BCL-2 inhibitors

Abstract

Disclosed herein is a compound of Formula (I) for inhibiting both Bcl-2 wild type and mutated Bcl-2, specifically Bcl-2 G101V and D103Y, and a method of using the compound disclosed herein to treat a disorder of dysregulated apoptosis.

Description

[0001] This application is a divisional application of Chinese patent application No. 202180029718.1 (filed on April 14, 2021, invention title: BCL-2 inhibitor). Technical Field

[0002] This application discloses a compound of formula (I) for inhibiting both wild-type and mutant Bcl-2, and a method for treating dysapoptotic diseases using the compound disclosed in this application. Background Technology

[0003] The B-cell lymphoma 2 (Bcl-2) gene family is a group of proteins homologous to Bcl-2 proteins, encoding more than 20 proteins that regulate intrinsic apoptosis pathways. The Bcl-2 family of proteins, composed of pro-apoptotic and anti-apoptotic molecules, can be divided into three subfamilies based on sequence homology within the four BH domains (BH1, BH2, BH3, and BH4): (1) a subfamily with sequence homology in all four BH domains, such as the anti-apoptotic Bcl-2, Bcl-xl, and Bcl-w; (2) a subfamily with sequence homology in BH1, BH2, and BH4, such as the pro-apoptotic Bax and Bak; and (3) a subfamily with sequence homology only in BH3, such as the pro-apoptotic Bik, Bid, and HRK. The BH1, BH2, and BH4 domains are required for anti-apoptotic activity. Conversely, the BH3 domain is essential for pro-apoptotic activity and is sufficient on its own to induce pro-apoptotic activity.

[0004] Similar to oncogene addiction (where tumor cells depend on a single dominant gene to survive), tumor cells can also become dependent on Bcl-2 to survive. Bcl-2 overexpression is commonly seen in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), relapsed / refractory chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), non-Hodgkin's lymphoma (NHL), and 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 DrugTargets 2008, 8, 207-222; Cancer 2011, 3, 1527-1549). Dysregulation of the apoptotic pathway is also associated with the pathology of other important diseases such as neurodegenerative diseases (upregulated apoptosis) (e.g., Alzheimer's disease), proliferative diseases (downregulated apoptosis) (e.g., cancer, autoimmune diseases), and prethrombotic diseases. Many small-molecule BH3 mimics targeting Bcl-2 or Bcl-xl have been reported. Several small-molecule Bcl-2 inhibitors have been investigated at different stages of drug development: the Bcl-2 / Bcl-xl inhibitor ABT-263 (navitoclax, WO2009155386) has shown promising clinical activity in lymphocytic malignancies such as chronic lymphocytic leukemia. However, its efficacy in these conditions 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 selective Bcl-2 inhibitors, venetoclax (ABT-199 / GDC-0199), has shown potent activity in these cancers without harming 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 under clinical trial investigation.Currently, venetum (formerly known as ABT-199) is the only FDA-approved selective Bcl-2 inhibitor for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) with 17p deletion.

[0005] Despite its high clinical activity and favorable safety profile, patients can still develop acquired resistance to venetum with continued treatment over time. Recently, a novel Gly101Val (G101V) mutation was identified in Bcl-2 after 19 to 42 months of treatment with the Bcl-2 inhibitor venetum (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 venetum without disrupting the binding of pro-apoptotic proteins to Bcl-2. The novel Gly101Val mutation in Bcl-2 was identified in 7 out of 15 patients during progression, but these patients were not included in the study. The Bcl-2 Asp103Tyr (D103Y) mutation, observed in CLL patients, is also predicted to impair the binding of Bcl-2 to venetum, leading to reduced patient fitness (Haematologica [Hematology] 104, e434-e437, 2019). The Bcl-2 Phel04lle (F104I) mutation in FL (follicular lymphoma) patients treated with venetum has also been described as being associated with significantly reduced binding to venetum and sufficient to confer cellular resistance (Br J Haematol [British Journal of Hematology], 186 (6): e188-e191, 2019).

[0006] Furthermore, wild-type Bcl-2 is important for the survival of neutrophil precursors, therefore neutropenia is the most common adverse reaction to Bcl-2 inhibitor therapy. In CLL patients treated with venetum, the onset of neutropenia is usually observed during dose escalation, although its incidence decreases with prolonged treatment (ClinCancer Res; 24 (18), 2018). That is, excessive inhibition of wild-type Bcl-2 protein can result in the intermediate-target toxicity and side effect of neutropenia.

[0007] WO 2019210828 disclosed a novel class of Bcl-2 inhibitors. However, there remains 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 found in patients who have progressed after long-term treatment with venetum). Summary of the Invention

[0008] The inventors of this disclosure have discovered that the compounds disclosed in this application exhibit nearly equal inhibitory activity against both wild-type Bcl-2 and Bcl-2 mutations (including G101V and D103Y), demonstrating novel potential Bcl-2 inhibitors without resistance issues. This disclosure also proposes the potential for novel therapies with effective and safe dosages for clinically relapsed patients with mutations after treatment with venetumola.

[0009] This application discloses a compound having formula (I).

[0010] (I),

[0011] Or its pharmaceutically acceptable salt or its stereoisomer.

[0012] in

[0013] X is independently selected from N or CH;

[0014] p is an integer selected from 1 or 2;

[0015] v is an integer selected from 1 or 2;

[0016] m is an integer selected from 1, 2, or 3;

[0017] n is an integer selected from 0, 1, or 2;

[0018] t is an integer selected from 1 or 2;

[0019] Ring A is , or ,in This refers to the position where it connects to the phenyl portion of formula (I);

[0020] Ring B is aryl, 5-membered, or 6-membered heteroaryl;

[0021] L 2 It is a direct key, -(CR) a R b ) q -, -O-, -S-, -S(O)-, -SO2-, -C(O)-, C(O)O-, -OC(O)-, -NR a -、-C(O)NR a -、-NRa C(O)-、-NR a C(O)O-、-NR a C(O)NR b -、-SO2NR a -、-NR a SO2-, -NR a S(O)2NR b -、-NR a S(O)NR b -、-C(O)NR a SO2-、-C(O)NR a SO-, -C(=NR) a )NR b -or cycloalkyl, where q is a number from 1 to 7;

[0022] R 11 It is -C 1-3 Alkyl, -C3- 10 Cycloalkyl, aryl, 5- or 6-membered monocyclic heteroaryl, 7- to 10-membered bicyclic heteroaryl, 3- to 6-membered monocyclic heterocyclic, 7- to 14-membered bicyclic heterocyclic, each independently and optionally substituented by 1, 2, 3 or 4 R groups. 11X replace,

[0023] R 11X Each time it appears, it is independently a halogen, -C 1-8 Alkyl, Halogenated C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 3-8 Cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR 11a -SO2R 11a -COR 11a -CO2R 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 CO2R 11b -NR 1a SONR 11b R 11c -NR 11aSO2NR 11b R 11c -P(=O)R 11a R 11b or -NR 11a SO2R 11b Wherein C 3-8 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be substituted with: halogen, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 alkoxy or -halogenated C 1-8 Alkoxy;

[0024] R 11a R 11b and R 11c Each is independently hydrogen, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 3-8 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the C 3-8 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be substituted with: halogen, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 alkoxy or -halogenated C 1-8 Alkoxy;

[0025] R 12 It is hydrogen, halogen, -C 1-8 Alkyl, Halogenated C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 3-8 Cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR 1a -SO2R 1a -COR 1a -CO2R 1a -CONR 1a R 1b -C(=NR) 1a )NR 1b R 1c -NR 1a R 1b -NR 1a COR 1b -NR 1a CONR 1b R 1c -NR 1a CO2R 1b -NR1a SONR 1b R 1c -NR 1a SO2NR 1b R 1c or -NR 1a SO2R 1b ;

[0026] R 1a and R 1b Each is independently hydrogen, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0027] R 1c It is hydrogen, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0028] R 2 Independently selected from halogens, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl or -C 3-6 cycloalkyl; wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl or -C 3-6 Each cycloalkyl group may be independently and optionally substituted with: halogen, hydroxyl, C 1-6 alkoxy or amino, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, C 3-6 cycloalkyl or C 3-6 Heterocyclic groups;

[0029] R 3 Yes -L 1 -CyC,

[0030] in

[0031] L 1 It is a direct key, -(CR) a R b ) 1-4 -、-O-(CR a R b ) 0-3 -、-NH-(CR a R b) 1-3 or -NH;

[0032] CyC is a cycloalkyl or heterocyclic group, each optionally substituented by one, two, three, or four R groups. 3a replace;

[0033] R 3a Independently selected from hydrogen, halogen, cyano, oxo, -OR 3b -NR 3b R 3c -COR 3b -SO2R 3b -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl or heterocyclic, wherein the -C 1-8 Each of the alkyl and heterocyclic groups is optionally substituented by one or two R groups. 3e Substitution, the substituent R 3e Selected from hydrogen, halogen, cyano, -OR 3f -C 1-8 Alkyl, cycloalkyl, or heterocyclic groups;

[0034] Where R 3b and R 3c Each is independently hydrogen, -C 1-8 Alkyl, cycloalkyl, or heterocyclic groups, wherein the -C 1-8 Alkyl groups are optionally substituted with one or two substituents R. 5e Substitution, the substituent R 5e It is hydrogen, -NR 3f R 3g -cycloalkyl or heterocyclic groups;

[0035] R 3f and R 3g Each is independently hydrogen or -C 1-8 alkyl;

[0036] Or two adjacent R on the phenyl ring 3 Together with the phenyl ring, a benzo[a] ring is formed, which may optionally be substituted with a heteroaryl group;

[0037] R a and R b It is hydrogen and -C independently. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; and

[0038] R 4 and R 5 Each of these can be independently represented as hydrogen, halogen, cyano, -NO2, or -C.1-8 Alkyl, -C 2-8 alkenyl or -C 2-8 Alkyne group.

[0039] In some embodiments, X is N.

[0040] In some embodiments, ring B is phenyl, furanyl, isoxazolyl, pyridyl, pyrazolyl, or pyrimidinyl.

[0041] In some embodiments, R 2 It is halogenated, -C 1-6 Alkyl or -C 3-4 cycloalkyl; wherein the -C 1-6 Alkyl and -C 3-4 Each cycloalkyl group is optionally substituted independently with the following: hydrogen, -C 1-3 Alkyl, C 3-6 cycloalkyl or C 3-6 Heterocyclic group.

[0042] In some embodiments, R 2 It is fluorine, methyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, or morpholine methyl.

[0043] In some embodiments, n is 0, and L 2 It is -(CH2) q - or -O-, where q is a number from 1 to 3, preferably 1.

[0044] In some embodiments, R 11 It is -C3- 10 Cycloalkyl, aryl, 5- or 6-membered monocyclic heteroaryl, 7- to 10-membered bicyclic heteroaryl, 3- to 6-membered monocyclic heterocyclic, 7- to 14-membered bicyclic heterocyclic, each independently and optionally substituented by 1, 2 or 3 R groups. 11X Replace, where R 11X As defined in equation (I).

[0045] In some embodiments, R 11 It is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a 3- to 6-membered heterocyclic alkyl group, containing one or two heteroatoms selected from oxygen and nitrogen atoms.

[0046] In some embodiments, R 11 Selected from cyclohexyl, bicyclo[1.1.1]pentyl, tetrahydro-2H-pyran-1-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yloxazol-2-yl, oxazol-4-ylmethyl or oxazol-5-yl.

[0047] In some embodiments, R 11Selected from phenyl or 8- to 10-membered dicyclic aryl groups, optionally with 1, 2, or 3 substituents R 11X replace.

[0048] In some embodiments, R 11 Selected from phenyl or 8- to 10-membered dicyclic aryl groups, optionally with 1 to 2 substituents R 11X replace.

[0049] In some embodiments, R 11 It is chromyl, benzo[b][1,4]dioxinyl, 5,6,7,8-tetrahydronaphthyl, octahydro-5H-2,5-methanolindenyl (preferably octahydro-5H-2,5-methanolinden-5-yl), 2,3,4,5-tetrahydrobenzo[b]oxazideyl (preferably 2,3,4,5-tetrahydrobenzo[b]oxazide-7-yl), adamantyl (preferably adamantane-1-yl), each optionally marked with one or two R... 11X replace.

[0050] In some embodiments, R 11X It is halogen, cyano, hydroxyl, -C 1-8 Alkyl, Halogenated C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, heterocyclic, C 3-6 Cycloalkoxy, -NH2, -NH(C 1-8 alkyl), -N(C) 1-8 Alkyl group (2) or heterocyclic group -O-.

[0051] In some embodiments, R 11x Yes - OR 11a , where R 11a It is -C 1-8 Alkyl, preferably methyl (-CH3), ethyl, propyl, isopropyl, butyl, or tert-butyl. In some embodiments, R 11x Yes - OR 11a , where R 11a It is optionally rich in deuterium-C 1-8 Alkyl groups, for example, -CD3 or -CD2CD3.

[0052] In some embodiments, R 11x Yes - OR 11a , where R 11a It is C 3-6 Cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0053] In some embodiments, R11 It is independently selected from one, two, or three of the following substituents R 11X Substituted phenyl:

[0054] a) Cyano, fluorine, chlorine, bromine, 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

[0055] b) -OR 11a , where R 11a It is C 3-6 Cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0056] In some embodiments, R 11 It is a phenyl group that has been substituted with the following: cyano, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, difluoromethyl, trifluoromethyl, or trifluoromethoxy.

[0057] In some embodiments, R 11 It is a phenyl group that has been substituted with the following: cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0058] In some embodiments, R 11 It is cyclohexyl, 4-methoxycyclohexyl, bicyclo[1.1.1]pentan-1-yl, tetrahydro-2H-pyran-4-yl, oxazol-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-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-methoxyphenyl, 4-(trifluoromethoxy)phenyl 2,4-dimethoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, chroman-6-yl, chroman-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-tetrahydronaphth-2-yl or 5,6,7,8-tetrahydronaphth-1-yl, bicyclo[4.2.0]octa-1(6), 2,4-trien-7-yl.

[0059] In some embodiments, R 11It is furanyl, isoxazolyl, pyridyl, pyrazolyl, pyrimidinyl, quinoxalinyl, benzo[b]thiophenyl, benzofuranyl or 2,3-dihydrobenzofuran-5-yl.

[0060] In some embodiments, R 11 It is furan-2-yl, isoxazol-4-yl, pyridin-3-yl, pyridin-2-yl, 1H-pyrazol-4-yl, pyrimidin-2-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-4-yl, benzofuran-5-yl, benzofuran-4-yl, 2,3-dihydrobenzo[b][1,4]dioxin-5-yl, benzo[b][1,4]oxazin-5-yl, dihydro-[1,4]dioxin[2,3-b]pyridin-8-yl or 3,4-dihydro-2H-benzo[b][1,4]dioxazine-7-yl.

[0061] In some embodiments, R 11 -L 2 - Selected from furan-2-ylmethyl, isoxazol-4-ylmethyl, (pyridin-3-yl)methyl, (6-methoxypyridin-3-yl)methyl, (5-methoxypyridin-2-yl)methyl, (1-methyl-1H-pyrazol-4-yl)methyl, (3-methoxy-1-methyl-1H-pyrazol-4-yl)methyl, (1-cyclopropyl-1H-pyrazol-4-yl)methyl, (5-methoxypyrimidin-2-yl)methyl, benzo[b]thiophene-5-ylmethyl, benzo[b]thiophene-4-ylmethyl, benzofuran-5-ylmethyl, or benzofuran-4-ylmethyl.

[0062] In some embodiments, R 11 -L 2 - is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 1,2,3,4-tetrahydronaphth-1-yl, 3-phenylcyclobutyl-1-yl, 3-phenylcyclopentyl-1-yl, 4-phenylcyclohexyl-1-yl or 3-(4-methoxyphenyl)cyclopentyl-1-yl.

[0063] In some embodiments, R 11 -L 2 - is selected from the following 3- to 6-membered monocyclic heterocyclic groups: oxetane, tetrahydrofuranyl or tetrahydro-2H-pyranyl, preferably oxetane-3-yl, tetrahydrofuran-3-yl and tetrahydro-2H-pyran-4-yl.

[0064] In some embodiments, R 12 It is hydrogen.

[0065] In some embodiments, L 2 It is -SO2- or -CO-, and R 11 It is -C 1-3 Alkyl or phenyl, each optionally C1-3 Alkyl-substituted.

[0066] In some embodiments, R a It is either hydrogen or methyl.

[0067] In some embodiments, m is 1, R 3 Yes -L 1 -CyC, and L 1 It is a direct bond, -(CH2) 0-2 -、-N(CH2) 0-2 Or -O(CH2) 0-2 .

[0068] In some embodiments, CyC is selected from monocyclic C. 3-8 cycloalkyl or bridged cycloalkyl ( C3-6 cycloalkyl groups, each optionally substituent by one or two R groups. 3a replace.

[0069] In some embodiments, CyC is cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one or two substituents R. 3a replace.

[0070] In some embodiments, CyC is:

[0071] a) Heterocyclic groups selected from the following: monocyclic 4- to 9-membered heterocyclic groups containing one nitrogen, oxygen, or sulfur heteroatom as a ring member; monocyclic 4- to 9-membered heterocyclic groups containing two heteroatoms selected from oxygen, sulfur, and nitrogen as ring members;

[0072] b) 5- to 10-membered spiroheterocyclic groups, comprising one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members, or...

[0073] c) A 5- to 10-membered bridging heterocyclic group, which contains one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members;

[0074] Each of them is optionally substituent with one, two, three or four R groups 3a replace.

[0075] In some embodiments, CyC is a monocyclic 4- to 6-membered heterocyclic group containing a nitrogen, oxygen, or sulfur heteroatom as a ring member.

[0076] In some embodiments, Cyc is selected from oxetane, tetrahydrofuranyl, tetrahydropyranyl, azirnebutane, pyrrolidinyl, and piperidinyl.

[0077] In some embodiments, CyC is selected from oxetane-2-yl, oxetane-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, azirane-3-yl, azirane-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidin-4-yl, piperidin-2-yl, and piperidin-3-yl.

[0078] In some embodiments, CyC is a monocyclic 6-membered heterocyclic group containing two heteroatoms selected from oxygen and nitrogen as ring members.

[0079] In some embodiments, CyC is dioxyl, morpholino, morpholino, or piperazine.

[0080] 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.

[0081] In some embodiments, CyC is a quaternary / quaternary, tertiary / quinary, quaternary / quinary, quaternary / sixary, quinary / quinary, or quinary / sixary monospirocyclic heterocyclic group containing one or two nitrogen or oxygen as ring members.

[0082] In some embodiments, CyC is (7-oxa-2-azaspiro[3.5]nonane-2-yl) or (2-oxaspiro[3.5]nonane-7-yl).

[0083] In some embodiments, R 3a Independently selected from hydrogen, halogen, cyano, oxo, -OR 3b -NR 3b R 3c -C(=O)R 3b -SO2R 3b -C 1-6 Alkyl, monocyclic C 3-6 A cycloalkyl or monocyclic 4- to 9-membered heterocyclic group containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms as ring members, wherein the -C 1-6 Each of the alkyl and monocyclic 4- to 9-membered heterocyclic groups is optionally substituented by one or two R groups. 3e replace.

[0084] In some embodiments, as R 3a The cycloalkyl group is C 3-6 Cycloalkyl; more preferably cyclopropyl.

[0085] In some embodiments, as R 3aThe heterocyclic group is a 4- to 6-membered heterocyclic group, which contains one or two heteroatoms selected from nitrogen, oxygen or sulfur heteroatoms as ring members.

[0086] In some embodiments, as R 3a The heterocyclic group is oxoheterobutyl, tetrahydrofuranyl, tetrahydropyranyl, piperazineyl, or morpholinyl.

[0087] In some embodiments, as R 3a The heterocyclic group is oxetane-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, or morphine-4-yl.

[0088] In some embodiments, as R 3e The heterocyclic group is a monocyclic 4- to 9-membered heterocyclic group, which contains one or two heteroatoms selected from nitrogen, oxygen or sulfur heteroatoms as ring members.

[0089] In some embodiments, as R 3e The heterocyclic group is tetrahydro-pyran-4-yl.

[0090] In some embodiments, R 3a Yes -NR 3b R 3c , where R 3b It is hydrogen and R 3c It is a heterocyclic group.

[0091] In some embodiments, R 3a Yes -NR 3b R 3c , where R 3b It is hydrogen and R 3c It is tetrahydro-pyran-4-yl.

[0092] In some embodiments, R 3a Yes -NR 3b R 3c , where R 3b and R 3c Each is independently hydrogen or -C substituted with cycloalkyl groups. 1-6 Alkyl groups, preferably monocyclic C 3-6 cycloalkyl-substituted -C 1-6 alkyl.

[0093] In some embodiments, R 3a Yes - OR 3b or -SO2R 3b , where R 3b Is it hydrogen or C? 1-8 Alkyl group, preferably methyl group.

[0094] In some embodiments, R 3a It is -COR3b , where R 3b Is it hydrogen or optionally -NR 3f R 3g Replacement C 1-6 Alkyl, wherein R 3f and R 3g Each is independently hydrogen or C 1-6 Alkyl group, preferably methyl group.

[0095] In some embodiments, two adjacent R on the phenyl ring 3 Together with the phenyl ring, it forms an indazole group substituted with a tetrahydropyranyl group.

[0096] In some embodiments, m is 1, and R 3 Choose from the following groups:

[0097] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0098] In some embodiments, R 4 It is a halogen selected from the following: fluorine (-F), chlorine (-Cl) or bromine (-Br), preferably fluorine (-F).

[0099] In some embodiments, R 4 At position 3 of the pyrrolo[2,3-b]pyridine-5-yl ring.

[0100] In some embodiments, the compound is selected from the example compounds.

[0101] In some embodiments, the compound is selected from

[0102] i)

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] ,or

[0113] ii)

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123] ,

[0124] Where R 4 It is selected from the following halogens: fluorine (-F), chlorine (-Cl) or bromine (-Br).

[0125] In some embodiments, the compound is

[0126] or , where R 4 It is a halogen selected from the following: fluorine (-F), chlorine (-Cl), or bromine (-Br), and Rx is selected from...

[0127]

[0128] In some embodiments, the compound is selected from

[0129]

[0130] The pyrrole ring on the pyrrolo[2,3-b]pyridine-5-yl ring is optionally selected from one of the following substituents R. 4 Substitution: Fluorine (-F), chlorine (-Cl), or bromine (-Br).

[0131] Furthermore, Ry is selected from

[0132] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

[0133] , , , , , , , , or .

[0134] The compounds disclosed in this application have an additional aromatic or carbocyclic moiety attached to the phenylpiperazine or phenylpiperidine moiety in the molecule via a linker -L2- (especially -CH2-, -O-). This key structural feature not only confers comparable or slightly better inhibitory activity against the wild-type Bcl-2 protein, but also unexpectedly exhibits potent efficacy against Bcl2 mutants (including G101V and D103Y). The IC50 of Bcl-2 G101V / Bcl-2 wt is... 50 The rates are very low. These results indicate that the compounds disclosed in this application are novel potential Bcl-2 inhibitors without resistance issues related to mutations such as G101V and D103Y. From the perspective of neutropenia as an adverse reaction, these compounds demonstrate the potential for effective and safe doses of this novel therapy for clinically relapsed patients with mutations after treatment with venetum.

[0135] In human and mouse species, the disclosed compounds exhibit a relatively long in vitro half-life (T0). 1 / 2 ) and low intrinsic clearance rate (CL) int Furthermore, the compounds disclosed herein exhibit significantly improved metabolic stability in liver microsomes.

[0136] Furthermore, the disclosed compound exhibits significantly favorable PK, AUC, and Cmax in mice. Moreover, the intravenous CL value of the disclosed compound is also lower, consistent with its in vitro clearance data.

[0137] This application discloses a pharmaceutical composition comprising the compound disclosed herein or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

[0138] This application discloses a method for treating dysplastic apoptosis, the method comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. In some embodiments, the dysplastic apoptosis is a neurodegenerative disease, a proliferative disease, or a prethrombotic disease. In other embodiments, the proliferative disease is cancer. In some embodiments, the dysplastic apoptosis is associated with a mutation in Bcl-2. In other embodiments, the Bcl-2 mutation comprises Bcl-2 G101V and / or Bcl-2 D103Y. In yet another embodiment, the Bcl-2 mutation is either Bcl-2 G101V or Bcl-2 D103Y. Attached Figure Description

[0139] Figure 1 (a) shows the conformation and electron density plot of example 19a synthesized from intermediate 19-1a in method A.

[0140] Figure 1 (b) is the eutectic structure of instance 19a with the Bcl-2 G101V mutant. Detailed Implementation

[0141] definition

[0142] Unless specifically defined elsewhere in this application, all other technical and scientific terms used in this application have the meanings commonly understood by one of ordinary skill in the art.

