Parp7 inhibitors and uses thereof

Abstract

This relates to a compound of formula (I) that has PARP7 inhibitory activity, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, and its use and preparation method.

Description

Technical Field

[0001] This disclosure relates to the pharmaceutical field, and in particular to a compound with PARP7 inhibitory activity, its uses and preparation method. Background Technology

[0002] Poly-ADP-ribose polymerases (PARPs) are a family of proteins composed of 17 different members in the human body, each playing an important role in various biological processes, including inflammation, viral infection, and tumor cell stress. The PARP family can be divided into three categories based on catalytic activity: polyPARPs (4 members, including PARP1, PARP2, PARP5a, and PARP5b), monoPARPs (12 members, including PARP3, PARP4, PARP6, PARP7, PARP8, PARP9, PARP10, PARP11, PARP12, PARP14, PARP15, and PARP16), and non-catalytically inactive PARPs (1 member, PARP13). Most research on PARPs has focused on polyPARPs (PARP1, 2, 5a, and 5b), particularly the role of PARP1 / 2 in DNA damage repair. DNA damage refers to the permanent alteration of the DNA nucleotide sequence during DNA replication, leading to changes in genetic characteristics. If DNA damage or abnormal changes in genetic information cannot be corrected, it will affect cell function or survival. DNA damage repair is a programmed, orderly, multi-stage, and precise process involving multiple factors. PARP is an important protein in the DNA repair process, participating in a series of important cellular processes, including DNA repair and maintenance of genome stability. Several PARP inhibitors are available: niraparib and talazoparib target PARP1 and PARP2; olaparib and rucaparib target PARP1, PARP2, and PARP3. Olaparib (first-in-class), represented by the PARP1 / 2 inhibitor developed by AstraZeneca, has become a blockbuster drug with significant anti-cancer efficacy, and its indications can be gradually expanded through combination therapy.

[0003] Studies on monoPARPs targeting ADP-riboylation are relatively limited. As mentioned above, most members of the PARP family (12 in total) are monoPARPs. Recent research on monoPARPs has revealed that PARP7 plays an important role in immunity and cancer. Specifically, studies suggest that PARP7 is one of the target genes of AHR (anti-inflammatory neuropathy), and is part of a negative feedback loop regulating AHR activity. AHR can regulate immune function, inflammation, and play a role in cancer. It can be induced by cancer-related stresses, such as harmful chemicals in tobacco. In-depth studies on lung cancer, esophageal cancer, and head and neck cancer, which are strongly correlated with smoking, have revealed amplification and high expression of the gene locus where PARP7 is located. Research has found that PARP7 is overactive in tumor cells, and many cancer cells rely on PARP7 for cell survival. Studies have also shown that PARP7 can enable cancer cells to evade immune system attacks. Inhibiting PARP7 can effectively suppress cancer cell growth, restore interferon signaling, and reverse immunosuppression. In several cancer models, PARP7 inhibitors have shown durable tumor growth inhibition and interferon signaling restoration effects. In summary, PARP7 plays a crucial role in cancer and immune responses, making it a potentially ideal cancer target. However, earlier studies lacked selective chemical probes for PARP7, relying primarily on genetic methods to elucidate its function, thus failing to distinguish between enzymatic activity and the entire protein and its interactions. Furthermore, the absence of mature high-throughput on-target activity screening methods hindered the development of corresponding drugs targeting PARP7. Given the increasing number of PARP7-related research findings in recent years, PARP7 has become a relatively ideal anti-cancer target. Therefore, timely research and development of new, safe, and effective PARP7 inhibitors is of great significance. In addition to its important role in tumors, as mentioned above, PARP7 also plays a key role in immune disorders, inflammation, and viral infections. Therefore, PARP7 inhibitors, besides their anti-cancer effects, are expected to have potential applications in other diseases such as those related to immunity, inflammation, and viral infections. Summary of the Invention

[0004] The purpose of this disclosure is to provide a compound having PARP7 inhibitory activity or a pharmaceutically acceptable salt thereof.

[0005] Specifically, this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof having the structure shown in formula (I):

[0006]

[0007] in,

[0008] X is selected from NH, O, S, sulfoxide, sulfone, or carbonyl;

[0009] Y is selected from CH2, NH, O, S, or a chemical single bond;

[0010] Z is selected from CH2, NH, O, S, carbonyl group, or chemical single bond;

[0011] V is selected from CH or N;

[0012] W is selected from CH2 or carbonyl group;

[0013] M is selected from CH2 or carbonyl; preferably, M is CH2;

[0014] U and T are each independently selected from CH or N;

[0015] n is selected from 1 or 2;

[0016] R 1 R 2 Each of the following is independently selected from H, D, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C1-C3 alkylthio, C1-C3 alkylsulfonyl, C1-C3 alkylsulfoxide, halogen or cyano, wherein the C1-C3 alkyl group is optionally substituted with one or more halogens;

[0017] R 3 The components are selected from H, D, C1-C6 alkyl, C2-C6 enalkyl, C2-C6 alkynyl, C3-C9 cycloalkyl, 3-9 membered heterocyclic, 5-6 membered heterocyclic aryl, or phenyl, wherein the C1-C6 alkyl, C2-C6 enalkyl, C2-C6 alkynyl, C3-C9 cycloalkyl, 3-9 membered heterocyclic, 5-6 membered heterocyclic aryl, or phenyl may be substituted with one or more R.

[0018] R 4 R 5 Each is independently selected from H, D, halogen, cyano, C1-C6 alkyl, C2-C6 enylalkyl, C2-C6 alkynyl, C3-C9 cycloalkyl, 3-9 membered heterocyclic, 5-6 membered heterocyclic aryl, phenyl, -NR 10 R 11 -OR 7 -SR 7 -S(O)R 7 -S(O)2R 7 -C(O)R 7 The R 7 R 10 R 11 C1-C6 alkyl, C2-C6 enalkyl, C2-C6 alkynyl, C3-C9 cycloalkyl, 3-9 membered heterocyclic, 5-6 membered heterocyclic aryl, and phenyl can be substituted by one or more R;

[0019] The R is selected from halogen, hydroxyl, cyano, carboxyl, ester, amide, sulfonamide, C1-C3 alkyl, C3-C9 cycloalkyl, 3-9 membered heterocyclic, 5-6 membered heterocyclic aryl, phenyl, -NR 10 R 11 -OR 7 -SR 7 -S(O)R 7 -S(O)2R 7 -C(O)R 7 ;

[0020] R 6 Selected from H, D, halogen, cyano, C1-C6 alkyl, C2-C6 enalkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -NR 10 R 11 -OR 7 -SR 7 -S(O)R 7 -S(O)2R 7 -C(O)R 7 The R 7 R 10 R 11 C1-C6 alkyl, C2-C6 enalkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, which may be substituted by one or more halogens, hydroxyl groups, ester groups, amide groups, or sulfonamide groups;

[0021] R 7 R 10 R 11 They are independently selected from H, C1-C6 alkyl, C1-C5 haloalkyl, and C3-C6 cycloalkyl;

[0022] R 8 R 9 The group is independently selected from H, D, halogen, hydroxyl, amino, amide, ester, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C1-C3 alkylthio, C1-C3 alkylamino, C1-C3 alkylsulfonyl or C1-C3 alkylsulfoxide, cyano, wherein the C1-C3 alkyl group is optionally substituted with one or more halogens;

[0023] A rings are 5-7 membered saturated or unsaturated heterocycles containing N, O, or S atoms.

[0024] Preferably, the compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug has the structure shown in formula (Ia):

[0025]

[0026] Among them, X, Y, Z, V, W, U, T, n, R 1 R 2 R 3 R 4 R 5 R 6 Each of the A rings is a custom compound of formula (I);

[0027] Preferably, ring A is a 5-7 member unsaturated heterocycle containing N, O, or S atoms.

[0028] Preferably, X is selected from NH.

[0029] Preferably, Y is selected from CH2, O, S or a chemical single bond.

[0030] Preferably, Z is selected from O, carbonyl, or a chemical single bond.

[0031] Preferably, R 1 and R 2 The radicals are independently selected from H, D, halogen, cyano, methyl, trifluoromethyl, methoxy, ethyl, isopropyl, cyclopropyl, methylthio, methyl sulfone, and methyl sulfoxide, respectively.

[0032] Preferably, R 1 Selected from trifluoromethyl.

[0033] Preferably, R 2 Selected from H.

[0034] Preferably R 3 It is a C1-C6 alkyl group.

[0035] Preferably R 3 The derivatives are methyl, ethyl, propyl, and isopropyl.

[0036] Preferably R 3 It is a methyl group.

[0037] Preferably R 4 R 5 They were each independently selected from H, F, Cl, Br, and I.

[0038] Preferably R 4 R 5 They were selected independently from H and F, respectively.

[0039] Preferably R 4 R 5 All are H.

[0040] Preferably, R 3 and R 4They can each form 3-7 membered rings with the carbon atoms they are attached to, and the formed rings may optionally be converted to one or more halogens, hydroxyl groups, cyano groups, carboxyl groups, ester groups, amide groups, sulfonamide groups, C1-C3 alkyl groups, C3-C9 cycloalkyl groups, 3-9 membered heterocyclic groups, 5-6 membered heterocyclic aryl groups, phenyl groups, or -NR groups. 10 R 11 -OR 7 -SR 7 -S(O)R 7 -S(O)2R 7 -C(O)R 7 replace.

[0041] Preferably, the formula (I) or formula (Ia) shown Selected from the following groups: -NHCH(CH3)CH2-, -NHCH(CH3)CH2O-, -NHCH(CH3)CH2S-, -NHCH(CH3)CH2CH2-, -NHCH(CH3)CH2NH-, -NHCH(CH3)CH2F-.

[0042] Preferably, R 6 Selected from H, D, halogen, cyano, C1-C6 alkyl, C2-C6 enylalkyl, C2-C6 ynylalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic groups containing at least one O, N or S heteroatom, -NR 10 R 11 -OR 7 -SR 7 -S(O)R 7 -S(O)2R 7 -C(O)R 7 The R 7 R 10 R 11 C1-C6 alkyl, C2-C6 enalkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, which may be substituted by one or more halogens, hydroxyl groups, ester groups, amide groups, or sulfonamide groups.

[0043] Preferably, R 6 Selected from H, D, halogen, cyano, methyl, trifluoromethyl, methoxy, ethyl, isopropyl, cyclopropyl, methylthio, methyl sulfone, or methyl sulfoxide.

[0044] Preferably, R 6 Selected from trifluoromethyl.

[0045] Preferably, as shown in formula (I) Selected from the following groups:

[0046] Preferably, as shown in formula (Ia) Selected from the following groups:

[0047] Among them, R 6 The definition is the same as before.

[0048] Preferably, ring A is selected from:

[0049]

[0050]

[0051] Preferably, ring A is selected from:

[0052]

[0053] Preferably, ring A is selected from:

[0054]

[0055] Preferably, ring A is selected from:

[0056]

[0057] Preferably, ring A is selected from:

[0058]

[0059] Preferably, ring A is selected from:

[0060]

[0061] R 8 R 9 The group is independently selected from H, D, halogen, hydroxyl, amino, amide, ester, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C1-C3 alkylthio, C1-C3 alkylamino, C1-C3 alkylsulfonyl or C1-C3 alkylsulfoxide, cyano, wherein the C1-C3 alkyl group is optionally substituted with one or more halogens.

[0062] Preferably, R 8 R 9 Each is independently selected from H, D, halogen, hydroxyl, amino, methyl, trifluoromethyl, methoxy, ethyl, cyclopropyl, isopropyl, methylthio, methylamino, amide, ester, methyl sulfone, and methyl sulfoxide.

[0063] Preferably, R 8 R 9 Each of the following is independently selected from H, D, F, Cl, Br, and methyl groups.

[0064] Preferably, R8 R 9 Each of the following is independently selected from H, F, Cl, and methyl.

[0065] Preferably, the compounds disclosed herein, their pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs have the structures shown in formula (II), (III), or (IV):

[0066]

[0067] Preferably, the compounds, pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof disclosed herein have the structures shown in formula (IIa), (IIIa), or (IVa):

[0068]

[0069]

[0070] Preferably, the compounds, pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof disclosed herein have the structures shown in formula (IIb), (IIIb), or (IVb):

[0071]

[0072] in,

[0073] R 1 R 6 The definitions of Y, T, U, V, W, and M are the same as those in claim 1.

[0074] This disclosure also provides the following compounds, their pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs:

[0075]

[0076]

[0077]

[0078]

[0079] This disclosure also provides a pharmaceutical composition comprising any of the foregoing compounds, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof and a pharmaceutically acceptable excipient thereof.

[0080] This disclosure also provides the use of any of the foregoing compounds, their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, and the foregoing pharmaceutical compositions in the preparation of medicaments for treating patients with PARP-mediated conditions.

[0081] This disclosure also provides the use of any of the foregoing compounds, their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, and the foregoing pharmaceutical compositions in the preparation of PARP inhibitors.

[0082] This disclosure also provides the use of any of the foregoing compounds, their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, and the foregoing pharmaceutical compositions in the preparation of PARP7 inhibitors.

[0083] This disclosure also provides a method for inhibiting PARP in a patient in need, the method comprising administering to the patient any of the foregoing compounds, their pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs.

[0084] This disclosure also provides a method for inhibiting PARP in a biological sample, comprising contacting the biological sample with any of the aforementioned compounds, their pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof.

[0085] This disclosure also provides a method for treating a patient in need of a PARP-mediated condition, comprising administering to the patient any of the foregoing compounds, their pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs.

[0086] Preferably, the PARP-mediated conditions include, but are not limited to, one or more of tumors, immune diseases, inflammatory diseases, and viral infections. Detailed Implementation

[0087] Based on the above content of this disclosure, and in accordance with common technical knowledge and practices in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical ideas of this disclosure.

[0088] definition

[0089] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated elements or components without excluding other elements or other components.

[0090] The compounds disclosed herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. Racemic, diastereomer, and enantiomers are all included within the scope of this disclosure.

[0091] The disclosed compounds also include tautomer forms. Tautomer forms arise from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton.

[0092] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0093] The numerical ranges mentioned in this article refer to the integers within a given range. For example, "C1-C6" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms; "C3-C6" means that the group can have 3, 4, 5, or 6 carbon atoms.

[0094] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom or group by a substituent, provided that the valence state of the particular atom or group is normal and the resulting compound is stable. When the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are substituted. Unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis.

[0095] When any variable (e.g., R) n When a substituent appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 1-5 Rs, the group can optionally be substituted by up to 5 Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0096] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 2,2-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group. The present disclosure preferably includes methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0097] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio. The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0098] The term "cycloalkyl" refers to a saturated hydrocarbon system without heteroatoms or double bonds, and can be monocyclic, fused, bridged, or spirocyclic. Examples of the term "C3-C9 cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0099] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, which can be monocyclic, fused, bridged, or spirocyclic, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; even more preferably, it contains a 3-8 membered heterocyclic group containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spirocyclic groups, or nitrogen-containing fused heterocyclic groups.

[0100] Non-limiting examples of monocyclic heterocyclic groups include pyrrolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, cycloheptyl, 1,4-diazaheptanyl, pyranyl, etc., with pyrrolyl, morpholinyl, piperidinyl, cycloheptyl, 1,4-diazaheptanyl, and piperazinyl being preferred. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0101] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include...

[0102]

[0103] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, cyano, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0104] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated p2 electron system, preferably 6- to 12-membered, such as phenyl and thalyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo5- to 10-membered heteroaryl, benzo3- to 8-membered cycloalkyl, and benzo3- to 8-membered heteroalkyl, preferably benzo5- to 6-membered heteroaryl, benzo3- to 6-membered cycloalkyl, and benzo3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further include a ternary nitrogen-containing fused ring containing a benzene ring.

[0105] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0106] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl, pyrroleyl, and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0107]

[0108] wait.

[0109] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0110] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydrogen, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester.

[0111] The term "alkathio" refers to -S- (alkyl) and -S- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkathio groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, and cyclohexylthio. Alkathio groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkathio, alkylamino, halogen, thio, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkathio, heterocycloalkylthio, carboxyl, or carboxylic acid ester.

[0112] "Alkylthio-alkyl" refers to an alkylthio group attached to an alkyl group, where the alkyl and alkylthio groups are as defined above.

[0113] "alkylaminocarbonyl" refers to (alkyl)-NC(O)-, where alkyl is defined as described above.

[0114] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0115] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0116] "Haloalkoxy" refers to an alkylthio group substituted by one or more halogens, wherein the alkylthio group is as defined above.

[0117] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0118] "Alkenyl" refers to an alkenyl group, also known as an olefinic group. The alkenyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0119] "Alynyl" refers to (CH≡C-), wherein the alkynyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, cyano, nitro, phenolic, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0120] The term "alkenyl carbonyl" refers to -C=(O)-(alkenyl), where alkenyl is defined as described above. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, and butenyl carbonyl. Alkenyl carbonyl can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0121] "Hydroxy" refers to the -OH group.

[0122] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0123] "Amino" refers to -NH2.

[0124] “Cyano” refers to -CN.

[0125] "Nitro" refers to -NO2.

[0126] "Carbonyl" refers to -C(O)-.

[0127] "Carboxyl group" refers to -C(O)OH.

[0128] "THF" refers to tetrahydrofuran.

[0129] “EtOAc” refers to ethyl acetate.

[0130] “MeOH” refers to methanol.

[0131] "DMF" refers to N,N-dimethylformamide.

[0132] "DIPEA" refers to diisopropylethylamine.

[0133] "TFA" refers to trifluoroacetic acid.

[0134] “MeCN” refers to Yi Qing.

[0135] "DMA" refers to N,N-dimethylacetamide.

[0136] “DCE” refers to 1,2-dichloroethane.

[0137] “NBS” refers to N-bromosuccinimide.

[0138] “NIS” refers to N-iodosuccinimide.

[0139] "cbz-cr refers to benzyl chloroformate".

[0140] "Pd2(dba)3" refers to tris(dibenzylacetone)dipalladium.

[0141] “Dppf” refers to 1,1'-bis(diphenylphosphine)ferrocene.

[0142] “HATU” refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0143] "KHMDS" refers to potassium hexamethyldisilamide.

[0144] "LiHMDS" refers to lithium bis(trimethylsilyl)amine.

[0145] “MeLi” refers to methyl lithium.

[0146] “n-BuLi” refers to n-butyllithium.

[0147] "NaBH(OAc)3" refers to sodium triacetoxyborohydride. "SEM" refers to (trimethylsilyl)ethoxymethyl. The different expressions such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning: X can be any one or more of A, B, and C.

[0148] All hydrogen atoms described in this disclosure can be replaced by their isotope deuterium.

[0149] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0150] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0151] It refers to the junction of chemical bonds.

[0152] The space between the two C atoms in the structural formula This refers to a compound whose stereostructure is not clearly defined, for example, The space between the 3rd and 4th carbon atoms of piperidone in the structure This indicates that the three-dimensional configuration is unclear.

[0153] Drugs or drug compositions

[0154] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications in proportion to a reasonable benefit / risk ratio.

[0155] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of the free acid or base of a particular compound without any adverse biological effects. Examples include acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases).

[0156] The pharmaceutically acceptable salts disclosed herein can be synthesized from parent compounds containing an acid radical or a base using conventional chemical methods. Generally, such salts are prepared by reacting these compounds, in their free acid or base form, with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0157] The pharmaceutical products or pharmaceutical compositions disclosed herein can be administered orally, topically, parenterally, or via mucosal routes (e.g., sublingually, by inhalation, or rectally) in dosage units comprising a conventional, non-toxic, pharmaceutically acceptable carrier. Oral administration is generally preferred. The active agent can be administered orally in capsule, tablet, or other similar forms (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0158] For oral administration in tablet or capsule form, the active pharmaceutical ingredient may be combined with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol, and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl docosanoate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium hydroxyacetic acid starch); or wetting agents (e.g., sodium lauryl sulfate), colorants and flavorings, gelatin, sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth, or alginate), buffer salts, carboxymethyl cellulose, polyethylene glycol, waxes, etc. For oral administration in liquid form, the pharmaceutical component may be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), an anti-settling agent (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., almond oil, esters, ethanol, or fractionated vegetable oils), and a preservative (e.g., methylparaben, propylparaben, or sorbic acid). Stabilizers such as antioxidants (BHA, BHT, propyl iodide, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.

[0159] Tablets containing the active compound can be coated using methods well known in the art. The compositions of this disclosure containing a compound of formula I as the active compound can also incorporate beads, microspheres, or microcapsules, for example, constructed from polyglycolic acid / lactic acid (PGLA). Liquid formulations for oral administration can take the form of, for example, solutions, syrups, emulsions, or suspensions, or they can be presented as dry products reconstituted with water or other suitable excipients prior to use. Formulations for oral administration can be suitably formulated to allow for controlled or delayed release of the active compound.

[0160] The pharmaceutical products or pharmaceutical compositions disclosed herein can be delivered parenterally, i.e., administered intravenously (IV), intraventricularly (ICV), subcutaneously (SC), intraperitoneally (IP), intramuscularly (IM), subcutaneously (SD), or intradermally (ID), by direct injection, such as rapid concentration or continuous infusion. Formulations for injection may be presented in unit dosage forms, such as in ampoules or multi-dose containers with added preservatives. The compositions may be in the form of excipients, suspensions, solutions, or emulsions in oil or aqueous carriers, and may contain formulation agents such as anti-settling agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be reconstituted in powder form with a suitable carrier (e.g., sterile, pyrogen-free water) prior to use.

[0161] The pharmaceutical or pharmaceutical composition disclosed herein can also be formulated for rectal administration, for example as a suppository or retention enema (e.g., containing a conventional suppository base such as cocoa butter or other glycerides).

[0162] The term "treatment" includes suppressing, alleviating, preventing, or eliminating one or more symptoms or side effects associated with the disease, condition, or disorder being treated.

[0163] The terms “reduction,” “inhibition,” “mitigation,” or “reduction” are used relative to a control. Those skilled in the art will readily determine the appropriate control for each experiment. For example, a reduced response in a subject or cell treated with the compound is compared to a response in a subject or cell not treated with the compound.

[0164] As used herein, the term "effective dose" or "therapeutic effective dose" refers to a dose sufficient to treat, suppress, or alleviate one or more symptoms of the treated disease state or otherwise provide the desired pharmacological and / or physiological effect. The precise dose will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or illness, and the treatment administered. The effect of an effective dose can be relative to a control. These controls are known in the art and discussed herein, and can be, for example, the condition of the subject before or without administration of the drug or combination of drugs, or, in the case of a combination of drugs, the combined effect can be compared to the effect of administration of only one drug.

[0165] The term "excipient" is used herein to include any other compound that is not therapeutic or biologically active and may be contained in or on microparticles. Therefore, excipients should be pharmaceutically or biologically acceptable or relevant, for example, excipients that are generally non-toxic to the subject. "Excipient" includes a single such compound and is also intended to include multiple compounds.

[0166] The term "pharmaceutical composition" means a composition comprising the compounds described in this disclosure or their pharmaceutically acceptable salts, and at least one pharmaceutically acceptable ingredient selected from the following, depending on the manner of administration and the nature of the dosage form: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, thermosensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

[0167] Uses and treatments

[0168] The terms “patient,” “subject,” “individual,” etc., are used interchangeably herein and refer to any animal or its cells, whether in vitro or in situ, that conform to the methods described herein. In some non-limiting embodiments, the patient, subject, or individual is a person.

[0169] According to the methods disclosed herein, compounds or compositions may be administered in any amount and via any route of administration that are effective in treating or reducing the severity of PARP-related diseases.

[0170] This disclosure relates to a method for inhibiting PARP in a biological sample, comprising the step of contacting the biological sample with a compound of this disclosure or a composition containing the compound.

[0171] The term "biological sample" includes (but is not limited to) cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof. Inhibition of enzymes in biological samples can be used to achieve a variety of purposes known to those skilled in the art. Examples of such purposes include (but are not limited to) bioanalysis, gene expression studies, and identification of biological targets.

[0172] The present disclosure discloses a method for inhibiting PARP in a patient, comprising the step of administering the disclosed compound or a composition comprising the compound to the patient.

[0173] The provided compounds are PARP inhibitors, including but not limited to PARP7 inhibitors, and are therefore intended for the treatment of one or more conditions associated with PARP activity. Accordingly, in some embodiments, this disclosure provides a method for treating PARP-mediated conditions comprising the step of administering a compound of this disclosure or a pharmaceutically acceptable combination thereof to a patient in need.

[0174] As used herein, the term "PARP-mediated" refers to any disease, ailment, and / or symptom where PARP or its mutants are known to act. Therefore, another embodiment of this disclosure relates to treating or reducing the severity of one or more diseases where PARP or its mutants are known to act.

[0175] This disclosure provides a method for treating one or more conditions, diseases, and / or symptoms, wherein the condition, disease, or symptom is a proliferative disease, such as cancer, inflammatory conditions, or viral infections.

[0176] In some embodiments, this disclosure provides a method of treating cancer or another proliferative condition, comprising administering a compound or composition of the disclosed invention to a patient suffering from cancer or another proliferative condition. In some embodiments, the method of treating cancer or another proliferative condition comprises administering a compound or composition of the disclosed invention to a mammal. In some embodiments, the mammal is a human.

[0177] As used herein, the terms “cancer inhibition” and “cancer cell proliferation inhibition” refer to inhibiting the growth, division, maturation, or survival of cancer cells, and / or causing cancer cell death through cytotoxicity, nutrient depletion, or induction of apoptosis, individually or collectively with other cancer cells.

[0178] Examples of tissues containing cancer cells whose proliferation is inhibited by the compounds and compositions described herein and to which the methods described herein are applicable include (but are not limited to) the breast, prostate, brain, blood, bone marrow, liver, pancreas, epidermis, kidney, colon, ovary, lung, testis, penis, thyroid gland, parathyroid gland, pituitary gland, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gallbladder, rectum, salivary glands, adrenal glands, pharynx, esophagus, lymph nodes, sweat glands, sebaceous glands, muscles, heart, and stomach.

[0179] Cancers treated by the compounds or compositions disclosed herein include melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, or colon cancer. In some embodiments, the cancer is primary exudative lymphoma (PEL).

