Bcl-2 inhibitors

Abstract

To provide new small molecules that selectively inhibit Bcl-2 proteins for the treatment of dysregulated apoptotic diseases such as cancers, autoimmune diseases and prothrombotic diseases.SOLUTION: The invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. A method for treating apoptotic diseases comprises administering, to a subject in need thereof, a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application is based on International Patent Application No. PCT / China Patent Application Publication ... Patent Application No. 2018 / 085217 and PCT / Chinese Patent Application No. 2018 / 085217 filed on September 21, 2018 This application claims the benefit of U.S. Patent Application Publication No. 2018 / 107134, , the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0002] Inhibition of Bcl-2 and diseases associated with undesired bcl-2 activity (Bcl-2-related compounds of formula (I) for treating neurodegenerative diseases, such as Alzheimer's disease; and dysregulated apoptosis, including proliferative disorders, such as cancer, autoimmune disorders, and prothrombotic disorders. Methods of using the compounds disclosed herein to treat diseases of apoptosis and the use thereof Disclosed herein are pharmaceutical compositions comprising the same. [Background technology]

[0003] Programmed cell death, or apoptosis, is a process that occurs when cells undergo cell death to eliminate damaged or unwanted cells. It occurs in multicellular organisms and is important for normal tissue homeostasis (Br.J. Cancer 1972, 26, 239). However, defective apoptotic processes The process is believed to be involved in a variety of diseases. Excessive apoptosis leads to atrophy. However, insufficient apoptosis leads to uncontrolled cell proliferation, such as cancer (Cell 2011,144,646). Resistance to apoptotic cell death is a hallmark of cancer. It contributes to chemotherapy resistance (Nat Med. 2004, 10, 789-799). Several key pathways that regulate apoptosis are commonly altered in cancer. Some factors, such as receptors and caspases, promote apoptosis, while proteins Several members of the interstitial B-cell lymphoma 2 (Bcl-2) family mediate apoptosis. Negative regulation of apoptosis inhibits cell death signaling pathways, preventing tumor growth. It promotes evasion of death and induces drug resistance.

[0004] There are two different apoptotic pathways, including the extrinsic pathway and the intrinsic pathway. , which is activated in response to the binding of death-inducing ligands to cell surface death receptors (NatR ev Drug Discov.2017 16,273-284). B-cell lymphoma 2 The (BCL-2) gene family, a group of proteins homologous to Bcl-2 proteins, It encodes over 20 proteins that regulate the intrinsic apoptotic pathway. Milli proteins contain four conserved Bcl-2 homology (BH) domains (BH1, BH2, BH3 and BH4) (Nat. Re v.Cancer 2008,8,121;Mol.Cell 2010,37,299 ;Nat.Rev.Mol.Cell Biol.2014,15,49). Apoptosis The Bcl-2 family of proteins, consisting of pro- and anti-apoptotic molecules, is a family of four B They can be classified into three subfamilies based on sequence homology within the H domain: (1) Subfamily members such as anti-apoptotic Bcl-2, Bcl-XL, and Bcl-w (2) Pro-apoptotic Bax, which shares sequence homology within all four BH domains Subfamilies such as Bak and Bak share sequence homology within BH1, BH2, and BH4. (3) The pro-apoptotic Bik, Bid, and HRK subfamily members are involved in BH 3, a unique feature of the Bcl-2 family of proteins. heterodimerization between anti-apoptotic and pro-apoptotic proteins which is thought to inhibit the biological activity of their partners. Heterodimerization consists of BH1, BH2, and BH3 from anti-apoptotic proteins The BH3 domain of proapoptotic proteins is inserted into the hydrophobic cleft where the apoptosis is mediated. In addition to BH1 and BH2, the BH4 domain is required for anti-apoptotic activity. In contrast, the BH3 domain is important and is sufficient by itself for pro-apoptotic activity. minutes.

[0005] Similar to oncogene addiction, where tumor cells depend on a single dominant gene for survival, tumor cells Bcl-2 overexpression may also lead to acute myeloid leukemia (AML) and other myeloma (AML)-associated myeloma (AML)-associated myeloma (AML). Myeloid leukemia (AML), acute lymphocytic leukemia (ALL), relapsed / refractory chronic lymphoma Myeloid leukemia (CLL), follicular lymphoma (FL), non-Hodgkin's lymphoma (NHL) and It is commonly seen in solid tumors such as pancreatic, prostate, breast, and small cell and non-small cell lung cancers ( Cancer 2001,92,1122-1129;Cancer Biol.200 3;13:115-23;Curr.Cancer Drug Targets 200 8,8,207-222;Cancers 2011,3,1527-1549). Atonal The key apoptotic pathways are involved in neurodegenerative diseases (upregulated apoptosis), e.g., arachidonic acid. Zheimer's disease; and proliferative diseases (downregulated apoptosis), e.g., cancer, autoimmune It has also been implicated in the pathology of other serious diseases such as thrombotic disorders and prothrombotic disorders. Many small molecule BH3 mimetics target either Bcl-2 or Bcl-xL. (Recent Patents on Anti-Cancer Drug Disc overy,2008,3,20-30;Bioorg.Med.Chem.Lett. 2016,26,2105-2114;Nature Reviews Drug Di scovery 2017,16,273-284; International Publication No. 2002024636 Brochure; International Publication No. 2005049593 Brochure; International Publication No. 20061 27364 Brochure; International Publication No. 2006023778 Brochure; International Publication Pamphlet No. 2007040650; Pamphlet No. WO 2008030836 International Publication No. 2009152082; International Publication No. 2009036051 No. Brochure; International Publication No. 2010065824 Brochure; International Publication No. 2010 International Publication No. 065865; International Publication No. 2010083441; International Publication International Publication No. 2010083442 Brochure; International Publication No. 2010067067 Brochure International Publication No. 2011029842; International Publication No. 201106856 1 Brochure; International Publication No. 2011119345 Brochure; International Publication No. 201 1149492 Brochure; International Publication No. 2011150016 Brochure; International Publication No. 2012058392 Brochure; International Publication No. 2012017251 Brochure Lett.; International Publication No. 2012162365 Brochure; International Publication No. 20121030 59 Brochure; International Publication No. 2013053045 Brochure; International Publication No. 20 International Publication No. 13185202; International Publication No. 2013096060; Country International Publication No. 2013096059 Brochure; International Publication No. 2013096055 Pan FRET; International Publication No. 2013096051 Brochure; International Publication No. 2013096 049; U.S. Patent Application Publication No. 2011312969; International Publication No. 2014158 528 Brochure; International Publication No. 2014113413 Brochure; International Publication No. Brochure No. 018027097; Brochure No. WO 2018041248; International Publication No. 2018009444; Chinese Patent Application Publication No. 10674923 3; Chinese Patent Application Publication No. 106565706 Several Bcl-2 small molecule inhibitors are being investigated at various stages of drug development: Bcl-2 / Bcl-xL inhibitor ABT-263 (navitoclax, International Publication No. 200 Pamphlet No. 9155386) is for lymphatic malignant tumors such as chronic lymphocytic leukemia. However, its efficacy in these settings remains uncertain. Limited by platelet death and subsequent thrombocytopenia caused by l-xL inhibition (Lancet Oncol. 2010, 11, 1149; J. Clin. Onc ol.2011,29,909;J.Clin.Oncol.2012,30,488) A new generation of BCL-2 selective inhibitor, venetoclax (ABT-199 / GDC-0199) ) has been developed, which has not only shown robust activity in these cancers but also inhibits platelet Intact (spared platelet) (Journal of Hematology tology&Oncology 2015,8,129;Clinical Adva nces in Hematology&Oncology 2017,15,210) S55746 (also known as BCL201), APG-101, APG-12 52 is currently being tested in clinical trials. 9) is a clinical trial for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) with 17p deletion. It is the only Bcl-2 selective inhibitor approved by the FDA for the treatment of patients with glaucoma. However, recently, a novel Gly101Val mutation in BCL2 was identified in 1 patient. Patients treated with the Bcl-2 inhibitor venetoclax (ABT-199) for 9 to 42 months This was later confirmed (Cancer Discov. 2019, 9, 342-353). This mutation was associated with a decreased response to venetoclax (ABT-199) in cell-based assays. The binding affinity of Bcl-2 to the agonist was significantly reduced by approximately 180-fold. Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, dysregulated apoptosis in diseases such as cancer, autoimmune diseases, and prothrombotic disorders is a major concern. There is a need for novel small molecules that selectively inhibit Bcl-2 proteins for the treatment of diseases. Unexpectedly, the inventors of the present application have discovered that some of the compounds disclosed herein , which exhibits much higher potency and selectivity as well as much lower CYP2C9 inhibition. This leads to potentially better efficacy and lower potential for drug-drug interactions (DDIs). The inventors of the present application also believe that the compounds disclosed herein may be effective against Bc The results showed inhibitory activity against both wild-type Bcl-2 and the G101V mutant Bcl-2. This suggests a novel potential Bcl-2 inhibitor with no resistance concerns. There are. [Means for solving the problem]

[0007] Formula (I) [ka] (In the formula, L 1 , L 2 , L 3 and L 4 are each independently a direct bond, -(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 -, -SO 2NR a -, -NR a SO2-, -NR a S(O)NR b -, -NR aS(O)NR b -, -C(O)NR a SO2-, -C(O)NR a SO- or -C(=NR a )NR b - where t and v, independently at each occurrence, are numbers from 1 to 7, and -(C R 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 of CR a R b The moiety may be unsubstituted or may be selected from O, S, SO, SO2, C(O), and NR a mosquito substituted with one or more moieties selected from: Each ring A has 1 to 4 substituents R 2 cycloalkyl optionally substituted with cycloalkenyl, cycloalkynyl, aryl, heterocyclyl or heteroaryl. the law of nature; R 2 is independently hydrogen, halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl, oxo, -CN, -NO2, -OR 2a , -SO2R 2a , -COR 2a , -CO2R 2a , -CONR2a R 2b , -C(=NR 2a )NR 2b R 2c , -NR 2 a 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 -C 1~8 Alkyl, -C 2~8 Alkenyl , -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Each of the groups is a halogen, hydroxy, -C 1~8 Alkyloxy, cycloalkyl, optionally substituted with heterocyclyl, aryl, or heteroaryl; R 2a , R 2b and R 2c are each independently hydrogen, -C 1~8 Alkyl, -C2 ~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl or is heteroaryl, and the -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, respectively is halogen, hydroxy or -C 1~8 optionally substituted with alkyloxy; Each ring B has 1 to 4 substituents R 1 cycloalkyl optionally substituted with cycloalkenyl, cycloalkynyl, aryl, heterocyclyl or heteroaryl. the law of nature; R 1 is independently hydrogen, halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl, oxo, -CN, -NO2, -OR 1a , -SO2R 1a , -COR 1a , -CO2R 1a , -CONR 1a R 1b , -C(=NR 1a )NR 1b R 1c , -NR 1 a 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 said -C 1~8 Alkyl, -C 2~8 a Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heterocyclyl Each aryl independently has 1 to 4 substituents R 1d optionally substituted with R1a , R 1b and R 1c are each independently hydrogen, -C 1~8 Alkyl, -C2 ~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl or is heteroaryl, and the -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, respectively is halogen, hydroxy or -C 1~8 optionally substituted with alkyloxy; R 1d represents independently at each occurrence a halogen, -C 1~8 Alkyl, -C 2~8 Al Kenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaromatic Lille, Oxo, -CN, -NO2, -OR Ba , -SO2R Ba , -COR Ba , -C O2R 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 SO 2nd RoundBb wherein said -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each each independently having 1 to 4 substituents R Bd optionally replaced by; R Ba , R Bb and R Bc are each independently hydrogen, -C 1~8 Alkyl, -C2 ~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl or is heteroaryl, and the -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, respectively is halogen, hydroxy, -NH2 or -N(C 1~6 alkyl)2, -C 1~8 alkyloxy, cycloalkyl, heterocyclyl, aryl or heteroaryl selectively substituted; R Bd is independently represented by each occurrence as hydrogen, halogen, oxo, -CN, -NO2, - C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, is tetracyclyl, aryl or heteroaryl, and 1~8 Alkyl, -C 2~ 8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl or Each heteroaryl may be selected from halogen, hydroxy, -C 1~8 Alkyloxy, Cyclo optionally substituted with alkyl, heterocyclyl, aryl, or heteroaryl; R 3 is hydrogen, halogen, C 1~8 Alkyl, C 2~8 Alkenyl, C 2~8 Alkini cycloalkyl, aryl, heterocyclyl, or heteroaryl, 1~ 8 alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, cycloalkyl, aryl, Each tetracyclyl or heteroaryl may have 1 to 4 substituents R 3a Optionally with Replaced; R 3a is independently a halogen, cyano, -NO2, -OR 3b , -S R 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 3 d , -N(R 3b )S(O)NR 3c R 3d , -N(R 3b )S(O)NR 3c R 3d , -NR 3b SO2R 3c , -C 1~8 Alkyl, -C 2~8Alkenyl, -C 2~8 a selected from alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Re; R 3b , R 3c and R 3d are independently hydrogen, -C 1~8 Alkyl, -C 2~8 Al Kenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl or hetero aryl, and the -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkini Each of halo, cycloalkyl, heterocyclyl, aryl or heteroaryl is Gen, hydroxy or -C 1~8 optionally substituted with alkyloxy; R 4 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)NR 4b R 4c , -NR4a SO2R 4b , -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -cycloa alkyl, heterocyclyl, aryl or heteroaryl, 1~8 Alkyl , -C 2~8 Alkenyl, -C 2~8 alkynyl, -cycloalkyl, heterocyclyl, Each aryl or heteroaryl may contain one or two substituents R 4d Independently and optionally substituted; R 4a , R 4b and R 4c are independently hydrogen, -C 1~8 Alkyl, -C 2~8 Al Kenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl or hetero aryl, and the -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkini Each of halo, cycloalkyl, heterocyclyl, aryl or heteroaryl is Gen, hydroxy or -C 1~8 optionally substituted with alkyloxy; R 4d is independently represented at each occurrence by hydrogen, oxo, -CN, -NO2, halogen, - C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, is tetracyclyl, aryl or heteroaryl, and 1~8 Alkyl, -C 2~ 8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl or Each heteroaryl may be selected from halogen, hydroxy, or -C 1~8 Alkyloxy optionally substituted; m is an integer from 1 to 4; R 5 Ha-L 5 -CyC, where L 5 is a direct bond, -(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)-, -N R a C(O)O-, -NR a C(O)NR b -,-SO2NR a -, -NR a SO2-, -NR a S(O)NR 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 the output Each occurrence is independently a number between 1 and 7, 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 The moiety is unsubstituted or O, S, SO, SO2, C(O) and NR a Place one or more parts selected from Converted; Each CyC has one or two substituents R 5a cycloalkane optionally substituted with alkyl, heterocyclyl, aryl or heteroaryl; R 5a is independently represented by each occurrence as 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(R5b )S(O)2 NR 5c R 5d , -NR 5b SO2R 5c , -C 1~8 Alkyl, -C 2~8 Alkenyl , -C 2~8 Alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Archi Each of -nyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl is one or two substituents R 5e optionally replaced by; where R 5b , R 5c and R 5d are each independently hydrogen, -C 1~8 Alkyl , -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, a aryl or heteroaryl, 1~8 Alkyl, -C 2~8 Alkenyl, C 2~8 Alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl each of which contains one or two substituents R 5e optionally replaced by; R 5e is independently represented by each occurrence as 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(=NR5f )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)2 NR 5g R 5h , -NR 5f SO2R 5g , -C 1~8 Alkyl, -C 2~8 Alkenyl , -C 2~8 Alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl Selected from the rules; R 5f , R 5g and R 5h are each independently hydrogen, -C 1~8 Alkyl, -C2 ~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl or is heteroaryl; or Two adjacent R on a phenyl ring 5 together with the phenyl ring to form a benzo ring, The ring is halogen, oxo, cyano, -NO2, -OR 5i , -SR 5i , -NR 5i R 5 j , -COR 5i , -SO2R 5i , -C(=O)OR 5i , -C(=O)NR 5i R 5 j , -C(=NR 5i)NR 5j R 5k , -N(R 5i )C(=O)R 5j , -N(R 5 i )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)NR 5j R 5k , -NR 5i SO2R 5 k , -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -cycloalkenyl optionally substituted with alkyl, heterocyclyl, aryl, or heteroaryl; R 5i , R 5j and R 5k are independently hydrogen, -C 1~8 Alkyl, -C 2~8 Al Kenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl or hetero aryl, and the -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkini Each of halo, cycloalkyl, heterocyclyl, aryl or heteroaryl is Gen, hydroxy or -C 1~8 optionally substituted with alkyloxy; R a , R b , R c and R d are independently hydrogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8Alkynyl, cycloalkyl, heterocyclyl, aryl alkyl or heteroaryl, 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is Independently, -CN, halogen, -NO2, -NR e R f , oxo, -OR e or -SR e is replaced by; where R e and R f are each independently hydrogen, C 1~8 Alkyl, C 1~8 Al Koxi-C 1~8 Alkyl-, C 2~8 Alkenyl, C 2~8 Alkynyl, cycloalkynyl aryl, heterocyclyl, or heteroaryl) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is disclosed herein. .

[0008] In one embodiment, R a , R b , R c and R d is independently hydrogen or is C 1~6 Alkyl, preferably hydrogen or methyl.

[0009] In one embodiment, L 1 is a direct bond or -(CR a R b ) t -, where R a , R b and t is defined as in formula (I). In some embodiments, t is 1 or In a preferred embodiment, L 1is a direct bond or -(CR a R b )-in where R a and R b is hydrogen or C 1~6 Alkyl, preferably hydrogen. In a preferred embodiment, L 1 is a direct bond.

[0010] In one embodiment, L 2 is a direct bond, -(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 defined as in formula (I). In some embodiments, t or v is 1 In a preferred embodiment, L 2 is a direct bond, -(CR a R b ) 1~ 5-, -(CR a R b ) 1~3 —(C≡C)—, —O—, or —NR a -where: R a , R b and R c is independently at each occurrence hydrogen or C 1~6 is alkyl, and - (CRa R b ) 1~5 -, -(CR a R b ) 1~3 One or two Cs in -(C≡C)- R a R b The moieties are O, S, SO, SO2, C(O) and NR a One or two pieces from In a further preferred embodiment, L 2 is a direct bond, -(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 is independently at each occurrence hydrogen or C 1~6 alkyl, -(C R a R b ) 1~5 -, -(CR a R b )-(C≡C)- in which one or two CR a R b Department Minutes are O or NR a and is substituted with one or two heteroatoms from a is hydrogen or C 1~6 alkyl, preferably hydrogen or CH. In another embodiment, L 2 is a direct bond, -CH2-, -O-, -NH-, [ka] where: * 3 refers to the position attached to ring A, and ** 4 is attached to the phenyl ring In the most preferred embodiment, L 2is a direct bond.

[0011] In a preferred embodiment, L 1 and L 2 are both direct bonds, or L 1 teeth , -CH2- or -CH2-CH2-, and L 2 is a direct bond.

[0012] In one embodiment, L 3 is a direct bond, -(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 defined as in formula (I). Preferably, R a and R b are independently hydrogen or C 1~6 alkyl, and t is 1 or 2. In a preferred embodiment, L 3 is -O-, -CH2-, a direct bond or -C(O)- More preferably, L 3 is -O-.

[0013] In one embodiment, R 3 is one or two substituents R defined as in formula (I) 3 a Preferably, R is heteroaryl optionally substituted with 3 is a halogen, - C 1~8 Alkyl or -NR 3b R 3c one or two substituents R selected from 3a At the discretion of optionally substituted heteroaryl, where R 3b and R 3c is, independently, Hydrogen or -C 1~8 It is alkyl.

[0014] In one embodiment, R 3 is a halogen, -C 1~8 Alkyl or -NR 3b R 3c mosquito one or two substituents R selected from 3a 5-7 membered nitrogen-containing monocyclic alkyl group optionally substituted with cyclic heteroaryl, where R 3b and R 3c are independently hydrogen or -C 1~ 8 alkyl. Preferably, R 3 are halogen and -C, respectively. 1~8 Alkyl or - NR 3b R 3c one or two substituents R selected from 3a Optionally replaced by Trazolyl, trizolyl, pyrazolyl, pyrrolyl, pyridinyl, pyrazolyl rimidinyl, where R 3b and R 3c are independently hydrogen or -C 1~8 Archi It is.

[0015] In one embodiment, R 3 is an 8-12 membered alkylene compound containing one, two, or three nitrogen atoms. Preferably, R 3 are halogen and -C, respectively. 1~8 Al Kill or -NR 3b R 3c one or two substituents R selected from 3a Optionally place substituted indolyl, pyrrolopyridinyl, or pyrazolopyridinyl, where R 3b and R 3c are independently hydrogen or -C 1~8More preferably, R 3 teeth , indol-4-yl, pyrrolo[2,3-b]pyridin-5-yl, pyrazolo[4,3 -b]pyridin-1-yl.

[0016] In one embodiment, R 3 is a halogen, -C 1~8 Alkyl or -NR 3b R 3c mosquito one or two substituents R selected from 3a or is an 11- to 14-membered tricyclic heteroaryl containing 3, 4, or 5 nitrogen atoms; , where R 3b and R 3c are independently hydrogen or -C 1~8 It is preferably alkyl. Kuha, R 3 pyrazolo[4,3-b]pyrrolo[3,2-e]pyridine-1(5i)-i It is.

[0017] In one embodiment, L 3 is -O- and R 3 is pyrrolo[2,3-b]pyr ... It is jin-5-yl.

[0018] In one embodiment, L 4 is -C(O)NR a SO2-, where R a is water Element and C 1~6 is alkyl; preferably hydrogen. In a preferred embodiment, L 4 teeth, * -C(O)NR a SO2- ** where R a is hydrogen and C 1~6 Al is alkyl; preferably hydrogen, where *indicates the position attached to ring C, and ** indicates the position attached to ring D.

[0019] In one embodiment, R 4 is -NO2, F, Cl, Br, cyano or -SO2R 4a where R 4a is defined as in formula (I). 4 teeth , -NO2, F, Cl, Br, cyano or -SO2R 4a where R 4a Ha, ha -C optionally substituted with halogen 1~8 alkyl, preferably -CF3. In a preferred embodiment, R 4 is -NO2.

[0020] In one embodiment, each ring A contains 1 to 4 substituents R 2 optionally substituted with cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl Preferably, R 2 is hydrogen, halogen (e.g., F, Cl, or Br), or halo C optionally substituted with alkyl (e.g., F, Cl, or Br) 1~6 Alkyl (e.g. For example, methyl).

[0021] In a preferred embodiment, ring A is 1,2-phenylene, 1,3-phenylene or 1 ,4-phenylene is a phenyl ring.

[0022] In a preferred embodiment, ring A is C 3~8 a cycloalkyl ring that is a cycloalkyl In a more preferred embodiment, ring A is cyclobutyl, cyclopentyl, cyclopentyl, In particular, ring A is selected from 1,2-cyclobutylene, 1,2-cyclohexyl, and 1,2-cycloheptyl. , 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 .

[0023] 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.

[0024] In a preferred embodiment, ring A is heteroaryl. Preferably, ring A is nitrogen. containing one, two, three, or four heteroatoms selected from hydrogen, oxygen, and sulfur; In particular, ring A is a monocyclic 5- or 6-membered heteroaryl, including pyridine, pyrazole, thiazole, Preferably, ring A is an 8- to 12-membered bicyclic heteroaryl. In particular, ring A is a pyrazolopyrimidine (e.g., pyrazolo[1,5-a]pyrimidine). thiophene), benzothiophene (benzo[b]thiophene) or pyrazolopyridine (e.g. , pyrazolo[1,5-a]pyridine) group.

[0025] In a preferred embodiment, ring A is heterocyclyl. a) one or two heteroatoms selected from nitrogen, oxygen, or sulfur as ring members; a monocyclic 4- to 9-membered heterocyclyl group containing b) containing, as ring members, one or two heteroatoms selected from nitrogen, sulfur and oxygen 5- to 12-membered spiroheterocyclyl; c) containing one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members 5- to 12-membered fused heterocyclyl; and d) containing one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members 5-12-membered bridged heterocyclyl is selected from.

[0026] In a more preferred embodiment, ring A is selected from nitrogen, sulfur, and oxygen as ring members. In particular, the ring is a 5- to 12-membered spiroheterocyclyl containing one or two heteroatoms. A is a 4 / 4, 3 / 5, or 4 / 5 ring containing one or two nitrogen or oxygen ring members. 4-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl. A is a 4 / 4 or 4 / 6 membered monospiroheterocyclyl containing one nitrogen ring member; More particularly, ring A is [ka] (7-azaspiro[3.5]nonane-2,7-diyl), [ka] (2-azaspiro[3.5]nonane-2,7-diyl), [ka] (3-azaspiro[5.5]undecane-3,9-diyl), [ka] (2-azaspiro[3.3]heptane-2,6-diyl), [ka] (8-azaspiro[4.5]decane-2,8-diyl), [ka] (2-azaspiro[4.5]decane-2,8-diyl).

[0027] In particular, ring A is selected from the group consisting of piperidine, pyrrolidine and azetidine; 7-azaspiro[3.5]no nan, 2-azaspiro[3.5]nonane, 8-azabicyclo[3.2.1]octane; Tetrahydrothienopyridines (e.g., 4,5,6,7-tetrahydrothieno[2,3-c ]pyridine), tetrahydropyrrolopyrazines (e.g., 1,2,3,4-tetrahydropyridine), pyrrolo[1,2-a]pyrazine), tetrahydropyrrolopyrazine (e.g., 1,2,3,4 -tetrahydropyrrolo[1,2-a]pyrazine), hexahydroindolizines (e.g., 1,2,3,5,8,8a-hexahydroindolizine), dihydropyrrolothiazole ( For example, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazole) or isoindoli It is a heterocyclic compound.

[0028] In a further preferred embodiment, ring A is [ka] (7-azaspiro[3.5]nonane-2,7-diyl), [ka] (2-azaspiro[3.5]nonane-2,7-diyl), [ka] (8-azabicyclo[3.2.1]octane-3,8-diyl), [ka] (3-azaspiro[5.5]undecane-3,9-diyl), [ka] (2-azaspiro[3.3]heptane-2,6-diyl), [ka] (8-azaspiro[4.5]decane-2,8-diyl), [ka] (2-azaspiro[4.5]decane-2,8-diyl), [ka] wherein: * 1 is L 1 and ** 2 is, L 2 It refers to the position where it is bonded to

[0029] In the most preferred embodiment, ring A is [ka] is.

[0030] In one embodiment, each ring B contains 1 to 4 substituents R 1 optionally substituted with cycloalkyl, cycloalkenyl, aryl, or heterocyclyl; R 1 represents independently at each occurrence a halogen, -C 1~8 Alkyl, -C 2~8 Arke Nil, -C 2~8 Alkynyl, cycloalkyl, aryl, heteroaryl, oxo, - CN or -OR 1a wherein said -C 1~8 Alkyl, -C2 ~8 Alkenyl, -C 2~8Alkynyl, aryl or heteroaryl are each independently and 1 to 4 substituents R 1d optionally substituted with R 1a is hydrogen or -C 1~8 alkyl, and the -C 1~8 Alkyl is halogen , hydroxy or -C 1~8 optionally substituted with alkyloxy; R 1d represents independently at each occurrence a halogen, -C 1~8 Alkyl, -C 2~8 Al Kenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaromatic Reel, -CN, -OR Ba , -SO2R Ba , -CONR Ba R Bb , -NR Ba R B b , -NR Ba COR Bb or -NR Ba SO2R Bb wherein said -C 1~8 Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each Independently, 1 to 4 substituents R Bd optionally replaced by; R Ba and R Bb are each independently hydrogen, -C 1~8 Alkyl, cycloalkyl or aryl, wherein the -C 1~8 alkyl, cycloalkyl or aryl, respectively is halogen, hydroxy, -C 1~8 Alkyloxy, cycloalkyl, heterocyclyl optionally substituted with aryl, aryl, or heteroaryl; R Bdis independently hydrogen, halogen, -CN, -C 1~8 Alkyl, -C 2~8 alkynyl, cycloalkyl or aryl, 1~8 Alkyl, -C 2~8 Each of the alkynyl or aryl groups may be selected from halogen, hydroxy, -C 1~8 a alkyloxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally are selectively replaced.

[0031] In one embodiment, cycloalkyl as ring B is a monocyclic C 3~8 cycloalkyl , preferably R 1 In one embodiment, the cyclopentyl or cyclohexyl is substituted with Hey, R 1 is a monocyclic C 3~8 R is cycloalkyl 1d is optionally replaced by It is an aryl group (eg, phenyl).

[0032] In one embodiment, the cycloalkenyl as ring B is a monocyclic C 3~8 Cycloalkane nyl, preferably one, two, or three R 1 cyclopentenyl or cyclopentenyl substituted with In one embodiment, R 1 is a halogen R 1d Select any one with C 1~8 Alkyl (e.g., C 1~6 alkyl, preferably methyl) or It is an aryl group (eg, phenyl).

[0033] In one embodiment, the heterocyclyl as ring B is each selected from 1 to 4 substituents R 1 monocyclic 4- to 9-membered heterocyclyl, 5- to 20-membered spiroheterocyclyl optionally substituted with heterocyclyl, a 5- to 20-membered fused heterocyclyl, or a 5- to 20-membered bridged heterocyclyl.

[0034] In one embodiment, the monocyclic heterocyclyl has as ring members NH, O, S, SO or SO2 heteroatoms and monocyclic 4- to 9-membered rings containing one or more heteroatoms selected from the group consisting of heteroatoms It is a heterocyclyl.

[0035] In one embodiment, a monocyclic heterocyclyl is a monocyclic heterocycle containing one nitrogen atom as a ring member. In a preferred embodiment, the ring is a 4- to 9-membered heterocyclyl. Monocyclic 4- to 9-membered heterocyclyl containing a ring is C-bonded or N-bonded. In another embodiment, a monocyclic 4- to 9-membered heterocyclyl containing one nitrogen atom as a ring member is , saturated. In particular, saturated heterocyclyl includes, but is not limited to, aziridin-1-yl , azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, azepan-1 N-linked, including azocan-1-yl and azocan-1-yl, preferably pyrrolidin-1-yl Particularly, saturated heterocyclyl includes, but is not limited to, aziridinyl. azetidin-2-yl, azetidin-3-yl, pyrrolidin-2-yl, Pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4 -yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, azocan-2 C-bonds, including azocan-3-yl, azocan-4-yl and azocan-5-yl In another more preferred embodiment, the ring members are saturated heterocyclyls bonded to each other. Monocyclic 4- to 9-membered heterocyclyl containing one nitrogen atom is unsaturated. In a preferred embodiment, a monocyclic 4- to 9-membered heterocyclyl containing one nitrogen atom as a ring member is contains one carbon-carbon double bond. In particular, a monocyclic ring containing one nitrogen atom as a ring member The formula 4-9 membered heterocyclyl is dihydropyrrolyl, for example 2,3-dihydro-1H-pyrrolyl. aryl and 2,5-dihydro-1H-pyrrolyl or tetrahydropyridinyl.

[0036] In another embodiment, a monocyclic heterocyclyl has one nitrogen atom and N as ring members. one additional heteroatom selected from the group consisting of H, O, S, SO, or SO2 heteroatoms In a preferred embodiment, the ring members are monocyclic 4- to 9-membered heterocyclyl. and one nitrogen atom and one heteroatom selected from the group consisting of NH, O, S, SO, or SO. Monocyclic 4- to 9-membered heterocyclyl containing one additional heteroatom is C-bonded or N-bonded. In a further preferred embodiment, the monocyclic heterocyclyl is saturated. In an even more preferred embodiment, the saturated monocyclic heterocyclyl is N-linked. In another even more preferred embodiment, the saturated monocyclic heterocyclyl is C-linked. It is being done.

[0037] In a preferred embodiment, ring B contains 1 to 4 substituents R 1 Pyrrolidine substituted with - It is 1-yl.

[0038] In one embodiment, R 1 is a phenyl group.

[0039] In a more preferred embodiment, Ring B is aziridin-1-yl, azetidin-1-yl pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, azepan- 1-yl or azocan-1-yl, preferably substituted at the 2-position with a phenyl group, and One, two, or three substituents R in the pyrrolidinyl ring 1 Optionally place substituted pyrrolidin-1-yl, and the phenyl group at the 2-position is Defined R 1d is optionally replaced by

[0040] In one aspect of this embodiment, R 1 represents independently at each occurrence a halogen, -C1 ~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, aryl aryl, heteroaryl, oxo, -CN or -OR 1a is selected from the group consisting of: Said-C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkynyl The aryl, aryl or heteroaryl may be one to four substituents R 1d optionally substituted with where R 1a is hydrogen or C 1~8 alkyl, preferably methyl, and R 1d teeth , halogen, -C 1~8 Alkyl or -OR Ba where R Ba is hydrogen or - C 1~8 In another embodiment, R 1 is heteroaryl, preferably fluorine; In one embodiment, R 1 is a monocyclic The heterocyclyl is substituted at the 2-position.

[0041] In one aspect of this embodiment, R 1d is a phenyl group (aziridinyl) at the 2-position of ring B. benzoyl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, Piperidin-1-yl, azepan-1-yl or azocan-1-yl, preferably pyrrolidin When substituted in a group (including a diphenyl-1-yl group), independently, halogen, -C 1~8 a Lukil, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl Aryl, aryl, heteroaryl, -CN, -OR Ba , -SO2R Ba , -CONR Ba R Bb , -NO2, -NR Ba R Bb , -NR Ba COR Bb or -NR Ba SO2R B b wherein said -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Archi cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently and 1 to 4 substituents R defined in formula (I). Bd , preferably defined by formula (I) one or two substituents R Bd In another embodiment, one R 1 d is at the 2-position of the phenyl ring at the 2-position of ring B.

[0042] In one embodiment, R 1d -C as 1~8 Alkyl is halogen, phenyl, cyclo Alkyl (e.g., C3~8 cycloalkyl, preferably cyclopropyl), C 1~6 a heterocyclyl optionally substituted with alkyl (e.g., piperazinyl, piperidinyl) ) 1 to 4 substituents R Bd In particular, R 1d is R Bd methyl, ethyl, isopropyl, propyl, tert- -C selected from butyl and isobutyl 1~8 In another embodiment, 2 One methyl group is at the 2-position of the phenyl ring in the 2-position of ring B.

[0043] In one embodiment, R 1d Cycloalkyl as a group can be substituted with halogen, cyano, C 2~8 Al C optionally substituted with ynyl (preferably ethynyl) or halogen 1~8 Alkyl (preferably CF3) Bd is further optionally substituted with In particular, R 1d is R Bd cyclopropyl, cyclobutyl, cyclopropyl ... C selected from cyclopentyl and cyclohexyl 3~8 Another example is cycloalkyl. In the analogy, one cyclopropyl is at the 2-position of the phenyl ring at the 2-position of ring B.

[0044] In one embodiment, R 1d -C as 2~8 Alkenyl is prop-1-en-2-yl It is.

[0045] In one embodiment, R 1d -C as 2~8 Alkynyl is ethynyl.

[0046] In one embodiment, R 1d as -OR Ba In the definition of R Ba is hydrogen, C 1~ 8 alkyl (selected from methyl, ethyl, propyl and isopropyl), C 3~8 S cycloalkyl (preferably cyclopropyl or cyclohexyl), aryl (preferably phenyl), where C 1~8 Alkyl, C 3~8 Cycloalkyl and aryl are , each independently, halogen, heterocyclyl (preferably monocyclic 4- to 9-membered heterocyclyl) acrylate, more preferably morpholino), hydroxy or -C 1~8 Alkoxy (preferably It is substituted with (e.g., methoxyl).

[0047] In one embodiment, R 1d is aryl which is phenyl.

[0048] In one embodiment, R 1d is a ring member selected from nitrogen, oxygen, and sulfur; Monocyclic 4- to 9-membered heterocyclyl group containing one or two heteroatoms, preferably Monocyclic 4- to 6-membered heterocyclyl containing one oxygen atom as a ring member or one or two It is a monocyclic 6-membered heterocyclyl containing two nitrogen atoms.

[0049] In one embodiment, R 1d is heteroaryl, preferably thiophenyl or furanyl; be.

[0050] In one embodiment, ring B is substituted with a naphthyl group, preferably at the 2-position. It is pyrrolidin-1-yl substituted with ethyl.