[0143] As used in this application, including the appended claims, the singular forms of "a," "an," and "the" include their respective plural references, unless the context clearly indicates otherwise.

[0144] Unless the context clearly indicates otherwise, the term “or” means the term “and / or” and is used interchangeably with the term “and / or”.

[0145] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups containing 1 to 18 carbon atoms (e.g., 1 to 12, further, for example, 1 to 10, even further, for example, 1 to 8, 1 to 6, or 1 to 4). Alkyl groups containing 1 to 6 carbon atoms (i.e., C64) 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 sec-butyl (“s-Bu”), 1,1-dimethylethyl or tert-butyl (“t-Bu”), 1-pentyl, 2- The alkyl groups include 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 groups may optionally be rich in deuterium, such as -CD3, -CD2CD3, etc.

[0146] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0147] 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 fluorine, chlorine, bromine, and iodine). Examples of haloalkyl groups include halogenated C-type alkyl groups. 1-8 Alkyl, Halogenated C 1-6 Alkyl or halogenated C 1-4 Alkyl groups, but not limited to -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0148] The term "alkyloxy" or "alkoxy" refers to an alkyl group, as defined above, that is attached to a parent molecule via an oxygen atom. Alkyloxy groups (e.g., C1646) 1-6 Alkyloxy or C 1-4 Examples of alkyloxy groups include, but are not limited to: methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, and hexoxy.

[0149] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cycloalkyl groups that contain monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyl groups.

[0150] For example, the cycloalkyl group can contain 3 to 12, for example, 3 to 10, further for example, 3 to 8, further for example, 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even further, for example, the cycloalkyl group can be selected from monocyclic groups containing 3 to 12, for example, 3 to 10, further for example, 3 to 8, or 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, saturated monocyclic cycloalkyl groups (e.g., C16, C26, C36, C46, ​​C56, C6 ... 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embodiment, the cycloalkyl group is a monocyclic ring (abbreviated as C16) containing 3 to 6 carbon atoms. 3-6 Cycloalkyl groups, including but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms, having a fused bicyclic arrangement (selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems) or having a bridged bicyclic arrangement (selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane). Other examples of bicyclic cycloalkyl groups include those arranged in bicyclic arrangements selected from the [5,6] and [6,6] ring systems, such as... and The wavy line represents the connection point. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but not fully conjugated, and is non-aromatic, as defined in this application.

[0151] The term "spirocycloalkyl" refers to a cyclic structure containing a carbon atom and consisting of at least two rings sharing a single atom. The term "7- to 10-membered spirocycloalkyl" refers to a cyclic structure containing 7 to 10 carbon atoms and consisting of at least two rings sharing a single atom.

[0152] The term "fused cycloalkyl" refers to a fused ring containing carbon atoms and formed by two or more rings sharing two adjacent atoms. The term "quadrivalent to decavalent cycloalkyl" refers to a fused ring containing 4 to 10 cyclic carbon atoms and formed by two or more rings sharing two adjacent atoms.

[0153] Examples include, but are not limited to, 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, naphthane, and benzo3- to 8-membered cycloalkyl, benzoC 4-6Cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8- to 9-membered fused cycloalkenes, referring to the ring structures containing 8 to 9 ring atoms in the above examples.

[0154] The term "bridged cycloalkyl" refers to a ring structure containing carbon atoms and consisting of at least two rings sharing two non-adjacent atoms. The term "7- to 10-membered bridged cycloalkyl" refers to a ring structure containing 7 to 12 carbon atoms and consisting of at least two rings sharing two non-adjacent atoms. Examples include, but are not limited to, octahydro-5H-2,5-methanolindenyl (preferably octahydro-5H-2,5-methanolinden-5-yl) or adamantyl (preferably adamantane-1-yl).

[0155] The term "aryl" used alone or in combination with other terms refers to a group selected from the following:

[0156] a) 5- and 6-membered carbon-ring aromatic rings, such as phenyl;

[0157] b) Bicyclic systems (e.g., 7- to 12-membered bicyclic systems), wherein at least one ring is a carbocyclic and aromatic, such as naphthyl and indanyl; and,

[0158] c) Tricyclic systems (e.g., decacyclic to 15-membered tricyclic systems), wherein at least one ring is a carbocyclic and aromatic, such as fluorene.

[0159] The terms "aromatic ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic ring has 5 to 10 cyclic carbon atoms (i.e., C10). 5-10 Aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthraceneyl, phenanthrene, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthyl ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0160] The term "heteroaryl" refers to a group selected from the following:

[0161] a) A 5-, 6-, or 7-membered aromatic monocyclic ring comprising at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O) (e.g., from 1 to 4, or in some embodiments from 1 to 3, and in some embodiments from 1 to 2 heteroatoms), wherein the remaining ring atoms are carbon;

[0162] b) An 8- to 12-membered bicyclic ring comprising at least one heteroatom selected from N, O, and S, for example, from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0163] c) An 11- to 14-membered tricyclic ring comprising at least one heteroatom selected from N, O, and S (e.g., from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2 heteroatoms), wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0164] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle does not exceed 1. When a heteroaryl group contains more than one heteroatom ring member, these heteroatoms can be the same or different. The nitrogen atom in one or more rings of a heteroaryl group can be oxidized to form an N-oxide. As used herein, the term "C-linked heteroaryl" means a heteroaryl group that is linked to the core molecule via a bond from a C-atom of the heteroaryl ring.

[0165] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout the disclosure of this application. In some embodiments, a monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 cyclic members, wherein 1, 2, 3, or 4 heteroatom ring members are independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members are carbon. In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a 5- to 6-membered heteroaryl ring, which is monocyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring, which is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0166] Examples of heteroaryl groups or monocyclic or bicyclic aromatic heterocycles include, but are not limited to: (numbered starting from the linking position designated as priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cyclophosphino, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl) (e.g., thiophene-2-yl, thiophene-3-yl), triazine, benzothiophene, furanyl or furanyl, benzofuranyl, benzimidazolyl, indole, isoyindolyl, dihydroindolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrroleyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl or 1,3,4-triazolyl) ), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), benzofuranyl, benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purineyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thio The following are listed: 2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazolyl, benzothiophenyl, benzothiazolyl, benzooxanetrox, quinazolinyl, quinoxolinyl, naphthidyl, fluoropyridinyl, benzothiazolyl (e.g., benzo[d]thiazolyl-6-yl), indazole (e.g., 1H-indazole-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0167] "Heterocyclic group", "heterocyclic" or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclic group (containing one or more heteroatoms selected from the group consisting of NH, O, S, SO or SO2 heteroatoms as ring members, wherein the remaining ring members are carbon), including monocyclic, fused, bridged and spirocyclic, i.e. containing monocyclic heterocyclic groups, bridged heterocyclic groups, spirocyclic groups and fused heterocyclic groups.

[0168] The term "monocyclic heterocyclic group" refers to a monocyclic group in which at least one ring member is a heteroatom selected from the group consisting of NH, O, S, SO, or SO2. The heterocycle can be saturated or partially saturated.

[0169] Exemplary monocyclic 4- to 9-membered heterocyclic groups include, but are not limited to: (numbered starting from the connection position designated as priority 1) pyrrolid-1-yl, pyrrolid-2-yl, pyrrolid-3-yl, imidazolidine-2-yl, imidazolidine-4-yl, pyrrolid-2-yl, pyrrolid-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, ethylene oxide, aziridine- 1-yl, azircyclo-2-yl, azircyclooct-1-yl, azircyclooct-2-yl, azircyclooct-3-yl, azircyclooct-4-yl, azircyclooct-5-yl, thiiranyl, azircyclobutane-1-yl, azircyclobutane-2-yl, azircyclobutane-3-yl, oxetane, thiobutane, 1,2-thiocyclobutane, 1,3-thiocyclobutane, dihydropyridyl, tetrahydropyridyl, thiomorpholinyl, oxothiohexane, piperazine, homopiperazine High piperidinyl, aziridine-1-yl, aziridine-2-yl, aziridine-3-yl, aziridine-4-yl, oxacycloheptyl, thiazepanyl, 1,4-oxothiazepanyl, 1,4-dioxacycloheptyl, 1,4-oxothiazepanyl, 1,4-oxazazepanyl, 1,4-dithiazepanyl, 1,4-diazepanyl, 1,4-dithiazepanyl, 1,4-azazepanyl Alkyl, oxazolidinyl, diazazidinyl, thioazolidinyl, dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxane, 1,3-dioxolane, pyrazolinyl, pyrazolylalkyl, dithiaalkyl, dithiopentane, pyrazolylalkyl, imidazolinyl, pyrimidinoneyl, or 1,1-dioxo-thiomorpholinyl.

[0170] The term "spiroheterocyclic group" or "heterospirocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group having rings linked by a common carbon atom (called a spiro atom), comprising one or more heteroatoms selected from the group consisting of NH, O, S, SO, or SO2 heteroatoms as ring members, and the remaining ring members being carbon. One or more rings of the spiroheterocyclic group may contain one or more double bonds, but none of the rings has a fully coupled π-electron system. Preferably, the spiroheterocyclic group is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of common spiro atoms, spiroheterocyclic groups are classified as monospirocyclic, dispirocyclic, or polyspirocyclic, and preferably monospirocyclic or dispirocyclic, and more preferably 4 / 4, 3 / 5, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic. Representative examples of spiroheterocyclic groups include, but are not limited to, 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), 2-oxa-6-azaspiro[3,4]octane (e.g., 2-oxa-6-azaspiro[3,4]octane-6-yl). , 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]non-7-yl), 7-oxaspiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.

[0171] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group (where each ring in the system shares an adjacent pair of atoms (carbon and carbon or carbon and nitrogen) with another ring), comprising one or more heteroatoms selected from the group consisting of NH, O, S, SO, or SO2 as ring members, and the remaining ring members being carbon. One or more rings of a fused heterocyclic group may contain one or more double bonds, but none of the rings has a fully coupled π-electron system. Preferably, the fused heterocyclic group is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of member rings, fused heterocyclic groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, and more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Representative examples of fused heterocycles include, but are not limited to, the following groups: octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrole-2-yl), octahydropyrrolo[3,4-c]pyrroleyl, octahydroisoindolyl, isoindololinyl (e.g., isoindololin-2-yl), octahydro-benzo[b][1,4]dioxin, dihydrobenzofuranyl, benzo[d][1,3]dioxacyclopentenyl or 2,3,4,5-tetrahydrobenzo[b]oxazolidinyl (preferably 2,3,4,5-tetrahydrobenzo[b]oxazolidin-7-yl).

[0172] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group (where each pair of rings in the system shares two discontinuous atoms), comprising one or more heteroatoms selected from the group consisting of NH, O, S, SO, or SO2 as ring members, wherein the remaining ring members are carbon. One or more rings of the bridged heterocyclic group may contain one or more double bonds, but none of the rings has a fully coupled π-electron system. Preferably, the bridged heterocyclic group is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of member rings, bridged heterocyclic groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, and preferably bicyclic, tricyclic, or tetracyclic bridged heterocyclic groups, and more preferably bicyclic or tricyclic bridged heterocyclic groups. Representative examples of bridging heterocyclic groups 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.

[0173] Heterocyclic rings can be fused with aryl, heteroaryl, or cycloalkyl rings, wherein the ring structure is attached together to the parent heterocyclic group.

[0174] The term “heterocyclic group -O-” refers to a heterocyclic group as defined above that is attached to the parent molecule via an oxygen atom.

[0175] The term "C-linked heterocyclic group" refers to a heterocyclic group that is directly bonded to other parts of the molecule via a carbon atom from the heterocyclic ring.

[0176] The term "N-linked heterocyclic group" refers to a heterocyclic group that is directly bonded to other parts of the molecule via a nitrogen atom from the heterocyclic ring.

[0177] The compounds disclosed in this application may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other. When the compounds disclosed in this application have two or more chiral centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a broader category of stereoisomers. This is intended to include all possible stereoisomers, such as substantially pure, resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. This is intended to include stereoisomers of all compounds disclosed in this application and / or their pharmaceutically acceptable salts. Unless otherwise specifically stated, reference to one isomer applies to any possible isomer. Whenever the composition of an isomer is not specified, all possible isomers are included.

[0178] As used in this application, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight, for example no more than 30%, further for example no more than 25%, or even further for example no more than 20% of any one or more other stereoisomers. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight, for example no more than 5%, or for example no more than 1% of any one or more other stereoisomers.

[0179] When the compounds disclosed in this application contain olefin double bonds, such double bonds are intended to include E and Z geometric isomers unless otherwise stated.

[0180] When the compounds disclosed in this application contain a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring can be formed in cis and trans arrangements. Cis formation means that both substituents are located above the two substituent positions on the carbon atom, while trans formation means that they are located on opposite sides.

[0181] Separating the reaction products from each other and / or from the starting materials may be advantageous. The desired products of each step or series of steps are separated and / or purified (hereinafter referred to as separation) to the desired homogeneity using 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 many methods, including, for example, reversed-phase and normal-phase; size exclusion; ion exchange; high, medium, and low-pressure liquid chromatography and apparatus; small-scale analysis; simulated moving bed (“SMB”) and preparative thin-layer or thick-layer chromatography, as well as techniques for small-scale thin-layer and rapid chromatography. Those skilled in the art will apply the techniques most likely to achieve the desired separation.

[0182] "Diastereoisomers" refer to stereoisomers of compounds having two or more chiral centers that are not mirror images of each other. Mixtures of diastereoisomers can be separated into their individual diastereoisomers based on their physicochemical differences using methods well known to those skilled in the art (e.g., by chromatography and / or stepwise crystallization). Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers, and converting (e.g., hydrolyzing) the individual diastereoisomers into their corresponding pure enantiomers. Enantiomers can also be separated using chiral HPLC columns.

[0183] A single stereoisomer (e.g., a substantially pure enantiomer) can be obtained by resolving a racemic mixture using an optically active resolving agent to form a diastereomer. Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. Stereochemistry of organic compounds New York: John Wiley & Sons, Inc. [New York: John Willie & Son Publishing Company], 1994; Lochmuller, C. H. et al. “Chromatographic resolution of enantiomers: Selective review. [Chromatographic Separation of Enantiomers: A Selectivity Review] ” J. Chromatogr. [Chromatography Journal] , 113 (3) (1975): pp. 283-302 The racemic mixtures of the chiral compounds of the present invention can be separated and isolated by any suitable method comprising: (1) forming ionic diastereomeric salts with the chiral compounds and separating them by fractional crystallization or other methods; (2) forming diastereomeric compounds with chiral derivatizing agents, separating these diastereomeric compounds and converting them into pure stereoisomers; and (3) directly separating substantially pure or enriched stereoisomers under chiral conditions. See also: Wainer, Irving W., ed. Drug Stereochemistry: Analytical Methods and Pharmacology. [Pharmaceutical Stereochemistry: Analytical Methods and Pharmacology] New York: Marcel Dekker, Inc. [New York: Marcel Decker & Co.], 1993 .

[0184] The term "pharmaceutically acceptable salt" refers to salts that, to the extent of reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compounds disclosed in this application, or separately by reacting a free basic group with a suitable organic acid, or separately by reacting an acidic group with a suitable base.

[0185] Furthermore, if the compound disclosed in this application is obtained as an acid addition salt, the free base can be obtained by alkalizing the solution of the acid salt. Conversely, if the product is a free base, the addition salt (e.g., a pharmaceutically acceptable addition salt) can be produced by following the conventional procedure for preparing acid addition salts from base compounds, by dissolving the free base in a suitable organic solvent and treating the solution with acid. Those skilled in the art will recognize a variety of synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts without excessive experimentation.

[0186] As defined in this application, a “pharmaceutically acceptable salt” includes a salt of at least one compound of formula (I), and a salt of a stereoisomer of a compound of formula (I), such as an enantiomer salt, and / or a diastereomer salt.

[0187] The terms "administration" and "administering" as used in this application, when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refer to the contact of an exogenous pharmaceutical, therapeutic, or diagnostic agent or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. Cell treatment encompasses contact between a reagent and a cell, as well as contact between a reagent and a fluid, wherein the fluid contacts the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment of cells, for example, by means of a reagent, diagnostic agent, conjugated compound, or another cell. The term "subject" as used in this application includes any biological entity, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit), and most preferably a human.

[0188] The term "effective amount" or "therapeutic effective amount" refers to the amount of an active ingredient (e.g., a compound) that, when administered to a subject to treat at least one clinical symptom of a disease or disorder, is sufficient to affect the treatment of such disease, disorder, or symptom. "Therapeutic effective amount" can vary depending on the compound, the disease, disorder, and / or the symptom of the disease or disorder, the severity of the disease, disorder, and / or the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given situation will be obvious to those skilled in the art or can be determined by routine experiments. In some embodiments, "therapeutic effective amount" is the amount of at least one compound disclosed in this application and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, as defined above, that is effective in treating a subject's disease or disorder. In the case of combination therapies, "therapeutic effective amount" refers to the total amount of the combination of substances used to effectively treat a disease, disorder, or symptom.

[0189] Pharmaceutical compositions containing the compounds disclosed in this application may be administered to subjects in need via oral, inhalation, rectal, parenteral, or topical administration. For oral administration, the pharmaceutical composition may be a conventional solid formulation, such as tablets, powders, granules, capsules, etc.; a liquid formulation, such as an aqueous or oil suspension; or other liquid formulations, such as syrups, solutions, suspensions, etc. For parenteral administration, the pharmaceutical composition may be a solution, aqueous solution, oil suspension concentrate, lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. The pharmaceutical composition may be administered as a single unit with a precise dosage. In addition, the pharmaceutical composition may further contain other active ingredients.

[0190] All formulations of the pharmaceutical compositions disclosed in this application can be produced using conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients to form the desired formulation. "Pharmaceutically acceptable excipients" refer to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as: diluents, mediators (e.g., water, various organic solvents), fillers (e.g., starch, sucrose), binders (e.g., cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone (PVP)); wetting agents, such as glycerin; disintegrants, such as agar, calcium carbonate, and sodium bicarbonate; absorption enhancers, such as quaternary ammonium compounds; surfactants, such as hexadecyl alcohol; absorbent carriers, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical compositions may also contain other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, aromatic compounds, sweeteners, and dyes.

[0191] The term “disease” refers to any illness, discomfort, ailment, symptom, or indication and is interchangeable with the terms “disorder” or “symptom”.

[0192] Throughout this specification and the appended claims, unless the context otherwise requires, the term "comprise" and variations such as "comprises" and "comprising" are intended to specify the presence of the following feature but do not exclude the presence or addition of one or more other features. When used in this application, the term "comprise" may be replaced by the terms "containing" or "including," or sometimes by "having."

[0193] Throughout this specification and the appended claims, the term "C" is used. n-m The indicator includes the range of endpoints, where n and m are integers, and indicates the number of carbons. Examples include C. 1-8 C 1-6 wait.

[0194] Unless specifically defined elsewhere in this application, all other technical and scientific terms used in this invention have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0195] Example

[0196] The invention is further illustrated by the following examples, but is not limited to these examples.

[0197] In the following examples, the following abbreviations are used:

[0198]

[0199]

[0200] The following examples are intended to be purely illustrative and should not be considered as limiting in any way. While efforts have been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), some experimental errors and biases should be accounted for. Unless otherwise specified, temperatures are in degrees Celsius. Reagents are purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and unless otherwise specified, no further purification is required for use.

[0201] Unless otherwise stated, the reactions described below are carried out under positive pressure of nitrogen or argon or in anhydrous solvent using a drying tube; the reaction flask is equipped with a rubber septum for introducing the substrate and reagents via a syringe; and the glassware is oven-dried and / or heated to dry.

[0202] Recording on an Agilent instrument operating at 400 MHz 1 ¹H NMR spectra were obtained using CDCl₃, CD₂Cl₂, CD₃OD, D₂O, d₆-DMSO, d₆-acetone, or (CD₃)₂CO as solvents, and tetramethylsilane (0.00 ppm) or residual solvents (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 reference standards. 1 HNMR spectra. When reporting the number of multiplets, use the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad peak), dd (double doublet), dt (double triplet). If the coupling constant is given, report it in Hertz (Hz).

[0203] LC-MS spectrometer (Agilent 1260) detector: MWD (190-400 nm), mass detector: 6120 SQ

[0204] Mobile phase: A: Acetonitrile containing 0.1% formic acid; B: Water containing 0.1% formic acid.

[0205] Column: Poroshell 120 EC-C18, 4.6 × 50 mm, 2.7 µm

[0206] Gradient method: Flow rate: 1.8 mL / min

[0207]

[0208] Preparative HPLC was performed on a column (150 × 21.2 mm ID, 5 μm, Gemini NX-C18) at different flow rates and injection volumes at room temperature and detected by UV at 214 nm and 254 nm.

[0209] Preparation of intermediates:

[0210] Intermediate 2-1 : 2-(4-ethyl-2-(2-isopropylphenyl)piperazin-1-yl)-7- azaspiro[3.5]nonane.

[0211]

[0212] Step 1: tert-butyl 4-ethyl-2-(2-isopropylphenyl)-3-oxopiperazine-1-carboxylate.

[0213] NaH (301.47 mg, 7.54 mmol) was added to a solution of tert-butyl 2-(2-isopropylphenyl)-3-oxopiperazine-1-carboxylate (2.0 g, 6.28 mmol) in THF (20 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min, and then C2H5I (1.18 g, 7.54 mmol) was added at 0 °C. The mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. The compound tert-butyl 4-ethyl-2-(2-isopropylphenyl)-3-oxopiperazine-1-carboxylate (1.7 g, yield: 78%) was given as a yellow oil. 1 H NMR (400 MHz, 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).

[0214] Step 2: 1-Ethyl-3-(2-isopropylphenyl)piperazin-2-one.

[0215] A mixture of tert-butyl-4-ethyl-2-(2-isopropylphenyl)-3-oxopiperazin-1-carboxylate (1.7 g, 4.91 mmol) in DCM (10 mL) and TFA (10 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (10 mL) and Na2CO3 was added to pH = 9. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The compound 1-ethyl-3-(2-isopropylphenyl)piperazin-2-one (1.2 g, yield: 99%) was given as a yellow oil. MS (ESI, m / e) [M+1] + 247.1.

[0216] Step 3: tert-butyl 2-(4-ethyl-2-(2-isopropylphenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0217] At 20 °C, AcOH (585 mg, 9.74 mmol) and NaBH(OAc)3 (2.06 g, 9.74 mmol) were added to a solution of 1-ethyl-3-(2-isopropylphenyl)piperazin-2-one (1.2 g, 4.87 mmol) and tert-butyl-2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (1.4 g, 5.85 mmol) in DCE (20 mL). The mixture was stirred at 50 °C for 12 hours. The reaction mixture was poured into aqueous Na2CO3 (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC to give tert-butyl 2-(4-ethyl-2-(2-isopropylphenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate as a yellow oil (1.2 g, yield: 52%). MS (ESI, m / e) [M+1] + 470.3.

[0218] Step 4: tert-butyl 2-(4-ethyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0219] A mixture of tert-butyl 2-(4-ethyl-2-(2-isopropylphenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, 2.56 mmol) in BH3·THF (10 mL) was stirred at 70 °C for 12 h. The reaction mixture was quenched at 0 °C with MeOH (10 mL) and stirred at 25 °C for 30 min. The mixture was concentrated under reduced pressure to give tert-butyl 2-(4-ethyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.1 g, crude) as a colorless oil. MS (ESI, m / e) [M+1] + 456.3.

[0220] Step 5: 2-(4-ethyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0221] A mixture of tert-butyl 2-(4-ethyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.1 g, 2.41 mmol) in DCM (5 mL) and TFA (5 mL) was stirred at 25 °C for 1 hr. 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 pH = 9. The mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The compound 2-(4-ethyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (440 mg, yield: 51%) was given as a yellow oil. 1 H 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 = 6.8 Hz, 3H), 1.20(d, J = 6.8 Hz, 3H), 1.10-1.05 (m, 3H). MS (ESI, m / e) [M+1] + 356.2.

[0222] Intermediate 4-1 : 2-(4-cyclopropyl-2-(2-isopropylphenyl)piperazin-1-yl)-7- azaspiro[3.5]nonane.

[0223]

[0224] Step 1: tert-butyl 2-(4-cyclopropyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0225] A solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.5 g, 3.4 mmol) in MeOH (20 mL) was mixed with (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). The mixture was stirred at 25 °C for 12 hours. The mixture was poured into aqueous NaHCO3 (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 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 give tert-butyl 2-(4-cyclopropyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.1 g, yield: 70%) as a yellow oil. 1 H NMR (400 MHz, CDCl3)δ ppm: 7.31-7.28 (m, 1H),7.26-7.22 (m, 1H), 7.11 (m, 1H), 6.99 (d, J = 8.0 Hz, 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).