[0180] The compounds disclosed herein may be used to treat proliferative diseases selected from the following: benign or malignant tumors or carcinomas of the brain, kidneys, liver, adrenal glands, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lungs, vagina, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone, or thyroid gland; sarcomas, glioblastomas, neuroblastomas, multiple myeloma, or gastrointestinal cancers (especially colon cancer or colorectal adenomas) or tumors of the neck and head; epidermal hyperplasia; psoriasis; benign prostatic hyperplasia; tumor formation; epithelial-characteristic tumor formation; adenoma; adenocarcinoma; keratoacanthoma; epidermoid carcinoma; large cell carcinoma; non-small cell lung cancer; Hodgkin's and non-Hodgkin's lymphomas; breast cancer; follicular carcinoma; undifferentiated tumors; papillary carcinoma; seminoma; melanoma; MYD88-driven diseases; DLBCL; ABC. DLBCL, IL-1 driven diseases, mild or indolent multiple myeloma or leukemia.

[0181] The cancers described in this disclosure include (but are not limited to) leukemias (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphomas (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenström's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphoendothelial sarcoma, synovoma, mesothelioma, Ewing's tumor). Tumor), leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver tumor, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

[0182] In some specific embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0183] In some specific embodiments, the cancer is an acoustic neuroma, an astrocytoma (e.g., grade I - pilocytic astrocytoma, grade II - low-grade astrocytoma, grade III - pleomorphic astrocytoma, or grade IV - glioblastoma (GBM)), a chordoma, a CNS lymphoma, a craniopharyngioma, a brainstem glioma, an ependymoma, a mixed glioma, an optic nerve glioma, a subependymal ependymoma, a medulloblastoma, a meningioma, a metastatic brain tumor, an oligodendroglioma, a pituitary tumor, a primary neuroectodermal tumor (PNET), or a schwannoma. In some embodiments, the cancer is a type more common in children than in adults, such as a brainstem glioma, a craniopharyngioma, an ependymoma, a juvenile pilocytic astrocytoma (JPA), a medulloblastoma, an optic nerve glioma, a pineal tumor, a primary neuroectodermal tumor (PNET), or a rhabdoid tumor. In some embodiments, the patient is an adult patient. In some embodiments, the patient is a child or a pediatric patient.

[0184] In another specific embodiment, cancers include (but are not limited to): mesothelioma, hepatobiliary (liver and bile ducts), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, melanoma of the skin or eye, ovarian cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal cancer (stomach, colon, rectum, and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancers, thyroid cancer, parathyroid cancer, Adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin's lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, bile duct carcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or one or more of the above cancers.

[0185] In some specific embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine serous papillary carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; bile duct hepatocellular carcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; pleomorphic thyroid carcinoma; adrenocortical adenoma; pancreatic cancer; pancreatic duct carcinoma or pancreatic cancer; gastrointestinal / stomach (GIST) cancer; lymphoma; head and neck squamous cell carcinoma (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenström's macroglobulinemia; or medulloblastoma.

[0186] The term "primary tumor" is relative to secondary tumors. A primary tumor refers to a tumor that first appears in a certain location, such as the lungs, liver, intestines, head, or skin. It can be called primary lung cancer, primary liver cancer, primary intestinal cancer, etc.

[0187] The term "inflammatory disease" includes the aforementioned autoimmune, allergic, and inflammatory conditions, such as those selected from arthritis, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, gastritis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, rheumatic fever, gout, organ or transplant rejection, acute or chronic graft-versus-host disease, chronic allogeneic graft rejection, Bechtel's disease, uveitis, psoriasis, dermatitis, atopic dermatitis, dermatomyositis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjögren's syndrome, and blistering conditions (e.g., pemphigus vulgaris), antibody-mediated vasculitis syndromes, including ANCA-associated vasculitis, purpura, and immune complex vasculitis (stage I or II cancer or infection). The aforementioned allergic conditions may be particularly selected from contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollen and related allergens, and beryllium poisoning. The respiratory conditions mentioned may be selected in particular from asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoma, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, primary pulmonary hypertension, and emphysema.

[0188] The term "viral infection" includes, but is not limited to, retroviral infection, hepatitis virus infection, COVID-19 infection, Zika virus infection, dengue virus infection, etc.

[0189] combination therapy

[0190] This disclosure provides combination therapies using compounds as described herein in combination with other therapeutic agents. As used herein, the term "combination therapy" includes the sequential administration of these agents, i.e., each therapeutic agent is administered at different times, and the administration of these agents, or at least two agents, substantially simultaneously. The order, or substantially simultaneous administration, of each agent may be influenced by any suitable route, including, but not limited to, oral, intravenous, intramuscular, subcutaneous routes, and direct absorption through mucosal tissues. Agents may be administered via the same or different routes. For example, a first agent may be administered orally, while a second agent may be administered intravenously. Furthermore, selected combinations may be administered intravenously, while other agents in the combination may be administered orally. Alternatively, for example, two or more agents may be administered intravenously or subcutaneously.

[0191] Example

[0192] The present disclosure is further illustrated below with reference to embodiments. The description of specific exemplary embodiments of the present disclosure is for illustrative and explanatory purposes. These descriptions are not intended to limit the present disclosure to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the teachings of this specification. The exemplary embodiments were chosen and described in order to explain the specific principles of the present disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the present disclosure, as well as various different choices and variations.

[0193] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0194] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0195] Instruments and reagents:

[0196] NMR: Agilent 400MR DD2 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents and tetramethylsilane (TMS) as the internal standard.

[0197] Liquid chromatography-mass spectrometry (LC-MS): Agilent 1260 Infinity II-InfinityLab LC / MSD mass spectrometer.

[0198] HPLC: Agilent 1260 Infinity II high-performance liquid chromatograph (Sunfire C18 5um 150 x 4.6mm column).

[0199] Thin-layer chromatography silica gel plates: HSGF254 silica gel plates (Yantai Jiangyou Silica Gel Development Co., Ltd.), specifications 0.9mm-1mm.

[0200] TLC silicone sheet: GF254 silicone sheet (Yu Cheng Chemical (Shanghai) Co., Ltd.), specifications 0.2mm = 0.25mm.

[0201] Column chromatography: 300-400 mesh silica gel (Qingdao Hailang Silica Gel Desiccant Co., Ltd.), Flash column (Claricep Flash amorphous silica gel purification column).

[0202] Reagents: 1,1-Cyclopropyldicarboxylic acid monomethyl ester, 1,1-cyclopropanediethanol and Pd / C (Shanghai Haohong Biomedical Technology Co., Ltd.), 4N dioxane hydrochloride solution (Shanghai Kaiman Chemical Technology Co., Ltd.), other reagents and starting materials were purchased from Shanghai Bid Reagent Co., Ltd., or synthesized using methods known in the art.

[0203] Unless otherwise specified, all reactions in this disclosure are carried out under continuous magnetic stirring, in dry nitrogen or argon atmosphere, in dry solvent, and at temperatures in degrees Celsius.

[0204]

[0205]

[0206] Synthesis of intermediates

[0207] Intermediate I-1: Synthesis of 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one

[0208]

[0209] Step 1: Preparation of 4,5-dibromo-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (I-1a)

[0210] Under nitrogen protection at 0 °C, sodium hydride (9.45 g, 236 mol, 60% purity) was added dropwise to a stirred solution of 4,5-dibromopyridin-3(2H)-one (40 g, 157.55 mmol) in 250 mL of N,N-dimethylformamide. The resulting solution was stirred at room temperature for 0.5 h, then cooled to 0 °C, and (2-(chloromethoxy)ethyl)trimethylsilane (28.89 g, 173.31 mmol) was added dropwise. The reaction mixture was heated to room temperature and stirred for 2 h, then quenched with 250 mL of water. The resulting reaction mixture was extracted three times with 250 mL of ethyl acetate each time, and the combined organic phase extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 4,5-dibromo-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (I-1a) (63.38 g). ESI[M+Na] + =407.0, ESI[2M+Na] + =791.0

[0211] Step 2: Preparation of 4-bromo-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (I-1b)

[0212] Lithium chloride (6.99 g, 164.99 mol) was added to a solution of 4,5-dibromo-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (I-1a) (63.38 g, 164.99 mmol) in 250 mL of N-methylpyrrolidone under stirring. The resulting solution was heated to 95 °C and stirred for 4 h. The reaction mixture was then cooled to room temperature and quenched with 250 mL of water. The resulting reaction mixture was extracted with 3 × 250 mL of ethyl acetate, and the organic layers were combined. The organic layers were washed with 3 × 250 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Flash column chromatography (ethyl acetate:petroleum ether = 1:50) to give compound 4-bromo-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (I-1b) (38.96 g, yield 69.51%). ESI [2M+Na] + =701.1

[0213] Step 3: Preparation of 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (I-1)

[0214] At room temperature, 4.37 g (22.90 mmol) of 4-bromo-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (I-1b) (38.96 g, 114.69 mmol) in N-methylpyrrolidone (250 mL) was added to iodide ketone (22.90 mmol), followed by dropwise addition of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (66.10 g, 344.07 mmol). The resulting solution was stirred at 80 °C for 2 hours. The reaction was quenched with 250 mL of water and extracted with 3 × 250 mL of ethyl acetate. The organic layers were combined, washed with 3 × 250 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (ethyl acetate:petroleum ether = 1:100) to give compound 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (I-1) (24.01 g, yield 63.67%). ESI [M+Na] + =351.1, ESI[2M+Na] + =679.0

[0215] Intermediate I-2: 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride

[0216]

[0217] Step 1: Preparation of tert-butyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylic acid (I-2a)

[0218] 2-Chloro-5-(trifluoromethyl)pyrimidine (1825 mg, 10 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1862 mg, 10 mmol) were dissolved in N-methylpyrrolidone (30 ml), and potassium carbonate (2764 mg, 20 mmol) was added. The mixture was reacted at 80 °C for 1 hour. Water (100 ml) was added, the solid was collected by filtration, and dried under vacuum to give the target product 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-2a) (2.9 g, yield 87%).

[0219] Step 2: Preparation of 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (I-2)

[0220] 332 mg (1 mmol) of 3-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-2a) was dissolved in 4 M ethyl acetate (5 mL) and reacted at room temperature for 2 hours. The reaction solution was filtered, and the solid was washed with petroleum ether to give the target product, 2-(piperazine-1-yl)-5-(trifluoromethyl)pyrimidinium hydrochloride (I-2) (289 mg, 94% yield). ESI[M+H] + =233.1, 1 H NMR (400MHz, dmso) δ9.48 (s, 2H), 8.78 (s, 2H), 4.06 (s, 4H), 3.18 (s, 4H).

[0221] Intermediate I-3: (S)-2-((tert-Butoxycarbonyl)amino)propyl 4-toluenesulfonate

[0222]

[0223] (S)-(1-hydroxypropyl-2-yl)carbamate tert-butyl ester (1751 mg, 10 mmol) was dissolved in dichloromethane (10 mL), and 4-dimethylaminopyridine (1833 mg, 15 mmol) was added. The mixture was cooled to 0 °C, and p-toluenesulfonyl chloride (2097 mg, 11 mmol) was dissolved in dichloromethane (10 mL) and added dropwise to the flask. The reaction was carried out at room temperature for 2 hours. The organic phase was washed twice with pure water and once with brine. The organic phase was dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and purified by Flash column chromatography (ethyl acetate: petroleum ether) to give the target product (S)-2-((tert-butyloxycarbonyl)amino)propyl 4-toluenesulfonate (I-3) (2.1 g, yield 65%). ESI [M+H-56] = 274.1, ESI [M+H-100] + =230.1, ESI[2M+H]+ =659.4

[0224] Intermediate I-4: (S)-(1-Iodopropane-2-yl)tert-butyl carbamate

[0225]

[0226] Imidazole (1184 mg, 17.4 mmol) and triphenylphosphine (4561 mg, 17.4 mmol) were dissolved in tetrahydrofuran (25 ml) under nitrogen protection. The temperature was controlled at 0 °C. Iodine (4.8 g, 18.9 mmol) was added in batches at this temperature. After the addition was complete, the mixture was stirred at 0 °C for 30 minutes. (S)-(1-hydroxypropyl-2-yl) tert-butyl carbamate (2537 mg, 14.5 mmol) was dissolved in tetrahydrofuran (8 ml) and slowly added to the above mixture at 0 °C. After the reaction was completed, the mixture was reacted at 0 °C for 4 hours, and then the reaction was carried out at room temperature for 6 hours. After the reaction was complete, 60 ml of ethyl acetate was added to the mixture, filtered, and the filtrate was washed with saturated sodium thiosulfate (30 ml * 3). The organic phase was then washed with saturated sodium chloride solution (30 ml * 3), and finally dried over anhydrous sodium sulfate. After concentration, a Flash column chromatography was performed to obtain the target product (S)-(1-iodopropane-2-yl)carbamate tert-butyl ester (I-4) (2090 mg, yield 50.6%). ESI [M+H-56] + =230.0, ESI[2M+H] + =571.3

[0227] Intermediate I-5: 1-(4-(trifluoromethyl)phenyl)piperazine

[0228]

[0229] Step 1: Preparation of tert-butyl 4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxylic acid (I-5a)

[0230] At room temperature, 1-bromo-4-(trifluoromethyl)benzene (5.0 g, 22.2 mmol), piperazine-1-carboxylic acid tert-butyl ester (7.36 g, 22.2 mmol), and cesium carbonate (21.7 g, 66.6 mmol) were dissolved in 1,4-dioxane (150 mL) and ethyl acetate (150 mL). Palladium acetate (498 mg, 2.22 mmol) and 1,1′-binaphthyl-2,2′-bis(diphenylphosphine) (1.38 g, 2.22 mmol) were added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred overnight at 100 °C. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 2:1) to give tert-butyl 4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxylic acid (I-5a) (5.5 g, yield: 75.3%). ESI [M+H] + =331.1

[0231] Step 2: Preparation of 1-(4-(trifluoromethyl)phenyl)piperazine (I-5)

[0232] At room temperature, 1.0 g (3.03 mmol) of 1-(4-(trifluoromethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (I-5a) was dissolved in 10 mL of dichloromethane, and dioxane hydrochloride (4 M, 3 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction proceeded until the starting material disappeared on a TLC plate, indicating completion. The reaction mixture was then concentrated under reduced pressure to obtain (1-(4-(trifluoromethyl)phenyl)piperazine (I-5) (850 mg, crude product). ESI[M+H] + =231.1

[0233] Intermediate I-6: 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine

[0234]

[0235] Step 1: Preparation of tert-butyl 4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid (I-6a)

[0236] At room temperature, 2-chloro-5-(trifluoromethyl)pyridine (2.0 g, 11.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (2.04 g, 11.0 mmol) were dissolved in N-methylpyrrolidone (20 mL), and potassium carbonate (4.55 g, 33.0 mmol) was added with stirring. After the addition was complete, the reaction mixture was stirred at 95 °C for 3 hours. The reaction mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give (4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-6a) (3.5 g, yield: 96.4%). ESI[M+H] + =332.1

[0237] Step 2: Preparation of 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine (I-6)

[0238] At room temperature, tert-butyl (4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid (I-6a) (3.5 g, 10.6 mmol) was dissolved in dichloromethane (20 mL), and dioxane hydrochloride (4 M) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine hydrochloride (I-6) (3.0 g, crude product). ESD[M+H] + =232.0

[0239] Intermediate I-7: 6-(piperazin-1-yl)nicotinonitrile

[0240]

[0241] Step 1: Preparation of tert-butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate (I-7a)

[0242] N-Boc-piperazine (100 mg, 1 M) was dissolved in N,N-dimethylformamide (4 mL), and 6-chloro-3-cyanopyridine (75 mg, 1 M) and potassium carbonate (148 mg, 2 M) were added. The mixture was stirred at 80 °C for 1 hour. An aqueous solution (10 mL) was added dropwise to the reaction mixture. The aqueous layer was extracted with ethyl acetate (7 mL × 3). The mixed organic layer was washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The organic layer was concentrated under reduced pressure to give the crude product 4-(5-cyanopyridine-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-7a) (190 mg, purity 80%, yield 98.18%). ESI [M+H] + =289.20

[0243] Step 2: Preparation of 6-(piperazin-1-yl)nicotinonitrile (I-7)

[0244] A solution of 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (I-7a) (190 mg, 80% purity, 1 M) dissolved in DCM (2 mL) was added dropwise at 0 °C, followed by the dropwise addition of trifluoroacetic acid (2 mL). The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the resulting mixture was concentrated under vacuum to give compound 6-(piperazine-1-yl)nicotinonitrile (I-7) (120 mg, 80% purity, 96.75% yield). ESI [M+H] + =189.20

[0245] Preparation of intermediate I-8: 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (I-8)

[0246]

[0247] At room temperature, 2-chloro-5-(trifluoromethyl)pyrimidine (1.0 g, 5.48 mmol) and piperazine-2-one (548 mg, 5.48 mmol) were dissolved in N-methylpyrrolidone (10 mL), and potassium carbonate (1.51 g, 11.0 mmol) was added with stirring. After the addition was complete, the reaction mixture was stirred at 95 °C for 4 hours. The reaction mixture was quenched with water (100 mL) and filtered to give 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-2-one (I-8) (1.2 g, yield 88.9%). ESI[M+H] + =247.0

[0248] Example 1: Preparation of (S)-5-((1-((4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (1)

[0249]

[0250] Step 1: Preparation of 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (I-8)

[0251] At room temperature, 2-chloro-5-(trifluoromethyl)pyrimidine (1.0 g, 5.48 mmol) and piperazine-2-one (548 mg, 5.48 mmol) were dissolved in N-methylpyrrolidone (10 mL), and potassium carbonate (1.51 g, 11.0 mmol) was added with stirring. After the addition was complete, the reaction mixture was stirred at 95 °C for 4 hours. The reaction mixture was quenched with water (100 mL) and filtered to give 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-2-one (I-8) (1.2 g, yield 88.9%). ESI[M+H] + =247.0

[0252] Step 2: Preparation of tert-butyl(S)-(1-((4-bromopyridin-2-yl)oxy)propane-2-yl)carbamate (1-a)

[0253] Under ice bath conditions, 4-bromo-2-hydroxypyridine (1 g, 5.75 mmol), N-Boc-L-propanol (1.31 g, 7.48 mmol), and triphenylphosphine (1.96 g, 7.58 mmol) were dissolved in tetrahydrofuran (10 mL). Diisopropyl azodicarbonate (1.31 g, 7.48 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (10 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1:1) to give tert-butyl(S)-(1-((4-bromopyridin-2-yl)oxy)propane-2-yl)carbamate (30.0 mg, yield: 15.7%) and compound tert-butyl(S)-(1-(4-bromo-2-oxypyridin-1(2H)-yl)propane-2-yl)carbamate (1-a) (300.0 mg, yield: 15.7%). 1 H NMR (400MHz, CDCl3) δ7.96 (d, J=5.5Hz, 1H), 7.03 (dd, J=5.5, 1.6Hz, 1H), 6.97 (d, J=1.6Hz, 1H), 4. 78 (s, 1H), 4.25 (dd, J=4.8, 1.7Hz, 2H), 4.08 (d, J=13.8Hz, 1H), 1.44 (s, 9H), 1.24 (d, J=6.8Hz, 3H).

[0254] Step 3: Preparation of tert-butyl (S)-(1-((4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)carbamate (1-b)

[0255] At room temperature, tert-butyl(S)-(1-((4-bromopyridin-2-yl)oxy)propane-2-yl)carbamate (1-a) (300 mg, 0.906 mmol), 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (I-8) (210 mg, 0.906 mmol), and potassium carbonate (375 mg, 2.718 mmol) were dissolved in 1,4-dioxane (10 mL). N,N′-dimethylethylenediamine (15.9 mg, 0.181 mmol) and cuprous iodide (34.4 mg, 0.181 mmol) were added under argon-purified stirring. After the addition of reactants, the reaction mixture was stirred at 110°C for 4 hours. The mixture was then concentrated under reduced pressure and purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give tert-butyl-(1-((4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)carbamate (1-b) (200 mg, yield: 44.5%). ESI [M+H] + =497.3

[0256] Step 4: Preparation of (S)-1-(2-(2-aminopropoxy)pyridin-4-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one hydrochloride (1-c)

[0257] At room temperature, tert-butyl-(1-((4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)carbamate (1-b) (200 mg, 0.403 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain (S)-1-(2-(2-aminopropoxy)pyridin-4-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one hydrochloride (1-c) (200 mg, crude product), ESI [M+H]. + =397.1

[0258] Step 5: Preparation of (S)-5-((1-((4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (1-d)

[0259] At room temperature, (S)-1-(2-(2-aminopropoxy)pyridin-4-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one hydrochloride (1-c) (200 mg, 0.505 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (496 mg, 1.515 mmol), and triethylamine (153.3 mg, 1.515 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour, and the reaction was completed by LC-MS. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 2:3) to obtain (S)-5-((1-((4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (1-d) (60 mg, yield 17.3%).

[0260] Step 6: Preparation of (S)-5-((1-((4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (1)

[0261] At room temperature, (S)-5-((1-((4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (1-d) (60 mg, 0.087 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC to obtain (S)-5-((1-((4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (1) (25.48 mg, yield 52.4%). ESI [M+H] + =559.1, 1H NMR (400MHz, CDCl3) δ10.27 (s, 1H), 8.59 (s, 2H), 8.17 (d, J=5.8Hz, 1H), 7.82 (s, 1H), 7.14 (d, J=5.8Hz, 1H), 6.91 (s, 1H), 6.3 0 (s, 1H), 4.68 (s, 2H), 4.64-4.55 (m, 1H), 4.41 (d, J = 9.2Hz, 1H), 4.24 (d, J = 23.8Hz, 3H), 3.92 (s, 2H), 1.42 (d, J = 6.5Hz, 3H).

[0262] Example 2: Preparation of (S)-5-((1-(4-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(4H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (2)

[0263]

[0264] Step 1: Preparation of ethyl 4-oxo-4H-pyran-3-carboxylate (2-a)

[0265] Under ice bath conditions, ethyl formate (23.6 mL, 292 mmol) was slowly added to tetrahydrofuran (50 mL) containing potassium tert-butoxide (6.06 g, 54.0 mmol). After stirring the reaction mixture for 15 minutes, a solution of ethyl 2-[(dimethylamino)methylene]-3-oxobutyrate (5 g, 27.0 mmol) tetrahydrofuran (45 mL), pre-cooled to 0 °C, was slowly added to the above solution. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with hydrochloric acid (1 M, 80 mL) and extracted with ethyl acetate (3 x 25 mL). The organic phase was dried, filtered, concentrated under reduced pressure, and purified by column chromatography to give ethyl 4-oxo-4H-pyran-3-carboxylic acid (2-a) (320 mg, yield 7.05%). ESI [M+H] + =169.2

[0266] Step 2: Preparation of (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester (2-b)

[0267] Ethyl 4-oxo-4H-pyran-3-carboxylate (2-a) (300 mg, 1.79 mmol) and (S)-(1-aminopropane-2-yl)carbamate tert-butyl ester (470 mg, 2.7 mmol) were dissolved in ethanol (10 mL) at room temperature. After the addition was complete, the reaction mixture was stirred at 90 °C for 6 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to give ethyl (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (2-b) (270 mg, yield: 47.4%). ESI [M+H] + 325.0

[0268] Step 3: Preparation of (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (2-c)

[0269] Ethyl (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (2-b) (270 mg, 0.833 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL) at room temperature. Water and lithium hydroxide (175 mg, 4.17 mmol) were added under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 6–7 with hydrochloric acid and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (2-c) (300 mg). ESI [M+H] + =297.0

[0270] Step 4: Preparation of tert-butyl(S)-(1-(4-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(4H)-yl)propyl-2-yl)carbamate (2-d)

[0271] At room temperature, (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (2-c) (300 mg, 10.1 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2) (234 mg, 10.1 mmol), HATU (768 mg, 20.2 mmol), and diisopropylethylamine (391 mg, 30.3 mmol) were dissolved in N,N-dimethylformamide (10 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to give tert-butyl(S)-(1-(4-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(4H)-yl)propyl-2-yl)carbamate (2-d) (130 mg, yield: 25.2%). ESI [M+H] + =511.1

[0272] Step 5: Preparation of (S)-1-(2-aminopropyl)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-4(1H)-one (2-e)

[0273] At room temperature, tert-butyl (S)-(1-(4-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(4H)-yl)propyl-2-yl)carbamate (2-d) (130 mg, 0.254 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain (S)-1-(2-aminopropyl)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-4(1H)-one (2-e) (120 mg). ESI [M+H] + =411.6

[0274] Step 6: Preparation of (S)-5-((1-(4-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(4H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (2-f)

[0275] At room temperature, (S)-1-(2-aminopropyl)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-4(1H)-one (2-e) (100 mg, 0.24 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (120 mg, 0.365 mmol), and triethylamine (49 mg, 0.487 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (dichloromethane:methanol = 10:1) to give (S)-5-((1-(4-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(4H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (2-f) (50 mg, yield 29.58%). ESI [M+H] + =703.4

[0276] Step 7: Preparation of (S)-5-((1-(4-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(4H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (2)

[0277] At room temperature, (S)-5-((1-(4-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(4H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (2-f) (2-f) (2-f) (50 mg, 0.071 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by TLC to give (S)-5-((1-(4-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(4H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (2) (11.13 mg, yield: 26.7%). ESI[M+H] + =573.3, 1H NMR (400MHz, DMSO) δ12.50 (s, 1H), 8.73 (s, 2H), 7.87 (d, J = 2.2Hz, 1H), 7.66 (s, 1H), 7.63 (d, J = 7.8Hz, 1H), 6.56 (d, J = 6.4Hz, 1H), 6.15 (d, J = 7 .6Hz, 1H), 4.48 (s, 1H), 4.14 (dd, J=13.9, 3.8Hz, 1H), 4.04-3.87 (m, 4H), 3.83-3.70 (m, 3H), 3.51 (s, 1H), 3.18 (s, 2H), 1.23 (d, J=6.3Hz, 3H).

