BCL-2 inhibitor

Abstract

Disclosed herein are compounds of formula (I) for inhibiting both wild-type and mutant Bcl-2, particularly Bcl-2 G101V and D103Y, and methods of using the compounds disclosed herein for the treatment of dysregulated apoptosis diseases.

Description

[Technical Field]

[0001] This specification discloses compounds of formula (I) for inhibiting both wild-type and mutant Bcl-2, as well as methods for using the compounds disclosed herein for the treatment of dysregulated apoptotic diseases. [Background technology]

[0002] The B-cell lymphoma 2 (Bcl-2) gene family is a group of proteins homologous to the Bcl-2 protein, encoding more than 20 proteins that regulate the endogenous apoptotic pathway. The Bcl-2 family proteins consist of pro-apoptotic and anti-apoptotic molecules and can be classified into the following three subfamilies according to sequence homology within the four BH domains (BH1, BH2, BH3, and BH4): (1) a subfamily that shares sequence homology within all four BH domains, e.g., the anti-apoptotic Bcl-2, Bcl-xl, and Bcl-w; (2) a subfamily that shares sequence homology within BH1, BH2, and BH4, e.g., the pro-apoptotic Bax and Bak; (3) a subfamily that shares sequence homology only within BH3, e.g., the pro-apoptotic Bik, Bid, and HRK. The BH1, BH2, and BH4 domains are required for the anti-apoptotic effect. In contrast, the BH3 domain is essential and is sufficient on its own to promote apoptosis.

[0003] Similar to oncogene toxicity, where tumor cells depend on a single dominant gene for survival, tumor cells may also depend on Bcl-2 for survival. Bcl-2 overexpression is common in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), relapsed / refractory chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), non-Hodgkin lymphoma (NHL), as well as solid tumors, such as pancreatic cancer, prostate cancer, breast cancer, and small cell and non-small cell lung cancer (Cancer 2001,92,1122-1129, Cancer Biol.2003;13:115-23, Curr. Cancer Drug Targets 2008,8,207-222, Cancers 2011,3,1527-1549). Dysregulated apoptotic pathways have been linked to the pathology of other important diseases, such as neurodegenerative conditions (upward-regulated apoptosis), e.g., Alzheimer's disease, and proliferative disorders (downward-regulated apoptosis), e.g., cancer, autoimmune diseases, and prothrombotic conditions. Several small molecule BH3 mimetics targeting either Bcl-2 or Bcl-xl have been reported. Some Bcl-2 small molecule inhibitors have been studied at various stages of drug discovery: the Bcl-2 / Bcl-xl inhibitor ABT-263 (Navitocrax, WO2009155386) showed promising clinical activity in lymphoid malignancies, e.g., chronic lymphocytic leukemia. However, their effectiveness in these settings is limited by platelet death and associated thrombocytopenia caused by Bcl-xl inhibition (Lancet Oncol. 2010, 11, 1149; J. Clin. Oncol. 2011, 29, 909; J. Clin. Oncol. 2012, 30, 488). A new generation of Bcl-2 selective inhibitors, venetoclax (ABT-199 / GDC-0199), has advanced, demonstrating robust activity in these cancers while preserving platelets (Journal of Hematology & Oncology 2015, 8, 129; Clinical Advances in Hematology & Oncology 2017, 15, 210). S55746 (also known as BCL201), APG-101, and APG-1252 are currently being tested in clinical trials.Currently, venetoclax (formerly ABT-199) is the only Bcl-2 selective inhibitor approved by the FDA for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) with 17p deletion.

[0004] Despite high clinical activity and a favorable safety profile, patients may gradually develop acquired resistance to venetoclax with continued treatment. Recently, a novel Gly101Val (G101V) mutation in Bcl2 was identified after 19–42 months of treatment with the Bcl-2 inhibitor venetoclax (ABT-199) (Cancer Discov. 2019, 9, 342-353; Haematologica 104, e434-e437, 2019). Blombery et al demonstrated that the Gly101Val mutation in Bcl-2 confers acquired refractory by reducing the binding affinity of venetoclax without interfering with the binding of pro-apoptotic proteins to Bcl-2. The novel Gly101Val mutation in Bcl-2 was not identified at trial enrollment but was identified in 7 out of 15 patients at disease progression. The Bcl-2 Asp103Tyr(D103Y) mutation observed in CLL patients was predicted to interfere with Bcl-2 binding to venetoclax, leading to reduced patient suitability (Haematologica 104,e434-e437,2019). The Bcl-2 Phe104Ile(F104I) mutation in FL (follicular lymphoma) patients treated with venetoclax has also been described as being associated with a significant decrease in venetoclax binding, which is sufficient to confer cellular resistance (Br J Haematol,186(6):e188-e191,2019).

[0005] In addition, wild-type Bcl-2 is important for the survival of neutrophil precursors, and neutropenia was the most common side effect of Bcl-2 inhibitor therapy. In CLL patients treated with venetoclax, the development of neutropenia was commonly observed during dose escalation, but its incidence decreased with longer treatment duration (Clin Cancer Res;24(18),2018). In other words, excessive inhibition of wild-type Bcl-2 protein may lead to on-target toxicity and neutropenic side effects.

[0006] WO2019210828 disclosed a novel class of Bcl-2 inhibitors. There is a strong need for new small molecules that inhibit both wild-type Bcl-2 protein and Bcl-2 mutations, such as G101V and D103Y mutations, seen in patients with disease progression after long-term venetoclax treatment. [Overview of the Initiative] [Means for solving the problem]

[0007] The inventors of this disclosure have found that the compounds disclosed herein exhibit nearly equal inhibitory activity against both wild-type Bcl-2 and Bcl-2 mutations, including G101V and D103Y, suggesting a novel type of potential Bcl-2 inhibitor that does not raise resistance concerns. This disclosure also offers the potential for novel therapies at effective and safe doses for clinically relapsed patients with mutations after treatment with venetoclax.

[0008] Disclosed herein are compounds of formula (I). [ka] [During the ceremony, X is independently selected from N or CH; p is an integer selected from 1 or 2; v is an integer selected from 1 or 2; m is an integer selected from 1, 2, or 3; n is an integer selected from 0, 1 or 2; t is an integer selected from 1 or 2; Ring A is

Chemical formula

[0009] In some embodiments, X is N.

[0010] In some embodiments, ring B is phenyl, furanyl, isoxazolyl, pyridinyl, pyrazolyl, or pyrimidinyl.

[0011] In some embodiments, R 2 is, halo, -C 1-6 Alkyl or -C 3-4 It is a cycloalkyl, and the above -C 1-6 Alkyl and -C 3-4 Each cycloalkyl group independently contains hydrogen, -C 1-3 Alkyl, C 3-6 Cycloalkyl or C 3-6 It is selectively substituted with heterocyclines.

[0012] In some embodiments, R 2 These are fluoromethyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, or morpholinomethyl.

[0013] In some embodiments, n is 0, and L 2 is, -(CH2) q It is - or -O-, where q is a number between 1 and 3, preferably 1.

[0014] In some embodiments, R 11 is -C 3-10 These are cycloalkyl, aryl, 5- or 6-membered monocyclic heteroaryl, 7- to 10-membered bicyclic heteroaryl, 3- to 6-membered monocyclic heterocyclil, and 7- to 14-membered bicyclic heterocyclil, each of which independently has 1, 2, or 3 substituents R 11X It is optionally replaced in R 11X This is defined with respect to equation (I).

[0015] In some embodiments, R 11 This is a 3- to 6-membered heterocycloalkyl compound containing one or two heteroatoms selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or oxygen and nitrogen atoms.

[0016] In some embodiments, R 11 The compound is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, tetrahydro-2H-pyran-1-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl oxazole-2-yl, oxazole-4-ylmethyl, or oxazole-5-yl.

[0017] In some embodiments, R 11 is 1, 2, or 3 substituents R 11X The phenyl or 8-10 membered bicyclic aryl is selected from those optionally substituted.

[0018] In some embodiments, R 11 is 1-2 substituents R 11X The phenyl or 8-10 membered bicyclic aryl is selected from those optionally substituted.

[0019] In some embodiments, R 11 These are chromanil, benzo[b][1,4]dioxynil), 5,6,7,8-tetrahydronaphthalenyl, octahydro-5H-2,5-methanoindenyl (preferably octahydro-5H-2,5-methanoinden-5-yl), 2,3,4,5-tetrahydrobenzo[b]oxepinyl (preferably 2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl), and adamantanil (preferably adamantan-1-yl), each of which contains one or two R 11X It is being replaced by an arbitrary choice.

[0020] In some embodiments, R 11X These are halogen, cyano, hydroxy, and -C 1-8 Alkyl, Halo C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkinyl, C 1-6 Alkoxyl, Halo C 1-6 Alkoxyl, C 3-6 Cycloalkyl, heterocyclyl, C 3-6Cycloalkoxyl, -NH 2、 -NH(C 1-8 Alkyl), -N(C 1-8 It is alkyl)2 or heterocyclyl-O-.

[0021] In some embodiments, R 11x は-OR 11a And R 11a is -C 1-8 Alkyl, preferably methyl (-CH3), ethyl, propyl, isopropyl, butyl or tert-butyl. In some embodiments, R 11x は-OR 11a And R 11a It is selectively deuterium-rich, -C 1-8 Alkyl, for example, -CD3 or -CD2CD3.

[0022] In some embodiments, R 11x は-OR 11a And R 11a C 3-6 The cycloalkyl group is preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0023] In some embodiments, R 11 It consists of 1, 2, or 3 independent a) Cyano, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetane-3-yl, -NH2 or -NH(CH3); or b)R 11a to C 3-6 Cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, -OR 11a Selected substitution R 11X It is phenyl substituted with [a specific compound].

[0024] In some embodiments, R 11 This is a phenyl compound substituted with cyano, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, difluoromethyl, trifluoromethyl, or trifluoromethoxy.

[0025] In some embodiments, R 11 It is a phenyl compound substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0026] In some embodiments, R 11 This includes cyclohexyl, 4-methoxylcyclohexyl, bicyclo[1.1.1]pentan-1-yl, tetrahydro-2H-pyran-4-yl, oxazole-4-yl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 4-cyanophenyl, 4-methylphenyl, 4-(trifluoromethyl)phenyl, 2-methoxylphenyl, 3-methoxylphenyl, 4-methoxylphenyl, 4-ethoxylphenyl, 4-methoxylphenyl, 4-( These are trifluoromethoxyl(phenyl), 2,4-dimethoxylphenyl, 2,3-dimethoxylphenyl, 3,4-dimethoxylphenyl, 3,5-dimethoxylphenyl, 3,4,5-trimethoxylphenyl, croman-6-yl, croman-4-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzo[b][1,4]dioxin-5-yl, or 5,6,7,8-tetrahydronaphthalene-2-yl, or 5,6,7,8-tetrahydronaphthalene-1-yl, and bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl.

[0027] In some embodiments, R 11These are furanil, isoxazolyl, pyridinyl, pyrazolyl, pyrimidinyl, quinoxalinyl, benzo[b]thiophenyl, benzofuranil, or 2,3-dihydrobenzofuran-5-yl.

[0028] In some embodiments, R 11 These are furan-2-yl, isoxazole-4-yl, pyridine-3-yl, pyridine-2-yl, 1H-pyrazole-4-yl, pyrimidine-2-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-4-yl, benzofuran-5-yl, benzofuran-4-yl, 2,3-dihydrobenzo[b][1,4]dioxin-5-yl, benzo[b][1,4]oxazine-5-yl, dihydro-[1,4]dioxyno[2,3-b]pyridine-8-yl, or 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl.

[0029] In some embodiments, R 11 -L 2 - is selected from furan-2-ylmethyl, isoxazole-4-ylmethyl, (pyridine-3-yl)methyl, (6-methoxypyridine-3-yl)methyl, (5-methoxypyridine-2-yl)methyl, (1-methyl-1H-pyrazole-4-yl)methyl, (3-methoxy-1-methyl-1H-pyrazole-4-yl)methyl, (1-cyclopropyl-1H-pyrazole-4-yl)methyl, (5-methoxypyrimidine-2-yl)methyl, benzo[b]thiophene-5-ylmethyl, benzo[b]thiophene-4-ylmethyl, benzofuran-5-ylmethyl, or benzofuran-4-ylmethyl.

[0030] In some embodiments, R 11 -L 2 - is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or 1,2,3,4-tetrahydronaphthalene-1-yl, 3-phenylcyclobuta-1-yl, 3-phenylcyclopenta-1-yl, 4-phenylcyclohexa-1-yl, or 3-(4-methoxylphenyl)cyclopenta-1-yl.

[0031] In some embodiments, R 11 -L 2 - is a 3- to 6-membered monocyclic heterocycline selected from oxetanyl, tetrahydrofuranyl, or tetrahydro-2H-pyranyl, preferably from oxetan-3-yl, tetrahydrofuran-3-yl, and tetrahydro-2H-pyran-4-yl.

[0032] In some embodiments, R 12 It is hydrogen.

[0033] In some embodiments, L 2 is -SO2- or -CO-, and R 11 is -C 1-3 They are alkyl or phenyl, and each of these is C 1-3 It is optionally substituted with an alkoxyl.

[0034] In some embodiments, R a It is hydrogen or methyl.

[0035] In some embodiments, m is 1, and R 3 ha-L 1 -CyC and L 1 This is a direct bond, -(CH2) 0-2 -, -N(CH2) 0-2 , or -O(CH2) 0-2 That is the case.

[0036] In some embodiments, CyC is a monocyclic C 3-8 Cycloalkyl or cross-linked cycloalkyl [ka] A C3-6 cycloalkyl selected from, each of which has one or two substituents R 3a It is being replaced by an arbitrary choice.

[0037] In some embodiments, CyC is cyclobutyl, cyclopentyl, or cyclohexyl, each of which has one or two substituents R 3a It is being replaced by an arbitrary choice.

[0038] In some embodiments, CyC is: a) A monocyclic 4- to 9-membered heterocyclyl group containing one nitrogen, oxygen, or sulfur heteroatom as a ring member; a heterocyclyl selected from a monocyclic 4- to 9-membered heterocyclyl group containing two heteroatoms selected from oxygen, sulfur, and nitrogen as ring members. b) A 5- to 10-membered spirotype heterocycline containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members, or c) 5- to 10-membered cross-linked heterocyclines containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members. Each of these has 1, 2, 3, or 4 substituents R 3a It is being replaced by an arbitrary choice.

[0039] In some embodiments, CyC is a monocyclic 4- to 6-membered heterocycline group containing one nitrogen, oxygen, or sulfur heteroatom as a ring member.

[0040] In some embodiments, Cyc is selected from oxetanil, tetrahydrofuranil, tetrahydropyranil, azetidinil, pyrrolidinil, and piperidinil.

[0041] In some embodiments, CyC is selected from oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, azetidine-3-yl, azetidine-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-4-yl, piperidine-2-yl, and piperidine-3-yl.

[0042] In some embodiments, CyC is a monocyclic six-membered heterocyclyl group containing two heteroatoms selected from oxygen and nitrogen as ring members.

[0043] In some embodiments, CyC is dioxanyl, morpholino, morpholinyl, or piperazinyl.

[0044] In some embodiments, CyC is 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,4-dioxan-2-yl, morpholin-1-yl, morpholin-2-yl, or morpholin-3-yl.

[0045] In some embodiments, CyC is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirotype heterocyclyl containing one or two nitrogen or oxygen atoms as ring members.

[0046] In some embodiments, CyC is [ka] or [ka] That is the case.

[0047] In some embodiments, R 3a These are independently hydrogen, halogen, cyano, oxo, -OR 3b , -NR 3b R 3c -C(=O)R 3b , -SO2R 3b , -C 1-6 Alkyl, monocyclic C 3-6 Selected from a cycloalkyl or a monocyclic 4- to 9-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms as ring members, and the above-C 1-6 Each alkyl and monocyclic 4- to 9-membered heterocyclyl group has one or two substituents R3e It is being replaced by an arbitrary choice.

[0048] In some embodiments, R 3a Cycloalkyl as C 3-6 It is cycloalkyl, more preferably cyclopropyl.

[0049] In some embodiments, R 3a A heterocyclyl is a 4- to 6-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms as ring members.

[0050] In some embodiments, R 3a Heterocyclyls include oxetanil, tetrahydrofuranil, tetrahydropyranil, piperazinil, or morpholinil.

[0051] In some embodiments, R 3a The heterocyclyls are oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, or morphin-4-yl.

[0052] In some embodiments, R 3e A heterocyclyl is a monocyclic 4- to 9-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms as ring members.

[0053] In some embodiments, R 3e The heterocyclyl is tetrahydropyran-4-yl.

[0054] In some embodiments, R 3a -NR 3b R 3c And R 3b is hydrogen, R 3c It is a heterocycline.

[0055] In some embodiments, R3a -NR 3b R 3c And R 3b is hydrogen, R 3c It is tetrahydropyran-4-yl.

[0056] In some embodiments, R 3a -NR 3b R 3c And R 3b and R 3c Each of these is independently either hydrogen or a cycloalkyl-substituted -C 1-6 Alkyl, preferably monocyclic C 3-6 Cycloalkyl-substituted -C 1-6 It is alkyl.

[0057] In some embodiments, R 3a は-OR 3b or -SO2R 3b And R 3b is hydrogen or C 1-8 Alkyl, preferably methyl.

[0058] In some embodiments, R 3a ha-COR 3b And R 3b is hydrogen, or -NR 3f R 3g C is optionally replaced by 1-6 It is alkyl, R 3f and R 3g Each is independently hydrogen or C 1-6 The alkyl group is preferably methyl.

[0059] In some embodiments, two adjacent Rs on the phenyl ring 3 It combines with the phenyl ring to form an indazolyl molecule substituted with tetrahydropyranyl.

[0060] In some embodiments, m is 1, and R 3 teeth: [ka] [ka] It is selected from the group consisting of the following.

[0061] In some embodiments, R 4 The halogen is selected from fluoro(-F), chloro(-Cl), or bromo(-Br), preferably fluoro(-F).

[0062] In some embodiments, R 4 It is located at the 3rd position of the pyrrolo[2,3-b]pyridine-5-yl ring.

[0063] In some embodiments, the compound is selected from the exemplified compounds.

[0064] In some embodiments, the compound is [ka] [ka] [ka] [ka] Selected from, R in the formula 4 This is a halogen selected from fluoro(-F), chloro(-Cl), or bromo(-Br).

[0065] In some embodiments, the compound is [ka] And R 4 is a halogen selected from fluoro(-F), chloro(-Cl), or bromo(-Br), and Rx is, [ka] Selected from.

[0066] In some embodiments, the compound is [ka] Selected from, the pyrrole ring on the pyrrolo[2,3-b]pyridine-5-yl ring is a single substitution R selected from fluoro(-F), chloro(-Cl), or bromo(-Br). 4 It is optionally replaced by Ry is [ka] [ka] Selected from.

[0067] The compounds disclosed herein have an additional aromatic ring or carbocyclic moiety linked to the phenylpiperazine or phenylpiperidine moiety in the molecule by a linker -L2- (particularly -CH2-, -O-). This crucial structural feature not only confers comparable or slightly better inhibitory activity against Bcl-2 wild-type protein, but also unexpectedly exhibits robust efficacy against Bcl2 variants, including G101V and D103Y. IC2 of Bcl-2 G101V / Bcl-2 wt 50 The proportion is very low. These results suggest that the compounds disclosed herein are a type of novel potential Bcl-2 inhibitor that does not have the resistance concerns associated with mutations such as G101V and D103Y. From the perspective of neutropenia as a side effect, these compounds offer the potential for novel therapies at effective and safe doses for clinically relapsed patients with mutations after treatment with venetoclax.

[0068] In human and mouse species, the compounds disclosed herein have long in vitro half-lives (T 1 / 2 ) and low intrinsic clearance (CL) int This demonstrates that the metabolic stability of the compounds of this disclosure in liver microsomes is significantly improved.

[0069] Furthermore, the compounds disclosed herein exhibit remarkably favorable PK, AUC, and Cmax in mice. In addition, IV administration of the compounds disclosed herein results in considerably low CL values, which is consistent with their in vitro clearance data.

[0070] Disclosed herein are pharmaceutical compositions comprising at least one of the compounds disclosed herein, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0071] Disclosed herein are methods for treating dysregulated apoptotic diseases, comprising administering a therapeutically effective amount of one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, to a subject in need thereof. In some embodiments, dysregulated apoptotic diseases are neurodegenerative conditions, proliferative disorders, and prothrombotic conditions. In other embodiments, the proliferative disorder is cancer. In some embodiments, dysregulated apoptotic diseases are associated with mutations in Bcl-2. In other embodiments, the Bcl-2 mutations include Bcl-2 G101V and / or Bcl-2 D103Y. In yet another embodiment, the Bcl-2 mutation is Bcl-2 G101V or Bcl-2 D103Y. [Modes for carrying out the invention]

[0072] definition Unless otherwise specified elsewhere in this document, all other scientific and technical terms used herein have meanings that are generally understood by those skilled in the art.

[0073] When used herein, including in the claims set forth herein, singular words, such as "a," "an," and "the," imply their corresponding plural meanings, unless the context clearly indicates otherwise.

[0074] The term "or" is used to mean and interchangeably with the term "and / or," unless the context clearly indicates otherwise.

[0075] The term "alkyl" refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups containing 1 to 18 carbon atoms, for example, 1 to 12, or even 1 to 10, or more specifically, 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups. The alkyl group can be optionally deuterium-rich, such as -CD3 or -CD2CD3.

[0076] The term "halogen" refers to fluoro(F), chloro(Cl), bromo(Br), and iodine(I).

[0077] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms, such as fluoro, chloro, bromo, and iodine. An example of a haloalkyl is halo-C. 1-8 Alkyl, Halo C 1-6 Alkyl or Halo C 1-4Alkyl groups are examples, and while not limited to them, examples include -CF3, -CH2Cl, -CH2CF3, -CCl2, and CF3.

[0078] The terms "alkyloxy" or "alkoxy" refer to a molecule in which an alkyl group, as defined above, is bonded to the parent molecule via an oxygen atom. For example, an alkyloxy is C 1-6 Alkyloxy or C 1-4 Examples of alkyloxys include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, and hexoxy.

[0079] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including condensed, cross-linked, or spiro-type cycloalkyl groups.

[0080] For example, a cycloalkyl group may contain 3 to 12 carbon atoms, for example 3 to 10, more specifically 3 to 8, more specifically 3 to 6, 3 to 5, or 3 to 4. More specifically, a cycloalkyl group may be selected from monocyclic groups containing 3 to 12 carbon atoms, for example 3 to 10, more specifically 3 to 8, or 3 to 6. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, saturated monocyclic cycloalkyl groups, for example C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, the cycloalkyl group is a monocyclic group (abbreviated as C) containing 3 to 6 carbon atoms. 3-6These are cycloalkyl groups, which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms, arranged as condensed dicyclic groups selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as bridging dicyclic groups selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as dicyclic groups selected from the [5,6] and [6,6] ring systems, for example, [ka] [In the formula, the wavy line represents a connection point.] Examples include: The ring may be saturated or may have at least one double bond (i.e., partially unsaturated), but not fully conjugated, and not aromatic, for example, aromatic as defined herein.

[0081] The term "spiro-cycloalkyl" refers to a cyclic structure formed by at least two rings containing carbon atoms and sharing one atom. The term "7-10 membered spiro-cycloalkyl" refers to a cyclic structure formed by at least two rings containing 7-10 carbon atoms and sharing one atom.

[0082] The term "condensed cycloalkyl" refers to a condensed ring formed by two or more rings containing carbon atoms and sharing two adjacent atoms. The term "4-10 membered condensed cycloalkyl" refers to a condensed ring formed by two or more rings containing 4-10 ring carbon atoms and sharing two adjacent atoms.

[0083] Examples include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo3-8 membered cycloalkyls, benzoC 4-6 Examples include, but are not limited to, cycloalkenyls, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, and 1,4-dihydronaphthyl. Preferred embodiments are 8-9 membered condensed cyclyls, meaning cyclic structures containing 8-9 ring atoms as in the above examples.

[0084] The term "crosslinked cycloalkyl" refers to a cyclic structure formed by two rings containing carbon atoms and sharing two non-adjacent atoms. The term "7-10 membered crosslinked cycloalkyl" refers to a cyclic structure formed by two rings containing 7-12 carbon atoms and sharing two non-adjacent atoms. Examples include, but are not limited to, octahydro-5H-2,5-methanoindenyl (preferably octahydro-5H-2,5-methanoinden-5-yl) or adamantanyl (preferably adamantan-1-yl).

[0085] The term “aryl,” used alone or in combination with other terms, a) Five-membered and six-membered carbocyclic aromatic rings, e.g., phenyl; b) Bicyclic ring systems, e.g., 7-12 membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, e.g., naphthyl and indanyl; and c) A tricyclic ring system in which at least one ring is carbocyclic and aromatic, e.g., fluorenyl, e.g., a 10-15 member tricyclic ring system It refers to the base selected from among them.

[0086] The terms “aromatic hydrocarbon ring” and “aryl” are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 (aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthal-1-yl, naphthal-2-yl, anthracenyl, and phenantrenyl. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthal-1-yl or naphthal-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0087] The term "heteroaryl" means a) A 5-membered, 6-membered, or 7-membered aromatic monoring comprising at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), e.g., 1 to 4, or in some embodiments 1 to 3, in some embodiments 1 to 2 heteroatoms, with the remaining ring atom being carbon; b) An 8-12 membered diring comprising at least one heteroatom selected from N, O, and S, e.g., 1-4, or 1-3 in some embodiments, or 1-2 in other embodiments, the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom located within the aromatic ring; and c) An 11-14 membered triring comprising at least one heteroatom selected from N, O, and S, e.g., 1-4 heteroatoms, or 1-3 heteroatoms in some embodiments, or 1-2 heteroatoms in other embodiments, the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom located within the aromatic ring. It refers to the base selected from among them.

[0088] If the total number of S and O atoms in a heteroaryl group is greater than 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group is not greater than 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is not greater than 1. If a heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group may be oxidized to form N oxides. As used herein, the term “C-bonded heteroaryl” means that the heteroaryl group is linked to the core molecule by a bond from the C atom of the heteroaryl ring.

[0089] The terms “aromatic heterocycle” and “heteroaryl” are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 ring members, with 1, 2, 3, or 4 heteroatoms independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members being carbon. In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring containing one or two heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic 5- to 6-membered heteroaryl ring that is monocyclic and has one or two heteroatoms independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring that is bicyclic and independently has one or two heteroatom ring members selected from nitrogen, sulfur, and oxygen.

[0090] Examples of heteroaryl groups or monocyclic or bicyclic aromatic heterocycles include (assigned priority 1 to bond positions and numbered accordingly) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), Tetrazolyl, thienyl (e.g., thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, indlinyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridadinyl, pyrrolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl 1-Oxa-2,3-diazolyl, 1-Oxa-2,4-diazolyl, 1-Oxa-2,5-diazolyl, 1-Oxa-3,4-diazolyl, 1-Thi-2,3-diazolyl, 1-Thi-2 Examples include, but are not limited to, 4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, flazanyl (e.g., flazan-2-yl, flazan-3-yl), benzoflazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinil, quinoxalinil, naphthilidinil, phlopyridinil, benzothiazolyl (e.g., benzo[d]thiazole-6-yl), indazolyl (e.g., 1H-indazole-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0091] "Heterocyclyl," "heterocyclic," or "heterocyclic formula" are interchangeable and refer to a non-aromatic heterocyclyl group in which one or more heteroatoms selected from the group consisting of NH, O, S, SO, or SO2 heteroatoms are included as ring members, with the remaining ring members being carbon. This includes monocyclic, condensed, bridging, and spiro-type rings, i.e., monocyclic heterocyclyl, bridging heterocyclyl, spiro-type heterocyclyl, and condensed heterocyclic groups are included.

[0092] The term "monocyclic heterocyclyl" refers to a monocyclic group having at least one heteroatom selected from the group consisting of NH, O, S, SO, or SO2 as a ring member. The heterocycle can be saturated or partially unsaturated.

[0093] Examples of monocyclic 4- to 9-membered heterocyclyl groups include (when assigned priority 1 to the binding position and numbered accordingly) pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidine-2-yl, pyrazolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2- Il, Morpholin-3-yl, Oxyranil, Aziridin-1-yl, Aziridin-2-yl, Azocan-1-yl, Azocan-2-yl, Azocan-3-yl, Azocan-4-yl, Azocan-5-yl, Thiiranil, Azethidine-1-yl, Azethidine-2-yl, Azethidine-3-yl, Oxetanil, Thietanil, 1,2-Dithietanil, 1,3-Dithietanil, Dihydropyridinyl, Tetrahydropyridinyl, Thiomorpholinil, Thioxanil, Piperazinil, Homo Piperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanil, thiepanil, 1,4-oxathianil, 1,4-dioxepanil, 1,4-oxathiepanil, 1,4-oxazepanil, 1,4-dithiepanil, 1,4-thiazepanil and 1,4-diazepanil, 1,4-dithianil, 1,4-azathanil, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranil, Examples include, but are not limited to, dihydrofuranil, tetrahydrofuranil, tetrahydrothienyl, tetrahydropyranil, tetrahydrothiopyranil, 1-pyrrolinil, 2-pyrrolinil, 3-pyrrolinil, indolinil, 2H-pyranil, 4H-pyranil, 1,4-dioxanil, 1,3-dioxolanil, pyrazolinil, pyrazolidinil, dithianil, dithiolanil, pyrazolidinil, imidazolinil, pyrimidinol, or 1,1-dioxo-thiomorpholinil.

[0094] The term "spiro-type heterocyclyl" or "heterospiro-type cyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl in which the rings are linked via a single common carbon atom (called a spiro atom), and which contains one or more heteroatoms selected from the group consisting of NH, O, S, SO, or SO2 heteroatoms as ring members, with the remaining ring members being carbon atoms. One or more rings of the spiro-type heterocyclyl group may contain one or more double bonds, but no ring has a fully conjugated pi electron system. Preferably, spiro-type heterocyclyls are 6- to 14 members, more preferably 7- to 10 members. Depending on the number of shared spiro atoms, spiro-type heterocyclils are classified into monospiro-type heterocyclils, dispiro-type heterocyclils, or polyspiro-type heterocyclils, preferably monospiro-type heterocyclils or dispiro-type heterocyclils, more preferably 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiro-type heterocyclils.Representative examples of spirotype heterocyclyls include the following groups: 2,3-dihydrospiro[indene-1,2'-pyrrolidine] (e.g., 2,3-dihydrospiro[indene-1,2'-pyrrolidine]-1'-yl), 1,3-dihydrospiro[indene-2,2'-pyrrolidine] (e.g., 1,3-dihydrospiro[indene-2,2'-pyrrolidine]-1'-yl), azaspiro[2.4]heptane (e.g., 5-azaspiro[2.4]heptane-5-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane-6-yl), and 2-oxa-6-azaspiro[3.4]octane (e.g., 2-oxa-6-azaspiro[3.4]octane-6-yl). Examples include, but are not limited to, azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane-6-yl), 7-azaspiro[3.5]nonane (e.g., 7-azaspiro[3.5]nonane-7-yl), 2-azaspiro[3.5]nonane (e.g., 2-azaspiro[3.5]nonane-2-yl), 1,7-dioxaspiro[4.5]decane, 2-oxa-7-azaspiro[4.4]nonane (e.g., 2-oxa-7-azaspiro[4.4]nonane-7-yl), 7-oxaspiro[3.5]nonyl, and 5-oxaspiro[2.4]heptyl.

[0095] The term "condensed heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclil group in which each ring in the system shares a pair of adjacent atoms (carbon-carbon or carbon-nitrogen) with another ring, and which contains one or more heteroatoms selected from the group consisting of NH, O, S, SO, or SO2 heteroatoms as ring members, with the remaining ring members being carbon. One or more rings of a condensed heterocyclic group may contain one or more double bonds, but no ring has a fully conjugated pi electron system. Preferably, condensed heterocyclils are 6- to 14 members, more preferably 7- to 10 members. Depending on the number of rings forming the group, condensed heterocyclils are classified into bicyclic, tricyclic, tetracyclic, or polycyclic condensed heterocyclils, preferably bicyclic or tricyclic condensed heterocyclils, more preferably 5-membered / 5-membered, or 5-membered / 6-membered bicyclic condensed heterocyclils. Representative examples of condensed heterocycles include, but are not limited to, the following groups: octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrole-2-yl), octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolinyl (e.g., isoindolin-2-yl), octahydro-benzo[b][1,4]dioxin, dihydrobenzofuranyl, benzo[d][1,3]dioxolyl, or 2,3,4,5-tetrahydrobenzo[b]oxepinyl (preferably 2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl).

