Bcl-2 inhibitor

Abstract

To provide new small molecules that selectively inhibit Bel-2 proteins for the treatment of dysregulated apoptotic diseases such as cancers, autoimmune diseases and pro-thrombotic conditions.SOLUTION: The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] This application claims the benefit of International Patent Application No. PCT / CN2018 / 085217, filed on April 29, 2018, and PCT / CN2018 / 107134, filed on September 21, 2018, the disclosures of which are hereby incorporated by reference in their entirety for all purposes.

[0002] Compounds of formula (I) for inhibiting Bcl-2 and treating diseases associated with undesirable bcl-2 activity (Bcl-2 related diseases), neurodegenerative diseases such as Alzheimer's disease; and proliferative diseases such as cancer, autoimmune diseases and thrombotic promoting diseases, methods of using the compounds disclosed herein for treating unregulated apoptosis diseases including, and pharmaceutical compositions containing the same are disclosed herein.

Background Art

[0003] Programmed cell death or apoptosis occurs in multicellular organisms to eliminate damaged or unwanted cells, which is important for the homeostasis of normal tissues (Br. J. Cancer 1972, 26, 239). However, defective apoptotic processes are thought to be involved in a variety of diseases. Excessive apoptosis causes atrophy, while insufficient apoptosis leads to uncontrolled cell growth such as cancer (Cell 2011, 144, 646). Resistance to apoptotic cell death is a characteristic of cancer and contributes to chemotherapy resistance (Nat Med. 2004, 10, 789-799). Some important pathways that regulate apoptosis are commonly altered in cancer. Some factors such as the Fas receptor and caspases promote apoptosis, while some members of the B-cell lymphoma 2 (Bcl-2) family of proteins inhibit apoptosis. Negative regulation of apoptosis inhibits the cell death signaling pathway, promotes tumor escape from cell death, and gives rise to drug resistance.

[0004] There are two distinct apoptotic pathways, including the extrinsic pathway and the intrinsic pathway. The extrinsic pathway is activated in response to the binding of cell death-inducing ligands to cell surface death receptors (Nat Rev Drug Discov. 2017 16, 273-284). The B-cell lymphoma 2 (BCL-2) gene family, a group of proteins homologous to Bcl-2 protein, encodes more than 20 proteins that regulate the intrinsic apoptotic pathway. Bcl-2 family proteins are characterized by containing at least one of four conserved Bcl-2 homology (BH) domains (BH1, BH2, BH3, and BH4) (Nat. Rev. Cancer 2008, 8, 121; Mol. Cell 2010, 37, 299; Nat. Rev. Mol. Cell Biol. 2014, 15, 49). Bcl-2 family proteins, consisting of apoptosis-promoting and anti-apoptotic molecules, can be classified into the following three subfamilies according to the sequence homology within the four BH domains: (1) The subfamily of anti-apoptotic Bcl-2, Bcl-XL, and Bcl-w share sequence homology within all four BH domains; (2) The subfamily of apoptosis-promoting Bax and Bak share sequence homology within BH1, BH2, and BH4; (3) The subfamily of apoptosis-promoting Bik, Bid, and HRK share sequence homology only within BH3. One of the unique features of Bcl-2 family proteins is the heterodimerization between anti-apoptotic proteins and apoptosis-promoting proteins, which is thought to inhibit the biological activity of their partners. This heterodimerization is mediated by the insertion of the BH3 region of the apoptosis-promoting protein into the hydrophobic cleft composed of BH1, BH2, and BH3 from the anti-apoptotic protein. In addition to BH1 and BH2, the BH4 domain is required for anti-apoptotic activity. In contrast, the BH3 domain is important and sufficient by itself for apoptosis-promoting activity.

[0005] Similar to oncogene dependence, in which tumor cells rely on a single dominant gene for survival, tumor cells can also become dependent on Bcl-2 for survival. Bcl-2 overexpression is frequently observed in solid tumors such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), relapsed / refractory chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), non-Hodgkin lymphoma (NHL), as well as pancreatic cancer, prostate cancer, breast cancer, and small cell and non-small cell lung cancer (Cancer 2001, 92, 1122-1129; Cancer Biol. 2003; 13: 115-23; Curr. Cancer Drug Targets 2008, 8, 207-222; Cancers 2011, 3, 1527-1549). Dysregulated apoptosis pathways are also thought to be involved in the pathology of other major diseases, including neurodegenerative diseases (upregulated apoptosis), such as Alzheimer's disease, and proliferative diseases (downregulated apoptosis), such as cancer, autoimmune diseases, and thrombotic diseases. Targeting either Bcl-2 or Bcl-xL, many small molecule BH3 mimetics have been developed (Recent Patents on Anti-Cancer Drug Discovery, 2008, 3, 20-30; Bioorg. Med. Chem. Lett. 2016, 26, 2105-2114; Nature Reviews Drug Discovery 2017, 16, 273-284; WO 2002024636; WO 2005049593; WO 2006127364; WO 2006023778; WO 2007040650; WO 2008030836; WO 2009152082; WO 2009036051; WO 2010065824; WO 2010065865; WO 2010083441; WO 2010083442; WO 2010067067; WO 2011029842; WO 2011068561; WO 2011119345;WO 2011 / 149492; WO 2011 / 150016; WO 2012 / 058392; WO 2012 / 017251; WO 2012 / 162365; WO 2012 / 103059; WO 2013 / 053045; WO 2013 / 185202; WO 2013 / 096060; WO 2013 / 096059; WO 2013 / 096055; WO 2013 / 096051; WO 2013 / 096049; US 2011 / 312969; WO 2014 / 158528; WO 2014 / 113413; WO 2018 / 027097; WO 2018 / 041248; WO 2018 / 009444; CN 106749233; CN 106565706). Some Bcl-2 small molecule inhibitors have been investigated at various stages of drug development: The Bcl-2 / Bcl-xL inhibitor ABT-263 (navitoclax, WO 2009 / 155386) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its effectiveness in these settings is limited by platelet death caused by Bcl-xL inhibition and the accompanying thrombocytopenia (Lancet Oncol. 2010, 11, 1149; J. Clin. Oncol. 2011, 29, 909; J. Clin. Oncol. 2012, 30, 488). The next-generation BCL-2 selective inhibitor venetoclax (ABT-199 / GDC-0199) has been developed, which has shown robust activity in these cancers and spared platelets (Journal of Hematology & Oncology 2015, 8, 129;Clinical Advances in Hematology&Oncology 2017, 15, 210). S55746 (also known as BCL201), APG-101, and APG-1252 are being tested in clinical trials. Currently, venetoclax (previously ABT-199) is the only Bcl-2 selective inhibitor approved by the FDA for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) with 17p deletion. However, recently, a new Gly101Val mutation in BCL2 was identified after patients were treated with the Bcl-2 inhibitor venetoclax (ABT-199) for 19 to 42 months (Cancer Discov. 2019, 9, 342 - 353). This mutation significantly decreased the binding affinity of Bcl-2 for venetoclax (ABT-199) by approximately 180-fold in cell-based assays.; Summary of the Invention Problems to be Solved by the Invention

[0006] Therefore, there is a need for novel small molecules that selectively inhibit the Bcl-2 protein for the treatment of diseases of unregulated apoptosis, such as cancer, autoimmune diseases, and thrombotic diseases. Unexpectedly, the inventors of the present application have found that several of the compounds disclosed herein exhibit not only much higher potency and selectivity but also much lower CYP2C9 inhibition, which indicates potentially better efficacy and a lower potential risk of drug-drug interactions (DDIs). In addition, the inventors of the present application have found that the compounds disclosed herein exhibit inhibitory activity against both Bcl-2 wild-type and Bcl-2 G101V mutant types, suggesting a new type of potential Bcl-2 inhibitor without concerns of resistance.; Means for Solving the Problems

[0007] Formula (I)

Chemical Formula

[0008] In one embodiment, R a , Rb and R c and R d each independently, every time it appears, is hydrogen or 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 are defined as in formula (I). In certain embodiments, t is a number from 1 or 2. In a preferred embodiment, L 1 is a direct bond or -(CR a R b )-, where R a and R b are hydrogen or C 1~6 alkyl, preferably hydrogen. In the most 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 certain embodiments, t or v is a number from 1 to 4. 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 are, each time they appear, independently hydrogen or C 1~6 alkyl, and one or two of the CR a R b ) 1~5 -, -(CR a R b ) 1~3 - in -(C≡C)- are replaced by one or two moieties selected from O, S, SO, SO a R b 2, C(O), and NR 2 2. In a further preferred embodiment, L a is a direct bond, -(CR 2 R a ) b -, -(CR 1~5 ) a R b ) 1~3 -(C≡C)-, or -NR a -, where R a , R b and R c are, each time they appear, independently hydrogen or C 1~6 alkyl, and one or two of the CR a R b ) 1~5 -, -(CR a R b )-(C≡C)- are replaced by one or two heteroatoms selected from O or NR a R b 2, where R a is hydrogen or C a alkyl, preferably hydrogen or CH 1~6 3. In another embodiment, L 3 is a direct bond, -CH 2 2-, -O-, -NH-, 2

Chemical Formula

[0011] In a preferred embodiment, L 1 and L 2 are both direct bonds, or L 1 is -CH 2 - or -CH 2 -CH 2 -, 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)-, -SO 2 -, -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-, -CH 2 -, a direct bond or -C(O)-. More preferably, L 3 is -O-.

[0013] In one embodiment, R 3 is a heteroaryl optionally substituted with one or two substituents R 3a as defined in formula (I). Preferably, R 3 is a heteroaryl optionally substituted with one or two substituents R 1~8 selected from halogen, -C 3b alkyl or -NR 3c R 3a , wherein R3b and R 3c is, independently, hydrogen or -C 1~8 alkyl.

[0014] In one embodiment, R 3 is halogen, -C 1~8 alkyl or -NR 3b R 3c One or two substituents R 3a selected from are optionally substituted 5- to 7-membered nitrogen-containing monocyclic heteroaryl, where R 3b and R 3c is, independently, hydrogen or -C 1~8 alkyl. Preferably, R 3 is, respectively, halogen, -C 1~8 alkyl or -NR 3b R 3c One or two substituents R 3a selected from are optionally substituted tetrazolyl, trizolyl, pyrazolyl, pyrrolyl, pyridinyl, pyrimidinyl, where R 3b and R 3c is, independently, hydrogen or -C 1~8 alkyl.

