Bcl-2 inhibitors

Abstract

The present invention relates to Bcl-2 inhibitors. Disclosed herein is a compound of Formula (I) for inhibiting Bcl-2 and treating diseases associated with undesirable bcl-2 activity (Bcl-2 associated diseases), a method of using the compounds disclosed herein to treat dysregulated apoptotic diseases including cancer and to treat autoimmune diseases, and a pharmaceutical composition comprising the compounds.

Description

[0001] This application is a divisional application of Chinese patent application No. 201980029015.1, entitled "Bcl-2 Inhibitor", filed on April 29, 2019 (PCT application No. PCT / CN2019 / 085001).

[0002] This application claims the benefits of International Patent Application No. PCT / CN 2018 / 085217, filed on April 29, 2018, and International Patent Application No. PCT / CN 2018 / 107134, filed on September 21, 2018, the disclosures of which are hereby incorporated by reference in their entirety for all purposes. Technical Field

[0003] This document discloses a compound of formula (I) for inhibiting Bcl-2 and treating diseases associated with unwanted Bcl-2 activity (Bcl-2-related diseases), a method of treating disordered apoptosis diseases, including neurodegenerative diseases (such as Alzheimer's disease), proliferative diseases (such as cancer), autoimmune diseases, and pro-thrombotic diseases, using the compound disclosed herein, and a pharmaceutical composition comprising said compound. Background Technology

[0004] Programmed cell death, or apoptosis, occurs in multicellular organisms to dispose of damaged or unwanted cells, which is essential for normal tissue homeostasis (Br.J. Cancer 1972, 26, 239). However, defective apoptotic processes are involved in a variety of diseases. Excessive apoptosis leads to shrinkage, while insufficient apoptosis leads to uncontrolled cell proliferation, such as in cancer (Cell 2011, 144, 646). Resistance to apoptotic cell death is characteristic of cancer and contributes to chemoresistance (Nat Med. 2004, 10, 789-799). Several key pathways controlling apoptosis are often altered in cancer. Some factors, such as the Fas receptor and caspase, promote apoptosis, while some members of the B-cell lymphoma 2 (Bcl-2) protein family inhibit it. Negative regulation of apoptosis suppresses cell death signaling pathways, helping tumors evade cell death and develop drug resistance.

[0005] There are two distinct apoptosis pathways: the extrinsic pathway and the intrinsic pathway. The extrinsic pathway is activated in response to the binding of death-inducing ligands to cell surface death receptors (Nat Rev Drug Discov. 2017 16, 273-284). The B-cell lymphoma 2 (BCL-2) gene family is a group of proteins homologous to Bcl-2, encoding more than 20 proteins that regulate the intrinsic apoptosis pathway. Bcl-2 family proteins are characterized by containing at least one of four conserved Bcl-2 homologous (BH) domains (BH1, BH2, BH3, and BH4) (Nat. Rev. Cancer 2008, 8, 121; Mol. Cell 2010, 37, 299; Nat. Rev. Mol. Cell Biol. 2014, 15, 49). 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: (1) subfamilies with sequence homology in all four BH domains, such as the anti-apoptotic Bcl-2, Bcl-XL, and Bcl-w; (2) subfamilies with sequence homology in BH1, BH2, and BH4, such as the pro-apoptotic Bax and Bak; and (3) subfamilies with sequence homology only in BH3, such as the pro-apoptotic Bik, Bid, and HRK. One of the unique characteristics of the Bcl-2 family of proteins is heterodimerization between anti-apoptotic and pro-apoptotic proteins, which is thought to inhibit the biological activity of their counterparts. This heterodimerization is mediated by the insertion of the BH3 region of the pro-apoptotic protein into a hydrophobic cleft formed by the BH1, BH2, and BH3 regions of the anti-apoptotic proteins. In addition to BH1 and BH2, the BH4 domain is essential for anti-apoptotic activity. In contrast, the BH3 domain is required and is sufficient on its own for pro-apoptotic activity.

[0006] Similar to oncogene addiction (where tumor cells depend on a single dominant gene for survival), tumor cells may also depend on Bcl-2 for survival. Bcl-2 overexpression is 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 lung cancer and non-small cell lung cancer) (Cancer 2001, 92, 1122-1129; Cancer Biol. 2003; 13: 115-23; Curr. Cancer Drug Targets 2008, 8, 207-222; Cancer 2011, 3, 1527-1549). Dysregulated apoptosis pathways are also involved in the pathology of other important diseases, such as neurodegenerative diseases (upregulated apoptosis), such as Alzheimer's disease; and proliferative diseases (downregulated apoptosis), such as cancer, autoimmune diseases, and prothrombotic disorders.Numerous small-molecule BH3 mimics have been reported for Bcl-2 or Bcl-xL (Recent Patents on Anti-Cancer Drug Discovery, 2008, 3, 20-30; Bioorg. Med. Chem. Lett. 2016, 26, 2105-2114; Nature Reviews Drug Discovery 2017, 16, 273-284; WO 2002024636; WO 2005049593; WO 2006127364; WO 2006023778; WO2007040650; WO 2008030836; WO 2009152082; WO 2009036051; WO 2010065824; WO2010065865; WO 2010083441; WO 2010083442; WO 2010067067; WO 2011029842; WO2011068561; WO 2011119345; WO 2011149492; WO 2011150016; WO 2012058392; WO2012017251; WO 2012162365; WO 2012103059; WO 2013053045; WO 2013185202; WO2013096060; WO 2013096059; WO 2013096055; WO 2013096051; WO 2013096049; US2011312969; WO 2014158528; WO 2014113413; WO 2018027097; WO 2018041248; WO2018009444; CN 106749233; CN 106565706). Several Bcl-2 small molecule inhibitors have been investigated at various stages of drug development: the Bcl-2 / Bcl-xL inhibitor ABT-263 (navitola, WO 2009155386) has shown promising clinical activity in lymphocytic malignancies such as chronic lymphocytic leukemia. However, its efficacy in these environments 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).The next-generation selective BCL-2 inhibitor venetum (ABT-199 / GDC-0199) has been studied, demonstrating robust activity in these cancers without damaging 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 investigation in clinical trials. 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. However, recently, a novel Gly101Val mutation was identified in BCL2 after patients were treated with the Bcl-2 inhibitor venetum (ABT-199) for 19 to 42 months (Cancer Discov. 2019, 9, 342-353). In cell-based assays, this mutation significantly reduced the binding affinity of Bcl-2 to venetum (ABT-199) by approximately 180-fold.

[0007] Therefore, there is a need for novel small molecules that selectively inhibit the Bcl-2 protein to treat dysregulation of apoptosis, such as cancer, autoimmune diseases, and prothrombotic disorders. Unexpectedly, the inventors of this application have found that some of the compounds disclosed herein not only exhibit higher potency and selectivity but also lower CYP2C9 inhibition, suggesting potentially better efficacy and a lower risk of drug-drug interactions (DDI). Furthermore, the inventors of this application have found that the compounds disclosed herein exhibit inhibitory activity against both wild-type and Bcl-2 G101V mutants, indicating a novel potential Bcl-2 inhibitor without resistance issues. Summary of the Invention

[0008] This article discloses compounds of formula (I).

[0009]

[0010] Or its pharmaceutically acceptable salt, or its stereoisomer,

[0011] in

[0012] L 1 L 2 L 3 and L 4 Each is an independent direct key, -(CR) a R b )t -、-(CR a R b ) t-1 -(CR c =CR d )-(CR a R b ) v-1 -、-(CR a R b ) t-1 -(C≡C)-(CR a R b ) v-1 -, -O-, -S-, -S(O)-, -SO2-, -C(O)-, C(O)O-, -OC(O)-, -NR a -、-C(O)NR a -、-NR a 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- or -C (=NR) a )NR b -, where t and v are independently numbers from 1 to 7 each time they appear, and -(CR a R b ) t -、-(CR a R b ) t-1 -(CR c =CR d )-(CR a R b ) v-1 -、-(CR a R b ) t-1 -(C≡C)-(CR a R b ) v-1 - one or two CRs a R b Some of the components were not replaced or were replaced by one or more of the components selected from O, S, SO, SO2, C(O) and NR. a Partial replacement;

[0013] Ring A is a cycloalkyl, cycloalkenyl, cycloynyl, aryl, heterocyclic, or heteroaryl group, each optionally substituented by one to four R groups. 2 replace;

[0014] R 2 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR 2a -SO2R 2a -COR 2a -CO2R 2a -CONR 2a R 2b -C(=NR) 2a )NR 2b R 2c -NR 2a R 2b -NR 2a COR 2b -NR 2a CONR 2b R 2c -NR 2a CO2R 2b -NR 2a SONR 2b R 2c -NR 2a SO2NR 2b R 2c or -NR 2a SO2R 2b The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally conjugated by a halogen, hydroxyl, or -C. 1-8 Alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl substitutions;

[0015] R 2a R 2b and R 2c Each is independently hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally conjugated by a halogen, hydroxyl, or -C.1-8 Alkyl substitution;

[0016] Ring B is a cycloalkyl, cycloalkenyl, cycloynyl, aryl, heterocyclic, or heteroaryl group, each optionally substituented by one to four R groups. 1 replace;

[0017] R 1 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, 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 -NR 1a SONR 1b R 1c -NR 1a SO2NR 1b R 1c or -NR 1a SO2R 1b ; wherein -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each independently and optionally substituented by 1 to 4 R groups. 1d replace,

[0018] R 1a R 1b and R 1c Each is independently hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally conjugated by a halogen, hydroxyl, or -C. 1-8 Alkyl substitution;

[0019] R 1d Each time it appears, it is independently a halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR Ba -SO2R Ba -COR Ba -CO2R Ba -CONR Ba R Bb -C(=NR) Ba )NR Bb R Bc -NR Ba R Bb -NR Ba COR Bb -NR Ba CONR Bb R Bc -NR Ba CO2R Bb -NR Ba SONR Bb R Bc -NR Ba SO2NR Bb R Bc or -NR Ba SO2R Bb ; wherein C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each independently and optionally substituented by 1 to 4 R groups. Bd replace;

[0020] R Ba R Bb and R Bc Each is independently hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally coated with a halogen, hydroxyl group, -NH2, or -N(C) group. 1-6 Alkyl)2, -C 1-8Alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl substitutions;

[0021] R Bd Each time it appears, it is independently hydrogen, halogen, oxo group, -CN, -NO2, -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally conjugated by a halogen, hydroxyl group, or -C group. 1-8 Alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl substitutions;

[0022] R 3 It is hydrogen, halogen, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 Alkynyl, cycloalkyl, aryl, heterocyclic or heteroaryl, wherein C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 Each of the alkynyl, cycloalkyl, aryl, heterocyclic, or heteroaryl groups is optionally substituented by 1 to 4 R groups. 3a replace;

[0023] R 3a Each time it appears, it is independently selected from halogen, cyano, -NO2, -OR. 3b -SR 3b -NR 3b R 3c -COR 3b -SO2R 3b -C(=O)OR 3b -C(=O)NR 3b R 3c -C(=NR) 3b )NR 3c R 3d -N(R) 3b )C(=O)R 3c -N(R) 3b )C(=O)OR 3c -N(R) 3b )C(O)NR 3c R 3d -N(R) 3b )S(O)NR 3c R 3d -N(R) 3b )S(O)2NR 3c R 3d -NR3b SO2R 3c -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0024] R 3b R 3c and R 3d It is hydrogen and -C independently. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally conjugated by a halogen, hydroxyl, or -C. 1-8 Alkyl substitution;

[0025] R 4 It is hydrogen, halogen, cyano, -NO2, -OR 4a -SR 4a -NR 4a R 4b -COR 4a -SO2R 4a -C(=O)OR 4a -C(=O)NR 4a R 4b -C(=NR) 4a )NR 4b R 4c -N(R) 4a )C(=O)R 4b -N(R) 4a )C(=O)OR 4b -N(R) 4a )C(O)NR 4b R 4c -N(R) 4a )S(O)NR 4b R 4c -N(R) 4a )S(O)2NR 4b R 4c -NR 4a SO2R 4b -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is independently and optionally substituented by one or two R groups. 4d replace;

[0026] R 4a R 4b and R 4c It is hydrogen and -C independently. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally conjugated by a halogen, hydroxyl, or -C. 1-8 Alkyl substitution;

[0027] R 4d Each time it appears, it is independently of hydrogen, oxo group, -CN, -NO2, halogen, or -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally conjugated by a halogen, hydroxyl, or -C. 1-8 Alkyl substitution;

[0028] m is an integer from 1 to 4;

[0029] R 5 Yes -L 5 -CyC

[0030] Where L 5 It is a direct key, -(CR) a R b ) t -、-(CR a R b ) t-1 -(CR c =CR d )-(CR a R b ) v-1 -、-(CR a R b ) t-1 -(C≡C)-(CR a R b ) v-1-, -O-, -S-, -S(O)-, -SO2-, -C(O)-, C(O)O-, -OC(O)-, -NR a -、-C(O)NR a -、-NR a 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- or -C (=NR) a )NR b -, where t and v are independently numbers from 1 to 7 each time they appear, and -(CR a R b ) t -、-(CR a R b ) t-1 -(CR c =CR d )-(CR a R b ) v-1 -、-(CR a R b ) t-1 -(C≡C)-(CR a R b ) v-1 - one or two CRs a R b Some of the components were not replaced or were replaced by one or more of the components selected from O, S, SO, SO2, C(O) and NR. a Partial replacement;

[0031] CyC is a cycloalkyl, heterocyclic, aryl, or heteroaryl group, each optionally substituented by one or two R groups. 5a replace;

[0032] R 5a Each time it appears, it is independently selected from hydrogen, halogen, cyano, oxo, -NO2, -OR. 5b -SR 5b -NR 5b R 5c -COR 5b -SO2R 5b-C(=O)OR 5b -C(=O)NR 5b R 5c -C(=NR) 5b )NR 5c R 5d -N(R) 5b )C(=O)R 5c -N(R) 5b )C(=O)OR 5c -N(R) 5b )C(O)NR 5c R 5d -N(R) 5b )S(O)NR 5c R 5d -N(R) 5b )S(O)2NR 5c R 5d -NR 5b SO2R 5c -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituented by one or two R groups. 5e replace;

[0033] Where R 5b R 5c and R 5d Each is independently hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituented by one or two R groups. 5e replace;

[0034] R 5e Each time it appears, it is independently selected from hydrogen, halogen, cyano, oxo, -NO2, -OR. 5f -SR 5f -NR 5f R 5g -COR 5f -SO2R 5f -C(=O)OR 5f-C(=O)NR 5f R 5g -C(=NR) 5f )NR 5g R 5h -N(R) 5f )C(=O)R 5g -N(R) 5f )C(=O)OR 5g -N(R) 5f )C(O)NR 5g R 5h -N(R) 5f )S(O)NR 5g R 5h -N(R) 5f )S(O)2NR 5g R 5h -NR 5f SO2R 5g -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0035] R 5f R 5g and R 5h Each is independently hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0036] Or two adjacent R on the benzene ring 5 Together with the benzene ring, a benzo[a] ring is formed, wherein the ring is optionally surrounded by a halogen, an oxo group, a cyano group, -NO2, or -OR. 5i -SR 5i -NR 5i R 5j -COR 5i -SO2R 5i -C(=O)OR 5i -C(=O)NR 5i R 5j -C(=NR) 5i )NR 5j R 5k -N(R) 5i )C(=O)R 5j -N(R) 5i )C(=O)OR 5j -N(R) 5i )C(O)NR 5j R 5k -N(R)5i )S(O)NR 5j R 5k -N(R) 5i )S(O)2NR 5j R 5k -NR 5i SO2R 5k -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl substitutions;

[0037] R 5i R 5j and R 5k It is hydrogen and -C independently. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally conjugated by a halogen, hydroxyl, or -C. 1-8 Alkyl substitution;

[0038] R a R b R c and R d Each time it appears, it is independently hydrogen and -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each independently prefixed with -CN, halogen, -NO2, or -NR. e R f , Oxide group, -OR e or -SR e Replace; and

[0039] Where R e and R f Each is independently hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 alkyl-,

[0040] C 2-8 alkenyl, C 2-8 Alkyne, cycloalkyl, aryl, heterocyclic or heteroaryl.

[0041] In one implementation, R a R b R c and R d Each time it appears, it is independently either hydrogen or C. 1-6 Alkyl, preferably hydrogen or methyl.

[0042] In one implementation, L 1 Is it a direct key, or -(CR) a R b ) t -, where R a R b And t are as defined with respect to equation (I). In some embodiments, t is the number 1 or 2. In a preferred embodiment, L 1 Is it a direct key or -(CR)? a R b )-, where R a and R b Is it hydrogen or C? 1-6 Alkyl, preferably hydrogen. In the most preferred embodiment, L 1 It is a direct key.

[0043] In one implementation, L 2 It is a direct key, -(CR) a R b ) t -、-(CR a R b ) t-1 -(CR c =CR d )-(CR a R b ) v-1 -、-(CR a R b ) t-1 -(C≡C)-(CR a R b ) v-1 -、-O- or -NR a -, where R a R b R c t and v are as defined with respect to equation (I). In some embodiments, t or v is a number from 1 to 4. In a preferred embodiment, L 2 It is a direct key, -(CR) a R b ) 1-5 -、-(CR a R b ) 1-3 -(C≡C)-, -O-, or -NR a -, where Ra R b and R c Each time it appears, it is independently either hydrogen or C. 1-6 Alkyl, and -(CR a R b ) 1-5 -、-(CR a R b ) 1-3 One or both CRs in -(C≡C)- a R b Partially derived from O, S, SO, SO2, C(O) and NR a One or both parts are replaced. In even the preferred embodiment, L 2 It is a direct key, -(CR) a R b ) 1-5 -、-(CR a R b ) 1-3 -(C≡C)- or -NR a -, where R a R b and R c Each time it appears, it is independently either hydrogen or C. 1-6 Alkyl, and -(CR a R b ) 1-5 -、-(CR a R b One or both CRs in )-(C≡C)- a R b Partially from O or NR a One or two heteroatoms are substituted, where R a Is it hydrogen or C? 1-6 Alkyl groups, preferably hydrogen or CH3. In another embodiment, L 2 It is a direct bond, -CH2-, -O-, -NH-, Where *3 indicates the position attached to ring A, and **4 indicates the position attached to the benzene ring. In the most preferred embodiment, L 2 It is a direct key.

[0044] In the preferred embodiment, L 1 and L 2 All are direct keys, or L 1 It is -CH2- or -CH2-CH2- and L 2 It is a direct key.

[0045] In one implementation, L 3 It is a direct key, -(CR)a R b ) t -, -O-, -S-, -S(O)-, -SO2-, -C(O)-, C(O)O-, -OC(O)- or -NR a -, where R a R b And t are as defined with respect to equation (I). Preferably, R a and R b Independently hydrogen or C 1-6 Alkyl group, and t is 1 or 2. In a preferred embodiment, L 3 It is -O-, -CH2-, a direct bond, or -C(O)-. More preferably, L 3 Yes -O-.

[0046] In one implementation, R 3 It is optionally substituent R as defined in equation (I). 3a Substituted heteroaryl groups. Preferably, R 3 It is optionally selected from halogen, -C 1-8 Alkyl or -NR 3b R 3c One or two substituents R 3a Substituted heteroaryl groups, wherein R 3b and R 3c It is hydrogen or -C independently 1-8 alkyl.

[0047] In one implementation, R 3 It is optionally selected from halogen, -C 1-8 Alkyl or -NR 3b R 3c One or two substituents R 3a Substituted 5- to 7-membered nitrogen-containing monocyclic heteroaryl groups, wherein R 3b and R 3c It is hydrogen or -C independently 1-8 Alkyl group. Preferably, R 3 It is a tetrazolyl, triazolyl, pyrazolyl, pyrroleyl, pyridyl, or pyrimidinyl group, each optionally selected from halogens, -C 1-8 Alkyl or -NR 3b R 3c One or two substituents R 3a Replace, where R 3b and R 3c It is hydrogen or -C independently 1-8 alkyl.

[0048] In one implementation, R 3 It is an 8- to 12-membered bicyclic heteroaryl group containing one, two, or three nitrogen atoms. Preferably, R3 It is indolyl, pyrrolopyridyl, or pyrazolopyridyl, each optionally selected from halogen, -C 1-8 Alkyl or -NR 3b R 3c One or two substituents R 3a Replace, where R 3b and R 3c It is hydrogen or -C independently 1-8 Alkyl group. More preferably, R 3 It is indole-4-yl, pyrrolo[2,3-b]pyridin-5-yl, and pyrazolo[4,3-b]pyridin-1-yl.

[0049] In one implementation, R 3 It is an 11- to 14-membered tricyclic heteroaryl group containing 1, 2, 3, 4, or 5 nitrogen atoms, optionally selected from halogens, -C 1-8 Alkyl or -NR 3b R 3c One or two substituents R 3a Replace, where R 3b and R 3c It is hydrogen or -C independently 1-8 Alkyl group. Preferably, R 3 It is pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5i)-yl.

[0050] In one implementation, L 3 It is -O-, and R 3 It is pyrrolo[2,3-b]pyridin-5-yl.

[0051] In one implementation, L 4 It is -C(O)NR a SO2-, where R a It is hydrogen and C 1-6 Alkyl group, preferably hydrogen. In a preferred embodiment, L 4 It is *-C(O)NR a SO2-**, where R a It is hydrogen and C 1-6 Alkyl, preferably hydrogen, wherein * indicates a position attached to ring C and ** indicates a position attached to ring D.

[0052] In one implementation, R 4 It is -NO2, F, Cl, Br, cyano, or -SO2R 4a , where R 4a It is as defined in equation (I). In one implementation, R 4 It is -NO2, F, Cl, Br, cyano, or -SO2R 4a, where R 4a -C is optionally replaced by halogens 1-8 Alkyl group, preferably -CF3. In a preferred embodiment, R 4 It is -NO2.

[0053] In one embodiment, ring A is a cycloalkyl, cycloalkenyl, aryl, heterocyclic, or heteroaryl group, each optionally substituented by one to four R groups. 2 Replacement. Preferably, R 2 It is a carbon that is hydrogen, a halogen (such as F, Cl, or Br), or optionally substituted with a halogen (such as F, Cl, or Br). 1-6 Alkyl groups (such as methyl groups).

[0054] In a preferred embodiment, ring A is a benzene ring, which is 1,2-phenylene, 1,3-phenylene, or 1,4-phenylene.

[0055] In a preferred embodiment, ring A is a cycloalkyl ring, which is C10. 3-8 Cycloalkyl. In a more preferred embodiment, ring A is selected from cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Specifically, ring A is 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2-cyclopentylene, 1,3-cyclopentylene, 1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene, 1,2-cycloheptylene, 1,3-cycloheptylene, or 1,4-cycloheptylene.

[0056] In a preferred embodiment, ring A is C. 3-8 Cycloalkenyl. Preferably, ring A is cyclohexenyl. More preferably, ring A is cyclohex-3-enyl or cyclohex-2-enyl.

[0057] In a preferred embodiment, ring A is a heteroaryl group. Preferably, ring A is a monocyclic 5- or 6-membered heteroaryl group containing one, two, three, or four heteroatoms selected from nitrogen, oxygen, and sulfur. Specifically, ring A is pyridine, pyrazole, thiophene, or pyrimidine. Preferably, ring A is an 8- to 12-membered bicyclic heteroaryl ring. Specifically, ring A is a pyrazolopyrimidine (e.g., pyrazolo[1,5-a]pyrimidine), benzo[b]thiophene, or pyrazolopyridine (e.g., pyrazolo[1,5-a]pyridine) group.

[0058] In a preferred embodiment, ring A is a heterocyclic group. Preferably, ring A is selected from...

[0059] a) Monocyclic 4- to 9-membered heterocyclic groups containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur as ring members;

[0060] b) A 5- to 12-membered spiroheterocyclic group containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members;

[0061] c) A 5- to 12-membered fused heterocyclic group containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members; and

[0062] d) A 5- to 12-membered bridging heterocyclic group containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members.

[0063] In a more preferred embodiment, ring A is a 5- to 12-membered spiroheterocyclic group comprising one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members. Specifically, ring A is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclic group comprising one or two nitrogen or oxygen atoms as ring members. More specifically, ring A is a 4-membered / 4-membered or 4-membered / 6-membered monospiroheterocyclic group comprising one nitrogen atom as a ring member. More specifically, ring A is... (7-azaspiro[3.5]nonane-2,7-diyl), (2-azaspiro[3.5]nonane-2,7-diyl), (3-azaspiro[5.5]undecane-3,9-diyl), (2-azaspiro[3.3]heptane-2,6-diyl), (8-azaspiro[4.5]decane-2,8-diyl), (2-azaspiro[4.5]decane-2,8-diyl).

[0064] Specifically, ring A is a heterocycle, which is piperidine, pyrrolidine, and azacyclobutane; 7-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 8-azabicyclo[3.2.1]octane; tetrahydrothienopyridine (e.g., 4,5,6,7-tetrahydrothieno[2,3-c]pyridine), tetrahydropyrrolopyrazine (e.g., 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine), tetrahydropyrrolopyrazine (e.g., 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine), hexahydro-nitrogen indene (e.g., 1,2,3,5,8,8a-hexahydro-nitrogen indene), dihydropyrrolothiazole (e.g., 5,6-dihydro-4H-pyrrolo[3,4-d]thiazole), or isoindoline.

[0065] In even the preferred embodiment, ring A is selected from:

[0066] (7-azaspiro[3.5]nonane-2,7-diyl), (2-azaspiro[3.5]nonane-2,7-diyl), (8-azabicyclo[3.2.1]octane-3,8-diyl), (3-azaspiro[5.5]undecane-3,9-diyl), (2-azaspiro[3.3]heptane-2,6-diyl), (8-azaspiro[4.5]decane-2,8-diyl), (2-azaspiro[4.5]decane-2,8-diyl), *1 refers to being attached to L 1 The position, and **2 refers to the attachment to L. 2 The location.

[0067] In the most preferred embodiment, ring A is

[0068] In one embodiment, ring B is a cycloalkyl, cycloalkenyl, aryl, or heterocyclic group, each optionally substituented by one to four R groups. 1 replace;

[0069] R 1 Each time it appears, it is independently selected from halogens and -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, aryl, heteroaryl, oxo, -CN or -OR 1a ; wherein -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, aryl, or heteroaryl groups are each independently and optionally substituented by 1 to 4 R groups. 1d replace,

[0070] R 1a Is it hydrogen or -C? 1-8 Alkyl, the -C 1-8 Alkyl groups are optionally surrounded by hydrogen, hydroxyl groups, or -C. 1-8 Alkyl substitution;

[0071] R 1d Each time it appears, it is independently a halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, -CN, -OR Ba -SO2R Ba -CONR Ba R Bb -NR Ba R Bb -NR Ba COR Bb or -NR Ba SO2R Bb ; wherein -C 1-8Alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each independently and optionally substituented by 1 to 4 R groups. Bd replace;

[0072] R Ba and R Bb Each is independently hydrogen, -C 1-8 Alkyl, cycloalkyl or aryl, wherein the -C 1-8 Each of the alkyl, cycloalkyl, or aryl groups is optionally conjugated with a halogen, hydroxyl group, or -C group. 1-8 Alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl substitutions;

[0073] R Bd Each time it appears, it is independently hydrogen, halogen, -CN, or -C. 1-8 Alkyl, -C 2-8 alkynyl, cycloalkyl or aryl, wherein the -C 1-8 Alkyl, -C 2-8 Each of the alkynyl or aryl groups is optionally surrounded by a halogen, hydroxyl group, or -C group. 1-8 Alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl substitutions.

[0074] In one embodiment, the cycloalkyl group as ring B is R 1 Replaced monocyclic C 3-8 Cycloalkyl, preferably cyclopentyl or cyclohexyl. In one embodiment, R 1 Is it arbitrarily R 1d (It is a single-ring C) 3-8 Cycloalkyl-substituted aryl groups (such as phenyl).

[0075] In one embodiment, the cycloalkenyl group as ring B is surrounded by one, two, or three R groups. 1 Replaced monocyclic C 3-8 Cycloalkenyl, preferably cyclopentenyl or cyclohexenyl. In one embodiment, R 1 Is it arbitrarily R 1d (It is a halogen) substituted C 1-8 Alkyl (e.g., C) 1-6 Alkyl (preferably methyl) or aryl (such as phenyl).

[0076] In one embodiment, the heterocyclic group as ring B is a monocyclic 4- to 9-membered heterocyclic group, a 5- to 20-membered spirocyclic group, a 5- to 20-membered fused heterocyclic group, or a 5- to 20-membered bridging heterocyclic group, each optionally being substituented by 1 to 4 substituents R. 1 replace.

[0077] In one embodiment, the monocyclic heterocyclic group is a monocyclic 4- to 9-membered heterocyclic group comprising one or more heteroatoms selected from NH, O, S, SO or SO2 heteroatoms as ring members.

[0078] In one embodiment, the monocyclic heterocyclic group is a monocyclic 4- to 9-membered heterocyclic group containing one nitrogen atom as a ring member. In a preferred embodiment, the monocyclic 4- to 9-membered heterocyclic group containing one nitrogen atom as a ring member is C-linked or N-linked. In even a more preferred embodiment, the monocyclic 4- to 9-membered heterocyclic group containing one nitrogen atom as a ring member is saturated. Specifically, the saturated heterocyclic group is an N-linked saturated heterocyclic group, including but not limited to aziridin-1-yl, azircyclic butane-1-yl, pyrrolidine-1-yl, piperidin-1-yl, azircyclic heptane-1-yl, and azircyclic octane-1-yl, preferably pyrrolidine-1-yl. Specifically, the saturated heterocyclic group is a C-linked saturated heterocyclic group, including but not limited to aziridin-2-yl, aziridine-2-yl, aziridine-3-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, aziridine-2-yl, aziridine-3-yl, aziridine-4-yl, aziridine-2-yl, aziridine-3-yl, aziridine-4-yl, and aziridine-5-yl. In another, even preferred, embodiment, the monocyclic 4- to 9-membered heterocyclic group containing one nitrogen atom as a ring member is unsaturated. In yet another, even more preferred, embodiment, the monocyclic 4- to 9-membered heterocyclic group containing one nitrogen atom as a ring member contains one carbon-carbon double bond. Specifically, the monocyclic 4- to 9-membered heterocyclic group containing a nitrogen atom as a ring member is a dihydropyrrole group, such as 2,3-dihydro-1H-pyrrole and 2,5-dihydro-1H-pyrrole, or tetrahydropyridyl.

[0079] In another embodiment, the monocyclic heterocyclic group is a monocyclic 4- to 9-membered heterocyclic group comprising a nitrogen atom and another heteroatom selected from NH, O, S, SO, or SO2 as a ring member. In a preferred embodiment, the monocyclic 4- to 9-membered heterocyclic group comprising a nitrogen atom and another heteroatom selected from NH, O, S, SO, or SO2 as a ring member is C-linked or N-linked. In even more preferred embodiments, the monocyclic heterocyclic group is saturated. In still more preferred embodiments, the saturated monocyclic heterocyclic group is N-linked. In yet another, even more preferred embodiment, the saturated monocyclic heterocyclic group is C-linked.

[0080] In a preferred embodiment, ring B is replaced by 1 to 4 substituents R. 1 Substituted pyrrolidine-1-yl.

[0081] In one implementation, R 1 It is phenyl.

[0082] In a more preferred embodiment, ring B is aziridin-1-yl, aziridine-1-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, piperidin-1-yl, aziridine-1-yl, or aziridine-1-octane-1-yl, preferably pyrrolidine-1-yl, wherein the pyrrolidine-1-yl is substituted with a phenyl group at the 2-position and further optionally with one, two, or three substituents R on the pyrrolyl ring. 1 Substitution, and the phenyl group at the 2-position is optionally replaced by R as defined in formula (I). 1d replace.

[0083] In one aspect of this implementation plan, R 1 Each time it appears, it is independently selected from halogens and -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, aryl, heteroaryl, oxo, -CN or -OR 1a ; wherein -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, aryl, or heteroaryl groups are optionally substituted with 1 to 4 R groups. 1d Replace, where R 1a Is it hydrogen or C? 1-8 Alkyl, preferably methyl, and R 1d It is halogen, -C 1-8 Alkyl, or -OR Ba , where R Ba Is it hydrogen or -C? 1-8 Alkyl group. On the other hand, R 1 It is a heteroaryl group, preferably furanyl, more preferably furan-3-yl. In some embodiments, R 1 It is substituted at the 2 position of the monocyclic heterocyclic group.

[0084] In one aspect of this embodiment, when R is substituted at the 2-position of the phenyl group (including the aziridin-1-yl, azircyclobutan-1-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, piperidin-1-yl, azircycloheptane-1-yl, or azircyclooctane-1-yl, preferably pyrrolidine-1-yl) 1d It is halogen, -C independently 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, -CN, -OR Ba -SO2R Ba -CONR Ba R Bb -NO2, -NR Ba R Bb -NR BaCOR Bb or -NR Ba SO2R Bb ; wherein -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each independently and optionally substituents R as defined in formula (I). Bd Substitution, preferably by one or two substituents R as defined in formula (I). Bd Replacement. On the other hand, an R 1d It is located at the 2-position of the benzene ring in ring B.

[0085] On the one hand, as R 1d -C 1-8 The alkyl group is further optionally substituented by 1 to 4 R groups. Bd Substitution, the substituent R Bd It is halogen, phenyl, cycloalkyl (such as C 3-8 cycloalkyl (preferably cyclopropyl), optionally C 1-6 Alkyl-substituted heterocyclic groups (such as piperazinyl and piperidinyl). Specifically, R 1d It is a -C selected from methyl, ethyl, isopropyl, propyl, tert-butyl, and isobutyl. 1-8 Alkyl, optionally R Bd Substitution. On the other hand, the two methyl groups are located at the 2-position of the benzene ring B.

[0086] On the one hand, as R 1d The cycloalkyl group is further optionally substituented by 1 to 4 R groups. Bd Substitution, the substituent R Bd It is halogen, cyano, C 2-8 Alkyne (preferably ethynyl) or C substituted with halogen 1-8 Alkyl group (preferably CF3). Specifically, R 1d It is a C-type compound selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 3-8 cycloalkyl, optionally R Bd Substitution. On the other hand, a cyclopropyl group is located at the 2-position of the benzene ring at the 2-position of ring B.

[0087] On the one hand, as R 1d -C 2-8 The alkenyl group is prop-1-en-2-yl.

[0088] On the one hand, as R 1d -C 2-8 The alkynyl group is the acetylenyl group.

[0089] On the one hand, in defining -OR Ba As R1d At that time, R Ba It is hydrogen, C 1-8 Alkyl (selected from methyl, ethyl, propyl, and isopropyl), C 3-8 Cycloalkyl (preferably cyclopropyl or cyclohexyl), aryl (preferably phenyl), wherein C 1-8 Alkyl, C 3-8 The cycloalkyl and aryl groups are each independently converted by a halogen, a heterocyclic group (preferably a monocyclic 4- to 9-membered heterocyclic group, more preferably a morpholino group), a hydroxyl group, or a -C group. 1-8 Alkyl (preferably methoxy) substitution.

[0090] On the one hand, R 1d It is an aryl group of phenyl.

[0091] On the one hand, R 1d It is a heterocycle, which is a monocyclic 4- to 9-membered heterocycle group containing one or two heteroatoms selected from nitrogen, oxygen or sulfur as ring members, preferably a monocyclic 4- to 6-membered heterocycle group containing one oxygen atom as a ring member, or a monocyclic 6-membered heterocycle group containing one or two nitrogen atoms as ring members.

[0092] On the one hand, R 1d It is a heteroaryl group, preferably thienyl or furanyl.

[0093] In one embodiment, ring B is a pyrrolidine-1-yl group substituted with a naphthyl group, preferably substituted with a naphthyl group at the 2-position.

[0094] In one embodiment, ring B is a pyrrolidine-1-yl group substituted with a heteroaryl group, preferably substituted at the 2-position. In one aspect, the heteroaryl group is a 5- to 6-membered heteroaryl group comprising 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur. Preferably, the heteroaryl group is pyridyl, furanyl, thiophenyl, or pyrazolyl. In another aspect, the heteroaryl group is optionally substituted with a halogen or C... 3-8 Cycloalkyl (preferably cyclopropyl) substitution.

[0095] In one implementation, ring B is -C 1-8 Alkyl, -C 2-8 alkenyl or -C 2-8 Alkyne substitution, preferably at the 2-position with -C 1-8 Alkyl, -C 2-8 alkenyl or -C 2-8 Alkyne-substituted pyrrolidine-1-yl, wherein -C 1-8 Alkyl, -C 2-8 alkenyl or -C 2-8 Each of the alkynyl groups is either unsubstituted or substituted with a phenyl group, which is optionally substituted with a halogen or C. 3-8Cycloalkyl (preferably cyclopropyl) substitution. In a preferred aspect, ring B is a pyrrolidine-1-yl group substituted with methyl, vinyl, or ethynyl groups, each of which is optionally substituted with a phenyl group as described above.

[0096] In a preferred embodiment, ring B is optionally substituent R as defined in formula (I). 1 Substituted pyrrolidine-1-yl.