[0226] Step 2: tert-butyl 2-(4-cyclopropyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0227] A mixture of tert-butyl 2-(4-cyclopropyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.1 g, 2.28 mmol) and BH3·THF (10 mL, 10 mmol) was heated to 70 °C for 12 hours. After cooling to 0 °C, the mixture was carefully quenched with MeOH (10 mL). The mixture was concentrated under vacuum to give tert-butyl 2-(4-cyclopropyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.8 g, yield: 80%) as a yellow oil, which could be used for the next step without further purification. MS (ESI, m / e) [M+1] + 468.4.

[0228] Step 3: 2-(4-cyclopropyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0229] TFA (10 mL) was added to a solution of tert-butyl-2-(4-cyclopropyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (800 mg, 1.7 mmol) in DCM (30 mL). The mixture was stirred at 25 °C for 2 h. After concentration under reduced pressure, the residue was dissolved in water (20 mL). The mixture was then extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 2-(4-cyclopropyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (405 mg, yield: 64%) as a yellow solid. 1H NMR (400 MHz, 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

[0230] Intermediate 5-1 : 2-(4-cyclobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7- azaspiro[3.5]nonane.

[0231]

[0232] Step 1: tert-butyl 2-(4-cyclobutyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0233] Cyclobutanone (0.24 g, 3.40 mmol) and HOAc (0.27 g, 4.52 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in DCE (20 mL). After stirring at 25 °C for 1 hr, NaBH(OAc)3 (0.96 g, 4.52 mmol) was added. The mixture was stirred at 25 °C for 12 h. Then, aqueous NH4Cl (20 mL) was added to the mixture, and the mixture was then extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL × 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 give tert-butyl 2-(4-cyclobutyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.85 g, yield: 76%) as a yellow solid. 1 H NMR (400 MHz, 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 = 6.8 Hz, 3H), 1.27-1.25(m, 3H).

[0234] Step 2: tert-butyl 2-(4-cyclobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0235] A mixture of tert-butyl 2-(4-cyclobutyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (850 mg, 1.71 mmol) and BH3·THF (20 mL, 17.1 mmol) was heated to 70 °C for 12 hours. MeOH (10 mL) was then carefully added to the mixture, and the mixture was concentrated under vacuum to give tert-butyl 2-(4-cyclobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (800 mg, yield: 97%) as a yellow oil, which could be used directly without further purification. MS (ESI, m / e) [M+1] + 482.4.

[0236] Step 3: 2-(4-cyclobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0237] HCl / MeOH (10 mL) was added to a solution of tert-butyl 2-(4-cyclobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, 1.45 mmol) in MeOH (20 mL). The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated under vacuum under reduced pressure to give 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 (400 MHz, 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 = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H). MS (ESI, m / e) [M+1] + 382.4.

[0238] Intermediate 6-1 : 2-(2-(2-isopropylphenyl)-4-(oxetan-3-yl)piperazin-1-yl)-7- azaspiro[3.5]nonane Intermediate 6-1a:

[0239]

[0240] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0241] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (3.6 g, 8.15 mmol) in BH3·THF (40 mL) was stirred at 70 °C for 12 h. The reaction mixture was quenched at 0 °C with MeOH (40 mL) and stirred at 25 °C for 30 min. The mixture was concentrated to give tert-butyl 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (3.6 g, crude) as a white solid. MS (ESI, m / e) [M+1] + 428.3.

[0242] Step 2: tert-butyl 2-(2-(2-isopropylphenyl)-4-(oxecyclobutane-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0243] NaBH3CN (191.04 mg, 3.04 mmol) was added to a solution of tert-butyl-2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.34 mmol) and oxetane-3-one (219.08 mg, 3.04 mmol) in MeOH (20 mL). The mixture was stirred at 45 °C for 36 h. The reaction mixture was diluted with aqueous Na2CO3 (40 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. The compound tert-butyl 2-(2-(2-isopropylphenyl)-4-(oxecyclobutane-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (420 mg, yield: 37%) was obtained as a yellow oil. MS (ESI, m / e) [M+1] + 484.3.

[0244] Step 3: 2-(2-(2-isopropylphenyl)-4-(oxacyclobutane-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0245] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-4-(oxetane-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (420 mg, 868.33 μmol) in DCM (3 mL) and TFA (1 mL) was stirred at 25 °C for 2 h. 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) and Na2CO3 was added to pH = 9 and extracted with EtOAc (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-(2-(2-isopropylphenyl)-4-(oxetane-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane (203 mg, yield: 61%) as a yellow oil. 1 H NMR(400 MHz, 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), 1.92-1.75 (m, 4H), 1.72-1.63 (m, 1H), 1.44-1.31 (m, 4H), 1.27 (d, J =6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H). MS (ESI, m / e) [M+1] + 384.2.

[0246] Intermediate 6-1b:2-(2-(2-isopropylphenyl)-4-(oxacyclobutane-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 i.d. 10 μm; mobile phase: A was CO2 and B was MeOH (0.1% NH3.H2O); gradient: B% = 30% isocratic mode; flow rate: 60 g / min; wavelength: 220 nm; column temperature: 40 °C; system back pressure: 100 bar).

[0247]

[0248] (R or S)-2-(2-(2-isopropylphenyl)-4-(oxecyclobutane-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane (728 mg, retention time: 1.40 min), yield: 32.1%. 1 H NMR (400 MHz, CDCl3)δ ppm:7.45 (d, J = 6.0 Hz, 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 = 9.0 Hz, 1H), 3.48 (m,1H), 3.37 (s, 1H), 3.01 (d, J = 11.2 Hz, 1H), 2.97-2.68 (m, 6H), 2.53 (d, J =11.2 Hz, 1H), 2.35-2.25 (m, 1H), 2.24-2.13 (m, 1H), 2.05 (t, J = 10.6 Hz, 1H), 1.82 (d, J = 3.4 Hz, 1H), 1.76-1.68 (m, 1H), 1.65-1.45 (m, 4H), 1.38-1.29 (m,1H), 1.25 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.3 Hz, 3H), 1.15 (d, J = 5.1 Hz, 1H). MS (ESI, m / e) [M+1] + 384.2.

[0249] Intermediate 7-1 : 2-(4-cyclopentyl-2-(2-isopropylphenyl)piperazin-1-yl)-7- azaspiro[3.5]nonane. (S or R)-2-(2-(2-isopropylphenyl)-4-(oxecyclobutan-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane (649 mg, retention time: 1.51 min, yield: 28.6%). MS (ESI, m / e) [M+1] + 384.2.

[0250] Intermediate 8-1 : 2-(2-(2-isopropylphenyl)-4-(tetrahydrofuran-3-yl)piperazin-1- yl)-7-azaspiro[3.5]nonane.

[0251]

[0252] Step 1: tert-butyl 2-(4-cyclopentyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0253] Cyclopentanone (285.7 mg, 3.40 mmol) and AcOH (272.0 mg, 5.57 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in DCE (15 mL) for 30 min, 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 h. The reaction mixture was poured into aqueous NaHCO3 (50 mL) and extracted with DCM (50 mL × 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 give tert-butyl 2-(4-cyclopentyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 1.96 mmol, yield: 86%) as a yellow oil. 1H NMR (400 MHz, 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).

[0254] Step 2: tert-butyl 2-(4-cyclopentyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0255] At 25 °C, BH3·THF (20 mL, 1 M) was added to a mixture of tert-butyl 2-(4-cyclopentyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 1.96 mmol) in THF (10 mL). The mixture was stirred at 70 °C for 12 hours. The reaction mixture was cooled to 0 °C–5 °C. Then, MeOH (10 mL) was added dropwise at 5 °C to quench the reaction. The mixture was concentrated under reduced pressure to give tert-butyl 2-(4-cyclopentyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, crude) as a white solid, which could be used directly for the next step without further reaction. MS (ESI, m / e) [M+1] + 496.5

[0256] Step 3: 2-(4-cyclopentyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0257] At 25 °C, HCl / MeOH (10 mL, 4 M) was added to a solution of tert-butyl 2-(4-cyclopentyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.02 mmol) in MeOH (5 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to remove most of the MeOH. Then, HCl / H₂O (1 M) solution was added to adjust the pH to 2-3, and it was extracted with EtOAc (10 mL). Saturated Na₂CO₃ was added to the aqueous phase to pH 9-10, and it was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-(4-cyclopentyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane as a yellow oil (577 mg, 1.46 mmol, yield: 72%). 1 H NMR (400 MHz, CDCl3)δ ppm: 7.52 (br d, J = 7.2 Hz, 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), 1.57-1.49 (m, 2H), 1.49-1.29 (m, 8H), 1.25 (d, J = 6.8 Hz, 3H), 1.20(d, J = 6.8 Hz, 3H). MS (ESI, m / e) [M+1] + 396.4.

[0258] Intermediate 9-1 : 2-(4-cyclohexyl-2-(2-isopropylphenyl)piperazin-1-yl)-7- azaspiro[3.5]nonane. Intermediate 10-1 : 2-(2-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin- 1-yl)-7-azaspiro[3.5]nonane.

[0259]

[0260] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0261] HOAc (271.9 mg, 4.53 mmol) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) and dihydrofuran-3(2H)-one (292.4 mg, 3.40 mmol) in a DCE (10 mL). The solution was stirred at 25 °C for 5 min and NaBH(OAc)3 (1.06 g, 4.98 mmol) was added. The solution was stirred at 25 °C for 12 h. Aqueous NaHCO3 was added to the reaction mixture to pH = 7, and the mixture was extracted with DCM (10 mL × 3). The combined organic layers were 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 give tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, yield: 86.3%) as a yellow oil.

[0262] Step 2: tert-butyl 2-(2-(2-isopropylphenyl)-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0263] BH3·THF (15 mL) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 1.95 mmol) in THF (15 mL). The solution was stirred at 70 °C for 12 h. After cooling to room temperature, MeOH (10 mL) was added to quench the reaction. The reaction was evaporated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, crude) as a white solid, which could be used directly without further purification. MS (ESI, m / e) [M+1] + 498.4.

[0264] Step 3: 2-(2-(2-isopropylphenyl)-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0265] TFA (5 mL) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-(tetrahydrofuran-3-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.7 g, 1.41 mmol) in DCM (10 mL). The solution was then stirred at 25 °C for 2 hours. The mixture was poured into aqueous NaHCO3 to adjust the pH to 7 and extracted with DCM (10 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and evaporated under reduced pressure to give 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(400 MHz, 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), 2.64-2.85 (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.

[0266] Intermediate 11-1 : 2-(4-isobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7- azaspiro[3.5]nonane.

[0267]

[0268] Step 1: tert-butyl 2-(4-cyclohexyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0269] Cyclohexanone (0.34 g, 3.40 mmol) and HOAc (0.27 g, 4.52 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in DCE (20 mL). After stirring at 25 °C for 1 hr, NaBH(OAc)3 (0.96 g, 4.52 mmol) was added. The mixture was stirred at 25 °C for 12 h. Then, aqueous NH4Cl (20 mL) was added to the mixture, and the mixture was then extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL × 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 give tert-butyl 2-(4-cyclohexyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate as a yellow solid (750 mg, yield: 63%). 1 H NMR (400 MHz, 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).

[0270] Step 2: tert-butyl 2-(4-cyclohexyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0271] A mixture of tert-butyl 2-(4-cyclohexyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.75 g, 1.43 mmol) and BH3·THF (14 mL, 14.3 mmol) was heated to 70 °C for 12 hours. MeOH (10 mL) was then carefully added to the mixture and the mixture was concentrated under vacuum to give tert-butyl 2-(4-cyclohexyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.7 g, yield: 96%) as a yellow oil, which could be used directly without further purification. MS (ESI, m / e) [M+1] + 510.4.

[0272] Step 3: 2-(4-cyclohexyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0273] A solution of HCl / MeOH (10 mL) was added to a solution of tert-butyl 2-(4-cyclohexyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, 1.37 mmol) in MeOH (20 mL). The mixture was stirred at 25 °C for 1 hr. After solvent removal, the residue was dissolved in water (20 mL). The pH of the mixture was adjusted to 9-10 using aqueous Na₂CO₃. The mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give 2-(4-cyclohexyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (380 mg, yield: 68%) as a yellow solid. 1 H NMR (400 MHz, 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 (brs, 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.

[0274] Intermediate 12-1 : 2-(2-(2-isopropylphenyl)-4-neopentylpiperazin-1-yl)-7- azaspiro[3.5]nonane Intermediate 13-1 : 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin-1-yl)-7- azaspiro[3.5]nonane

[0275]

[0276] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0277] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 a DCE (20 mL) was stirred at 25 °C for 30 min. Then, NaBH(OAc)3 (1.44 g, 6.79 mmol) was added to the mixture in portions and stirred at 25 °C for 12 h. 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 × 3). The combined organic phases were 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 give tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.05 g, yield: 88%) as a yellow solid. 1H NMR (400 MHz, CDCl3)δppm: 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), 2.45-2.34 (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).

[0278] Step 2: tert-butyl 2-(2-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0279] At 20 °C, BH3·THF (30 mL, 30 mmol) was added dropwise to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (900 mg, 1.71 mmol) in THF (15 mL). The mixture was heated to 70 °C for 20 hours. The reaction was quenched with ethanol (5 mL) and concentrated under vacuum to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (876 mg, crude) as a colorless oil, which could be used directly for the next step without further purification. MS (ESI, m / e) [M+1] + 512.4.

[0280] Step 3: 2-(2-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0281] A solution of 20 mL of HCl / MeOH (4 M) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (900 mg, 1.76 mmol) in MeOH (2 mL). The solution was stirred at 25 °C for 4 h. The reaction solution was concentrated under vacuum. The crude product was purified by preparative HPLC and lyophilized. The residue, free of saturated NaHCO3 (20 mL), was extracted with EtOAc (50 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 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 gel. 1 H NMR (400 MHz, CDCl3)δ ppm: 7.50 (d, J = 5.6 Hz, 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.

[0282] Intermediate 13-1a: (R or S)-2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin- 1-yl)-7-azaspiro[3.5]nonane

[0283]

[0284] Step 1: tert-butyl 2-(4-isobutyl-2-(2-isopropylphenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0285] At 0 °C, NaH (362.28 mg, 9.06 mmol) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (2.0 g, 4.53 mmol) in THF (20 mL). The mixture was stirred at 0 °C for 10 min. 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 hr. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. The compound tert-butyl 2-(4-isobutyl-2-(2-isopropylphenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.14 (m, 6H).

[0286] Step 2: tert-butyl 2-(4-isobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0287] A mixture of tert-butyl 2-(4-isobutyl-2-(2-isopropylphenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.1 g, 2.21 mmol) in BH3·THF (10 mL) was stirred at 70 °C for 12 h. The reaction mixture was quenched at 0 °C with MeOH (5 mL) and stirred at 25 °C for 30 min. The mixture was then concentrated under reduced pressure to give tert-butyl 2-(4-isobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.05 g, crude) as a colorless oil. MS (ESI, m / e) [M+1] + 484.3.

[0288] Step 3: 2-(4-isobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0289] A mixture of tert-butyl-2-(4-isobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.05 g, 2.17 mmol) in HCl / EtOAc (10 mL) was stirred at 25 °C for 2 h. 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 pH = 9. The mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The compound 2-(4-isobutyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (461 mg, 1.18 mmol, yield: 54.26%) was given as a yellow oil. 1 H NMR (400 MHz, CDCl3)δ ppm: 7.50 (d, J = 4.5 Hz, 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 = 6.8 Hz, 3H), 0.88 (m, 6H). MS (ESI, m / e) [M+1] + 384.4.

[0290] Intermediate 13-1b:

[0291]

[0292] Step 1: 2-Isopropylbenzaldehyde.

[0293] At -78 °C, n-BuLi (44 mL, 0.11 mol, 2.5 M, in hexane) was added dropwise to a solution of 1-bromo-2-isopropylbenzene (20 g, 0.1 mol) in THF (200 mL). After stirring at -78 °C for 1 hr, DMF (8.0 g, 0.11 mol) was added to the mixture. The mixture was stirred at -60 °C for 1 hr. Then, aqueous NH4Cl (1 M, 100 mL) was added to the mixture. The mixture was extracted with EtOAc (300 mL × 3). The combined organic phases were washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE). The compound 2-isopropylbenzaldehyde (14 g, yield: 94%) was given as a yellow oil. 1 H NMR (400 MHz, CDCl3)δppm: 10.38 (s, 1H), 7.83 (dd, J = 8.0 Hz, 1.6 Hz, 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 = 6.8 Hz, 6H).

[0294] Step 2: (E)-N-(2-isopropylbenzyl)-2-methylpropane-2-sulfinamide.

[0295] 2-Methylpropane-2-sulfinamide (18 g, 0.148 mmol) was added to a solution of 2-isopropylbenzaldehyde (20 g, 0.135 mol) in THF (200 mL). After cooling to 0 °C, Ti(OEt)4 (62 g, 0.27 mol) was added. The mixture was stirred at 25 °C for 12 h. The reaction mixture was carefully quenched with water (100 mL) and then filtered through a diatomaceous earth mat. The filtrate was extracted with EtOAc (100 mL × 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 to 20 / 1). The compound (E)-N-(2-isopropylbenzyl)-2-methylpropane-2-sulfinamide (32.5 g, yield: 96%) was obtained as a yellow oil. 1 H NMR (400 MHz, CDCl3)δ ppm: 9.00 (s, 1H), 7.96(dd, J = 8.0 Hz, 2.0 Hz, 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).

[0296] Step 3: N-(1-(2-isopropylphenyl)-2-nitroethyl)-2-methylpropane-2-sulfinamide.

[0297] At 0 °C, t-BuOK (21 g, 0.19 mol) was added in several portions to a solution of (E)-N-(2-isopropylbenzyl)-2-methylpropane-2-sulfinamide (32 g, 0.13 mol) in THF (300 mL). After stirring at 0 °C for 1 hr, nitromethane (77 g, 1.27 mmol) was added. The mixture was stirred at 25 °C for 12 h. Water (100 mL) was then added to the mixture, and the mixture was then extracted with EtOAc (100 mL × 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 give N-(1-(2-isopropylphenyl)-2-nitroethyl)-2-methylpropane-2-sulfinamide (26.5 g, yield: 67%) as a yellow oil. 1H NMR (400 MHz, 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)

[0298] Step 4: N-(2-amino-1-(2-isopropylphenyl)ethyl)-2-methylpropane-2-sulfinamide

[0299] Raney nickel (5.0 g) was added to a solution of N-(1-(2-isopropylphenyl)-2-nitroethyl)-2-methylpropane-2-sulfinamide (23 g, 0.074 mol) in MeOH (200 mL). The mixture was stirred at 25 °C under a H2 (15 psi) atmosphere for 12 hours. After filtration through a diatomaceous earth pad, the filtrate was concentrated under reduced pressure to give N-(2-amino-1-(2-isopropylphenyl)ethyl)-2-methylpropane-2-sulfinamide (17.6 g, yield: 84%) as a brown solid, which could be used for the next step without further purification. MS (ESI, m / e) [M+1] + 283.1.

[0300] Step 5: N-(2-((tert-butylsulfinyl)amino)-2-(2-isopropylphenyl)ethyl)-4-methylbenzenesulfonamide.

[0301] TEA (24.5 g, 0.243 mol) was added to a solution of N-(2-amino-1-(2-isopropylphenyl)ethyl)-2-methylpropane-2-sulfinamide (23 g, 0.081 mol) in DCM (300 mL). After cooling to 0 °C, TsCl (17 g, 0.09 mol) was added in several batches. The mixture was stirred at 25 °C for 2 hours. Then, aqueous NH4Cl (1 M, 100 mL) was added to the mixture, and the mixture was extracted with DCM (100 mL × 3). The combined organic phases were washed with brine (100 mL × 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 give N-(2-((tert-butylsulfinyl)amino)-2-(2-isopropylphenyl)ethyl)-4-methylbenzenesulfonamide (23 g, yield: 65%) as a yellow solid. 1 H NMR (400 MHz, CDCl3)δppm: 7.79 (d, J = 8.4 Hz, 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 = 7.6 Hz, 4H), 3.07-2.97 (m, 1H), 2.41 (s, 3H), 1.42 (t, 6H), 1.23 (s, 9H).

[0302] Step 6: N-(2-amino-2-(2-isopropylphenyl)ethyl)-4-methylbenzenesulfonamide.

[0303] HCl (gas) in MeOH (10 mL, 4 M) was added to a solution of N-(2-((tert-butylsulfinyl)amino)-2-(2-isopropylphenyl)ethyl)-4-methylbenzenesulfonamide (5.0 g, 11 mmol) in MeOH (20 mL). The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure. The residue was dissolved in water (50 mL), and then aqueous Na₂CO₃ was added to adjust the pH to 9. The mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum to give N-(2-amino-2-(2-isopropylphenyl)ethyl)-4-methylbenzenesulfonamide (3.8 g, yield: 99%) as a yellow oil. 1H NMR (400 MHz, 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, 8.8 Hz, 1H), 2.43 (s, 3H), 1.21-1.18 (m, 6H).

[0304] Step 7: tert-butyl 2-((1-(2-isopropylphenyl)-2-(4-methylphenyl)sulfonylamino)ethyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate.

[0305] Tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (3.2 g, 0.013 mol) and HOAc (1.44 g, 0.024 mol) were added to a solution of N-(2-amino-2-(2-isopropylphenyl)ethyl)-4-methylbenzenesulfonamide (4.0 g, 0.012 mol) in DCE (50 mL). After stirring at 25 °C for 1 hr, NaBH(OAc)3 (5.1 g, 0.024 mol) was added. The mixture was stirred at 25 °C for 12 h. Then, aqueous NH4Cl (50 mL) was added to the mixture, and the mixture was extracted with DCM (50 mL × 3). The combined organic phases were washed with brine (50 mL × 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 give tert-butyl 2-((1-(2-isopropylphenyl)-2-(4-methylphenyl)sulfonylamino)ethyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate (4.3 g, yield: 64%) as a yellow solid. 1 H NMR (400 MHz, CDCl3)δ ppm: 7.73(d, J= 8.0 Hz, 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).

[0306] Step 8: tert-butyl 2-(2-chloro-N-(1-(2-isopropylphenyl)-2-(4-methylphenyl)sulfonylamino)ethyl)acetamido)-7-azaspiro[3.5]nonane-7-carboxylate.

[0307] TEA (1.56 g, 15.48 mmol) was added to a solution of tert-butyl 2-((1-(2-isopropylphenyl)-2-(4-methylphenyl)sulfonylamino)ethyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate (4.3 g, 7.74 mmol) in THF (50 mL). 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 aqueous NH4Cl (1 M, 50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (50 mL × 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 give tert-butyl 2-(2-chloro-N-(1-(2-isopropylphenyl)-2-(4-methylphenyl)sulfonylamino)ethyl)acetamido)-7-azaspiro[3.5]nonane-7-carboxylate (4.6 g, yield: 94%) as a yellow solid. 1 H NMR (400 MHz, CDCl3)δ ppm: 7.74 (d, J = 8.0 Hz,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= 2.8 Hz, 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).

[0308] Step 9: tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-toluenesulfonylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0309] K₂CO₃ (2.0 g, 14.55 mmol) was added to a solution of tert-butyl 2-(2-chloro-N-(1-(2-isopropylphenyl)-2-(4-methylphenyl)sulfonylamino)ethyl)acetamido)-7-azaspiro[3.5]nonane-7-carboxylate (4.6 g, 7.28 mmol) in DMF (50 mL). The mixture was stirred at 60 °C for 1 hr. Water (50 mL) was then added to the mixture, and the mixture was then extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (50 mL × 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 give tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-toluenesulfonylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (2.6 g, yield: 62%) as a yellow solid. 1 H NMR (400 MHz, CDCl3)δ ppm: 7.47 (d, J = 8.4 Hz, 2H), 7.36-7.30 (m, 2H), 7.23 (d, J = 8.4 Hz,2H), 7.16-7.10 (m, 1H), 6.89 (d, J= 7.75 Hz, 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).

[0310] Step 10: tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0311] Mg (1.07 g, 44.7 mmol) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-toluenesulfonylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 EtOAc (50 mL) and then filtered through a diatomaceous earth mat. The filtrate was extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (50 mL × 2), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.3 g, yield: 66%) as a brown oil. 1 HNMR (400 MHz, CDCl3)δ ppm: 7.40-7.36 (d, J = 7.2 Hz, 1H), 7.32 (t, 1H), 7.20(t, 1H), 7.00 (d, J= 8.0 Hz, 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).

[0312] Step 11: tert-butyl 2-(2-(2-isopropylphenyl)-4-neopentyl-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0313] Neopentaldehyde (0.29 g, 3.40 mmol) and HOAc (0.27 g, 4.52 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in DCE (20 mL). After stirring at 25 °C for 1 hr, NaBH(OAc)3 (0.96 g, 4.52 mmol) was added. The mixture was stirred at 25 °C for 12 h. The mixture was poured into aqueous NH4Cl (1 M, 20 mL) and extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL × 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 give tert-butyl 2-(2-(2-isopropylphenyl)-4-neopentyl-6-oxoperpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.68 g, yield: 59%) as a yellow solid. 1 H NMR (400 MHz, 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= 16.76 Hz, 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).