[0278] Example 3: Preparation of 5-(((2S)-1-(2-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)piperidin-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (3)

[0279]

[0280] Step 1: Preparation of methyl 2-hydroxynicotinic acid (3-a)

[0281] At room temperature, 2-hydroxynicotinic acid (2.0 g, 14.33 mmol) was dissolved in methanol (20 mL), and thionyl chloride (10 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain methyl 2-hydroxynicotinic acid (3-a) (1.8 g). ESI [M+H] + =154.0

[0282] Step 2: Preparation of (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester (3-b)

[0283] Methyl 2-oxo-1,2-dihydropyridine-3-carboxylic acid (3-a) (1.8 g, 11.7 mmol), (S)-(1-hydroxypropyl-2-yl)-tert-butylcarbamate (2.04 g, 11.7 mmol), and triphenylphosphine (3.06 g, 11.7 mmol) were dissolved in tetrahydrofuran (20 mL) under ice bath conditions. Diisopropyl azodicarbonate (2.36 g, 11.7 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred overnight at room temperature. Most of the tetrahydrofuran was distilled off from the reaction mixture, and the crude product was diluted with ethyl acetate (10 mL). The organic phase was washed with brine (10 mL), and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give (S)-1-(2-((tert-butoxycarbonyl)amino)propyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester (3-b) (600 mg). ESI [M+H] + =311.1

[0284] Step 3: Preparation of methyl 1-((S)-2-((tert-Butoxycarbonyl)amino)propyl)-2-oxoperidine-3-carboxylic acid (3-c)

[0285] Methyl (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (3-b) (600 mg, 1.94 mmol) was dissolved in methanol (20 mL) at room temperature, and palladium on carbon (100 mg, 10%) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours under hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give methyl 1-((S)-2-((tert-Butoxycarbonyl)amino)propyl)-2-oxoperidine-3-carboxylic acid (3-c) (158 mg, yield 26.0%). 1 HNMR (400MHz, CDCl3) δ4.85 (d, J=20.6Hz, 1H), 3.92 (d, J=6.8Hz, 1H), 3.73 (d, J=1.4Hz, 3H), 3.71-3.64 (m, 1H), 3.52-3.44 (m , 1H), 3.05-2.77(m, 2H), 2.58-2.33(m, 2H), 2.20-2.06(m, 1H), 2.03-1.92(m, 1H), 1.42(s, 9H), 1.14(dd, J=6.5, 2.1Hz.3H).

[0286] Step 4: Preparation of methyl 1-((S)-2-aminopropyl)-2-oxoperidine-3-carboxylic acid (3-d)

[0287] At room temperature, methyl 1-((S)-2-((tert-Butoxycarbonyl)amino)propyl)-2-oxoperidin-3-carboxylic acid (3-c) (158 mg, 0.503 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give methyl 1-((S)-2-aminopropyl)-2-oxoperidin-3-carboxylic acid (3-d) (130 mg). ESI [M+H] + =215.1

[0288] Step 5: Preparation of methyl 2-oxo-1-((S)-2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)piperidine-3-carboxylic acid (3-e)

[0289] At room temperature, methyl 1-((S)-2-aminopropyl)-2-oxoperidin-3-carboxylic acid (3-d) (130 mg, 0.607 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (300 mg, 0.911 mmol), and triethylamine (184 mg, 1.82 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give methyl 2-oxo-1-((S)-2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)piperidine-3-carboxylic acid (3-e) (65 mg, yield: 21.1%). ESI [M+H] + =507.6

[0290] Step 6: Preparation of 2-oxy-1-((S)-2-((6-oxy-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridin-4-yl)amino)propyl)piperidine-3-carboxylic acid (3-f)

[0291] At room temperature, methyl 2-oxo-1-((S)-2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridin-4-yl)amino)propyl)piperidine-3-carboxylic acid (3-e) (65 mg, 0.128 mmol) was dissolved in tetrahydrofuran (10 mL), and hydrochloric acid (12 M, 10 mL) was added under stirring. After the addition was complete, the reaction solution was stirred at 50 °C for 5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain 2-oxy-1-((S)-2-((6-oxy-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridin-4-yl)amino)propyl)piperidine-3-carboxylic acid (3-f) (60.0 mg).

[0292] Step 7: Preparation of 5-(2S)-1-(2-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)piperidin-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (3-g)

[0293] At room temperature, 2-oxy-1-((S)-2-((6-oxy-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridin-4-yl)amino)propyl)piperidin-3-carboxylic acid (3-f) (60.0 mg, 0.122 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2) (28.3 mg, 0.122 mmol), and diisopropylethylamine (0.1 mL, 0.366 mmol) were dissolved in N,N-dimethylformamide (4 mL), and HATU (46.4 mg, 0.122 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours, diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-(2S)-1-(2-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)piperazine-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (3 g) (58 mg, yield: 67.4%).

[0294] Step 8: Preparation of 5-(((2S)-1-(2-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)piperidin-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (3)

[0295] At room temperature, 5-(2S)-1-(2-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)piperazin-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (3 g) (58 mg, 0.082 mmol) was dissolved in difluoromethane (10 mL), and trifluoroacetic acid (1 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by preparative HPLC to obtain 5-(((2S)-1-(2-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)piperazin-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (3) (18.7 mg, yield: 39.7%). ESI [M+H] + =577.2, 1 H NMR (400MHz, MeOD) δ8.60 (s, 2H), 7.96 (d, J=12.2Hz, 1H), 4.33 (d, J=35.9Hz, 1H), 4.03-3.84 (m, 5H), 3.66 (dd, J=14.9, 6.4Hz, 5H) , 3.55-3.46 (m, 1H), 3.43-3.38 (m, 1H), 3.24-3.11 (m, 1H), 2.44 (td, J=8.5, 5.5Hz, 2H), 2.07-1.82 (m, 2H), 1.30 (d, J=6.4Hz, 3H).

[0296] Example 4: (S)-5-((1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (4)

[0297]

[0298] Step 1: Preparation of (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (4-a)

[0299] At room temperature, methyl 6-hydroxynicotinic acid (2.00 g, 13.1 mmol) and potassium carbonate (5.43 g, 39.3 mmol) were dissolved in N,N-dimethyl (10 mL). Under argon-purified stirring, (S)-2-((tert-butyloxycarbonyl)amino)propyl 4-toluenesulfonate (I-3) (4.32 g, 13.1 mmol) was added to the above solution. After the addition was complete, the reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 3:1-1:1) to give (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (4-a) (626 mg, yield: 15.4%). ESI[M+H] + =311.1

[0300] Step 2: Preparation of (S)-1-(2-aminopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (4-b)

[0301] At room temperature, methyl (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (4-a) (626 mg, 2.01 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain methyl (S)-1-(2-aminopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (4-b) (311 mg). ESI[M+H] + =211.2.

[0302] Step 3: Preparation of (S)-6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carboxylic acid methyl ester (4-c)

[0303] At room temperature, methyl (S)-1-(2-aminopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (4-b) (311 mg, 1.26 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (414 mg, 1.26 mmol), and triethylamine (382 mg, 3.78 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to give (S)-6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carboxylic acid methyl ester (4-c) (311 mg, yield: 41.8%). ESI [M+H]+: 503.2

[0304] Step 4: Preparation of (S)-6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carboxylic acid (4-d)

[0305] At room temperature, methyl (S)-6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carboxylic acid (4-c) (112 mg, 0.222 mmol) was dissolved in hydrochloric acid (6 N, 10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 24 hours. The reaction mixture was concentrated under reduced pressure to give (S)-6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carboxylic acid (4-d) (60 mg). ESI [M+H]+==359.0

[0306] Step 5: Preparation of (S)-5-((1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (4)

[0307] At room temperature, (S)-6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carboxylic acid (4-d) (60 mg, 0.167 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2) (38.8 mg, 0.167 mmol), and diisopropylethylamine (64.7 mg, 0.501 mmol) were dissolved in N,N-dimethylformamide (3 mL), and HATU (63.5 mg, 0.167 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC to yield (S)-5-((1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (4) (23.68 mg, yield: 24.7%). ESI [M+H] + =573.3, 1 H NMR (400MHz, CDCl3) δ10.55 (s, 1H), 8.58 (s, 2H), 7.74 (d, J = 18.8Hz, 2H), 7.42 (d, J = 9.9Hz, 1H), 6.62 (d, J = 9.5Hz , 1H), 6.06 (s, 1H), 4.37 (s, 1H), 4.14-4.06 (m, 1H), 4.04-3.93 (m, 5H), 3.73-3.59 (m, 4H), 1.41 (d, J=6.1Hz, 3H).

[0308] Example 5: Preparation of 5-(((2S)-1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)piperidin-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (5)

[0309]

[0310] Step 1: Preparation of methyl 1-((S)-2-((tert-Butoxycarbonyl)amino)propyl)-6-oxoperidine-3-carboxylic acid (5-a)

[0311] At room temperature, methyl (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (400 mg, 1.29 mmol) was dissolved in methanol (20 mL), and palladium on carbon (100 mg) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours under hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give methyl 1-((S)-2-((tert-Butoxycarbonyl)amino)propyl)-6-oxoperidine-3-carboxylic acid (5-a) (326 mg, yield: 80.5%). 1 H NMR (400MHz, Chloroform-d), δ4.94 (dd, J=26.9, 8.3Hz, 1H), 4.00-3.75 (m, 2H), 3.73 (d, J=1.4Hz, 3H), 3.70-3.65 (m, 1H), 3.55-3 .45 (m, 1H), 3.09-2.79 (m, 2H), 2.56-2.34 (m, 2H), 2.19-2.07 (m, 1H), 2.04-1.94 (m, 1H), 1.42 (s, 9H), 1.14 (dd, J=6.5, 2.1Hz, 3H).

[0312] Step 2: Preparation of methyl 1-((S)-2-aminopropyl)-6-oxoperidine-3-carboxylic acid (5-b)

[0313] Methyl 1-((S)-2-((tert-Butoxycarbonyl)amino)propyl)-6-oxoperidin-3-carboxylic acid (5-a) (326 mg, 1.04 mmol) was dissolved in dichloromethane (15 mL) at room temperature, and dioxane hydrochloride (4 M) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give methyl 1-((S)-2-aminopropyl)-6-oxoperidin-3-carboxylic acid (5-b) (300 mg). ESI [M+H] + =215.0

[0314] Step 3: Preparation of methyl 6-oxo-1-((S)-2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)piperidine-3-carboxylic acid (5-c)

[0315] At room temperature, methyl 1-((S)-2-aminopropyl)-6-oxoperidin-3-carboxylic acid (5-b) (200 mg, 0.935 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (459 mg, 1.40 mmol), and triethylamine (189 mg, 1.87 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give methyl 6-oxo-1-((S)-2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)piperidine-3-carboxylic acid (5-c) (150 mg, yield: 31.6%). ESI [M+H] + =507.2

[0316] Step 4: Preparation of 6-oxo-1-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)piperidine-3-carboxylic acid (5-d)

[0317] Methyl 6-oxo-1-((S)-2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)piperidine-3-carboxylic acid (5-c) (150 mg, 0.296 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, and hydrochloric acid (12 M, 10 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at 50 °C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain 6-oxo-1-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)piperidine-3-carboxylic acid (5-d) (62.0 mg, yield: 57.9%). ESI [M+H] + =363.1

[0318] Step 5: Preparation of 5-(((2S)-1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)piperidin-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (5)

[0319] At room temperature, 6-oxo-1-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)piperidin-3-carboxylic acid (5-d) (62.0 mg, 0.171 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2) (39.7 mg, 0.171 mmol), and diisopropylethylamine (0.1 mL, 0.513 mmol) were dissolved in N,N-dimethylformamide (5 mL), and HATU (65.0 mg, 0.171 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was prepared by HPLC to yield 5-(((2S)-1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)piperidin-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (5) (4.92 mg, yield: 0.050%). ESI [M+H] + =577.3, 1 H NMR (400MHz, CDCl3) δ10.05 (s, 1H), 8.54 (d, J = 14.7Hz, 2H), 7.77 (s, 1H), 3.96 (s, 5H), 3.71 (s, 2H), 3.59 (d, J = 3.5Hz , 2H), 3.30 (t, J=21.5Hz, 1H), 3.07 (d, J=24.8Hz, 1H), 2.62-2.38 (m, 2H), 2.03 (dd, J=28.3, 15.1Hz, 3H), 1.35 (s, 5H).

[0320] Example 6: Preparation of (S)-5-((1-(2-oxo-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (6)

[0321]

[0322] Step 1: Preparation of (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (6-a)

[0323] Methyl (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (4-a) (680 mg, 2.19 mmol) was dissolved in methanol (10 mL) and water (4 mL) at room temperature. Water and lithium hydroxide (184 mg, 4.38 mmol) were added under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 6–7 with hydrochloric acid and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (6-a) (360 mg). ESI [M+H] + =297.1

[0324] Step 2: Preparation of tert-butyl(S)-(1-(2-oxo-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)carbamate (6-b)

[0325] At room temperature, (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (6-a) (360 mg, 1.22 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-6) (282 mg, 1.22 mmol), HATU (464 mg, 1.22 mmol), and diisopropylethylamine (472 mg, 3.66 mmol) were dissolved in N,N-dimethylformamide (10 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to give tert-butyl(S)-(1-(2-oxo-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)carbamate (6-b) (150 mg, yield: 24.1%). ESI [M+H] + =510.1

[0326] Step 3: Preparation of (S)1-(2-aminopropyl)-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)pyridin-2(1H)-ketohydrochloride (6-c)

[0327] At room temperature, tert-butyl(S)-1-(2-oxo-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-propyl-2-yl)carbamate (6-b) (150 mg, 0.295 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain (S)-1-(2-aminopropyl)-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-carbonyl)pyridin-2(1H)-one hydrochloride (6-c) (130 mg, crude product). ESI[M+H] + =410.2

[0328] Step 4: Preparation of (S)-5-((1-(2-oxo-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (6-d)

[0329] At room temperature, (S)-1-(2-aminopropyl)-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-carbonyl)pyridin-2(1H)-one hydrochloride (6-c) (130 mg, 0.318 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (157 mg, 0.477 mmol), and triethylamine (196.4 mg, 0.954 mmol) were dissolved in ethanol (10 mL). After the addition of the reactants, the reaction mixture was stirred at 60 °C for 1 hour, and LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0:1) to obtain (S)-5-((1-(2-oxo-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (6-d) (30 mg, yield: 13.5%). ESI [M+H] + =702.3

[0330] Step 5: Preparation of (S)-5-((1-(2-oxo-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (6)

[0331] At room temperature, (S)-5-((1-(2-oxo-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (6-d) (6-d) (30 mg, 0.043 mmol)) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC to obtain (S)-5-((1-(2-oxo-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (6) (11.03 mg, yield: 45.8%), ESI[M+H). + =572.1, 1 H NMR (400MHz, Chloroform-d) δ 8.45 (s, 1H), 7.73 (d, J = 35.4Hz, 3H), 7.44 (d, J = 9.3Hz, 1H), 6.78 (s, 1H), 6.63 (d, J = 9.3Hz, 1H), 5.85 (s, 1H), 5.62 (d, J = 9.8Hz, 1H), 5.24 (d, J = 10.0Hz, 1H), 4.42 (s, 1H), 4.16 (s, 1H), 3.98 (s, 1H), 3.76 (s, 6H), 1.42 (s, 3H).

[0332] Example 7: Preparation of (S)-5-((1-(2-oxo-4-(4-(trifluoromethyl)phenyl)piperazine-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (7)

[0333]

[0334] Step 1: Preparation of (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid methyl ester (7-a)

[0335] At room temperature, methyl 2-hydroxypyridine-4-carboxylate (2.00 g, 13.1 mmol) was dissolved in N,N-dimethylformamide (10 mL). Potassium carbonate (5.43 g, 39.3 mmol) and (S)-2-((tert-butyloxycarbonyl)amino)propyl 4-toluenesulfonate (I-3) (4.32 g, 13.1 mmol) were added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 3:1-1:1) to give (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-2-oxo-1,2-dihydropyridine-4-carboxylate (7-a) (300 mg, yield: 7.40%). ESI [M+H] + =311.0

[0336] Step 2: Preparation of (S)-1-(2-aminopropyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid methyl ester (7-b)

[0337] At room temperature, methyl (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (7-a) (300 mg, 0.966 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain methyl (S)-1-(2-aminopropyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (7-b) (200 mg). ESI [M+H]+==211.23.

[0338] Step 3: Preparation of (S)-2-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,2-dihydropyridine-4-carboxylic acid methyl ester (7-c)

[0339] At room temperature, methyl (S)-1-(2-aminopropyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (7-b) (200 mg, 0.811 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (I-1) (266 mg, 0.811 mmol), and triethylamine (164 mg, 1.62 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to give (S)-2-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,2-dihydropyridine-4-carboxylic acid methyl ester (7-c) (100 mg, yield: 21.0%). ESI [M+H]+==503.3

[0340] Step 4: Preparation of (S)-2-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,2-dihydropyridine-4-carboxylic acid (7-d)

[0341] At room temperature, methyl (S)-2-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,2-dihydropyridine-4-carboxylic acid (7-c) (100 mg, 0.199 mmol) was dissolved in methanol (2 mL) and water (H₂O) (2 mL). Water and lithium hydroxide (16.7 mg, 0.398 mmol) were added under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 6-7 with hydrochloric acid and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-2-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,2-dihydropyridine-4-carboxylic acid (7-d) (92 mg, yield: 94.8%). ESI[M+H] + =489.2

[0342] Step 5: Preparation of (S)-5-((1-(2-oxo-4-(4-(trifluoromethyl)phenyl)piperazine-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (7-e)

[0343] At room temperature, (S)-2-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,2-dihydropyridine-4-carboxylic acid (7-d) (90 mg, 0.184 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-5) (49.0 mg, 0.184 mmol), and diisopropylethylamine (71.3 mg, 0.552 mmol) were dissolved in N,N-dimethylformamide (3 mL), and HATU (69.9 mg, 0.184 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was prepared by preparative HPLC to give (S)-5-((1-(2-oxo-4-(4-(trifluoromethyl)phenyl)piperazine-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (7-e) (78 mg, yield: 60.5%). ESI [M+H] + =701.1

[0344] Step 6: Preparation of (S)-5-((1-(2-oxo-4-(4-(trifluoromethyl)phenyl)piperazine-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (7)

[0345] At room temperature, (S)-5-((1-(2-oxo-4-(4-(trifluoromethyl)phenyl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (7-e) ... The reaction solution was concentrated under reduced pressure and prepared by preparative HPLC to obtain (S)-5-((1-(2-oxo-4-(4-(trifluoromethyl)phenyl)piperazine-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (7) (26.79 mg, yield: 42.2%). ESI [M+H] + =571.2, 1H NMR (400MHz, CDCl3) δ10.55 (s, 1H), 8.58 (s, 2H), 7.74 (d, J = 18.8Hz, 2H), 7.42 (d, J = 9.9Hz, 1H), 6.62 (d, J = 9.5Hz , 1H), 6.06 (s, 1H), 4.37 (s, 1H), 4.14-4.06 (m, 1H), 4.04-3.93 (m, 5H), 3.73-3.59 (m, 4H), 1.41 (d, J=6.1Hz, 3H).

[0346] Example 8: Preparation of (S)-5-((1-(2-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (8)

[0347]

[0348] Step 1: Preparation of ethyl 2-hydroxynicotinic acid (8-a)

[0349] At room temperature, 2-hydroxynicotinic acid (2.78 g, 20 mmol) and concentrated sulfuric acid (2 mL) were dissolved in ethanol (20 mL). After the addition was complete, the reaction mixture was stirred at 90 °C for 8 hours. The reaction mixture was concentrated, diluted with water (20 mL), and adjusted to pH 7-8 with sodium bicarbonate powder. The reaction mixture was extracted three times with chloroform, and the organic phase was concentrated under reduced pressure to obtain ethyl 2-hydroxynicotinic acid (8-a) (2.2 g, yield 65.9%). ESI[M+H] + =168.1

[0350] Step 2: Preparation of (R)-1-(2-hydroxypropyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid ethyl ester (8-b)

[0351] At room temperature, ethyl 2-hydroxynicotinic acid (8-a) (1.0 g, 5.98 mmol), (R)-propylene oxide (696 mg, 11.96 mmol), and diisoethylamine (2.3 g, 17.94 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was then concentrated under reduced pressure to give ethyl (R)-1-(2-hydroxypropyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (8-b) (1.0 g, yield 76.9%), ESI [M+H]. + =226.1

[0352] Step 3: Preparation of (R)-1-(2-((methanesulfonyl)oxy)propyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid ethyl ester (8-c)

[0353] Ethyl (R)-1-(2-hydroxypropyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (8-b) (1.0 g, 4.44 mmol) and triethylamine (898 mg, 8.88 mmol) were dissolved in dichloromethane (20 mL) under ice bath conditions. Methyl xanthyl chloride (763 mg, 6.66 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 3). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl (R)-1-(2-((methanesulfonyl)oxy)propyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (8-c) (1.2 g, yield: 92.3%). ESI [M+H] + =304.1

[0354] Step 4: Preparation of (S)-1-(2-azidopropyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid ethyl ester (8-d)

[0355] Ethyl (R)-1-(2-((methanesulfonyl)oxy)propyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (8-c) (1.2 g, 3.96 mmol) was dissolved in dimethyl sulfoxide (30 mL) at room temperature, and sodium azide (2.57 g) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at 70 °C for 16 hours. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl (S)-1-(2-azidopropyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (8-d) (873 mg, yield 88.2%). ESI[M+H] + =251.1

[0356] Step 5: Preparation of (S)-1-(2-azidopropyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (8-e)

[0357] Ethyl (S)-1-(2-azidopropyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (8-d) (700 mg, 2.79 mmol) was dissolved in methanol (10 mL) and water (2 mL) at room temperature. Water and lithium hydroxide (175.8 mg, 4.19 mmol) were added under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (60 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-1-(2-azidopropyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (8-e) (440 mg, yield: 70.8%). ESI [M+H] + =223.0

[0358] Step 6: Preparation of (S)-1-(2-azidopropyl)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-2(1H)-one (8-f)

[0359] At room temperature, (S)-1-(2-azidopropyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (8-e) (100 mg, 0.450 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2) (104.5 mg, 0.450 mmol), and diisopropylethylamine (174.5 mg, 1.35 mmol) were dissolved in N,N-dimethylformamide. HATU (171.1 mg, 0.450 mmol) was added under stirring. After the addition of reactants, the reaction mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure, and the crude product was purified by TLC (100% ethyl acetate) to give (S)-1-(2-azidopropyl)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-2(1H)-one (8-f) (183 mg, yield: 93.3%). ESI[M+H] + =437.0

[0360] Step 7: Preparation of (S)-1-(2-aminopropyl)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-2(1H)-one (8-g)

[0361] At room temperature, (S)-1-(2-azidopropyl)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-2(1H)-one (8-f) (100 mg, 0.229 mmol) and triphenylphosphine (72.1 mg, 0.275 mmol) were dissolved in N,N-dimethylformamide. After the addition was complete, the reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with water (60 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound (8-g) (82 mg, yield: 87.2%). ESI[M+H] + =411.1

[0362] Step 8: Preparation of (S)-5-((1-(2-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (8-h)

[0363] At room temperature, (S)-1-(2-aminopropyl)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-2(1H)-one (8 g) (60.0 mg, 0.146 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (48.0 mg, 0.146 mmol), and triethylamine (44.3 mg, 0.438 mmol) were dissolved in ethanol. The reaction mixture was stirred at 60 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to give (S)-5-((1-(2-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (8-h) (23 mg, yield 22.3%). ESI [M+H] + =703.2

[0364] Step 9: Preparation of (S)-5-((1-(2-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (8)

[0365] At room temperature, (S)-5-((1-(2-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (8-h) (23 mg, 0.032 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added with stirring. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC to yield (S)-5-((1-(2-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (8) (3.6 mg, yield 19.3%). ESI [M+H] + =573.2, 1 H NMR (400MHz, CDCl3) δ10.47 (s, 1H), 8.52 (s, 2H), 7.77 (m, 2H), 7.43 (dd, J=9.4, 2.5Hz, 1H), 6.61 (d, J=9.4Hz, 1H), 6.06 (m, 1H), 4.36 (m, 1H), 4.21 (dd, J=13.5, 8.0Hz, 1H), 3.95 (m, 5H), 3.66 (s, 4H), 1.40 (d, J=6.4Hz, 3H).

[0366] Example 9: Preparation of (S)-5-((1-(3-chloro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (9)

[0367]

[0368] Step 1: Preparation of (S)-1-(2-((tert-Butoxycarbonylamino)propyl)-5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (9-a)

[0369] At room temperature, (S)-1-(2-((tert-butyloxycarbonylamino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (4-a) (180 mg, 0.581 mmol) and N-chlorosuccinimide (117 mg, 0.871 mmol) were dissolved in N,N-dimethylformamide (10 mL). After the addition was complete, the reaction mixture was stirred overnight at 50 °C. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (9-a) (200.0 mg, crude product). ESI[M+H] + =345.2

[0370] Step 2: Preparation of (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (9-b)

[0371] Methyl (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (9-a) (200 mg, 0.580 mmol) was dissolved in methanol (10 mL) and water (5 mL) at room temperature. Lithium hydroxide (48.7 mg, 1.16 mmol) was added. After stirring the reaction mixture at room temperature for 3 hours, the pH was adjusted to 6-7 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (9-b) (300 mg, crude). ESI[M+H] + =331.1

[0372] Step 3: Preparation of (S)-(1-(3-chloro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)tert-butylcarbamate (9-c)

[0373] At room temperature, (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (9-b) (300 mg, 0.906 mmol), diisopropylethylamine (351 mg, 2372 mmol), and HATU (344 mg, 0.906 mmol) were dissolved in N,N-dimethylformamide (10 mL). After stirring the reaction mixture at room temperature for 30 min, 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2) (210 mg, 0.906 mmol) was added, and stirring continued at room temperature for 1 h. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by TLC (petroleum ether:ethyl acetate = 2:3) to give (S)-(1-(3-chloro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)tert-butylcarbamate (9-c) (150 mg, yield: 39.5%). ESI[M+H] + =545.1

[0374] Step 4: Preparation of (S)-1-(2-aminopropyl)-3-chloro-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-2(1H)-one (9-d)

[0375] At room temperature, (S)-(1-(3-chloro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)tert-butylcarbamate (9-c) (150 mg, 0.275 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M, 10 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure to give (S)-1-(2-aminopropyl)-3-chloro-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-2(1H)-one (9-d) (100 mg, crude product). ESI [M+H] + =445.0

[0376] Step 5: Preparation of (S)-5-((1-(3-chloro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (9-e)

[0377] At room temperature, (S)-1-(2-aminopropyl)-3-chloro-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-2(1H)-one (9-d) (100 mg, 0.225 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (111 mg, 0.338 mmol), and triethylamine (68.0 mg, 0.675 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour, and LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0:1) to obtain (S)-5-((1-(3-chloro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (9-e) (30 mg, yield: 18.1%). ESI[M+H + =737.3

[0378] Step 6: Preparation of (S)-5-((1-(3-chloro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (9)

[0379] At room temperature, (S)-5-((1-(3-chloro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (9-e) (9-e) (9-e) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC to obtain (S)-5-((1-(3-chloro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (9) (5.57 mg, yield: 22.5%). ESI [M+H] + =607.2, 1H NMR (400MHz, MeOD) δ8.50 (s, 2H), 7.78 (dd, J=5.8, 2.3Hz, 2H), 7.74 (s, 1H), 4. 41(s, 1H), 4.16-4.08(m, 2H), 3.89(d, J=2.6Hz, 4H), 3.57(s, 4H), 1.27(s, 3H).