[0097] In a preferred embodiment, Selected from:

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109] In a preferred embodiment, ring B is a 2-substituted pyrrolidine-1-yl group, L1 is a direct bond, and L... 2It is a direct bond, and ring A is a 1,4-phenylene ring or a 5 to 12-membered spiroheterocyclic group containing one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members, preferably a 5 to 12-membered spiroheterocyclic group containing one or two nitrogen atoms as ring members; more preferably a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclic group containing one or two nitrogen or oxygen atoms as ring members; most preferably ring A is 7-azaspiro[3.5]nonane-2,7-diyl, 2-azaspiro[3.5]nonane-2,7-diyl, 3-azaspiro[5.5]undecane-3,9-diyl, 2-azaspiro[3.3]heptane-2,6-diyl, 8-azaspiro[4.5]decane-2,8-diyl or 2-azaspiro[4.5]decane-2,8-diyl. In a more preferred embodiment, ring B is a 2-(substituted phenyl)pyrrolidine-1-yl group, L1 is a direct bond, and L... 2 It is a direct bond, and ring A is a 1,4-phenylene ring or a 5 to 12-membered spiroheterocyclic group containing one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members; preferably, it is a 5 to 12-membered spiroheterocyclic group containing one or two nitrogen atoms as ring members; more preferably, it is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclic group containing one or two nitrogen atoms or oxygen atoms as ring members; most preferably, ring A is 7-azaspiro[3.5]nonane-2,7-diyl, 2-azaspiro[3.5]nonane-2,7-diyl, 3-azaspiro[5.5]undecane-3,9-diyl, 2-azaspiro[3.3]heptane-2,6-diyl, 8-azaspiro[4.5]decane-2,8-diyl or 2-azaspiro[4.5]decane-2,8-diyl. In even more preferred embodiments, ring B is a 2-(2-substituted phenyl)pyrrolidine-1-yl group or a 2-(3-substituted phenyl)pyrrolidine-1-yl group, L1 is a direct bond, L2 is a direct bond, and ring A is a 1,4-phenylene ring or 7-azaspiro[3.5]nonane-2,7-diyl, 2-azaspiro[3.5]nonane-2,7-diyl, 3-azaspiro[5.5]undecane-3,9-diyl, 2-azaspiro[3.3]heptane-2,6-diyl, 8-azaspiro[4.5]decane-2,8-diyl or 2-azaspiro[4.5]decane-2,8-diyl, wherein the phenyl group at the 2-position of the pyrrolidine-1-yl group is replaced by 1 to 4 substituents R as defined in formula (I). 1dSubstitution. In alternative preferred embodiments, ring B is a 2-(2-substituted phenyl)pyrrolidine-1-yl group or a 2-(3-substituted phenyl)pyrrolidine-1-yl group, L1 is a direct bond, ring A is a 1,4-cyclohexene ring or a 1,4-cyclohex-3-enyl or a 1,4-cyclohex-2-enyl or a 1,4-cyclohex-1-enyl or 7-azaspiro[3.5]nonane-2,7-diyl, 2-azaspiro[3.5]nonane-2,7-diyl, 3-azaspiro[5.5]undecane-3,9-diyl, 2-azaspiro[3.3]heptane-2,6-diyl, 8-azaspiro[4.5]decane-2,8-diyl or 2-azaspiro[4.5]decane-2,8-diyl, L 2 It is a direct bond, wherein the phenyl group at the 2-position of the pyrrolidine-1-yl group is replaced by 1 to 4 substituents R as defined in formula (I). 1d Substitution. In one implementation, a substituent R 1d The phenyl group at the 2-position of the pyrrolidone-1-yl group is substituted.

[0110] In one implementation, m is 1.

[0111] In one implementation, L 5 It is a direct key, -(CR) a R b ) t -or-NR a -, where t is a number from 1 to 7, and -(CR a R b ) t - one or two CRs a R b Some parts were not replaced or were selected from one or more of O and NR. a Partial replacement, where R a and R b It is as defined in equation (I).

[0112] In the preferred embodiment, L 5 It is a direct key, -(CR) a R b ) 1-4 -、-O-(CR a R b ) 1-3 -、-NH-(CR a R b ) 1-3 Or -NH-, where R a and R b As defined for equation (I), such that -L 5 The -CyC part refers to CyC and -(CR) respectively. a R b) 1-4 -CyC、-O-(CR a R b ) 1-3 -CyC, -NH-(CR) a R b ) 1-3 -CyC or -NH-CyC. More preferably, L 5 It is a direct bond, -(CH2) 1-4 -、-O-(CH2) 1-3 -、-NH-(CR a R b )-(CH2)2- or -NH-, where R a It is hydrogen and R b C is optionally substituted with phenyl-S-. 1-8 Alkyl groups, making -L 5 The -CyC part consists of CyC and -(CH2). 1-4 -CyC、-O-(CH2) 1-3 -CyC, -NH-(CR) a R b -(CH2)2-CyC or -NH-CyC. More preferably, L 5 It is a direct bond, -CH2-, -O-CH2-, -NH-CH2-, or -NH-, such that -L 5 The -CyC part can be CyC, -CH2-CyC, -O-CH2-CyC, -NH-CH2-CyC, or -NH-CyC.

[0113] In one embodiment, CyC is a cycloalkyl or heterocyclic group, each optionally substituent by one or two R groups. 5a replace;

[0114] R 5a Independently selected from hydrogen, halogen, cyano, oxo, -OR 5b -NR 5b R 5c -COR 5b -SO2R 5b -C 1-8 Alkyl, -C 2-8 Alkyne, cycloalkyl or heterocyclic, wherein the -C 1-8 Each of the alkyl and heterocyclic groups is optionally selected by one or two groups chosen from hydrogen, halogen, cyano, -OR 5f -C 1-8 Substituents R of alkyl, cycloalkyl or heterocyclic groups 5e replace;

[0115] Where R 5b and R5c Each is independently hydrogen, -C 1-8 Alkyl or heterocyclic group, 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 5f R 5g or -cycloalkyl;

[0116] R 5f and R 5g Each is independently hydrogen or -C 1-8 alkyl;

[0117] Or two adjacent R on the benzene ring 5 Together with the benzene ring, a benzo[a] ring is formed, wherein the ring is optionally substituted with a heteroaryl group.

[0118] In one implementation, CyC is selected from monocyclic C. 3-8 cycloalkyl or bridged cycloalkyl Cycloalkyl groups, each optionally substituent by one or two R groups. 5a Substitution. Preferably, CyC is cyclopentyl or cyclohexyl, each optionally replaced by one or two substituents R. 5a replace.

[0119] In one implementation, CyC is a heterocyclic group selected from the following:

[0120] a) Monocyclic 4- to 9-membered heterocyclic groups containing a nitrogen, oxygen, or sulfur heteroatom as a ring member;

[0121] b) Monocyclic 4- to 9-membered heterocyclic groups containing two heteroatoms selected from oxygen, sulfur, and nitrogen as ring members; and

[0122] c) 5- to 20-membered spiroheterocyclic groups containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members.

[0123] They are each arbitrarily assigned to one or two Rs. 5a replace.

[0124] In a preferred embodiment, CyC is a monocyclic 4- to 6-membered heterocyclic group containing a nitrogen, oxygen, or sulfur heteroatom as a ring member. More preferably, CyC is selected from oxetane-2-yl, tetrahydrofuranyl, tetrahydropyranyl, azirne-2-yl, pyrrolylyl, and piperidinyl; even more preferably, CyC is selected from oxetane-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, azirne-3-yl, azirne-2-yl, pyrrolyl-3-yl, piperidin-4-yl, piperidin-2-yl, and piperidin-3-yl.

[0125] In a preferred embodiment, CyC is a monocyclic 6-membered heterocyclic group comprising two heteroatoms selected from oxygen and nitrogen as ring members. More preferably, CyC is dioxyl, morpholino, morpholino, or piperazine, and even more preferably 1,3-dioxane-2-yl, 1,3-dioxane-4-yl, 1,4-dioxane-2-yl, morpholino-1-yl, morpholino-2-yl, or morpholino-3-yl.

[0126] In a preferred embodiment, CyC is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic heterocyclic group containing one or two nitrogen or oxygen atoms as ring members. More preferably, CyC is... (7-oxa-2-azaspiro[3.5]nonane-2-yl) or (2-oxaspiro[3.5]nonane-7-yl).

[0127] In the preferred embodiment, R 5a Independently selected from hydrogen, halogen, cyano, oxo, -OR 5b -NR 5b R 5c -COR 5b -SO2R 5b -C 1-8 Alkyl, -C 2-8 Alkyne group, monocyclic C 3-8 Cycloalkyl or monocyclic 4- to 9-membered heterocyclic groups comprising one or two heteroatoms selected from nitrogen, oxygen, or sulfur as ring members, wherein the -C 1-8 Each of the alkyl and monocyclic 4- to 9-membered heterocyclic groups is optionally substituented by one or two R groups. 5e Replacement. Preferably, as R 5a The cycloalkyl group is C 3-6 Cycloalkyl; more preferably cyclopropyl. Preferably, as R 5a The heterocyclic group is a 4- to 6-membered heterocyclic group containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur as ring members. More preferably, as R 5aThe heterocyclic group is oxoheterobutyl, tetrahydrofuranyl, tetrahydropyranyl, piperazineyl, or morpholinyl. Even more preferably, as R... 5a The heterocyclic group is oxetane-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, or morpholin-4-yl.

[0128] In one implementation, as R 5e The heterocyclic group is a monocyclic 4- to 9-membered heterocyclic group containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur as ring members. Preferably, as R 5e The heterocyclic group is tetrahydro-pyran-4-yl.

[0129] In one implementation, R 5a Yes -NR 5b R 5c , where R 5b It is hydrogen and R 5c It is a heterocyclic group. In a more preferred embodiment, R 5a Yes -NR 5b R 5c , where R 5b It is hydrogen, and R 5c It is tetrahydro-pyran-4-yl. In one embodiment, R 5a Yes -NR 5b R 5c , where R 5b and R 5c Each is independently hydrogen or -C substituted with cycloalkyl groups. 1-6 Alkyl groups, preferably monocyclic C 3-8 cycloalkyl-substituted -C 1-6 alkyl.

[0130] In one implementation, R 5a Yes - OR 5b or -SO2R 5b , where R 5b Is it hydrogen or C? 1-8 Alkyl group, preferably methyl group.

[0131] In one implementation, R 5a It is -COR 5b , where R 5b Is it hydrogen or optionally -NR 5f R 5g Replacement C 1-8 Alkyl, wherein R 5f and R 5g Each is independently hydrogen or C 1-8 Alkyl group, preferably methyl group.

[0132] In one implementation, two adjacent R on the benzene ring 5Together with the benzene ring, it forms an indazole group substituted with a tetrahydropyranyl group.

[0133] In the preferred embodiment, -L 5 -CyC is selected from:

[0134]

[0135]

[0136] This article also discloses compounds of formula (II).

[0137]

[0138] Or its pharmaceutically acceptable salt, or its stereoisomer,

[0139] in

[0140] Ring A is a benzene ring as a 1,4-phenylene ring; or a 5- to 12-membered spiroheterocyclic group comprising one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members, each optionally substituented by one to four R groups. 2 replace;

[0141] R 2 Each occurrence is independently selected from hydrogen, halogen, or -C optionally substituted with halogen. 1-8 alkyl;

[0142] Ring B is a monocyclic 4- to 9-membered heterocyclic group containing a nitrogen atom as a ring member, or a monocyclic 4- to 9-membered heterocyclic group containing a nitrogen atom and another heteroatom selected from NH, O, S, SO or SO2 as a ring member, wherein the ring is N-linked.

[0143] R 1 R 5 And m are defined by equation (I).

[0144] The compound of formula (II) corresponds to the compound of formula (I), wherein

[0145] L 1 and L 2 Each is an independent direct bond, and L 4 It is -C(O)NHSO2-;

[0146] L 3 It is -O-, and R 3 It is pyrrolo[2,3-b]pyridin-5-yl;

[0147] R 4 It is -NO2.

[0148] In some embodiments, ring A is 1,4-phenylene. In some embodiments, ring A is a 5- to 12-membered spiroheterocyclic group comprising one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members; preferably, ring A is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered spiroheterocyclic group comprising one or two nitrogen or oxygen as ring members; more preferably, ring A is... (7-azaspiro[3.5]nonane-2,7-diyl), (2-azaspiro[3.5]nonane-2,7-diyl), (3-azaspiro[5.5]undecane-3,9-diyl), (2-azaspiro[3.3]heptane-2,6-diyl), wherein *1 refers to the position attached to the pyrrolidinyl ring and **2 refers to the position attached to the benzene ring.

[0149] In some embodiments, ring B is aziridin-1-yl, aziridine-1-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, piperidin-1-yl, aziridine-1-yl, or aziridine-1-octane, preferably pyrrolidine-1-yl, wherein the pyrrolidine-1-yl is substituted with a phenyl group at the 2-position and further optionally with one, two, or three substituents R on the pyrrolyl ring. 1 Substitution, and the phenyl group at the 2-position (i.e., the ortho-position) is optionally replaced by R as defined in formula (I). 1d replace.

[0150] When ring B is pyrrolidine-1-yl, it is substituted with a phenyl group at the 2-position, and the phenyl group at the 2-position (e.g., ortho-position) is optionally replaced with an R group as defined in formula (I). 1d The compound is replaced by the following formula (III).

[0151]

[0152] In one embodiment of equation (III), ring A is (7-azaspiro[3.5]nonane-2,7-diyl), (2-azaspiro[3.5]nonane-2,7-diyl), (3-azaspiro[5.5]undecane-3,9-diyl), (2-azaspiro[3.3]heptane-2,6-diyl), where *1 indicates the position attached to the pyrrolidinyl ring and **2 indicates the position attached to the benzene ring, such that the compound of formula (III) can be represented by the following subformulas (III-A), (III-B), (III-C), (III-D), or (III-E).

[0153]

[0154] Where variable R 1d R 2 R 5 And m are defined by equation (I).

[0155] In some embodiments of subgenus formulas (II), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), wherein R 2 It is hydrogen.

[0156] In some embodiments of subgenus formulas (II), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R 1d This refers to the formula (I). Preferably, when R is substituted at the 2-position of the phenyl group in ring B (including the aziridin-1-yl, aziridine-1-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, piperidin-1-yl, aziridine-1-yl, or aziridine-1-octane-1-yl, preferably pyrrolidine-1-yl), 1d It is halogen, -C independently 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, -CN, -OR Ba -SO2R Ba -CONR Ba R Bb -NO2, -NR Ba R Bb -NR Ba COR Bb or -NR Ba SO2R Bb ; wherein -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each independently and optionally substituents R as defined in formula (I). Bd Substitution, preferably by one or two substituents R as defined in formula (I). Bd Replacement. On the other hand, an R 1d It is located at the 2-position of the benzene ring in ring B.

[0157] In some preferred embodiments of subgenus formulas (II), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R 1dIt is methyl, ethyl, isopropyl, propyl or methoxymethyl, or two methyl groups at the benzene ring position; or propenyl; or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or ethoxy or isopropoxy; or amino or dimethylamino.

[0158] In some preferred embodiments of subforms (III), (III-A), (III-B), (III-C), (III-D), or (III-E), the 2-(2-substituted phenyl)pyrrolidine-1-yl moiety of ring B is selected from:

[0159]

[0160]

[0161] In some preferred embodiments of subgenus (II), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), m is 1; and L 5 It is a direct key, -(CR) a R b ) t -or-NR a -, where t is a number from 1 to 7, and -(CR a R b ) t - one or two CRs a R b Some parts were not replaced or were selected from one or more of O and NR. a Partial replacement, where R a and R b It is as defined in equation (I).

[0162] In the preferred embodiment, L 5 It is a direct key, -(CR) a R b ) 1-4 -、-O-(CR a R b ) 1-3 -、-NH-(CR a R b ) 1-3 Or -NH-, where R a and R b As defined for equation (I), such that -L 5 The -CyC part refers to CyC and -(CR) respectively. a R b ) 1-4 -CyC、-O-(CR a R b ) 1-3-CyC, -NH-(CR) a R b ) 1-3 -CyC or -NH-CyC. More preferably, L5 is a direct bond, -(CH2). 1-4 -、-O-(CH2) 1-3 -、-NH-(CR a R b )-(CH2)2- or -NH-, where Ra is hydrogen and Rb is a C1-8 alkyl group optionally substituted with phenyl-S-, such that -L 5 The -CyC part consists of CyC and -(CH2). 1-4 -CyC、-O-(CH2) 1-3 -CyC, -NH-(CR) a R b )-(CH2)2-CyC or -NH-CyC, more preferably, L 5 It is a direct bond, -CH2-, -O-CH2-, -NH-CH2-, or -NH-, such that -L 5 The -CyC part can be CyC, -CH2-CyC, -O-CH2-CyC, -NH-CH2-CyC, or -NH-CyC.

[0163] In one embodiment, CyC is a cycloalkyl or heterocyclic group, each optionally substituent by one or two R groups. 5a replace;

[0164] R 5a Independently selected from hydrogen, halogen, cyano, oxo, -OR 5b -NR 5b R 5c -COR 5b -SO2R 5b -C 1-8 Alkyl, -C 2-8 Alkyne, cycloalkyl or heterocyclic, wherein the -C 1-8 Each of the alkyl and heterocyclic groups is optionally selected by one or two groups chosen from hydrogen, halogen, cyano, -OR 5f -C 1-8 Substituents R of alkyl, cycloalkyl or heterocyclic groups 5e replace;

[0165] Where R 5b and R 5c Each is independently hydrogen, -C 1-8 Alkyl or heterocyclic group, 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, -NR5f R 5g or -cycloalkyl;

[0166] R 5f and R 5g Each is independently hydrogen or -C 1-8 alkyl;

[0167] Or two adjacent R on the benzene ring 5 Together with the benzene ring, a benzo[a] ring is formed, wherein the ring is optionally substituted with a heteroaryl group.

[0168] In one implementation, CyC is selected from monocyclic C. 3-8 cycloalkyl or bridged cycloalkyl Cycloalkyl groups, each optionally substituent by one or two R groups. 5a Substitution. Preferably, CyC is cyclopentyl or cyclohexyl, each optionally replaced by one or two substituents R. 5a replace.

[0169] In one implementation, CyC is a heterocyclic group selected from the following:

[0170] a) Monocyclic 4- to 9-membered heterocyclic groups containing a nitrogen, oxygen, or sulfur heteroatom as a ring member;

[0171] b) Monocyclic 4- to 9-membered heterocyclic groups containing two heteroatoms selected from oxygen, sulfur, and nitrogen as ring members; and

[0172] c) 5- to 20-membered spiroheterocyclic groups containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members.

[0173] They are each arbitrarily assigned to one or two Rs. 5a replace.

[0174] In a preferred embodiment, CyC is a monocyclic 4- to 6-membered heterocyclic group containing a nitrogen, oxygen, or sulfur heteroatom as a ring member. More preferably, CyC is selected from oxetane-2-yl, tetrahydrofuranyl, tetrahydropyranyl, azirne-2-yl, pyrrolylyl, and piperidinyl; even more preferably, CyC is selected from oxetane-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, azirne-3-yl, azirne-2-yl, pyrrolyl-3-yl, piperidin-4-yl, piperidin-2-yl, and piperidin-3-yl.

[0175] In a preferred embodiment, CyC is a monocyclic 6-membered heterocyclic group comprising two heteroatoms selected from oxygen and nitrogen as ring members. More preferably, CyC is dioxyl, morpholino, morpholino, or piperazine, and even more preferably 1,3-dioxane-2-yl, 1,3-dioxane-4-yl, 1,4-dioxane-2-yl, morpholino-1-yl, morpholino-2-yl, or morpholino-3-yl.

[0176] In a preferred embodiment, CyC is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic heterocyclic group containing one or two nitrogen or oxygen atoms as ring members. More preferably, CyC is... (7-oxa-2-azaspiro[3.5]nonane-2-yl) or (2-oxaspiro[3.5]nonane-7-yl).

[0177] In the preferred embodiment, R 5a Independently selected from hydrogen, halogen, cyano, oxo, -OR 5b -NR 5b R 5c -COR 5b -SO2R 5b -C 1-8 Alkyl, -C 2-8 Alkyne group, monocyclic C 3-8 Cycloalkyl or monocyclic 4- to 9-membered heterocyclic groups comprising one or two heteroatoms selected from nitrogen, oxygen, or sulfur as ring members, wherein the -C 1-8 Each of the alkyl and monocyclic 4- to 9-membered heterocyclic groups is optionally substituented by one or two R groups. 5e Replacement. Preferably, as R 5a The cycloalkyl group is C 3-6 Cycloalkyl; more preferably cyclopropyl. Preferably, as R 5a The heterocyclic group is a 4- to 6-membered heterocyclic group containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur as ring members. More preferably, as R 5a The heterocyclic group is oxoheterobutyl, tetrahydrofuranyl, tetrahydropyranyl, piperazineyl, or morpholinyl. Even more preferably, as R... 5a The heterocyclic group is oxetane-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, or morpholin-4-yl.

[0178] In one implementation, as R 5e The heterocyclic group is a monocyclic 4- to 9-membered heterocyclic group containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur as ring members. Preferably, as R 5e The heterocyclic group is tetrahydro-pyran-4-yl.

[0179] In one implementation, R 5a Yes -NR 5b R 5c , where R 5b It is hydrogen and R 5c It is a heterocyclic group. In a more preferred embodiment, R 5a Yes -NR 5b R 5c , where R 5b It is hydrogen, and R 5c It is tetrahydro-pyran-4-yl. In one embodiment, R 5a Yes -NR 5b R 5c , where R 5b and R 5c Each is independently hydrogen or -C substituted with cycloalkyl groups. 1-6 Alkyl groups, preferably monocyclic C 3-8 cycloalkyl-substituted -C 1-6 alkyl.

[0180] In one implementation, R 5a Yes - OR 5b or -SO2R 5b , where R 5b Is it hydrogen or C? 1-8 Alkyl group, preferably methyl group.

[0181] In one implementation, R 5a It is -COR 5b , where R 5b Is it hydrogen or optionally -NR 5f R 5g Replacement C 1-8 Alkyl, wherein R 5f and R 5g Each is independently hydrogen or C 1-8 Alkyl group, preferably methyl group.

[0182] In one implementation, two adjacent R on the benzene ring 5 Together with the benzene ring, it forms an indazole group substituted with a tetrahydropyranyl group.

[0183] In some implementations, m is 1 and R 5 It is selected from the following -L 5 -CyC:

[0184]

[0185]

[0186] In the preferred embodiment, m is 1 and R 5 yes

[0187] In some embodiments, the carbon atom at the 2-position of the pyrrolidinium ring is in the (S)-configuration, and the carbon atom is attached to a benzene ring in subformulas (III), (III-A), (III-B), (III-C), (III-D), or (III-E).

[0188] In some embodiments, the compound of formula (I) has the characteristics of formula (IV).

[0189]

[0190] Where variable R 1 R 1d R 5 And m are defined by equation (I).

[0191] In some embodiments, the carbon atom at the 2-position of the piperazine ring is in the (S)- or (R)- configuration, and the carbon atom is attached to the benzene ring in subformula (IV).

[0192] The inventors of this application have discovered that compounds of formula (III), including subforms (III-A), (III-B), (III-C), (III-D), or (III-E) and formula (IV), are more efficient and highly selective due to the optimal combination of the spiro or phenylene moiety in the compounds disclosed herein with phenyl substitution at the nitrogen-linked heterocyclic position (particularly for the 2-(2-substituted phenyl)pyrrolidine-1-yl moiety of formula (III) and the 2-(2-substituted phenyl)piperazin-1-yl moiety of formula (IV)).

[0193] This article discloses intermediate compounds selected from the following compounds: R is C 1-12 alkyl, R is C 1-12 alkyl.

[0194] This document discloses a method for treating dysregulated apoptosis, comprising administering to a subject in need a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. In one embodiment, the dysregulated apoptosis is cancer, such as bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, T-cell or B-cell-derived lymphoma, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, and spleen cancer.

[0195] In one implementation, the disordered apoptosis is an autoimmune disease, such as systemic lupus erythematosus (SLE).

[0196] This document discloses a pharmaceutical composition comprising the compound disclosed herein, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier. Detailed Implementation

[0197] definition

[0198] The following terms have indicative meanings throughout the specification:

[0199] As used herein (including the appended claims), unless the context clearly indicates otherwise, singular forms such as “a,” “an,” and “the” include their corresponding plural indicators.

[0200] Unless the context clearly specifies otherwise, the term “or” is used to mean the terms “and / or” and is used interchangeably with them.

[0201] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups, containing 1 to 18 (e.g., 1 to 12, further, 1 to 10, even further, 1 to 8, or 1 to 6, or 1 to 4) carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C64) are also considered alkyl groups. 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-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. The alkyl group may optionally be rich in deuterium, such as -CD3, -CD2CD3, etc.

[0202] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0203] 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 C1-6 Alkyl or halogenated C 1-4 Alkyl groups, but not limited to -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0204] The term "alkenyl" refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups, containing at least one C=C double bond and 2 to 18 (e.g., 2 to 8, further such as 2 to 6) carbon atoms. Alkenyl (e.g., C...) 2-6 Examples of alkenyl groups include, but are not limited to, methine or vinyl, propenyl, propenyl-2-alkenyl, 2-methylpropenyl, butenyl, butenyl-2-alkenyl, butenyl-3-alkenyl, butenyl-1,3-dienyl, 2-methylbutenyl-1,3-dienyl, hexenyl-1-alkenyl, hexenyl-2-alkenyl, hexenyl-3-alkenyl, hexenyl-4-alkenyl, and hexenyl-1,3-dienyl.

[0205] The term "alkynyl" refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups, containing at least one C≡C triple bond and 2 to 18 (e.g., 2 to 8, further such as 2 to 6) carbon atoms. Alkynyl (e.g., C...) 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propynyl), 1-butynyl, 2-butynyl and 3-butynyl.

[0206] The term "alkyloxy" or "alkoxy" refers to an alkyl group as defined above, which is attached to a portion of the parent molecule via an oxygen atom. An example of an alkoxy group is C0. 1-6 Alkoxy or C 1-4 Alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, and hexoxy.

[0207] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused cycloalkyl, bridged cycloalkyl, or spirocycloalkyl.

[0208] For example, a cycloalkyl group may contain 3 to 12 (e.g., 3 to 10, further, 3 to 8, further, 3 to 6, 3 to 5, or 3 to 4) carbon atoms. Even further, for example, the cycloalkyl group may be selected from monocyclic groups containing 3 to 12 (e.g., 3 to 10, further, 3 to 8, 3 to 6) carbon atoms. Examples of said monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Specifically, saturated monocyclic cycloalkyl groups (e.g., C16, C26, C36, C46, ​​C56, C6 ... 3-8Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred embodiment, the cycloalkyl group is a monocyclic ring (abbreviated as C10) 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 arranged in a fused bicyclic arrangement selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or bridged bicyclic groups 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 bicyclic arrangements selected from the [5,6] and [6,6] ring systems (such as...). Those, where the wavy line indicates the attachment point. The ring can be saturated or have at least one double bond (i.e., partially unsaturated), but is not fully conjugated and is not aromatic, as aromatic is defined herein.

[0209] The term "spirocycloalkyl" refers to a cyclic structure containing a carbon atom and formed by at least two rings sharing a common atom. The term "7- to 10-membered spirocycloalkyl" refers to a cyclic structure containing 7 to 10 carbon atoms and formed by at least two rings sharing a common atom.

[0210] 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 "4- to 10-membered fused cycloalkyl" refers to a fused ring containing 4 to 10 cyclic carbon atoms and formed by two or more rings sharing two adjacent atoms.

[0211] 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, decahydronaphthalene, and benzo[3 to 8]-membered cycloalkyl, benzo[C] 4-6 Cycloalkenyl, 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, which refer to cyclic structures containing 8 to 9 ring atoms in the above examples.

[0212] The term "bridged cycloalkyl" refers to a cyclic structure consisting of two rings containing carbon atoms and sharing two non-adjacent atoms. The term "7- to 10-membered bridged cycloalkyl" refers to a cyclic structure consisting of 7 to 12 carbon atoms and sharing two non-adjacent atoms.

[0213] The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group having 3 to 10 carbon atoms, having one or more rings and at least one double bond, preferably 1 to 2 double bonds. In one embodiment, the cycloalkenyl group is cyclopentenyl or cyclohexenyl, preferably cyclohexenyl.

[0214] The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group having 5 to 10 carbon atoms, having one or more rings and having at least one triple bond.

[0215] The term "aryl" used alone or in combination with other terms refers to a group selected from the following:

[0216] a) 5- and 6-membered carbon rings, such as phenyl;

[0217] b) Bicyclic systems, such as 7- to 12-membered bicyclic systems, wherein at least one ring is a carbocyclic and aromatic, for example, naphthyl and indanyl; and

[0218] c) Tricyclic systems, such as 10- to 15-membered tricyclic systems, wherein at least one ring is a carbocyclic and aromatic, such as fluorene.

[0219] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the published text herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 cyclic carbon atoms (i.e., C64, C16, C2 ... 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.

[0220] The term "heteroaryl" refers to a group selected from the following:

[0221] a) A 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom, such as 1 to 4, or in some embodiments 1 to 3, or in some embodiments 1 to 2 heteroatoms, the heteroatoms being selected from nitrogen (N), sulfur (S), and oxygen (O), the remaining ring atoms being carbon;

[0222] b) An 8- to 12-membered bicyclic ring comprising at least one heteroatom selected from N, O, and S, for example, 1 to 4, or in some embodiments 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

[0223] c) A tricyclic ring of 11 to 14 members, comprising at least one heteroatom selected from N, O and S, for example 1 to 4, or 1 to 3 in some embodiments, or 1 or 2 heteroatoms in other embodiments, 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.

[0224] 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 is no greater than 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is no greater than 1. When a heteroaryl group contains more than one heteroatom ring member, the 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 that the heteroaryl group is linked to the core molecule by a bond from a C atom in the heteroaryl ring.

[0225] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout the disclosed text herein. In some embodiments, the monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 cyclic members, wherein 1, 2, 3, or 4 heteroatomic ring members are independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a 5- to 6-membered heteroaryl ring, which is monocyclic and has 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring, which is bicyclic and has 1 or 2 heteroatomic ring members independently selected from nitrogen, sulfur, and oxygen.

[0226] Examples of heteroaryl or monocyclic or bicyclic aromatic heterocycles include, but are not limited to (as numbered from the linking position specified 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, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetracycline, etc. Azolyl, thiophene (e.g., thiophene-2-yl, thiophene-3-yl), triazine, benzothiophene, furanyl (furyl or furanyl), benzofuranyl, benzimidazolyl, indole, isoindole, indolinyl, 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 compounds include 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), benzofurazanyl, benzothiophene, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxolinyl, naphthidyl, furan-pyridinyl, benzothiazolyl (e.g., benzo[d]thiazolyl-6-yl), indazole (e.g., 1H-indazole-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0227] "Heterocyclic group", "heterocyclic", or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclic group that contains one or more heteroatoms selected from NH, O, S, SO or SO2 as ring members and the remaining ring members are carbon, including monocyclic, fused, bridging and spirocyclic groups, i.e. monocyclic heterocyclic groups, bridging heterocyclic groups, spirocyclic groups and fused heterocyclic groups.

[0228] The term "monocyclic heterocyclic group" refers to a monocyclic group in which at least one ring member is a heteroatom selected from NH, O, S, SO, or SO2. The heterocycle can be saturated or partially saturated.

[0229] Exemplary monocyclic 4- to 9-membered heterocyclic groups include, but are not limited to (as numbered from the connection position specified 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, aziridin-1-yl, and nitrogen Propyridine-2-yl, aziridine-1-yl, aziridine-2-yl, aziridine-3-yl, aziridine-4-yl, aziridine-5-yl, cyclothioethane, aziridine-1-yl, aziridine-2-yl, aziridine-3-yl, oxetane, thiobutane, 1,2-dithiobutane, 1,3-dithiobutane, dihydropyridine, tetrahydropyridine, thiomorpholinyl, thiooxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, aziridine-heptane Alkyl-1-yl, azircycloheptane-2-yl, azircycloheptane-3-yl, azircycloheptane-4-yl, oxacycloheptyl, thiocycloheptyl, 1,4-oxathiocyclohexyl, 1,4-dioxacycloheptyl, 1,4-oxathiocycloheptyl, 1,4-oxaazacycloheptyl, 1,4-dithiocycloheptyl, 1,4-thioazacycloheptyl and 1,4-diazacycloheptyl, 1,4-dithiocyclohexyl, 1,4-azirthiocyclohexyl, oxaazacyclohexyl , diazaphenyl, thiazaphenyl, 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, pyrazolane, dithiacyclohexane, dithiacyclone, pyrazolane, imidazolinyl, pyrimidinoneyl, or 1,1-dioxo-thiomorpholinyl.

[0230] 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 NH, O, S, SO, or SO2 heteroatoms as ring members, with 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 conjugated π-electron system. Preferably, the spiroheterocyclic group is 6 to 14-membered, and more preferably 7 to 10-membered. Based on the common number of spiro atoms, spiroheterocyclic groups are classified as monospirocyclic, dispirocyclic, or polyspirocyclic, and preferably refer to monospirocyclic or dispirocyclic groups, and more preferably 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic groups. Representative examples of spirochetal 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). -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-oxa-spiro[3.5]nonyl and 5-oxa-spiro[2.4]heptyl.

[0231] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group, wherein each ring in the system shares an adjacent pair of atoms (carbon and carbon or carbon and nitrogen) with another ring, including one or more heteroatoms selected from NH, O, S, SO, or SO2 heteroatoms as ring members, and the remaining ring members are carbon. One or more rings of the fused heterocyclic group may contain one or more double bonds, but no ring has a fully conjugated 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 rings, fused heterocyclic groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably referring to 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, isoindolyl (e.g., isoindololin-2-yl), octahydro-benzo[b][1,4]dioxin, dihydrobenzofuranyl, and benzo[d][1,3]dioxacyclopentenyl.

[0232] The term "bridging heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group, wherein each pair of rings shares two discontinuous atoms, comprising one or more heteroatoms selected from NH, O, S, SO, or SO2 heteroatoms as ring members, with the remaining ring members being carbon. One or more rings of the bridging heterocyclic group may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the bridging heterocyclic group is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of rings, bridging heterocyclic groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocyclic groups, and preferably refer to bicyclic, tricyclic, or tetracyclic bridging heterocyclic groups, more preferably bicyclic or tricyclic bridging 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.

[0233] The heterocyclic ring can be fused with an aryl, heteroaryl, or cycloalkyl ring, wherein the ring structure is connected to the parent heterocyclic group.

[0234] The term "C-linked heterocyclic group" refers to a heterocyclic group that is connected to another part of the molecule through a direct bond from a carbon atom of the heterocyclic ring.

[0235] The “N-linked heterocyclic group” used refers to a heterocyclic group that is connected to another part of the molecule through a direct bond from the nitrogen atom of the heterocyclic ring.

[0236] The compounds disclosed herein 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. Where the compounds disclosed herein have two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. This is intended to include all such possible stereoisomers as substantially pure enantiomers, their racemic mixtures, and mixtures of diastereomers. This is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically mentioned, reference to one isomer applies to all possible isomers. Whenever an isomer composition is not specified, all possible isomers are included.

[0237] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% (e.g., no more than 30%, further, no more than 25%, even further, no more than 20%) (by weight) of any other one or more stereoisomers. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% (e.g., no more than 5%, such as no more than 1%) (by weight) of any other one or more stereoisomers.

[0238] When the compounds disclosed herein contain alkene double bonds, such double bonds are intended to include both E and Z geometric isomers, unless otherwise stated.

[0239] When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl group, the substituents on the cyclohexyl or cyclobutyl ring can be formed in cis and trans configurations. The cis configuration means that both substituents are located above the two substituent positions on the carbon atom, while the trans configuration means that they are located on opposite sides.

[0240] Separating the reaction products from each other and / or from the starting material may be advantageous. The desired products of each step or series of steps are separated and / or purified (hereinafter, separated) to the desired homogeneity using techniques commonly used 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 methods and apparatus; small-scale analytical; simulated moving bed (“SMB”) and preparative thin-layer or thick-layer chromatography; and 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.

[0241] "Diarrhetinic isomers" refer to stereoisomers of compounds having two or more chiral centers, but which are not mirror images of each other. Using methods well known to those skilled in the art, such as chromatography and / or stepwise crystallization, diastereomer mixtures can be separated into their individual diastereomers based on their physicochemical differences. Enantiomers can be separated by reacting an enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride) to convert the enantiomer mixture into a diastereomer mixture, separating the diastereomers, and converting (e.g., hydrolyzing) the respective diastereomers into their corresponding pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

[0242] Single stereoisomers, such as substantially pure enantiomers, can be obtained by resolving racemic mixtures using a method, such as using an optically active resolving agent to form diastereomers (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH, et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3)(1975): pp. 283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) forming ionic diastereomer salts with chiral compounds and separating them by fractional crystallization or other methods; (2) forming diastereomer compounds with chiral derivatizing agents, separating the diastereomers and converting them to pure stereoisomers; and (3) directly separating substantially pure or enriched stereoisomers under chiral conditions. See: Wainer, Irving W. ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0243] "Pharmaceutically acceptable salts" are those salts that, within reasonable medical judgment, are suitable for use in contact with the tissues of humans and lower animals without excessive 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 herein, or by reacting a free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base.

[0244] Furthermore, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt (such as a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize that non-toxic, pharmaceutically acceptable addition salts can be prepared using various synthetic methods without excessive experimentation.

[0245] As defined herein, “pharmaceutically acceptable salts” include salts of at least one compound of formula (I) and salts of stereoisomers of the compound of formula (I), such as enantiomer salts and / or diastereomer salts.

[0246] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, the terms "administration," "administering," "treating," and "treatment" mean contact between an exogenous agent, therapeutic agent, diagnostic agent, or composition and the animal, human, subject, cell, tissue, organ, or biological fluid. Cellular treatment encompasses contact between the agent and the cell, as well as contact between the agent and a fluid, wherein the fluid contacts the cell. The terms "administration" and "treatment" also mean in vitro and ex vivo treatment of, for example, cells by means of an agent, diagnostic agent, conjugated compound, or another cell. The term "subject" as used herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit), and most preferably a human.

[0247] The term "effective amount" or "therapeutic effective amount" refers to an amount of an active ingredient (such as a compound) that is sufficient to affect such treatment of a disease, disorder, or symptom when the compound is given to a subject to treat at least one clinical symptom of the disease, disorder, or symptom. "Therapeutic effective amount" can vary with the following: the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. In any given example, the appropriate amount will be clear 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 herein and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof effective in "treating" (as defined above) a subject's disease or disorder. In the case of combination therapy, "therapeutic effective amount" refers to the total amount of the combination of substances used to effectively treat the disease, disorder, or symptom.

[0248] Pharmaceutical compositions comprising the compounds disclosed herein can 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 can be administered as a single unit with a precise dose. Furthermore, the pharmaceutical composition may also contain additional active ingredients.

[0249] All formulations of the pharmaceutical compositions disclosed herein can be prepared using conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients to prepare the desired formulation. "Pharmaceutically acceptable excipients" refer to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as: diluents, media (e.g., water, various organic solvents, etc.), fillers (e.g., starch, sucrose, etc.), 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 cetyl alcohol; absorption 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, flavorings, sweeteners, and dyes.

[0250] The term “disease” refers to any illness, discomfort, ailment, symptom, or indication and is interchangeable with the terms “disorder” or “symptom”.