[0051] In one embodiment, ring B is substituted with a heteroaryl group, preferably at the 2-position. In one embodiment, the heteroaryl group is pyrrolidin-1-yl. Heteroaryl is a five-membered heteroaryl containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur. 6-membered heteroaryl. Preferably, the heteroaryl is pyridinyl, furanyl, or the like. In another embodiment, heteroaryl is halogen, thiophenyl, or pyrazolyl. or C 3~8 It is optionally substituted with cycloalkyl (preferably cyclopropyl).

[0052] In one embodiment, ring B is -C 1~8 Alkyl, -C 2~8 Alkenyl or -C2 ~8 alkynyl-substituted, preferably at the 2-position -C 1~8 Alkyl, -C 2~8 Alkenyl or -C 2~8 pyrrolidin-1-yl substituted by alkynyl, C 1~8 Alkyl, -C 2~8 Alkenyl or -C 2~8 Each alkynyl is a non-substituted or substituted with a phenyl group, the phenyl group being substituted with a halogen or 3~8 Shik In a preferred embodiment, wherein ring B is optionally substituted with a phenyl group, each optionally substituted as described above. It is a pyrrolidin-1-yl substituted with methyl, ethenyl or ethynyl.

[0053] In a preferred embodiment, ring B contains 1 to 4 substituents R as defined in formula (I). 1 At the discretion of optionally substituted pyrrolidin-1-yl.

[0054] In a preferred embodiment, [ka] teeth, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0055] In a preferred embodiment, Ring B is a 2-substituted pyrrolidin-1-yl group, and L1 is a direct bond, and L 2 is a direct bond, and ring A is a 1,4-phenylene ring or a ring member 5 to 1 carbon atoms containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen 2-membered spiroheterocyclyl, preferably 5-12-membered containing one or two nitrogen ring members spiroheterocyclyl; more preferably 4 containing one or two nitrogen or oxygen ring members 3-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiro 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 2-(substituted phenyl)-2,8-diyl. L is a direct bond; L 2 is a direct bond and ring A is a 1,4-phenylene ring or ring member selected from nitrogen, sulfur, and oxygen. 5- to 12-membered spiroheterocyclyl containing one or two heteroatoms, preferably 5-12 membered spiroheterocyclyl containing one or two nitrogen atoms as ring members; more preferably 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl; most preferably, the ring A is 7-azaspiro[3.5]nonane-2,7-diyl, 2-azaspiro[3.5]nonane Nan-2,7-diyl, 3-azaspiro[5.5]undecane-3,9-diyl, 2-azaspiro[5.5]undecane-3,9-diyl 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 preferred embodiment, Ring B is a 2-(2-substituted phenyl)pyrrolidin-1-yl group or is a 2-(3-substituted phenyl)pyrrolidin-1-yl group, L1 is a direct bond, L 2 is a direct bond, and ring A is a 1,4-phenylene ring or a 7-azaspiro[3.5] Nonane-2,7-diyl, 2-azaspiro[3.5]nonane-2,7-diyl, 3-aza Spiro[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 2-position of pyrrolidin-1-yl. The phenyl group in 1d is replaced by. In a particularly preferred embodiment, Ring B is 2-(2-substituted phenyl)pyrrolidin-1-yl or a 2-(3-substituted phenyl)pyrrolidin-1-yl group, and L1 is a direct bond. Ring A is a 1,4-cyclohexylene ring or 1,4-cyclohex-3-enyl, or or 1,4-cyclohex-2-enyl or 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, and L 2 is a direct bond, where the phenyl group at the 2-position of pyrrolidin-1-yl is (I) 1 to 4 substituents R 1d In one embodiment, one Substituent R 1d is substituted at the 2-position of the phenyl group at the 2-position of the pyrrolidin-1-yl can be.

[0056] In one embodiment, m is 1.

[0057] In one embodiment, L 5 is a direct bond, -(CR a R b ) t -or-NR a - and , where t is a number from 1 to 7, and -(CR a R b ) t -One or two CRs a R b The moiety is unsubstituted or is selected from O and NR a Replace with one or more parts selected from where R a and R b is defined as in formula (I).

[0058] In a preferred embodiment, L 5 is a direct bond, -(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 is defined as in formula (I), whereby -L 5 -CyC part is CyC, -(CR 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 is a direct bond, -(CH2) 1~4 -, -O-(CH2) 1~3 -, -NH-(CR a R b )-(CH2)2- or -NH-, where R a is hydrogen and R b teeth, C optionally substituted with phenyl-S- 1~8 alkyl, whereby -L 5 The -CyC moieties are CyC and -(CH2), respectively. 1~4 -CyC, -O-(CH2) 1~ 3-CyC, -NH-(CR a R b )-(CH2)2-CyC or -NH-CyC More preferably, L 5 is a direct bond, -CH2-, -O-CH2-, -NH-CH2- or -NH-, whereby -L 5 The -CyC moieties are CyC and -CH2-, respectively. CyC, -O-CH2-CyC, -NH-CH2-CyC or -NH-CyC

[0059] In one embodiment, CyC each contains one or two substituents R 5a Optionally with is a substituted cycloalkyl or heterocyclyl; R 5a are independently hydrogen, halogen, cyano, oxo, -OR 5b , -NR 5b R 5 c , -COR 5b , -SO2R 5b , -C 1~8 Alkyl, -C 2~8 Alkynyl, - chloroalkyl or heterocyclyl, wherein said -C 1~8 Alkyl and heterocyclic Each of the alkyl groups is hydrogen, halogen, cyano, -OR 5f , -C 1~8 Alkyl, -cyclo one or two substituents R selected from alkyl, aryl, or heterocyclyl;5e Optional in is replaced by; where R 5b and R 5c are each independently hydrogen, -C 1~8 Alkyl or Hetero -C is cyclocyclyl; 1~8 Alkyl is hydrogen, -NR 5f R 5g Or -cycloa one or two substituents R which are alkyl; 5e optionally replaced by; R 5f and R 5g are each independently hydrogen or -C 1~8 is alkyl; or Two adjacent R on a phenyl ring 5 together with the phenyl ring to form a benzo ring, can be.

[0060] In one embodiment, CyC each contains one or two substituents R 5a Optionally with Substituted monocyclic C 3~8 Cycloalkyl or bridged cycloalkyl [ka] and preferably, each CyC is one or two Substituent R 5a and cyclopentyl or cyclohexyl optionally substituted with

[0061] In one embodiment, CyC each has one or two R 5a Optionally replaced by can be, a) a monocyclic 4- to 9-membered ring containing one nitrogen, oxygen, or sulfur heteroatom as a ring member; heterocyclyl groups; b) a monocyclic ring containing, as ring members, two heteroatoms selected from oxygen, sulfur and nitrogen a 4- to 9-membered heterocyclyl group of formula; and c) containing one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members 5-20 membered spiroheterocyclyl is a heterocyclyl selected from:

[0062] In a preferred embodiment, CyC has one nitrogen, oxygen, or sulfur ring member. Cyc is a monocyclic 4- to 6-membered heterocyclyl group containing a hetero atom. More preferably, Cyc is , oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrolyl Even more preferably, CyC is selected from oxetane, benzophenone, benzothiazolin ... -2-yl, oxetan-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydrofuran-3-yl Hydropyran-3-yl, tetrahydropyran-4-yl, azetidin-3-yl, azetidin-4-yl 2-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 4-pyrrolidinyl The aryl is selected from piperidin-2-yl, piperidin-3-yl and piperidin-4-yl.

[0063] In a preferred embodiment, CyC has two ring members selected from oxygen and nitrogen. More preferably, CyC is a monocyclic 6-membered heterocyclyl group containing a heteroatom of , dioxanyl, morpholino, morpholinyl or piperidinyl, even more preferably 1 ,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,4-dioxan-2 -yl, morpholin-1-yl, morpholin-2-yl or morpholin-3-yl .

[0064] In a preferred embodiment, CyC contains one or two nitrogen or oxygen ring members. 4 member / 4 member, 3 member / 5 member, 4 member / 5 member, 4 member / 6 member, 5 member / 5 member or 5 member / 6 member monospin More preferably, CyC is [ka] (7-oxa-2-azaspiro[3.5]nonan-2-yl), or [ka] (2-oxaspiro[3.5]nonan-7-yl).

[0065] In a preferred embodiment, R 5a are independently hydrogen, halogen, cyano, oxo, -OR 5b , -NR 5b R 5c , -COR 5b , -SO2R 5b , -C 1~8 Alkyl, -C 2~8 Alkynyl, monocyclic C 3~8 cycloalkyl or nitrogen as a ring member, or Contains one or two heteroatoms selected from oxygen or sulfur heteroatoms monocyclic 4- to 9-membered heterocyclyl groups, 1~8 Alkyl and monocyclic 4- Each of the 9-membered heterocyclyl groups may contain one or two substituents R 5e Optionally replaced by Preferably, R 5a Cycloalkyl as C 3~6 Cycloalkyl; more preferably Preferably, R is cyclopropyl. 5a Heterocyclyl as a ring member and and one or two heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms. More preferably, R 5a Heterosyc as Aryl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or Even more preferably, R is morpholinyl. 5a Heterocyclyl as an oxy group Cetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4- yl or morpholin-4-yl.

[0066] In one embodiment, R 5e Heterocyclyl as the ring member is a ring having nitrogen or oxygen. or a monocyclic 4-9 ring containing one or two heteroatoms selected from sulfur heteroatoms Preferably, R 5e Heterocyclyl as a tetrahydrogen It is 4-pyran-4-yl.

[0067] In one embodiment, R 5a is -NR 5b R 5c where R 5b is hydrogen Yes and R 5c is heterocyclyl. In a more preferred embodiment, R 5a teeth , -NR 5b R 5c where R 5b is hydrogen and R 5c is tetrahydro In one embodiment, R 5a is -NR 5b R 5c and , where R 5b and R 5c are each independently substituted with hydrogen or cycloalkyl. Ru-C 1~6 Alkyl, preferably monocyclic C 3~8 -C substituted with cycloalkyl 1~ 6 alkyl.

[0068] In one embodiment, R 5a -OR 5b or -SO2R 5b where R 5 b is hydrogen or C 1~8 It is alkyl, preferably methyl.

[0069] In one embodiment, R 5a -COR 5b where R 5b is hydrogen or - NR 5f R 5g C optionally substituted with 1~8 alkyl, where R 5f and R 5g are each independently hydrogen or C 1~8 It is alkyl, preferably methyl.

[0070] In one embodiment, two adjacent R on the phenyl ring 5 together with the phenyl ring, Forming an indazolyl substituted with tetrahydropyranyl.

[0071] In a preferred embodiment, -L 5 -CyC is [ka] [ka] [ka] is selected from the group consisting of:

[0072] Formula (II) [ka] (In the formula, Each ring A has 1 to 4 substituents R2 1,4-phenylene optionally substituted with or a phenyl ring having one or more ring members selected from nitrogen, sulfur, and oxygen; a 5- to 12-membered spiroheterocyclyl containing two heteroatoms; R 2 is independently at each occurrence hydrogen, halogen, or an optionally substituted halogen. Reru-C 1~8 selected from the group consisting of alkyl; Ring B is a monocyclic 4- to 9-membered heterocyclyl containing one nitrogen atom as a ring member or and one nitrogen atom and a heteroatom selected from the group consisting of NH, O, S, SO, or SO. and a monocyclic 4- to 9-membered heterocyclyl containing one additional heteroatom selected from the group consisting of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, is N-bonded; R 1 , R 5 and m is defined in formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is also disclosed herein. .

[0073] The compound of formula (II) is a compound of formula (I) L 1 and L 2 are each independently a direct bond, and L 4 is -C(O)NHS O2-; L 3 is -O- and R 3 is pyrrolo[2,3-b]pyridin-5-yl ; R 4 corresponds to the compound -NO2.

[0074] In some embodiments, ring A is 1,4-phenylene. Ring A contains, as ring members, one or two heteroatoms selected from nitrogen, sulfur, and oxygen. Preferably, ring A is a 5- to 12-membered spiroheterocyclyl containing 1 or 2 ring members. 4 / 4, 3 / 5, 4 / 5, 4 / 6, 5 / 5 containing two nitrogen or oxygen atoms or 5-membered / 6-membered monospiroheterocyclyl; more preferably, ring A is [ka] (7-azaspiro[3.5]nonane-2,7-diyl), [ka] (2-azaspiro[3.5]nonane-2,7-diyl), [ka] (3-azaspiro[5.5]undecane-3,9-diyl), [ka] (2-azaspiro[3.3]heptane-2,6-diyl, wherein * 1 is pyrrolidin refers to the position attached to the nyl ring, and ** 2 refers to the position attached to the phenyl ring.

[0075] In certain embodiments, Ring B is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, Lysin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, azepan-1-yl or azocan-1-yl, preferably substituted with a phenyl group at the 2-position and pyrrolidinyl One, two, or three substituents R in the nyl ring 1 is further optionally substituted with pyrrolidin-1-yl, and the phenyl group at the 2-position (i.e., the ortho-position) is , R defined in formula (I) 1d is optionally replaced by

[0076] When ring B is pyrrolidin-1-yl substituted with a phenyl group at the 2-position, (i.e., ortho position) is R defined in formula (I). 1d Select arbitrarily The compound is optionally substituted and has the following formula (III): [ka] is expressed by

[0077] In one embodiment for formula (III), ring A is [ka] , [ka] (7-azaspiro[3.5]nonane-2,7-diyl), [ka] (2-azaspiro[3.5]nonane-2,7-diyl), [ka] (3-azaspiro[5.5]undecane-3,9-diyl), [ka] (2-azaspiro[3.3]heptane-2,6-diyl, wherein * 1 is pyrrolidin refers to the position attached to the nyl ring, and ** 2 indicates the position attached to the phenyl ring, Thus, the compounds of formula (III) are of the following subgeneric formulae (III-A), (III-B), (III-C), (III-D) or (III-E) [ka] (wherein the variable R 1d , R2 , R 5 and m is defined in formula (I) It can be represented by:

[0078] Subgeneric formulae (II), (III), (III-A), (III-B), (III-C), In some embodiments for (III-D) or (III-E), R 2 is hydrogen do.

[0079] Formula (II), (III), (III-A), (III-B), (III-C), (II In some embodiments for (III-I-D) or (III-E), R 1d is defined by formula (I) Preferably, R 1d The phenyl group (aziridine-1-yl) at the 2-position of ring B azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidine -1-yl, azepan-1-yl or azocan-1-yl, preferably pyrrolidin-1-yl When substituted in the alkyl group (including aryl groups), independently, halogen, -C 1~8 Alkyl, - C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl 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 and; Here, the -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cyclo The alkyl, heterocyclyl, aryl, or heteroaryl each independently represent a group of the formula ( I) 1 to 4 substituents R Bd , preferably one or two of the groups defined in formula (I) The substituents R Bd In another embodiment, one R 1d is ring B It is at the 2-position of the phenyl ring at the 2-position of the

[0080] Subgeneric formulae (II), (III), (III-A), (III-B), (III-C), In certain preferred embodiments for (III-D) or (III-E), R 1d teeth , methyl, ethyl, isopropyl, propyl or methoxymethyl, or at the position of the phenyl ring two methyl groups in the same position; or propenyl; or cyclopropyl, cyclobutyl, cyclo Pentyl or cyclohexyl; or ethoxy or isopropoxy; or amino or Preferably it is dimethylamino.

[0081] Subgeneric formula (III), (III-A), (III-B), (III-C), (III- In certain preferred embodiments for (III-D) or (III-E), 2-( The 2-substituted phenyl)pyrrolidin-1-yl moiety is [ka] [ka] is selected from the group consisting of:

[0082] Subgeneric formulae (II), (III), (III-A), (III-B), (III-C), In certain preferred embodiments for (III-D) or (III-E), m is 1 and L5 is a direct bond, -(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 portion is unsubstituted or is O and NR a wherein So, R a and R b is defined as in formula (I).

[0083] In a preferred embodiment, L 5 is a direct bond, -(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 is defined as in formula (I), whereby -L 5 -CyC part is CyC, -(CR 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 is a direct bond, -(CH2) 1~4 -, -O-(CH2) 1~3 -, -NH-(CR a R b)-(CH2)2- or -NH-, where R a is hydrogen and R b teeth, C optionally substituted with phenyl-S- 1~8 alkyl, whereby -L 5 The -CyC moieties are CyC and -(CH2), respectively. 1~4 -CyC, -O-(CH2) 1~ 3-CyC, -NH-(CR a R b )-(CH2)2-CyC or -NH-CyC More preferably, L 5 is a direct bond, -CH2-, -O-CH2-, -NH-CH2- or -NH-, whereby -L 5 The -CyC moieties are CyC and -CH2-, respectively. CyC, -O-CH2-CyC, -NH-CH2-CyC or -NH-CyC.

[0084] In one embodiment, CyC each contains one or two substituents R 5a Optionally with is a substituted cycloalkyl or heterocyclyl; R 5a are independently hydrogen, halogen, cyano, oxo, -OR 5b , -NR 5b R 5 c , -COR 5b , -SO2R 5b , -C 1~8 Alkyl, -C 2~8 Alkynyl, - chloroalkyl or heterocyclyl, wherein said -C 1~8 Alkyl and heterocyclic Each of the alkyl groups is hydrogen, halogen, cyano, -OR 5f , -C 1~8 Alkyl, -cyclo one or two substituents R selected from alkyl, aryl, or heterocyclyl; 5eOptional in is replaced by; where R 5b and R 5c are each independently hydrogen, -C 1~8 Alkyl or Hetero -C is cyclocyclyl; 1~8 Alkyl is hydrogen, -NR 5f R 5g Or -cycloa one or two substituents R which are alkyl; 5e optionally replaced by; R 5f and R 5g are each independently hydrogen or -C 1~8 is alkyl; or Two adjacent R on a phenyl ring 5 together with the phenyl ring to form a benzo ring, The ring is optionally substituted with heteroaryl.

[0085] In one embodiment, CyC each contains one or two substituents R 5a Optionally with Substituted monocyclic C 3~8 Cycloalkyl or bridged cycloalkyl [ka] and preferably, each CyC is one or two Substituent R 5a and cyclopentyl or cyclohexyl optionally substituted with

[0086] In one embodiment, CyC each has one or two R 5a Optionally replaced by can be, a) a monocyclic 4- to 9-membered ring containing one nitrogen, oxygen, or sulfur heteroatom as a ring member; heterocyclyl groups; b) a monocyclic ring containing, as ring members, two heteroatoms selected from oxygen, sulfur and nitrogen a 4- to 9-membered heterocyclyl group of formula; and c) containing one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members 5-20 membered spiroheterocyclyl is a heterocyclyl selected from:

[0087] In a preferred embodiment, CyC has one nitrogen, oxygen, or sulfur ring member. Cyc is a monocyclic 4- to 6-membered heterocyclyl group containing a hetero atom. More preferably, Cyc is , oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrolyl Even more preferably, CyC is selected from oxetane, benzophenone, benzothiazolin ... -2-yl, oxetan-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydrofuran-3-yl Hydropyran-3-yl, tetrahydropyran-4-yl, azetidin-3-yl, azetidin-4-yl 2-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 4-pyrrolidinyl The aryl is selected from piperidin-2-yl, piperidin-3-yl and piperidin-4-yl.

[0088] In a preferred embodiment, CyC has two ring members selected from oxygen and nitrogen. More preferably, CyC is a monocyclic 6-membered heterocyclyl group containing a heteroatom of , dioxanyl, morpholino, morpholinyl or piperidinyl, even more preferably 1 ,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,4-dioxan-2 -yl, morpholin-1-yl, morpholin-2-yl or morpholin-3-yl .

[0089] In a preferred embodiment, CyC contains one or two nitrogen or oxygen ring members. 4 member / 4 member, 3 member / 5 member, 4 member / 5 member, 4 member / 6 member, 5 member / 5 member or 5 member / 6 member monospin More preferably, CyC is [ka] (7-oxa-2-azaspiro[3.5]nonan-2-yl), or [ka] (2-oxaspiro[3.5]nonan-7-yl).

[0090] In a preferred embodiment, R 5a are independently hydrogen, halogen, cyano, oxo, -OR 5b , -NR 5b R 5c , -COR 5b , -SO2R 5b , -C 1~8 Alkyl, -C 2~8 Alkynyl, monocyclic C 3~8 cycloalkyl or nitrogen as a ring member, or Contains one or two heteroatoms selected from oxygen or sulfur heteroatoms monocyclic 4- to 9-membered heterocyclyl groups, 1~8 Alkyl and monocyclic 4- Each of the 9-membered heterocyclyl groups may contain one or two substituents R 5e Optionally replaced by Preferably, R 5a Cycloalkyl as C 3~6 Cycloalkyl; more preferably Preferably, R is cyclopropyl. 5a Heterocyclyl as a ring member and and one or two heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms. More preferably, R 5a Heterosyc as Aryl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or Even more preferably, R is morpholinyl. 5a Heterocyclyl as an oxy group Cetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4- yl or morpholin-4-yl.

[0091] In one embodiment, R 5e Heterocyclyl as the ring member is a ring having nitrogen or oxygen. or a monocyclic 4-9 ring containing one or two heteroatoms selected from sulfur heteroatoms Preferably, R 5e Heterocyclyl as a tetrahydrogen It is 4-pyran-4-yl.

[0092] In one embodiment, R 5a is -NR 5b R 5c where R 5b is hydrogen Yes and R 5c is heterocyclyl. In a more preferred embodiment, R 5a teeth , -NR 5b R 5c where R 5b is hydrogen and R 5c is tetrahydro In one embodiment, R 5a is -NR 5b R 5c and , where R 5b and R 5c are each independently substituted with hydrogen or cycloalkyl. Ru-C 1~6 Alkyl, preferably monocyclic C 3~8-C substituted with cycloalkyl 1~ 6 alkyl.

[0093] In one embodiment, R 5a -OR 5b or -SO2R 5b where R 5 b is hydrogen or C 1~8 It is alkyl, preferably methyl.

[0094] In one embodiment, R 5a -COR 5b where R 5b is hydrogen or - NR 5f R 5g C optionally substituted with 1~8 alkyl, where R 5f and R 5g are each independently hydrogen or C 1~8 It is alkyl, preferably methyl.

[0095] In one embodiment, two adjacent R on the phenyl ring 5 together with the phenyl ring, Forming an indazolyl substituted with tetrahydropyranyl.

[0096] In some embodiments, m is 1 and R 5 teeth, [ka] [ka] -L selected from the group consisting of 5 -CyC.

[0097] In a preferred embodiment, m is 1 and R 5 teeth, [ka] is.

[0098] In some embodiments, the compounds of the subgenus formula (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (III-I ... Pyrrolidine to which the phenyl ring in (II-C), (III-D) or (III-E) is bonded The carbon atom at position 2 of the nyl ring has the (S)-configuration.

[0099] In certain embodiments, the compound of formula (I) has formula (IV): [ka] (wherein the variable R 1 , R 1d , R 5 and m is defined in formula (I) It has.

[0100] In one embodiment, the phenyl ring in sub-genus formula (IV) is attached to piperazinyl The carbon atom at position 2 of the ring has either the (S)-configuration or the (R)-configuration.

[0101] The inventors of the present application have discovered compounds of the subgenus formula (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (III-I), (III-J ... Compounds of formula (III) and formula (IV), including (III-D) or (III-E), are described herein. The spiro or phenylene moiety and nitrogen-bonded heterocyclyl of the compounds disclosed in Substitution of the phenyl group at position (especially 2-(2-substituted phenyl) phenyl for formula (III) For the roridin-1-yl moiety and formula (IV), 2-(2-substituted phenyl)piperazine- 1-yl) resulted in higher potency and higher selectivity. .

[0102] [ka] Disclosed herein are intermediate compounds selected from compounds selected from:

[0103] A method for treating a disease of dysregulated apoptosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof or In one embodiment, a method is disclosed herein comprising administering a stereoisomer of Diseases of dysregulated apoptosis are described in WO 2005049593 and Bladder cancer, brain tumor, etc., as disclosed in the pamphlet of International Publication No. 2005049594 , breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer, hepatocellular carcinoma, lymphoma Blastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, bone Myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, splenic cancer, etc. Which cancer is it?

[0104] In one embodiment, the disease of dysregulated apoptosis is systemic lupus erythematosus (SLEP). E) and other autoimmune diseases.

[0105] A compound disclosed herein or a pharmaceutically acceptable salt thereof or a stereoisomer thereof Disclosed herein is a pharmaceutical composition comprising:

[0106] definition The following terms have the meanings indicated below throughout this specification.

[0107] As used herein, including the appended claims, "a" or "an" Singular terms such as "an" and "the" refer to that one or more unless the context clearly indicates otherwise. These corresponding plural referents are included.

[0108] The term "or" does not imply the term "and / or" unless the context clearly indicates otherwise. Used to taste and synonymously with it.

[0109] The term "alkyl" refers to groups having 1 to 18, such as 1 to 12, and more particularly, 1 to 10, Further, straight and branched chain alkyl groups containing, for example, 1 to 8, or 1 to 6, or 1 to 4 carbon atoms are also usable. refers to a hydrocarbon group selected from the group consisting of alkyl, cyclic, and cyclic saturated hydrocarbon groups containing 1 to 6 carbon atoms. group (i.e., C 1~6 Examples of alkyl include, but are not limited to, methyl, ethyl, 1 -propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i- 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1 , 1-dimethylethyl or t-butyl (“t-Bu”), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl 2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl -3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3 -dimethyl-2-butyl groups. Alkyl groups can be deuterium-containing, e.g., -CD3, -C D2CD3, etc. may be optionally enriched.

[0110] The term "halogen" includes fluoro (F), chloro (Cl), bromo (Br) and iodine. Refers to the code (I).

[0111] The term "haloalkyl" refers to alkyl groups in which one or more hydrogen atoms are replaced with fluoro, chloro, bromo, and iodine. It refers to an alkyl group substituted with one or more halogen atoms, such as methyl, ... Hello, Haro C 1~8 Alkyl, HaloC 1~6 Alkyl or haloC 1~4 Alkyl, limited Examples include -CF3, -CH2Cl, -CH2CF3, -CCl2, and CF3. can be done.

[0112] The term "alkenyl" refers to an alkyl group having at least one C=C double bond and 2 to 18 carbon atoms, e.g. Selected from linear and branched hydrocarbon groups containing 2 to 8, further for example 2 to 6, carbon atoms. The term refers to a hydrocarbon group selected from the group consisting of alkenyl groups, e.g., C 2~6 Examples of alkenyl include, but are not limited to, Although not limited, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2- methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, Buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hexa-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl Examples thereof include a hydroxyl group.

[0113] The term "alkynyl" refers to an alkynyl group having at least one C≡C triple bond and 2 to 18 carbon atoms, e.g. Selected from linear and branched hydrocarbon groups containing 2 to 8, further for example 2 to 6, carbon atoms. The term "alkynyl group" refers to a hydrocarbon group selected from the group consisting of alkynyl groups, e.g., C 2~6 Examples of alkynyl include, but are not limited to, Although not limited, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl Examples include butynyl, 2-butynyl and 3-butynyl groups.

[0114] The terms "alkyloxy" or "alkoxy" are linked to the parent molecular moiety through an oxygen atom. refers to an alkyl group as defined above to which the alkyl group is bonded. 1~6 Alkyl Oxy or C 1~4 Examples of alkyloxy include, but are not limited to, methoxy, ethoxy, , isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy and hexoxy and the like.

[0115] The term "cycloalkyl" refers to monocyclic cycloalkyls, including fused, bridged, or spirocycloalkyls. and saturated cyclic hydrocarbon groups, including polycyclic (e.g., bicyclic and tricyclic) groups. Refers to the hydride group.

[0116] For example, the cycloalkyl group may have 3 to 12, for example 3 to 10, further for example 3 to 8, It may further contain, for example, 3 to 6, 3 to 5, or 3 to 4 carbon atoms. The cycloalkyl group may have 3 to 12, for example 3 to 10, further for example 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, ... propyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, cyclohexyl cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl groups. In particular, saturated monocyclic cycloalkyl groups such as C 3~ Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopropyl ... Examples include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups. In a preferred embodiment, cycloalkyl includes, but is not limited to, cyclopropyl ... Monocyclic rings containing 3 to 6 carbon atoms, including cyclobutyl, cyclopentyl, and cyclohexyl Ring (C 3~6 Examples of bicyclic cycloalkyl groups include: is selected from the group consisting of [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems; as a fused bicyclic ring or bicyclo[2.2.1]heptane, bicyclo[2.2.2]o arranged as a bridged bicyclic ring selected from octane and bicyclo[3.2.2]nonane Further examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms. are arranged as bicyclic rings selected from [5,6] and [6,6] ring systems, e.g. For example, [ka] (wherein the wavy line indicates the point of attachment) The ring may be saturated or have at least one double bond (i.e., partially unsaturated), not fully conjugated, and not aromatic, which is defined herein as aromatic. It is defined as follows.

[0117] The term "spirocycloalkyl" refers to a group of cycloalkyl groups containing carbon atoms and having one atom in common. It refers to a cyclic structure formed by at least two rings. The term "carbon" refers to a group of carbon atoms containing 7 to 10 carbon atoms and at least two carbon atoms that share one atom. It refers to the ring structure formed by the rings.

[0118] The term "fused cycloalkyl" refers to a group containing carbon atoms and two adjacent atoms sharing the same carbon atom. "4- to 10-membered fused cycloalkyl" refers to a fused ring formed by two or more rings. The term refers to two or more rings containing 4 to 10 ring carbon atoms and sharing two adjacent atoms. It refers to a fused ring formed by the rings

[0119] 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[3.1.0]hexyl Cyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin and benzoyl 3-8 membered cycloalkyl, benzo C 4~6 Cycloalkenyl, 2,3-dihydro-1H -indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydronaphthyl, etc. A preferred embodiment is an 8- to 9-membered fused cyclyl It is a ring structure containing 8 to 9 ring atoms in the above examples.

[0120] The term "bridged cycloalkyl" refers to a cycloalkyl group containing carbon atoms that are not adjacent to each other. It refers to a ring structure formed by two rings that share two atoms. The term "chloroalkyl" refers to two non-adjacent groups containing 7 to 12 carbon atoms. It refers to a ring structure formed by two rings that share atoms.

[0121] The term "cycloalkenyl" refers to a group having single or multiple rings and at least one double bond. A non-aromatic cyclic alkylene compound having 3 to 10 carbon atoms and preferably having one or two double bonds. In one embodiment, cycloalkenyl refers to a cyclopentenyl or cycloalkyl group. and hexenyl, preferably cyclohexenyl.

[0122] The term "cycloalkynyl" refers to a group having single or multiple rings and at least one triple cyclic ring. refers to a non-aromatic cycloalkyl group of 5 to 10 carbon atoms having a bond.

[0123] The term "aryl" used alone or in combination with other terms means: refers to a group selected from: a) 5- and 6-membered carbocyclic aromatic rings, such as phenyl; b) bicyclic ring systems, such as 7- to 12-membered bicyclic ring systems (wherein at least one ring is a carbon atom). cyclic and aromatic, for example naphthyl and indanyl); and c) tricyclic ring systems, such as 10-15 membered tricyclic ring systems (wherein at least one ring is a carbon atom). and aromatic, such as fluorenyl).

[0124] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In one embodiment, the monocyclic or bicyclic aromatic hydrocarbon ring is 0 ring-forming carbon atoms (i.e., C 5~10 aryl). Monocyclic or bicyclic aromatic Examples of hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, -yl, anthracenyl, phenanthrenyl, and the like. The aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0125] The term "heteroaryl" refers to a group selected from: a) at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O); children, for example 1 to 4, or in some embodiments 1 to 3, in some embodiments 1 to 2 a 5-, 6-, or 7-membered aromatic monocyclic ring containing a heteroatom of the formula: b) at least one heteroatom, for example 1 to 4, selected from N, O and S, or In some embodiments, 1 to 3 heteroatoms, or in other embodiments, 1 or 2 heteroatoms the remaining ring atoms are carbon, at least one ring is aromatic, and at least one an 8- to 12-membered bicyclic ring, wherein the heteroatom is present in an aromatic ring; and c) at least one heteroatom selected from N, O and S, for example 1 to 4, or In some embodiments, 1 to 3 heteroatoms, or in other embodiments, 1 or 2 heteroatoms the remaining ring atoms are carbon, at least one ring is aromatic, and at least one 11- to 14-membered tricyclic rings, wherein the heteroatom is present in an aromatic ring.

[0126] When the total number of S and O atoms in the heteroaryl group exceeds 1, the heteroatoms must be In some embodiments, the total number of S and O atoms in the heteroaryl group is 1 to 10. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is If a heteroaryl group contains two or more heteroatom ring members, the heteroatom The nitrogen atoms in the ring of a heteroaryl group may be oxidized to As used herein, a "C-linked heteroaryl" may form an N-oxide. The term "aryl" refers to a heteroaryl group that is attached by a bond from a C atom of the heteroaryl ring. This means that the hydroxyl group is bound to the core molecule via the hydroxyl group.

[0127] The terms "heteroaromatic ring" and "heteroaryl" are used interchangeably throughout this disclosure. In certain embodiments, the monocyclic or bicyclic heteroaromatic ring is ), 1, 2, 3, or 4 heteroatoms independently selected from sulfur (S) and oxygen (O); 5-, 6-, 7-, 8-, 9- or 10-ring formation with the remaining ring members being carbon In certain embodiments, the monocyclic or bicyclic heteroaromatic ring has at least one nitrogen (N), sulfur (B), or aryl group. A single ring containing one or two heteroatom ring members independently selected from sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic heteroaromatic ring is a 5-ring or bicyclic ring. a 1- to 6-membered heteroaryl ring, which is monocyclic and has nitrogen (N), sulfur (S) and and has one or two heteroatom ring members independently selected from oxygen (O). In one embodiment, the monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring; It is bicyclic and contains one or two heterocyclic rings independently selected from nitrogen, sulfur, and oxygen. It has two atomic ring members.

[0128] Examples of heteroaryl groups or monocyclic or bicyclic aromatic heterocycles include, but are not limited to: However, (counting from the bond position assigned to priority 1) pyridyl (2-pyridyl, 3 -pyridyl or 4-pyridyl, etc.), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl , 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (1,2,3-thiadiazole) azolyl, 1,2,4-thiadiazolyl or 1,3,4-thiadiazolyl, etc.), tetra Zolyl, thienyl (thien-2-yl, thien-3-yl, etc.), triazinyl, benzo Thienyl, furyl or furanyl, benzofuryl, benzimidazolyl, indolyl, iso Indolyl, indolinyl, oxadiazolyl (1,2,3-oxadiazolyl, 1,2 ,4-oxadiazolyl or 1,3,4-oxadiazolyl, etc.), phthalazinyl, pyrazinyl pyridazinyl, pyrrolyl, triazolyl (1,2,3-triazolyl, 1,2, 4-triazolyl or 1,3,4-triazolyl, etc.), quinolinyl, isoquinolinyl, Pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl) , pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), Zofranil, benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteryl Dinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl , 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2, 3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1- Thia-3,4-diazolyl, furazanyl (furazan-2-yl, furazan-3-yl, etc.) ), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, Quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl ( benzo[d]thiazol-6-yl, etc.), indazolyl (1H-indazol-5-yl, etc.), and 5,6,7,8-tetrahydroisoquinoline.

[0129] "Heterocyclyl", "heterocycle" or "heterocyclic" are synonymous and include NH as a ring member. one or more heteroatoms selected from the group consisting of O, S, SO, or SO heteroatoms; refers to a non-aromatic heterocyclyl group in which the remaining ring members are carbon, which includes monocyclic, fused , bridged and spiro rings, i.e., monocyclic heterocyclyl, bridged heterocyclyl, spiro rings. It includes heterocyclyl and fused heterocyclic groups.

[0130] The term "monocyclic heterocyclyl" refers to a heterocyclic ring in which at least one ring member is selected from the group consisting of NH, O, S, S A heterocycle refers to a monocyclic group in which the heteroatom is selected from the group consisting of O or SO2. It may be a sum or partially saturated.

[0131] Exemplary monocyclic 4- to 9-membered heterocyclyl groups include, but are not limited to, (Priority 1 (counting from the bond position assigned to Pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazo Lysin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl , morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxirane Nyl, aziridin-1-yl, aziridin-2-yl, azocan-1-yl, azocan- 2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranyl (thiiranyl), azetidin-1-yl, azetidin-2-yl, azetidin- 3-yl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, Dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, pipetyl Razinyl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2- yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1,4- Oxatianil, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxa Azepanil, 1,4-dithiepanyl, 1,4-thiazepanil and 1,4-diazepanil, 1,4-dithianil, 1,4-azathiani, oxazepinyl, diazepinyl, thiazepinyl nyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl , tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyro Indolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyra nyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl , dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl or 1 , 1-dioxo-thiomorpholinyl.