[0380] Example 10: Preparation of (S)-5-((1-((3-fluoro-4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (10)

[0381]

[0382] Step 1: Preparation of (S)-(1-((3-fluoro-4-iodopyridin-2-yl)oxy)prop-2-yl)tert-butylcarbamate (10-a)

[0383] 2,3-Difluoro-4-iodopyridine (1.0 g, 4.15 mmol), (S)-(1-hydroxy-2-yl) tert-butylcarbamate (727.15 mg, 4.15 mmol), and potassium tert-butoxide (1.40 g, 12.45 mmol) were dissolved in tert-butanol (20 mL). The mixture was then stirred at 50 °C for 16 hours. The remaining residue was purified by rapid silica gel column chromatography (PE:EA = 3:1) to obtain (S)-(1-((3-fluoro-4-iodopyridine-2-yl)oxy)propyl-2-yl) tert-butylcarbamate (10-a) (1.5 g, yield 90.9%).

[0384] Step 2: Preparation of (S)-(1-((3-fluoro-4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propyl-2-yl)tert-butylcarbamate (10-b)

[0385] At room temperature, (S)-(1-((3-fluoro-4-iodopyridin-2-yl)oxy)propyl-2-yl)tert-butylcarbamate (10-a) (340 mg, 0.859 mmol), 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (I-8) (211 mg, 0.859 mmol), and potassium carbonate (356 mg, 2.58 mmol) were dissolved in 1,4-dioxane (10 mL). N,N′-dimethylethylenediamine (15.1 mg, 0.172 mmol) and cuprous iodide (33.0 mg, 0.181 mmol) were added under argon-purified stirring. After the addition of reactants, the reaction solution was stirred at 110°C for 4 hours. The reaction solution was then concentrated under reduced pressure and purified by column chromatography (PE∶EA=1∶1) to obtain (S)-(1-((3-fluoro-4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propyl-2-yl)tert-butylcarbamate (10-b) (60 mg, yield: 13.6%), ESI[M+H). + =515.2.

[0386] Step 3: Preparation of (S)-1-(2-(2-aminopropoxy)-3-fluoropyridin-4-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one hydrochloride (10-c)

[0387] At room temperature, (S)-(1-((3-fluoro-4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)prop-2-yl)tert-butylcarbamate (10-b) (60 mg, 0.117 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain (S)-1-(2-(2-aminopropoxy)-3-fluoropyridin-4-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one hydrochloride (10-c) (55 mg, crude product). ESI [M+H] + =415.1

[0388] Step 4: Preparation of (S)-5-((1-((3-fluoro-4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (10-d)

[0389] At room temperature, (S)-1-(2-(2-aminopropoxy)-3-fluoropyridin-4-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one hydrochloride (10-c) (55.0 mg, 0.132 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (65.0 mg, 0.198 mmol), and triethylamine (40.0 mg, 0.396 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour, and LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (PE∶EA=2∶3) to obtain (S)-5-((1-((3-fluoro-4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (10-d) (18.0 mg, yield: 19.1%). ESI[M+H] + =703.3

[0390] Step 5: Preparation of (S)-5-((1-((3-fluoro-4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (10)

[0391] At room temperature, (S)-5-((1-((3-fluoro-4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (10-d) (18.0 mg, 0.025 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was reverse-phase to prepare (S)-5-((1-((3-fluoro-4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (10) (5.87 mg, yield 40.1%), ESI[M+H) + =577.1, 1H NMR (400MHz, CDCl3) δ10.18 (s, 1H), 8.59 (s, 2H), 7.94 (d, J = 5.1Hz, 1H), 7.85 (s, 1H), 6.96 (s, 1H), 6.16 (s, 1H), 4.69 (s, 2H), 4.62 (dd, J=11.5, 6.6Hz, 1H), 4.41 (dd, J=11.2, 4.1Hz, 1H), 4.32-4.18 (m, 4H), 3.84 (s, 2H), 1.44 (d, J=6.5Hz, 3H).

[0392] Example 11: Preparation of (S)-5-((1-(3-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)phenoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (11)

[0393]

[0394] Step 1: Preparation of tert-butyl(S)-(1-(3-bromophenoxy)propane-2-yl)carbamate (11-a)

[0395] At room temperature, (S)-(1-hydroxy-2-yl)-tert-butylcarbamate (1.0 g, 5.78 mmol) and 3-bromophenol (1.01 g, 5.78 mmol) were dissolved in tetrahydrofuran (20 mL). Triphenylphosphine (1.51 g, 5.78 mmol) and diisopropyl azodicarbonate (1.17 g, 5.78 mmol) were added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred overnight at 60 °C. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (20 mL). The organic phase was washed with brine (20 mL), and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give tert-butyl(S)-(1-(3-bromophenoxy)propane-2-yl)carbamate (11-a) (1.2 g, yield: 62.8%). ESI [M+H] + =333.1.

[0396] Step 2: Preparation of tert-butyl(S)-(1-(3-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)phenoxy)propyl-2-yl)carbamate (11-b)

[0397] At room temperature, tert-butyl(S)-(1-(3-bromophenoxy)propane-2-yl)carbamate (11-a) (300 mg, 0.909 mmol) and 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (I-8) (224 mg, 0.909 mmol) were dissolved in 1,4-dioxane (10 mL), and N,N-dimethylethylenediamine (16.0 mg, 0.182 mmol), potassium carbonate (376 mg, 2.727 mmol), and cuprous iodide (34.6 mg, 0.182 mmol) were added under argon-purified stirring. After the addition of reactants, the reaction mixture was stirred at 110°C for 4 hours. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to obtain tert-butyl(S)-(1-(3-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)phenoxy)propyl-2-yl)carbamate (11-b) (150 mg, yield: 33.3%). ESI [M+H] + =496.2

[0398] Step 3: Preparation of (S)-1-(3-(2-aminopropoxy)phenyl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (11-c)

[0399] At room temperature, tert-butyl (S)-(1-(3-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)phenoxy)propyl-2-yl)carbamate (11-b) (150 mg, 0.302 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give (S)-1-(3-(2-aminopropoxy)phenyl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (11-c) (140 mg). ESI [M+H] + =396.4

[0400] Step 4: Preparation of (S)-5-((1-(3-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)phenoxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (11-d)

[0401] At room temperature, (S)-1-(3-(2-aminopropoxy)phenyl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (11-c) (140 mg, 0.354 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (175 mg, 0.531 mmol), and triethylamine (108 mg, 1.07 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1:1) to obtain (S)-5-((1-(3-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)phenoxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (11-d) (65 mg, yield: 26.7%).

[0402] Step 5: Preparation of (S)-5-((1-(3-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)phenoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (11)

[0403] At room temperature, (S)-5-((1-(3-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)phenoxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (11-d) (65 mg, 0.095 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC to obtain (S)-5-((1-(3-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)phenoxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (11) (24.27 mg, yield 46.1%). ESI [M+H] + =558.2, 1H NMR (400MHz, CDCl3) δ10.28 (s, 1H), 8.58 (s, 2H), 7.75 (s, 1H), 7.35 (t, J=8.1Hz, 1H), 6.93 (t, J=5.3Hz, 2H), 6.82 (dd, J=8.3, 1.9Hz, 1H), 5.76 (s, 1H ), 4.65 (s, 2H), 4.29-4.24 (m, 2H), 4.18 (s, 1H), 4.10 (dd, J=9.4, 4.0Hz, 1 H), 3.98 (dd, J=9.4, 5.5Hz, 1H), 3.87-3.82 (m, 2H), 1.45 (d, J=6.5Hz, 3H).

[0404] Example 12: (S)-5-((1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrimidin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (12)

[0405]

[0406] Step 1: Preparation of (2-chloropyrimidin-5-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (12-a)

[0407] At room temperature, 2-chloropyrimidine-5-carboxylic acid (300 mg, 1.89 mmol), diisopropylethylamine (1 mL, 5.67 mmol), and HATU (718 mg, 1.89 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 30 minutes, then 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2) (438 mg, 1.89 mmol) was added, and stirring continued at room temperature for 1 hour. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by TLC (PE:EA = 1:1) to give (2-chloropyrimidin-5-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (12-a) (350 mg, yield: 49.9%). ESI [M+H] + =373.1

[0408] Step 2: Preparation of (2-hydroxypyrimidin-5-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (12-b)

[0409] (2-Chloropremine-5-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (12-a) (350 mg, 0.938 mmol) was dissolved in glacial acetic acid (10 mL), and then stirred at 100 °C for 48 hours. After the reaction was complete, the mixture was concentrated to obtain (2-hydroxypyrimidin-5-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (12-b) (300 mg, crude product). ESI[M+H] + =354-9

[0410] Step 3: Preparation of (R)1-(2-hydroxypropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrimidin-2(1H)-one (12-c)

[0411] (2-hydroxypyrimidin-5-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (12-b) (205 mg, 3.53 mmol) was dissolved in ethanol (10 mL), and then (R)-2-methylethylene oxide (250 mg, 0.706 mmol) was added. The mixture was stirred at 70 °C for 3 h. After the reaction was complete, the mixture was concentrated to give (R)1-(2-hydroxypropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrimidin-2(1H)-one (12-c) (260 mg, crude product), ESI [M+H]. + =413.2.

[0412] Step 4: Preparation of (R)-1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrimidin-1(2H)-yl)propyl-2-yl methanesulfonate (12-d)

[0413] (R)-1-(2-hydroxypropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrimidin-2(1H)-one (12-c) (260 mg, 0.631 mmol) and triethylamine (191 mg, 1.89 mmol) were dissolved in dichloromethane (20 mL), followed by the addition of methanesulfonyl chloride (109 mg, 0.945 mmol) and stirring at room temperature for 3 hours. LC-MS showed that the reaction was complete. The mixture was then added to water (30 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (R)-1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrimidin-1(2H)-yl)propyl-2-yl methanesulfonate (12-d) (300 mg, yield: 97.1%). ESI[M+H] +=491.1

[0414] Step 5: Preparation of (S)-1-(2-azidopropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrimidin-2(1H)-one (12-e)

[0415] (R)-1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrimidin-1(2H)-yl)propyl-2-yl methanesulfonate (12-d) (300 mg, 0.612 mmol) was dissolved in N,N-dimethylformamide (30 mL), sodium azide (700 mg) was added, and the mixture was stirred at 70 °C for 16 h. LC-MS showed that the reaction was complete. The mixture was added to water (60 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (S)-1-(2-azidopropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrimidin-2(1H)-one (12-e) (250 mg, yield: 93.6%). ESI[M+H] + =438.2

[0416] Step 6: Preparation of (S)-1-(2-aminopropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrimidin-2(1H)-one (12-f)

[0417] (S)-1-(2-Azidepropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrimidin-2(1H)-one (12-e) (250 mg, 0.572 mmol) and triphenylphosphine (225 mg, 0.858 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 16 h. LC-MS showed that the reaction was complete. The mixture was added to water (60 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (S)-1-(2-aminopropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrimidin-2(1H)-one (12-f) (130 mg, yield: 55.3%). ESI[M+H] + =412.1

[0418] Step 7: Preparation of (S)-5-((1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrimidin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (12-g)

[0419] At room temperature, (S)-1-(2-aminopropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrimidin-2(1H)-one (12-f) (130 mg, 0.316 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (156 mg, 0.474 mmol), and triethylamine (95.7 mg, 0.948 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour, and the reaction was completed by LC-MS. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (PE∶EA=0∶1) to obtain (S)-5-((1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrimidin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (12-g) (30mg, yield 13.5%). ESI[M+H + =704.3

[0420] Step 8: Preparation of ((S)-5-((1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrimidin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (12)

[0421] At room temperature, (S)-5-((1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrimidin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (12 g) (30 mg, 0.043 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was reverse-phase to prepare ((S)-5-((1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrimidin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (12) (9.99 mg, yield: 40.9%). ESI[M+H] + =574.2, 1 H NMR (400MHz, MeOD) δ 8.78 (d, J=2.9Hz, 1H), 8.63 (s, 3H), 8.39 (d, J=3.0Hz, 1H), 7.91 (s, 1H), 4.02 (s, 5H), 3.72 (s, 6H), 1.40 (d, J=6.5Hz, 3H).

[0422] Example 13: Preparation of 3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (13)

[0423]

[0424] Step 1: Preparation of 4-(benzyloxy)-3-hydroxy-4-oxobutyric acid (13-a)

[0425] Under ice bath conditions, DL-malic acid (1 g, 7.4 mmol) and trifluoroacetic anhydride (1.55 g, 7.4 mmol) were dissolved in dichloromethane (15 mL), and benzyl alcohol (0.799 g, 7.4 mmol) was added with stirring under argon displacement. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give 4-(benzyloxy)-3-hydroxy-4-oxobutyric acid (13-a) (500 mg, yield 30.0%). 1H NMR (400MHz, CDCl3) δ7.45-7.25 (m, 5H), 5.23 (d, J=8.6Hz, 2H), 4.65-4.44 (m, 1H), 3.10-2.67 (m, 2H).

[0426] Step 2: Preparation of 2-oxooxazolidine-5-carboxylic acid benzyl ester (13-b)

[0427] At room temperature, 4-(benzyloxy)-3-hydroxy-4-oxobutyric acid (13-a) (1.0 g, 4.46 mmol) and triethylamine (901 mg, 8.92 mmol) were dissolved in toluene (20 mL), and diphenyl azidophosphate (1.27 g, 4.46 mmol) was added with stirring. After the addition was complete, the reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give 2-oxooxazolidine-5-carboxylic acid benzyl ester (13-b) (300 mg, yield 30.4%). 1 HNMR (400MHz, CDCl3) δ7.36 (s, 5H), 6.19 (s, 1H), 5.24 (d, J=1.9Hz, 2H), 5.02 (dd, J=9.6, 5.5Hz, 1H), 3.84 (t, J=9.4Hz, 1H), 3.64 (dd, J=9.1, 5.6Hz, 1H).

[0428] Step 3: Preparation of 2-oxooxazolidine-5-carboxylic acid (13-c)

[0429] At room temperature, 500 mg (2.26 mmol) of benzyl 2-oxooxazolidine-5-carboxylic acid (13-b) was dissolved in 20 mL of methanol, and 100 mg of palladium on carbon was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours under hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give 2-oxooxazolidine-5-carboxylic acid (13-c) (280 mg, yield 94.6%). ESI [M+H] + =132.1

[0430] Step 4: Preparation of 5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (13-d)

[0431] At room temperature, 2-oxooxazolidine-5-carboxylic acid (13-c) (300.0 mg, 2.29 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2) (53.0 mg, 2.29 mmol), and diisopropylethylamine (1 mL, 10.5 mmol) were dissolved in N,N-dimethylformamide (30 mL), and HATU (870 mg, 2.29 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (40 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was prepared by HPLC to yield 5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (13-d) (300.0 mg, yield: 38.0%). ESI [M+H] + =346.0

[0432] Step 5: Preparation of 3-(2-hydroxypropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)oxazolidin-2-one (13-e)

[0433] At room temperature, 5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (13-d) (350 mg, 1.01 mmol), propylene oxide (117 mg, 2.02 mmol), and cesium carbonate (987 mg, 3.03 mmol) were dissolved in dimethyl sulfoxide (30 mL). After the addition was complete, the reaction mixture was stirred at 75 °C for 16 hours. The reaction mixture was then diluted with water (60 mL) and filtered to give 3-(2-hydroxypropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (13-e) (250 mg, yield: 61.4%). ESI [M+H] + =404.6

[0434] Step 6: Preparation of 1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidine-3-yl)propyl-2-yl methanesulfonate (13-f)

[0435] Under ice bath conditions, 3-(2-hydroxypropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (13-e) (250 mg, 0.62 mmol) and triethylamine (188 mg, 1.86 mmol) were dissolved in dichloromethane (30 mL), and methyl xanthyl chloride (106 mg, 0.93 mmol) was added with stirring under argon purging. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (60 mL) and extracted with dichloromethane (50 mL x 3). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidine-3-yl)propyl-2-yl methanesulfonate (13-f) (240 mg, yield 80.5%), ESI [M+H + =482.1

[0436] Step 7: Preparation of 3-(2-azidopropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (13-g)

[0437] 1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-3-yl)propyl-2-yl methanesulfonate (13-f) (240 mg, 0.498 mmol) was dissolved in N,N-dimethylformamide at room temperature, and sodium azide (700 mg) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-(2-azidopropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (13-g) (200 mg, yield: 93.7%). ESI [M+H] + =429.3

[0438] Step 8: Preparation of 3-(2-aminopropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (13-h)

[0439] At room temperature, 13 g (200 mg, 0.467 mmol) of 3-(2-azidopropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (200 mg, 0.467 mmol) was dissolved in 30 mL of methanol, and 500 mg of palladium on carbon was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours under hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give 13 h (170 mg, 90.5% yield) of 3-(2-aminopropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (200 mg, 0.467 mmol, 13 g ... + =403.6

[0440] Step 9: Preparation of 3-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (13-i)

[0441] At room temperature, 3-(2-aminopropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (13-h) (150 mg, 0.373 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (245 mg, 0.746 mmol), and triethylamine (75 mg, 0.746 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by TLC (petroleum ether:ethyl acetate = 1:1) to give 3-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-5-(4-(5-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (13-i) (50 mg, yield 19.3%). ESI [M+H] + =695.3

[0442] Step 10: Preparation of 3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (13)

[0443] At room temperature, 50 mg (0.072 mmol) of 3-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (13-i) was dissolved in 10 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by preparative HPLC to obtain 3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)oxazolidin-2-one (13) (10.87 mg, yield: 26.7%). ESI [M+H] + =565.2, 1 H NMR (400MHz, CDCl3) δ10.77 (d, J=24.2Hz, 1H), 8.53 (s, 2H), 7.73 (d, J=15.4Hz, 1H), 7.15-6.95 (m, 1H), 5.13 (d, J=7.3Hz, 1H), 4.63 (ddd, J=43.6, 1 4.4, 7.0Hz, 1H), 4.14 (dt, J=13.0, 6.9Hz, 1H), 4.07-3.68 (m, 8H), 3.65-3 .40 (m, 3H), 3.30-3.07 (m, 1H), 2.01 (s, 1H), 1.38 (dd, J=38.3, 6.3Hz, 3H).

[0444] Example 14: Preparation of (S)-5-((1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-2,3-dihydro-1H-imidazol-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (14)

[0445]

[0446] Step 1: Preparation of 2-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)acetic acid (14-a)

[0447] Ethyl 2-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)acetate (2.0 g, 11.76 mmol) was dissolved in methanol (20 mL) and water (4 mL), then potassium hydroxide (300 mg, 5.36 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give 2-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)acetic acid (14-a) (2.1 g, crude). ESI[M+H] + =143.1

[0448] Step 2: Preparation of 1-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-1,3-dihydro-2H-imidazol-2-one (14-b)

[0449] At room temperature, 2-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)acetic acid (14-a) (500 mg, 3.52 mmol), diisopropylethylamine (1.74 mL, 10.6 mmol), and HATU (1.34 g, 3.52 mmol) were dissolved in N,N-dimethylformamide (10 mL). After stirring the reaction mixture at room temperature for 30 minutes, 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2) (817 mg, 3.52 mmol) was added, and stirring continued at room temperature for 1 hour. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by TLC (petroleum ether:ethyl acetate = 2:3) to give 1-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-1,3-dihydro-2H-imidazol-2-one (14-b) (800 mg, yield: 63.6%). ESI [M+H] + =357.0

[0450] Step 3: Preparation of tert-butyl (S)-(1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-2,3-dihydro-1H-imidazol-1-yl)propyl-2-yl)carbamate (14-c)

[0451] At room temperature, 1-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-1,3-dihydro-2H-imidazol-2-one (14-b) (200 mg, 0.562 mmol), cesium carbonate (550 mg, 1.686 mmol), and (S)-2-((tert-butyloxycarbonyl)amino)propyl 4-toluenesulfonate (I-3) (370 mg, 1.12 mmol) were dissolved in acetonitrile (10 mL). The reaction mixture was stirred at room temperature for 30 min, then stirred at 60 °C for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by TLC (petroleum ether:ethyl acetate = 0:1) to give tert-butyl(S)-(1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-2,3-dihydro-1H-imidazol-1-yl)propyl-2-yl)carbamate (14-c) (40.0 mg, yield 13.8%). ESI[M+H] + =514.3

[0452] Step 4: Preparation of (S)-1-(2-aminopropyl)-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (14-d)

[0453] At room temperature, tert-butyl (S)-(1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-2,3-dihydro-1H-imidazol-1-yl)propyl-2-yl)carbamate (14-c) (40 mg, 0.078 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M, 5 mL) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain (S)-1-(2-aminopropyl)-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (14-d) (20 mg, crude product), ESI [M+H]. + =414.1.

[0454] Step 5: Preparation of (S)-5-((1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-2,3-dihydro-1H-imidazol-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (14-e)

[0455] At room temperature, (S)-1-(2-aminopropyl)-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (14-c) (75 mg, 0.181 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (119 mg, 0.362 mmol), and triethylamine (54.9 mg, 0.543 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour, and the reaction was completed by LC-MS. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 2:3) to obtain (S)-5-((1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-2,3-dihydro-1H-imidazol-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (14-e) (43 mg, yield: 33.6%). ESI [M+H] + =706.3

[0456] Step 6: Preparation of (S)-5-((1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-2,3-dihydro-1H-imidazol-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (14)

[0457] At room temperature, (S)-5-((1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-2,3-dihydro-1H-imidazol-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (14-e) (14-e) (14-e) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by preparative HPLC to obtain (S)-5-((1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-2,3-dihydro-1H-imidazol-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (14) (13.99 mg, yield 39.9%) ESI[M+H) + =576.1 1 H NMR (400MHz, CDCl3) δ10.19 (s, 1H), 8.52 (s, 2H), 7.73 (s, 1H), 6.36 (d, J = 3.0Hz, 1H), 6.20 (d, J = 3.0Hz, 1H), 6.04 (s, 1H), 4 .50 (dd, J=36.6, 16.0Hz, 2H), 4.16 (s, 1H), 4.04-3.87 (m, 4H), 3.72 (ddd, J=42.9, 22.1, 17.1Hz, 6H), 1.35 (d, J=6.5Hz, 3H).

[0458] Example 15: Preparation of (S)-5-((1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)imidazolin-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (15)

[0459]

[0460] Step 1: Preparation of tert-butyl (S)-(1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)imidazoline-1-yl)propyl-2-yl)carbamate (15-a)

[0461] tert-butyl(S)-(1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-2,3-dihydro-1H-imidazol-1-yl)propyl-2-yl)carbamate (14-d) (100 mg, 0.194 mmol) was dissolved in methanol (10 mL). Palladium on carbon (10% wt, 10 mg) was added to the solution, and hydrogen was purged three times. The mixture was stirred at room temperature for 15 h. The mixture was filtered, and the filtrate was concentrated to give tert-butyl(S)-(1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)imidazol-1-yl)propyl-2-yl)carbamate (15-a) (82 mg crude product), ESI[M+H). + =516.2.

[0462] Step 2: Preparation of (S)-1-(2-aminopropyl)-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)imidazolin-2-one (15-b)

[0463] (S)-1-(2-aminopropyl)-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)imidazolin-2-one (15-a) (82.0 mg, 0.159 mmol) was dissolved in dichloromethane (5 mL), then dioxane hydrochloride solution (4 M) was added and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give (S)-1-(2-aminopropyl)-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)imidazolin-2-one (15-b) (52 mg, crude), ESI [M+H] + =416.0.

[0464] Step 3: Preparation of (S)-5-((1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)imidazolin-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (15-c)

[0465] At room temperature, (S)-1-(2-aminopropyl)-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)imidazolin-2-one (15-b) (52 mg, 0.125 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (41.09 mg, 0.125 mmol), and triethylamine (37.9 mg, 0.375 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour, and LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to obtain (S)-5-((1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)imidazolin-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (15-c) (38 mg, yield 42.9%). ESI [M+H] + =708.1

[0466] Step 4: Preparation of (S)-5-((1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)imidazolin-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (15)

[0467] At room temperature, (S)-5-((1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)imidazolin-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (15-c) (15-c) (15-c) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC to obtain (S)-5-((1-(2-oxo-3-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)imidazolin-1-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (15) (9.32 mg, yield 30.06%). ESI [M+H] + =578.1, 1H NMR (400MHz, CDCl3) δ9.80 (s, 1H), 8.51 (s, 2H), 7.71 (s, 1H), 6.07 (s, 1H), 4.07 (s, 2H), 3.95 (m, 5H), 3.68 (s, 2H), 3.53 (t, J=7.3Hz, 5H), 3.44 (dd, J=14.5, 9.4Hz, 2H), 3.26 (d, J=4.8Hz, 1H), 1.33 (d, J=6.4Hz, 3H).