[0251] Throughout the specification and the following claims, unless the context otherwise requires, the term "comprising" and its variations ("comprises" and "comprising") are intended to describe the presence of the following feature but do not exclude the presence or addition of one or more other features. When used herein, the term "comprising" may be replaced by the terms "containing," "including," or sometimes "having."

[0252] Throughout the specification and subsequent claims, the term "C" is used. n-m The instruction includes a range of endpoints, where n and m are integers representing the number of carbons. Examples include C. 1-8 C 1-6 wait.

[0253] Unless otherwise expressly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Attached Figure Description

[0254] Figure 1 The eutectic structure of A4a is shown.

[0255] Figure 2 The ABT-199 analogue is shown (PDB code: 4MAN).

[0256] Figure 3 The binding postures of A4a and ABT-199 analogs (PDB code: 4MAN) with Bcl2 protein are shown.

[0257] Figure 4 The diagram shows: a. the eutectic structure of F22 and Bcl-2; b. the eutectic structure of an ABT-199 analogue and Bcl-2 (PDB code: 4MAN); c. the bonding orientation alignment between F22 and the ABT-199 analogue.

[0258] Figure 5 This illustrates: a. A sub-pocket of Bcl-2 induced by the cyclopropyl group of F22 in the crystal structure. b. A similar sub-pocket induced at the same position in the ABT-199 analogue without substituents (PDB code: 4MAN). c. Pocket surface alignment between F22 and the ABT-199 analogue.

[0259] Figure 6 a. A water bridge between F22 and Bcl-2 protein is shown. b. No such water bridge was observed between the ABT-199 analog and Bcl-2.

[0260] Figure 7 This illustrates the sulfur-π interaction between a.Met115 and the 2-cyclopropylphenyl group of F22. b. Similar interactions between Met115 and 4-chlorophenyl analogues of ABT-199

[0261] Example

[0262] The following examples are intended to be illustrative only and should not be considered as limiting in any way. Efforts have been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but some experimental errors and biases should be accounted for. Temperatures are in degrees Celsius unless otherwise stated. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or Tokyo Chemical Industries, Ltd. (TCI), and unless otherwise stated, these reagents were used without further purification.

[0263] Unless otherwise specified, the reactions listed below are carried out under positive pressure of nitrogen or argon or in anhydrous solvent using a drying tube; the reaction flasks are equipped with rubber septa for introducing substrates and reagents via syringe; and the glassware is dried and / or heat-dried.

[0264] Recorded on an Agilent instrument running at 400MHz 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 1H NMR spectra. When reporting peak multiplicity, use the following abbreviations: s (single), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad peak), dd (double doublet), dt (double triplet). When given, the coupling constant is reported in Hertz (Hz).

[0265] LC-MS spectrometer (Agilent 1260) detector: MWD (190-400nm), mass detector: 6120SQ

[0266] Mobile phase: A: Acetonitrile containing 0.1% formic acid; B: Water containing 0.1% formic acid.

[0267] Column: Poroshell 120EC-C18, 4.6×50mm, 2.7μm

[0268] Gradient method: Flow rate: 1.8 mL / min

[0269]

[0270] 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 under UV detection at 214 nm and 254 nm.

[0271] In the following embodiments, the following abbreviations are used:

[0272] AcOH or HOAc acetic acid

[0273] aq. Aqueous phase

[0274] BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)

[0275] BH3 Borane

[0276] Salt water saturated sodium chloride aqueous solution

[0277] Boc2O di-tert-butyl carbonate

[0278] BSA (Bovine Serum Albumin)

[0279] DAST diethylaminosulfuric acid

[0280] DBN 1,5-diazabicyclo[4.3.0]-non-5-ene

[0281] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0282] DCE 1,2-Dichloroethane

[0283] DCM dichloromethane

[0284] DMAP 4-Dimethylaminopyridine

[0285] CH3MgBr methyl magnesium bromide

[0286] DIPEA N,N-Diisopropylethylamine

[0287] DMF N,N-dimethylformamide

[0288] DMAC (dimethylacetamide)

[0289] DMSO (dimethyl sulfoxide)

[0290] EA (ethyl acetate)

[0291] EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0292] EDTA (ethylenediaminetetraacetic acid)

[0293] EtOH (ethanol)

[0294] h or hr hours

[0295] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide hexafluorophosphate

[0296] Hexane

[0297] 1 H NMR proton nuclear magnetic resonance

[0298] H2O2 Hydrogen peroxide

[0299] HOBt Hydroxybenzotriazole

[0300] IPA(i-PrOH) isopropanol

[0301] KOAc potassium acetate

[0302] LAH Lithium Aluminum Hydrogen

[0303] LC-MS (Liquid Chromatography-Mass Spectrometry)

[0304] LDA diisopropylaminolithium

[0305] MeOH (methanol)

[0306] MsOH Methanesulfonic Acid

[0307] min minutes

[0308] MTBE (methyl tert-butyl ether)

[0309] n-BuLi n-Butyllithium

[0310] Sodium hydride (NaH)

[0311] NaBH(OAc)3 sodium triacetoxyborohydride

[0312] NaBH3CN Sodium cyanoborohydride

[0313] NH4Cl ammonium chloride

[0314] Pd / C Palladium Carbon Powder

[0315] Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0316] Pd(PPh3)4 tetra(triphenylphosphine)palladium(0)

[0317] Pd(OAc)2 Palladium acetate

[0318] Pd(OH)2 / C Palladium hydroxide carbon powder

[0319] PE petroleum ether

[0320] pH - lg (hydrogen ion concentration)

[0321] Preparative HPLC; Preparative high-performance liquid chromatography

[0322] Preparative MPLC; Preparative medium-pressure liquid chromatography

[0323] Preparative SFC Preparative Supercritical Fluid Chromatography

[0324] Preparative TLC (Preparative Thin-Layer Chromatography)

[0325] p-TsOH p-Toluenesulfonic acid

[0326] rt or RT room temperature

[0327] sat. saturated

[0328] t-BuOK potassium tert-butoxide

[0329] TBS tert-butyldimethylsilyl

[0330] THF Tetrahydrofuran

[0331] TEA Triethylamine

[0332] TFA (trifluoroacetic acid)

[0333] TMSCF3 Trimethyl(trifluoromethyl)silane

[0334] Preparation of intermediates:

[0335] Intermediate 1-a: methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate

[0336]

[0337] A mixture of methyl 4-bromo-2-fluorobenzoate (116.5 g, 0.5 mol), 1H-pyrrolo[2,3-b]pyridine-5-ol (67 g, 0.5 mol), and K₂CO₃ (138 g, 1.0 mol) in DMF (500 mL) was heated at 95 °C for approximately 16 h. The reaction mixture was cooled to ambient temperature, filtered, and the filtrate was diluted with DCM (1 L). The resulting solution was washed with H₂O (500 mL × 2) and concentrated. The residue was recrystallized from EA (200 mL) and PE (400 mL), and the filter cake (68 g) was collected as the first batch. The filtrate was concentrated and dissolved in EA (500 mL). The solution was washed with H₂O (200 mL × 2), concentrated, and slurried under reflux with EA (25 mL) and PE (25 mL) for 1 h. After cooling to ambient temperature, the product (38 g) was filtered to obtain the second batch. The two batches of products were combined to obtain a brown solid product (106 g, 61.3%). MS (ESI, m / e) [M+1] + 346.9, 348.9.

[0338] Intermediate 1-b: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate tert-butyl ester

[0339]

[0340] A mixture of tert-butyl 4-bromo-2-fluorobenzoate (238.5 g, 867.3 mmol), 1H-pyrrolo[2,3-b]pyridine-5-ol (116.2 g, 867.3 mmol), and K₂CO₃ (239.4 g, 1734.5 mmol) in DMF (1 L) was heated at 80 °C for approximately 16 h. Another batch of K₂CO₃ (100 g, 724.6 mmol) and 1H-pyrrolo[2,3-b]pyridine-5-ol (10 g, 74.6 mmol) was added to the reaction mixture, and the mixture was stirred at 100 °C for another 4 h. The reaction mixture was cooled to ambient temperature, filtered, and the mother liquor was concentrated to remove approximately half the volume of DMF. Add DCM (200 mL) and EA (200 mL) and stir. Filter the resulting mixture, concentrate the filtrate, and slurry the residue in EA (200 mL) and PE (200 mL) at ambient temperature for 1 h. Filter and dry the precipitate to obtain a product (155 g, 46.1%) as a yellow solid. MS (ESI, m / e) [M+1] + 389.0, 391.0.

[0341] Intermediate 1-c: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzoate tert-butyl ester

[0342]

[0343] Pd(dppf)Cl2 (24.5 g, 66.8 mmol) was added to a mixture of tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate (130 g, 334.2 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane) (127 g, 501.3 mmol), and KOAc (98.3 g, 1002.3 mmol) in 1,4-dioxane (1.3 L). The mixture was stirred at 85 °C under N2 for about 4 h. The reaction mixture was cooled to ambient temperature and concentrated. The residue was slurried in DCM (1 L), filtered, and the mother liquor was concentrated and purified by silica column chromatography (EA / DCM = 1 / 1) to give the crude product. The crude product was recrystallized from EA (100 mL) / PE (100 mL) and dried to provide a product as a brown powder (114.5 g, 78.6%). MS (ESI, m / e) [M+1] + 437.2,355.1

[0344] Intermediate 1-d: methyl 2-((6-amino-5-chloropyridin-3-yl)oxy)-4-fluorobenzoate

[0345]

[0346] Step 1: Methyl 4-fluoro-2-((6-nitropyridin-3-yl)oxy)benzoate

[0347] A mixture of 5-chloro-2-nitropyridine (2.5 g, 15.75 mmol), methyl 4-fluoro-2-hydroxybenzoate (2.44 g, 14.38 mmol), and K₂CO₃ (3.96 g, 28.65 mmol) in DMSO (30 mL) was stirred at 110 °C for 1 hour. TLC showed complete consumption of the reactants. The reaction mixture was cooled to room temperature and poured into water, then extracted with EA (40 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na₂SO₄, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (elution: PE / EA = 50 / 1 to 1 / 1) to give methyl 4-fluoro-2-((6-nitropyridine-3-yl)oxy)benzoate (1.3 g). MS (ESI, m / e) [M+1] + 293.5.

[0348] Step 2: Methyl 2-((6-aminopyridin-3-yl)oxy)-4-fluorobenzoate

[0349] A mixture of methyl 4-fluoro-2-((6-nitropyridin-3-yl)oxy)benzoate (50 g, 3.42 mmol) and Pd / C (0.8 g) in EtOH (20 mL) was stirred at 25 °C for 3 h under H2 (50 Psi). TLC showed complete consumption of the reactants. The mixture was filtered and concentrated to remove the solvent. The residue was purified by preparative MPLC (elution buffer: PE / EA = 20 / 1 to 5 / 1) to give methyl 2-((6-aminopyridin-3-yl)oxy)-4-fluorobenzoate (1.3 g, 4.96 mmol, yield: 72.49%). MS (ESI, m / e) [M+1] + 263.3.

[0350] Step 3: Methyl 2-((6-amino-5-chloropyridin-3-yl)oxy)-4-fluorobenzoate

[0351] NCS (1 g, 76.28 μol) was added to a solution of methyl 2-((6-aminopyridin-3-yl)oxy)-4-fluorobenzoate (1 g, 38.14 μol) in DMF (10 mL). The mixture was stirred at 25 °C for 4 hours. TLC showed complete consumption of the reactants. The mixture was concentrated to remove the solvent. The residue was purified by preparative MPLC (elution buffer: PE / EA = 20 / 1 to 5 / 1) to give methyl 2-((6-amino-5-chloropyridin-3-yl)oxy)-4-fluorobenzoate (169 mg). 1 ¹H NMR (400MHz, CDCl₃) δppm: 7.84

[0352] -7.98(m,2H),7.77(d,J=2.6Hz,1H),7.26(d,J=2.6Hz,1H),6.77(ddd,J=8. 7,7.6,2.4Hz,1H),6.48(dd,J=10.0,2.4Hz,1H),4.88(s,2H),3.81(s,3H). MS(ESI,m / e)[M+1] + 297.2.

[0353] Intermediate 2-a: 2-(2-cyclopropylphenyl)pyrrolidine

[0354]

[0355] Step 1: tert-butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate

[0356]

[0357] A mixture of 2-(2-bromophenyl)pyrrolidine (1.13 g, 5 mmol), Boc₂O (2.16 g, 10 mmol), TEA (1.01 g, 10 mmol), and DMAP (catalytic amount) in DCM (20 mL) was stirred at room temperature for 16 hours. The mixture was then concentrated, and the residue was purified by silica gel chromatography (eluting with 100% PE to PE / EA = 5 / 1) to give a product (1.6 g, 98.1%) as a colorless oil. MS (ESI, m / e) [M+1] + 270.0, 272.0

[0358] Step 2: tert-butyl 2-(2-cyclopropylphenyl)pyrrolidine-1-carboxylate

[0359]

[0360] Under a nitrogen atmosphere, a mixture of tert-butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate (1.56 g, 4.7 mmol), cyclopropylboronic acid (1.23 g, 14.3 mmol), Pd(PPh3)4 (540 mg, 0.47 mmol), and K2CO3 (1.99 g, 14.3 mmol) in 1,4-dioxane / H2O (9:1, 20 mL) was stirred at 90 °C for 16 hours. The reaction mixture was then filtered and concentrated, and the crude product (1.4 g) was used directly in the next step without purification. MS (ESI, m / e) [M+1] + 232.1.

[0361] Step 3: 2-(2-cyclopropylphenyl)pyrrolidine

[0362]

[0363] A mixture of 1.4 g of 2-(2-cyclopropylphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester and 5 mL of TFA in 50 mL of DCM was stirred at room temperature for 16 hours. The mixture was then concentrated to give a product (1.2 g, crude product) as a yellow oil. MS (ESI, m / e) [M+1] + 188.1.

[0364] Intermediate 2-b: 2-(2-isopropylphenyl)pyrrolidine

[0365]

[0366] Step 1: 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0367]

[0368] 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester was prepared using a similar procedure to that used for 2-(2-cyclopropylphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester. 1 H NMR (400MHz, DMSO-d6) δppm:7.32-7.14(m,2H),7.14-6.99(m,2H),5.25(s,1H),4.95-4.81(m,2H),3.67-3.54(m, 1H),3.53-3.40(m,1H),2.29-2.23(m,1H),2.05(s,3H),1.92-1.73(m,2H),1.64(s,1H),1.36(s,3H),1.07(s,6H). MS(ESI,m / e)[M+1] + 232.1.

[0369] Step 2: tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate

[0370]

[0371] A mixture of tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate (983 mg, 3.41 mmol) and Pd(OH)₂ / C (100 mg) in MeOH (20 mL) was stirred overnight at room temperature under a H₂ balloon. The reaction mixture was then filtered and concentrated to give the desired product (803 mg, 81%) as a colorless oil, which was used without further purification in the next step of deprotection with TFA. 1 H NMR(400MHz, DMSO-d6)δppm:7.27(d,J=7.0Hz,1H),7.15(t,J=2.5,7.0Hz,2H),6.97(d,J=7.0Hz,1H),5.10-5.05(m,1H),3.64-3.52(m,1H),3.49-3 .43(m,1H),3.24-3.10(m,1H),2.31-2.26(m,1H),1.84-1.80(m,2H),1.5 9-1.53(m,1H),1.38(s,3H),1.28-1.16(m,6H),1.09(s,3H),1.08(s,3H).

[0372] Step 3: 2-(2-isopropylphenyl)pyrrolidine

[0373]

[0374] A solution of tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (803 mg, 2.77 mmol) in DCM (5 mL) and TFA (2 mL) was stirred at room temperature for 4 h. After removing the solvent, the resulting residue was dissolved in DCM (50 mL) and washed with aqueous NaHCO3 (30 mL x 2). The organic layer was collected, dried over anhydrous Na2SO4, filtered, and concentrated to give the desired product (522 mg) as a colorless oil. 1H NMR (400MHz, DMSO-d6) δppm: 7.52 (d, J = 6.7Hz, 1H), 7.24-7.22 (m, 1H), 7.19-7.05 (m, 2H), 4.29 (t, J = 7.6Hz, 1H), 3.30-3.23 (m, 1H),3.27-3.02(m,1H),2.91-2.82(m,1H),2.14-2.06(m,1H),1.79-1.71(m,2H),1.41-1.32(m,1H),1.19(s,3H),1.17(s,3H). MS(ESI,m / e)[M+1] + 190.1.

[0375] Intermediate 2-C: 2-(4-cyclopropylphenyl)pyrrolidine

[0376]

[0377] Step 1: tert-butyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate

[0378]

[0379] A mixture of 2-(4-bromophenyl)pyrrolidine (2.0 g, 8.85 mmol), Boc₂O (2.9 g, 13.3 mmol), Et₃N (1.8 g, 17.7 mmol), and DMAP (110 mg, 0.9 mmol / L) in 20 mL of DCM was stirred at room temperature for 16 hours. The mixture was concentrated and purified by silica gel column chromatography using EA / PE (1 / 10) as eluent to give 2.2 g (78.6%) of tert-butyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate as a yellow oil. MS (ESI) m / e [M+1] + 325.0, 327.0.

[0380] Step 2: tert-butyl 2-(4-cyclopropylphenyl)pyrrolidine-1-carboxylate

[0381]

[0382] A mixture of tert-butyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate (1.0 g, 3.07 mmol), cyclopropylboronic acid (790 mg, 9.21 mmol), Pd(PPh3)4 (358 mg, 0.31 mmol), and K2CO3 (1.27 g, 9.21 mmol) in dioxane (10 mL) was heated to 100 °C under N2 and maintained for 16 hours. The mixture was filtered and the filtrate was concentrated to give a crude product, which was further purified by silica gel column chromatography using EA / PE (1 / 10, v / v) as eluent to give 600 mg (68.1%) of tert-butyl 2-(4-cyclopropylphenyl)pyrrolidine-1-carboxylate as a yellow oil. MS (ESI) m / e [M+1-56] + 232.1.

[0383] Step 3: 2-(4-cyclopropylphenyl)pyrrolidine

[0384]

[0385] A solution of tert-butyl 2-(4-cyclopropylphenyl)pyrrolidine-1-carboxylate (1.2 g, 4.18 mmol) in TFA / DCM (2 mL / 10 mL) was stirred at room temperature for 16 hours. The mixture was concentrated to remove the solvent, and the residue was partitioned between NaHCO3 solution (10 mL) and DCM (10 mL). The organic layer was collected and dried over Na2SO4, and concentrated to give 620 mg (79.2%) of 2-(4-cyclopropylphenyl)pyrrolidine. MS (ESI, m / e) [M+1] + 188.0.

[0386] Intermediate 2-d: 2-(2-methoxyphenyl)pyrrolidine

[0387]

[0388] Cuprous bromide (158.6 mg, 1.1 mmol) and sodium methoxide (358 mg, 6.6 mmol) were added to a solution of 2-(2-bromophenyl)-pyrrolidine (500 mg, 2.2 mmol) in MeOH (50 mL). The mixture was heated to reflux and stirred overnight. After cooling to room temperature, the mixture was filtered and concentrated, and purified by silica chromatography (EA / PE = 1 / 1) to give a product (300 mg, 76.6%) as a yellow oil. MS (ESI, m / e) [M+1] + 178.1.

[0389] Intermediate 2-e: 2-(2-chloro-6-fluorophenyl)pyrrolidine

[0390]

[0391] Step 1: 3-(2-chloro-6-fluorobenzoyl)-1-vinylpyrrolidine-2-one

[0392]

[0393] A dry 100 mL three-necked round-bottom flask equipped with a mechanical stirrer, feeding funnel, heating mantle, and reflux condenser was filled with 0.6 g (15 mmol) of 60% sodium hydride and 25 mL of anhydrous toluene. The stirred suspension was heated to reflux while a mixture of 1.1 g (10 mmol) of vinylpyrrolidone-2-one and 1.9 g (10 mmol) of methyl 2-chloro-6-fluorobenzoate was slowly added. Heating was continued for 10 hours. The reaction mixture was cooled to room temperature, and the resulting thick slurry was carefully diluted with 25 mL of saturated ammonium chloride aqueous solution. The layers were separated, and the aqueous layer was extracted again with 25 mL of toluene. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 3-(2-chloro-6-fluorobenzoyl)-1-vinylpyrrolidone-2-one as the crude product. [M+1] + 268.0.

[0394] Step 2: 5-(2-chloro-6-fluorophenyl)-3,4-dihydro-2H-pyrrole

[0395]

[0396] A mixture of 3-(2-chloro-6-fluorobenzoyl)-1-vinylpyrrolidone-2-one (1 g, crude) and HCl (6 M, 10 mL) was heated to reflux for 10 h. The mixture was cooled to room temperature and alkalized to pH 10, then extracted with DCM. The organic layer was dried over anhydrous Na₂SO₄ and concentrated. The residue (300 mg, crude) was used for the next step without further purification. MS (ESI, m / e) [M+1] + 198.0

[0397] Step 3: 2-(2-chloro-6-fluorophenyl)pyrrolidine

[0398]

[0399] NaBH4 (50 mg) was added to a solution of 5-(2-chloro-6-fluorophenyl)-3,4-dihydro-2H-pyrrole (300 mg, crude) in MeOH, and the mixture was stirred at room temperature for 1 h. Excess MeOH was then removed under reduced pressure. The residue was added to water and extracted with DCM. The organic layer was concentrated to give 2-(2-chloro-6-fluorophenyl)pyrrole, which was used in the next step without further purification (100 mg, crude). MS (ESI, m / e) [M+1] +200.1.

[0400] Intermediate 2-f: 2-cyclohexylpyrrolidine

[0401]

[0402] A mixture of 2-phenylpyrrolidine (3.5 g, 23.77 mmol), PtO2 (1.08 g, 4.75 mmol), and AcOH (1.14 g, 19.02 mmol, 1.09 mL) in THF (60 mL) was degassed and purged three times with H2. The mixture was then stirred at 65 °C for 12 hours under an H2 atmosphere (50 psi). LC-MS showed that the reaction was complete and detected a main peak of the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (TFA conditions) to give a product (4 g, TFA salt) as a yellow oil. The product (1 g, TFA salt) was released by passing it through an Amberlyst A-21 ion exchange resin in MeOH (60 mL), filtered, and concentrated to obtain the final product. The product was neutralized with saturated Na2CO3 (5 mL), extracted with DCM (80 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain a yellow oily product (640 mg). 1 H NMR (400MHz, CDCl3) δppm: 4.37 (br s,1H),3.13-3.01(m,1H),2.95-2.90(m,1H),2.83-2.72(m,1H),2.00-1.59(m,8H),1.48-1.06(m,5H),1.06-0.88(m,2H).

[0403] Intermediate 2-g: 2-(2-(trifluoromethyl)phenyl)pyrrolidine

[0404]

[0405] Step 1: (4-oxo-4-(2-(trifluoromethyl)phenyl)butyl)carbamate tert-butyl ester

[0406]

[0407] At -78 °C, n-BuLi (2.5 M, 3.56 mL) was added to a solution of 1-bromo-2-(trifluoromethyl)benzene (2 g, 8.89 mmol, 1.21 mL) in THF (15 mL). The reaction was stirred at -78 °C for 15 min, and then added at -78 °C to a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.65 g, 8.89 mmol, 1.51 mL) in THF (15 mL). After the addition, the reaction mixture was heated to 15 °C and stirred at 15 °C for 1 h. TLC showed a good reaction. The mixture was quenched with saturated NH4Cl (20 mL) and extracted with EA (20 mL x 2). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel (PE:EA = 50:1 to 10:1) to give tert-butyl (4-oxo-4-(2-(trifluoromethyl)phenyl)butyl)carbamate (2 g, 6.04 mmol, yield 67.91%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm: 7.72 (d, J = 7.4Hz, 1H), 7.64-7.53 (m, 2H), 7.44 (d, J = 7.4Hz, 1H), 4.63 (br s, 1H), 3.23 (q, J = 6.4Hz, 2H), 2.90 (t, J = 7.0Hz, 2H), 1.93 (quin, J = 7.0Hz, 2H), 1.44 (s, 9H).

[0408] Step 2: 4-Amino-1-(2-(trifluoromethyl)phenyl)but-1-one

[0409]

[0410] TFA (30.80 g, 270.13 mmol, 20 mL) was added to a mixture of (4-oxo-4-(2-(trifluoromethyl)phenyl)butyl)carbamate (2.8 g, 8.45 mmol) in DCM (30 mL). The mixture was stirred at 15 °C for 1 hour. The solvent was removed to give 4-amino-1-(2-(trifluoromethyl)phenyl)but-1-one (3.5 g, 7.24 mmol, 85.67%, TFA) as a brown oil. 1 H NMR (400MHz, CDCl3) δppm: 9.14 (br s,3H),7.87-7.83(m,1H),7.80-7.73(m,2H),7.69-7.64(m,1H),4.44-4.29(m,2H),3.45(t,J=7.9Hz,2H),2.58-2.43(m,2H).

[0411] Step 3: 2-(2-(trifluoromethyl)phenyl)pyrrolidine

[0412]

[0413] NaBH3CN (697.85 mg, 11.10 mmol) was added to a mixture of 4-amino-1-(2-(trifluoromethyl)phenyl)but-1-one (3 g, 6.53 mmol, 2 TFA) in EtOH (72 mL) and AcOH (8 mL). The mixture was stirred at 15 °C for 12 hours. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (100 mL). The mixture was concentrated. The residue was dissolved in EA (100 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated to give 2-(2-(trifluoromethyl)phenyl)pyrrolidine (0.71 g, 3.16 mmol, 48.33%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm: 7.83 (d, J=7.8Hz, 1H), 7.63-7.52 (m, 2H), 7.38-7.29 (m, 1H), 4.54 (t, J=7.8Hz, 1H), 3.27-3 .25(m,1H),3.18-3.03(m,2H),2.27(td,J=4.9,7.8Hz,1H),2.07-1.97(m,1H),1.94-1.80(m,1H),1.69-1.59(m,1H). MS(ESI,m / e)[M+1] + 216.1 / 217.1.

[0414] Intermediate 2-h: 4,4-Dimethyl-2-phenylpyrrolidine

[0415]

[0416] Step 1: 2,2-Dimethyl-4-oxo-4-phenylbutyric acid

[0417]

[0418] In an ice-water bath, benzene (14.04 g, 180 mmol) was added dropwise to a solution of 3,3-dimethyldihydrofuran-2,5-dione (15.3 g, 120 mmol) and AlCl3 (31.92 g, 240 mmol) in DCM (200 mL). The mixture was slowly heated to room temperature and stirred overnight. It was poured onto ice, diluted with DCM (400 mL), concentrated hydrochloric acid (50 mL) was added, and stirred until no precipitate formed. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was slurried with MTBE and PE to give the desired product (22.52 g, 99%) as a white solid. 1 H NMR (400MHz, CDCl3) δppm: 7.95 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 3.31 (s, 2H), 1.36 (s, 6H). MS(ESI,m / e)[M+1] + 205.1.

[0419] Step 2: N-(2,4-dimethoxybenzyl)-2,2-dimethyl-4-oxo-4-phenylbutyramide

[0420]

[0421] A solution of 2,2-dimethyl-4-oxo-4-phenylbutyric acid (18.03 g, 87.5 mmol), (2,4-dimethoxyphenyl)methylamine (14.62 g, 87.5 mmol), HATU (33.25 g, 87.5 mmol), and Et3N (13.3 g, 131.25 mmol) in DCM (200 mL) was stirred overnight at room temperature. The DCM was removed. The residue was purified by a rapid silica gel column elution with EA / PE = 1 / 4 to 1 / 1 (v / v) to give the desired product (30.2 g, 97%) as a brown oil. MS (ESI, m / e) [M+1] + 356.1.

[0422] Step 3: 1-(2,4-Dimethoxybenzyl)-3,3-dimethyl-5-phenyl-1,3-dihydro-2H-pyrrole-2-one

[0423]

[0424] A solution of N-(2,4-dimethoxybenzyl)-2,2-dimethyl-4-oxo-4-phenylbutyramide (30.2 g, 85.1 mmol) in toluene (180 mL) and AcOH (10 mL) was refluxed overnight. The solution was cooled to room temperature and the solvent was removed. The residue was purified by a rapid silica gel column elution with EA / PE = 1 / 10 to 1 / 1 (v / v) to give a crude product (10 g, 30% yield) as a yellow oil. MS (ESI, m / e) [M+1] + 388.1.

[0425] Step 4: 3,3-Dimethyl-5-phenyl-1,3-dihydro-2H-pyrrole-2-one

[0426]

[0427] A solution of 1-(2,4-dimethoxybenzyl)-3,3-dimethyl-5-phenyl-1,3-dihydro-2H-pyrrolo-2-one (9 g, 26.6 mmol) in TFA (50 mL) was stirred at 95 °C for 1 h. The solution was cooled to room temperature, and the TFA was removed. The residue was purified by a rapid silica gel column elution with EA / PE = 1 / 1 to give a crude product (4.4 g, 88% yield) as a brown oil. MS (ESI, m / e) [M+1] + 188.1.

[0428] Step 5: 4,4-Dimethyl-2-phenylpyrrolidine

[0429]

[0430] A solution of 1-(2,4-dimethoxybenzyl)-3,3-dimethyl-5-phenyl-1,3-dihydro-2H-pyrrolo-2-one (2.4 g, 12.8 mmol) in THF (100 mL) and BH3-THF (64 mL, 1 mol / L) was refluxed for 2 h. The solution was cooled to room temperature and hydrochloric acid (6 M, 20 mL) was slowly added. The solution was then refluxed for 30 min. The solvent was removed, and the residue was used directly in the next step.

[0431] Intermediate 2-i: 1-Phenylopyridine-2-carboxaldehyde

[0432]

[0433] Step 1: Phenylacetic acid

[0434]

[0435] L-proline (11.5 g, 100 mmol), potassium carbonate (27.6 g, 200 mmol), copper iodide (I) (3.8 g, 20 mmol), iodobenzene (24.4 g, 120 mmol), and DMF (150 ml) were added to a sealed tube purged with nitrogen. The mixture was heated at 90 °C for 48 hours and then cooled to room temperature. Water was added and the pH was adjusted to <3 with concentrated hydrochloric acid. The aqueous phase was extracted four times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0 to 100% EtOAc / hexane gradient) and used directly in the next step. MS (ESI, m / e) [M+1] + 192.1

[0436] Step 2: (1-Phenylopyridine-2-yl)methanol

[0437]

[0438] BH3-THF (1M, 15.6mL) was added to a solution of phenylproline (1.5g, 7.8mmol) in THF (50mL). The reaction was refluxed for 1 hour. The reaction was then cooled to room temperature and quenched with MeOH (5mL). The solvent was removed, and the residue was purified by chromatography to give (1.3g) of (1-phenylpyrrolidone-2-yl)methanol as a colorless oil. MS (ESI, m / e) [M+1] + 192.1

[0439] Step 3: 1-Phenylopyridine-2-carboxaldehyde

[0440]

[0441] Dysmart reagent (1.9 g, 4.5 mmol) was added fractionally to a solution of (1-phenylpyrrolidone-2-yl)methanol (531 mg, 3 mmol) in DCM (25 mL). The mixture was stirred overnight at room temperature, then washed with saturated NaHCO3 solution, and the organic layer was concentrated and purified by chromatography to give 1-phenylpyrrolidone-2-carboxaldehyde (100 mg) as a colorless oil. MS (ESI, m / e) [M+1] + 176.1

[0442] Intermediate 2-j: 1-(4-bromophenyl)-2-methyl-2-phenylpyrrolidine

[0443]

[0444] Step 1: (4-oxo-4-phenylbutyl)carbamate tert-butyl ester

[0445]

[0446] A solution of PhBr (8 g, 50.95 mmol, 5.37 mL) in THF (150 mL) was cooled to -78 °C and n-BuLi (2.5 M, 26.50 mL) was added. The mixture was stirred at -78 °C for 15 min. Then, tert-butyl 2-oxopyrrolidine-1-carboxylate (10.38 g, 56.05 mmol, 9.52 mL) in THF (20 mL) was added at -78 °C. The mixture was stirred at -78 °C for 15 min. TLC and LC-MS showed that the reaction was complete and the main peak was the title product. H2O (100 mL) was added. The mixture was extracted with EA (200 mL). The organic layer was washed with water and brine, dried with Na2SO4, filtered, and concentrated to give tert-butyl (4-oxo-4-phenylbutyl)carboxylate (14 g, crude) as a yellow solid.

[0447] Step 2: 5-Phenyl-3,4-dihydro-2H-pyrrole

[0448]

[0449] HCl (12 M, 8.56 mL) was added to a mixture of tert-butyl (4-oxo-4-phenylbutyl)carbamate (12.3 g, 46.71 mmol) and toluene (61.5 mL). The mixture was stirred at 65 °C for 12 h. TLC showed that the reaction was complete. The reaction mixture was extracted with EA (50 mL). The aqueous layer was collected, adjusted to pH 10 with saturated NaHCO3 solution, and extracted with EA (50 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel (eluent: PE:EA = 50:1 to 10:1) to give 5-phenyl-3,4-dihydro-2H-pyrrole (3.5 g, 22.90 mmol, 49.03% yield) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δppm: 7.89-7.81 (m, 2H), 7.44-7.41 (m, 2H), 4.08 (br t, J = 7.4Hz, 2H), 2.96 (br t, J = 8.2Hz, 2H), 2.05 (dd, J = 7.4, 8.5Hz, 2H).

[0450] Step 3: 2-Methyl-2-phenylpyrrolidine

[0451]

[0452] BF3Et2O (7.82 g, 55.10 mmol, 6.80 mL) was added to a stirred solution of 5-phenyl-3,4-dihydro-2H-pyrrole (2 g, 13.77 mmol) in THF (60 mL) at -78 °C. The mixture was stirred at -78 °C for 45 min. Then MeLi (1.6 M, 34.44 mL) was added at -78 °C. The mixture was stirred at -78 °C for 2.5 h, then heated to 15 °C and stirred at 15 °C for 12 h. TLC showed that the reaction was complete. The mixture was poured into water (100 mL), adjusted to pH 12 with saturated NaOH solution, and extracted with DCM (100 mL × 2). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel (elution buffer: PE:EA = 100:1 to 20:1) to give 2-methyl-2-phenylpyrrolidine (0.9 g, 5.30 mol, 38.50% yield) as a red oil. 1 H NMR (400MHz, CDCl3) δppm:7.52-7.46(m,2H),7.36-7.29(m,2H),7.2-7.18(m,1H),3.17-3.09(m ,1H),3.04-2.96(m,1H),2.14-2.05(m,1H),1.94-1.85(m,2H),1.80-1.70(m,2H),1.45(s,3H).

[0453] Step 4: 1-(4-bromophenyl)-2-methyl-2-phenylpyrrolidine

[0454]

[0455] A solution of 1-bromo-4-iodobenzene (4.21 g, 14.88 mmol), 2-methyl-2-phenylpyrrolidine (0.6 g, 3.72 mmol), Pd2(dba)3 (340.75 mg, 372.11 μmol), BINAP (463.40 mg, 744.22 μmol), and t-BuOK (1.25 g, 11.16 mmol) in toluene (40 mL) was stirred at 90 °C for 12 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC. After removing the mobile phase, the residue was dissolved in EA (20 mL), adjusted to pH 8 with saturated NaHCO3 solution, separated, and concentrated to give 1-(4-bromophenyl)-2-methyl-2-phenylpyrrolidine (0.43 g, 33.31% yield) as a brown oil. 1H NMR (400MHz, CDCl3) δppm:7.34-7.29(m,2H),7.27-7.22(m,3H),7.14-7.12(m,2H),6. 31-6.26(m,2H),3.64-3.55(m,2H),2.15-2.10(m,2H),2.01-1.96(m,2H),1.77(s,3H). MS(ESI,m / e)[M+1] + 316.1, 318.1.

[0456] Intermediate 2-k: 1-(azacyclobutane-3-ylmethyl)-2-(2-cyclopropylphenyl)pyrrolidine

[0457]

[0458] Step 1: 3-((2-(2-cyclopropylphenyl)pyrrolidone-1-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0459] 2-(2-cyclopropylphenyl)pyrrolidine (0.195 g, 647.19 μmol) was dissolved in DCE (6 mL), and tert-butyl 3-formylazetane-1-carboxylate (359.62 mg, 1.94 mmol) and NaBH(OAc)3 (274.33 mg, 1.29 mmol) were added. After stirring at 15 °C for 4 h, HOAc (116.59 mg, 1.94 mmol) was added. Stirring was continued at 15 °C for 24 h. The reaction mixture was then poured into a saturated aqueous solution of NaHCO3 (4 mL). The mixture was extracted three times with CH2Cl2 (3 × 5 mL). The combined organic phase extracts were washed with brine (5 mL), dried over Na2SO4, and concentrated. The residues were purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 5 / 1). 0.18 g of tert-butyl 3-((2-(2-cyclopropylphenyl)pyrrolidone-1-yl)methyl)azacyclobutane-1-carboxylate was obtained as a yellow liquid.

[0460] Step 2: 1-(azacyclobutane-3-ylmethyl)-2-(2-cyclopropylphenyl)pyrrolidine

[0461] TFA (2.24 g, 19.64 mmol) was added to a solution of tert-butyl 3-((2-(2-cyclopropylphenyl)pyrrolidone-1-yl)methyl)azacyclobutane-1-carboxylate (0.7 g, 1.96 mol) in CH2Cl2 (4.8 mL) at 0 °C under N2. The mixture was stirred at 15 °C for 2 hours. The solution was concentrated under reduced pressure. The residue was adjusted to pH 14 with 1 N NaOH solution and extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were dried and concentrated under reduced pressure. 475 mg of 1-(azacyclobutane-3-ylmethyl)-2-(2-cyclopropylphenyl)pyrrolidine was given as a yellow liquid.

[0462] Intermediate 2-l: 1-Methyl-4-(2-(pyrrolidone-2-yl)phenyl)-1,2,3,6-tetrahydropyridine

[0463]

[0464] Step 1: 1-(2-(2-bromophenyl)pyrrolidone-1-yl)-2,2,2-trifluoroethyl-1-one

[0465] Under an inert N2 atmosphere, TEA (3.57 g, 35.36 mmol) was added to a solution of 2-(2-bromophenyl)pyrrolidine (4 g, 17.68 mmol) in DCM (100 mL) at 0 °C, followed by dropwise addition of trifluoroacetic anhydride (4.46 g, 21.22 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was then poured into 100 mL of water, extracted with DCM (100 mL), washed with 50 mL of brine, and dried over anhydrous Na2SO4. The solution was filtered and concentrated to give crude 1-(2-(2-bromophenyl)pyrrolidine-1-yl)-2,2,2-trifluoroethyl-1-one (5.0 g) as a brown oil, which was used in the next step without further purification.