[0314] Step 12: tert-butyl 2-(2-(2-isopropylphenyl)-4-neopentylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0315] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-4-neopentyl-6-oxoperpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (680 mg, 1.33 mmol) and BH3·THF (13 mL, 13.3 mmol) was heated to 70 °C for 12 hours. After cooling to 0 °C, the mixture was carefully quenched with MeOH (10 mL). The mixture was concentrated under vacuum to give tert-butyl 2-(2-(2-isopropylphenyl)-4-neopentylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.6 g, yield: 91%) as a yellow oil, which could be used for the next step without further purification. MS (ESI, m / e) [M+1] + 498.4

[0316] Step 13: 2-(2-(2-isopropylphenyl)-4-neopentylpiperazin-1-yl)-7-azaspiro[3.5]nonane.

[0317] A solution of HCl / MeOH (10 mL, 4 M) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-neopentylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (600 mg, 1.21 mmol) in MeOH (20 mL). The mixture was stirred at 25 °C for 1 hr. After concentration under reduced pressure, the residue was dissolved in water (20 mL). The mixture was adjusted to pH = 9-10 with aqueous Na₂CO₃. The mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give 2-(2-(2-(2-isopropylphenyl)-4-neopentylpiperazin-1-yl)-7-azaspiro[3.5]nonane (400 mg, 83.5% yield) as a yellow solid.1 H 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.

[0318] ​ ​

[0319]

[0320] Step 1: tert-butyl 2-(2-isopropylphenyl)-4-(2-methoxyethyl)-3-oxopiperazine-1-carboxylate.

[0321] At 20 °C, tert-butyl 2-(2-isopropylphenyl)-3-oxopiperazine-1-carboxylate (1.5 g, 4.7 mmol) and 1-bromo-2-methoxyethane (0.72 g, 5.2 mmol) in THF (15 mL) were added in portions with NaH (136 mg, 5.6 mmol). The mixture was stirred at 50 °C for 24 hours. The mixture was quenched with MeOH (2 mL) and concentrated under reduced pressure. The residue was decanted into brine (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 2-(2-isopropylphenyl)-4-(2-methoxyethyl)-3-oxopiperazine-1-carboxylate (1.5 g, crude) as a yellow oil, which could be used directly for the next step without further purification.

[0322] Step 2: 3-(2-isopropylphenyl)-1-(2-methoxyethyl)piperazin-2-one.

[0323] A solution of tert-butyl 2-(2-isopropylphenyl)-4-(2-methoxyethyl)-3-oxopiperazin-1-carboxylate (1.4 g, 3.8 mmol) in TFA (5 mL) and DCM (5 mL) was stirred at 27 °C for 2 hours. The mixture was concentrated under reduced pressure. The residue was poured into saturated NaHCO3 (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow oily substance of 3-(2-isopropylphenyl)-1-(2-methoxyethyl)piperazin-2-one (1.0 g, crude), which could be used directly for the next step without further purification.

[0324] Step 3: tert-butyl 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0325] To a solution of 3-(2-isopropylphenyl)-1-(2-methoxyethyl)piperazin-2-one (1.0 g, 3.7 mmol) in DCE (10 mL), tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (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 then poured into saturated NaHCO3 (50 mL) and extracted with DCM (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.6 g, crude), which was a yellow oil and could be used directly in the next step without further purification.

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

[0327] A solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.4 g, 2.8 mmol) in BH3-THF (10 mL) was stirred at 70 °C for 10 h. The mixture was quenched with MeOH (10 mL) and concentrated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (2.4 g, crude), which was a yellow oil and could be used directly for the next step without further purification.

[0328] Step 5: 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0329] A solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.3 g, 2.7 mmol) in TFA (3 mL) and DCM (6 mL) was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by conventional HPLC (TFA). The compound 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (791 mg, yield: 77%) was given as a colorless oil. 1 H NMR (400 MHz, CH3OH- d 4)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, 1H), 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, 3 H), 1.88-1.79 (m, 1H), 1.72-1.63 (m,1H), 1.44-1.25 (m, 8H), 1.20 (d, J = 6.8 Hz, 3H), 1.15-1.03 (m, 1H). MS (ESI, m / e) [M+1] + 386.4.

[0330] ​ ​

[0331]

[0332] 2-(2-(2-isopropylphenyl)-4-(2-methoxyethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane was separated by an SFC (instrument: Waters SFC80 preparative SFC; column: Phenomenex-Cellulose-2 (250 × 30 mm id 10 uM); mobile phase: A was CO2 and B was MeOH (0.1% NH3·H2O); 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), yield: 30%. 1 HNMR (400 MHz, 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.

[0333] ​ (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.

[0334] Intermediate 15-1: 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5] nonane

[0335]

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

[0337] At 25 °C, NaBH(OAc)3 (959 mg, 4.53 mmol) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol), cyclopentaneformaldehyde (333 mg, 3.40 mmol), and AcOH (339 mg, 5.66 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched with saturated Na2CO3 (10 mL) and extracted with EtOAc (10 mL × 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 give tert-butyl 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, yield: 84%) as a pale yellow oil.

[0338] Step 2: tert-butyl 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0339] At 0 °C, a mixture of tert-butyl 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 1.91 mmol) was added to BH3·THF (57 mL, 57.28 mmol) in 20 mL of THF. The mixture was stirred at 80 °C for 12 hours. At 0 °C, MeOH (20 mL) was added to the reaction solution to quench the reaction and the solution was concentrated under reduced pressure to give tert-butyl 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, crude) as a yellow oil, which could be used directly for the next step without further purification.

[0340] Step 3: 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0341] At 0 °C, HCl / MeOH (40 mL) was added to a mixture of tert-butyl 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 1.96 mmol) for 2 hours. The reaction mixture was poured into saturated Na2CO3 (40 mL) and extracted with EtOAc (40 mL × 3). The combined organic phases were washed with brine (40 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(4-(cyclopentylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (712 mg, yield: 88%) as a light pink oil. 1 H NMR (400 MHz, 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, 6H), 1.28-1.25 (d, J = 6.8 Hz, 3H), 1.20-1.22 (d, J = 6.8 Hz, 3H), 1.16 (m, 2H). MS (ESI, m / e) [M+1] + 410.3.

[0342] Intermediate 16-1: 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5] nonane

[0343]

[0344] Step 1: tert-butyl 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0345] Cyclohexane formaldehyde (0.38 g, 3.40 mmol) and HOAc (0.27 g, 4.52 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in DCE (20 mL). After stirring at 25 °C for 1 hr, NaBH(OAc)3 (0.96 g, 4.52 mmol) was added. The mixture was stirred at 25 °C for 12 h. Then, aqueous NH4Cl (20 mL) was added to the mixture, and the mixture was then extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL × 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 give tert-butyl 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate as a yellow solid (1.0 g, yield: 83%). MS (ESI, m / e) [M+1] + 538.4.

[0346] Step 2: tert-butyl 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0347] A mixture of tert-butyl 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 1.86 mmol) and BH3·THF (19 mL, 18.6 mmol) was heated to 70 °C for 12 hours. MeOH (10 mL) was then carefully added to the mixture. The mixture was concentrated under vacuum to give tert-butyl 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.6 g, yield: 65%) as a yellow oil, which could be used directly for the next step without further purification. MS (ESI, m / e) [M+1] + 524.4

[0348] Step 3: 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0349] A solution of HCl / MeOH (10 mL, 4 M) was added to a solution of tert-butyl 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (600 mg, 0.99 mmol) in MeOH (20 mL). The mixture was stirred at 25 °C for 1 hr. After solvent removal, the residue was dissolved in water (20 mL). The pH of the mixture was adjusted to 9–10 using aqueous Na₂CO₃. The mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give 2-(4-(cyclohexylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (450 mg, yield: 83%) as a yellow solid. 1 H NMR(400 MHz, 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 = 6.8 Hz, 3H), 1.16 (m, 3H), 0.91-0.83 (m, 2H). MS (ESI, m / e) [M+1] + 424.5.

[0350] Intermediate 17-1: 2-(2-(2-isopropylphenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)- 7-Zazaspiro[3.5]nonane

[0351]

[0352] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0353] At 25 °C, AcOH (339 mg, 5.66 mmol), tetrahydro-2H-pyran-4-carboxaldehyde (387 mg, 3.40 mmol), and NaBH(OAc)3 (959 mg, 4.53 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.06 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was poured into saturated Na2CO3 (10 mL) and extracted with EtOAc (10 mL × 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 give tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, yield: 82%) as a pale yellow oil.

[0354] Step 2: tert-butyl 2-(2-(2-isopropylphenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0355] At 80 °C, a mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, 1.30 mmol) was added to BH3·THF (38 mL, 38.91 mmol) in THF (20 mL) for 12 hours. The reaction was quenched by MeOH (20 mL) and concentrated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (660 mg, crude) as a yellow gel, which could be used directly for the next step without further purification.

[0356] Step 3: 2-(2-(2-isopropylphenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0357] At 0 °C, a solution of HCl / MeOH (40 mL) was added to a mixture of tert-butyl 2-(2-(2-isopropylphenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, 1.30 mmol) for 2 hours. The reaction mixture was poured into saturated Na2CO3 (40 mL). The mixture was extracted with EtOAc (40 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 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 light pink oil. 1 H NMR (400 MHz, CDCl3)δ ppm: 7.59-7.44 (m,1H), 7.26-7.19 (m, 2H), 7.17-7.10 (m, 1H), 4.04-3.91 (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 = 6.8 Hz, 3H). MS (ESI, m / e) [M+1] + 426.4.

[0358] Intermediate 18-1: 2-(4-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-(2-isopropylphenyl)piperazine-1- (-7-azaspiro[3.5]nonane)

[0359]

[0360] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)-4-(3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carbonyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0361] At 0 °C, EDCI (1.63 g, 8.49 mmol) was added to a mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (2.5 g, 5.66 mmol) and 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (1.16 g, 6.76 mmol) with HOBt (1.15 g, 8.49 mmol) and TEA (1.14 g, 11.32 mmol) in THF (30 mL). The mixture was stirred at 20 °C for 12 hours. The mixture was quenched with H2O (20 mL) and extracted with DCM (100 mL). The combined organic layers were 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 give tert-butyl 2-(2-(2-isopropylphenyl)-4-(3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carbonyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (2.8 g, yield: 85%) as a white solid. MS (ESI, m / e) [M-55] + 538.3.

[0362] Step 2: 3-(4-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonane-2-yl)-3-(2-isopropylphenyl)-5-oxopiperazine-1-carbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid.

[0363] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-4-(3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carbonyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (2.8 g, 4.71 mmol) and LiOH·H2O (0.79 g, 18.86 mmol) in MeOH (50 mL) 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 EtOAc (100 mL x 2). The organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 0.6 g (crude) of 3-(4-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonane-2-yl)-3-(2-isopropylphenyl)-5-oxopiperazine-1-carbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid as a white solid. MS (ESI, m / e) [M+Na]+ 602.3.

[0364] Step 3: tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(3-(((2-thiopyridine-1(2H)-yl)oxy)carbonyl)bicyclo[1.1.1]pentane-1-carbonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0365] A mixture of 3-(4-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonane-2-yl)-3-(2-isopropylphenyl)-5-oxopiperazine-1-carbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (0.5 g, 0.86 mmol) and 1-hydroxypyridine-2(1H)-thione (142 mg, 1.12 mmol), 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 give tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(3-((((2-thiopyridin-1(2H)-yl)oxy)carbonyl)bicyclo[1.1.1]pentane-1-carbonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.5 g, crude), as a yellow solid, which can be used directly without further purification. MS (ESI, m / e) [M+1] + 689.1.

[0366] Step 4: tert-butyl 2-(4-(bicyclo[1.1.1]pentane-1-carbonyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0367] Under a W lamp (300 W), a mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(3-((((2-thiopyridin-1(2H)-yl)oxy)carbonyl)bicyclo[1.1.1]pentane-1-carbonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (2.0 g, 2.63 mmol) and Bu3SnH (2.3 g, 7.9 mmol), AIBN (36 mg, 0.22 mmol) in toluene (35 mL) was stirred at 60 °C for 1 hr. The mixture was quenched with KF solution (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were 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 give 0.95 g of tert-butyl 2-(4-(bicyclo[1.1.1]pentane-1-carbonyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate as a grayish-white solid. MS (ESI, m / e) [M+Na] + 558.4.

[0368] Step 5: tert-butyl 2-(4-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0369] A mixture of tert-butyl 2-(4-(bicyclo[1.1.1]pentan-1-carbonyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 h. The reaction mixture was cooled to 25 °C and slowly quenched with MeOH (20 mL). The mixture was concentrated under reduced pressure to give tert-butyl 2-(4-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, crude) as a white solid, which could be used directly without further purification. MS (ESI, m / e) [M+1] + 508.5.

[0370] Step 6: 2-(4-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0371] A mixture of tert-butyl 2-(4-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 1.97 mmol) in HCl / MeOH (8 mL, 4 M) was stirred at 20 °C for 3 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (0.1% TFA), followed by pH adjustment to 9 with Na₂CO₃ solution. The solution was extracted with EtOAc (20 mL × 2). The combined organic matter was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 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. 1 HNMR (400 MHz, 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), 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.

[0372] Intermediate 20-1: 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro [3.5]Nonane

[0373]

[0374] Step 1: tert-butyl 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0375] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol), furan-3-carboxaldehyde (326.37 mg, 3.40 mmol), and HOAc (271.97 mg, 4.53 mmol) in a DCE (20 mL) was stirred at 25 °C for 30 min. Then, NaBH(OAc)3 (1.44 g, 6.79 mmol) was added in portions to the mixture and stirred at 25 °C for 10 h. 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 × 3). The combined organic phases were 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 give tert-butyl 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.05 g, 89% yield) as a pale yellow solid. 1 H NMR (400 MHz, 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 = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H).

[0376] Step 2: tert-butyl 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0377] At 25 °C, tert-butyl 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.05 g, 2.01 mmol) was added dropwise to a solution of tert-butyl 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.02 g, crude) as a white solid. MS (ESI, m / e) [M+1] + 508.4.

[0378] Step 3: 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0379] At 25 °C, TFA (3 mL) was added dropwise to a solution of tert-butyl 2-(4-(furan-3-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (200 mg, 393.93 μmol) in DCM (3 mL). 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 lyophilized. The residue, free of saturated Na2CO3 (20 mL), was extracted with EtOAc (30 mL × 5). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 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 gel. 1H 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), 1.60-1.51 (m, 2H), 1.37-1.31 (m, 1H), 1.30-1.20 (m, 5H),1.17 (d, J = 6.8 Hz, 3H). MS (ESI, m / e) [M+1] + 408.3.

[0380] Intermediate 21-1: 4-((3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl) Methyl oxazole

[0381]

[0382] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)-4-(oxazol-4-ylmethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0383] Oxazol-4-carboxaldehyde (329.7 mg, 3.40 mmol) and AcOH (272 mg, 4.53 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in DCE (15 mL) for 30 min. Then, NaBH(OAc)3 (1.2 g, 5.66 mmol) was added at 25 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into saturated NH4Cl (50 mL) and extracted with DCM (50 mL × 2). The combined organic phases were washed with brine (20 mL × 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 give tert-butyl 2-(2-(2-isopropylphenyl)-4-(oxazol-4-ylmethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate as a yellow oil (360 mg, 707.69 μmol, yield: 30.26%). MS (ESI, m / e) [M+1] + 509.3.

[0384] Step 2: 4-((3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)methyl)oxazole.

[0385] TFA (0.5 mL) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-(oxazol-4-ylmethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (300 mg, 1.32 mmol) in DCM (2 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 EtOAc (50 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 4-((3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)methyl)oxazol as a yellow oil (390 mg, 374.47 μmol, yield: 63%). 1H NMR (400 MHz, 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 = 6.8 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H). MS(ESI, m / e) [M+1] + 409.3.

[0386] Intermediate 22-1: 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazine-1- (-7-azaspiro[3.5]nonane)

[0387]

[0388] step 1: tert-butyl 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0389] AcOH (326.36 mg, 5.43 mmol) and 1-methyl-1H-pyrazole-4-carboxaldehyde (329.14 mg, 2.99 mmol) were added to a solution of tert-butyl-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, 2.72 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 1 hr. Then NaBH(OAc)3 (1.73 g, 8.15 mmol) was added and the mixture was stirred at 25 °C for another 12 h. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 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 to 2 / 1) to give tert-butyl 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.9 g, yield: 62%) as a yellow oil.

[0390] Step 2: tert-butyl 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0391] A mixture of 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.9 g, 1.68 mmol) and BH3·THF (16.80 mL, 16.8 mmol) in 20 mL of THF was stirred at 70 °C for 12 h. The reaction solution was quenched with MeOH (20 mL) and stirred at 0 °C for 1 hr. The mixture was concentrated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate as a white oil, which could be used directly for the next step without further purification. MS (ESI, m / e) [M+1] + 522.4.

[0392] Step 3: 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0393] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 EtOAc (20 mL × 2). The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (518 mg, yield: 71%) as a yellow solid. 1 H 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.

[0394] Intermediate 22-1a: (R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl) Piperazine-1-yl)-7-azaspiro[3.5]nonane

[0395]

[0396] 20 g (45.29 mmol) of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate was separated by SFC (instrument: Thaler SFC350 preparative SFC; column: REGIS(s,s)WHELK-O1, 250 × 50 mm id: 10 μm; mobile phase: A was CO2 and B was 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)-tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate was obtained (retention time: 2.55 min, 8.4 g), yield: 43%. (S or R)-tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate was obtained (retention time: 2.73 min, 8.3 g), yield: 42%.

[0397] Step 1: tert-butyl(R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0398] AcOH (271.97 mg, 4.53 mmol) and NaBH(OAc)3 (1.44 g, 6.79 mmol) were added to a solution of tert-butyl(R or S)-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) and 1-methyl-1H-pyrazole-4-carboxaldehyde (274.28 mg, 2.49 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was extracted with aqueous Na2CO3 (10 mL) and DCM (10 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. The compound tert-butyl(R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (950 mg, 1.77 mmol, yield: 78%) was obtained as a yellow oil. 1H NMR (400 MHz, 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, 1H), 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).

[0399] Step 2: tert-butyl(R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0400] A mixture of tert-butyl(R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (950 mg, 1.77 mmol) in BH3·THF (15 mL) was stirred at 70 °C for 12 h. The reaction mixture was quenched at 0 °C with MeOH (20 mL) and stirred at 25 °C for 30 min. The mixture was then concentrated under reduced pressure to give tert-butyl(R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (900 mg, 1.73 mmol, crude) as a white solid. MS (ESI, m / e) [M+1] + 522.3.

[0401] Step 3: (R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0402] A mixture of tert-butyl(R or S)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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) and Na2CO3 was added to pH = 9. The mixture was extracted with EtOAc (10 mL × 3), 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-pyrazol-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 (400 MHz, 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), 2.96-2.86 (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.

[0403] Following a similar procedure to intermediate 22-1a: using (S or R)-tert-butyl2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate as the starting material, (S or R)-2-(2-(2-isopropylphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (607 mg, intermediate 22-1b) was obtained in 82% yield. MS (ESI, m / e) [M+1] + 422.4.

[0404] Intermediate 23-1: 2-(4-benzyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane

[0405]

[0406] Step 1: tert-butyl 2-(4-benzyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0407] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol), benzaldehyde (360.46 mg, 3.40 mmol), and AcOH (271.97 mg, 4.53 mmol) in a DCE (20 mL) was stirred at 25 °C for 30 min. Then, NaBH(OAc)3 (1.44 g, 6.79 mmol) was added to the mixture in portions and stirred at 20 °C for 3 h. The mixture was washed with saturated NaHCO3 (20 mL × 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 give tert-butyl 2-(4-benzyl-2-(2-isopropylphenyl)-6-oxoperpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate as a white solid (1.0 g, 1.88 mmol, yield: 83%). 1 H NMR (400 MHz, 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 = 6.8 Hz,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 = 6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H).

[0408] Step 2: tert-butyl 2-(4-benzyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0409] At 25 °C, BH3·THF (30 mL, 30 mmol) was added dropwise to a solution of tert-butyl 2-(4-benzyl-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 1.88 mmol) in THF (10 mL). The mixture was heated to 75 °C for 12 hours. The reaction was quenched with ethanol (10 mL) and concentrated under reduced pressure to give tert-butyl 2-(4-benzyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (970 mg, crude) as a white solid. MS (ESI, m / e) [M+1] + 518.5.

[0410] Step 3: 2-(4-benzyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0411] At 25 °C, HCl / MeOH (10 mL, 4 M) was added dropwise to a solution of tert-butyl 2-(4-benzyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (970 mg, 1.82 mmol) in MeOH (10 mL). 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 EtOAc (10 mL × 2). The aqueous phase was adjusted to pH 8 with NaHCO3 and extracted with EtOAc (20 mL × 5). The combined organic phases were dried with anhydrous Na2SO4, filtered and concentrated to give 2-(4-benzyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane as a white solid (529 mg, 1.27 mmol, yield: 68%). 1 H NMR (400 MHz, CDCl3)δ ppm: 7.47 (d, J = 4.4 Hz, 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= 6.8 Hz, 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), 1.53-1.39 (m, 4H), 1.35-1.28 (m, 1H), 1.25-1.22 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H). MS (ESI, m / e) [M+1] + 418.4.

[0412] Intermediate 24-1: 2-(2-(2-isopropylphenyl)-4-(1-phenylethyl)piperazin-1-yl)-7-azaspiro[3.5] nonane

[0413]

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

[0415] A solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in DMF (10 mL) was mixed with (1-bromoethyl)benzene (0.84 g, 4.53 mmol) and Cs₂CO₃ (2.21 g, 6.79 mmol). The mixture was stirred at 80 °C for 2 hours. Saturated NH₄Cl (50 mL) was added to the mixture, and it was extracted with EtOAc (30 mL × 3). The combined organic phases were 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 give tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(1-phenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, yield: 73%) as a colorless oil.

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

[0417] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(1-phenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.1 g, 2.02 mmol) and BH3·THF (10 mL) in THF (10 mL) was stirred at 70 °C for 16 hours. After cooling to 0 °C, MeOH (20 mL) was added dropwise to the mixture and it was concentrated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(1-phenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.1 g, crude) as a colorless oil, which could be used directly for the next step without purification. MS (ESI, m / e) [M+1] + 532.4.

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

[0419] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-4-(1-phenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 1.88 mmol) in HCl / EtOAc (10 mL, 4 M) was stirred at 20 °C for 16 h. After solvent removal, 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 aqueous NaOH (2 M). The mixture was extracted with EtOAc (10 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(2-(2-isopropylphenyl)-4-(1-phenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (537 mg, yield: 66%) as a white gel. 1HNMR (400 MHz, 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, 1H), 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.

[0420] Intermediate 25-1: 2-(2-(2-isopropylphenyl)-4-(1,2,3,4-tetrahydronaphth-1-yl)piperazin-1-yl)-7-nitrogen Spiro[3.5]nonane

[0421]

[0422] Step 1: 1,2,3,4-Tetrahydronaphthalene-1-ol.

[0423] At 0 °C, NaBH4 (8.24 g, 219 mmol) was added to a solution of 3,4-dihydronaphthyl-1(2H)-one (8.0 g, 54.72 mmol) in THF (100 mL). The mixture was stirred at 20 °C for 4 hours. The mixture was poured into H2O (80 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 1,2,3,4-tetrahydronaphthyl-1-ol (6.0 g, yield: 74%) as a yellow oil, which could be used directly in the next step without further purification.

[0424] Step 2: 1-Bromo-1,2,3,4-Tetrahydronaphthalene.

[0425] A mixture of 1,2,3,4-tetrahydronaphthyl-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 EtOAc (20 mL × 3). The combined organic phases were 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 give 1-bromo-1,2,3,4-tetrahydronaphthyl (5.0 g, yield: 87%) as a yellow oil.

[0426] Step 3: tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(1,2,3,4-tetrahydronaphth-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0427] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 EtOAc (30 mL × 2). The combined organic phases were 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 give tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(1,2,3,4-tetrahydronaphthyl-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.9 g, yield: 69%) as a yellow oil. MS (ESI, m / e) [M+1] + 572.4.