[0015] In one embodiment, R 3 is 8- to 12-membered bicyclic heteroaryl containing one, or two, or three nitrogen atoms. Preferably, R 3 is, respectively, halogen, -C 1~8 alkyl or -NR 3b R 3c One or two substituents R 3a selected from are optionally substituted indolyl, pyrrolopyridinyl or pyrazolopyridinyl, where R 3b and R 3c is, independently, hydrogen or -C 1~8 alkyl. More preferably, R 3 is 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 11- to 14-membered tricyclic heteroaryl containing one, or two, or three, or four, or five nitrogen atoms optionally substituted with one or two substituents R 1~8 selected from halogen, -C 3b alkyl or -NR 3c R 3a , where R 3b and R 3c are independently hydrogen or -C 1~8 alkyl. Preferably, R 3 is pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5i)-yl.

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

[0018] In one embodiment, L 4 is -C(O)NR a SO 2 -, where R a is hydrogen and C 1~6 alkyl; preferably hydrogen. In a preferred embodiment, L 4 is * -C(O)NR a SO 2 - ** , where R a is hydrogen and C 1~6 alkyl; preferably hydrogen, where * refers to the position bonded to ring C and ** refers to the position bonded to ring D.

[0019] In one embodiment, R 4 is -NO 2 , F, Cl, Br, cyano or -SO 2 R 4a , where R 4a is defined as in formula (I). In one embodiment, R 4 is -NO 2, F, Cl, Br, cyano or -SO 2 R 4a wherein R 4a is -C 1~8 alkyl optionally substituted with halogen, preferably -CF 3 . In a preferred embodiment, R 4 is -NO 2 .

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

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

[0022] In a preferred embodiment, ring A is a cycloalkyl ring which is C 3~8 cycloalkyl. In a more preferred embodiment, ring A is selected from cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In particular, ring A is 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2-cyclopentylene, 1,3-cyclopentylene, 1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene, 1,2-cycloheptylene, 1,3-cycloheptylene or 1,4-cycloheptylene.

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

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

[0026] In a more preferred embodiment, ring A is a 5- to 12-membered spiroheterocyclyl containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members. In particular, ring A is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl containing one or two nitrogens or oxygens as ring members. In particular, ring A is a 4-membered / 4-membered or 4-membered / 6-membered monospiroheterocyclyl containing one nitrogen as a ring member. More specifically, ring A is

Chemical Formula

[0027] In particular, ring A is a heterocyclic ring such as piperidine, pyrrolidine, and azetidine; 7-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 8-azabicyclo[3.2.1]octane; tetrahydrothienopyridine (e.g., 4,5,6,7-tetrahydrothieno[2,3-c]pyridine), tetrahydropyrrolopyrazine (e.g., 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine), tetrahydropyrrolopyrazine (e.g., 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine), hexahydroindolizine (e.g., 1,2,3,5,8,8a-hexahydroindolizine), dihydropyrrolothiazole (e.g., 5,6-dihydro-4H-pyrrolo[3,4-d]thiazole), or isoindoline.

[0028] In a more preferred embodiment, ring A is [Chemical formula] (7-azaspiro[3.5]nonane-2,7-diyl), [Chemistry] (2-azaspiro[3.5]nonane-2,7-diyl), [Chemistry] (8-azabicyclo[3.2.1]octane-3,8-diyl), [Chemistry] (3-azaspiro[5.5]undecane-3,9-diyl), [Chemistry] (2-azaspiro[3.3]heptane-2,6-diyl), [Chemistry] (8-azaspiro[4.5]decane-2,8-diyl), [Chemistry] (2-azaspiro[4.5]decane-2,8-diyl), [Chemistry] selected from the group consisting of, wherein, * 1 refers to the position bonded to L 1 and ** 2 refers to the position bonded to L 2 .

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

[0030] In one embodiment, ring B is cycloalkyl, cycloalkenyl, aryl or heterocyclyl optionally substituted with from 1 to 4 substituents R 1 ; R1 independently each time it appears, is selected from the group consisting of halogen, -C 1~8 alkyl, -C 2~8 alkenyl, -C 2~8 alkynyl, cycloalkyl, aryl, heteroaryl, oxo, -CN or -OR 1a ; wherein said -C 1~8 alkyl, -C 2~8 alkenyl, -C 2~8 alkynyl, aryl or heteroaryl is each independently optionally substituted with 1 to 4 substituents R 1d ; R 1a is hydrogen or -C 1~8 alkyl, and said -C 1~8 alkyl is optionally substituted with halogen, hydroxy or -C 1~8 alkyloxy; R 1d independently each time it appears, is halogen, -C 1~8 alkyl, -C 2~8 alkenyl, -C 2~8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR Ba , -SO 2 R Ba , -CONR Ba R Bb , -NR Ba R Bb , -NR Ba COR Bb or -NR Ba SO 2 R Bb ; wherein said -C 1~8 alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is each independently optionally substituted with 1 to 4 substituents R Bd ; R Ba and R Bb are each independently hydrogen, -C 1~8 alkyl, cycloalkyl or aryl, and each of said -C 1~8 alkyl, cycloalkyl or aryl is halogen, hydroxy, -C 1~8Optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R Bd is, each time it appears, independently hydrogen, halogen, -CN, -C 1~8 alkyl, -C 2~8 alkynyl, cycloalkyl or aryl, wherein said -C 1~8 alkyl, -C 2~8 alkynyl or aryl is each optionally substituted with halogen, hydroxy, -C 1~8 alkyloxy, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0031] In one embodiment, the cycloalkyl as ring B is monocyclic C 3~8 cycloalkyl, preferably cyclopentyl or cyclohexyl substituted with R 1 . In one embodiment, R 1 is an aryl group (e.g., phenyl) optionally substituted with R 3~8 which is monocyclic C 1d cycloalkyl.

[0032] In one embodiment, the cycloalkenyl as ring B is monocyclic C 3~8 cycloalkenyl, preferably cyclopentenyl or cyclohexenyl substituted with one, or two, or three R 1 . In one embodiment, R 1 is C 1d alkyl (e.g., C 1~8 alkyl, preferably methyl) or an aryl group (e.g., phenyl) optionally substituted with R 1~6 which is halogen.

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

[0034] In one embodiment, the monocyclic heterocyclyl is a monocyclic 4- to 9-membered heterocyclyl containing one or more heteroatoms selected from the group consisting of NH, O, S, SO or SO 2 as ring members, where the heteroatoms are heteroatoms.

[0035] In one embodiment, the monocyclic heterocyclyl is a monocyclic 4- to 9-membered heterocyclyl containing one nitrogen atom as a ring member. In a preferred embodiment, the monocyclic 4- to 9-membered heterocyclyl containing one nitrogen atom as a ring member is C-bonded or N-bonded. In a further preferred embodiment, the monocyclic 4- to 9-membered heterocyclyl containing one nitrogen atom as a ring member is saturated. In particular, the saturated heterocyclyl includes, but is not limited to, aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl and azocan-1-yl, preferably an N-bonded saturated heterocyclyl containing pyrrolidin-1-yl. In particular, the saturated heterocyclyl includes, but is not limited to, aziridin-2-yl, 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-yl, azocan-3-yl, azocan-4-yl and azocan-5-yl, a C-bonded saturated heterocyclyl. In another further preferred embodiment, the monocyclic 4- to 9-membered heterocyclyl containing one nitrogen atom as a ring member is unsaturated. In an even more preferred embodiment, the monocyclic 4- to 9-membered heterocyclyl containing one nitrogen atom as a ring member contains one carbon-carbon double bond. In particular, the monocyclic 4- to 9-membered heterocyclyl containing one nitrogen atom as a ring member is dihydropyrrolyl, such as 2,3-dihydro-1H-pyrrolyl and 2,5-dihydro-1H-pyrrolyl or tetrahydropyridinyl.

[0036] In another embodiment, the monocyclic heterocyclyl has, as ring members, one nitrogen atom and NH, O, S, SO or SO 2It is a monocyclic 4- to 9-membered heterocyclyl containing one additional heteroatom selected from the group consisting of heteroatoms. In a preferred embodiment, as ring members, one nitrogen atom and NH, O, S, SO or SO 2 The monocyclic 4- to 9-membered heterocyclyl containing one additional heteroatom selected from the group consisting of heteroatoms is C-bonded or N-bonded. In a more preferred embodiment, the monocyclic heterocyclyl is saturated. In an even more preferred embodiment, the saturated monocyclic heterocyclyl is N-bonded. In another even more preferred embodiment, the saturated monocyclic heterocyclyl is C-bonded.

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

[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 with a phenyl group at the 2-position and with one, or two, or three substituents R 1 optionally further substituted on the pyrrolidinyl ring, and the phenyl group at the 2-position is optionally substituted with R 1d as defined in formula (I).

[0040] In one aspect of this embodiment, R 1 is, each time it appears, independently selected from the group consisting of halogen, -C 1~8 alkyl, -C 2~8 alkenyl, -C 2~8 alkynyl, cycloalkyl, aryl, heteroaryl, oxo, -CN or -OR 1a wherein the -C 1~8 alkyl, -C 2~8 alkenyl, -C2~8 Alkynyl, cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents R 1d wherein R 1a is hydrogen or C 1~8 alkyl, preferably methyl, and R 1d is halogen, -C 1~8 alkyl or -OR Ba wherein R Ba is hydrogen or -C 1~8 alkyl. In another embodiment, R 1 is heteroaryl, preferably furanyl, more preferably furan-3-yl. In certain embodiments, R 1 is substituted at the 2-position of the monocyclic heterocyclyl.

[0041] In one aspect of this embodiment, when R 1d is substituted in the phenyl group (including aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, azepan-1-yl or azocan-1-yl, preferably pyrrolidin-1-yl group) at the 2-position of ring B, it is independently halogen, -C 1~8 alkyl, -C 2~8 alkenyl, -C 2~8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR Ba , -SO 2 R Ba , -CONR Ba R Bb , -NO 2 , -NR Ba R Bb , -NR Ba COR Bb or -NR Ba SO 2 R Bb wherein the -C 1~8 alkyl, -C 2~8 alkenyl, -C 2~8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently 1 to 4 substituents R defined by formula (I) Bd, preferably one or two substituents R defined by formula (I) Bd is optionally substituted. In another embodiment, one R 1d is at the 2-position of the phenyl ring at the 2-position of ring B.

[0042] In one embodiment, -C 1d as R 1~8 alkyl is further optionally substituted with one to four substituents R 3~8 which are halogen, phenyl, cycloalkyl (e.g., C 1~6 cycloalkyl, preferably cyclopropyl), heterocyclyl optionally substituted with C Bd alkyl (e.g., piperazinyl, piperidinyl). In particular, R 1d is -C Bd alkyl selected from methyl, ethyl, isopropyl, propyl, tert-butyl and isobutyl, optionally substituted with R 1~8 . In another embodiment, two methyl groups are at the 2-position of the phenyl ring at the 2-position of ring B.