[0132] The term "spiroheterocyclyl" or "heterospirocyclyl" refers to any of the following ring members: one or more heteroatoms selected from the group consisting of NH, O, S, SO, or SO2 heteroatoms The remaining ring members are carbon atoms, and the other ring members are carbon atoms. It refers to a 5- to 20-membered polycyclic heterocyclyl having a ring connected via a spiroheterocyclyl. One or more rings of the alkyl group may contain one or more double bonds, but none of the rings are completely covalent. Preferably, the spiroheterocyclyl has 6 to 14 members, more preferably Preferably, it is 7 to 10-membered. Depending on the number of common spiro atoms, spiroheterocyclyl can be , monospiroheterocyclyl, dispiroheterocyclyl or polyspiroheterocyclyl Preferably, monospiroheterocyclyl or dispiroheterocyclyl, more preferably or 4-member / 4-member, 3-member / 5-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member or 5-member / 6-member models Representative examples of spiroheterocyclyl include, but are not limited to, However, the following group: 2,3-dihydrospiro[indene-1,2'-pyrrolidine] (e.g. , 2,3-dihydrospiro[indene-1,2'-pyrrolidin]-1'-yl), 1,3 -dihydrospiro[indene-2,2'-pyrrolidine] (e.g., 1,3-dihydrospiro 2,2'-pyrrolidin-1'-yl), azaspiro[2.4]heptane (e.g., 5-azaspiro[2.4]heptan-5-yl), azaspiro[3.4]octan- 6-azaspiro[3.4]octan-6-yl), 2-oxa-6-aza Spiro[3.4]octane (e.g., 2-oxa-6-azaspiro[3.4]octane- 6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane) octan-6-yl), 7-azaspiro[3.5]nonane (e.g., 7-azaspiro[3. 5]nonan-7-yl), 2-azaspiro[3.5]nonane (e.g., 2-azaspiro[ 3.5]nonan-2-yl), 1,7-dioxaspiro[4.5]decane, 2-oxa- 7-Aza-spiro[4.4]nonane (e.g., 2-oxa-7-aza-spiro[4.4] non-7-yl), 7-oxa-spiro[3.5]nonyl and 5-oxa-spiro[2. 4]heptyl.

[0133] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclyl group, Each ring shares adjacent pairs of atoms (carbon and carbon atoms or carbon and nitrogen atoms) with another ring. , one selected from the group consisting of NH, O, S, SO or SO2 heteroatoms as ring members At least one ring of a fused heterocyclic group may be: It may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, the fused heterocyclyl is 6 to 14 membered, more preferably 7 to 10 membered. Depending on the number of ring members, a fused heterocyclyl can be a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl. Preferably, the heterocyclyl is a bicyclic or tricyclic fused heterocyclyl, more preferably It refers to a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Representative examples of fused heterocycles are: Examples include, but are not limited to, the following groups: octahydrocyclopenta[c]pyrrole (e.g., For example, octahydrocyclopenta[c]pyrrol-2-yl), octahydropyrrolo[3, 4-c]pyrrolyl, octahydroisoindolyl, isoindolinyl (e.g., isoindolinyl drin-2-yl), octahydro-benzo[b][1,4]dioxin, dihydrobenzo[b][1,4]dioxin Examples include zofranil and benzo[d][1,3]dioxolyl.

[0134] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group; Here, every other ring in the system shares two separate atoms and has the following ring members: NH, O , S, SO, or SO2 heteroatoms. and the remaining ring members are carbon. One or more rings of a bridged heterocyclyl group may have one or more double bonds. Preferably, the rings may contain rings having a completely conjugated π-electron system. The bridged heterocyclyl is preferably 6 to 14 membered, more preferably 7 to 10 membered. Bridged heterocyclyls are divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyls. Preferably, it is a bicyclic, tricyclic or tetracyclic bridged heterocyclyl, more preferably a bicyclic Representative examples of bridged heterocyclyls include, but are not limited to, Although not specified, the following groups are also included: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3. 1.0]hexyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3 .3.2] decyl is an example.

[0135] The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring; The ring structures are linked together to a parent heterocyclic group.

[0136] As used herein, "C-linked heterocyclyl" refers to a heterocyclyl ring that is bonded to a carbon atom of the heterocyclyl ring. refers to a heterocyclyl group that is attached to the rest of the molecule by a direct bond.

[0137] As used herein, "N-linked heterocyclyl" refers to a heterocyclyl ring that is attached to a nitrogen atom of the heterocyclyl ring. refers to a heterocyclyl group that is attached to the rest of the molecule by a direct bond.

[0138] The compounds disclosed herein may contain asymmetric centers and therefore exist as enantiomers. "Enantiomers" are two forms of a compound that are non-superimposable mirror images of one another. When the compounds disclosed herein have two or more asymmetric centers, , they may additionally exist as diastereomers. Enantiomers and Diastereomers - is included in the broader class of stereoisomers. Substantially pure resolved enantiomers, All such possible configurations, including racemic and diastereomeric mixtures thereof, are The compounds disclosed herein and / or their pharmaceutical compositions are intended to include all isomeric forms. All stereoisomers of physiologically acceptable salts are intended to be included unless otherwise stated. Thus, a reference to one isomer applies to any of the possible isomers. Whenever not specified, all possible isomers are included.

[0139] As used herein, the term "substantially pure" refers to a compound that is substantially pure in the desired stereoisomer. The polymeric component is 35% by weight or less, for example 30% by weight or less, further for example 25% by weight or less, For example, this means containing 20% by weight or less of any other stereoisomer. In this context, the term "substantially pure" means that the target stereoisomer is present in an amount of 10% by weight or less, e.g. For example, it means containing no more than 5% by weight, for example no more than 1% by weight, of any other stereoisomer. do.

[0140] When the compounds disclosed herein contain olefinic double bonds, unless otherwise specified, , such double bonds are meant to include both E and Z geometric isomers.

[0141] The compounds disclosed herein may contain disubstituted cyclohexyl or cyclobutyl groups. When the ring is cyclohexyl or cyclobutyl, the substituents found on the ring may be in cis and trans configurations. The cis configuration is when both substituents are found on the top of the two substituent arrangement on the carbon. Trans would mean they were on the other side, while trans would mean they were on the other side.

[0142] It may be advantageous to separate reaction products from each other and / or from the starting materials. The desired product of the series of steps may be prepared to the desired degree of homogeneity by techniques common in the art. Typically, such separation is carried out in a multi-step process. phase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography includes, for example, reversed and normal phase; size exclusion; ion exchange; high pressure, medium High-Pressure and Low-Pressure Liquid Chromatography Methods and Apparatus; Small-Scale Analysis; Simulated Moving Bed Method ("SM" B") and preparative thin-layer or thick-layer chromatography and small-scale thin-layer and flash chromatography. The techniques of separation and purification may include a number of methods, including lithography. Those skilled in the art will be able to achieve the desired separation. The most likely technology will be applied.

[0143] "Diastereomers" are isomers of compounds with two or more chiral centers that are not mirror images of one another. A diastereomeric mixture is a mixture of the physical forms of the individual diastereomers. Based on chemical differences, methods well known to those skilled in the art, such as chromatography and / or fractional crystallization, may be used to separate the compounds. The enantiomers can be separated into their individual diastereomers by suitable photochemical methods. Optically active compounds (e.g., chiral auxiliaries such as chiral alcohols or Mosher's acid chlorides) The enantiomeric mixture is converted into a diastereomeric mixture by reaction with and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g. Enantiomers can be separated by the use of a chiral HPLC column. They can also be separated by use.

[0144] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by diastereolysis using optically active resolving agents. It can be obtained by resolution of the racemic mixture using methods such as the formation of stereoisomers (Elie l, E. and Wilen, S. Stereochemistry of Organ ic Compounds.New York:John Wiley&Sons,In c.,1994;Lochmuller,CH,et al.“Chromatog raphic resolution of enantiomers:Selecti ve review”.J.Chromatogr.,113(3)(1975):pp The racemic mixture of the chiral compound of the present invention can be prepared by (1) mixing the chiral compound with the (2) formation of ionic diastereomeric salts and separation by fractional crystallization or other methods; Formation of diastereomeric compounds with diastereomeric derivatization reagents, separation of diastereomers, and purification of pure diastereomers (3) direct conversion of substantially pure or enriched stereoisomers under chiral conditions. The compounds can be separated and isolated by any suitable method, including separation of stereoisomers. r,Irving W.,Ed.Drug Stereochemistry:Anal ytical Methods and Pharmacology.New York See: Marcel Dekker, Inc., 1993.

[0145] "Pharmaceutically acceptable salts" are defined as salts that, within the scope of sound medical judgment, do not cause excessive toxicity, irritation, or and are suitable for use in contact with human and lower animal tissues without causing allergic reactions, etc. A pharmaceutically acceptable salt is a salt that is suitable for use in a pharmaceutical product with a reasonable risk-benefit ratio. , in situ or separately during the final isolation and purification of the compounds disclosed herein. By reacting the basic functional group with a suitable organic acid or the acidic group with a suitable base. It can be prepared by reacting

[0146] Additionally, when the compounds disclosed herein are obtained as acid addition salts, the free base may be Conversely, if the product is the free base, In some cases, addition salts, for example pharmaceutically acceptable addition salts, are prepared by preparing acid addition salts from base compounds. According to conventional procedures for the preparation of hydroxybenzoates, the free base is dissolved in a suitable organic solvent and the solution is treated with an acid. Those skilled in the art will appreciate that non-toxic pharmaceutically acceptable addition salts can be prepared by To this end, one will recognize various synthetic methods that may be employed without undue experimentation.

[0147] As defined herein, "a pharmaceutically acceptable salt thereof" refers to a compound of formula (I) Salts of at least one compound and salts of stereoisomers of compounds of formula (I), e.g. enantiomers This includes salts and / or diastereomeric salts.

[0148] As used herein, the terms "administration," "administering," "treating," and "treatment" The term, when applied to an animal, human, experimental subject, cell, tissue, organ, or body fluid, refers to an animal, human, Attachment of an exogenous pharmaceutical, therapeutic, diagnostic agent or composition to a subject, cell, tissue, organ or body fluid Treatment of cells refers to contact of a reagent with the cells as well as the flow when a fluid comes into contact with the cells. The terms "administration" and "treatment" include contacting a reagent, diagnostic agent, binding agent, or It also refers to in vitro and ex vivo treatment, e.g., of a cell, with a compound or another cell. The term "subject" as used herein refers to any living organism, preferably an animal, more preferably a mammal. This includes animals (eg, rats, mice, dogs, cats, rabbits), most preferably humans.

[0149] The term "effective amount" or "therapeutically effective amount" refers to an amount of a drug that reduces the severity of a disease or a clinical symptom of a disease or disorder. When administered to a subject to treat at least one of the diseases, disorders, or symptoms, "Therapeutic efficacy" refers to the amount of an active ingredient, such as a compound, that is sufficient to affect a treatment such as "Effective amount" refers to the amount of a compound, disease, disorder, and / or symptom of a disease or disorder, The severity of the symptoms of the disease or disorder, the age of the subject to be treated and / or the age of the subject to be treated The appropriate amount in any given case will be apparent to those skilled in the art. It is possible or can be determined by routine experimentation. In some embodiments, "therapeutically effective" The "amount" is effective to "treat" a disease or disorder in a subject as defined above. , at least one compound disclosed herein and / or at least one steric analog thereof isomers and / or at least one pharmaceutically acceptable salt thereof. In this case, a "therapeutically effective amount" is the amount of a combination of the objects for effective treatment of a disease, disorder, or condition. Refers to the total amount.

[0150] Pharmaceutical compositions comprising the compounds disclosed herein can be administered orally to a subject in need thereof, It can be administered by inhalation, rectal administration, parenteral administration or topical administration. For oral administration, the pharmaceutical composition The product may be in the form of a typical solid preparation such as a tablet, powder, granule, or capsule, or a water or oil suspension, or It may be a liquid formulation such as a syrup, solution, suspension, or other liquid formulation; for parenteral administration The pharmaceutical composition may be a liquid, an aqueous solution, an oil suspension concentrate, a lyophilized powder, or the like. For example, the pharmaceutical composition may be formulated as a tablet, coated tablet, capsule, suppository, or nasal spray. or injections, more preferably tablets or capsules. In addition, the pharmaceutical composition may further comprise an additional active ingredient. It may include.

[0151] All formulations of the pharmaceutical compositions disclosed herein may be prepared by conventional methods in the pharmaceutical art. For example, the active ingredient may be mixed with one or more excipients and then the desired formulation may be prepared. "Pharmaceutically acceptable excipients" are any conventional excipients suitable for the desired pharmaceutical formulation. Pharmaceutical carriers, such as diluents, vehicles such as water, various organic solvents, starch, sucrose Fillers such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone ( binders such as PVP; humectants such as glycerol; agar, calcium carbonate, and bicarbonate Disintegrants such as sodium; absorption enhancers such as quaternary ammonium compounds; hexadecanol surfactants such as talc, calcium stearate; absorbent carriers such as kaolin and soap clay; This refers to lubricants such as calcium, magnesium stearate, and polyethylene glycol. Additionally, pharmaceutical compositions may contain dispersing agents, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, The composition may further comprise other pharmaceutically acceptable excipients such as flavoring agents, sweeteners, and dyes.

[0152] The term "disease" refers to any disease, ailment, illness, symptom or sign, and is not intended to be construed as a "disorder" or may be synonymous with the term "pathological condition."

[0153] Throughout this specification and the claims that follow, unless the context requires otherwise, "comprises" and "comprises" and "comprises" are intended to specify the presence of the following feature, does not preclude the presence or addition of one or more other features. The term "comprise" may be substituted for the terms "contain," "include," or sometimes "have." It can be replaced.

[0154] Throughout this specification and the claims that follow, "C n~m The term " In the above formula, n and m are integers that represent the number of carbon atoms. 1~ 8. C 1~6 Examples include:

[0155] All other terms used herein are intended to be used interchangeably unless otherwise defined elsewhere in this specification. Technical and scientific terms are commonly understood by those skilled in the art to which this invention belongs. It has meaning. [Brief explanation of the drawings]

[0156] [Figure 1] The co-crystal structure of A4a is shown. [Figure 2] An ABT-199 analog (PDB code: 4MAN) is shown. [Figure 3] A comparison of the binding pose of A4 with the ABT-199 analog (PDB code: 4MAN) to the Bcl2 protein is shown. [Figure 4] a) Co-crystal structure of F22 with Bcl-2. b) Co-crystal structure of ABT-199 analog with Bcl-2 (PDB code: 4MAN). c) Alignment of the binding pose between F22 and ABT-199 analog. [Figure 5] a. Induced subpocket of Bcl-2 by cyclopropyl of F22 in the crystal structure. b. None of the substituents in the ABT-199 analog induces a similar subpocket at the same position (PDB code: 4MAN). c. Alignment of the pocket surface between F22 and the ABT-199 analog is shown. [Figure 6] a Water bridge between F22 and Bcl-2 protein. b Such water bridges could not be observed between the ABT-199 analog and Bcl-2. [Figure 7] a) Sulfur-π interaction between Met115 and the 2-cyclopropylphenyl of F22 (4.41 Å). b) A similar interaction between Met115 and the 4-chlorophenyl of the ABT-199 analog (5.00 Å). DETAILED DESCRIPTION OF THE INVENTION

[0157] The following examples are intended to be merely illustrative and are not to be construed as limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.). While every effort has been made to ensure accuracy, some experimental error and deviation should be accounted for. Temperatures are given in °C unless otherwise noted. Reagents were purchased from Sigma-Aldrich, Alfa Ae These compounds were purchased from commercial suppliers such as sar or TCI and were not further purified unless otherwise indicated. was used without

[0158] Unless otherwise indicated, the reactions described below were carried out under a positive pressure of nitrogen or argon. The reaction flask was charged with the substrate and Rubber septa are fitted for the introduction of reagents; glassware is oven-dried and / or heat-dried. I did.

[0159] 1 H NMR spectra were recorded on an Agilent instrument operating at 400 MHz. It was recorded. 1 HNMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone or (CD3)2CO and tetrahydrofuran as the reference standard methylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3 OD:3.31ppm;D2O:4.79ppm;d6-DMSO:2.50ppm;d 6-acetone: 2.05; (CD3)2CO: 2.05). When multiplicity is recorded, the following abbreviations are used: s (single), d (double), t (triple). sx (sextet), m (multiplet), br (broad) , dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when indicated, are It is recorded in Hz.

[0160] LC-MS spectrometer (Agilent 1260) Detector: MWD (190~400nm ), mass detector: 6120 SQ Mobile phase: A: acetonitrile containing 0.1% formic acid, B: water containing 0.1% formic acid Column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 μm Gradient method: Flow rate: 1.8 mL / min

[0161] [Table 1]

[0162] Preparative HPLC was performed at room temperature and with UV detection at 214 nm and 254 nm on different flow rates. The column (150 × 21.2 mm inner diameter, 5 μm, Gemini NX-C) was used for the injection volume and injection volume. 18).

[0163] In the examples below, the following abbreviations are used: AcOH or HOAc acetic acid aq. aqueous solution BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) BH3 Borane Salt water Saturated sodium chloride solution Boc2O Di(tert-butyl) carbonate BSA Bovine serum albumin DAST Diethylaminosulfur trifluoride DBN 1,5-diazabicyclo[4.3.0]non-5-ene DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DCM dichloromethane DMAP 4-dimethylaminopyridine CH3MgBr Methylmagnesium Bromide DIPEA N,N-Diisopropylethylamine DMF N,N-dimethylformamide DMAC Dimethylacetamide DMSO dimethyl sulfoxide EA Ethyl acetate EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride EDTA Ethylenediaminetetraacetic acid EtOH Ethyl alcohol h or hr Time HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxide hexafluorophosphate Hex 1 H NMR proton nuclear magnetic resonance H2O2 Hydrogen Peroxide HOBt Hydroxybenzotriazole IPA (i-PrOH) Isopropyl alcohol KOAc Potassium Acetate LAH Lithium aluminum hydride LC-MS Liquid Chromatography-Mass Spectrometry LDA Lithium diisopropylamide MeOH Methanol MsOH methanesulfonic acid min MTBE Methyl tert-butyl ether n-BuLi n-butyllithium NaH sodium hydride NaBH(OAc)3 Sodium triacetoxyborohydride NaBH3CN Sodium cyanoborohydride NH4Cl Ammonium chloride Pd / C Palladium / carbon powder Pd(dppf)Cl2[1,1'-bis(diphenylphosphino)ferrocene]di Chloropalladium(II) Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) Pd(OAc)2 Palladium Acetate Pd(OH)2 / C Palladium hydroxide / carbon powder PE Petroleum Ether pH -lg (hydrogen ion concentration) Preparative HPLC Preparative High Pressure Liquid Chromatography Preparative MPLC Preparative Medium Pressure Liquid Chromatography Preparative SFC Preparative Supercritical Fluid Chromatography Preparative TLC Preparative Thin-Layer Chromatography p-TsOH p-toluenesulfonic acid rt or RT room temperature sat. saturation t-BuOK Potassium tert-butoxide TBS tert-butyldimethylsilyl THF tetrahydrofuran TEA Triethylamine TFA trifluoroacetic acid TMSCF3 Trimethyl(trifluoromethyl)silane [Example]

[0164] Preparation of intermediates: Intermediate 1-a: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy) )-4-Bromobenzoate [ka] Methyl 4-bromo-2-fluorobenzoate (116.5 mL) in DMF (500 mL) g, 0.5 mol), 1H-pyrrolo[2,3-b]pyridin-5-ol (67 g, 0. A mixture of K2CO3 (138 g, 1.0 mol) and K2CO3 (1.5 mol) was heated at 95°C for approximately 16 hours. 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 diluted with EA (200 mL The cake (68 g) was collected as the first batch. The filtrate was concentrated and dissolved in EA (500 mL). The solution was diluted with H2O (200 mL × 2), concentrated, and then added to EA (25 mL) and PE (25 mL) at reflux for 1 h. L), cooled to ambient temperature, and filtered to obtain a second batch of product (38 g). The two batches of product were combined to give the product (106 g, 61.3%) as a brown solid. MS (ESI, m / e) [M+1] + 346.9, 348.9.

[0165] Intermediate 1-b: tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl) (aryl)oxy)-4-bromobenzoate [ka] tert-Butyl 4-bromo-2-fluorobenzoate (238) in DMF (1 L) 0.5g, 867.3mmol), 1H-pyrrolo[2,3-b]pyridin-5-ol (1 16.2 g, 867.3 mmol) and K2CO3 (239.4 g, 1734.5 mmol) A mixture of K2CO3 (100 g, 724.6 mmHg) was heated at 80 °C for approximately 16 h. ol) and 1H-pyrrolo[2,3-b]pyridin-5-ol (10 g, 74.6 mmol) Another batch of l) was added to the reaction mixture and the reaction mixture was stirred at 100° C. for another 4 hours. The reaction mixture was cooled to ambient temperature, filtered, and the mother liquor was concentrated to remove approximately half the volume of DMF. DCM (200 mL) and EA (200 mL) were added and stirred, and the resulting mixture was After filtration, the filtrate was concentrated and the residue was diluted with EA (200 mL) and The precipitate was filtered and dried to give the product (155 g, 46.1%) as a yellow solid. MS (ESI, m / e) [M+1] + 389 .0, 391.0.

[0166] Intermediate 1-c: tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzoate [ka] 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'-bi( 1,3,2-dioxaborolane) (127 g, 501.3 mmol) and KOAc (98 A mixture of Pd(dppf)Cl2 (24.5 g, 6 6.8 mmol) was added and the mixture was stirred at 85° C. under N 2 for about 4 h. The reaction mixture was cooled to ambient temperature, concentrated, and the residue was slurried in DCM (1 L) and filtered. The mother liquor was concentrated and applied to a chromatography column on silica (EA / DCM=1 / 1). The crude product was purified by EA (100 mL) / PE (100 mL) ) and dried to give the product as a brown powder (114.5 g, 78.6%). MS (ESI, m / e) [M+1] + 437.2, 355.1

[0167] Intermediate 1-d: methyl 2-((6-amino-5-chloropyridin-3-yl)oxy)- 4-Fluorobenzoate [ka] Step 1: Methyl 4-fluoro-2-((6-nitropyridin-3-yl)oxy)benzo Et 5-Chloro-2-nitropyridine (2.5 g, 15.75 m) in DMSO (30 mL) mol), methyl 4-fluoro-2-hydroxybenzoate (2.44 g, 14.38 A mixture of K2CO3 (3.96 g, 28.65 mmol) and K2CO3 (3.96 g, 28.65 mmol) was heated at 110 °C for 1 h. The reaction mixture was stirred for 1 hour. TLC showed that the reactants were completely consumed. It was cooled to room temperature, poured into water, and then extracted with EA (40 mL x 3). Wash with brine (50 mL x 2), dry over Na2SO4, filter, and concentrate to give a residue The residue was purified by column chromatography on silica gel (eluent: PE / EA=50 Purification by HPLC / 1~1 / 1 yielded methyl 4-fluoro-2-((6-nitropyridine- 3-yl)oxy)benzoate (1.3 g). MS (ESI, m / e) [M+1 ] + 293.5.

[0168] Step 2: Methyl 2-((6-aminopyridin-3-yl)oxy)-4-fluorobenzoate Et Methyl 4-fluoro-2-((6-nitropyridine-3-yl)methyl) ... A mixture of (hydroxy)benzoate (50 g, 3.42 mmol) and Pd / C (0.8 g) The mixture was stirred under H2 (50 Psi) at 25 °C for 3 h. TLC showed that the reactants were complete. The mixture was filtered and concentrated to remove the solvent. The residue was Purification by preparative MPLC (eluent: PE / EA = 20 / 1 to 5 / 1) gave 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.

[0169] Step 3: Methyl 2-((6-amino-5-chloropyridin-3-yl)oxy)-4-furan Fluorobenzoate Methyl 2-((6-aminopyridin-3-yl)oxy)-4 in DMF (10 mL) -Fluorobenzoate (1 g, 38.14 umol) in a solution of NCS (1 g, 76. The mixture was stirred at 25°C for 4 hours. TLC showed that the reaction was complete. The mixture was concentrated to remove the solvent. The residue was purified by preparative MP The product was purified by LC (eluent: PE / EA = 20 / 1 to 5 / 1) to give methyl 2-((6- Amino-5-chloropyridin-3-yl)oxy)-4-fluorobenzoate (169 mg) was obtained. 1 H NMR (400MHz, CDCl3)δppm:7.84-7.9 8(m,2H), 7.77(d,J=2.6Hz, 1H), 7.26(d,J=2.6H z, 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.

[0170] Intermediate 2-a: 2-(2-cyclopropylphenyl)pyrrolidine [ka] Step 1: tert-Butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate to [ka] 2-(2-bromophenyl)pyrrolidine (1.13 g, 5 mmHg) in DCM (20 mL) ol), Boc2O (2.16g, 10mmol), TEA (1.01g, 10mmol The mixture solution of ) and DMAP (catalytic amount) was stirred at room temperature for 16 hours. The mixture was concentrated and the residue was purified by chromatography on silica gel (100% PE to PE / EA). The product (1.6 g, 98.1%) was purified by HPLC (eluting with HPLC = 5 / 1) to give the product as a colorless oil. MS (ESI, m / e) [M+1] + 270.0, 272.0

[0171] Step 2: tert-Butyl 2-(2-cyclopropylphenyl)pyrrolidine-1-carbohydrate Xylates [ka] Under a nitrogen atmosphere, tert-butyl ether was dissolved in 1,4-dioxane / H2O (9:1, 20 mL). ethyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate (1.56 g, 4. 7 mmol), cyclopropylboronic acid (1.23 g, 14.3 mmol), Pd(PP h3)4 (540 mg, 0.47 mmol) and K2CO3 (1.99 g, 14.3 mmol) The mixture of (ol) was stirred at 90° C. for 16 hours. The reaction mixture was then filtered and concentrated to give the crude product. The product (1.4 g) was used directly in the next step without purification. MS (ESI, m / e) [M +1] + 232.1.

[0172] Step 3: 2-(2-cyclopropylphenyl)pyrrolidine [ka] tert-Butyl 2-(2-cyclopropylphenyl)pyrrolidine in DCM (50 mL) A mixture of 1.4 g of dimethylformamide (DMSO) and 5 mL of TFA was added at room temperature. After stirring for 16 hours, the mixture was then concentrated to give the product (1.2 g, crude) as a yellow oil. MS (ESI, m / e) [M+1] + 188.1.

[0173] Intermediate 2-b: 2-(2-isopropylphenyl)pyrrolidine [ka] Step 1: tert-Butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidone Zin-1-carboxylate [ka] tert-Butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine- 1-carboxylate, tert-butyl 2-(2-cyclopropylphenyl)pyrrolidine It was prepared using a similar procedure to that for zinzine-1-carboxylate. 1 H NMR (400MH z, 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] + 2 32.1.

[0174] Step 2: tert-Butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate Silate [ka] tert-Butyl 2-(2-(prop-1-en-2-yl)methyl)propanol in MeOH (20 mL) )phenyl)pyrrolidine-1-carboxylate (983 mg, 3.41 mmol) and A mixture of Pd(OH)2 / C (100 mg) was stirred under a balloon of H2 at room temperature overnight. The reaction mixture was then filtered and concentrated to provide further protection for the next deprotection step with TFA. Without further purification, the desired product was obtained as a colorless oil (803 mg, 81%). 1 HN MR(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), 1.59-1.53(m,1H), 1.38 (s,3H), 1.28-1.16(m,6H), 1.09(s,3H), 1.08(s ,3H)..

[0175] Step 3: 2-(2-isopropylphenyl)pyrrolidine [ka] tert-Butyl 2-(2-isopropyl)acetate in DCM (5 mL) and TFA (2 mL) Solution of (phenyl)pyrrolidine-1-carboxylate (803 mg, 2.77 mmol) The mixture was stirred at room temperature for 4 hours. After removing the solvent, the resulting residue was dissolved in DCM (50 mL). The organic layer was collected and washed with anhydrous NaHCO3 (30 mL x 2). Drying over SO4, filtering, and concentration gave the desired product as a colorless oil (522 mg). Ta. 1 H 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,1 H), 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.

[0176] Intermediate 2-c: 2-(4-cyclopropylphenyl)pyrrolidine [ka] Step 1: tert-Butyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate to [ka] 2-(4-bromophenyl)pyrrolidine (2.0 g, 8.85 m) in 20 mL of DCM mol), Boc2O (2.9g, 13.3mmol), Et3N (1.8g, 17.7 A mixture of 100 mmol) and DMAP (110 mg, 0.9 mmol) was stirred at room temperature for 16 hours. The mixture was concentrated and purified by column chromatography on silica gel using EA / PE (1 / 10) as eluent. Purification by column chromatography gave 2.2 g (78.6%) of tert-butyl 2 -(4-bromophenyl)pyrrolidine-1-carboxylate was obtained as a yellow oil. S(ESI)m / e[M+1] + 325.0, 327.0.

[0177] Step 2: tert-Butyl 2-(4-cyclopropylphenyl)pyrrolidine-1-carbohydrate Xylate [ka] tert-Butyl 2-(4-bromophenyl)pyrrolidine in dioxane (10 mL) -1-carboxylate (1.0 g, 3.07 mmol), cyclopropylboronic acid (7 90mg, 9.21mmol), Pd(PPh3)4(358mg, 0.31mmol) A mixture of K2CO3 (1.27 g, 9.21 mmol) was stirred under N2 for 16 h. The mixture was filtered and the filtrate was concentrated to give the crude product, which was then washed with ethyl acetate and 100° C. Column chromatography on silica gel using EA / PE (1 / 10, v / v) was performed. Further purification by HCl gave 600 mg (68.1%) of tert-butyl 2-(4-cyclohexyl)propanol. (4-Hydroxypropylphenyl)pyrrolidine-1-carboxylate was obtained as a yellow oil. MS( ESI)m / e[M+1-56] + 232.1.

[0178] Step 3: 2-(4-cyclopropylphenyl)pyrrolidine [ka] tert-Butyl 2-(4-cyclopropyl)acetate in TFA / DCM (2 mL / 10 mL) A solution of phenyl)pyrrolidine-1-carboxylate (1.2 g, 4.18 mmol) The mixture was concentrated to remove the solvent, and the residue was dissolved in NaHCO3 The organic layer was collected and dried over Na2SO4. Drying and concentration gave 620 mg (79.2%) of 2-(4-cyclopropylphenyl)pyrimidinium chloride. Roridin was obtained. MS (ESI, m / e) [M+1] + 188.0.

[0179] Intermediate 2-d: 2-(2-methoxyphenyl)pyrrolidine [ka] 2-(2-bromophenyl)pyrrolidine (500 mg, 2. 2 mmol), cuprous bromide (158.6 mg, 1.1 mmol) and sodium Methanolate (358 mg, 6.6 mmol) was added. The mixture was heated to reflux and stirred overnight. After cooling to room temperature, the mixture was filtered, concentrated and purified by chromatography on silica. The product (300 mg, 76.6%) was purified by column (EA / PE=1 / 1). Obtained as a yellow oil. MS (ESI, m / e) [M+1] + 178.1.

[0180] Intermediate 2-e: 2-(2-chloro-6-fluorophenyl)pyrrolidine [ka] Step 1: 3-(2-chloro-6-fluorobenzoyl)-1-vinylpyrrolidin-2-one hmm [ka] Prepare a dry 10-gas oven equipped with a mechanical stirrer, dropping funnel, heating mantle, and reflux condenser. In a 0 mL three-necked round-bottom flask, add 60% sodium hydride (0.6 g, 15 mmol) and 25 mL of dry toluene. The stirred suspension was heated at reflux while , 1.1 g (10 mmol) vinylpyrrolidin-2-one and 1.9 g (10 mmol) A mixture of methyl 2-chloro-6-fluorobenzoate and 2-chloro-6-fluorobenzoate was slowly added. The reaction mixture was allowed to cool to room temperature and the resulting thick slurry was diluted with 25 mL of saturated The layers were separated and the aqueous layer was diluted carefully with 25 mL of toluene. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. 3-(2-chloro-6-fluorobenzoyl)-1-vinylpyrrolidin-2-one was obtained as a crude product. Obtained as product. [M+1] + 268.0.

[0181] Step 2: 5-(2-chloro-6-fluorophenyl)-3,4-dihydro-2H-pyrrole L [ka] 3-(2-chloro-6-fluorobenzoyl)-1-vinylpyrrolidin-2-one (1 A mixture of HCl (6M, 10 ml) and HCl (6 g, crude) was heated to reflux for 10 hours. The mixture was cooled to room temperature, basified to pH=10, and extracted with DCM. The layer was dried over anhydrous Na2SO4 and concentrated. The residue was used in the next step without further purification. (300 mg, crude). MS (ESI, m / e) [M+1] +198.0

[0182] Step 3: 2-(2-chloro-6-fluorophenyl)pyrrolidine [ka] 5-(2-chloro-6-fluorophenyl)-3,4-dihydro-2H- in MeOH To a solution of pyrrole (300 mg, crude), NaBH4 (50 mg) was added and the mixture was stirred at room temperature for 1 hour. After stirring, excess MeOH was removed under reduced pressure. The residue was taken up in water and extracted with DCM. The organic layer was concentrated to give 2-(2-chloro-6-fluorophenyl)pyrrolidine, which This was used in the next step without further purification (100 mg, crude). MS (ESI, m / e) [M+1] + 200.1.

[0183] Intermediate 2-f: 2-cyclohexylpyrrolidine [ka] 2-phenylpyrrolidine (3.5 g, 23.77 mmol) in THF (60 mL), PtO2 (1.08g, 4.75mmol), AcOH (1.14g, 19.02mmol) The mixture was degassed and purged with H2 three times, and then the mixture was purged with H2 atmosphere. The mixture was stirred at 65° C. under pressure (50 psi) for 12 hours. LC-MS showed the reaction was complete. The reaction mixture was filtered, indicating completion of the reaction, with one major peak having the desired mass. The residue was purified by preparative HPLC (TFA conditions). The product (4 g, TFA salt) was obtained as a yellow oil. , liberated by Amberlyst A-21 ion exchange resin in MeOH (60 mL) The product was neutralized with saturated Na2CO3 (5 mL). Extract with DCM (80 mL), dry over Na2SO4, filter, and concentrate under reduced pressure. The product (640 mg) was obtained as a yellow oil. 1 H NMR (400 MHz, CDCl 3) δppm:4.37(br s,1H), 3.13-3.01(m,1H), 2.9 5-2.90(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).

[0184] Intermediate 2-g: 2-(2-(trifluoromethyl)phenyl)pyrrolidine [ka] Step 1: tert-butyl(4-oxo-4-(2-(trifluoromethyl)phenyl) Butyl)carbamate [ka] 1-Bromo-2-(trifluoromethyl)benzene in THF (15 mL) at −78 °C (2 g, 8.89 mmol, 1.21 mL) was added to a solution of n-BuLi (2.5 M, 3.5 The reaction was stirred at -78°C for 15 min, then THF (15 ml) was added at -78°C. tert-Butyl 2-oxopyrrolidine-1-carboxylate (1.65 g, A solution of 1.51 mL of 1,4-dichlorobenzofuran (8.89 mmol, 1.51 mL) was added. After the addition, the reaction mixture was warmed to 15°C. The mixture was stirred at 15°C for 1 hour. TLC showed that the reaction was successful. The mixture was quenched with saturated NH4Cl (20 mL) and EA (20 mL) * 2) Extracted with organic The layers were separated, washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting solution was purified by silica gel (PE:EA = 50:1 to 10:1) and purified as tert-butyl (4 -oxo-4-(2-(trifluoromethyl)phenyl)butyl)carbamate (2g, 6.04 mmol, 67.91% yield) was obtained as a yellow oil. 1 H NMR (400 MHz, 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,1 H), 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).

[0185] Step 2: 4-amino-1-(2-(trifluoromethyl)phenyl)butan-1-one [ka] tert-Butyl (4-oxo-4-(2-(trifluoromethyl)methyl)methyl)methyl)methyl) in DCM (30 mL) To a mixture solution of 2.8g (8.45mmol) of 2,4-dimethylphenyl-2,4-dimethylbutylcarbamate Then, TFA (30.80 g, 270.13 mmol, 20 mL) was added. The mixture was stirred at 15°C. The mixture was stirred at rt for 1 h. The solvent was removed to give 4-amino-1-(2-(trifluoromethyl)phenyl)- (phenyl)butan-1-one (3.5 g, 7.24 mmol, 85.67%, TFA) was added to brown Obtained as a colored oil. 1 H NMR (400MHz, CDCl3)δppm:9.14(b rs,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).