[0466] Step 2: 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0467] To a solution of 1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethyl-1-one (5 g, 15.5 mmol) in toluene (10 mL), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (7.2 g, 23.25 mmol), Pd(OAc)2 (350 mg, 1.55 mmol), tricyclohexylphosphine (870 mg, 3.1 mmol), and K3PO4 (11.5 g, 54.25 mmol) were added. The suspension was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was further purified by silica gel column chromatography (elution: petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give 6.1 g of tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid, which was a yellow oil.

[0468] Step 3: 2,2,2-trifluoro-1-(2-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidine-1-yl)ethyl-1-one

[0469] At 0 °C, TFA (20 mL) was added to a solution of tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (6.1 g, 14.5 mmol) in DCM (100 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 8-9 using an aqueous solution of Na2CO3, and then extracted with DCM. The organic layer was dried, filtered, and the filtrate was concentrated under reduced pressure to give 2,2,2-trifluoro-1-(2-(2-(1,2,3,6-tetrahydropyridine-4-yl)phenyl)pyrrolidine-1-yl)ethyl-1-one (3.8 g) as a brown oil, which was used in the next step without further purification.

[0470] Step 4: 2,2,2-trifluoro-1-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidine-1-yl)ethyl-1-one

[0471] To a solution of 2,2,2-trifluoro-1-(2-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidone-1-yl)ethyl-1-one (1 g, 3.08 mmol) in MeOH (50 mL), HCHO (37%, 1.5 g, 18.49 mmol) and NaBH3CN (774 mg, 12.32 mmol) were added. The suspension was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then diluted with water (15 mL) and EA (30 mL) with stirring. The organic layer was separated and washed with brine, and then dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution buffer: DCM / MeOH = 20 / 1) to obtain 0.8 g of 2,2,2-trifluoro-1-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidine-1-yl)ethyl-1-one, which was a brown oil.

[0472] Step 5: 1-Methyl-4-(2-(pyrrolidone-2-yl)phenyl)-1,2,3,6-tetrahydropyridine

[0473] LiOH·H2O (0.2 g, 4.73 mmol) was added to a solution of 2,2,2-trifluoro-1-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidine-1-yl)ethyl-1-one (0.8 g, 2.36 mmol) in MeOH (50 mL) and H2O (50 mL). After addition, the mixture was heated to 60 °C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then diluted with water (15 mL) and EA (30 mL) with stirring. The organic layer was separated and washed with brine, and then dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: DCM / MeOH = 50 / 1) to give 1-methyl-4-(2-(pyrrolidine-2-yl)phenyl)-1,2,3,6-tetrahydropyridine (500 mg) as a brown oil. 1HNMR (400MHz, CDCl3) δppm: 7.51 (dd, J=0.98, 7.83Hz, 1H), 7.24-7.29 (m, 1H), 7.18 (dt, J=1.34, 7.40Hz,1H),7.08(dd,J=1.22,7.58Hz,1H),5.55(td,J=1.60,3.27Hz,1H),4.29(t,J=7.83Hz,1H ),3.23(ddd,J=5.14,7.43,9.93Hz,1H),3.10(q,J=2.81Hz,2H),2.94-3.04(m,1H),2.63-2.70(m ,2H),2.43(s,3H),2.12(dtd,J=4.89,7.81,12.50Hz,1H),1.80-1.90(m,1H),1.59-1.70(m,1H). MS(ESI,m / e)[M+1] + 243.1.

[0474] Intermediate 2-m: 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine

[0475]

[0476] Step 1: tert-butyl 2-(2-bromophenyl)-4-fluoropyrrolidine-1-carboxylate

[0477] DAST (1.77 g, 10.96 mmol) was added dropwise to a solution of 2-(2-bromophenyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2.5 g, 7.31 mmol) in DCM (30 mL). The solution was then stirred at 20 °C for 12 hours. The reaction mixture was quenched with ice water (30 mL). The organic layer was separated, washed with saturated NaHCO3 solution (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 20 / 1 to 10 / 1) to give 2-(2-bromophenyl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (1.6 g) as a yellow oil.

[0478] Step 2: tert-butyl 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine-1-carboxylate

[0479] To a solution of tert-butyl 2-(2-bromophenyl)-4-fluoropyrrolidine-1-carboxylate (1.5 g, 4.36 mmol) and cyclopropylboronic acid (1.1 g, 13.1 mmol) in toluene (20 mL), Pd(OAc)₂ (98 mg, 0.436 mmol), tricyclohexylphosphine (245 mg, 0.872 mmol), K₃PO₄ (3.2 g, 15.3 mmol), and H₂O (1 mL) were added. The suspension was heated at 100 °C and stirred under a nitrogen atmosphere for 12 hours. Water (20 mL) and EtOAc (20 mL) were added to the reaction mixture. The organic layer was separated, washed with brine (20 mL), dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography (elution buffer: PE / EA = 20 / 1) to obtain tert-butyl 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine-1-carboxylate (1.1 g), which was a brown oil.

[0480] Step 3: 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine

[0481] A solution of tert-butyl 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine-1-carboxylate (1.1 g, 3.6 mmol) in HCl solution (20 mL, 4 M in EA) was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was diluted with saturated Na₂CO₃ solution (20 mL) and EA (20 mL). The organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 4 / 1 to 1 / 1) to give 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine (620 mg) as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm: 7.55 (dd, J=7.5, 1.4Hz, 1H), 7.15-7.28 (m, 2H), 7.01-7.09 (m, 1H), 5.22-5.48 (m, 1H), 4.71-5.10 (m,1H),3.31-3.61(m,1H),2.91-3.11(m,1H),2.52-2.75(m,1H),1.70-2.14(m,3H),0.89-1.06(m,2H),0.60-0.82(m,2H). MS(ESI,m / e)[M+1] + 206.1.

[0482] Intermediate 2-n: 2-chloro-N,N-dimethyl-6-(pyrrolidone-2-yl)aniline

[0483]

[0484] Step 1: (4-(3-chloro-2-(dimethylamino)phenyl)-4-oxobutyl)carbamate tert-butyl ester

[0485] At -70 °C, n-BuLi (6 mL, 2.5 M in hexane) was added to a solution of 2-bromo-6-chloro-N,N-dimethylaniline (3.5 g, 14.92 mmol) and tert-butyl 2-oxopyrrolidine-1-carboxylate (2.76 g, 14.92 mmol) in THF (50 mL), and the mixture was stirred for 2 hours. An aqueous solution of NH4Cl (50 mL) was added to the reaction mixture, and the mixture was extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution: PE / EA = 5 / 1) to give tert-butyl (4-(3-chloro-2-(dimethylamino)phenyl)-4-oxobutyl)carboxylate (1.8 g) as a yellow oil.

[0486] Step 2: 4-Amino-1-(3-chloro-2-(dimethylamino)phenyl)but-1-one

[0487] TFA (1 mL) was added to a solution of tert-butyl (4-(3-chloro-2-(dimethylamino)phenyl)-4-oxobutyl)carbamate (1.7 g, 4.99 mmol) in DCM (10 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give crude 4-amino-1-(3-chloro-2-(dimethylamino)phenyl)but-1-one (1.2 g, crude product) as a yellow oil.

[0488] Step 3: 2-Chloro-N,N-dimethyl-6-(pyrrolidone-2-yl)aniline

[0489] To a solution of 4-amino-1-(3-chloro-2-(dimethylamino)phenyl)but-1-one (1.2 g, 4.98 mmol) in EtOH (20 mL), NaBH3CN (939.77 mg, 14.95 mmol) and HOAc (2 mL) were added, and the mixture was stirred at room temperature for 36 hours. The reaction mixture was quenched with water (80 mL) and extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (HCl). The pH of the solution of the target peak was adjusted to 10 and extracted with DCM (30 mL × 3). The organic phase was dried over Na2SO4 and concentrated to give 2-chloro-N,N-dimethyl-6-(pyrrolidone-2-yl)aniline (297 mg) as a colorless oil. 1H NMR (400MHz, CDCl3) δppm: 7.40 (dd, J=1.3, 7.7Hz, 1H), 7.19 (dd, J=1.5, 7.9Hz, 1H), 7.12-7.05 (m, 1H), 4.56 (t, J=7.9Hz, 1H), 3.19 (d dd,J=5.4,7.4,9.9Hz,1H),3.09-2.99(m,1H),2.85(s,6H),2.24(dtd,J=5.0,7.7,12.6Hz,1H),1.95-1.80(m,2H),1.58-1.45(m,1H). MS(ESI,m / e)[M+1] + 225.2.

[0490] Intermediate 2-O: 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-2-(trifluoromethyl)pyrrolidine

[0491]

[0492] Step 1: N-(4-bromophenyl)-1-(2-cyclopropylphenyl)-2,2,2-trifluoroethyl-1-imine

[0493] A solution of N-(4-bromophenyl)-1,1,1-triphenyl-15-phosphanimine (1.8 g, 4.16 mmol) and 1-(2-cyclopropylphenyl)-2,2,2-trifluoroethyl-1-one (891.83 mg, 4.16 mmol) in toluene (20 mL) was stirred at 110 °C for 12 hours. The reaction mixture was cooled and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (elution: PE / EA = 50 / 1 to 10 / 1) to give N-(4-bromophenyl)-1-(2-cyclopropylphenyl)-2,2,2-trifluoroethyl-1-imine (1.1 g, 2.99 mmol) as a yellow oil.

[0494] Step 2: 4-Bromo-N-(2-(2-cyclopropylphenyl)-1,1,1-trifluoropent-4-en-2-yl)aniline

[0495] At -20°C, allyl magnesium bromide (1M, 14.94mL) was added to a solution of N-(4-bromophenyl)-1-(2-cyclopropylphenyl)-2,2,2-trifluoroethyl-1-imine (1.1g, 2.99mmol) in DCM (10mL), and the mixture was stirred for 2 hours. The reaction mixture was then quenched with an aqueous solution of HN4Cl (10mL) and extracted with EA (10mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution: PE) to give 1.20g of 4-bromo-N-(2-(2-cyclopropylphenyl)-1,1,1-trifluoropent-4-en-2-yl)aniline as a white solid.

[0496] Step 3: 4-((4-bromophenyl)amino)-4-(2-cyclopropylphenyl)-5,5,5-trifluoropent-1-ol

[0497] At 0 °C, BH3·THF (1 M, 14.62 mL) was added to a solution of 4-bromo-N-(2-(2-cyclopropylphenyl)-1,1,1-trifluoropent-4-en-2-yl)aniline (1.20 g, 2.92 mmol) in THF (10 mL), and the mixture was stirred for 1 hour. Then, NaOH (2.5 M, 2.92 mL) and H2O2 (1.49 g, 43.87 mmol) were added to the reaction mixture at 0 °C. After the addition, the mixture was stirred further at room temperature for 1.5 hours. The reaction mixture was then quenched with an aqueous solution of HN4Cl (10 mL) and extracted with EA (10 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution buffer: PE / EA = 50 / 1 to 5 / 1) to give 0.6 g of 4-((4-bromophenyl)amino)-4-(2-cyclopropylphenyl)-5,5,5-trifluoropent-1-ol, which was a yellow oil.

[0498] Step 4: 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-2-(trifluoromethyl)pyrrolidine

[0499] TEA (469.17 mg, 4.64 mmol) and MsCl (265.56 mg, 2.32 mmol) were added to a solution of 4-((4-bromophenyl)amino)-4-(2-cyclopropylphenyl)-5,5,5-trifluoropentane-1-ol (0.6 g, 1.55 mmol) in dioxane (10 mL), and the mixture was stirred at room temperature for 1.5 h. The mixture was then heated to 80 °C and stirred for 1 h. The reaction mixture was then quenched with an aqueous solution of NH4Cl (10 mL) and extracted with DCM (10 mL × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 10 / 1) to give 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-2-(trifluoromethyl)pyrrolidine (306 mg) as a white solid. 1 H NMR (400MHz, CDCl3) δppm: 7.63(td,J=2.6,6.6Hz,1H),7.26-7.22(m,2H),7.06(d,J=9.3Hz,2H),6.88-6.83(m,1H),6.32(d,J=9.0Hz,2H ),3.73-3.56(m,2H),2.94-2.68(m,2H),2.44-2.31(m,1H),2.27-2.16(m,1H),1.63-1.58(m,1H),0.96-0.85(m,1H),0.60-0.47(m,3H). MS(ESI,m / e)[M+1] + 410.0.

[0500] Intermediate 2-p: 2-(2-cyclopropylbenzyl)pyrrolidine

[0501]

[0502] Step 1: 2-((2-cyclopropylphenyl)(hydroxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0503] At -70°C under N2, n-BuLi (9.84 mL, 2.5 M) was added to a solution of 1-bromo-2-cyclopropylbenzene (4.50 g, 22.84 mmol) in THF (50 mL), and the mixture was stirred for 10 min. Then, tert-butyl 2-formylpyrrolidine-1-carboxylate (3.5 g, 17.57 mmol) was added to the mixture, and the mixture was stirred for another 2 h. The mixture was quenched with saturated NH4Cl solution (30 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 200 / 1 to 5 / 1) to give tert-butyl 2-((2-cyclopropylphenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (3.40 g, 10.72 mmol) as a yellow oil.

[0504] Step 2: 2-(((1H-imidazol-1-thiocarbonyl)oxo)(2-cyclopropylphenyl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0505] A solution of tert-butyl 2-(((2-cyclopropylphenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (3.40 g, 10.72 mmol), di(1H-imidazol-1-yl)methanethione (5.73 g, 32.16 mol), and DMAP (1.32 g, 1072 mmol) in DCM (30 mL) was stirred at room temperature for 24 hours. The mixture was poured into hydrochloric acid (30 mL, 1 M) and extracted with DCM (50 mL × 3). The organic phase was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 200 / 1 to 5 / 1) to give tert-butyl 2-(((1H-imidazol-1-thiocarbonyl)oxo)(2-cyclopropylphenyl)methyl)pyrrolidine-1-carboxylate (3.0 g, 7.02 mmol) as a yellow oil.

[0506] Step 3: 2-(2-cyclopropylbenzyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0507] Tributyltin hydride (2.55 g, 8.778 mmol) and a catalytic amount of AIBN (192.06 g, 1.1704 mmol) were added to a solution of 2-(((1H-imidazol-1-thiocarbonyl)oxo)(2-cyclopropylphenyl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.5 g, 5.852 mmol) in toluene (10 mL). The mixture was stirred at 100 °C for 2 h. The mixture was washed with saturated KF aqueous solution (50 mL) and extracted with EA (50 mL × 3). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (NaHCO3) to give 2-(2-cyclopropylbenzyl)pyrrolidine-1-carboxylic acid tert-butyl ester (650 mg) as a yellow oil.

[0508] Step 4: 2-(2-Cyclopropylbenzyl)pyrrolidine

[0509] 2-(2-cyclopropylbenzyl)pyrrolidine-1-carboxylic acid tert-butyl ester (600.00 mg, 1.992 mmol) was added to a solution of MTBE / HCl (10 mL, 4 M). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the pH was adjusted to 10 with saturated Na₂CO₃ solution, then stirred for 15 min and extracted with EA (30 mL × 3). The organic phase was dried over Na₂SO₄, filtered, and concentrated to give 2-(2-cyclopropylbenzyl)pyrrolidine (302.00 mg) as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm:7.22-7.18(m,1H),7.15-7.10(m,2H),6.98-6.92(m,1H),3.43-3.32(m,1H),3.13- 2.80(m,4H),2.05-1.96(m,1H),1.93-1.66(m,6H),1.52-1.40(m,1H),1.01-0.90(m,2H),0.74-0.62(m,2H). MS(ESI,m / e)[M+1] + 202.2.

[0510] Intermediate 2-q: 2-(2-(azacyclobutan-1-yl)phenyl)-1-(4-bromophenyl)pyrrolidine

[0511]

[0512] Step 1: 2-(azacyclobutane-1-yl)benzaldehyde

[0513] K₂CO₃ (33.4 g, 241.17 mmol) was added to a solution of 2-fluorobenzaldehyde (10 g, 80.6 mmol) and azacyclobutane (9.04 g, 96.7 mmol) in DMSO (50 mL), and the mixture was stirred at 80 °C for 24 hours. The mixture was poured into water (300 mL) and extracted with EA (100 mL × 3). The combined organic phases were washed with brine (400 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 100 / 1 to 20 / 1) to give 2-(azacyclobutane-1-yl)benzaldehyde (9 g, crude) as a yellow oil.

[0514] Step 2: 1-(2-(azacyclobutane-1-yl)phenyl)-N-(4-bromophenyl)methylimine

[0515] Add 4-methylbenzenesulfonic acid (854 mg, 4.96 mmol) to a mixture of 2-(azacyclobutan-1-yl)benzaldehyde (4 g, 24.81 mmol) and 4-bromoaniline (4.27 g, 24.81 mmol) in toluene (40 mL). Molecular sieve (4 g). The mixture was stirred at 140 °C for 6 hours and then concentrated under vacuum. Crude 1-(2-(azacyclobutane-1-yl)phenyl)-N-(4-bromophenyl)methylimine (9 g) as a yellow solid was obtained and used in the next step without further purification.

[0516] Step 3: N-(1-(2-(azacyclobutan-1-yl)phenyl)but-3-en-1-yl)-4-bromoaniline was added to a mixture of 1-(2-(azacyclobutan-1-yl)phenyl)-N-(4-bromophenyl)methylimine (9 g, 28.55 mmol) in DCM (50 mL) at -20 °C under N2. The mixture was stirred at room temperature for 2 hours. The mixture was then poured into saturated NH4Cl (200 mL) and extracted with EA (200 mL × 3). The combined organic phases were washed with brine (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1 to 1 / 1) to obtain N-(1-(2-(azacyclobutan-1-yl)phenyl)but-3-en-1-yl)-4-bromoaniline (3 g), which was a yellow oil.

[0517] Step 4: 4-(2-(azacyclobutan-1-yl)phenyl)-4-((4-bromophenyl)amino)but-1-ol

[0518] BH3 THF (25 g, 25.19 mmol) was added to a solution of N-(1-(2-(azacyclobutan-1-yl)phenyl)but-3-en-1-yl)-4-bromoaniline (3 g, 8.4 mmol) in THF (20 mL) at 0 °C under a N2 atmosphere. The mixture was stirred at 25 °C for 2 hours. NaOH (1.01 g, 25.19 mmol) and H2O2 (9.5 g, 83.97 mmol) were added at 0 °C, and the mixture was stirred for 3 hours. The mixture was poured into H2O (50 mL) and extracted with EA (100 mL × 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution buffer: PE:EA = 1 / 1 to 0 / 1) to obtain 0.9 g of 4-(2-(azacyclobutan-1-yl)phenyl)-4-((4-bromophenyl)amino)but-1-ol, which was a yellow oil.

[0519] Step 5: 2-(2-(azacyclobutan-1-yl)phenyl)-1-(4-bromophenyl)pyrrolidine

[0520] At 0 °C, TEA (960 mg, 9.59 mmol) and MsCl (329 mg, 2.88 μmol) were added to a solution of 4-(2-(azacyclobutan-1-yl)phenyl)-4-((4-bromophenyl)amino)but-1-ol (0.9 g, 2.4 mmol) in THF (5 mL). After stirring at 25 °C for 2 hours, the reaction mixture was concentrated under vacuum. The residue was purified by preparative TLC (silica gel, eluent: PE / EA = 1 / 1) to give 2-(2-(azacyclobutan-1-yl)phenyl)-1-(4-bromophenyl)pyrrolidine (388.6 mg) as a yellow oil. 1 H NMR(400MHz, CDCl3)δppm:7.24-7.18(m,2H),7.17-7.11(m,1H),6.94(dd,J=1.4,7.6Hz,1H),6.74-6.66(m,1H),6.55(dd,J=0.8,8.0Hz,1H), 6.39-6.31(m,2H),4.80(d,J=7.5Hz,1H),4.11-3.91(m,4H),3.69-3.5 7(m,1H),3.36(q,J=8.8Hz,1H),2.38-2.21(m,3H),2.17-1.89(m,4H). MS(ESI,m / e)[M+1] + 357.1.

[0521] Intermediate 2r: 2-(2-(1,1-difluoroethyl)phenyl)pyrrolidine

[0522]

[0523] Step 1: 1-Bromo-2-(1,1-Difluoroethyl)benzene

[0524] 1-(2-bromophenyl)ethyl-1-one (5 g, 25.120 mmol) was added in portions to DAST (25 mL) at room temperature. The resulting mixture was stirred overnight at 50 °C under a nitrogen atmosphere. The reaction mixture was diluted with CH2Cl2 (100 mL) and then poured into ice / saturated NaHCO3 aqueous solution (250 mL), and extracted with CH2Cl2 (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 50 / 1) to give 1-bromo-2-(1,1-difluoroethyl)benzene (3.5 g) as a yellow liquid.

[0525] Step 2: 2-(2-(1,1-difluoroethyl)phenyl)-1H-pyrrole-1-carboxylic acid tert-butyl ester

[0526] Add [1-[(tert-butoxy)carbonyl]-1H-pyrrolo-2-yl]boronic acid (1.44 g, 6.824 mmol), X-Phos (0.65 g, 1.363 mmol), K3PO4 (4.34 g, 20.446 mmol), and Pd(OAc)2 (152.8 mg, 0.680 mmol) to a stirred solution of 1-bromo-2-(1,1-difluoroethyl)benzene (1.5 g, 6.786 mmol) in THF (18 mL) and H2O (1.8 mL). After stirring at 70 °C for 4.5 hours under a nitrogen atmosphere, dilute the reaction mixture with water (50 mL) and extract with EA (3 × 30 mL). Wash the combined organic layers with brine (50 mL), dry with anhydrous Na2SO4, and concentrate. The residue was purified by silica gel column chromatography (elution buffer: PE / EA = 50 / 1) to obtain 2.2729 g of crude 2-[2-(1,1-difluoroethyl)phenyl]-1H-pyrrole-1-carboxylic acid tert-butyl ester, which was a dark yellow oil.

[0527] Step 3: 2-(2-(1,1-difluoroethyl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0528] PtO2 (1.1365 g, 5.005 mmol) and concentrated hydrochloric acid (4 mL) were added in portions to a stirred solution of 2-[2-(1,1-difluoroethyl)phenyl]-1H-pyrrolo-1-carboxylic acid tert-butyl ester (2.2729 g, 7.395 mmol) in EtOH (45 mL). The resulting mixture was stirred at room temperature under a H2 atmosphere (1 atm) for 5 hours. After filtering off PtO2, the filtrate was concentrated. The residue was diluted with a saturated aqueous solution of NaHCO3 (200 mL) at 0 °C and then extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated to give 1.7408 g (crude product) of 2-[2-(1,1-difluoroethyl)phenyl]pyrrolo-1-carboxylic acid tert-butyl ester, which was a deep yellow oil.

[0529] Step 4: 2-(2-(1,1-difluoroethyl)phenyl)pyrrolidine

[0530] A solution of 4 mL of HCl (4N in 1,4-dioxane) was added fractionally to a solution of 1.7408 g (5.591 mmol) of 2-[2-(1,1-difluoroethyl)phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester in DCM (35 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. After adjusting the pH to 8 with a saturated aqueous solution of NaHCO3, the mixture was extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (0.05% NH4HCO3), 10% to 61% gradient over 25 min; detector, UV 220 nm. The resulting eluent was extracted with DCM (3 × 100 mL). The combined organic layers were then concentrated to obtain a yellow oily substance (2-[2-(1,1-difluoroethyl)phenyl]pyrrolidine) (703.1 mg). 1 H NMR (400MHz, chloroform-d) δppm: 7.74 (d, J=7.9Hz, 1H), 7.50–7.39 (m, 2H), 7.27 (t, J=7.7Hz, 2H), 4.56 (t, J=7.8Hz, 1H), 3.27 (ddd, J=9.8, 7.4, 5.1Hz ,1H),3.06(dt,J=9.8,7.4Hz,1H),2.23(dtd,J=12.8,7.8,4.9Hz,1H), 2.05(s,1H),2.03–1.94(m,5H),1.94–1.81(m,1H),1.78–1.58(m,1H). MS(ESI,m / e)[M+1] + 212.1.

[0531] Intermediate 2S: 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)piperidine

[0532]

[0533] Step 1: 1-Bromo-2-cyclopropylbenzene

[0534] To a stirred solution of 1-bromo-2-iodobenzene (40 g, 141.390 mmol) in dioxane (400 mL), K₂CO₃ (58.62 g, 424.151 mmol), cyclopropylboronic acid (36.44 g, 424.214 mmol), and Pd(dppf)Cl₂ (10.35 g, 14.14 mmol) were added. The mixture was stirred at 70 °C under a nitrogen atmosphere for 48 hours. The mixture was diluted with water (1000 mL) and extracted with EA (3 × 400 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 100 / 1) to give 1-bromo-2-cyclopropylbenzene (22.0 g) as a colorless oil.

[0535] Step 2: 2-(2-Cyclopropylphenyl)pyridine

[0536] 2-(tributyltinyl)pyridine (26.90 g, 73.069 mmol) and Pd(PPh3)4 (7.04 g, 6.089 mmol) were added to a stirred solution of 1-bromo-2-cyclopropylbenzene (12 g, 60.891 mmol) in dioxane (120 mL). The mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was quenched by adding water (100 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with 50 mL of brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 70 / 1) to give 2-(2-cyclopropylphenyl)pyridine (5.80 g) as a pale yellow oil.

[0537] Step 3: 2-(2-Cyclopropylphenyl)piperidine

[0538] Hydrochloric acid (concentrated HCl, 3.5 mL) and PtO2 (0.875 g, 3.846 mmol) were added to a stirred solution of 2-(2-cyclopropylphenyl)pyridine (2.5 g, 12.820 mmol) in EtOH (100 mL). The resulting mixture was stirred at room temperature under a H2 (1 atm) atmosphere for 4 hours. After filtering out the PtO2, the filtrate was concentrated. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, 0.05% TFA aqueous solution and CH3CN, 0% to 10% gradient over 30 min; detector, UV 220 nm, yielding 900 mg of crude product. This crude product was then purified by preparative HPLC under the following conditions (column: XBridgePrep OBD C18 column 30×150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 25% B to 37% B over 9 min; 254 nm and 220 nm; Rt: 7.92 min), yielding 280 mg of 2-(2-cyclopropylphenyl)piperidine as a yellow oil.

[0539] Step 4: 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)piperidine

[0540] At room temperature, 2-(2-cyclopropylphenyl)piperidine (2.50 g, 12.437 mmol), (4-bromophenyl)boronic acid (4.975 g, 24.874 mmol), Cu(OAc)₂ (5.627 g, 31.093 mmol) and activated... Molecular sieve (2.0 g) was added dropwise to a mixture in DCM (250 mL) with DIPEA (4.011 g, 31.093 mmol). The resulting mixture was stirred at room temperature under an O2 atmosphere for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column 30 × 150 mm 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 43% B to 46% B over 9 min; 254 nm and 220 nm; Rt: 7.40 min) to give 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)piperidine (310 mg) as a brown solid. 1H NMR (300MHz, methanol-d4) δppm: 7.46 (s, 2H), 7.31 (d, J = 8.5Hz, 2H), 7.21-7.09 (m, 2H), 6.91 (d, J = 7.3Hz, 1H), 5.30 (s, 1H), 3.78 (s, 2H), 2.20 (s, 1H), 2.13 (s, 4H), 1.00 (d, J = 8.4Hz, 2H), 0.60 (d, J = 6.0Hz, 1H), 0.50 (d, J = 5.6Hz, 1H). MS(ESI,m / e)[M+1] + 357.9.

[0541] Intermediate 2-t: 2-(2-cyclopropylphenyl)-4-methylpyrrolidine

[0542]

[0543] Step 1: Methyl 3-methyl-4-nitrobutyrate

[0544] DBN (4.60 mg, 39.95 mmol) was added to a solution of (E)-methylbutyrate-2-enoate (20 g, 199.77 mmol) and CH3NO2 (48.78 g, 799.07 mmol) in MeOH (200 mL). The mixture was stirred at 60 °C under a nitrogen atmosphere for 6 hours. TLC indicated complete consumption of the reactants. MTBE (700 mL) was added to the reaction mixture, and the mixture was washed with 1 M HCl (500 mL) and H2O (500 mL). The organic phase was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1). Methyl 3-methyl-4-nitrobutyrate (23 g, yield: 71.44%) was given as a yellow liquid. 1 HNMR (400MHz, CDCl3) δppm: 4.27-4.49 (m, 2H), 3.66 (s, 3H), 2.75 (m, 1H), 2.28-2.48 (m, 2H), 1.06 (d, J = 6.84Hz, 3H).

[0545] Step 2: 4-Methylpyrrolidone-2-one

[0546] Raney Ni (728.41 mg, 12.41 mmol) was added to a solution of methyl 3-methyl-4-nitrobutyrate (20 g, 124.10 mmol) in DMF (200 L). The mixture was stirred at 50 °C under a H2 atmosphere for 4 hours. TLC indicated that the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to give 10 g of 4-methylpyrrolidone-2-one as a yellow solid, which was used in the next step without further purification.

[0547] Step 3: 4-Methyl-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester

[0548] Add (Boc)₂O (44.03 g, 201.75 mmol) to a mixture of 4-methylpyrrolidone-2-one (10 g, 100.88 mmol), DMAP (6.16 g, 50.44 mmol), and TEA (10.21 g, 100.88 mmol) in THF (100 mL). Stir the mixture at 25 °C for 3 hours. TLC indicated the reaction was complete. Filter the reaction mixture and concentrate under reduced pressure to give the residue. Purify the residue by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1). Give tert-butyl 4-methyl-2-oxopyrrolidone-1-carboxylate (13 g, 64.68% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δppm: 3.87 (dd, J=10.7, 7.6Hz, 1H), 3.29 (dd, J=10.7, 6.9Hz, 1H), 2.64 (dd, J=17.0, 8 .1Hz,1H),2.39(dd,J=14.6,7.5Hz,1H)2.16(dd,J=17.0,8.1Hz,1H),1.53(s,9H),1.14(d,J=6.6Hz,3H).

[0549] Step 4: (4-(2-cyclopropylphenyl)-2-methyl-4-oxobutyl)carbamate tert-butyl ester

[0550] A mixture of 1-bromo-2-cyclopropylbenzene (3.5 g, 17.76 mmol) in THF (50 mL) was degassed and purged three times with N2. Then, n-BuLi (1.04 g, 16.28 mmol) was added dropwise to the mixture at -68 °C. After stirring for 10 min, tert-butyl 4-methyl-2-oxopyrrolidine-1-carboxylate (2.95 g, 14.80 mmol) in THF (10 mL) was added to the mixture. The mixture was then stirred at -68 °C under N2 atmosphere for 2 h. TLC indicated the reaction was complete. The reaction was quenched with NH4Cl aqueous solution (20 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1). 3.6 g of (4-(2-cyclopropylphenyl)-2-methyl-4-oxobutyl)carbamate (76.63% yield) was obtained as a yellow oil. 1H NMR (400MHz, CDCl3) δppm: 7.44 (dd, J=7.7, 1.10Hz, 1H), 7.32-7.38 (m, 1H), 7.17- 7.24(m,1H),7.03(d,J=7.9Hz,1H),4.68(s,1H),3.12(t,J=6.3Hz,2H),3.00(dd, J=16.8,5.51Hz,2H),2.77(dd,J=16.8,7.72Hz,1H),2.24-2.50(m,3H),1.44(s,1 0H),1.24-1.36(m,1H),0.94-1.03(m,5H),0.88-0.94(m,2H),0.61-0.72(m,2H).

[0551] Step 5: 4-Amino-1-(2-cyclopropylphenyl)-3-methylbut-1-one

[0552] The solution of tert-butyl (4-(2-cyclopropylphenyl)-2-methyl-4-oxobutyl)carbamate (3.5 g, 11.03 mmol) in DCM (50 mL) was degassed and purged three times with N2, and then TFA (12.57 g, 110.26 mmol) was added. The mixture was stirred at 20 °C under N2 atmosphere for 1 hour. TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give the residue. The crude product (2.0 g) was used in the next step without purification. 1 H NMR (400MHz, CDCl3) δppm: 7.52 (d, J = 7.7Hz, 1H), 7.27-7.44 (m, 8H), 7.24 (d, J =1.1Hz,1H),7.08-7.19(m,4H),6.97(d,J=7.7Hz,3H),4.46(t,J=7.2Hz,1H),4 .11-4.25(m,3H),3.61-3.75(m,3H),3.08-3.19(m,3H),2.48-2.71(m,9H),2. 37(d,J=5.5Hz,3H),1.08-1.20(m,12H),0.89-0.98(m,9H),0.65-0.71(m,4H).

[0553] Step 6: 2-(2-Cyclopropylphenyl)-4-methylpyrrolidine

[0554] The solution of 4-amino-1-(2-cyclopropylphenyl)-3-methylbut-1-one (2.0 g, 9.20 mmol) in EtOH (20 mL) and HOAc (2 mL) was degassed and purged three times with N2. Then, NaBH3CN (983.23 mg, 15.56 mmol) was added to the solution in portions. The mixture was stirred at 25 °C under N2 atmosphere for 2 hours. LC / MS showed the reaction was complete. The reaction mixture was adjusted to pH 10 with aqueous Na2CO3 solution (1 N) and extracted with EA (20 mL × 5). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (TFA conditions). 2-(2-cyclopropylphenyl)-4-methylpyrrolidine (421 mg) was given as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm: 7.48-7.59 (m, 1H), 7.11-7.25 (m, 2H), 7.01 (d, J = 7.3H z,1H),4.82-4.91(m,1H),3.39(dd,J=9.9,6.8Hz,1H),3.24(dd,J=10.1,7.5Hz,1 H),2.77(dd,J=10.2,7.8Hz,1H),2.29-2.51(m,2H),2.00(dd,J=8.3,5.5Hz,1H) ,1.35(d,J=9.8Hz,1H),1.08-1.15(m,3H),0.88-0.98(m,2H),0.61-0.71(m,2H). MS(ESI,m / e)[M+1] + 202.1.

[0555] Intermediate 2-u: (S)-2-(2-cyclopropylphenyl)-1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)spiro[3,5]non-6-en-2-yl)pyrrolidine

[0556]

[0557] Step 1: (S)-2-(2-cyclopropylphenyl)-1-(8,11-dioxadispiro[3.2.47.24]tetran-2-yl)pyrrolidine

[0558] A solution of 8,11-dioxabisspiro[3.2.47.24]tridecane-2-one (2.5 g, 13.35 mmol), (S)-2-(2-cyclopropylphenyl)pyrrolidine (2.36 g, 12.01 mmol), and HOAc (2.4 g, 40.05 mmol) in DCE (30 mL) was stirred at 15 °C for 2 h. Then, Na(OAc)3Bh (5.6 g, 26.7 mmol) was added to the mixture, and the mixture was stirred at 15 °C for 12 h. TLC showed the reaction was complete. The mixture was adjusted to pH 10 with a saturated aqueous solution of Na2CO3. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 20 / 1 to 7 / 1) to give the target product (2.5 g, crude) as a yellow oil.

[0559] Step 2: (S)-2-(2-(2-cyclopropylphenyl)pyrrolidine-1-yl)spiro[3.5]nonane-7-one

[0560] 1N hydrochloric acid (27 mL, 27.25 mmol) was added to a solution of (S)-2-(2-cyclopropylphenyl)-1-(8,11-dioxadispiro[3.2.47.24]tetran-2-yl)pyrrolidine (2 g, 5.45 mmol) in acetone (27 mL). The mixture was stirred at 15 °C for 6 hours. TLC showed that the reaction was complete. After removing the solvent, the residue was dissolved in EA (20 mL) and the pH was adjusted to 9 with a saturated aqueous solution of NaHCO3. The organic layer was washed with water and brine, dried with Na2SO4, filtered and concentrated to give (S)-2-(2-(2-cyclopropylphenyl)pyrrolidine-1-yl)spiro[3.5]non-7-one (1.7 g, crude product) as a yellow oil.

[0561] Step 3: (S)-2-(2-(2-cyclopropylphenyl)pyrrolidine-1-yl)spiro[3.5]non-6-en-7-yl trifluoromethanesulfonate

[0562] A mixture of (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)spiro[3.5]non-7-one (1.6 g, 4.95 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.12 g, 5.94 mmol) in THF (20 mL) was cooled to -78 °C. LDA (2.97 mL, 5.94 mmol) was then added and the mixture was stirred for 2 hours. The mixture was heated to 15 °C and stirred for 12 hours. TLC showed the reaction was complete. The mixture was poured into a saturated aqueous solution of NH4Cl and extracted with EA. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution buffer: PE / EA = 50 / 1 to 5 / 1) to obtain (S)-2-(2-(2-cyclopropylphenyl)pyrrolidine-1-yl)spiro[3.5]non-6-en-7-yl trifluoromethanesulfonate (2.4 g, crude product), which was a yellow oil.

[0563] Step 4: (S)-2-(2-cyclopropylphenyl)-1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)spiro[3,5]non-6-en-2-yl)pyrrolidine

[0564] A mixture of (S)-2-(2-(2-cyclopropylphenyl)pyrrolidine-1-yl)spiro[3.5]non-6-en-7-yl trifluoromethanesulfonate (2.2 g, 4.83 mmol), B2PIN2 (1.84 g, 7.25 mmol), KOAc (1.42 g, 14.49 mmol), and Pd(dppf)Cl2 (351 mg, 0.48 mmol) in dioxane (20 mL) was stirred at 85 °C for 3 hours. TLC showed the reaction was complete. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (elution buffer: PE / EA = 10 / 1 to 5 / 1) to give (S)-2-(2-cyclopropylphenyl)-1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)spiro[3.5]non-6-en-2-yl)pyrrolidine (700 mg, 33% yield) as a yellow solid. 1H NMR (400MHz, CDCl3) δppm: 7.66 (t, J = 6.1Hz, 1H), 7.33-7.28 (m, 1H), 7.25-7 .12(m,4H),7.04-6.99(m,1H),6.35(s,1H),4.39(s,1H),3.40(s,1H),3.28 -3.10(m,1H),2.73(s,1H),2.38-2.25(m,1H),2.05(s,2H),1.99-1.80(m,5 H),1.78-1.31(m,4H),1.25(s,13H),1.00-0.86(m,2H),0.71-0.57(m,2H). MS(ESI,m / e)[M+1] + 434.1.