[0043] In one embodiment, cycloalkyl as R 1d is further optionally substituted with one to four substituents R 2~8 which are halogen, cyano, C 1~8 alkynyl (preferably ethynyl) or C 3 alkyl optionally substituted with halogen (preferably CF Bd ). In particular, R 1d is C Bd cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted with R 3~8 . In another embodiment, one cyclopropyl is at the 2-position of the phenyl ring at the 2-position of ring B.

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

[0045] In one embodiment, R 1d as - C 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 cycloalkyl (preferably cyclopropyl or cyclohexyl), aryl (preferably phenyl), where C 1~8 alkyl, C 3~8 cycloalkyl and aryl are each independently substituted with halogen, heterocyclyl (preferably monocyclic 4 - to 9 - membered heterocyclyl, more preferably morpholino), hydroxy or - C 1~8 alkoxyl (preferably methoxyl).

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

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

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

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

[0051] In one embodiment, ring B is pyrrolidin-1-yl substituted with a heteroaryl group, preferably substituted with a heteroaryl group at the 2-position. In one aspect, the heteroaryl is a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. Preferably, the heteroaryl is pyridinyl, furanyl, thiophenyl, or pyrazolyl. In another aspect, the heteroaryl is optionally substituted with a halogen or C 3~8 Optionally substituted with cycloalkyl (preferably cyclopropyl).

[0052] In one embodiment, ring B is -C 1~8 alkyl, -C 2~8 alkenyl or -C 2~8 alkynyl substituted, preferably pyrrolidin-1-yl substituted with -C 1~8 alkyl, -C 2~8 alkenyl or -C 2~8 alkynyl at the 2-position, and each of the -C 1~8 alkyl, -C 2~8 alkenyl or -C 2~8 alkynyl is unsubstituted or substituted with a phenyl group, and the phenyl group is optionally substituted with a halogen or C 3~8 Optionally substituted with cycloalkyl (preferably cyclopropyl). In a preferred embodiment, ring B is pyrrolidin-1-yl optionally substituted with a phenyl group optionally substituted as described above, and substituted with methyl, ethenyl, or ethynyl optionally substituted with a phenyl group optionally substituted as described above.

[0053] In a preferred embodiment, ring B is pyrrolidin-1-yl optionally substituted with 1 to 4 substituents R 1 as defined by formula (I).

[0054] In a preferred embodiment,

Chemical formula

Chemical formula

[0055] In a preferred embodiment, ring B is a 2-substituted pyrrolidin-1-yl group, L 1 is a direct bond, L 2 is a direct bond, ring A is a 1,4-phenylene ring or a 5- to 12-membered spiroheterocyclyl containing one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members, preferably a 5- to 12-membered spiroheterocyclyl containing one or two nitrogens as ring members; more preferably a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl containing one or two nitrogens or oxygens as ring members; most preferably, ring A is 7-azaspiro[3.5]nonane-2,7-diyl, 2-azaspiro[3.5]nonane-2,7-diyl, 3-azaspiro[5.5]undecane-3,9-diyl, 2-azaspiro[3.3]heptane-2,6-diyl, 8-azaspiro[4.5]decane-2,8-diyl or 2-azaspiro[4.5]decane-2,8-diyl. In a more preferred embodiment, ring B is a 2-(substituted phenyl)pyrrolidin-1-yl group, L 1is a direct bond, L 2 is a direct bond, ring A is a 1,4-phenylene ring or a 5- to 12-membered spiroheterocyclyl containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members, preferably a 5- to 12-membered spiroheterocyclyl containing one or two nitrogens as ring members; more preferably a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl containing one or two nitrogens or oxygens as ring members; most preferably, ring A is 7-azaspiro[3.5]nonane-2,7-diyl, 2-azaspiro[3.5]nonane-2,7-diyl, 3-azaspiro[5.5]undecane-3,9-diyl, 2-azaspiro[3.3]heptane-2,6-diyl, 8-azaspiro[4.5]decane-2,8-diyl or 2-azaspiro[4.5]decane-2,8-diyl. In an even more preferred embodiment, ring B is a 2-(2-substituted phenyl)pyrrolidin-1-yl group or a 2-(3-substituted phenyl)pyrrolidin-1-yl group, L 1 is a direct bond, L 2 is a direct bond, ring A is a 1,4-phenylene ring or 7-azaspiro[3.5]nonane-2,7-diyl, 2-azaspiro[3.5]nonane-2,7-diyl, 3-azaspiro[5.5]undecane-3,9-diyl, 2-azaspiro[3.3]heptane-2,6-diyl, 8-azaspiro[4.5]decane-2,8-diyl or 2-azaspiro[4.5]decane-2,8-diyl, wherein the phenyl group at the 2-position of pyrrolidin-1-yl is substituted with 1 to 4 substituents R 1d as defined by formula (I). In an alternative preferred embodiment, ring B is a 2-(2-substituted phenyl)pyrrolidin-1-yl group or a 2-(3-substituted phenyl)pyrrolidin-1-yl group, L 1is a direct bond, ring A is a 1,4 - cyclohexylene ring or 1,4 - cyclohex - 3 - enyl, 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 substituted with 1 to 4 substituents R 1d as defined by formula (I). In one embodiment, one substituent R 1d is substituted at the 2 - position of the phenyl group at the 2 - position of pyrrolidin - 1 - yl.

[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 -, where t is a number from 1 to 7, and one or two CR a R b ) t - moieties in -(CR a R b ) a - are unsubstituted or substituted with one or more moieties selected from O and NR a , where R b and R are 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 Rb ) 1~3 or -NH-, where R a and R b are defined as in formula (I), whereby -L 5 -CyC moieties are each 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, -(CH 2 ) 1~4 -, -O-(CH 2 ) 1~3 -, -NH-(CR a R b )-(CH 2 ) 2 - or -NH-, where R a is hydrogen and R b is C 1~8 alkyl optionally substituted with phenyl-S-, whereby -L 5 -CyC moieties are each CyC, -(CH 2 ) 1~4 -CyC, -O-(CH 2 ) 1~3 -CyC, -NH-(CR a R b )-(CH 2 ) 2 -CyC or -NH-CyC. More preferably, L 5 is a direct bond, -CH 2 -, -O-CH 2 -, -NH-CH 2 - or -NH-, whereby -L 5 -CyC moieties are each CyC, -CH 2 -CyC, -O-CH 2 -CyC, -NH-CH 2 -CyC or -NH-CyC

[0059] In one embodiment, CyC is a cycloalkyl or heterocyclyl optionally substituted with one or two substituents R 5a each; R 5a is independently hydrogen, halogen, cyano, oxo, -OR 5b , -NR 5b R 5c , -COR 5b , -SO 2 R 5b , -C 1~8 alkyl, -C 2~8 alkynyl, -cycloalkyl or heterocyclyl, each of the -C 1~8 alkyl and heterocyclyl being optionally substituted with one or two substituents R 5f selected from hydrogen, halogen, cyano, -OR 1~8 , -C 5e alkyl, -cycloalkyl or heterocyclyl; wherein R 5b and R 5c are each independently hydrogen, -C 1~8 alkyl or heterocyclyl, the -C 1~8 alkyl being optionally substituted with one or two substituents R 5f R 5g selected from hydrogen, -NR 5e R R 5f and R 5g are each independently hydrogen or -C 1~8 alkyl; or two adjacent Rs on the phenyl ring together with the phenyl ring form a benzo ring, as described above. 5

[0060] In one embodiment, CyC is a monocyclic C 5a cycloalkyl or bridged cycloalkyl optionally substituted with one or two substituents R 3~8 each;

Chemical formula

[0061] In one embodiment, CyC is each one or two R 5a optionally substituted with, a) a monocyclic 4- to 9-membered heterocyclyl group containing one nitrogen, oxygen, or sulfur heteroatom as a ring member; b) a monocyclic 4- to 9-membered heterocyclyl group containing two heteroatoms selected from oxygen, sulfur, and nitrogen as ring members; and c) a 5- to 20-membered spiroheterocyclyl containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members is a heterocyclyl selected from.

[0062] In a preferred embodiment, CyC is a monocyclic 4- to 6-membered heterocyclyl group containing one nitrogen, oxygen, or sulfur heteroatom as a ring member. More preferably, Cyc is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, and piperidinyl. Even more preferably, CyC is selected from oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, azetidin-3-yl, azetidin-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-2-yl, and piperidin-3-yl.

[0063] In a preferred embodiment, CyC is a monocyclic 6-membered heterocyclyl group containing two heteroatoms selected from oxygen and nitrogen as ring members. More preferably, CyC is 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 is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl containing one or two nitrogens or oxygens as ring members. More preferably, CyC is

Chemical formula

Chemical formula

[0065] In a preferred embodiment, R 5a is independently hydrogen, halogen, cyano, oxo, -OR 5b , -NR 5b R 5c , -COR 5b , -SO 2 R 5b , -C 1~8 alkyl, -C 2~8 alkynyl, monocyclic C 3~8 cycloalkyl or a monocyclic 4- to 9-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen, or oxygen, or sulfur heteroatoms as ring members, each of said -C 1~8 alkyl and monocyclic 4- to 9-membered heterocyclyl group is optionally substituted with one or two substituents R 5e . Preferably, cycloalkyl as R 5a is C 3~6Cycloalkyl; more preferably cyclopropyl. Preferably, R 5a The heterocyclyl as R is a 4- to 6-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms as ring members. More preferably, R 5a The heterocyclyl as R is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or morpholinyl. Even more preferably, R 5a The heterocyclyl as R is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl or morpholin-4-yl.

[0066] In one embodiment, R 5e The heterocyclyl as R is a monocyclic 4- to 9-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms as ring members. Preferably, R 5e The heterocyclyl as R is tetrahydro-pyran-4-yl.

[0067] In one embodiment, R 5a is -NR 5b R 5c wherein R 5b is hydrogen and R 5c is heterocyclyl. In a more preferred embodiment, R 5a is -NR 5b R 5c wherein R 5b is hydrogen and R 5c is tetrahydro-pyran-4-yl. In one embodiment, R 5a is -NR 5b R 5c wherein R 5b and R 5c are each independently hydrogen or -C 1~6 alkyl substituted with cycloalkyl, preferably -C 3~8 alkyl substituted with monocyclic C 1~6 cycloalkyl.

[0068] In one embodiment, R 5a is -OR 5b or -SO 2 R 5b wherein R 5b is hydrogen or C 1~8 alkyl, preferably methyl.

