.64 (m,3H), 4.40(d, J = 13.6 Hz, 2H), 3.94 (s, 1H), 3.71 (dd, J = 9.6, 3.8 Hz, 1H),3.54 (dd, J = 9.6, 5.6 Hz, 1H), 3.18 – 2.99 (m, 2H), 2.29 (d, J = 10.9Hz,2H), 2.07 (tt, J = 12.0, 6.1 Hz, 2H), 1.30 (d, J = 6.6 Hz, 3H)。

[0537] Example 66: Synthesis of 4-(trifluoromethyl)-5-((1-((1-(5-(trifluoromethyl)pyrimidin-2- yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)- one

[0538] Step 1: To a solution of 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(1-{1-[5- (trifluoromethyl)pyrimidin-2-yl]tetrahydro-1H-pyrrol-3-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan- 2-yl)amino]-3H,2H-1,2-diazin-3-one (85 mg, 0.13 mmol) in ACN (10 ml) was added K2CO3 (17.95 mg, 0.13 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine (28.49 mg, 0.16 mmol), the reaction was stirred at 80 °C for 18 hours. The reaction was concentrated in vacuum. The mixture was purified by silica gel column chromatography (PE:EA=1:10) to give 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(1-{1-[5- (trifluoromethyl)pyrimidin-2-yl]tetrahydro-1H-pyrrol-3-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan- 2-yl)amino]-3H,2H-1,2-diazin-3-one (80 mg, 0.12 mmol, 94.12%) white oil. ESI-MS m / z: 653.7 [M+H] + .

[0539] Step 2: 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(1-{1-[5-(trifluoromethyl)pyrimidin- 2-yl]tetrahydro-1H-pyrrol-3-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-3H,2H-1,2- diazin-3-one (100 mg, 0.15 mmol) was added to TFA (2 ml) and TfOH (0.5 ml), the mixture was stirred at room temperature for 30 minutes, then the mixture was diluted with DCM and saturated NaHCO3 solution. The organic layer was separated, washed with saturated sodium chloride solution, then concentrated in vacuum. The mixture was purified by Prep-HPLC to give 4-(trifluoromethyl)-5-[(1-{[(1-{1-[5-(trifluoromethyl)pyrimidin-2-yl]tetrahydro-1H-pyrrol-3-yl}- 1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-3H,2H-1,2-diazin-3-one (10 mg, 0.02 mmol, 12.25%) white solid. ESI-MS m / z: 534.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 11.39 (s, 1H), 8.54 (s, 2H), 7.66(s,1H), 7.53 (d, J = 3.1 Hz, 1H), 5.75 – 5.62 (m, 1H), 5.33 (tt, J = 10.6, 5.3Hz, 1H), 4.67 (s, 2H), 4.23 – 4.10 (m, 2H), 3.92 (dt, J = 11.6, 8.2Hz, 3H), 3.71 (dd, J = 9.6, 3.8 Hz, 1H), 3.54 (dd, J = 9.6, 5.8 Hz, 1H),2.72 – 2.56(m, 2H), 1.30 (d, J = 6.6 Hz, 3H).

[0540] Example 67: Synthesis of 4-(trifluoromethyl)-5-((1-((1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propyl-2-yl)amino)pyridazine-3(2H)-one

[0541] Step 1: Add K₂CO₃ (50.75 mg, 0.37 mmol) and 2-fluoro-5-(trifluoromethyl)pyridin-2-yl]tetrahydro-1H-pyrrolo-3-yl}-1,2,3-triazol-4-yl)methyl]oxy}propyl-2-yl)amino]-3H,2H-1,2-diazin-3-one (80 mg, 0.12 mmol) to a solution of 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(1-{1-[5-(trifluoromethyl)pyridin-2-yl]tetrahydro-1H-pyrrolo-3-yl}-1,2,3-triazol-4-yl)methyl]oxy}propyl-2-yl)amino]-3H,2H-1,2-diazin-3-one (80 mg, 0.12 mmol) in ACN (3 ml) and 2-fluoro-5-(trifluoromethyl)pyridine (24.29 mg, 0.15 mmol). The reaction is carried out at 80 °C. o The mixture was stirred at C for 18 h. The reactants were concentrated under vacuum and purified by silica gel column chromatography (PE:EA = 1:10) to give 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(1-{1-[5-(trifluoromethyl)pyridin-2-yl]tetrahydro-1H-pyrrolo-3-yl}-1,2,3-triazol-4-yl)methyl]oxy}propyl-2-yl)amino]-3H,2H-1,2-diazin-3-one (30 mg, 0.05 mmol, 37.50%), a white oil. ESI-MS m / z: 652.7 [M+H] + .