[0428] Step 4: tert-butyl 2-(2-(2-isopropylphenyl)-4-(1,2,3,4-tetrahydronaphth-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0429] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(1,2,3,4-tetrahydronaphthyl-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.8 g, 1.4 mmol) and BH3·THF (5 mL, 5 mmol) in THF (5 mL) was stirred at 70 °C for 16 hours. After cooling to 0 °C, MeOH (10 mL) was added dropwise to the mixture and it was concentrated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(1,2,3,4-tetrahydronaphthyl-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.8 g, crude) as a colorless oil, which could be used directly for the next step without purification.

[0430] Step 5: 2-(2-(2-isopropylphenyl)-4-(1,2,3,4-tetrahydronaphth-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0431] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-4-(1,2,3,4-tetrahydronaphth-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, 1.25 mmol) in HCl / EtOAc (10 mL, 4 M) was stirred at 20 °C for 3 h. After solvent removal, 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 (1 M). The mixture was extracted with EtOAc (10 mL × 3). The combined organic phases were dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to give 2-(2-(2-isopropylphenyl)-4-(1,2,3,4-tetrahydronaphthyl-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane (365 mg, yield: 64%) as a white solid. 1 H NMR (400 MHz, 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.

[0432] Intermediate 26-1: 2-(2-(2-isopropylphenyl)-4-phenylethylpiperazin-1-yl)-7-azaspiro[3.5]nonane

[0433]

[0434] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-phenylethylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0435] 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 to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, 1.59 mmol) in a DCE (10 mL). The solution was stirred at 25 °C for 12 h. The reaction mixture was poured into saturated NaHCO3 until pH = 7, and 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 give tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-phenylethylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.5 g, yield: 58%) as a yellow oil. 1 H NMR(400 MHz, 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 = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H).

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

[0437] A solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-phenylethylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.6 g, 1.1 mmol) in BH3·THF (10 mL, 1 M) was stirred at 70 °C for 12 h. The reaction was quenched at 0 °C with MeOH (5 mL) and stirred at 25 °C for 30 min. The mixture was concentrated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)-4-phenylethylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (600 mg, crude) as a yellow oil. MS (ESI, m / e) [M+1] + 532.5.

[0438] Step 3: 2-(2-(2-isopropylphenyl)-4-phenylethylpiperazin-1-yl)-7-azaspiro[3.5]nonane.

[0439] A solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-phenylethylpiperazin-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 h. The reaction mixture was poured into aqueous Na2CO3 (300 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (HCl) to give 2-(2-(2-isopropylphenyl)-4-phenylethylpiperazin-1-yl)-7-azaspiro[3.5]nonane as a white solid (130 mg, HCl salt, yield: 27% (via two steps)). 1 H NMR (400 MHz, CH3OH- d 4) δ ppm: 7.96 (d, J= 7.6 Hz,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 = 6.8 Hz, 3H), 1.28(d, J = 6.8 Hz, 3H). MS (ESI, m / e) [M+1] + 432.4.

[0440] Intermediate 28-1: 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonyl alkyl

[0441]

[0442] Step 1: tert-butyl 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0443] To a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 pH = 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 give tert-butyl 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.5 g, yield: 57.3%) as a yellow oil. 1H NMR (400 MHz, 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 = 6.8 Hz, 3H), 0.85 (d, J =6.8 Hz, 3H).

[0444] Step 2: tert-butyl 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0445] A solution of tert-butyl 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.5 g, 0.91 mmol) in BH3·THF (10 mL) was stirred at 60 °C for 12 h. The reaction mixture was quenched at 0 °C with MeOH (10 mL) and stirred at 25 °C for 30 min. The mixture was concentrated under reduced pressure to give tert-butyl 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (600 mg, crude) as a yellow oil, which could be used directly without further purification. MS (ESI, m / e) [M+1] + 536.4.

[0446] Step 3: 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0447] TFA (1 mL) was added to a solution of tert-butyl 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.6 g, 1.12 mmol) in DCM (10 mL). The solution was stirred at 25 °C for 12 hours. The mixture was concentrated under reduced pressure. The residue was poured into aqueous Na2CO3 (30 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (300 mg, yield: 62%) as a yellow solid. 1 H NMR (400 MHz, 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 = 6.8 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). MS (ESI, m / e) [M+1] + 436.3.

[0448] Intermediate 28-1a: (R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-aza Spiro[3.5]nonane

[0449]

[0450] Step 1: tert-butyl(R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0451] To a solution of tert-butyl(R or S)-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in a 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 mixture until pH = 9, and the mixture was extracted with DCM (10 mL × 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 give tert-butyl(R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.9 g, yield: 72%) as a yellow oil.

[0452] Step 2: tert-butyl(R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0453] A solution of tert-butyl(R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.9 g, 1.64 mmol) in BH3·THF (16.5 mL) was stirred at 70 °C for 12 h. The reaction mixture was quenched with MeOH (10 mL) at 0 °C and stirred at 25 °C for 30 min. The mixture was concentrated under reduced pressure to give tert-butyl(R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, crude), which was a yellow oil and could be used directly without further purification. MS (ESI, m / e) [M+1] + 536.5.

[0454] Step 3: (R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0455] HCl (4.67 mL) was added to a solution of tert-butyl(R or S)-2-(4-(4-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 1.87 mmol) in MeOH (10 mL). 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 × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (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 (400 MHz, 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 = 6.8 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). MS (ESI, m / e) [M+1] + 436.3

[0456] Intermediate 29-1: 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonyl alkyl

[0457]

[0458] Step 1: tert-butyl 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0459] AcOH (326.36 mg, 5.43 mmol) and 4-chlorobenzaldehyde (420.71 mg, 2.99 mmol) were added to a solution of tert-butyl-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, 2.72 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 1 hr. 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 h. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 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 to 2 / 1) to give tert-butyl 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, 2.12 mmol, yield: 78%) as a yellow oil.

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

[0461] A mixture of tert-butyl 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 h. The reaction solution was quenched with MeOH (10 mL) and concentrated under reduced pressure to give tert-butyl 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, crude), which can be used directly for the next step without further reaction.

[0462] Step 3: 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0463] A mixture of tert-butyl 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 h. The reaction solution was concentrated under reduced pressure. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (445 mg, 1.36 mmol, yield: 45%) as an off-white solid. 1 H NMR (400 MHz, 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 = 8.8 Hz, 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.

[0464] Intermediate 29-1a: (R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-aza Spiro[3.5]nonane

[0465]

[0466] Step 1: tert-butyl(R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0467] AcOH (271.97 mg, 4.53 mmol) and 4-chlorobenzaldehyde (477.46 mg, 3.40 mmol) were added to a solution of tert-butyl(R or S)-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in DCE (15 mL). The mixture was stirred at 20 °C for 30 min, then NaBH(OAc)3 (959.86 mg, 4.53 mmol) was added and the mixture was stirred at 20 °C for another 12 h. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 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 to 2 / 1) to give tert-butyl(R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, yield: 78%) as a yellow oil.

[0468] Step 2: tert-butyl(R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0469] A mixture of tert-butyl(R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 1.77 mmol) and BH3·THF (17.66 mL, 17.66 mmol) in THF (15 mL) was stirred at 70 °C for 12 hours. The reaction solution was quenched with MeOH (10 mL) and concentrated under reduced pressure to give tert-butyl(R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, crude), which can be used directly for the next step without further reaction.

[0470] Step 3: (R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0471] A mixture of tert-butyl(R or S)-2-(4-(4-chlorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 1.81 mmol) in MeOH (5 mL) was added to a solution of HCl / MeOH (5 mL, 4 M). The mixture was stirred at 20 °C for 2 h. The reaction solution was concentrated under reduced pressure. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (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 (400 MHz, CDCl3)δ ppm: 7.50 (br s, 1H), 7.27 (s, 4H), 7.25-7.19 (m, 2H), 7.15 (d, J = 6.8 Hz,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 = 6.8 Hz, 4H), 1.16 (br d, J = 6.4 Hz, 4H). MS (ESI,m / e) [M+1] + 452.4.

[0472] Intermediate 30-1: 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)piperazin-1-yl)-7- Nitrogenous spirals [3.5] nonane

[0473]

[0474] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0475] AcOH (326.36 mg, 5.43 mmol) and 4-methylbenzaldehyde (359.13 mg, 2.72 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, 2.72 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 1 hr. 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 h. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 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 to 2 / 1) to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)-6-oxoperpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.18 g, 2.16 mmol, yield: 79.6%) as a yellow oil.

[0476] Step 2: tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0477] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 quenched with MeOH (10 mL) and concentrated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.18 g, crude), which could be used directly for the next step without further purification.

[0478] Step 3: 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0479] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 h. The reaction solution was concentrated under reduced pressure. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(2-(2-isopropylphenyl)-4-(4-methylbenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (589 mg, 1.36 mmol, yield: 61.5%) as an off-white solid. 1 H NMR (400 MHz, 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, 3H), 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.

[0480] Intermediate 31-1: 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenylethyl)piperazin-1-yl)-7-azaspiro [3.5]Nonane

[0481]

[0482] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenethyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0483] A solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in DCE (20 mL) was mixed with 2-(4-methoxyphenyl)acetaldehyde (510 g, 3.40 mmol) and HOAc (0.27 g, 4.52 mmol). After stirring at 25 °C for 1 hr, NaBH(OAc)3 (0.96 g, 4.52 mmol) was added. The mixture was stirred at 25 °C for 12 h. Then, aqueous NH4Cl (20 mL) was added to the mixture and extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL × 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 give tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenethyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.85 g, yield: 65%) as a yellow solid. 1 H NMR (400 MHz, 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 = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 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).

[0484] Step 2: tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0485] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenethyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.85 g, 1.48 mmol) and BH3·THF (15 mL, 14.8 mmol) was heated to 70 °C for 12 hours. MeOH (10 mL) was carefully added to the mixture, and the mixture was concentrated under vacuum to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.8 g, yield: 96%) as a yellow oil, which could be used in the next step without further purification. MS (ESI, m / e) [M+1] + 562.4.

[0486] Step 3: 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0487] A solution of HCl / MeOH (10 mL) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (800 mg, 1.42 mmol) in MeOH (20 mL). The mixture was stirred at 25 °C for 1 hr. After removing the solvent, the residue was dissolved in water (20 mL). The pH of the mixture was adjusted to 9-10 using aqueous Na₂CO₃. The mixture was then extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give 2-(2-(2-isopropylphenyl)-4-(4-methoxyphenylethyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (600 mg, yield: 91%) as a yellow solid. 1 H NMR (400 MHz, CDCl3)δ ppm: 7.51 (br s, 1H), 7.27-7.21 (m, 2H), 7.17-7.07 (m, 3H), 6.81 (d, J= 8.4 Hz, 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.

[0488] Intermediate 34-1: 2-(4-(4-methoxybenzyl)-2-(o-tolyl)piperazin-1-yl)-7-azaspiro[3.5]nonyl alkyl

[0489]

[0490] Step 1: Tert-butyl (2-((4-methoxybenzyl)(2-oxo-2-(o-tolyl)ethyl)amino)ethyl)carbamate.

[0491] At -78 °C, n-BuLi (6.37 mL, 15.92 mmol, 2.5 M) was added to a solution of 1-bromo-2-methylbenzene (2.8 g, 16.39 mmol) in THF (30 mL), and the mixture was stirred at -78 °C for 10 min. Then, tert-butyl 4-(4-methoxybenzyl)-2-oxopiperazine-1-carboxylate (5.0 g, 15.61 mmol) was added to THF (20 mL), and the mixture was stirred at -78 °C for 2 h. The reaction mixture was quenched with aqueous NH4Cl (50 mL) and extracted with EtOAc (50 mL × 3), washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. The compound tert-butyl(2-((4-methoxybenzyl)(2-oxo-2-(o-tolyl)ethyl)amino)ethyl)carbamate (3.1 g, 7.51 mmol, yield: 48.15%) was obtained as a yellow oil. MS (ESI, m / e) [M+1] + 413.3.

[0492] Step 2: 1-(4-methoxybenzyl)-5-(o-tolyl)-1,2,3,6-tetrahydropyrazine.

[0493] TFA (5.8 g, 50.91 mmol) was added to a mixture of tert-butyl(2-((4-methoxybenzyl)(2-oxo-2-(o-tolyl)ethyl)amino)ethyl)carbamate (2.1 g, 5.09 mmol) in DCM (20 mL). The mixture was stirred at 20 °C for 12 h. The residue was diluted with H2O (20 mL) and Na2CO3 was added to pH = 9. Extraction was performed with EtOAc (20 mL × 3), washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 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.

[0494] Step 3: 1-(4-methoxybenzyl)-3-(o-tolyl)piperazine.

[0495] To a solution of 1-(4-methoxybenzyl)-5-(o-tolyl)-1,2,3,6-tetrahydropyrazine (1.4 g, 4.76 mmol) in MeOH (20 mL), NaBH4 (719.66 mg, 19.02 mmol) was added. The mixture was stirred at 25 °C for 12 h. The mixture was quenched with H2O and concentrated under reduced pressure. The residue was diluted with H2O (20 mL) and extracted with DCM (20 mL × 3), washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. A yellow oily compound, 1-(4-methoxybenzyl)-3-(o-tolyl)piperazine (550 mg, 1.75 mmol, yield: 39.02%), was obtained. MS (ESI, m / e) [M+1] + 297.3

[0496] Step 4: tert-butyl 2-(4-(4-methoxybenzyl)-2-(o-tolyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0497] AcOH (210.7 mg, 3.15 mmol) and NaBH(OAc)3 (1.12 g, 5.36 mmol) were added to a solution of 1-(4-methoxybenzyl)-3-(o-tolyl)piperazine (520 mg, 1.75 mmol) and tert-butyl-2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (419.83 mg, 1.75 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was extracted with aqueous Na2CO3 (20 mL) and DCM (10 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. The compound tert-butyl 2-(4-(4-methoxybenzyl)-2-(o-tolyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (630 mg, 1.21 mmol, yield: 69.1%) was obtained as a yellow oil. MS (ESI, m / e) [M+1] + 520.6

[0498] Step 5: 2-(4-(4-methoxybenzyl)-2-(o-tolyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0499] A mixture of tert-butyl 2-(4-(4-methoxybenzyl)-2-(o-tolyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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) and Na2CO3 was added to pH = 9. The mixture was extracted with EtOAc (10 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to remove the solvent. The compound 2-(4-(4-methoxybenzyl)-2-(o-tolyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (109 mg, 294.83 μmol, yield: 20.57%) was given as a yellow oil. 1H NMR (400 MHz, 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.

[0500] Intermediate 35-1: 2-(2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro [3.5]Nonane

[0501]

[0502] Step 1: tert-butyl 4-(4-methoxybenzyl)-2-(2-(2-methylprop-1-en-1-yl)phenyl)piperazine-1-carboxylate.

[0503] Under N2, Cs2CO3 (1.13 g, 3.46 mmol) and Pd(dppl)Cl2·CH2Cl2 (143 mg, 0.173 mmol) were added to a solution of 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-methylprop-1-en-1-yl)-1,3,2-dioxane-pentaborane (208 mg, 2.08 mmol) in dioxane (20 mL) and H2O (4 mL). 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. The compound tert-butyl 4-(4-methoxybenzyl)-2-(2-(2-methylprop-1-en-1-yl)phenyl)piperazine-1-carboxylate (0.63 g, yield: 83%) was obtained as a brown oil. MS (ESI, m / e) [M+1] + 437.3.

[0504] Step 2: tert-butyl 2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate.

[0505] Pt / C (0.5 g) was added to a solution of tert-butyl 4-(4-methoxybenzyl)-2-(2-(2-methylprop-1-en-1-yl)phenyl)piperazine-1-carboxylate (0.63 g, 1.44 mmol) in MeOH (20 mL). The mixture was stirred at 25 °C for 12 hours under H2 (15 Psi). The solution was filtered and concentrated under reduced pressure. The compound tert-butyl 2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate (0.6 g, yield: 95%) was given as a yellow oil. MS (ESI, m / e) [M+1] + 439.3.

[0506] Step 3: 3-(2-isobutylphenyl)-1-(4-methoxybenzyl)piperazine.

[0507] A solution of tert-butyl 2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate (0.6 g, 1.37 mmol) in MeOH (10 mL) was added to a solution of HCl / MeOH (5 mL, 4 M). The mixture was stirred at 20 °C for 2 h. The solution was concentrated under reduced pressure. The residue was diluted with H₂O (50 mL) and aqueous Na₂CO₃ solution was added to pH = 9. The aqueous layer was extracted with EtOAc (50 mL × 3). The combined organic layers were dried and concentrated under reduced pressure. The compound 3-(2-isobutylphenyl)-1-(4-methoxybenzyl)piperazine (0.42 g, yield: 91%) was given as a red oil. MS (ESI, m / e) [M+1] + 339.3.

[0508] Step 4: tert-butyl 2-(2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0509] Tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (356 mg, 1.49 mmol) and HOAc (149 mg, 2.48 mmol) were added to a solution of 3-(2-isobutylphenyl)-1-(4-methoxybenzyl)piperazine (420 mg, 1.24 mmol) in DCE (20 mL). After stirring at 25 °C for 1 hr, NaBH(OAc)3 (0.79 g, 3.72 mmol) was added. The mixture was stirred at 25 °C for 12 h. Aqueous NaHCO3 (50 mL) was then added to the mixture, and the mixture was then extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL × 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 give tert-butyl 2-(2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate as a yellow oil (400 mg, yield: 58%). MS (ESI, m / e) [M+1] + 562.5.

[0510] Step 5: 2-(2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0511] HCl / MeOH (5 mL, 4 M) was added to a solution of tert-butyl 2-(2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (400 mg, 0.71 mmol) in MeOH (10 mL). The mixture was stirred at 20 °C for 2 h. The solution was concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and an aqueous Na2CO3 solution was added to pH = 9. The aqueous layer was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The compound 2-(2-(2-isobutylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (300 mg, yield: 91%) was given as a brown solid. 1H NMR (400 MHz, CDCl3) δppm: 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), 1.44-1.36 (m, 4H), 1.30–1.23 (m, 2H), 0.91 (d, J = 6.4 Hz, 3H), 0.82 (d, J = 6.4 Hz, 3H). MS (ESI, m / e) [M+1] + 462.3

[0512] Intermediate 36-1: 2-(2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro [3.5]Nonane

[0513]

[0514] Step 1: tert-butyl(2-((2-(2-bromophenyl)-2-oxoethyl)(4-methoxybenzyl)amino)ethyl)carbamate.

[0515] At -70 °C, i-PrMgCl·LiCl (30 mL, 1 M, in THF) was added to a solution of 1-bromo-2-iodobenzene (10 g, 35 mmol) in THF (100 mL). After stirring for 0.5 hr, tert-butyl 4-(4-methoxybenzyl)-2-oxopiperazine-1-carboxylate (10.5 g, 33 mmol) was added. The mixture was stirred at 20 °C for 3 h. The reaction mixture was quenched at 0 °C by adding NH4Cl (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 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 give tert-butyl(2-((2-(2-bromophenyl)-2-oxoethyl)(4-methoxybenzyl)amino)ethyl)carbamate (14 g, yield: 84%) as a yellow oil. 1H NMR (400 MHz, CDCl3)δppm: 7.85 (dd, J = 1.6, 8.0 Hz, 1H), 7.54 (dd, J = 1.2, 8.0 Hz, 1H), 7.33-7.28(m, 1H), 7.22 (m, 2H), 7.10 (m, 1H), 6.88-6.82 (d, J = 8.4 Hz, 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).

[0516] Step 2: 3-(2-bromophenyl)-1-(4-methoxybenzyl)piperazine.

[0517] TFA (25 mL) was added to a solution of tert-butyl(2-((2-(2-bromophenyl)-2-oxoethyl)(4-methoxybenzyl)amino)ethyl)carbamate (5.0 g, 10 mmol) in DCM (25 mL). The mixture was stirred at 20 °C for 30 min. 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 hr. The reaction mixture was concentrated under reduced pressure to remove the solvent. The reaction mixture was extracted with DCM (10 mL × 3), washed with aqueous NaHCO3 (10 mL × 2), dried over Na2SO4, filtered, and concentrated to give 3-(2-bromophenyl)-1-(4-methoxybenzyl)piperazine (3.5 g, yield: 99%) as a brown oil, which could be used for the next step without further purification. MS (ESI, m / e) [M+1] + 361.2, 363.2.

[0518] Step 3: tert-butyl 2-(2-bromophenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate.

[0519] TEA (1.9 g, 18.8 mmol) was added to a solution of 3-(2-bromophenyl)-1-(4-methoxybenzyl)piperazine (3.4 g, 9.4 mmol) in DCM (50 mL). Boc₂O (2.5 g, 11.29 mmol) was then added. The mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched at 0 °C by adding NH₄Cl (50 mL) and then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 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 give tert-butyl 2-(2-bromophenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate (2.9 g, yield: 68%) as a yellow oil. 1 H 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 = 8.4 Hz, 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).

[0520] Step 4: tert-butyl 2-(2-(cyclopent-1-en-1-yl)phenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate.

[0521] Under N2, Cs2CO3 (1.4 g, 4.34 mmol) and Pd(dppl)Cl2·CH2Cl2 (180 mg, 0.217 mmol) were added to a solution of tert-butyl 2-(2-bromophenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate (1.0 g, 2.17 mmol) and 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane-1-dioxane (0.5 g, 2.6 mmol) in dioxane (20 mL) and H2O (4 mL). The mixture was stirred at 100 °C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. The residue was purified by MPLC. The compound tert-butyl 2-(2-(cyclopent-1-en-1-yl)phenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate (0.73 g, yield: 75%) was obtained as a white solid. MS (ESI, m / e) [M+1] + 449.4.

[0522] Step 5: tert-butyl 2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate.

[0523] Pt / C (0.5 g) was added to a solution of tert-butyl 2-(2-(cyclopent-1-en-1-yl)phenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate (0.73 g, 1.63 mmol) in MeOH (20 mL). The mixture was stirred at 25 °C under H2 (15 Psi) for 12 hr. The solution was filtered and concentrated under reduced pressure. The compound tert-butyl 2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate (0.7 g, yield: 96%) was given as a yellow oil. MS (ESI, m / e) [M+1] + 451.3.

[0524] Step 6: 3-(2-cyclopentylphenyl)-1-(4-methoxybenzyl)piperazine.

[0525] HCl / MeOH (5 mL, 4 M) was added to a solution of tert-butyl 2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate (0.89 g, 1.98 mmol) in MeOH (10 mL). The mixture was stirred at 20 °C for 2 h. The solution was concentrated under reduced pressure. The residue was diluted with H₂O (50 mL) and Na₂CO₃ solution was added to pH = 9. The aqueous layer was extracted with EtOAc (50 mL × 3). The combined organic layers were dried and concentrated under reduced pressure. The compound 3-(2-cyclopentylphenyl)-1-(4-methoxybenzyl)piperazine (0.6 g, yield: 87%) was given as a red oil. MS (ESI, m / e) [M+1] + 351.3.

[0526] Step 7: tert-butyl 2-(2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0527] Tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (491 mg, 2.05 mmol) and HOAc (205 mg, 3.42 mmol) were added to a solution of 3-(2-cyclopentylphenyl)-1-(4-methoxybenzyl)piperazine (600 mg, 1.71 mmol) in DCE (20 mL). After stirring at 25 °C for 1 hr, NaBH(OAc)3 (1.09 g, 5.13 mmol) was added. The mixture was stirred at 25 °C for 12 h. Then, aqueous NaHCO3 (50 mL) was added to the mixture, and the mixture was then extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL × 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 give a yellow oily tert-butyl 2-(2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, yield: 71%). MS (ESI, m / e) [M+1] + 574.4.

[0528] Step 8: 2-(2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0529] A solution of tert-butyl 2-(2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, 1.22 mmol) in MeOH (10 mL) was added to a solution of HCl / MeOH (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 pH = 9. The aqueous layer was extracted with EtOAc (50 mL × 3). The combined organic layers were dried and concentrated under reduced pressure. The compound 2-(2-(2-cyclopentylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (500 mg, yield: 87%) was given as a brown solid. 1 H NMR (400 MHz, 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), 2.94-2.84 (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.

[0530] Intermediate 37-1: 4-(2-(4-(4-methoxybenzyl)-1-(7-azaspiro[3.5]nonane-2-yl)piperazine-2- (Benyl)morpholine

[0531]

[0532] Step 1: tert-butyl 4-(4-methoxybenzyl)-2-(2-vinylphenyl)piperazine-1-carboxylate.

[0533] Under N2 conditions, Cs2CO3 (1.41 g, 4.33 mmol) and Pd(dppf)Cl2 (158.59 mg, 216.74 μmol) were added to a solution of 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). 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 EtOAc (10 mL × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by MPLC. The compound tert-butyl 4-(4-methoxybenzyl)-2-(2-vinylphenyl)piperazine-1-carboxylate (800 mg, 1.96 mmol, yield: 90.35%) was obtained as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ ppm: 7.84-7.80 (m, 1H), 7.47-7.42 (m,1H), 7.26-7.22 (m, 2H), 7.16 (m, 2H), 7.08 (m, 1H), 6.82 (d, J = 8.8 Hz, 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).