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

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

[0071] In a preferred embodiment, -L 5 -CyC is

Chemical formula

Chemical formula

Chemical formula

[0072] Formula (II)

Chemical formula

[0073] Compounds of formula (II) are those of formula (I) wherein L 1 and L 2 are each independently a direct bond and L 4 is -C(O)NHSO 2 -; L 3 is -O- and R 3 is pyrrolo[2,3-b]pyridin-5-yl; R 4 is -NO 2 ).

[0074] In certain embodiments, ring A is 1,4-phenylene. In certain embodiments, ring A is a 5- to 12-membered spiroheterocyclyl containing one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members; preferably, ring A is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl containing one or two nitrogens or oxygens as ring members; more preferably, ring A is [Chemistry] (7-azaspiro[3.5]nonane-2,7-diyl), [Chemistry] (2-azaspiro[3.5]nonane-2,7-diyl), [Chemistry] (3-azaspiro[5.5]undecane-3,9-diyl), [Chemistry] (2-azaspiro[3.3]heptane-2,6-diyl), wherein, * 1 refers to the position bonded to the pyrrolidinyl ring, and ** 2 refers to the position bonded to the phenyl ring.

[0075] In certain embodiments, 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 with a phenyl group at the 2-position and further optionally substituted with one, or two, or three substituents R 1 in the pyrrolidin-1-yl ring, and the phenyl group at the 2-position (i.e., the ortho-position) is optionally substituted with R 1d as defined in formula (I).

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

[0077] In one embodiment of formula (III), ring A is

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0078] In certain embodiments of the sub-genus of formula (II), (III), (III-A), (III-B), (III-C), (III-D) or (III-E), R 2 is hydrogen.

[0079] In certain embodiments of formula (II), (III), (III-A), (III-B), (III-C), (III-D) or (III-E), R 1d is defined by formula (I). Preferably, R 1d when substituted on the phenyl group (aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, azepan-1-yl or azocan-1-yl, preferably containing a pyrrolidin-1-yl group) at the 2-position of ring B, is independently halogen, -C 1~8 alkyl, -C 2~8 alkenyl, -C 2~8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR Ba , -SO 2 R Ba , -CONR Ba R Bb , -NO 2 , -NR Ba R Bb , -NR Ba COR Bb or -NR Ba SO 2 R Bb ; wherein said -C 1~8 alkyl, -C 2~8 alkenyl, -C 2~8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is each independently optionally substituted with 1 to 4 substituents R Bd as defined by formula (I), preferably 1 or 2 substituents R Bd as defined by formula (I). In another aspect, one R 1d is at the 2-position of the phenyl ring at the 2-position of ring B.

[0080] In certain preferred embodiments of subgenus formula (II), (III), (III-A), (III-B), (III-C), (III-D) or (III-E), R 1dis methyl, ethyl, isopropyl, propyl or methoxymethyl or two methyls at the position of the phenyl ring; or propenyl; or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or ethoxy or isopropoxy; or amino or dimethylamino.

[0081] In certain preferred embodiments for the subgenus of formula (III), (III-A), (III-B), (III-C), (III-D) or (III-E), the 2-(2-substituted phenyl)pyrrolidin-1-yl moiety as ring B is

Chemical formula

Chemical formula

[0082] In certain preferred embodiments for the subgenus of formula (II), (III), (III-A), (III-B), (III-C), (III-D) or (III-E), m is 1; and L 5 is a direct bond, -(CR a R b ) t - or -NR a -, where t is a number from 1 to 7, and one or two CR a R b ) t - in the CR a R b moieties are unsubstituted or substituted with one or more moieties selected from O and NR a , where R a and R b are 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 are defined as in formula (I), whereby the -L 5 -CyC moieties are each 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, -(CH 2 ) 1~4 -, -O-(CH 2 ) 1~3 -, -NH-(CR a R b )-(CH 2 ) 2 - or -NH-, where R a is hydrogen and R b is C 1~8 alkyl optionally substituted with phenyl-S-, whereby the -L 5 -CyC moieties are each CyC, -(CH 2 ) 1~4 -CyC, -O-(CH 2 ) 1~3 -CyC, -NH-(CR a R b )-(CH 2 ) 2 -CyC or -NH-CyC. More preferably, L 5 is a direct bond, -CH 2 -, -O-CH 2 -, -NH-CH 2 - or -NH-, whereby the -L 5 -CyC moieties are each CyC, -CH 2 -CyC, -O-CH 2 -CyC, -NH-CH 2 -CyC or -NH-CyC.

[0084] In one embodiment, CyC is a cycloalkyl or heterocyclyl optionally substituted with one or two substituents R 5a each; R 5a is independently hydrogen, halogen, cyano, oxo, -OR 5b , -NR 5b R 5c , -COR 5b , -SO 2 R 5b , -C 1~8 alkyl, -C 2~8 alkynyl, -cycloalkyl or heterocyclyl, each of said -C 1~8 alkyl and heterocyclyl being optionally substituted with one or two substituents R 5f each independently selected from hydrogen, halogen, cyano, -OR 1~8 , -C 5e alkyl, -cycloalkyl or heterocyclyl; wherein R 5b and R 5c are each independently hydrogen, -C 1~8 alkyl or heterocyclyl, said -C 1~8 alkyl being optionally substituted with one or two substituents R 5f R 5g each independently selected from hydrogen, -NR 5e R or -cycloalkyl; 5f wherein R 5g and R 1~8 are each independently hydrogen or -C alkyl; or 5 two adjacent R

[0085] In one embodiment, CyC is a monocyclic C 5a cycloalkyl or bridged cycloalkyl optionally substituted with one or two substituents R 3~8 each;

Chemical formula

[0086] In one embodiment, CyC is each one or two R 5a optionally substituted with, a) a monocyclic 4- to 9-membered heterocyclyl group containing one nitrogen, oxygen, or sulfur heteroatom as a ring member; b) a monocyclic 4- to 9-membered heterocyclyl group containing two heteroatoms selected from oxygen, sulfur, and nitrogen as ring members; and c) a 5- to 20-membered spiroheterocyclyl containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members is a heterocyclyl selected from.

[0087] In a preferred embodiment, CyC is a monocyclic 4- to 6-membered heterocyclyl group containing one nitrogen, oxygen, or sulfur heteroatom as a ring member. More preferably, Cyc is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, and piperidinyl. Even more preferably, CyC is selected from oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, azetidin-3-yl, azetidin-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-2-yl, and piperidin-3-yl.

[0088] In a preferred embodiment, CyC is a monocyclic 6-membered heterocyclyl group containing two heteroatoms selected from oxygen and nitrogen as ring members. More preferably, CyC is 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 is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl containing one or two nitrogens or oxygens as ring members. More preferably, CyC is

Chemical formula

Chemical formula

[0090] In a preferred embodiment, R 5a is independently hydrogen, halogen, cyano, oxo, -OR 5b , -NR 5b R 5c , -COR 5b , -SO 2 R 5b , -C 1~8 alkyl, -C 2~8 alkynyl, monocyclic C 3~8 cycloalkyl or a monocyclic 4- to 9-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen, or oxygen, or sulfur heteroatoms as ring members, wherein each of said -C 1~8 alkyl and monocyclic 4- to 9-membered heterocyclyl group is optionally substituted with one or two substituents R 5e . Preferably, cycloalkyl as R 5a is C 3~6Cycloalkyl; more preferably cyclopropyl. Preferably, R 5a The heterocyclyl as R is a 4- to 6-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms as ring members. More preferably, R 5a The heterocyclyl as R is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or morpholinyl. Even more preferably, R 5a The heterocyclyl as R is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl or morpholin-4-yl.

[0091] In one embodiment, R 5e The heterocyclyl as R is a monocyclic 4- to 9-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms as ring members. Preferably, R 5e The heterocyclyl as R is tetrahydro-pyran-4-yl.

[0092] In one embodiment, R 5a is -NR 5b R 5c wherein R 5b is hydrogen and R 5c is heterocyclyl. In a more preferred embodiment, R 5a is -NR 5b R 5c wherein R 5b is hydrogen and R 5c is tetrahydro-pyran-4-yl. In one embodiment, R 5a is -NR 5b R 5c wherein R 5b and R 5c are each independently hydrogen or -C 1~6 alkyl substituted with cycloalkyl, preferably -C 3~8 alkyl substituted with monocyclic C 1~6 cycloalkyl.

[0093] In one embodiment, R 5a is -OR 5b or -SO 2 R 5b wherein R 5b is hydrogen or C 1~8 alkyl, preferably methyl.

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

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

[0096] In certain embodiments, m is 1 and R 5 is

Chemical formula

Chemical formula

[0097] In preferred embodiments, m is 1 and R 5 is

Chemical formula

[0098] In certain embodiments, the carbon atom at the 2-position of the pyrrolidinyl ring to which the phenyl ring in subgenus of formula (III), (III-A), (III-B), (III-C), (III-D) or (III-E) is attached has an (S)-configuration.

[0099] In certain embodiments, the compound of formula (I) is of formula (IV)

Chemical formula

[0100] In certain embodiments, the carbon atom at the 2-position of the piperazinyl ring to which the phenyl ring in subgenus of formula (IV) is attached has an (S)-configuration or an (R)-configuration.

[0101] The inventors of the present application have found that compounds of formula (III) and formula (IV) including subgenus of formula (III-A), (III-B), (III-C), (III-D) or (III-E) are more potent and more selective due to the optimal combination of substitution of the phenyl group at the spiro or phenylene moiety and the position of the nitrogen-bonded heterocyclyl of the compounds disclosed herein (especially the 2-(2-substituted phenyl)pyrrolidin-1-yl moiety for formula (III) and 2-(2-substituted phenyl)piperazin-1-yl for formula (IV)).

[0102]

Chemical formula

[0103] A method for treating a disease of unregulated apoptosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or stereoisomer thereof is disclosed herein. In one embodiment, the disease of unregulated apoptosis is cancer such as bladder cancer, brain tumor, breast cancer, myeloid cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies derived from T cells or B cells, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, etc., which are disclosed in WO 2005 / 049593 pamphlet and WO 2005 / 049594 pamphlet.

[0104] In one embodiment, the disease of unregulated apoptosis is an autoimmune disease such as systemic lupus erythematosus (SLE).

[0105] A pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier is disclosed herein.

[0106] Definitions The following terms have the meanings set forth below throughout this specification.

[0107] As used herein, including in the appended claims, singular terms such as "a", "an", and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0108] The term "or" is used to mean "and / or" and is used synonymously therewith unless the context clearly dictates otherwise.

[0109] The term "alkyl" refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups containing 1 to 18, for example 1 to 12, further for example 1 to 10, even further for example 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. An alkyl group containing 1 to 6 carbon atoms (i.e., C 1~6 alkyl) includes, but is not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl groups. The alkyl group can be optionally enriched with deuterium, such as -CD 3 , -CD 2 CD 3 , etc.