[0468] Example 16: Preparation of (S)-6-(4-(6-oxo-1-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-4-yl)aminopropyl)-1,6-dihydropyridin-3-carbonyl)piperazin-1-ylnicotinonitrile (16)

[0469]

[0470] Step 1: Preparation of (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (16-a)

[0471] Methyl (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (4-a) (160 mg, 1 M) and lithium hydroxide monohydrate (32 mg, 1.5 M) were added to a solution of methanol (1 mL) and water (1 mL) and stirred for 16 hours at 25 °C. The reaction was confirmed to be complete by LC-MS, and the solution was concentrated under vacuum to give an oily product (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (16-a) (100 mg, yield 65.46%). ESI [M+H] + =297.20

[0472] Step 2: Preparation of tert-butyl(S)-(1-(5-(4-(5-cyanopyridin-2-yl)piperazin-1-carbonyl)-2-oxopyridin-1(2H)-yl)propyl-2-yl)carbamate (16-b)

[0473] (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (16-a) (100 mg, 1 M) was prepared in a solution of N,N-dimethylformamide (5 mL), and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylhexafluorourea (128 mg, 1 M), 6-(piperazin-1-yl)nicotinonitrile (I-7) (64 mg, 1 M) and N,N-diisopropylethylamine (130 mg, 3 M) were added and stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS. An aqueous solution (50 mL) was added dropwise to the reaction mixture, and the solution was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, and filtered. The organic layers were concentrated under reduced pressure to provide the crude product. Purification via a Flash column (10 g) with a methanol:dichloromethane ratio of 10:1 yielded tert-butyl(S)-(1-(5-(4-(5-cyanopyridin-2-yl)piperazin-1-carbonyl)-2-oxopyridin-1(2H)-yl)propyl-2-yl)carbamate (16-b) (130 mg, 82.57% yield). ESI[M+H] + =467.30

[0474] Step 3: Preparation of (S)-6-(4-(1-(2-aminopropyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)piperazin-1-yl)nicotinonitrile (16-c)

[0475] 130 mg (1 M) of tert-butyl (S)-(1-(5-(4-(5-cyanopyridin-2-yl)piperazin-1-carbonyl)-2-oxopyridin-1(2H)-yl)propyl-2-yl)carbamate (16-b) was dissolved in 1.2 mL of dichloromethane at 0 °C, followed by dropwise addition of trifluoroacetic acid (1.9 g, 60 M). The reaction mixture was stirred at 25 °C for 1 hour. The reaction was confirmed to be complete by LC-MS, and the resulting mixture was concentrated under vacuum to give (S)-6-(4-(1-(2-aminopropyl)-6-oxo-1,6-dihydropyridin-3-carbonyl)piperazin-1-yl)nicotinonitrile (16-c) (70 mg, 68.56% yield) solid. ESI [M+H] + =367.30

[0476] Step 4: Preparation of (S)-6-(4-(6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carbonyl)piperazin-1-yl)nicotinonitrile (16-d)

[0477] (S)-6-(4-(1-(2-aminopropyl)-6-oxo-1,6-dihydropyridin-3-carbonyl)piperazin-1-yl)nicotinonitrile (16-c) (70 mg, 1.00 M) was dissolved in ethanol (2 mL), and then triethylamine (58 mg, 3.00 M) and 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (75 mg, 1.2 M) were added dropwise. The reaction mixture was stirred at 60 °C for 2 hours, the solid was filtered off, and the resulting mixture was concentrated under reduced pressure. The residue was purified by Flash column chromatography (10 g) with ethyl acetate:petroleum ether = 1:0 polarity to give solid (S)-6-(4-(6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carbonyl)piperazin-1-yl)nicotinonitrile (16-d) (30 mg, 23.84% yield). ESI[M+H] + =659.40

[0478] Step 5: Preparation of (S)-6-(4-(6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carbonyl)piperazin-1-yl)nicotinonitrile (16)

[0479] (S)-6-(4-(6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carbonyl)piperazin-1-yl)nicotinonitrile (16-d) (20 mg, 1 M) was added to a solution of 4N ethyl acetate (2 mL). The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS to determine its completeness. The resulting mixture was concentrated under vacuum to give the crude product. The crude product was purified by preparative stencil (dichloromethane:methanol = 10:1) to give a solid product (S)-6-(4-(6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carbonyl)piperazin-1-yl)nicotinonitrile (16) (2.1 mg, 13.09% yield). ESI[M+H] + =529.30, 1H NMR (400MHz, DMSO-d6) δ12.45 (s, 1H), 8.49 (s, 1H), 7.89 (s, 2H), 7.66 (s, 1H), 7.50 (d, J = 11.0Hz, 1H), 6.90 (d, J = 9.2Hz, 1H), 6.69 (s, 1 H), 6.42 (d, J = 9.4Hz, 1H), 5.29 (s, 1H), 5.14 (s, 1H), 4.38 (s, 2H), 4.16 (d, J = 13.4Hz, 1H), 3.67 (s, 3H), 3.51 (s, 3H), 1.33-1.25 (m, 3H).

[0480] Example 17: Preparation of (S)-5-((1-(3-fluoro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (17)

[0481]

[0482] Step 1: Preparation of 1-oxide of 3-fluoro-5-(methoxycarbonyl)pyridine (17-a)

[0483] 5-Fluoronic acid methyl ester (2.00 g, 12.89 mmol) was dissolved in dichloromethane (30 mL), cooled to 0 °C, and m-CPBA (3.30 g, 19.18 mmol) was added. The reaction was allowed to proceed at room temperature for 2 days. The reaction mixture was diluted with dichloromethane (30 mL), the organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by Flash column chromatography (ethyl acetate: petroleum ether) to give the target product, 3-fluoro-5-(methoxycarbonyl)pyridine 1-oxide (17-a) (1.90 g, yield 86.4%). ESI [M+H] + =172.1

[0484] Step 2: Preparation of methyl 5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (17-b)

[0485] 1.00 g (5.84 mmol) of 1-oxide 3-fluoro-5-(methoxycarbonyl)pyridine was placed in a sealed tube, and acetic anhydride (10 mL) was added. The reaction was carried out at 140 °C for 5 hours. The reaction mixture was concentrated under reduced pressure and purified by Flash column chromatography (ethyl acetate:petroleum ether) to give the target product, methyl 5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (17-b) (385 mg, yield 38.5%). ESI [M+H] + =172.1

[0486] Step 3: Preparation of methyl(S)-1-(2-((tert-butoxycarbonyl)amino)propyl)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylate (17-c)

[0487] Methyl 5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylate (17-b) (385 mg, 2.25 mmol) was dissolved in N,N-dimethylformamide (15 ml), and potassium carbonate (621 mg, 4.50 mmol) and (S)-2-((tert-butyloxycarbonyl)amino)propyl 4-toluenesulfonate (I-3) (1108 mg, 3.37 mmol) were added. The reaction was carried out at 80 °C for 2 hours. The reaction was quenched with saturated brine (100 ml), extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by Flash column chromatography (ethyl acetate: petroleum ether) to give the target product methyl (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylate (17-c) (430 mg, yield 58.1%). ESI[M+H] + =329.1

[0488] Step 4: Preparation of (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (17-d)

[0489] Methyl (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (17-c) (430 mg, 1.30 mmol) was dissolved in methanol (2 ml), and water (1 ml) and lithium hydroxide monohydrate (65 mg, 1.60 mmol) were added. The reaction mixture was reacted at room temperature for 2 hours. The pH of the reaction solution was adjusted to 7 with 1 N hydrochloric acid, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the target product (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (17-d) (349 mg, yield 84.8%). ESI [M+H] + =315.1

[0490] Step 5: Preparation of tert-butyl(S)-(1-(3-fluoro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)carbamate (17-e)

[0491] (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (17-d) (349 mg, 1.11 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2) (306 mg, 1.32 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (836 mg, 2.20 mmol), and N,N-diisopropylethylamine (567 mg, 4.40 mmol) were dissolved in dichloromethane (12 mL). The reaction was carried out at room temperature for 16 hours. Quenching was performed with saturated ammonium chloride solution (10 ml), followed by extraction with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified using a pre-treatment plate (dichloromethane:methanol = 20:1) to obtain the target product tert-butyl(S)-(1-(3-fluoro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)carbamate (17-e) (500 mg, yield 84.9%). ESI[M+H] + =529.3

[0492] Step 6: Preparation of (S)-1-(2-aminopropyl)-3-fluoro-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-2(1H)-one (17-f)

[0493] Tert-butyl (S)-(1-(3-fluoro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)carbamate (17-e) was dissolved in dichloromethane (2 ml), and trifluoroacetic acid (0.1 ml) was added. The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give the target product (S)-1-(2-aminopropyl)-3-fluoro-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-2(1H)-one (17-f) (40 mg, 100% yield). ESI[M+H] + =429.3

[0494] Step 7: Preparation of (S)-5-((1-(3-fluoro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (17-g)

[0495] (S)-1-(2-aminopropyl)-3-fluoro-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-2(1H)-one (17-f) (40 mg, 0.09 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (49 mg, 0.15 mmol), and triethylamine (20 mg, 0.20 mmol) were dissolved in anhydrous ethanol (3 ml) and reacted at 60 °C for 1 hour. The reaction solution was concentrated under reduced pressure and then purified using a preparative plate (dichloromethane:methanol = 20:1) to obtain the target product (S)-5-((1-(3-fluoro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (17 g) (50 mg, yield 74.4%). ESI [M+H] + =721.4

[0496] Step 8: Preparation of (S)-5-((1-(3-fluoro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (17)

[0497] (S)-5-((1-(3-fluoro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (17-g) (50 mg, 0.07 mmol) was dissolved in 4 M ethyl acetate (2 ml) and reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and then purified using a preparative plate (dichloromethane:methanol = 20:1) to obtain the target product (S)-5-((1-(3-fluoro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (17) (5 mg, yield 12%). ESI [M+H] + =519.3, 1H NMR (400MHz, dmso) δ12.47 (s, 1H), 8.73 (s, 2H), 7.75 (d, J = 25.1Hz, 2H), 7.53 (d, J = 10.1Hz, 1H), 6.62 (d, J = 4.7Hz, 1H), 4.41 (s, 1H), 4.22 (dd, J=13.0, 4.1Hz, 1H), 4.10 (dd, J=12.9, 9.1Hz, 1H), 3.86 (d, J=4.8Hz, 4H), 3.54 (s, 4H), 1.25-1.19 (m, 3H).

[0498] Example 18: Preparation of (S)-5-(1-(2-oxy-3-(3-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (18)

[0499]

[0500] Step 1: Preparation of tert-butyl(S)-(1-(2-oxy-3-((3-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)carbamate (18-a)

[0501] At room temperature, tert-butyl(S)-(1-(3-(chloromethyl)-2-oxapyridin-1(2H)-yl)propane-2-yl)carbamate (18-a, 100 mg, 0.33 mmol), 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (81 mg, 0.33 mmol), and potassium carbonate (138 mg, 0.99 mmol) were dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (17 mg, 0.09 mmol) was added under argon-purified stirring. After the addition of the reactants, the reaction mixture was stirred at 110°C for 4 hours. The reaction mixture was then concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 3:1 to 0:1) to obtain tert-butyl(S)-(1-(2-oxy-3-((3-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)carbamate (18-a, 65 mg, yield 38.23%).

[0502] Step 2: Preparation of (S)-4-((1-(2-aminopropyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (18-b)

[0503] At room temperature, tert-butyl(S)-(1-(2-oxy-3-((3-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)carbamate (18-a, 65 mg, 0.127 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (2 mL, 4 M) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain (S)-4-((1-(2-aminopropyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (18-b, 53 mg, crude product)

[0504] Step 3: Preparation of (S)-5-(1-(2-oxy-3-(3-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (18-c)

[0505] At room temperature, (S)-4-((1-(2-aminopropyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (18-b, 53 mg, 0.129 mmol) and triethylamine (26 mg, 0.258 mmol) were dissolved in ethanol (5 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour, and the reaction was completed according to liquid chromatography-mass spectrometry. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain (S)-5-((1-(2-oxy-3-((3-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (18-c, 36 mg, yield 39.7%).

[0506] Step 4: Preparation of (S)-5-((1-(2-oxy-3-(3-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (18)

[0507] At room temperature, (S)-5-((1-(2-oxy-3-((3-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (18-c, 36 mg, 0.051 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. Liquid chromatography-mass spectrometry showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was reverse-phase to prepare (S)-5-((1-(2-oxy-3-(3-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (18) (13.8 mg, yield 12.96%). ESI[M+H] + =573.3, 1 H NMR (400MHz, CDCl3) δ10.61 (s, 1H), 7.74 (s, 1H), 7.59 (d, J = 8.6Hz, 2H), 7.26 (s, 3H), 6.60 (s, 1H), 6.27 (d, J = 6.7Hz, 1H), 5.86 (s, 1H), 4.41-4.38 (m, 1H), 4.12-4.03 (m, 4H), 3.75-3.64 (m, 2H), 3.45-3.30 (m, 4H), 1.41 (d, J=6.4Hz, 3H).

[0508] Example 19: Preparation of (S)-4-(trifluoromethyl)-5-((1-(4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)amino)pyridazine-3(2H)-one (19)

[0509]

[0510] Step 1: Preparation of 1H-pyrazole-4-carboxylic acid (19-a)

[0511] A solution of methyl 1H-pyrazole-4-carboxylate (200 mg, 1 M) and lithium hydroxide (100 mg, 1.5 M) in methanol (2 mL) and water (2 mL) was stirred for 7 hours at 25 °C. The resulting mixture was concentrated under vacuum to give an oily product, 1H-pyrazole-4-carboxylic acid (19-a) (340 mg, 50% purity, 95.64% yield). ESI[M+H] + =297.20

[0512] Step 2: Preparation of (1H-pyrazol-4-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (19-b)

[0513] 1H-pyrazole-4-carboxylic acid (19-a) (340 mg, 50% purity, 1 M) was dissolved in N,N-dimethylformamide (18 mL), followed by the addition of 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylhexafluorourea (576 mg, 1 M), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2) (352 mg, 1 M), and N,N-diisopropylethylamine (587 mg, 3 M). The reaction mixture was stirred at 25 °C for 2 hours. The reaction was confirmed by LC-MS. An aqueous solution (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 3), washing the combined organic layers with brine (30 mL x 2), drying with anhydrous sodium sulfate, and filtering. The organic layer was concentrated under reduced pressure to give an oily substance (1H-pyrazol-4-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl) methyl ketone (19-b) (600 mg, 50% purity, 60.62% yield). ESI[M+H] + =327.20

[0514] Step 3: Preparation of tert-butyl(S)-(1-(4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)carbamate (19-c)

[0515] (1H-pyrazol-4-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (19-b) (150 mg, 1 M) was dissolved in N,N-dimethylformamide (8 mL), followed by the addition of cesium carbonate (449 mg, 3 M) and (S)-(1-iodopropane-2-yl)carbamate tert-butyl ester (I-4) (196 mg, 1.5 M). The mixture was stirred at 80 °C for 1 hour. The reaction was monitored by LC-MS to confirm its completion. An aqueous solution (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The organic layers were concentrated under reduced pressure to provide the crude product. The residue was purified by Flash silica gel column chromatography (10 g) and with polar ethyl acetate / petroleum ether (1:0) to give tert-butyl(S)-(1-(4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)carbamate (19-c) as a yellow solid (120 mg, 53.98% yield). ESI[M+H] + =484.30

[0516] Step 4: Preparation of (S)-(1-(2-aminopropyl)-1H-pyrazol-4-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (19-d)

[0517] Tert-butyl (S)-(1-(4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)carbamate (19-c) (60 mg, 1 M) was dissolved in difluoromethane (0.55 mL) at 0 °C, followed by dropwise addition of trifluoroacetic acid (849 mg, 60 M). The reaction mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS to determine completion. The resulting mixture was concentrated under vacuum to give (S)-(1-(2-aminopropyl)-1H-pyrazol-4-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (19-d) (65 mg, 70% purity, 95.64% yield) solid. ESI [M+H] + =384.30

[0518] Step 5: Preparation of (S)-4-(trifluoromethyl)-5-((1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (19-e)

[0519] (S)-(1-(2-aminopropyl)-1H-pyrazol-4-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (19-d) (65 mg, 70% purity, 1.00 M) was added to ethanol (2 mL), followed by triethylamine (36 mg, 3.00 M) and 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (39 mg, 1 M). The reaction mixture was stirred at 60 °C for 1 hour, the solid was filtered off, and the resulting mixture was concentrated under reduced pressure. The residue was purified by Flash silica gel column chromatography (4 g) and with polar ethyl acetate / petroleum ether (1:0) to give (S)-4-(trifluoromethyl)-5-((1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (19-e) (50 mg, 62.35% yield). ESI[M+H] + =676.40

[0520] Step 6: Preparation of (S)-4-(trifluoromethyl)-5-((1-(4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)amino)pyridazine-3(2H)-one (19)

[0521] A solution of (S)-4-(trifluoromethyl)-5-((1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (19-e) (80 mg, 1 M) in 4 N ethyl acetate (3 mL). The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS to determine its completeness. The resulting mixture was concentrated under vacuum to give the crude product. The crude product was purified by preparative stencil (dichloromethane:methanol = 10:1) to give product (S)-4-(trifluoromethyl)-5-((1-(4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)amino)pyridazine-3(2H)-one (19) (4.5 mg, 6.97% yield). ESI[M+H] + =546.40, 1 H NMR (400MHz, DMSO) δ12.41 (s, 1H), 8.72 (s, 2H), 8.04 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 6.68 (d, J=4.3H z, 1H), 4.44 (s, 1H), 4.31 (d, J=6.0Hz, 2H), 3.89-3.83 (m, 4H), 3.68-3.60 (m, 4H), 1.18 (d, J=6.4Hz, 3H).

[0522] Example 20: Preparation of 4-(trifluoromethyl)-5-(((S)-1-((R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-yl)propane-2-yl)amino)pyridazine-3(2H)-one (20)

[0523]

[0524] Step 1: Preparation of (R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (20-a)

[0525] (R)-1-(tert-Butoxycarbonyl)pyrrolidine-3-carboxylic acid (100 mg, 0.46 mmol) was dissolved in dichloromethane (5 ml), and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylhexafluorourea (265 mg, 0.70 mmol) was added. The mixture was stirred at room temperature for 20 minutes, and then 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (161 mg, 0.46 mmol) and N,N-diisopropylethylamine (202 μL, 2.16 mmol) were added. The mixture was stirred at room temperature for 1 hour. Quenching was performed with saturated ammonium chloride solution (5 ml), followed by extraction with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by Flash column (dichloromethane) to obtain the target product (R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (20-a) (74 mg, yield 37.1%).

[0526] Step 2: Preparation of (R)-pyrrolidine-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone trifluoroacetate (20-b)

[0527] (R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (20-a) (74 mg, 0.17 mmol) was dissolved in dichloromethane (4 ml), and trifluoroacetic acid (0.5 ml) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the target product (R)-pyrrolidine-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone trifluoroacetate (20-b) (120 mg, yield 157.1%).

[0528] Step 3: Preparation of tert-butyl ((S)-1-((R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)propyl-2-yl)carbamate (20-c)

[0529] (R)-pyrrolidine-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone trifluoroacetate (20-b) (40 mg, 0.12 mmol) was dissolved in ultra-dry dichloromethane (5 ml), and then added... Molecular sieves were dried for 30 minutes. Then, (S)-(1-oxopropane-2-yl)carbamate tert-butyl ester (32 mg, 0.18 mmol) and sodium triacetate borohydride (52 mg, 0.25 mmol) were added. The mixture was stirred at room temperature for 30 minutes, filtered, and the filtrate was concentrated and dried under reduced pressure to obtain the target product, tert-butyl((S)-1-((R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)propyl-2-yl)carbamate. ESI[M+H] + =487.4

[0530] Step 4: Preparation of ((R)-1-((S)-2-aminopropyl)pyrrolidine-3-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone trifluoroacetate (20-d)

[0531] tert-butyl((S)-1-((R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)propyl-2-yl)carbamate (20-c) (59 mg, 0.12 mmol) was dissolved in dichloromethane (5 ml), and trifluoroacetic acid (4.5 ml) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give the target product ((R)-1-((S)-2-aminopropyl)pyrrolidine-3-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone trifluoroacetate (20-d) (70 mg, yield 115.3%). ESI[M+H] + =387.3

[0532] Step 5: Preparation of 4-(trifluoromethyl)-5-(((S)-1-((R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)propane-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (20-e)

[0533] Dissolve ((R)-1-((S)-2-aminopropyl)pyrrolidine-3-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone trifluoroacetate (20-d) (70 mg, 0.14 mmol) in ethanol (5 ml), add triethylamine (49 μL, 0.35 mmol) and 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (46 mg, 0.14 mmol), and stir at 60 °C for 2 hours. The reaction solution was concentrated, the residue was dissolved in dichloromethane, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by plate preparation (dichloromethane:methanol = 10:1) to give the target product 4-(trifluoromethyl)-5-(((S)-1-((R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-yl)propane-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (20-e) (12 mg, yield 12.6%). ESI[M+H + =679.5

[0534] Step 6: Preparation of 4-(trifluoromethyl)-5-(((S)-1-((R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-yl)propane-2-yl)amino)pyridazine-3(2H)-one (20)

[0535] 12 mg (0.018 mmol) of 4-(trifluoromethyl)-5-(((S)-1-((R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)propane-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (20-e) (20-e) was dissolved in ethyl hydrochloride solution (2 ml, 4 mol / L) and stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure and then purified using a preparative plate (dichloromethane:methanol = 10:1) to obtain the target product 4-(trifluoromethyl)-5-(((S)-1-((R)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-yl)propane-2-yl)amino)pyridazine-3(2H)-one (20) (5 mg, yield 51.5%). ESI[M+H] + =549.40

[0536] Example 21: 4-(trifluoromethyl)-5-(((S)-1-((S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)propane-2-yl)amino)pyridazin-3(2H)-one (21)

[0537]

[0538] Step 1: Preparation of (S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (21-a)

[0539] (S)-1-(tert-Butoxycarbonyl)pyrrolidine-3-carboxylic acid (200 mg, 1 M) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylhexafluorourea (353 mg, 1 M), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2) (216 mg, 1 M), and N,N-diisopropylethylamine (360 mg, 3 M), and the mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS to confirm its completion. An aqueous solution (60 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL x 3), washing of the combined organic layers with brine (20 mL x 2), drying with anhydrous sodium sulfate, and filtering. The organic layers were concentrated under reduced pressure to provide the crude product. The residue was purified by Flash silica gel column chromatography (10 g) and with polar ethyl acetate / petroleum ether (1:1) to give (S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (21-a) (380 mg, 95.23% yield). ESI [M+H] + =430.30

[0540] Step 2: Preparation of (S)-pyrrolidine-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (21-b)

[0541] (S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (21-a) (240 mg, 1 M) was dissolved in dichloromethane (2.5 mL) at 0 °C, followed by dropwise addition of trifluoroacetic acid (3.8 g, 60 M). The reaction mixture was stirred at 25 °C for 1 hour. LC-MS analysis confirmed the reaction was complete. The resulting mixture was concentrated under vacuum to give an oily product (S)-pyrrolidine-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (21-b) (200 mg, 80% purity, 86.93% yield). ESI [M+H] + =330.20

[0542] Step 3: Preparation of tert-butyl ((S)-1-((S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)propyl-2-yl)carbamate (21-c)

[0543] (S)-pyrrolidine-3-yl(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (21-b) (200 mg, 1 M) was dissolved in dichloromethane (5 mL), followed by the addition of sodium triacetoxyborohydride (192 mg, 1.5 M) and (S)-(1-oxopropane-2-yl)carbamate tert-butyl ester (125 mg, 1.2 M). The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS to confirm its completeness. An aqueous solution (0.2 mL) was added dropwise to the reaction mixture, which was dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure to provide the crude product. The residue was purified by Flash silica gel column chromatography (10 g) and with polar ethyl acetate / petroleum ether (1:1) to give tert-butyl((S)-1-((S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)propyl-2-yl)carbamate (21-c) (270 mg, 91.38% yield). ESI [M+H] + =487.40

[0544] Step 4: Preparation of ((S)-1-((S)-2-aminopropyl)pyrrolidine-3-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (21-d)

[0545] tert-butyl((S)-1-((S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)propyl-2-yl)carbamate (21-c) (270 mg, 1 M) was added to 3 mL of dichloromethane at 0 °C, followed by dropwise addition of trifluoroacetic acid (3.8 g, 60 M). The reaction mixture was stirred at 25 °C for 1 hour. The reaction was confirmed to be complete by LC-MS and concentrated under vacuum to give ((S)-1-((S)-2-aminopropyl)pyrrolidine-3-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (21-d) (250 mg, 80% purity, 93.27% yield).

[0546] Step 5: Preparation of 4-(trifluoromethyl)-5-(((S)-1-((S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)propane-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (21-e)

[0547] ((S)-1-((S)-2-aminopropyl)pyrrolidine-3-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (21-d) (200 mg, 1.00 M) was added to an ethanol (5 mL) solution, followed by dropwise addition of triethylamine (157 mg, 3.00 M) and 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (204 mg, 1.2 M). The reaction mixture was stirred at 60 °C for 1 hour. LC-MS analysis showed that the starting material was completely consumed. The solids were filtered and the resulting mixture was concentrated under reduced pressure. The residue was purified by Flash silica gel column chromatography (10 g) and with polar ethyl acetate / petroleum ether (1:1) to give solid 4-(trifluoromethyl)-5-(((S)-1-((S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)propane-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (21-e) (130 mg, 37.01% yield). ESI[M+H] + =679.50

[0548] Step 6: Preparation of 4-(trifluoromethyl)-5-(((S)-1-((S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-yl)propane-2-yl)amino)pyridazine-3(2H)-one (21)

[0549] 75 mg (1 M) of 4-(trifluoromethyl)-5-(((S)-1-((S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)propane-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (21-e) was added to 4 N ethyl acetate (10 mL). The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS to determine its completeness. The resulting mixture was concentrated under vacuum to give the crude product. The crude product was purified by preparative stencil (dichloromethane:methanol = 10:1) to give 4-(trifluoromethyl)-5-(((S)-1-((S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-yl)propane-2-yl)amino)pyridazine-3(2H)-one (21) (8 mg, 13.20% yield). ESI[M+H] + =549.30, 1H NMR (400MHz, dmso) δ12.43 (s, 1H), 8.72 (s, 1H), 8.04 (s, 2H), 7.90 (s, 1H), 3.89-3.74 (m, 3H), 3.52 (d, J= 29.6Hz, 5H), 2.51 (s, 2H), 2.03-1.83 (m, 3H), 1.46 (s, 3H), 1.30 (t, J=8.2Hz, 2H), 0.82 (d, J=7.0Hz, 3H).