[0096] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group in which any two rings in the system share two unconnected atoms, and which contains one or more heteroatoms selected from the group consisting of NH, O, S, SO, or SO2 heteroatoms as ring members, with the remaining ring members being carbon. One or more rings of the bridged heterocyclyl group may contain one or more double bonds, but no ring has a fully conjugated pi electron system. Preferably, bridged heterocyclyls are 6- to 14 members, more preferably 7- to 10 members. Depending on the number of rings forming the group, bridged heterocyclyls are classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyls, preferably bicyclic, tricyclic, or tetracyclic bridged heterocyclyls, more preferably bicyclic or tricyclic bridged heterocyclyls. Representative examples of cross-linked heterocyclyls include, but are not limited to, the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0097] The heterocyclyl ring may be fused with an aryl, heteroaryl, or cycloalkyl ring, in which case the ring structure is linked together to the parent heterocyclic group.

[0098] The term "heterocyclyl-O-" used here refers to a heterocyclyl, as defined above, that is bonded to its parent molecule via an oxygen atom.

[0099] The term "C-bonded heterocyclyl" used here refers to a heterocyclyl group that is linked to other parts of the molecule by direct bonds from the carbon atoms of the heterocyclyl ring.

[0100] The term "N-bonded heterocyclyl" used here refers to a heterocyclyl group that is linked to other parts of the molecule by a direct bond from the nitrogen atom of the heterocyclyl ring.

[0101] The compounds disclosed herein may contain chiral centers and thus may exist as enantiomers. “Enantiomer” refers to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed. If a compound disclosed herein has two or more chiral centers, they may also exist as diastereomers. Enantiomers and diastereomers are included in a broader category of stereoisomers. It is intended to include all such possible stereoisomers as substantially pure, divided enantiomers, their racemic mixtures, and mixtures of diastereomers. It is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specified, a reference to an isomer applies to any of the possible isomers. Where isomer composition is not specified, all possible isomers are included.

[0102] As used herein, the term “substantially pure” means that the stereoisomer of interest contains any other stereoisomer(s) in an amount of 35% or less by weight, e.g., 30% or less, more like 25% or less, or even more like 20% or less. In some embodiments, the term “substantially pure” means that the stereoisomer of interest contains any other stereoisomer(s) in an amount of 10% or less by weight, e.g., 5% or less, or even 1% or less.

[0103] Where a compound disclosed herein contains an olefinic double bond, unless otherwise specified, such double bond is intended to include both E-type and Z-type geometric isomers.

[0104] When a compound disclosed herein contains a disubstituted cyclohexyl or cyclobutyl group, the substituents on the cyclohexyl or cyclobutyl ring may be in cis or trans configuration. The cis configuration means that both substituents are located on the upper side of the two- substituent arrangement on the carbon, while the trans configuration means they are on opposite sides.

[0105] It may be beneficial to separate reaction products from each other and / or from the starting materials. The desired products of a nuclear step or a series of steps are separated and / or purified (hereinafter, separated) to the desired degree of homogeneity by techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods, including, for example, reversed-phase and normal-phase; size exclusion; ion exchange; high, medium and low-pressure liquid chromatography methods and apparatus; small-scale analytical; pseudo-moving bed ("SMB") and preparative thin-layer or thick-layer chromatography, as well as small-scale thin-layer and flash chromatography techniques. Those skilled in the art will apply the technique that is most likely to achieve the desired separation.

[0106] A "diastereomer" refers to a stereoisomer of a compound that has two or more chiral centers but is not a mirror image of each other. A mixture of diastereomers can be separated into their individual diastereomers by methods well known to those skilled in the art based on their physical and chemical differences, for example by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary, e.g., a chiral alcohol or moscheric acid chloride), separating the diastereomers, and converting the individual diastereoisomers into their corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by the use of a chiral HPLC column.

[0107] A single stereoisomer, for example, a substantially pure enantiomer, can be obtained by the resolution of a racemic mixture using methods such as the formation of a diastereomer with an optically active resolving agent (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH, et al. “Chromatographic resolution of enantiomers: Selective review.” J. Chromatogr., 113(3)(1975): pp.283-302). The racemic mixture of the chiral compound of the present invention can be separated and isolated by any preferred method, including (1) the formation of an ionic diastereomer salt with the chiral compound and separation by fractional crystallization or other methods; (2) the formation of a diastereomer compound with a chiral derivatizing reagent, separation of the diastereomer and conversion to a pure stereoisomer; and (3) the direct separation of substantially pure or concentrated stereoisomers under chiral conditions. See Wainer, Irving W., Ed., Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0108] A "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with human and lower animal tissues within the bounds of sound medical judgment without excessive toxicity, irritation, or allergic reactions, and that is commensurate with a reasonable benefit / risk ratio. A pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by the reaction of a free base functional group with a suitable organic acid, or an acidic group with a suitable base.

[0109] In addition, when the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acid salt. Conversely, when the product is a free base, the addition salt, such as a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize the various synthetic methodologies that can be used to prepare non-toxic, pharmaceutically acceptable addition salts without unnecessary experimentation.

[0110] As defined herein, “a pharmaceutically acceptable salt thereof” includes salts of at least one compound of formula (I), as well as salts of stereoisomers of the compound of formula (I), such as salts of enantiomers and / or diastereomers.

[0111] In this specification, the terms “administer,” “administer,” “treat,” and “treat” mean, when applied to animals, humans, subjects, cells, tissues, organs, or biological fluids, the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. Therapy of cells includes contacting a reagent with cells and, when the fluid is in contact with cells, contacting a reagent with a fluid. The terms “administer” and “treat” also mean the treatment of cells, for example, in vitro and in vitro, with a reagent, diagnostic compound, binding compound, or with another cell. In this specification, the term “subject” includes any living organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit), most preferably a human.

[0112] The terms “effective dose” or “therapeutic effective dose” refer to the amount of an active ingredient, such as a compound, that, when administered to a subject to treat a disease or at least one of the clinical symptoms of a disease or disorder, is sufficient to have an effect on such treatment for the disease, disorder or symptom. “Therapeutic effective dose” can vary depending on the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the symptoms of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. An appropriate amount in any given case may be obvious to those skilled in the art or may be determined by customary experiment. In some embodiments, “therapeutic effective dose” is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof that is effective in “treating” the disease or disorder in a subject as defined above. In the case of combination therapy, “therapeutic effective dose” refers to the total amount of the combination for an effective treatment of the disease, disorder or symptom.

[0113] Pharmaceutical compositions comprising the compounds disclosed herein may be administered orally, by inhalation, rectally, parenterally, or topically to the target requiring it. For oral administration, the pharmaceutical composition may be a conventional solid formulation, such as tablets, powders, granules, or capsules; a liquid formulation, such as a water or oil suspension; or another liquid formulation, such as a syrup, solution, suspension, or similar; for parenteral administration, the pharmaceutical composition may be a solution, aqueous solution, oil suspension concentrate, lyophilized powder, or similar. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, and more preferably from tablets or capsules. The pharmaceutical composition may be a single unit dose with a precise dosage. In addition, the pharmaceutical composition may further contain additional active ingredients.

[0114] All formulations of the pharmaceutical compositions disclosed herein can be manufactured by conventional methods of the pharmaceutical field. For example, an active ingredient may be mixed with one or more excipients to form a desired formulation. "Pharmacologically acceptable excipients" refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as diluents, vehicles, such as water and various organic solvents; fillers, such as starch and sucrose; binders, such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone (PVP); wetting agents, such as glycerol; disintegrants, such as agar, calcium carbonate and sodium bicarbonate; absorption enhancers, such as quaternary ammonium compounds; surfactants, such as hexadecanol; absorbent carriers, such as kaolin and soap clay; lubricants, such as talc, calcium stearate, magnesium stearate and polyethylene glycol. In addition, the pharmaceutical composition further comprises other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, aromatic compounds, sweeteners, and colorants.

[0115] The term “disease” refers to any disease, ailment, illness, symptom, or sign, and may be interchangeable with the terms “disorder” or “symptom.”

[0116] Throughout this specification and the subsequent claims, the term “comprise,” and its variations, such as “comprises” and “contains,” are intended to indicate the presence of a subsequent feature but not to exclude the presence or addition of one or more other features, unless the context requires otherwise. Where used herein, the term “comprising” may be replaced by the terms “contains,” “including,” or sometimes “having.”

[0117] Throughout this specification and the subsequent claims, "C n-m The term "C" represents a range including the endpoints, where n and m are integers representing the number of carbon atoms. For example, C 1-8 , C 1-6These are some examples.

[0118] Unless otherwise specified elsewhere in this document, all other scientific and technical terms used herein have meanings that are generally understood by those skilled in the art to which the present invention pertains. [Examples]

[0119] The present invention is further illustrated by the following examples illustrating this specification, but is not limited to these examples.

[0120] In the following examples, the following abbreviations will be used: [Table 1-1] [Table 1-2]

[0121] The following examples are for illustrative purposes only and should not be considered limiting. While efforts have been made to ensure accuracy with respect to the numbers used (e.g., quantities, temperatures), some experimental error and deviation should be taken into account. Unless otherwise indicated, temperatures are in Celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI and used without further purification unless otherwise indicated.

[0122] Unless otherwise specified, the reactions described below were carried out under positive pressure of nitrogen or argon, or in anhydrous solvent using a drying tube, the reaction flasks were fitted with septums for the introduction of substances and reagents by syringe, and the glassware was oven-dried and / or heat-dried.

[0123] 1 The 1H NMR spectrum was recorded using an Agilent instrument operating at 400 MHz. 11H NMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone, or (CD3)2CO as solvents, with tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm, CD3OD: 3.31 ppm, D2O: 4.79 ppm, d6-DMSO: 2.50 ppm, d6-acetone: 2.05 ppm, (CD3)2CO: 2.05 ppm) as a reference. When peak multiplicity is reported, the following abbreviations are used: s (singular), d (double), t (tripular), q (quadular), qn (quintular), sx (sextuplet), m (multiple), br (broad), dd (double double), dt (double triple). Coupling constants are reported in Hertz (Hz) where indicated.

[0124] LC-MS spectrometer (Agilent 1260) Detector: MWD (190~400nm), Mass detector: 6120 SQ Mobile phase: A: Acetonitrile containing 0.1% formic acid, B: Water containing 0.1% formic acid Column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 μm Gradient method: Flow rate: 1.8 mL / min Time (minutes) A(%) B(%) 0.00 5 95 1.5 95 5 2.0 95 5 2.1 5 95 3.0 5 95

[0125] Preparative HPLC was performed at room temperature using a column (150 × 21.2 mm inner diameter, 5 μm, Gemini NX-C18) at various flow rates and injection volumes, and UV detection was performed at 214 nm and 254 nm.

[0126] Preparation of intermediates: Intermediate 2-1:2-(4-ethyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane. [ka]

[0127] Step 1: 4-ethyl-2-(2-isopropylphenyl)-3-oxopiperazine-1-carboxylate tert-butyl.

[0128] 2-(2-isopropylphenyl)-3-oxopiperazine-1-carboxylate tert-butyl (2.0 g, 6.28 mmol) was dissolved in THF (20 mL) and NaH (301.47 mg, 7.54 mmol) was added at 0°C. The mixture was stirred at 0°C for 10 minutes, and then C2H5I (1.18 g, 7.54 mmol) was added at 5°C. The mixture was stirred at 50°C for 16 hours. The reaction mixture was poured into H2O (20 mL) and extracted with siRNA (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. Compound 4-ethyl-2-(2-isopropylphenyl)-3-oxopiperazine-1-carboxylate tert-butyl (1.7 g, yield: 78%) was obtained as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.36(m,1H),7.31-7.28(m,1H),7.15-7.10(m,1H),7.09-7.06(m,1H),5.97(s,1H),3.75-3.64(m ,1H),3.62-3.53(m,2H),3.46-3.27(m,4H),1.46(s,9H),1.29(m,3H),1.25-1.23(m,3H),1.18(m,3H).

[0129] Step 2: 1-Ethyl-3-(2-isopropylphenyl)piperazine-2-one.

[0130] A mixture of DCM (10 mL) containing 4-ethyl-2-(2-isopropylphenyl)-3-oxopiperazine-1-carboxylate tert-butyl (1.7 g, 4.91 mmol) and TFA (10 mL) was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (10 mL), and Na2CO3 was added to adjust the pH to 9. The mixture was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Compound 1-ethyl-3-(2-isopropylphenyl)piperazine-2-one (1.2 g, yield: 99%) was obtained as a yellow oil. MS(ESI, m / e)[M+1] + 247.1.

[0131] Step 3: 2-(4-ethyl-2-(2-isopropylphenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0132] A solution containing 1-ethyl-3-(2-isopropylphenyl)piperazine-2-one (1.2 g, 4.87 mmol) and 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.4 g, 5.85 mmol) in DCE (20 mL) was prepared by adding AcOH (585 mg, 9.74 mmol) and NaBH(OAc)3 (2.06 g, 9.74 mmol) at 20°C. The mixture was stirred at 50°C for 12 hours. The reaction mixture was poured into an aqueous solution of Na2CO3 (20 mL) and extracted with DCM (20 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC to obtain 2-(4-ethyl-2-(2-isopropylphenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, yield: 52%) as a yellow oil. MS(ESI,m / e)[M+1] + 470.3.

[0133] Step 4: 2-(4-ethyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0134] A mixture containing 1.2 g, 2.56 mmol of 2-(4-ethyl-2-(2-isopropylphenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl in BH3.THF (10 mL) was stirred at 70°C for 12 hours. The reaction mixture was deactivated with 10 mL of MeOH at 0°C and stirred at 25°C for 30 minutes. The mixture was concentrated under reduced pressure to obtain 1.1 g, crude 2-(4-ethyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl as a colorless oil. MS(ESI,m / e)[M+1] + 456.3.

[0135] Step 5: 2-(4-ethyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0136] A mixture of DCM (5 mL) containing 2-(4-ethyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.1 g, 2.41 mmol) and TFA (5 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA conditions). The residue was diluted with H2O (10 mL) and Na2CO3 was added to bring the pH to 9. The mixture was extracted with ELISA (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Compound 2-(4-ethyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (440 mg, yield: 51%) was obtained as a yellow oil. 1H NMR(400MHz,CDCl3)δ ppm:7.50(m,1H),7.26-7.20(m,2H),7.16-7.10(m,1H),3.66(m,2H),3.45-3.35 (m,1H),3.01(t,2H),2.94-2.88(m,1H),2.75-2.61(m,5H),2.46-2.38(m,2H),2 .35-2.21(m,2H),2.11(t,1H),1.79(m,1H),1.74-1.65(m,1H),1.49-1.37(m,4H ),1.32(m,1H),1.24(d,J=6.8Hz,3H),1.20(d,J=6.8Hz,3H),1.10-1.05(m,3H). MS(ESI,m / e)[M+1] + 356.2.

[0137] Intermediate 4-1:2-(4-cyclopropyl-2-(2-isopropylphenyl)piperazine-1-yl)-7-azaspiro[3.5]nonane. [ka]

[0138] Step 1: 2-(4-cyclopropyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0139] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.5 g, 3.4 mmol) in MeOH (20 mL), (1-ethoxycyclopropoxy)trimethylsilane (2.96 g, 17 mmol), HOAc (1.43 g, 23.8 mmol), 4A MS (500 mg), and NaBH3CN (641 mg, 10.2 mmol) were added. The mixture was stirred at 25°C for 12 hours. The mixture was poured into an aqueous solution of NaHCO3 (20 mL) and extracted with siRNA (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 20 / 1 to 10 / 1) to obtain 2-(4-cyclopropyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.1 g, yield: 70%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.31-7.28(m,1H),7.26-7.22(m,1H),7.11(m,1H),6.99(d,J=8.0Hz,1H),4.99(br t, 1H),4.26-4.14(m,1H),3.49-3.42(m,1H),3.38-3.32(m,1H),3.39-3.31(m,1H),3.30-3.12(m,6H),3.07(m,1H),2.71(m,1H),2.20(br s, 1H), 1.98(br t, 1H), 1.84(br s, 1H), 1.64 (m, 2H), 1.41 (s, 9H), 1.39-1.32 (m, 3H), 1.29 (m, 6H), 0.45-0.39 (m, 1H), 0.34 (m, 2H), -0.01 (br s, 1H).

[0140] Step 2: 2-(4-cyclopropyl-2-(2-isopropylphenyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0141] A mixture of 2-(4-cyclopropyl-2-(2-isopropylphenyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.1 g, 2.28 mmol) and BH3.THF (10 mL, 10 mmol) was heated at 70°C for 12 hours. After cooling to 0°C, the mixture was carefully deactivated with MeOH (10 mL). The mixture was concentrated under vacuum to obtain 2-(4-cyclopropyl-2-(2-isopropylphenyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.8 g, yield: 80%) as a yellow oil, which was used in the next step without further purification. MS(ESI,m / e)[M+1] + 468.4.

[0142] Step 3: 2-(4-cyclopropyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0143] 2-(4-cyclopropyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (800 mg, 1.7 mmol) was dissolved in DCM (30 mL) and TFA (10 mL) was added. The mixture was stirred at 25°C for 2 hours. After concentration under reduced pressure, the residue was dissolved in water (20 mL). The mixture was then extracted with siRNA (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(4-cyclopropyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (405 mg, yield: 64%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.52(br s, 1H),7.26-7.19(m,2H),7.16-7.11(m,1H),3.57(m,1H),3.38(m,1H),3.03(br t, 2H), 2.94-2.87 (m, 1H), 2.81 (m, 1H), 2.67-2.58 (m, 4H), 2.56-2.48 (m, 1H), 2.39 (br t, 1H), 2.22 (br t, 1H), 1.93 (br s, 1H), 1.75 (br s, 1H), 1.68 (m, 1H), 1.64-1.60 (m, 1H), 1.42-1.28 (m, 6H), 1.24 (m, 3H), 1.20 (m, 3H), 0.44 (m, 2H), 0.41 (m, 2H). MS(ESI,m / e)[M+1] + 368.3.

[0144] Intermediate 5-1:2-(4-cyclobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane. [ka]

[0145] Step 1: 2-(4-cyclobutyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0146] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) in DCE (20 mL), cyclobutanone (0.24 g, 3.40 mmol) and HOAc (0.27 g, 4.52 mmol) were added. After stirring at 25°C for 1 hour, NaBH(OAc)3 (0.96 g, 4.52 mmol) was added. The mixture was stirred at 25°C for 12 hours. Then, an aqueous solution of NH4Cl (20 mL) was added to the mixture, and the mixture was extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1) to obtain 2-(4-cyclobutyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.85 g, yield: 76%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.33-7.27(m,2H),7.19-7.14(m,1H),7.08(m,1H),5.05(m,1H),3.29-3.10(m,8H),2.81-2.72(m,2H),2.35(m,1H),2.25 -2.19(m,1H),2.04-1.75(m,6H),1.68-1.52(m,5H),1.41(s,9H),1.38-1.35(m,2H),1.29(d,J=6.8Hz,3H),1.27-1.25(m,3H).

[0147] Step 2: 2-(4-cyclobutyl-2-(2-isopropylphenyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl. A mixture of 2-(4-cyclobutyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (850 mg, 1.71 mmol) and BH3.THF (20 mL, 17.1 mmol) was heated at 70°C for 12 hours. Then, MeOH (10 mL) was carefully added to the mixture, and it was concentrated under vacuum to obtain 2-(4-cyclobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (800 mg, yield: 97%) as a yellow oil, which was used without further purification. MS(ESI,m / e)[M+1] + 482.4.

[0148] Step 3: 2-(4-cyclobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0149] 2-(4-cyclobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (700 mg, 1.45 mmol) was dissolved in MeOH (20 mL) and HCl / MeOH (10 mL) was added. The mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain 2-(4-cyclobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (400 mg, yield: 83%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:8.84(m,2H),8.11(br s, 1H),7.45(m,2H),7.31(m,1H),5.32(br s, 1H),3.60-3.48(m,4H),3.38(m,4H),2.84-2.75(m,4H),2.44-2.34(m,3H),2.24-2.13(m,4H),1.77-1.60(m,5H),1.52(br s, 2H), 1.44-1.41 (m, 2H), 1.29 (d, J=6.8Hz, 3H), 1.18 (d, J=6.8Hz, 3H). MS(ESI,m / e)[M+1] + 382.4.

[0150] Intermediate 6-1:2-(2-(2-isopropylphenyl)-4-(oxetan-3-yl)piperazine-1-yl)-7-azaspiro[3.5]nonane [ka]

[0151] Step 1: 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0152] A mixture containing 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (3.6 g, 8.15 mmol) in BH3.THF (40 mL) was stirred at 70°C for 12 hours. The reaction mixture was inactivated with MeOH (40 mL) at 0°C and stirred at 25°C for 30 minutes. The mixture was concentrated to obtain 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (3.6 g, crude) as a white solid. MS(ESI, m / e)[M+1] + 428.3.

[0153] Step 2: 2-(2-(2-isopropylphenyl)-4-(oxetan-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0154] 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.34 mmol) and oxetane-3-one (219.08 mg, 3.04 mmol) were dissolved in MeOH (20 mL), to which NaBH3CN (191.04 mg, 3.04 mmol) was added. The mixture was stirred at 45°C for 36 hours. The reaction mixture was diluted with Na2CO3 aqueous solution (40 mL) and extracted with ELISA (40 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. Compound 2-(2-(2-isopropylphenyl)-4-(oxetan-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (420 mg, yield: 37%) was obtained as a yellow oil. MS(ESI,m / e)[M+1] + 484.3.

[0155] Step 3: 2-(2-(2-isopropylphenyl)-4-(oxetan-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0156] A mixture of DCM (3 mL) containing 2-(2-(2-isopropylphenyl)-4-(oxetan-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (420 mg, 868.33 umol) and TFA (1 mL) was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA conditions). The residue was diluted with H2O (5 mL), Na2CO3 was added to bring the pH to 9, and extracted with siRNA (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(oxetan-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane (203 mg, yield: 61%) as a yellow oil. 1H NMR(400MHz,CDCl3)δ ppm:7.52-7.41(m,1H),7.27-7.19(m,2H),7.16-7.11(m,1H),4.71-4.62(m,2H),4.62-4.55(m,2H ),3.75-3.63(m,1H),3.53-3.45(m,1H),3.44-3.35(m,1H),3.11-3.02(m,1H),2.98-2.89(m,1H),2 .84(m,1H),2.72-2.57(m,4H),2.53(m,1H),2.33(m,1H),2.25-2.16(m,1H),2.10-2.04(m,1H),1.9 2-1.75(m,4H),1.72-1.63(m,1H),1.44-1.31(m,4H),1.27(d,J=6.8Hz,3H),1.21(d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 384.2.

[0157] Intermediate 6-1a: 2-(2-(2-isopropylphenyl)-4-(oxetan-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane was purified by SFC (instrument: Waters SFC 80 preparative SFC; column: Chiralcel OD, 250 × 30 mm inner diameter 10 μm; mobile phase: A in CO2 and B in MeOH (0.1% NH3.H2O); gradient: B%=30% no-gradient mode; flow rate: 60 g / min; wavelength: 220 nm; column temperature: 40 °C; system back pressure: 100 bar). [ka]

[0158] (R or S)-2-(2-(2-isopropylphenyl)-4-(oxetan-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane (728 mg, retention time: 1.40 min) was obtained, with a yield of 32.1%. 1H NMR(400MHz,CDCl3)δ ppm:7.45(d,J=6.0Hz,1H),7.27-7.19(m,2H),7.16-7.08(m,1H),6.45-6.05(m,1H),4.72-4.62(m,2H),4.61-4. 52(m,2H),3.68(d,J=9.0Hz,1H),3.48(m,1H),3.37(s,1H),3.01(d,J=11.2Hz,1H),2.97-2.68(m,6H),2.53(d,J =11.2Hz,1H),2.35-2.25(m,1H),2.24-2.13(m,1H),2.05(t,J=10.6Hz,1H),1.82(d,J=3.4Hz,1H),1.76-1.68(m ,1H),1.65-1.45(m,4H),1.38-1.29(m,1H),1.25(d,J=6.8Hz,3H),1.20(d,J=6.3Hz,3H),1.15(d,J=5.1Hz,1H). MS(ESI,m / e)[M+1] + 384.2.

[0159] Intermediate 6-1b: (S or R)-2-(2-(2-isopropylphenyl)-4-(oxetan-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane (649 mg, retention time: 1.51 min, yield: 28.6%) was obtained. MS(ESI,m / e)[M+1] + 384.2.

[0160] Intermediate 7-1:2-(4-cyclopentyl-2-(2-isopropylphenyl)piperazine-1-yl)-7-azaspiro[3.5]nonane. [ka]

[0161] Step 1: 2-(4-cyclopentyl-2-(2-isopropylphenyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0162] To a 15 mL solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) in DCE (15 mL), cyclopentanone (285.7 mg, 3.40 mmol) and AcOH (272.0 mg, 5.57 mmol) were added over 30 minutes at 25°C, followed by the addition of NaBH(OAc)3 (1.44 g, 6.79 mmol) at 25°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into a 50 mL aqueous solution of NaHCO3 and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 10 / 1 to 0 / 1) to obtain 2-(4-cyclopentyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.96 mmol, yield: 86%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.33-7.28(m,1H),7.25(br s,1H),7.16(m,1H),7.09(s,1H),5.06(br s, 1H),3.37-3.08(m,7H),3.00-2.89(m,1H),2.58-2.43(m,2H),2.27-2.18(m,1H),2.04-1.95(m,1H),1.94-1.83(m,1H),1.74(br s, 2H), 1.67-1.46 (m, 8H), 1.42 (s, 9H), 1.40-1.31 (m, 4H), 1.31-1.26 (m, 7H), 1.25-1.09 (m, 2H).

[0163] Step 2: 2-(4-cyclopentyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0164] 2-(4-cyclopentyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.96 mmol) was added to a mixture containing THF (10 mL) and BH3.THF (20 mL, 1 M) at 25 °C. The mixture was stirred at 70 °C for 12 hours. The reaction mixture was cooled to 0-5 °C. Then, MeOH (10 mL) was added dropwise at 5 °C to deactivate the reaction product. The mixture was concentrated under reduced pressure to obtain 2-(4-cyclopentyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, crude) as a white solid, which was used directly in the next step without further reaction. MS(ESI, m / e)[M+1] + 496.5.

[0165] Step 3: 2-(4-cyclopentyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0166] 2-(4-cyclopentyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.02 mmol) was added to a 5 mL MeOH solution with HCl / MeOH (10 mL, 4 M) at 25°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to remove most of the MeOH. Then, an HCl / H2O (1 M) solution was added to adjust the pH to 2-3, and the mixture was extracted with HCl (10 mL). Saturated Na2CO3 was added to the aqueous phase to adjust the pH to 9-10, and the mixture was extracted with HCl (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(4-cyclopentyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (577 mg, 1.46 mmol, yield: 72%) as a yellow oil. 1H NMR(400MHz,CDCl3)δ ppm:7.52(br d,J=7.2Hz,1H),7.26-7.10(m,3H),3.67(m,1H),348-3.33(m,1H),3.05(m,2H) ,2.96-2.86(m,1H),2.78(m,1H),2.69-2.57(m,4H),2.48(m,1H),2.36-2.24(m, 2H),2.18-2.10(m,2H),1.91-1.85(m,1H),1.77(m,2H),1.72-1.63(m,3H),1.5 7-1.49(m,2H),1.49-1.29(m,8H),1.25(d,J=6.8Hz,3H),1.20(d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 396.4.

[0167] Intermediate 8-1:2-(2-(2-isopropylphenyl)-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane. [ka]

[0168] Step 1: 2-(2-(2-isopropylphenyl)-6-oxo-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0169] 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) and dihydrofuran-3(2H)-one (292.4 mg, 3.40 mmol) were mixed in a 10 mL DCE solution to which HOAc (271.9 mg, 4.53 mmol) was added. The solution was stirred at 25°C for 5 minutes, and NaBH(OAc)3 (1.06 g, 4.98 mmol) was added. The solution was stirred at 25°C for 12 hours. An aqueous solution of NaHCO3 was added to the reaction product to adjust the pH to 7, and the mixture was extracted with DCM (10 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 10 / 1 to 1 / 1) to obtain 2-(2-(2-isopropylphenyl)-6-oxo-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, yield: 86.3%) as a yellow oil.

[0170] Step 2: 2-(2-(2-isopropylphenyl)-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl. 2-(2-(2-isopropylphenyl)-6-oxo-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.95 mmol) was dissolved in THF (15 mL) and BH3.THF (15 mL) was added. The solution was stirred at 70°C for 12 hours. After cooling to room temperature, MeOH (10 mL) was added to deactivate the reaction product. The reaction product was evaporated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (700 mg, crude) as a white solid, which was used without further purification. MS(ESI, m / e)[M+1] + 498.4.

[0171] Step 3: 2-(2-(2-isopropylphenyl)-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0172] 2-(2-(2-isopropylphenyl)-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.7 g, 1.41 mmol) was added to a 10 mL solution of DCM with 5 mL of TFA. The solution was then stirred at 25°C for 2 hours. The mixture was poured into an aqueous solution of NaHCO3 to adjust the pH to 7 and extracted with 3 x 10 mL of DCM. The combined organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane (342 mg) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.50(s,1H),7.28-7.14(m,4H),3.93-3.66(m,5H),3.03-2.64(m,4H),2.64-2.8 5(m,5H),2.77-2.46(m,3H),2.17-1.66(m,7H),1.45-1.36(m,4H),1.20-1.36(m,3H). MS(ESI,m / e)[M+1] + 398.3.

[0173] Intermediate 9-1:2-(4-cyclohexyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane. [ka]

[0174] Step 1: 2-(4-cyclohexyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0175] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) in DCE (20 mL), cyclohexanone (0.34 g, 3.40 mmol) and HOAc (0.27 g, 4.52 mmol) were added. After stirring at 25°C for 1 hour, NaBH(OAc)3 (0.96 g, 4.52 mmol) was added. The mixture was stirred at 25°C for 12 hours. Then, an aqueous solution of NH4Cl (20 mL) was added to the mixture, and the mixture was extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1) to obtain 2-(4-cyclohexyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (750 mg, yield: 63%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.32-7.28(m,1H),7.25(br s, 1H),7.14(t, 1H),7.09-7.06(m,1H),5.01(br s, 1H),4.26-4.15(m,1H),3.38(m,2H),3.26-3.13(m,6H),2.95(m,1H),2.62(m,1H),2.20(br s, 2H),1.98(br s, 1H),1.84(br s, 1H),1.68(br s, 3H), 1.61 (br s, 6H), 1.42 (s, 10H), 1.35 (m, 2H), 1.31-1.28 (m, 6H), 1.12 (br s, 2H).

[0176] Step 2: 2-(4-cyclohexyl-2-(2-isopropylphenyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0177] A mixture of 2-(4-cyclohexyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.75 g, 1.43 mmol) and BH3.THF (14 mL, 14.3 mmol) was heated at 70°C for 12 hours. Then, MeOH (10 mL) was carefully added to the mixture, and it was concentrated under vacuum to obtain 2-(4-cyclohexyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.7 g, yield: 96%) as a yellow oil, which was used without further purification. MS(ESI,m / e)[M+1] + 510.4.

[0178] Step 3: 2-(4-cyclohexyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0179] 2-(4-cyclohexyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (700 mg, 1.37 mmol) was added to a 20 mL MeOH solution with HCl / MeOH solution (10 mL). The mixture was stirred at 25°C for 1 hour. After removing the solvent, the residue was dissolved in water (20 mL). The mixture was adjusted to pH 9-10 using an aqueous Na2CO3 solution. The mixture was extracted with siRNA (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(4-cyclohexyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (380 mg, yield: 68%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.50(m,1H),7.26-7.19(m,2H),7.15-7.11(m,1H),3.61(br d,J=8.4Hz,1H),3.40(br s, 1H), 3.05 (m, 1H), 2.97 (m, 1H), 2.93-2.87 (m, 1H), 2.75-2.56 (m, 6H), 2.50 (m, 1H), 2.36-2.18 (m, 5H), 1.89 (br s, 2H), 1.76 (br s, 3H), 1.69 (m, 1H), 1.60 (m, 1H), 1.39-1.30 (m, 5H), 1.25 (m, 3H), 1.20 (m, 7H). MS(ESI,m / e)[M+1] + 410.4.