[0110] The term "halogen" refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I).

[0111] The term "haloalkyl" refers to an alkyl group in which one or more hydrogens are substituted with one or more halogen atoms such as fluoro, chloro, bromo and iodo. Examples of haloalkyl include, but are not limited to, haloC 1~8 alkyl, haloC 1~6 alkyl or haloC 1~4 alkyl, such as -CF 3 , -CH 2 Cl, -CH 2 CF 3 , -CCl 2 , CF 3 , etc.

[0112] The term "alkenyl" refers to a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18, for example 2 to 8, and further for example 2 to 6 carbon atoms. An alkenyl group, for example C 2~6 Examples of alkenyl include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl groups.

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

[0114] The term "alkyloxy" or "alkoxy" refers to an alkyl group as defined above that is bonded to the parent molecular moiety via an oxygen atom. Alkyloxy, for example C 1~6 Alkyloxy or C 1~4 Examples of alkyloxy include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0115] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups including fused, bridged, or spirocycloalkyl.

[0116] For example, a cycloalkyl group may contain 3 to 12, such as 3 to 10, more particularly such as 3 to 8, still more particularly such as 3 to 6, 3 to 5 or 3 to 4 carbon atoms. Further, for example, the cycloalkyl group may be selected from monocyclic groups containing 3 to 12, such as 3 to 10, more particularly such as 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl groups. In particular, a saturated monocyclic cycloalkyl group, such as C 3~8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups. In a preferred embodiment, the cycloalkyl is a monocyclic ring (C 3~6 abbreviated as cycloalkyl) containing 3 to 6 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems, such as

Chemical formula

[0117] The term "spirocycloalkyl" refers to a cyclic structure containing carbon atoms and formed by at least two rings sharing one atom. The term "7- to 10-membered spirocycloalkyl" refers to a cyclic structure containing 7 to 10 carbon atoms and formed by at least two rings sharing one atom.

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

[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[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin and benzo 3- to 8-membered cycloalkyl, benzo C 4~6 cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydronaphthyl, and the like. Preferred embodiments are 8- to 9-membered fused cyclics, which refer to a cyclic structure containing 8 to 9 ring atoms among the above examples.

[0120] The term "bridged cycloalkyl" refers to a cyclic structure containing carbon atoms and formed by two rings sharing two atoms that are not adjacent to each other. The term "7- to 10-membered bridged cycloalkyl" refers to a cyclic structure containing 7 to 12 carbon atoms and formed by two rings sharing two atoms that are not adjacent to each other.

[0121] The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group having a single or multiple rings, having at least one double bond and preferably 1 to 2 double bonds, and having 3 to 10 carbon atoms. In one embodiment, the cycloalkenyl is cyclopentenyl or cyclohexenyl, preferably cyclohexenyl.

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

[0123] The term "aryl", used alone or in combination with other terms, refers to a group selected from the following: 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 carbocyclic and aromatic, such as naphthyl and indanyl); and c) tricyclic ring systems, such as 10- to 15-membered tricyclic ring systems (wherein at least one ring is carbocyclic and aromatic, such as fluorenyl).

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

[0125] The term "heteroaryl" refers to a group selected from the following: a) A 5-, 6- or 7-membered aromatic monocyclic ring containing at least one heteroatom selected from nitrogen (N), sulfur (S) and oxygen (O), for example 1 to 4 or in certain embodiments 1 to 3 or in certain embodiments 1 to 2 heteroatoms, with the remaining ring atoms being carbon; b) An 8- to 12-membered bicyclic ring containing at least one heteroatom selected from N, O and S, for example 1 to 4, or in certain embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, with the remaining ring atoms being carbon, at least one ring being aromatic and at least one heteroatom being present in the aromatic ring; and c) An 11- to 14-membered tricyclic ring containing at least one heteroatom selected from N, O and S, for example 1 to 4, or in certain embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, with the remaining ring atoms being carbon, at least one ring being aromatic and at least one heteroatom being present in the aromatic ring.

[0126] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In certain embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In certain embodiments, the total number of S and O atoms in the aromatic heterocyclic ring is 1 or less. When the heteroaryl group contains two or more heteroatomic ring members, the heteroatoms can be the same or different. The nitrogen atoms in the ring of the heteroaryl group can be oxidized to form N-oxides. As used herein, the term "C-bonded heteroaryl" means that the heteroaryl group is bonded to the core molecule by a bond from a C atom of the heteroaryl ring.

[0127] The terms "aromatic heterocycle" and "heteroaryl" are used synonymously throughout the disclosure herein. In certain embodiments, a monocyclic or bicyclic aromatic heterocycle has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring members being carbon, and has 5-, 6-, 7-, 8-, 9-, or 10-ring-forming members. In certain embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In certain embodiments, a monocyclic or bicyclic aromatic heterocycle is a 5- to 6-membered heteroaryl ring, which is monocyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In certain embodiments, a monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring, which is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0128] Examples of the heteroaryl group or monocyclic or bicyclic aromatic heterocyclic ring include, but are not limited to, pyridyl (such as 2-pyridyl, 3-pyridyl or 4-pyridyl, counted from the bonding position assigned priority 1), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl or 1,3,4-thiadiazolyl), tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl or 1,3,4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzofuranyl, benzoxazolyl (such as benzo[d]oxazol-6-yl), pteridinyl, 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, phthalazinyl (such as phthalazin-2-yl, phthalazin-3-yl), benzophthalazinyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo[d]thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl) and 5,6,7,8-tetrahydroisoquinoline.

[0129] "Heterocyclyl", "heterocyclic" or "heterocyclic ring" are synonymous and, as ring members, NH, O, S, SO or SO2 Refers to a non-aromatic heterocyclyl group containing one or more heteroatoms selected from the group consisting of heteroatoms, with the remaining ring members being carbon, which includes monocyclic, fused, bridged and spiro rings, i.e., contains monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl and fused heterocyclic groups.

[0130] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member is a heteroatom selected from the group consisting of NH, O, S, SO or SO 2 The heterocyclic ring can be saturated or partially saturated.

[0131] Exemplary monocyclic 4- to 9-membered heterocyclyl groups include, but are not limited to, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridin-1-yl, aziridin-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl or 1,1-dioxo-thiomorpholinyl (counting from the bond position assigned the highest priority).

[0132] The term "spiroheterocyclyl" or "heterospirocyclic" includes, as ring members, NH, O, S, SO or SO 2Refers to a 5- to 20-membered polycyclic heterocyclyl having a ring formed by one common carbon atom (referred to as a spiro atom) that contains one or more heteroatoms selected from the group consisting of heteroatoms and the remaining ring members are carbon. One or more rings of the spiroheterocyclyl group may contain one or more double bonds, but none of the rings have a completely conjugated π-electron system. Preferably, the spiroheterocyclyl is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of common spiro atoms, the spiroheterocyclyl is divided into monospiroheterocyclyl, dispiroheterocyclyl or polyspiroheterocyclyl, preferably monospiroheterocyclyl or dispiroheterocyclyl, more preferably 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl. Representative examples of spiroheterocyclyl include, but are not limited to, the following groups: 2,3-dihydrospiro[indene-1,2'-pyrrolidine] (e.g., 2,3-dihydrospiro[indene-1,2'-pyrrolidine]-1'-yl), 1,3-dihydrospiro[indene-2,2'-pyrrolidine] (e.g., 1,3-dihydrospiro[indene-2,2'-pyrrolidine]-1'-yl), azaspiro[2.4]heptane (e.g., 5-azaspiro[2.4]heptane-5-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane-6-yl), 2-oxa-6-azaspiro[3.4]octane (e.g., 2-oxa-6-azaspiro[3.4]octane-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane-6-yl), 7-azaspiro[3.5]nonane (e.g., 7-azaspiro[3.5]nonane-7-yl), 2-azaspiro[3.5]nonane (e.g., 2-azaspiro[3.5]nonane-2-yl), 1,7-dioxaspiro[4.5]decane, 2-oxa-7-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, where each ring in the system shares a pair of adjacent atoms (carbon and carbon atoms or carbon and nitrogen atoms) with another ring and contains, as ring members, one or more heteroatoms selected from the group consisting of NH, O, S, SO or SO 2 and the remaining ring members are carbon. One or more rings of the fused heterocyclic group may contain one or more double bonds, but none of the rings have 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 member rings, the fused heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic fused heterocyclyl, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Representative examples of the fused heterocyclic ring include, but are not limited to, the following groups: octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrol-2-yl), octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolinyl (e.g., isoindolin-2-yl), octahydro-benzo[b][1,4]dioxin, dihydrobenzofuranyl, benzod[d][1,3]dioxolyl.

[0134] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group, where every other ring in the system shares two separated atoms and contains, as ring members, NH, O, S, SO or SO 2It contains one or more heteroatoms selected from the group consisting of heteroatoms, and the remaining ring members are carbon. One or more rings of the bridged heterocyclyl group may contain one or more double bonds, but none of the rings have a fully conjugated π - electron system. Preferably, the bridged heterocyclyl is 6 - to 14 - membered, more preferably 7 - to 10 - membered. Depending on the number of member rings, the bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, preferably referring to bicyclic, tricyclic or tetracyclic bridged heterocyclyl, more preferably bicyclic or tricyclic bridged heterocyclyl. Representative examples of the bridged heterocyclyl include, but are not limited to, the following groups: 2 - azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2 - azabicyclo[2.2.2]octyl and 2 - azabicyclo[3.3.2]decyl.

[0135] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, and the ring structure is attached together to the parent heterocyclic group.

[0136] When used, "C - bonded heterocyclyl" refers to a heterocyclyl group bonded to another part of the molecule by a direct bond from a carbon atom of the heterocyclyl ring.

[0137] When used, "N - bonded heterocyclyl" refers to a heterocyclyl group bonded to another part of the molecule by a direct bond from a nitrogen atom of the heterocyclyl ring.

[0138] The compounds disclosed herein may contain asymmetric centers and thus may exist as enantiomers. "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other. If the compounds disclosed herein have more than one asymmetric center, they may further exist as diastereomers. Enantiomers and diastereomers are included in the broader class of stereoisomers. It is intended to include all such possible stereoisomers, such as substantially pure separated enantiomers, their racemic mixtures, and mixtures of diastereomers. It is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. Whenever the composition of the isomers is not specified, all possible isomers are always included.

[0139] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight, such as no more than 30% by weight, more particularly no more than 25% by weight, and even more particularly no more than 20% by weight of any other stereoisomer. In certain embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight, such as no more than 5% by weight, and such as no more than 1% by weight of any other stereoisomer.