[0542] Step 2: 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(1-{1-[5-(trifluoromethyl)pyridin-2-yl]tetrahydro-1H-pyrrol-3-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-3H,2H-1,2-diazin-3-one (50 mg, 0.08 mmol) was taken in TFA (2 ml) and TfOH (0.5 ml) and the mixture was stirred at Rt for 30 minutes, then the mixture was diluted with DCM and saturated NaHCO3solution. The organic layer was separated and washed with saturated sodium chloride solution and then concentrated under vacuum. The mixture was purified by Prep-HPLC to get 4-(trifluoromethyl)-5-[(1-{[(1-{1-[5-(trifluoromethyl)pyridin-2-yl]tetrahydro-1H-pyrrol-3-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-3H,2H-1,2-diazin-3-one (7 mg, 0.01 mmol, 17.16%) as white solid. ESI-MS m / z: 533.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 10.93 (s, 1H), 8.42 (s, 1H), 7.66 (dd, J= 10.7, 4.2 Hz, 2H), 7.50 (d, J = 5.2 Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H),5.67(s, 1H), 5.34 (dt, J = 6.0, 5.2 Hz, 1H), 4.66 (s, 2H), 4.07 (qd, J =11.9, 4.8Hz, 2H), 3.94 (s, 1H), 3.74 (ddd, J = 18.5, 10.0, 3.2 Hz, 3H),3.53 (ddd, J =9.6, 5.8, 1.6 Hz, 1H), 2.75 – 2.56 (m, 2H), 1.28 (t, J =9.5 Hz, 3H)。

[0543] Example 68: Synthesis of 6-(3-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)nicotinonitrile

[0544] Step 1 : To a solution of 2-[(4-methoxyphenyl)methyl]-5-{[1-({[1-(tetrahydro-1H- pyrrol-3-yl)-1,2,3-triazol-4-yl]methyl}oxy)propan-2-yl]amino}-4-(trifluoromethyl)- 3H,2H-1,2-diazin-3-one (100 mg, 0.20 mmol) in ACN (3 mL) was added K2CO3 (82.92 mg, 0.60 mmol) and 6-fluoropyridine-3-carbonitrile (36.09 mg, 0.30 mmol) and the mixture was stirred under microwave at 60 °C for 1 h. The reaction was concentrated in vacuo and purified by silica gel column chromatography (PE:EA = 1:10) to give 6-{3-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]tetrahydro- 1H-pyrrol-1-yl}pyridine-3-carbonitrile (100 mg, 0.16 mmol, 83.25%). ESI-MS m / z: 609.7 [M+H] o C under microwave for 1 h. The reaction was concentrated in vacuo and purified by silica gel column chromatography (PE:EA = 1:10) to give 6-{3-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]tetrahydro- 1H-pyrrol-1-yl}pyridine-3-carbonitrile (100 mg, 0.16 mmol, 83.25%). ESI-MS m / z: 609.7 [M+H] + .

[0545] Step 2: To a solution of 6-{3-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5- (trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]tetrahydro- 1H-pyrrol-1-yl}pyridine-3-carbonitrile (130 mg, 0.21 mmol) was added TFA (2 mL) and TfOH (0.5 mL) and stirred at room temperature for 30 min. The mixture was diluted with DCM and saturated NaHC03solution. The organic layer was separated and washed with saturated NaCl solution and concentrated in vacuo. The mixture was purified by Prep-HPLC to give 6-[3-(4-{[(2-{[6-oxo-5-(trifluoromethyl)-1H-1,2-diazin-4- yl]amino}propyl)oxy]methyl}-1,2,3-triazol-1-yl)tetrahydro-1H-pyrrol-1-yl]pyridine-3- carbonitrile (22 mg, 0.04 mmol, 21.08%) as a white solid. ESI-MS m / z: 489.7 [M+H] + . 1H NMR (400MHz, CDC13) δ 11.17 (s, 1H), 8.43 (d, J = 2.1 Hz, 1H), 7.65 (dd, J = 6.7, 2.1 Hz, 2H), 7.51 (d, J = 3.4 Hz, 1H), 6.45 (dd, J = 8.9, 2.0 Hz, 1H), 5.67 (s, 1H), 5.33 (d, J = 3.4 Hz, 1H), 4.64 (d, J = 12.6 Hz, 2H), 4.14 - 4.02 (m, 2H), 3.96 (s, 1H), 3.87 - 3.67 (m, 3H), 3.54 (dd, J = 9.5, 5.9 Hz, 1H), 2.66 (dt, J = 12.2, 6.2 Hz, 2H), 1.30 (d, J = 6.6 Hz, 3H).