[0550] Example 22: (S)-4-(trifluoromethyl)-5-((1-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)amino)pyridazine-3(2H)-one (22)

[0551]

[0552] Step 1: Preparation of 1H-pyrazole-3-carboxylic acid (22-a)

[0553] A solution of methyl 1H-pyrazole-3-carboxylic acid (200 mg, 1 M) and lithium hydroxide (100 mg, 1.5 M) was added to methanol (2 mL) and water (2 mL) and stirred for 4 hours at 25 °C. Plate preparation (dichloromethane:methanol = 10:1) showed complete consumption of the starting material and the discovery of new spots. The resulting mixture was concentrated under vacuum to give the target product, 1H-pyrazole-3-carboxylic acid (22-a) (350 mg, 50% purity, 98.45% yield).

[0554] Step 2: Preparation of (1H-pyrazol-3-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (22-b)

[0555] 1H-pyrazole-3-carboxylic acid (22-a) (350 mg, 50%, 1 M) was added to N,N-dimethylformamide (20 mL), followed by the addition of 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylhexafluorourea (593 mg, 1 M), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-1) (362 mg, 1 M), and N,N-diisopropylethylamine (604 mg, 3 M). The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS. An aqueous solution (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The organic layer was concentrated under reduced pressure to give the target product (1H-pyrazol-3-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (22-b) (600 mg, 50% purity, 58.89% yield). ESI [M+H] + =327.20

[0556] Step 3: Preparation of tert-butyl(S)-(1-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)carbamate (22-c)

[0557] (1H-pyrazol-3-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (22-b) (150 mg, 1 M) was added to N,N-dimethylformamide (8 mL), followed by cesium carbonate (449 mg, 3 M) and (S)-(1-iodopropane-2-yl)carbamate tert-butyl ester (I-4) (196 mg, 1.5 M). The mixture was stirred at 80 °C for 1 hour. The reaction was monitored by LC-MS to confirm its completion. An aqueous solution (30 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (15 mL x 3), and the combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The organic layers were concentrated under reduced pressure to provide the crude product. The crude product was purified by preparative stencil (petroleum ether:ethyl acetate = 1:1) to obtain the target product, tert-butyl(S)-(1-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)carbamate (22-c) (170 mg, 76.48% yield). ESI[M+H] + =484.30

[0558] Step 4: Preparation of (S)-(1-(2-aminopropyl)-1H-pyrazol-3-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (22-d)

[0559] tert-butyl (S)-(1-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)carbamate (22-c) (150 mg, 1 M) was dissolved in dichloromethane (1.4 mL) at 0 °C, followed by dropwise addition of trifluoroacetic acid (2.1 g, 60 M). The reaction mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS to confirm completion. The resulting mixture was concentrated under vacuum to give the target product (S)-(1-(2-aminopropyl)-1H-pyrazol-3-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (22-d) (170 mg, 60% purity, 85.76% yield). ESI [M+H] + =384.30

[0560] Step 5: Preparation of (S)-4-(trifluoromethyl)-5-((1-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (22-e)

[0561] (S)-(1-(2-aminopropyl)-1H-pyrazol-3-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (22-d) (170 mg, 60% purity, 1.00 M) was added to ethanol (3 mL), followed by dropwise addition of triethylamine (81 mg, 3.00 M) and 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (87 mg, 1 M)). The reaction mixture was stirred at 60 °C for 1 hour. LC-MS analysis showed that the starting material was completely consumed. The solids were filtered and the resulting mixture was concentrated under reduced pressure. The target product (S)-4-(trifluoromethyl)-5-((1-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (22-e) (179 mg, 99.57% yield) was obtained by Flash silica gel column chromatography (10 g) and purification of the residue with polar ethyl acetate / petroleum ether (1:0). + =676.40

[0562] Step 6: Preparation of (S)-4-(trifluoromethyl)-5-((1-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)amino)pyridazine-3(2H)-one (22)

[0563] (S)-4-(trifluoromethyl)-5-((1-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (22-e) (160 mg, 1 M) was added to 4N ethyl acetate (6 mL). The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS to determine its completeness. The resulting mixture was concentrated under vacuum to give the crude product. The crude product was purified by preparative stencil (dichloromethane:methanol = 10:1) to give the target product (S)-4-(trifluoromethyl)-5-((1-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-1H-pyrazol-1-yl)propyl-2-yl)amino)pyridazine-3(2H)-one (22) (13.8 mg, 10.68% yield). ESI[M+H] + =546.30, 1H NMR (400MHz, DMSO) δ12.37 (s, 1H), 8.72 (s, 2H), 7.71 (d, J = 2.2Hz, 1H), 7.63 (s, 1H), 6.60 (d, J = 5.2Hz, 1H), 6.54 (d , J=2.2Hz, 1H), 4.48 (s, 1H), 4.34 (qd, J=13.8, 6.4Hz, 2H), 3.89 (t, J=24.9Hz, 6H), 3.68 (s, 2H), 1.22-1.20 (m, 3H).

[0564] Example 23: Preparation of 4-(trifluoromethyl)-5-(((2S)-1-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-carbonyl)pyrrolidine-3-yl)oxy)propane-2-yl)amino)pyridazine-3(2H)-one (23)

[0565]

[0566] Step 1: Preparation of methyl 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-4-carboxylic acid (23-a)

[0567] 2-Chloro-5-(trifluoromethyl)pyrimidine (500 mg, 2.75 mmol) was dissolved in N-methylpyrrolidone (30 mL), potassium carbonate (1.14 g, 8.25 mmol) was added, and the mixture was stirred overnight at 80 °C. The mixture was poured into ice water, and the aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether-ethyl acetate = 3:1) to give methyl 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-4-carboxylic acid (23-a, 750 mg, yield 94.2%), ESI [M+H]. + =290.1.

[0568] Step 2: Preparation of 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-4-carboxylic acid (23-b)

[0569] Methyl 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-4-carboxylic acid (23-a, 500 mg, 1.72 mmol) was dissolved in methanol (10 mL), followed by the addition of lithium hydroxide monohydrate (145 mg, 3.46 mmol) and water (2 mL). The mixture was stirred at 40 °C for 16 hours. Liquid chromatography-mass spectrometry (LC-MS) showed normal results. The mixture was concentrated, and the pH was adjusted to approximately 4 with the remaining water. The precipitated solid yielded 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-4-carboxylic acid (23-b, 400 mg, yield 84.2%). ESI [M+H] + =276.1

[0570] Step 3: Preparation of (3-hydroxypyrrolidone-1-yl)(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)methyl ketone (23-c)

[0571] At room temperature, 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-4-carboxylic acid (23-b, 400 mg, 1.45 mmol) and pyrrolidine-3-ol (139 mg, 1.60 mmol) were dissolved in N,N-dimethylformamide (20 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (608 mg, 1.60 mmol) and N,N-diisopropylethylamine (619 mg, 4.80 mmol) were added. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried, and concentrated. The reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 10:1) to give (3-hydroxypyrrolidone-1-yl)(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)methyl ketone (23-c, 40 mg, yield 80%). ESI [M+H+ =345.0

[0572] Step 4: Preparation of tert-butyl ((2S)-1-(1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-carbonyl)pyrrolidine-3-yl)oxy)propyl-2-yl)carbamate (23-d)

[0573] Under ice bath conditions, (3-hydroxypyrrolidone-1-yl)(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)methyl ketone (23-c, 400 mg, 1.16 mmol) was dissolved in N,N-dimethylformamide (20 mL). Sodium hydrogen (56 mg, 1.40 mmol) was added under nitrogen purging. Tert-butyl(S)-4-methyl-1,2,3-oxothiazolidin-3-carboxylate 2,2-dioxide (400 mg, 1.23 mmol) was dissolved in N,N-dimethylformamide (30 mL) and added to the reaction mixture. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was quenched in ice water, and the aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried, and concentrated. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give tert-butyl((2S)-1-(1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-carbonyl)pyrrolidine-3-yl)oxy)propyl-2-yl)carbamate (23-d, 450 mg, yield 77.3%). ESI [M+H] + =502.3

[0574] Step 5: Preparation of (3-(S)-2-aminopropoxy)pyrrolidine-1-yl)(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)methyl ketone hydrochloride (23-e)

[0575] At room temperature, ((2S)-1-(1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-carbonyl)pyrrolidine-3-yl)oxy)prop-2-yl)carbamate (23-d, 450 mg, 0.896 mmol) was dissolved in dichloromethane (30 mL), and dioxane hydrochloride (4 M) (5 mL) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain (3-(S)-2-aminopropoxy)pyrrolidine-1-yl)(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)methyl ketone hydrochloride (23-e, 350 mg, crude product). ESI[M+H] + =402.2

[0576] Step 5: Preparation of 4-(trifluoromethyl)-5-(2S)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-carbonyl)pyrrolidine-3-yl)oxy)propane-2-yl)amino)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (23-f)

[0577] At room temperature, (3-(S)-2-aminopropoxy)pyrrolidine-1-yl)(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)methyl ketone hydrochloride (23-e, 350 mg, 0.87 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1, 428 mg, 1.30 mmol), and triethylamine (264 mg, 2.61 mmol) were dissolved in ethanol (30 mL). After the addition of the reactants, the reaction mixture was stirred at 70 °C for 12 hours, and the reaction was completed according to liquid chromatography-mass spectrometry. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 4-(trifluoromethyl)-5-(2S)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-carbonyl)pyrrolidine-3-yl)oxy)propane-2-yl)amino)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (23-f, 300 mg, yield 49.7%). ESI [M+H + =694.3

[0578] Step 6: Preparation of 4-(trifluoromethyl)-5-(((2S)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-carbonyl)pyrrolidine-3-yl)oxy)propane-2-yl)amino)pyridazine-3(2H)-one (23)

[0579] At room temperature, 4-(trifluoromethyl)-5-(2S)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-carbonyl)pyrrolidine-3-yl)oxy)propane-2-yl)amino)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (23-f, 200 mg, 0.288 mmol) was dissolved in dichloromethane (20 mL). Trifluoroacetic acid (3 mL) was added under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. Liquid chromatography-mass spectrometry showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was reverse-phase prepared to obtain 4-(trifluoromethyl)-5-(((2S)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-carbonyl)pyrrolidine-3-yl)oxy)propane-2-yl)amino)pyridazine-3(2H)-one (23) (105 mg, yield 64.8%). Resolution yielded 23-P1 (38.7 mg) and 23-P2 (47.7 mg).

[0580] 23-P1: ESI[M+H] + =564.2, 1 H NMR (400MHz, CDCl3) δ10.74 (d, 1H), 8.48 (s, 2H), 7.70-7.59 (m, 1H), 5.95-5.61 (m, 1H), 4.87 (d, 2H), 4.28-3.30 (m, 9H), 3.16-2.99 (m, 2H), 2.74-2.53 (m, 1H), 2.10 (d, 5H).1.32 (t, 3H).

[0581] 23-P2: ESI[M+H] + =564.2, 1 H NMR (400MHz, CDCl3) δ10.50 (d, 1H), 8.49 (s, 2H), 7.70-7.61 (m, 1H), 5.8 (m, 1H), 4.87 ( d, 2H), 4.24-3.31 (m, 9H), 3.08 (m, 2H), 2.66 (dd, 1H), 2.21-1.86 (dd, 5H). 1.32 (t, 3H).

[0582] Example 24: (S)-5-((1-(2-oxo-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (24)

[0583]

[0584] Step 1: Preparation of tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylic acid (24-a)

[0585] Under ice bath conditions, 6-chloropyridin-3-ol (3.0 g, 23.1 mmol), 4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (4.64 g, 23.1 mmol), and triphenylphosphine (6.05 g, 23.1 mmol) were dissolved in tetrahydrofuran (30 mL). Diisopropyl azodicarbonate (4.67 g, 23.1 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give 4-((6-chloropyridin-3-yl)oxy)piperidin-1-carboxylic acid tert-butyl ester (24-a) (4.3 g, yield: 59.7%). ESI [M+H] + =313.1

[0586] Step 2: Preparation of 2-chloro-5-(piperidin-4-oxy)pyridine (24-b)

[0587] At room temperature, 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (24-a) (4.3 g, 13.7 mmol) was dissolved in dichloromethane (20 mL), and dioxane hydrochloride (4 M) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain 2-chloro-5-(piperidine-4-oxy)pyridine hydrochloride (24-b) (3.8 g, crude product). ESI [M+H] + =213.1

[0588] Step 3: Preparation of 2-(4-((6-chloropyridin-3-yl)oxy)piperidin-1-yl)-5-(trifluoromethyl)pyrimidine (24-c)

[0589] At room temperature, 2-chloro-5-(trifluoromethyl)pyridine (604 mg, 3.30 mmol) and 2-chloro-5-(piperidin-4-oxy)pyridine hydrochloride (24-b) (700 mg, 3.30 mmol) were dissolved in N-methylpyrrolidone (10 mL), and potassium carbonate (1.37 g, 9.90 mmol) was added with stirring. After the addition was complete, the reaction mixture was stirred at 95 °C for 3 hours. The reaction mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give 2-(4-((6-chloropyridin-3-yl)oxy)piperidin-1-yl)-5-(trifluoromethyl)pyrimidine (24-c) (656 mg, yield: 55.6%). ESI [M+H] + =359.0

[0590] Step 4: Preparation of 5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridine-2-ol (24-d)

[0591] At room temperature, 2-(4-((6-chloropyridin-3-yl)oxy)piperidin-1-yl)-5-(trifluoromethyl)pyrimidine (24-c) (656 mg, 1.83 mmol) was dissolved in a mixture of 1,4-dioxane and water (10 mL / 2 mL). Tris(2-benzylacetone) palladium (339 mg, 0.37 mmol), t-BuXphos (157 mg, 0.37 mmol), and potassium hydroxide (307 mg, 5.49 mmol) were added under stirring. After the addition was complete, the reaction mixture was stirred at 106 °C for 16 hours. The reaction mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 3:1) to give 5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2-ol (24-d) (230 mg, yield: 37.0%). ESI [M+H] + =341.3

[0592] Step 5: Preparation of (R)-1-(2-hydroxypropyl)-5-((1-(5-(trifluoropyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2(1H)-one (24-e)

[0593] 5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridine-2-ol (24-d) (230 mg, 0.676 mmol) was dissolved in ethanol (10 mL), and then (R)-2-methylethylene oxide (196 mg, 3.38 mmol) was added. The mixture was stirred at 70 °C for 16 h. After the reaction was complete, the mixture was concentrated to give (R)-1-(2-hydroxypropyl)-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridine-2(1H)-one (24-e) (130 mg, crude product). 1 H NMR (400MHz, CDCl3) δ8.48 (d, J=0.5Hz, 2H), 7.27 (dd, J=9.5, 3.4Hz, 1H), 7.04 (d, J=3.0Hz, 1H), 6.58 (d, J=9.8Hz, 1H), 4.26-4.14 (m, 4H), 4. 10 (dd, J=13.5, 2.7Hz, 1H), 3.83-3.73 (m, 3H), 1.97 (ddd, J=11.3, 7.3, 3.5Hz, 2H), 1.79 (tdd, J=11.4, 7.5, 3.9Hz, 2H), 1.26 (d, J=6.3Hz, 3H).

[0594] Step 6: Preparation of (R)-1-(2-oxo-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-1(2H)-yl)propyl-2-yl methanesulfonate (24-f)

[0595] (R)-1-(2-hydroxypropyl)-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2(1H)-one (24-e) (130 mg, 0.327 mmol) and triethylamine (99.1 mg, 0.981 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of methanesulfonyl chloride (56.5 mg, 0.491 mmol) and stirring at room temperature for 3 hours. LC-MS showed that the reaction was complete. The mixture was then added to water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (R)-1-(2-oxo-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-1(2H)-yl)propyl-2-yl methanesulfonate (24-f) (150 mg, crude). ESI[M+H] + =477.2

[0596] Step 7: Preparation of (S)-1-(2-azidopropyl)-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2(1H)-one (24 g)

[0597] ((R)-1-(2-oxo-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-1(2H)-yl)propyl-2-yl methanesulfonate (24-f) (150 mg, 0.315 mmol) was dissolved in dimethyl sulfoxide (10 mL), sodium azide (200 mg) was added, and the mixture was stirred at 70 °C for 16 h. LC-MS showed that the reaction was complete. The mixture was added to water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (S)-1-(2-azidopropyl)-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2(1H)-one (24-g) (120 mg, crude). ESI[M+H] + =424.1

[0598] Step 8: Preparation of (S)1-(2-aminopropyl)-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2(1H)-one (24-h)

[0599] (S)-1-(2-azidopropyl)-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2(1H)-one (24 g) (120 mg, 0.284 mmol) and triphenylphosphine (112 mg, 0.426 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 16 h. LC-MS showed that the reaction was complete. The mixture was then added to water (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was concentrated, dissolved in dichloromethane, adjusted to acidic pH with 1N hydrochloric acid, extracted, and the aqueous phase was freeze-dried to give (S)-1-(2-aminopropyl)-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2(1H)-one (24-h) (30 mg, yield: 26.8%). ESI[M+H] + =398.2

[0600] Step 9: Preparation of (S)-5-((1-(2-oxo-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (24-i)

[0601] At room temperature, (S)-1-(2-aminopropyl)-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-2(1H)-one (24-h) (30 mg, 0.076 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (37.5 mg, 0.114 mmol), and triethylamine (23.0 mg, 0.228 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour, and LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0:1) to obtain (S)-5-((1-(2-oxo-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (24-i) (10 mg, yield: 19.2%). ESI [M+H] + =690.2

[0602] Step 10: Preparation of (S)-5-((1-(2-oxo-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (24)

[0603] At room temperature, (S)-5-((1-(2-oxo-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (24-i) (10 mg, 0.014 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC to obtain (S)-5-((1-(2-oxo-5-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (24) (3.35 mg, yield: 41.4%). ESI [M+H] + =560.2, 1 HNMR (400MHz, CDCl3) δ10.45-9.90 (m, 1H), 8.48 (s, 2H), 7.77 (s, 1H), 6.90 (s, 1H), 6.60 (s, 1H), 6.05 (s, 1H), 4.32 (s, 1H), 4.18 (s, 3H), 4.03 (s, 2H), 3.74 (s, 2H), 1.93 (s, 2H), 1.74 (s, 2H), 1.39 (s, 3H).

[0604] Example 25: (S)-5-((1-(2-thiooxy-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (25)

[0605]

[0606] Step 1: Preparation of (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (25-a)

[0607] Methyl (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (4-a) (680 mg, 2.19 mmol) was dissolved in methanol (10 mL) and water (4 mL) at room temperature. Water and lithium hydroxide (184 mg, 4.38 mmol) were added under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 6–7 with hydrochloric acid and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (25-a) (360 mg). ESI [M+H] + =297.1

[0608] Step 2: Preparation of tert-butyl(S)-(1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)carbamate (25-b)

[0609] At room temperature, (S)-1-(2-((tert-butyloxycarbonyl)amino)propyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (25-c) (360 mg, 1.22 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2) (282 mg, 1.22 mmol), HATU (464 mg, 1.22 mmol), and diisopropylethylamine (472 mg, 3.66 mmol) were dissolved in N,N-dimethylformamide (10 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to give tert-butyl(S)-(1-(2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)carbamate (25-b) (350 mg, yield: 56.3%). ESI [M+H] + =511.3

[0610] Step 3: Preparation of (S)1-(2-aminopropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridine-2(1H)-one (25-c)

[0611] At room temperature, tert-butyl-1-(2-oxy-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridine-1(2H)-propyl-2-yl)carbamate (25-b) (350 mg, 0.684 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain (S)1-(2-aminopropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridine-2(1H)-one hydrochloride (25-c, 300 mg, crude product), ESI[M+H]. + =411.2

[0612] Step 4: Preparation of (S)-(1-(2-aminopropyl)-6-thiooxy-1,6-dihydropyridin-3-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (25-d)

[0613] At room temperature, (S)1-(2-aminopropyl)-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridine-2(1H)-one (25-c) (300 mg, 0.732 mmol) was dissolved in toluene (20 mL), followed by the addition of Lawson's reagent (296 mg, 0.732 mmol). The reaction mixture was stirred overnight at 110 °C under argon-purified stirring. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to give (S)-(1-(2-aminopropyl)-6-thiooxy-1,6-dihydropyridin-3-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (25-d) (90 mg, yield: 28.8%). ESI [M+H] + =427.1

[0614] Step 5: Preparation of (S)-5-((1-(2-thiooxy-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (25-e)

[0615] At room temperature, (S)-(1-(2-aminopropyl)-6-thiooxy-1,6-dihydropyridin-3-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl) methyl ketone (25-d) (90.0 mg, 0.211 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (104 mg, 0.317 mmol), and triethylamine (63.9 mg, 0.633 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour, and LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0:1) to give (S)-5-((1-(2-thiooxy-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (25-e) (20 mg, yield: 13.2%). ESI [M+H] + =719.2

[0616] Step 6: Preparation of (S)-5-((1-(2-thiooxy-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (25)

[0617] At room temperature, (S)-5-((1-(2-thiooxy-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (25-e) ... The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC to obtain (S)-5-((1-(2-thiooxy-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)-one (25) (3.84 mg, yield: 23.4%). ESI [M+H] + =589.1, 1H NMR (400MHz, CDCl3) δ10.21 (s, 1H), 8.54 (s, 2H), 7.81-7.72 (m, 2H), 7.31 (dd, J=9.5, 2.5Hz, 1H), 6.56 (d, J=9 .5Hz, 1H), 5.98 (s, 1H), 4.35 (s, 2H), 4.15 (dd, J=13.4, 8.1Hz, 2H), 4.10-3.60 (m, 7H), 1.41 (d, J=6.4Hz, 3H).

[0618] Example 26: (S)-5-((1-((2-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-4-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (26)

[0619]

[0620] Step 1: Preparation of tert-butyl(S)-(1-((2-chloropyridin-4-yl)oxy)propane-2-yl)carbamate (26-a)

[0621] Under ice bath conditions, 2-chloropyridin-4-ol (1.0 g, 7.69 mmol), N-Boc-L-propanol (1.35 g, 7.69 mmol), and triphenylphosphine (3.03 g, 11.54 mmol) were dissolved in tetrahydrofuran (30 mL). Diisopropyl azodicarbonate (2.33 g, 11.54 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 2:1) to give tert-butyl(S)-(1-((2-chloropyridin-4-yl)oxy)propane-2-yl)carbamate (26-a) (1.8 g, yield: 81.8%). ESI [M+H] + =287.1

[0622] Step 2: Preparation of tert-butyl (S)-(1-((2-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-4-yl)oxy)propyl-2-yl)carbamate (26-b)

[0623] At room temperature, tert-butyl(S)-(1-((2-chloropyridin-4-yl)oxy)propane-2-yl)carbamate (26-a) (200 mg, 0.174 mmol), 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (I-8) (171.9 mg, 0.174 mmol), and potassium carbonate (289 mg, 0.522 mmol) were dissolved in 1,4-dioxane (10 mL). N,N′-dimethylethylenediamine (11.62 mg, 0.035 mmol) and cuprous iodide (25 mg, 0.132 mmol) were added under argon-purified stirring. After the addition of reactants, the reaction mixture was stirred at 110°C for 16 hours. The crude product was concentrated under reduced pressure and purified by silica gel chromatography (petroleum ether:ethyl acetate = 2:1) to give tert-butyl(S)-(1-((2-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-4-yl)oxy)propyl-2-yl)carbamate (26-b) (120 mg, yield: 34.7%). ESI[M+H] + =497.1

[0624] Step 3: Preparation of (S)-1-(3-(2-aminopropoxy)phenyl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (26-c)

[0625] At room temperature, tert-butyl (S)-(1-((2-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-4-yl)oxy)propyl-2-yl)carbamate (26-b) (120 mg, 0.242 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain (S)-1-(3-(2-aminopropoxy)phenyl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one hydrochloride (26-c) (38.0 mg, crude product). ESI [M+H] + =397.1

[0626] Step 4: Preparation of (S)-5-((1-((2-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-4-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (26-d)

[0627] At room temperature, (S)-1-(3-(2-aminopropoxy)phenyl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one hydrochloride (26-c) (80.0 mg, 0.201 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (198.26 mg, 0.603 mmol), and triethylamine (61.0 mg, 0.603 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour, and the reaction was completed by LC-MS. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 2:3) to give (S)-5-((1-((2-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-4-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (26-d) (58 mg, yield: 42.02%). ESI [M+H] + =698.1

[0628] Step 5: Preparation of (S)-5-((1-((2-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-4-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one) (26)

[0629] At room temperature, (S)-5-((1-((2-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-4-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (26-d) (58 mg, 0.087 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC to obtain (S)-5-((1-((2-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-4-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (26) (4.91 mg, yield: 30.3%). ESI [M+H] + =559.1, 1H NMR (400MHz, CDCl3) δ10.32 (s, 1H), 8.58 (s, 2H), 8.26 (d, J=5.7Hz, 1H), 8.04 (s, 1H), 7.73 (d, J=17.3Hz, 2H), 6.68 (d, J=5.7H z, 1H), 5.67 (s, 1H), 4.67 (s, 2H), 4.33-4.27 (m, 2H), 4.18 (dd, J=17.3, 11.2Hz, 4H), 4.10-4.02 (m, 1H), 1.47 (d, J=6.3Hz, 3H).

[0630] Example 27: (S)-5-((1-((6-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (27)

[0631]

[0632] Step 1: Preparation of tert-butyl(.S)-(1-((6-chloropyridin-2-yl)oxy)propane-2-yl)carbamate (27-a)

[0633] Under ice bath conditions, 6-chloropyridin-2-ol (1.0 g, 7.69 mmol), N-Boc-L-propanol (1.35 g, 7.69 mmol), and triphenylphosphine (2.02 g, 7.69 mmol) were dissolved in tetrahydrofuran (20 mL). Diisopropyl azodicarbonate (1.55 mg, 7.69 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give tert-butyl(S)-(1-((6-chloropyridin-2-yl)oxy)propane-2-yl)carbamate (27-a) (2.0 g, yield: 90.9%), ESI [M+H]. + =287.3.