[0565] Intermediate 2-V: tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)phenyl)piperazine-1-carboxylate

[0566]

[0567] Step 1: 4-(2-formylphenyl)piperazine-1-carboxylic acid tert-butyl ester

[0568] K₂CO₃ (44.52 g, 322.15 mmol) was added to a solution of 2-fluorobenzaldehyde (13.33 g, 107.38 mmol) and piperazine-1-carboxylate tert-butyl ester (30.0 g, 161.07 mmol) in DMSO (150 mL). The mixture was stirred at 100 °C for 12 h. TLC indicated complete consumption of the reactants. The reaction mixture was cooled to room temperature and poured into H₂O (150 mL) and extracted with EA (150 mL × 3). The extract was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (silica gel, PE / EA = 100 / 1 to 30 / 1). 8.5 g of 4-(2-formylphenyl)piperazine-1-carboxylate tert-butyl ester was given as a yellow solid. 1 HNMR (400MHz, CDCl3) δppm: 1.50 (s, 9H), 3.02-3.08 (m, 4H), 3.61-3.66 (m, 4H), 7.11 (d, J = 8.2 Hz,1H),7.17(t,J=7.5Hz,1H),7.52-7.58(m,1H),7.83(dd,J=7.7,1.8Hz,1H),10.36(s,1H).

[0569] Step 2: (E)-4-(2-(((4-bromophenyl)imino)methyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0570] Add to a solution of tert-butyl 4-(2-formylphenyl)piperazine-1-carboxylate (8 g, 27.55 mmol) and 4-bromoaniline (4.74 g, 27.55 mmol) in toluene (100 mL) Molecular sieve (5 g) and TsOH (474.45 mg, 2.76 mmol). The mixture was stirred at 120 °C for 12 hours. TLC indicated complete consumption of the reactants. The reaction mixture was concentrated under reduced pressure to remove the solvent. 8 g of crude (E)-4-(2-(((4-bromophenyl)imino)methyl)phenyl)piperazinyl-1-carboxylic acid tert-butyl ester was obtained as a brown oil. 1 H NMR(400MHz, CDCl3)δppm:1.49(s,9H),2.98(br,4H),3.60(br,4H),7.08-7.13(m,3 H),7.17-7.26(m,2H),7.46(td,J=7.7,1.6Hz,1H),7.50-7.54(m,2H),8.83(s,1H).

[0571] Step 3: Tert-butyl 4-(2-(1-((4-bromophenyl)amino)but-3-en-1-yl)phenyl)piperazin-1-carboxylate was added to a solution of (E)-4-(2-((((4-bromophenyl)imino)methyl)phenyl)piperazin-1-carboxylate (8 g, 18.0 mmol) in DCM (100 mL) at -20 °C. The mixture was stirred at -20 °C for 2 hours. TLC indicated complete consumption of the reactants. The reaction mixture was poured into an aqueous solution of NH4Cl (150 mL) and extracted with EA (150 mL × 3). The extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether). 6.0 g of tert-butyl 4-(2-(1-((4-bromophenyl)amino)but-3-en-1-yl)phenyl)piperazine-1-carboxylate was obtained as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm: 1.51 (s, 9H), 2.47-2.66 (m, 2H), 2.83-2.98 (m, 5H), 3.48-3.75 (m, 3H), 4.23 (s, 1H), 4.89 (dd, J = 8.1, 4.9Hz, 1H), 5.10- 5.21(m,2H),5.79(ddt,J=17.0,10.1,6.9Hz,1H),6.40-6.44(m,2H),7.1 0-7.20(m,4H),7.24(dd,J=7.2,1.5Hz,1H),7.34(dd,J=7.6,1.5Hz,1H).

[0572] Step 4: 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0573] BH3 THF (1M, 185.02 mL) was added to a solution of tert-butyl 4-(2-(1-((4-bromophenyl)amino)but-3-en-1-yl)phenyl)piperazin-1-carboxylate (6 g, 12.33 mmol) in 100 mL of THF at 0 °C. The mixture was stirred at 25 °C for 12 h. Then, NaOH (1.23 g, 30.84 mmol) and H2O2 (6.29 g, 185.02 mmol) were added to the mixture at 0 °C. The mixture was stirred at 25 °C for 8 h. TLC indicated that reactant 4 was completely consumed. The reaction mixture was poured into an aqueous solution of NH4Cl (150 mL) and extracted with EA (150 mL × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, PE / EA = 100 / 1 to 30 / 1). 3.5 g of tert-butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenyl)piperazine-1-carboxylate was obtained as a yellow solid. 1 HNMR (400MHz, CDCl3) δppm: 1.50 (s, 10H), 1.56-1.80 (m, 3H), 1.83-1.99 (m, 2H), 2.80-2.94 (m, 4H), 3.38-3.76 ( m,5H),4.88(dd,J=7.9,5.5Hz,1H),6.46-6.51(m,2H),7.11-7.18(m,4H),7.21-7.24(m,1H),7.31-7.34(m,1H).

[0574] Step 5: 4-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0575] MsCl (715.29 mg, 6.24 mmol) was added to a solution of tert-butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenyl)piperazine-1-carboxylate (3.5 g, 6.94 mmol) in DCM (50 mL) and TEA (3.51 g, 34.69 mmol) at 0 °C, and the mixture was stirred at 25 °C for 1.5 h. LC-MS showed complete consumption of the reactants and observed a main peak with the desired MS. The reaction mixture was poured into an aqueous solution of NH4Cl (150 mL) and extracted with EA (150 mL × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, PE / EA = 10 / 1). 3.0 g of tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)phenyl)piperazine-1-carboxylate was given as a white solid. 1 H NMR(400MHz, CDCl3)δppm:1.47-1.54(m,9H),1.90-1.98(m,1H),1.98-2.17(m,2H),2.40-2.52(m,1H),2.86-3.02(m,4H),3.35-3.43(m,1 H),3.55-3.67(m,3H),3.67-3.75(m,1H),5.07-5.12(m,1H),6.27-6.34(m,2H),7.01-7.07(m,1H),7.08-7.12(m,1H),7.15-7.26(m,4H). MS(ESI,m / e)[M+1] + 486.1.

[0576] Intermediate 2-w: 6-(2-cyclopropylphenyl)-5-azaspiro[2,4]heptane

[0577]

[0578] Step 1: 2-(2-cyclopropylphenyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

[0579] Boc₂O (1.9 g, 8.9 mmol) was added to a solution of 5-(2-cyclopropylphenyl)pyrrolidine-3-ol (1.8 g, 8.9 mmol) and Et₃N (0.9 g, 8.9 mmol) in DCM (20 mL). The mixture was then stirred at 20 °C for 12 hours. TLC showed that the reaction was complete. The reaction mixture was washed with hydrochloric acid (1 N, 20 mL), a saturated aqueous solution of NaHCO₃ (20 mL), and brine (20 mL), dried over Na₂SO₄, and concentrated to give 2-(2-cyclopropylphenyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2.3 g, crude product) as a yellow oil.

[0580] Step 2: tert-butyl 2-(2-cyclopropylphenyl)-4-oxopyrrolidine-1-carboxylate

[0581] To a solution of 2-(2-cyclopropylphenyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2.3 g, 7.6 mmol) in DCM (30 mL), NaHCO3 (640 mg, 7.6 mmol) and Dess-Martin periodinane (3.2 g, 7.6 mmol) were added. The mixture was stirred at 20 °C for 12 hours. TLC showed that the reaction was complete. The reaction mixture was quenched with a saturated aqueous solution of Na2SO3 (30 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated to give 2-(2-cyclopropylphenyl)-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester (2.1 g, crude product) as a yellow oil.

[0582] Step 3: 2-(2-cyclopropylphenyl)-4-methylenepyrrolidine-1-carboxylic acid tert-butyl ester

[0583] To Ph3P + MeBr - t-BuOK (1.7 g, 15.3 mmol) was added in a single batch to a mixture of 5.5 g (15.3 mmol) in THF (25 mL). The mixture was stirred at 20 °C for 1 h. Then, tert-butyl 2-(2-cyclopropylphenyl)-4-oxopyrrolidine-1-carboxylate (2.3 g, 7.64 mmol) was added, and the mixture was stirred at 20 °C for 12 h. TLC showed that the reaction was complete. The reaction mixture was quenched with saturated aqueous NH4Cl solution (25 mL) and then extracted with EA (25 mL). The organic layer was washed with brine (25 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluted with PE / EA = 10 / 1 to give tert-butyl 2-(2-cyclopropylphenyl)-4-methylenepyrrolidine-1-carboxylate (1.3 g, yield: 56%).

[0584] Step 4: tert-butyl 6-(2-cyclopropylphenyl)-5-azaspiro[2,4]heptane-5-carboxylate

[0585] At 0 °C, ClCH₂I (5.3 g, 30 mmol) was added to a mixture of tert-butyl 2-(2-cyclopropylphenyl)-4-methylenepyrrolidine-1-carboxylate (1.3 g, 4.3 mmol) and Et₂Zn (1 M in toluene, 15 mL, 15 mmol). The mixture was then stirred at 20 °C for 12 hours. TLC showed the formation of new spots with no remaining material. The reaction mixture was quenched with a saturated aqueous solution of NH₄Cl (50 mL) and extracted with EA (50 mL). The organic layer was washed with brine (50 mL), dried over Na₂SO₄, and concentrated to give tert-butyl 6-(2-cyclopropylphenyl)-5-azaspiro[2.4]heptane-5-carboxylate (1 g, crude) as a yellow oil, which was used directly in the next step.

[0586] Step 5: 6-(2-cyclopropylphenyl)-5-azaspiro[2,4]heptane

[0587] A solution of tert-butyl 6-(2-cyclopropylphenyl)-5-azaspiro[2.4]heptane-5-carboxylate (1 g, 3.2 mmol) in HCl / EA (10 mL, 4 M) was stirred at 20 °C for 2 h. The reaction was confirmed by LC / MS. The mixture was concentrated. The residue was purified by preparative HPLC (0.1% TFA conditions). The target eluent was alkalized to pH 10 with saturated Na₂CO₃ aqueous solution and then extracted with EA (200 mL × 4). The organic layers were combined, dried over Na₂SO₄, and concentrated to give 293 mg of 6-(2-cyclopropylphenyl)-5-azaspiro[2.4]heptane as a pale yellow oil. 1 H NMR (400MHz, CDCl3) δppm: 7.60 (dd, J=7.6, 1.3Hz, 1H), 7.13-7.25 (m, 2H), 7.01 (d, J=7.5Hz, 1H), 4.97 (t, J=7.8Hz, 1H), 3.02-3.1 3(m,2H),2.34(s,1H),2.14(dd,J=12.3,7.2Hz,1H),2.04(t,J=8.4,1H),1.81-1.90(m,1H),0.87-1.02(m,2H),0.53-0.76(m,6H). MS(ESI,m / e)[M+1] + 214.1.

[0588] Intermediate 2-x: (R)-1-(2-(1-(4-bromophenyl)pyrrolidine-2-yl)benzyl)-4-methylpiperazine

[0589]

[0590] Step 1: (R)-1-(2-(2-bromophenyl)pyrrolidone-1-yl)-2,2,2-trifluoroethyl ketone

[0591] At 0 °C, TEA (13.5 g, 132.69 mmol) was added dropwise to a mixture of (R)-2-(2-bromophenyl)pyrrolidine (10 g, 44.23 mmol) and TFAA (18.58 g, 88.45 mmol) in DCM (100 mL). The mixture was stirred at 20 °C for 10 h. TLC indicated complete consumption of the reactants. The reaction mixture was washed with saturated aqueous NH4Cl solution (100 mL × 2), and the organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, PE / EA = 100 / 1 to 50 / 1). (R)-1-(2-(2-bromophenyl)pyrrolidine-1-yl)-2,2,2-trifluoroethyl ketone (13 g) was given as a yellow solid.

[0592] Step 2: (R)-2,2,2-trifluoro-1-(2-(2-vinylphenyl)pyrrolidone-1-yl)ketene

[0593] At 20 °C, Pd(dppf)Cl2 (567 mg, 776 μmol) was added to a solution of (R)-1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethyl ketone (5 g, 15.52 mmol), potassium trifluoro(vinyl)borate (2.91 g, 21.73 mmol), and Cs₂CO₃ (10.11 g, 31.04 mmol) in dioxane (120 mL) and H₂O (12 mL). The mixture was purged three times with N₂ and then heated to 100 °C and held for 5 hours. TLC and LC / TLC indicated complete consumption of the reactants. The reaction mixture was concentrated under vacuum (about 30 mL). The residue was poured into ice water (50 mL). The aqueous phase was extracted with EA (50 mL × 3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, PE / EA = 100 / 1 to 50 / 1). A yellow oil (R)-2,2,2-trifluoro-1-(2-(2-vinylphenyl)pyrrolidone-1-yl)acetone (3.4 g, 12.63 mmol, yield 81.34%) was obtained. 1H NMR (400MHz, CDCl3) δppm:7.44-7.51(m,1H),7.21-7.27(m,2H),6.88-7.07(m,2H),5.61-5.71(m,1 H),5.46-5.60(m,1H),5.33-5.45(m,1H),3.75-4.03(m,2H),2.27-2.41(m,1H),1.82-2.12(m,3H). MS(ESI,m / e)[M+1] + 270.1.

[0594] Step 3: (R)-2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)benzaldehyde

[0595] NaIO4 (10.8 g, 50.51 mmol) was added in portions to a mixture of (R)-2,2,2-trifluoro-1-(2-(2-vinylphenyl)pyrrolidone-1-yl)acetone (3.4 g, 12.63 mmol) and K2OSO4·2H2O (186 mg, 505.1 μm) in THF (60 mL) and H2O (60 mL) at 10 °C. The mixture was stirred at 10 °C for 2 hours. TLC indicated complete consumption of the reactants. The reaction mixture was concentrated to remove THF. The aqueous phase was extracted with EA (50 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. (R)-2-(1-(2,2,2-trifluoroacetyl)pyrrolidone-2-yl)benzaldehyde (3.4 g, crude) was obtained as a brown oil. MS (ESI, m / e) [M+1] + 272.1.

[0596] Step 4: (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)benzyl)piperazine-1-carboxylic acid tert-butyl ester

[0597] NaBH(OAc)3 (10.6 g, 50.16 mmol) was added fractionally to a mixture of (R)-2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)benzaldehyde (3.4 g, 12.54 mmol) and piperazine-1-carboxylic acid tert-butyl ester (4.67 g, 25.07 mmol) in a DCE (100 mL) at 10 °C. The mixture was stirred at 10 °C for 10 hours. TLC indicated complete consumption of the reactants. The reaction mixture was washed with NaHCO3 (50 mL) and then the organic phase was separated. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)benzyl)piperazine-1-carboxylic acid tert-butyl ester (3.5 g) was given as a yellow oil. MS (ESI, m / e) [M+1] + 442.3.

[0598] Step 5: (R)-4-(2-(pyrrolidone-2-yl)benzyl)piperazine-1-carboxylic acid tert-butyl ester

[0599] NaBH4 (662.13 mg, 16.44 mmol) was added in portions to a solution of (R)-4-(2-pyrrolidone-2-yl)benzyl)piperazine-1-carboxylate (3.3 g, 7.47 mmol) in EtOH (50 mL) at 20 °C. The mixture was stirred at 20 °C for 4 hours. TLC indicated complete consumption of the reactants. The reaction mixture was concentrated to remove EtOH (approximately 10 mL) and poured into ice water (20 mL). The aqueous phase was extracted with EA (50 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. This yielded (R)-4-(2-pyrrolidone-2-yl)benzyl)piperazine-1-carboxylate (2.55 g, crude) as a yellow oil. MS (ESI, m / e) [M+1] + 346.3.

[0600] Step 6: (R)-4-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)benzyl)piperazine-1-carboxylic acid tert-butyl ester

[0601] Pd(OAc)₂ (166 mg, 738 μmol) was added to a mixture of (R)-4-(2-(pyrrolidone-2-yl)benzyl)piperazin-1-carboxylic acid tert-butyl ester (2.55 g, 7.38 mmol), 1-bromo-4-iodobenzene (3.13 g, 11.07 mmol), X-phos (703 mg, 1.48 mmol), and Cs₂CO₃ (4.81 g, 14.76 mmol) in toluene (100 mL) at 20 °C. The mixture was purged three times with N₂ and then heated to 105 °C and held for 10 h. TLC indicated complete consumption of the reactants. The reaction mixture was poured into ice water (50 mL), and the organic phase was separated. The organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated. 1.25 g of (R)-4-(2-(1-(4-bromophenyl)pyrrolidine-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester was obtained as an orange solid. 1 H NMR (400MHz, CDCl3) δppm: 7.05-7.24 (m, 6H) 6.40 (d, J = 8.9Hz, 2H) 5.28-5.37 (m, 1H) 3.68-3.86 ( m,2H)3.29-3.53(m,6H)2.35-2.59(m,5H)1.98-2.15(m,2H)1.79-1.88(m,1H)1.41-1.51(m,9H).

[0602] Step 7: (R)-1-(2-(1-(4-bromophenyl)pyrrolidine-2-yl)benzyl)piperazine

[0603] A solution of (R)-4-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)benzyl)piperazine-1-carboxylic acid tert-butyl ester (1.25 g, 2.50 mmol) in TFA (20 mL) and DCM (60 mL) was stirred for 12 hours at 20 °C. LC / MS indicated that the reactants were completely consumed and the desired compound was produced. The reaction solution was concentrated. The residue was diluted with EA (50 mL). The organic phase was washed with saturated NaHCO3 aqueous solution (50 mL) and separated. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. (R)-1-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)benzyl)piperazine (1 g, crude) was given as a yellow oil. MS (ESI, m / e) [M+1] + 400.2.

[0604] Step 8: (R)-1-(2-(1-(4-bromophenyl)pyrrolidine-2-yl)benzyl)-4-methylpiperazine

[0605] NaBH(OAc)3 (2.1 g, 10 mmol) was added fractionally to a mixture of (R)-1-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)benzyl)piperazine (1 g, 2.50 mmol) and HCHO (374.99 mg, 12.49 mmol) in a DCE (50 mL) at 20 °C. The mixture was stirred at 20 °C for 1 hour. LC / MS indicated that the reactants were completely consumed and the desired compound was produced. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative HPLC (Phenomenex Luna C18 250 mm × 100 mm × 10 μm; mobile phase: [water (0.1% TAF)-ACN]). The purified solution was concentrated. The aqueous phase was alkalized with saturated NaHCO3 and then extracted with EA (50 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. (R)-1-(2-(1-(4-bromophenyl)pyrrolidine-2-yl)benzyl)-4-methylpiperazine (440 mg) was obtained as a yellow solid. 1 H NMR (400MHz, CDCl3) δppm: 7.01-7.24 (m, 6H), 6.36 (d, J = 8.8Hz, 2H), 5.22 (d, J = 8.2Hz, 1H), 3.88 (d, J = 12.8 Hz, 1H), 3.72 (t, J = 7.4Hz, 1H), 3.33-3.50 (m, 2H), 2.34-3.14 (m, 12H), 2.06 (s, 2H), 1.84 (d, J = 5.7Hz, 1H). MS(ESI,m / e)[M+1] + 414.2.

[0606] Intermediate 2-y: (R)-4-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)benzyl)piperidine-1-carboxylic acid tert-butyl ester

[0607]

[0608] Step 1: (E)-4-((2-Toluenesulfonylhydrazinyl)methyl)piperidine-1-carboxylic acid tert-butyl ester

[0609] A mixture of tert-butyl 4-formylpiperidin-1-carboxylate (1.75 g, 9.38 mmol) and 4-methylbenzenesulfonylhydrazine (2.0 g, 9.38 mmol) in EtOH (30 mL) was stirred at 20 °C for 15 hours. TLC indicated complete consumption of the reactants. The reaction mixture was concentrated under vacuum. (E)-4-((2-toluenesulfonylhydrazine)methyl)piperidin-1-carboxylate (3.4 g, crude product) was given as a colorless oil.

[0610] Step 2: (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)benzyl)piperidine-1-carboxylic acid tert-butyl ester

[0611] At 20 °C, Pd(PPh3)2Cl2 (670.5 mg, 931 μmol) was added to a mixture of (R)-1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethyl ketone (3 g, 9.31 mmol), (E)-4-((2-toluenesulfonylhydrazine)methyl)piperidine-1-carboxylic acid tert-butyl ester (5.33 g, 13.97 mmol), and t-BuOLi (2.98 g, 37.24 mmol) in dioxane (100 mL). The mixture was purged three times with N2 and then heated to 100 °C and held for 3 hours. TLC indicated complete consumption of the reactants. The reaction mixture was concentrated under vacuum (about 20 mL). The residue was poured into ice water (30 mL) and extracted with EA (50 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, PE / EA = 30 / 1 to 10 / 1). A red oily substance, (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidone-2-yl)benzyl)piperidine-1-carboxylic acid tert-butyl ester (2.17 g, 4.95 mmol, yield 53.08%), was obtained. 1 H NMR (400MHz, CDCl3) δppm:7.16-7.25(m,2H),7.04-7.11(m,1H),6.92-7.01(m,1H),6.29-6.46(m,1H),5.29-5.45( m,1H),3.75-4.00(m,2H),3.12-3.69(m,4H),2.16-2.41(m,4H),1.83-2.15(m,3H),1.70-1.82(m,1H),1.47(s,9H). MS(ESI,m / e)[M+1] + 339.2.

[0612] Step 3: (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)benzyl)piperidine-1-carboxylic acid tert-butyl ester

[0613] Pd / C (300 mg, 10% wet) was added to a solution of (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)benzyl)piperidine-1-carboxylate (2.3 g, 5.25 mmol) in MeOH (30 mL). The mixture was purged three times with H2 and then stirred at 20 °C for 10 h at 15 PsiH2. LC / MS indicated that the reactants were completely consumed and the desired compound was formed. The reaction mixture was filtered through diatomaceous earth and washed with MeOH. The filtrate was concentrated. This yielded (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)benzyl)piperidine-1-carboxylate (2.3 g, crude) as a brown solid. 1 H NMR (400MHz, CDCL3) δppm:7.07-7.23(m,3H),6.86-6.98(m,1H),5.34-5.52(m,1H),3.73-4.24(m,4 H),2.44-2.83(m,4H),2.31-2.44(m,1H),1.56-2.21(m,6H),1.37-1.55(m,9H),1.05-1.33(m,2H).

[0614] Step 4: (R)-4-(2-(pyrrolidone-2-yl)benzyl)piperazine-1-carboxylic acid tert-butyl ester

[0615] At 20 °C, LiOH·H₂O (438.5 mg, 10.44 mmol) was added to a solution of (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)benzyl)piperidine-1-carboxylic acid tert-butyl ester (2.3 g, 5.22 mmol) in MeOH (10 mL), H₂O (10 mL), and THF (10 mL). The mixture was heated to 50 °C and maintained for 1 hour. TLC indicated complete consumption of the reactants. The reaction mixture was concentrated under vacuum to remove MeOH and THF. The aqueous phase was extracted with EA (30 mL × 3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated. (1.76 g, crude) (R)-4-(2-pyrrolidine-2-yl)benzyl)piperidine-1-carboxylic acid tert-butyl ester was given as a yellow oil. MS (ESI, m / e) [M+1] + 345.2.

[0616] Step 5: (R)-4-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)benzyl)piperidine-1-carboxylic acid tert-butyl ester

[0617] Pd(OAc)₂ (90 mg, 406 μmol) was added to a mixture of (R)-4-(2-(pyrrolidone-2-yl)benzyl)piperidin-1-carboxylic acid tert-butyl ester (1.4 g, 4.06 mmol), 1-bromo-4-iodobenzene (1.72 g, 6.10 mmol), X-phos (387 mg, 812 μmol), and Cs₂CO₃ (2.64 g, 8.12 mmol) in toluene (50 mL) at 20 °C. The mixture was purged three times with N₂ and then heated to 100 °C and held for 5 h. TLC indicated complete consumption of the reactants. The reaction mixture was cooled to room temperature and poured into ice water (30 mL), and then separated. The organic phase was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, eluent: PE / EA = 100 / 1 to 50 / 1). (R)-4-(2-(1-(4-bromophenyl)pyrrolidine-2-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (720 mg) was obtained as a yellow solid. 1 H NMR (400MHz, CDCl3) δppm: 7.00-7.24 (m, 6H) 6.27 (d, J = 9.0Hz, 2H) 4.80-4.92 (m, 1H) 4.02-4.27 (m, 2H) 3.65-3.78 (m, 1H) 3.35-3.47 ( m,1H)2.57-2.83(m,4H)2.36-2.51(m,1H)1.97-2.12(m,2H)1.80-1.95(m,2H)1.71(d,J=12.1Hz,2H)1.48(s,9H)1.23-1.31(m,2H). MS(ESI,m / e)[M+1] + 498.9.

[0618] Intermediate 2-z: (S)-N,N-dimethyl-2-(pyrrolidone-2-yl)aniline

[0619]

[0620] Step 1: (S)-2-(2-((diphenylmethylene)amino)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0621] Diphenylmethyleneimine (1.67 g, 9.20 mmol), Cs₂CO₃ (3.99 g, 12.26 mmol), Pd₂(dba)₃ (561.4 mg, 6.13 mmol), and Xant-phos (1.06 g, 1.84 mmol) were added to a solution of (S)-2-(2-bromophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.0 g, 6.13 mmol) in 1,4-dioxane (50 mL). The mixture was stirred at 105 °C under N₂ protection for 36 h. LC / MS showed complete consumption of (S)-2-(2-bromophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester and showed a main peak with the desired mass signal. The mixture was evaporated under vacuum. The residue was used directly in the next step. MS (ESI, m / e) [M⁻¹] - 427.2.

[0622] Step 2: (S)-2-(2-aminophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0623] Add 10 mL of 0.5 N hydrochloric acid to a solution of (S)-2-(2-((diphenylmethylene)amino)phenyl)pyrrolidine-1-carboxylate (262 mg, 613 μmol, 1 equivalent) in THF (5 mL). Stir the mixture overnight at 20 °C. TLC showed complete consumption of (S)-2-(2-((diphenylmethylene)amino)phenyl)pyrrolidine-1-carboxylate. Adjust the pH of the mixture to approximately 8 with saturated NaHCO3 aqueous solution, and then extract with EA (20 mL). Wash the organic phase with brine, dry with Na2SO4, and evaporate under vacuum. Purify the residue by silica gel column chromatography (elution: PE / EA = 10 / 1 to 1 / 1) to give (S)-2-(2-aminophenyl)pyrrolidine-1-carboxylate (50 mg). 1 H NMR (400MHz, CDCl3) δppm:6.91-7.16(m,2H),6.70-6.87(m,1H),6.62-6.70(m,1H),4.60- 5.06(m,1H),3.36-3.97(m,4H),2.13-2.35(m,1H),1.83-2.01(m,3H),1.16-1.54(m,9H).

[0624] Step 3: (S)-2-(2-(dimethylamino)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0625] To a solution of (S)-2-(2-aminophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (6.5 g, 22.87 mmol) in MeOH (200 mL), an aqueous solution of HCHO (37%, 11.14 g, 137.22 mmol) and NaH3CN (5.95 g, 114.35 mmol) were added. The mixture was stirred at 20 °C for 14 h. TLC showed complete consumption of (S)-2-(2-aminophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester. The mixture was evaporated under vacuum. The residue was dissolved in DCM (100 mL), washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 100 / 1 to 30 / 1) to give (S)-2-(2-(dimethylamino)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (5.9 g). 1 H NMR(400MHz, CDCl3)δppm:6.93-7.15(m,4H),5.12-5.37(m,1H),3.36-3.69(m,2 H),2.60(s,6H),2.20-2.37(m,1H),1.64-1.87(m,3H),1.39(s,2H),1.10(s,6H).

[0626] Step 4: (S)-N,N-Dimethyl-2-(pyrrolidone-2-yl)aniline

[0627] TFA (30 mL) was added to a solution of (S)-2-(2-(dimethylamino)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (5.90 g, 20.32 mmol) in DCM (30 mL). The mixture was stirred at 20 °C for 2 hours. TLC showed complete consumption of (S)-2-(2-(dimethylamino)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester. The mixture was poured into water and then adjusted to pH approximately 10 with aqueous NaOH solution (2N). The mixture was extracted with DCM (50 mL × 3), washed with brine and water, and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to give (S)-N,N-dimethyl-2-(pyrrolidine-2-yl)aniline (3.248 g). 1HNMR (400MHz, CDCl3) δppm: 7.38-7.52 (m, 1H) 7.18-7.24 (m, 1H) 7.03-7.16 (m, 2H) 4.59 (t, J = 7.9Hz, 1H), 3.24 (ddd, J = 10.0, 7.6 ,5.1Hz,1H),3.00(dt,J=9.8,7.7Hz,1H),2.71(br,6H),2.17-2.33(m,1H),2.14(s,1H),1.80-2.04(m,2H),1.54-1.77(m,1H). MS(ESI,m / e)[M+1] + 191.3.

[0628] Intermediate 2-z1: (S)-N,N-bis(methyl-d3)-2-(pyrrolidone-2-yl)aniline

[0629]

[0630] Step 1: (S)-2-(2-(d6-dimethylamino)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0631] At 0 °C, NaH (457.4 mg, 11.44 mmol) and CD3I (2.21 g, 15.25 mmol) were added to a solution of (S)-2-(2-aminophenyl)pyrrolidine-1-carboxylate (6.5 g, 22.87 mmol) in DMF (20 mL). The mixture was stirred at 45 °C for 14 hours. TLC showed complete consumption of (S)-2-(2-aminophenyl)pyrrolidine-1-carboxylate. The mixture was poured into water (50 mL), extracted with EA, and concentrated under vacuum to give (S)-2-(2-(bis(methyl-d3)amino)phenyl)pyrrolidine-1-carboxylate (880 mg), which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3) δppm: 7.00-7.22(m,4H),5.20-5.43(m,1H),3.49-3.72(m,2H),2.26-2.45(m,1H),1.72-1.95(m,3H),1.47(s,2H),1.18(s,7H). MS(ESI,m / e)[M+1] + 297.4.

[0632] Step 2: (S)-N,N-bis(methyl-d3)-2-(pyrrolidine-2-yl)aniline

[0633] TFA (5 mL) was added to a solution of (S)-2-(2-(bis(methyl-d3)amino)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (275 mg, 927.68 μmol) in DCM (10 mL). The mixture was stirred at 20 °C for 2 hours. TLC showed complete consumption of the reactants. The mixture was concentrated under vacuum to give a residue. The residue was dissolved in DCM (20 mL), washed with a saturated aqueous solution of Na2CO3 (20 mL), dried over Na2SO4, and concentrated under vacuum to give (S)-N,N-bis(methyl-d3)-2-(pyrrolidine-2-yl)aniline (100 mg). 1 H NMR (400MHz, CDCl3) δppm: 7.42 (dd, J=7.7, 1.3Hz, 1H), 7.19-7.26 (m, 1H), 7.07-7.18 (m, 2H), 4.63 (t, J=7.9Hz, 1H ), 3.24(ddd,J=10.3,7.4,5.4Hz,1H),3.04-3.11(m,1H),2.18-2.30(m,1H),1.87-2.06(m,2H),1.66-1.77(m,1H). MS(ESI,m / e)[M+1] + 197.3.

[0634] Intermediate 2-z2: 2-((1-(2-cyclopropylphenyl)pyrrolidone-2-yl)methyl)-2,6-diazaspiro[3.3]heptane

[0635]

[0636] Step 1: (1-(2-cyclopropylphenyl)pyrrolidine-2-yl)methanol

[0637] A solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(2-cyclopropylphenyl)pyrrolidine (1.5 g, 4.52 mmol) in MeOH / HCl (20 mL) was stirred for 1 hour at 20 °C. TLC indicated complete consumption of the reactants. The reaction mixture was concentrated to give (1-(2-cyclopropylphenyl)pyrrolidine-2-yl)methanol (0.8 g, crude). 1H NMR (400MHz, CDCl3) δppm: 7.81 (d, J=7.7Hz, 1H), 7.34-7.40 (m, 1H), 7.28-7.34 (m, 1H), 7.04 (dd, J=7.7, 1.2Hz, 1H), 4.55 (br, 1H), 4.19 (s, 1H), 4 .11(d,J=13.9Hz,1H),3.85-4.15(m,2H),3.59-3.81(m,3H),2.52-2.64 (m,1H),2.48(s,2H),2.37(s,2H),1.22-1.35(m,2H),0.77-0.98(m,2H). MS(ESI,m / e)[M+1] + 217.9.

[0638] Step 2: 1-(2-Cyclopropylphenyl)pyrrolidine-2-carboxaldehyde

[0639] At -65°C, DMSO (862.93 mg, 11.04 mmol) was added dropwise to a solution of (COCl)₂ (700.9 mg, 5.52 mmol) in DCM (20 mL). The mixture was stirred at -65°C for 0.5 h. Then, (1-(2-cyclopropylphenyl)pyrrolidine-2-yl)methanol (800.0 mg, 3.68 mmol) in DCM (2 mL) was added dropwise at -65°C. The mixture was stirred further at -65°C for 1 h. TLC indicated complete consumption of the reactants. TEA (2.89 g, 29.45 mmol) was added to the reaction mixture, and the mixture was heated to 20°C and maintained for 0.5 h. The reaction mixture was poured into water, extracted with DCM, dried over anhydrous Na₂SO₄, and concentrated under vacuum to give 1-(2-cyclopropylphenyl)pyrrolidine-2-carboxaldehyde (1.2 g, crude). 1 H NMR (400MHz, CDCl3) δppm: 12.10 (s, 1H), 9.39 (d, J = 3.8Hz, 1H), 7.06-7.16 (m, 1 H),6.85-7.03(m,3H),4.19(td,J=7.1,3.9Hz,1H),3.86-3.96(m,1H),3.05-3.1 6(m,6H),2.62(s,1H),2.12-2.26(m,2H),2.00-2.12(m,2H),1.90-2.00(m,1H), 1.42(t,J=7.3Hz,9H),1.00-1.10(m,1H),0.75-0.94(m,2H),0.59-0.67(m,1H).

[0640] Step 3: 6-((1-(2-cyclopropylphenyl)pyrrolidone-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0641] At 0 °C, NaBH(OAc)3 (1.18 g, 5.57 mmol) was slowly added to a solution of 1-(2-cyclopropylphenyl)pyrrolidine-2-carboxaldehyde (600 mg, 2.79 mmol) in DCM (10 mL). Then, tert-butyl oxalate 2,6-diazaspiro[3.3]heptane-2-carboxylic acid was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 1 hour. TLC indicated complete consumption of the reactants. The reaction mixture was poured into water, extracted with DCM (10 mL), and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 100 / 1 to 0 / 1). 600 mg of tert-butyl 6-((1-(2-cyclopropylphenyl)pyrrolidine-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid was obtained. 1 H NMR (400MHz, CDCl3) δppm:7.07-7.14(m,1H),7.01(d,J=7.9Hz,1H),6.90-6.97(m,1H) ,6.83-6.88(m,1H),3.95(s,4H),3.61-3.75(m,2H),3.16-3.43(m,4H),2.86(td,J=8.5 ,5.1Hz,1H),2.11-2.21(m,2H),2.06(s,1H),1.87-1.99(m,2H),1.74-1.87(m,2H),1. 57-1.74(m,1H),1.42(s,9H),0.95-1.13(m,1H),0.70-0.95(m,3H),0.52-0.62(m,1H). MS(ESI,m / e)[M+1] + 398.1.

[0642] Step 4: 2-((1-(2-cyclopropylphenyl)pyrrolidine-2-yl)methyl)-2,6-diazaspiro[3.3]heptane

[0643] TFA (2 mL) was added to a solution of 6-((1-(2-cyclopropylphenyl)pyrrolidone-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (600 mg, 1.51 mmol) in DCM (8 mL) at 20 °C. The mixture was stirred at 20 °C for 1 hour. TLC indicated complete consumption of the reactants. The reaction mixture was concentrated to give 326 mg of 2-((1-(2-cyclopropylphenyl)pyrrolidone-2-yl)methyl)-2,6-diazaspiro[3.3]heptane as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm: 7.10 (t, J = 7.3Hz, 1H), 6.99-7.04 (m, 1H), 6.91 (s, 1H), 6.80-6.88 (m, 1H), 3.78 (br, 4H), 3.57-3.74 (m, 2H), 3.22-3. 40(m,4H),2.80-3.03(m,3H),2.55(d,J=12.6Hz,1H),2.10-2.28(m,3H) ,1.90(s,1H),1.67-1.84(m,2H),0.82-1.10(m,2H),0.51-0.81(m,2H). MS(ESI,m / e)[M+1] + 298.2.

[0644] Intermediate 2-z3: (S)-4-(3-(2-(2-cyclopropylphenyl)pyrrolidone-1-yl)cyclobutyl)piperidine

[0645]

[0646] Step 1: tert-butyl 4-(2,2-dichloro-3-oxocyclobutyl)piperidine-1-carboxylate

[0647] 4-Vinylpiperidin-1-carboxylate tert-butyl ester (5.0 g, 23.66 mmol) was added to a mixture of Zn (4.64 g, 70.99 mmol) in dioxane (50 mL) at 20 °C under a N2 atmosphere. Then, CCl3COCl (6.45 g, 35.49 mmol) was added at 20 °C. The mixture was stirred at 20 °C for 12 hours. An aqueous solution of NaHCO3 (50 mL) was added to the reaction mixture at 0 °C. The mixture was then extracted with EA (50 mL × 5), and the combined organic phases were dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (SiO2, PE / EA = 50 / 1 to 20 / 1). 4-(2,2-dichloro-3-oxocyclobutyl)piperidin-1-carboxylate tert-butyl ester (3.0 g) was given. 1H NMR (400MHz, CDCl3) δppm: 4.05-4.21 (m, 2H) 3.04-3.27 (m, 2H) 2.77 (br, 2H) 2.60 (q, J = 10.4 Hz,1H)2.03-2.10(m,1H)1.84-1.97(m,1H)1.52-1.63(m,1H)1.46(s,9H)1.16-1.41(m,3H).