[0546] Example 69: Synthesis of 4-(trifluoromethyl)-5-((1-((1-(5-(trifluoromethyl)pyridin-2- yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0547] Step 1: To a solution of 5-{[1-({[1-(azetidin-3-yl)-1,2,3-triazol-4-yl]methyl}oxy)propan-2- yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-3H,2H-1,2-dioxazin-3-one (150 mg, 0.30 mmol) in ACN (2 ml) was added K2CO3(126.02 mg, 0.91 mmol) and 2-chloro-5- (trifluoromethyl)pyridine (82.77 mg, 0.46 mmol). The mixture was stirred at 60 °C for 17 h. The residue was purified by column chromatography on silica gel (PE:EA = 100:1-1:100) to give 2-[(4- methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(1-{1-[5-(trifluoromethyl)pyridin-2-yl]azetidin-3- yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-3H,2H-1,2-dioxazin-3-one (100 mg, 0.16 mmol, 51.52%) as a white solid. ESI-MS m / z: 638.7 [M+H] o C under stirring for 17 h. The residue was purified by column chromatography on silica gel (PE:EA = 100:1-1:100) to give 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(1-{1-[5- (trifluoromethyl)pyridin-2-yl]azetidin-3-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-3H,2H- 1,2-dioxazin-3-one (100 mg, 0.16 mmol, 51.52%) as a white solid. ESI-MS m / z: 638.7 [M+H] + .

[0548] Step 2: 2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-5-[(1-{[(1-{1-[5-(trifluoromethyl)pyridin-2-yl]azetidin-3-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-3H,2H-1,2-diazin-3-one (60 mg, 0.09 mmol) was taken in TFA (2 ml) and TfOH (0.5 ml) and the mixture was stirred at 25 °C for 17 h. The reaction was quenched with sat. NaHCO3solution and the mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to get 4-(trifluoromethyl)-5-[(1-{[(1-{1-[5-(trifluoromethyl)pyridin-2-yl]azetidin-3-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-3H,2H-1,2-diazin-3-one (6 mg, 0.01 mmol, 12.32%) as white solid. ESI-MS m / z: 518.7 [M+H] o C was stirred for 17 h, sat. NaHCO3solution was added to adjust the pH to 7. The reaction was diluted with water and extracted with dichloromethane. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to get 4-(trifluoromethyl)-5-[(1-{[(1-{1-[5-(trifluoromethyl)pyridin-2-yl]azetidin-3-yl}-1,2,3-triazol-4-yl)methyl]oxy}propan-2-yl)amino]-3H,2H-1,2-diazin-3-one (6 mg, 0.01 mmol, 12.32%) as white solid. ESI-MS m / z: 518.7 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.22(s, 1H), 8.43 (s, 1H), 7.82 – 7.58 (m, 3H), 6.44 (d, J = 8.7 Hz, 1H), 5.72 –5.49 (m, 2H), 4.79 – 4.62 (m, 4H), 4.47 (dt, J = 8.9, 4.3 Hz, 2H), 3.96 (s,1H), 3.74 (dd, J = 9.6, 3.7 Hz, 1H), 3.56 (dd, J = 9.6, 5.8 Hz, 1H), 1.30 (t,J = 9.2 Hz, 3H).

[0549] Example 70: Synthesis of 2-(3-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)thiazole-5-carbonitrile

[0550] Step 1: Add 2-chloro-1,3-thiazolyl-5-carboxynitrile (85.46 mg, 0.59 mmol) and potassium carbonate (108.92 mg, 0.79 mmol) to a CH3CN (3 ml) solution of 2-[(4-methoxyphenyl)methyl]-5-{[1-({[1-(tetrahydro-1H-pyrrolo-3-yl)-1,2,3-triazol-4-yl]methyl}oxy)propyl-2-yl]amino}-4-(trifluoromethyl)-2H,3H-1,2-diazin-3-one (200 mg, 0.39 mmol) ⇌ 2-chloro-1,3-thiazolyl-5-carboxynitrile (85.46 mg, 0.59 mmol) and potassium carbonate (108.92 mg, 0.79 mmol). Then, heat the reaction mixture at 60 °C. o The mixture was stirred in a microwave at C for 1 hour. The reactants were purified by silica gel column chromatography (EA:PE = 0–100%) to give 2-{3-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]tetrahydro-1H-pyrrolo-1-yl}-1,3-thiazolyl-5-carboxynitrile (130 mg, 0.21 mmol, 53.58%). ESI-MS m / z: 616.2 [M+H] + .