[0186] Step 3: 2-(2-(trifluoromethyl)phenyl)pyrrolidine [ka] 4-Amino-1-(2-(trifluoromethyl)phenyl)-2-(2-hydroxybenzoyl)-1,3-dimethyl-2,4-dihydro ... Mixture of (2-methylphenyl)butan-1-one (3 g, 6.53 mmol, 2 TFA) To the product solution was added NaBH3CN (697.85 mg, 11.10 mmol). The mixture was stirred at 15° C. for 12 hours. The reaction mixture was diluted with saturated NaHCO3 solution in water (100 mL The mixture was quenched with EA (100 mL). The mixture was concentrated. The residue was dissolved in EA (100 mL) and added with water and salt. Wash with water, dry over Na2SO4, filter, and concentrate to give 2-(2-(trifluoromethyl)- ... (methyl)phenyl)pyrrolidine (0.71 g, 3.16 mmol, 48.33%) in yellow solution was obtained as an 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.

[0187] Intermediate 2-h: 4,4-dimethyl-2-phenylpyrrolidine [ka] Step 1: 2,2-dimethyl-4-oxo-4-phenylbutanoic acid [ka] 3,3-Dimethyldihydrofuran-2,5-dione (15. A solution of AlCl3 (31.92 g, 240 mmol) and AlCl3 (31.92 g, 240 mmol) was added to ice Using a water bath, benzene (14.04 g, 180 mmol) was added dropwise. It was slowly warmed to room temperature and stirred overnight, then poured onto ice and diluted with DCM (400 mL). Then, concentrated HCl (50 mL) was added and stirred until the precipitate disappeared. The residue was slurried with MTBE and PE to give a 200 ml solution of 100 ml of ethyl acetate. The desired product was obtained as a white solid (22.52 g, 99%). 1 H NMR (400 MHz, CDCl3)δppm:7.95(d,J=8.0Hz, 2H), 7.56(t ,J=8.0Hz, 1H), 7.46(t,J=8.0Hz, 2H), 3.31(s,2 H), 1.36(s,6H).MS(ESI, m / e)[M+1] + 205.1.

[0188] Step 2: N-(2,4-dimethoxybenzyl)-2,2-dimethyl-4-oxo-4-furan Phenylbutanamide [ka] 2,2-Dimethyl-4-oxo-4-phenylbutanoic acid (1 8.03g, 87.5mmol), (2,4-dimethoxyphenyl)methanamine (14 0.62g, 87.5mmol), HATU (33.25g, 87.5mmol) and Et A solution of 3N (13.3 g, 131.25 mmol) was stirred at room temperature overnight. The residue was purified by silica gel elution with EA / PE = 1 / 4 to 1 / 1 (v / v). The desired product was purified by column flash elution to give a brown oil (30.2 g, 97%). MS (ESI, m / e) [M+1] + 356.1.

[0189] Step 3: 1-(2,4-dimethoxybenzyl)-3,3-dimethyl-5-phenyl-1, 3-Dihydro-2H-pyrrol-2-one [ka] N-(2,4-dimethoxybenzophenone) in toluene (180 mL) and AcOH (10 mL) (diethyl)-2,2-dimethyl-4-oxo-4-phenylbutanamide (30.2 g, 85 A solution of 1.0001 mmol) was refluxed overnight. It was cooled to room temperature and the solvent was removed. The residue was Column flow on silica gel eluted with EA / PE = 1 / 10 to 1 / 1 (v / v) The crude product was purified by HPLC to give a yellow oil (10 g, 30% yield). S(ESI, m / e)[M+1] + 388.1.

[0190] Step 4: 3,3-dimethyl-5-phenyl-1,3-dihydro-2H-pyrrol-2-one hmm [ka] 1-(2,4-Dimethoxybenzyl)-3,3-dimethyl-5 in TFA (50 mL) -Phenyl-1,3-dihydro-2H-pyrrol-2-one (9 g, 26.6 mmol) The solution was stirred at 95° C. for 1 hour. It was cooled to room temperature and the TFA was removed. The residue was treated with A Purification by column flash on silica gel eluted with PEG / PE=1 / 1 gave crude The product was obtained as a brown oil (4.4 g, 88% yield). MS (ESI, m / e) [M +1] + 188.1.

[0191] Step 5: 4,4-Dimethyl-2-phenylpyrrolidine [ka] 1-(2, 4-Dimethoxybenzyl)-3,3-dimethyl-5-phenyl-1,3-dihydro-2H A solution of 2.4 g of 12.8 mmol of 2-pyrrol-2-one was refluxed for 2 hours. The mixture was cooled to room temperature, and HCl acid (6 M, 20 mL) was added slowly. The solvent was removed and the residue was used directly in the next step.

[0192] Intermediate 2-i: 1-phenylpyrrolidine-2-carbaldehyde [ka] Step 1: Phenylproline [ka] In a sealed tube flushed with nitrogen, L-proline (11.5 g, 100 mmol), charcoal Potassium iodide (27.6 g, 200 mmol), copper(I) iodide (3.8 g, 20 mmol) ), iodobenzene (24.4 g, 120 mmol) and DMF (150 ml) were added. The mixture was heated at 90°C for 48 hours and then cooled to room temperature. Water was added and concentrated HCl was used to The pH value was adjusted to less than 3. The aqueous phase was extracted four times with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-100% EtOAc / hexane gradient) This gave the crude product which was used directly in the next step. MS (ESI, m / e) [M+1] + 192.1

[0193] Step 2: (1-phenylpyrrolidin-2-yl)methanol [ka] To a solution of phenylproline (1.5 g, 7.8 mmol) in THF (50 mL), H3-THF (1M, 15.6 mL) was added. The reaction was refluxed for 1 hour. The mixture was cooled to room temperature and quenched with MeOH (5 mL). The solvent was removed and the residue was purified by chromatographic analysis. The product was purified by chromatography to give (1-phenylpyrrolidin-2-yl)methanol (1 0.3 g) was obtained as a colorless oil. MS (ESI, m / e) [M+1] + 192.1

[0194] Step 3: 1-Phenylpyrrolidine-2-carbaldehyde [ka] (1-phenylpyrrolidin-2-yl)methanol (531 m) in DCM (25 mL) g, 3 mmol) was added a little Dess-Martin reagent (1.9 g, 4.5 mmol) The mixture was stirred at room temperature overnight, and then the mixture was washed with saturated NaHCO3 solution and The organic layer was concentrated and purified by chromatography to give 1-phenylpyrrolidine-2-carboxylate. Rubaldehyde (100 mg) was obtained as a colorless oil. MS (ESI, m / e) [M+1] + 176.1

[0195] Intermediate 2-j: 1-(4-bromophenyl)-2-methyl-2-phenylpyrrolidine [ka] Step 1: tert-butyl (4-oxo-4-phenylbutyl)carbamate [ka] Solution PhBr (8g, 50.95mmol, 5.37mL) in THF (150mL) The mixture was cooled to -78°C and n-BuLi (2.5M, 26.50 mL) was added. The mixture was stirred at 78° C. for 15 min. Then, tert-butyl 2-oxoacetate in THF (20 mL) was added. Pyrrolidine-1-carboxylate (10.38 g, 56.05 mmol, 9.52 mL) ) was added at -78°C. The mixture was stirred at -78°C for 15 minutes. TLC and LC-MS showed The reaction was complete and the main peak was the title product. L) was added. The mixture was extracted with EA (200 mL). The organic layer was washed with water and brine. Dry over Na2SO4, filter, and concentrate to give tert-butyl(4-oxo-4-furan). The resulting product was purified by HPLC to give 14 g (crude) phenylbutyl carbamate as a yellow solid.

[0196] Step 2: 5-phenyl-3,4-dihydro-2H-pyrrole [ka] tert-Butyl(4-oxo-4-phenylbutyl) in toluene (61.5 mL) A mixture of carbamate (12.3 g, 46.71 mmol) was added to HCl (12 M, 8.5 6 mL) was added. The mixture was stirred at 65° C. for 12 hours. The reaction was complete by TLC. The reaction mixture was extracted with EA (50 mL). The aqueous layer was collected and washed with saturated Na The pH was adjusted to 10 with HCO3 solution and extracted with EA (50 mL). The residue was purified by filtration using silica gel (eluent PE:EA = 50:1 to 10:1) to obtain 5-phenyl-3,4-dihydro- rho-2H-pyrrole (3.5 g, 22.90 mmol, 49.03% yield) Obtained as a solid. 1 H NMR (400MHz, CDCl3)δppm:7.89-7. 81(m,2H), 7.44-7.41(m,2H), 4.08(br t,J=7.4 Hz, 2H), 2.96(br t,J=8.2Hz, 2H), 2.05(dd,J=7 .4, 8.5Hz, 2H).

[0197] Step 3: 2-methyl-2-phenylpyrrolidine [ka] 5-Phenyl-3,4-dihydro-2H-pyrrole (2 g, 1 To a stirred solution of BF3.Et2O (7.82 g, 55.1 mmol) was added BF3.Et2O (7.82 g, 55.1 mmol) at -78 °C. 0 mmol, 6.80 mL) was added. The mixture was stirred at -78 °C for 45 min. eLi (1.6 M, 34.44 mL) was added at −78° C. The mixture was incubated at −78° C. for 2.5 hours. The mixture was stirred for 1 hour, then warmed to 15°C and stirred at 15°C for 12 hours. The reaction was complete by TLC. The mixture was poured into water (100 mL) and adjusted to pH = 0.05 with saturated NaOH solution. The mixture was adjusted to 12 and extracted with DCM (100 mL x 2). The organic layer was washed with brine and The residue was dried over O, filtered and concentrated. The residue was purified by silica gel (eluent: PE:EA=10 0:1 to 20:1 to obtain 2-methyl-2-phenylpyrrolidine (0.9 g , 5.30 mmol, 38.50% yield) was obtained as a red oil. 1 H NMR (40 0MHz, CDCl3)δppm:7.52-7.46(m,2H), 7.36-7.2 9(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).

[0198] Step 4: 1-(4-bromophenyl)-2-methyl-2-phenylpyrrolidine [ka] 1-Bromo-4-iodobenzene (4.21 g, 14.88 mL) in toluene (40 mL) mmol), 2-methyl-2-phenylpyrrolidine (0.6 g, 3.72 mmol), P d2(dba)3(340.75mg, 372.11umol), BINAP(463. 40mg, 744.22umol), t-BuOK (1.25g, 11.16mmol) The solution 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 removal of the mobile phase, the residue was washed with EA (20 mL). Dissolve and adjust pH to 8 with saturated NaHCO3 solution, separate and concentrate to give 1- (4-bromophenyl)-2-methyl-2-phenylpyrrolidine (0.43 g, 33.3 1% yield) as a brown oil. 1 H NMR (400 MHz, CDCl3) δpp m: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.

[0199] Intermediate 2-k: 1-(azetidin-3-ylmethyl)-2-(2-cyclopropylphenyl)- (I)pyrrolidine [ka] Step 1: tert-Butyl 3-((2-(2-cyclopropylphenyl)pyrrolidine-1 -yl)methyl)azetidine-1-carboxylate 2-(2-cyclopropylphenyl)pyrrolidine (0.195g, 647.19umo l) was dissolved in DCE (6 mL) and tert-butyl 3-formylazetidine-1-carboxylate was added. Carboxylate (359.62 mg, 1.94 mmol) and NaBH(OAc)3 (2 After stirring at 15°C for 4 hours, HOAc( 116.59 mg, 1.94 mmol) was added. Stirring was continued at 15° C. for 24 hours. The reaction mixture was poured into saturated aqueous NaHCO3 (4 mL). The combined organic extracts were washed with brine (5 mL) and The residue was purified by column chromatography (SiO2, The mixture was purified by petroleum ether / ethyl acetate (20 / 1 to 5 / 1). -((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)azetidine The -1-carboxylate (0.18 g) was obtained as a yellow liquid.

[0200] Step 2: 1-(azetidin-3-ylmethyl)-2-(2-cyclopropylphenyl)pyridine Roridin tert-Butyl 3-((2-(2-cyclopropyl) Phenyl)pyrrolidin-1-yl)methyl)azetidine-1-carboxylate (0.7 g, 1.96 mmol) was added to a solution of TFA (2.24 g, 19.64 mmol) 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 using NaOH solution and extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were dried and concentrated under reduced pressure. (2-(2-methylmethyl)-2-(2-cyclopropylphenyl)pyrrolidine (475 mg) is a yellow liquid was obtained as a body.

[0201] Intermediate 2-l: 1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2 ,3,6-Tetrahydropyridine [ka] Step 1: 1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trimethylpyrrolidin-1-yl Fluoroethan-1-one 2-(2-bromophenyl)pyrrolidine in DCM (100 mL) under an inert N2 atmosphere A solution of ethanol (4 g, 17.68 mmol) in TEA (3.57 g, 35.36 mmol) was added at 0 °C. mol) and then trifluoroacetic anhydride (4.46 g, 21.22 mmol) was added dropwise. The mixture was stirred at room temperature overnight. The reaction mixture was then poured into 100 mL of water and M (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- (2,2,2-trifluoroethan-1-one) (5.0 g) was obtained as a brown oil. It was used in the next step without further purification.

[0202] Step 2: tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidone) Lysin-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxyle Route 1-(2-(2-bromophenyl)pyrrolidin-1-yl) in toluene (10 mL) To a solution of 2,2,2-trifluoroethan-1-one (5 g, 15.5 mmol), ert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (7.2 g, 2 3.25 mmol), Pd(OAc)2 (350 mg, 1.55 mmol), tricyclo Hexylphosphine (870 mg, 3.1 mmol) and K3PO4 (11.5 g, 54 The suspension was stirred at 100°C for 12 hours under a N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The eluent was petroleum ether / ethyl acetate (50 / 1 to 10 / 1). This was further purified to give tert-butyl 4-(2-(1-(2,2,2-trifluoroacetate). (2H)-phenyl)pyrrolidin-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate The carboxylate (6.1 g) was obtained as a yellow oil.

[0203] Step 3: 2,2,2-trifluoro-1-(2-(2-(1,2,3,6-tetrahydro- Pyridin-4-yl)phenyl)pyrrolidin-1-yl)ethan-1-one tert-Butyl 4-(2-(1-(2,2,2-trifluoromethyl)phenyl)-2,4-dimethyl-2,5-dimethyl-1,6-dimethyl-2,6 ... (2-Oroacetyl)pyrrolidin-2-yl)phenyl)-3,6-dihydropyridine-1(2 To a solution of 1H-carboxylate (6.1 g, 14.5 mmol) was added TFA (20 mL) was added, and then the mixture was stirred at room temperature for 1 hour. The pH of the mixture was adjusted to 8-9 and then extracted with DCM. The organic layer was dried and filtered. The solution was concentrated under reduced pressure to give 2,2,2-trifluoro-1-(2-(2-(1,2,3,6 -tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)ethan-1-ol The compound (3.8 g) was obtained as a brown oil, which was used in the next step without further purification.

[0204] Step 4: 2,2,2-trifluoro-1-(2-(2-(1-methyl-1,2,3,6- Tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)ethan-1-one 2,2,2-trifluoro-1-(2-(2-(1,2,3 ,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)ethane-1 To a solution of HCl (37%, 1.5 g, 18.49 mmol), The suspension was added with NaBH3CN (774 mg, 12.32 mmol) and NaBH3CN (774 mg, 12.32 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in water ( The organic layer was separated, washed with brine and then dried. The residue was purified by column chromatography on silica gel (eluent: D CM / MeOH=20 / 1) to give 2,2,2-trifluoro-1-(2- (2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyridin Roridin-1-yl)ethan-1-one (0.8 g) was obtained as a brown oil.

[0205] Step 5: 1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6 -Tetrahydropyridine 2,2,2-Trifluoro-1-((2,2,2-trifluoromethyl-1-methyl-2,2,2-trifluoro ... 2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl )pyrrolidin-1-yl)ethan-1-one (0.8 g, 2.36 mmol), LiOH.HO (0.2 g, 4.73 mmol) was added. After the addition, the mixture was heated to 60 °C. The reaction mixture was concentrated under reduced pressure and the residue was then dissolved in water with stirring. (15 mL) and EA (30 mL). The organic layer was separated, washed with brine, and then dried. The residue was purified by column chromatography on silica gel (eluent: Purification with DCM / MeOH=50 / 1 gave 1-methyl-4-(2-pyrrolidinedione). (2-yl)phenyl)-1,2,3,6-tetrahydropyridine (500 mg) in brown was obtained as an oil. 1 H NMR (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, 7.58 Hz, 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), 1.5 9-1.70(m,1H).MS(ESI, m / e)[M+1] + 243.1.

[0206] Intermediate 2-m: 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine [ka] Step 1: tert-butyl 2-(2-bromophenyl)-4-fluoropyrrolidine-1- Carboxylate tert-Butyl 2-(2-bromophenyl)-4-hydroxybenzoate in DCM (30 mL) A solution of cypirrolidine-1-carboxylate (2.5 g, 7.31 mmol) was added to DAS T (1.77 g, 10.96 mmol) was added dropwise. The solution was then heated at 20° C. for 12 hours. The reaction mixture was quenched with ice water (30 mL). The organic layer was separated and then The mixture was washed with saturated NaHCO3 solution (30 mL), brine (30 mL), and dried over Na2SO4. The residue was purified by column chromatography on silica gel (eluent: PE / E A=20 / 1 to 10 / 1, and purified to obtain tert-butyl 2-(2-bromophenytoin). (4-fluoropyrrolidine-1-carboxylate) (1.6 g) was obtained as a yellow oil. Ta.

[0207] Step 2: tert-Butyl 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine Benzene-1-carboxylate tert-Butyl 2-(2-bromophenyl)-4-fluorobenzoate in toluene (20 mL) cyclopropylpyrrolidine-1-carboxylate (1.5 g, 4.36 mmol) and cyclopropyl A solution of 1.1 g of boronic acid (13.1 mmol) was added to Pd(OAc) (98 mg, 0.436mmol), tricyclohexylphosphine (245mg, 0.872mmol ), K3PO4 (3.2 g, 15.3 mmol) and H2O (1 mL) were added. The mixture was heated to 100° C. and stirred under a N atmosphere for 12 hours. and EtOAc (20 mL) were added. The organic layer was separated and washed with brine (20 mL) and The residue was purified by column chromatography on silica gel. (eluent: PE / EA=20 / 1) to obtain tert-butyl 2-(2-methyl-2-phenylpropanol). (chloropropylphenyl)-4-fluoropyrrolidine-1-carboxylate (1.1g) was obtained as a brown oil.

[0208] Step 3: 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine tert-Butyl 2-(2-cyclopropyl) HCl solution (20 mL, 4 M in EA) phenyl)-4-fluoropyrrolidine-1-carboxylate (1.1 g, 3.6 mmol) The solution of l) was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was diluted with saturated NaCO The mixture was diluted with 3 solution (20 mL) and EA (20 mL). The organic layer was separated and washed with anhydrous NaSO. The mixture was dried over 4 and concentrated. The residue was purified by column chromatography on silica gel (elution The product was purified using a solvent mixture of PE / EA (4 / 1 to 1 / 1) to give 2-(2-cyclopropylphenyl) To this was obtained (620 mg) 4-fluoropyrrolidine as a yellow oil. 1 H NMR(4 00MHz, 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.

[0209] Intermediate 2-n: 2-chloro-N,N-dimethyl-6-(pyrrolidin-2-yl)aniline [ka] Step 1: tert-butyl(4-(3-chloro-2-(dimethylamino)phenyl)-4 (oxobutyl)carbamate 2-Bromo-6-chloro-N,N-dimethylaniline (3.5 mL) in THF (50 mL) g, 14.92 mmol) and tert-butyl 2-oxopyrrolidine-1-carboxylate A solution of 2.76 g of propyl acetate (14.92 mmol) was added to 6 mL of n-BuLi at -70 °C. , 2.5M in hexane) was added and then stirred for 2 hours. The reaction mixture was added with aqueous NH4Cl ( The combined organic layer was extracted with EA (50 mL x 3). The mixture was dried over 2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel. The product was purified by column chromatography (eluent: PE / EA=5 / 1) to give tert-butyl(4-( 3-chloro-2-(dimethylamino)phenyl)-4-oxobutyl)carbamate (1 0.8g) as a yellow oil.

[0210] Step 2: 4-amino-1-(3-chloro-2-(dimethylamino)phenyl)butane-1 -on tert-Butyl (4-(3-chloro-2-(dimethylamino)methyl)amino)-3-methyl-2 ... )phenyl)-4-oxobutyl)carbamate (1.7 g, 4.99 mmol) solution To the mixture was added TFA (1 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)butane-1- The compound (1.2 g, crude) was obtained as a yellow oil.

[0211] Step 3: 2-chloro-N,N-dimethyl-6-(pyrrolidin-2-yl)aniline 4-amino-1-(3-chloro-2-(dimethylamino)phenyl)propanol in EtOH (20 mL) To a solution of NaBH3CN( 939.77 mg, 14.95 mmol) and HOAc (2 mL) were added, and then the mixture was stirred at room temperature for 3 The reaction mixture was stirred for 6 hours, 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 1. The temperature was adjusted to 0°C and extracted with DCM (30 mL x 3). The organic phase was dried over Na2SO4 and Concentration gave 2-chloro-N,N-dimethyl-6-(pyrrolidin-2-yl)aniline (2 97 mg) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl) δ ppm: 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, 1 H), 3.19(ddd,J=5.4, 7.4, 9.9Hz, 1H), 3.09-2.9 9(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.

[0212] Intermediate 2-o: 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-2 -(trifluoromethyl)pyrrolidine [ka] Step 1: N-(4-bromophenyl)-1-(2-cyclopropylphenyl)-2,2, 2-Trifluoroethane-1-imine N-(4-bromophenyl)-1,1,1-triphenyl- in toluene (20 mL) 15-Phosphanimine (1.8 g, 4.16 mmol) and 1-(2-cyclopropyl phenyl)-2,2,2-trifluoroethan-1-one (891.83 mg, 4.16 A solution of (2,2'-dichloromethane) ... The solvent was removed by column chromatography on silica gel (eluent: P E / EA=50 / 1 to 10 / 1), and N-(4-bromophenyl)-1- (2-cyclopropylphenyl)-2,2,2-trifluoroethan-1-imine (1. 1 g, 2.99 mmol) as a yellow oil.

[0213] Step 2: 4-Bromo-N-(2-(2-cyclopropylphenyl)-1,1,1-triphenyl)- (fluoropenta-4-en-2-yl)aniline N-(4-bromophenyl)-1-(2-cyclopropylphenyl)- (2,2,2-trifluoroethane-1-imine) (1.1 g, 2.99 mmol) Allylmagnesium bromide (1M, 14.94mL) was added to the solution at -20°C, and 2 The reaction mixture was then quenched with aqueous HN4Cl (10 mL) and EA (10 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE). , 4-bromo-N-(2-(2-cyclopropylphenyl)-1,1,1-trifluoro Pent-4-en-2-yl)aniline (1.20 g) was obtained as a white solid.

[0214] Step 3: 4-((4-bromophenyl)amino)-4-(2-cyclopropylphenyl) -5,5,5-trifluoropentan-1-ol 4-Bromo-N-(2-(2-cyclopropylphenyl)-1H-pyridin ... ,1,1-trifluoropent-4-en-2-yl)aniline (1.20g, 2.92 To a solution of 1 mmol, BH3.THF (1 M, 14.62 mL) was added at 0°C and stirred for 1 hour. Next, NaOH (2.5 M, 2.92 mL) and H2O2 (1.49 g, 43. 87 mmol) was added to the reaction mixture at 0° C. After the addition, the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then quenched with aqueous HN4Cl (10 mL) and EA (10 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA=50 / 1 5 / 1) to give 4-((4-bromophenyl)amino)-4-(2-cyclohexyl)-2-methyl-4-(4-bromophenyl)amino-4-(2-cyclohexyl)-2-methyl-4-methyl-2 ... Propylphenyl)-5,5,5-trifluoropentan-1-ol (0.6 g) Obtained as a colored oil.

[0215] Step 4: 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-2-(trimethylsilyl)phenyl (trifluoromethyl)pyrrolidine 4-((4-bromophenyl)amino)-4-(2-cyclohexyl)-2-methyl-2-oxo-1,2-dioxane (10 mL) (1,3-Dimethylpropylphenyl)-5,5,5-trifluoropentan-1-ol (0.6 g, To a solution of 1.55 mmol of TEA (469.17 mg, 4.64 mmol) and MsC l (265.56 mg, 2.32 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The mixture was then heated to 80°C and stirred for 1 hour. The mixture was quenched with 10 mL of HCl, extracted with DCM (10 mL x 3), dried over Na2SO4, and The residue was purified by column chromatography on silica gel (elution The product was purified by PE / EA (10 / 1) and 1-(4-bromophenyl)-2-(2 -cyclopropylphenyl)-2-(trifluoromethyl)pyrrolidine (306 mg) Obtained 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.

[0216] Intermediate 2-p: 2-(2-cyclopropylbenzyl)pyrrolidine [ka] Step 1: tert-butyl 2-((2-cyclopropylphenyl)(hydroxy)methyl ) Pyrrolidine-1-carboxylate 1-Bromo-2-cyclopropylbenzene (4.50 g, 22 A solution of n-BuLi (9.84 mL, 2.5 mmol) was added to the solution at -70 °C under N2. M) was added and stirred for 10 minutes, followed by tert-butyl 2-formylpyrrolidine-1-carboxylate. carboxylate (3.5 g, 17.57 mmol) was added to the mixture and stirred for another 2 hours. The mixture was quenched with saturated NH4Cl solution (30 mL) and added to ethyl acetate (50 mL x 10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was Column chromatography on gel (eluent: PE / EA = 200 / 1 to 5 / 1) Purification was carried out using tert-butyl 2-((2-cyclopropylphenyl)(hydroxyphenyl)- )methyl)pyrrolidine-1-carboxylate (3.40 g, 10.72 mmol) in yellow Obtained as a colored oil.

[0217] Step 2: tert-Butyl 2-(((1H-imidazole-1-carbonothioyl))oxide (2-Cyclopropylphenyl)methyl)pyrrolidine-1-carboxylate tert-Butyl 2-((2-cyclopropylphenyl)(hydroxybenzoate)) in DCM (30 mL) (hydroxymethyl)pyrrolidine-1-carboxylate (3.40 g, 10.72 mmol) l), di(1H-imidazol-1-yl)methanethione (5.73 g, 32.16 mo A solution of 1.32 g of HCl and DMAP (1072 mmol) was stirred at room temperature for 24 hours. The mixture was poured into HCl 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 column chromatography on silica gel. Purification was carried out by chromatography (eluent: PE / EA = 200 / 1 to 5 / 1) to obtain ert-butyl 2-(((1H-imidazole-1-carbonothioyl)oxy)(2- Cyclopropylphenyl)methyl)pyrrolidine-1-carboxylate (3.0 g, 7. 02 mmol) as a yellow oil.

[0218] Step 3: tert-Butyl 2-(2-cyclopropylbenzyl)pyrrolidine-1-carbohydrate Xylate tert-Butyl 2-(((1H-imidazole-1-carboxylate) in toluene (10 mL) (Vonothioyl)oxy)(2-cyclopropylphenyl)methyl)pyrrolidine-1-carboxylate A solution of 2.5 g of carboxylate (5.852 mmol) was added to the solution of 2. 55 g, 8.778 mmol) and a catalytic amount of AIBN (192.06 g, 1.1704 m mol) was added. The mixture was stirred at 100°C for 2 hours. The mixture was then added with saturated aqueous KF (50 The organic phase was dried over Na2SO4 and extracted with EA (50 mL x 3). The residue was purified by preparative HPLC (NaHCO3) to give tert-butyl 2-[4-(2-methyl-2-propanol)-2-one. t-Butyl 2-(2-cyclopropylbenzyl)pyrrolidine-1-carboxylate (6 50 mg) was obtained as a yellow oil.

[0219] Step 4: 2-(2-cyclopropylbenzyl)pyrrolidine tert-Butyl 2-(2-cyclopropylbenzyl)pyrrolidine-1-carboxylate The methyl methyl acrylate (600.00 mg, 1.992 mmol) was dissolved in a solution of MTBE / HCl (10 mL The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and added to saturated Na The pH was adjusted to 10 using CO3 solution, then stirred for 15 min and diluted with EA (30 mL × 3). The organic phase was dried over Na2SO4, filtered, and concentrated to give 2-(2-cyclohexanediamine). (Propylbenzyl)pyrrolidine (302.00 mg) was obtained as a yellow oil. 1 HNM R(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.

[0220] Intermediate 2-q: 2-(2-(azetidin-1-yl)phenyl)-1-(4-bromophenyl)- Nyl)pyrrolidine [ka] Step 1: 2-(azetidin-1-yl)benzaldehyde 2-Fluorobenzaldehyde (10 g, 80.6 mmol) in DMSO (50 mL) ) and azetidine (9.04 g, 96.7 mmol), , 241.17 mmol) was added and stirred at 80° C. for 24 hours. The mixture was diluted with water (300 mL ) and extracted with EA (100 mL × 3). The combined organic phase was poured into brine (400 mL). The residue was washed with HCl, dried over anhydrous NaSO, filtered, and concentrated. By column chromatography (eluent: PE / EA = 100 / 1 to 20 / 1) Upon purification, 2-(azetidin-1-yl)benzaldehyde (9 g, crude) was obtained as a yellow oil. And got it.

[0221] Step 2: 1-(2-(azetidin-1-yl)phenyl)-N-(4-bromophenyl) Methanimine 2-(azetidin-1-yl)benzaldehyde (4 g, 2 4.81 mmol) and 4-bromoaniline (4.27 g, 24.81 mmol) The mixture was diluted with 4-methylbenzenesulfonic acid (854 mg, 4.96 mmol) and 4 Å molecular sieves. (4 g) was added. The mixture was stirred at 140° C. for 6 h and then concentrated under reduced pressure. -(2-(azetidin-1-yl)phenyl)-N-(4-bromophenyl)methanimine The compound (9 g) was obtained as a yellow solid, which was used in the next step without further purification.

[0222] Step 3: N-(1-(2-(azetidin-1-yl)phenyl)but-3-en-1-yl) (I)-4-Bromoaniline 1-(2-(azetidin-1-yl)phenyl)-N-(4- To a mixture of bromophenyl)methanimine (9 g, 28.55 mmol) under N2, - Allylmagnesium bromide (128.5 mL, 1 M) was added at 20° C. The mixture was cooled to room temperature The mixture was stirred at rt for 2 h. Then, the mixture was poured into saturated NH4Cl (200 mL) and The combined organic phase was washed with brine (400 mL) and extracted with anhydrous Na The mixture was dried over 2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel. The product was purified by a solvent (PE / EA = 20 / 1 to 1 / 1) to give N-(1-(2-azetyl)- (Diphenyl)but-3-en-1-yl)-4-bromoaniline (3g) was obtained as a yellow oil.

[0223] Step 4: 4-(2-(azetidin-1-yl)phenyl)-4-((4-bromophenyl )Amino)butan-1-ol N-(1-(2-(azetidin-1-yl)phenyl)buta- in THF (20 mL) A solution of (3-en-1-yl)-4-bromoaniline (3 g, 8.4 mmol) was added to a BH3THF (25 g, 25.19 mmol) was added at 0°C under atmospheric pressure. The mixture was stirred at 5°C for 2 hours. NaOH (1.01 g, 25.19 mmol) and H2O2 (9 0.5 g, 83.97 mmol) was added at 0° C., and then the mixture was stirred for 3 h. The combined organic phase was poured into 20 (50 mL) and extracted with EA (100 mL × 3). The residue was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. Column chromatography on silica gel (eluent: PE:EA = 1 / 1 to 0 / 1) Purification by 4-(2-(azetidin-1-yl)phenyl)-4-((4-bromo) To this was obtained (0.9 g) of (3-amino-4-(4-chlorophenyl)amino)butan-1-ol as a yellow oil.

[0224] Step 5: 2-(2-(azetidin-1-yl)phenyl)-1-(4-bromophenyl) Pyrrolidine 4-(2-(azetidin-1-yl)phenyl)-4-((4- To a solution of (bromophenyl)amino)butan-1-ol (0.9 g, 2.4 mmol), TEA (960 mg, 9.59 mmol) and MsCl (329 mg, 2.88 mmol) ) was added at 0° C. After stirring at 25° C. for 2 hours, the reaction mixture was concentrated under reduced pressure. , which was purified by preparative TLC (silica gel, eluent: PE / EA=1 / 1) to give 2-(2 -(azetidin-1-yl)phenyl)-1-(4-bromophenyl)pyrrolidine (38 8.6 mg) was obtained as a yellow oil. 1 H NMR (400 MHz, CDCl3) δpp m:7.24-7.18(m,2H), 7.17-7.11(m,1H), 6.94(d d,J=1.4, 7.6Hz, 1H), 6.74-6.66(m,1H), 6.55(d d,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), 3.69-3.57(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.

[0225] Intermediate 2r: 2-(2-(1,1-difluoroethyl)phenyl)pyrrolidine [ka] Step 1: 1-Bromo-2-(1,1-difluoroethyl)benzene DAST (25 mL) was diluted with 1-(2-bromophenyl)ethan-1-one (5 g, 25 The resulting mixture was heated under a nitrogen atmosphere for 50 minutes. The reaction mixture was stirred at 4°C overnight. The reaction mixture was diluted with CH2Cl2 (100 mL) and then cooled to 10°C with ice / saturated N Poured into aqueous aHCO3 (250 mL) and extracted with CH2Cl2 (2 x 100 mL). The combined organic layers were dried over anhydrous NaSO and concentrated. The residue was purified by silica gel chromatography. Purification by column chromatography (eluent: PE / EA=50 / 1) on 1-Bromo-2-(1,1-difluoroethyl)benzene (3.5 g) was obtained as a yellow liquid. I got it.

[0226] Step 2: tert-butyl 2-(2-(1,1-difluoroethyl)phenyl)-1H- Pyrrole-1-carboxylate 1-Bromo-2-(1,1-difluoromethyl)propanol in THF (18 mL) and HO (1.8 mL) To a stirred solution of [1-[(tetraethyl)benzene (1.5 g, 6.786 mmol)] rt-butoxy)carbonyl]-1H-pyrrol-2-yl]boronic acid (1.44 g, 6 .824mmol), X-Phos(0.65g, 1.363mmol), K3PO4( 4.34 g, 20.446 mmol) and Pd(OAc)2 (152.8 mg, 0.68 After stirring under nitrogen atmosphere at 70°C for 4.5 hours, the reaction mixture was It was diluted with water (50 mL) and extracted with EA (3×30 mL). The residue was washed with water (50 mL), dried over anhydrous Na2SO4, and concentrated. The product was purified by column chromatography on a 1000-ml gel (eluent: PE / EA = 50 / 1). , tert-butyl 2-[2-(1,1-difluoroethyl)phenyl]-1H-pyrrolidone 2.2729 g (crude) of benzoyl-1-carboxylate was obtained as a dark yellow oil.

[0227] Step 3: tert-Butyl 2-(2-(1,1-difluoroethyl)phenyl)pyrrolidine Benzene-1-carboxylate tert-Butyl 2-[2-(1,1-difluoroethyl) phenyl]-1H-pyrrole-1-carboxylate (2.2729 g, 7.395 mm To a stirred solution of PtO2 (1.1365 g, 5.005 mmol) and concentrated HCl acid (4 mL) was added in small portions. The resulting mixture was stirred at room temperature for 5 min under a H2 atmosphere (1 atm). The mixture was stirred for 1 hour. After filtering off the PtO2, the filtrate was concentrated. The residue was The mixture was diluted with aqueous NaHCO3 (200 mL) and then extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. , concentrated, and tert-butyl 2-[2-(1,1-difluoroethyl)phenyl]pyrrolidone was obtained. 1.7408 g (crude) of lysine-1-carboxylate was obtained as a dark yellow oil.

[0228] Step 4: 2-(2-(1,1-difluoroethyl)phenyl)pyrrolidine tert-Butyl 2-[2-(1,1-difluoroethyl)fluor]propanol in DCM (35 mL) [phenyl]pyrrolidine-1-carboxylate (1.7408 g, 5.591 mmol) To the solution was added HCl solution (4 mL, 4N in 1,4-dioxane) in small portions. The mixture was stirred at room temperature under N2 atmosphere for 4 hours. After adjusting the pH value to 8, the resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by reversed-phase flash chromatography under the following conditions: Mobile phase, CH3CN (0.05% NH4HCO3) in water, 2 Gradient: 10% to 61% in 5 min; detector: UV 220 nm. The resulting eluent was diluted with DCM (3× The combined organic layers were then concentrated to give (2-[2-(1, 1-Difluoroethyl)phenyl]pyrrolidine (703.1 mg) was obtained as a yellow oil. Ta. 1 H NMR (400 MHz, chloroform-d) δ ppm: 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), 2.0 3-1.94(m,5H), 1.94-1.81(m,1H), 1.78-1.58(m , 1H).MS(ESI, m / e)[M+1] + 212.1.