[0180] Intermediate 10-1:2-(2-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazine-1-yl)-7-azaspiro[3.5]nonane. [ka]

[0181] Step 1: 2-(2-(2-isopropylphenyl)-6-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0182] A mixture containing 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol), dihydro-2H-pyran-4(3H)-one (340.06 mg, 3.40 mmol), and HOAc (271.97 mg, 4.53 mmol) in DCE (20 mL) was stirred at 25°C for 30 minutes. Then, NaBH(OAc)3 (1.44 g, 6.79 mmol) was added to the mixture in several batches, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into ice water (20 mL) and the pH was adjusted to 8 with NaHCO3. The resulting mixture was extracted with DCM (30 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 3 / 1 to 1 / 1) to obtain 2-(2-(2-isopropylphenyl)-6-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.05 g, yield: 88%) as a yellow solid. 1 1H NMR (400MHz, CDCl3)δ ppm:7.30(m,1H),7.14(m,1H),7.09-7.01(m,1H),5.02(m,1H),4.25(s,1H),3. 95-3.81(m,2H),3.54-3.04(m,10H),2.98-2.93(m,1H),2.70-2.65(m,1H),2.4 5-2.34(m,1H),2.26-2.17(m,1H),1.97(m,1H),1.82(s,1H),1.66-1.59(m,2H) ,1.57-1.52(m,1H),1.46-1.40(m,12H),1.37-1.33(m,2H),1.32-1.27(m,6H).

[0183] Step 2: 2-(2-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl

[0184] 2-(2-(2-isopropylphenyl)-6-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (900 mg, 1.71 mmol) was added dropwise to a solution of THF (15 mL) with BH3.THF (30 mL, 30 mmol) at 20°C. The mixture was heated to 70°C for 20 hours. The reaction product was deactivated with ethanol (5 mL) and concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (876 mg, crude) as a colorless oil, which was used directly in the next step without further purification. MS(ESI,m / e)[M+1] + 512.4.

[0185] Step 3: 2-(2-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0186] 2-(2-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (900 mg, 1.76 mmol) was added to a 2 mL MeOH solution with HCl / MeOH solution (20 mL, 4 M). The solution was stirred at 25°C for 4 hours. The reaction solution was concentrated under vacuum. The crude product was purified by preparative HPLC and lyophilization. The residue was liberated with saturated NaHCO3 (20 mL) and extracted with siRNA (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane (390 mg, yield: 54%) as a white viscous substance. 1H NMR(400MHz,CDCl3)δ ppm:7.50(d,J=5.6Hz,1H),7.27-7.20(m,2H),7.17-7.11(m,1H),4.03-4. 00(td, 2H), 3.63(m, 1H), 3.35-3.25(m, 3H), 3.13-2.99(m, 2H), 2.91(m, 1H) ,2.75(m,1H),2.70-2.51(m,4H),2.46-2.33(m,2H),2.33-2.20(m,2H),1. 90-1.72(m,4H),1.71-1.63(m,1H),1.65-1.55(m,2H),1.48-1.01(m,14H). MS(ESI,m / e)[M+1] + 412.5.

[0187] Intermediate 11-1:2-(4-isobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane. [ka]

[0188] Step 1: 2-(4-isobutyl-2-(2-isopropylphenyl)-3-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0189] 2-(2-(2-isopropylphenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (2.0 g, 4.53 mmol) was added to a solution of THF (20 mL) with NaH (362.28 mg, 9.06 mmol) at 0°C. The mixture was stirred at 0°C for 10 minutes. Then, 1-iodo-2-methylpropane (1.67 g, 9.06 mmol) was added at 0°C. The mixture was stirred at 65°C for 48 hours. The reaction mixture was poured into H2O (20 mL) and extracted with siRNA (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. Compound 2-(4-isobutyl-2-(2-isopropylphenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.1 g, 2.21 mmol, yield: 48%) was obtained as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.27-7.21(m,3H),7.12-7.06(m,1H),4.81(m,1H),4.09(s,1H),3.52-3.39(m, 2H),3.29(m,1H),3.27-3.23(m,2H),3.19-3.15(m,2H),3.13(m,1H),2.97(m,1H),2 .38(m,1H),1.96-1.88(m,1H),1.71-1.60(m,2H),1.45(m,2H),1.42(s,9H),1.41-1 .37(m,2H),1.32(s,1H),1.30(d,J=6.8Hz,3H),1.18(d,J=6.8Hz,3H),1.14(m,6H).

[0190] Step 2: 2-(4-isobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0191] A mixture containing 1.1 g, 2.21 mmol of 2-(4-isobutyl-2-(2-isopropylphenyl)-3-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl in BH3.THF (10 mL) was stirred at 70°C for 12 hours. The reaction mixture was deactivated with 5 mL of MeOH at 0°C and stirred at 25°C for 30 minutes. The mixture was then concentrated under reduced pressure to obtain 1.05 g, crude 2-(4-isobutyl-2-(2-isopropylphenyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl as a colorless oil. MS(ESI, m / e)[M+1] + 484.3.

[0192] Step 3: 2-(4-isobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0193] A mixture containing 2-(4-isobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.05 g, 2.17 mmol) in HCl / siRNA (10 mL) was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (HCl conditions). The residue was diluted with H₂O (10 mL) and Na₂CO₃ was added to bring the pH to 9. The mixture was extracted with siRNA (10 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Compound 2-(4-isobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (461 mg, 1.18 mmol, yield: 54.26%) was obtained as a yellow oil. 11H NMR (400MHz, CDCl3)δ ppm:7.50(d,J=4.5Hz,1H),7.27-7.19(m,2H),7.16-7.10(m,1H),3.62(m,1H) ,3.41(m,1H),2.99(m,1H),2.95-2.85(m,2H),2.71-2.54(m,5H),2.34-2.19( m,2H),2.14-2.04(m,3H),1.85(s,2H),1.80-1.72(m,2H),1.72-1.64(m,1H), 1.43-1.29(m,5H),1.27(d,J=6.8Hz,3H),1.21(d,J=6.8Hz,3H),0.88(m,6H). MS(ESI,m / e)[M+1] + 384.4.

[0194] Intermediate 12-1:2-(2-(2-isopropylphenyl)-4-neopentylpiperazine-1-yl)-7-azaspiro[3.5]nonane [ka]

[0195] Step 1: 2-Isopropylbenzaldehyde.

[0196] 1-bromo-2-isopropylbenzene (20 g, 0.1 mol) was dissolved in THF (200 mL) and n-BuLi (44 mL, 0.11 mol, 2.5 M in hexane) was added dropwise at -78 °C. After stirring at -78 °C for 1 hour, DMF (8.0 g, 0.11 mol) was added to the mixture. The mixture was stirred at -60 °C for 1 hour. Then, aqueous NH4Cl solution (1 M, 100 mL) was added to the mixture. The mixture was extracted with ELISA (300 mL x 3). The combined organic phases were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE). Compound 2-isopropylbenzaldehyde (14 g, yield: 94%) was obtained as a yellow oil. 1H NMR(400MHz,CDCl3)δ ppm:10.38(s,1H),7.83(dd,J=8.0Hz,1.6Hz,1H),7.60-7.53(m,1H),7.49-7.45(m,1H),7.36(t,1H),3.99(t,1H),1.32(d,J=6.8Hz,6H).

[0197] Step 2: (E)-N-(2-isopropylbenzylidene)-2-methylpropane-2-sulfonamide.

[0198] 2-Isopropylbenzaldehyde (20 g, 0.135 mol) was dissolved in THF (200 mL) and 2-methylpropane-2-sulfonamide (18 g, 0.148 mmol) was added. After cooling to 0°C, Ti(OEt)4 (62 g, 0.27 mol) was added. The mixture was stirred at 25°C for 12 hours. The reaction mixture was carefully deactivated with water (100 mL) and then filtered through a Celite pad. The filtrate was extracted with siRNA (100 mL x 3) and washed with brine (100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 100 / 1~20 / 1). Compound (E)-N-(2-isopropylbenzylidene)-2-methylpropane-2-sulfonamide (32.5 g, yield: 96%) was obtained as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:9.00(s,1H),7.96(dd,J=8.0Hz,2.0Hz,1H),7.51-7.45(m,1H),7.44-7.40(m,1H),7.32-7.27(m,1H),3.72(t,1H),1.33-1.25(m,15H).

[0199] Step 3: N-(1-(2-isopropylphenyl)-2-nitroethyl)-2-methylpropane-2-sulfonamide.

[0200] (E)-N-(2-isopropylbenzylidene)-2-methylpropane-2-sulfonamide (32 g, 0.13 mol) was added in several batches to a solution of THF (300 mL) with t-BuOK (21 g, 0.19 mol) at 0°C. After stirring at 0°C for 1 hour, nitromethane (77 g, 1.27 mmol) was added. The mixture was stirred at 25°C for 12 hours. Then, water (100 mL) was added to the mixture, and the mixture was extracted with siRNA (100 mL x 3). The organic layer was dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA (v / v) = 10 / 1 to 2 / 1) to obtain N-(1-(2-isopropylphenyl)-2-nitroethyl)-2-methylpropane-2-sulfonamide (26.5 g, yield: 67%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.40-7.34(m,2H),7.34-7.28(m,1H),7.26-7.21(m,1H),5.53-5.44(m,1H),4.88-4.78(m,1H ),4.76-4.65(m,1H),4.30-4.20(m,1H),3.35-3.22(m,1H),1.34-1.26(m,6H),1.27-1.20(m,9H).

[0201] Step 4: N-(2-amino-1-(2-isopropylphenyl)ethyl)-2-methylpropane-2-sulfonamide

[0202] Raney Ni (5.0 g) was added to a solution of N-(1-(2-isopropylphenyl)-2-nitroethyl)-2-methylpropane-2-sulfonamide (23 g, 0.074 mol) in MeOH (200 mL). The mixture was stirred at 25 °C under an H2 (15 psi) atmosphere for 12 hours. After filtration through a Celite pad, the filtrate was concentrated under reduced pressure to obtain N-(2-amino-1-(2-isopropylphenyl)ethyl)-2-methylpropane-2-sulfonamide (17.6 g, yield: 84%) as a brown solid, which was used in the next step without further purification. MS(ESI,m / e)[M+1] + 283.1.

[0203] Step 5: N-(2-((tert-butylsulfinyl)amino)-2-(2-isopropylphenyl)ethyl)-4-methylbenzenesulfonamide.

[0204] TEA (24.5 g, 0.243 mol) was added to a solution of N-(2-amino-1-(2-isopropylphenyl)ethyl)-2-methylpropane-2-sulfonamide (23 g, 0.081 mol) in DCM (300 mL). After cooling to 0°C, TsCl (17 g, 0.09 mol) was added in several portions. The mixture was stirred at 25°C for 2 hours. Then, an aqueous solution of NH4Cl (1 M, 100 mL) was added to the mixture, and the mixture was extracted with DCM (100 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA (v / v) = 20 / 1 to 5 / 1) to obtain N-(2-((tert-butylsulfinyl)amino)-2-(2-isopropylphenyl)ethyl)-4-methylbenzenesulfonamide (23 g, yield: 65%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.79(d,J=8.4Hz,2H),7.32-7.26(m,4H),7.20-7.12(m,1H),4.82-4.69(m,1H),4.25(br s,1H),3.14(br d,J=7.6Hz,4H),3.07-2.97(m,1H),2.41(s,3H),1.42(t,6H),1.23(s,9H).

[0205] Step 6: N-(2-amino-2-(2-isopropylphenyl)ethyl)-4-methylbenzenesulfonamide.

[0206] To a solution of N-(2-((tert-butylsulfinyl)amino)-2-(2-isopropylphenyl)ethyl)-4-methylbenzenesulfonamide (5.0 g, 11 mmol) in MeOH (20 mL), MeOH (10 mL, 4 M) containing HCl (gas) was added. The mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure. The residue was dissolved in water (50 mL), and then aqueous Na2CO3 solution was added to adjust the pH to 9. The mixture was extracted with ELISA (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain N-(2-amino-2-(2-isopropylphenyl)ethyl)-4-methylbenzenesulfonamide (3.8 g, yield: 99%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.74(d,J=8.0Hz,2H),7.32-7.23(m,5H),7.21-7.13(m,1H),4.36(m,1H),3 .17-3.03(m,2H),2.93(dd,J=12.8,8.8Hz,1H),2.43(s,3H),1.21-1.18(m,6H).

[0207] Step 7: 2-((1-(2-isopropylphenyl)-2-(4-methylphenyl)sulfonamide)ethyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0208] To a 50 mL solution of N-(2-amino-2-(2-isopropylphenyl)ethyl)-4-methylbenzenesulfonamide (4.0 g, 0.012 mol) in DCE (50 mL), 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (3.2 g, 0.013 mol) and HOAc (1.44 g, 0.024 mol) were added. After stirring at 25°C for 1 hour, NaBH(OAc)3 (5.1 g, 0.024 mol) was added. The mixture was stirred at 25°C for 12 hours. Then, an aqueous solution of NH4Cl (50 mL) was added to the mixture and extracted with DCM (50 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA (v / v) = 10 / 1 to 5 / 1) to obtain 2-((1-(2-isopropylphenyl)-2-(4-methylphenyl)sulfonamide)ethyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (4.3 g, yield: 64%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.73(d,J=8.0Hz,2H),7.32-7.25(m,4H),7.19-7.13(m,2H),4.02(m,1H),3.30- 3.22(m,4H),3.09-2.98(m,3H),2.88(m,1H),2.43(s,3H),2.02-1.88(m,2H),1.75(br s, 3H), 1.44 (s, 9H), 1.40 (m, 3H), 1.17 (m, 6H).

[0209] Step 8: 2-(2-chloro-N-(1-(2-isopropylphenyl)-2-(4-methylphenyl)sulfonamide)ethyl)acetamide)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0210] 2-((1-(2-isopropylphenyl)-2-(4-methylphenyl)sulfonamide)ethyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (4.3 g, 7.74 mmol) was added to a THF (50 mL) solution with TEA (1.56 g, 15.48 mmol). After cooling to 0°C, 2-chloroacetyl chloride (0.96 g, 8.51 mmol) was added dropwise. The mixture was stirred at 25°C for 2 hours. The mixture was poured into an NH4Cl aqueous solution (1 M, 50 mL) and extracted with siRNA (50 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 20 / 1 to 5 / 1) to obtain 2-(2-chloro-N-(1-(2-isopropylphenyl)-2-(4-methylphenyl)sulfonamide)ethyl)acetamide)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (4.6 g, yield: 94%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.74(d,J=8.0Hz,2H),7.32-7.27(m,4H),7.20(m,1H),7.15-7.10(m,1H),5.31-5.20(m,1H),5.08(br s, 1H),4.22(d,J=2.8Hz,2H),4.13(m,2H),3.30(m,2H),3.23(m,3H),2.38(s,3H),2.05(s,3H),1.65(br s, 3H), 1.48-1.45(m, 3H), 1.44(s, 9H), 1.27(m, 6H).

[0211] Step 9: 2-(2-(2-isopropylphenyl)-6-oxo-4-tosylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0212] 2-(2-chloro-N-(1-(2-isopropylphenyl)-2-(4-methylphenyl)sulfonamide)ethyl)acetamide)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (4.6 g, 7.28 mmol) was dissolved in DMF (50 mL) and K2CO3 (2.0 g, 14.55 mmol) was added. The mixture was stirred at 60°C for 1 hour. Then, water (50 mL) was added to the mixture, and the mixture was extracted with ELISA (50 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 20 / 1 to 5 / 1) to obtain 2-(2-(2-isopropylphenyl)-6-oxo-4-tosylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (2.6 g, yield: 62%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.47(d,J=8.4Hz,2H),7.36-7.30(m,2H),7.23(d,J=8.4Hz,2H),7.16-7.10(m,1H),6.89(d,J=7.75Hz,1H),5.07(t,1H),4.30(br s, 1H),4.16-4.10(m,1H),3.97-3.88(m,1H),3.81-3.70(m,1H),3.39(m,2H),3.27-3.21(m,2H), 3.21-3.13(m,2H),3.12-3.06(m,1H),2.99-2.85(m,1H),2.41(s,3H),2.22-2.14(m,1H),1.85(br t, 1H), 1.73-1.58 (m, 2H), 1.46 (m, 2H), 1.41 (s, 9H), 1.30-1.26 (m, 6H).

[0213] Step 10: 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0214] Mg (1.07 g, 44.7 mmol) was added to a solution of 2-(2-(2-isopropylphenyl)-6-oxo-4-tosylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (2.6 g, 4.47 mmol) in MeOH (50 mL). The mixture was stirred at 100 °C for 2 hours. The mixture was diluted with water (50 mL) and ethyl acetate (50 mL), and then filtered through a Celite pad. The filtrate was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.3 g, yield: 66%) as a brown oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.40-7.36(d,J=7.2Hz,1H),7.32(t,1H),7.20(t,1H),7.00(d,J=8.0Hz,1H),5.02(br s,1H),4.55(br s, 1H), 3.60 (m, 2H), 3.49 (s, 1H), 3.33 (m, 1H), 3.29-3.24 (m, 2H), 3.21-3.11 (m, 3H), 2.97-2.91 (m, 1H), 2.27-2.20 (m, 1H), 1.90 (br t, 1H), 1.74-1.64 (m, 5H), 1.47-1.44 (m, 2H), 1.42 (s, 9H), 1.29 (t, 6H).

[0215] Step 11: 2-(2-(2-isopropylphenyl)-4-neopentyl-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0216] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) in DCE (20 mL), pivalaldehyde (0.29 g, 3.40 mmol) and HOAc (0.27 g, 4.52 mmol) were added. After stirring at 25°C for 1 hour, NaBH(OAc)3 (0.96 g, 4.52 mmol) was added. The mixture was stirred at 25°C for 12 hours. The mixture was poured into an aqueous solution of NH4Cl (1 M, 20 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 20 / 1 to 5 / 1) to obtain 2-(2-(2-isopropylphenyl)-4-neopentyl-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.68 g, yield: 59%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.29-7.27(m,2H),7.15-7.10(m,2H),4.93(br s, 1H),4.45(br s, 1H),3.55(br d,J=16.76Hz,1H),3.50(s,1H),3.31-3.07(m,8H),2.96(m,1H),2.76(m,1H),2.22(m,1H),2.01(br s,2H),1.94(m,1H),1.74(br s, 2H), 1.49-1.45 (m, 3H), 1.42 (s, 9H), 1.30-1.26 (m, 6H), 0.53 (br s, 9H).

[0217] Step 12: 2-(2-(2-isopropylphenyl)-4-neopentylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0218] A mixture of 2-(2-(2-isopropylphenyl)-4-neopentyl-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (680 mg, 1.33 mmol) and BH3.THF (13 mL, 13.3 mmol) was heated at 70°C for 12 hours. After cooling to 0°C, the mixture was carefully deactivated with MeOH (10 mL). The mixture was concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-neopentylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.6 g, yield: 91%) as a yellow oil, which was used in the next step without further purification. MS(ESI,m / e)[M+1] + 498.4.

[0219] Step 13: 2-(2-(2-isopropylphenyl)-4-neopentylpiperazin-1-yl)-7-azaspiro[3.5]nonane.

[0220] A solution of 2-(2-(2-isopropylphenyl)-4-neopentylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (600 mg, 1.21 mmol) in MeOH (20 mL) was mixed with HCl / MeOH (10 mL, 4 M). The mixture was stirred at 25°C for 1 hour. After concentration under reduced pressure, the residue was dissolved in water (20 mL). The mixture was adjusted to pH 9-10 with Na2CO3 aqueous solution. The mixture was extracted with siRNA (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-neopentylpiperazin-1-yl)-7-azaspiro[3.5]nonane (400 mg, yield 83.5%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.49(m,1H),7.26-7.18(m,2H),7.15-7.10(m,1H),3.61(m,1H),3.41(br s, 1H), 2.97-2.88 (m, 2H), 2.82 (m, 1H), 2.68-2.52 (m, 6H), 2.39 (br t, 1H), 2.32-2.26 (m, 1H), 2.11-2.01 (m, 3H), 1.78-1.72 (m, 1H), 1.69 (m, 1H), 1.45-1.30 (m, 5H), 1.28 (m, 3H), 1.19 (m, 3H), 0.85 (s, 9H). MS(ESI,m / e)[M+1] + 398.4.

[0221] Intermediate 13-1: 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0222] Step 1: 2-(2-isopropylphenyl)-4-(2-methoxyethyl)-3-oxopiperazine-1-carboxylate tert-butyl.

[0223] 2-(2-isopropylphenyl)-3-oxopiperazine-1-carboxylate tert-butyl (1.5 g, 4.7 mmol) and 1-bromo-2-methoxyethane (0.72 g, 5.2 mmol) were mixed in THF (15 mL) at 20°C, to which NaH (136 mg, 5.6 mmol) was added in several portions. The mixture was stirred at 50°C for 24 hours. The mixture was deactivated with MeOH (2 mL) and concentrated under reduced pressure. The residue was poured into brine (20 mL) and extracted with ELISA (20 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2-isopropylphenyl)-4-(2-methoxyethyl)-3-oxopiperazine-1-carboxylate tert-butyl (1.5 g, crude) as a yellow oil, which was used directly in the next step without further purification.

[0224] Step 2: 3-(2-isopropylphenyl)-1-(2-methoxyethyl)piperazine-2-one. A solution containing 1.4 g, 3.8 mmol of tert-butyl 2-(2-isopropylphenyl)-4-(2-methoxyethyl)-3-oxopiperazine-1-carboxylate in 5 mL of TFA and 5 mL of DCM was stirred at 27°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was poured into 30 mL of saturated NaHCO3 and extracted with 30 mL x 3 of ELISA. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 1.0 g, crude 3-(2-isopropylphenyl)-1-(2-methoxyethyl)piperazine-2-one as a yellow oil, which was used directly in the next step without further purification.

[0225] Step 3: 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0226] To a solution of 3-(2-isopropylphenyl)-1-(2-methoxyethyl)piperazine-2-one (1.0 g, 3.7 mmol) in DCE (10 mL), 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (874 mg, 3.7 mmol) and NaBH(OAc)3 (1.6 g, 7.3 mmol) were added. The mixture was stirred at 27°C for 10 hours. The mixture was poured into saturated NaHCO3 (50 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.6 g, crude) as a yellow oil, which was used directly in the next step without further purification.

[0227] Step 4: 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0228] A solution of 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)-3-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.4 g, 2.8 mmol) in BH3-THF (10 mL) was stirred at 70°C for 10 hours. The mixture was inactivated with MeOH (10 mL) and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (2.4 g, crude) as a yellow oil, which was used directly in the next step without further purification.

[0229] Step 5: 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0230] A solution containing 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.3 g, 2.7 mmol) in TFA (3 mL) and DCM (6 mL) was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA). Compound 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (791 mg, yield: 77%) was obtained as a colorless oil. 1H NMR(400MHz,CH3OH-d4)δ ppm:7.48(br,1H),7.32-7.27(m,1H),7.23(m,1H),7.18-7.09(m,1H),3.74(m,1 H),3.55-3.50(m,2H),3.44(m,1H),3.33-3.31(m,3H),3.09-2.99(m,2H),2.93(m ,1H),2.76-2.69(m,1H),2.67-2.45(m,6H),2.42-2.22(m,3H),1.88-1.79(m,1H) ,1.72-1.63(m,1H),1.44-1.25(m,8H),1.20(d,J=6.8Hz,3H),1.15-1.03(m,1H). MS(ESI,m / e)[M+1] + 386.4.

[0231] Intermediate 13-1a: (R or S)-2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0232] 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane was separated by SFC (apparatus: Waters SFC80 preparative SFC; column: Phenomenex-Cellulose-2 (250 × 30 mm inner diameter, 10 μM); mobile phase: CO2 with A, and MeOH (0.1% NH3, H2O) with B; gradient: B%=40%; flow rate: 70 g / min; wavelength: 220 nm; column temperature: 40 °C; system back pressure: 100 bar). (R or S)-2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (452 ​​mg, retention time: 1.59 min) was obtained, with a yield of 30%. 1H NMR(400MHz,CDCl3)δ ppm:7.50(s,1H),7.25-7.20(m,2H),7.13(m,1H),3.73-3.67(m,1H),3.50(m,2H),3.40(br s, 1H), 3.33 (s, 3H), 3.00 (m, 2H), 2.93-2.87 (m, 1H), 2.74-2.65 (m, 4H), 2.58 (t, 2H) ,2.33(m,2H),2.23-2.14(m,2H),1.80-1.75(m,2H),1.44-1.34(m,6H),1.22(m,6H). MS(ESI,m / e)[M+1] + 386.3.

[0233] Intermediate 13-1b: (S or R)-2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (441 mg, retention time: 1.78 min, yield: 29%) was obtained. MS(ESI,m / e)[M+1] + 386.3.

[0234] Intermediate 15-1:2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0235] Step 1: 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0236] 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol), cyclopentanecarbaldehyde (333 mg, 3.40 mmol), and AcOH (339 mg, 5.66 mmol) were dissolved in DCE (10 mL) and NaBH(OAc)3 (959 mg, 4.53 mmol) was added at 25°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was inactivated with saturated Na2CO3 (10 mL) and extracted with ELISA (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA (v / v) = 50 / 1 to 0 / 1) to obtain 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, yield: 84%) as a pale yellow oil.

[0237] Step 2: 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0238] To a mixture of 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.91 mmol), THF (20 mL) containing BH3.THF (57 mL, 57.28 mmol) was added at 0°C. The mixture was stirred at 80°C for 12 hours. MeOH (20 mL) was added to the reaction solution at 0°C to deactivate the reactants, and the mixture was concentrated under reduced pressure to obtain 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, crude product) as a yellow oil, which was used directly in the next step without further purification.

[0239] Step 3: 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0240] A mixture of 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.96 mmol) was mixed with HCl / MeOH (40 mL) over 2 hours at 0°C. The reaction mixture was poured into saturated Na2CO3 (40 mL) and extracted with ELISA (40 mL x 3). The combined organic phases were washed with brine (40 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (712 mg, yield: 88%) as a pale pink oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.58-7.46(m,1H),7.26-7.19(m,2H),7.17-7.10(m,1H),3.68-3.59 (m,1H),3.42(s,1H),3.03-2.88(m,3H),2.73-2.57(m,5H),2.28(m,4H), 2.16-2.09(m,1H),1.79-1.64(m,9H),1.61-1.56(m,2H),1.41-1.30(m,6 H),1.28-1.25(d,J=6.8Hz,3H),1.20-1.22(d,J=6.8Hz,3H),1.16(m,2H). MS(ESI,m / e)[M+1] + 410.3.

[0241] Intermediate 16-1:2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0242] Step 1: 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0243] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) in DCE (20 mL), cyclohexanecarboaldehyde (0.38 g, 3.40 mmol) and HOAc (0.27 g, 4.52 mmol) were added. After stirring at 25°C for 1 hour, NaBH(OAc)3 (0.96 g, 4.52 mmol) was added. The mixture was stirred at 25°C for 12 hours. Then, an aqueous solution of NH4Cl (20 mL) was added to the mixture, and the mixture was extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1) to obtain 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, yield: 83%) as a yellow solid. MS(ESI,m / e)[M+1] + 538.4.

[0244] Step 2: 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0245] A mixture of 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.86 mmol) and BH3.THF (19 mL, 18.6 mmol) was heated at 70°C for 12 hours. Then, MeOH (10 mL) was carefully added to the mixture. The mixture was concentrated under vacuum to obtain 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.6 g, yield: 65%) as a yellow oil, which was used directly in the next step without further purification. MS(ESI,m / e)[M+1] + 524.4

[0246] Step 3: 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0247] A solution of 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (600 mg, 0.99 mmol) in MeOH (20 mL) was mixed with HCl / MeOH (10 mL, 4 M). The mixture was stirred at 25°C for 1 hour. After removing the solvent, the residue was dissolved in water (20 mL). The pH of the mixture was adjusted to 9-10 using an aqueous solution of Na2CO3. The mixture was extracted with ELISA (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (450 mg, yield: 83%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.49(br s, 1H),7.25-7.19(m,2H),7.15-7.10(m,1H),3.62(m,1H),3.46-3.34(m,1H),3.02( m,1H),3.00(m,1H),2.94-2.86(m,2H),2.66-2.57(m,5H),2.31-2.21(m,2H),2.15- 2.09(m,2H),1.81-1.73(m,3H),1.71-1.63(m,5H),1.45(m,2H),1.35-1.29(m,5H), 1.28-1.25(d,J=6.8Hz,3H),1.21(d,J=6.8Hz,3H),1.16(m,3H),0.91-0.83(m,2H). MS(ESI,m / e)[M+1] + 424.5.

[0248] Intermediate 17-1: 2-(2-(2-isopropylphenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0249] Step 1: 2-(2-(2-isopropylphenyl)-6-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl. To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.06 mmol) in DCE (10 mL), AcOH (339 mg, 5.66 mmol), tetrahydro-2H-pyran-4-carbaldehyde (387 mg, 3.40 mmol), and NaBH(OAc)3 (959 mg, 4.53 mmol) were added at 25°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into saturated Na2CO3 (10 mL) and extracted with siRNA (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA (v / v) = 50 / 1 to 0 / 1) to obtain 2-(2-(2-isopropylphenyl)-6-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, yield: 82%) as a pale yellow oil.

[0250] Step 2: 2-(2-(2-isopropylphenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl. To a mixture of 2-(2-(2-isopropylphenyl)-6-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (700 mg, 1.30 mmol), THF (20 mL) containing BH3.THF (38 mL, 38.91 mmol) was added at 80°C over 12 hours. The reaction mixture was inactivated with MeOH (20 mL) and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (660 mg, crude) as a yellow viscous substance, which was used directly in the next step without further purification.

[0251] Step 3: 2-(2-(2-isopropylphenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane. A mixture of 2-(2-(2-isopropylphenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (700 mg, 1.30 mmol) was added to an HCl / MeOH (40 mL) solution at 0°C over 2 hours. The reaction mixture was poured into saturated Na2CO3 (40 mL). The mixture was extracted with ELISA (40 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (541 mg, yield: 75%) as a pale pink oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.59-7.44(m,1H),7.26-7.19(m,2H),7.17-7.10(m,1H),4.04-3.9 1(m,2H),3.60(m,1H),3.45-3.30(m,3H),3.04-2.97(m,1H),2.96-2.84 (m,2H),2.67-2.57(m,4H),2.31-2.24(m,2H),2.23-2.16(m,2H),2.14- 2.07(m,1H),1.85-1.67(m,5H)1.41-1.28(m,4H),1.21(d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 426.4.

[0252] Intermediate 18-1: 2-(4-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0253] Step 1: 2-(2-(2-isopropylphenyl)-4-(3-(methoxycarbonyl)bicyclo[1.1.1]pentan-1-carbonyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0254] A mixture containing 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (2.5 g, 5.66 mmol), 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (1.16 g, 6.76 mmol), HOBt (1.15 g, 8.49 mmol), and TEA (1.14 g, 11.32 mmol) in THF (30 mL) was mixed with EDCI (1.63 g, 8.49 mmol) at 0°C. The mixture was stirred at 20°C for 12 hours. The mixture was deactivated with H2O (20 mL) and extracted with DCM (100 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA (v / v) = 1 / 8) to obtain 2-(2-(2-isopropylphenyl)-4-(3-(methoxycarbonyl)bicyclo[1.1.1]pentan-1-carbonyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (2.8 g, yield: 85%) as a white solid. MS(ESI,m / e)[M-55] + 538.3.

[0255] Step 2: 3-(4-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-yl)-3-(2-isopropylphenyl)-5-oxopiperazine-1-carbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid.

[0256] A mixture of 2-(2-(2-isopropylphenyl)-4-(3-(methoxycarbonyl)bicyclo[1.1.1]pentan-1-carbonyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (2.8 g, 4.71 mmol), MeOH (50 mL) containing LiOH.H2O (0.79 g, 18.86 mmol), and H2O (10 mL) was stirred at 20°C for 5 hours. The mixture was concentrated under reduced pressure. The residue was diluted with H2O (30 mL), acidified to pH=4-5 with citric acid, and filtered. The filtrate was extracted with ELISA (100 mL x 2). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 3-(4-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-yl)-3-(2-isopropylphenyl)-5-oxopiperazine-1-carbonyl)bicyclo[1.1.1]pentan-1-carboxylic acid (0.6 g, crude product) as a white solid. MS(ESI,m / e)[M+Na] + 602.3.

[0257] Step 3: 2-(2-(2-isopropylphenyl)-6-oxo-4-(3-(((2-thioxopyridine-1(2H)-yl)oxy)carbonyl)bicyclo[1.1.1]pentan-1-carbonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl

[0258] A mixture containing 3-(4-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-yl)-3-(2-isopropylphenyl)-5-oxopiperazine-1-carbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (0.5 g, 0.86 mmol), 1-hydroxypyridine-2(1H)-thione (142 mg, 1.12 mmol), and DCC (231 mg, 1.12 mmol) in DCM (13 mL) was stirred at 0°C for 2 hours. The mixture was filtered and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-6-oxo-4-(3-(((2-thioxopyridine-1(2H)-yl)oxy)carbonyl)bicyclo[1.1.1]pentan-1-carbonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.5 g, crude product) as a yellow solid, which was used without further purification. MS(ESI,m / e)[M+1] + 689.1.