[0551] Step 2: Add 2-{3-[4-({[2-({1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,2-diazin-4-yl}amino)propyl]oxy}methyl)-1,2,3-triazol-1-yl]tetrahydro-1H-pyrrolo-1-yl}-1,3-thiazolyl-5-carboxynitrile (110 mg, 0.18 mmol) to TFA (2 ml) and trifluoromethanesulfonic acid (0.5 ml). Then at 25 o The reaction mixture was stirred at C for 10 minutes. The reactants were quenched with K₂CO₃ solution and extracted with DCM (20 ml * 2). The organic layers were combined, washed with brine, dried on Na₂SO₄, and concentrated to obtain the crude product. The crude product was purified by Prep-HPLC to give 2-[3-(4-{[(2-{[3-oxo-4-(trifluoromethyl)-2H-1,2-diazin-5-yl]amino}propyl)oxy]methyl}-1,2,3-triazol-1-yl)tetrahydro-1H-pyrrolo-1-yl]-1,3-thiazolyl-5-carboxynitrile (30 mg, 0.06 mmol, 33.89%). ESI-MS m / z: 495.7 [M+H] + . 1H NMR (400 MHz, CDC13) δ 10.64 (s, 1H), 7.73 (d, J = 1.5 Hz, 1H), 7.65 (d, J = 4.1 Hz, 1H), 7.51 (d, J = 4.9 Hz, 1H), 5.65 (s, 1H), 5.37 - 5.25 (m, 1H), 4.67 (s, 2H), 4.12 (dd, J = 11.8, 6.3 Hz, 1H), 4.09 - 4.01 (m, 1H), 3.96 (s, 1H), 3.91 - 3.79 (m, 1H), 3.78 - 3.68 (m, 2H), 3.54 (dd, J = 9.6, 6.0 Hz, 1H), 2.78 - 2.62 (m, 2H), 1.31 (d, J = 6.6 Hz, 3H).

[0552] Example 71: Synthesis of 5-((1-((1-(1-(5-chloropyridin-2-yl)pyrrolidin-3-yl)-1H-1,2,3- triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0553] Step 1: To a solution of 2-[(4-methoxyphenyl)methyl]-5...

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: ###0001### wherein: ring A is a substituted or unsubstituted heterocycloalkene or a substituted or unsubstituted heteroaryl; ring A is not a substituted or unsubstituted piperidinylidene or a substituted or unsubstituted pyrrolidinylidene; ring B is a substituted or unsubstituted heterocycloalkene; ring C is a substituted or unsubstituted heteroaryl. (I); 4. The compound of any one of claims 1 to 3, wherein ring A is a substituted or unsubstituted piperazinyl, a substituted or unsubstituted imidazolinyl, a substituted or unsubstituted oxadiazolinyl, or a substituted or unsubstituted triazolinyl.

5. The compound of any one of claims 1 to 3, wherein ring A is a substituted or unsubstituted piperazinylalkenone, a substituted or unsubstituted imidazolidinylalkenone, a substituted or unsubstituted 1,2,4-oxadiazolylalkene, a substituted or unsubstituted 1,3,4-oxadiazolylalkene, or a substituted or unsubstituted 1,2,3-triazolylalkene.

6. The compound of any one of claims 1 to 3, wherein ring A is an unsubstituted piperazinylalkenone, an unsubstituted imidazolidinylalkenone, an unsubstituted 1,2,4-oxadiazolylalkene, an unsubstituted 1,3,4-oxadiazolylalkene, or an unsubstituted 1,2,3-triazolylalkene.

7. The compound of any one of claims 1 to 6, wherein ring B is a substituted or unsubstituted piperidinylidene, a substituted or unsubstituted 8-azabicyclooctane, a substituted or unsubstituted pyrrolidinylidene, or a substituted or unsubstituted azetidinylidene.