[0229] Intermediate 2s: 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)piperidine gin [ka] Step 1: 1-Bromo-2-cyclopropylbenzene 1-Bromo-2-iodobenzene (40 g, 141.3 mL) in dioxane (400 mL) To a stirred solution of 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) was added. The mixture was heated under a N2 atmosphere The mixture was stirred at 70° C. for 48 h. The mixture was diluted with water (1000 mL) and diluted with EA (3×400 mL). The combined organic layers were washed with brine (400 mL) and anhydrous NaSO The mixture was dried over 4 and concentrated. The residue was purified by column chromatography on silica gel (elution The product was purified by PE / EA (100 / 1) to give 1-bromo-2-cyclopropylbenzoate. Zene (22.0 g) was obtained as a colorless oil.

[0230] Step 2: 2-(2-cyclopropylphenyl)pyridine 1-Bromo-2-cyclopropylbenzene (12 g, 6 mL) in dioxane (120 mL) To a stirred solution of 2-(tributylstannyl)pyridine (26.9 mmol) 0g, 73.069mmol) and Pd(PPh3)4 (7.04g, 6.089mmol The mixture was stirred overnight at 100° C. under a N atmosphere. The reaction was diluted with water (1 The mixture was quenched by the addition of EA (3×50 mL). The combined organic layers were washed with 50 mL of brine and dried over anhydrous Na2SO4. The residue was purified by column chromatography on silica gel (eluent: PE / EA). =70 / 1) to give 2-(2-cyclopropylphenyl)pyridine (5.8 0 g) was obtained as a pale yellow oil.

[0231] Step 3: 2-(2-cyclopropylphenyl)piperidine 2-(2-cyclopropylphenyl)pyridine (2.5 g) in EtOH (100 mL) To a stirred solution of HCl acid (concentrated, 3.5 mL) and PtO2 ( The resulting mixture was placed under a H2 (1 atm) atmosphere. The mixture was stirred at room temperature under atmospheric pressure for 4 hours. After filtering off the PtO2, the filtrate was concentrated. The residue was purified under the following conditions: column, C18 silica gel, mobile phase, water and 0.05% CH3CN TFA, gradient 0% to 10% in 30 min; detector, reversed-phase flash chromatography at UV 220 nm The crude product was purified by chromatography to give 900 mg, which was purified under the following conditions: (Column: XBridge Prep OBD C18 Column 30×150m m 5 μm; Mobile phase A: water (10 mM NH4HCO3), Mobile phase B: CH3C N; flow rate: 60 mL / min; gradient: 25% B to 37% B in 9 min; 254 and 220n m; Rt: 7.92 min) to give 2-(2-cyclopropyl (phenyl)piperidine (280 mg) was obtained as a yellow oil.

[0232] Step 4: 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)piperidine 2-(2-cyclopropylphenyl)piperidine (2.50 mL) in DCM (250 mL) g, 12.437 mmol), (4-bromophenyl)boronic acid (4.975 g, 24. 874 mmol), Cu(OAc)2 (5.627 g, 31.093 mmol) and activity To a stirred mixture of 4 Å molecular sieves (2.0 g), DIPEA (4.011 g, 31.0 The resulting mixture was stirred at room temperature for 3 h under an O2 atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified under the following conditions: RAM: XBridge Prep OBD C18 Column 30×150mm 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: CH3CN; Flow rate: 60 mL / min; Gradient: 43% B to 46% B in 9 min; 254 and 220 nm; Rt: 7.40 Purification by preparative HPLC at 27°C (min) yielded 1-(4-bromophenyl)-2-(2-cyclohexyl)- (310 mg)chloropropylphenylpiperidine was obtained as a brown solid. 1 H NMR (300MHz, methanol-d4) δ ppm: 7.46 (s, 2H), 7.31 (d, J=8.5Hz, 2H), 7.21-7.09(m,2H), 6.91(d,J=7.3 Hz, 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.

[0233] Intermediate 2-t: 2-(2-cyclopropylphenyl)-4-methylpyrrolidine [ka] Step 1: Methyl 3-methyl-4-nitrobutanoate (E)-Methylbut-2-enoate (20 g, 199. 77 mmol), CH3NO2 (48.78 g, 799.07 mmol), DB N (4.60 mg, 39.95 mmol) was added. The mixture was heated under N2 atmosphere at 60 °C. The reaction mixture was stirred at rt for 6 h. TLC showed that the reactants were completely consumed. To the mixture was added MTBE (700 mL), 1 M HCl (500 mL) and HO (500 mL). The organic phase was concentrated under reduced pressure to give a residue. The mixture was purified by silica gel chromatography (petrol / ethyl acetate = 50 / 1). 3-methyl-4-nitrobutanoate (23 g, yield: 71.44%) was obtained as a yellow liquid. This was obtained. 1 H NMR (400MHz, CDCl3)δppm:4.27-4.4 9(m,2H), 3.66(s,3H), 2.75(m,1H), 2.28-2.48( m,2H), 1.06(d,J=6.84Hz, 3H).

[0234] Step 2: 4-Methylpyrrolidin-2-one Methyl 3-methyl-4-nitrobutanoate (20 g, 1 Raney Ni (728.41 mg, 12.41 mmol) in a solution of 24.10 mmol The mixture was stirred under H2 atmosphere at 50 °C for 4 h. TLC showed that the reaction The reaction mixture was filtered and concentrated under reduced pressure to give 4-methylpyrrolidine. The resulting product was methyl-2-one (10 g) as a yellow solid, which was carried on to the next step without further purification. Used.

[0235] Step 3: tert-butyl 4-methyl-2-oxopyrrolidine-1-carboxylate 4-Methylpyrrolidin-2-one (10 g, 100.88 m) in THF (100 mL) mol), DMAP (6.16g, 50.44mmol), TEA (10.21g, 10 0.88 mmol) to a mixture of (Boc)O (44.03 g, 201.75 mmol) ) was added. The mixture was stirred at 25°C for 3 hours. TLC showed that the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. by lithography (silica gel, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) Purified: tert-butyl 4-methyl-2-oxopyrrolidine-1-carboxylate (13 g, 64.68% yield) was obtained as a white solid. 1 H NMR (400M Hz, 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).

[0236] Step 4: tert-butyl(4-(2-cyclopropylphenyl)-2-methyl-4-on (xobutyl)carbamate 1-Bromo-2-cyclopropylbenzene (3.5 g, 17.5 mL) in THF (50 mL) A mixture of n-BuLi (1.04 g, 76 mmol) was degassed and purged with N2 three times, and then , 16.28 mmol) was added dropwise to the mixture at -68°C. After stirring for 10 minutes, , followed by tert-butyl 4-methyl-2-oxopyrrolidine-1 in THF (10 mL) -carboxylate (2.95 g, 14.80 mmol) was added to the mixture. The mixture was stirred under N2 atmosphere at -68 °C for 2 h. TLC showed the reaction was complete. The reaction was quenched with aqueous NH4Cl (20 mL) and EA (50 mL × The combined organic layers were washed with brine (20 mL) and extracted with Na2SO4. Drying and concentration under reduced pressure gave a residue, which was purified by column chromatography (silica The product was purified by tert-gel chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1). Butyl(4-(2-cyclopropylphenyl)-2-methyl-4-oxobutyl)carba The mate (3.6 g, 76.63% yield) was obtained as a yellow oil. 1 H NMR(4 00MHz, 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, 2 H), 3.00(dd,J=16.8, 5.51Hz, 2H), 2.77(dd,J=1 6.8, 7.72Hz, 1H), 2.24-2.50(m,3H), 1.44(s,10 H), 1.24-1.36(m,1H), 0.94-1.03(m,5H), 0.88- 0.94(m,2H), 0.61-0.72(m,2H).

[0237] Step 5: 4-amino-1-(2-cyclopropylphenyl)-3-methylbutan-1-ol hmm tert-Butyl (4-(2-cyclopropylphenyl)-2- diol) in DCM (50 mL) -methyl-4-oxobutyl)carbamate (3.5 g, 11.03 mmol) Degass and purge with N2 three times, then add TFA (12.57 g, 110.26 mmol). The mixture was stirred under N2 atmosphere at 20 °C for 1 h. TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product (2.0 g ) was used in the next step without purification. 1 H NMR (400 MHz, CDCl3) δp pm: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,4 H).

[0238] Step 6: 2-(2-cyclopropylphenyl)-4-methylpyrrolidine 4-amino-1-(2-cyclopropyl)propanol in EtOH (20 mL) and HOAc (2 mL) A solution of (2.0 g, 9.20 mmol)-3-methylbutan-1-one The mixture was degassed and purged with N2 three times. Then, NaBH3CN (983.23 mg, 15.56 The mixture was stirred under N2 atmosphere at 25 °C for 2 h. LC / MS showed the reaction was complete. The reaction mixture was adjusted to pH 10 using ethanol and extracted with EA (20 mL x 5). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA conditions). (chloropropylphenyl)-4-methylpyrrolidine (421 mg) was obtained as a yellow oil. Ta. 1 H NMR (400MHz, CDCl3)δppm:7.48-7.59(m,1 H), 7.11-7.25(m,2H), 7.01(d,J=7.3Hz, 1H), 4. 82-4.91(m,1H), 3.39(dd,J=9.9, 6.8Hz, 1H), 3. 24(dd,J=10.1, 7.5Hz, 1H), 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,3 H), 0.88-0.98(m,2H), 0.61-0.71(m,2H).MS(ES I, m / e) [M+1] + 202.1.

[0239] Intermediate 2-u: (S)-2-(2-cyclopropylphenyl)-1-(7-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[3.5]nona (6-en-2-yl)pyrrolidine [ka] Step 1: (S)-2-(2-cyclopropylphenyl)-1-(8,11-dioxazolidinyl) Pyrro[3.2.47.24]tridecan-2-yl)pyrrolidine 8,11-Dioxadispiro[3.2.47.24]trideca in DCE (30 mL) phen-2-one (2.5 g, 13.35 mmol), (S)-2-(2-cyclopropylphenyl)- (phenyl)pyrrolidine (2.36 g, 12.01 mmol) and HOAc (2.4 g, 40 A solution of Na(OAc)3BH(5.05 mmol) was stirred at 15°C for 2 hours. 6g, 26.7mmol) was added to the mixture, which was then stirred at 15°C for 12 hours. The reaction was completed. The mixture was adjusted to pH 7. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA=20 / 1-7 / 1) to give the target product (2.5 g, crude) as a yellow oil.

[0240] Step 2: (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)sulfonyl Pyro[3.5]nonan-7-one (S)-2-(2-cyclopropylphenyl)-1-(8, 11-Dioxadispiro[3.2.47.24]tridecan-2-yl)pyrrolidine(2 g, 5.45 mmol) was dissolved in 1 N HCl acid (27 mL, 27.25 mmol). The mixture was stirred at 15°C for 6 hours. TLC showed that the reaction was complete. After removal of the solvent, the residue was dissolved in EA (20 mL) and washed with saturated aqueous NaHCO3. The organic layer was washed with water and brine, dried over Na2SO4, and filtered. and concentrated to give (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl) To give 1.7 g (crude)spiro[3.5]nonan-7-one as a yellow oil.

[0241] Step 3: (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)sulfonyl Pyro[3.5]non-6-en-7-yl trifluoromethanesulfonate (S)-2-(2-(2-cyclopropylphenyl)pyrrolidine) in THF (20 mL) (3.5)nonan-7-one (1.6 g, 4.95 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl) A mixture of methanesulfonamide (2.12 g, 5.94 mmol) was cooled to -78°C. Next, LDA (2.97 mL, 5.94 mmol) was added and stirred for 2 hours. The mixture was warmed to 15°C and stirred for 12 hours. TLC showed the reaction was complete. The mixture was poured into saturated aqueous NH4Cl and extracted with EA. The organic layer was washed with water and brine. The residue was purified by column chromatography on silica gel. The product was purified by chromatography (eluent: PE / EA = 50 / 1 to 5 / 1) to give (S)- 2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)spiro[3.5]no Thio-6-en-7-yl trifluoromethanesulfonate (2.4 g, crude) was dissolved in a yellow oil was obtained as.

[0242] Step 4: (S)-2-(2-cyclopropylphenyl)-1-(7-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[3.5]nona-6- (en-2-yl)pyrrolidine (S)-2-(2-(2-cyclopropylphenyl)pyrrolidone) in dioxane (20 mL) Lysin-1-yl)spiro[3.5]non-6-en-7-yltrifluoromethanesulfonate phonate (2.2 g, 4.83 mmol), B2PIN2 (1.84 g, 7.25 mmol) l), KOAc (1.42 g, 14.49 mmol) and Pd(dppf)Cl2 (35 The mixture solution of 1 mg of methylcellulose (0.48 mmol) was stirred at 85°C for 3 hours. The reaction was shown to be complete. The mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel. The product was purified by column chromatography (eluent: PE / EA = 10 / 1 to 5 / 1), (S)-2-(2-cyclopropylphenyl)-1-(7-(4,4,5,5-tetramethylphenyl ... (1,3,2-dioxaborolan-2-yl)spiro[3.5]non-6-ene-2 -yl)pyrrolidine (700 mg, 33% yield) was obtained as a yellow solid. 1 HNM R(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,1 H), 2.05(s,2H), 1.99-1.80(m,5H), 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.

[0243] Intermediate 2-v: tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidine- 2-yl)phenyl)piperazine-1-carboxylate [ka] Step 1: tert-Butyl 4-(2-formylphenyl)piperazine-1-carboxylate Route 2-Fluorobenzaldehyde (13.33 g, 107. 38 mmol) and tert-butyl piperazine-1-carboxylate (30.0 g, 161.07 mmol) to a solution of K2CO3 (44.52 g, 322.15 mmol) The mixture was stirred at 100°C for 12 hours. TLC showed that the reactants were completely consumed. The reaction mixture was cooled to room temperature, poured into H2O (150 mL), and EA ( The mixture was extracted with 150 mL of ethyl acetate, dried over Na2SO4, filtered, and concentrated. Purification was performed by column chromatography (silica gel, PE / EA = 100 / 1 to 30 / 1). tert-Butyl 4-(2-formylphenyl)piperazine-1-carboxylate The ester (8.5 g) was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl 3)δppm:1.50(s,9H), 3.02-3.08(m,4H), 3.61-3 .66(m,4H), 7.11(d,J=8.2Hz, 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).

[0244] Step 2: (E)-tert-butyl 4-(2-(((4-bromophenyl)imino)methyl) (phenyl)phenyl)piperazine-1-carboxylate tert-Butyl 4-(2-formylphenyl)piperazine in toluene (100 mL) 4-Bromoaniline (4. A solution of 74 g (27.55 mmol) of 4 Å molecular sieves (5 g) and TsOH (474.4 The mixture was stirred at 120°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. (E)-tert-butyl 4-(2-(((4-bromophenyl)imino) Methyl)phenyl)piperazine-1-carboxylate (8 g, crude) as a brown oil Obtained. 1 H NMR (400MHz, CDCl3)δppm:1.49(s,9H) , 2.98(br,4H), 3.60(br,4H), 7.08-7.13(m,3H) , 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).

[0245] Step 3: tert-butyl 4-(2-(1-((4-bromophenyl)amino)buta-3 (-en-1-yl)phenyl)piperazine-1-carboxylate (E)-tert-butyl-4-(2-(((4-bromo-2-methyl-4-phenylindole)) in DCM (100 mL) (phenyl)imino)methyl)phenyl)piperazine-1-carboxylate (8g, 18. 0 mmol) at -20 °C in allylmagnesium bromide (1 M, 18.0 mL) The mixture was stirred at -20°C for 2 hours. TLC showed that the reactants were completely consumed. The reaction mixture was poured into aqueous NH4Cl (150 mL) and EA (150 mL) was added. The residue was extracted with 1 mL of ethyl acetate, dried over Na2SO4, filtered, and concentrated. The product was purified by chromatography (silica gel, petroleum ether). -(2-(1-((4-bromophenyl)amino)but-3-en-1-yl)phenyl ) Piperazine-1-carboxylate (6.0 g) was obtained as a yellow oil. 1 HN MR(400MHz, CDCl3)δppm:1.51(s,9H), 2.47-2.6 6(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), 7.10-7.20(m,4H), 7.24(d d,J=7.2, 1.5Hz, 1H), 7.34(dd,J=7.6, 1.5Hz, 1H ).

[0246] Step 4: tert-Butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybenzoate Hydroxybutylphenylpiperazine-1-carboxylate tert-Butyl 4-(2-(1-((4-bromophenyl)methyl ... )amino)but-3-en-1-yl)phenyl)piperazine-1-carboxylate ( To a solution of 6 g (12.33 mmol) of BH3.THF (1 M, 185.02 mL) at 0 °C ) was added. The mixture was stirred at 25°C for 12 hours, and then NaOH (1.23g, (30.84 mmol) and H2O2 (6.29 g, 185.02 mmol) were mixed at 0°C. The mixture was stirred at 25°C for 8 hours. TLC showed that Reagent 4 had completely disappeared. The reaction mixture was poured into an aqueous solution of NH4Cl (150 mL) and EA ( The mixture was extracted with 150 mL of ethyl acetate, dried over Na2SO4, filtered, and concentrated. Purification was performed by column chromatography (silica gel, PE / EA = 100 / 1 to 30 / 1). tert-Butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybenzoate (hydroxybutyl)phenyl)piperazine-1-carboxylate (3.5 g) is a yellow solid. was obtained as a body. 1 H NMR (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).

[0247] Step 5: tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)methyl)pyrrolidin-2-yl (phenyl)phenyl)piperazine-1-carboxylate tert-Br in DCM (50 mL) and TEA (3.51 g, 34.69 mmol) 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenyl) To a solution of 0.5g of 1-(2-methyl-2-pyrazine-1-carboxylate (3.5g, 6.94mmol), MsCl (715.29 mg, 6.24 mmol) was added at 25 °C, and the mixture was stirred for 1.5 min at 25 °C. LCMS showed complete consumption of the reactants and the desired MS One major peak corresponding to the NH4Cl ion was observed. The reaction mixture was poured into an aqueous solution (150 mL). The mixture was washed with EA (150 mL×3), dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by column chromatography (silica gel, PE / EA=10 / 1). tert-Butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl) )phenyl)piperazine-1-carboxylate (3.0 g) was obtained as a white solid. Ta. 1 H NMR (400MHz, CDCl3)δppm:1.47-1.54(m,9 H), 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,1 H), 7.08-7.12(m,1H), 7.15-7.26(m,4H).MS(ES I, m / e) [M+1] + 486.1.

[0248] Intermediate 2-w: 6-(2-cyclopropylphenyl)-5-azaspiro[2.4]hepta hmm [ka] Step 1: tert-butyl 2-(2-cyclopropylphenyl)-4-hydroxypyrrolidone Zin-1-carboxylate 5-(2-cyclopropylphenyl)pyrrolidin-3-ol in DCM (20 mL) (1.8 g, 8.9 mmol) and EtN (0.9 g, 8.9 mmol), OC2O (1.9 g, 8.9 mmol) was added. The mixture was then stirred at 20 °C for 12 h. TLC showed the reaction was complete. The reaction mixture was diluted with HCl acid (1N, Wash with saturated aqueous NaHCO3 (20 mL), brine (20 mL), and Na2 Dry over SO4, concentrate and tert-butyl 2-(2-cyclopropylphenyl) -4-Hydroxypyrrolidine-1-carboxylate (2.3 g, crude) as a yellow oil I got it.

[0249] Step 2: tert-Butyl 2-(2-cyclopropylphenyl)-4-oxopyrrolidine -1-carboxylate tert-Butyl 2-(2-cyclopropylphenyl)-4- in DCM (30 mL) To a solution of hydroxypyrrolidine-1-carboxylate (2.3 g, 7.6 mmol), NaHCO3 (640 mg, 7.6 mmol) and Dess-Martin periodinane (3 0.2 g, 7.6 mmol) was added. The mixture was stirred at 20° C. for 12 hours. The reaction mixture was diluted with saturated aqueous NaSO (30 mL) The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated. and tert-butyl 2-(2-cyclopropylphenyl)-4-oxopyrrolidine- The 1-carboxylate (2.1 g, crude) was obtained as a yellow oil.

[0250] Step 3: tert-butyl 2-(2-cyclopropylphenyl)-4-methylenepyrrolidine Benzene-1-carboxylate Ph3P in THF (25 mL) + MeBr - (5.5g, 15.3mmol) To the mixture was added t-BuOK (1.7 g, 15.3 mmol) in one portion. The mixture was stirred for 1 hour. Then, tert-butyl 2-(2-cyclopropylphenyl)-4-ol was added. hexopyrrolidine-1-carboxylate (2.3 g, 7.64 mmol) was added and the mixture The mixture was stirred at 20° C. for 12 hours. TLC showed that the reaction was complete. The mixture was quenched with saturated aqueous NH4Cl (25 mL) and then extracted with EA (25 mL). The organic layer was washed with brine (25 mL), dried over Na2SO4, and concentrated. By column chromatography on silica gel eluted with PE / EA=10 / 1, and purified to give tert-butyl 2-(2-cyclopropylphenyl)-4-methylenepyrrolidone. Lysine-1-carboxylate (1.3 g, yield: 56%) was obtained.

[0251] Step 4: tert-Butyl 6-(2-cyclopropylphenyl)-5-azaspiro[2. 4]Heptane-5-carboxylate tert-Butyl 2-(2-cyclopropylphenyl)-4-methylenepyrrolidine-1 -carboxylate (1.3 g, 4.3 mmol) and EtZn (1 M in toluene, 1 To a mixture of 1000 ml of HCl (5 mL, 15 mmol), ClCHI (5.3 g, 30 mmol) was added at 0 °C. The mixture was then stirred at 20°C for 12 hours. A new spot was formed by TLC. The reaction mixture was diluted with saturated NH₄Cl₄ and HCl. The mixture was quenched with aqueous 1H2O (50 mL) and extracted with EA (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, concentrated and purified to give tert-butyl 6-(2-cyclohexyl) chloropropylphenyl)-5-azaspiro[2.4]heptane-5-carboxylate ( 1 g, crude) as a yellow oil, which was used directly in the next step.

[0252] Step 5: 6-(2-cyclopropylphenyl)-5-azaspiro[2.4]heptane tert-Butyl 6-(2-cyclopropylphenyl)-2 ... nyl)-5-azaspiro[2.4]heptane-5-carboxylate (1 g, 3.2 mm The solution of 1,2-dichloromethane (2,4-dichloromethane) was stirred at 20° C. for 2 hours. LC / MS showed the reaction was complete. The mixture was concentrated, and the residue was purified by preparative HPLC (0.1% TFA). The desired eluent was basified with saturated aqueous Na2CO3 until pH = 10. The organic layers were combined and washed with Na2SO4 The resulting mixture was dried over ice and concentrated to give 6-(2-cyclopropylphenyl)-5-azaspiro[2. 4]Heptane (293 mg) was obtained as a pale yellow oil. 1 H NMR (400 MHz, C DCl3)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), 3.02-3.13(m,2H), 2.34(s,1H), 2.14( dd,J=12.3, 7.2Hz, 1H), 2.04(t,J=8.4, 1H), 1.8 1-1.90(m,1H), 0.87-1.02(m,2H), 0.53-0.76(m ,6H).MS(ESI, m / e)[M+1] + 214.1.

[0253] Intermediate 2-x: (R)-1-(2-(1-(4-bromophenyl)pyrrolidin-2-yl )benzyl)-4-methylpiperazine [ka] Step 1: (R)-1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2, 2-Trifluoroethanone (R)-2-(2-bromophenyl)pyrrolidine (10 g, To a mixture of TFAA (18.58 g, 88.45 mmol) and TFAA (44.23 mmol), TEA (13.5 g, 132.69 mmol) was added dropwise at 0° C. The mixture was heated to 20° C. The reaction mixture was stirred at rt for 10 h. TLC showed that the reactants were completely consumed. The mixture was washed with saturated aqueous NH4Cl (100 mL × 2), and the organic phase was dried over Na2SO4. The residue was purified by column chromatography (silica gel, The (R)-1-(2-bromo)-2-(2-methyl-2-propanol (PE / EA = 100 / 1 to 50 / 1) was purified. (13g)-2,2,2-trifluoroethanone (1-methyl-2,2,2-trifluorophenyl)pyrrolidin-1-yl Obtained as a yellow solid.

[0254] Step 2: (R)-2,2,2-trifluoro-1-(2-(2-vinylphenyl)pyrrolidone) Zin-1-yl)ethenon (R)-1-(2-bromo)-2-(2-bromo)-2-(2-bromo-2-methylpropional)-1 ... (phenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethanone (5g, 15. 52 mmol), potassium trifluoro(vinyl)borate (2.91 g, 21.73 m mol) and Cs2CO3 (10.11 g, 31.04 mmol), Pd (d ppf)Cl2 (567 mg, 776 umol) was added at 20 °C. The mixture was heated for 3 min with N2. The mixture was purged 1 time and then heated to 100° C. for 5 hours. TLC and LC / MS showed The reaction mixture was concentrated under reduced pressure (approximately 30 mL). The residue was poured into ice water (50 mL). The aqueous phase was extracted with EA (50 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated. Purified by silica gel chromatography (PE / EA = 100 / 1 to 50 / 1). (R)-2,2,2-trifluoro-1-(2-(2-vinylphenyl)pyrrolidine) (1-phenyl-1-yl)ethanone (3.4 g, 12.63 mmol, 81.34% yield) was obtained as a yellow was obtained as an oil. 1 H NMR (400MHz, CDCl3)δppm:7.44- 7.51(m,1H), 7.21-7.27(m,2H), 6.88-7.07(m,2 H), 5.61-5.71(m,1H), 5.46-5.60(m,1H), 5.33- 5.45(m,1H), 3.75-4.03(m,2H), 2.27-2.41(m,1 H), 1.82-2.12(m,3H).MS(ESI, m / e)[M+1] + 270. 1.

[0255] Step 3: (R)-2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl) Benzaldehyde (R)-2,2,2-trifluoro-1 in THF (60 mL), HO (60 mL) -(2-(2-vinylphenyl)pyrrolidin-1-yl)ethanone (3.4 g, 12.6 3mmol) and K2O S Mixture of O4.2H2O (186 mg, 505.1 umol) To the mixture, NaIO4 (10.8 g, 50.51 mmol) was added in small portions at 10 °C. The mixture was stirred for 2 hours at 10° C. TLC showed that the reactants were completely consumed. The reaction mixture was concentrated to remove THF, and the aqueous phase was extracted with EA (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. (R)-2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzyl The aldehyde (3.4 g, crude) was obtained as a brown oil. MS (ESI, m / e) [M+1] + 272.1.

[0256] Step 4: (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetate) 2-pyrrolidin-2-yl)benzyl)piperazine-1-carboxylate (R)-2-(1-(2,2,2-trifluoroacetyl)methyl)-2,2-difluoroacetylacetone in DCE (100 mL) (pyrrolidin-2-yl)benzaldehyde (3.4 g, 12.54 mmol) and ter Mixture of t-butylpiperazine-1-carboxylate (4.67 g, 25.07 mmol) To the mixture, NaBH(OAc)3 (10.6 g, 50.16 mmol) was added in small portions at 10°C. The mixture was stirred at 10° C. for 10 hours. TLC showed that the reactants were completely consumed. The reaction mixture was washed with NaHCO3 (50 mL), and the organic phase was then separated. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzoyl)benzoate Dimethylpiperazine-1-carboxylate (3.5 g) was obtained as a yellow oil. (ESI, m / e)[M+1] + 442.3.

[0257] Step 5: (R)-tert-butyl 4-(2-(pyrrolidin-2-yl)benzyl)piperazine Rhazin-1-carboxylate (R)-tert-butyl 4-(2-(1-(2,2,2- Trifluoroacetyl)pyrrolidin-2-yl)benzyl)piperazine-1-carboxy A solution of 1.2g of methylpropanol (3.3g, 7.47mmol) was added to the solution of NaBH4 (662.13mg, 16 0.44 mmol) was added portionwise at 20° C. The mixture was stirred at 20° C. for 4 hours. TLC The reaction mixture was concentrated and diluted with EtOH ( Approximately 10 mL of the extract was removed and poured into ice water (20 mL). The aqueous phase was extracted with EA (50 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and Concentrated. (R)-tert-butyl 4-(2-(pyrrolidin-2-yl)benzyl)pyrimidin Perazine-1-carboxylate (2.55 g, crude) was obtained as a yellow oil. (ESI, m / e)[M+1] + 346.3.

[0258] Step 6: (R)-tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidine) (2-yl)benzyl)piperazine-1-carboxylate (R)-tert-butyl 4-(2-pyrrolidine-2-yl)propanol in toluene (100 mL) (yl)benzyl)piperazine-1-carboxylate (2.55 g, 7.38 mmol) , 1-bromo-4-iodobenzene (3.13 g, 11.07 mmol), X-phos (703 mg, 1.48 mmol) and CsCO (4.81 g, 14.76 mmol) To the mixture of Pd(OAc)2 (166 mg, 738 umol) was added at 20°C. The mixture was purged with N2 three times and then heated to 105 °C for 10 h. This indicated that the reactants had been completely consumed. The reaction mixture was poured into ice water (50 mL) and The organic phase was separated, dried over anhydrous Na2SO4, filtered and concentrated. (R)- tert-Butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)benzoate (Dimethyl)piperazine-1-carboxylate (1.25 g) was obtained as an orange solid. It was. 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).

[0259] Step 7: (R)-1-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)benzoate Di)piperazine (R)-tert-butyl 4-(2- (1-(4-bromophenyl)pyrrolidin-2-yl)benzyl)piperazine-1-carboxamide A solution of carboxylate (1.25 g, 2.50 mmol) was stirred at 20° C. for 12 h. C / MS showed that the reactants were completely consumed and the desired compound was produced. The reaction mixture was concentrated. The residue was diluted with EA (50 mL). The organic phase was washed with saturated aqueous NaHCO3. The organic phase was dried over anhydrous Na2SO4 and washed with HCl (50 mL). Filtration and concentration were carried out. (R)-1-(2-(1-(4-bromophenyl)pyrrolidine-2- (Benzyl)piperazine (1 g, crude) was obtained as a yellow oil. MS (ESI, m / e)[M+1] + 400.2.

[0260] Step 8: (R)-1-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)benzoate (di)-4-methylpiperazine (R)-1-(2-(1-(4-bromophenyl)pyrrolidine) in DCE (50 mL) (2-yl)benzyl)piperazine (1 g, 2.50 mmol) and HCHO (374. A mixture of NaBH(OAc)3 (2.1 g, 10 m mol) was added portionwise at 20°C. The mixture was stirred at 20°C for 1 hour. This indicated that the reactants were completely consumed and the desired compound was produced. After filtration, the filtrate was concentrated. The crude product was purified by preparative HPLC (Phenomenex luna C18 250mm * 100mm * 10 μm; Mobile phase: [Water (0.1% TAF)-A The purified solution was concentrated. The aqueous phase was washed with saturated NaHCO3. The combined organic phase was washed with anhydrous Na2 Dried over SO4, filtered and concentrated. (R)-1-(2-(1-(4-bromophenyl )Pyrrolidin-2-yl)benzyl)-4-methylpiperazine (440 mg) is a yellow solid. was obtained as a body. 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=12.8Hz, 1H), 3.72(t,J=7.4 Hz, 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.

[0261] Intermediate 2-y: tert-butyl(R)-4-(2-(1-(4-bromophenyl)pyrrolidone) Lysin-2-yl)benzyl)piperidine-1-carboxylate [ka] Step 1: (E)-tert-butyl 4-((2-tosylhydrazono)methyl)piperidine -1-carboxylate tert-Butyl 4-formylpiperidine-1-carboxylate in EtOH (30 mL) methylpropane (1.75 g, 9.38 mmol) and 4-methylbenzenesulfonohydrazide ( A mixture of 2.0 g of methylcellulose (9.38 mmol) was stirred at 20°C for 15 hours. The reaction mixture was concentrated under reduced pressure. rt-Butyl 4-((2-tosylhydrazono)methyl)piperidine-1-carboxylate The compound (3.4 g, crude) was obtained as a colorless oil.

[0262] Step 2: (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetate) (I)pyrrolidin-2-yl)benzylidene)piperidine-1-carboxylate (R)-1-(2-(2-bromophenyl)pyrrolidine) in dioxane (100 mL) (E)-1-yl)-2,2,2-trifluoroethanone (3 g, 9.31 mmol), -tert-butyl 4-((2-tosylhydrazono)methyl)piperidine-1-carboxylate silane (5.33 g, 13.97 mmol) and t-BuOLi (2.98 g, 37. 24 mmol) at 20 °C. The mixture was purged with N2 three times and then heated to 100°C for 3 hours. The reaction mixture was heated to 25°C. TLC showed that the reactants were completely consumed. The mixture was concentrated under reduced pressure (approximately 20 mL). The residue was poured into ice water (30 mL) and diluted with EA (50 mL x 3). The combined organic phase was washed with brine (50 mL) and dried over anhydrous Na2SO4. The crude product was purified by column chromatography (silica gel, PE Purification was carried out using (R)-tert-butyl 4-(2- (1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzylidene)pi Peridine-1-carboxylate (2.17 g, 4.95 mmol, 53.08% yield) ) was obtained as a red oil. 1 H NMR (400 MHz, CDCl) δ ppm: 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.

[0263] Step 3: (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetate) 2-pyrrolidin-2-yl)benzyl)piperidine-1-carboxylate (R)-tert-butyl 4-(2-(1-(2,2,2- Trifluoroacetyl)pyrrolidin-2-yl)benzylidene)piperidine-1-carbo A solution of hydroxylate (2.3 g, 5.25 mmol) was added to Pd / C (300 mg, 10% wet The mixture was then purged with H2 three times and then heated at 20°C for 1 hour under 15 psi of H2. The mixture was stirred for 0 h. LC / MS showed complete consumption of the reactants and formation of the desired compound. The reaction mixture was filtered through Celite and washed with MeOH. (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetate) benzyl)pyrrolidin-2-yl)piperidine-1-carboxylate (2.3 g, Crude) was obtained as a brown solid. 1 H NMR (400 MHz, CDCL3) δpp m:7.07-7.23(m,3H), 6.86-6.98(m,1H), 5.34-5 .52(m,1H), 3.73-4.24(m,4H), 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).

[0264] Step 4: (R)-tert-butyl 4-(2-(pyrrolidin-2-yl)benzyl)piperazine Lysine-1-carboxylate (R)-tert-butyl 2-(2-methyl-1,2-dioxo-2,3-dioxane) in MeOH (10 mL), HO (10 mL), THF (10 mL) t-Butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl) (2.3 g, 5.22 mmol) of 1-benzyl piperidine-1-carboxylate To the solution was added LiOH.H2O (438.5 mg, 10.44 mmol) at 20°C. The mixture was heated to 50° C. for 1 hour. TLC showed that the reactants were completely consumed. The reaction mixture was concentrated under reduced pressure to remove MeOH and THF. The extract was extracted with EA (30 mL × 3). The combined organic phase was dried over anhydrous Na2SO4. The resulting mixture was filtered and concentrated. (R)-tert-butyl 4-(2-pyrrolidin-2-yl) (benzyl)piperidine-1-carboxylate (1.76 g, crude) was obtained as a yellow oil. MS(ESI, m / e)[M+1] + 345.2.

[0265] Step 5: (R)-tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidine) -2-yl)benzyl)piperidine-1-carboxylate (R)-tert-butyl 4-(2-pyrrolidin-2-yl)pyrrolidin-2-yl in toluene (50 mL) (1.4 g, 4.06 mmol), -Bromo-4-iodobenzene (1.72 g, 6.10 mmol), X-phos(38 A mixture of Cs2CO3 (2.64g, 8.12mmol) and Cs2CO3 (2.64g, 8.12mmol) To the solution was added Pd(OAc)2 (90 mg, 406 umol) at 20 °C. The mixture was then heated under N2 The mixture was purged with 0.5% CO₂ three times and then heated to 100°C for 5 hours. TLC showed that the reactants were complete. The reaction mixture was cooled to room temperature and poured into ice water (30 mL). The organic phase was then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel, eluent: PE / EA=100 / The product was purified by HPLC using a HPLC-MS / MS HPLC system (1-50 / 1). bromophenyl)pyrrolidin-2-yl)benzyl)piperidine-1-carboxylate ( 720 mg) was obtained as a yellow solid. 1 H NMR (400 MHz, 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,2 H).MS(ESI, m / e)[M+1] + 498.9.