[0534] Step 2: tert-butyl 2-(2-formylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate.

[0535] At 5 °C, K₂O₄·H₂O (28.86 mg, 78.33 μmol) and NaIO₄ (1.68 g, 7.83 mmol) were added to a solution of tert-butyl 4-(4-methoxybenzyl)-2-(2-vinylphenyl)piperazine-1-carboxylate (800 mg, 1.96 mmol) in THF (5 mL) and H₂O (5 mL), and the mixture was stirred at 25 °C for 3 hours. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (10 mL × 3), washed with aqueous Na₂SO₃ (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give tert-butyl 2-(2-formylphenyl)-4-(4-methoxybenzyl)piperazine-1-carboxylate (800 mg, 1.95 mmol, yield: 99.52%) as a yellow oil. MS (ESI, m / e) [M+1] + 411.2.

[0536] Step 3: tert-butyl 4-(4-methoxybenzyl)-2-(2-(morpholinomethyl)phenyl)piperazine-1-carboxylate.

[0537] DCE (10 mL) was added to a solution of 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). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was poured into aqueous Na2CO3 (10 mL) and extracted with DCM (10 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC. The obtained yellow oily substance was tert-butyl 4-(4-methoxybenzyl)-2-(2-(morpholinomethyl)phenyl)piperazine-1-carboxylate (400 mg, 830.52 μmol, yield: 42.62%). 1 H NMR (400 MHz, CDCl3) δ ppm: 7.83 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 2.8 Hz, 1H), 7.21-7.15 (m,2H), 7.10 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2 H), 5.27 (d, J= 2.4 Hz, 1H), 3.92 (m, 1 H), 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 = 12.8 Hz, 1H), 2.91 (d, J = 11.2 Hz, 2H), 2.44 (m, 1H), 2.41-2.25 (m, 3H), 2.23-2.16 (m, 2H), 1.30 (s, 9H).

[0538] Step 4: 4-(2-(4-(4-methoxybenzyl)piperazin-2-yl)benzyl)morpholine.

[0539] A mixture of tert-butyl 4-(4-methoxybenzyl)-2-(2-(morpholinomethyl)phenyl)piperazine-1-carboxylate (400 mg, 830.52 μmol) in HCl / EtOAc (5 mL) was stirred at 25 °C for 6 hours. The reaction mixture was concentrated to remove the solvent. The residue was diluted with H2O (5 mL) and Na2CO3 was added to pH = 9. The mixture was extracted with EtOAc (5 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to remove the solvent. The compound 4-(2-(4-(4-methoxybenzyl)piperazine-2-yl)benzyl)morpholine (300 mg, 786.35 μmol, yield: 94.68%) was given as a yellow oil. MS (ESI, m / e) [M+1] + 382.2.

[0540] Step 5: tert-butyl 2-(4-(4-methoxybenzyl)-2-(2-(morpholinomethyl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0541] DCE (6 mL) was added to a solution of 4-(2-(4-(4-methoxybenzyl)piperazin-2-yl)benzyl)morpholine (300 mg, 786.35 μmol), tert-butyl-2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (225.82 mg, 943.62 μmol), AcOH (94.44 mg, 1.57 mmol), and NaBH(OAc)3 (499.58 mg, 2.36 mmol). The mixture was stirred at 25 °C for 48 hours. The reaction mixture was extracted with aqueous Na2CO3 (10 mL) and DCM (10 mL × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by conventional HPLC (TFA conditions). The compound tert-butyl 2-(4-(4-methoxybenzyl)-2-(2-(morpholinomethyl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (255 mg, 421.61 μmol, yield: 53.62%) was obtained as a white solid. MS (ESI, m / e) [M+1] + 605.4.

[0542] Step 6: 4-(2-(4-(4-methoxybenzyl)-1-(7-azaspiro[3.5]nonane-2-yl)piperazin-2-yl)benzyl)morpholine.

[0543] A mixture of tert-butyl 2-(4-(4-methoxybenzyl)-2-(2-(morpholinomethyl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (255 mg, 421.61 μmol) in DCM (4 mL) and TFA (2 mL) was stirred at 25 °C for 1 hr. The reaction mixture was diluted with H2O (5 mL) and aqueous Na2CO3 was added to pH = 9. The mixture was extracted with DCM (5 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to remove the solvent. The compound 4-(2-(4-(4-methoxybenzyl)-1-(7-azaspiro[3.5]nonane-2-yl)piperazin-2-yl)benzyl)morpholine (135 mg, 267.48 μmol, yield: 63.44%) was given as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ ppm: 7.58 (d, J = 7.6 Hz,1H), 7.25-7.19 (m, 3H), 7.17-7.09 (m, 2H), 6.83 (d, J= 8.8 Hz, 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.

[0544] Intermediate 39-1: 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-nitrogen Spiro[3.5]nonane

[0545]

[0546] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0547] At 25 °C, AcOH (244.77 mg, 4.08 mmol) and 4-(trifluoromethoxy)benzaldehyde (426.21 mg, 2.24 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (900 mg, 2.04 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 1 hr. Then NaBH(OAc)3 (1.3 g, 6.11 mmol) was added and the mixture was stirred at 25 °C for another 12 h. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 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 to 2 / 1) to give tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (820 mg, yield: 64%) as a yellow oil.

[0548] Step 2: tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0549] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (800 mg, 1.30 mmol) and BH3·THF (12.99 mL, 12.99 mmol) in THF was stirred at 70 °C for 12 hours. The reaction solution was quenched with MeOH (10 mL) and concentrated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (800 mg, crude), which was ready for use in the next step without further purification.

[0550] Step 3: 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0551] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (800 mg, 1.33 mmol) and HCl / MeOH (15 mL, 4 M) 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 EtOAc (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (606 mg, 90% yield) as a white solid. 1 H NMR (400 MHz, CDCl3)δ ppm: 7.48 (brs, 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.

[0552] Intermediate 40-1: 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro [3.5]Nonane

[0553]

[0554] Step 1: tert-butyl 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0555] At 25 °C, AcOH (244.77 mg, 4.08 mmol) and 4-ethoxybenzaldehyde (333.66 mg, 2.24 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (900 mg, 2.04 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 1 hr. Then NaBH(OAc)3 (1.3 g, 6.11 mmol) was added and the mixture was stirred at 25 °C for another 12 h. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 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 to 2 / 1) to give tert-butyl 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (800 mg, yield: 68%) as a yellow oil.

[0556] Step 2: tert-butyl 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0557] A mixture of tert-butyl 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (800 mg, 1.39 mmol) and BH3·THF (13.89 mL, 13.89 mmol) in THF was stirred at 70 °C for 12 hours. The reaction solution was quenched with MeOH (10 mL) and concentrated under reduced pressure to give tert-butyl 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (800 mg, crude), which was used directly in the next step without further purification.

[0558] Step 3: 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0559] A mixture of tert-butyl 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (800 mg, 1.42 mmol) and HCl (3.56 mL, 14.24 mmol) in MeOH (10 mL) was stirred at 25 °C for 2 h. The reaction solution was concentrated under reduced pressure. The residue was poured into saturated NaHCO3 (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(4-(4-ethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (562 mg, yield: 62%) as a white solid. 1 H NMR (400 MHz, CDCl3)δ ppm: 7.48 (br s, 1H), 7.25-7.16 (m, 4H), 7.15-7.07 (m, 1H), 6.81 (d, J = 8.4 Hz, 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 = 6.8 Hz, 4H). MS (ESI, m / e) [M+1] + 462.4.

[0560] Intermediate 41-1: 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-aza Spiro[3.5]nonane

[0561]

[0562] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0563] AcOH (337 mg, 5.61 mmol) and 4-(trifluoromethyl)benzaldehyde (179 mg, 2.03 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (800 mg, 1.87 mmol) in DCE (10 mL). The mixture was stirred at 20 °C for 1 hr, and then NaBH(OAc)3 (1.19 g, 5.61 mmol) was added. The mixture was stirred at 20 °C for 16 h. Then saturated NaHCO3 (10 mL) and EtOAc (10 mL) were added. The mixture was stirred at 20 °C for 0.2 hr. The organic layer was separated, dried over Na2SO4, and evaporated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA (v / v) = 10 / 1 to 1 / 1) to give tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (500 mg, yield: 49%) as a yellow solid. MS (ESI, m / e) [M+1] + 600.5

[0564] Step 2: tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0565] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (500 mg, 0.88 mmol) and BH3·THF (8.8 mL, 8.8 mmol) was heated to 70 °C for 12 hours. After cooling to 0 °C, the mixture was quenched with MeOH (10 mL). The mixture was concentrated under vacuum to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (400 mg, yield: 80%) as a yellow solid, which could be used for the next step without further purification. MS (ESI, m / e) [M+1] + 586.3.

[0566] Step 3: 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0567] Add HCl / MeOH solution (10 mL) to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (400 mg, 0.68 mmol) in MeOH (10 mL). Stir the mixture at 25 °C for 2 hours. After vacuum concentration, dissolve the residue in water (20 mL). Adjust the pH of the mixture to 9-10 using aqueous Na₂CO₃. Extract the mixture with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give 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 (400 MHz, 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

[0568] Intermediate 42-1: 4-((3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl) Methylbenzylnitrile

[0569]

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

[0571] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 h. The reaction solution was quenched with MeOH (20 mL) and stirred at 0 °C for 1 hr. The mixture was concentrated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (900 mg, crude) as a white oil, which could be used directly for the next step without further purification. MS (ESI, m / e) [M+1] + 428.3.

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

[0573] AcOH (252.78 mg, 4.21 mmol) and 4-formylbenzyl nitrile (303.5 mg, 2.32 mmol) were added to a solution of tert-butyl-2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (900 mg, 2.10 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 1 hr, then NaBH(OAc)3 (1.34 g, 6.31 mmol) was added and stirred at 25 °C for another 12 h. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 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 to 2 / 1) to give tert-butyl 2-(4-(4-cyanobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (270 mg, yield: 23%) as a yellow oil.

[0574] Step 3: 4-((3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)methyl)benzylnitrile

[0575] A mixture of 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 EtOAc (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4-((3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)methyl)benzyl nitrile (102 mg, yield: 46.32%) as a yellow solid. 1 H NMR (400 MHz, CDCl3)δ ppm: 7.59 (d, J = 8.4Hz, 2H), 7.45 (d, J = 8.0 Hz, 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 = 6.8 Hz, 3H), 0.88 (m, 3H). MS (ESI, m / e)[M+1] + 443.3.

[0576] Intermediate 43-1: 2-(4-(3-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonyl alkyl

[0577]

[0578] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0579] At 0 °C, LiAlH4 (0.17 g, 4.53 mol) was added in portions to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mol) in THF (20 mL). The mixture was stirred at 20 °C for 1 hr. Then, H2O (10 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give tert-butyl 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.9 g, yield: 94%) as a yellow oil. MS (ESI, m / e) [M+1] + 428.4.

[0580] Step 2: tert-butyl 2-(4-(3-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0581] 3-fluorobenzaldehyde (0.31 g, 2.5 mmol) and HOAc (0.25 g, 4.2 mmol) were added to a solution of tert-butyl-2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.9 g, 2.1 mmol) in DCE (20 mL). After stirring at 25 °C for 1 hr, NaBH(OAc)3 (0.89 g, 4.2 mmol) was added. The mixture was stirred at 25 °C for 12 h. Then, aqueous NH4Cl (20 mL) was added to the mixture and extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL × 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 give tert-butyl 2-(4-(3-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate as a yellow solid (0.5 g, yield: 45%). MS (ESI, m / e) [M+1] + 536.5.

[0582] Step 3: 2-(4-(3-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0583] Add HCl / MeOH solution (10 mL) to a solution of tert-butyl 2-(4-(3-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (500 mg, 0.934 mmol) in MeOH (20 mL). Stir the mixture at 25 °C for 1 hr. After removing the solvent, dissolve the residue in water (20 mL). Adjust the pH of the mixture to 9-10 with aqueous Na2CO3. Extract the mixture with EtOAc (20 mL × 3). Wash the combined organic phases with brine (20 mL × 2), dry with anhydrous Na2SO4, filter and concentrate under vacuum to give 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.

[0584] Intermediate 44-1: 2-(2-(2-isopropylphenyl)-4-(3-methoxybenzyl)piperazin-1-yl)-7-azaspiro [3.5]Nonane

[0585]

[0586] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)-4-(3-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0587] At 25 °C, AcOH (280 mg, 4.68 mmol) and 3-methoxybenzaldehyde (477 mg, 3.5 mmol) were added to a solution of tert-butyl-2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.34 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 1 hr, then NaBH(OAc)3 (991 mg, 4.68 mmol) was added, and the mixture was stirred at 25 °C for another 12 h. The reaction mixture was quenched with saturated Na2CO3 (10 mL) and extracted with EtOAc (10 mL × 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 give tert-butyl 2-(2-(2-isopropylphenyl)-4-(3-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate as a pale yellow oil (0.3 g, 0.547 mmol, 23% yield).

[0588] Step 2: 2-(2-(2-isopropylphenyl)-4-(3-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0589] At 0 °C, a mixture of tert-butyl 2-(2-(2-isopropylphenyl)-4-(3-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (300 mg, 0.547 mmol) was added to a solution of HCl / MeOH (10 mL, 4 M) for 2 hours. The reaction mixture was poured into saturated Na2CO3 (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(2-(2-isopropylphenyl)-4-(3-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (183 mg, yield: 75%) as a light pink oil. 1 H NMR (400 MHz, 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= 9.2 Hz, 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 = 6.8 Hz, 3H), 1.15 (d, J = 6.8 Hz, 3H). MS (ESI, m / e) [M+1] + 448.2.

[0590] Intermediate 46-1: 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonyl alkyl

[0591]

[0592] Step 1: tert-butyl 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0593] AcOH (271.97 mg, 4.53 mmol) and 2-fluorobenzaldehyde (342.88 mg, 2.76 mmol) were added to a solution of tert-butyl-2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 1 hr, then NaBH(OAc)3 (1.44 g, 6.79 mmol) was added and stirred at 25 °C for another 12 h. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 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 to 2 / 1) to give tert-butyl 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, yield: 96%) as a yellow oil.

[0594] Step 2: tert-butyl 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0595] A mixture of tert-butyl 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 h. The reaction solution was quenched with MeOH (20 mL) and stirred at 0 °C for 1 hr. The mixture was concentrated under reduced pressure to give tert-butyl 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.07 mg, crude) as a white oil, which could be used directly for the next step without further purification. MS (ESI, m / e) [M+1] + 536.4.

[0596] Step 3: 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0597] A mixture of tert-butyl 2-(4-(2-fluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 EtOAc (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 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 (400 MHz, 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= 11.2 Hz, 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 = 6.8 Hz, 4H). MS (ESI, m / e) [M+1] + 436.3.

[0598] Intermediate 47-1: 2-(2-(2-isopropylphenyl)-4-(2-methoxybenzyl)piperazin-1-yl)-7-azaspiro [3.5]Nonane

[0599]

[0600] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)-4-(2-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0601] HOAc (280.6 mg, 4.68 mmol) was added to a solution of tert-butyl-2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.34 mmol) and 2-methoxybenzaldehyde (477.5 mg, 3.51 mmol) in a DCE (10 mL). The solution was stirred at 25 °C for 30 min. Then, NaBH(OAc)3 (1.09 g, 5.14 mmol) was added to the above reaction and stirred at 25 °C for 12 h. Saturated NaHCO3 was added to the reaction until pH = 7, and the solution 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 give tert-butyl 2-(2-(2-isopropylphenyl)-4-(2-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (230 mg, yield: 18%) as a yellow oil.

[0602] Step 2: 2-(2-(2-isopropylphenyl)-4-(2-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0603] A solution of 230 mg (0.42 mmol) of tert-butyl 2-(2-(2-isopropylphenyl)-4-(2-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-(2-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonane 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 aqueous Na₂CO₃ (30 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 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 (400 MHz, 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 = 6.8 Hz, 3H). MS (ESI, m / e) [M+1] + 448.3.

[0604] Intermediate 48-1: 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-aza Spiro[3.5]nonane

[0605]

[0606] Step 1: tert-butyl 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0607] AcOH (326.36 mg, 5.43 mmol) and 2,4-dimethoxybenzaldehyde (496.71 mg, 2.99 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, 2.72 mmol) in DCE (10 mL), and the mixture was stirred at 25 °C for 1 hr. 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 h. The reaction mixture was extracted with EtOAc (100 mL × 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 to 2 / 1) to give tert-butyl 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, 2.72 mmol, yield: 75%) as a white oil.

[0608] Step 2: 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0609] A mixture of tert-butyl 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 quenched with MeOH (10 mL) and concentrated under reduced pressure to give tert-butyl 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, crude) as a white gel, which can be used directly for the next step without further reaction.

[0610] Step 3: 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0611] A mixture of tert-butyl 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 aqueous NaHCO3 to adjust the pH to 9 and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane as a white solid (651 mg, 1.36 mmol, yield: 65.2%). 1 H NMR (400 MHz, CDCl3)δ ppm: 7.47 (brs, 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 = 6.8 Hz, 5H). MS (ESI, m / e) [M+1] + 478.3.

[0612] Intermediate 48-1a: (R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazine-1- (-7-azaspiro[3.5]nonane)

[0613]

[0614] Step 1: tert-butyl(R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0615] AcOH (271.97 mg, 4.53 mmol) and 2,4-dimethoxybenzaldehyde (564.44 mg, 3.40 mmol) were added to a solution of tert-butyl(R or S)-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in DCE (15 mL), and the mixture was stirred at 20 °C for 30 min. 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 h. The reaction mixture was extracted with EtOAc (100 mL × 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 to 2 / 1) to give tert-butyl(R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.13 g, 84% yield) as a white oil.

[0616] Step 2: tert-butyl(R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0617] A mixture of tert-butyl(R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.13 g, 1.91 mmol) and BH3·THF (19.09 mL, 19.09 mmol, 1 M) in THF (15 mL) was stirred at 70 °C for 12 hours. The reaction solution was quenched with MeOH (10 mL) and concentrated under reduced pressure to give tert-butyl(R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, crude) as a white gel, which can be used directly for the next step without further reaction.

[0618] Step 3: (R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0619] Add HCl / MeOH solution (10 mL, 4 M) to a mixture of tert-butyl(R or S)-2-(4-(2,4-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 1.73 mmol) in MeOH (10 mL). Stir the mixture at 20 °C for 3 hours. Concentrate the reaction solution under reduced pressure. Pour the residue into aqueous NaHCO3 to adjust the pH to 9 and extract with EtOAc (100 mL × 2). The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (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. 1 H NMR (400 MHz, 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, 1H),1.67-1.65 (m, 1H), 1.69-1.61 (m, 1H), 1.43-1.28 (m, 4H), 1.25 (d, J = 6.8 Hz, 4H), 1.17 (d, J = 6.8 Hz, 4H). MS (ESI, m / e) [M+1] + 478.5.

[0620] Intermediate 49-1: 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-aza Spiro[3.5]nonane

[0621]

[0622] Step 1: tert-butyl 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0623] 3,5-Dimethoxybenzaldehyde (0.56 g, 3.40 mmol) and HOAc (0.27 g, 4.52 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in DCE (20 mL). After stirring at 25 °C for 1 hr, NaBH(OAc)3 (0.96 g, 4.52 mmol) was added. The mixture was stirred at 25 °C for 12 h. Then, aqueous NH4Cl (20 mL) was added to the mixture, and the mixture was extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL × 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 give tert-butyl 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.1 g, yield: 82%) as a yellow solid. 1 H NMR (400 MHz, 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 (brs, 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 = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H).

[0624] Step 2: tert-butyl 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0625] A mixture of tert-butyl 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.1 g, 1.86 mmol) and BH3·THF (18 mL, 18.6 mmol) was heated to 70 °C for 12 hours. MeOH (10 mL) was carefully added to the mixture, and the mixture was concentrated under vacuum to a yellow oily product of tert-butyl 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.9 g, yield: 84%), which was ready for use in the next step without further purification. MS (ESI, m / e) [M+1] + 578.4.

[0626] Step 3: 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane

[0627] HCl / MeOH (10 mL) was added to a solution of tert-butyl 2-(4-(3,5-dimethoxybenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (900 mg, 1.56 mmol) in MeOH (20 mL). The mixture was stirred at 25 °C for 1 hr. After removing the solvent, the residue was dissolved in water (20 mL). The pH of the mixture was adjusted to 9-10 using aqueous Na₂CO₃. The mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give 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 (400 MHz, 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, 1 H), 1.70-1.64 (m, 1H), 1.41-1.29 (m, 5H), 1.26 (br d, J = 6.8 Hz, 3H), 1.15 (br d, J = 6.8Hz, 3H). MS (ESI, m / e) [M+1] + 478.4.

[0628] Intermediate 50-1: 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro [3.5]Nonane

[0629]

[0630] Step 1: tert-butyl 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0631] AcOH (326.36 mg, 5.43 mmol) and 2,4-difluorobenzaldehyde (424.76 mg, 2.99 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, 2.72 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 1 hr, then NaBH(OAc)3 (1.73 g, 8.15 mmol) was added and stirred at 25 °C for another 12 h. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 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 to 2 / 1) to give tert-butyl 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 1.76 mmol, yield: 64%) as a yellow oil.

[0632] Step 2: tert-butyl 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0633] A mixture of tert-butyl 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 h. The reaction solution was quenched with MeOH (10 mL) and concentrated under reduced pressure to give tert-butyl 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, crude), which can be used directly for the next step without further reaction.

[0634] Step 3: 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane

[0635] A mixture of tert-butyl 2-(4-(2,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 EtOAc (100 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 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 (400 MHz, 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), 1.25 (br d, J = 6.8Hz, 3H), 1.15 (br d, J = 6.8 Hz, 3H). MS (ESI, m / e) [M+1] + 454.3.

[0636] Intermediate 51-1: 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro [3.5]Nonane

[0637]

[0638] Step 1: tert-butyl 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0639] AcOH (337 mg, 5.61 mmol) and 3,5-difluorobenzaldehyde (292 mg, 2.06 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (800 mg, 1.87 mmol) in DCE (10 mL). The mixture was stirred at 20 °C for 1 hr. Then NaBH(OAc)3 (1.19 g, 5.61 mmol) was added. The mixture was stirred at 20 °C for 16 h. Then saturated NaHCO3 (10 mL) and EtOAc (10 mL) were added. The mixture was stirred at 20 °C for 0.2 hr. The organic layer was separated, dried over Na2SO4, and evaporated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA (v / v) = 10 / 1 to 1 / 1) to give tert-butyl 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (500 mg, yield: 50%) as a yellow solid. MS (ESI, m / e) [M+1] + 568.5

[0640] Step 2: tert-butyl 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0641] A mixture of tert-butyl 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (500 mg, 0.88 mmol) and BH3·THF (8.8 mL, 8.8 mmol) was heated to 70 °C for 12 hours. After cooling to 0 °C, the mixture was quenched with MeOH (10 mL). The mixture was concentrated under vacuum to give tert-butyl 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (400 mg, yield: 80%) as a yellow solid, which could be used for the next step without further purification. MS (ESI, m / e) [M+1] + 554.2.

[0642] Step 3: 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0643] HCl / MeOH (10 mL) was added to a solution of tert-butyl 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (400 mg, 0.71 mmol) in MeOH (10 mL). The mixture was stirred at 25 °C for 2 hours, concentrated under vacuum, and the residue was dissolved in water (20 mL). The pH of the mixture was adjusted to 9-10 with aqueous Na₂CO₃. The mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give 2-(4-(3,5-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (225 mg, yield: 70%) as a brown solid. 1 H 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), 2.32-2.22 (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

[0644] Intermediate 52-1: 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro [3.5]Nonane

[0645]

[0646] Step 1: tert-butyl 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0647] AcOH (239.33 mg, 3.99 mmol) and 3,4-difluorobenzaldehyde (311.49 mg, 2.19 mmol) were added to a solution of tert-butyl-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (880 mg, 1.99 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 1 hr. Then NaBH(OAc)3 (1.27 g, 5.98 mmol) was added and the mixture was stirred at 25 °C for another 12 h. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 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 to 2 / 1) to give tert-butyl 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, yield: 85%) as a yellow oil.

[0648] Step 2: tert-butyl 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0649] A mixture of tert-butyl 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 quenched with MeOH (10 mL) and concentrated under reduced pressure to give tert-butyl 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (750 mg, crude) as a yellow oil, which could be used directly for the next step without further purification.

[0650] Step 3: 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0651] A mixture of tert-butyl 2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 EtOAc (20 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 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 (400 MHz, 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 = 6.8 Hz, 4H). MS (ESI, m / e) [M+1] + 454.3.