8. The compound of any one of claims 1 to 6, wherein ring B is an unsubstituted piperidinylidene, an unsubstituted pyrrolidinylidene, or an unsubstituted azetidinylidene. L 1 is substituted or unsubstituted 2 to 10 membered heteroalkylene; R 1 is hydrogen, -CN, halogen, -NH2, -OH, -COOH, -CONH2, substituted or unsubstituted C1-C6alkyl, -C(O)H, -CHX 1 2, -CX 1 3or substituted or unsubstituted 2 to 6 membered heteroalkyl; and X 1 independently -F, -Cl, -Br, or -I.

2. The compound of claim 1, wherein the substituted C1-C6 alkyl is -C(O)R 1A wherein R 1A is unsubstituted C1-C5 alkyl.

3. The compound of claim 1, wherein R 1 is -CF3.

9. The compound of any one of claims 1 to 8, wherein ring C is a substituted or unsubstituted pyrimidinyl, a substituted or unsubstituted pyridinyl, a substituted or unsubstituted thiazolyl, or a substituted or unsubstituted thiadiazolyl.

10. The compound of any one of claims 1 to 8, wherein ring C is a substituted or unsubstituted 1,3,4-thiadiazolyl.

15. The compound of any one of claims 1 to 8, wherein ring C is 5-(trifluoromethyl)pyrimidinyl, 5-(difluoromethyl)pyrimidinyl, 5-fluoropyrimidinyl, 5-bromopyrimidinyl, 5-chloropyrimidinyl, 5-methylpyrimidinyl, pyrimidine-5-carbonitrile, or 5-cyclopropylpyrimidinyl.

16. The compound of any one of claims 1 to 8, wherein ring C is 3-(trifluoromethyl)pyridinyl, 3-(difluoromethyl)pyridinyl, 3-fluoropyridinyl, 3-fluoropyridinyl, 3-methylpyridinyl, nicotinonitrile, or nicotinaldehyde.

17. The compound of any one of claims 1 to 8, wherein ring C is 5-(trifluoromethyl)pyridazinyl.

18. The compound of any one of claims 1 to 8, wherein ring C is thiazole-5-carbonitrile, 5-chlorothiazolyl, 5-methylthiazolyl, thiazole-5-carbonyl, thiazole-4-carbonyl, or 2-(trifluoromethyl)-1,3,4-thiadiazolyl.

25. The compound of claim 1, selected from the following list: ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068### ###0069### ###0070### ###0071### ###0072### ###0073### ###0074### ###0075### ###0076### ###0077### ###0078### ###0079### ###0080### ###0081### ###0082### ###0083### ###0084### ###0085### ###0086### ###0087### ###0088### ###0089### ###0090### ###0091### ###0092### ###0093### ###0094### ###0095### ###0096### ###0097### ###0098### ###0099### ###0100### ###0101### ###0102### ###0103### ###0104### ###0105### ###0106### ###0107### ###0108### ###0109### ###0110### ###0111### ###0112### ###0113### ###0114### ###0115### ###0116### ###0117### ###0118### ###0119### ###0120### ###0121### ###0122### ###0123### ###0124### ###0125### ###0126### ###0127### ###0128### ###0129### ###0130### ###0131### ###0132### ###0133### ###0134### ###0135### ###0136### ###0137### ###0138### ###0139### ###0140### ###0141### ###0142### ###0143### ###0144### ###0145### ###0146### ###0147### ###0148### ###0149### ###0150### ###0151### ###0152### ###0153### ###0154### ###0155### ###0156### ###0157### ###0158### ###0159### ###0160### ###0161### ###0162### ###0163### ###0164### ###0165### ###0166### ###0167### ###0168### ###0169### ###0170### ###0171### ###0172### ###0173### ###0174### ###0175### ###0176### ###0177### ###0178### ###0179### ###0180### ###0181### ###0182### ###0183### ###0184### ###0185### ###0186### ###0187### ###0188### ###0189### ###0190### ###0191### ###0192### ###0193### ###0194### ###0195### ###0196### ###0197### ###0198### ###0199### ###0200### ###0201### ###0202### ###0203### ###0204### ###0205### ###0206### ###0207### ###0208### ###0209### ###0210### ###0211### ###0212### ###0213### ###0214### ###0215### ###0216### ###0217### ###0218### ###0219### ###0220### ###0221### ###0222### ###0223### ###0224### ###0225### ###0226### ###0227### ###0228### ###0229### ###0230### ###0231### ###0232### ###0233### ###0234### ###0235### ###0236### ###0237### ###0238### ###0239### ###0240### ###0241### ###0242### ###0243### ###0244### ###0245### ###0246### ###0247### ###0248### ###0249### ###0250### ###0251### ###0252### ###0253### ###0254### ###0255### ###0256### ###0257### ###0258### ###0259### ###0260### ###0261### ###0262### ###0263### ###0264### ###0265### ###0266### ###0267### ###0268### ###0269### ###0270### ###0271### ###0272### 11. The compound of any one of claims 1 to 8, wherein ring C is R 2 - substituted or unsubstituted pyrimidinyl, R 2 - substituted or unsubstituted pyridinyl, R 2 - substituted or unsubstituted thiazolyl, or R 2 substituted or unsubstituted thiadiazolyl; R 2 independently halogen, -CN, -NH2, -OH, -COOH, -CONH2, -C(O)H, -CX 2 3、-CHX 2 2、substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, or substituted or unsubstituted C3-C8cycloalkyl; and X 2 independently -F, -Cl, -Br, or -I.