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

[0141] When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring may exist in cis and trans forms. The cis form means that both substituents are found on the upper side of the arrangement of the two substituents on carbon, while trans would mean that they are on opposite sides.

[0142] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter "separated") to the desired degree of homogeneity by techniques common in the art. Typically, such separation includes liquid-liquid extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include, for example, reverse phase and normal phase; size exclusion; ion exchange; high pressure, medium pressure, and low pressure liquid chromatography methods and apparatus; small scale analysis; simulated moving bed processes ("SMB") and preparative thin or thick layer chromatography and small scale thin layer and flash chromatography techniques. One of ordinary skill in the art will apply the technique most likely to achieve the desired separation.

[0143] "Diastereomers" refer to stereoisomers of a compound having two or more chiral centers that are not mirror images of each other. A mixture of diastereomers can be separated into its individual diastereomers by methods well known to those of skill in the art, such as chromatography and / or fractional crystallization, based on the physicochemical differences of the individual diastereomers. Enantiomers can be separated by converting a mixture of enantiomers to a mixture of diastereomers by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereoisomers to the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by use of a chiral HPLC column.

[0144] A single stereoisomer, for example a substantially pure enantiomer, can be obtained by resolution of a racemic mixture using methods such as formation of diastereomers with an optically active resolving agent (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C. H., et al. “Chromatographic resolution of enantiomers: Selective review”. J. Chromatogr., 113(3)(1975): pp. 283-302). The racemic mixture of the chiral compounds of the present invention can be separated and isolated by any suitable method including (1) formation of ionic diastereomeric salts with the chiral compound and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers and conversion to the pure stereoisomers, and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions. See Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0145] “Pharmaceutically acceptable salts” refers to salts that are suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc., and that have a reasonable risk-benefit ratio. Pharmaceutically acceptable salts can be prepared in situ or separately during the final isolation and purification of the compounds disclosed herein by reacting the free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base.

[0146] Furthermore, when the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acidic salt. Conversely, when the product is a free base, addition salts, such as pharmaceutically acceptable addition salts, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. One of ordinary skill in the art will recognize various synthetic methods that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0147] As defined herein, "its pharmaceutically acceptable salts" includes salts of at least one compound of formula (I) and salts of stereoisomers of the compounds of formula (I), such as salts of enantiomers and / or salts of diastereomers.

[0148] As used herein, the terms "administer", "administering", "treating" and "treatment", when applied to an animal, human, subject, cell, tissue, organ or body fluid, mean the contact of an exogenous pharmaceutical, therapeutic, diagnostic or composition with the animal, human, subject, cell, tissue, organ or body fluid. Treatment of a cell includes contact of a reagent with the cell and, when a fluid contacts the cell, contact of a reagent with the fluid. The terms "administer" and "treatment" also mean in vitro and ex vivo treatment of cells, for example, by a reagent, diagnostic, binding compound or another cell. As used herein, the term "subject" includes any living organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit), and most preferably a human.

[0149] The terms "effective amount" or "therapeutically effective amount" refer to the amount of an active ingredient, such as a compound, which is sufficient to affect such treatment of a disease, disorder or condition when administered to a subject for treating at least one of the clinical symptoms of the disease or disease or disorder. The "therapeutically effective amount" can vary depending on the compound, the disease, the disorder and / or the symptoms of the disease or disorder, the severity of the disease, the disorder and / or the symptoms of the disease or disorder, the age of the subject being treated and / or the weight of the subject being treated. The appropriate amount in any given case can be apparent to those skilled in the art or can be determined by routine experimentation. In certain embodiments, the "therapeutically effective amount" is the amount of at least one compound disclosed herein and / or at least one of its stereoisomers and / or at least one of its pharmaceutically acceptable salts that is effective to "treat" a disease or disorder in a subject as defined above. In the case of combination therapy, the "therapeutically effective amount" refers to the total amount of the combination of agents for the effective treatment of a disease, disorder or condition.

[0150] The pharmaceutical compositions containing the compounds disclosed herein can be administered to a subject in need thereof by oral administration, inhalation, rectal administration, parenteral or topical administration. In the case of oral administration, the pharmaceutical composition can be a liquid formulation such as a conventional solid formulation such as tablets, powders, granules, capsules, or other liquid formulations such as aqueous or oily suspensions or syrups, solutions, suspensions; in the case of parenteral administration, the pharmaceutical composition can be a solution, aqueous solution, oily suspension concentrate, lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays or injections, more preferably tablets or capsules. The pharmaceutical composition can be a single unit dose at the exact dosage. Further, the pharmaceutical composition can further contain additional active ingredients.

[0151] All formulations of the pharmaceutical compositions disclosed herein can be manufactured by conventional methods in the pharmaceutical art. For example, the active ingredient can be mixed with one or more excipients and then the desired formulation can be prepared. "Pharmaceutically acceptable excipients" include conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as diluents, vehicles such as water and various organic solvents, fillers such as starch and sucrose, binders such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone (PVP); wetting agents such as glycerol; disintegrants such as agar, calcium carbonate and sodium bicarbonate; absorption promoters such as quaternary ammonium compounds; surfactants such as cetyl alcohol; absorbent carriers such as kaolin and soap clay; lubricants such as talc, calcium stearate, magnesium stearate and polyethylene glycol. Further, the pharmaceutical composition may further contain other pharmaceutically acceptable excipients such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, fragrances, sweeteners and dyes.

[0152] The term "disease" refers to any disease, discomfort, illness, symptom or sign and may be synonymous with the terms "disorder" or "pathology".

[0153] Throughout this specification and the claims that follow, unless the context requires otherwise, the term "comprise" and variations such as "comprises" and "comprising" are intended to specify the presence of the stated features but do not preclude the presence or addition of one or more other features. As used herein, the term "comprise" can be replaced with the terms "contain", "include" or sometimes "have".

[0154] Throughout this specification and the claims that follow, n~m the term "C 1~8 " indicates a range including the endpoints, where n and m are integers indicating the number of carbon atoms. Examples include C 1~6 and the like.

[0155] Unless otherwise defined in other parts of this specification, all other technical and scientific terms used in this specification shall have the meanings commonly understood by those skilled in the technical field to which the present invention pertains.

Brief Description of Drawings

[0156]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Modes for Carrying Out the Invention

[0157] The following examples are intended to be merely illustrative and are not to be regarded as limiting in any way. Although efforts have been made to ensure accuracy with respect to the numerical values used (e.g., amounts, temperatures, etc.), some experimental errors and deviations should be accounted for. Unless otherwise indicated, temperatures are in °C. Reagents were purchased from commercial suppliers such as Sigma - Aldrich, Alfa Aesar, or TCI and were used without further purification unless otherwise indicated.

[0158] Unless otherwise indicated, the reactions described below were carried out under a positive pressure of nitrogen or argon or in an anhydrous solvent using a drying tube; the reaction flasks were equipped with rubber septa for the introduction of substrates and reagents via syringe; glassware was oven - dried and / or heat - dried.

[0159] 1 1H NMR spectra were recorded on an Agilent instrument operating at 400 MHz. 1 1H NMR spectra were recorded using CDCl 3 3, CD 2 3Cl 2 3, CD 3 3OD, D 2 2O, d 6 6 - DMSO, d 6 6 - acetone or (CD 3 ) 2 2CO as solvents and tetramethylsilane (0.00 ppm) or residual solvent (CDCl 3 3: 7.25 ppm; CD 3 3OD: 3.31 ppm; D 2 2O: 4.79 ppm; d 6 6 - DMSO: 2.50 ppm; d6 - acetone: 2.05; (CD 3 ) 2 2CO: 2.05) as reference standards. When the multiplicity of peaks was recorded, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when shown, were recorded in Hertz (Hz).

[0160] LC-MS spectrometer (Agilent 1260) detector: MWD (190 - 400 nm), 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, 4.6×50 mm, 2.7 μm Gradient method: Flow rate: 1.8 mL / min

[0161]

Table 1

[0162] Preparative HPLC was performed at room temperature and UV detection at 214 nm and 254 nm, with different flow rates and injection volumes, on a column (inner diameter 150×21.2 mm, 5 μm, Gemini NX-C18).

[0163] In the following examples, the following abbreviations are used. AcOH or HOAc acetic acid aq. aqueous solution BINAP (2,2’-bis(diphenylphosphino)-1,1’-binaphthyl) BH 3 borane brine saturated aqueous sodium chloride solution Boc 2 O 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 CH 3 MgBr 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 Ethanol h or hr hour HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate Hex Hexane 1 H NMR Proton nuclear magnetic resonance H 2 O 2 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 minute MTBE Methyl tert-butyl ether n-BuLi n-Butyllithium NaH Sodium hydride NaBH(OAc) 3 Sodium triacetoxyborohydride NaBH 3 CN Sodium cyanoborohydride NH 4 Cl Ammonium chloride Pd / C Palladium / carbon powder Pd(dppf)Cl 2[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh 3 ) 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 performance 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 r.t. or RT Room temperature sat. Saturated t-BuOK Potassium tert-butoxide TBS tert-Butyldimethylsilyl THF Tetrahydrofuran TEA Triethylamine TFA Trifluoroacetic acid TMSCF 3 Trimethyl(trifluoromethyl)silane

Example

[0164] Preparation of intermediate: Intermediate 1-a: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate

Chem.