[0259] Step 4: 2-(4-(bicyclo[1.1.1]pentan-1-carbonyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0260] A mixture containing 2-(2-(2-isopropylphenyl)-6-oxo-4-(3-(((2-thioxopyridine-1(2H)-yl)oxy)carbonyl)bicyclo[1.1.1]pentan-1-carbonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (2.0 g, 2.63 mmol), Bu3SnH (2.3 g, 7.9 mmol), and AIBN (36 mg, 0.22 mmol) in toluene (35 mL) was stirred at 60°C for 1 hour under a W lamp (300 W). The mixture was inactivated with KF solution (50 mL) and extracted with ELISA (100 mL x 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (0.1% TFA, followed by neutralization) to obtain 2-(4-(bicyclo[1.1.1]pentan-1-carbonyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.95 g) as a grayish-white solid. MS(ESI,m / e)[M+Na] + 558.4.

[0261] Step 5: 2-(4-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-(2-isopropylphenyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0262] A mixture containing 2-(4-(bicyclo[1.1.1]pentan-1-carbonyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.95 g, 1.77 mmol) and BH3.THF (1 M, 10 mL) in THF (5 mL) was stirred at 70°C for 12.4 hours. The reaction mixture was cooled to 25°C and slowly deactivated with MeOH (20 mL). The mixture was concentrated under reduced pressure to obtain 2-(4-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, crude) as a white solid, which was used without further purification. MS(ESI,m / e)[M+1] + 508.5.

[0263] Step 6: 2-(4-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0264] A mixture containing 2-(4-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.97 mmol) in HCl / MeOH (8 mL, 4 M) was stirred at 20°C for 3 hours. The mixture was concentrated under reduced pressure and purified by preparative HPLC (0.1% TFA), then adjusted to pH=9 with Na2CO3 solution. The solution was extracted with ELISA (20 mL x 2). The combined organic matter was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(4-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (327 mg, yield: 40%) as a pale yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.57-7.40(m,1H),7.26-7.19(m,2H),7.16-7.10(m,1H),3.70-3. 59(m,1H),3.51-3.31(m,1H),3.03-2.86(m,4H),2.77-2.65(m,5H),2.4 6-2.43(m,1H),2.40-2.37(m,2H),2.34-2.28(m,2H),2.21-2.05(m,2H) ,1.75(m,8H),1.48-1.30(m,5H),1.28-1.24(m,3H),1.23-1.20(m,3H). MS(ESI,m / e)[M+1] + 408.4.

[0265] Intermediate 20-1: 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0266] Step 1: 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl. A mixture containing 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol), furan-3-carbaldehyde (326.37 mg, 3.40 mmol), and HOAc (271.97 mg, 4.53 mmol) in DCE (20 mL) was stirred at 25°C for 30 minutes. Then, NaBH(OAc)3 (1.44 g, 6.79 mmol) was added to the mixture in several portions, and the mixture was stirred at 25°C for 10 hours. The reaction mixture was poured into ice water (20 mL) and the pH was adjusted to 8 with NaHCO3. The resulting mixture was extracted with DCM (50 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA (v / v) = 2 / 1 to 1 / 1) to obtain 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.05 g, yield 89%) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.29(m,2H),7.23-7.14(m,2H),7.12-7.07(m,1H),6.91(s,1H),5.86(s,1H), 4.97(s,1H),4.38(s,1H),3.53-3.38(m,2H),3.32-2.98(m,7H),2.75-2.64(m,2H), 2.28-2.18(m,1H),1.94(m,1H),1.83-1.74(m,1H),1.72-1.62(m,2H),1.50-1.46(m ,1H),1.42(s,9H),1.36-1.30(m,2H),1.25(d,J=6.8Hz,3H),1.10(d,J=6.8Hz,3H).

[0267] Step 2: 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0268] 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.05 g, 2.01 mmol) was added dropwise to a solution of THF (15 mL) with BH3.THF (30 mL, 30 mmol) at 25 °C. The mixture was heated to 70 °C for 15 hours. The reaction product was deactivated with ethanol (10 mL) and concentrated under reduced pressure to obtain 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.02 g, crude) as a white solid. MS(ESI, m / e)[M+1] + 508.4.

[0269] Step 3: 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0270] 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (200 mg, 393.93 umol) was added dropwise to a solution of DCM (3 mL) with TFA (3 mL) at 25°C. The solution was stirred at 25°C for 12 hours. The reaction solution was concentrated under vacuum. The crude product was purified by preparative HPLC and lyophilization. The residue was liberated with saturated Na2CO3 (20 mL) and extracted with Â(30 mL × 5). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (265 mg, 0.52 mmol, yield: 27%) as a white viscous substance. 11H NMR (400MHz, CDCl3)δ ppm:7.46(s,1H),7.36(m,1H),7.31(s,1H),7.26-7.20(m,2H),7.15-7.09( m,1H),6.38(m,1H),3.64(m,1H),3.40(s,3H),3.03-2.85(m,4H),2.83-2.70 (m,4H),2.67(s,1H),2.33-2.24(m,2H),2.15(m,1H),1.83-1.68(m,2H),1.6 0-1.51(m,2H),1.37-1.31(m,1H),1.30-1.20(m,5H),1.17(d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 408.3.

[0271] Intermediate 21-1: 4-((3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)methyl)oxazole [ka]

[0272] Step 1: 2-(2-(2-isopropylphenyl)-4-(oxazol-4-ylmethyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0273] To a solution of 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) in DCE (15 mL), oxazole-4-carbaldehyde (329.7 mg, 3.40 mmol) and AcOH (272 mg, 4.53 mmol) were added over 30 minutes at 25°C. Subsequently, NaBH(OAc)3 (1.2 g, 5.66 mmol) was added at 25°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into saturated NH4Cl (50 mL) and extracted with DCM (50 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=10 / 1 to EA / MeOH(v / v)=10 / 1) to obtain 2-(2-(2-isopropylphenyl)-4-(oxazole-4-ylmethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (360 mg, 707.69 umol, yield: 30.26%) as a yellow oil. MS(ESI,m / e)[M+1] + 509.3.

[0274] Step 2: 4-((3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)methyl)oxazole.

[0275] 2-(2-(2-isopropylphenyl)-4-(oxazol-4-ylmethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (300 mg, 1.32 mmol) was added to a solution of DCM (2 mL) with TFA (0.5 mL) at 25°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into saturated Na2CO3 (20 mL) and extracted with siRNA (50 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 4-((3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)methyl)oxazole (390 mg, 374.47 mL, yield: 63%) as a yellow oil. 1 1H NMR (400MHz, CDCl3)δ ppm:7.83(s,1H),7.55(s,1H),7.53-7.45(m,1H),7.26-7.09(m,3H),3.72-3 .64(m,1H),3.59-3.46(m,2H),3.42-3.34(m,1H),3.07-2.95(m,2H),2.95-2 .86(m,1H),2.73(m,1H),2.69-2.55(m,4H),2.43-2.29(m,2H),2.25(m,1H), 1.71(m,4H),1.37-1.29(m,4H),1.25(d,J=6.8Hz,3H),1.17(d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 409.3.

[0276] Intermediate 22-1: 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)piperazine-1-yl)-7-azaspiro[3.5]nonane [ka]

[0277] Step 1: 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0278] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.72 mmol) in DCE (10 mL), AcOH (326.36 mg, 5.43 mmol) and 1-methyl-1H-pyrazole-4-carbaldehyde (329.14 mg, 2.99 mmol) were added. The mixture was stirred at 25°C for 1 hour. Then, NaBH(OAc)3 (1.73 g, 8.15 mmol) was added, and the mixture was stirred at 25°C for another 12 hours. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1~2 / 1) to obtain 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.9 g, yield: 62%) as a yellow oil.

[0279] Step 2: 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0280] 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.9 g, 1.68 mmol) and BH3.THF (16.80 mL, 16.8 mmol) were mixed in THF (20 mL) and stirred at 70°C for 12 hours. The reaction solution was deactivated with MeOH (20 mL) and stirred at 0°C for 1 hour. The mixture was concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl as a white oil, which was used directly in the next step without further purification. MS(ESI,m / e)[M+1] + 522.4.

[0281] Step 3: 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0282] A mixture containing 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (900 mg, 1.73 mmol) and HCl (4.31 mL, 17.25 mmol) in MeOH (10 mL) was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure. The reaction mixture was poured into saturated NaHCO3 (10 mL) and extracted with ELISA (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (518 mg, yield: 71%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.47(br s, 1H),7.38(s,1H),7.25-7.19(m,2H),7.13(t,1H),3.85(s,4H),3.65(m,1H),3.49(s,2H),3.44-3.32( m,3H),3.02(m,1H),2.70-2.55(m,6H),2.31-2.05(m,4H),1.71-1.60(m,3H),1.25(m,4H),1.17(m,6H). MS(ESI,m / e)[M+1] + 422.4.

[0283] Intermediate 22-1a: (R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0284] 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (20 g, 45.29 mmol) was separated by SFC (instrument: Thar SFC350 preparative SFC; column: REGIS(s,s)WHELK-O1, 250 × 50 mm inner diameter: 10 μm; mobile phase: A in CO2 and B in MeOH (0.1% NH3.H2O); gradient: B%=45%; flow rate: 200 g / min; wavelength: 220 nm; column temperature: 40 °C; system back pressure: 100 bar). (R or S)-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (retention time: 2.55 min, 8.4 g) was obtained. Yield: 43%. (S or R)-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (retention time: 2.73 min, 8.3 g) was obtained. Yield: 42%.

[0285] Step 1: (R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0286] (R or S)-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) and 1-methyl-1H-pyrazole-4-carbaldehyde (274.28 mg, 2.49 mmol) were mixed in a solution in DCE (10 mL), to which AcOH (271.97 mg, 4.53 mmol) and NaBH(OAc)3 (1.44 g, 6.79 mmol) were added. The mixture was stirred at 25°C for 12 hours. The reaction mixture was extracted with aqueous Na2CO3 (10 mL) and DCM (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. Compound (R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (950 mg, 1.77 mmol, yield: 78%) was obtained as a yellow oil. 1 1H NMR (400MHz, CDCl3)δ ppm:7.35-7.30(m,2H),7.22-7.17(m,1H),7.10(m,1H),7.07(s,1H),6.37(s,1 H),4.96(s,1H),4.43(s,1H),3.66(s,3H),3.53-3.45(m,2H),3.29-3.12(m,6H ),3.02(m,1H),2.66(s,2H),2.29-2.19(m,1H),1.92(m,1H),1.82-1.67(m,2H) ,1.53-1.45(m,2H),1.41(s,9H),1.36-1.31(m,2H),1.24(m,3H),1.03(m,3H).

[0287] Step 2: (R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl. A mixture containing (R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (950 mg, 1.77 mmol) in BH3.THF (15 mL) was stirred at 70°C for 12 hours. The reaction mixture was inactivated with MeOH (20 mL) at 0°C and stirred at 25°C for 30 minutes. The mixture was then concentrated under reduced pressure to obtain (R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (900 mg, 1.73 mmol, crude) as a white solid. MS(ESI,m / e)[M+1] + 522.3.

[0288] Step 3: (R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0289] A mixture containing (R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (900 mg, 1.73 mmol) in HCl / MeOH (10 mL) solution was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (10 mL), Na2CO3 was added to bring the pH to 9, and the mixture was extracted with ELISA (10 mL x 3). The mixture was dried over Na2SO4, filtered, and concentrated under reduced pressure to remove the solvent. The compound (R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (492 mg, 1.07 mmol, yield: 62.24%) was obtained as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.47(m,1H),7.38(s,1H),7.27-7.20(m,3H),7.15-7.09(m,1H),3.84(s,3H),3.69-3.60(m,1H),3.48-3.35(m,3H),2.99(m,1H),2.9 6-2.86(m,2H),2.68(m,5H),2.26(m,2H),2.22-2.06(m,2H),1.83-1. 73(m,1H),1.67(m,1H),1.50-1.32(m,5H),1.24(m,3H),1.17(m,3H). MS(ESI,m / e)[M+1] + 422.3.

[0290] Following the same procedure as for intermediate 22-1a, (S or R)-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl was used as the starting material to obtain (S or R)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazole-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (607 mg, intermediate 22-1b), with a yield of 82%. MS(ESI,m / e)[M+1] + 422.4.

[0291] Intermediate 23-1: 2-(4-benzyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0292] Step 1: 2-(4-benzyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0293] A mixture containing 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol), benzaldehyde (360.46 mg, 3.40 mmol), and AcOH (271.97 mg, 4.53 mmol) in DCE (20 mL) was stirred at 25°C for 30 minutes. Then, NaBH(OAc)3 (1.44 g, 6.79 mmol) was added to the mixture in several portions, and the mixture was stirred at 20°C for 3 hours. The mixture was washed with saturated NaHCO3 (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 5 / 1 to 1 / 1) to obtain 2-(4-benzyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.88 mmol, yield: 83%) as a white solid. 11H NMR (400MHz, CDCl3)δ ppm:7.33-7.29(m,1H),7.26-7.17(m,2H),7.16-7.04(m,4H),6.85(d,J=6.8Hz ,2H),4.95(s,1H),4.43(s,1H),3.61(m,1H),3.52(m,1H),3.35-3.12(m,7H),2. 96(m,1H),2.73-2.56(m,2H),2.23(m,1H),1.94(m,1H),1.67-1.82(m,2H),1.48 (m,2H),1.42(s,9H),1.33(s,1H),1.21(d,J=6.8Hz,3H),0.92(d,J=6.8Hz,3H).

[0294] Step 2: 2-(4-benzyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0295] 2-(4-benzyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.88 mmol) was added dropwise to a solution of THF (10 mL) with BH3.THF (30 mL, 30 mmol) at 25°C. The mixture was heated at 75°C for 12 hours. The reaction product was inactivated with ethanol (10 mL) and concentrated under reduced pressure to obtain 2-(4-benzyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (970 mg, crude) as a white solid. MS(ESI, m / e)[M+1] + 518.5.

[0296] Step 3: 2-(4-benzyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0297] 2-(4-benzyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (970 mg, 1.82 mmol) was added dropwise to a 10 mL MeOH (MeOH) solution at 25°C with HCl / MeOH (10 mL, 4 M). The solution was stirred at 20°C for 4 hours. The reaction solution was concentrated under vacuum. The residue was diluted with HCl (5 mL, 1 M) and extracted with siRNA (10 mL x 2). The aqueous phase was adjusted to pH=8 with NaHCO3 and extracted with siRNA (20 mL x 5). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to obtain 2-(4-benzyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (529 mg, 1.27 mmol, yield: 68%) as a white solid. 1 1H NMR (400MHz, CDCl3)δ ppm:7.47(d,J=4.4Hz,1H),7.28(m,4H),7.24-7.15(m,3H),7.14-7.06(m,1H), 3.83-3.56(m,2H),3.51(s,2H),3.37(d,J=6.8Hz,1H),3.01-2.86(m,3H),2.80- 2.59(m,5H),2.38-2.25(m,2H),2.22-2.13(m,1H),1.84-1.54(m,3H),1.53-1.3 9(m,4H),1.35-1.28(m,1H),1.25-1.22(d,J=6.8Hz,3H),1.12(d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 418.4.

[0298] Intermediate 24-1: 2-(2-(2-isopropylphenyl)-4-(1-phenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0299] Step 1: 2-(2-(2-isopropylphenyl)-6-oxo-4-(1-phenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0300] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) in DMF (10 mL), (1-bromoethyl)benzene (0.84 g, 4.53 mmol) and Cs2CO3 (2.21 g, 6.79 mmol) were added. The mixture was stirred at 80°C for 2 hours. Saturated NH4Cl (50 mL) was added to the mixture and extracted with siRNA (30 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1) to obtain 2-(2-(2-isopropylphenyl)-6-oxo-4-(1-phenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, yield: 73%) as a colorless oil.

[0301] Step 2: 2-(2-(2-isopropylphenyl)-4-(1-phenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0302] 2-(2-(2-isopropylphenyl)-6-oxo-4-(1-phenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.1 g, 2.02 mmol) and BH3.THF (10 mL) were mixed in THF (10 mL) and stirred at 70°C for 16 hours. After cooling to 0°C, MeOH (20 mL) was added dropwise to the mixture and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(1-phenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.1 g, crude) as a colorless oil, which was used directly in the next step without further purification. MS(ESI, m / e)[M+1] + 532.4.

[0303] Step 3: 2-(2-(2-isopropylphenyl)-4-(1-phenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0304] A mixture containing 2-(2-(2-isopropylphenyl)-4-(1-phenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.88 mmol) in HCl / siRNA (10 mL, 4 M) was stirred at 20°C for 16 hours. After removing the solvent, the residue was purified by preparative HPLC (TFA). The mixture was concentrated under vacuum, H2O (50 mL) was added, and the pH was adjusted to 11 using NaOH (2 M). The mixture was extracted with siRNA (10 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(1-phenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (537 mg, yield: 66%) as a white viscous substance. 1 1H NMR (400MHz, CDCl3)δ ppm:7.57-7.35(m,2H),7.31(m,2H),7.27-7.22(m,3H),7.18-7.05(m,2H) ,3.69-3.53(m,1H),3.40-3.34(m,1H),3.16-3.05(m,1H),3.02-2.82(m,3H ),2.75-2.52(m,5H),2.46-2.25(m,3H),2.24-2.09(m,2H),1.71-1.64(m,1 H),1.37(m,3H),1.33(m,3H),1.31-1.26(m,2H),1.22(m,3H),1.01(m,1H). MS(ESI,m / e)[M+1] + 432.4.

[0305] Intermediate 25-1: 2-(2-(2-isopropylphenyl)-4-(1,2,3,4-tetrahydronaphthalene-1-yl)piperazine-1-yl)-7-azaspiro[3.5]nonane [ka]

[0306] Step 1: 1,2,3,4-tetrahydronaphthalene-1-ol.

[0307] 3,4-Dihydronaphthalene-1(2H)-one (8.0 g, 54.72 mmol) was dissolved in THF (100 mL) and NaBH4 (8.24 g, 219 mmol) was added at 0°C. The mixture was stirred at 20°C for 4 hours. The mixture was poured into H2O (80 mL) and extracted with siRNA (50 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 1,2,3,4-tetrahydronaphthalene-1-ol (6.0 g, yield: 74%) as a yellow oil, which was used directly in the next step without further purification.

[0308] Step 2: 1-bromo-1,2,3,4-tetrahydronaphthalene.

[0309] A mixture of 1,2,3,4-tetrahydronaphthalene-1-ol (4.0 g, 26.99 mmol) and TMSBr (4.96 g, 32.39 mmol) was stirred at 20°C for 16 hours. The mixture was poured into H2O (50 mL) and extracted with ELISA (20 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA (v / v) = 5 / 1) to obtain 1-bromo-1,2,3,4-tetrahydronaphthalene (5.0 g, yield: 87%) as a yellow oil.

[0310] Step 3: 2-(2-(2-isopropylphenyl)-6-oxo-4-(1,2,3,4-tetrahydronaphthalene-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0311] A mixture containing 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol), 1-bromo-1,2,3,4-tetrahydronaphthalene (956 mg, 14.53 mmol), and Cs2CO3 (2.21 g, 6.79 mmol) in DMF (10 mL) was stirred at 80°C for 16 hours. The mixture was poured into saturated NH4Cl (50 mL) and extracted with ELISA (30 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=6 / 1) to obtain 2-(2-(2-isopropylphenyl)-6-oxo-4-(1,2,3,4-tetrahydronaphthalene-1-yl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.9g, yield: 69%) as a yellow oil. MS(ESI,m / e)[M+1] + 572.4.

[0312] Step 4: 2-(2-(2-isopropylphenyl)-4-(1,2,3,4-tetrahydronaphthalene-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0313] 2-(2-(2-isopropylphenyl)-6-oxo-4-(1,2,3,4-tetrahydronaphthalene-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.8 g, 1.4 mmol) and BH3.THF (5 mL, 5 mmol) were mixed in THF (5 mL) and stirred at 70°C for 16 hours. After cooling to 0°C, MeOH (10 mL) was added dropwise to the mixture and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(1,2,3,4-tetrahydronaphthalene-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.8 g, crude) as a colorless oil, which was used directly in the next step without purification.

[0314] Step 5: 2-(2-(2-isopropylphenyl)-4-(1,2,3,4-tetrahydronaphthalene-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0315] A mixture containing 2-(2-(2-isopropylphenyl)-4-(1,2,3,4-tetrahydronaphthalene-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (700 mg, 1.25 mmol) in HCl / siRNA (10 mL, 4 M) was stirred at 20°C for 3 hours. After removing the solvent, the residue was purified by preparative HPLC (TFA). The mixture was concentrated under vacuum and the pH was adjusted to 9-10 using aqueous NaOH solution (1 M). The mixture was extracted with siRNA (10 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-(1,2,3,4-tetrahydronaphthalene-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane (365 mg, yield: 64%) as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.76(m,1H),7.57-7.42(m,1H),7.24-7.12(m,4H),7.09-6.98(m,2H),3.89-3.39(m,4H),3.16-2.85(m,4H),2.73 -2.60(m,6H),2.55-2.33(m,2H),2.24-2.15(m,1H),1.95(m,2H),1.73-1.62(m,4H),1.37-1.22(m,11H),1.02(m,1H). MS(ESI,m / e)[M+1] + 458.3.

[0316] Intermediate 26-1: 2-(2-(2-isopropylphenyl)-4-phenethylpiperazine-1-yl)-7-azaspiro[3.5]nonane [ka]

[0317] Step 1: 2-(2-(2-isopropylphenyl)-6-oxo-4-phenethylpiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0318] To a 10 mL solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (700 mg, 1.59 mmol) in DCE (10 mL), 2-phenylacetaldehyde (285.7 mg, 2.38 mmol), HOAc (190.38 mg, 3.17 mmol), and NaBH(OAc)3 (739.1 mg, 3.49 mmol) were added. The solution was stirred at 25°C for 12 hours. The reaction mixture was poured into saturated NaHCO3 until the pH became 7, and extracted with DCM (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 10 / 1 to 2 / 1) to obtain 2-(2-(2-isopropylphenyl)-6-oxo-4-phenethylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.5 g, yield: 58%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.34-7.28(m,2H),7.25-7.03(m,6H),6.85(d,J=7.2Hz,2H),4.95(br s, 1H),4.42(br s, 1H), 3.68-3.46 (m, 2H), 3.37-3.09 (m, 7H), 2.97 (t, 1H), 2.73-2.56 (m, 2H), 2.32-2.18 (m, 1H), 2.02-1.85(m,1H),1.83-1.67(m,2H),1.42(s,9H),1.22(d,J=6.8Hz,3H),0.93(d,J=6.8Hz,3H).

[0319] Step 2: 2-(2-(2-isopropylphenyl)-4-phenethylpiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0320] A solution of 2-(2-(2-isopropylphenyl)-6-oxo-4-phenethylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.6 g, 1.1 mmol) in BH3.THF (10 mL, 1 M) was stirred at 70°C for 12 hours. The reaction mixture was inactivated with MeOH (5 mL) at 0°C and stirred at 25°C for 30 minutes. The mixture was concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-phenethylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (600 mg, crude) as a yellow oil. MS(ESI, m / e)[M+1] + 532.5.

[0321] Step 3: 2-(2-(2-isopropylphenyl)-4-phenethylpiperazin-1-yl)-7-azaspiro[3.5]nonane.

[0322] A solution containing tert-butyl 2-(2-(2-isopropylphenyl)-4-phenethylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.6 g, 1.1 mmol) in TFA (1 mL) and DCM (10 mL) was stirred at 20°C for 12 hours. The reaction mixture was poured into an aqueous solution of Na2CO3 (300 mL) and extracted with DCM (20 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (HCl) to obtain 2-(2-(2-isopropylphenyl)-4-phenethylpiperazin-1-yl)-7-azaspiro[3.5]nonane (130 mg, HCl salt, yield: 27% in 2 steps) as a white solid. 1H NMR(400MHz,CH3OH-d4)δ ppm:7.96(d,J=7.6Hz,1H),7.51-7.49(m,2H),7.36-7.26(m,5H),5.25(s,1H),4.05(m,1H),3.85-3.54(m,4H),3.54-3.31(m,4H),3. 20-3.17(m,2H),3.03-2.95(m,4H),2.33(m,1H),1.75-1.71(m,3H),1.64-1.61(m,2H),1.38(d,J=6.8Hz,3H),1.28(d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 432.4.

[0323] Intermediate 28-1: 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0324] Step 1: 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0325] To a 10 mL solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (700 mg, 1.59 mmol) in DCE (10 mL), 4-fluorobenzaldehyde (671.9 mg, 3.17 mmol), HOAc (190.38 mg, 3.17 mmol), and NaBH(OAc)3 (190.38 mg, 3.17 mmol) were added. The solution was stirred at 25°C for 12 hours. Saturated NaHCO3 was added to the reaction mixture until the pH reached 7, and the mixture was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 10 / 1 to 2 / 1) to obtain 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.5 g, yield: 57.3%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.23-7.03(m,3H),6.70-6.67(m,4H),4.85(s,3H),4.37(s,1H),3.51-3.43(m,2H),3.20-3.04(m,6H),2.57-2.54(m,1H),2.20-2.10(m ,2H),1.82-1.91(m,1H),1.66-1.58(m,2H),1.45-1.38(m,2H),1.20-1 .17(m,2H),1.34(s,9H),1.14(d,J=6.8Hz,3H),0.85(d,J=6.8Hz,3H).

[0326] Step 2: 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0327] A solution of 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.5 g, 0.91 mmol) in BH3.THF (10 mL) was stirred at 60°C for 12 hours. The reaction mixture was inactivated with MeOH (10 mL) at 0°C and stirred at 25°C for 30 minutes. The mixture was concentrated under reduced pressure to obtain 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (600 mg, crude) as a yellow oil, which was used without further purification. MS(ESI,m / e)[M+1] + 536.4.

[0328] Step 3: 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0329] 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.6 g, 1.12 mmol) was added to a solution of DCM (10 mL) with TFA (1 mL). The solution was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure. The residue was poured into an aqueous solution of Na2CO3 (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (300 mg, yield: 62%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.47(s,1H),7.25-7.12(m,3H),6.99-6.95(m,2H),3.64-3.63(m,1H),3.48(s,1H),2.98-2.87(m,2H),2.65-2.59(m,4H) ),2.30-2.29(m,3H),1.92(m,4H),1.75(m,1H),1.65(t,1H),1.35-1.32(m,4H),1.25(d,J=6.8Hz,3H),1.13(d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 436.3.

[0330] Intermediate 28-1a: (R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0331] Step 1: (R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl. To a solution of (R or S)-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) in DCE (10 mL), 4-fluorobenzaldehyde (353.97 mg, 2.49 mmol), HOAc (271.97 mg, 4.53 mmol), and NaBH(OAc)3 (1.44 g, 6.79 mmol) were added. The mixture was stirred at 25°C for 12 hours. Saturated NaHCO3 was added to the reaction product until the pH reached 9, and the mixture was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 10 / 1 to 2 / 1) to obtain (R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.9 g, yield: 72%) as a yellow oil.

[0332] Step 2: (R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl. A solution of (R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.9 g, 1.64 mmol) in BH3.THF (16.5 mL) was stirred at 70°C for 12 hours. The reaction mixture was inactivated with MeOH (10 mL) at 0°C and stirred at 25°C for 30 minutes. The mixture was concentrated under reduced pressure to obtain (R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, crude) as a yellow oil, which was used without further purification. MS(ESI,m / e)[M+1] + 536.5.

[0333] Step 3: (R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0334] (R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.87 mmol) was dissolved in MeOH (10 mL) and HCl (4.67 mL) was added. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was poured into saturated Na2CO3 (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain (R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (435 mg, yield: 58%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.48(br s, 1H),7.27-7.18(m,2H),7.16-7.10(m,1H),6.97(t,2H),3.63(m,1H),3.48(s,2H),3.36(br s, 1H),3.05-2.97(m,1H),2.94-2.84(m,2H),2.66-2.56(m,3H),2.35-2.25(m,2H),2.20-2.13( m,2H),1.86-1.57(m,4H),1.28-1.47(m,5H),1.24-1.27(d,J=6.8Hz,3H),1.13(d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 436.3

[0335] Intermediate 29-1: 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0336] Step 1: 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0337] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.72 mmol) in DCE (10 mL), AcOH (326.36 mg, 5.43 mmol) and 4-chlorobenzaldehyde (420.71 mg, 2.99 mmol) were added. The mixture was stirred at 25°C for 1 hour. Then, NaBH(OAc)3 (1.73 g, 8.15 mmol) was added to the solution. The mixture was stirred at 25°C for another 12 hours. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1~2 / 1) to obtain 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.12 mmol, yield: 78%) as a yellow oil.

[0338] Step 2: 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl. A mixture containing 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.12 mmol) and BH3.THF (21.19 mL, 21.19 mmol) in THF (10 mL) was stirred at 70°C for 12 hours. The reaction solution was inactivated with MeOH (10 mL) and concentrated under reduced pressure to obtain 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, crude product), which was used directly in the next step without further reaction.

[0339] Step 3: 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0340] A mixture containing 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.17 mmol) and HCl (5.43 mL, 21.73 mmol) in MeOH (30 mL) was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (445 mg, 1.36 mmol, yield: 45%) as a grayish-white solid. 1H NMR(400MHz,CDCl3)δ ppm:7.49(br s, 1H),7.36-7.28(m,2H),7.26-7.11(m,5H),3.65(br d,J=8.8Hz,1H),3.50(s,3H),3.05-2.97(m,2H),2.96-2.86(m,3H),2.68-2 .58(m,7H),2.36-2.14(m,4H),1.71-1.64(m,3H),1.28(m,4H),1.16(m,6H). MS(ESI,m / e)[M+1] + 452.3.

[0341] Intermediate 29-1a: (R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0342] Step 1: (R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0343] (R or S)-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) was dissolved in DCE (15 mL) and AcOH (271.97 mg, 4.53 mmol) and 4-chlorobenzaldehyde (477.46 mg, 3.40 mmol) were added. The mixture was stirred at 20°C for 30 minutes, then NaBH(OAc)3 (959.86 mg, 4.53 mmol) was added and the mixture was stirred at 20°C for another 12 hours. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1~2 / 1) to obtain (R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, yield: 78%) as a yellow oil.

[0344] Step 2: (R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0345] (R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.77 mmol) and BH3.THF (17.66 mL, 17.66 mmol) were mixed in THF (15 mL) and stirred at 70°C for 12 hours. The reaction solution was inactivated with MeOH (10 mL) and concentrated under reduced pressure to obtain (R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, crude product), which was used directly in the next step without further reaction.

[0346] Step 3: (R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0347] (R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.81 mmol) was added to a mixture containing MeOH (5 mL) and HCl / MeOH solution (5 mL, 4 M). The mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with ELISA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain (R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (322 mg, yield: 39%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.50(br s, 1H),7.27(s,4H),7.25-7.19(m,2H),7.15(d,J=6.8Hz,1H),3.67(br s, 2H), 3.45-3.29 (m, 1H), 3.04-2.87 (m, 3H), 2.69-2.56 (m, 5H), 2.36-2.27 (m ,2H),2.24-2.16(m,1H),1.78(s,1H),1.73-1.63(m,2H),1.33(m,3H),1.28(br d,J=6.8Hz,4H),1.16(br d,J=6.4Hz,4H). MS(ESI,m / e)[M+1] + 452.4.

[0348] Intermediate 30-1: 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0349] Step 1: 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0350] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.72 mmol) in DCE (10 mL), AcOH (326.36 mg, 5.43 mmol) and 4-methylbenzaldehyde (359.13 mg, 2.72 mmol) were added. The mixture was stirred at 25°C for 1 hour. Then, NaBH(OAc)3 (1.73 g, 8.15 mmol) was added to the solution. The mixture was stirred at 25°C for another 12 hours. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1~2 / 1) to obtain 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.18 g, 2.16 mmol, yield: 79.6%) as a yellow oil.

[0351] Step 2: 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl. A mixture containing 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.18 g, 2.16 mmol) and BH3.THF (21.62 mL, 21.62 mmol) in THF (10 mL) was stirred at 70°C for 12 hours. The reaction solution was inactivated with MeOH (10 mL) and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.18 g, crude product), which was used directly in the next step without further purification.

[0352] Step 3: 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0353] A mixture containing 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.18 g, 2.22 mmol) and HCl (5.55 mL, 22.19 mmol) in MeOH (30 mL) was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (589 mg, 1.36 mmol, yield: 61.5%) as a grayish-white solid. 1H NMR(400MHz,CDCl3)δ ppm:7.48(br s, 1H),7.25-7.16(m,4H),7.15-7.07(m,3H),3.65(m,1H),3.54-3.44(m,2H),3.02-2.87(m,3 H),2.69-2.57(m,5H),2.36-2.21(m,6H),1.79-1.62(m,4H),1.39-1.21(m,9H),1.15(m,4H). MS(ESI,m / e)[M+1] + 432.3.