[0634] Step 2: Preparation of tert-butyl-(1-((6-(2-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propyl-2-yl)carbamate (27-b)

[0635] At room temperature, tert-butyl(S)-(1-((6-chloropyridin-2-yl)oxy)propane-2-yl)carbamate (27-a) (200 mg, 0.174 mmol), 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (Ia) (171.9 mg, 0.174 mmol), and potassium carbonate (289 mg, 0.522 mmol) were dissolved in 1,4-dioxane (10 mL). N,N′-dimethylethylenediamine (11.616 mg, 0.035 mmol) and cuprous iodide (25 mg, 0.132 mmol) were added under argon-purified stirring. After the addition of the reactants, the reaction mixture was stirred at 110°C for 4 hours. The reaction mixture was then concentrated under reduced pressure and purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give tert-butyl-(1-((6-(2-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propyl-2-yl)carbamate (27-b) (48.0 mg, yield: 13.87%). ESI [M+H] + =497.1

[0636] Step 3: Preparation of (S)-1-(6-(2-aminopropoxy)pyridin-2-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (27-c)

[0637] At room temperature, tert-butyl-(1-((6-(2-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propyl-2-yl)carbamate (27-b) (32.0 mg, 0.065 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (4 M) was added under stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain (S)-1-(6-(2-aminopropoxy)pyridin-2-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one hydrochloride (27-c) (38.0 mg, crude product), ESI [M+H]. + =397.1

[0638] Step 4: Preparation of (S)-5-((1-((6-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (27-d)

[0639] At room temperature, (S)-1-(6-(2-aminopropoxy)pyridin-2-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one hydrochloride (27-c) (28.0 mg, 0.071 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (35.2 mg, 0.107 mmol), and triethylamine (21.5 mg, 0.213 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour, and the reaction was completed by LC-MS. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 2:3) to obtain (S)-5-((1-((6-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (27-d) (20 mg, yield 57.5%). ESI [M+H] + =397.1

[0640] Step 5: Preparation of (S)-5-((1-((6-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (27)

[0641] At room temperature, (S)-5-((1-((4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (27-d) (60 mg, 0.087 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC to obtain (S)-5-((1-((4-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (27) (4.91 mg, yield 30.3%). ESI [M+H] + =559.1, 1H NMR (400MHz, CDCl3) δ9.98 (s, 1H), 8.58 (s, 2H), 7.82 (s, 1H), 7.68 (t, J = 7.9Hz, 1H), 7.61 (d, J = 7.3Hz, 1H), 6.61 (d, J = 7.4Hz, 1H), 5.69 (s, 1 H), 4.68 (d, J=6.6Hz, 2H), 4.40 (dd, J=11.0, 5.6Hz, 1H), 4.29 (dd, J=11.1, 5.0Hz, 1H), 4.18 (dt, J=15.3, 5.3Hz, 5H), 1.44 (d, J=6.5Hz, 3H).

[0642] Example 28: (S)-5-((1-((3-fluoro-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (28)

[0643]

[0644] Step 1: Preparation of tert-butyl (S)-(1-(((3-fluoro-4-iodopyridin-2-yl)oxy)prop-2-yl)carbamate (28-a)

[0645] At room temperature, 2,3-difluoro-4-iodopyridine (1.0 g, 4.15 mmol) and tert-butyl(S)-(1-hydroxypropane-2-yl)carbamate (3.63 g, 20.75 mmol) were dissolved in tert-butanol (50 mL). Potassium tert-butoxide (1.39 g, 12.45 mmol) was added with stirring at room temperature. After the addition was complete, the reaction mixture was stirred overnight at 45 °C. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 5:1) to give tert-butyl(S)-(1-((3-fluoro-4-iodopyridine-2-yl)oxy)propane-2-yl)carbamate (28-a) (1.0 g, yield: 62.5%). ESI [M+H] + =397.0

[0646] Step 2: Preparation of tert-butyl(S)-(3-fluoro-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propyl-2-yl)carbamate (28-b)

[0647] At room temperature, tert-butyl(S)-(1-((3-fluoro-4-iodopyridin-2-yl)oxy)propyl-2-yl)carbamate (28-a) (250 mg, 0.631 mmol) and 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2) (249.9 mg, 0.757 mmol) were dissolved in toluene (30 mL). Cesium carbonate (617.1 mg, 1.893 mmol), 2-bicyclohexylphosphine-2′,6′-diisopropoxybiphenyl (44.2 mg, 0.095 mmol), and chloro(2-dicyclohexylphosphine-2′,6′-di-isopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II) (73.8 mg, 0.095 mmol) were added under nitrogen-purged stirring. After the addition of reactants, the reaction mixture was stirred at 100°C for 12 hours. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 4:1) to obtain tert-butyl(S)-(3-fluoro-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propyl-2-yl)carbamate (28-b) (200 mg, yield 63.5%). ESI [M+H] + =501.6

[0648] Step 3: Preparation of (S)-1-((3-fluoro-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-amine (28-c)

[0649] At room temperature, tert-butyl(S)-(3-fluoro-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)carbamate (28-b) (200 mg, 0.4 mmol) was dissolved in dichloromethane (30 mL), and dioxane hydrochloride (4 M) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain (S)-1-((3-fluoro-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-amine (28-c) (160 mg). ESI [M+H] + =401.3

[0650] Step 4: Preparation of ((S)-5-((1-((3-fluoro-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (28-d)

[0651] At room temperature, (S)-1-((3-fluoro-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-amine (28-c) (160 mg, 0.4 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1) (196.8 mg, 0.6 mmol), and triethylamine (121.1 mg, 1.2 mmol) were dissolved in ethanol (50 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 2:1) to obtain ((S)-5-((1-((3-fluoro-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (28-d) (230 mg, yield 83.0%). ESI[M+H + =693.2

[0652] Step 5: Preparation of (S)-5-((1-((3-fluoro-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (28)

[0653] At room temperature, ((S)-5-((1-((3-fluoro-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (28-d) (230 mg, 0.332 mmol) was dissolved in dichloromethane (20 mL). Trifluoroacetic acid was added under stirring. (4 mL). After the addition was complete, the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by preparative HPLC to obtain (S)-5-((1-((3-fluoro-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)oxy)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (28) (44.28 mg, yield: 23.6%). ESI [M+H] + =563.4, 1H NMR (400MHz, DMSO) δ11.99 (s, 1H), 9.11 (d, J=0.7Hz, 2H), 8.46 (s, 1H), 8.19 (dd, J=5.8, 0.7Hz, 1H), 7.17 (t, J=5.9Hz, 1H), 6.90 (s, 1H), 5.07 (dd, J=10.8, 6.5Hz, 1H), 4.99-4.86 (m, 2H), 4.53 (dd, J=9.9, 4.6Hz, 4H), 3.91-3.85 (m, 4H), 1.88 (d, J=6.4Hz, 3H).

[0654] Example 29: Preparation of (S)-5-(1-(5-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)thiazo-2-yl)oxo)propyl-2-yl)amino)-4-(trifluoromethyl)pyrazin-3(2H)-one (29)

[0655]

[0656] Step 1: Preparation of tert-butyl (S)-(1-(((5-bromothiazol-2-yl)oxy)propyl-2-yl)carbamate (29-a)

[0657] At room temperature, 2,5-dibromothiazolium (1.0 g, 4.12 mmol) and tert-butyl(S)-(1-hydroxypropane-2-yl)carbamate (3.7 g, 20.58 mmol) were dissolved in tert-butanol (20 mL), followed by the addition of potassium tert-butoxide (1.4 g, 12.35 mmol). After the addition was complete, the reaction system was purged with nitrogen, heated to 100 °C, and stirred for 6 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and diluted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give tert-butyl(S)-(1-((5-bromothiazol-2-yl)oxy)propane-2-yl)carbamate (29-a, 0.81 g, yield 81.3%). ESI [M+H] + : 337.1, 339.1.

[0658] Step 2: Preparation of tert-butyl(S)-(1-(5-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)thiazo-2-yl)oxo)propyl-2-yl)carbamate (29-b)

[0659] At room temperature, tert-butyl(S)-(1-(((5-bromothiazol-2-yl)oxy)propyl-2-yl)carbamate (29-a, 150 mg, 0.445 mmol) was dissolved in 1,4-dioxane (10 mL). N,N′-dimethylethylenediamine (39.2 mg, 0.445 mmol) and cuprous iodide (8.46 mg, 0.0445 mmol) were added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give tert-butyl(S)-(1-((5-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)thiazol-2-yl)oxy)propyl-2-yl)carbamate (29-b, 70 mg, yield 3.2%).

[0660] Step 3: Preparation of (S)-1-(2-(2-aminopropoxy)thiazolyl-5-yl)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (29-c)

[0661] At room temperature, tert-butyl(S)-(1-(5-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)thiazolyl)oxo)propyl-2-yl)carbamate (29-b, 50 mg, 0.099 mmol) was dissolved in dichloromethane (5 mL), and 4M dioxane hydrochloride (2 mL) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain (S)-1-(2-(2-aminopropoxy)thiazolyl)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one hydrochloride (29-c, 35.0 mg, crude product).

[0662] Step 4: Preparation of (S)-5-(1-(5-(2-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)thiazo-2-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (29-d)

[0663] At room temperature, (S)-1-(2-(2-aminopropoxy)thiazolyl-5-yl)-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (29-c, 50.0 mg, 0.124 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1, 61 mg, 0.186 mmol), and triethylamine (38 mg, 0.372 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 70 °C for 1 hour, and the reaction was completed according to liquid chromatography-mass spectrometry. The reaction solution was concentrated under reduced pressure, and the crude product was purified by TLC (petroleum ether: ethyl acetate = 2:3) to obtain (S)-5-(1-(5-(2-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)thiazolyl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (29-d, 30 mg, yield 60%).

[0664] Step 5: Preparation of (S)-5-((1-(5-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)thiazo-2-yl)oxo)propyl-2-yl)amino)-4-(trifluoromethyl)pyrazin-3(2H)-one (29)

[0665] At room temperature, (S)-5-(1-(5-(2-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)thiazolyl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (29-d, 30 mg, 0.043 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. Liquid chromatography-mass spectrometry showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was reverse-phase to prepare (S)-5-((1-(5-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)thiazolyl)oxo)propyl-2-yl)amino)-4-(trifluoromethyl)pyrazin-3(2H)-one (29) (11.8 mg, yield 36.9%). ESI[M+H] + =565.1, 1H NMR (400MHz, CDCl3) δ10.30 (s, 1H), 8.58 (s, 2H), 7.80 (s, 1H), 7.26 (s, 3H), 6.82 (s, 1H), 6.32 (s, 1H), 4.72 (s, 2H), 4. 57 (dd, J=11.3, 6.2Hz, 1H), 4.50-4.27 (m, 3H), 4.22 (s, 1H), 3.89 (t, J=5.3Hz, 2H), 1.74 (s, 6H), 1.41 (d, J=6.5Hz, 3H).

[0666] Example 30: Preparation of (S)-5-(1-(2-oxo-3-((2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (30)

[0667]

[0668] Step 1: Preparation of 3-(hydroxymethyl)pyridin-2(1H)-one (30-a)

[0669] Methyl 2-oxo-1,2-dihydropyridine-3-carboxylic acid (2.0 g, 13.07 mmol) was dissolved in tetrahydrofuran (20 mL), and a tetrahydrofuran solution of borane (4 mL) was added to the mixture. The mixture was then stirred at room temperature for 4 hours. Liquid chromatography-mass spectrometry showed no abnormalities. The mixture was concentrated, and the remaining residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give 3-(hydroxymethyl)pyridine-2(1H)-one (30-a, 1.5 g, yield 92.02%).

[0670] Step 2: Preparation of 3-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2(1H)-one (30-b)

[0671] At room temperature, 3-(hydroxymethyl)pyridin-2(1H)-one (30-a, 1.5 g, 12 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (3.1 g, 24 mmol) and tert-butyldimethylchlorosilane (2.7 g, 18 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours. Liquid chromatography-mass spectrometry showed no abnormalities. The mixture was concentrated, and the remaining residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give 3-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2(1H)-one (30-b, 2.0 g, yield 69.93%).

[0672] Step 3: Preparation of tert-butyl(S)-(1-(3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyridin-1(2H)-yl)propane-2-yl)carbamate (30-c)

[0673] At room temperature, 3-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2(1H)-one (30-b, 2.0 g, 8.36 mmol) was dissolved in N,N-dimethylformamide (20 mL), and (S)-2-(tert-butyloxycarbonyl)amino)propyl 4-toluenesulfonate (I-3, 5.50 g, 16.72 mmol) and potassium carbonate (2.307 g, 16.72 mmol) were added. The reaction mixture was stirred at 80 °C for 6 hours. Liquid chromatography-mass spectrometry showed no abnormalities. The mixture was concentrated, and the remaining residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give tert-butyl(S)-(1-(3-((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyridin-1(2H)-yl)propane-2-yl)carbamate (30-c, 1.5 g, yield 45.45%).

[0674] Step 4: Preparation of tert-butyl(S)-(1-(3-(hydroxymethyl)-2-oxopyridin-1(2H)-yl)propyl-2-yl)carbamate (30-d)

[0675] At room temperature, tert-butyl(S)-(1-(3-((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyridin-1(2H)-yl)propane-2-yl)carbamate (30-c, 1.4 g, 3.53 mmol) was dissolved in tetrahydrofuran (15 mL), and a tetrabutylammonium fluoride solution in tetrahydrofuran (4.24 mL, 4.24 mmol, 1 M) was added. The reaction mixture was stirred at room temperature for 2 hours. Liquid chromatography-mass spectrometry showed no abnormalities. The mixture was concentrated, and the remaining residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give tert-butyl(S)-(1-(3-(hydroxymethyl)-2-oxopyridin-1(2H)-yl)propyl-2-yl)carbamate (30-d, 1.1 g, crude product).

[0676] Step 5: Preparation of tert-butyl(S)-(1-(3-(chloromethyl)-2-oxopyridin-1(2H)-yl)propyl-2-yl)carbamate (30-e)

[0677] At room temperature, tert-butyl(S)-(1-(3-(hydroxymethyl)-2-oxopyridin-1(2H)-yl)propyl-2-yl)carbamate (30-d, 800 mg, 2.836 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (674 mg, 5.67 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. Liquid chromatography-mass spectrometry showed no abnormalities. The mixture was concentrated, and the remaining residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to give tert-butyl(S)-(1-(3-(chloromethyl)-2-oxopyridin-1(2H)-yl)propyl-2-yl)carbamate (30-e, 486 mg, yield 57.10%).

[0678] Step 6: Preparation of tert-butyl(S)-(1-(2-oxy-3-((2-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)carbamate (30-f)

[0679] At room temperature, tert-butyl(S)-(1-(3-(chloromethyl)-2-oxopyridin-1(2H)-yl)propyl-2-yl)carbamate (30-e, 100 mg, 0.33 mmol), 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (I-8, 81 mg, 0.33 mmol), and potassium carbonate (138 mg, 0.99 mmol) were dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (17 mg, 0.09 mmol) was added under argon-purified stirring. After the addition of the feed was complete, the reaction solution was stirred at 110°C for 4 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 3:1 to 0:1) to obtain tert-butyl(S)-(1-(2-oxy-3-((2-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)carbamate (30-f, 65 mg, yield 38.23%).

[0680] Step 7: Preparation of (S)-1-((1-(2-aminopropyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (30 g)

[0681] At room temperature, tert-butyl(S)-(1-(2-oxy-3-((2-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)carbamate (30-f, 65 mg, 0.127 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride (2 mL, 4 M) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain (S)-1-(1-(2-aminopropyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (30-g, 53 mg, crude product). ESI[M+H] + =411.1

[0682] Step 8: Preparation of (S)-5-(1-(2-oxy-3-(2-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (30-h)

[0683] At room temperature, (S)-1-(1-(2-aminopropyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (30 g, 53 mg, 0.129 mmol), 5-chloro-4-(trifluoromethyl)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1, 53 mg, 0.155 mmol), and triethylamine (26 mg, 0.258 mmol) were dissolved in ethanol (5 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour, and the reaction was completed according to liquid chromatography-mass spectrometry. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain (S)-5-(1-(2-oxy-3-(2-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (30-h, 36 mg, yield 39.7%). ESI [M+H + =702.3

[0684] Step 9: Preparation of (S)-5-((1-(2-oxo-3-((2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (68)

[0685] At room temperature, (S)-5-(1-(2-oxy-3-(2-oxy-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (30-h, 36 mg, 0.051 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. Liquid chromatography-mass spectrometry showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was reverse-phase to prepare (S)-5-((1-(2-oxo-3-((2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (68) (3.8 mg, yield 12.96%). ESI[M+H] + =573.2, 1 H NMR (400MHz, CDCl3) δ10.61 (s, 1H), 7.74 (s, 1H), 7.59 (d, J = 8.6Hz, 2H), 7.26 (s, 3H), 6.60 (s, 1H), 6.27 (d, J = 6.7Hz, 1H), 5.86 (s, 1H), 4.41-4.38 (m, 1H), 4.12-4.03 (m, 4H), 3.75-3.64 (m, 2H), 3.45-3.30 (m, 4H), 1.41 (d, J=6.4Hz, 3H).

[0686] Example 31: Preparation of (S)-5-((1-(6-chloro-2-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (31)

[0687]

[0688] Step 1: Preparation of ethyl 6-chloro-2-oxo-1,2-dihydropyridine-3-carboxylate (31-a)

[0689] At room temperature, 2.0 g (11.56 mmol) of 6-chloro-2-oxo-1,2-dihydropyridine-3-carboxylic acid was dissolved in 20 mL of methanol, and 10 mL of thionyl chloride was added with stirring. After the addition was complete, the reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain ethyl 6-chloro-2-oxo-1,2-dihydropyridine-3-carboxylic acid (31-a, 1.8 g).

[0690] Step 2: Preparation of (S)-1-(2-(tert-butoxycarbonyl)amino)propyl)-6-chloro-2-oxy-1,2-dihydropyridine-3-carboxylic acid ethyl ester (31-b)

[0691] At room temperature, ethyl 6-chloro-2-oxo-1,2-dihydropyridine-3-carboxylate (31-a, 370 mg, 1.83 mmol) was dissolved in N,N-dimethylformamide (20 mL). Potassium carbonate (760 mg, 5.51 mmol) and (S)-2-((tert-butyloxycarbonyl)amino)propyl 4-toluenesulfonate (I-3, 3.02 g, 9.17 mmol) were added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at 70 °C for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1-1:1) to give (S)-1-(2-(tert-butoxycarbonyl)amino)propyl)-6-chloro-2-oxy-1,2-dihydropyridine-3-carboxylic acid ethyl ester (31-b, 300 mg, yield: 7.40%). ESI [M+H] + =311.0

[0692] Step 3: Preparation of (S)-1-(2-aminopropyl)-6-chloro-2-oxo-1,2-dihydropyridine-3-carboxylic acid ethyl ester (31-c)

[0693] Ethyl (S)-1-(2-(tert-butoxycarbonyl)amino)propyl)-6-chloro-2-oxy-1,2-dihydropyridine-3-carboxylate (31-b, 192 mg, 0.535 mmol) was dissolved in 10 mL of dichloromethane at room temperature, and 10 mL of 4 M dioxane hydrochloride was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain ethyl (S)-1-(2-aminopropyl)-6-chloro-2-oxy-1,2-dihydropyridine-3-carboxylate (31-c, 180 mg). ESI[M+H] + =211.23.

[0694] Step 4: Preparation of ethyl(S)-6-chloro-2-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,2-dihydropyridine-3-carboxylic acid ester (31-d)

[0695] At room temperature, ethyl (S)-1-(2-aminopropyl)-6-chloro-2-oxo-1,2-dihydropyridine-3-carboxylate (31-c, 180 mg, 0.695 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (I-1, 686 mg, 2.08 mmol), and diisopropylethylamine (268 mg, 2.08 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to give ethyl (S)-6-chloro-2-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,2-dihydropyridine-3-carboxylic acid ester (31-d, 89 mg, yield: 23.2%). ESI [M+H] + =503.3

[0696] Step 5: Preparation of (S)-6-chloro-2-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,2-dihydropyridine-3-carboxylic acid (31-e)

[0697] At room temperature, ethyl (S)-6-chloro-2-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,2-dihydropyridine-3-carboxylic acid ester (31-d, 89 mg, 0.161 mmol) was dissolved in tetrahydrofuran (5 mL) and hydrochloric acid (6 M) (2 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 2 days. The reaction mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-6-chloro-2-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,2-dihydropyridine-3-carboxylic acid (31-e, 68 mg). ESI [M+H] + =489.2

[0698] Step 6: Preparation of (S)-5-((1-(6-chloro-2-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (31)

[0699] At room temperature, ((S)-6-chloro-2-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,2-dihydropyridine-3-carboxylic acid (31-e, 68 mg, 0.173 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2, 40.0 mg, 0.173 mmol), and diisopropylethylamine (67 mg, 0.519 mmol) were dissolved in N,N-dimethylformamide (3 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (67 mg, 0.173 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then diluted with water (10 mL) and ethyl acetate (20 mL x 3) Extraction. The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to reverse-phase extraction to obtain (S)-5-((1-(6-chloro-2-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (31.78 mg, yield: 60.5%). ESI[M+H] + =607.2, 1 H NMR (400MHz, CDCl3) δ10.17 (s, 1H), 8.54 (s, 2H), 7.93 (d, J=27.5Hz, 1H), 7.62 (s, 1H), 6.77 (t, J=14.9Hz, 1H), 5.62 (d, J=39.8Hz, 1H), 4.44 (s , 1H), 4.24 (s, 1H), 4.01 (dd, J=30.0, 20.4Hz, 5H), 3.83 (s, 1H), 3.39 (d, J=46.7Hz, 2H), 1.45 (d, J=6.2Hz, 3H).

[0700] Example 32: Preparation of (S)-5-((1-(6-chloro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propyl-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (32)

[0701]

[0702] Step 1: Preparation of ethyl 2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (32-a)

[0703] At room temperature, 2-hydroxynicotinic acid (1.0 g, 5.76 mmol) was dissolved in ethanol (20 mL), and concentrated sulfuric acid (2 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at 80 °C for 16 hours. After cooling, the pH was adjusted to weakly alkaline by adding saturated sodium bicarbonate solution, followed by extraction. The organic phase was concentrated under reduced pressure to obtain ethyl 2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (32-a, 800 mg, crude product).

[0704] Step 2: Preparation of (S)-1-(2-(tert-Butoxycarbonyl)amino)propyl)-2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (32-b)

[0705] Ethyl 2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (32-a, 800 mg, 3.96 mmol), (S)-2-((tert-butyloxycarbonyl)amino)propyl 4-toluenesulfonate (I-3, 2.61 g, 7.92 mmol), and potassium carbonate (1.64 g, 11.9 mmol) were dissolved in N,N-dimethylformamide (20 mL) under ice bath conditions. After the addition was complete, the reaction mixture was stirred overnight at 80°C. Most of the tetrahydrofuran was concentrated under reduced pressure, and the crude product was diluted with ethyl acetate (20 mL). The organic phase was washed with brine (10 mL), and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give (S)-1-(2-(tert-butoxycarbonyl)amino)propyl)-2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (32-b, 330 mg, yield: 23.2%). ESI [M+H] + =359.1

[0706] Step 3: Preparation of methyl 1-((S)-2-aminopropyl)-2-oxoperidine-3-carboxylic acid (32-c)

[0707] Ethyl (S)-1-(2-(tert-butoxycarbonyl)amino)propyl)-2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (32-b, 330 mg, 0.919 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and 4M dioxane hydrochloride (10 mL) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain ethyl (S)-1-(2-aminopropyl)-2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (32-c, 328 mg, crude product).

[0708] Step 4: Preparation of ethyl(S)-2-chloro-6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carboxylic acid ester (32-d)

[0709] At room temperature, ethyl (S)-1-(2-aminopropyl)-2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (32-c, 328 mg, 1.34 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (I-1, 661 mg, 2.01 mmol), and triethylamine (406 mg, 4.02 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give ethyl(S)-2-chloro-6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carboxylic acid ester (32-d, 200 mg, yield: 27.8%). ESI [M+H] + =551.0

[0710] Step 5: Preparation of (S)-2-chloro-6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carboxylic acid (32-e)

[0711] At room temperature, ethyl(S)-2-chloro-6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carboxylic acid ester (32-d, 200 mg, 0.372 mmol) was dissolved in tetrahydrofuran (10 mL), and hydrochloric acid (12 M, 10 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at 70 °C for 5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to give (S)-2-chloro-6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carboxylic acid (32-e, 40.0 mg, yield 27.4%). ESI [M+H] + =393.0

[0712] Step 6: Preparation of (S)-5-((1-(6-chloro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (32)

[0713] At room temperature, (S)-2-chloro-6-oxo-1-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)-1,6-dihydropyridine-3-carboxylic acid (32-e, 40.0 mg, 0.102 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2, 23.7 mg, 0.102 mmol) and diisopropylethylamine (39.0 mg, 0.306 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (39.0 mg, 0.102 mmol) was added under argon-purified stirring. After the addition of reactants, the reaction mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was reverse-phase to prepare (S)-5-((1-(6-chloro-2-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-1(2H)-yl)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (32, 5.27 mg, yield: 8.60%). ESI[M+H] + =607.0, 1 H NMR (400MHz, CDCl3) δ10.25 (s, 1H), 8.52 (s, 2H), 7.92 (d, J=29.1Hz, 1H), 7.62 (s, 1H), 6.78 (dd, J=19.6, 8.4H z, 1H), 5.61 (d, J=30.2Hz, 1H), 4.44 (s, 1H), 4.30-3.75 (m, 8H), 3.38 (d, J=43.8Hz, 2H), 1.44 (d, J=6.0Hz, 3H).

[0714] Example 33: Preparation of (S)-5-((1-((2-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-4-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (33)

[0715]

[0716] Step 1: Preparation of tert-butyl(S)-(1-((2-chloropyridin-4-yl)oxy)propane-2-yl)carbamate (33-a)

[0717] At room temperature, 2-chloro-4-fluoropyridine (377 mg, 2.87 mmol), (S)-(1-aminopropane-2-yl)oxycarbamate tert-butyl ester (500 mg, 2.87 mmol), and potassium carbonate (1.19 g, 8.61 mmol) were dissolved in N,N-dimethylformamide (20 mL). After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction mixture was then extracted with water (10 mL) and ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give tert-butyl(S)-(1-((2-chloropyridin-4-yl)oxy)propane-2-yl)carbamate (33-a, 503 mg, yield 61.3%).