[0652] Intermediate 52-1a: (R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7- Azaspiro[3.5]nonane

[0653]

[0654] Step 1: tert-butyl(R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0655] AcOH (271.97 mg, 4.53 mmol) and 3,4-difluorobenzaldehyde (309.15 mg, 2.49 mmol) were added to a solution of tert-butyl(R or S)-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 1 h, and then NaBH(OAc)3 (1.44 g, 6.79 mmol) was added, followed by stirring at 25 °C for another 12 h. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 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 to 2 / 1) to give tert-butyl(R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.15 g, yield: 88%) as a yellow oil.

[0656] Step 2: tert-butyl(R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0657] A mixture of tert-butyl(R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.15 g, 2.03 mmol) and BH3·THF (20.26 mL, 20.26 mmol) in THF was stirred at 70 °C for 12 hours. The reaction solution was quenched with MeOH (10 mL) and concentrated under reduced pressure to give t-tert-butyl(R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.1 g, crude), which was used directly in the next step without further purification.

[0658] Step 3: (R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0659] A mixture of tert-butyl(R or S)-2-(4-(3,4-difluorobenzyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.1 g, 1.99 mmol) and HCl (4.97 mL, 19.87 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 EtOAc (20 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (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. 1 H NMR (400 MHz, 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 = 6.8 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H). MS (ESI, m / e) [M+1] + 454.3.

[0660] Intermediate 53-1: 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro [3.5]Nonane

[0661]

[0662] Step 1: tert-butyl 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0663] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol), chroman-6-carboxaldehyde (404 mg, 2.49 mmol), and AcOH (271.97 mg, 4.53 mmol) in a DCE (20 mL) was stirred at 20 °C for 30 min. Then, NaBH(OAc)3 (1.44 g, 6.79 mmol) was added in portions to the mixture, and the mixture was stirred at 30 °C for 2 h. 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 give tert-butyl 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.25 g, yield: 94%) as a white solid. 1 H NMR (400 MHz, 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, 3 H), 1.54-1.38 (m, 11H), 1.37-1.29 (m, 2H), 1.25-1.17 (m, 3H), 0.95 (d, J = 6.8 Hz, 3H). MS (ESI, m / e) [M+1] + 588.4.

[0664] Step 2: tert-butyl 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0665] At 20 °C, BH3·THF (30 mL, 30 mmol) was added dropwise to a solution of tert-butyl 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.25 g, 2.13 mmol) in THF (15 mL). The mixture was heated to 70 °C for 12 hours. The reaction was quenched with methanol (5 mL) and concentrated under reduced pressure to give tert-butyl 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.22 g, crude) as a white solid. MS (ESI, m / e) [M+1] + 574.5.

[0666] Step 3: 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0667] At 20 °C, HCl / MeOH (20 mL, 4 M) was added dropwise to a solution of tert-butyl 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.20 g, 2.09 mmol) in MeOH (5 mL). 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 EtOAc (20 mL × 2). The aqueous phase was adjusted to pH 8 with NaHCO3 and extracted with EtOAc / MeOH (20 / 1, 40 mL × 5). The combined organic phases were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(4-(chroman-6-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane as a white solid (740 mg, yield: 75%). 1 H NMR (400 MHz, 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= 8.19 Hz, 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 = 6.85 Hz, 3H), 1.14 (d, J = 6.85 Hz, 3H). MS (ESI, m / e) [M+1] + 474.4.

[0668] Intermediate 54-1: 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphth-2-yl)methyl)piperazine-1- (-7-azaspiro[3.5]nonane)

[0669]

[0670] Step 1: 5,6,7,8-Tetrahydronaphthalene-2-carboxaldehyde and 5,6,7,8-Tetrahydronaphthalene-1-carboxaldehyde.

[0671] A solution of 1,2,3,4-tetrahydronaphthalene (3.0 g, 22.69 mmol) in DCM (50 mL) was cooled to 0 °C with vigorous stirring. All SnCl4 (10.4 g, 39.94 mmol) was added at once via syringe, followed by dropwise introduction of dichloro(methoxy)methane (2.61 g, 22.69 mmol) over 10 min. After the addition, the reaction was stirred at 0 °C for 0.5 hr. The mixture turned deep red and then yellow. The reaction mixture was quenched with ice. The organic phase was washed with water (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a mixture (3.3 g, crude) of 5,6,7,8-tetrahydronaphthalene-2-carboxaldehyde and 5,6,7,8-tetrahydronaphthalene-1-carboxaldehyde as a deep yellow oil. 1 H NMR (400 MHz, CDCl3)δppm: 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).

[0672] Step 2: tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-((5,6,7,8-tetrahydronaphth-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate and tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-((5,6,7,8-tetrahydronaphth-1-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0673] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol), AcOH (271.97 mg, 4.53 mmol), and a mixture of 5,6,7,8-tetrahydronaphthalene-2-carboxaldehyde and 5,6,7,8-tetrahydronaphthalene-1-carboxaldehyde (435.35 mg, 2.72 mmol) in a DCE (20 mL) was stirred at 20 °C for 30 min. NaBH(OAc)3 (1.44 g, 6.79 mmol) was added in portions to the above mixture, and then stirred at 20 °C for 3 h. The reaction mixture was diluted with DCM (30 mL), washed with saturated Na2CO3, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by conventional HPLC, pH adjusted to 8 with NaHCO3, concentrated, and extracted with EtOAc (50 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-((5,6,7,8-tetrahydronaphthyl-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (500 mg, 0.86 mmol) as a pale yellow solid. 1 H NMR (400 MHz, 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 = 7.6 Hz, 1H), 6.65 (d, J= 7.6 Hz, 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 = 6.8 Hz, 3H), 0.95(d, J = 6.8 Hz, 3H).

[0674] tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-((5,6,7,8-tetrahydronaphthyl-1-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (370 mg, 0.63 mmol), a white solid. 1 H NMR (400MHz, CDCl3)δ ppm: 7.27-7.16 (m, 3H), 7.12 (td, 1H), 7.03 (d, J = 7.6 Hz, 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 = 6.8 Hz, 3 H), 0.91 (d, J = 6.8 Hz, 3H).

[0675] Step 3: tert-butyl 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphth-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0676] At 20 °C, BH3·THF (16 mL, 16 mmol) was added dropwise to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-((5,6,7,8-tetrahydronaphthyl-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (500 mg, 0.86 mmol) in THF (8 mL). The mixture was heated to 70 °C for 12 hours. The reaction was quenched with methanol (5 mL) and concentrated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthyl-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (488 mg, crude) as a white solid. MS (ESI, m / e) [M+1] + 572.5.

[0677] Step 4: 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthyl-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0678] At 20 °C, HCl / MeOH (15 mL, 4 M) was added dropwise to a solution of tert-butyl-2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthyl-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (488 mg, 0.85 mmol) in MeOH (5 mL). 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 EtOAc (10 mL × 2). The aqueous phase was adjusted to pH 8 with NaHCO3 and extracted with EtOAc (20 mL × 3). The combined organic phases were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthyl-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane as a white solid (311 mg, yield: 77%). 1H NMR (400 MHz, 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.

[0679] Intermediate 55-1: 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphth-2-yl)methyl)piperazine-1- (-7-azaspiro[3.5]nonane)

[0680]

[0681] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthyl-1-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0682] At 20 °C, BH3·THF (12 mL, 12 mmol) was added dropwise to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-((5,6,7,8-tetrahydronaphthyl-1-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (370 mg, 0.63 mmol) in THF (6 mL). The mixture was heated to 70 °C for 12 hours. The reaction was quenched with methanol (5 mL) and concentrated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthyl-1-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (361 mg, crude) as a white solid, which could be used directly in the next step without further purification. MS (ESI, m / e) [M+1] + 572.5.

[0683] Step 2: 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphth-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane

[0684] At 20 °C, HCl / MeOH (10 mL, 4 M) was added dropwise to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthyl-1-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (361 mg, 0.63 mmol) in MeOH (5 mL). 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 EtOAc (10 mL × 2). The aqueous phase was adjusted to pH 8 with NaHCO3 and extracted with EtOAc (20 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 2-(2-(2-isopropylphenyl)-4-((5,6,7,8-tetrahydronaphthyl-2-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonane as a white solid (245 mg, yield: 83%). 1 H NMR (400 MHz, 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.

[0685] MS (ESI, m / e) [M+1] + 472.4.

[0686] Intermediate 57-1: 2-(4-(chroman-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro [3.5]Nonane

[0687]

[0688] Step 1: Color-4-formonitrile.

[0689] At 0 °C, TosMIC (11.9 g, 40.50 mmol) and t-BuOK (4.5 g, 40.50 mmol) were added to a solution of chroman-4-one (2.0 g, 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 EtOAc (50 mL × 3). The combined organic phases were washed with brine (20 mL × 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 to 1 / 1) to give chroman-4-carboxynitrile (800 mg, 5.03 mmol, yield: 37%) as a yellow oil. MS (ESI, m / e) [M+1] + 160.0.

[0690] Step 2: Chromium-4-formic acid.

[0691] At 20 °C, NaOH (2.0 g, 50.26 mmol) was added to a mixture of chromonitrile (1.6 g, 10.06 mmol) in MeOH (30 mL) and H₂O (5 mL). The mixture was stirred at 100 °C for 12 hours. HCl (1 M) was added to the reaction solution to pH = 1, and the solution was extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give chromonitrile-4-carboxylic acid (850 mg, crude) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.77-12.47 (m, 1H), 7.20 (d, J = 7.6 Hz,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).

[0692] Step 3: tert-butyl 2-(4-(chroman-4-carbonyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0693] A solution of serotonin-4-carboxylic acid (646 mg, 3.62 mmol) in DMF (20 mL) was supplemented with DIEA (585 mg, 4.53 mmol), HATU (1.03 g, 2.72 mmol), and tert-butyl-2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) for 3 hours (at 20 °C). The reaction mixture was decanted into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, 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 give tert-butyl 2-(4-(chroman-4-carbonyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate as a white solid (1.1 g, 1.83 mmol, yield: 82%). 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).

[0694] Step 4: tert-butyl 2-(4-(chroman-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0695] A solution of tert-butyl 2-(4-(chroman-4-carbonyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.1 g, 1.83 mmol) in BH3·THF (20 mL, 1 M, in THF) was continuously incubated 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 give tert-butyl 2-(4-(chroman-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.05 g, crude) as a white solid. MS (ESI, m / e) [M+1] + 574.4.

[0696] Step 5: 2-(4-(chroman-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0697] At 20 °C, HCl / MeOH (20 mL, 4 M) was added to a solution of tert-butyl 2-(4-(chroman-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 1.74 mmol) in MeOH (5 mL). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under vacuum, poured into H2O (20 mL), and extracted with EtOAc (20 mL). Saturated Na2CO3 was added to the aqueous phase to pH = 10, and it was extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give 2-(4-(chroman-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane as a white solid (615 mg, 374.47 μmol, yield: 74%). 1H NMR (400 MHz, 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.

[0698] Intermediate 58-1: 2-(4-(benzo[b]thiophene-5-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7- Azaspiro[3.5]nonane

[0699]

[0700] Step 1: Benzo[b]thiophene-5-carboxaldehyde

[0701] At -60 °C, i-PrMgCl·LiCl (25 mL, 32.50 mmol) was added to a solution of 5-bromobenzo[b]thiophene (1.0 g, 4.69 mmol) in THF (30 mL). The mixture was stirred at 25 °C for 12 hours. DMF (5 mL) was then added dropwise. The reaction mixture was quenched with aqueous NH4Cl (50 mL) and extracted with EtOAc (100 mL × 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 give benzo[b]thiophene-5-carboxaldehyde (452 ​​mg, yield: 59%) as a yellow oil.

[0702] Step 2: tert-butyl 2-(4-(benzo[b]thiophene-5-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0703] AcOH (271.97 mg, 4.53 mmol) and benzo[b]thiophene-5-carboxaldehyde (404.05 mg, 2.49 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 1 hr, and then NaBH(OAc)3 (1.44 g, 6.79 mmol) was added. The mixture was stirred at 25 °C for another 12 h. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 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 to 2 / 1) to give tert-butyl 2-(4-(benzo[b]thiophene-5-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, 2.04 mmol, yield: 90%) as a yellow oil.

[0704] Step 3: tert-butyl 2-(4-(benzo[b]thiophene-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0705] A mixture of tert-butyl 2-(4-(benzo[b]thiophene-5-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, 2.04 mmol) and BH3·THF (20.41 mL, 20.41 mmol) in THF was stirred at 70 °C for 12 h. The reaction solution was quenched with MeOH (10 mL) and concentrated under reduced pressure to give tert-butyl 2-(4-(benzo[b]thiophene-5-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.26 g, crude), a yellow oil, which could be used directly for the next step without further reaction. MS (ESI, m / e) [M+1] + 574.3.

[0706] Step 4: 2-(4-(benzo[b]thiophene-5-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0707] A mixture of tert-butyl 2-(4-(benzo[b]thiophene-5-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 EtOAc (100 mL × 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 adjust the pH to 9, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-(4-(benzo[b]thiophene-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 (400 MHz, CDCl3)δ ppm: 7.80 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.48(br s, 1H), 7.42 (d, J = 5.6 Hz, 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.

[0708] Intermediate 59-1: 2-(4-(benzo[b]thiophene-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7- Azaspiro[3.5]nonane

[0709]

[0710] Step 1: Benzo[b]thiophene-4-ylmethanol.

[0711] At 0 °C, LAH (383.36 mg, 10.10 mmol) was added to a solution of benzo[b]thiophene-4-carboxylic acid (900 mg, 5.05 mmol) in DCM (10 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched with aqueous NaOH (0.8 mL, 25%) and extracted with EtOAc (100 mL × 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 to 2 / 1) to give benzo[b]thiophene-4-ylmethanol (800 mg, 4.87 mmol, yield: 96%) as a yellow oil.

[0712] Step 2: Benzo[b]thiophene-4-carboxaldehyde.

[0713] A mixture of 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 h. The reaction was filtered and extracted with EtOAc (100 mL × 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 to 2 / 1) to give benzo[b]thiophene-4-carboxaldehyde (625 mg, 3.85 mmol, yield: 79%) as a yellow oil. 1 H NMR (400 MHz, CDCl3)δ ppm: 10.29-10.20 (s,1H), 8.39 (d, J = 5.6 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 5.6 Hz, 1H), 7.58-7.46 (m, 1H).

[0714] Step 3: tert-butyl 2-(4-(benzo[b]thiophene-4-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0715] AcOH (326.36 mg, 5.43 mmol) and benzo[b]thiophene-4-carboxaldehyde (484.86 mg, 2.99 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, 2.72 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 1 hr, 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 h. The reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL × 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 to 2 / 1) to give tert-butyl 2-(4-(benzo[b]thiophene-4-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (900 mg, 1.53 mmol, yield: 56%) as a yellow oil.

[0716] Step 4: tert-butyl 2-(4-(benzo[b]thiophene-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0717] A mixture of tert-butyl 2-(4-(benzo[b]thiophene-4-ylmethyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (900 mg, 1.53 mmol) and BH3 (15.31 mL, 15.31 mmol) in DCM (10 mL) was stirred at 70 °C for 12 h. The reaction solution was quenched with MeOH (10 mL) and concentrated under reduced pressure to give 2-(4-(benzo[b]thiophene-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (850 mg, crude), which could be used directly for the next step without further purification.

[0718] Step 5: 2-(4-(benzo[b]thiophene-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0719] A mixture of 2-(4-(benzo[b]thiophene-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 EtOAc (100 mL × 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) according to HPLC. The residue was diluted with H2O (20 mL), Na2CO3 was added to adjust the pH to 9, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-(4-(benzo[b]thiophene-4-ylmethyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (183 mg, 386.31 µmol, yield: 26%) as a yellow oil. 1 H NMR (400 MHz, CDCl3)δ ppm: 7.78 (d, J = 7.6 Hz, 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 = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H). MS (ESI, m / e) [M+1] + 474.3.

[0720] Intermediate 60-1: (3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)(benzene methyl ketone

[0721]

[0722] Step 1: tert-butyl 2-(4-benzoyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0723] TEA (1.04 g, 10.29 mmol) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.1 g, 2.57 mmol) in DCM (10 mL) for 30 min at 25 °C. Benzoyl chloride (723.2 mg, 5.14 mmol) was then added dropwise at 0 °C. The mixture was stirred at 0 °C for 1 hr. 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 give tert-butyl 2-(4-benzoyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, 1.32 mmol, yield: 51%) as a yellow oil. 1 H NMR (400 MHz, 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 = 7.2 Hz, 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).

[0724] Step 2: (3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)(phenyl)methyl ketone

[0725] At 25 °C, TFA (3 mL) was added to a mixture of tert-butyl 2-(4-benzoyl-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, 1.32 mmol) in DCM (100 mL). The mixture was stirred at 25 °C for 45 min. Water (40 mL) was added to the reaction solution, which was then extracted with EtOAc (50 mL). The pH of the aqueous phase was adjusted to 9–10 with saturated Na2CO3. The resulting mixture was extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a yellow oily substance (3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)(phenyl) methyl ketone (390 mg, 903.59 μmol, yield: 68%). 1 H NMR (400 MHz, CDCl3)δ ppm: 7.83 (d, J = 7.2 Hz, 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.

[0726] Intermediate 61-1: (3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)(4- Methoxyphenyl methyl ketone

[0727]

[0728] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0729] BH3·THF (30 mL, 22.5 mmol) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (2.0 g, 4.53 mmol) in THF (20 mL). The mixture was heated to 70 °C and stirred at 70 °C for 12 h. After cooling to 0 °C, the mixture was quenched with MeOH (10 mL). The mixture was concentrated under vacuum to give a crude product, which was purified by column chromatography to give tert-butyl 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.7 g, yield: 50%) as a white solid. MS (ESI, m / e) [M+1] + 428.5

[0730] Step 2: tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-methoxybenzoyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0731] HATU (685 mg, 1.8 mmol) and Et3N (364 mg, 3.6 mmol) were added to a solution of tert-butyl-2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, 1.64 mmol) and 4-methoxybenzoic acid (274 mg, 1.8 mmol) in DCM (10 mL). 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 phases were 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 to 2 / 1) to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-methoxybenzoyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.4 g, yield: 60%) as a yellow oil. MS (ESI, m / e) [M+1] + 562.3.

[0732] Step 3: (3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)(4-methoxyphenyl)methyl ketone.

[0733] HCl / MeOH (10 mL) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-(4-methoxybenzoyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (400 mg, 0.71 mmol) in MeOH (10 mL). The mixture was stirred at 25 °C for 2 hours. After vacuum concentration, the residue was dissolved in water (20 mL). The pH of the mixture was adjusted to 9-10 with aqueous Na₂CO₃. The mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give (3-(2-isopropylphenyl)-4-(7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)(4-methoxyphenyl) methyl ketone (305 mg, yield: 93%) as a white solid. 1 H NMR (400 MHz, 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

[0734] Intermediate 62-1: 2-(2-(2-isopropylphenyl)-4-(methanesulfonyl)piperazin-1-yl)-7-azaspiro[3.5] nonane

[0735]

[0736] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0737] TEA (206 mg, 2.04 mmol) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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 × 3). The combined organic phases were concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluent: PE / EA (v / v) = 20 / 1 to 10 / 1) to give tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.6 g, yield: 91%) as a yellow oil. MS (ESI, m / e) [M+1] + 582.3

[0738] Step 2: tert-butyl 2-(2-(2-isopropylphenyl)-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0739] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.6 g, 1.03 mmol) and BH3·THF (5 mL, 5 mmol) was heated to 70 °C for 12 hours. After cooling to 0 °C, the mixture was quenched with MeOH (10 mL). The mixture was concentrated under vacuum to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.45 g, yield: 65%) as a yellow oil. MS (ESI, m / e) [M+1] + 568.2.

[0740] Step 3: 2-(2-(2-isopropylphenyl)-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane

[0741] HCl / MeOH (10 mL) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (450 mg, 0.79 mmol) in MeOH (10 mL). The mixture was stirred at 25 °C for 2 h. After vacuum concentration, the residue was dissolved in water (20 mL). The pH of the mixture was adjusted to 9-10 with aqueous Na2CO3. The mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried with anhydrous Na2SO4, filtered, and vacuum concentrated to give 2-(2-(2-isopropylphenyl)-4-(phenylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (310 mg, yield: 94%) as a white solid. 1 H 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, 3H), 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

[0742] Intermediate 63-1: 2-(2-(2-isopropylphenyl)-4-(1-phenylbut-2-yn-1-yl)piperazin-1-yl)-7-nitrogen Spiro[3.5]nonane

[0743]

[0744] Step 1: 1-Phenylacet-2-yne-1-ol.

[0745] At -70°C, prop-1-yn-1-ylmagnesium bromide (90.5 mL, 45.23 mmol) in THF (0.5 M) was added dropwise to a solution of benzaldehyde (4.0 g, 37.69 mmol) in THF (100 mL). The mixture was heated to 20°C and stirred at 20°C for 12 hours. After cooling to 0°C, the mixture was quenched with saturated aqueous NH4Cl (100 mL). The mixture was extracted with EtOAc (50 mL × 2). The organic layer was dried over Na2SO4 and evaporated under vacuum to give 1-phenylbut-2-yn-1-ol (5.0 g, yield: 90%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ ppm: 7.46-7.44 (d, J =6.8 Hz, 2H), 7.31-7.24 (m, 3H), 5.34 (s, 1H), 2.17 (s, 1H), 1.83 (s, 3H).

[0746] Step 2: 1-Phenylacet-2-yne-1-ylmethanesulfonate.

[0747] MsCl (2.15 g, 18.8 mmol) was added to a solution of 1-phenylbut-2-yn-1-ol (2.5 g, 17 mmol) and Et3N (5.1 g, 51 mmol) in DCM (25 mL) at 25 °C. The mixture was stirred at 25 °C for 1 hr. The mixture was poured into H2O (20 mL) and extracted with DCM (20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a residue (2.6 g, yield: 95%) as a yellow oil, which was used directly for the next step without further purification.

[0748] Step 3: tert-butyl 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0749] BH3·THF (30 mL, 22.5 mmol) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (2.0 g, 4.53 mmol) in THF (20 mL). The mixture was heated to 70 °C and stirred at 70 °C for 12 hours. After cooling to 0 °C, the mixture was quenched with MeOH (10 mL). The mixture was concentrated under vacuum to give a crude product, which was purified by column chromatography to give tert-butyl 2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.7 g, yield: 50%) as a white solid.

[0750] Step 4: tert-butyl 2-(2-(2-isopropylphenyl)-4-(1-phenylbut-2-yn-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0751] A solution of tert-butyl-2-(2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.7 g, 1.64 mmol) in CH3CN (20 mL) was mixed with K2CO3 (0.68 g, 4.91 mmol) and 1-phenylbut-2-yn-1-ylmethanesulfonate (0.55 g, 2.46 mmol). The mixture was stirred at 50 °C for 1 hr. After vacuum concentration, the residue was dissolved in water (20 mL). The mixture was extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (10 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(1-phenylbut-2-yn-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (240 mg, yield: 27%) as a yellow oil.

[0752] Step 5: 2-(2-(2-isopropylphenyl)-4-(1-phenylbut-2-yn-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0753] HCl / MeOH (10 mL) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-(1-phenylbut-2-yn-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (240 mg, 0.43 mmol) in MeOH (10 mL). The mixture was stirred at 25 °C for 2 hours. After vacuum concentration, the residue was dissolved in water (10 mL). The pH of the mixture was adjusted to 9-10 using aqueous Na₂CO₃. The mixture was extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (10 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give 2-(2-(2-isopropylphenyl)-4-(1-phenylbut-2-yn-1-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane (170 mg, yield: 73%) as a yellow solid. 1 H NMR (400 MHz, 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.

[0754] Intermediate 64-1: 2-(2-(2-isopropylphenyl)-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro [3.5]Nonane

[0755]

[0756] Step 1: 3-Phenylon-1-one.

[0757] Phenylated boric 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 to a solution of cyclopentan-1-one (3.0 g, 36 mmol) in toluene (80 mL) and CHCl₃ (0.4 mL). 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 give 3-phenylcyclopentan-1-one (2.8 g, yield: 48%) as a brown oil. 1 H NMR (400 MHz, 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).

[0758] Step 2: tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0759] 3-Phenycyclopentane-1-one (540 mg, 3.40 mmol) and HOAc (0.27 g, 4.52 mmol) were added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol) in DCE (20 mL). After stirring at 25 °C for 1 hr, NaBH(OAc)3 (0.96 g, 4.52 mmol) was added. The mixture was stirred at 25 °C for 12 h. Then, aqueous NH4Cl (20 mL) was added to the mixture, and the mixture was extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL × 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 give tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.66 g, yield: 50%) as a yellow solid. 1H NMR (400 MHz, 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 = 5.25 Hz, 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).