[0354] Intermediate 31-1: 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0355] Step 1: 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenethyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0356] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) in DCE (20 mL), 2-(4-methoxyphenyl)acetaldehyde (510 g, 3.40 mmol) and HOAc (0.27 g, 4.52 mmol) were added. After stirring at 25°C for 1 hour, NaBH(OAc)3 (0.96 g, 4.52 mmol) was added. The mixture was stirred at 25°C for 12 hours. Then, an aqueous solution of NH4Cl (20 mL) was added to the mixture and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=1 / 1) to obtain 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenethyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.85 g, yield: 65%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.36-7.29(m,2H),7.19-7.13(m,1H),7.08-7.05(m,1H),6.90(br d,J=8.4Hz,2H),6.73(d,J=8.4Hz,2H),5.05(m,1H),4.23(br s, 1H), 3.77 (s, 3H), 3.39 (m, 1H), 3.27-3.15 (m, 6H), 2.88 (m, 1H), 2.67 (m, 1H), 2.61-2.48 (m, 4H), 2.22 (m, 1H), 1.97 (br s, 1H), 1.82 (br s, 1H), 1.61(br s, 1H), 1.42 (s, 10H), 1.33-1.38 (m, 2H), 1.29 (m, 6H).

[0357] Step 2: 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0358] A mixture of 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenethyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.85 g, 1.48 mmol) and BH3.THF (15 mL, 14.8 mmol) was heated at 70°C for 12 hours. MeOH (10 mL) was carefully added to the mixture and concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.8 g, yield: 96%) as a yellow oil, which was used in the next step without further purification. MS(ESI,m / e)[M+1] + 562.4.

[0359] Step 3: 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0360] 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (800 mg, 1.42 mmol) was added to a solution of HCl / MeOH (10 mL) in MeOH (20 mL). The mixture was stirred at 25°C for 1 hour. After removing the solvent, the residue was dissolved in water (20 mL). The mixture was adjusted to pH 9-10 using an aqueous solution of Na2CO3. The mixture was then extracted with ELISA (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (600 mg, yield: 91%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.51(br s, 1H),7.27-7.21(m,2H),7.17-7.07(m,3H),6.81(d,J=8.4Hz,2H),4.55-4.28(m,1H),3.78(s,3H),3.67(m,1H),3.41(br s, 1H), 3.03 (m, 2H), 2.94-2.87 (m, 1H), 2.80-2.68 (m, 6H), 2.60-2.52 (m, 2H), 2.41-2.13 (m, 4H), 1.79 (br s, 1H), 1.70 (m, 1H), 1.51-1.38 (m, 4H), 1.23 (m, 6H), 1.15 (br s, 1H). MS(ESI,m / e)[M+1] + 462.5.

[0361] Intermediate 34-1:2-(4-(4-methoxybenzyl)-2-(o-tolyl)piperazine-1-yl)-7-azaspiro[3.5]nonane [ka]

[0362] Step 1: (2-((4-methoxybenzyl)(2-oxo-2-(o-tolyl)ethyl)amino)ethyl) tert-butyl carbamate.

[0363] To a solution of 1-bromo-2-methylbenzene (2.8 g, 16.39 mmol) in THF (30 mL), n-BuLi (6.37 mL, 15.92 mmol, 2.5 M) was added at -78°C, and the mixture was stirred at -78°C for 10 minutes. Then, THF (20 mL) containing 4-(4-methoxybenzyl)-2-oxopiperazine-1-carboxylate tert-butyl (5.0 g, 15.61 mmol) was added, and the mixture was stirred at -78°C for 2 hours. The reaction mixture was inactivated with aqueous NH4Cl (50 mL), extracted with siRNA (50 mL x 3), washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. The compound (2-((4-methoxybenzyl)(2-oxo-2-(o-tolyl)ethyl)amino)ethyl)carbamate tert-butyl (3.1 g, 7.51 mmol, yield: 48.15%) was obtained as a yellow oil. MS(ESI,m / e)[M+1] + 413.3.

[0364] Step 2: 1-(4-methoxybenzyl)-5-(o-tolyl)-1,2,3,6-tetrahydropyrazine.

[0365] (2-((4-methoxybenzyl)(2-oxo-2-(o-tolyl)ethyl)amino)ethyl)carbamate tert-butyl (2.1 g, 5.09 mmol) was added to a mixture containing DCM (20 mL) with TFA (5.8 g, 50.91 mmol). The mixture was stirred at 20°C for 12 hours. The residue was diluted with H2O (20 mL), Na2CO3 was added to adjust the pH to 9, extracted with ELISA (20 mL x 3), washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-(4-methoxybenzyl)-5-(o-tolyl)-1,2,3,6-tetrahydropyrazine (1.4 g, 4.76 mmol, crude) as a yellow oil. MS(ESI, m / e)[M+1] + 295.3.

[0366] Step 3: 1-(4-methoxybenzyl)-3-(o-tolyl)piperazine.

[0367] 1-(4-methoxybenzyl)-5-(o-tolyl)-1,2,3,6-tetrahydropyrazine (1.4 g, 4.76 mmol) was dissolved in MeOH (20 mL) and NaBH4 (719.66 mg, 19.02 mmol) was added. The mixture was stirred at 25°C for 12 hours. The mixture was deactivated with H2O and concentrated under reduced pressure. The residue was diluted with H2O (20 mL), extracted with DCM (20 mL x 3), washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. Compound 1-(4-methoxybenzyl)-3-(o-tolyl)piperazine (550 mg, 1.75 mmol, yield: 39.02%) was obtained as a yellow oil. MS(ESI, m / e)[M+1] + 297.3

[0368] Step 4: 2-(4-(4-methoxybenzyl)-2-(o-tolyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0369] A solution containing 1-(4-methoxybenzyl)-3-(o-tolyl)piperazine (520 mg, 1.75 mmol) and 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (419.83 mg, 1.75 mmol) in DCE (10 mL) was prepared, to which AcOH (210.7 mg, 3.15 mmol) and NaBH(OAc)3 (1.12 g, 5.36 mmol) were added. The mixture was stirred at 25°C for 12 hours. The reaction mixture was extracted with aqueous Na2CO3 (20 mL) and DCM (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. Compound 2-(4-(4-methoxybenzyl)-2-(o-tolyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (630 mg, 1.21 mmol, yield: 69.1%) was obtained as a yellow oil. MS(ESI,m / e)[M+1] + 520.6

[0370] Step 5: 2-(4-(4-methoxybenzyl)-2-(o-tolyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0371] A mixture containing 2-(4-(4-methoxybenzyl)-2-(o-tolyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (630 mg, 1.21 mmol) in HCl / MeOH (10 mL) was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (TFA conditions). The residue was diluted with H2O (10 mL), Na2CO3 was added to bring the pH to 9, the mixture was extracted with siRNA (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to remove the solvent. Compound 2-(4-(4-methoxybenzyl)-2-(o-tolyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (109 mg, 294.83 mL, yield: 20.57%) was obtained as a yellow oil. 1 1H NMR (400MHz, CDCl3)δ ppm:7.45(m,1H),7.22(m,2H),7.17-7.06(m,2H),7.11-7.06(m,1H),6.83(m ,2H),3.79(s,3H),3.51(m,1H),3.46(s,2H),3.02-2.96(m,1H),2.90(m,2H), 2.69-2.62(m,3H),2.61-2.54(m,2H),2.35(s,3H),2.27(m,2H),2.15(m,1H) ,1.79-1.72(m,1H),1.68-1.62(m,1H),1.37-1.26(m,5H),1.20-1.12(m,1H). MS(ESI,m / e)[M+1] + 420.3.

[0372] Intermediate 35-1: 2-(2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0373] Step 1: 4-(4-methoxybenzyl)-2-(2-(2-methylpropa-1-en-1-yl)phenyl)piperazine-1-carboxylate tert-butyl.

[0374] A solution containing tert-butyl 2-(2-bromophenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate (0.8 g, 1.73 mmol) and 4,4,5,5-tetramethyl-2-(2-methylpropane-1-en-1-yl)-1,3,2-dioxaborane (208 mg, 2.08 mmol) in dioxane (20 mL) and H2O (4 mL) was prepared. Cs2CO3 (1.13 g, 3.46 mmol) and Pd(dppl)Cl2.CH2Cl2 (143 mg, 0.173 mmol) were added under N2 conditions. The mixture was stirred at 100°C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by MPLC. Compound 4-(4-methoxybenzyl)-2-(2-(2-methylpropane-1-en-1-yl)phenyl)piperazine-1-carboxylate tert-butyl (0.63 g, yield: 83%) was obtained as a brown oil. MS(ESI,m / e)[M+1] + 437.3.

[0375] Step 2: 2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl.

[0376] 4-(4-methoxybenzyl)-2-(2-(2-methylpropane-1-en-1-yl)phenyl)piperazine-1-carboxylate tert-butyl (0.63 g, 1.44 mmol) was dissolved in MeOH (20 mL) and Pt / C (0.5 g) was added. The mixture was stirred at 25 °C under H2 (15 Psi) for 12 hours. The solution was filtered and concentrated under reduced pressure. Compound 2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl (0.6 g, yield: 95%) was obtained as a yellow oil. MS(ESI, m / e)[M+1] + 439.3.

[0377] Step 3: 3-(2-isobutylphenyl)-1-(4-methoxybenzyl)piperazine.

[0378] 2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl (0.6 g, 1.37 mmol) was added to a 10 mL MeOH solution with HCl / MeOH solution (5 mL, 4 M). The mixture was stirred at 20°C for 2 hours. The solution was concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and Na2CO3 solution was added to adjust the pH to 9. The aqueous layer was extracted with ELISA (50 mL x 3). The combined organic layers were dried and concentrated under reduced pressure. Compound 3-(2-isobutylphenyl)-1-(4-methoxybenzyl)piperazine (0.42 g, yield: 91%) was obtained as a red oil. MS(ESI, m / e)[M+1] + 339.3.

[0379] Step 4: 2-(2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0380] To a 20 mL solution of 3-(2-isobutylphenyl)-1-(4-methoxybenzyl)piperazine (420 mg, 1.24 mmol) in DCE (20 mL), 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (356 mg, 1.49 mmol) and HOAc (149 mg, 2.48 mmol) were added. After stirring at 25°C for 1 hour, NaBH(OAc)3 (0.79 g, 3.72 mmol) was added. The mixture was stirred at 25°C for 12 hours. Then, an aqueous solution of NaHCO3 (50 mL) was added to the mixture, and the mixture was extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1) to obtain 2-(2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (400 mg, yield: 58%) as a yellow oil. MS(ESI,m / e)[M+1] + 562.5.

[0381] Step 5: 2-(2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0382] 2-(2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (400 mg, 0.71 mmol) was dissolved in MeOH (10 mL) and HCl / MeOH (5 mL, 4 M) was added. The mixture was stirred at 20°C for 2 hours. The solution was concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and an aqueous solution of Na2CO3 was added to bring the pH to 9. The aqueous layer was extracted with ELISA (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Compound 2-(2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (300 mg, yield: 91%) was obtained as a brown solid. 1H NMR(400MHz,CDCl3)δ ppm:7.48(m,1H),7.21(m,2H),7.15-7.10(m,2H),7.05-7.00(m,1H),6.82(m,2H) ),3.78(s,3H),3.48-3.38(m,2H),2.99(m,1H),2.89(m,2H),2.70-2.57(m,6H), 2.45-2.38(m,1H),2.36-2.22(m,3H),2.23-2.06(m,1H),1.82-1.60(m,4H),1.4 4-1.36(m,4H),1.30-1.23(m,2H),0.91(d,J=6.4Hz,3H),0.82(d,J=6.4Hz,3H). MS(ESI,m / e)[M+1] + 462.3

[0383] Intermediate 36-1: 2-(2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazine-1-yl)-7-azaspiro[3.5]nonane [ka]

[0384] Step 1: (2-((2-(2-bromophenyl)-2-oxoethyl)(4-methoxybenzyl)amino)ethyl) tert-butyl carbamate.

[0385] To a solution of 1-bromo-2-iodobenzene (10 g, 35 mmol) in THF (100 mL), i-PrMgCl.LiCl (30 mL, 1 M in THF) was added at -70°C. After stirring for 0.5 hours, 4-(4-methoxybenzyl)-2-oxopiperazine-1-carboxylate tert-butyl (10.5 g, 33 mmol) was added. The mixture was stirred at 20°C for 3 hours. The reaction mixture was inactivated at 0°C by adding NH4Cl (100 mL) and extracted with ELISA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=10 / 1) to obtain (2-((2-(2-bromophenyl)-2-oxoethyl)(4-methoxybenzyl)amino)ethyl) tert-butyl carbamate (14 g, yield: 84%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.85(dd,J=1.6,8.0Hz,1H),7.54(dd,J=1.2,8.0Hz,1H),7.33-7.28(m,1H),7.22(m,2H),7.10(m,1H),6.88-6.82(d,J=8.4H) z,2H),4.47(s,1H),3.91(m,1H),3.81(s,3H),3.57-3.44(m,3H),2.97-2.88(m,2H),2.64-2.55(m,2H),1.27(m,2H),1.14(s,9H).

[0386] Step 2: 3-(2-bromophenyl)-1-(4-methoxybenzyl)piperazine.

[0387] TFA (25 mL) was added to a solution of (2-((2-(2-bromophenyl)-2-oxoethyl)(4-methoxybenzyl)amino)ethyl)carbamate tert-butyl (5.0 g, 10 mmol) in DCM (25 mL). The mixture was stirred at 20°C for 30 minutes. After removing the solvent under reduced pressure, the residue was dissolved in DCE (50 mL). Then, NaBH(OAc)3 (2.2 g, 10 mmol) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent. The reaction mixture was extracted with DCM (10 mL x 3), then washed with aqueous NaHCO3 solution (10 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain 3-(2-bromophenyl)-1-(4-methoxybenzyl)piperazine (3.5 g, yield: 99%) as a brown oil, which was used in the next step without further purification. MS(ESI,m / e)[M+1] + 361.2, 363.2.

[0388] Step 3: 2-(2-bromophenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl.

[0389] 3-(2-bromophenyl)-1-(4-methoxybenzyl)piperazine (3.4 g, 9.4 mmol) was dissolved in DCM (50 mL) and TEA (1.9 g, 18.8 mmol) was added. Then Boc2O (2.5 g, 11.29 mmol) was added. The mixture was stirred at 20°C for 12 hours. The reaction mixture was inactivated at 0°C by adding NH4Cl (50 mL) and then extracted with ELISA (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA (v / v) = 10 / 1) to obtain 2-(2-bromophenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl (2.9 g, yield: 68%) as a yellow oil. 1H NMR(400MHz,CDCl3)δ ppm:7.58(m,1H),7.52(m,1H),7.31-7.27(m,1H),7.13-7.09(m,1H),7.06(d,J=8.4Hz,2H),6.79-6.75(m,2H),5.33(m,1H),3. 94-3.89(m,1H),3.78(s,3H),3.53-3.46(m,1H),3.43(m,2H),3.00(m,1H),2.84(m,1H),2.52(m,1H),2.22(m,1H),1.31(s,9H).

[0390] Step 4: 2-(2-(cyclopenta-1-en-1-yl)phenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl.

[0391] A solution containing tert-butyl 2-(2-bromophenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate (1.0 g, 2.17 mmol) and 2-(cyclopenta-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (0.5 g, 2.6 mmol) in dioxane (20 mL) and H2O (4 mL) was prepared. Cs2CO3 (1.4 g, 4.34 mmol) and Pd(dppl)Cl2.CH2Cl2 (180 mg, 0.217 mmol) were added under N2 conditions. The mixture was stirred at 100°C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by MPLC. Compound 2-(2-(cyclopenta-1-en-1-yl)phenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl (0.73 g, yield: 75%) was obtained as a white solid. MS(ESI,m / e)[M+1] + 449.4.

[0392] Step 5: 2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl.

[0393] 2-(2-(cyclopenta-1-en-1-yl)phenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl (0.73 g, 1.63 mmol) was dissolved in MeOH (20 mL) and Pt / C (0.5 g) was added. The mixture was stirred at 25°C H2 (15 Psi) for 12 hours. The solution was filtered and concentrated under reduced pressure. Compound 2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl (0.7 g, yield: 96%) was obtained as a yellow oil. MS(ESI, m / e)[M+1] + 451.3.

[0394] Step 6: 3-(2-cyclopentylphenyl)-1-(4-methoxybenzyl)piperazine.

[0395] 2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl (0.89 g, 1.98 mmol) was dissolved in MeOH (10 mL) and HCl / MeOH (5 mL, 4 M) was added. The mixture was stirred at 20°C for 2 hours. The solution was concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and Na2CO3 solution was added to adjust the pH to 9. The aqueous layer was extracted with ELISA (50 mL x 3). The combined organic layers were dried under reduced pressure and concentrated. Compound 3-(2-cyclopentylphenyl)-1-(4-methoxybenzyl)piperazine (0.6 g, yield: 87%) was obtained as a red oil. MS(ESI, m / e)[M+1] + 351.3.

[0396] Step 7: 2-(2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0397] To a 20 mL solution of 3-(2-cyclopentylphenyl)-1-(4-methoxybenzyl)piperazine (600 mg, 1.71 mmol) in DCE (20 mL), 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (491 mg, 2.05 mmol) and HOAc (205 mg, 3.42 mmol) were added. After stirring at 25°C for 1 hour, NaBH(OAc)3 (1.09 g, 5.13 mmol) was added. The mixture was stirred at 25°C for 12 hours. Then, an aqueous solution of NaHCO3 (50 mL) was added to the mixture, and the mixture was extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1) to obtain 2-(2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (700 mg, yield: 71%) as a yellow oil. MS(ESI,m / e)[M+1] + 574.4.

[0398] Step 8: 2-(2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0399] 2-(2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (700 mg, 1.22 mmol) was added to a solution of HCl / MeOH (5 mL, 4 M) in MeOH (10 mL). The mixture was stirred at 20°C for 2 hours. The solution was concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and Na2CO3 solution was added to bring the pH to 9. The aqueous layer was extracted with ELISA (50 mL x 3). The combined organic layers were dried and concentrated under reduced pressure. Compound 2-(2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (500 mg, yield: 87%) was obtained as a brown solid. 1H NMR(400MHz,CDCl3)δ ppm:7.48(s,1H),7.25-7.18(m,4H),7.15-7.08(m,1H),6.85-6.81(m,2H),3.79( s,3H),3.71-3.59(m,1H),3.50-3.42(m,2H),3.41-3.26(m,1H),2.99(m,1H),2.9 4-2.84(m,2H),2.75-2.55(m,5H),2.32-2.23(m,2H),2.16(m,1H),2.04-1.96(m, 1H), 1.89-1.73(m, 4H), 1.72-1.56(m, 4H), 1.55-1.20(m, 7H), 1.19-1.07(m, 1H). MS(ESI,m / e)[M+1] + 474.4.

[0400] Intermediate 37-1: 4-(2-(4-(4-methoxybenzyl)-1-(7-azaspiro[3.5]nonane-2-yl)piperazine-2-yl)benzyl)morpholine [ka]

[0401] Step 1: 4-(4-methoxybenzyl)-2-(2-vinylphenyl)piperazine-1-carboxylate tert-butyl.

[0402] To a solution containing tert-butyl 2-(2-bromophenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate (1.0 g, 2.17 mmol) and potassium vinyltrifluoroborate (406.44 mg, 3.03 mmol) in dioxane (10 mL) and H2O (1 mL), Cs2CO3 (1.41 g, 4.33 mmol) and Pd(dppf)Cl2 (158.59 mg, 216.74 mmol) were added under N2. The mixture was stirred at 90°C for 12 hours. The reaction mixture was filtered and concentrated. The residue was extracted with H2O (10 mL) and ELISA (10 mL x 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by MPLC. Compound 4-(4-methoxybenzyl)-2-(2-vinylphenyl)piperazine-1-carboxylate tert-butyl (800 mg, 1.96 mmol, yield: 90.35%) was obtained as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.84-7.80(m,1H),7.47-7.42(m,1H),7.26-7.22(m,2H),7.16(m,2 H),7.08(m,1H),6.82(d,J=8.8Hz,2H),5.51(m,1H),5.37(m,1H),5.21( m,1H),3.87-3.81(m,1H),3.80(s,3H),3.48-3.38(m,2H),3.25-3.15(m ,1H),3.07(m,1H),2.79(m,1H),2.45(m,1H),2.17(m,1H),1.41(s,9H).

[0403] Step 2: 2-(2-formylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl.

[0404] 4-(4-methoxybenzyl)-2-(2-vinylphenyl)piperazine-1-carboxylate tert-butyl (800 mg, 1.96 mmol) was dissolved in THF (5 mL) and H2O (5 mL). K2OsO4.H2O (28.86 mg, 78.33 mL) and NaIO4 (1.68 g, 7.83 mmol) were added at 5 °C, and the mixture was stirred at 25 °C for 3 hours. The reaction mixture was diluted with H2O (10 mL), extracted with siRNA (10 mL x 3), washed with aqueous Na2SO3 solution (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2-formylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate tert-butyl (800 mg, 1.95 mmol, yield: 99.52%) as a yellow oil. MS(ESI,m / e)[M+1] + 411.2.

[0405] Step 3: 4-(4-methoxybenzyl)-2-(2-(morpholinomethyl)phenyl)piperazine-1-carboxylate tert-butyl.

[0406] A solution containing tert-butyl 2-(2-formylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate (800 mg, 1.95 mmol), morpholine (203.74 mg, 2.34 mmol), AcOH (234.06 mg, 3.90 mmol), and NaBH(OAc)3 (1.24 g, 5.85 mmol) was mixed with 10 mL of DCE. The mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into 10 mL of aqueous Na2CO3 solution, extracted with 3 x 10 mL of DCM, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. Compound 4-(4-methoxybenzyl)-2-(2-(morpholinomethyl)phenyl)piperazine-1-carboxylate tert-butyl (400 mg, 830.52 umol, yield: 42.62%) was obtained as a yellow oil. 1H NMR(400MHz,CDCl3)δ ppm:7.83(d,J=8.0Hz,1H),7.25(d,J=2.8Hz,1H),7.21-7.15(m,2H),7.10(d,J=8. 4Hz,2H),6.73(d,J=8.8Hz,2H),5.27(d,J=2.4Hz,1H),3.92(m,1H),3.89-3.83(m,1 H),3.75(s,3H),3.57-3.47(m,4H),3.45-3.28(m,3H),3.07(d,J=12.8Hz,1H),2.91 (d,J=11.2Hz,2H),2.44(m,1H),2.41-2.25(m,3H),2.23-2.16(m,2H),1.30(s,9H).

[0407] Step 4: 4-(2-(4-(4-methoxybenzyl)piperazine-2-yl)benzyl)morpholine.

[0408] A mixture containing 4-(4-methoxybenzyl)-2-(2-(morpholinomethyl)phenyl)piperazine-1-carboxylate tert-butyl (400 mg, 830.52 umol) in HCl / siRNA (5 mL) was stirred at 25°C for 6 hours. The reaction mixture was concentrated and the solvent was removed. The residue was diluted with H₂O (5 mL), Na₂CO₃ was added to bring the pH to 9, the mixture was extracted with siRNA (5 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to remove the solvent. Compound 4-(2-(4-methoxybenzyl)piperazine-2-yl)benzyl)morpholine (300 mg, 786.35 umol, yield: 94.68%) was obtained as a yellow oil. MS(ESI, m / e)[M+1] + 382.2.

[0409] Step 5: 2-(4-(4-methoxybenzyl)-2-(2-(morpholinomethyl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0410] A solution containing 4-(2-(4-(4-methoxybenzyl)piperazin-2-yl)benzyl)morpholine (300 mg, 786.35 ml), 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (225.82 mg, 943.62 ml), AcOH (94.44 mg, 1.57 mmol), and NaBH(OAc)3 (499.58 mg, 2.36 mmol) was mixed with DCE (6 mL). The mixture was stirred at 25°C for 48 hours. The reaction mixture was extracted with aqueous Na2CO3 (10 mL) and DCM (10 mL x 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (TFA conditions). Compound 2-(4-(4-methoxybenzyl)-2-(2-(morpholinomethyl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (255 mg, 421.61 umol, yield: 53.62%) was obtained as a white solid. MS(ESI,m / e)[M+1] + 605.4.

[0411] Step 6: 4-(2-(4-(4-methoxybenzyl)-1-(7-azaspiro[3.5]nonan-2-yl)piperazine-2-yl)benzyl)morpholine.

[0412] A mixture containing 2-(4-(4-methoxybenzyl)-2-(2-(morpholinomethyl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (255 mg, 421.61 umol) in DCM (4 mL) and TFA (2 mL) was stirred at 25°C for 1 hour. The reaction mixture was diluted with H2O (5 mL), and an aqueous solution of Na2CO3 was added to bring the pH to 9. The mixture was extracted with DCM (5 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to remove the solvent. Compound 4-(2-(4-(4-methoxybenzyl)-1-(7-azaspiro[3.5]nonane-2-yl)piperazin-2-yl)benzyl)morpholine (135 mg, 267.48 umol, yield: 63.44%) was obtained as a yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.58(d,J=7.6Hz,1H),7.25-7.19(m,3H),7.17-7.09(m,2H),6.83(d,J=8.8Hz ,2H),3.78(s,3H),3.66-3.50(m,5H),3.39(s,2H),3.32(m,1H),3.22(m,1H),2.97( m,2H),2.85(m,1H),2.76-2.59(m,5H),2.42-2.22(m,6H),2.01(m,1H),1.84-1.76( m,1H),1.70-1.63(m,1H),1.46-1.32(m,4H),1.29-1.23(m,1H),1.11-1.03(m,1H). MS(ESI,m / e)[M+1] + 505.4.

[0413] Intermediate 39-1: 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0414] Step 1: 2-(2-(2-isopropylphenyl)-6-oxo-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0415] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (900 mg, 2.04 mmol) in DCE (10 mL), AcOH (244.77 mg, 4.08 mmol) and 4-(trifluoromethoxy)benzaldehyde (426.21 mg, 2.24 mmol) were added at 25°C. The mixture was stirred at 25°C for 1 hour. Then, NaBH(OAc)3 (1.3 g, 6.11 mmol) was added, and the mixture was stirred at 25°C for another 12 hours. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1~2 / 1) to obtain 2-(2-(2-isopropylphenyl)-6-oxo-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (820 mg, yield: 64%) as a yellow oil.

[0416] Step 2: 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0417] 2-(2-(2-isopropylphenyl)-6-oxo-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (800 mg, 1.30 mmol) and BH3.THF (12.99 mL, 12.99 mmol) were mixed in THF and stirred at 70°C for 12 hours. The reaction solution was inactivated with MeOH (10 mL) and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (800 mg, crude) as a yellow oil, which was used directly in the next step without further purification.

[0418] Step 3: 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0419] 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (800 mg, 1.33 mmol) and HCl / MeOH (15 mL, 4 M) were mixed in MeOH (10 mL) and stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was poured into saturated NaHCO3 (10 mL) and extracted with siRNA (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (606 mg, yield 90%) as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.48(br s, 1H),7.33(br s, 2H),7.23(br s, 2H),7.14(br s, 3H),3.71-3.27(m,4H),3.07-2.85(m,3H),2.61(br s, 5H), 2.37-2.11 (m, 2H), 1.91-1.52 (m, 4H), 1.47-0.82 (m, 12H). MS(ESI,m / e)[M+1] + 502.4.

[0420] Intermediate 40-1: 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0421] Step 1: 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0422] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (900 mg, 2.04 mmol) in DCE (10 mL), AcOH (244.77 mg, 4.08 mmol) and 4-ethoxybenzaldehyde (333.66 mg, 2.24 mmol) were added at 25°C. The mixture was stirred at 25°C for 1 hour. Then, NaBH(OAc)3 (1.3 g, 6.11 mmol) was added, and the mixture was stirred at 25°C for another 12 hours. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried, filtered over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1~2 / 1) to obtain 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (800 mg, yield: 68%) as a yellow oil.

[0423] Step 2: 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0424] 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (800 mg, 1.39 mmol) and BH3.THF (13.89 mL, 13.89 mmol) were mixed in THF and stirred at 70°C for 12 hours. The reaction solution was inactivated with MeOH (10 mL) and concentrated under reduced pressure to obtain 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (800 mg, crude) as a yellow oil, which was used directly in the next step without further purification.

[0425] Step 3: 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0426] A mixture containing 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (800 mg, 1.42 mmol) and HCl (3.56 mL, 14.24 mmol) in MeOH (10 mL) was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was poured into saturated NaHCO3 (10 mL) and extracted with siRNA (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (562 mg, yield: 62%) as a white solid. 1H NMR(400MHz,CDCl3)δ ppm:7.48(br s, 1H),7.25-7.16(m,4H),7.15-7.07(m,1H),6.81(d,J=8.4Hz,2H),4.01(q,2H),3.64(m,1H),3.50-3.31(m,3H),3.01-2.84(m,3H),2. 70-2.52(m,5H),2.33-2.23(m,2H),2.21-2.07(m,2H),1.79-1.61(m,2H),1.43-1.32(m,6H),1.31-1.21(m,5H),1.14(d,J=6.8Hz,4H). MS(ESI,m / e)[M+1] + 462.4.

[0427] Intermediate 41-1: 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0428] Step 1: 2-(2-(2-isopropylphenyl)-6-oxo-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl. AcOH (337 mg, 5.61 mmol) and 4-(trifluoromethyl)benzaldehyde (179 mg, 2.03 mmol) were added to a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (800 mg, 1.87 mmol) in DCE (10 mL). The mixture was stirred at 20°C for 1 hour, then NaBH(OAc)3 (1.19 g, 5.61 mmol) was added. The mixture was stirred at 20°C for 16 hours. Then saturated NaHCO3 (10 mL) and siRNA (10 mL) were added. The mixture was stirred at 20°C for 0.2 hours. The organic layer was separated and dried over Na2SO4. 、The solution was evaporated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 10 / 1 to 1 / 1) to obtain 2-(2-(2-isopropylphenyl)-6-oxo-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (500 mg, yield: 49%) as a yellow solid. MS(ESI,m / e)[M+1] + 600.5

[0429] Step 2: 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0430] A mixture of 2-(2-(2-isopropylphenyl)-6-oxo-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (500 mg, 0.88 mmol) and BH3.THF (8.8 mL, 8.8 mmol) was heated at 70°C for 12 hours. After cooling to 0°C, the mixture was deactivated with MeOH (10 mL). The mixture was concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (400 mg, yield: 80%) as a yellow solid, which was used in the next step without further purification. MS(ESI,m / e)[M+1] + 586.3.

[0431] Step 3: 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0432] 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (400 mg, 0.68 mmol) was added to a 10 mL MeOH solution with HCl / MeOH solution (10 mL). The mixture was stirred at 25°C for 2 hours. After concentration under vacuum, the residue was dissolved in water (20 mL). The mixture was adjusted to pH 9-10 using an aqueous Na2CO3 solution. The mixture was extracted with ELISA (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous sodium 2SO4, filtered, and concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (220 mg, yield: 66%) as a brown solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.55-7.43(m,5H),7.27-7.21(m,2H),7.14-7.11(m,1H),3.66-3.56(m,3H),3.48-3.25(m,1H),3.22-3 .02(m,1H),2.91-2.87(m,2H),2.64-2.61(m,5H),2.45-2.20(m,4H),1.80-1.60(m,2H),1.38-1.12(m,13H). MS(ESI,m / e)[M+1] + 486.3

[0433] Intermediate 42-1: 4-((3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonan-2-yl)piperazine-1-yl)methyl)benzonitrile [ka]

[0434] Step 1: 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0435] A mixture containing 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) and BH3.THF (22.64 mL, 22.64 mmol) in THF (20 mL) was stirred at 70°C for 12 hours. The reaction solution was deactivated with MeOH (20 mL) and stirred at 0°C for 1 hour. The mixture was concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (900 mg, crude) as a white oil, which was used directly in the next step without further purification. MS(ESI,m / e)[M+1] + 428.3.

[0436] Step 2: 2-(4-(4-cyanobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0437] To a solution of 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (900 mg, 2.10 mmol) in DCE (10 mL), AcOH (252.78 mg, 4.21 mmol) and 4-formylbenzonitrile (303.59 mg, 2.32 mmol) were added. The mixture was stirred at 25°C for 1 hour, then NaBH(OAc)3 (1.34 g, 6.31 mmol) was added, and the mixture was stirred at 25°C for another 12 hours. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1~2 / 1) to obtain 2-(4-(4-cyanobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (270 mg, yield: 23%) as a yellow oil.