[0165] Intermediate 1-b: tert-Butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate

Chemical Structure

[0166] Intermediate 1-c: tert-Butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Chemical Structure

[0167] Intermediate 1-d: Methyl 2-((6-amino-5-chloropyridin-3-yl)oxy)-4-fluorobenzoate

Chemical formula

[0168] Step 2: Methyl 2-((6-aminopyridin-3-yl)oxy)-4-fluorobenzoate A mixture of methyl 4-fluoro-2-((6-nitropyridin-3-yl)oxy)benzoate (50 g, 3.42 mmol) and Pd / C (0.8 g) in EtOH (20 mL) was under H 2It was stirred at 25 °C for 3 hours under (50 Psi). TLC indicated that the reactant was completely consumed. The mixture was filtered and concentrated to remove the solvent. The residue was purified by preparative MPLC (eluent: PE / EA = 20 / 1 to 5 / 1) to obtain 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-fluorobenzoate To a solution of methyl 2-((6-aminopyridin-3-yl)oxy)-4-fluorobenzoate (1 g, 38.14 μmol) in DMF (10 mL) was added NCS (1 g, 76.28 μmol). The mixture was stirred at 25 °C for 4 hours. TLC indicated that the reactant was completely consumed. The mixture was concentrated to remove the solvent. The residue was purified by preparative MPLC (eluent: PE / EA = 20 / 1 to 5 / 1) to obtain methyl 2-((6-amino-5-chloropyridin-3-yl)oxy)-4-fluorobenzoate (169 mg). 1 1H NMR (400 MHz, CDCl 3 ) δ ppm: 7.84 - 7.98 (m, 2H), 7.77 (d, J = 2.6 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 6.77 (ddd, J = 8.7, 7.6, 2.4 Hz, 1H), 6.48 (dd, J = 10.0, 2.4 Hz, 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

Chemical Structure

Chemical Structure

[0171] Step 2: tert-Butyl 2-(2-cyclopropylphenyl)pyrrolidine-1-carboxylate

Chemical formula

[0172] Step 3: 2-(2-Cyclopropylphenyl)pyrrolidine

Chemical formula

[0173] Intermediate 2-b: 2-(2-isopropylphenyl)pyrrolidine

Chemical Structure

Chemical Structure

[0174] Step 2: tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate

Chemical Structure

[0175] Step 3: 2-(2-Isopropylphenyl)pyrrolidine [Chemical formula] A solution of tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (803 mg, 2.77 mmol) in DCM (5 mL) and TFA (2 mL) was stirred at room temperature for 4 h. After removing the solvent, the resulting residue was dissolved in DCM (50 mL) and washed with aqueous NaHCO 3 solution (30 mL × 2). The organic layer was collected, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the desired product as a colorless oil (522 mg). 1 H NMR (400 MHz, DMSO-d 6)δ ppm: 7.52 (d, J = 6.7 Hz, 1H), 7.24 - 7.22 (m, 1H), 7.19 - 7.05 (m, 2H), 4.29 (t, J = 7.6 Hz, 1H), 3.30 - 3.23 (m, 1H), 3.27 - 3.02 (m, 1H), 2.91 - 2.82 (m, 1H), 2.14 - 2.06 (m, 1H), 1.79 - 1.71 (m, 2H), 1.41 - 1.32 (m, 1H), 1.19 (s, 3H), 1.17 (s, 3H). MS (ESI, m / e) [M + 1] + 190.1.

[0176] Intermediate 2 - c: 2-(4 - cyclopropylphenyl)pyrrolidine

Chemical Structure

Chemical Structure

[0177] Step 2: tert - butyl 2-(4 - cyclopropylphenyl)pyrrolidine - 1 - carboxylate

Chemical Structure

[0178] Step 3: 2-(4-Cyclopropylphenyl)pyrrolidine [Chemical formula] A solution of tert-butyl 2-(4-cyclopropylphenyl)pyrrolidine-1-carboxylate (1.2 g, 4.18 mmol) in TFA / DCM (2 mL / 10 mL) was stirred at room temperature for 16 h. The mixture was concentrated to remove the solvent, and the residue was partitioned between NaHCO 3 solution (10 mL) and DCM (10 mL). The organic layer was collected, dried over Na 2 SO 4 and concentrated to afford 620 mg (79.2%) of 2-(4-cyclopropylphenyl)pyrrolidine. MS (ESI, m / e) [M+1] + 188.0.

[0179] Intermediate 2-d: 2-(2-Methoxyphenyl)pyrrolidine [Chemical formula] A solution of 2-(2-bromophenyl)pyrrolidine (500 mg, 2.2 mmol) in MeOH (50 mL) was added with cuprous bromide (158.6 mg, 1.1 mmol) and sodium methoxide (358 mg, 6.6 mmol). The mixture was heated to reflux and stirred overnight. After cooling to room temperature, the mixture was filtered, concentrated, and purified by chromatography column on silica (EA / PE = 1 / 1) to obtain the product (300 mg, 76.6%) as a yellow oil. MS (ESI, m / e) [M+1] + 178.1

[0180] Intermediate 2-e: 2-(2-chloro-6-fluorophenyl)pyrrolidine [Chemical formula] Step 1: 3-(2-chloro-6-fluorobenzoyl)-1-vinylpyrrolidin-2-one [Chemical formula] A dry 100 mL three-necked round-bottom flask equipped with a mechanical stirrer, a dropping funnel, a heating mantle, and a reflux condenser was charged with 60% sodium hydride (0.6 g, 15 mmol) and 25 mL of dry toluene. While heating the stirred suspension to reflux, a mixture of 1.1 g (10 mmol) of vinylpyrrolidin-2-one and 1.9 g (10 mmol) of methyl 2-chloro-6-fluorobenzoate was slowly added. Heating was continued for 10 hours. The reaction mixture was cooled to room temperature, and the resulting thick slurry was carefully diluted with 25 mL of saturated aqueous ammonium chloride solution. The layers were separated, and the aqueous layer was extracted again with 25 mL of toluene. The combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure to obtain 3-(2-chloro-6-fluorobenzoyl)-1-vinylpyrrolidin-2-one as a crude product. [M+1] + 268.0

[0181] Step 2: 5-(2-chloro-6-fluorophenyl)-3,4-dihydro-2H-pyrrole

Chemistry

[0182] Step 3: 2-(2-chloro-6-fluorophenyl)pyrrolidine

Chemistry

[0183] Intermediate 2-f: 2-cyclohexylpyrrolidine

Chemistry

[0184] Intermediate 2-g: 2-(2-(Trifluoromethyl)phenyl)pyrrolidine

Chemical formula

Chemical formula

[0185] Step 2: 4-Amino-1-(2-(trifluoromethyl)phenyl)butan-1-one

Chemical Structure

[0186] Step 3: 2-(2-(Trifluoromethyl)phenyl)pyrrolidine

Chemical formula

[0187] Intermediate 2-h: 4,4-dimethyl-2-phenylpyrrolidine

Chemical Structure

Chemical Structure

[0188] Process 2: N-(2,4-Dimethoxybenzyl)-2,2-dimethyl-4-oxo-4-phenylbutanamide [Chemical formula] A solution of 2,2-dimethyl-4-oxo-4-phenylbutanoic acid (18.03 g, 87.5 mmol), (2,4-dimethoxyphenyl)methanamine (14.62 g, 87.5 mmol), HATU (33.25 g, 87.5 mmol) and Et 3 N (13.3 g, 131.25 mmol) in DCM (200 mL) was stirred overnight at room temperature. The DCM was removed. The residue was purified by column flash on silica gel eluted with EA / PE = 1 / 4 - 1 / 1 (v / v) to give the desired product as a brown oil (30.2 g, 97%). MS (ESI, m / e) [M+1] + 356.1.

[0189] Process 3: 1-(2,4-Dimethoxybenzyl)-3,3-dimethyl-5-phenyl-1,3-dihydro-2H-pyrrol-2-one [Chemical formula] A solution of N-(2,4-dimethoxybenzyl)-2,2-dimethyl-4-oxo-4-phenylbutanamide (30.2 g, 85.1 mmol) in toluene (180 mL) and AcOH (10 mL) was refluxed overnight. It was cooled to room temperature and the solvent was removed. The residue was purified by column flash on silica gel eluted with EA / PE = 1 / 10 - 1 / 1 (v / v) to give the crude product as a yellow oil (10 g, 30% yield). MS (ESI, m / e) [M+1] + 388.1.

[0190] Process 4: 3,3-Dimethyl-5-phenyl-1,3-dihydro-2H-pyrrol-2-one [Chemical formula] A solution of 1-(2,4-dimethoxybenzyl)-3,3-dimethyl-5-phenyl-1,3-dihydro-2H-pyrrol-2-one (9 g, 26.6 mmol) in TFA (50 mL) was stirred at 95 °C for 1 h. It was cooled to room temperature and the TFA was removed. The residue was purified by column flash on silica gel eluting with A / PE = 1 / 1 to afford the crude product 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

Chemical Structure

[0192] Intermediate 2-i: 1-Phenylpyrrolidine-2-carbaldehyde

Chemical Structure

Chemical Structure

[0193] Step 2: (1-Phenylpyrrolidin-2-yl)methanol

Chemical Structure

[0194] Step 3: 1-Phenylpyrrolidine-2-carbaldehyde

Chemical Structure

[0195] Intermediate 2-j: 1-(4-Bromophenyl)-2-methyl-2-phenylpyrrolidine

Chem.

Chem.

[0196] Step 2: 5-Phenyl-3,4-dihydro-2H-pyrrole

Chem.

[0197] Step 3: 2-Methyl-2-phenylpyrrolidine

Chemical formula

[0198] Step 4: 1-(4-Bromophenyl)-2-methyl-2-phenylpyrrolidine

Chemical Structure

[0199] Intermediate 2-k: 1-(azetidin-3-ylmethyl)-2-(2-cyclopropylphenyl)pyrrolidine [Chemical formula] Step 1: tert-Butyl 3-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)azetidine-1-carboxylate Dissolve 2-(2-cyclopropylphenyl)pyrrolidine (0.195 g, 647.19 μmol) in DCE (6 mL), and add tert-butyl 3-formylazetidine-1-carboxylate (359.62 mg, 1.94 mmol) and NaBH(OAc) 3 (274.33 mg, 1.29 mmol). Stir at 15 °C for 4 hours, then add HOAc (116.59 mg, 1.94 mmol). Continue stirring at 15 °C for 24 hours. Next, pour the reaction mixture into saturated NaHCO 3 aqueous solution (4 mL). Extract the mixture with CH 2 Cl 2 (3 × 5 mL) three times. Wash the combined organic phase extracts with brine (5 mL), dry over Na 2 SO 4 and concentrate. Purify the residue by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 20 / 1 - 5 / 1). tert-Butyl 3-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)azetidine-1-carboxylate (0.18 g) was obtained as a yellow liquid.

[0200] Step 2: 1-(Azetidin-3-ylmethyl)-2-(2-cyclopropylphenyl)pyrrolidine CH 2 Cl 2 To a solution of tert-butyl 3-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)azetidine-1-carboxylate (0.7 g, 1.96 mmol) in CH 2Below, it was TFA (2.24 g, 19.64 mmol) at 0 °C. The mixture was stirred at 15 °C for 2 hours. The solution was concentrated under reduced pressure. Using 1N NaOH solution, the residue was adjusted to pH = 14, and CH 2 Cl 2 (3 × 5 mL) was used for extraction. The combined organic layers were dried and concentrated under reduced pressure. 1-(Azetidin-3-ylmethyl)-2-(2-cyclopropylphenyl)pyrrolidine (475 mg) was obtained as a yellow liquid.

[0201] Intermediate 2-l: 1-Methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine

Chemical Structure

[0202] Step 2: tert-Butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate A solution of 1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethan-1-one (5 g, 15.5 mmol) in toluene (10 mL) was added with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (7.2 g, 23.25 mmol), Pd(OAc) 2 (350 mg, 1.55 mmol), tricyclohexylphosphine (870 mg, 3.1 mmol) and K 3 PO 4 (11.5 g, 54.25 mmol). The suspension was stirred at 100 °C for 12 h under a N 2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was further purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 50 / 1 - 10 / 1) to obtain tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (6.1 g) as a yellow oil.