[0266] Intermediate 2-z: (S)-N,N-dimethyl-2-(pyrrolidin-2-yl)aniline [ka] Step 1: (S)-tert-butyl 2-(2-((diphenylmethylene)amino)phenyl) (I)pyrrolidine-1-carboxylate (S)-tert-butyl 2-(2-bromophenoxyethanol) in 1,4-dioxane (50 mL) To a solution of di-(2-methyl-2-pyrrolidine-1-carboxylate (2.0 g, 6.13 mmol), Phenylmethanimine (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) was added. The mixture was heated under N2 protection. The mixture was stirred at 105°C for 36 hours. LC / MS revealed that the compound was (S)-tert-butyl 2-( The 2-bromophenyl)pyrrolidine-1-carboxylate was completely consumed and One major peak with the desired mass signal was observed. The mixture was evaporated under reduced pressure. The residue was used directly in the next step. MS (ESI, m / e) [M-1] - 427.2.

[0267] Step 2: (S)-tert-butyl 2-(2-aminophenyl)pyrrolidine-1-carbohydrate Xylates (S)-tert-butyl 2-(2-(diphenylmethylene)methyl)propanol in THF (5 mL) Amino)phenyl)pyrrolidine-1-carboxylate (262 mg, 613 umol, To a solution of 1 equivalent of HCl was added 10 mL of 0.5 N HCl acid. The mixture was stirred at 20°C overnight. TLC revealed that (S)-tert-butyl 2-(2-((diphenylmethylene)amine) It was shown that the (phenyl)pyrrolidine-1-carboxylate was completely consumed. The mixture was adjusted to pH 8 using saturated aqueous NaHCO3, and then washed with EA (20 ml). The organic phase was washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 10 / 1 to 1 / 1) and purified to obtain (S)-tert-butyl 2-(2-aminophenyl)pyrrolidine Din-1-carboxylate (50 mg) was obtained. 1H NMR (400 MHz, CDC) l3)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), 3.36-3.9 7(m,4H), 2.13-2.35(m,1H), 1.83-2.01(m,3H), 1.16-1.54(m,9H).

[0268] Step 3: (S)-tert-butyl 2-(2-(dimethylamino)phenyl)pyrrolidine -1-carboxylate (S)-tert-butyl 2-(2-aminophenyl)pyridinium chloride in MeOH (200 mL) A solution of loridine-1-carboxylate (6.5 g, 22.87 mmol) was added to HCl aqueous solution (37%, 11.14 g, 137.22 mmol) and NaH3CN (5.95 g (114.35 mmol) was added. The mixture was stirred at 20°C for 14 hours. (S)-tert-butyl 2-(2-aminophenyl)pyrrolidine-1-carboxylate The mixture was evaporated under reduced pressure. The residue was dissolved in DCM ( 100 mL), washed with brine, dried over Na2SO4 and concentrated. Column chromatography on silica gel (eluent: PE / EA = 100 / 1-30 Purification by HPLC (1999) was carried out to obtain (S)-tert-butyl 2-(2-(dimethylamino)phenyl)- To this, 5.9 g of methylpyrrolidine-1-carboxylate was obtained. 1 H NMR (400M Hz, CDCl3)δppm:6.93-7.15(m,4H), 5.12-5.37( m,1H), 3.36-3.69(m,2H), 2.60(s,6H), 2.20-2. 37(m,1H), 1.64-1.87(m,3H), 1.39(s,2H), 1.10 (s,6H).

[0269] Step 4: (S)—N,N-dimethyl-2-(pyrrolidin-2-yl)aniline (S)-tert-butyl 2-(2-(dimethylamino)phenyl)phenyl)propanol in DCM (30 mL) to a solution of (methyl)pyrrolidine-1-carboxylate (5.90 g, 20.32 mmol) Then, TFA (30 mL) was added. The mixture was stirred at 20° C. for 2 hours. TLC showed (S )-tert-butyl 2-(2-(dimethylamino)phenyl)pyrrolidine-1-carbo The mixture was poured into water and then into aqueous NaOH. The mixture was extracted with DCM (50 mL x 3) and adjusted to pH 10 with 2N dichloromethane. It was washed with brine and water, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. , (S)-N,N-dimethyl-2-(pyrrolidin-2-yl)aniline (3.248 g) obtained. 1 H NMR (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, 1 H), 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 .

[0270] Intermediate 2-z1: (S)-N,N-bis(methyl-d3)-2-(pyrrolidin-2-yl) ) Aniline [ka] Step 1: (S)-tert-butyl 2-(2-(d6-dimethylamino)phenyl)pyrrolidone Lysine-1-carboxylate (S)-tert-Butyl 2-(2-aminophenyl)pyrrolidine in DMF (20 mL) A solution of 1,2-diazine-1-carboxylate (6.5 g, 22.87 mmol) was added to the solution of NaH(45 7.4 mg, 11.44 mmol) and CD3I (2.21 g, 15.25 mmol) The mixture was added at 0° C. The mixture was stirred at 45° C. for 14 hours. TLC showed that (S)-tert- Butyl 2-(2-aminophenyl)pyrrolidine-1-carboxylate was completely consumed. The mixture was poured into water (50 mL), extracted with EA, and concentrated under reduced pressure to give tert-Butyl(S)-2-(2-(bis(methyl-d3)amino)phenyl)pyrrolyl The resulting zinzidine-1-carboxylate (880 mg) was used in the next step without further purification. was used. 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.

[0271] Step 2: (S)—N,N-bis(methyl-d3)-2-(pyrrolidin-2-yl)aniline hmm (S)-2-(2-(bis(methyl-d3)amino)phenyl)phenyl)-2-(2-(bis(methyl-d3)amino ... ) to a solution of pyrrolidine-1-carboxylate (275 mg, 927.68 umol), TFA (5 mL) was added and the mixture was stirred at 20°C for 2 hours. TLC showed that the reactants were Complete consumption was indicated. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by DC The mixture was dissolved in M (20 mL), washed with saturated aqueous Na2CO3 (20 mL), and then with Na2SO 4 and concentrated under reduced pressure to give (S)-N,N-bis(methyl-d3)-2-(pyrophorone). Lysin-2-yl)aniline (100 mg) was obtained. 1 H NMR (400 MHz, CD Cl3)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 .

[0272] Intermediate 2-z2: 2-((1-(2-cyclopropylphenyl)pyrrolidin-2-yl) Methyl)-2,6-diazaspiro[3.3]heptane [ka] Step 1: (1-(2-cyclopropylphenyl)pyrrolidin-2-yl)methanol 2-(((tert-butyldimethylsilyl)silane in MeOH / HCl (20 mL) at 20 °C (2-cyclopropyl)-1-(2-methyl-2-pyrrolidine) The mixture was stirred for 1 hour. TLC showed complete conversion of the reactants. The reaction mixture was concentrated to give (1-(2-cyclopropylphenyl)-2-methyl-2-propanol. To this was obtained (0.8 g, crude) (2-(2-methyl-1-pyrrolidin-2-yl)methanol. 1 H NMR(4 00MHz, 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.

[0273] Step 2: 1-(2-cyclopropylphenyl)pyrrolidine-2-carbaldehyde Dissolution of (COCl)2 (700.9 mg, 5.52 mmol) in DCM (20 mL) DMSO (862.93 mg, 11.04 mmol) was added dropwise to the solution at −65° C. The mixture was stirred at -65°C for 0.5 h. Then, (1-( 2-cyclopropylphenyl)pyrrolidin-2-yl)methanol (800.0 mg, 3 68) was added dropwise at -65°C. The mixture was further stirred at -65°C for 1 hour. LC showed that the reactants were completely consumed. The reaction mixture was added with TEA (2.8 9g, 29.45mmol) was added and the reaction mixture was warmed to 20°C over 0.5 hours. was poured into water, extracted with DCM, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 1- (2-Cyclopropylphenyl)pyrrolidine-2-carbaldehyde (1.2 g, crude) Got it. 1 H NMR (400MHz, CDCl3)δppm:12.10(s,1H), 9.39(d,J=3.8Hz, 1H), 7.06-7.16(m,1H), 6.85- 7.03(m,3H), 4.19(td,J=7.1, 3.9Hz, 1H), 3.86- 3.96(m,1H), 3.05-3.16(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).

[0274] Step 3: tert-Butyl 6-((1-(2-cyclopropylphenyl)pyrrolidine-2 -yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate 1-(2-cyclopropylphenyl)pyrrolidine-2-carba in DCM (10 mL) A solution of NaBH(OAc)3 (1.18 g, 5.57 mmol) was slowly added at 0°C. Azaspiro[3.3]heptane-2-carboxylate oxalate (803.46mg , 2.79 mmol) was added to the mixture at 0° C. The mixture was stirred at 20° C. for 1 hour. TLC showed that the reactants were completely consumed. The reaction mixture was poured into water and DC The mixture was extracted with M (10 mL) and concentrated under reduced pressure to give a residue. The mixture was purified by filtration (SiO2, PE / EA = 100 / 1 to 0 / 1). 6-((1-(2-cyclopropylphenyl)pyrrolidin-2-yl)methyl)-2-methyl ,6-diazaspiro[3.3]heptane-2-carboxylate (600 mg) was obtained. Ta. 1 H NMR (400MHz, CDCl3)δppm:7.07-7.14(m,1 H), 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.

[0275] Step 4: 2-((1-(2-cyclopropylphenyl)pyrrolidin-2-yl)methyl) -2,6-diazaspiro[3.3]heptane tert-Butyl 6-((1-(2-cyclopropylphenyl))) in DCM (8 mL) (pyrrolidin-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide To a solution of carboxylate (600 mg, 1.51 mmol) was added TFA (2 mL) at 20 °C. The mixture was stirred at 20°C for 1 hour. TLC showed that the reactants were completely consumed. The reaction mixture was concentrated to give 2-((1-(2-cyclopropylphenyl)pyridinium) (roridin-2-yl)methyl)-2,6-diazaspiro[3.3]heptane (326mg ) was obtained as a yellow oil.1 H NMR (400MHz, CDCl3)δppm:7.1 0(t,J=7.3Hz, 1H), 6.99-7.04(m,1H), 6.91(s,1 H), 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.

[0276] Intermediate 2-z3: (S)-4-(3-(2-(2-cyclopropylphenyl)pyrrolidine) -1-yl)cyclobutyl)piperidine [ka] Step 1: tert-Butyl 4-(2,2-dichloro-3-oxocyclobutyl)piperidinyl Benzene-1-carboxylate Under a N atmosphere, Zn (4.64 g, 70.99 mmol) in dioxane (50 mL) was dissolved in ) at 20°C. (5.0 g, 23.66 mmol) was added. Then, CCl3COCl (6.45 g, 3 5.49 mmol) was added at 20° C. The mixture was stirred at 20° C. for 12 hours. To the mixture was added aqueous NaHCO3 (50 mL) at 0 °C. Then, the mixture was diluted with EA (50 mL × 5), and the combined organic phases were dried over anhydrous Na2SO4 and concentrated. The resulting solution was purified by column chromatography (SiO2, PE / EA = 50 / 1 to 20 / 1). Purified tert-butyl 4-(2,2-dichloro-3-oxocyclobutyl)piperidin Din-1-carboxylate (3.0 g) was obtained. 1 H NMR (400 MHz, C DCl3)δppm:4.05-4.21(m,2H)3.04-3.27(m,2H) 2.77(br,2H)2.60(q,J=10.4Hz,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).

[0277] Step 2: tert-butyl 4-(3-oxocyclobutyl)piperidine-1-carboxy rate Under a N2 atmosphere, Zn (1.22 g) in HOAc (3.73 g, 62.07 mmol) To a mixture of 18.62 mmol) of tert-butyl 2-hydroxybenzoate in Diox (15 mL) at 15 °C, 4-(2,2-dichloro-3-oxocyclobutyl)piperidine-1-carboxylate (2.0 g, 6.21 mmol) was added and the mixture was stirred at 15°C for 12 hours. The mixture was adjusted to pH 9 using aqueous NaOH solution and extracted with EA (50 mL × 3). After drying and concentration, the residue was purified by column chromatography (SiO2, PE / EA Purification was carried out using a tert-butyl 4-(3-oxocyclobutene)-2-one (50 / 1 to 10 / 1) solvent. To this was obtained (1.0 g, 3.95 mmol) piperidine-1-carboxylate. 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).

[0278] Step 3: (S)-tert-butyl 4-(3-(2-(2-cyclopropylphenyl)phenyl)phenyl)-2-methyl-4-(2-cyclopropylphenyl)-2-methyl-4-methyl ... Roridin-1-yl)cyclobutyl)piperidine-1-carboxylate tert-Butyl 4-(3-oxocyclobutyl)piperidine in DCE (20 mL) (S)-2-(2-carboxylate) (0.7 g, 2.76 mmol, 1 equiv.) -cyclopropylphenyl)pyrrolidine (569.23 mg, 3.04 mmol) solution AcOH (331.86 mg, 5.53 mmol) and NaBH(OAc)3 (1. The mixture was stirred at 25°C for 1 hour. This indicated that the reactants were completely consumed. The mixture was quenched with EA (20 mL × 3), extracted with EA (20 mL × 3), dried over Na2SO4, and filtered. The residue was purified by preparative MPLC. -(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclobutyl) Piperidine-1-carboxylate (1.1 g) was obtained. MS (ESI, m / e) M+1] + 425.3.

[0279] Step 4: (S)-4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)- (butyl)cyclobutyl)piperidine (S)-tert-butyl 4-(3-(2H)-2H-pyridin-2-yl)propanol in DCM (5 mL) and TFA (5 mL) -(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclobutyl)piperidine- A mixture of 1-carboxylate (0.9 g, 2.12 mmol) was stirred at 25 °C for 1 h. LC / MS confirmed that the reactants were completely consumed and that the desired mass signals were present. One major peak was observed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by H The mixture was diluted with 20 (10 mL) and adjusted to pH 9 with saturated aqueous Na2CO3. The mixture was extracted with EA (10 mL x 3), dried over Na2SO4, filtered and concentrated. (S)-4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclopropyl) (tributyl)piperidine (643 mg) was obtained. 1 H NMR (400 MHz, CDC) l3)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,4H), 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 .

[0280] Intermediate 2-z4: 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl) (oxy)-1-methylpiperidine [ka] Step 1: tert-butyl 4-(2-formylphenoxy)piperidine-1-carboxy rate tert-Butyl 4-hydroxypiperidine-1-carboxamide in DMSO (150 mL) xylate (5.0 g, 24.84 mmol) and 2-fluorobenzaldehyde (6. A solution of 17 g, 49.69 mmol of K2CO3 (10.15 g, 74.53 mmol) l) was added. The mixture was stirred at 100°C for 6 hours. TLC showed that the reactants were completely consumed. The reaction mixture was cooled to room temperature, poured into H2O (50 mL), and EA ( The residue was extracted with 50 mL of ethyl acetate, dried over Na2SO4, filtered, and concentrated. The mixture was purified by column chromatography (SiO2, PE / EA = 20 / 1 to 10 / 1). , tert-butyl 4-(2-formylphenoxy)piperidine-1-carboxylate (6g) was obtained. MS (ESI, m / e) [M+1] + 306.1.

[0281] Step 2: (E)-tert-butyl 4-(2-(((4-bromophenyl)imino)methyl) (phenyl)phenoxy)piperidine-1-carboxylate tert-Butyl 4-(2-formylphenoxy)piperidinyl in toluene (43 mL) 4-bromoaniline ( 2.42g, 14.08mmol), TsOH (133.93mg, 0.7mmol) and A mixture of 4 Å molecular sieves (2.15 g) and 4 Å molecular sieves (2.15 g) was stirred at 140° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give crude (E)-tert -butyl 4-(2-(((4-bromophenyl)imino)methyl)phenoxy)piperidinyl The amine-1-carboxylate (7.5 g, crude) was obtained and used directly in the next step. .

[0282] Step 3: tert-butyl 4-(2-(1-((4-bromophenyl)amino)buta-3 -en-1-yl)phenoxy)piperidine-1-carboxylate (E)-tert-butyl 4-(2-(((4-bromophenytoin)) in DCM (50 mL) (Imino)methyl)phenoxy)piperidine-1-carboxylate (5.7 g) To the solution, allylmagnesium bromide (49.63 mL, 1 M in THF) was added dropwise at 0°C. The mixture was stirred at 0-15°C for 3 hours. TLC showed that the reaction was complete. The reaction mixture was poured into aqueous HN4Cl (50 mL) and extracted with EA (50 mL × 2). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. The residue was purified by column chromatography on silica gel (eluent). The resulting product was purified using a solvent (PE / EA = 50 / 1 to 20 / 1) to give tert-butyl 4-(2 -(1-((4-bromophenyl)amino)but-3-en-1-yl)phenoxy)pi Peridine-1-carboxylate (4.2 g) was obtained. MS (ESI, m / e) [M+1 ] + 502.2.

[0283] Step 4: tert-Butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybenzoate Hydroxybutyl)phenoxy)piperidine-1-carboxylate tert-Butyl 4-(2-(1-((4-bromophenyl)))-2-methyl-2-propanol in THF (50 mL) Amino)but-3-en-1-yl)phenoxy)piperidine-1-carboxylate ( To a solution of BH3.THF (65.8 mL, THF) at 0 °C The mixture was stirred at 0 °C for 3 h, and then H2O2 (6.58 m L, 65.81 mmol) was added dropwise and stirred at 0°C for 1 hour. 0.63g, 65.81mmol, 4M) was added dropwise and stirred at 0-15°C for 2 hours. TLC showed the reaction was complete. The mixture was washed with saturated aqueous NaSO (5 The mixture was poured into EA (100 mL × 2), stirred for 0.5 h, and extracted with EA (100 mL × 2). The organic layer was washed with saturated aqueous Na2S2O3 (50 mL), aqueous NaHCO3 (50 mL) and and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EA = 5 / 1 to 2 / 1). and purified to give tert-butyl 4-(2-(1-((4-bromophenyl)amino)-4 (Hydroxybutyl)phenoxy)piperidine-1-carboxylate (2.4 g) was obtained. MS (ESI, m / e) [M+1] + 520.3.

[0284] Step 5: tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)methyl)pyrrolidin-2-yl (phenyl)phenoxy)piperidine-1-carboxylate tert-Butyl 4-(2-(1-((4-bromophenyl)))-2-methyl-2-propanol in DCM (23 mL) Amino)-4-hydroxybutyl)phenoxy)piperidine-1-carboxylate(2 to a mixture of 1.34g (4.43mmol) and TEA (1.34g, 13.28mmol) MsCl (1.01 mg, 8.86 mmol) was added at 0°C, and the mixture was incubated at 25°C for 5 h. The reaction mixture was stirred. TLC showed the reaction was complete. The combined organic layer was poured into brine (20 mL) and extracted with DCM (20 mL x 2). L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was evaporated on silica By column chromatography on gel (eluent: PE / EA = 10 / 1 to 2 / 1), and purified to give tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidine-2-yl)methyl)-2-methyl-4-pyrrolidine-2-yl. (-yl)phenoxy)piperidine-1-carboxylate was obtained. MS (ESI, m / e )[M+1] + 502.2.

[0285] Step 6: 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenoxy) Piperidine tert-Butyl 4-(2-(1-(4-bromophenyl)phenyl)-2-pyridinyl)- ...pyridinyl)-4-pyridinyl Roridin-2-yl)phenoxy)piperidine-1-carboxylate (1.8 g, 3. To the mixture (59 mmol), TFA (7 mL) was added and stirred at 15° C. for 3 hours. The reaction was completed by HCl. The mixture was concentrated under reduced pressure to give 4-(2-(1- (4-bromophenyl)pyrrolidin-2-yl)phenoxy)piperidine (1.8 g, T FA salt, crude) was obtained. MS (ESI, m / e) [M+1] + 402.2.

[0286] Step 7: 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenoxy) -1-Methylpiperidine 4-(2-(1-(4-bromophenyl)pyrrolidine-2-yl)methyl)-2-(4-bromophenyl ... A solution of (methyl)phenoxy)piperidine (1.0 g, 2.49 mmol) in aqueous HCl solution (37%, 1.01 g, 12.46 mmol) and NaBH3CN (496.74 mg , 4.47 mmol) was added and stirred at 15°C for 3 hours. The reaction was complete by TLC. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in saturated aqueous NaHCO3 (20 The combined organic layer was poured into Na2SO4 The mixture was dried over ice, filtered, and concentrated. The residue was purified by column chromatography on silica gel. (Eluent: PE / EA = 1 / 1 to 1 / 10) to give 4-(2-(1-(4- Bromophenyl)pyrrolidin-2-yl)phenoxy)-1-methylpiperidine was obtained. 1 H 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(1 H, d, J=7.9Hz)4.60(1H,s)3.63-3.70(m,1H)3.3 2-3.41(m,1H)2.64-2.87(m,4H)2.46(s,3H)2.2 9-2.40(m,1H)2.14-2.24(m,2H)1.92-2.10(m,5 H).MS(ESI, m / e)[M+1] + 415.1.

[0287] Intermediate 2-z5: (S)-2-((2-(2-cyclopropylphenyl)pyrrolidine-1 -yl)methyl)-7-azaspiro[3.5]nonane [ka] Step 1: tert-butyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane -7-carboxylate (Methoxymethyl)triphenylphosphonium chloride (3 To a solution of t-BuOK (1 M in THF, 10.86 mmol) was added L, 10.86 mmol) was added. The mixture was stirred under N2 protection at 25 °C for 20 min. Next, tert-butyl 2-oxo-7-azaspiro[3 .5]nonane-7-carboxylate (2 g, 8.36 mmol) was added. The mixture was The mixture was stirred at 0° C. for 4 hours. TLC showed that the reactants were completely consumed. The mixture was quenched with aqueous NH4Cl (30 mL) and extracted with EA (50 mL × 3). The residue was purified by preparative MPLC. Prepared by tert-butyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane -7-carboxylate (1.2 g) was obtained. MS (ESI, m / e) [M+1] + 26 8.3.

[0288] Step 2: tert-Butyl 2-formyl-7-azaspiro[3.5]nonane-7-carbohydrate Xylates tert-Butylisothiazolinone in ACN (36 mL), HO (9 mL) and TFA (0.3 mL) 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate The mixture (1 g, 3.74 mmol) was stirred at 25° C. for 4 hours. The reaction mixture was diluted with aqueous NaHCO3 (20 mL). The mixture was quenched with EA (20 mL × 3), extracted with EA, dried over Na2SO4, filtered, and The mixture was concentrated under reduced pressure. The residue was purified by preparative MPLC. Fluoryl-7-azaspiro[3.5]nonane-7-carboxylate (390 mg) was obtained. It was. 1 H NMR (400MHz, CDCl3)δppm:9.76(d,J=1.5 Hz, 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).

[0289] Step 3: (S)-tert-butyl 2-((2-(2-cyclopropylphenyl)pyrrolidine) Zin-1-yl)methyl)-7-azaspiro[3.5]nonane-7-carboxylate tert-Butyl 2-formyl-7-azaspiro[3.5]nona in DCE (5 mL) Benzene-7-carboxylate (0.3 g, 1.18 mmol) and (S)-2-(2-cyclohexyl)- to a solution of (184.81 mg, 986.83 umol) , AcOH (118.52 mg, 1.97 mmol) and NaBH(OAc)3 (418 The mixture was stirred at 25°C for 2 hours. The reaction mixture was washed with an aqueous solution of Na2CO3 (5 mL), extracted with EA (5 mL x 3), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative MPLC. (S)-tert-butyl 2-((2- (2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-7-azaspiro[3 .5]nonane-7-carboxylate (300 mg, 0.7 mmol, 59.66% yield) MS (ESI, m / e) [M+1] + 425.3.

[0290] Step 4: (S)-2-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl) Methyl)-7-azaspiro[3.5]nonane (S)-tert-Butyl 2-( (2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-7-azaspipri A mixture of 2-[3.5]nonane-7-carboxylate (0.3 g, 0.7 mmol) The mixture was stirred at 5° C. for 1 hour. LC / MS showed complete consumption of the reactants and the desired quality. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (10 mL) and adjusted to pH 9 with Na2CO3. The mixture was extracted with EA (10 mL × 3), dried over Na2SO4, filtered, and concentrated. (S)-2-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)methyl ethyl)-7-azaspiro[3.5]nonane (180 mg) was obtained. 1 H NMR(4 00MHz, 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=7.1 Hz, 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), 2.5 8(dd,J=8.0, 11.8Hz, 1H), 2.41(td,J=7.8, 15.3 Hz, 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,2 H), 1.44-1.31(m,2H), 0.98-0.85(m,2H), 0.77- 0.67(m,1H), 0.66-0.55(m,1H).MS(ESI, m / e)[M +1] + 325.3.

[0291] Intermediate 2-z6: 1-(2-cyclopropylphenyl)-1,9-diazaspiro[5.5 ]Undecane [ka] Step 1: tert-Butyl 4-(but-3-en-1-yl)-4-((2-cyclopropyl) (Phenyl)amino)piperidine-1-carboxylate tert-Butyl 4-((2-cyclopropylphenyl)imide) in DCM (50 mL) (n) A solution of piperidine-1-carboxylate (5 g, 15.90 mmol) was added to -20 But-3-en-1-yl magnesium bromide (0.5 M, 159 mL, 79.5 °C) 1 mmol) was added. The mixture was stirred at -20°C for 2 hours. TLC showed that the reactants were complete. The reaction mixture was quenched with aqueous HN4Cl (100 mL). The mixture was cooled, extracted with DCM (100 mL × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative MPLC and then tert-butyl 4-(but-3-ene- 1-yl)-4-((2-cyclopropylphenyl)amino)piperidine-1-carboxamide The sylate (2.5 g) was obtained as a yellow oil. MS (ESI, m / e) [M+1] + 371.3.

[0292] Step 2: tert-butyl 4-((2-cyclopropylphenyl)amino)-4-(4- Hydroxybutyl)piperidine-1-carboxylate tert-Butyl 4-(but-3-en-1-yl)-4-( (2-cyclopropylphenyl)amino)piperidine-1-carboxylate (2.5g , 6.75 mmol) at 0 °C, BH3.THF (1 M, 33.74 mL, 33. 74 mmol) was added. 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) was added at 0° C. The mixture was stirred at 25° C. for 2 hours. The reaction mixture was diluted with aqueous NaSO (100 mL). Pour into ethanol, extract with EA (100 mL × 3), dry over Na2SO4, filter, and concentrate. The residue was purified by preparative MPLC and then tert-butyl 4-((2-cyclopropyl)- (4-(4-hydroxybutyl)piperidine-1-carboxylate The ester (1.2 g) was obtained. 1 H NMR (400 MHz, CDCl) δ ppm: 7 .09(d,J=7.5Hz, 1H), 7.07-7.01(m,1H), 6.74(d ,J=7.9Hz, 1H), 6.61(t,J=7.4Hz, 1H), 3.95(s,1 H), 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=11.7 Hz, 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).

[0293] Step 3: tert-Butyl 1-(2-cyclopropylphenyl)-1,9-diazaspiro [5.5]Undecane-9-carboxylate tert in DCM (10 mL) and TEA (520.87 mg, 5.51 mmol) -butyl 4-((2-cyclopropylphenyl)amino)-4-(4-hydroxybutyl ) A solution of piperidine-1-carboxylate (1 g, 2.57 mmol) was added to Ms Cl (294.82 mg, 2.57 mmol) was added and the mixture was stirred at 25° C. for 2 h. TLC showed that the reactants were completely consumed. The reaction mixture was diluted with HN4Cl Quenched with aqueous solution (10 mL), extracted with DCM (10 mL x 3), and washed with Na2SO4 The residue was dried, filtered and concentrated. The residue was purified by preparative MPLC and then purified by tert-butyl ether. 1-(2-cyclopropylphenyl)-1,9-diazaspiro[5.5]undecane The 9-carboxylate (0.7 g) was obtained as a yellow oil. MS (ESI, m / e) [M+1] + 371.4.

[0294] Step 4: 1-(2-cyclopropylphenyl)-1,9-diazaspiro[5.5]undecane Can tert-Butyl 1-(2-cyclopropyl)propanol in DCM (4 mL) and TFA (4 mL) phenyl)-1,9-diazaspiro[5.5]undecane-9-carboxylate(0 A mixture of 1.7 g (1.89 mmol) of 1,000 sachets ... The reagent was completely consumed and one major peak with the desired mass signal was observed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (10 mL). The pH was adjusted to about 9 using Na2CO3. Then, the mixture was diluted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over Na2CO3, filtered, and Concentration affords 1-(2-cyclopropylphenyl)-1,9-diazaspiro[5.5]un Decane (452 mg) was obtained. 1 H NMR (400 MHz, CDCl) δ ppm: 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, 3 H), 0.94(dd,J=1.8, 8.6Hz, 2H), 0.75-0.66(m,1 H), 0.61-0.54(m,1H).MS(ESI, m / e)[M+1] + 271. 4.

[0295] Intermediate 2-z7: 5-(2-cyclopropylphenyl)-N,N-dimethylpyrrolidine- 3-Amine [ka] Step 1: 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyridine Roridin-3-one 1-(tert-butylsulfonyl)-5-(2-cyclopropyl)-2-propanol in DCM (50 mL) (pyrphenyl)pyrrolidin-3-ol (5.0 g, 15.46 mmol), DMP (8 A mixture of NaHCO3 (1.43g, 17.0mmol) and NaHCO3 (1.52g, 20.1mmol) The mixture was stirred at 20°C for 3 hours. TLC showed that the reaction was complete. The mixture was quenched with Na2S2O3 (20 mL) and then diluted with aqueous Na2CO3. The mixture was extracted with DCM (50 mL × 3) and then combined. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography. After purification by filtration (SiO2, PE / EA = 50 / 1 to 15 / 1), 1-( tert-Butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidine-3- The compound (3.5 g) was obtained. 1 H NMR (400 MHz, CDCl) δ ppm: 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=18.7H z, 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).

[0296] Step 2: 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)- N,N-Dimethylpyrrolidin-3-amine 1-(tert-butylsulfonyl)-5-(2-cyclopropyl)-2-propanol in DCE (40 mL) (3.5g, 10.89mmol), dimethylamine To a mixture of benzophenone hydrochloride (3.55 g, 43.55 mmol), NaBH(OAc)3 (6. The mixture was stirred under N2 atmosphere at 20°C for 2 hours. The mixture was concentrated and purified by preparative HPLC. (TFA conditions). (chloropropylphenyl)-N,N-dimethylpyrrolidin-3-amine (2.2 g, 6.2 8 mmol, 57.64% yield). MS (ESI, m / e) [M+1]+ 3 51.3.

[0297] Step 3: 5-(2-cyclopropylphenyl)-N,N-dimethylpyrrolidine-3-amine hmm 1-(tert-butylsulfonyl)-5-(2-cyclopropyl)-2-propanol in TFA (10 mL) (pyrphenyl)-N,N-dimethylpyrrolidin-3-amine (1.0 g, 2.85 mmol) The mixture of l) was stirred at 70°C for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated and adjusted to pH 10 with saturated aqueous Na2CO3 (10 mL). The mixture was extracted with EA (10 mL × 5), and the combined organic layers were washed with anhydrous NaSO 4 and then concentrated. The obtained product was pyrrolidin-3-amine (170 mg). 1 H NMR (400 MHz, C DCl3)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), 3.0 7-3.42(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, 9.8H z, 1H), 0.89-0.98(m,2H), 0.62-0.76(m,1H).MS (ESI, m / e)[M+1] + 231.3.

[0298] Intermediate 2-z8: tert-butyl (R)-4-(2-(1-(4-bromophenyl)phenyl)phenyl)-4-(2-(1-(4-bromo ... Roridin-2-yl)phenyl)piperidine-1-carboxylate [ka] Step 1: (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetate) (2H)-pyrrolidin-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-chlor Boxylate (R)-1-(2-bromo-2-methylpropional) in toluene (100 mL) and HO (5 mL) (phenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethanone (8g, 24.8 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-diol), (Xaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (11.5g, 37.2mmol), Pd(OAc)2(560mg, 2.48mmol ), tricyclohexylphosphine (1.4 g, 4.96 mmol) and K3PO4 (1 A mixture of 5.8 g, 74.4 mmol, 3.0 equiv. of HCl was heated to 100 °C under N2 protection. The mixture was stirred for 5 hours. TLC showed the reaction was complete. The mixture was cooled to room temperature. The mixture was diluted with EA (50 mL), washed with water (100 mL), brine (100 mL), and The residue was purified by column chromatography on silica gel. (eluent: PE / EA=5 / 1 to 2 / 1) to obtain (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl) (2H)-5,6-dihydropyridine-1(2H)-carboxylate (9 g, crude) was added to a brown MS (ESI, m / e) [M+1] + 425.2.

[0299] Step 2: (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetate) (phenyl)pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate (R)-tert-butyl 4-(2-(1-(2,2, 2-Trifluoroacetyl)pyrrolidin-2-yl)phenyl)-5,6-dihydropyridine Diazin-1(2H)-carboxylate (9 g, 21.2 mmol) and Pd / C (10% , 2 g) was stirred at 20 °C under H atmosphere (15 psi) for 12 h. LC / MS showed the reaction was complete. The mixture was filtered and the filtrate was concentrated. (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl) )pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate (7.5 g, crude (manufactured by Sigma-Aldrich) was obtained as an off-white solid. MS (ESI, m / e) [M+1] + 427.3 .

[0300] Step 3: (R)-tert-butyl 4-(2-(pyrrolidin-2-yl)phenyl)piperazine Lysine-1-carboxylate (R)-tert-butyl 4-(2-(1-(2,2,2)- -trifluoroacetyl)pyrrolidin-2-yl)phenyl)piperidine-1-carboxamide A solution of silane (7.5 g, 17.6 mmol) in HO (30 mL) was added to the solution of NaOH ( A solution of 2.8 g (70.4 mmol) of HCl was added. The mixture was then heated to 40° C. and stirred for 2 h. The mixture was concentrated under reduced pressure to give a 100% aqueous solution of 1,2-dichloro-2,3-dichloro-2,4-dichloro-2,5 ... The organic solvent was removed and the remaining aqueous solution was extracted with EA (100 mL). The organic layer was washed with brine (10 0 mL), dried over Na2SO4, and concentrated to give (R)-tert-butyl 4 -(2-(pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate (6g , crude). MS (ESI, m / e) [M+1] + 331.3.

[0301] Step 4: (R)-tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidine) -2-yl)phenyl)piperidine-1-carboxylate (R)-tert-butyl 4-(2-pyrrolidin-2-yl)pyrrolidin-2-yl in toluene (20 mL) (phenyl)phenyl)piperidine-1-carboxylate (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-Bu A mixture of OK (1.4 g, 12.2 mmol) was heated to 100 °C under N2 protection, and 12 The mixture was stirred for 1 hour. 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), brine (20 mL), and added Na2SO4 The mixture was dried over ice and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel. (Eluent: PE / EA = 20 / 1 to 15 / 1) to obtain (R)-tert-Br 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)piperidine Din-1-carboxylate (2 g) was obtained. 1 H NMR (400 MHz, CDCl )δppm:7.29(1H, s), 7.22-7.26(1H, m), 7.18-7. 22(2H, m), 7.01-7.12(2H, m), 6.23-6.31(2H, m) , 4.91 (1H, d, J=6.8Hz), 4.31 (2H, s), 3.65-3.75 (1H, m), 3.35-3.47(1H, m), 2.95-3.07(1H, m), 2 .82(2H, s), 2.41-2.55(1H, m), 1.97-2.10(2H, m ), 1.79-1.93(3H, m), 1.61-1.74(2H, m), 1.51(9 H, s).MS(ESI, m / e)[M+1] + 487.8.

[0302] Intermediate 2-z9: 1-(azetidin-3-yl)-2-(2-cyclopropylphenyl) Pyrrolidine [ka] Step 1: tert-butyl 3-(2-(2-cyclopropylphenyl)pyrrolidine-1- yl)azetidine-1-carboxylate 2-(2-cyclopropylphenyl)pyrrolidine (700 mg) in DCM (10 mL) , 3.7 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (632 mg, 3.7 mmol) was added to a solution of NaBH(OAc)3 (600 mg, 3 mmol). The mixture was stirred at room temperature for 14 hours. Then, saturated aqueous NH4Cl (30 mL) was added to the reaction mixture with stirring. The organic phase was separated and washed with brine (10 mL). The mixture was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1 g of crude product. ESI, m / e)[M+1] + 343.0.