[0438] Step 3: 4-((3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)methyl)benzonitrile

[0439] A mixture containing 2-(4-(4-cyanobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (270 mg, 497.46 μmol) and TFA (0.38 mL, 4.97 mmol) in DCM (10 mL) was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure. The reaction mixture was poured into saturated NaHCO3 (10 mL) and extracted with siRNA (20 mL x 2). The combined organic layers were washed with brine, dried, filtered over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 4-((3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)methyl)benzonitrile (102 mg, yield: 46.32%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.59(d,J=8.4Hz,2H),7.45(d,J=8.0Hz,3H),7.26-7.19(m,3H),7.15-7.09(m,1H),3.65-3.59(m,1H),3.56(m,2H),3.35(br s、3H),3.02-2.83(m,3H),2.72(m,5H),2.59(m,1H),2.39-2.26(m,3H), 2.26-2.15(m,2H),1.96(s,2H),1.46(m,3H),1.30-1.23(m,6H),1.13(br d,J=6.8Hz,3H),0.88(m,3H). MS(ESI,m / e)[M+1] + 443.3.

[0440] Intermediate 43-1: 2-(4-(3-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0441] Step 1: 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0442] 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mol) was added in 20 mL of THF to LiAlH4 (0.17 g, 4.53 mol) in several portions at 0°C. The mixture was stirred at 20°C for 1 hour. Then, H2O (10 mL) was added to the mixture and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.9 g, yield: 94%) as a yellow oil. MS(ESI, m / e)[M+1] + 428.4.

[0443] Step 2: 2-(4-(3-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0444] To a solution of 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.9 g, 2.1 mmol) in DCE (20 mL), 3-fluorobenzaldehyde (0.31 g, 2.5 mmol) and HOAc (0.25 g, 4.2 mmol) were added. After stirring at 25°C for 1 hour, NaBH(OAc)3 (0.89 g, 4.2 mmol) was added. The mixture was stirred at 25°C for 12 hours. Then, an aqueous solution of NH4Cl (20 mL) was added to the mixture and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1) to obtain 2-(4-(3-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.5 g, yield: 45%) as a yellow solid. MS(ESI,m / e)[M+1] + 536.5.

[0445] Step 3: 2-(4-(3-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0446] 2-(4-(3-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (500 mg, 0.934 mmol) was added to a 20 mL MeOH solution with HCl / MeOH solution (10 mL). The mixture was stirred at 25°C for 1 hour. After removing the solvent, the residue was dissolved in water (20 mL). The mixture was adjusted to pH 9-10 with an aqueous Na2CO3 solution. The mixture was extracted with siRNA (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(4-(3-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (370 mg, yield: 91%) as a yellow solid.1 H NMR(400MHz,CDCl3)δ ppm:7.47(br s, 1H),7.23-7.19(m,3H),7.14-7.10(m,1H),7.10-7.05(m,2H),6.91(m,1H) ,3.64(m,1H),3.51(s,2H),3.38(m,1H),3.02-2.96(m,1H),2.95-2.87(m,2H) ,2.75-2.61(m,5H),2.35-2.27(m,2H),2.18(m,1H),1.81-1.73(m,1H),1.70( m,1H),1.48-1.37(m,4H),1.36-1.32(m,2H),1.25(m,3H),1.15-1.12(m,3H). MS(ESI,m / e)[M+1] + 436.3.

[0447] Intermediate 44-1: 2-(2-(2-isopropylphenyl)-4-(3-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0448] Step 1: 2-(2-(2-isopropylphenyl)-4-(3-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0449] To a solution of 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.34 mmol) in DCE (10 mL), AcOH (280 mg, 4.68 mmol) and 3-methoxybenzaldehyde (477 mg, 3.51 mmol) were added at 25°C. The mixture was stirred at 25°C for 1 hour, then NaBH(OAc)3 (991 mg, 4.68 mmol) was added, and the mixture was stirred at 25°C for another 12 hours. The reaction mixture was inactivated with saturated Na2CO3 (10 mL) and extracted with siRNA (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=50 / 1~0 / 1) to obtain 2-(2-(2-isopropylphenyl)-4-(3-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.3 g, 0.547 mmol, yield 23%) as a pale yellow oil.

[0450] Step 2: 2-(2-(2-isopropylphenyl)-4-(3-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0451] A mixture of 2-(2-(2-isopropylphenyl)-4-(3-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (300 mg, 0.547 mmol) was added to an HCl / MeOH (10 mL, 4 M) solution over 2 hours at 0°C. The reaction mixture was poured into saturated Na2CO3 (10 mL) and extracted with siRNA (10 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(3-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (183 mg, yield: 75%) as a pale pink oil. 1H NMR(400MHz,CDCl3)δ ppm:7.55-7.44(m,1H),7.25-7.19(m,3H),7.15-7.09(m,1H),6.91-6.88(m,2H),6. 77(m,1H),3.80(s,3H),3.65(d,J=9.2Hz,1H),3.50(s,2H),3.37(m,1H),3.03-2.89 (m,3H),2.69-2.60(m,5H),2.33-2.28(m,2H),2.24-2.11(m,3H),1.76(m,1H),172- 1.64(m,1H),1.42-1.31(m,4H),1.27-1.25(d,J=6.8Hz,3H),1.15(d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 448.2.

[0452] Intermediate 46-1: 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0453] Step 1: 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0454] To a solution of 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) in DCE (10 mL), AcOH (271.97 mg, 4.53 mmol) and 2-fluorobenzaldehyde (342.88 mg, 2.76 mmol) were added. The mixture was stirred at 25°C for 1 hour, then NaBH(OAc)3 (1.44 g, 6.79 mmol) was added, and the mixture was stirred at 25°C for another 12 hours. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1~2 / 1) to obtain 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, yield: 96%) as a yellow oil.

[0455] Step 2: 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0456] A mixture containing 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.18 mmol) and BH3.THF (24.01 mL, 24.01 mmol) in THF (20 mL) was stirred at 70°C for 12 hours. The reaction solution was deactivated with MeOH (20 mL) and stirred at 0°C for 1 hour. The mixture was concentrated under reduced pressure to obtain 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.07 mg, crude) as a white oil, which was used directly in the next step without further purification. MS(ESI,m / e)[M+1] + 536.4.

[0457] Step 3: 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0458] A mixture containing 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.07 mg, 2 mmol) and HCl (4.99 mL, 19.97 mmol) in MeOH (10 mL) was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure. The reaction mixture was poured into saturated NaHCO3 (10 mL) and extracted with siRNA (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (481 mg, yield: 55.28%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.46(br s, 1H),7.37(t, 1H),7.26-7.17(m,3H),7.16-6.96(m,3H),3.72-3.54(m,3H),3.39(br s, 1H),3.00(br d,J=11.2Hz,1H),2.96-2.85(m,2H),2.73-2.57(m,6H),2.44-2.35(m,1H),2.33-2.21(m,2H),1. 80-1.71(m,1H),1.71-1.60(m,1H),1.46-1.30(m,4H),1.29-1.21(m,4H),1.15(d,J=6.8Hz,4H). MS(ESI,m / e)[M+1] + 436.3.

[0459] Intermediate 47-1: 2-(2-(2-isopropylphenyl)-4-(2-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0460] Step 1: 2-(2-(2-isopropylphenyl)-4-(2-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0461] 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.34 mmol) and 2-methoxybenzaldehyde (477.5 mg, 3.51 mmol) were added to a solution in DCE (10 mL), to which HOAc (280.6 mg, 4.68 mmol) was added. The solution was stirred at 25°C for 30 minutes. Then, NaBH(OAc)3 (1.09 g, 5.14 mmol) was added to the reaction mixture, and the mixture was stirred at 25°C for 12 hours. Saturated NaHCO3 was added to the reaction mixture until the pH reached 7, and the mixture was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 5 / 1 to 1 / 1) to obtain 2-(2-(2-isopropylphenyl)-4-(2-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (230 mg, yield: 18%) as a yellow oil.

[0462] Step 2: 2-(2-(2-isopropylphenyl)-4-(2-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0463] 2-(2-(2-isopropylphenyl)-4-(2-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (230 mg, 0.42 mmol) was added to a solution of HCl / MeOH (2 mL) in MeOH (10 mL). The solution was then stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure. The residue was poured into an aqueous solution of Na2CO3 (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(2-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (146 mg, yield: 78%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.47(s,1H),7.34(s,1H),7.27-7.18(m,5H),6.90-6.83(m,2H),3.78(s,3H),3.67-3.58(m,4H),2.99-2. 71(m,3H),2.65-2.60(m,5H),2.32-2.25(m,3H),1.69-1.60(m,3H),1.35-1.25(m,9H),1.16(d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 448.3.

[0464] Intermediate 48-1: 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0465] Step 1: 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0466] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.72 mmol) in DCE (10 mL), AcOH (326.36 mg, 5.43 mmol) and 2,4-dimethoxybenzaldehyde (496.71 mg, 2.99 mmol) were added, and the mixture was stirred at 25°C for 1 hour. NaBH(OAc)3 (1.73 mg, 8.15 mmol) was added to the solution, and the mixture was stirred at 25°C for another 12 hours. The reaction mixture was extracted with siRNA (100 mL x 2) at pH=9. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1~2 / 1) to obtain 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.72 mmol, yield: 75%) as a white oil.

[0467] Step 2: 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0468] A mixture containing 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.03 mmol) and BH3.THF (20.28 mL, 20.28 mmol, 1 M) in THF (10 mL) was stirred at 70°C for 12 hours. The reaction solution was deactivated with MeOH (10 mL) and concentrated under reduced pressure to obtain 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, crude) as a white viscous substance, which was used directly in the next step without further reaction.

[0469] Step 3: 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0470] A mixture of 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.08 mmol) and HCl / MeOH (30 mL, 4 M) was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was poured into an aqueous solution of NaHCO3 to adjust the pH to 9 and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (651 mg, 1.36 mmol, yield: 65.2%) as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.47(br s, 1H),7.26-7.17(m,4H),7.15-7.07(m,1H),6.45-6.39(m,2H),3.78(m,6H),3.72-3.62(m,2H),3.59-3.46(m,3H),3.41(br s, 1H), 3.07-2.83 (m, 4H), 2.75-2.54 (m, 7H), 2.42-2.16 (m, 4H), 2.00-1.61 (m, 6H), 1.28-1.23 (m, 6H), 1.17 (d, J=6.8Hz, 5H). MS(ESI,m / e)[M+1] + 478.3.

[0471] Intermediate 48-1a: (R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0472] Step 1: (R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl. To a 15 mL solution of (R or S)-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) in DCE (15 mL), AcOH (271.97 mg, 4.53 mmol) and 2,4-dimethoxybenzaldehyde (564.44 mg, 3.40 mmol) were added, and the mixture was stirred at 20°C for 30 minutes. NaBH(OAc)3 (959.86 mg, 4.53 mmol) was added to the solution, and the mixture was stirred at 20°C for another 12 hours. The reaction mixture was extracted with siRNA (100 mL x 2) at pH=9. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1~2 / 1) to obtain (R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.13 g, yield 84%) as a white oil.

[0473] Step 2: (R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl. (R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.13 g, 1.91 mmol) and BH3.THF (19.09 mL, 19.09 mmol, 1 M) were mixed in THF (15 mL) and stirred at 70°C for 12 hours. The reaction solution was deactivated with MeOH (10 mL) and concentrated under reduced pressure to obtain (R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, crude) as a white viscous substance, which was used directly in the next step without further reaction.

[0474] Step 3: (R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0475] (R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.73 mmol) was added to a mixture containing MeOH (10 mL) and HCl / MeOH solution (10 mL, 4 M). The mixture was stirred at 20°C for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was poured into an aqueous solution of NaHCO3 to adjust the pH to 9 and extracted with ELISA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain (R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (500 mg, yield: 60.5%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.47(br s, 1H),7.26-7.17(m,3H),7.15-7.06(m,1H),6.51-6.30(m,2H),3.81(s,1H),3.79(s,3H),3.76(s,3H),3.66(br s, 1H), 3.60-3.46(m, 2H), 3.40(br s, 1H),3.02-2.84(m,3H),2.73-2.55(m,4H),2.39-2.19(m,4H),2.15(m,1H),1.75(m,1H),1.84-1.68(m,1 H),1.67-1.65(m,1H),1.69-1.61(m,1H),1.43-1.28(m,4H),1.25(d,J=6.8Hz,4H),1.17(d,J=6.8Hz,4H). MS(ESI,m / e)[M+1] + 478.5.

[0476] Intermediate 49-1: 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0477] Step 1: 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0478] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) in DCE (20 mL), 3,5-dimethoxybenzaldehyde (0.56 g, 3.40 mmol) and HOAc (0.27 g, 4.52 mmol) were added. After stirring at 25°C for 1 hour, NaBH(OAc)3 (0.96 g, 4.52 mmol) was added. The mixture was stirred at 25°C for 12 hours. Then, an aqueous solution of NH4Cl (20 mL) was added to the mixture and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=1 / 1) to obtain 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.1 g, yield: 82%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.27(s,2H),7.18-7.13(m,2H),6.24(s,1H),6.12(s,2H),4.94(br s,1H),4.41(br s, 1H),3.63-3.57(m,2H),3.55(s,6H),3.29-3.08(m,7H),3.02-2.94(m,1H),2.75-2.64(m,2H),2.26-2.19(m,1H),1.92( m,1H),1.74-1.63(m,3H),1.49-1.44(m,2H),1.42(s,9H),1.34-1.29(m,2H),1.23(d,J=6.8Hz,3H),0.98(d,J=6.8Hz,3H).

[0479] Step 2: 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0480] A mixture of 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.1 g, 1.86 mmol) and BH3.THF (18 mL, 18.6 mmol) was heated at 70°C for 12 hours. MeOH (10 mL) was carefully added to the mixture and concentrated under vacuum to obtain 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.9 g, yield: 84%) as a yellow oil, which was used in the next step without further purification. MS(ESI,m / e)[M+1] + 578.4.

[0481] Step 3: 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane

[0482] 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (900 mg, 1.56 mmol) was dissolved in MeOH (20 mL) and HCl / MeOH (10 mL) was added. The mixture was stirred at 25°C for 1 hour. After removing the solvent, the residue was dissolved in water (20 mL). The mixture was adjusted to pH 9-10 using an aqueous solution of Na2CO3. The mixture was extracted with ELISA (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous sodium 2SO4, filtered, and concentrated under vacuum to obtain 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (550 mg, yield: 74%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.48(br s, 1H),7.25-7.17(m,2H),7.15-7.09(m,1H),6.50(m,2H),6.33(s,1H),3.77(s,6H),3.65(m,1H),3.46(s,2H), 3.41(m,1H),3.00(m,1H),2.96-2.87(m,2H),2.72-2.54(m,5H),2.35-2.26(m,2H),2.20-2.14(m,1H),1.93(br s, 1H),1.79-1.72(m,1H),1.70-1.64(m,1H),1.41-1.29(m,5H),1.26(br d,J=6.8Hz,3H),1.15(br d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 478.4.

[0483] Intermediate 50-1: 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0484] Step 1: 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0485] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.72 mmol) in DCE (10 mL), AcOH (326.36 mg, 5.43 mmol) and 2,4-difluorobenzaldehyde (424.76 mg, 2.99 mmol) were added. The mixture was stirred at 25°C for 1 hour, then NaBH(OAc)3 (1.73 g, 8.15 mmol) was added, and the mixture was stirred at 25°C for another 12 hours. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1~2 / 1) to obtain 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.76 mmol, yield: 64%) as a yellow oil.

[0486] Step 2: 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0487] A mixture containing 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.76 mmol) and BH3 (19.38 mL, 19.38 mmol) in THF (10 mL) was stirred at 70°C for 12 hours. The reaction solution was deactivated with MeOH (10 mL) and concentrated under reduced pressure to obtain 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, crude product), which was used directly in the next step without further reaction.

[0488] Step 3: 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane

[0489] A mixture of 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.17 mmol) and HCl / MeOH (35 mL, 4 M) was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with ELISA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (515 mg, 1.14 mmol, yield: 52%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.46(br s, 1H),7.38-7.30(m,1H),7.23(m,2H),7.16-7.09(m,1H),6.85-6.72(m,2H),3.65-3.51(m,3H),3.37(br s, 1H), 3.00 (m, 1H), 2.90 (m, 2H), 2.69-2.56 (m, 5H), 2.42-2.21 (m, 4H), 1.80-1.61 (m, 2H), 1.44-1.28 (m, 5H), 1.25 (br d,J=6.8Hz,3H),1.15(br d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 454.3.

[0490] Intermediate 51-1: 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0491] Step 1: 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0492] AcOH (337 mg, 5.61 mmol) and 3,5-difluorobenzaldehyde (292 mg, 2.06 mmol) were added to a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (800 mg, 1.87 mmol) in DCE (10 mL). The mixture was stirred at 20°C for 1 hour. Then, NaBH(OAc)3 (1.19 g, 5.61 mmol) was added. The mixture was stirred at 20°C for 16 hours. Then, saturated NaHCO3 (10 mL) and siRNA (10 mL) were added. The mixture was stirred at 20°C for 0.2 hours. The organic layer was separated and dried over Na2SO4. 、 The solution was evaporated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 10 / 1 to 1 / 1) to obtain 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (500 mg, yield: 50%) as a yellow solid. MS(ESI,m / e)[M+1] + 568.5

[0493] Step 2: 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0494] A mixture of 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (500 mg, 0.88 mmol) and BH3.THF (8.8 mL, 8.8 mmol) was heated at 70°C for 12 hours. After cooling to 0°C, the mixture was deactivated with MeOH (10 mL). The mixture was concentrated under vacuum to obtain 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (400 mg, yield: 80%) as a yellow solid, which was used in the next step without further purification. MS(ESI,m / e)[M+1] + 554.2.

[0495] Step 3: 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0496] 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (400 mg, 0.71 mmol) was added to a 10 mL MeOH solution, and HCl / MeOH (10 mL) was added. The mixture was stirred at 25°C for 2 hours. After concentration under vacuum, the residue was dissolved in water (20 mL). The mixture was adjusted to pH 9-10 with an aqueous Na2CO3 solution. The mixture was extracted with ELISA (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (225 mg, yield: 70%) as a brown solid. 1H NMR(400MHz,CDCl3)δ ppm:7.52-7.47(s,1H),7.27-7.21(m,2H),7.14-7.12(m,1H),6.89-6.87 (m,2H),6.68-6.66(m,1H),3.65-3.63(m,1H),3.48-3.47(m,2H),3.46-3 .38(m,1H),3.22-3.02(m,1H),3.02-2.88(m,2H),2.67-2.60(m,5H),2.3 2-2.22(m,2H),2.22-2.15(m,1H),1.80-1.60(m,2H),1.38-1.14(m,13H). MS(ESI,m / e)[M+1] + 454.3

[0497] Intermediate 52-1: 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0498] Step 1: 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0499] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (880 mg, 1.99 mmol) in DCE (10 mL), AcOH (239.33 mg, 3.99 mmol) and 3,4-difluorobenzaldehyde (311.49 mg, 2.19 mmol) were added. The mixture was stirred at 25°C for 1 hour. Then, NaBH(OAc)3 (1.27 g, 5.98 mmol) was added, and the mixture was stirred at 25°C for another 12 hours. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1~2 / 1) to obtain 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, yield: 85%) as a yellow oil.

[0500] Step 2: 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0501] A mixture containing 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.76 mmol) and BH3.THF (17.61 mL, 17.61 mmol) in THF (15 mL) was stirred at 70°C for 12 hours. The reaction solution was inactivated with MeOH (10 mL) and concentrated under reduced pressure to obtain 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (750 mg, crude) as a yellow oil, which was used directly in the next step without further purification.

[0502] Step 3: 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0503] A mixture containing 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (750 mg, 1.35 mmol) and HCl (3.39 mL, 13.54 mmol) in MeOH (10 mL) was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was poured into saturated NaHCO3 (10 mL) and extracted with ELISA (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (423 mg, yield: 68%) as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.47(br s, 1H), 7.26-6.96 (m, 6H), 3.63 (m, 1H), 3.51-3.28 (m, 3H), 3.09-2.79 (m, 3H), 2.70-2.53 (m ,5H),2.36-2.23(m,3H),2.21-1.97(m,3H),1.80-1.63(m,2H),1.46-1.21(m,10H),1.14(br d,J=6.8Hz,4H). MS(ESI,m / e)[M+1] + 454.3.

[0504] Intermediate 52-1a: (R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0505] Step 1: (R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0506] (R or S)-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) was added to a DCE (10 mL) solution with AcOH (271.97 mg, 4.53 mmol) and 3,4-difluorobenzaldehyde (309.15 mg, 2.49 mmol). The mixture was stirred at 25°C for 1 hour, then NaBH(OAc)3 (1.44 g, 6.79 mmol) was added, and the mixture was stirred at 25°C for another 12 hours. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1~2 / 1) to obtain (R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.15 g, yield: 88%) as a yellow oil.

[0507] Step 2: (R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0508] (R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.15 g, 2.03 mmol) and BH3.THF (20.26 mL, 20.26 mmol) were mixed in THF and stirred at 70°C for 12 hours. The reaction solution was deactivated with MeOH (10 mL) and concentrated under reduced pressure to obtain t (R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.1 g, crude) as a yellow oil, which was used directly in the next step without further purification.

[0509] Step 3: (R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0510] (R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.1 g, 1.99 mmol) and HCl (4.97 mL, 19.87 mmol) were mixed in MeOH (10 mL) and stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was poured into saturated NaHCO3 (10 mL) and extracted with ELISA (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain (R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (420 mg, yield: 47%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.48(br s, 1H),7.26-7.15(m,3H),7.15-7.04(m,2H),7.01(m,1H),3.63(m,1H),3.45(s,2H),3.39(m,1H),3.01(m,1H),2.95-2.85(m,2H),2.71 -2.57(m,4H),2.36-2.24(m,3H),2.23-2.12(m,3H),1.82-1.55(m,2H),1.45-1.30(m,5H),1.26(d,J=6.8Hz,3H),1.14(d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 454.3.

[0511] Intermediate 53-1: 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0512] Step 1: 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0513] A mixture containing 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol), chroman-6-carbaldehyde (404 mg, 2.49 mmol), and AcOH (271.97 mg, 4.53 mmol) in DCE (20 mL) was stirred at 20°C for 30 minutes. Then, NaBH(OAc)3 (1.44 g, 6.79 mmol) was added to the mixture in several portions, and the mixture was stirred at 30°C for 2 hours. The reaction mixture was diluted with DCM (30 mL) and washed with saturated NaHCO3 (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 3 / 1 to 1 / 1) to obtain 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.25 g, yield: 94%) as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.34-7.28(m,1H),7.27(s,1H),7.24-7.16(m,1H),7.15-7.09(m,1H),6.68-6.58(m,1H),6. 57-6.50(m,1H),6.40(s,1H),4.93(s,1H),4.44(s,1H),4.15-4.10(m,1H),3.59-3.46(m,2H),3. 33-3.06(m,6H),2.97(t,1H),2.63(s,2H),2.56-2.36(m,2H),2.23(t,1H),1.98-1.83(m,3H),1. 81-1.57(m,3H),1.54-1.38(m,11H),1.37-1.29(m,2H),1.25-1.17(m,3H),0.95(d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 588.4.

[0514] Step 2: 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0515] 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.25 g, 2.13 mmol) was dissolved in THF (15 mL) and BH3.THF (30 mL, 30 mmol) was added dropwise at 20 °C. The mixture was heated at 70 °C for 12 hours. The reaction product was deactivated with methanol (5 mL) and concentrated under reduced pressure to obtain 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.22 g, crude) as a white solid. MS(ESI, m / e)[M+1] + 574.5.

[0516] Step 3: 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0517] 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.20 g, 2.09 mmol) was added dropwise to a 5 mL solution of MeOH (5 mL) with HCl / MeOH (20 mL, 4 M) at 20 °C. The solution was stirred at 20 °C for 2 hours. The reaction solution was concentrated under vacuum. The residue was diluted with HCl (10 mL, 1 M) and extracted with HCl (20 mL x 2). The aqueous phase was adjusted to pH=8 with NaHCO3 and extracted with HCl / MeOH (20 / 1, 40 mL x 5). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (740 mg, yield: 75%) as a white solid. 1H NMR(400MHz,CDCl3)δ ppm:7.47(s,1H),7.17-7.25(m,2H),7.08-7.15(m,1H),6.92-7.04(m,2H),6.70(d,J=8 .19Hz,1H),4.12-4.21(m,2H),3.57-3.80(m,3H),3.41(s,3H),2.83-3.05(m,3H),2.56- 2.82(m,7H),2.21-2.33(m,2H),2.08-2.19(m,1H),1.92-2.03(m,2H),1.60-1.80(m,2H ),1.35-1.54(m,4H),1.28-1.34(m,1H),1.24(d,J=6.85Hz,3H),1.14(d,J=6.85Hz,3H). MS(ESI,m / e)[M+1] + 474.4.

[0518] Intermediate 54-1: 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthalene-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0519] Step 1: 5,6,7,8-tetrahydronaphthalene-2-carboaldehyde and 5,6,7,8-tetrahydronaphthalene-1-carboaldehyde.

[0520] A 50 mL solution of 1,2,3,4-tetrahydronaphthalene (3.0 g, 22.69 mmol) in DCM was cooled to 0°C with vigorous stirring. SnCl4 (10.4 g, 39.94 mmol) was added all at once using a syringe, followed by the dropwise addition of dichloro(methoxy)methane (2.61 g, 22.69 mmol) over 10 minutes. After the addition, the reaction mixture was stirred at 0°C for 0.5 hours. The color of the mixture changed from deep red to yellow. The reaction mixture was deactivated with ice. The organic phase was washed with water (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a mixture of 5,6,7,8-tetrahydronaphthalene-2-carboaldehyde and 5,6,7,8-tetrahydronaphthalene-1-carboaldehyde (3.3 g, crude product) as a dark yellow oil. 1 H NMR (400MHz, CDCl3) δ ppm: 10.39-9.83(m,1H), 7.67-7.56(m,1H), 7.34-7.20(m,1H), 7.12-7.04(m,1H), 1.69-3.37(m,8H).

[0521] Step 2: 2-(2-(2-isopropylphenyl)-6-oxo-4-((5,6,7,8-tetrahydronaphthalene-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl, and 2-(2-(2-isopropylphenyl)-6-oxo-4-((5,6,7,8-tetrahydronaphthalene-1-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0522] A mixture containing 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol), AcOH (271.97 mg, 4.53 mmol), and a mixture of 5,6,7,8-tetrahydronaphthalene-2-carboaldehyde and 5,6,7,8-tetrahydronaphthalene-1-carboaldehyde (435.35 mg, 2.72 mmol) in DCE (20 mL) was stirred at 20°C for 30 minutes. NaBH(OAc)3 (1.44 g, 6.79 mmol) was added to the mixture in several portions, and the mixture was then stirred at 20°C for 3 hours. The reaction mixture was diluted in DCM (30 mL), washed with saturated Na2CO3, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC, adjusted to pH=8 with NaHCO3, concentrated, and extracted with siRNA (50 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-6-oxo-4-((5,6,7,8-tetrahydronaphthalene-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (500 mg, 0.86 mmol) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.33-7.27(m,2H),7.22-7.17(m,1H),7.15-7.10(m,1H),6.82(d,J=7.6Hz,1H),6.65(d,J= 7.6Hz,1H),6.51(s,1H),4.96(s,1H),4.49-4.31(m,1H),3.62-3.48(m,2H),3.28-3.12(m,6H),3 .03-2.92(m,1H),2.71-2.61(m,4H),2.55-2.40(m,2H),2.27-2.19(m,1H),1.93(t,1H),1.81-1 .68(m,6H),1.56-1.41(m,11H),1.36-1.31(m,2H),1.22(d,J=6.8Hz,3H),0.95(d,J=6.8Hz,3H).

[0523] 2-(2-(2-isopropylphenyl)-6-oxo-4-((5,6,7,8-tetrahydronaphthalene-1-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (370 mg, 0.63 mmol) was obtained as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.27-7.16(m,3H),7.12(td,1H),7.03(d,J=7.6Hz,1H),6.96-6.81(m,2H),6.72 (m,1H),4.92(s,1H),4.48(s,1H),3.57-3.49(m,2H),3.30-3.04(m,6H),2.94(m,1H) ,2.73-2.57(m,4H),2.36-2.10(m,4H),1.90(t,1H),1.71(m,2H),1.63-1.58(m,1H), 1.55-1.41(m,13H),1.36-1.29(m,2H),1.20(d,J=6.8Hz,3H),0.91(d,J=6.8Hz,3H).

[0524] Step 3: 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthalene-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0525] 2-(2-(2-isopropylphenyl)-6-oxo-4-((5,6,7,8-tetrahydronaphthalene-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (500 mg, 0.86 mmol) was added dropwise to a solution of THF (8 mL) with BH3.THF (16 mL, 16 mmol) at 20°C. The mixture was heated to 70°C for 12 hours. The reaction product was deactivated with methanol (5 mL) and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthalene-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (488 mg, crude) as a white solid. MS(ESI,m / e)[M+1] + 572.5.

[0526] Step 4: 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthalene-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0527] 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthalene-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (488 mg, 0.85 mmol) was added dropwise to a 5 mL MeOH solution with HCl / MeOH (15 mL, 4 M) at 20°C. The solution was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was diluted with HCl (10 mL, 1 M) and extracted with HCl (10 mL x 2). The aqueous phase was adjusted to pH=8 with NaHCO3 and extracted with HCl (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthalene-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (311 mg, yield: 77%) as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.47(s,1H),7.26-7.15(m,2H),7.11(t,1H),6.99(m,3H),3.66(m,1H),3.48-3.30(m,3H),3 .03-2.82(m,3H),2.82-2.39(m,10H),2.37-2.08(m,3H),1.79-1.60(m,6H),1.41-1.11(m,12H). MS(ESI,m / e)[M+1] + 472.4.

[0528] Intermediate 55-1: 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthalene-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0529] Step 1: 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthalene-1-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0530] 2-(2-(2-isopropylphenyl)-6-oxo-4-((5,6,7,8-tetrahydronaphthalene-1-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (370 mg, 0.63 mmol) was added dropwise to a solution of THF (6 mL) with BH3.THF (12 mL, 12 mmol) at 20 °C. The mixture was heated to 70 °C for 12 hours. The reaction product was inactivated with methanol (5 mL) and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthalene-1-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (361 mg, crude) as a white solid, which was used directly in the next step without further purification. MS(ESI,m / e)[M+1] + 572.5.

[0531] Step 2: 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthalene-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane

[0532] 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthalene-1-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (361 mg, 0.63 mmol) was added dropwise to a 5 mL solution of MeOH (5 mL) with HCl / MeOH (10 mL, 4 M) at 20°C. The solution was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was diluted with HCl (10 mL, 1 M) and extracted with HCl (10 mL x 2). The aqueous phase was adjusted to pH=8 with NaHCO3 and extracted with HCl (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthalene-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (245 mg, yield: 83%) as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.51(s,1H),7.21(m,2H),7.16-7.09(m,2H),7.02(t,1H),6.99-6.92(m,1H),3.64(s,2H),3.45-3.36 (m,2H),3.08-2.86(m,3H),2.82-2.45(m,10H),2.39-2.14(m,3H),1.83-1.63(m,6H),1.42-1.06(m,12H). MS(ESI,m / e)[M+1] + 472.4. MS(ESI,m / e)[M+1] + 472.4.

[0533] Intermediate 57-1: 2-(4-(chroman-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0534] Step 1: Chroman-4-carbonitrile.

[0535] TosMIC (11.9g, 40.50 mmol) and t-BuOH (4.5g, 40.50 mmol) were added at 0°C to a solution containing chroman-4-one (2.0g, 13.50 mmol) in DME (20 mL) and t-BuOH (5 mL). The mixture was stirred at 20°C for 12 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (silica gel, eluent: PE / EA (v / v) = 100 / 1~1 / 1) to obtain chroman-4-carbonitrile (800 mg, 5.03 mmol, yield: 37%) as a yellow oil. MS(ESI, m / e)[M+1] + 160.0.

[0536] Step 2: Chroman-4-carboxylic acid.

[0537] A mixture containing chroman-4-carbonitride (1.6 g, 10.06 mmol) in MeOH (30 mL) and H2O (5 mL) was mixed with NaOH (2.0 g, 50.26 mmol) at 20°C. The mixture was stirred at 100°C for 12 hours. The reaction solution was added to HCl (1 M) to adjust the pH to 1 and extracted with ELISA (50 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain chroman-4-carboxylic acid (850 mg, crude product) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ ppm:12.77-12.47(m,1H),7.20(d,J=7.6Hz,1H),7.16-7.09(m,1H),6.85(m ,1H),6.79-6.74(m,1H),4.20-4.09(m,2H),3.75(m,1H),2.21-2.01(m,2H).