[0648] Step 2: 4-(3-oxocyclobutyl)piperidine-1-carboxylic acid tert-butyl ester

[0649] At 15°C under a nitrogen atmosphere, tert-butyl 4-(2,2-dichloro-3-oxocyclobutyl)piperidine-1-carboxylate (2.0 g, 6.21 mmol) in Diox (15 mL) was added to a mixture of Zn (1.22 g, 18.62 mmol) in HOAc (3.73 g, 62.07 mmol). The mixture was stirred at 15°C for 12 hours. The pH of the mixture was adjusted to approximately 9 with 33% NaOH aqueous solution and extracted with EA (50 mL × 3). After drying and concentration, the residue was purified by column chromatography (SiO2, PE / EA = 50 / 1 to 10 / 1). Tert-butyl 4-(3-oxocyclobutyl)piperidine-1-carboxylate (1.0 g, 3.95 mmol) was obtained. 1 H NMR (400MHz, CDCl3) δppm: 4.14 (s, 2H) 3.02-3.17 (m, 2H) 2.64-2.83 (m, 4H) 2.05-2.18 ( m,1H)1.72(d,J=12.8Hz,2H)1.35-1.36(m,1H)1.47(s,8H)1.15(d,J=12.3,4.3Hz,2H).

[0650] Step 3: (S)-4-(3-(2-(2-cyclopropylphenyl)pyrrolidone-1-yl)cyclobutyl)piperidine-1-carboxylic acid tert-butyl ester

[0651] To a solution of tert-butyl 4-(3-oxocyclobutyl)piperidin-1-carboxylate (0.7 g, 2.76 mmol, 1 equivalent) and (S)-2-(2-cyclopropylphenyl)pyrrolidine (569.23 mg, 3.04 mmol) in DCE (20 mL), AcOH (331.86 mg, 5.53 mmol) and NaBH(OAc)3 (1.17 mg, 5.53 mmol) were added. The mixture was stirred at 25 °C for 1 h. TLC showed complete consumption of the reactants. The reaction mixture was quenched with an aqueous solution of Na2CO3 (20 mL) and extracted with EA (20 mL × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative MPLC. 1.1 g of (S)-4-(3-(2-(2-cyclopropylphenyl)pyrrolidine-1-yl)cyclobutyl)piperidin-1-carboxylate was given. MS(ESI,m / e)[M+1] + 425.3.

[0652] Step 4: (S)-4-(3-(2-(2-cyclopropylphenyl)pyrrolidone-1-yl)cyclobutyl)piperidine

[0653] A mixture of (S)-4-(3-(2-(2-cyclopropylphenyl)pyrrolidone-1-yl)cyclobutyl)piperidine-1-carboxylic acid tert-butyl ester (0.9 g, 2.12 mmol) in DCM (5 mL) and TFA (5 mL) was stirred at 25 °C for 1 hour. LC / MS showed complete consumption of the reactants and a single main peak with the desired mass signal. The reaction mixture was concentrated under vacuum to remove the solvent. The residue was diluted with H2O (10 mL) and adjusted to pH approximately 9 with a saturated aqueous solution of Na2CO3. The mixture was extracted with EA (10 mL × 3), dried over Na2SO4, filtered, and concentrated. (S)-4-(3-(2-(2-cyclopropylphenyl)pyrrolidone-1-yl)cyclobutyl)piperidine (643 mg) was obtained. 1 H NMR (400MHz, CDCl3) δppm: 7.66-7.56 (m, 1H), 7.21-7.08 (m, 2H), 6.97 (d, J = 7.5Hz, 1H), 6.34 (s, 1H), 3.96 (q, J = 7.7Hz, 1H), 3.30-2.83 (m, 4 H),2.75-2.60(m,2H),2.46-2.31(m,1H),2.29-2.14(m,1H),2.06-1.44(m,10H),1.40-1.03(m,4H),0.98-0.85(m,2H),0.74-0.55(m,2H). MS(ESI,m / e)[M+1] + 325.3.

[0654] Intermediate 2-z4: 4-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)phenoxy)-1-methylpiperidine

[0655]

[0656] Step 1: 4-(2-formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester

[0657] K₂CO₃ (10.15 g, 74.53 mmol) was added to a solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (5.0 g, 24.84 mmol) and 2-fluorobenzaldehyde (6.17 g, 49.69 mmol) in DMSO (150 mL). The mixture was stirred at 100 °C for 6 hours. TLC indicated complete consumption of the reactants. The reaction mixture was cooled to room temperature and poured into H₂O (50 mL) and extracted with EA (50 mL × 3). The extract was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, PE / EA = 20 / 1 to 10 / 1) to give 4-(2-formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (6 g). MS (ESI, m / e) [M+1] + 306.1.

[0658] Step 2: (E)-4-(2-(((4-bromophenyl)imino)methyl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester

[0659] 4-(2-formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (4.30 g, 14.08 mmol), 4-bromoaniline (2.42 g, 14.08 mmol), TsOH (133.93 mg, 0.7 mmol) and The mixture of molecular sieve (2.15 g) and toluene (43 mL) was stirred at 140 °C for 12 h. TLC indicated that the reaction was complete. The reaction mixture was concentrated under vacuum to give crude (E)-4-(2-(((4-bromophenyl)imino)methyl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester (7.5 g, crude product), which was used directly in the next step.

[0660] Step 3: 4-(2-(1-((4-bromophenyl)amino)but-3-en-1-yl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester

[0661] At 0 °C, allyl magnesium bromide (49.63 mL, 1 M in THF) was added dropwise to a solution of (E)-4-(2-(((4-bromophenyl)imino)methyl)phenoxy)piperidine-1-carboxylate (5.7 g) in DCM (50 mL). The mixture was stirred at 0–15 °C for 3 hours. TLC indicated the reaction was complete. The reaction mixture was poured into an aqueous solution of HN4Cl (50 mL) and extracted with EA (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (elution: PE / EA = 50 / 1 to 20 / 1) to give 4-(2-(1-((4-bromophenyl)amino)but-3-en-1-yl)phenoxy)piperidine-1-carboxylate (4.2 g). MS (ESI, m / e) [M+1] + 502.2.

[0662] Step 4: 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester

[0663] BH3 THF (65.8 mL, 1 M in THF) was added to a solution of tert-butyl 4-(2-(1-((4-phenoxy)amino)but-3-en-1-yl)phenoxy)piperidin-1-carboxylate (3.3 g, 6.58 mmol) in 50 mL of THF at 0 °C. The mixture was stirred at 0 °C for 3 h. Then, H2O2 (6.58 mL, 65.81 mmol) was added dropwise, and the mixture was stirred at 0 °C for 1 h. NaOH aqueous solution (2.63 g, 65.81 mmol, 4 M) was added dropwise, and the mixture was stirred at 0–15 °C for 2 h. TLC indicated that the reaction was complete. The mixture was poured into a saturated Na2S2O3 aqueous solution (50 mL) and stirred for 0.5 h, and extracted with EA (100 mL × 2). The combined organic layers were washed with saturated Na₂S₂O₃ aqueous solution (50 mL), NaHCO₃ aqueous solution (50 mL), and brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, PE / EA = 5 / 1 to 2 / 1) to give 2.4 g of tert-butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenoxy)piperidine-1-carboxylic acid. MS (ESI, m / e) [M+1] + 520.3.

[0664] Step 5: 4-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester

[0665] At 0 °C, MsCl (1.01 mg, 8.86 mmol) was added to a mixture of tert-butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenoxy)piperidine-1-carboxylate (2.3 g, 4.43 mmol) and TEA (1.34 g, 13.28 mmol) in DCM (23 mL), and the mixture was stirred at 25 °C for 5 h. TLC showed that the reaction was complete. The reaction mixture was poured into H2O (20 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (elution: PE / EA = 10 / 1 to 2 / 1) to give tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidine-2-yl)phenoxy)piperidine-1-carboxylate. MS(ESI,m / e)[M+1] + 502.2.

[0666] Step 6: 4-(2-(1-(4-bromophenyl)pyrrolidine-2-yl)phenoxy)piperidine

[0667] TFA (7 mL) was added to a mixture of tert-butyl piperidine-1-carboxylate (1.8 g, 3.59 mmol) in DCM (20 mL), and the mixture was stirred at 15 °C for 3 hours. TLC indicated the reaction was complete. The mixture was concentrated under vacuum to give 4-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)phenoxy)piperidine (1.8 g, TFA salt, crude). MS (ESI, m / e) [M+1] + 402.2.

[0668] Step 7: 4-(2-(1-(4-bromophenyl)pyrrolidine-2-yl)phenoxy)-1-methylpiperidine

[0669] To a solution of 4-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)phenoxy)piperidine (1.0 g, 2.49 mmol) in MeOH (10 mL), an aqueous solution of HCHO (37%, 1.01 g, 12.46 mmol) and NaBH3CN (496.74 mg, 4.47 mmol) were added, and the mixture was stirred at 15 °C for 3 hours. The reaction was indicated by TLC to be complete. The reaction mixture was concentrated under vacuum. The residue was poured into a saturated aqueous solution of NaHCO3 (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 1 / 1 to 1 / 10) to give 4-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)phenoxy)-1-methylpiperidine. 1H NMR(400MHz, CDCl3)δppm:7.15-7.24(m,3H)6.99(dd,J=7.5,1.3Hz,1H)6.88(d,J=8.1Hz,1H)6.79-6.85(1H,m)6.30(2H,d,J=9.0Hz)4.96(1H,d ,J=7.9Hz)4.60(1H,s)3.63-3.70(m,1H)3.32-3.41(m,1H)2.64-2.87(m ,4H)2.46(s,3H)2.29-2.40(m,1H)2.14-2.24(m,2H)1.92-2.10(m,5H). MS(ESI,m / e)[M+1] + 415.1.

[0670] Intermediate 2-z5: (S)-2-((2-(2-cyclopropylphenyl)pyrrolidone-1-yl)methyl)-7-azaspiro[3.5]nonane

[0671]

[0672] Step 1: 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0673] t-BuOK (1M in THF, 10.86mL, 10.86mmol) was added to a solution of (methoxymethyl)triphenylphosphonium chloride (3.72g, 10.86mmol) in toluene (30mL). The mixture was stirred at 25°C under N2 protection for 20min. Then, 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (2g, 8.36mmol) was added to toluene (20mL). The mixture was stirred at 70°C for 4h. TLC showed complete consumption of the reactants. The reaction mixture was quenched with aqueous HN4Cl solution (30mL) and extracted with EA (50mL × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative MPLC to give 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (1.2g). MS (ESI, m / e) [M+1] + 268.3.

[0674] Step 2: 2-Formyl-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0675] At 25 °C, a mixture of 1 g (3.74 mmol) of 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester was stirred for 4 hours in ACN (36 mL), H2O (9 mL), and TFA (0.3 mL). TLC showed complete consumption of the reactants. The reaction mixture was quenched with an aqueous solution of NaHCO3 (20 mL) and extracted with EA (20 mL × 3), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative MPLC. 2-Formyl-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (390 mg) was given. 1 H NMR (400MHz, CDCl3) δppm: 9.76 (d, J = 1.5Hz, 1H), 3.39-3.32 (m, 2H), 3.31-3.25 (m,2H),3.20-3.10(m,1H),2.11-1.95(m,4H),1.64-1.56(m,2H),1.44(s,9H).

[0676] Step 3: (S)-2-((2-(2-cyclopropylphenyl)pyrrolidone-1-yl)methyl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0677] AcOH (118.52 mg, 1.97 mmol) and NaBH(OAc)3 (418.30 mg, 1.97 mmol) were added to a solution of 2-formyl-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (0.3 g, 1.18 mmol) and (S)-2-(2-cyclopropylphenyl)pyrrolidine (184.81 mg, 986.83 μmol) in DCE (5 mL). The mixture was stirred at 25 °C for 2 h. TLC showed complete consumption of the reactants. The reaction mixture was poured into an aqueous solution of Na2CO3 (5 mL) and extracted with EA (5 mL × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative MPLC. (S)-2-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (300 mg, 0.7 mmol, yield 59.66%) was obtained. MS (ESI, m / e) [M+1] + 425.3.

[0678] Step 4: (S)-2-((2-(2-cyclopropylphenyl)pyrrolidine-1-yl)methyl)-7-azaspiro[3.5]nonane

[0679] A mixture of (S)-2-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (0.3 g, 0.7 mmol) in DCM (1.5 mL) and TFA (1.5 mL) was stirred at 25 °C for 1 h. LC / MS showed complete consumption of the reactants and a single main peak with the desired mass signal. The reaction mixture was concentrated under vacuum to remove the solvent. The residue was diluted with H2O (10 mL) and adjusted to pH approximately 9 with Na2CO3. The mixture was extracted with EA (10 mL × 3), dried over Na2SO4, filtered, and concentrated. (180 mg) of (S)-2-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-7-azaspiro[3.5]nonane was obtained. 1 H NMR (400MHz, CDCl3) δppm: 7.58 (d, J = 7.7Hz, 1H), 7.23-7.17 (m, 1H), 7.17-7.11 (m, 1H), 7.00 (d, J = 7.1Hz ,1H),3.81(t,J=8.3Hz,1H),3.27(t,J=7.7Hz,1H),2.95-2.84(m,2H),2.83-2.72(m,2H),2.58(dd,J=8. 0,11.8Hz,1H),2.41(td,J=7.8,15.3Hz,1H),2.30-2.15(m,2H),2.13-1.98(m,2H),1.97-1.87(m,3H),1 .83(d,J=14.3Hz,1H),1.74-1.64(m,2H),1.63-1.53(m,1H),1.53-1.45(m,2H),1.44-1.31(m,2H),0.98

[0680] -0.85(m,2H),0.77-0.67(m,1H),0.66-0.55(m,1H). MS(ESI,m / e)[M+1] + 325.3.

[0681] Intermediate 2-z6: 1-(2-cyclopropylphenyl)-1,9-diazaspiro[5.5]undecane

[0682]

[0683] Step 1: 4-(but-3-en-1-yl)-4-((2-cyclopropylphenyl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0684] At -20°C, but-3-en-1-yl magnesium bromide (0.5 M, 159 mL, 79.51 mmol) was added to a solution of tert-butyl 4-((2-cyclopropylphenyl)imino)piperidin-1-carboxylate (5 g, 15.90 mmol) in DCM (50 mL). The mixture was stirred at -20°C for 2 hours. TLC indicated complete consumption of the reactants. The reaction mixture was quenched with 100 mL of aqueous HN4Cl solution and extracted with DCM (100 mL × 3), dried over Na2SO4, filtered, and concentrated. After purification of the residue by preparative MPLC, 2.5 g of tert-butyl 4-(but-3-en-1-yl)-4-((2-cyclopropylphenyl)amino)piperidin-1-carboxylate (2.5 g) was obtained as a yellow oil. MS (ESI, m / e) [M+1] + 371.3.

[0685] Step 2: 4-((2-cyclopropylphenyl)amino)-4-(4-hydroxybutyl)piperidine-1-carboxylic acid tert-butyl ester

[0686] At 0 °C, BH3·THF (1 M, 33.74 mL, 33.74 mmol) was added to a solution of tert-butyl 4-(but-3-en-1-yl)-4-((2-cyclopropylphenyl)amino)piperidin-1-carboxylate (2.5 g, 6.75 mmol) in 25 mL of THF. The mixture was stirred at 25 °C for 2 hours. Then, NaOH (2.5 M, 6.75 mL, 6.75 mmol) and H2O2 (11.48 g, 101.21 mmol) were added to the mixture at 0 °C. The mixture was stirred at 25 °C for 2 hours. TLC indicated complete consumption of the reactants. The reaction mixture was poured into an aqueous solution of Na2SO3 (100 mL) and extracted with EA (100 mL × 3), dried over Na2SO4, filtered, and concentrated. After purifying the residue by preparative MPLC, tert-butyl 4-((2-cyclopropylphenyl)amino)-4-(4-hydroxybutyl)piperidine-1-carboxylic acid was obtained (1.2 g). 1H NMR (400MHz, CDCl3) δppm: 7.09 (d, J = 7.5Hz, 1H), 7.07-7.01 (m, 1H), 6.74 (d, J = 7.9H z,1H),6.61(t,J=7.4Hz,1H),3.95(s,1H),3.77-3.67(m,1H),3.63-3.50(m,1H),3. 11-2.93(m,2H),2.55-2.41(m,1H),2.00(d,J=11.7Hz,1H),1.92-1.70(m,4H),1.66 -1.56(m,1H),1.46(s,9H),1.36-1.29(m,1H),0.98-0.86(m,5H),0.67-0.57(m,2H).

[0687] Step 3: 1-(2-Cyclopropylphenyl)-1,9-diazaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester

[0688] MsCl (294.82 mg, 2.57 mmol) was added to a solution of tert-butyl 4-((2-cyclopropylphenyl)amino)-4-(4-hydroxybutyl)piperidine-1-carboxylate (1 g, 2.57 mmol) in DCM (10 mL) and TEA (520.87 mg, 5.51 mmol) at 0 °C, and the mixture was stirred at 25 °C for 2 h. TLC indicated complete consumption of the reactants. The reaction mixture was quenched with an aqueous solution of HN4Cl (10 mL) and extracted with DCM (10 mL × 3), dried over Na2SO4, filtered, and concentrated. After purification of the residue by preparative MPLC, 0.7 g of tert-butyl 1-(2-cyclopropylphenyl)-1,9-diazaspiro[5.5]undecane-9-carboxylate was obtained as a yellow oil. MS (ESI, m / e) [M+1] + 371.4.

[0689] Step 4: 1-(2-Cyclopropylphenyl)-1,9-diazaspiro[5.5]undecane

[0690] A mixture of tert-butyl 1-(2-cyclopropylphenyl)-1,9-diazaspiro[5.5]undecane-9-carboxylate (0.7 g, 1.89 mmol) in DCM (4 mL) and TFA (4 mL) was stirred at 20 °C for 1 h. LC / MS showed complete consumption of the reactants and a single main peak with the desired mass signal. The reaction mixture was concentrated under vacuum to remove the solvent. The residue was diluted with H2O (10 mL) and adjusted to pH 9 with Na2CO3. The mixture was then extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried with Na2CO3, filtered, and concentrated to give 1-(2-cyclopropylphenyl)-1,9-diazaspiro[5.5]undecane (452 ​​mg). 1 H NMR(400MHz, CDCl3)δppm:7.25-7.20(m,1H),7.11-7.04(m,2H),6.73-6.66(m,1H), 3.40-3.27(m,2H),3.04-2.92(m,2H),2.81-2.58(m,3H),2.48-2.42(m,1H),2.33-2. 22(m,1H),1.82-1.67(m,2H),1.67-1.54(m,2H),1.22(dt,J=4.0,12.8Hz,1H),1.11 (d, J=6.8Hz, 3H), 0.94 (dd, J=1.8, 8.6Hz, 2H), 0.75-0.66 (m, 1H), 0.61-0.54 (m, 1H). MS(ESI,m / e)[M+1] + 271.4.

[0691] Intermediate 2-z7: 5-(2-cyclopropylphenyl)-N,N-dimethylpyrrolidine-3-amine

[0692]

[0693] Step 1: 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidine-3-one

[0694] A mixture of 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidine-3-ol (5.0 g, 15.46 mmol), DMP (8.52 g, 20.1 mmol), and NaHCO3 (1.43 g, 17.0 mmol) in DCM (50 mL) was prepared. The mixture was stirred at 20 °C for 3 hours. TLC indicated the reaction was complete. The mixture was quenched with Na2S2O3 (20 mL) and the pH was adjusted to approximately 10 with an aqueous solution of Na2CO3. After extraction of the mixture with DCM (50 mL × 3), the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE / EA = 50 / 1 to 15 / 1) to give 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidine-3-one (3.5 g). 1 H NMR (400MHz, CDCl3) δppm: 7.18-7.23 (m, 2H), 7.12-7.16 (m, 1H), 7.02-7.08 (m, 1H), 6.33 (d, J = 8.8Hz, 1H), 4.54 (d, J = 18.7Hz, 1H), 3.83 (d, J = 18.7Hz, 1H),3.21(dd,J=17.9,10.03Hz,1H),2.50(d,J=17.9Hz,1H),1.85-1.95(m, 1H),1.26(s,8H),0.93-1.08(m,2H),0.70-0.79(m,1H),0.58-0.65(m,1H).

[0695] Step 2: 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)-N,N-dimethylpyrrolidine-3-amine

[0696] NaBH(OAc)3 (6.92 g, 32.67 mmol) was added to a mixture of 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidine-3-one (3.5 g, 10.89 mmol) and dimethylamine hydrochloride (3.55 g, 43.55 mmol) in DCE (40 mL). The mixture was stirred at 20 °C under a N2 atmosphere for 2 h. The reaction was indicated by TLC to be complete. The mixture was concentrated and purified by preparative HPLC (TFA conditions). 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)-N,N-dimethylpyrrolidine-3-amine (2.2 g, 6.28 mmol, yield 57.64%) was given. MS (ESI, m / e) [M+1] + 351.3.

[0697] Step 3: 5-(2-Cyclopropylphenyl)-N,N-Dimethylpyrrolidine-3-amine

[0698] A mixture of 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)-N,N-dimethylpyrrolidine-3-amine (1.0 g, 2.85 mmol) in TFA (10 mL) was stirred at 70 °C for 12 h. TLC showed the reaction was complete. The mixture was concentrated and adjusted to pH approximately 10 with saturated aqueous Na₂CO₃ solution (10 mL). The mixture was extracted with EA (10 mL × 5), and the combined organic layers were dried over anhydrous Na₂SO₄ and then concentrated. 5-(2-cyclopropylphenyl)-N,N-dimethylpyrrolidine-3-amine (170 mg) was given. 1 H NMR (400MHz, CDCl3) δppm: 7.52-7.63 (m, 1H), 7.11-7.24 (m, 2H), 7.00 (d, J = 7.5Hz, 1H), 4.70-4.92 (m, 1H), 3.07-3.42 (m, 2H), 2.81-2.99(m,1H),2.38-2.50(m,1H),2.25-2.35(m,4H),1.63(dt,J=11.9,9.8Hz,1H),0.89-0.98(m,2H),0.62-0.76(m,1H). MS(ESI,m / e)[M+1] + 231.3.

[0699] Intermediate 2-z8: (R)-4-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

[0700]

[0701] Step 1: (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0702] A mixture of (R)-1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethyl ketone (8 g, 24.8 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (11.5 g, 37.2 mmol), Pd(OAc)2 (560 mg, 2.48 mmol), tricyclohexylphosphine (1.4 g, 4.96 mmol), and K3PO4 (15.8 g, 74.4 mmol, 3.0 equivalents) in toluene (100 mL) and H2O (5 mL) was heated to 100 °C and stirred for 5 hours under N2 protection. The reaction was complete by TLC. The mixture was cooled to room temperature and diluted with EA (50 mL), washed with water (100 mL) and brine (100 mL), dried over Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography (elution buffer: PE / EA = 5 / 1 to 2 / 1) to give (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (9 g, crude) as a brown solid. MS (ESI, m / e) [M+1] + 425.2.

[0703] Step 2: (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidone-2-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

[0704] A mixture of (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (9 g, 21.2 mmol) and Pd / C (10%, 2 g) in CH3OH (200 mL)) was stirred at 20 °C under a H2 atmosphere (15 psi) for 12 hours. LC / MS showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated to give (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (7.5 g, crude) as a grayish-white solid. MS (ESI, m / e) [M+1] + 427.3.

[0705] Step 3: (R)-4-(2-(pyrrolidone-2-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

[0706] A solution of NaOH (2.8 g, 70.4 mmol) in H₂O (30 mL) was added to a solution of (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidine-2-yl)phenyl)piperidine-1-carboxylate (7.5 g, 17.6 mmol) in CH₃OH (50 mL). The mixture was then heated to 40 °C and stirred for 2 hours. TLC showed that the reaction was complete. The mixture was concentrated under vacuum to remove the organic solvent, and the remaining aqueous solution was extracted with EA (100 mL). The organic layer was washed with brine (100 mL), dried over Na₂SO₄, and concentrated to give (R)-4-(2-(pyrrolidine-2-yl)phenyl)piperidine-1-carboxylate (6 g, crude). MS (ESI, m / e) [M+1] + 331.3.

[0707] Step 4: (R)-4-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

[0708] A mixture of (R)-4-(2-(pyrrolidone-2-yl)phenyl)piperidin-1-carboxylic acid tert-butyl ester (2 g, 6.1 mmol), 1-bromo-4-iodobenzene (3.5 g, 12.2 mmol), Pd2(dba)3 (559 mg, 0.61 mmol), BINAP (760 mg, 1.22 mmol), and t-BuOK (1.4 g, 12.2 mmol) in toluene (20 mL) was heated to 100 °C and stirred for 12 hours under N2 protection. TLC showed that the reaction was complete. The mixture was cooled to room temperature and diluted with EA (20 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (elution buffer: PE / EA = 20 / 1 to 15 / 1) to give (R)-4-(2-(1-(4-bromophenyl)pyrrolidone-2-yl)phenyl)piperidin-1-carboxylic acid tert-butyl ester (2 g). MS (ESI, m / e) [M+1] + 487.8.

[0709] Intermediate 2-z9: 1-(azacyclobutane-3-yl)-2-(2-cyclopropylphenyl)pyrrolidine

[0710]

[0711] Step 1: tert-butyl 3-(2-(2-cyclopropylphenyl)pyrrolidone-1-yl)azacyclobutane-1-carboxylate

[0712] NaBH(OAc)3 (600 mg, 3 mmol) was added to a solution of 2-(2-cyclopropylphenyl)pyrrolidine (700 mg, 3.7 mmol) and tert-butyl 3-oxoazacyclobutane-1-carboxylate (632 mg, 3.7 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 14 hours. Then, a saturated aqueous solution of NH4Cl (30 mL) was added to the reaction mixture with stirring. The organic phase was separated and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to give 1 g of crude product. MS (ESI, m / e) [M+1] + 343.0.

[0713] Step 2: 1-(azacyclobutane-3-yl)-2-(2-cyclopropylphenyl)pyrrolidine

[0714] TFA (2 mL) was added to a solution of 680 mg (2.0 mmol) of tert-butyl 3-(2-(2-cyclopropylphenyl)pyrrolidone-1-yl)azacyclobutane-1-carboxylate in 10 mL of DCM. The mixture was stirred at room temperature for 4 hours. The solvent was removed to give 700 mg of 1-(azacyclobutane-3-yl)-2-(2-cyclopropylphenyl)pyrrolidone. MS (ESI, m / e) [M+1] + 243.0.

[0715] Intermediate 2-z10: 6-((2-(2-cyclopropylphenyl)pyrrolidone-1-yl)methyl)-2-azaspiro[3.3]heptane

[0716] Step 1: 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0717] t-BuOK (2.0 g, 0.018 mol) was added to a solution of 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3 g, 0.014 mol) in toluene (50 mL). The mixture was stirred at 25 °C for 20 min under N2 atmosphere. Then, a solution of (methoxymethyl)triphenylphosphonium chloride (6.2 g, 0.018 mol) in toluene (20 mL) was added. The mixture was stirred at 70 °C for 4 h. TLC indicated the reaction was complete. After removing the solvent, the residue was purified by silica gel column chromatography (elution: PE / EA = 20 / 1) to give 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1 g). 1 H NMR (400MHz, CDCl3) δppm: 5.81 (s, 1H), 3.86-4.00 (s, 4H), 3.55 (s, 3H), 2.86 (s, 2H), 2.79 (s, 2H), 1.43 (s, 9H).

[0718] Step 2: 6-Formyl-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0719] TFA (1 mL) was added to a solution of 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1 g, 4.18 mmol) in CH3CN (36 mL) and H2O (9 mL), and the mixture was stirred at room temperature for 2 hours. TLC indicated that the reaction was complete. The reaction mixture was adjusted to pH 8–9 with aqueous Na2CO3 solution and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried, filtered, and concentrated to give 6-formyl-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (0.9 g), which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3) δppm: 9.71 (d, J = 1.7Hz, 1H), 3.94 (s, 2H), 3.85-3.86 (m, 1H), 3 .80-3.84(m,1H),3.82(s,1H),2.98-3.20(m,1H),2.30-2.46(m,4H),1.41(s,9H).

[0720] Step 3: 6-((2-(2-cyclopropylphenyl)pyrrolidone-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0721] 2-(2-cyclopropylphenyl)pyrrolidine (0.68 g, 3.63 mmol) and HOAc (436 mg, 7.26 mmol) were added to a solution of 6-formyl-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (0.9 g, 4.0 mmol) in DCE (30 mL). The mixture was stirred at room temperature for 30 min, and then NaBH(OAc)3 (1.54 g, 7.26 mmol) was added, followed by stirring for another 2 h. The reaction was shown to be complete by LC / MS. The reaction was quenched with an aqueous solution of Na2CO3 (10 mL) and then extracted with EA (3 × 50 mL). The organic layer was dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 2 / 1) to give 6-((2-(2-cyclopropylphenyl)pyrrolidine-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (0.8 g). MS(ESI,m / e)[M+1] + 397.3.

[0722] Step 4: 6-((2-(2-cyclopropylphenyl)pyrrolidine-1-yl)methyl)-2-azaspiro[3.3]heptane

[0723] At 0 °C, TFA (10 mL) was added dropwise to a solution of tert-butyl 6-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylate (0.8 g, 2.0 mmol) in DCM (20 mL). The mixture was then stirred at room temperature for 2 hours. TLC indicated that the reaction was complete. The reaction mixture was adjusted to pH 8-9 using an aqueous solution of Na2CO3 and then extracted with DCM. The organic layer was dried, filtered, and concentrated to give 6-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-2-azaspiro[3.3]heptane (250 mg). 1 H NMR (400MHz, CDCl3) δppm: 7.57 (d, J = 7.4Hz, 1H), 7.15-7.23 (m, 1H), 7.13 (dt, J = 1 .3,7.4Hz,1H),6.98(d,J=7.4Hz,1H),3.70-3.84(m,1H),3.62(d,J=1.7Hz,2H),3 .41(s,2H),3.26(t,J=8.3Hz,1H),2.43-2.56(m,1H),2.39(s,1H),2.17-2.27(m, 5H),1.95-2.05(m,2H),1.47-1.95(m,5H),0.82-1.00(m,2H),0.54-0.75(m,2H). MS(ESI,m / e)[M+1] + 297.3.

[0724] Intermediate 2-z11: 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexane

[0725]

[0726] Step 1: 2-(2-cyclopropylphenyl)-4-(toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0727] At 20 °C, NaH (0.71 g, 17.8 mmol) was added to a solution of 4.5 g (14.8 mmol) of 2-(2-cyclopropylphenyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester in THF (50 mL), and the mixture was stirred for 30 min. Then, TosCl (3.4 g, 17.8 mmol) was added to the mixture, and the mixture was stirred further at 20 °C for 12 h. TLC showed the reaction was complete. The reaction mixture was quenched with water (100 mL) and extracted with EA (100 mL). The organic layer was washed with brine (100 mL), dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 10 / 1 to 5 / 1) to give 2-(2-cyclopropylphenyl)-4-(toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.9 g). MS (ESI, m / e) [M+1] + 458.2.

[0728] Step 2: tert-butyl 2-(2-cyclopropylphenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate

[0729] t-BuOK (1.4 g, 12.6 mmol) was added fractionally to a solution of 2-(2-cyclopropylphenyl)-4-(toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.9 g, 6.3 mmol) in THF (50 mL). After addition, the mixture was stirred at 20 °C for 12 h. TLC showed the reaction was complete. The mixture was quenched with saturated NH4Cl aqueous solution (50 mL) and extracted with EA (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 100 / 1) to give 2-(2-cyclopropylphenyl)-2,3-dihydro-1H-pyrrolidine-1-carboxylic acid tert-butyl ester (900 mg). MS (ESI, m / e) [M+1] + 286.4.

[0730] Step 3: 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

[0731] At 0 °C, Et₂Zn (1 M in toluene, 15.8 mL, 15.8 mmol) and ClCH₂I (5.56 g, 32 mmol) were added to a solution of 2-(2-cyclopropylphenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate tert-butyl ester (900 mg, 3.2 mmol) in toluene (20 mL). The mixture was then stirred at 20 °C for 4 hours. TLC showed the reaction was complete. The reaction mixture was quenched with saturated aqueous NH₄Cl solution (20 mL) and extracted with EA (30 mL × 2). The organic layer was washed with brine (20 mL), dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 30 / 1) to give 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate tert-butyl ester (500 mg). MS (ESI, m / e) [M+1] + 300.2.

[0732] Step 4: 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexane

[0733] A solution of tert-butyl 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (500 mg, 1.7 mmol) in HCl (4 M, 10 mL) in EA was stirred at 20 °C for 2 hours. TLC showed the reaction was complete. The mixture was quenched with a saturated aqueous solution of Na₂CO₃ (20 mL) and extracted with EA (20 mL × 2). The organic layer was washed with brine (20 mL), dried over Na₂SO₄, and concentrated to give 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexane (293 mg). 1 H NMR (400MHz, CDCl3) δppm: 7.63 (dd, J=7.7, 1.3Hz, 1H), 7.18-7.23 (m, 1H), 7.11-7.16 (m, 1H), 6.98 (d ,J=7.2Hz,1H),4.54(dd,J=10.0,7.0Hz,1H),3.00(td,J=6.0,2.6Hz,1H),2.37(dd,J=12.3,7.0Hz,1H ),1.91-2.02(m,1H),1.72-1.83(m,1H),1.48-1.59(m,1H),0.87-1.03(m,1H),0.87-1.03(m,1H),0.7 7-0.84(m,1H),0.60-0.73(m,2H),0.60-0.73(m,2H),0.42(dt,J=8.1,5.9Hz,1H),0.37-0.47(m,1H). MS(ESI,m / e)[M+1] + 200.2.

[0734] Intermediate 2-z12: 1-(2-cyclopropylphenyl)octahydrocyclopentano[c]pyrrole

[0735]

[0736] Step 1: 3-(2-cyclopropylphenyl)hexahydrocyclopentan[c]pyrrole-1(2H)-one

[0737] At -78°C under a N2 atmosphere, n-BuLi (21 mL, 0.052 mol, 2.5 M in hexane) was added to a solution of 1-bromo-2-cyclopropylbenzene (8.5 g, 0.043 mol) in THF (20 mL). The mixture was then stirred at -78°C for 1 hour. At -78°C under a N2 atmosphere, n-BuLi (13 mL, 0.035 mol, 2.5 M in hexane) was added to a solution of tetrahydrocyclopentan[c]pyrrole-1,3(2H,3aH)-dione (4 g, 0.029 mol) in THF (20 mL). The mixture was then stirred at 0°C for 1 hour. At -78°C, a solution of 1-bromo-2-cyclopropylbenzene was added dropwise to a solution of tetrahydrocyclopentan[c]pyrrole-1,3(2H,3aH)-dione. The resulting mixture was stirred at room temperature for 3 hours. TLC showed that tetrahydrocyclopentane[c]pyrrole-1,3(2H,3aH)-dione was consumed. NaBH3CN (2.2 g, 0.035 mol) was added to the mixture, followed by the addition of 6N hydrochloric acid (20 mL) at 0 °C, and further stirring for 1 hour at room temperature. Na2CO3 (50 mL) was added to the mixture to adjust the pH to 8–9. The mixture was then extracted with EA (50 mL × 3), and the organic layer was washed with brine (50 mL × 2). The combined organic layers were dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 10 / 1) to give 3-(2-cyclopropylphenyl)hexahydrocyclopentane[c]pyrrole-1(2H)-one (2.8 g). 1H NMR (400MHz, CDCl3) δppm:7.19-7.23(m,1H),7.11-7.16(m,2H),6.95-7.01 (m,1H),6.20(s,1H),5.44(d,J=7.7Hz,1H),3.08-3.24(m,1H),2.93-3.04(m ,1H),2.73-2.87(m,1H),1.91-2.06(m,1H),1.73-1.83(m,2H),1.51-1.64(m ,1H),1.40-1.49(m,2H),1.33(s,1H),1.10-1.20(m,1H),0.52-0.73(m,2H). MS(ESI,m / e)[M+1] + 242.3.

[0738] Step 2: 1-(2-cyclopropylphenyl)octahydrocyclopentane[c]pyrrole

[0739] BH3·DMS (4.2 mL, 41.5 mmol, 1 equivalence) was added dropwise to a solution of 3-(2-cyclopropylphenyl)hexahydrocyclopentan[c]pyrrole-1(2H)-one (1.0 g, 4.15 mmol, 1 equivalence) in THF (20 mL) at 0 °C. After the addition, the mixture was stirred at room temperature for 12 h. TLC showed complete consumption of the reactants. MeOH (2 mL) and 1 N HCl (20 mL) were carefully added to the reaction mixture at 0 °C. The mixture was then stirred at room temperature for 1 h. The reaction was quenched with an aqueous solution of Na2CO3 (50 mL) and adjusted to pH approximately 9. The mixture was extracted with EA (50 mL × 3). The organic layer was washed with brine (50 mL × 2), dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 5 / 1) to give the target product (300 mg). 1 H NMR (400MHz, CDCl3) δppm:7.54-7.59(m,1H),7.12-7.19(m,2H),6.95-7.01(m,1H) ),4.53(d,J=6.97Hz,1H),3.02-3.09(m,1H),2.89-3.02(m,2H),2.65(quin,J=7. 86Hz,1H),1.91-2.03(m,2H),1.55-1.64(m,1H),1.24-1.39(m,1H),1.18-1.39(m ,1H),1.18-1.20(m,1H),1.11-1.21(m,1H),0.87-0.99(m,3H),0.61-0.78(m,2H). MS(ESI,m / e)[M+1] +228.5.

[0740] Intermediate 2-z13: 2-((5-(2-cyclopropylphenyl)pyrrolidone-3-yl)oxy)-N,N-dimethylethyl-1-amine

[0741]

[0742] Step 1: 2-((1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidine-3-yl)oxy)-N,N-dimethylacetamide

[0743] NaH (1.43 g, 35.71 mmol, 60%) was added dropwise to a solution of 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidine-3-ol (10.5 g, 32.46 mmol) in DMF (250 mL) at 10 °C. The mixture was stirred at 10 °C for 30 min. Then, 2-chloro-N,N-dimethylacetamide (4.14 g, 34.09 mmol) was added dropwise at 10 °C. The mixture was stirred at 10 °C for 2 h. TLC indicated complete consumption of the reactants. The reaction mixture was quenched with saturated aqueous NH4Cl solution (50 mL) and extracted with EA (100 mL × 3). The combined organic phases were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE / EA = 5 / 1 to 0 / 1) to give 2-((1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidine-3-yl)oxy)-N,N-dimethylacetamide (8.48 g). MS (ESI, m / e) [M+1] + 410.1.