[0303] Step 2: 1-(azetidin-3-yl)-2-(2-cyclopropylphenyl)pyrrolidine hmm tert-Butyl 3-(2-(2-cyclopropylphenyl)methyl)-2-(2-cyclopropylphenyl ... Pyrrolidin-1-yl)azetidine-1-carboxylate (680 mg, 2.0 mmol) To the solution of l) was added TFA (2 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed. 700 mg of 1-(azetidin-3-yl)-2-(2-cyclopropylphenyl) ) pyrrolidine was obtained. MS (ESI, m / e) [M+1] + 243.0.

[0304] Intermediate 2-z10: 6-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl )Methyl)-2-azaspiro[3.3]heptane Step 1: tert-Butyl 6-(methoxymethylene)-2-azaspiro[3.3]hepta Benzene-2-carboxylate tert-Butyl 6-oxo-2-azaspiro[3.3]heptane in toluene (50 mL) A solution of 2-butyl-2-carboxylate (3 g, 0.014 mol) was added to t-BuOK (2 The mixture was stirred under N2 atmosphere at 25°C for 20 minutes. Next, (methoxymethyl)triphenylphosphonium nitrite in toluene (20 mL) was added. Chloride (6.2 g, 0.018 mol) was added, and the mixture was stirred at 70° C. for 4 hours. TLC showed the reaction was complete. After removing the solvent, the residue was purified by silica gel column chromatography. The product was purified by column chromatography (eluent: PE / EA=20 / 1) to give te rt-Butyl 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate The carboxylate (1 g) was obtained. 1 H NMR (400 MHz, CDCl) δ ppm: 5 .81(s,1H), 3.86-4.00(s,4H), 3.55(s,3H), 2.8 6(s, 2H), 2.79(s, 2H), 1.43(s,9H).

[0305] Step 2: tert-Butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate Boxylate tert-Butyl 6-(methoxymethyl)-2-methylpropional in CH3CN (36 mL) and H2O (9 mL) ethylene)-2-azaspiro[3.3]heptane-2-carboxylate (1g, 4.18 To a solution of 1 mmol) TFA (1 mL) was added and the mixture was then stirred at room temperature for 2 hours. LC showed the reaction was complete. The reaction mixture was purified with aqueous Na2CO3. The pH was adjusted to 8-9 and extracted with EA (20 mL × 3). Washed with tert-butyl 6-formyl-2-azaspirillum, dried, filtered and concentrated to give tert-butyl 6-formyl-2-azaspirillum. 2[3.3]heptane-2-carboxylate (0.9 g) was obtained, which was further purified It was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ ppm: 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).

[0306] Step 3: tert-Butyl 6-((2-(2-cyclopropylphenyl)pyrrolidine-1 -yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylate tert-Butyl 6-formyl-2-azaspiro[3.3]heptane in DCE (30 mL) To a solution of 2-(2-cyclohexyl)-2-butanecarboxylate (0.9 g, 4.0 mmol), (43-Dimethylpropylphenyl)pyrrolidine (0.68 g, 3.63 mmol) and HOAc (43 6 mg, 7.26 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then NaBH( OAc)3 (1.54 g, 7.26 mmol) was added, followed by stirring for an additional 2 h. MS indicated the reaction was complete. The reaction was diluted with aqueous Na2CO3 (10 ml The mixture was quenched with EA (3×50 mL) and then extracted with EA (3×50 mL). The organic layer was dried, filtered, and The residue was purified by column chromatography on silica gel (eluent: PE / EA=2 / 1) and purified by tert-butyl 6-((2-(2-cyclopropylphenyl) Pyrrolidin-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxy The yield was 0.8 g. MS (ESI, m / e) [M+1] + 397.3.

[0307] Step 4: 6-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl) -2-Azaspiro[3.3]heptane tert-Butyl 6-((2-(2-cyclopropylphenyl)methyl ... )pyrrolidin-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxamide To a solution of silane (0.8 g, 2.0 mmol), TFA (10 mL) was added dropwise at 0°C. The mixture was then stirred at room temperature for 2 hours. TLC showed that the reaction was complete. The reaction mixture was adjusted to pH 8-9 with aqueous Na2CO3, and then diluted with DCM. The organic layer was dried, filtered, and concentrated to give 6-((2-(2-cyclopropylphenyl)methylpropional. (phenyl)pyrrolidin-1-yl)methyl)-2-azaspiro[3.3]heptane (250 mg) was obtained. 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.

[0308] Intermediate 2-z11: 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1. 0]Hexane [ka] Step 1: tert-butyl 2-(2-cyclopropylphenyl)-4-(tosyloxy) Pyrrolidine-1-carboxylate tert-Butyl 2-(2-cyclopropylphenyl)-4- To a solution of hydroxypyrrolidine-1-carboxylate (4.5 g, 14.8 mmol) NaH (0.71 g, 17.8 mmol) was added and the mixture was stirred at 20° C. for 30 min. Next, TosCl (3.4 g, 17.8 mmol) was added to the mixture, and the mixture was heated at 20°C for 12 hours. The reaction mixture was stirred for an additional 2 hours. TLC showed that the reaction was complete. The mixture was quenched with EA (100 mL) and extracted with EA (100 mL). The organic layer was washed with brine (100 mL). The residue was purified by column chromatography on silica gel. The product was purified by chromatography (eluent: PE / EA = 10 / 1 to 5 / 1) to obtain tertiary t-Butyl 2-(2-cyclopropylphenyl)-4-(tosyloxy)pyrrolidine-1 -carboxylate (2.9 g). MS (ESI, m / e) [M+1] + 458. 2.

[0309] Step 2: tert-Butyl 2-(2-cyclopropylphenyl)-2,3-dihydro-1 H-pyrrole-1-carboxylate tert-Butyl 2-(2-cyclopropylphenyl)-4- (Tosyloxy)pyrrolidine-1-carboxylate (2.9 g, 6.3 mmol) To the solution, t-BuOK (1.4 g, 12.6 mmol) was added little by little. After the addition, the mixture The mixture was stirred at 20° C. for 12 hours. TLC showed that the reaction was complete. The mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EA (50 mL). The layer was washed with brine (50 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography. Purification by column chromatography on gel (eluent: PE / EA=100 / 1) tert-Butyl 2-(2-cyclopropylphenyl)-2,3-dihydro-1H -pyrrole-1-carboxylate (900 mg) was obtained. MS (ESI, m / e) [M +1] + 286.4.

[0310] Step 3: tert-Butyl 3-(2-cyclopropylphenyl)-2-azabicyclo[3 .1.0]hexane-2-carboxylate tert-Butyl 2-(2-cyclopropylphenyl)- ... )-2,3-dihydro-1H-pyrrole-1-carboxylate (900 mg, 3.2 m To a solution of EtZn (1M in toluene, 15.8 mL, 15.8 mmol) and and ClCHI (5.56 g, 32 mmol) were added. The mixture was then heated at 20°C for 4 h. The reaction mixture was stirred. TLC showed the reaction was complete. The reaction mixture was diluted with saturated NH The mixture was quenched with 1H2O (20 mL) and extracted with EA (30 mL × 2). The residue was washed with 20 mL of HCl, dried over NaSO, and concentrated. Purification by column chromatography (eluent: PE / EA=30 / 1) gave ter t-Butyl 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexadecyl 500 mg of benzo-2-carboxylate was obtained. MS (ESI, m / e) [M+1] + 300.2.

[0311] Step 4: 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexa hmm tert-Butyl 3-(2-cyclopropylphenyl)propanediol in HCl (4 M, 10 mL) in EA (phenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (500m g, 1.7 mmol) was stirred at 20° C. for 2 hours. The reaction was complete by TLC. The mixture was quenched with saturated aqueous Na2CO3 (20 mL) and EA ( The organic layer was washed with brine (20 mL) and dried over Na2SO4. and concentrated to give 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0 ]Hexane (293 mg) was obtained. 1 H NMR (400 MHz, CDCl) δ ppm :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), 0.77-0.84( 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.

[0312] Intermediate 2-z12: 1-(2-cyclopropylphenyl)octahydrocyclopenta[c ]pyrrole [ka] Step 1: 3-(2-cyclopropylphenyl)hexahydrocyclopenta[c]pyrrole -1(2H)-On 1-Bromo-2-cyclopropylbenzene (8.5 g, 0.0 A solution of n-BuLi (21 mL, 0.05 mol) was added to the solution at -78 °C under N2 atmosphere. 2 mol, 2.5 M in hexane) was added, and the mixture was then stirred at -78°C for 1 hour. Tetrahydrocyclopenta[c]pyrrole-1,3(2H,3a) in THF (20 mL) A solution of 4 g of 1H-dione (0.029 mol) was heated at -78 °C under a N atmosphere. uLi (13 mL, 0.035 mol, 2.5 M in hexane) was added. The mixture was then The mixture was stirred at 0° C. for 1 hour. The solution formed from 1-bromo-2-cyclopropylbenzene was , tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dihydropyrrole at -78 °C The resulting mixture was stirred at room temperature for 3 hours. C, tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione It was shown that NaBH3CN (2.2 g, 0.035 mol) was added to the mixture. After adding the mixture to the flask, 6N HCl acid (20 mL) was added at 0°C, and the mixture was further stirred at room temperature for 1 hour. Na2CO3 (50 mL) was added to the mixture to adjust the pH to 8-9. The mixture was extracted with EA (50 mL x 3), and the organic layer was washed with brine (50 mL x 2). The combined organic layer was dried, filtered, and concentrated. The residue was purified by column chromatography on silica gel. The product was purified by chromatography (eluent: PE / EA=10 / 1) to give 3-(2-cyclopropyl phenyl)hexahydrocyclopenta[c]pyrrol-1(2H)-one (2.8g) obtained. 1 H NMR (400MHz, CDCl3)δppm:7.19-7.23(m ,1H), 7.11-7.16(m,2H), 6.95-7.01(m,1H), 6.2 0(s,1H), 5.44(d,J=7.7Hz, 1H), 3.08-3.24(m,1 H), 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,1 H), 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] + 2 42.3.

[0313] Step 2: 1-(2-cyclopropylphenyl)octahydrocyclopenta[c]pyrrole 3-(2-cyclopropylphenyl)hexahydrocyclopene in THF (20 mL) To a solution of ta[c]pyrrol-1(2H)-one (1.0 g, 4.15 mmol, 1 equiv.) , BH3.DMS (4.2 mL, 41.5 mmol, 10 equiv., 10 M in DMS) at 0 °C After the addition, the mixture was stirred at room temperature for 12 hours. At 0° C., MeOH (2 mL) and 1 N HCl (20 mL) were added. mL) was carefully added to the reaction mixture. The mixture was then stirred at room temperature for 1 hour. The mixture was quenched with aqueous Na2CO3 (50 mL) and adjusted to pH 9. The organic layer was washed with brine (50 mL x 2), dried, and filtered. The residue was purified by column chromatography on silica gel (eluent: PE / EA=5 Purification by HPLC (HPLC: 1000 mg / 1000 sq. ml) gave the target product (300 mg). 1 H NMR (400M Hz, 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(q uin,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.

[0314] Intermediate 2-z13: 2-((5-(2-cyclopropylphenyl)pyrrolidin-3-yl )Oxy)-N,N-dimethylethan-1-amine [ka] Step 1: 2-((1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)- N,N-dimethylacetamide 1-(tert-butylsulfonyl)-5-(2-cyclopropyl)-2-isopropyl ether in DMF (250 mL) to a solution of (propylphenyl)pyrrolidin-3-ol (10.5 g, 32.46 mmol) Then, NaH (1.43 g, 35.71 mmol, 60%) was added in portions at 10°C. The mixture was stirred at 10°C for 30 minutes. Then, 2-chloro-N,N-dimethylacetamide (4 The mixture was stirred at 10°C for 2 hours. The reaction mixture was stirred. TLC showed that the reactants were completely consumed. It was quenched with aqueous NH4Cl (50 mL) and extracted with EA (100 mL x 3). The combined organic phase was washed with brine (50 mL × 2), dried over anhydrous Na2SO4, and The residue was purified by column chromatography (SiO2, PE / EA=5 / 1-0 / 1) and purified by 2-((1-(tert-butylsulfonyl)-5-(2 -Cyclopropylphenyl)pyrrolidin-3-yl)oxy)-N,N-dimethylacetoacetate The amide (8.48 g) was obtained. MS (ESI, m / e) [M+1] + 410.1.

[0315] Step 2: 2-((5-(2-cyclopropylphenyl)pyrrolidin-3-yl)oxy) -N,N-dimethylacetamide 2-((1-(tert-butylsulfonyl)-5-(2- Cyclopropylphenyl)pyrrolidin-3-yl)oxy)-N,N-dimethylacetate A solution of amide (8.4 g, 20.56 mmol) was stirred at 75° C. for 12 hours. LC / MS indicated complete consumption of the reactants and the desired mass signal. The mixture was concentrated under reduced pressure to approximately 20 mL and poured into saturated aqueous NaHCO3 (50 mL). The pH was adjusted to about 8 with EA. The aqueous phase was extracted with EA (100 mL x 3). The organic phase was washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. 2-((5-(2-cyclopropylphenyl)pyrrolidin-3-yl)oxy)-N ,N-dimethylacetamide (22 g, crude) was obtained. MS (ESI, m / e) [M +1] + 289.3.

[0316] Step 3: 2-((5-(2-cyclopropylphenyl)pyrrolidin-3-yl)oxy) -N,N-dimethylethanamine 2-((5-(2-cyclopropylphenyl)pyrrolidine-3)-3 in THF (50 mL) (-yl)oxy)-N,N-dimethylacetamide (1.2 g, 4.16 mmol) BH3.DMS (8.32 mL, 83.2 mmol, 10N in DMS) was added to the solution at 20°C. The mixture was heated to 70° C. and stirred for 10 hours. The reaction mixture was quenched with MeOH (10 mL). and decomplexed with HCl / MeOH (4N, 20 mL) at reflux for 2 h. LC / MS showed that the desired compound was formed. The reaction mixture was reduced The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Xtimate C18 10 μL, 250 mm Hg). * 50 mm; mobile phase: [water (0.1% TFA)-ACN]). (5-(2-cyclopropylphenyl)pyrrolidin-3-yl)oxy)-N,N-dimethyl Thioethylethanamine (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 equiv.) was added to the solution. The mixture was added in one portion and then stirred at 20° C. for 2 hours. The mixture was filtered and the filtrate was concentrated to give 2- ((5-(2-cyclopropylphenyl)pyrrolidin-3-yl)oxy)-N,N-di Methylethanamine (385 mg) was obtained. 1 H NMR (400 MHz, CDCl3) δppm:7.46-7.57(m,1H), 7.10-7.20(m,2H), 6.9 3-7.02(m,1H), 4.91(t,J=8.0Hz, 1H), 4.10-4.2 0(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.

[0317] Intermediate 2-z14: (S)-2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl )-7-Azaspiro[3.5]nonane [ka] Step 1: (S)-2-(2-ethoxyphenyl)pyrrolidine (S)-2-(2-bromophenyl)pyrrolidine (1.5 g) in EtOH (15 mL) , 6.63 mmol) and EtONa (1.35 g, 19.90 mmol), CuBr (475.81 mg, 3.32 mmol) was added. The mixture was then heated at 90°C for 1 Stirred for 2 hours. LC / MS showed the reaction was complete and had the desired mass signal. The mixture was cooled to room temperature and adjusted to a pH of about 11 with aqueous Na2CO3. The combined organic layer was diluted with Na2SO4 The mixture was dried over 100°C, filtered, and concentrated. The residue was purified by preparative HPLC (TFA conditions). (S)-2-(2-ethoxyphenyl)pyrrolidine (0.7 g) was obtained. MS( ESI, m / e)[M+1] + 192.3.

[0318] Step 2: (S)-tert-butyl 2-(2-(2-ethoxyphenyl)pyrrolidine-1 -yl)-7-azaspiro[3.5]nonane-7-carboxylate (S)-2-(2-ethoxyphenyl)pyrrolidine (0.5 g, 2.61 mmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane -7-carboxylate (568.71 mg, 2.38 mmol), HOAc (428. The mixture of NaBH(OAc) (13 mg, 7.13 mmol) was stirred at 20°C for 2 hours. 3 (1.01 g, 4.75 mmol) was added to the mixture, and the mixture was further stirred at 20 °C for 12 h. TLC showed the reaction was complete. The mixture was washed with aqueous Na2CO3. The mixture was adjusted to pH 11 and then extracted with EA (20 mL x 3). The extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel. The product was purified by chromatography (eluent: PE / EA = 20 / 1 to 10 / 1) to obtain (S)- tert-Butyl 2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl)-7-a The obtained zaspiro[3.5]nonane-7-carboxylate (0.6 g) was obtained. MS (ES I, m / e) [M+1] + 415.4.

[0319] Step 3: (S)-2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl)-7-a Zaspiro [3.5] Nonan (S)-tert-butyl 2-(2-ethoxyphenyl)-2-methylpropional in DCM (10 mL) ) pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate ( To a solution of 0.6g (1.45mmol) TFA (1.65g, 14.47mmol) was added The mixture was stirred at 20° C. for 1 hour. TLC showed the formation of one new spot. The reaction mixture was adjusted to pH 8-9 using an aqueous solution of Na2CO3. The combined organic layer was washed with brine and then extracted with DCM (10 mL x 5). The mixture was dried over 2SO4 and concentrated. (S)-2-(2-(2-ethoxyphenyl)pyrrolidone Zin-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= 7.1Hz, 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), 1.7 3-1.94(m,5H), 1.47-1.73(m,8H), 1.41(t,J=6. 95Hz, 3H).MS(ESI, m / e)[M+1] + 315.3.

[0320] Intermediate 2-z15: 2-(2'-cyclopropyl-[1,1'-biphenyl]-2-yl )-7-Azaspiro[3.5]nonane [ka] Step 1: tert-Butyl 2-(2-tosylhydrazono)-7-azaspiro[3.5]no Nan-7-carboxylate tert-Butyl 2-oxo-7-azaspiro[3.5] in EtOH (100 mL) Nonane-7-carboxylate (10.00 g, 41.79 mmol) and 4-methylbenzyl A mixture of benzenesulfonohydrazide (9.34 g, 50.14 mmol) was heated at 80°C for 1 hour. The mixture was stirred for 1 hour. TLC showed that the reaction was complete. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 2-(2-tosylhydrazono)-7 -azaspiro[3.5]nonane-7-carboxylate (8.0 g, crude) was obtained. NMR(400MHz, CDCl3)δppm:7.84(d,J=8.1Hz, 2H ), 7.39(s,1H), 7.33(d,J=8.0Hz, 2H), 3.22-3.3 9(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).

[0321] Step 2: tert-Butyl 2-(2-methoxyphenyl)-7-azaspiro[3.5]no Nan-7-carboxylate tert-Butyl 2-(2-tosylhydrazono)-7- in dioxane (100 mL) Azaspiro[3.5]nonane-7-carboxylate (8.0 g, 19.63 mmol) and (2-methoxyphenyl)boronic acid (8.95 g, 58.89 mmol), CsC A mixture of O3 (19.19 g, 58.89 mmol) was stirred at 110 °C for 4 h. C indicated the reaction was complete. The mixture was filtered and concentrated. The residue was purified by silica gel chromatography. Purification was carried out by column chromatography on gel (eluent: PE). 2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxymethyl The yield was 3.0 g. MS (ESI, m / e) [M+1] + 332.3.

[0322] Step 3: tert-Butyl 2-(2-hydroxyphenyl)-7-azaspiro[3.5] Nonane-7-carboxylate tert-Butyl 2-(2-methoxyphenyl)-2- dibenzofuran (DCM) (30 mL) was added under N2 atmosphere. 3.0g, 9.05m To a solution of 1.25 mol) was added BBr3 (9.07 g, 36.20 mmol) at -78 °C. After the addition, the mixture was stirred at 20° C. for 6 hours. LC / MS showed the reaction was complete. The mixture was quenched with aqueous Na2CO3 and extracted with DCM (20 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The product was purified by column chromatography on silica gel (eluent: PE / EA=20 / 1). It was purified by tert-butyl 2-(2-hydroxyphenyl)-7-azaspiro[3 1.3 g of 5-nonane-7-carboxylate was obtained. MS (ESI, m / e) [M+1] + 318.4.

[0323] Step 4: tert-butyl 2-(2-(((trifluoromethyl)sulfonyl)oxy) (phenyl)-7-azaspiro[3.5]nonane-7-carboxylate tert-Butyl 2-(2-hydroxyphenyl)-7-aza in DCM (10 mL) Spiro[3.5]nonane-7-carboxylate (1.3 g, 4.10 mmol) and T A solution of EA (1.24 g, 6.14 mmol) was added to TfO (1 0.73 g, 12.29 mmol) was added. The mixture was then stirred at 25° C. for 1 hour. LC showed the reaction was complete. The mixture was diluted with H2O (10 mL) and NH4 The mixture was quenched with Cl (10 mL) and extracted with DCM (10 mL x 3). The organic phase was washed with brine. The residue was purified by column chromatography on silica gel. Purification by chromatography (eluent: PE / EA=40 / 1) gave ert-butyl. 2-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-7-azas Pyro[3.5]nonane-7-carboxylate (1.84 g) was obtained. MS (ESI, m / e)[M+1] + 450.2.

[0324] Step 5: tert-Butyl 2-(2'-cyclopropyl-[1,1'-biphenyl]-2 -yl)-7-azaspiro[3.5]nonane-7-carboxylate Compound tert-butyl 2-(2-(((trifluoromethyl)methyl)methyl)methyl) in dioxane (10 mL) (ethyl)sulfonyl)oxy)phenyl)-7-azaspiro[3.5]nonane-7-carbo Xylate (1.4 g, 3.11 mmol), 2-(2-cyclopropylphenyl)-4 ,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.52 g, 6.23 m A mixture of Cs2CO3 (3.04 g, 9.34 mmol) and Cs2CO3 (3.04 g, 9.34 mmol) was added under a N2 atmosphere. Pd(dppf)Cl2 (1.14 g, 1.56 mmol) was added at 90°C. The mixture was stirred at rt for 12 h. TLC showed that the reactants were completely consumed and one new It was shown that a pot had formed. The mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel. The product was purified by column chromatography (eluent: PE / EA=50 / 1) at t ert-butyl 2-(2'-cyclopropyl-[1,1'-biphenyl]-2-yl)- 7-Azaspiro[3.5]nonane-7-carboxylate (0.6 mg) was obtained. MS( ESI, m / e)[M+1] + 418.5.

[0325] Step 6: 2-(2'-cyclopropyl-[1,1'-biphenyl]-2-yl)-7-a Zaspiro [3.5] Nonan tert-Butyl 2-(2'-cyclopropyl-[1,1'-biphenyl]-2-methyl-2-methyl-2-methyl-1,1'-biphenyl] in DCM (5 mL) phenyl]-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate(0 To a mixture of 1.6g (1.44mmol) and TFA (1.39g, 14.37mmol) The mixture was stirred at 25° C. for 2 hours. LC / MS showed the reaction was complete. The reaction mixture was adjusted to pH 10 using aqueous Na2CO3, and then DCM ( The combined organic layer was washed with brine and dried over Na2SO4. It was dried and concentrated. 2-(2'-cyclopropyl-[1,1'-biphenyl]-2-yl )-7-Azaspiro[3.5]nonane (340 mg) was obtained. 1 H NMR (400 MHz, 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.

[0326] Intermediate 2-z16: 4-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl )Methyl)benzaldehyde [ka] Step 1: Methyl 4-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)methyl thyl)benzoate 2-(2-cyclopropylphenyl)pyrrolidine (1.5 g, 8.01 mmol), methyl 4-formylbenzoate (1.14 g, 7.29 mmol ) solution, CH3COOH (0.87 g, 14.58 mmol), NaBH(OAc) 3 (3.09 g, 14.58 mmol) was added. The mixture was stirred at 25° C. for 4 h. LC showed that the reactants were completely consumed. The reaction mixture was diluted with HO (50 mL The combined organic layer was poured into brine (25 mL× EA) and extracted with EA (20 mL× 3). 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. By column chromatography on gel (eluent: PE / EA = 50 / 1 to 1 / 1), and purified to give methyl 4-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl )methyl)benzoate (1.8 g). MS (ESI, m / e) [M+1] + 33 6.5.

[0327] Step 2: (4-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl )phenyl)methanol Methyl 4-((2-(2-cyclopropylphenyl)pyrrolidine)) in THF (30 mL) A solution of 4-(4-methyl-1-benzoyl)methylbenzoate (2 g, 6 mmol) was added to the solution of LiAlH4 (4 6g, 17.28mmol) was slowly added at 0°C. The mixture was stirred at 0°C for 30 minutes. TLC showed that the reactants were completely consumed. The residue was dissolved in saturated aqueous NH4Cl. The mixture was quenched with EA (50 mL) and extracted with EA (50 mL). The organic phase was washed with brine and Dry over Na2SO4 and concentrate to give (4-((2-(2-cyclopropylphenyl) (Pyrrolidin-1-yl)methyl)phenyl)methanol (1.5 g) was obtained. MS (ES I, m / e) [M+1] + 308.3.

[0328] Step 3: 4-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl) benzaldehyde (4-((2-(2-cyclopropylphenyl)pyrrolidine- To a solution of (1-yl)methyl)phenyl)methanol (1.5 g, 4.89 mmol), MP (4.14 g, 9.78 mmol) was added. The mixture was stirred at 25° C. for 4 hours. C / MS confirmed that the reactants were completely consumed and that one The reaction mixture was diluted with Na2S2O3 (25 ml) and NaHCO3 (1 The mixture was quenched by the addition of 5 ml of EA and extracted with EA (30 mL x 3). The organic layer was washed with brine (30 mL × 2), dried over Na2SO4, and concentrated to give 4-( (2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)benzaldehyde The compound (1.5 g) was obtained. 1 H NMR (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, 1 H), 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), 1.68-1.9 1(m,2H), 1.63(dd,J=9.7, 2.4Hz, 1H), 0.80-0.9 5(m,2H), 0.63-0.74(m,1H), 0.48-0.61(m,1H).

[0329] Intermediate 2-z17a and Intermediate 2-z17b: (S or R)-2-(3-chloro-2-phenyl)-2-(2 ... (R or S)-2-(3-chloro-2-cyclopropylphenyl)pyrrolidine; (R or S)-2-(3-chloro-2-cyclopropylphenyl)pyrrolidine (Pyrphenyl)pyrrolidine [ka] Step 1: 1-Bromo-3-chloro-2-cyclopropylbenzene 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) A mixture of 1.0 eq. of 1H 2 O (1.0 eq.) was heated at 70°C under N2 protection for 12 hours. This indicated that the reaction was complete and a new spot had formed. It was cooled and diluted with EtOAc (150 mL) and H2O (50 mL). The organic phase was separated. , washed with water (150 mL), brine (150 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE). This gave 1-bromo-3-chloro-2-cyclopropylbenzene (3 g, crude), which This was used directly in the next step.

[0330] Step 2: tert-butyl(4-(3-chloro-2-cyclopropylphenyl)-4-ol) (xobutyl)carbamate 1-Bromo-3-chloro-2-cyclopropylbenzene (3 g) in THF (30 mL) , 13 mmol) into a solution of n-BuLi (2.5 M, 5.7 mL, 14.3 mmol) was added dropwise at −70° C. After stirring at −70° C. for 30 min, t in THF (5 mL) was added ert-butyl 2-oxopyrrolidine-1-carboxylate (2.64 g, 14.3 m A solution of 1.1 eq) of 1,2-dimethyl-3-propanol (1.1 mol, 1.1 eq) was added dropwise to the mixture at -70°C. The mixture was further stirred at 2° C. for 2 hours. 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). The residue was washed with 1 mL of ethyl acetate, dried over Na2SO4, and concentrated. The product was purified by column chromatography (eluent: PE / EA=5 / 1) to give tert-bromo- thyl(4-(3-chloro-2-cyclopropylphenyl)-4-oxobutyl)carbamate As a result, 1.3 g of methylpropional was obtained. 1 H NMR (400MHz, CDCl3)δppm:7.3 5(dd,J=7.6, 1.7Hz, 1H), 7.06-7.15(m,2H), 4.5 6(s,1H), 3.14(q,J=6.3Hz, 2H), 2.89(t,J=7.2H z, 2H), 1.78-1.95(m,3H), 1.37(s,9H), 0.92-1. 03(m,2H), 0.35-0.45(m,2H).

[0331] Step 3: 4-amino-1-(3-chloro-2-cyclopropylphenyl)butan-1-ol hmm tert-Butyl (4-(3-chloro-2-cyclopropyl)phenyl)propanol in DCM (20 mL) To a solution of (phenyl)-4-oxobutyl)carbamate (1.3 g, 3.8 mmol), FA (4.4 g, 38 mmol) was added. The mixture was then stirred at 20° C. for 2 hours. LC showed the reaction was complete. The mixture was concentrated under reduced pressure to give 4-amino- 1-(3-chloro-2-cyclopropylphenyl)butan-1-one (900 mg, crude ) was obtained. MS (ESI, m / e) [M+1] + 237.9.

[0332] Step 4: 2-(3-chloro-2-cyclopropylphenyl)pyrrolidine 4-Amino-1-(3-chloro-2-cyclopropylphenyl)-2-(2-methyl-2-propanol) in EtOH (10 mL) A solution of (methyl)butan-1-one (900 mg, 3.8 mmol) and AcOH (0.5 mL) The mixture was heated to 65°C and stirred for 3 hours. Then, the mixture was cooled to room temperature and added with NaBH3CN( To this was added 360 mg, 5.7 mmol, 1.5 eq. The mixture was left at room temperature for 1 hour. The reaction mixture was quenched and stirred for 1 hour. TLC showed the reaction was complete. Adjust the pH to about 10 using saturated aqueous Na2CO3, then add EtOAc (20 mL x 3). The organic layers were combined, dried over Na2SO4, and concentrated. Column chromatography on silica gel (eluent: EA / MeOH = 10 / 0-10 / 1) to obtain racemic 2-(3-chloro-2-cyclopropylphenyl)pyrrolidone. Lysine was obtained.

[0333] The racemic product was purified by SFC (instrument: Thar SFC350 preparative SFC; column: Ch iralpak AD, 250 * 50mm inner diameter 10u; Mobile phase: CO2 for A and B MeOH (0.1% NH3.H2O); Gradient: B% = 20%; Flow rate: 200g / min; wavelength: 220 nm; column temperature: 40 °C; system back pressure: 100 bar) and purification to give two isomers: a faster isomer (715 mg, retention time: 2.4 min) is (S or R)-2-(3-chloro-2-cyclopropylphenyl)pyrrolidine the slower isomer (737 mg, retention time: 2.7 min) was (R or S)-2-(3-chloro- It is (2-cyclopropylphenyl)pyrrolidine.

[0334] Intermediate 3-a: 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl )Amino)benzenesulfonamide [ka] 4-Fluoro-3-nitrobenzenesulfonamide (36. 3g, 0.165mol) in a solution of (tetrahydro-2H-pyran-4-yl)methane Amine (20.9 g, 0.182 mol) and TEA (20.0 g, 0.198 mol) was added at 0-5°C, and the reaction was allowed to warm slowly to room temperature and stirred for about 16 hours. L) was added to the reaction and the mixture was diluted with saturated NaH2PO4 (100 mL) and saturated NaCl solution (100 mL), dried over anhydrous NaSO, filtered and concentrated to give the product ( 49.1 g, 95.0% yield) as a yellow solid.

[0335] Intermediate 3-b: 4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy) )-3-Nitrobenzenesulfonamide [ka] Compound 4-fluoro-3-nitrobenzenesulfonate in i-PrOH (1.5 mL) amide (540 mg, 2.45 mmol) and Na2CO3 (155.97 mg, 1.47 A mixture of 20 mmol of compound (4-fluorotetrahydro-2H- Pyran-4-yl)methanol (489.89 mg, 3.68 mmol) was added, and the mixture The mixture was stirred at 60°C for 2 hours. The mixture was filtered and washed with water. Compound 4-((4- Fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonyl The amide (758 mg) was obtained as a yellow solid. 1 H NMR (400 MHz, 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.

[0336] Intermediate 3-c: 3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)a) Zetidin-3-yl)amino)benzenesulfonamide [ka] Step 1: tert-Butyl (1-(tetrahydro-2H-pyran-4-yl)azetidine -3-yl)carbamate [ka] Tetrahydro-4H-pyran-4-one (1.162 g, 11 0.6 mmol) was added to a solution of tert-butyl azetidin-3-ylcarbamate (1 g, 5.8 mmol) was added. The mixture was stirred at room temperature for 2 hours. Then, NaBH (OAc)3 (3.687 g, 17.4 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with DCM (200 ml), washed with brine (200 ml × 2), and The residue was dried over SO4 and concentrated. The elution was carried out with MeOH / DCM=1 / 20 (v / v). The product (800 ml) was purified by chromatography on silica using a methyl methylcellulose. g) was obtained as a yellow oil. MS (ESI, m / e) [M+1] + 257.1.

[0337] Step 2: 1-(tetrahydro-2H-pyran-4-yl)azetidin-3-amine dihydrochloride salt [ka] A solution of 4N HCl (g) in dioxane (30 mL) was added to tert-butyl (1-(tert-butyl) Trihydro-2H-pyran-4-yl)azetidin-3-yl)carbamate (300m g, 1.17 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give The crude product (250 mg) was obtained.

[0338] Step 3: 3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)azetidinyl) (3-(phenyl-3-yl)amino)benzenesulfonamide [ka] 1-(tetrahydro-2H-pyran-4-yl)azetidine- in THF (50 mL) 3-Amine dihydrochloride (206 mg, 0.899 mmol) and 4-fluoro-3-nitro A solution of benzenesulfonamide (282 mg, 1.28 mmol) in triethylamine (540.4 mg, 5.35 mmol) was added. The mixture was stirred at room temperature for 4 hours. The material was filtered to give the product (300 mg, 93.6%) as a yellow solid. 1 HNM R(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), 1.6 3(d,J=10.4Hz, 2H), 1.20-1.19(m,2H).

[0339] Intermediate 3-d: 4-(((1-methylpiperidin-4-yl)methyl)amino)-3-di Benzene sulfonamide [ka] 4-Fluoro-3-nitrobenzenesulfonamide (1.15 mL) in THF (12 mL) g, 5.2 mmol) and (1-methylpiperidin-4-yl)methanamine (640 m To a solution of 1.01 g (5 mmol) of TEA (1.01 g, 10 mmol) was added. The mixture was stirred at room temperature for 3 hours, and some solids were formed. The mixture was filtered. The solid (55 0 mg) was collected as a yellow solid. MS (ESI, m / e) [M+1] + 328.8 .

[0340] Intermediate 3-e: 3-nitro-4-(7-oxa-2-azaspiro[3.5]nonane-2- (yl)benzenesulfonamide [ka] 7-Oxa-2-azaspiro[3.5]nonane hydrochloride (556 mg, 3.4 mmol) and 4-fluoro-3-nitrobenzenesulfonamide (500 mg, 2.27 mmol) was added to a solution of triethylamine (688 mg, 6.81 mmol) ) was added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and diluted with EA / PE=1 / 1 Purification by chromatography on silica with an eluent of (v / v), The product (600 mg, 80.7% yield) was obtained as a yellow solid. 1 H NMR (40 0MHz, DMSO-d6)δppm:8.17(d,J=2.0Hz, 1H), 7.7 9(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] + 3 28.

[0341] Intermediate 3-f: 3-nitro-4-((1-(oxetan-3-yl)piperidin-4-yl) (I)amino)benzenesulfonamide [ka] Step 1: tert-Butyl(1-(oxetan-3-yl)piperidin-4-yl)carbamate Bamet [ka] tert-Butyl piperidin-4-ylcarbamate (1 g, 5 mmol), oxetan-3-one (1.08 g, 15 mmol), HOAC (0.2 ml) was added. The mixture was stirred at room temperature for 2 hours. Then, NaBH( OAc)3 (3.18 g, 15 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (200 ml) and added saturated aqueous NaHCO3 (100 ml), brine (2 The reaction residue was washed with 1000 ml of HCl, dried over NaSO, and concentrated. The product was purified by chromatography (MeOH / DCM=1 / 20) at 77°C. The product (1 g, 78%) was obtained as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6) 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,11 H).MS(ESI, m / e)[M+1] + 257.1.

[0342] Step 2: 1-(oxetan-3-yl)piperidin-4-amine bis(2,2,2-trimethylsilyl) trifluoroacetate) [ka] tert-Butyl (1-(oxetan-3-yl)piperidine) in DCM (30 mL) To a solution of 1-4-yl)carbamate (1 g, 3.9 mmol), TFA (5 ml) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated to give the product (1.4 g, 93.4%). was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δppm:1 1.02(s,1H), 8.23(s,3H), 4.82-4.63(m,4H), 4. 43-4.21(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.