[0538] Step 3: 2-(4-(chroman-4-carbonyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0539] To a 20 mL solution of chroman-4-carboxylic acid (646 mg, 3.62 mmol) in DMF (20 mL), DIEA (585 mg, 4.53 mmol), HATU (1.03 g, 2.72 mmol), and 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl (1.0 g, 2.26 mmol) were added over 3 hours at 20°C. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium 2 SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 100 / 1 to 1 / 1) to obtain 2-(4-(chroman-4-carbonyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.1 g, 1.83 mmol, yield: 82%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm:7.50-7.39(m,1H),7.37-7.19(m,2H),7.17(s,1H),7.04-6.90(m,1H),6.89-6.69(m,2H),6.68-6.54(m,1H),5.41 -5.27(m,1H),4.82-4.45(m,2H),4.37-4.15(m,1H),4.13-3.94(m,2H),3.92-3.70(m,1H),3.60-3.38(m,2H),3.20(br s, 2H),3.09(br s, 2H), 2.17-1.73 (m, 4H), 1.68-1.52 (m, 2H), 1.49-1.39 (m, 2H), 1.35 (s, 9H), 1.30-1.15 (m, 8H), 0.91-0.56 (m, 1H).

[0540] Step 4: 2-(4-(chroman-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0541] A solution of 2-(4-(chroman-4-carbonyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.1 g, 1.83 mmol) in BH3.THF (20 mL, 1 M in THF) was allowed to stand at 20°C for 12 hours. The reaction mixture was cooled to 0°C. Then, MeOH (10 mL) was added dropwise at 0°C, and the mixture was concentrated under vacuum to obtain 2-(4-(chroman-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.05 g, crude product) as a white solid. MS(ESI, m / e)[M+1] + 574.4.

[0542] Step 5: 2-(4-(chroman-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0543] A solution of 2-(4-(chroman-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 1.74 mmol) in MeOH (5 mL) was mixed with HCl / MeOH (20 mL, 4 M) at 20 °C. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under vacuum and poured into H2O (20 mL), and extracted with ELISA (20 mL). The aqueous phase was added to saturated Na2CO3 to adjust the pH to 10, and extracted with ELISA (50 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous sodium 2SO4, filtered, and concentrated under vacuum to obtain 2-(4-(chroman-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (615 mg, 374.47 umol, yield: 74%) as a white solid. 1H NMR(400MHz,CDCl3)δ ppm:7.61-7.40(m,1H),7.28-6.98(m,5H),6.92-6.72(m,2H),4.21-4.10(m,2H),3.73-3.59(m,1H),3.49-3.33(m,1H) ),3.07-2.80(m,4H),2.65-2.44(m,6H),2.37-2.07(m,4H),2.05-1.87(m,2H),1.82-1.64(m,2H),1.39-1.14(m,13H). MS(ESI,m / e)[M+1] + 474.4.

[0544] Intermediate 58-1: 2-(4-(benzo[b]thiophen-5-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0545] Step 1: Benzo[b]thiophene-5-carboaldehyde

[0546] 5-bromobenzo[b]thiophene (1.0 g, 4.69 mmol) was dissolved in THF (30 mL) and i-PrMgCl.LiCl (25 mL, 32.50 mmol) was added at -60°C. The mixture was stirred at 25°C for 12 hours. Then, DMF (5 mL) was added dropwise. The reaction mixture was inactivated with aqueous NH4Cl (50 mL) and extracted with ELISA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA (v / v) = 20 / 1 to 10 / 1) to obtain benzo[b]thiophene-5-carboaldehyde (452 ​​mg, yield: 59%) as a yellow oil.

[0547] Step 2: 2-(4-(benzo[b]thiophen-5-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0548] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) in DCE (10 mL), AcOH (271.97 mg, 4.53 mmol) and benzo[b]thiophene-5-carboaldehyde (404.05 mg, 2.49 mmol) were added, and the mixture was stirred at 25°C for 1 hour, then NaBH(OAc)3 (1.44 g, 6.79 mmol) was added. The mixture was stirred at 25°C for another 12 hours. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1~2 / 1) to obtain 2-(4-(benzo[b]thiophene-5-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.04 mmol, yield: 90%) as a yellow oil.

[0549] Step 3: 2-(4-(benzo[b]thiophen-4-ylmethyl)-2-(2-isopropylphenyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0550] A mixture containing 2-(4-(benzo[b]thiophene-5-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.04 mmol) and BH3.THF (20.41 mL, 20.41 mmol) in THF was stirred at 70°C for 12 hours. The reaction solution was inactivated with MeOH (10 mL) and concentrated under reduced pressure to obtain 2-(4-(benzo[b]thiophene-5-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.26 g, crude) as a yellow oil, which was used directly in the next step without further reaction. MS(ESI,m / e)[M+1] + 574.3.

[0551] Step 4: 2-(4-(benzo[b]thiophen-5-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0552] A mixture of 2-(4-(benzo[b]thiophen-5-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.26 g, 2.20 mmol) and TFA (5.1 mL, 43.92 mmol) was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure. The mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA conditions). The residue was diluted with H2O (20 mL), Na2CO3 was added to bring the pH to 9, and the mixture was extracted with siRNA (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(4-(benzo[b]thiophen-5-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (132 mg, 278.65 μmol, yield: 13%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.80(d,J=8.4Hz,1H),7.75(s,1H),7.48(br s, 1H),7.42(d,J=5.6Hz,1H),7.33(m,2H),7.18-7.25(m,2H),7.09-7.15(m,1H),3.64(m,2H),3 .30-3.48(m,1H),2.86-3.02(m,2H),2.72(m,4H),2.20-2.38(m,3H),1.62-1.83(m,3H),1.42(br s, 4H), 1.23-1.28(m, 4H), 1.13(m, 4H), 0.89(br s, 2H). MS(ESI,m / e)[M+1] + 474.3.

[0553] Intermediate 59-1: 2-(4-(benzo[b]thiophen-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0554] Step 1: Benzo[b]thiophene-4-ylmethanol.

[0555] 900 mg, 5.05 mmol of benzo[b]thiophene-4-carboxylic acid was added to a 10 mL solution of DCM with LAH (383.36 mg, 10.10 mmol) at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was inactivated with an aqueous solution of NaOH (0.8 mL, 25%) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 5 / 1~2 / 1) to obtain benzo[b]thiophene-4-ylmethanol (800 mg, 4.87 mmol, yield: 96%) as a yellow oil.

[0556] Step 2: Benzo[b]thiophene-4-carboaldehyde.

[0557] A mixture containing benzo[b]thiophene-4-ylmethanol (800 mg, 4.87 mmol) and MnO2 (4.24 g, 48.71 mmol) in DCM (10 mL) was stirred at 50°C for 3 hours. The reaction product was filtered and extracted with siRNA (100 mL x 2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 5 / 1 to 2 / 1) to obtain benzo[b]thiophene-4-carboaldehyde (625 mg, 3.85 mmol, yield: 79%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:10.29-10.20(s,1H),8.39(d,J=5.6Hz,1H),8.14(d,J=8.0Hz,1H),7.86(d,J=7.6Hz,1H),7.73(d,J=5.6Hz,1H),7.58-7.46(m,1H).

[0558] Step 3: 2-(4-(benzo[b]thiophene-4-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl

[0559] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.72 mmol) in DCE (10 mL), AcOH (326.36 mg, 5.43 mmol) and benzo[b]thiophene-4-carboaldehyde (484.86 mg, 2.99 mmol) were added. The mixture was stirred at 25°C for 1 hour, and NaBH(OAc)3 (1.73 g, 8.15 mmol) was added to the solution. The mixture was stirred at 25°C for another 12 hours. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1~2 / 1)2-(4-(benzo[b]thiophene-4-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (900 mg, 1.53 mmol, yield: 56%) as a yellow oil.

[0560] Step 4: 2-(4-(benzo[b]thiophen-4-ylmethyl)-2-(2-isopropylphenyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0561] A mixture containing tert-butyl 2-(4-(benzo[b]thiophene-4-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate in 10 mL of DCM was stirred at 70°C for 12 hours. The reaction solution was inactivated with 10 mL of MeOH and concentrated under reduced pressure to obtain 2-(4-(benzo[b]thiophene-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (850 mg, crude), which was used directly in the next step without further purification.

[0562] Step 5: 2-(4-(benzo[b]thiophen-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0563] A mixture containing 2-(4-(benzo[b]thiophen-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (850 mg, 1.48 mmol) and HCl (3.70 mL, 14.81 mmol) in MeOH (30 mL) was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was poured into saturated NaHCO3 (50 mL) and extracted with siRNA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA conditions). The residue was diluted with H2O (20 mL), Na2CO3 was added to bring the pH to 9, and the mixture was extracted with siRNA (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(4-(benzo[b]thiophen-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (183 mg, 386.31 μmol, yield: 26%) as a yellow oil. 1H NMR(400MHz,CDCl3)δ ppm:7.78(d,J=7.6Hz,1H),7.71-7.63(m,1H),7.52-7.43(m,2H),7.32-7.29(m,1H),7.23-7.20(m,2H),7.15-7.07(m,2H), 3.83(s,2H),3.63(m,1H),3.02-2.87(m,4H),2.71-2.61(m,6H),2.41-2.24(m,4H),1.70-1.62(m,2H),1.35(m,4H),1.25(br s, 3H), 1.14 (d, J=6.8Hz, 3H), 1.07 (d, J=6.8Hz, 3H). MS(ESI,m / e)[M+1] + 474.3.

[0564] Intermediate 60-1: (3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonan-2-yl)piperazine-1-yl)(phenyl)methanone [ka]

[0565] Step 1: 2-(4-benzoyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0566] To a solution of 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.1 g, 2.57 mmol) in DCM (10 mL), TEA (1.04 g, 10.29 mmol) was added at 25°C for 30 minutes. Then, benzoyl chloride (723.2 mg, 5.14 mmol) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was poured into saturated NH4Cl (50 mL), extracted with DCM (50 mL), and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 100 / 1 to 10 / 1) to obtain 2-(4-benzoyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (700 mg, 1.32 mmol, yield: 51%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.54-7.29(m,6H),7.25-7.02(m,3H),4.81-4.67(m,1H),4.55-4.43(m,1H),3.83(br d,J=7.2Hz,1H),3.46(br s, 2H), 3.28-3.07 (m, 7H), 3.03-2.92 (m, 2H), 2.33-2.18 (m, 1H), 1.85-1.52 (m, 4H), 1.41 (s, 9H), 1.36-1.10 (m, 12H), 0.94 (br s, 2H).

[0567] Step 2: (3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)(phenyl)methanone

[0568] A mixture containing 2-(4-benzoyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (700 mg, 1.32 mmol) in DCM (100 mL) was mixed with TFA (3 mL) at 25°C. The mixture was stirred at 25°C for 45 minutes. Water (40 mL) was added to the reaction solution and extracted with ELISA (50 mL). The aqueous phase was adjusted to pH 9-10 with saturated Na2CO3. The residual mixture was extracted with ELISA (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain (3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)(phenyl)methanone (390 mg, 903.59 umol, yield: 68%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.83(d,J=7.2Hz,1H),7.57-7.30(m,7H),7.22-7.09(m,2H),4.74(m,1H),4.41-4.79(m,1H),3.63-3.39(m,2H),3.21- 3.07(m,2H),3.07-2.83(m,2H),2.75-2.49(m,4H),2.31-2.13(m,1H),1.69(m,2H),1.42-1.15(m,10H),1.06-0.81(m,1H). MS(ESI,m / e)[M+1] + 432.3.

[0569] Intermediate 61-1: (3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonan-2-yl)piperazine-1-yl)(4-methoxyphenyl)methanone [ka]

[0570] Step 1: 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0571] 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (2.0 g, 4.53 mmol) was dissolved in THF (20 mL) and BH3.THF (30 mL, 22.5 mmol) was added. The mixture was heated to 70°C and stirred at 70°C for 12 hours. After cooling to 0°C, the mixture was deactivated with MeOH (10 mL). The mixture was concentrated under vacuum to obtain the crude product, which was purified by column chromatography to obtain 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.7 g, yield: 50%) as a white solid. MS(ESI,m / e)[M+1] + 428.5

[0572] Step 2: 2-(2-(2-isopropylphenyl)-4-(4-methoxybenzoyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0573] 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (700 mg, 1.64 mmol) and 4-methoxybenzoic acid (274 mg, 1.8 mmol) were dissolved in DCM (10 mL), to which HATU (685 mg, 1.8 mmol) and Et3N (364 mg, 3.6 mmol) were added. The mixture was stirred at 25°C for 16 hours. The mixture was poured into H2O (20 mL) and extracted with DCM (20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=20 / 1~2 / 1) to obtain 2-(2-(2-isopropylphenyl)-4-(4-methoxybenzoyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.4g, yield: 60%) as a yellow oil. MS(ESI,m / e)[M+1] + 562.3.

[0574] Step 3: (3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)(4-methoxyphenyl)methanone.

[0575] 2-(2-(2-isopropylphenyl)-4-(4-methoxybenzoyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (400 mg, 0.71 mmol) was dissolved in MeOH (10 mL) and HCl / MeOH (10 mL) was added. The mixture was stirred at 25°C for 2 hours. After concentration under vacuum, the residue was dissolved in water (20 mL). The mixture was adjusted to pH 9-10 with Na2CO3 aqueous solution. The mixture was extracted with ELISA (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous sodium 2SO4, filtered, and concentrated under vacuum to obtain (3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)(4-methoxyphenyl)methanone (305 mg, yield: 93%) as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.45-7.38(m,3H),7.27-7.14(m,3H),7.00-6.87(m,2H),3.80(s,3H),3.52-3.48(m,3H),3 .10-2.91(m,3H),2.70-2.55(m,4H),2.25-2.17(m,1H),1.80-1.61(m,2H),1.52-0.89(m,14H). MS(ESI,m / e)[M+1] + 462.3

[0576] Intermediate 62-1: 2-(2-(2-isopropylphenyl)-4-(methylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0577] Step 1: 2-(2-(2-isopropylphenyl)-6-oxo-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0578] TEA (206 mg, 2.04 mmol) was added to a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.5 g, 1.13 mmol) in DCM (6 mL). After cooling to 0°C, benzenesulfonyl chloride (300 mg, 1.7 mmol) was added. The mixture was stirred at 25°C for 2 hours. The mixture was poured into water (10 mL) and extracted with DCM (20 mL x 3). The combined organic phase was concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=20 / 1~10 / 1) to obtain 2-(2-(2-isopropylphenyl)-6-oxo-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.6g, yield: 91%) as a yellow oil. MS(ESI,m / e)[M+1] + 582.3

[0579] Step 2: 2-(2-(2-isopropylphenyl)-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0580] A mixture of 2-(2-(2-isopropylphenyl)-6-oxo-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.6 g, 1.03 mmol) and BH3.THF (5 mL, 5 mmol) was heated at 70°C for 12 hours. After cooling to 0°C, the mixture was deactivated with MeOH (10 mL). The mixture was concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.45 g, yield: 65%) as a yellow oil. MS(ESI,m / e)[M+1] + 568.2.

[0581] Step 3: 2-(2-(2-isopropylphenyl)-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane

[0582] 2-(2-(2-isopropylphenyl)-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (450 mg, 0.79 mmol) was dissolved in MeOH (10 mL) and HCl / MeOH (10 mL) was added. The mixture was stirred at 25°C for 2 hours. After concentration under vacuum, the residue was dissolved in water (20 mL). The mixture was adjusted to pH 9-10 with Na2CO3 aqueous solution. The mixture was extracted with siRNA (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (310 mg, yield: 94%) as a white solid. 1H NMR(400MHz,CDCl3)δ ppm:7.74-7.72(m,2H),7.61(m,1H),7.55-7.53(m,2H),7.28-7.25(m,3 H),7.09-7.07(m,1H),3.83-3.80(m,1H),3.74-3.71(m,1H),3.52-3.49 (m,1H),3.03-3.00(m,1H),2.88-2.85(m,1H),2.62-2.60(m,6H),2.38- 2.35(m,3H),1.77-1.74(m,1H),1.59-1.56(m,1H),1.34-1.24(m,11H). MS(ESI,m / e)[M+1] + 468.3

[0583] Intermediate 63-1: 2-(2-(2-isopropylphenyl)-4-(1-phenylbuta-2-in-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0584] Step 1: 1-phenylbuta-2-in-1-ol.

[0585] To a solution of benzaldehyde (4.0 g, 37.69 mmol) in THF (100 mL), THF (0.5 M) (90.5 mL, 45.23 mmol) containing propane-1-in-1-ylmagnesium bromide was added dropwise at -70°C. The mixture was warmed to 20°C and stirred at 20°C for 12 hours. After cooling to 0°C, the mixture was deactivated with saturated NH4Cl aqueous solution (100 mL). The mixture was extracted with  (50 mL x 2). The organic layer was dried over Na2SO4. 、 Under vacuum, 1-phenylbuta-2-in-1-ol (5.0 g, yield: 90%) was obtained as a yellow oil by evaporation. 1 H NMR (400MHz, CDCl3) δ ppm:7.46-7.44(d,J=6.8Hz,2H),7.31-7.24(m,3H),5.34(s,1H),2.17(s,1H),1.83(s,3H).

[0586] Step 2: 1-phenylbuta-2-in-1-yl methanesulfonate.

[0587] A solution containing 1-phenylbuta-2-in-1-ol (2.5 g, 17 mmol) and Et3N (5.1 g, 51 mmol) in DCM (25 mL) was prepared, to which MsCl (2.15 g, 18.8 mmol) was added at 25 °C. The mixture was stirred at 25 °C for 1 hour. The mixture was poured into H2O (20 mL) and extracted with DCM (20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue (2.6 g, yield: 95%) as a yellow oil, which was used directly in the next step without further purification.

[0588] Step 3: 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0589] 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (2.0 g, 4.53 mmol) was dissolved in THF (20 mL) and BH3.THF (30 mL, 22.5 mmol) was added. The mixture was heated to 70°C and stirred at 70°C for 12 hours. After cooling to 0°C, the mixture was deactivated with MeOH (10 mL). The mixture was concentrated under vacuum to obtain the crude product, which was purified by column chromatography to obtain 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.7 g, yield: 50%) as a white solid.

[0590] Step 4: 2-(2-(2-isopropylphenyl)-4-(1-phenylbuta-2-in-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0591] To a solution of 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.7 g, 1.64 mmol) in CH3CN (20 mL), K2CO3 (0.68 g, 4.91 mmol) and 1-phenylbuta-2-in-1-yl methanesulfonic acid (0.55 g, 2.46 mmol) were added. The mixture was stirred at 50°C for 1 hour. After concentration under vacuum, the residue was dissolved in water (20 mL). The mixture was extracted with siRNA (10 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous sodium 2SO4, filtered, and concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-(1-phenylbuta-2-in-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (240 mg, yield: 27%) as a yellow oil.

[0592] Step 5: 2-(2-(2-isopropylphenyl)-4-(1-phenylbuta-2-in-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0593] 2-(2-(2-isopropylphenyl)-4-(1-phenylbuta-2-in-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (240 mg, 0.43 mmol) was dissolved in MeOH (10 mL) and HCl / MeOH (10 mL) was added. The mixture was stirred at 25°C for 2 hours. After concentration under vacuum, the residue was dissolved in water (10 mL). The mixture was adjusted to pH = 9-10 using an aqueous Na2CO3 solution. The mixture was extracted with ELISA (10 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-(1-phenylbuta-2-in-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane (170 mg, yield: 73%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.54-7.28(m,5H),7.25-7.08(m,4H),4.71-4.50(d,1H),3.68-3.51(m,1H),3.49-3.20(m,1H),3.10-2.93(m,1H),2.92 -2.89(m,2H),2.71-2.65(m,6H),2.42-2.19(m,3H),1.90(s,3H),1.72-1.66(m,2H),1.50-1.10(m,11H),1.02-0.98(m,2H). MS(ESI,m / e)[M+1] + 456.4.

[0594] Intermediate 64-1: 2-(2-(2-isopropylphenyl)-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0595] Step 1: 3-phenylcyclopentan-1-one.

[0596] To a solution containing cyclopenta-2-en-1-one (3.0 g, 36 mmol) in toluene (80 mL) and CHCl3 (0.4 mL), phenylboronic acid (5.27 g, 43 mmol), Pd(OAc)2 (0.81 g, 3.6 mmol), PPh3 (1.9 g, 7.2 mmol), and Cs2CO3 (23 g, 72 mmol) were added. The mixture was heated to 80°C for 4 hours. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 10 / 1) to obtain 3-phenylcyclopentan-1-one (2.8 g, yield: 48%) as a brown oil. 1 H NMR (400MHz, CDCl3) δ ppm:7.39-7.34(m,2H),7.28(m,3H),3.52-3.38(m,1H),2.70(m,1H),2.52-2.29(m,4H),2.09-1.95(m,1H).

[0597] Step 2: 2-(2-(2-isopropylphenyl)-6-oxo-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0598] To a solution of 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol) in DCE (20 mL), 3-phenylcyclopentan-1-one (540 mg, 3.40 mmol) and HOAc (0.27 g, 4.52 mmol) were added. After stirring at 25°C for 1 hour, NaBH(OAc)3 (0.96 g, 4.52 mmol) was added. The mixture was stirred at 25°C for 12 hours. Then, aqueous solution of NH4Cl (20 mL) was added to the mixture and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=1 / 1) to obtain 2-(2-(2-isopropylphenyl)-6-oxo-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.66 g, yield: 50%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.33-7.27(m,3H),7.26-7.24(m,1H),7.21-7.14(m,3H),7.13-7.07(m,2H),5.09(br d,J=5.25Hz,1H),4.25-4.10(m,1H),3.44-3.10(m,8H),3.09-2.88(m,2H),2.82-2.65(m,1H),2.64-2.47(m,1H),2.32-2 .09(m,2H),2.05-1.95(m,2H),1.94-1.78(m,2H),1.76-1.51(m,5H),1.42(s,9H),1.39-1.35(m,2H),1.31-1.25(m,6H).

[0599] Step 3: 2-(2-(2-isopropylphenyl)-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0600] A mixture of 2-(2-(2-isopropylphenyl)-6-oxo-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.66 g, 1.13 mmol) and BH3.THF (11 mL, 11.3 mmol) was heated at 70°C for 12 hours. Then, MeOH (10 mL) was added dropwise to deactivate the reaction. The mixture was concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.6 g, yield: 93%) as a yellow oil, which was used without further purification. MS(ESI,m / e)[M+1] + 572.4.

[0601] Step 4: 2-(2-(2-isopropylphenyl)-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0602] 2-(2-(2-isopropylphenyl)-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (600 mg, 1.05 mmol) was dissolved in MeOH (20 mL) and HCl / MeOH (10 mL) was added. The mixture was stirred at 25°C for 1 hour. After removing the solvent, the residue was dissolved in water (20 mL). The mixture was adjusted to pH 9-10 using an aqueous solution of Na2CO3. The mixture was then extracted with ELISA (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(2-(2-isopropylphenyl)-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (450 mg, yield: 91%) as a yellow solid.1 H NMR(400MHz,CDCl3)δ ppm:7.52(br s, 1H),7.32-7.28(m,1H),7.26-7.11(m,7H),3.70(br s,1H),3.40(br s,1H),3.13-3.00(m,3H),2.92(br s, 1H), 2.80 (m, 1H), 2.72-2.60 (m, 5H), 2.39-2.25 (m, 3H), 2.23-2.03 (m, 4H), 1.98- 1.85 (m, 1H), 1.78 (m, 2H), 1.73-1.57 (m, 3H), 1.46-1.32 (m, 5H), 1.26-1.17 (m, 6H). MS(ESI,m / e)[M+1] + 472.5.

[0603] Intermediate 65-1: 2-(2-(2-isopropylphenyl)-4-phenylpiperazine-1-yl)-7-azaspiro[3.5]nonane [ka]

[0604] Step 1: 2-(2-isopropylphenyl)-3-oxo-4-phenylpiperazine-1-carboxylate tert-butyl.

[0605] To a solution of tert-butyl 2-(2-isopropylphenyl)-3-oxopiperazine-1-carboxylate (1.5 g, 4.7 mmol) in DCE (150 mL), phenylboronic acid (2.3 g, 18.8 mmol), Cu(OAc)2 (1.4 g, 9.4 mmol), 4A MS (1.5 g), and TEA (9.5 g, 94.2 mmol) were added. The mixture was stirred under O2 at 75°C for 12 hours. The mixture was filtered and concentrated to obtain a residue, which was extracted with 1 M HCl (50 mL) and EA (20 mL x 3). The combined organic layers were dried and concentrated to obtain a residue, which was purified by column chromatography (silica gel, eluent: PE / EA (v / v) = 20 / 1). Compound 2-(2-isopropylphenyl)-3-oxo-4-phenylpiperazine-1-carboxylate tert-butyl (1.2 g, yield: 64%) was obtained as a brown oil.

[0606] Step 2: 3-(2-isopropylphenyl)-1-phenylpiperazine-2-one.

[0607] A solution containing 2-(2-isopropylphenyl)-3-oxo-4-phenylpiperazine-1-carboxylate tert-butyl (1.1 g, 2.8 mmol) in TFA (5 mL) and DCM (5 mL) was stirred at 27°C for 2 hours. The mixture was concentrated to obtain a residue, which was extracted with EA (30 mL x 3) and saturated NaHCO3 (30 mL). The combined organic layers were dried and concentrated to obtain 3-(2-isopropylphenyl)-1-phenylpiperazine-2-one (0.82 g, crude) as a brown oil, which was used as is.

[0608] Step 3: 2-(2-(2-isopropylphenyl)-3-oxo-4-phenylpiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0609] To a solution of 3-(2-isopropylphenyl)-1-phenylpiperazine-2-one (820 mg, 2.8 mmol) in DCE (10 mL), 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (666 mg, 2.8 mmol) and NaBH(OAc)3 (1.2 g, 5.6 mmol) were added. The mixture was stirred at 27°C for 10 hours. The mixture was extracted with saturated NaHCO3 (50 mL) and DCM (20 mL x 3) to obtain 2-(2-(2-isopropylphenyl)-3-oxo-4-phenylpiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.3 g, crude product) as a yellow oil, which was used as is.

[0610] Step 4: 2-(2-(2-isopropylphenyl)-4-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl. A solution of 2-(2-(2-isopropylphenyl)-3-oxo-4-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.3 mmol) in BH3-THF (10 mL) was stirred at 70°C for 10 hours. The mixture was deactivated with MeOH (10 mL) and concentrated to obtain 2-(2-(2-isopropylphenyl)-4-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (2.1 g, crude product) as a yellow oil, which was used as is.

[0611] Step 5: 2-(2-(2-isopropylphenyl)-4-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane.

[0612] A solution of 2-(2-(2-isopropylphenyl)-4-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.1 g, 2.2 mmol) in TFA (3 mL) and DCM (6 mL) was stirred at 20°C for 2 hours. The mixture was concentrated to obtain a residue, which was purified by preparative HPLC (TFA). Compound 2-(2-(2-isopropylphenyl)-4-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane (570 mg, 65% yield) was obtained as a white solid. 1H NMR(400MHz, methanol-d4)δ ppm:7.53(d,J=7.6Hz,1H),7.36-7.31(m,1H),7.29-7.14(m,4H),6.93(d,J=7.9Hz,2H),6.83(t,J=7.3Hz,1H),3.82-3.70(m,2H),3.49(br d,J=6.3Hz,1H),3.35(td,J=2.6Hz,12.2Hz,1H),3.17(td,J=2.5Hz,11.5Hz,1H),3.03-2.91(m,2H),2.85(dd,J=10.8Hz,12.1Hz,1H),2.68-2. 48(m,4H),2.39(dt,J=3.0Hz,11.8Hz,1H),1.92-1.83(m,1H),1.75-1. 68(m,1H),1.46-1.28(m,9H),1.24(d,J=6.9Hz,3H),1.18-1.10(m,1H). MS(ESI,m / e)[M+1] + 404.4.

[0613] Intermediate 66-1: 2-(2-(2-isopropylphenyl)-4-(methylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0614] Step 1: 2-(2-(2-isopropylphenyl)-4-(methylsulfonyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0615] 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.1 g, 2.5 mmol) was dissolved in DCM (20 mL) and TEA (506 mg, 5.0 mmol) was added. After cooling to 0°C, MsCl (340 mg, 3.0 mmol) was added. The mixture was stirred at 25°C for 2 hours. The mixture was poured into an aqueous solution of NH4Cl (1 M, 20 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 20 / 1 to 10 / 1) to obtain 2-(2-(2-isopropylphenyl)-4-(methylsulfonyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.07 g, yield: 82%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.41-7.37(m,1H),7.36-7.31(m,1H),7.18(t,1H),6.97(d,J=7.6Hz,1H),5.11(br s, 1H),4.52(br s, 1H),4.18-4.08(m,2H),4.01-3.94(m,1H),3.71-3.54(m,2H),3.30-3.09(m,5H),2.37(s,3H),2.26(m,1H),1.93(br t, 1H), 1.82-1.70 (m, 2H), 1.59 (m, 1H), 1.53-1.46 (m, 2H), 1.42 (s, 9H), 1.36 (m, 3H), 1.30 (m, 3H).

[0616] Step 2: 2-(2-(2-isopropylphenyl)-4-(methylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0617] A mixture of 2-(2-(2-isopropylphenyl)-4-(methylsulfonyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.07 g, 2.06 mmol) and BH3.THF (10 mL, 10 mmol) was heated at 70°C for 12 hours. After cooling to 0°C, the mixture was deactivated with MeOH (10 mL). The mixture was concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-(methylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.8 g, yield: 80%) as a yellow oil, which was used in the next step without further purification. MS(ESI,m / e)[M+1] + 506.3.

[0618] Step 3: 2-(2-(2-isopropylphenyl)-4-(methylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0619] 2-(2-(2-isopropylphenyl)-4-(methylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (800 mg, 1.58 mmol) was dissolved in MeOH (20 mL) and HCl / MeOH (10 mL) was added. The mixture was stirred at 25°C for 2 hours. After concentration under vacuum, the residue was dissolved in water (20 mL). The mixture was adjusted to pH 9-10 using an aqueous solution of Na2CO3. The mixture was extracted with  (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-(methylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (570 mg, yield: 89%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.45(m,1H),7.31-7.27(m,2H),7.18-7.13(m,1H),3.80(m,1H),3.67(m,1H),3.50(m,1H),3.35(br s, 1H), 3.12 (m, 1H), 2.99-2.91 (m, 2H), 2.77 (s, 3H), 2.67-2.57 (m, 4H), 2.33 (m, 1H), 1.91- 1.75(m,3H),1.66-1.60(m,1H),1.39-1.29(m,5H),1.25(m,3H),1.20-1.13(m,3H),1.16(br s, 1H). MS(ESI,m / e)[M+1] + 406.3.

[0620] Intermediate 67-1: 2-(4-benzyl-2-(2-isopropylphenyl)piperidine-1-yl)-7-azaspiro[3.5]nonane. [ka]

[0621] Step 1: 2-(2-isopropylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-benzyl carboxylate.

[0622] Benzyl carbonochloride (3.2 mL, 22 mmol) was added dropwise to a solution of 4-methoxypyridine (1.82 g, 17 mmol) in anhydrous THF (50 mL) at -20°C. The mixture was stirred at -20°C for 1 hour. In a separate flask, THF (20 mL) containing magnesite (0.9 g, 38 mmol) was added under N2 at 25°C. A small amount of I2 (22 mg, 0.17 mmol) was added, followed by the dropwise addition of 1-bromo-2-isopropylbenzene (5.0 g, 25 mmol). The mixture was heated at 70°C for 1 hour until the brown color completely disappeared. The resulting Grignard reagent solution was added dropwise to the pyridinium salt at -20°C. The mixture was stirred at -20°C for 1 hour. The mixture was poured into HCl (1 M, 50 mL) and extracted with siRNA (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=10 / 1) to obtain 2-(2-isopropylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate benzyl (5.5 g, yield: 92%) as a brown oil. 1 H NMR(400MHz,CDCl3)δ ppm:8.23(d,J=8.4Hz,1H),7.36-7.32(m,1H),7.31-7.22(m,4H),7.15-7.06(m,2H),7.05-7.00(m,1H),5.97(d,J=8.4Hz, 1H),5.37(d,J=8.4Hz,1H),5.22-5.11(m,2H),3.38(m,1H),3.06(t,1H),2.24(m,1H),1.23(d,J=6.8Hz,3H),1.05(m,3H).

[0623] Step 2: 2-(2-isopropylphenyl)-4-oxypiperidine-1-carboxylate benzyl.