[0744] Step 2: 2-((5-(2-cyclopropylphenyl)pyrrolidine-3-yl)oxy)-N,N-dimethylacetamide

[0745] A solution of 2-((1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidine-3-yl)oxy)-N,N-dimethylacetamide (8.4 g, 20.56 mmol) in TFA (100 mL) was stirred at 75 °C for 12 h. LC / MS was performed to indicate that the reactants were completely consumed and the desired mass signal was obtained. The reaction mixture was concentrated to approximately 20 mL under vacuum and poured into a saturated aqueous solution of NaHCO3 (50 mL) to adjust the pH to approximately 8. The aqueous phase was extracted with EA (100 mL × 3). The combined organic phases were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. 2-((5-(2-cyclopropylphenyl)pyrrolidine-3-yl)oxy)-N,N-dimethylacetamide (22 g, crude) was given. MS (ESI, m / e) [M+1]+ 289.3.

[0746] Step 3: 2-((5-(2-cyclopropylphenyl)pyrrolidine-3-yl)oxy)-N,N-dimethylethylamine was added dropwise to a solution of 2-((5-(2-cyclopropylphenyl)pyrrolidine-3-yl)oxy)-N,N-dimethylacetamide (1.2 g, 4.16 mmol) in THF (50 mL) at 20 °C. BH3·DMS (8.32 mL, 83.2 mmol, 10 N in DMS) was added dropwise. The mixture was heated to 70 °C and stirred for 10 hours. LC / MS indicated complete consumption of the reactants. The reaction mixture was quenched with MeOH (10 mL) and decomplexed by reflux for 2 hours using HCl / MeOH (4 N, 20 mL). LC / MS indicated the formation of the desired compound. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (Xtimate C18 10u 250mm*50mm; mobile phase: [water (0.1% TFA)-ACN]). 2-((5-(2-cyclopropylphenyl)pyrrolidine-3-yl)oxy)-N,N-dimethylethylamine (1.4 g, TFA salt) was obtained. This salt was dissolved in CH3CN (100 mL), and K2CO3 (560.9 mg, 4.07 mmol, 1.5 equivalence) was added to the solution in one step, followed by stirring at 20 °C for 2 hours. The mixture was filtered, and the filtrate was concentrated to give 2-((5-(2-cyclopropylphenyl)pyrrolidine-3-yl)oxy)-N,N-dimethylethylamine (385 mg). 1 H NMR (400MHz, CDCl3) δppm:7.46-7.57(m,1H),7.10-7.20(m,2H),6.93-7.02(m,1H) ,4.91(t,J=8.0Hz,1H),4.10-4.20(m,1H),3.50-3.58(m,2H),3.34(dd,J=11.3,5. 1Hz,1H),3.05-3.18(m,1H),2.54(t,J=5.8Hz,2H),2.35-2.46(m,1H),2.19-2.33( m,6H),1.92-2.03(m,1H),1.54-1.91(m,2H),0.84-1.00(m,2H),0.56-0.73(m,2H). MS(ESI,m / e)[M+1] + 275.1.

[0747] Intermediate 2-z14: (S)-2-(2-(2-ethoxyphenyl)pyrrolidone-1-yl)-7-azaspiro[3.5]nonane

[0748]

[0749] Step 1: (S)-2-(2-ethoxyphenyl)pyrrolidine

[0750] CuBr (475.81 mg, 3.32 mmol) was added to a mixture of (S)-2-(2-bromophenyl)pyrrolidine (1.5 g, 6.63 mmol) and EtONa (1.35 g, 19.90 mmol) in EtOH (15 mL). The mixture was then stirred at 90 °C for 12 h. LC / MS showed that the reaction was complete and showed a peak with the desired mass signal. The mixture was cooled to room temperature and adjusted to pH approximately 11 with aqueous Na₂CO₃ solution, and then extracted with EA (20 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative HPLC (TFA conditions). (S)-2-(2-ethoxyphenyl)pyrrolidine (0.7 g) was given. MS (ESI, m / e) [M+1] + 192.3.

[0751] Step 2: (S)-2-(2-(2-ethoxyphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0752] A mixture of (S)-2-(2-ethoxyphenyl)pyrrolidine (0.5 g, 2.61 mmol), tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (568.71 mg, 2.38 mmol), and HOAc (428.13 mg, 7.13 mmol) in a DCE (5 mL) was stirred at 20 °C for 2 h. NaBH(OAc)3 (1.01 g, 4.75 mmol) was added to the mixture, and the mixture was stirred at 20 °C for another 12 h. TLC showed the reaction was complete. The mixture was adjusted to pH approximately 11 with an aqueous solution of Na₂CO₃ and then extracted with EA (20 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution buffer: PE / EA = 20 / 1 to 10 / 1) to give (S)-2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (0.6 g). MS (ESI, m / e) [M+1] + 415.4.

[0753] Step 3: (S)-2-(2-(2-ethoxyphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonane

[0754] TFA (1.65 g, 14.47 mmol) was added to a solution of (S)-2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (0.6 g, 1.45 mmol) in DCM (10 mL). The mixture was stirred at 20 °C for 1 hour. TLC indicated the formation of a new spot. The reaction mixture was adjusted to pH 8-9 using aqueous Na2CO3 solution and then extracted with DCM (10 mL × 5). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. (S)-2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (360 mg) was obtained. 1 H NMR (400MHz, CDCl3) δppm: 7.49-7.58(m,1H),7.13-7.21(m,1H),6.93(t,J=7.4Hz,1H),6.82(d,J=7.4Hz,1H),4.04(d,J=7.1Hz,2H),3.91(t,J=7.1H z,1H),3.07-3.21(m,2H),2.72-2.90(m,4H),2.40(q,J=8.4Hz,1H),2.14- 2.26(m,1H),1.73-1.94(m,5H),1.47-1.73(m,8H),1.41(t,J=6.95Hz,3H). MS(ESI,m / e)[M+1] + 315.3.

[0755] Intermediate 2-z15: 2-(2'-cyclopropyl-[1,1'-diphenyl]-2-yl)-7-azaspiro[3.5]nonane

[0756]

[0757] Step 1: 2-(2-Toluenesulfonylhydrazinyl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0758] A mixture of 10.00 g (41.79 mmol) of 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester and 4-methylbenzenesulfonylhydrazine (9.34 g (50.14 mmol)) in EtOH (100 mL) was stirred at 80 °C for 1 hour. TLC showed that the reaction was complete. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum to give 8.0 g (crude) of 2-(2-toluenesulfonylhydrazinyl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester. 1H NMR (400MHz, CDCl3) δppm: 7.84 (d, J = 8.1 Hz, 2H), 7.39 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 3.22 -3.39(m,5H),2.64(s,2H),2.49(s,2H),2.44(s,3H),1.54(t,J=5.5Hz,4H),1.45(s,10H).

[0759] Step 2: 2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0760] A mixture of tert-butyl 2-(2-toluenesulfonylhydrazine)-7-azaspiro[3.5]nonane-7-carboxylate (8.0 g, 19.63 mmol) and (2-methoxyphenyl)boronic acid (8.95 g, 58.89 mmol), Cs₂CO₃ (19.19 g, 58.89 mmol) in dioxane (100 mL) was stirred at 110 °C for 4 hours. TLC showed the reaction was complete. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (elution: PE). 2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (3.0 g) was given. MS (ESI, m / e) [M+1] + 332.3.

[0761] Step 3: tert-butyl 2-(2-hydroxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

[0762] BBr3 (9.07 g, 36.20 mmol) was added to a solution of tert-butyl 2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (3.0 g, 9.05 mmol) in DCM (30 mL) at -78 °C under a N2 atmosphere. After addition, the mixture was stirred at 20 °C for 6 hours. LC / MS indicated the reaction was complete. The mixture was quenched with aqueous Na2CO3 solution and extracted with DCM (20 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (elution: PE / EA = 20 / 1). 1.3 g of tert-butyl 2-(2-hydroxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate was given. MS (ESI, m / e) [M+1] + 318.4.

[0763] Step 4: 2-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0764] Under a nitrogen atmosphere and at 0 °C, Tf₂O (1.73 g, 12.29 mmol) was added to a solution of tert-butyl 2-(2-hydroxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (1.3 g, 4.10 mmol) and TEA (1.24 g, 6.14 mmol) in DCM (10 mL). The mixture was then stirred at 25 °C for 1 hour. TLC indicated the reaction was complete. The mixture was quenched with H₂O (10 mL) and NH₄Cl (10 mL) and extracted with DCM (10 mL × 3). The organic phase was washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel column chromatography (elution: PE / EA = 40 / 1) to give tert-butyl 2-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (1.84 g). MS(ESI,m / e)[M+1] + 450.2.

[0765] Step 5: 2-(2'-cyclopropyl-[1,1'-diphenyl]-2-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0766] Under a nitrogen atmosphere, Pd(dppf)Cl2 (1.14 g, 1.56 mmol) was added to a mixture of tert-butyl 2-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (1.4 g, 3.11 mmol), 2-(2-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (1.52 g, 6.23 mmol), and Cs2CO3 (3.04 g, 9.34 mmol) in dioxane (10 mL). The mixture was stirred at 90 °C for 12 hours. TLC indicated that the reactants were completely consumed and a new spot was formed. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (elution buffer: PE / EA = 50 / 1) to give 0.6 mg of tert-butyl 2-(2'-cyclopropyl-[1,1'-diphenyl]-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate. MS (ESI, m / e) [M+1] + 418.5.

[0767] Step 6: 2-(2'-cyclopropyl-[1,1'-diphenyl]-2-yl)-7-azaspiro[3.5]nonane

[0768] TFA (1.39 g, 14.37 mmol) was added to a mixture of tert-butyl 2-(2'-cyclopropyl-[1,1'-diphenyl]-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.6 g, 1.44 mmol) in DCM (5 mL). The mixture was stirred at 25 °C for 2 h. The reaction was indicated to be complete by LC / MS. The reaction mixture was adjusted to pH approximately 10 with aqueous Na₂CO₃ solution and then extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated. 2-(2'-cyclopropyl-[1,1'-diphenyl]-2-yl)-7-azaspiro[3.5]nonane (340 mg) was given. 1 H NMR (400MHz, CDCl3) δppm: 7.34-7.46 (m, 2H), 7.22-7.32 (m, 3H), 7.13-7.22 (m, 2H), 7.06 (d, J = 7.5Hz, 1H), 6.83 (d, J = 7.7Hz, 1H), 3 .46(m,J=9.15Hz,1H),3.30(s,2H),2.70-2.84(m,4H),1.68-2.03(m,5H),1.45-1.64(m,5H),0.72-0.83(m,2H),0.61-0.71(m,2H). MS(ESI,m / e)[M+1] + 318.1.

[0769] Intermediate 2-z16: 4-((2-(2-cyclopropylphenyl)pyrrolidone-1-yl)methyl)benzaldehyde

[0770]

[0771] Step 1: Methyl 4-((2-(2-cyclopropylphenyl)pyrrolidone-1-yl)methyl)benzoate

[0772] CH3COOH (0.87 g, 14.58 mmol) and NaBH(OAc)3 (3.09 g, 14.58 mmol) were added to a solution of 2-(2-cyclopropylphenyl)pyrrolidine (1.5 g, 8.01 mmol), methyl 4-formylbenzoate (1.14 g, 7.29 mmol), and dissolved in water in 20 mL of DCE. The mixture was stirred at 25 °C for 4 hours. TLC showed complete consumption of the reactants. The reaction mixture was poured into water (50 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (25 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution: PE / EA = 50 / 1 to 1 / 1) to give methyl 4-((2-(2-cyclopropylphenyl)pyrrolidine-1-yl)methyl)benzoate (1.8 g). MS(ESI,m / e)[M+1] + 336.5.

[0773] Step 2: (4-((2-(2-cyclopropylphenyl)pyrrolidone-1-yl)methyl)phenyl)methanol

[0774] At 0 °C, LiAlH4 (46 g, 17.28 mmol) was slowly added to a solution of methyl 4-((2-(2-cyclopropylphenyl)pyrrolidone-1-yl)methyl)benzoate (2 g, 6 mmol) in THF (30 mL). The mixture was stirred at 0 °C for 30 min. TLC showed complete consumption of the reactants. The residue was quenched with saturated NH4Cl (50 mL) aqueous solution and extracted with EA (50 mL). The organic phase was washed with brine, dried over Na2SO4, and concentrated to give (4-((2-(2-cyclopropylphenyl)pyrrolidone-1-yl)methyl)phenyl)methanol (1.5 g). MS (ESI, m / e) [M+1] + 308.3.

[0775] Step 3: 4-((2-(2-cyclopropylphenyl)pyrrolidone-1-yl)methyl)benzaldehyde

[0776] DMP (4.14 g, 9.78 mmol) was added to a solution of (1.5 g, 4.89 mmol) in THF (20 mL). The mixture was stirred at 25 °C for 4 h. LC / MS showed complete consumption of the reactants and a main peak with the desired mass signal. The reaction mixture was quenched by adding Na₂S₂O₃ (25 mL) and NaHCO₃ (15 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over Na₂SO₄ and concentrated to give 4-((2-(2-cyclopropylphenyl)pyrrolidone-1-yl)methyl)benzaldehyde (1.5 g). 1 HNMR (400MHz, CDCl3) δppm: 9.91 (s, 1H), 7.74 (d, J = 8.1Hz, 2H), 7.68 (d, J = 7.7Hz, 1H), 7.43 (d, J = 7.9Hz ,2H),7.14-7.18(m,1H),7.09(td,J=7.4,1.2Hz,1H),6.94(d,J=7.5Hz,1H),3.96(t,J=8.2Hz,1H),3.86 (d,J=13.8Hz,1H),2.98-3.14(m,2H),2.18-2.32(m,1H),2.14(q,J=8.8Hz,1H),1.98(d,J=7.7Hz,1H),1 .68-1.91(m,2H),1.63(dd,J=9.7,2.4Hz,1H),0.80-0.95(m,2H),0.63-0.74(m,1H),0.48-0.61(m,1H).

[0777] Intermediates 2-z17a and 2-z17b: (S or R)-2-(3-chloro-2-cyclopropylphenyl)pyrrolidine; (R or S)-2-(3-chloro-2-cyclopropylphenyl)pyrrolidine

[0778]

[0779] Step 1: 1-Bromo-3-chloro-2-cyclopropylbenzene

[0780] A mixture of 1-bromo-3-chloro-2-iodobenzene (7 g, 22.1 mmol), cyclopropylboronic acid (3.8 g, 44.2 mmol), Pd(dppf)Cl2 (1.6 g, 2.21 mmol), and K2CO3 (2 g, 7.3 mmol, 1.0 equivalence) in dioxane (100 mL) was heated at 70 °C for 12 h under N2 protection. TLC showed that the reaction was complete and new spots were formed. The mixture was cooled to room temperature and diluted with EtOAc (150 mL) and H2O (50 mL). The organic phase was separated and washed with water (150 mL) and brine (150 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (elution: PE) to give 1-bromo-3-chloro-2-cyclopropylbenzene (3 g, crude), which was used directly in the next step.

[0781] Step 2: (4-(3-chloro-2-cyclopropylphenyl)-4-oxobutyl)carbamate tert-butyl ester

[0782] At -70 °C, n-BuLi (2.5 M, 5.7 mL, 14.3 mmol) was added dropwise to a solution of 1-bromo-3-chloro-2-cyclopropylbenzene (3 g, 13 mmol) in THF (30 mL). After stirring at -70 °C for 30 min, a solution of 2-oxopyrrolidine-1-carboxylic acid tert-butyl ester (2.64 g, 14.3 mmol, 1.1 equivalents) in THF (5 mL) was added dropwise to the mixture at -70 °C. The mixture was further stirred at -70 °C for 2 h. TLC showed that the reaction was complete. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (elution buffer: PE / EA = 5 / 1) to obtain tert-butyl (4-(3-chloro-2-cyclopropylphenyl)-4-oxobutyl)carbamate (1.3 g). 1 H NMR (400MHz, CDCl3) δppm: 7.35 (dd, J=7.6, 1.7Hz, 1H), 7.06-7.15 (m, 2H), 4.56 (s, 1H), 3.14 (q, J=6.3 Hz, 2H), 2.89 (t, J = 7.2Hz, 2H), 1.78-1.95 (m, 3H), 1.37 (s, 9H), 0.92-1.03 (m, 2H), 0.35-0.45 (m, 2H).

[0783] Step 3: 4-Amino-1-(3-chloro-2-cyclopropylphenyl)but-1-one

[0784] TFA (4.4 g, 38 mmol) was added to a solution of tert-butyl (4-(3-chloro-2-cyclopropylphenyl)-4-oxobutyl)carbamate (1.3 g, 3.8 mmol) in DCM (20 mL). The mixture was then stirred at 20 °C for 2 hours. TLC showed that the reaction was complete. The mixture was concentrated under vacuum to give 4-amino-1-(3-chloro-2-cyclopropylphenyl)but-1-one (900 mg, crude). MS (ESI, m / e) [M+1] + 237.9.

[0785] Step 4: 2-(3-chloro-2-cyclopropylphenyl)pyrrolidine

[0786] A solution of 4-amino-1-(3-chloro-2-cyclopropylphenyl)but-1-one (900 mg, 3.8 mmol) and AcOH (0.5 mL) in EtOH (10 mL) was heated to 65 °C and stirred for 3 hours. The mixture was then cooled to room temperature and NaBH3CN (360 mg, 5.7 mmol, 1.5 equivalence) was added. The mixture was stirred further at room temperature for 1 hour. TLC showed that the reaction was complete. The reaction mixture was quenched and adjusted to pH approximately 10 with a saturated aqueous solution of Na2CO3, and then extracted with EtOAc (20 mL × 3). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (elution: EA / MeOH = 10 / 0 to 10 / 1) to give racemic 2-(3-chloro-2-cyclopropylphenyl)pyrrolidine.

[0787] The racemic product was purified by SFC (instrument: Thar SFC350 preparative SFC; column: Chiralpak AD, 250*50mm id10u; mobile phase: A is CO2, B is MeOH (0.1% NH3.H2O); gradient: B% = 20%; flow rate: 200g / min; wavelength: 220nm; column temperature: 40℃; system back pressure: 100bar) to obtain two isomers: the faster isomer (715mg, retention time: 2.4min) is (S or R)-2-(3-chloro-2-propylphenyl)pyrrolidine; the slower isomer (737mg, retention time: 2.7min) is (R or S)-2-(3-chloro-2-cyclopropylphenyl)pyrrolidine.

[0788] Intermediate 3-a: 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide

[0789]

[0790] At 0℃-5℃, (tetrahydro-2H-pyran-4-yl)methylamine (20.9 g, 0.182 mol) and TEA (20.0 g, 0.198 mol) were added to a solution of 4-fluoro-3-nitrobenzenesulfonamide (36.3 g, 0.165 mol) in THF (500 mL). The reaction was slowly heated to room temperature and stirred for about 16 hours. EA (1.5 L) was added to the reaction mixture, and the mixture was washed with saturated NaH2PO4 (100 mL) and saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a product as a yellow solid (49.1 g, 95.0% yield).

[0791] Intermediate 3-b: 4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide

[0792]

[0793] Under N2 at 20°C, the compound (4-fluorotetrahydro-2H-pyran-4-yl)methanol (489.89 mg, 3.68 mmol) was added to a mixture of 4-fluoro-3-nitrobenzenesulfonamide (540 mg, 2.45 mmol) and Na2CO3 (155.97 mg, 1.47 mmol) in i-PrOH (1.5 mL). The mixture was stirred at 60°C for 2 hours. The mixture was filtered and washed with water. A yellow solid of the compound 4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide (758 mg) was obtained. 1 H NMR (400MHz, DMSO-d6) δppm: 8.58 (br t, J = 6.0Hz, 1H), 8.46 (d, J = 6.0Hz, 1H), 7.81 (dd, J = 1.7, 9.3Hz, 1H), 7.40 (br d, J = 9.3Hz, 1H), 7.30 (br s,2H),3.81-3.70(m,4H),3.56-3.45(m,2H),1.89-1.69(m,4H). MS(ESI,m / e)[M+1] + 334.0.

[0794] Intermediate 3-C: 3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)azacyclobutane-3-yl)amino)benzenesulfonamide

[0795]

[0796] Step 1: (1-(tetrahydro-2H-pyran-4-yl)azacyclobutane-3-yl)tert-butyl carbamate

[0797]

[0798] A solution of tetrahydro-4H-pyran-4-one (1.162 g, 11.6 mmol) in DCM (50 mL) was added to tert-butyl azacyclobutane-3-ylcarbamate (1 g, 5.8 mmol). The mixture was stirred at room temperature for 2 hours. Then, NaBH(OAc)3 (3.687 g, 17.4 mmol) was added to the mixture. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (200 mL), washed with brine (200 mL × 2), dried over Na2SO4, and concentrated. The residue was purified by silica chromatography with an eluent of MeOH / DCM = 1 / 20 (v / v) to give a product (800 mg) as a yellow oil. MS (ESI, m / e) [M+1] + 257.1.

[0799] Step 2: 1-(tetrahydro-2H-pyran-4-yl)azacyclobutane-3-amine dihydrochloride

[0800]

[0801] Add tert-butyl 1-(tetrahydro-2H-pyran-4-yl)azacyclobutane-3-yl)carbamate (300 mg, 1.17 mmol) to a solution of 4N HCl (g) in dioxane (30 mL). Stir the mixture at room temperature for 2 hours. Concentrate the mixture to give the crude product (250 mg).

[0802] Step 3: 3-Nitro-4-((1-(tetrahydro-2H-pyran-4-yl)azacyclobutane-3-yl)amino)benzenesulfonamide

[0803]

[0804] Triethylamine (540.4 mg, 5.35 mmol) was added to a solution of 1-(tetrahydro-2H-pyran-4-yl)azacyclobutane-3-amine dihydrochloride (206 mg, 0.899 mmol) and 4-fluoro-3-nitrobenzenesulfonamide (282 mg, 1.28 mmol) in THF (50 mL). The mixture was stirred at room temperature for 4 hours. The mixture was filtered to give a product as a yellow solid (300 mg, 93.6%). 1H NMR (400MHz, DMSO-d6) δppm: 8.48 (s, 1H), 8.40 (s, 1H), 7.86 (d, J = 9.0Hz, 1H), 7.39 (s, 2H), 7.10 (d, J = 9.0Hz, 1H), 4. 46-4.21(m,1H),3.97-3.56(m,4H),3.47-3.14(m,4H),2.46-2.19(m,1H),1.63(d,J=10.4Hz,2H),1.20-1.19(m,2H).

[0805] Intermediate 3-d: 4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0806]

[0807] TEA (1.01 g, 10 mmol) was added to a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.15 g, 5.2 mmol) and (1-methylpiperidin-4-yl)methylamine (640 mg, 5 mmol) in THF (12 mL). The mixture was stirred at room temperature for 3 hours. Some solids appeared. The mixture was filtered. The solid (550 mg) that was yellow was collected. MS (ESI, m / e) [M+1] + 328.8.

[0808] Intermediate 3-e: 3-nitro-4-(7-oxa-2-azaspiro[3.5]nonane-2-yl)benzenesulfonamide

[0809]

[0810] Triethylamine (688 mg, 6.81 mmol) was added to a solution of 7-oxa-2-azaspiro[3.5]nonane hydrochloride (556 mg, 3.4 mmol) and 4-fluoro-3-nitrobenzenesulfonamide (500 mg, 2.27 mmol) in THF (50 mL). The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and purified by chromatography using a silica column with EA / PE = 1 / 1 (v / v) as eluent to give a product as a yellow solid (600 mg, 80.7% yield). 1 H NMR (400MHz, DMSO-d6) δppm: 8.17 (d, J=2.0Hz, 1H), 7.79 (dd, J=9.0, 2.0Hz, 1H), 7.32 (s, 2H), 6.90 (d, J = 9.0Hz, 1H), 3.79 (s, 4H), 3.526 (t, J = 5.0Hz, 4H), 1.733 (t, J = 5.0Hz, 4H). MS(ESI,m / e)[M+1]+ 328.

[0811] Intermediate 3-f: 3-nitro-4-((1-(oxecyclobutane-3-yl)piperidin-4-yl)amino)benzenesulfonamide

[0812]

[0813] Step 1: (1-(oxetane-3-yl)piperidin-4-yl)tert-butyl carbamate

[0814]

[0815] Add oxetane-3-one (1.08 g, 15 mmol) and HOAC (0.2 ml) to a solution of piperidine-4-ylcarbamate tert-butyl ester (1 g, 5 mmol) in DCM (50 ml). Stir the mixture at room temperature for 2 hours. Then add NaBH(OAc)3 (3.18 g, 15 mmol) to the mixture. Stir the mixture at room temperature overnight. Dilute the mixture with DCM (200 ml), wash with saturated NaHCO3 aqueous solution (100 ml) and brine (200 ml × 2), dry with Na2SO4, and concentrate. Purify the reaction residue by silica chromatography (MeOH / DCM = 1 / 20) to give a product (1 g, 78%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δppm: 6.79 (d, J=6.3Hz, 1H), 4.59-4.24 (m, 4H), 3.32-3.26 (m ,1H),3.25-3.07(m,1H),2.72-2.50(m,3H),1.84-1.55(m,4H),1.47-1.13(m,11H). MS(ESI,m / e)[M+1] + 257.1.

[0816] Step 2: 1-(oxetane-3-yl)piperidin-4-aminebis(2,2,2-trifluoroacetate)

[0817]

[0818] TFA (5 mL) was added to a solution of (1-(oxecyclobutan-3-yl)piperidin-4-yl)carbamate (1 g, 3.9 mmol) in DCM (30 mL). The mixture was stirred overnight at room temperature. The mixture was concentrated to give a product (1.4 g, 93.4%) as a white solid. 1H NMR(400MHz,DMSO-d6)δppm:11.02(s,1H),8.23(s,3H),4.82-4.63(m,4H),4.43-4.2 1(m,1H),3.59-3.20(m,3H),3.04-2.76(m,2H),2.24-1.97(m,2H),1.91-1.63(m,2H). MS(ESI,m / e)[M+1] + 157.2.

[0819] Step 3: 3-Nitro-4-((1-(oxecyclobutane-3-yl)piperidin-4-yl)amino)benzenesulfonamide

[0820]

[0821] Triethylamine (1.03 g, 10.2 mmol) was added to a solution of 1-(oxetane-3-yl)piperidin-4-amine bis(2,2,2-trifluoroacetate) (784 mg, 2.04 mmol) and 4-fluoro-3-nitrobenzenesulfonamide (471.6 mg, 2.142 mmol) in THF (50 mL). The mixture was stirred at room temperature for 4 hours. The mixture was filtered to give a product as a yellow solid (500 mg, 68.8%). MS (ESI, m / e) [M+1] + 357.0

[0822] Intermediate 3-g: 4-(((3-((tert-butyldimethylsilyl)oxy)oxetane-3-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0823]

[0824] Step 1: (3-((tert-butyldimethylsilyl)oxy)oxetane-3-yl)methylamine

[0825]

[0826] To a solution of 3-(aminomethyl)oxetane-3-ol (500 mg, 4.85 mmol) in DCM (50 mL), add tert-butylchlorodimethylsilane (694 mg, 4.6 mmol) and triethylamine (1.47 g, 14.55 mmol). Stir the mixture overnight at room temperature. Then wash with saturated aqueous NaHCO3 solution (500 mL) and brine (50 mL × 2), dry with Na2SO4, concentrate to obtain the crude product, which is used directly in the next step.

[0827] Step 2: 4-(((3-((tert-butyldimethylsilyl)oxy)oxetane-3-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0828]

[0829] Add 4-fluoro-3-nitrobenzenesulfonamide (1.28 g, 5.82 mmol) to a solution of (3-((tert-butyldimethylsilyl)oxy)oxetane-3-yl)methylamine (1.054 g, 4.85 mmol) in THF (50 mL). Stir the mixture at room temperature for 4 hours. Filter the mixture to give a product as a yellow solid (1.2 g, 59.3%). 1 H NMR (400MHz, DMSO-d6) δppm: 8.49 (d, J = 2.2Hz, 1H), 8.41 (t, J = 4.8Hz, 1H), 7.41-7.34 (m, 3H), 4.60 (d, J =7.0Hz,2H),4.47(d,J=7.0Hz,2H),3.84(d,J=5.1Hz,2H),0.88(s,9H),0.13(s,6H),MS(ESI,m / e)[M+1] + 418.1

[0830] Intermediate 3-h: 4-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methoxy)-3-nitrobenzenesulfonamide

[0831]

[0832] Step 1: Ethyl 4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate

[0833]

[0834] To a solution of ethyl 4-hydroxycyclohexane-1-carboxylate (2 g, 11.61 mmol) in DMF (50 mL), tert-butylchlorodimethylsilane (1.575 g, 10.4 mmol) and imidazole (1.58 g, 23.22 mmol) were added. The mixture was stirred at room temperature for 2 days. The mixture was concentrated. The residue was dissolved in DCM (200 mL), washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica column chromatography (elution: EA / PE = 1 / 40) to give the product (2.32 g, 69.8%).

[0835] Step 2: (4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methanol

[0836]

[0837] LAH (369 mg, 9.72 mmol) was added to a solution of ethyl 4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate (2.32 g, 8.1 mmol) in MTBE (50 mL). The mixture was stirred under reflux for 2 hours. The mixture was quenched with MeOH (10 mL) at 0 °C. The mixture was concentrated. The residue was purified by silica chromatography (elution: EA / PE = 1 / 2) to give a product (1.5 g, 75.8%) as a yellow oil. MS (ESI, m / e) [M+1] + 245.1

[0838] Step 3: 4-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methoxy)-3-nitrobenzenesulfonamide

[0839]

[0840] NaH (576 mg, 14.4 mmol) was added to a solution of (4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methanol (587 mg, 2.4 mmol) in THF (50 mL). The mixture was stirred at room temperature for 0.5 h. Then, 4-fluoro-3-nitrobenzenesulfonamide (370 mg, 1.68 mmol) was added to the mixture. The mixture was stirred at room temperature overnight. The mixture was poured into a saturated NaHCO3 aqueous solution (200 mL), and the pH was adjusted to 5 to 6 with hydrochloric acid (1 M), followed by extraction with ethyl acetate (200 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography through a silica column (elution: EA / PE = 1 / 2) to give a product as a yellow solid. MS (ESI, m / e) [M+1] + 445.1.

[0841] Intermediate 3-i: 4-((4-fluoro-1-(tetrahydrofuran-3-yl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

[0842]

[0843] Step 1: 4-Fluoro-4-((2-nitro-4-aminosulfonylphenoxy)methyl)piperidine-1-carboxylic acid tert-butyl ester

[0844]

[0845] Under N2 and at 0 °C, NaH (726.61 mg, 18.17 mmol, 60% purity) was added in a single addition to a mixture of 4-fluoro-3-nitrobenzenesulfonamide (1 g, 4.54 mmol) and tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (1.06 g, 4.54 mmol) in THF (20 mL). The mixture was stirred at 15 °C for 14 h. TLC showed that the reaction was complete. 20 mL of saturated NH4Cl solution was added to the mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by recrystallization in EtOAc (10 mL) to give tert-butyl 4-fluoro-4-((2-nitro-4-aminosulfonylphenoxy)methyl)piperidine-1-carboxylate (1.17 g, 2.70 mmol, yield 59.4%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δppm: 8.31 (br s, 1H), 8.06 (brd, J = 8.6Hz, 1H), 7.64-7.54 (m, 1H), 7.25 (br s, 2H), 4.48-4.33 (m, 2H), 3.84 (br d,J=11.9Hz,2H),3.03(br s,2H),1.97-1.84(m,2H),1.82-1.61(m,2H),1.41(d,J=2.9Hz,9H).

[0846] Step 2: 4-((4-Fluoroperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

[0847]

[0848] Hydrochloric acid (4M, 78.00 mL) was added in a single step to a mixture of tert-butyl 4-fluoro-4-((2-nitro-4-aminosulfonylphenoxy)methyl)piperidine-1-carboxylate (1.17 g, 2.70 mmol) in EA under N2 and at 15 °C. The mixture was stirred at 15 °C for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under vacuum to give 4-((4-fluoropiperidine-4-yl)methoxy)-3-nitrobenzenesulfonamide (1 g, crude, HCl salt) as a yellow solid. This was used directly in the next step. 1H NMR (400MHz, methanol-d4) δppm: 8.37 (d, J = 2.3Hz, 1H), 8.12 (dd, J = 2.4, 8.9Hz, 1H), 7.50 (d ,J=8.9Hz,1H),4.43(d,J=10.0Hz,2H),3.50-3.40(m,2H),3.29-3.24(m,1H),2.33(br dd,J=10.0,12.8Hz,2H),2.23-2.10(m,2H).

[0849] Step 3: 4-((4-fluoro-1-(tetrahydrofuran-3-yl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

[0850]

[0851] Under N2 and at 0 °C, NaBH3CN (509.81 mg, 8.11 mmol) was added in a single batch to a mixture of 4-((4-fluoropiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide (1 g, 2.70 mmol, HCl) and dihydrofuran-3(2H)-one (698.40 mg, 8.11 mmol) in MeOH2 (20 mL). The mixture was stirred at 15 °C for 12 hours. LC-MS showed that the reaction was complete. The mixture was poured into a saturated NaHCO3 (20 mL) solution, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The mixture was dissolved in DCM and concentrated under vacuum to give a yellow solid. The crude product was purified by recrystallization from MTBE (15 mL) to give 4-((4-fluoro-1-(tetrahydrofuran-3-yl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide (0.666 g, 1.65 mmol, 61.05% yield, 96.19% purity) as a yellow solid. 1 H NMR (400MHz, methanol-d4) δppm: 8.34 (d, J=2.2Hz, 1H), 8.09 (dd, J=2.2, 8.8Hz, 1H) ,7.47(d,J=8.8Hz,1H),4.31(d,J=9.3Hz,2H),4.00-3.88(m,2H),3.83-3.72 (m,1H),3.66(dd,J=7.0,8.8Hz,1H),3.07(quin,J=7.2Hz,1H),2.90(d,J=11 .0Hz,1H),2.71(d,J=11.8Hz,1H),2.46(q,J=11.8Hz,2H),2.20-1.80(m,6H). MS(ESI,m / e)[M+1] +404.1.

[0852] Intermediate 3-j: 3-nitro-4-(((4-(oxecyclobutane-3-yl)morpholin-2-yl)methyl)amino)benzenesulfonamide

[0853]

[0854] Step 1: 2-(((2-nitro-4-aminosulfonylphenyl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester

[0855]

[0856] At 55–60 °C, Na₂CO₃ (735.09 mg, 6.94 mmol) and tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (3 g, 13.87 mmol) were added to a solution of 4-fluoro-3-nitrobenzenesulfonamide (2.55 g, 11.56 mmol) in IPA (90 mL). The mixture was stirred at 55–65 °C for 4 hours. TLC indicated that 4-fluoro-3-nitrobenzenesulfonamide was completely consumed and a new spot was formed. The mixture was concentrated and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. 2-(((2-nitro-4-aminosulfonylphenyl)amino)methyl)morpholine-4-carboxylate tert-butyl ester (4.3 g, 10.33 mmol, 89.33% yield) was given as a yellow solid. The product was used directly in the next step. 1 H NMR (400MHz, CDCl3) δppm: 8.78 (d, J = 2.2Hz, 1H), 8.61 (br s,1H),7.92(dd,J=2.1,9.2Hz,1H),6.98(d,J=9.0Hz,1H),4.83(s,2H),4.16-3.80(m ,3H),3.74(t,J=3.4,7.0,10.5Hz,1H),3.65-3.47(m,2H),3.46-3.37(m,1H),3.01(br s,1H),2.80(br s,1H),1.48(s,9H).

[0857] Step 2: 4-((morpholin-2-ylmethyl)amino)-3-nitrobenzenesulfonamide

[0858]

[0859] A mixture of 2-(((2-nitro-4-aminosulfonylphenyl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester (2.5 g, 6.00 mmol) in TFA (10 mL) and DCM (10 mL) was stirred at 25 °C for 1 hour. TLC indicated that the reactants were completely consumed and a new spot was formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. 4-((morpholine-2-ylmethyl)amino)-3-nitrobenzenesulfonamide (2.5 g, crude product), a yellow oil, was given and used directly in the next step. 1 H NMR (400MHz, DMSO-d6) δppm 8.57(br t,J=6.0Hz,1H),8.48(d,J=2.2Hz,1H),7.85(dd,J=2.1,9.2Hz,1H),7.36(br s,1H),7.30(d,J=9.2Hz,1H),4.08-3.89(m,2H),3.77-3.61(m,2H),3.61-3.51(m,1H),3.34(br d,J=12.6Hz,1H),3.20(br d,J=12.6Hz,1H),3.01(br,1H),2.90(m,1H).

[0860] Step 3: 3-nitro-4-(((4-(oxecyclobutane-3-yl)morpholin-2-yl)methyl)amino)benzenesulfonamide

[0861]

[0862] NaBH3CN (357.58 mg, 5.69 mmol) was added to a solution of 4-((morpholin-2-ylmethyl)amino)-3-nitrobenzenesulfonamide (600.00 mg, 1.90 mmol) and oxetane-3-one (410.05 mg, 5.69 mmol) in MeOH (60 mL). The mixture was stirred at 15 °C for 14 h. LC-MS showed complete consumption of 4-((morpholin-2-ylmethyl)amino)-3-nitrobenzenesulfonamide and a main peak with the desired m / z. The reaction mixture was quenched and concentrated by adding H2O (10 mL) and then extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was washed with EA (5 mL). 3-nitro-4-(((4-(oxecyclobutan-3-yl)morpholin-2-yl)methyl)amino)benzenesulfonamide (580 mg, 1.49 mmol, 78.76% yield) was given as a yellow solid. 1H NMR(400MHz,DMSO-d6)δppm:8.55(br t,J=5.5Hz,1H),8.47(d,J=2.0Hz,1H),7.84(dd,J=2.0,9.0Hz,1H),7.34(s ,2H),7.27(d,J=9.0Hz,1H),4.59-4.51(m,2H),4.49-4.41(m,2H),3.86(br d,J=11.0Hz,1H),3.75(br s,1H),3.62-3.52(m,1H),3.50-3.39(m,2H),2.75(br d,J=11.0Hz,1H),2.57(br d, J=11.0Hz, 1H), 1.96 (dt, J=2.9, 11.0Hz, 1H), 1.80 (t, J=11.0Hz, 1H). MS(ESI,m / e)[M+1] + 373.1.