[0343] Step 3: 3-nitro-4-((1-(oxetan-3-yl)piperidin-4-yl) Amino)benzenesulfonamide [ka] 1-(oxetan-3-yl)piperidin-4-amine bis( 2,2,2-trifluoroacetate) (784 mg, 2.04 mmol) and 4-fluoro Dissolved 471.6 mg (2.142 mmol) of 4-nitro-3-benzenesulfonamide To the solution was added triethylamine (1.03 g, 10.2 mmol). The mixture was stirred at room temperature for 4 The mixture was filtered to give the product (500 mg, 68.8%) as a yellow solid. MS (ESI, m / e) [M+1] + 357.0

[0344] Intermediate 3-g: 4-(((3-((tert-butyldimethylsilyl)oxy)oxetane (3-methyl)amino)-3-nitrobenzenesulfonamide [ka] Step 1: (3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl) Methanamine [ka] 3-(aminomethyl)oxetan-3-ol (500 mg, To a solution of 4.85 mmol) of tert-butylchlorodimethylsilane (694 mg, 4 0.6 mmol) and triethylamine (1.47 g, 14.55 mmol) were added. The mixture was stirred at room temperature overnight. It was then diluted with saturated aqueous NaHCO3 (500 ml), brine (50 ml × 2), dried over Na2SO4 and concentrated to give the crude product. This was used directly in the next step.

[0345] Step 2: 4-(((3-((tert-butyldimethylsilyl)oxy)oxetane-3 -yl)methyl)amino)-3-nitrobenzenesulfonamide [ka] (3-((tert-butyldimethylsilyl)oxy)oxene) in THF (50 mL) To a solution of 4-fluoro-3-methyl-2 ... Oro-3-nitrobenzenesulfonamide (1.28 g, 5.82 mmol) was added. The mixture was stirred at room temperature for 4 hours. The mixture was filtered to obtain the product (1.2 g, 59.3%). Obtained as a yellow solid. 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

[0346] Intermediate 3-h: 4-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl) (Ci)methoxy)-3-nitrobenzenesulfonamide [ka] Step 1: Ethyl 4-((tert-butyldimethylsilyl)oxy)cyclohexane-1 -carboxylate [ka] Ethyl 4-hydroxycyclohexane-1-carboxylate in DMF (50 ml) (2 g, 11.61 mmol) was added to a solution of tert-butylchlorodimethylsilane (1. 575g, 10.4mmol) and imidazole (1.58g, 23.22mmol) 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 evaporated on silica The product was purified by a chromatography column (eluent: EA / PE = 1 / 40) at 200°C. The product was obtained (2.32 g, 69.8%).

[0347] Step 2: (4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methano Rule [ka] Ethyl 4-((tert-butyldimethylsilyl)oxy) in MTBE (50 mL) A solution of cyclohexane-1-carboxylate (2.32 g, 8.1 mmol) was added to LA H (369 mg, 9.72 mmol) was added. The mixture was refluxed for 2 h. The mixture was quenched with MeOH (10 ml) at 0° C. The mixture was concentrated The residue was purified by chromatography on silica (eluent: EA / PE=1 / 2). The product (1.5 g, 75.8%) was obtained as a yellow oil. m / e)[M+1] + 245.1

[0348] Step 3: 4-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl) (Methoxy)-3-nitrobenzenesulfonamide [ka] (4-((tert-butyldimethylsilyl)oxy)cyclo To a solution of NaH (576 mg, 14.4 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. Then, 4 -fluoro-3-nitrobenzenesulfonamide (370 mg, 1.68 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was then added to saturated aqueous NaHCO3 (200 mL). Pour off, then adjust to pH 5-6 with HCl acid (1M), then add ethyl acetate (200m The combined organic phase was washed with brine, dried over Na2SO4 and extracted with HCl (3×L). The residue was purified by chromatography on silica (eluent: EA / PE=1 Purification by HPLC (MS / MS) gave the product as a yellow solid. +1] + 445.1.

[0349] Intermediate 3-i: 4-((4-fluoro-1-(tetrahydrofuran-3-yl)piperidinyl) (4-(4-methylphenyl)methoxy)-3-nitrobenzenesulfonamide [ka] Step 1: tert-butyl 4-fluoro-4-((2-nitro-4-sulfamoyl phenoxy) (Oxymethyl)piperidine-1-carboxylate [ka] 4-Fluoro-3-nitrobenzenesulfonamide (1 g, 4 0.54 mmol) and the compound tert-butyl 4-fluoro-4-(hydroxymethyl) A mixture of piperidine-1-carboxylate (1.06 g, 4.54 mmol) was added to N2 Add NaH (726.61 mg, 18.17 mmol, 60% purity) at 0°C in a single batch. The mixture was stirred at 15°C for 14 hours. TLC showed that the reaction was complete. 20 mL of saturated NH4Cl solution was added to the mixture, and the aqueous phase was diluted with ethyl acetate (20 mL × The combined organic phase was washed with brine (50 mL) and extracted with anhydrous Na2SO4 The crude product was reconstituted in EtOAc (10 mL). Purification by crystallization gave tert-butyl 4-fluoro-4-((2-nitro-4-sulfonyl) (sulfamoylphenoxy)methyl)piperidine-1-carboxylate (1.17g, 2 The compound (0.70 mmol, 59.4% yield) was obtained as a yellow solid. 1 H NMR (400M Hz, DMSO-d6)δppm:8.31(br s,1H), 8.06(br d, 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).

[0350] Step 2: 4-((4-fluoropiperidin-4-yl)methoxy)-3-nitrobenzene Sulfonamides [ka] tert-Butyl 4-fluoro-4-((2-nitro-4-sulfamoyl)fluoride in EA (phenoxy)methyl)piperidine-1-carboxylate (1.17 g, 2.70 mmol ) was added HCl acid (4 M, 78.00 mL) in one portion at 15° C. under N 2 . The mixture was stirred at 15° C. for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure to give 4-((4-fluoropiperidin-4-yl)methoxy)-3 1 g, crude HCl salt) as a yellow solid. This was used directly in the next step. 1 H NMR (400 MHz, methanol-d4) δp pm:8.37(d,J=2.3Hz, 1H), 8.12(dd,J=2.4, 8.9H z, 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), 2.3 3(br dd,J=10.0, 12.8Hz, 2H), 2.23-2.10(m,2H ).

[0351] Step 3: 4-((4-fluoro-1-(tetrahydrofuran-3-yl)piperidine-4 -yl)methoxy)-3-nitrobenzenesulfonamide [ka] 4-((4-fluoropiperidin-4-yl)methoxy)- in MeOH (20 mL) 3-Nitrobenzenesulfonamide (1 g, 2.70 mmol, HCl) and dihydrofuran A mixture of ran-3(2H)-one (698.40 mg, 8.11 mmol) was added under N Then, NaBH3CN (509.81 mg, 8.11 mmol) was added in one portion at 0°C. The mixture was stirred at 15° C. for 12 hours. LC-MS showed the reaction was complete. The mixture was poured into saturated NaHCO3 (20 mL) solution, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (30 mL) and dried over anhydrous Na2SO4. The mixture was dissolved in DCM and concentrated under reduced pressure to give a yellow A colored solid was obtained. 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, 6 1.05% yield, 96.19% purity) was obtained as a yellow solid. 1 H NMR (40 0 MHz, methanol-d4) δ ppm: 8.34 (d, J = 2.2 Hz, 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.

[0352] Intermediate 3-j: 3-nitro-4-(((4-(oxetan-3-yl)morpholin-2- methyl)amino)benzenesulfonamide [ka] Step 1: tert-butyl 2-(((2-nitro-4-sulfamoylphenyl)amino )Methyl)morpholine-4-carboxylate [ka] 4-Fluoro-3-nitrobenzenesulfonic acid in IPA (90 mL) at 55-60 °C A solution of 2.55 g (11.56 mmol) of Na2CO3 (735.09 mg, 6.94 mmol) and tert-butyl 2-(aminomethyl)morpholine-4-carbohydrate The mixture was stirred at 55-65°C for 4 hours. TLC showed that 4-fluoro-3-nitrobenzenesulfonamide was completely consumed. It was shown that the eluate was removed and one new spot was formed. The combined organic layers were washed with brine (30 mL) and extracted with Na Drying over SO4, filtering and concentrating under reduced pressure gave a residue. tert-Butyl 2-( ((2-nitro-4-sulfamoylphenyl)amino)methyl)morpholine-4-carbohydrate The carboxylate (4.3 g, 10.33 mmol, 89.33% yield) was obtained as a yellow solid. The product was used directly in the next step. 1 H NMR (400 MHz, CDC) l3)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).

[0353] Step 2: 4-((morpholin-2-ylmethyl)amino)-3-nitrobenzenesulfone amide [ka] tert-Butyl 2-(((2-nitrilo)methyl)-2-nitriloacetate in TFA (10 mL) and DCM (10 mL) (4-sulfamoylphenyl)amino)methyl)morpholine-4-carboxylate A mixture of (2.5 g, 6.00 mmol) was stirred at 25°C for 1 hour. It was shown that the reactant was completely consumed and one new spot was formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. (amino)-3-nitrobenzenesulfonamide (2.5 g, crude) was obtained as a yellow oil. It was used directly in the next step. 1 H NMR (400 MHz, DMSO-d6) δppm 8.57(br t,J=6.0Hz, 1H), 8.48(d,J=2.2H z, 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), 3.0 1(br,1H), 2.90(m,1H).

[0354] Step 3: 3-nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl) Methyl)amino)benzenesulfonamide [ka] 4-((morpholin-2-ylmethyl)amino)-3-nitrite in MeOH (60 mL) Isobenzenesulfonamide (600.00 mg, 1.90 mmol) and oxetane-3 A solution of NaBH3CN (357.5 mg, 5.69 mmol) was added to a solution of 1,2-dichloro-2,4-dione (410.05 mg, 5.69 mmol) 8 mg, 5.69 mmol) was added. The mixture was stirred at 15° C. for 14 hours. LC-MS 4-((morpholin-2-ylmethyl)amino)-3-nitrobenzenesulfone The reaction showed complete consumption of the amide and one major peak with the desired m / z. The reaction mixture was quenched by the addition of HO (10 mL), concentrated, and then diluted with EtOAc ( The combined organic layers were washed with brine (10 mL) and extracted with Na Drying over SO4, filtration and concentration under reduced pressure gave a residue. The residue was triturated with EA (5 mL). Washed. 3-nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl )methyl)amino)benzenesulfonamide (580 mg, 1.49 mmol, 78.7 6% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6) 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,2 H), 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), 3.7 5(br s,1H), 3.62-3.52(m,1H), 3.50-3.39(m,2 H), 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.

[0355] Intermediate 3-k: 4-(((4-cyclopropylmorpholin-2-yl)methyl)amino) -3-nitrobenzenesulfonamide [ka] 4-((morpholin-2-ylmethyl)amino)-3-nitrite in MeOH (30 mL) A solution of benzobenzenesulfonamide (1 g, 3.16 mmol) was added to 4 Å molecular sieves (0.5 g , 9.48mmol), AcOH (1.33g, 22.13mmol, 1.27mL), (1-ethoxycyclopropoxy)trimethylsilane (2.76 g, 15.81 mmol) , 3.18 mL) and NaBHCN (595.97 mg, 9.48 mmol) were added. The mixture was stirred at 70° C. for 5 hours. LC-MS showed 4-((morpholin-2-yl) The complete consumption of the (methyl)amino)-3-nitrobenzenesulfonamide and the desired The reaction mixture was concentrated and diluted with HO (20 mL). The combined organic layer was diluted with brine (20 mL). mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluent: PE / EA=10:1 to EA). Purify and obtain 4-(((4-cyclopropylmorpholin-2-yl)methyl)amino)-3- Nitrobenzenesulfonamide (300 mg, 25.82% yield) as a yellow solid Obtained. 1 H 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=9.3 Hz, 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(br d,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.

[0356] Intermediate 3-l: 3-nitro-4-(((1-(oxetan-3-yl)piperidine-4- (I)methyl)amino)benzenesulfonamide 2,2,2-trifluoroacetate [ka] Step 1: tert-butyl((1-(oxetan-3-yl)piperidin-4-yl)methyl)methyl thyl)carbamate [ka] tert-Butyl(piperidin-4-ylmethyl)carbamate in DCM (50 mL) A solution of oxetan-3-one (1.01 g, 14 mmol) was added to a solution of 1 g of acetone (4.67 mmol). The mixture was stirred at room temperature for 2 hours. To the mixture was added NaBH(OAc)3 (2.967 g, 14 mmol). The mixture was cooled to room temperature. The mixture was diluted with DCM (200 ml) and added saturated aqueous NaHCO3, salt The residue was washed with water (200 mL x 2), dried over Na2SO4, and concentrated. Purified by chromatography column (eluent: MeOH / DCM=1 / 20) The product (1.2 g, 95%) was obtained as a yellow oil. MS (ESI, m / e) [M +1] + 271.1.

[0357] Step 2: (1-(oxetan-3-yl)piperidin-4-yl)methanamine bis( 2,2,2-trifluoroacetate) [ka] tert-Butyl (1-(oxetan-3-yl)piperidinyl) in DCM (50 mL) To a solution of (4-methyl-4-phenyl)carbamate (1.2 g 4.44 mmol), TFA (15 mL) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated to give the product. The crude product was used directly in the next step.

[0358] Step 3: 3-nitro-4-(((1-(oxetan-3-yl)piperidin-4-yl )Methyl)amino)benzenesulfonamide 2,2,2-trifluoroacetate [ka] (1-(oxetan-3-yl)piperidin-4-yl)methanone in THF (50 mL) amine bis(2,2,2-trifluoroacetate) (1.77 g, 4.44 mmol) ) and 4-fluoro-3-nitrobenzenesulfonamide (1.026 g, 4.66 mm To a solution of 1.25 mmol of methylpropanol was added triethylamine (2.24 g, 22.2 mmol). The mixture was stirred at room temperature overnight. The product (900 mg, 41.8%) was filtered to give a yellow Obtained as a solid. MS (ESI, m / e) [M+1] + 371.1

[0359] Intermediate 3-m: (R)-4-(((1,4-dioxan-2-yl)methyl)amino)- 3-Nitrobenzenesulfonamide [ka] (R)-(1,4-dioxan-2-yl)methanamine (4 50 mg, 2.93 mmol) was added to a solution of 4-fluoro-3-nitrobenzenesulfonic acid amide (709.5 mg, 3.22 mmol) and triethylamine (1.48 g, 14. 65 mmol) was added. The mixture was stirred at room temperature for 4 hours. Then, the reaction mixture was filtered and The precipitate was washed with petroleum to give the product (540 mg, 58%). MS (ESI, m / e )[M+1] + 318.0.

[0360] Intermediate 3-n: 4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)- 3-((trifluoromethyl)sulfonyl)benzenesulfonamide [ka] 4-Fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide ( 469 mg, 1.53 mmol), (tetrahydro-2H-pyran-4-yl)methanamine amine (176 mg, 1.53 mmol) and EtN (232 mg, 2.3 mmol) The solution was stirred at room temperature for 4 hours. After removal of the solvent, the resulting residue was dissolved in EA (100 mL). The solution was dissolved, washed with brine (100 mL x 4), dried over anhydrous Na2SO4, filtered, and concentrated. Condensation gave the crude product as a white solid (747 mg). MS (ESI, m / e) [M +1]+403.1.

[0361] Intermediate 3-o: 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl )Amino)-3-nitrobenzenesulfonamide [ka] Step 1: 1,6-Dioxaspiro[2.5]octane-2-carbonitrile Oxan-4-one (100 g, 1 mol) in tert-butanol (100 mL) To this solution was added 2-chloroacetonitrile (70 g, 0.93 mol). The mixture was stirred at 25°C for 30 minutes, followed by 40 minutes of stirring at 25°C. A solution of t-BuOK (120 g, 1.07 mol) in ert-butanol (1 L) was added dropwise. The resulting mixture was stirred at room temperature overnight. It was diluted with 200 mL of water and added to 40 ml After quenching with 1 L of 10% hydrogen chloride, the resulting mixture was reduced to one-third of its volume. The mixture was concentrated with 500 ml of ether and then extracted with 3 x 400 ml of ether. L of brine, dried over anhydrous sodium sulfate, and concentrated to give 84.5 g (crude). 1,6-Dioxaspiro[2.5]octane-2-carbonitrile was obtained as a yellow oil. .

[0362] Step 2: 2-(4-fluorotetrahydro-2H-pyran-4-yl)-2-hydroxy Acetonitrile 1,6-Dioxaspiro[2.5]octane-2-carbonyl in 1 L of dichloromethane A solution of 169 g (1.22 mol) of 70% HF / Py (148 mL) was added to 0 The resulting mixture was stirred at room temperature overnight. 1000 mL of ethyl acetate was added dropwise. After dilution with NaHCO3 (saturated), the reaction mixture was poured into NaHCO3 (saturated) and solid NaHCO3 was added with stirring. The pH was adjusted to about 7 using 3. The aqueous phase was extracted with 3 x 1000 mL of ethyl acetate, and the organic phase was Combine the layers and then wash with 850 mL of 1% hydrogen chloride and 1 x 1000 mL of brine. It 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 And got it.

[0363] Step 3: (4-Fluorotetrahydro-2H-pyran-4-yl)methanol 2-(4-fluorooxazoline)diisopropyl ether in i-propanol / H2O (800 mL / 200 mL) A solution of (4-phenyl-2-hydroxyacetonitrile) (109 g, 685.5 mmol) To the solution, NaBH4 (39.1 g, 1028.3 mmol) was added little by little at 0°C. The resulting mixture was stirred at 0°C for 2 hours and then quenched by the addition of 220 mL of acetone. The mixture was stirred for an additional hour, and the solid was filtered off and washed with 200 mL of ethyl acetate. The filtrate was concentrated and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether). Purification by ethanol (ether = 3 / 1) gave 47.8 g of (4-fluorooxan-4-yl)methanone. The alcohol was obtained as a pale yellow oil.

[0364] Step 4: (4-Fluorotetrahydro-2H-pyran-4-yl)methyl methanesulfonate Route (4-fluorooxan-4-yl)methanol (5 A solution of 1000mg of TEVA (7.8g, 431.3mmol) and TEA (65.5g, 647.0mmol) To the resulting mixture, MsCl (73.2 g, 647.0 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. After quenching with 500 mL of water, the resulting mixture was diluted with 2× The combined organic layers were extracted with 500 mL of dichloromethane and washed with water over anhydrous sodium sulfate. and concentrated to give 105.8 g (crude) of (4-fluorooxan-4-yl)methyl The ethyl methanesulfonate was obtained as a yellow oil.

[0365] Step 5: 2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)isocyanate Endolin-1,3-dione (4-fluorooxan-4-yl)methyl methanesulfonate (1 L) in 1 L of DMF To a solution of potassium 1,3-dioxo-2,3-dihydrochloride (05.8 g, 499.1 mmol), dro-1H-isoindol-2-ide (138.5 g, 748.6 mmol) was added. The resulting mixture was stirred at 140°C overnight. After cooling to room temperature, the reaction mixture was diluted with 3 L of water. The filter cake was dried under reduced pressure to give 98 g (crude) of 2-((4 -fluorotetrahydro-2H-pyran-4-yl)methyl)isoindoline-1,3- The dione was obtained as an off-white solid.

[0366] Step 6: (4-Fluorotetrahydro-2H-pyran-4-yl)methanamine 2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl ... To a solution of ethyl)isoindoline-1,3-dione (98 g, 372.6 mmol), 2NH2.H2O (111.8 g, 2.24 mol) was added. The resulting mixture was heated to 70°C. After cooling to room temperature, the reaction mixture was concentrated and then diluted with 1 L of DCM. After removing the solids by filtration, the filtrate was concentrated and purified by silica gel column chromatography. (eluent: CH2Cl2 / MeOH=100 / 1) to give 30.2 g of (4 (-fluorooxan-4-yl)methanamine was obtained as a pale yellow oil.

[0367] Step 7: 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amine (o)-3-Nitrobenzenesulfonamide (4-fluorotetrahydro-2H-pyran-4-yl) ) methanamine (30 g, 225.6 mmol) and 4-fluoro-3-nitrobenzene A solution of 1-sulfonamide (41.4 g, 188.0 mmol) was added to a solution of Na2CO3 (1 The resulting mixture was stirred at 60°C for 2 hours and then precipitated. After filtration, the filter cake was washed with 3 x 100 mL of water and then with red Dry under ambient light to obtain 60.9 g of 4-[[(4-fluorooxan-4-yl)methyl [Il]amino]-3-nitrobenzene-1-sulfonamide was obtained as a yellow solid.

[0368] Intermediate 3-p: 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl )Methyl)amino)-3-nitrobenzenesulfonamide [ka] Step 1: 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol CHMgBr (344.0 ml, 1.032 mol, Et To a stirred solution of 1,4-dioxaspiro[4 methyl]propanol (3M in 20) in 350 ml of dry toluene A solution of .5]decan-8-one (70.0 g, 0.449 mol) was added dropwise. The resulting mixture was stirred at 5-10°C for 2 hours. The mixture was poured into saturated aqueous NH4Cl solution (3 L). The combined organic phase was washed with brine (1.5 L). The mixture was washed, dried over Na2SO4, and concentrated to give 8-methyl-1,4-dioxaspiro[4 .5]Decan-8-ol (70.0 g, crude) was obtained as a white solid.

[0369] Step 2: 4-Hydroxy-4-methylcyclohexan-1-one In a stirred solution of 0.05 N HCl (1800 mL) was added 8-methyl-1,4-dioxazol- Pyro[4.5]decan-8-ol (140.0 g, 0.814 mol) was added. The mixture was stirred at 70° C. for 2.5 hours. The resulting mixture was cooled to room temperature and saturated with NaCl. The solid was added and then extracted with EtOAc (5 x 700 mL). Dry over Na2SO4 and concentrate to give 4-hydroxy-4-methylcyclohexane-1 -one (105.0 g, crude) was obtained as a yellow oil.

[0370] Step 3: (S)-1-Methyl-4-(nitromethyl)cyclohex-3-en-1-ol L 4-Hydroxy-4-methylcyclohexane-1 in CH3NO2 (600.0 mL) To a stirred solution of 105.0 g of N-ion (0.820 mol), 1 ,N 1 -Dimethylethane HCl (7.216 g, 0.082 mol) was added to the mixture. The mixture was cooled to room temperature under a nitrogen atmosphere. The mixture was stirred at 100° C. under air for 2 hours. After cooling to room temperature, the reaction mixture was concentrated and Purification by silica gel column chromatography eluted with E=1 / 4 gave (S) -1-methyl-4-(nitromethyl)cyclohex-3-en-1-ol (96.0g ) was obtained as a yellow oil.

[0371] Step 4: (1r,4r)-1-Methyl-4-(nitromethyl)cyclohexane-1-ol L (S)-1-Methyl-4-(nitromethyl)cyclohexa-3 in DCM (1.5 L) To a stirred solution of 1-en-1-ol (96.0 g, 0.561 mol), Crabtree's catalyst (6.8 g, 0.008 mmol) was added. The mixture was heated under an atmosphere of H2 (30 atm) The mixture was stirred at 50° C. overnight. After cooling to room temperature, the reaction mixture was filtered and concentrated to give (1r,4 r)-1-methyl-4-(nitromethyl)cyclohexan-1-ol (100.0 g, crude) was obtained as a yellow oil.

[0372] Step 5: (1r,4r)-4-(aminomethyl)-1-methylcyclohexane-1-ol L (1r,4r)-1-Methyl-4-(nitromethyl)cyclohexane in MeOH (1.5 L) A stirred solution of hexane-1-ol (120.0 g, 0.694 mol) was added to a 10% wet Pd / C (30.0 g) was added, and the mixture was heated at 85 °C under H2 (30 atm). After cooling to room temperature, the reaction mixture was filtered and concentrated to give (1r,4r)-4- (Aminomethyl)-1-methylcyclohexan-1-ol (95.0 g, crude) was dissolved in brown water. was obtained as a solid. 1 H NMR (300 MHz, methanol-d4) δ ppm: 2.5 1(d,J=6.7Hz, 2H), 1.86-1.58(m,4H), 1.40-1.5 0(s,2H), 1.35-1.26(m,1H), 1.21(s,3H), 1.16- 0.95(m,2H).

[0373] Step 6: 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl (I)amino)-3-nitrobenzenesulfonamide (1r,4r)-4-(aminomethyl)-1-methylcyclohexyl in THF (1 L) To a stirred solution of 4-fluoro-3- Nitrobenzenesulfonamide (107.6 g, 0.489 mol) and TEA (141 0.2g, 1.389mol) was added. The mixture was stirred at room temperature overnight. Diluted with water (500 mL) and extracted with EtOAc (3 x 800 mL). The organic phase was washed with brine (1 L), dried over anhydrous Na2SO4, and concentrated. Purification by slurry in tOAc (800.0 mL) three times gave 4-((((1r,4 r)-4-Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobene The benzenesulfonamide (144.6 g) was obtained as a yellow solid. 1H NMR (300 M) Hz, 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.

[0374] Intermediate 3-q1: (4-((((1s,4s)-4-hydroxy-4-(trifluoromethyl) (ethyl)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide; [ka] Intermediate 3-q2: 4-((((1r,4r)-4-hydroxy-4-(trifluoromethyl) (Cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide [ka] Step 1: Ethyl 4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl Hexane carboxylate Ethyl 4-oxocyclohexanecarboxylate (10 g) in THF (100 mL) , 58.75 mmol) to a solution of TMSCF3 (12.53 g, 88.13 mmol) and CsF (8.92 g, 58.75 mmol) were added. The mixture was stirred at 20° C. for 6 hours. TLC showed that the reactants were completely consumed. The reaction mixture was diluted with saturated Na The mixture was washed with aqueous HCO3 solution (50 mL x 2) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL × 2), dried over anhydrous Na2SO4, and filtered. The residue was purified by column chromatography (silica gel, eluent: P Purification was carried out by ethanol / EA = 100 / 1 to 2 / 1). -4-((trimethylsilyl)oxy)cyclohexanecarboxylate (8.12 g) was obtained as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm: 4. 15(q,J=7.1Hz, 2H), 2.20-2.66(m,1H), 1.98-2. 08(m,1H), 1.63-1.95(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).

[0375] Step 2: (4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexane Xyl)methanol Ethyl 4-(trifluoromethyl)-4-((trimethylsilyl)methyl)silane in THF (50 mL) (25.93 mmol) of cyclohexanecarboxylate (8.10 g, 25.93 mmol) LAH (1.97 g, 51.86 mmol) was added to the solution at 0°C, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was stirred. TLC showed that the reactants were completely consumed. (15 mL) and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The material (6.2 g, crude) was used in the next step without further purification.

[0376] Step 3: (4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexane Xyl)methyl methanesulfonate (4-(trifluoromethyl)-4-((trimethylsilyl) (oxy)cyclohexyl)methanol (6.2 g, 22.93 mmol) and TEA (4 A solution of MsCl (5.91 g, 51.60 mmol) was added to the solution at 0 °C. mol) was added and the mixture was stirred at 0°C for 2 hours. TLC showed that the reactants were completely consumed. The reaction mixture was washed with saturated aqueous NaHCO3 (50 mL x 2) and Extraction was performed with DCM (50 mL x 2). The combined organic phase was washed with brine (50 mL x 2). The crude product (8.52 g) was purified by filtration, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. , crude) was used in the next step without further purification.

[0377] Step 4: ((4-(azidomethyl)-1-(trifluoromethyl)cyclohexyl)oxy) Trimethylsilane (4-(trifluoromethyl)-4-((trimethylsilyl) )oxy)cyclohexyl)methyl methanesulfonate (8.51g, 24.42mmol To the solution of l) was added NaN3 (7.94 g, 122.11 mmol) at 20 °C, and the mixture The mixture was stirred at 50° C. for 12 hours. TLC showed that the reactants were completely consumed. The mixture was diluted with water, extracted with MTBE (100 mL × 3), dried over anhydrous Na2SO4, and The combined organic layers were concentrated to give the crude product, which was directly carried on to the next step. was used in the process.

[0378] Step 5: (4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexane Xyl)methanamine ((4-(azidomethyl)-1-(trifluoromethyl)) in CHOH (50 mL) A mixture of (cyclohexyl)oxy)trimethylsilane (7.21 g, theoretical yield) and Pd HCl (2.5 g) was added and the mixture was stirred under H2 (30 psi) at 30 °C for 16 h. TLC showed that the reactants were completely consumed. The mixture was filtered and The mixture was concentrated with 4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexane. (4.67 g, crude) hexylmethanamine was obtained as a yellow oil. and used in the next step without further purification.

[0379] Step 6: 4-(((4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl (I)amino)-3-nitrobenzenesulfonamide 4-Fluoro-3-nitrobenzenesulfonamide (2.50 mL) in DMF (75 mL) g, 11.35 mmol) and (4-(trifluoromethyl)-4-((trimethylsilyl) Solution of (( ... DIPEA (2.94 g, 22.74 mmol) was added to the mixture, and the mixture was stirred at 55°C for 2 hours. The reaction mixture was stirred. TLC showed that the reactants were completely consumed. The reaction mixture was diluted with water (2 The combined organic phase was washed with brine (100 mL) and extracted with EA (100 mL x 3). (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was washed with PE / EA=5 / 1 (30 mL) and filtered. The filter cake was purified by preparative HPLC. C (neutral). 4-((((1s,4s)-4-hydroxy-4-(trimethylsilyl)-4-hydroxybenzoate) Fluoromethyl)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonami The compound (Intermediate 3-q1, retention time: 2.5 min) (1.04 g) was obtained as a yellow solid. . 1 H NMR (400 MHz, methanol-d4) δ ppm: 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] - 39 6.0;4-((((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl (hexyl)methyl)amino)-3-nitrobenzenesulfonamide (intermediate 3-q2, Retention time: 2.6 min) (842 mg) was obtained as a yellow solid. 1 H NMR (40 0 MHz, methanol-d4) δ ppm: 8.65 (d, J = 1.9 Hz, 1H), 8. 54(t,J=5.2Hz, 1H), 7.90(dd,J=9.1, 1.6Hz, 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,3 H), 1.42-1.69(m,4H).MS(ESI, m / e)[M-1] - 396. 0.

[0380] Intermediate 3-r: 4-(((3-oxabicyclo[3.1.0]hexan-6-yl)methyl (I)amino)-3-nitrobenzenesulfonamide [ka] Step 1: Ethyl 3-oxabicyclo[3.1.0]hexane-6-carboxylate 2,5-Dihydrofuran (10 g, 142.67 mmol) in DCM (250 mL) and ethyl 2-diazoacetate (32.56 g, 285.35 mmol), h(AcO)2 (63.06 mg, 2.85 mmol) was added. The mixture was stirred at 20 °C for 12 h. The reaction mixture was stirred for 1 hour. TLC showed that the reactants were completely consumed. Concentration under reduced pressure gave a residue which was purified by preparative MPLC to give ethyl 3-oxoacetate. Sabicyclo[3.1.0]hexane-6-carboxylate (10.0 g) was obtained. 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).

[0381] Step 2: 3-oxabicyclo[3.1.0]hexan-6-ylmethanol Ethyl 3-oxabicyclo[3.1.0]hexane-6-carboxamide in THF (50 mL) A solution of carboxylate (10 g, 64.03 mmol) was added to LiAlH4 (2.43 g, 64.03 mmol) was added. The mixture was stirred at 0°C for 4 hours. The reaction mixture was poured into HO (30 mL) and EA (30 mL x 3), dried over Na2SO4, filtered and concentrated. Bicyclo[3.1.0]hexan-6-ylmethanol (7.0 g, crude) was obtained. This was used in the next step without further purification.

[0382] Step 3: 3-oxabicyclo[3.1.0]hexan-6-ylmethyl methanesulfonate to 3-Oxabicyclo[3.1.0]hexan-6-ylmethanone in DCM (100 mL) A solution of ethanol (7.0 g, 61.33 mmol) was added to MsCl (21.08 g, 183. 98 mmol) and TEA (24.82 g, 245.31 mmol) were added. The mixture was stirred at 25°C for 5 hours. TLC showed that the reactants were completely consumed. The reaction mixture was quenched with aqueous NH4Cl (30 mL) and extracted with EA (30 mL × 3). The residue was purified by column chromatography. (SiO2, PE / EA = 100 / 1 to 30 / 1) and purified. 3.5g of 2[3.1.0]hexan-6-ylmethyl methanesulfonate was obtained. . 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, 2 H), 3.03(s,3H), 1.69-1.72(m,2H), 1.21-1.29( m,1H).

[0383] Step 4: 6-(azidomethyl)-3-oxabicyclo[3.1.0]hexane 3-Oxabicyclo[3.1.0]hexan-6-ylmethyl in DMF (20 mL) A solution of methanesulfonate (2 g, 10.4 mmol) was added to NaN3 (676.37 mg The mixture was stirred at 50°C for 12 hours. The reaction mixture was poured into HO (30 mL) and EA (30 mL x 3), dried over Na2SO4, filtered and concentrated. , which was used directly in the next step.

[0384] Step 5: 3-oxabicyclo[3.1.0]hexan-6-ylmethanamine 6-(azidomethyl)-3-oxabicyclo[3.1.0]he in DMF (15 mL) A solution of hexane (1.4 g, 10.06 mmol) was added to Pd / C (0.7 g, 1.006 mmol). The mixture was stirred under H2 atmosphere (15 Psi) at 25°C for 2 hours. LC / MS confirmed complete consumption of the reactants and the desired mass signal. Two major peaks were observed. The reaction mixture was filtered and used directly in the next step. , m / e)[M+1] + 114.0.

[0385] Step 6: 4-(((3-oxabicyclo[3.1.0]hexan-6-yl)methyl)a (amino)-3-nitrobenzenesulfonamide 4-Fluoro-3-nitrobenzenesulfonamide (1.5 g) in DMF (15 mL) , 6.8 mmol) and 3-oxabicyclo[3.1.0]hexan-6-ylmethanamine A solution of amine (1 g, 8.84 mmol) in DIEA (1.76 g, 13.6 mmol) The mixture was stirred at 60°C for 2 hours. LC / MS showed that 4-fluoro-3-nitrophenyl The 1-methyl-2-benzothiazolinone was confirmed to be completely consumed and had the desired mass signal. The reaction mixture was cooled to room temperature and stirred with H2O (50 mL). The precipitate was filtered, and the cake was washed with MTBE (10 mL) and dried under reduced pressure. 4-((3-oxabicyclo[3.1.0]hexan-6-ylmethyl)amino)- 3-Nitrobenzenesulfonamide (758 mg) was obtained. 1 H NMR (400M Hz, 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=7.9H) z, 2H), 3.36(s,2H), 1.71(s,2H), 1.05(s,1H).M S(ESI, m / e)[M+1] + 314.0.

[0386] 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-phenylpyrrolidin-1-yl)-[1,1'- Biphenyl]-4-carboxamide [ka] Step 1: 1-(4-bromophenyl)-2-phenylpyrrolidine [ka] 2-Phenylpyrrolidine (588 mg, 4 mmol) in toluene (25 ml), 1- Bromo-4-iodobenzene (1.132 g, 16 mmol), BINAP (497 mg To a degassed solution of K-OtBu (1.2 g, 12 mmol) was added P d2(dba)3 (366 mg, 0.4 mmol) was added. Nitrogen was applied for 5 min. The mixture was then heated to 90° C. and stirred overnight. After cooling to room temperature, The reaction mixture was washed with water and brine in turn. The organic layer was dried over anhydrous Na2SO4 and then The extract was filtered, concentrated, and then subjected to column chromatography using 5% to 20% EA / PE as the eluent. The compound was purified by HPLC to give 1-(4-bromophenyl)-2-phenylpyrrolidine (75 0 mg, 62%) as a colorless oil. MS (ESI, m / e) [M+1] + 302.0 , 304.1.

[0387] Step 2: tert-butyl-3-((1H-pyrrolo[2,3-b]pyridin-5-yl) Oxy)-4'-(2-phenylpyrrolidin-1-yl)-[1,1'-biphenyl]- 4-carboxylate [ka] Under a nitrogen atmosphere, 1-(4- (bromophenyl)-2-phenylpyrrolidine (525 mg, 1.74 mmol), ter t-Butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Pd(dppf)Cl2 (985 mg, 2.26 mmol), Pd(dppf)Cl2 (128 mg, 0.17 A mixture of K2CO3 (480 mg, 3.48 mmol) and K2CO3 (480 mg, 3.48 mmol) was stirred overnight. The mixture was h...

Claims

[Claim 1] The invention described in this specification.

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