[0718] Step 2: Preparation of tert-butyl-(1-((2-chloropyridin-4-yl)oxy)propane-2-yl)carbamate (33-b)

[0719] At room temperature, tert-butyl(S)-(1-((2-chloropyridin-4-yl)oxy)propane-2-yl)carbamate (33-a, 503 mg, 1.76 mmol), 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (I-8, 433 mg, 1.76 mmol), and potassium carbonate (729 mg, 5.28 mmol) were dissolved in 1,4-dioxane (10 mL). N,N′-dimethylethylenediamine (30.9 mg, 0.35 mmol) and cuprous iodide (66.5 mg, 0.35 mmol) were added under argon-purified stirring. After the addition of reactants, the reaction solution was stirred at 110°C for 16 hours. The reaction solution was then concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give tert-butyl-(1-((2-chloropyridin-4-yl)oxy)propane-2-yl)carbamate (33-b, 150 mg, yield: 17.2%). ESI [M+H] + =497.2

[0720] Step 3: Preparation of (S)-1-(4-(2-aminopropoxy)pyridin-2-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (33-c)

[0721] At room temperature, tert-butyl-(1-((2-chloropyridin-4-yl)oxy)propane-2-yl)carbamate (33-b, 120 mg, 0.242 mmol) was dissolved in dichloromethane (10 mL), and 4M dioxane hydrochloride (10 mL) was added with stirring. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain (S)-1-(4-(2-aminopropoxy)pyridin-2-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (33-c, 140 mg, crude product).

[0722] Step 4: Preparation of ((S)-5-((1-((2-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-4-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (33-d)

[0723] At room temperature, (S)-1-(4-(2-aminopropoxy)pyridin-2-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one hydrochloride (33-c, 140 mg, 0.354 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1, 175 mg, 0.531 mmol), and triethylamine (107 mg, 1.062 mmol) were dissolved in ethanol (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour, and the reaction was completed according to liquid chromatography-mass spectrometry. The reaction solution was concentrated under reduced pressure, and the crude product was purified by TLC (petroleum ether:ethyl acetate = 2:3) to obtain ((S)-5-((1-((2-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-4-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (33-d, 80 mg, yield 32.9%). ESI[M+H + =689.2

[0724] Step 5: Preparation of ((S)-5-((1-((2-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-4-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (33)

[0725] At room temperature, ((S)-5-((1-((2-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-4-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (33-d, 80 mg, 0.116 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added under stirring. After the addition was complete, the reaction proceeded... The mixture was stirred at room temperature for 16 hours, and liquid chromatography-mass spectrometry showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was reverse-phase to prepare ((S)-5-((1-((2-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyridin-4-yl)oxy)propane-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (11.59 mg, yield: 17.8%). ESI[M+H] + =558.1. 1 H NMR (400MHz, CDCl3) δ10.32 (s, 1H), 8.58 (s, 2H), 8.26 (d, J=5.7Hz, 1H), 8.04 (s, 1H), 7.73 (d, J=17.3Hz, 2H), 6.68 (d, J=5.7H z, 1H), 5.67 (s, 1H), 4.67 (s, 2H), 4.33-4.27 (m, 2H), 4.18 (dd, J=17.3, 11.2Hz, 4H), 4.10-4.02 (m, 1H), 1.47 (d, J=6.3Hz, 3H).

[0726] Example 34: Preparation of (S)-4-(trifluoromethyl)-5-((1-(2-(4-(5-trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazol-5-yl)propyl-2-yl)amino)pyridazin-3(2H)-one (34)

[0727]

[0728] Step 1: Preparation of ethyl 2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazol-5-carboxylate (34-a)

[0729] At room temperature, ethyl 2-bromooxazole-5-carboxylate (3.0 g, 13.65 mmol) and 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2, 3.18 g, 13.65 mmol) were dissolved in N,N-dimethylformamide (50 mL). Potassium carbonate (5.64 g, 40.95 mmol) was added with stirring at room temperature. After the addition was complete, the reaction mixture was stirred overnight at 45 °C. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give ethyl 2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazole-5-carboxylate (34-a, 3.2 g, yield 63.2%).

[0730] Step 2: Preparation of 2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazol-5-carboxaldehyde (34-b)

[0731] Ethyl 2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazol-5-carboxylate (34-a, 3.2 g, 8.63 mmol) was dissolved in tetrahydrofuran (30 mL) at room temperature, and diisobutylaluminum hydride (1.83 mL) was slowly added under stirring at -78 °C. After the addition was complete, the reaction mixture was stirred at -78 °C for 2 hours. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazol-5-carboxaldehyde (34-b, 820 mg, yield 29.1%).

[0732] Step 3: Preparation of (Z)-5-(2-nitroprop-1-en-1-yl)-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazole (34-c)

[0733] At room temperature, 2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazol-5-carboxaldehyde (34-b) and (2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazol-5-yl)methanol (300 mg, 0.917 mmol) were dissolved in nitrobetan (30 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give (Z)-5-(2-nitroprop-1-en-1-yl)-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazol (34-c, 202 mg, yield 57.4%).

[0734] Step 4: Preparation of 5-(2-nitropropyl)-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazole (34-d)

[0735] At room temperature, (Z)-5-(2-nitropropyl-1-en-1-yl)-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazole (34-c, 202 mg, 0.526 mmol) and sodium borohydride (29.8 mg, 0.789 mmol) were dissolved in tetrahydrofuran (50 mL). After the addition was complete, the reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give 5-(2-nitropropyl)-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazole (34-d, 56 mg, yield 27.6%). ESI [M+H] + =387.1

[0736] Step 5: Preparation of 1-(2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazol-5-yl)propyl-2-amine (34-e)

[0737] At room temperature, 5-(2-nitropropyl)-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazole (34-d, 46 mg, 0.119 mmol) was dissolved in methanol (20 mL). Raney nickel (3.49 mg, 0.0595 mmol) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 1-(2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazole-5-yl)propyl-2-amine (34-e, 43.2 mg).

[0738] Step 6: Preparation of (S)-4-(trifluoromethyl)-5-((1-(2-(4-(5-trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazol-5-yl)propyl-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (34-f)

[0739] At room temperature, 1-(2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazol-5-yl)propyl-2-amine (34-e, 43.2 mg, 0.121 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1, 39.7 mg, 0.121 mmol), and triethylamine (36.7 mg, 0.363 mmol) were dissolved in ethanol (30 mL). After the addition was complete, the reaction mixture was stirred at 70 °C for 2 hours, and the reaction was completed according to liquid chromatography-mass spectrometry. The reaction solution was concentrated under reduced pressure, and the crude product was purified by TLC (petroleum ether: ethyl acetate = 2:1) to obtain (S)-4-(trifluoromethyl)-5-((1-(2-(4-(5-trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazol-5-yl)propyl-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (34-f, 32 mg, yield 38.6%).

[0740] Step 7: Preparation of (S)-4-(trifluoromethyl)-5-((1-(2-(4-(5-trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazol-5-yl)propyl-2-yl)amino)pyridazin-3(2H)-one (34)

[0741] At room temperature, (S)-4-(trifluoromethyl)-5-((1-(2-(4-(5-trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazol-5-yl)propyl-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (34-f, 22 mg, 0.0322 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was added under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. Liquid chromatography-mass spectrometry showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was reverse-phase to prepare (S)-4-(trifluoromethyl)-5-((1-(2-(4-(5-trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)oxazol-5-yl)propyl-2-yl)amino)pyridazin-3(2H)-one (34) (4.68 mg, yield 28.1%). ESI[M+H] + =518.4. 1 H NMR (400MHz, CDCl3) δ9.92 (s, 1H), 8.53 (s, 2H), 7.78 (s, 1H), 7.08 (s, 1H), 4.31 (s, 1H) , 4.06 (s, 4H), 3.69 (s, 4H), 2.86 (d, J = 14.4Hz, 1H), 2.67 (s, 1H), 1.30 (d, J = 6.0Hz, 3H).

[0742] Example 35: Preparation of 4-(trifluoromethyl)-5-(1-(2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)thiazolyl)propane-2-yl)amino)pyridazine-3(2H)-one (35)

[0743]

[0744] Step 1: Preparation of ethyl 5-formylthiazole-2-carboxylate (35-a)

[0745] At room temperature, ethyl thiooxazone (5.0 g, 37.6 mmol) and 2-bromomaronaldehyde (5.68 g, 37.6 mmol) were added to ethylene glycol dimethyl ether (120 mL), and the reaction mixture was stirred for 10 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and evaporated. Ethyl 5-formylthiazolyl-2-carboxylate (35-a, 3.94 g, yield 56.6%) was given.

[0746] Step 2: Preparation of ethyl 5-(1,3-dioxane-2-yl)thiazole-2-carboxylate (35-b)

[0747] Ethyl 5-formylthiazol-2-carboxylate (35-a, 1.3 g, 7.03 mmol), ethylene glycol (2.90 g, 24.6 mmol), and p-toluenesulfonic acid monohydrate (1.33 g, 7.73 mmol) were dissolved in toluene (50 mL) at room temperature, and the mixture was heated to 110 °C for 3 hours. The toluene was evaporated, the residue was dissolved in dichloromethane, and the organic layer was washed with saturated sodium bicarbonate and brine. The solvent was evaporated to give ethyl 5-(1,3-dioxane-2-yl)thiazol-2-carboxylate (35-b, 936 mg, yield 58.4%).

[0748] Step 3: Preparation of 5-(1,3-dioxane-2-yl)thiazole-2-carboxylic acid (35-c)

[0749] Ethyl 5-(1,3-dioxane-2-yl)thiazol-2-carboxylic acid (35-b, 1.3 g, 5.67 mmol) was added to a solution in methanol / water (10.0 mL / 2.0 mL) at room temperature, and stirred for 1 hour at 25 °C under a nitrogen atmosphere. Liquid chromatography-mass spectrometry showed no abnormalities. The residue was concentrated to give 5-(1,3-dioxane-2-yl)thiazol-2-carboxylic acid (35-c) (1.2 g).

[0750] Step 4: Preparation of (5-(1,3-dioxane-2-yl)thiazolyl-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (35-d)

[0751] At room temperature, 5-(1,3-dioxane-2-yl)thiazolyl-2-carboxylic acid (35-c, 500 mg, 2.49 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (578 mg, 2.49 mmol), and diisopropylethylamine (964 mg, 7.47 mmol) were dissolved in N,N-dimethylformamide (20 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (946 mg, 2.49 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain (5-(1,3-dioxane-2-yl)thiazolyl-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl) methyl ketone (35-d, 320 mg, yield 31.0%).

[0752] Step 5: Preparation of 2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)thiazole-5-carbonal (35-e)

[0753] At room temperature, (5-(1,3-dioxane-2-yl)thiazolyl-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl) methyl ketone (35-d, 320 mg, 0.771 mmol) and p-toluenesulfonic acid (265 mg, 1.542 mmol) were dissolved in a mixed solvent of acetone / water (3:2, 10 mL, v / v) and reacted at 70 °C for 2.5 h. The reaction solution was poured into ice water and stirred for 10 min, filtered, and dried. 2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)thiazolyl-5-carbonal (35-e, 230 mg, crude) was obtained.

[0754] Step 6: Preparation of (Z)-(5-(2-nitro-1-en-1-yl)thiazolyl-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (35-f)

[0755] At room temperature, 2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)thiazol-5-carbonal (35-e, 230 mg, 0.620 mmol) and ammonium acetate (143 mg, 1.86 mmol) were dissolved in nitrobane (50 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give (Z)-(5-(2-nitro-1-en-1-yl)thiazol-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (35-f, 200 mg, yield 75.5%).

[0756] Step 7: Preparation of (5-(2-nitropropyl)thiazolyl-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (35-g)

[0757] At 0°C, (Z)-(5-(2-nitro-1-en-1-yl)thiazolyl-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (35-g, 200 mg, 0.467 mmol) was dissolved in tetrahydrofuran (30 mL). Sodium borohydride (35.3 mg, 0.934 mmol) was added under nitrogen purging and stirring, followed by methanol (1 mL). After the addition was complete, the reaction mixture was stirred at 0°C for 0.5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain (5-(2-nitropropyl)thiazolyl-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (35-g, 190 mg, crude product).

[0758] Step 8: Preparation of (5-(2-aminopropyl)furan-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (35-h)

[0759] At room temperature, (5-(2-nitropropyl)furan-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl) methyl ketone (35-g, 190 mg, 0.442 mmol) was dissolved in methanol (10 mL), and Raney nickel (50 mg) was added with stirring. After the addition was complete, hydrogen gas was introduced, and the mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain (5-(2-aminopropyl)thiazolyl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl) methyl ketone (35-g, 150 mg, crude product).

[0760] Step 9: Preparation of 4-(trifluoromethyl)-5-(1-(2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)thiazolyl)propane-2-yl)amino)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (35-i)

[0761] At room temperature, (5-(2-aminopropyl)thiazo-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl) methyl ketone (35-h, 150 mg, 0.375 mmol), triethylamine (75.8 mg, 0.749 mmol), and 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1, 370 mg, 1.125 mmol) were dissolved in ethanol (15 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 4-(trifluoromethyl)-5-(1-(2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)thiazolyl)propane-2-yl)amino)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (35-i, 80 mg, yield: 30.7%).

[0762] Step 10: Preparation of 4-(trifluoromethyl)-5-(1-(2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)thiazolyl)propane-2-yl)amino)pyridazine-3(2H)-one (35)

[0763] At room temperature, 4-(trifluoromethyl)-5-(1-(2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)thiazolyl)propane-2-yl)amino)-2-(2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (35-i, 80 mg, 0.118 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added under stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. Liquid chromatography-mass spectrometry showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was reverse-phase to prepare 4-(trifluoromethyl)-5-(1-(2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)thiazolyl)propane-2-yl)amino)pyridazine-3(2H)-one (35) (2.5 mg, yield 3.80%). ESI[M+H] + =593.2, 1H NMR (400MHz, CDCl3) δ12.1 (s, 1H), 9.12 (s, 2H), 8.50 (s, 1H), 8.20 (s, 1H), 7.49 (s, 1H), 6.85(s, 1H), 5.30(dd, 1H), 3.81-3.70(m, 2H), 2.90(t, 4H), 1.97(ddd, 4H), 1.86(d, 3H).

[0764] Example 36: Preparation of (S)-4-(trifluoromethyl)-5-((1-(5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)furan-2-yl)propane-2-yl)amino)pyridazine-3(2H)-one (36)

[0765]

[0766] Step 1: Preparation of 5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)furan-2-carboxaldehyde (36-a)

[0767] At room temperature, 5-formylfuran-2-carboxylic acid (1.0 g, 7.14 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (1.66 g, 7.14 mmol), and diisopropylethylamine (3.53 g, 21.4 mmol) were dissolved in N,N-dimethylformamide (20 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.7 g, 7.14 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give 5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)furan-2-carboxaldehyde (36-a, 1.9 g, yield 76.0%). ESI [M+H] + =355.0

[0768] Step 2: Preparation of (Z)-(5-(2-nitro-1-en-1-yl)furan-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (36-b)

[0769] At room temperature, 5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)furan-2-carboxaldehyde (36-a, 900 mg, 2.54 mmol) and ammonium acetate (392 mg, 5.08 mmol) were dissolved in nitrobenzene (50 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give (Z)-(5-(2-nitro-1-en-1-yl)furan-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (36-b, 856 mg, yield: 81.9%). ESI [M+H] + =412.0

[0770] Step 3: Preparation of (5-(2-nitropropyl)furan-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (36-c)

[0771] At 0°C, (Z)-(5-(2-nitro-1-en-1-yl)furan-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (36-b, 856 mg, 2.08 mmol) was dissolved in tetrahydrofuran (30 mL). Sodium borohydride (158 mg, 4.16 mmol) was added under nitrogen purging and stirring, followed by methanol (1 mL). After the addition was complete, the reaction mixture was stirred at 0°C for 0.5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain (5-(2-nitropropyl)furan-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (36-c, 800 mg, yield 93.5%). ESI [M+H] + =414.2

[0772] Step 4: Preparation of (5-(2-aminopropyl)furan-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (36-d)

[0773] At room temperature, (5-(2-nitropropyl)furan-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (36-c, 800 mg, 1.94 mmol) was dissolved in ethanol (10 mL). Raney nickel (50 mg) was added with stirring. After the addition was complete, hydrogen gas was introduced, and the mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain (5-(2-aminopropyl)furan-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (36-d, 700 mg, crude product). ESI [M+H] + =384.1

[0774] Step 5: Preparation of 4-(trifluoromethyl)-5-((1-(5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)furan-2-yl)propane-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (36-e)

[0775] At room temperature, (5-(2-aminopropyl)furan-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl) methyl ketone (36-d, 200 mg, 0.522 mmol) and 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (I-1, 258 mg, 0.783 mmol) were dissolved in ethanol (15 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give 4-(trifluoromethyl)-5-((1-(5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)furan-2-yl)propane-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (36-e, 80 mg, yield 22.7%). ESI [M+H + =676.3

[0776] Step 6: Preparation of (4-(trifluoromethyl)-5-((1-(5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)furan-2-yl)propane-2-yl)amino)pyridazine-3(2H)-one (36)

[0777] At room temperature, 4-(trifluoromethyl)-5-((1-(5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)furan-2-yl)propane-2-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (36-e, 80 mg, 0.118 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. Liquid chromatography-mass spectrometry showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was reverse-phase to prepare (4-(trifluoromethyl)-5-((1-(5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)furan-2-yl)propane-2-yl)amino)pyridazine-3(2H)-one (36) (10.25 mg, yield: 15.9%). ESI[M+H] + =546.1. 1H NMR (400MHz, CDCl3) δ10.43 (s, 1H), 8.53 (s, 2H), 7.51 (s, 1H), 6.88 (d, J = 3.4Hz, 1H), 6.25 (d, J = 3.4Hz, 1H), 5.45 (d, J = 7.4Hz, 1H), 4.18- 4.06 (m, 1H), 4.04-3.95 (m, 4H), 3.86 (d, J=4.3Hz, 4H), 3.05 (dd, J=15.0, 5.4Hz, 1H), 2.92 (dd, J=15.0, 6.8Hz, 1H), 1.39 (d, J=6.4Hz, 3H).

[0778] Example 37: Preparation of 4-(trifluoromethyl)-5-((1-(5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)thiophen-2-yl)propyl-2-yl)amino)pyridazine-3(2H)-one (37)

[0779]

[0780] Step 1: Preparation of (Z)-5-(2-nitroprop-1-en-1-yl)thiophene-2-carboxylic acid methyl ester (37-a)

[0781] At room temperature, methyl 5-formylthiophene-2-carboxylate (800 mg, 4.70 mmol) and ammonium acetate (1.08 g, 14.1 mmol) were dissolved in nitrobane (50 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain (Z)-5-(2-nitroprop-1-en-1-yl)thiophene-2-carboxylate (37-a, 680 mg, yield 63.7%).

[0782] Step 2: Preparation of methyl 5-(2-nitropropyl)thiophene-2-carboxylic acid (37-b)

[0783] At 0°C, (Z)-5-(2-nitropropyl-1-en-1-yl)thiophene-2-carboxylic acid methyl ester (37-a, 600 mg, 2.64 mmol) was dissolved in tetrahydrofuran (30 mL). Sodium borohydride (299.6 mg, 7.92 mmol) was added under nitrogen-purified stirring, followed by methanol (1 mL). After the addition was complete, the reaction mixture was stirred at 0°C for 0.5 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 5-(2-nitropropyl)thiophene-2-carboxylic acid methyl ester (37-b, 387 mg, yield: 63.9%).

[0784] Step 3: Preparation of methyl 5-(2-aminopropyl)thiophene-2-carboxylic acid (37-c)

[0785] Methyl 5-(2-nitropropyl)thiophene-2-carboxylate (37-b, 300 mg, 1.30 mmol) was dissolved in ethanol (10 mL) at room temperature. Raney nickel (50 mg) was added with stirring. After the addition was complete, hydrogen gas was introduced, and the mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give methyl 5-(2-aminopropyl)thiophene-2-carboxylate (37-c, 287 mg, crude product). ESI [M+H] + =200.1

[0786] Step 4: Preparation of methyl 5-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)thiophene-2-carboxylate (37-d)

[0787] At room temperature, methyl 5-(2-aminopropyl)thiophene-2-carboxylate (37-c, 250 mg, 1.25 mmol), 5-chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (I-1, 1.23 g, 3.76 mmol) and N,N-diisopropylethylamine (484 mg, 3.76 mmol) were dissolved in ethanol (15 mL). After the addition of reactants, the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain methyl 5-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)thiophene-2-carboxylate (37-d, 120 mg, yield 19.4%). ESI [M+H] + =492.2

[0788] Step 5: Preparation of 5-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)thiophene-2-carboxylic acid (37-e)

[0789] At room temperature, methyl 5-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)thiophene-2-carboxylic acid (37-d, 120 mg, 0.244 mmol) was dissolved in tetrahydrofuran (10 mL). Hydrochloric acid (3 mL, 5 M) was added with stirring. After the addition was complete, the reaction mixture was stirred at 60 °C for 2 days. The reaction mixture was concentrated under reduced pressure, and the crude product was reverse-phase to prepare 5-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)thiophene-2-carboxylic acid (37-e, 53 mg, yield 63.1%). ESI[M+H] + =348.1

[0790] Step 6: Preparation of 4-(trifluoromethyl)-5-((1-(5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)thiophen-2-yl)propane-2-yl)amino)pyridazine-3(2H)-one (37)

[0791] At room temperature, 5-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propyl)thiophene-2-carboxylic acid (37-e, 40.0 mg, 0.115 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2, 27 mg, 0.115 mmol), and diisopropylethylamine (44 mg, 0.345 mmol) were dissolved in N,N-dimethylformamide (5 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (44 mg, 0.115 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then subjected to preparative-grade HPLC to prepare 4-(trifluoromethyl)-5-((1-(5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)thiophene-2-yl)propane-2-yl)amino)pyridazine-3(2H)-one (37) (13.0 mg, yield: 20.1%). ESI [M+H] + =562.2. 1HNMR (400MHz, CDCl3) δ10.50 (s, 1H), 8.52 (s, 2H), 7.51 (s, 1H), 7.19 (s, 1H), 6.81 (s, 1H), 5.41 (s, 1H) ), 3.98 (s, 5H), 3.82 (s, 4H), 3.22-3.11 (m, 1H), 3.05 (dd, J=14.8, 6.2Hz, 1H), 1.40 (d, J=6.2Hz, 3H).

[0792] Example 38: Preparation of 4-(trifluoromethyl)-5-(1-(5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-1H-pyrrolo-2-yl)propane-2-yl)amino)pyridazine-3(2H)-one (38)

[0793]

[0794] Step 1: Preparation of 5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrole-2-carboxaldehyde (38-a)

[0795] At room temperature, 5-formylpyrrole-2-carboxylic acid (1.0 g, 7.14 mmol), 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (I-2, 1.66 g, 7.14 mmol), and diisopropylethylamine (3.53 g, 21.4 mmol) were dissolved in N,N-dimethylformamide (20 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.7 g, 7.14 mmol) was added under argon-purified stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give 5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolo-2-carboxaldehyde (38-a, 1.9 g, yield: 76.0%). ESI [M+H] + =355.0

[0796] Step 2: Preparation of (Z)-(5-(2-nitro-1-en-1-yl)pyrrolo-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (38-b)

[0797] At room temperature, 5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyrrolo-2-carboxaldehyde (38-a, 900 mg, 2.54 mmol) and ammonium acetate (392 mg, 5.08 mmol) were dissolved in nitrobane (50 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give (Z)-(5-(2-nitro-1-en-1-yl)pyrrolo-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (38-b, 856 mg, yield: 81.9%). ESI [M+H] + =412.0

[0798] Step 3: Preparation of (5-(2-nitropropyl)pyrrolo-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (38-c)

[0799] At 0°C, (Z)-(5-(2-nitro-1-en-1-yl)pyrrolo-2-yl)(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl ketone (38-b, 856 mg, 2.08 mmol) was dissolved in tetrahydrofuran (30 mL). Sodium borohydride (158 mg, 4.16 mmol) was added under nitrogen purging and stirring, followed by methanol (1 mL). After the addition was complete, the reaction mixture was stirred at 0°C for 0.5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to o...

Claims

1. The compound represented by formula (Ia) or its pharmaceutically acceptable salt or stereoisomer, having the structure shown in formula (Ia): (him) in, X is NH; Y is selected from CH2, O, S, or a chemical single bond; Z is selected from O, carbonyl group, or chemical single bond; V is N; W is selected from CH2 or carbonyl group; U and T are each independently selected from CH or N; n is selected from 1 or 2; R 1 Selected from trifluoromethyl; R 2 Selected from H; R 3 Selected from methyl, ethyl, propyl, and isopropyl; R 4 R 5 All are H; R 6 It is trifluoromethyl; Ring A is selected from: ； R 8 R 9 Each of the following is independently selected from H, F, Cl, and methyl.

2. The compound according to claim 1, its pharmaceutically acceptable salt, and its stereoisomer, characterized in that, It has the structure shown in formula (IIa), (IIIa) or (IVa): (IIa) (IIIa) (IVa); in, Ring A, R 1 R 6 The definitions of Y, T, U, V, and W are the same as those of compounds of formula (Ia).

3. The compound according to claim 1, its pharmaceutically acceptable salt, and its stereoisomer, characterized in that, It has the structure shown in formula (IIb), (IIIb) or (IVb): (IIb) (IIIb) (IVb); in, Ring A, R 1 R 6 The definitions of Y, T, U, V, and W are the same as those of compounds of formula (Ia).

4. The compound, its pharmaceutically acceptable salt, or its stereoisomer according to any one of claims 1-3, characterized in that, R 3 It is a methyl group.

5. The compound according to claim 1, its pharmaceutically acceptable salt, and its stereoisomer, characterized in that, As shown in equation (Ia) Selected from the following groups: -NHCH(CH3)CH2-, -NHCH(CH3)CH2O-, -NHCH(CH3)CH2S-, -NHCH(CH3)CH2CH2-.

6. The compound, its pharmaceutically acceptable salt, or its stereoisomer according to any one of claims 1-3, characterized in that, Equation (Ia) is shown Selected from the following groups: , , , ; Among them, R 6 The definition is as described in any one of claims 1-3.

7. The compound, its pharmaceutically acceptable salt, or its stereoisomer according to any one of claims 1-3, characterized in that, Ring A is selected from: 。 8. The following compounds, their pharmaceutically acceptable salts, and stereoisomers: 。 9. A pharmaceutical composition, characterized in that, The composition comprises the compound according to any one of claims 1-8, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and a pharmaceutically acceptable excipient.

10. The use of the compound of any one of claims 1-8, its pharmaceutically acceptable salt, stereoisomer, or the pharmaceutical composition of claim 9 in the preparation of a PARP7 inhibitor.

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