[0863] Intermediate 3-k: 4-(((4-cyclopropylmorpholin-2-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0864]

[0865] Add to a solution of 4-((morpholino-2-ylmethyl)amino)-3-nitrobenzenesulfonamide (1 g, 3.16 mmol) in MeOH (30 mL) Molecular sieve (0.5 g, 9.48 mmol), AcOH (1.33 g, 22.13 mmol, 1.27 mL), (1-ethoxycyclopropoxy)trimethylsilane (2.76 g, 15.81 mmol, 3.18 mL), and NaBH3CN (595.97 mg, 9.48 mmol). The mixture was stirred at 70 °C for 5 hours. LC-MS showed complete consumption of 4-((morpholino-2-ylmethyl)amino)-3-nitrobenzenesulfonamide and a main peak with the desired m / z. The reaction mixture was concentrated and diluted with H2O (20 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (elution buffer: PE / EA = 10:1 to EA) to give 4-(((4-cyclopropylmorpholino-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (300 mg, 25.82% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δppm: 8.57 (br t, J = 5.4Hz, 1H), 8.47 (d, J = 2.2Hz, 1H), 7.84 (dd, J = 2.2, 9.1Hz, 1H), 7.35 (s, 2H), 7.28 (d, J = 9.3Hz, 1H), 3.83 (br d,J=11.4Hz,1H),3.70-3.54(m,2H),3.52-3.39(m,2H),2.91(br d,J=10.5Hz,1H),2.73(brd,J=11.4Hz,1H),2.36-2.26(m,1H),2.13(t,J=10.5Hz,1H),1.70-1.61(m,1H),0.46-0.39(m,2H),0.36-0.28(m,2H). MS(ESI,m / e)[M+1] + 357.1.

[0866] Intermediate 3-l: 3-nitro-4-(((1-(oxecyclobutane-3-yl)piperidin-4-yl)methyl)amino)benzenesulfonamide 2,2,2-trifluoroacetate

[0867]

[0868] Step 1: ((1-(oxecyclobutane-3-yl)piperidin-4-yl)methyl)tert-butyl carbamate

[0869]

[0870] To a solution of tert-butyl (piperidin-4-ylmethyl)carbamate (1 g, 4.67 mmol) in DCM (50 mL), oxetane-3-one (1.01 g, 14 mmol) and HOAc (0.2 mL) were added. The mixture was stirred at room temperature for 2 hours. Then, NaBH(OAc)3 (2.967 g, 14 mmol) was added to the mixture. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (200 mL), washed with saturated NaHCO3 aqueous solution and brine (200 mL × 2), dried over Na2SO4, and concentrated. The residue was purified by silica column chromatography (elution: MeOH / DCM = 1 / 20) to give a product (1.2 g, 95%) as a yellow oil. MS (ESI, m / e) [M+1] + 271.1.

[0871] Step 2: (1-(oxetane-3-yl)piperidin-4-yl)methylaminebis(2,2,2-trifluoroacetate)

[0872]

[0873] Add 15 mL of TFA to a solution of tert-butyl ((1-(oxecyclobutan-3-yl)piperidin-4-yl)methyl)carbamate (1.2 g, 4.44 mmol) in 50 mL of DCM. Stir the mixture overnight at room temperature. Concentrate the mixture to give the product. Use the crude product directly in the next step.

[0874] Step 3: 3-Nitro-4-(((1-(oxecyclobutane-3-yl)piperidin-4-yl)methyl)amino)benzenesulfonamide 2,2,2-trifluoroacetate

[0875]

[0876] Triethylamine (2.24 g, 22.2 mmol) was added to a solution of (1-(oxetane-3-yl)piperidin-4-yl)methylamine bis(2,2,2-trifluoroacetate) (1.77 g, 4.44 mmol) and 4-fluoro-3-nitrobenzenesulfonamide (1.026 g, 4.66 mmol) in THF (50 mL). The mixture was stirred overnight at room temperature. The mixture was filtered to give a product as a yellow solid (900 mg, 41.8%). MS (ESI, m / e) [M+1] + 371.1

[0877] Intermediate 3-m: (R)-4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0878]

[0879] To a solution of (R)-(1,4-dioxane-2-yl)methylamine (450 mg, 2.93 mmol) in THF (50 mL), 4-fluoro-3-nitrobenzenesulfonamide (709.5 mg, 3.22 mmol) and triethylamine (1.48 g, 14.65 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was then filtered, and the precipitate was washed with petroleum ether to give the product (540 mg, 58%). MS (ESI, m / e) [M+1] + 318.0.

[0880] Intermediate 3-n: 4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide

[0881]

[0882] A solution of 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (469 mg, 1.53 mmol), (tetrahydro-2H-pyran-4-yl)methylamine (176 mg, 1.53 mmol), and Et3N (232 mg, 2.3 mmol) was stirred at room temperature for 4 hours. After removing the solvent, the resulting residue was dissolved in EA (100 mL) and washed with brine (100 mL × 4). The solution was dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product (747 mg) as a white solid. MS (ESI, m / e) [M+1] +403.1.

[0883] Intermediate 3-O: 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0884]

[0885] Step 1: 1,6-Dioxaspiro[2.5]octane-2-carboxylon

[0886] 2-Chloroacetonitrile (70 g, 0.93 mol) was added to a solution of oxane-4-one (100 g, 1 mol) in tert-butanol (100 mL). The resulting mixture was stirred at 25 °C for 30 min. Then, a solution of t-BuOK (120 g, 1.07 mol) in tert-butanol (1 L) was added dropwise with stirring at 25 °C for 40 min. The resulting mixture was stirred overnight at room temperature. After dilution with 200 mL of water and quenching with 40 mL of 10% hydrogen chloride, the resulting mixture was concentrated to one-third of its volume and then extracted with 3 × 400 mL of diethyl ether. The combined organic layers were washed with 500 mL of brine, dried over anhydrous sodium sulfate, and concentrated to give 84.5 g (crude) of 1,6-dioxane[2.5]octane-2-carboxynitrile as a yellow oil.

[0887] Step 2: 2-(4-fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile

[0888] At 0 °C, 70% HF / Py (148 mL) was added dropwise to a solution of 1,6-dioxane[2.5]octane-2-carboxylonitrile (169 g, 1.22 mol) in 1 L of dichloromethane. The resulting mixture was stirred overnight at room temperature. After dilution with 1000 mL of ethyl acetate, the reaction mixture was poured into saturated NaHCO3 and the pH was adjusted to approximately 7 with solid NaHCO3 while stirring. The aqueous phase was extracted with 3 × 1000 mL of ethyl acetate, the organic layers were combined, and then washed with 850 mL of 1% hydrogen chloride and 1 × 1000 mL of brine. The mixture was then dried over anhydrous sodium sulfate and concentrated to give 139 g (crude) of 2-(4-fluorooxan-4-yl)-2-hydroxyacetonitrile as a pale yellow oil.

[0889] Step 3: (4-Fluorotetrahydro-2H-pyran-4-yl)methanol

[0890] At 0 °C, NaBH4 (39.1 g, 1028.3 mmol) was added in portions to a solution of 2-(4-fluorooxan-4-yl)-2-hydroxyacetonitrile (109 g, 685.5 mmol) in isopropanol / H2O (800 mL / 200 mL). The resulting mixture was stirred at 0 °C for 2 h, then quenched by adding 220 mL of acetone and stirred again for 1 h. The solid was filtered off and washed with 200 mL of ethyl acetate. The filtrate was concentrated and purified by silica gel column chromatography (elution: ethyl acetate / petroleum ether = 3 / 1) to give 47.8 g of (4-fluorooxan-4-yl) methanol as a pale yellow oil.

[0891] Step 4: Methyl (4-fluorotetrahydro-2H-pyran-4-yl)methanesulfonate

[0892] At 0 °C, MsCl (73.2 g, 647.0 mmol) was added dropwise to a solution of (4-fluorooxan-4-yl)methanol (57.8 g, 431.3 mmol) and TEA (65.5 g, 647.0 mmol) in 500 mL of dichloromethane. The resulting mixture was stirred at room temperature for 2 h. After quenching with 500 mL of water, the mixture was extracted with 2 × 500 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 105.8 g (crude) methyl (4-fluorooxan-4-yl)methanesulfonate as a yellow oil.

[0893] Step 5: 2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)isoindoline-1,3-dione

[0894] Potassium 1,3-dioxo-2,3-dihydro-1H-isoindol-2-ide (138.5 g, 748.6 mmol) was added to a solution of methyl (4-fluorooxane-4-yl)methanesulfonate (105.8 g, 499.1 mmol) in 1 L of DMF. The resulting mixture was stirred overnight at 140 °C. After cooling to room temperature, the reaction mixture was poured into 3 L of water and then filtered. The filter cake was dried under vacuum to give 98 g (crude) of 2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)isoindololin-1,3-dione as a grayish-white solid.

[0895] Step 6: (4-Fluorotetrahydro-2H-pyran-4-yl)methylamine

[0896] NH₂NH₂·H₂O (111.8 g, 2.24 mol) was added to a solution of 2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)isoindoline-1,3-dione (98 g, 372.6 mmol) in 1 L of 1 mol of nitrate OH. The resulting mixture was stirred overnight at 70 °C. After cooling to room temperature, the reaction mixture was concentrated and then diluted with 1 L of DCM. After filtering to remove the solids, the filtrate was concentrated and purified by silica gel column chromatography (elution: CH₂Cl₂ / MeOH = 100 / 1) to give 30.2 g of (4-fluorooxan-4-yl)methylamine as a pale yellow oil.

[0897] Step 7: 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0898] Na₂CO₃ (12.0 g, 112.8 mmol) was added to a solution of (4-fluorotetrahydro-2H-pyran-4-yl)methylamine (30 g, 225.6 mmol) and 4-fluoro-3-nitrobenzene-1-sulfonamide (41.4 g, 188.0 mmol) in 500 mL of i-PrOH. The resulting mixture was stirred at 60 °C for 2 h, and a precipitate was formed. After filtration, the filter cake was washed with 3 × 100 mL of water and then dried under infrared light to give 60.9 g of 4-[[(4-fluorooxane-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide as a yellow solid.

[0899] Intermediate 3-p: 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide

[0900]

[0901] Step 1: 8-Methyl-1,4-dioxaspiro[4,5]dec-8-ol

[0902] A solution of 1,4-dioxaspiro[4.5]dec-8-one (70.0 g, 0.449 mol) in 350 mL of anhydrous toluene was added dropwise to a stirred solution of CH3MgBr (344.0 mL, 1.032 mol, 3 M in Et2O) in anhydrous toluene (2 L). The resulting mixture was stirred at 5 °C to 10 °C for 2 hours. The mixture was poured into a saturated aqueous solution of NH4Cl (3 L) and extracted with EtOAc (3 × 1 L). The combined organic phases were washed with brine (1.5 L), dried over Na2SO4, and concentrated to give 8-methyl-1,4-dioxaspiro[4.5]dec-8-ol (70.0 g, crude) as a white solid.

[0903] Step 2: 4-Hydroxy-4-methylcyclohexane-1-one

[0904] 8-Methyl-1,4-dioxaspiro[4.5]dec-8-ol (140.0 g, 0.814 mol) was added to a stirred solution of 0.05 N HCl (1800 mL). The mixture was stirred at 70 °C for 2.5 h. The resulting mixture was cooled to room temperature and NaCl solid was added to saturation, followed by extraction with EtOAc (5 × 700 mL). The combined organic phases were dried over Na2SO4 and concentrated to give 105.0 g, crude 4-hydroxy-4-methylcyclohexane-1-one as a yellow oil.

[0905] Step 3: (S)-1-Methyl-4-(nitromethyl)cyclohexyl-3-en-1-ol

[0906] N was added to a stirred solution of 105.0 g (0.820 mol) of 4-hydroxy-4-methylcyclohexane-1-one in 600.0 mL of CH3NO2. 1 N 1 -Dimethylethane-1,2-diamine (7.216 g, 0.082 mol). The mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel column chromatography, eluting with EA / PE = 1 / 4, to give (S)-1-methyl-4-(nitromethyl)cyclohexyl-3-en-1-ol (96.0 g) as a yellow oil.

[0907] Step 4: (1r,4r)-1-methyl-4-(nitromethyl)cyclohexane-1-ol

[0908] Crabtree catalyst (6.8 g, 0.008 mmol) was added to a stirred solution of (S)-1-methyl-4-(nitromethyl)cyclohexane-3-en-1-ol (96.0 g, 0.561 mol) in DCM (1.5 L). The mixture was stirred overnight at 50 °C under a H2 (30 atm) atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated to give (1r,4r)-1-methyl-4-(nitromethyl)cyclohexane-1-ol (100.0 g, crude product) as a yellow oil.

[0909] Step 5: (1r,4r)-4-(aminomethyl)-1-methylcyclohexane-1-ol

[0910] 10% wet Pd / C (30.0 g) was added to a stirred solution of (1r,4r)-1-methyl-4-(nitromethyl)cyclohexane-1-ol (120.0 g, 0.694 mol) in MeOH (1.5 L). The mixture was stirred overnight at 85 °C under a H2 (30 atm) atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated to give (1r,4r)-4-(aminomethyl)-1-methylcyclohexane-1-ol (95.0 g, crude product) as a brown solid. 1 ¹H NMR (300MHz, methanol-d⁴) δppm: 2.51 (d, J = 6.7Hz, 2H), 1.86–1.58 (m, 4H), 1.40–1.50 (s, 2H), 1.35–1.26 (m, 1H), 1.21 (s, 3H), 1.16–0.95 (m, 2H).

[0911] Step 6: 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide

[0912] Add 4-fluoro-3-nitrobenzenesulfonamide (107.6 g, 0.489 mol) and TEA (141.2 g, 1.389 mol) to a stirred solution of (1r,4r)-4-(aminomethyl)-1-methylcyclohexyl-1-ol (100.0 g, 0.699 mol) in THF (1 L). Stir the mixture overnight at room temperature. Dilute the resulting mixture with water (500 mL) and extract with EtOAc (3 × 800 mL). Wash the combined organic phases with brine (1 L), dry with anhydrous Na2SO4 and concentrate. Purify the residue three times by slurry in EtOAc (800.0 mL) to give 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (144.6 g) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δppm:8.52(t,J=5.9Hz,1H),8.45(d,J=2.3Hz,1H),7.80(dd,J=9.2,2.3Hz,1H),7.42-7.11(m,3H),4.24 (s, 1H), 3.31 (t, J = 6.3Hz, 2H), 1.66 (d, J = 11.5Hz, 3H), 1.53 (d, J = 12.7Hz, 2H), 1.31 (td, J = 12.4, 3.4Hz, 2H), 1.11-1.08 (m, 6H). MS(ESI,m / e)[M+1] + 343.9.

[0913] Intermediate 3-q1: (4-((((1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide;

[0914]

[0915] Intermediate 3-q2: 4-((((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide

[0916]

[0917] Step 1: 4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexanecarboxylate ethyl acetate

[0918] TMSCF3 (12.53 g, 88.13 mmol) and CsF (8.92 g, 58.75 mmol) were added to a solution of ethyl 4-oxocyclohexanecarboxylate (10 g, 58.75 mmol) in THF (100 mL). The mixture was stirred at 20 °C for 6 hours. TLC indicated complete consumption of the reactants. The reaction mixture was washed with saturated aqueous NaHCO3 solution (50 mL × 2) and extracted with ethyl acetate (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 = 100 / 1 to 2 / 1). 8.12 g of ethyl 4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexanecarboxylate was given as a yellow oil. 1H NMR (400MHz, CDCl3) δppm: 4.15 (q, J = 7.1Hz, 2H), 2.20-2.66 (m, 1H), 1.98-2.08 (m, 1H), 1.6 3-1.95(m,6H),1.53(td,J=13.4,4.2Hz,1H),1.27(t,J=7.1Hz,3H),0.17(d,J=4.5Hz,9H).

[0919] Step 2: (4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl)methanol

[0920] LAH (1.97 g, 51.86 mmol) was added to a solution of ethyl 4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexanecarboxylate (8.10 g, 25.93 mmol) in THF (50 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 h. TLC indicated complete consumption of the reactants. The reaction mixture was quenched by adding water (15 mL) and then extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product (6.2 g, crude) was used in the next step without further purification.

[0921] Step 3: Methyl (4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl)methanesulfonate

[0922] MsCl (5.91 g, 51.60 mmol) was added to a solution of (4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl)methanol (6.2 g, 22.93 mmol) and TEA (4.64 g, 45.86 mmol) in DCM (60 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 h. TLC indicated complete consumption of the reactants. The reaction mixture was washed with saturated NaHCO3 aqueous solution (50 mL × 2) and extracted with DCM (50 mL × 2). The combined organic phases were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product (8.52 g, crude product) was used for the next step without further purification.

[0923] Step 4: ((4-(azidomethyl)-1-(trifluoromethyl)cyclohexyl)oxy)trimethylsilane

[0924] At 20 °C, NaN3 (7.94 g, 122.11 mmol) was added to a solution of (4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl)methylmethanesulfonate (8.51 g, 24.42 mmol) in DMF (150 mL), and the mixture was stirred at 50 °C for 12 hours. TLC indicated complete consumption of the reactants. The mixture was diluted with water and extracted with MTBE (100 mL × 3), dried over anhydrous Na2SO4, and filtered. The combined organic layers were concentrated to give the crude product, which was used directly in the next step.

[0925] Step 5: (4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl)methylamine

[0926] Pd / C (2.5 g) was added to a mixture of ((4-(azidomethyl)-1-(trifluoromethyl)cyclohexyl)oxy)trimethylsilane (7.21 g, theoretical yield) in CH3OH (50 mL), and the mixture was stirred at 30 °C for 16 hours under H2 (30 psi). TLC indicated complete consumption of the reactants. The mixture was filtered and concentrated under reduced pressure. (4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl)methylamine (4.67 g, crude product) was given as a yellow oil. The crude product was used in the next step without further purification.

[0927] Step 6: 4-(((4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide

[0928] DIPEA (2.94 g, 22.74 mmol) was added to a solution of 4-fluoro-3-nitrobenzenesulfonamide (2.50 g, 11.35 mmol) and (4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl)methylamine (4.59 g, 17.04 mmol) in DMF (75 mL), and the mixture was stirred at 55 °C for 2 h. TLC indicated complete consumption of the reactants. The reaction mixture was washed with water (200 mL) and extracted with EA (100 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 washed with PE / EA = 5 / 1 (30 mL) and filtered. The filter cake was purified by preparative HPLC (neutral). 4-((((1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (intermediate 3-q1, retention time: 2.5 min) (1.04 g) was obtained as a yellow solid. 1 ¹H NMR (400MHz, methanol-d⁴) δppm: 8.65 (d, J = 1.9Hz, 1H), 8.49 (t, J = 4.7Hz, 1H), 7.91 (dd, J = 9.1, 1.63Hz, 1H), 7.17 (d, J = 9.3Hz, 1H), 3.46 (t, J = 6.3Hz, 2H), 2.06 (d, J = 4.1Hz, 1H), 1.84–2.00 (m, 4H), 1.52–1.70 (m, 4H). MS (ESI, m / e) [M⁻¹] -396.0; yielded a yellow solid of 4-((((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (intermediate 3-q2, retention time: 2.6 min) (842 mg). 1H NMR (400MHz, methanol-d4) δppm: 8.65 (d, J = 1.9 Hz, 1H), 8.54 (t, J = 5.2 Hz, 1H), 7.90 (dd, J = 9.1, 1.6 Hz, 1H), 7.17 (d, J=9.3Hz,1H),3.33-3.41(m,2H),1.24(s,1H),1.87(d,J=12.5Hz,2H),1.71-1.82(m,3H),1.42-1.69(m,4H). MS(ESI,m / e)[M-1] - 396.0.

[0929] Intermediate 3-r: 4-(((3-oxabicyclo[3.1.0]hexane-6-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0930]

[0931] Step 1: Ethyl 3-oxabicyclo[3.1.0]hexane-6-carboxylate

[0932] Rh(AcO)₂ (63.06 mg, 2.85 mmol) was added to a solution of 2,5-dihydrofuran (10 g, 142.67 mmol) and ethyl 2-diazoethyl ester (32.56 g, 285.35 mmol) in DCM (250 mL). The mixture was stirred at 20 °C for 12 hours. TLC indicated complete consumption of the reactants. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by preparative MPLC to give ethyl 3-oxabicyclo[3.1.0]hexane-6-carboxylate (10.0 g). 1 H NMR (400MHz, CDCl3) δppm: 4.08-4.16 (m, 2H), 3.92 (d, J = 8.6Hz, 2H), 3.74 (d, J = 8.4Hz, 2H), 2.13-2.17 (m, 2H), 1.59 (t, J = 3.1Hz, 1H), 1.23-1.28 (m, 3H).

[0933] Step 2: 3-oxabicyclo[3.1.0]hex-6-ylmethanol

[0934] At 0 °C, LiAlH4 (2.43 g, 64.03 mmol) was added to a solution of ethyl 3-oxabicyclo[3.1.0]hexane-6-carboxylate (10 g, 64.03 mmol) in THF (50 mL). The mixture was stirred at 0 °C for 4 hours. TLC indicated complete consumption of the reactants. The reaction mixture was poured into H2O (30 mL) and extracted with EA (30 mL × 3), dried over Na2SO4, filtered, and concentrated. 3-oxabicyclo[3.1.0]hexane-6-ylmethanol (7.0 g, crude) was given and used in the next step without further purification.

[0935] Step 3: Methyl 3-oxabicyclo[3.1.0]hex-6-ylmethanesulfonate

[0936] MsCl (21.08 g, 183.98 mmol) and TEA (24.82 g, 245.31 mmol) were added to a solution of 3-oxabicyclo[3.1.0]hex-6-ylmethanol (7.0 g, 61.33 mmol) in DCM (100 mL). The mixture was stirred at 25 °C for 5 hours. TLC indicated complete consumption of the reactants. The reaction mixture was quenched with an aqueous solution of NH4Cl (30 mL) and extracted with EA (30 mL × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE / EA = 100 / 1 to 30 / 1). Methyl 3-oxabicyclo[3.1.0]hex-6-ylmethanesulfonate (3.5 g) was given. 1 H NMR (400MHz, CDCl3) δppm: 4.15 (d, J = 7.5Hz, 2H), 3.90 (d, J = 8.4Hz, 2H), 3.71 (d, J = 8.4Hz, 2H), 3.03 (s, 3H), 1.69-1.72 (m, 2H), 1.21-1.29 (m, 1H).

[0937] Step 4: 6-(azidomethyl)-3-oxabicyclo[3.1.0]hexane

[0938] Add NaN3 (676.37 mg, 10.4 mmol) to a solution of methyl 3-oxabicyclo[3.1.0]hexyl-6-ylmethanesulfonate (2 g, 10.4 mmol) in DMF (20 mL). Stir the mixture at 50 °C for 12 hours. TLC indicates complete consumption of the reactants. Pour the reaction mixture into H2O (30 mL) and extract with EA (30 mL × 3), dry with Na2SO4, filter, and concentrate. Use the crude product directly in the next step.

[0939] Step 5: 3-oxabicyclo[3.1.0]hexyl-6-methylamine

[0940] Pd / C (0.7 g, 1.006 mmol) was added to a solution of 6-(azidomethyl)-3-oxabicyclo[3.1.0]hexane (1.4 g, 10.06 mmol) in DMF (15 mL). The mixture was stirred at 25 °C under a H2 atmosphere (15 Psi) for 2 hours. LC / MS showed complete consumption of the reactants and a dominant peak with the desired mass signal. The reaction mixture was filtered and used directly for the next step. MS (ESI, m / e) [M+1] + 114.0.

[0941] Step 6: 4-(((3-oxabicyclo[3.1.0]hex-6-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0942] DIEA (1.76 g, 13.6 mmol) was added to a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.5 g, 6.8 mmol) and 3-oxabicyclo[3.1.0]hexyl-6-ylmethylamine (1 g, 8.84 mmol) in DMF (15 mL). The mixture was stirred at 60 °C for 2 h. LC / MS showed complete consumption of 4-fluoro-3-nitrobenzenesulfonamide and a dominant peak with the desired mass signal. The reaction mixture was cooled to room temperature and poured into H2O (50 mL) with stirring. The precipitate was filtered, and the filter cake was washed with MTBE (10 mL) and dried under vacuum. 4-((3-oxabicyclo[3.1.0]hexyl-6-ylmethyl)amino)-3-nitrobenzenesulfonamide (758 mg) was given. 1 H NMR (400MHz, DMSO-d6) δppm: 8.59 (br, 1H), 8.47 (s, 1H), 7.84 (d, J = 8.8Hz, 1H), 7.37 (s, 2H), 7.28 (d ,J=9.2Hz,1H),3.72(d,J=8.2Hz,2H),3.55(d,J=7.9Hz,2H),3.36(s,2H),1.71(s,2H),1.05(s,1H). MS(ESI,m / e)[M+1] + 314.0.

[0943] Example A1: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-(2-phenylpyrrolidine-1-yl)-[1,1'-diphenyl]-4-carboxamide

[0944]

[0945] Step 1: 1-(4-bromophenyl)-2-phenylpyrrolidine

[0946]

[0947] Pd₂(dba)₃ (366 mg, 0.4 mmol) was added to a solution of degassed 2-phenylpyrrolidine (588 mg, 4 mmol), 1-bromo-4-iodobenzene (1.132 g, 16 mmol), BINAP (497 mg, 0.8 mmol), and K-OtBu (1.2 g, 12 mmol) in toluene (25 mL). Nitrogen gas was bubbled through the mixture for 5 min, then heated to 90 °C and stirred overnight. After cooling to room temperature, the reaction mixture was washed successively with water and brine. The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography using 5% to 20% EA / PE as eluent to give 1-(4-bromophenyl)-2-phenylpyrrolidine (750 mg, 62%) as a colorless oil. MS (ESI, m / e) [M+1] + 302.0, 304.1.

[0948] Step 2: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-phenylpyrrolidine-1-yl)-[1,1'-diphenyl]-4-carboxylic acid tert-butyl ester

[0949]

[0950] Under a nitrogen atmosphere, a mixture of 1-(4-bromophenyl)-2-phenylpyrrolidine (525 mg, 1.74 mmol), 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)benzoate tert-butyl ester (985 mg, 2.26 mmol), Pd(dppf)Cl2 (128 mg, 0.174 mmol), and K2CO3 (480 mg, 3.48 mmol) in 1,4-dioxane / H2O (50 mL / 10 mL) was heated to 90 °C with stirring overnight. After cooling to room temperature, the reaction mixture was washed successively with water and brine. The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography using 10% to 50% EA / PE as eluent to give tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-phenylpyrrolidine-1-yl)-[1,1'-diphenyl]-4-carboxylic acid (530 mg, 57.4%) as a white foam. MS (ESI, m / e) [M+1] + 532.3.

[0951] Step 3: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-phenylpyrrolidine-1-yl)-[1,1'-diphenyl]-4-carboxylic acid

[0952]

[0953] Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-phenylpyrrolidine-1-yl)-[1,1'-diphenyl]-4-carboxylic acid (531 mg, 1 mmol) in dichloromethane (25 mL). The reaction was stirred overnight at room temperature. The solvent was then removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography eluted with 5% methanol / dichloromethane to give 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-phenylpyrrolidine-1-yl)-[1,1'-diphenyl]-4-carboxylic acid (400 mg, 84.2%) as a white foam. MS (ESI, m / e) [M+1] + 476.2.

[0954] Step 4: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-1H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-(2-phenylpyrrolidine-2-yl)-[1,1'-diphenyl]-4-carboxamide

[0955]

[0956] HATU (114 mg, 0.3 mmol) and trimethylamine (0.2 mL) were added to a solution of 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-phenylpyrrolidine-1-yl)-[1,1'-diphenyl]-4-carboxylic acid (95 mg, 0.2 mmol) in dichloromethane (25 mL). The mixture was stirred at room temperature for 0.5 h. Then, 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (126 mg, 0.4 mmol) was added. After stirring overnight at room temperature, the reaction mixture was washed with water (10 mL), and the organic layer was dried over anhydrous Na2SO4 and then concentrated under vacuum. The residue was further purified by preparative HPLC to obtain the desired compound.

[0957] 1H NMR(400MHz,DMSO-d6)δppm:12.16(s,1H),11.68(s,1H),8.57(s,1H),8.54(s,1H),8.03(s,1H),7.80 (d,J=8.6Hz,1H),7.59-7.46(m,3H),7.33-7.25(m,5H),7.20-7.14(m,3H),7.08(d,J=8.1Hz,1H),6.8 9(s,1H),6.42(d,J=8.5Hz,2H),6.37(s,1H),4.78(d,J=7.4Hz,1H),3.84(d,J=8.4Hz,2H),3.68(s,1H ),3.31-3.20(m,3H),2.37-2.34(m,1H),1.94-1.80(m,4H),1.60(d,J=12.0Hz,2H),1.38-1.14(m,4H). MS(ESI,m / e)[M+1] + 773.3

[0958] Example A2: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(4-chlorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-diphenyl]-4-carboxamide

[0959]

[0960] The desired compound was synthesized starting from 2-(4-chlorophenyl)pyrrolidine and 1-bromo-4-iodobenzene, following a procedure similar to that in Example A1. 1H NMR (400MHz, DMSO-d6) δppm: 12.16 (s, 1H), 11.70 (s, 1H), 8.60 (s, 1H), 8.56 (s, 1H), 8.05 (d, J = 2.2Hz, 1H), 7. 82(d,J=8.4Hz,1H),7.59(s,1H),7.57-7.48(m,2H),7.34-7.28(m,5H),7.18(d,J=8.3Hz,2H),7.12(d,J=9.3H z,1H),6.89(s,1H),6.41(d,J=8.6Hz,2H),6.38(s,1H),4.78(d,J=7.1Hz,1H),3.84(d,J=8.4Hz,2H),3.67(t ,J=7.1Hz,1H),3.30-3.18(m,4H),2.37(m,1H),2.00-1.69(m,4H),1.60(d,J=12.4Hz,2H),1.34-1.13(m,3H). MS(ESI,m / e)[M+1] + 807.1

[0961] Example A3: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-chlorophenyl)pyrrolidine-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-diphenyl]-4-carboxamide

[0962]

[0963] The desired compound was synthesized starting from 2-(3-chlorophenyl)pyrrolidine and 1-bromo-4-iodobenzene, following a procedure similar to that in Example A1. 1H NMR(400MHz,DMSO-d6)δppm:12.17(s,1H),11.70(s,1H),8.59(s,1H),8.57(s,1H),8.05(s,1H),7 .83(d,J=9.0Hz,1H),7.60(s,1H),7.55-7.51(m,2H),7.36-7.21(m,6H),7.13(d,J=8.4Hz,2H),6.9 1(s,1H),6.43(d,J=8.4Hz,2H),6.39(s,1H),4.80(d,J=7.7Hz,1H),3.85(d,J=9.9Hz,2H),3.70(s, 1H),3.31-3.18(m,4H),2.36-2.31(m,1H),1.94-1.79(m,4H),1.60(d,J=12.5Hz,2H),1.25(m,3H). MS(ESI,m / e)[M+1] + 807.1

[0964] Example A4: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidine-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-diphenyl]-4-carboxamide

[0965]

[0966] The desired compound was synthesized starting from 2-(2-chlorophenyl)pyrrolidine and 1-bromo-4-iodobenzene, following a procedure similar to that in Example A1. 1 H NMR(400MHz,DMSO-d6)δppm:12.17(s,1H),11.70(s,1H),8.61(s,1H),8.57(s,1H),8.05(s,1H) ,7.83(d,J=9.4Hz,1H),7.60-7.41(m,4H),7.35-7.30(m,3H),7.25-7.12(m,3H),7.00(d,J=7.7H z,1H),6.90(s,1H),6.48-6.27(m,3H),4.97(d,J=7.4Hz,1H),3.85(d,J=11.3Hz,2H),3.74(s,1H ),3.31-3.19(m,4H),2.43-2.35(m,1H),1.99-1.83(m,4H),1.60(d,J=12.5Hz,2H),1.23(s,3H). MS(ESI,m / e)[M+1] + 807.1.

[0967] Example A4a: (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-diphenyl]-4-carboxamide;

[0968] Example A4b: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-diphenyl]-4-carboxamide

[0969]

[0970] Two enantiomers, A4a (the faster isomer) and A4b (the slower isomer), were separated by chiral preparative HPLC. The chiral separation conditions are shown below. The faster isomer eluted at a retention time of 1.1 min, yielding 252 mg of product. The slower isomer eluted at a retention time of 1.8 min, yielding 238 mg of product. The absolute configuration of the faster isomer was confirmed to be S by co-crystallization of Bcl2 and A4a; see the section "Protein Purification and Co-crystallization of Bcl2 and A4a".

[0971]

[0972]

[0973] Example A5: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3'-chloro-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-diphenyl]-4-carboxamide

[0974]

[0975] The desired compound was synthesized starting from 2-(2-chlorophenyl)pyrrolidine and 4-bromo-2-chloro-1-iodobenzene, following a procedure similar to that in Example A1. 1H NMR (400MHz, DMSO-d6) δppm: 12.32 (s, 1H), 11.70 (s, 1H), 8.61 (t, J = 5.7Hz, 1H), 8.55 (d, J = 2.0Hz, 1H), 8 .03(d,J=2.4Hz,1H),7.82(d,J=7.6Hz,1H),7.62-7.46(m,4H),7.44-7.34(m,2H),7.33-7.22(m,2H),7.2 2-7.15(m,2H),7.12(d,J=9.4Hz,1H),6.99(s,1H),6.71(d,J=8.8Hz,1H),6.37(s,1H),5.20(t,J=7.6Hz, 1H), 4.16 (m, 1H), 3.84 (d, J = 8.4Hz, 2H), 3.45-3.11 (m, 5H), 2.10-1.80 (m, 3H), 1.63 (m, 2H), 1.24 (m, 4H). MS(ESI,m / e)[M+1] + 841.1.

[0976] Example A6: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-(2-phenylpyrrolidine-1-yl)-3'-(trifluoromethyl)-[1,1'-diphenyl]-4-carboxamide

[0977]

[0978] Step 1: 1-(4-bromo-2-(trifluoromethyl)phenyl)-2-phenylpyrrolidine

[0979]

[0980] A mixture of 2-phenylpyrrolidine (1.46 g, 10 mmol), 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (4.8 g, 20 mmol), and N,N-diisopropylethylamine (2.5 g, 20 mmol) in dimethyl sulfoxide (50 mL) was heated to 150 °C overnight with stirring in a sealed tube. The mixture was cooled and poured into water (100 mL). The mixture was then extracted with EA (50 mL × 3), and the organic matter was washed with water and brine and dried over anhydrous Na₂SO₄. The solvent was removed under vacuum, and the residue was purified by petroleum column chromatography to give 1-(4-bromo-2-(trifluoromethyl)phenyl)-2-phenylpyrrolidine (180 mg, 4.9%) as a brown oil.

[0981] Then, following a similar procedure to that in Example A1, the desired compound was synthesized from 1-(4-bromo-2-(trifluoromethyl)phenyl)-2-phenylpyrrolidine. 1 H NMR(400MHz,DMSO-d6)δppm:12.32(s,1H),11.66(s,1H),8.56-8.53(m,2H),8.01(s,1H),7.78(s,1H), 7.66(s,1H),7.61-7.42(m,4H),7.39(d,J=8.0Hz,1H),7.30(d,J=7.2Hz,2H),7.23(t,J=7.2Hz,2H),7.1 -7.00(m,4H),6.35(s,1H),4.87(d,J=9.4Hz,1H),4.02-3.64(m,3H),3.26-3.22(m,4H),2.43-2.31(m,1 H), 2.00-1.98 (m, 1H), 1.93-1.81 (m, 2H), 1.72-1.67 (m, 1H), 1.60 (d, J = 12.0Hz, 2H), 1.29-1.19 (m, 3H). MS(ESI,m / e)[M+1] + 841.1.

[0982] Example A7: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(3-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-[1,1'-diphenyl]-4-carboxamide

[0983]

[0984] The desired compound was synthesized starting from 2-(3-(trifluoromethyl)phenyl)pyrrolidine and 1-bromo-4-iodobenzene, following a procedure similar to that in Example A1. 1H NMR(400MHz,DMSO-d6)δppm:12.17(s,1H),11.70(s,1H),8.61(s,1H),8.56(s,1H),8.05(d,J =2.0Hz,1H),7.82(d,J=9.2Hz,1H),7.64-7.42(m,7H),7.33(dd,J=14.2,8.5Hz,3H),7.13(d,J =9.2Hz,1H),6.90(s,1H),6.56-6.31(m,3H),4.90(d,J=7.4Hz,1H),3.84(d,J=8.5Hz,2H),3.7 3(t,J=7.1Hz,1H),3.31-3.22(m,5H),2.05-1.77(m,5H),1.60(d,J=12.1Hz,2H),1.28(s,2H). MS(ESI,m / e)[M+1] + 841.1.

[0985] Example A8: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidine-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-diphenyl]-4-carboxamide

[0986]

[0987] The desired compound was synthesized from 2-(2-cyclopropylphenyl)pyrrolidine and 1-bromo-4-iodobenzene following a similar procedure to that in Example A1. 1H NMR (400MHz, CDCl3) δppm: 10.31 (s, 1H), 9.14 (s, 1H), 8.93 (d, J = 2.0Hz, 1H), 8 .54(t,J=5.2Hz,1H),8.24(d,J=2.0Hz,1H),8.19(d,J=7.6Hz,1H),8.09(d,J= 8.6Hz,1H),7.71(d,J=2.0Hz,1H),7.45-7.41(m,1H),7.29(s,1H),7.20(d,J= 8.6Hz,2H),7.12(t,J=7.6Hz,1H),7.04-6.98(m,2H),6.93(d,J=8.6Hz,2H),6 .81(s,1H),6.53(s,1H),6.36(d,J=8.6Hz,2H),5.20(d,J=8.0Hz,1H),4.03(d d,J=11.0,3.6Hz,2H)...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, said compound being 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide: 。 2. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein the cancer is chronic lymphocytic leukemia.

3. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein the cancer is a lymphoma of T-cell or B-cell origin.

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