12. The compound of claim 11, wherein R 2 independently -CF3, -F, -CN, -CH3, -Cl, -CF (2) H , -Br, -C(O)H, substituted or unsubstituted C 1 -6 alkyl or substituted or unsubstituted C3-C8cycloalkyl.

13. The compound of claim 11, wherein R 2 is independently unsubstituted C3-C8cycloalkyl.

14. The compound of claim 11, wherein R 2 is independently unsubstituted cyclopropyl. ​ ​ ​ ​ 19. The compound of any one of claims 1 to 18, wherein L 1 is -N(R 3 )-L 2 -O-L 3 -; the nitrogen atom is attached to the pyridazinone, L 3 attached to the A ring; L 2 and L 3 independently substituted or unsubstituted C1-C4alkylene; and R 3 is hydrogen or unsubstituted C1-C4alkyl.

20. The compound of claim 19, wherein L 2 and L 3 are independently R 4 - substituted or unsubstituted C( 1) C4 alkylene; and R 4 independently unsubstituted C1-C4alkyl.

21. The compound of claim 20, wherein R 4 is unsubstituted methyl.

22. The compound of any one of claims 19 to 21, wherein R 3 is hydrogen.

23. The compound of any one of claims 19 to 22, wherein L 2 is -CH(CH3)-CH2-.

24. The compound of one of claims 19 to 23, wherein L 3 is unsubstituted methylene, unsubstituted ethylene or unsubstituted propylene. ​ 5-((1-(3-(2-oxo-4-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-(3-(2-oxo-3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)imidazolidin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-(3-(2-oxo-3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)imidazolidin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-(3-(2-oxo-3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)imidazolidin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 4-(trifluoromethyl)-5-(1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)pyridazin-3(2H)-one; 6-(4-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)nicotinonitrile; 4-(trifluoromethyl)-5-((1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 5-((1-((3-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((3-(1-(5-methylpyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 2-(4-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)thiazole-5-carbonitrile; 5-((1-((3-(1-(thiazol-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 4-(trifluoromethyl)-5-((1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)pyrimidine-5-carbonitrile; 4-(trifluoromethyl)-5-((1-((3-(1-(5-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)nicotinonitrile; 5-((1-((3-(1-(5-fluoropyridin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((3-(1-(5-chlorothiazol-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)thiazole-5-carbonitrile; (S) 4-(trifluoromethyl)-5-(1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)pyridazin-3(2H)-one; (R) 4-(trifluoromethyl)-5-(1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-ylamino)pyridazin-3(2H)-one; 5-((1-((3-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((3-(1-(5-chlorothiazol-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((3-(1-(5-methylpyrimidin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((3-((1-(5-(di fluoromethyl)pyrimidin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((3-(1-(5-methylthiazol-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 4-(trifluoromethyl)-5-((1-((3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 4-(trifluoromethyl)-5-((1-((3-(1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1-yl)thiazole-5-carbonitrile; 5-((1-((3-(1-(5-fluoropyrimidin-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((3-(1-(5-chloropyrimidin-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1-yl)nicotinonitrile; 5-((1-((3-(1-(5-methylpyridin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((3-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((3-(1-(5-chloropyrimidin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((3-(1-(5-(di fluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((3-((1-(5-(di fluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)nicotinaldehyde; 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)thiazole-5-carbaldehyde; 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile; 6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1-yl)nicotinaldehyde; 5-((1-((3-(1-(5-chlorothiazol-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1-yl)thiazole-5-carbaldehyde; 5-((1-((3-(1-(5-(di fluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)thiazole-4-carbaldehyde; 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)pyrrolidin-1-yl)thiazole-4-carbaldehyde; 5-((1-((3-(1-(5-chlorothiazol-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 4-(trifluoromethyl)-5-((1-((3-(1-(6-(trifluoromethyl)pyridazin-3-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 5-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)pyridinecarbonitrile; 4-(trifluoromethyl)-5-((1-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 4-(trifluoromethyl)-5-((1-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 6-(4-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)nicotinonitrile; 5-((1-((3-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-methylthiazol-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(thiazol-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 4-(trifluoromethyl)-5-((1-((1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-chloropyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-(difluoromethyl)pyridin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 