[0760] Step 3: tert-butyl 2-(2-(2-isopropylphenyl)-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0761] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxo-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.66 g, 1.13 mmol) and BH3·THF (11 mL, 11.3 mmol) was heated to 70 °C for 12 hours. The reaction was then quenched by dropwise addition of MeOH (10 mL). The mixture was concentrated under reduced pressure to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.6 g, yield: 93%) as a yellow oil, which could be used directly without further purification. MS (ESI, m / e) [M+1] + 572.4.

[0762] Step 4: 2-(2-(2-isopropylphenyl)-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0763] HCl / MeOH (10 mL) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-(3-phenylcyclopentyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (600 mg, 1.05 mmol) in MeOH (20 mL). The mixture was stirred at 25 °C for 1 hr. After solvent removal, the residue was dissolved in water (20 mL). The pH of the mixture was adjusted to 9-10 using Na2CO3, and then extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 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(400 MHz, 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.

[0764] Intermediate 65-1: 2-(2-(2-isopropylphenyl)-4-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane

[0765]

[0766] Step 1: tert-butyl 2-(2-isopropylphenyl)-3-oxo-4-phenylpiperazine-1-carboxylate.

[0767] Phenylated boric acid (2.3 g, 18.8 mmol), Cu(OAc)₂ (1.4 g, 9.4 mmol), 4AMS (1.5 g), and TEA (9.5 g, 94.2 mmol) were added to a solution of tert-butyl 2-(2-isopropylphenyl)-3-oxopiperazine-1-carboxylate (1.5 g, 4.7 mmol) in DCE (150 mL). The mixture was stirred at 75 °C for 12 h under O₂. The mixture was filtered and concentrated to obtain a residue, which was extracted with 1 M HCl (50 mL) and EA (20 mL × 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). The compound tert-butyl 2-(2-isopropylphenyl)-3-oxo-4-phenylpiperazine-1-carboxylate (1.2 g, yield: 64%) was obtained as a brown oil.

[0768] Step 2: 3-(2-isopropylphenyl)-1-phenylpiperazin-2-one.

[0769] A solution of tert-butyl 2-(2-isopropylphenyl)-3-oxo-4-phenylpiperazine-1-carboxylate (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 give a residue, which was extracted with EA (30 mL × 3) and saturated NaHCO3 (30 mL). The combined organic layers were dried and concentrated to give 3-(2-isopropylphenyl)-1-phenylpiperazine-2-one (0.82 g, crude), a brown oil, for direct use.

[0770] Step 3: tert-butyl 2-(2-(2-isopropylphenyl)-3-oxo-4-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0771] tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (666 mg, 2.8 mmol) and NaBH(OAc)3 (1.2 g, 5.6 mmol) were added to a solution of 3-(2-isopropylphenyl)-1-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.3 g, crude) in DCE (10 mL) for direct use. The mixture was stirred at 27 °C for 10 hours. The mixture was extracted with saturated NaHCO3 (50 mL) and DCM (20 mL × 3) to give tert-butyl 2-(2-(2-isopropylphenyl)-3-oxo-4-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.3 g, crude) as a yellow oil.

[0772] Step 4: tert-butyl 2-(2-(2-isopropylphenyl)-4-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0773] A solution of tert-butyl 2-(2-(2-isopropylphenyl)-3-oxo-4-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, 2.3 mmol) in BH3-THF (10 mL) was stirred at 70 °C for 10 hours. The mixture was quenched with MeOH (10 mL) and concentrated to give tert-butyl 2-(2-(2-isopropylphenyl)-4-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (2.1 g, crude), which is a yellow oil and ready for direct use.

[0774] Step 5: 2-(2-(2-isopropylphenyl)-4-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane.

[0775] A solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.1 g, 2.2 mmol) in TFA (3 mL) and DCM (6 mL) was stirred at 20 °C for 2 h. The mixture was concentrated to obtain a residue, which was purified by preparative HPLC (TFA). The compound 2-(2-(2-isopropylphenyl)-4-phenylpiperazin-1-yl)-7-azaspiro[3.5]nonane (570 mg, 65% yield) was given as a white solid. 1 H NMR (400 MHz, METHANOL-d4)δ ppm: 7.53 (d, J = 7.6 Hz, 1H), 7.36-7.31 (m, 1H), 7.29-7.14 (m,4H), 6.93 (d, J = 7.9 Hz, 2H), 6.83 (t, J = 7.3 Hz, 1H), 3.82-3.70 (m, 2H), 3.49(br d, J = 6.3 Hz, 1H), 3.35 (td, J = 2.6 Hz, 12.2 Hz, 1H), 3.17 (td, J = 2.5 Hz,11.5 Hz, 1H), 3.03-2.91 (m, 2H), 2.85 (dd, J= 10.8 Hz, 12.1 Hz, 1H), 2.68-2.48(m, 4H), 2.39 (dt, J = 3.0 Hz, 11.8 Hz, 1H), 1.92-1.83 (m, 1H), 1.75-1.68 (m,1H), 1.46-1.28 (m, 9H), 1.24 (d, J = 6.9 Hz, 3H), 1.18-1.10 (m, 1H). MS (ESI, m / e) [M+1] + 404.4.

[0776] Intermediate 66-1: 2-(2-(2-isopropylphenyl)-4-(methanesulfonyl)piperazin-1-yl)-7-azaspiro[3.5] nonane

[0777]

[0778] Step 1: tert-butyl 2-(2-(2-isopropylphenyl)-4-(methylsulfonyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0779] TEA (506 mg, 5.0 mmol) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.1 g, 2.5 mmol) in DCM (20 mL). 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 aqueous NH4Cl (1 M, 20 mL) and extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL × 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 give tert-butyl 2-(2-(2-isopropylphenyl)-4-(methanesulfonyl)-6-oxoperpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.07 g, yield: 82%) as a yellow oil. 1 H NMR (400 MHz, CDCl3)δ ppm: 7.41-7.37 (m, 1H), 7.36-7.31 (m, 1H), 7.18 (t, 1H), 6.97 (d, J=7.6 Hz, 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).

[0780] Step 2: tert-butyl 2-(2-(2-isopropylphenyl)-4-(methylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0781] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-4-(methanesulfonyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.07 g, 2.06 mmol) and BH3·THF (10 mL, 10 mmol) was heated to 70 °C for 12 hours. After cooling to 0 °C, the mixture was quenched with MeOH (10 mL). The mixture was concentrated under vacuum to give tert-butyl 2-(2-(2-isopropylphenyl)-4-(methanesulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.8 g, yield: 80%) as a yellow oil, which could be used for the next step without further purification. MS (ESI, m / e) [M+1] + 506.3.

[0782] Step 3: 2-(2-(2-isopropylphenyl)-4-(methylsulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0783] HCl / MeOH (10 mL) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-(methanesulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (800 mg, 1.58 mmol) in MeOH (20 mL). The mixture was stirred at 25 °C for 2 h. After vacuum concentration, the residue was dissolved in water (20 mL). The pH of the mixture was adjusted to 9-10 using aqueous Na₂CO₃. The mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried with anhydrous Na₂SO₄, filtered, and vacuum concentrated to give 2-(2-(2-isopropylphenyl)-4-(methanesulfonyl)piperazin-1-yl)-7-azaspiro[3.5]nonane (570 mg, yield: 89%) as a yellow solid. 1 H 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.

[0784] Intermediate 67-1: 2-(4-benzyl-2-(2-isopropylphenyl)piperidin-1-yl)-7-azaspiro[3.5]nonane.

[0785]

[0786] Step 1: Benzyl 2-(2-isopropylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate.

[0787] At -20°C, benzyl chloroformate (3.2 mL, 22 mmol) was added dropwise to a solution of 4-methoxypyridine (1.82 g, 17 mmol) in dry THF (50 mL). The mixture was stirred at -20°C for 1 hr. At 25°C under N2, magnesite (0.9 g, 38 mmol) in THF (20 mL) was added to another flask. A small amount of I2 (22 mg, 0.17 mmol) was added, followed by dropwise addition of 1-bromo-2-isopropylbenzene (5.0 g, 25 mmol). The mixture was heated to 70°C for 1 hr until the brown color completely disappeared. At -20°C, the resulting Grignard reagent solution was added dropwise to the above pyridinium salt. The mixture was stirred at -20°C for 1 hr. The mixture was poured into HCl (1 M, 50 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 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 give benzyl 2-(2-isopropylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (5.5 g, yield: 92%) as a brown oil. 1 H NMR(400 MHz, CDCl3)δ ppm: 8.23 ​​(d, J = 8.4 Hz, 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 =8.4 Hz, 1H), 5.37(d, J = 8.4 Hz, 1H), 5.22-5.11 (m, 2H), 3.38 (m, 1H), 3.06 (t, 1H), 2.24 (m,1H), 1.23 (d, J = 6.8 Hz, 3H), 1.05 (m, 3H).

[0788] Step 2: Benzyl 2-(2-isopropylphenyl)-4-oxopiperidin-1-carboxylate.

[0789] Zinc (10 g, 0.16 mmol) was added to a solution of benzyl 2-(2-isopropylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (5.5 g, 0.016 mmol) in HOAc (20 mL) at 25 °C. 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 EtOAc (50 mL) and washed with saturated NaHCO3 (30 mL × 2) and brine (30 mL × 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 give benzyl 2-(2-isopropylphenyl)-4-oxopiperidine-1-carboxylate (5.4 g, yield: 96%) as a brown oil. 1 H NMR (400 MHz, 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 = 6.8 Hz, 3H), 1.03 (d, J = 5.2 Hz, 3H).

[0790] Step 3: Benzyl(E)-4-benzylene-2-(2-isopropylphenyl)piperidine-1-carboxylate

[0791] At 0 °C, NaH (0.41 g, 10.24 mmol) was added in several portions to a mixture of benzyltriphenylphosphonium bromide (4.44 g, 10.24 mmol) in THF (40 mL). After stirring at 25 °C for 1 hr, benzyl 2-(2-isopropylphenyl)-4-oxopiperidin-1-carboxylate (3.0 g, 8.54 mmol) was added to THF (10 mL). The mixture was stirred at 25 °C for 12 h. The mixture was carefully poured into aqueous NH4Cl (10 mL) and extracted with EtOAc (50 mL × 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 give benzyl(E)-4-benzylene-2-(2-isopropylphenyl)piperidine-1-carboxylate (0.8 g, yield: 22%) as a yellow oil. MS (ESI, m / e) [M+1] + 426.4.

[0792] Step 4: 4-Benzyl-2-(2-isopropylphenyl)piperidine.

[0793] Pd(OH)₂ / C (0.5 g) was added to a solution of benzyl(E)-4-benzylene-2-(2-isopropylphenyl)piperidine-1-carboxylate (800 mg, 1.88 mmol) in MeOH (30 mL). The mixture was stirred at 30 °C for 12 hours under a H₂ (15 psi) atmosphere. After filtration, the filtrate was concentrated under vacuum to give 4-benzyl-2-(2-isopropylphenyl)piperidine (450 mg, yield: 82%) as a yellow oil, which could be used for the next step without further purification. MS (ESI, m / e) [M+1] + 294.4.

[0794] Step 5: tert-butyl 2-(4-benzyl-2-(2-isopropylphenyl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0795] A solution of 4-benzyl-2-(2-isopropylphenyl)piperidine (450 mg, 1.54 mmol), tert-butyl-2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (611 mg, 2.3 mmol), and AcOH (185 mg, 3.08 mmol) in a DCE (20 mL) was stirred at 25 °C for 1 hr, followed by the addition of NaBH(OAc)3 (954 mg, 4.5 mmol) in portions and stirring at 25 °C for 12 h. The mixture was poured into saturated NaHCO3 (20 mL) and extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL × 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 give tert-butyl 2-(4-benzyl-2-(2-isopropylphenyl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (300 mg, yield: 38%) as a brown oil. MS (ESI, m / e) [M+1] + 517.4.

[0796] Step 6: 2-(4-benzyl-2-(2-isopropylphenyl)piperidin-1-yl)-7-azaspiro[3.5]nonane.

[0797] Add HCl / MeOH solution (10 mL) to a solution of tert-butyl 2-(4-benzyl-2-(2-isopropylphenyl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (300 mg, 0.58 mmol) in MeOH (20 mL). Stir the mixture at 25 °C for 1 hr. After removing the solvent, pour the residue into water (20 mL). Adjust the pH of the mixture to 9-10 using aqueous Na2CO3. Extract the mixture with EtOAc (20 mL × 3). Wash the combined organic phases with brine (20 mL × 2), dry with anhydrous Na2SO4, filter, and concentrate under vacuum. The residue was purified by preparative HPLC (TFA) to give 2-(4-benzyl-2-(2-isopropylphenyl)piperidin-1-yl)-7-azaspiro[3.5]nonane as a TFA salt (200 mg, yield: 83%). 1 H NMR (400 MHz, CDCl3)δ ppm: 7.58 (d, J= 8.0 Hz, 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, 1 H), 3.07-2.93 (m, 6 H), 2.49-2.31 (m, 3H), 2.27-2.11 (m, 2H), 1.91 (m, 1H), 1.76-1.50 (m, 6H), 1.41 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H), 0.94-0.87 (m, 1H). MS (ESI, m / e) [M+1] + 417.4.

[0798] Intermediate 68-1: 2-(2-(2-isopropylphenyl)-4-phenoxypiperidin-1-yl)-7-azaspiro[3.5]nonane

[0799]

[0800] Step 1: Benzyl 4-hydroxy-2-(2-isopropylphenyl)piperidine-1-carboxylate.

[0801] At 0 °C, NaBH4 (0.56 g, 14.8 mmol) was added in several portions to a solution of benzyl 2-(2-isopropylphenyl)-4-oxopiridine-1-carboxylate (2.6 g, 7.4 mmol) in MeOH (20 mL). The mixture was stirred at 25 °C for 1 hr. The mixture was poured into H2O (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were 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 give benzyl 4-hydroxy-2-(2-isopropylphenyl)piperidine-1-carboxylate (2.02 g, yield: 78%) as a brown oil. MS (ESI, m / e) [M+1] + 354.4.

[0802] Step 2: Benzyl 2-(2-isopropylphenyl)-4-phenoxypiperidine-1-carboxylate.

[0803] Phenol (0.59 g, 6.59 mmol) and PPh3 (1.95 g, 7.42 mmol) were added to a solution of benzyl 4-hydroxy-2-(2-isopropylphenyl)piperidine-1-carboxylate (2.02 g, 5.71 mmol) in THF (50 mL). After cooling to 0 °C, DIAD (1.5 g, 7.42 mmol) was added dropwise. The mixture was stirred at 0 °C–25 °C for 12 h. 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 give benzyl 2-(2-isopropylphenyl)-4-phenoxypiperidine-1-carboxylate (1.5 g, yield: 61%) as a brown oil. MS (ESI, m / e) [M+1] + 430.4.

[0804] Step 3: 2-(2-isopropylphenyl)-4-phenoxypiperidine.

[0805] Pd(OH)₂ / C (0.5 g) was added to a solution of benzyl 2-(2-isopropylphenyl)-4-phenoxypiperidine-1-carboxylate (1.5 g, 3.5 mmol) in MeOH (30 mL). The mixture was stirred at 30 °C for 12 hours under H₂ (15 psi). After filtration, the filtrate was concentrated under vacuum to give 2-(2-isopropylphenyl)-4-phenoxypiperidine (1.0 g, yield: 99%) as a yellow oil, which could be used for the next step without further purification. MS (ESI, m / e) [M+1] + 286.4.

[0806] Step 4: tert-butyl 2-(2-(2-isopropylphenyl)-4-phenoxypiperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0807] Tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (1.8 g, 6.77 mmol) and AcOH (410 mg, 6.77 mmol) were added to a solution of 2-(2-isopropylphenyl)-4-phenoxypiperidine (1.0 g, 3.39 mmol) in DCE (20 mL). After stirring at 25 °C for 1 hr, NaBH(OAc)3 (2.15 g, 10.17 mmol) was added in portions. The mixture was stirred at 25 °C for 12 h. The mixture was poured into saturated NaHCO3 (20 mL) and extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL × 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 give tert-butyl 2-(2-(2-isopropylphenyl)-4-phenoxypiperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (400 mg, yield: 23%) as a brown oil. MS (ESI, m / e) [M+1] + 519.4.

[0808] Step 5: 2-(2-(2-isopropylphenyl)-4-phenoxypiperidin-1-yl)-7-azaspiro[3.5]nonane.

[0809] A solution of HCl / MeOH (10 mL, 4 M) was added to a solution of tert-butyl 2-(2-(2-isopropylphenyl)-4-phenoxypiperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (300 mg, 0.58 mmol) in MeOH (20 mL). The mixture was stirred at 25 °C for 2 hours. After solvent removal, the residue was dissolved in H2O (20 mL). The pH of the mixture was adjusted to 9-10 using aqueous Na2CO3. The mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 2-(2-(2-(2-isopropylphenyl)-4-phenoxypiperidin-1-yl)-7-azaspiro[3.5]nonane (160 mg, yield: 41%) as a yellow solid. 1 H 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= 8.4 Hz, 1H), 3.43-3.26 (m, 1H), 3.04-2.85 (m,2 H), 2.71-2.58 (m, 4 H), 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 = 6.8 Hz, 3H), 1.09 (m, 1H), 1.06-0.97 (d, J = 6.8 Hz, 3H). MS(ESI, m / e) [M+1] + 419.4.

[0810] Intermediate 70-1: 2-(4-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)-2-(2-isopropylphenyl)piperazine-1- (-7-azaspiro[3.5]nonane)

[0811]

[0812] Step 1: Ethyl 1-cyclopropyl-1H-pyrazole-4-carboxylate.

[0813] Cu(OAc)₂ (6.48 g, 35.68 mmol) was added to a mixture of ethyl 1H-pyrazole-4-carboxylate (5.0 g, 35.68 mmol), cyclopropylboronic acid (5.82 g, 67.79 mmol), bipyridine (5.57 g, 35.68 mmol), 4A MS (1.0 g), and Na₂CO₃ (7.18 g, 67.79 mmol) in a DCE (150 mL). The mixture was stirred at 70 °C for 16 hours under O₂ (15 psi). The mixture was diluted with EtOAc (300 mL) and filtered through diatomaceous earth. 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 give 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.

[0814] Step 2: (1-Cyclopropyl-1H-pyrazole-4-yl)methanol.

[0815] At 0 °C, LAH (1.24 g, 32.74 mmol) was added fractionally to a solution of ethyl 1-cyclopropyl-1H-pyrazole-4-carboxylate (5.9 g, 32.74 mmol) in THF (80 mL). The mixture was stirred at 20 °C for 2 hours. The mixture was poured into aqueous NaOH (4 M, 50 mL), filtered through diatomaceous earth, and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give (1-cyclopropyl-1H-pyrazole-4-yl)methanol (2.6 g, crude) as a yellow oil. MS (ESI, m / e) [M+1] + 139.2.

[0816] Step 3: 1-Cyclopropyl-1H-pyrazole-4-formaldehyde.

[0817] A mixture of (1-cyclopropyl-1H-pyrazole-4-yl)methanol (2.6 g, 18.82 mmol) and MnO2 (16.36 g, 188.18 mmol) in DCM (60 mL) was stirred at 20 °C for 20 hours. The mixture was diluted with DCM (200 mL) and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give 1-cyclopropyl-1H-pyrazole-4-carboxaldehyde (2.4 g, crude) as a yellow oil.

[0818] Step 4: tert-butyl 2-(4-((1-cyclopropyl-1H-pyrazole-4-yl)methyl)-2-(2-isopropylphenyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0819] A mixture of tert-butyl 2-(2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.26 mmol), 1-cyclopropyl-1H-pyrazole-4-carboxaldehyde (462.46 mg, 3.40 mmol), and AcOH (271.97 mg, 4.53 mmol) in a DCE (20 mL) was stirred at 20 °C for 0.5 hr. Then, NaBH(OAc)3 (1.44 g, 6.79 mmol) was added in portions to the mixture, and the mixture was stirred at 20 °C for 12 h. The mixture was poured into saturated NaHCO3 (30 mL) and extracted with DCM (30 mL × 2). The combined organic phases were 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 give tert-butyl 2-(4-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)-2-(2-isopropylphenyl)-6-oxopiperazine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, yield: 94%) as a yellow solid. 1 H NMR (400 MHz, CDCl3)δ ppm: 7.35-7.29 (m, 2H), 7.23-7.17 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H),7.06 (s, 1H), 6.59 (s, 1H), 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, 3 H), 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 = 5.6 Hz, 3H).

[0820] Step 5: tert-butyl 2-(4-((1-cyclopropyl-1H-pyrazole-4-yl)methyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0821] At 20 °C, BH3·THF (30 mL, 30 mmol, 1 M, in THF) was added dropwise to a solution of tert-butyl 2-(4-((1-cyclopropyl-1H-pyrazole-4-yl)methyl)-2-(2-isopropylphenyl)-6-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, 2.14 mmol) in THF (15 mL). The mixture was heated to 75 °C for 12 hours. The reaction was quenched with MeOH (5 mL) and concentrated under reduced pressure to give tert-butyl 2-(4-((1-cyclopropyl-1H-pyrazole-4-yl)methyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.17 g, crude) as a white solid. MS (ESI, m / e) [M+1] + 548.5.

[0822] Step 6: 2-(4-((1-cyclopropyl-1H-pyrazole-4-yl)methyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane.

[0823] A solution of tert-butyl 2-(4-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.17 g, 2.14 mmol) in HCl / EtOAc (20 mL, 4 M) was stirred at 20 °C for 4 h. The reaction solution was dried under vacuum. The residue was diluted with HCl (1 M, 10 mL) and extracted with EtOAc (10 mL × 2). The aqueous phase was adjusted to pH = 10 with aqueous Na2CO3 and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure to give 2-(4-((1-cyclopropyl-1H-pyrazol-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 (400 MHz, CDCl3)δ ppm: 7.46 (s, 1H), 7.35 (d, J= 7.6 Hz,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), 1.23 (d, J = 7.02 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H), 1.12-1.04 (m, 3H), 1.04-0.93 (m, 3H). MS (ESI, m / e) [M+1] + 448.3.

[0824] Intermediate 71-1: 2-(2-(2-isopropylphenyl)-4-((3-methoxy-1-methyl-1H-pyrazol-4-yl)methyl) Piperazine-1-yl)-7-azaspiro[3.5]nonane

[0825]

[0826] Step 1: Methyl 3-hydroxy-1H-pyrazole-4-carboxylate.

[0827] At 20 °C, N₂H₄·H₂O (8.62 g, 172.26 mmol) was added dropwise to a solution of dimethyl 2-(methoxymethylene)malonate (30 g, 172.26 mmol) in MeOH (300 mL). The mixture was heated to 70 °C for 12 hours. The reaction mixture was filtered, and the solid was washed with petroleum ether. The filter cake was dried under vacuum to give methyl 3-hydroxy-1H-pyrazole-4-carboxylate (23.5 g, crude) as a white solid. 1 H NMR (400 MHz, DMSO- d 6)δ ppm: 12.30 (s,1H), 10.47-9.71 (m, 1H), 7.93 (s, 1H), 3.67 (s, 3H).

[0828] Step 2: Methyl 3-methoxy-1-methyl-1H-pyrazole-4-carboxylate.

[0829] At 0 °C under N2 protection, NaH (7.04 g, 175.92 mmol) was added in portions to a mixture of methyl 3-hydroxy-1H-pyrazole-4-carboxylate (10 g, 70.37 mmol) and MeI (20.47 g, 144.25 mmol) in DMF (200 mL). The mixture was stirred at 20 °C for 2 h. The mixture was poured into saturated NH4Cl (300 mL) and extracted with EtOAc (500 mL × 3). The combined organic phases were 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 min, and filtered. The filter cake was washed with petroleum ether and dried under vacuum to give methyl 3-methoxy-1-methyl-1H-pyrazole-4-carboxylate (4.8 g, crude) as a yellow solid, which could be used directly for the next step without further purification. 1 H NMR (400 MHz, DMSO- d 6)δ ppm: 8.09 (s, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 3.66 (s, 3H).

[0830] ...

Claims

1. A compound or , Or a pharmaceutically acceptable salt thereof, wherein R 4 The halogen is selected from fluorine, chlorine, or bromine, and Rx is selected from... , , , , , , , , , or .

2. A compound selected from... , , , , , , , , , or , Or its pharmaceutically acceptable salt.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is .

4. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is .

5. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is .

6. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is .

7. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is .

8. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is .

9. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is .

10. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is .

11. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is .

12. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is .

13. A pharmaceutical composition comprising a compound as described in any one of claims 1-12 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

14. Use of the compound of any one of claims 1-12 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases of disordered apoptosis.

15. The application as described in claim 14, wherein the disordered apoptosis is a neurodegenerative disease, a proliferative disease, or a prethrombotic disease.

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