[0624] Zinc (10 g, 0.16 mmol) was added at 25°C to a solution of 2-(2-isopropylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-benzyl carboxylate (5.5 g, 0.016 mmol) in HOAc (20 mL). The mixture was stirred at 25°C for 12 hours. After filtering the mixture, the filtrate was concentrated under vacuum. The residue was dissolved in siRNA (50 mL) and washed with saturated NaHCO3 (30 mL x 2) and brine (30 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=1 / 1) to obtain 2-(2-isopropylphenyl)-4-oxypiperidine-1-benzyl carboxylate (5.4 g, yield: 96%) as a brown oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.33-7.28(m,5H),7.23-7.11(m,4H),5.87(br s, 1H),5.26-5.20(m,1H),5.19-5.06(m,1H),4.30(br s, 1H), 3.35-3.11 (m, 2H), 2.87-2.80 (m, 2H), 2.59-2.46 (m, 2H), 1.20 (d, J = 6.8Hz, 3H), 1.03 (d, J = 5.2Hz, 3H).

[0625] Step 3: (E)-4-benzylidene-2-(2-isopropylphenyl)piperidine-1-carboxylate benzyl

[0626] A mixture containing benzyltriphenylphosphonium bromide (4.44 g, 10.24 mmol) in THF (40 mL) was to which NaH (0.41 g, 10.24 mmol) was added in several portions at 0°C. After stirring at 25°C for 1 hour, THF (10 mL) containing 2-(2-isopropylphenyl)-4-oxypiperidine-1-carboxylate benzyl (3.0 g, 8.54 mmol) was added. The mixture was stirred at 25°C for 12 hours. The mixture was carefully poured into an aqueous solution of NH4Cl (10 mL) and extracted with ELISA (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=10 / 1) to obtain (E)-4-benzylidene-2-(2-isopropylphenyl)piperidine-1-carboxylate benzyl (0.8g, yield: 22%) as a yellow oil. MS(ESI,m / e)[M+1] + 426.4.

[0627] Step 4: 4-benzyl-2-(2-isopropylphenyl)piperidine.

[0628] (E)-4-benzylidene-2-(2-isopropylphenyl)piperidine-1-carboxylate benzyl (800 mg, 1.88 mmol) was dissolved in MeOH (30 mL) and Pd(OH)2 / C (0.5 g) was added. The mixture was stirred at 30°C for 12 hours under an H2 (15 psi) atmosphere. After filtration, the filtrate was concentrated under vacuum to obtain 4-benzyl-2-(2-isopropylphenyl)piperidine (450 mg, yield: 82%) as a yellow oil, which was used in the next step without further purification. MS(ESI,m / e)[M+1] + 294.4.

[0629] Step 5: 2-(4-benzyl-2-(2-isopropylphenyl)piperidine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0630] A solution containing 4-benzyl-2-(2-isopropylphenyl)piperidine (450 mg, 1.54 mmol), 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (611 mg, 2.3 mmol), and AcOH (185 mg, 3.08 mmol) in DCE (20 mL) was stirred at 25°C for 1 hour, then NaBH(OAc)3 (954 mg, 4.5 mmol) was added in several portions, and the mixture was stirred at 25°C for 12 hours. The mixture was poured into saturated NaHCO3 (20 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1) to obtain 2-(4-benzyl-2-(2-isopropylphenyl)piperidine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (300 mg, yield: 38%) as a brown oil. MS(ESI,m / e)[M+1] + 517. 4.

[0631] Step 6: 2-(4-benzyl-2-(2-isopropylphenyl)piperidine-1-yl)-7-azaspiro[3.5]nonane.

[0632] 2-(4-benzyl-2-(2-isopropylphenyl)piperidine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (300 mg, 0.58 mmol) was added to a 20 mL MeOH solution with HCl / MeOH solution (10 mL). The mixture was stirred at 25°C for 1 hour. After removing the solvent, the residue was poured into 20 mL of water. The mixture was adjusted to pH 9-10 using an aqueous Na2CO3 solution. The mixture was extracted with  (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (TFA) to obtain 2-(4-benzyl-2-(2-isopropylphenyl)piperidine-1-yl)-7-azaspiro[3.5]nonane (200 mg, yield: 83%) as the TFA salt. 1H NMR(400MHz,CDCl3)δ ppm:7.58(d,J=8.0Hz,1H),7.47-7.38(m,2H),7.33-7.23(m,5H),7.22-7.17(m,1H),4.84(br s, 1H), 3.82 (m, 1H), 3.58-3.44 (m, 2H), 3.42-3.34 (m, 1H), 3.07-2.93 (m, 6H), 2.49-2.31 (m, 3H), 2.27-2.1 1(m,2H),1.91(m,1H),1.76-1.50(m,6H),1.41(d,J=6.8Hz,3H),1.19(d,J=6.8Hz,3H),0.94-0.87(m,1H). MS(ESI,m / e)[M+1] + 417.4.

[0633] Intermediate 68-1: 2-(2-(2-isopropylphenyl)-4-phenoxypiperidine-1-yl)-7-azaspiro[3.5]nonane [ka]

[0634] Step 1: 4-hydroxy-2-(2-isopropylphenyl)piperidine-1-carboxylate benzyl.

[0635] 2-(2-isopropylphenyl)-4-oxypiperidine-1-carboxylate benzyl (2.6 g, 7.4 mmol) was added in MeOH (20 mL) solution to NaBH4 (0.56 g, 14.8 mmol) in several portions at 0°C. The mixture was stirred at 25°C for 1 hour. The mixture was poured into H2O (20 mL) and extracted with siRNA (20 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=10 / 1) to obtain 4-hydroxy-2-(2-isopropylphenyl)piperidine-1-carboxylate benzyl (2.02 g, yield: 78%) as a brown oil. MS(ESI,m / e)[M+1] + 354.4.

[0636] Step 2: 2-(2-isopropylphenyl)-4-phenoxypiperidine-1-carboxylate benzyl.

[0637] 4-hydroxy-2-(2-isopropylphenyl)piperidine-1-carboxylate benzyl (2.02 g, 5.71 mmol) was dissolved in THF (50 mL) and phenol (0.59 g, 6.59 mmol) and PPh3 (1.95 g, 7.42 mmol) were added. After cooling to 0°C, DIAD (1.5 g, 7.42 mmol) was added dropwise. The mixture was stirred at 0-25°C for 12 hours. The solvent was removed by concentration under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=10 / 1) to obtain 2-(2-isopropylphenyl)-4-phenoxypiperidine-1-carboxylate benzyl (1.5 g, yield: 61%) as a brown oil. MS(ESI,m / e)[M+1] + 430.4.

[0638] Step 3: 2-(2-isopropylphenyl)-4-phenoxypiperidine.

[0639] 2-(2-isopropylphenyl)-4-phenoxypiperidine-1-carboxylate benzyl (1.5 g, 3.5 mmol) was dissolved in MeOH (30 mL) and Pd(OH)2 / C (0.5 g) was added. The mixture was stirred under H2 (15 psi) at 30°C for 12 hours. After filtering the mixture, the filtrate was concentrated under vacuum to obtain 2-(2-isopropylphenyl)-4-phenoxypiperidine (1.0 g, yield: 99%) as a yellow oil, which was used in the next step without further purification. MS(ESI, m / e)[M+1] + 286.4.

[0640] Step 4: 2-(2-(2-isopropylphenyl)-4-phenoxypiperidine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0641] To a solution of 2-(2-isopropylphenyl)-4-phenoxypiperidine (1.0 g, 3.39 mmol) in DCE (20 mL), 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.8 g, 6.77 mmol) and AcOH (410 mg, 6.77 mmol) were added. After stirring at 25°C for 1 hour, NaBH(OAc)3 (2.15 g, 10.17 mmol) was added in several portions. The mixture was stirred at 25°C for 12 hours. The mixture was poured into saturated NaHCO3 (20 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA(v / v)=5 / 1) to obtain 2-(2-(2-isopropylphenyl)-4-phenoxypiperidine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (400 mg, yield: 23%) as a brown oil. MS(ESI,m / e)[M+1] + 519.4.

[0642] Step 5: 2-(2-(2-isopropylphenyl)-4-phenoxypiperidine-1-yl)-7-azaspiro[3.5]nonane.

[0643] A solution of 2-(2-(2-isopropylphenyl)-4-phenoxypiperidine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (300 mg, 0.58 mmol) in MeOH (20 mL) was mixed with HCl / MeOH (10 mL, 4 M). The mixture was stirred at 25°C for 2 hours. After removing the solvent, the residue was dissolved in H2O (20 mL). The mixture was adjusted to pH 9-10 using an aqueous solution of Na2CO3. The mixture was extracted with siRNA (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-phenoxypiperidine-1-yl)-7-azaspiro[3.5]nonane (160 mg, yield: 41%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.58-7.44(m,1H),7.28-7.09(m,5H),7.02-6.84(m,3H),4.67(br s, 1H),3.92(br d,J=8.4Hz,1H),3.43-3.26(m,1H),3.04-2.85(m,2H),2.71-2.58(m,4H),2.55-2.47(m,1H),2.18-2.11(m,1H),2.18-2.10(m,1H),2.06 -1.89(m,3H),1.84-1.76(m,1H),1.73-1.66(m,1H),1.48-1.30(m,5H),1.26(d,J=6.8Hz,3H),1.09(m,1H),1.06-0.97(d,J=6.8Hz,3H). MS(ESI,m / e)[M+1] + 419.4.

[0644] Intermediate 70-1: 2-(4-((1-cyclopropyl-1H-pyrazole-4-yl)methyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane [ka]

[0645] Step 1: 1-Cyclopropyl-1H-pyrazole-4-carboxylate ethyl.

[0646] Cu(OAc)2 (6.48g, 35.68mmol) was added to a mixture containing ethyl 1H-pyrazole-4-carboxylate (5.0g, 35.68mmol), cyclopropylboronic acid (5.82g, 67.79mmol), dipyridyl (5.57g, 35.68mmol), 4A MS (1.0g), and Na2CO3 (7.18g, 67.79mmol) in DCE (150mL). The mixture was stirred at 70°C for 16 hours under O2 (15psi). The mixture was diluted with toluene (300mL) and filtered through Celite. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: PE / EA(v / v) = 10 / 1 to 2 / 1) to obtain ethyl 1-cyclopropyl-1H-pyrazole-4-carboxylate (5.95 g, yield: 93%) as a pale yellow oil. MS(ESI, m / e)[M+1] + 181.2.

[0647] Step 2: (1-Cyclopropyl-1H-Pyrazole-4-yl)methanol.

[0648] 1-Cyclopropyl-1H-pyrazole-4-ethyl carboxylate (5.9 g, 32.74 mmol) was added in 80 mL of THF to LAH (1.24 g, 32.74 mmol) in several portions at 0°C. The mixture was stirred at 20°C for 2 hours. The mixture was poured into 50 mL of 4 M NaOH aqueous solution, filtered through Celite, and extracted with ELISA (100 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain (1-cyclopropyl-1H-pyrazole-4-yl)methanol (2.6 g, crude) as a yellow oil. MS(ESI,m / e)[M+1] + 139.2.

[0649] Step 3: 1-Cyclopropyl-1H-pyrazole-4-carboaldehyde.

[0650] A mixture containing (1-cyclopropyl-1H-pyrazole-4-yl)methanol (2.6 g, 18.82 mmol) and MnO2 (16.36 g, 188.18 mmol) in 60 mL of DCM was stirred at 20°C for 20 hours. The mixture was diluted with 200 mL of DCM and filtered through Celite. The filtrate was concentrated under reduced pressure to obtain 1-cyclopropyl-1H-pyrazole-4-carboaldehyde (2.4 g, crude product) as a yellow oil.

[0651] Step 4: 2-(4-((1-cyclopropyl-1H-pyrazole-4-yl)methyl)-2-(2-isopropylphenyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0652] A mixture containing 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol), 1-cyclopropyl-1H-pyrazole-4-carbaldehyde (462.46 mg, 3.40 mmol), and AcOH (271.97 mg, 4.53 mmol) in DCE (20 mL) was stirred at 20°C for 0.5 hours. Then, NaBH(OAc)3 (1.44 g, 6.79 mmol) was added to the mixture in several portions, and the mixture was stirred at 20°C for 12 hours. The mixture was poured into saturated NaHCO3 (30 mL) and extracted with DCM (30 mL x 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: EA / MeOH (v / v) = 1 / 0 to 100 / 1) to obtain 2-(4-((1-cyclopropyl-1H-pyrazole-4-yl)methyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, yield: 94%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ ppm:7.35-7.29(m,2H),7.23-7.17(m,1H),7.11(d,J=8.0Hz,1H),7.06(s,1H),6.59(s,1 H),4.96(s,1H),4.41(s,1H),3.53-3.41(m,2H),3.36(m,1H),3.30-3.10(m,6H),3.03(m ,1H),2.74-2.58(m,2H),2.28-2.17(m,1H),1.93(m,1H),1.83-1.54(m,3H),1.52-1.40( m,11H),1.36-1.33(m,1H),1.26-1.22(m,3H),1.12-1.00(m,4H),0.89(d,J=5.6Hz,3H).

[0653] Step 5: 2-(4-((1-cyclopropyl-1H-pyrazole-4-yl)methyl)-2-(2-isopropylphenyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0654] 2-(4-((1-cyclopropyl-1H-pyrazole-4-yl)methyl)-2-(2-isopropylphenyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.2 g, 2.14 mmol) was added dropwise to a solution of THF (15 mL) with BH3.THF (30 mL, 30 mmol, 1 M in THF) at 20°C. The mixture was heated at 75°C for 12 hours. The reaction product was inactivated with MeOH (5 mL) and concentrated under reduced pressure to obtain 2-(4-((1-cyclopropyl-1H-pyrazole-4-yl)methyl)-2-(2-isopropylphenyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.17 g, crude) as a white solid. MS(ESI,m / e)[M+1] + 548.5.

[0655] Step 6: 2-(4-((1-cyclopropyl-1H-pyrazole-4-yl)methyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0656] A solution of 2-(4-((1-cyclopropyl-1H-pyrazole-4-yl)methyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.17 g, 2.14 mmol) in HCl / siRNA (20 mL, 4 M) was stirred at 20°C for 4 hours. The reaction solution was dried under vacuum. The residue was diluted with HCl (1 M, 10 mL) and extracted with siRNA (10 mL x 2). The aqueous phase was adjusted to pH=10 with Na2CO3 aqueous solution and extracted with siRNA (30 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(4-((1-cyclopropyl-1H-pyrazole-4-yl)methyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (507 mg, yield: 53%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.46(s,1H),7.35(d,J=7.6Hz,2H),7.26-7.19(m,2H),7.15-7.09(m,1H),4 .56(s,1H),3.75-3.48(m,3H),3.44-3.29(m,3H),3.04-2.83(m,3H),2.68(m,4H) ,2.32-2.20(m,2H),2.17-2.08(m,1H),1.81-1.61(m,2H),1.49-1.32(m,4H),1.2 3(d,J=7.02Hz,3H),1.16(d,J=6.8Hz,3H),1.12-1.04(m,3H),1.04-0.93(m,3H). MS(ESI,m / e)[M+1] + 448.3.

[0657] Intermediate 71-1: 2-(2-(2-isopropylphenyl)-4-((3-methoxy-1-methyl-1H-pyrazole-4-yl)methyl)piperazine-1-yl)-7-azaspiro[3.5]nonane [ka]

[0658] Step 1: Methyl 3-hydroxy-1H-pyrazole-4-carboxylate.

[0659] Dimethyl 2-(methoxymethylene)malonate (30 g, 172.26 mmol) was added dropwise to a solution of MeOH (300 mL) with N2H4.H2O (8.62 g, 172.26 mmol) at 20°C. The mixture was heated to 70°C for 12 hours. The reaction mixture was filtered, and the solid was washed with petroleum ether. The filtered cake was dried under vacuum to obtain methyl 3-hydroxy-1H-pyrazole-4-carboxylate (23.5 g, crude) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ ppm: 12.30 (s, 1H), 10.47-9.71 (m, 1H), 7.93 (s, 1H), 3.67 (s, 3H).

[0660] Step 2: 3-Methoxy-1-methyl-1H-pyrazole-4-carboxylate methyl.

[0661] A mixture containing methyl 3-hydroxy-1H-pyrazole-4-carboxylate (10 g, 70.37 mmol) and MeI (20.47 g, 144.25 mmol) in DMF (200 mL) was to which NaH (7.04 g, 175.92 mmol) was added in several portions at 0°C under N2 protection. The mixture was stirred at 20°C for 2 hours. The mixture was poured into saturated NH4Cl (300 mL) and extracted with ELISA (500 mL x 3). The combined organic phase was washed with brine (1 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was diluted with H2O (50 mL), sonicated for 10 minutes, and filtered. The filtered cake was washed with petroleum ether and dried under vacuum to obtain methyl 3-methoxy-1-methyl-1H-pyrazole-4-carboxylate (4.8 g, crude) as a yellow solid, which was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ ppm: 8.09 (s, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 3.66 (s, 3H).

[0662] Step 3: (3-Methoxy-1-methyl-1H-pyrazole-4-yl)methanol.

[0663] LiAlH4 (1.07 g, 28.21 mmol) was added in several portions at 0°C to a solution of methyl 3-methoxy-1-methyl-1H-pyrazole-4-carboxylate (4.8 g, 28.21 mmol) in THF (72 mL). The mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into an aqueous solution of NaOH (4 M, 50 mL), filtered through Celite, and extracted with siRNA (100 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain (3-methoxy-1-methyl-1H-pyrazole-4-yl)methanol (2.7 g, crude) as a yellow oil, which was used directly in the next step without further purification. 1 H NMR(400MHz,CDCl3)δ ppm:7.16(s,1H)4.47(s,2H)3.92(s,3H)3.72(s,3H)

[0664] Step 4: 3-Methoxy-1-methyl-1H-pyrazole-4-carboaldehyde.

[0665] A mixture containing (3-methoxy-1-methyl-1H-pyrazole-4-yl)methanol (2.6 g, 18.29 mmol) and MnO2 (15.9 g, 182.90 mmol) in 60 mL of DCM was stirred at 20°C for 20 hours. The reaction mixture was diluted with 200 mL of DCM and filtered through Celite. The filtrate was concentrated under reduced pressure to obtain 3-methoxy-1-methyl-1H-pyrazole-4-carboaldehyde (2.4 g, crude) as a green solid, which was used directly in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ ppm: 9.72 (s, 1H), 7.67 (s, 1H), 3.94-4.04 (m, 3H), 3.78 (s, 3H).

[0666] Step 5: 2-(2-(2-isopropylphenyl)-4-((3-methoxy-1-methyl-1H-pyrazole-4-yl)methyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl. A mixture containing 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.0 g, 2.26 mmol), 3-methoxy-1-methyl-1H-pyrazole-4-carbaldehyde (476.01 mg, 3.40 mmol), and AcOH (271.97 mg, 4.53 mmol) in DCE (20 mL) was stirred at 20°C for 0.5 hours. Then, NaBH(OAc)3 (1.44 g, 6.79 mmol) was added to the mixture in several portions, and the mixture was stirred at 20°C for 12 hours. The mixture was poured into saturated NaHCO3 (30 mL) and extracted with DCM (30 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: EA / MeOH (v / v) = 1 / 0 to 100 / 1) to obtain 2-(2-(2-isopropylphenyl)-4-((3-methoxy-1-methyl-1H-pyrazole-4-yl)methyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.16 g, yield: 91%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.31(d,J=3.2Hz,2H),7.27-7.15(m,2H),7.12-7.06(m,1H),6.18(s,1H),4. 98(s,1H),4.35(s,1H),3.81(s,3H),3.52(s,3H),3.46-3.03(m,10H),2.76-2.60 (m,2H),2.37-2.15(m,1H),1.97-1.91(m,1H),1.78(s,1H),1.66(m,1H),1.51-1. 41(m,10H),1.34(d,J=4.88Hz,1H),1.26(d,J=6.8Hz,3H),1.11(d,J=6.8Hz,3H).

[0667] Step 6: 2-(2-(2-isopropylphenyl)-4-((3-methoxy-1-methyl-1H-pyrazole-4-yl)methyl)piperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl.

[0668] 2-(2-(2-isopropylphenyl)-4-((3-methoxy-1-methyl-1H-pyrazole-4-yl)methyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.16 g, 2.05 mmol) was added dropwise to a solution of THF (15 mL) with BH3.THF (30 mL, 30 mmol, 1 M in THF) at 20°C. The mixture was heated to 75°C for 12 hours. The reaction mixture was inactivated with MeOH (5 mL) and concentrated under vacuum to obtain 2-(2-(2-isopropylphenyl)-4-((3-methoxy-1-methyl-1H-pyrazole-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.13 g, crude) as a white solid. MS(ESI, m / e)[M+1] + 552.5.

[0669] Step 7: 2-(2-(2-isopropylphenyl)-4-((3-methoxy-1-methyl-1H-pyrazole-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0670] 2-(2-(2-isopropylphenyl)-4-((3-methoxy-1-methyl-1H-pyrazole-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.13 g, 2.05 mmol) was added dropwise to a solution of DCM (25 mL) with TFA (5 mL) at 20°C. The mixture was stirred at 20°C for 12 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC, the solution was concentrated, adjusted to pH=10 with Na2CO3, and extracted with ELISA (50 mL x 5). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to obtain 2-(2-(2-isopropylphenyl)-4-((3-methoxy-1-methyl-1H-pyrazole-4-yl)methyl)piperazin-1-yl)-...

Claims

1. Compound of formula (I) 【Chemistry 1】 [During the ceremony, X is either N or CH; p is an integer of 1; v is an integer of 1; m is an integer of 1, 2, or 3; t is an integer of 1 or 2; Ring A is, 【Chemistry 2】 And, ＊＊ 2 represents the position where it is bonded to phenyl; Ring B is phenyl, furanyl, isoxazolyl, pyridinyl, pyrazolyl, or pyrimidinyl; L ２ This is a direct bond, -(CH ２ ) ｑ - or -O-, where q is a number between 1 and 3; R １１ teeth, a) Chromanil, benzo[b][1,4]dioxynil, 5,6,7,8-tetrahydronaphthalenyl, octahydro-5H-2,5-methanoindenyl (preferably octahydro-5H-2,5-methanoinden-5-yl), 2,3,4,5-tetrahydrobenzo[b]oxepinyl (preferably 2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl), or adamantanil (preferably adamantan-1-yl), each of which contains one or two R １１Ｘ It is being optionally replaced by b) furan-2-yl, isoxazole-4-yl, pyridine-3-yl, pyridine-2-yl, 1H-pyrazole-4-yl, pyrimidine-2-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-4-yl, benzofuran-5-yl, or benzofuran-4-yl, c) Cyano, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, difluoromethyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetan-3-yl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, -NH ２ or -NH(CH ３ Phenyl substituted with; R １１Ｘ each independently represents halogen, -C １－８ alkyl, haloC １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C ３－８ cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ２ , -OR １１ａ , -SO ２ R １１ａ , -COR １１ａ , -CO ２ R １１ａ , -CONR １１ａ R １１ｂ , -C(=NR １１ａ )NR １１ｂ R １１ｃ , -NR １１ａ R １１ｂ , -NR １１ａ COR １１ｂ , -NR １１ａ CONR １１ｂ R １１ｃ , -NR １１ａ CO ２ R １１ｂ , -NR １１ａ SONR １１ｂ R １１ｃ , -NR １１ａ SO ２ NR １１ｂ R １１ｃ , -P(=O)R １１ａ [[ID=7২]]R １１ｂ , or -NR １１ａ SO ２ R １１ｂ and the C ３－８ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with halogen, -C １－８ alkyl, -haloC １－８ alkyl, -C １－８ alkoxyl or -haloC １－８ alkoxyl; R １１ａ , R １１ｂ and R １１ｃ Each of them is independently hydrogen, -C １－８ Alkyl, -halo C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C ３－８ The C is a cycloalkyl, heterocyclyl, aryl, or heteroaryl molecule. ３－８ Cycloalkyl, heterocyclyl, aryl, or heteroaryl are halogens, -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxyl or -Halo C １－８ It is optionally substituted with an alkoxyl; R ２ Each is independent of -C １－８ Alkyl or -C ３－６ It is a cycloalkyl, and the -C １－８ Alkyl or -C ３－６ Each cycloalkyl group is independently a halogen, hydroxyl, and C. １－６ Alkoxy, amino, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, C ３－６ Cycloalkyl, or C ３－６ It is optionally substituted with a heterocycline; R ３ is, -L １ -CyC, L １ is a direct bond, -(CR ａ R ｂ ), -O-(CR １－４ ), -NH-(CR ａ R ｂ ), -NHC(O)NR ０－３ -(CR ａ R ｂ ), or -NH-; １－３ is -NHC(O)NR ａ -(CR ａ R ｂ ), or -NH-; １－３ or is -NH-; CyC is either a cycloalkyl or heterocyclyl molecule, and each of these has 1, 2, 3, or 4 substituents R ３ａ It is optionally replaced by; R ３ａ each independently is halogen, cyano, oxo, -OR ３ｂ , -NR ３ｂ R ３ｃ , -COR ３ｂ , -SO ２ R ３ｂ , -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -cycloalkyl or heterocyclyl, wherein each of said -C １－８ alkyl and heterocyclyl is optionally substituted with one or two substituents R ３ｅ , and each R ３ｅ is selected from halogen, cyano, -OR ３ｆ , -C １－８ alkyl, -cycloalkyl and heterocyclyl; R ３ｂ and R ３ｃ Each of them independently produces hydrogen, -C １－８ Alkyl, -cycloalkyl or heterocyclyl, and the -C １－８ Alkyl has one or two substituents R ５ｅ It is optionally replaced by each R ５ｅ -NR ３ｆ R ３ｇ , -cycloalkyl or heterocyclyl; R ３ｆ and R ３ｇ Each of them independently becomes hydrogen or -C １－８ It is alkyl; Alternatively, two adjacent Rs on the phenyl ring ３ The group, together with the phenyl ring, forms a benzo ring, and the ring is optionally substituted with a heteroaryl group; R ａ and R ｂ Each of them is independently hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ It is alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ４ and R ５ These are, independently, hydrogen, halogen, cyano, and -NO. ２ , -C １－８ Alkyl, -C ２－８ Alkenyl or -C ２－８ Alkinnil], or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

2. R ２ However, -C １－６ Alkyl or -C ３－４ It is a cycloalkyl; the aforementioned -C １－６ Alkyl and the aforementioned -C ３－４ Each cycloalkyl group is independently -C １－３ Alkyl, C ３－６ Cycloalkyl or C ３－６ It is optionally substituted with a heterocycline; L ２ However, - (CH ２ ) ｑ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein q is a number from 1 to 3, preferably 1, and the compound is - or -O-.

3. R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein each of them is independently methyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, or morpholinomethyl.

4. R １１Ｘ However, halogen, cyano, hydroxy, -C １－８ Alkyl, Halo C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, C １－６ Alkoxyl, Halo C １－６ Alkoxyl, C ３－６ Cycloalkyl, heterocyclyl, C ３－６ Cycloalkoxyl, -NH ２、 -NH(C) １－８ Alkyl), -N(C １－８ Alkyl) ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which is heterocyclyl-O-.

5. m is 1, R ３ ga-L １ -CyC and L １ However, direct bonding, -(CH ２ ) ０－２ -, -N(CH ２ ) ０－２ -, or -O(CH ２ ) ０－２ - The compound according to claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

6. CyC, a) Monocyclic C ３－８ Cycloalkyl or cross-linked cycloalkyl 【Transformation 3】 Each of these has one or two substituents R ３ａ It is being optionally replaced by b) A monocyclic 4- to 9-membered heterocycline containing one nitrogen, oxygen, or sulfur heteroatom as a ring member; or a monocyclic 4- to 9-membered heterocycline containing two heteroatoms selected from oxygen, sulfur, and nitrogen as ring members, each of which contains 1, 2, 3, or 4 substituents R ３ａ It is being optionally replaced by c) 1, 2, 3 or 4 substituents R ３ａ It is a 5- to 10-membered spiro-type heterocycline containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members, which are optionally substituted. d) 1, 2, 3 or 4 substituents R ３ａ A 5- to 10-membered bridged heterocycline containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members, which are optionally substituted. e) A monocyclic six-membered heterocycline containing two heteroatoms selected from oxygen and nitrogen as ring members, or f) A 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirotype heterocyclyl containing one or two nitrogen or oxygen atoms as ring members. The compound described in claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

7. CyC, a) Cyclobutyl, cyclopentyl, or cyclohexyl, each of which has one or two substituents R ３ａ It is being optionally replaced by b) A monocyclic 4-6 member heterocycline containing one nitrogen, oxygen, or sulfur heteroatom as a ring member. c) Oxetanil, tetrahydrofuranil, tetrahydropyranil, azetidinil, pyrrolidinil, or piperidinil d) Dioxanil, morpholino, morpholinil or piperazinil, e) 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,4-dioxan-2-yl, morpholin-1-yl, morpholin-2-yl, or morpholin-3-yl The compound described in claim 6 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein CyC is selected from oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, azetidine-3-yl, azetidine-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-4-yl, piperidine-2-yl, and piperidine-3-yl.

9. CyC, 【Chemistry 4】 or 【Transformation 5】 The compound according to claim 6 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

10. R ３ａ Each of these independently produces halogen, cyano, oxo, and -OR ３ｂ , -NR ３ｂ R ３ｃ , -C(=O)R ３ｂ , -SO ２ R ３ｂ , -C １－６ Alkyl, monocyclic C ３－６ A cycloalkyl or monocyclic 4- to 9-membered heterocycline containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur as ring members, wherein the -C １－６ Each of the alkyl group and the monocyclic 4- to 9-membered heterocyclyl has one or two substituents R ３ｅ The compound according to claim 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which is optionally substituted with.

11. a) R ３ａ However, C ３－６ Cycloalkyl, more preferably cyclopropyl, b) R ３ａ However, it is a 4- to 6-membered heterocycline containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur as ring members. c) R ３ａ However, these are oxetanil, tetrahydrofuranil, tetrahydropyranil, piperazinil, or morpholinil. d) R ３ａ However, these are oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, or morpholin-4-yl. e) R ３ｅ However, it is a monocyclic 4- to 9-membered heterocycline containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur as ring members. f) R ３ｅ However, it is tetrahydropyran-4-yl. g) R ３ａ ga-NR ３ｂ R ３ｃ And R ３ｂ is hydrogen, R ３ｃ It is a heterocycline. h) R ３ａ ga-NR ３ｂ R ３ｃ And R ３ｂ is hydrogen, R ３ｃ is tetrahydropyran-4-yl, i) R ３ａ ga-NR ３ｂ R ３ｃ And R ３ｂ and R ３ｃ Each of these is independently either hydrogen or a cycloalkyl-substituted -C １－６ Alkyl, preferably monocyclic C ３－６ Cycloalkyl-substituted -C １－６ It is alkyl. j) R ３ａ ga- OR ３ｂ or -SO ２ R ３ｂ And R ３ｂ is hydrogen or C １－８ Alkyl, preferably methyl, or k) R ３ａ ga-COR ３ｂ And R ３ｂ However, is it hydrogen, or -NR ３ｆ R ３ｇ C is optionally replaced by １－６ It is alkyl, R ３ｆ and R ３ｇ Each of them independently contains hydrogen or C １－６ Alkyl, preferably methyl, The compound according to claim 10 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

12. m is 1, R ３ but: 【Transformation 6】 【Transformation 7】 【Transformation 8】 The compound described in claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

13. R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the halogen is selected from fluoro, chloro, and bromo, preferably fluoro.

14. R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound is located at the 3-position of the pyrrolo[2,3-b]pyridine-5-yl ring.

15. A compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the compound is 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 A compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from the above.

16. The aforementioned compound, 【Transformation 38】 The compound according to claim 15 or a pharmaceutically acceptable salt thereof.

17. The aforementioned compound, 【Chemistry 39】 The compound according to claim 15 or a pharmaceutically acceptable salt thereof.

18. The aforementioned compound, 【Chemistry 40】 The compound according to claim 15 or a pharmaceutically acceptable salt thereof.

19. The aforementioned compound, 【Chemistry 41】 The compound according to claim 15 or a pharmaceutically acceptable salt thereof.

20. The aforementioned compound, 【Chemistry 42】 The compound according to claim 15 or a pharmaceutically acceptable salt thereof.

21. The aforementioned compound, 【Chemistry 43】 The compound according to claim 15 or a pharmaceutically acceptable salt thereof.

22. The aforementioned compound, 【Chemistry 44】 The compound according to claim 15 or a pharmaceutically acceptable salt thereof.

23. The aforementioned compound, 【Chemistry 45】 The compound according to claim 15 or a pharmaceutically acceptable salt thereof.

24. The aforementioned compound, 【Chemistry 46】 The compound according to claim 15 or a pharmaceutically acceptable salt thereof.

25. The aforementioned compound, 【Chemistry 47】 The compound according to claim 15 or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

27. The pharmaceutical composition according to claim 26 for treating dysregulated apoptosis.

28. The pharmaceutical composition according to claim 27, wherein the dysregulated apoptotic disease is a neurodegenerative condition, a proliferative disorder, or a thrombotic condition.

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