6-(3-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)azetidin-1-yl)nicotinonitrile; 2-(4-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)pyrimidine-5-carbonitrile; 5-((1-((1-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 6-(3-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)nicotinonitrile; 5-((1-((1-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 2-(3-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)thiazole-5-carbonitrile; 5-((1-((1-(1-(5-chloropyridin-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-chlorothiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(thiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 2-(3-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile; 5-((1-((1-(1-(5-fluoropyrimidin-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-(difluoromethyl)pyrimidin-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-fluoropyridin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-methylpyridin-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-methylthiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 2-(3-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)azetidin-1-yl)pyrimidine-5-carbonitrile; 2-(3-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)thiazole-4-carbaldehyde; 2-(4-(4-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)thiazole-5-carbaldehyde; 5-((1-((1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; (R)-4-(trifluoromethyl)-5-((1-((1-(5-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; (R)-4-(trifluoromethyl)-5-((1-((1-(5-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 4-(trifluoromethyl)-5-((1-((1-(1-(6-(trifluoromethyl)pyridazin-3-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 4-(trifluoromethyl)-5-((1-((1-(1-(6-(trifluoromethyl)pyridazin-3-yl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 5-((1-((5-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 4-(trifluoromethyl)-5-((1-((5-(1-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 2-(4-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile; 5-((1-((5-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 2-(4-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)pyrimidine-4-carbonitrile; 4-(trifluoromethyl)-5-((1-((5-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 4-(trifluoromethyl)-5-((1-((5-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,3,4-oxadiazol-2-yl)azetidin-1-yl)nicotinonitrile; 4-(trifluoromethyl)-5-((1-((5-(1-(5-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one; 5-((1-((5-(1-(5-chloropyrimidin-2-yl)azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((5-(1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((5-(1-(5-(difluoromethyl)pyrimidin-2-yl)azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 2-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,3,4-oxadiazol-2-yl)azetidin-1-yl)pyrimidine-5-carbonitrile; 5-((1-((5-(1-(5-chloropyridin-2-yl)azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; (6-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,3,4-oxadiazol-2-yl)azetidin-1-yl)nicotinaldehyde; 5-((1-((5-(1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((5-(1-(5-methylpyrimidin-2-yl)azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((5-(1-(5-(difluoromethyl)pyridin-2-yl)azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((5-(1-(5-fluoropyridin-2-yl)azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-(3-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,3,4-oxadiazol-2-yl)azetidin-1-yl)picolinonitrile; 5-((1-((5-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 6-(4-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)nicotinaldehyde; 2-(4-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)pyrimidine-5-carbaldehyde; 5-((1-((3-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((3-(1-(5-(di fluoromethyl)pyridin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((3-(2-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((3-(2-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((3-(1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 2-(2-methyl-4-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)pyrimidine-5-carbonitrile; 6-(2-methyl-4-(5-((2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)methyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)nicotinonitrile; 5-((1-((3-(2,2-dimethyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((5-(1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((5-(1-(3-ethyl-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((5-(2-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((5-(2,2-dimethyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 5-((1-((1-(2-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1H-1,2,3- triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; 4-(trifluoromethyl)-5-((1-((8-(5-(trifluoromethyl)pyrimidin-2-yl)-8-azabicyclo[3.2.1] octan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)- one; 5-((1-((1-(8-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1H- 1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

26. A pharmaceutical composition comprising a compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

27. Use of a compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.

28. Use of a compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease associated with aberrant PARP7 activity.

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