[0203] Step 3: 2,2,2-Trifluoro-1-(2-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)ethan-1-one TFA (20 mL) was added to a solution of tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (6.1 g, 14.5 mmol) in DCM (100 mL) at 0 °C, and then the mixture was stirred at room temperature for 1 h. The pH of the reaction mixture was adjusted to 8 - 9 using an aqueous Na 2 CO 3 solution, and then extracted with DCM. The organic layer was dried, filtered, and the filtrate was concentrated under reduced pressure to obtain 2,2,2-trifluoro-1-(2-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)ethan-1-one (3.8 g) 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 To a solution of 2,2,2-trifluoro-1-(2-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)ethan-1-one (1 g, 3.08 mmol) in MeOH (50 mL), HCHO (37%, 1.5 g 18.49 mmol) and NaBH 3 CN (774 mg, 12.32 mmol) were added. The suspension was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and then the residue was diluted with water (15 mL) and EA (30 mL) with stirring. The organic layer was separated, washed with brine, then dried, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluent: DCM / MeOH = 20 / 1) to give 2,2,2-trifluoro-1-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)ethan-1-one (0.8 g) as a brown oil.

[0205] Step 5: 1-Methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine MeOH (50 mL) and H 2 To a solution of 2,2,2-trifluoro-1-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)ethan-1-one (0.8 g, 2.36 mmol) in MeOH (50 mL) and H 2O (0.2 g, 4.73 mmol) was added. After the addition, the mixture was heated to 60 °C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, and then the residue was diluted with water (15 mL) and EA (30 mL) with stirring. The organic layer was separated, washed with brine, then dried, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluent: DCM / MeOH = 50 / 1) to obtain 1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine (500 mg) as a brown oil. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.51 (dd, J = 0.98, 7.83 Hz, 1H), 7.24 - 7.29 (m, 1H), 7.18 (dt, J = 1.34, 7.40 Hz, 1H), 7.08 (dd, J = 1.22, 7.58 Hz, 1H), 5.55 (td, J = 1.60, 3.27 Hz, 1H), 4.29 (t, J = 7.83 Hz, 1H), 3.23 (ddd, J = 5.14, 7.43, 9.93 Hz, 1H), 3.10 (q, J = 2.81 Hz, 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, 12.50 Hz, 1H), 1.80 - 1.90 (m, 1H), 1.59 - 1.70 (m, 1H). MS (ESI, m / e) [[M+1]] + 243.1.

[0206] Intermediate 2-m: 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine

Chemical Structure

[0207] Step 2: tert-butyl 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine-1-carboxylate To a solution of tert-butyl 2-(2-bromophenyl)-4-fluoropyrrolidine-1-carboxylate (1.5 g, 4.36 mmol) and cyclopropylboronic acid (1.1 g, 13.1 mmol) in toluene (20 mL), Pd(OAc) 2 (98 mg, 0.436 mmol), tricyclohexylphosphine (245 mg, 0.872 mmol), K 3 PO 4 (3.2 g, 15.3 mmol) and H 2 O (1 mL) were added. The suspension was heated at 100 °C and stirred for 12 h under N 2 atmosphere. Water (20 mL) and EtOAc (20 mL) were added to the reaction mixture. The organic layer was separated, washed with brine (20 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 20 / 1) to obtain tert-butyl 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine-1-carboxylate (1.1 g) as a brown oil.

[0208] Step 3: 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine A solution of tert-butyl 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine-1-carboxylate (1.1 g, 3.6 mmol) in HCl solution (20 mL, 4 M in EA) was stirred at room temperature for 2 h. The reaction mixture was concentrated. The residue was dissolved in saturated Na 2CO 3 The solution (20 mL) was diluted with EA (20 mL). The organic layer was separated and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 4 / 1 - 1 / 1) to give 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine (620 mg) as a yellow oil. 1 1H NMR (400 MHz, CDCl 3 3) δ ppm: 7.55 (dd, J = 7.5, 1.4 Hz, 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

Chemical Structure

[0210] Step 2: 4-Amino-1-(3-chloro-2-(dimethylamino)phenyl)butan-1-one To a solution of tert-butyl (4-(3-chloro-2-(dimethylamino)phenyl)-4-oxobutyl)carbamate (1.7 g, 4.99 mmol) in DCM (10 mL) was added TFA (1 mL), and the mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to obtain crude 4-amino-1-(3-chloro-2-(dimethylamino)phenyl)butan-1-one (1.2 g, crude) as a yellow oil.

[0211] Step 3: 2-Chloro-N,N-dimethyl-6-(pyrrolidin-2-yl)aniline To a solution of 4-amino-1-(3-chloro-2-(dimethylamino)phenyl)butan-1-one (1.2 g, 4.98 mmol) in EtOH (20 mL) were added NaBH 3 CN (939.77 mg, 14.95 mmol) and HOAc (2 mL), and then the mixture was stirred at room temperature for 36 h. The reaction mixture was quenched with water (80 mL) and extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (HCl). The pH of the solution of the target peak was adjusted to 10 and extracted with DCM (30 mL × 3). The organic phase was dried over Na 2 SO 4 and concentrated to obtain 2-chloro-N,N-dimethyl-6-(pyrrolidin-2-yl)aniline (297 mg) as a colorless oil. 1 1H NMR (400 MHz, CDCl 3)δ ppm: 7.40 (dd, J = 1.3, 7.7 Hz, 1H), 7.19 (dd, J = 1.5, 7.9 Hz, 1H), 7.12 - 7.05 (m, 1H), 4.56 (t, J = 7.9 Hz, 1H), 3.19 (ddd, J = 5.4, 7.4, 9.9 Hz, 1H), 3.09 - 2.99 (m, 1H), 2.85 (s, 6H), 2.24 (dtd, J = 5.0, 7.7, 12.6 Hz, 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 [Chemical Structure] Step 1: N - (4 - Bromophenyl) - 1 - (2 - cyclopropylphenyl) - 2,2,2 - trifluoroethane - 1 - imine A solution of N - (4 - bromophenyl) - 1,1,1 - triphenyl - 1 - phosphaneimine (1.8 g, 4.16 mmol) and 1 - (2 - cyclopropylphenyl) - 2,2,2 - trifluoroethan - 1 - one (891.83 mg, 4.16 mmol) in toluene (20 mL) was stirred at 110 °C for 12 h. The reaction mixture was cooled and concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 50 / 1 - 10 / 1) to give N - (4 - bromophenyl) - 1 - (2 - cyclopropylphenyl) - 2,2,2 - trifluoroethane - 1 - imine (1.1 g, 2.99 mmol) as a yellow oil.

[0213] Step 2: 4 - Bromo - N - (2 - (2 - cyclopropylphenyl) - 1,1,1 - trifluoropent - 4 - en - 2 - yl)aniline To a solution of N-(4-bromophenyl)-1-(2-cyclopropylphenyl)-2,2,2-trifluoroethan-1-imine (1.1 g, 2.99 mmol) in DCM (10 mL) was added allylmagnesium bromide (1 M, 14.94 mL) at -20 °C, and the mixture was stirred for 2 h. Next, the reaction mixture was quenched with an aqueous solution of HN 4 Cl (10 mL) and extracted with EA (10 mL × 3). The organic layer was dried over Na 2 SO 4 and filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE) to give 4-bromo-N-(2-(2-cyclopropylphenyl)-1,1,1-trifluoropent-4-en-2-yl)aniline (1.20 g) as a white solid.

[0214] Step 3: 4-((4-Bromophenyl)amino)-4-(2-cyclopropylphenyl)-5,5,5-trifluoropentan-1-ol To a solution of 4-bromo-N-(2-(2-cyclopropylphenyl)-1,1,1-trifluoropent-4-en-2-yl)aniline (1.20 g, 2.92 mmol) in THF (10 mL) was added BH 3 .THF (1 M, 14.62 mL) at 0 °C, and the mixture was stirred for 1 h. Next, NaOH (2.5 M, 2.92 mL) and H 2 O 2 (1.49 g, 43.87 mmol) were added to the reaction mixture at 0 °C. After the addition, the mixture was stirred at room temperature for an additional 1.5 h. Next, the reaction mixture was quenched with an aqueous solution of HN 4 Cl (10 mL) and extracted with EA (10 mL × 3). The organic layer was dried over Na 2 SO 4 and filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 50 / 1 to 5 / 1) to give 4-((4-bromophenyl)amino)-4-(2-cyclopropylphenyl)-5,5,5-trifluoropentan-1-ol (0.6 g) as a yellow oil.

[0215] Step 4: 1-(4-Bromophenyl)-2-(2-cyclopropylphenyl)-2-(trifluoromethyl)pyrrolidine To a solution of 4-((4-bromophenyl)amino)-4-(2-cyclopropylphenyl)-5,5,5-trifluoropentan-1-ol (0.6 g, 1.55 mmol) in dioxane (10 mL) were added TEA (469.17 mg, 4.64 mmol) and MsCl (265.56 mg, 2.32 mmol), and the mixture was stirred at room temperature for 1.5 h. Next, the mixture was heated to 80 °C and stirred for 1 h. Next, the reaction mixture was quenched with an aqueous NH 4 Cl solution (10 mL), extracted with DCM (10 mL × 3), dried over Na 2 SO 4 and filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 10 / 1) to give 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-2-(trifluoromethyl)pyrrolidine (306 mg) as a white solid. 1 1H NMR (400 MHz, CDCl 3 ) δ ppm: 7.63 (td, J = 2.6, 6.6 Hz, 1H), 7.26 - 7.22 (m, 2H), 7.06 (d, J = 9.3 Hz, 2H), 6.88 - 6.83 (m, 1H), 6.32 (d, J = 9.0 Hz, 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

Chemical Structure

[0217] Step 2: tert-butyl 2-(((1H-imidazole-1-carbonothioyl)oxy)(2-cyclopropylphenyl)methyl)pyrrolidine-1-carboxylate A solution of tert-butyl 2-((2-cyclopropylphenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (3.40 g, 10.72 mmol), di(1H-imidazol-1-yl)methanethione (5.73 g, 32.16 mol) and DMAP (1.32 g, 1072 mmol) in DCM (30 mL) was stirred at room temperature for 24 hours. The mixture was poured into HCl acid (30 mL, 1 M) and extracted with DCM (50 mL × 3). The organic phase was dried over Na 2 SO 4 and filtered, then concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 200 / 1 - 5 / 1) to obtain tert-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-carboxylate To a solution of tert-butyl 2-(((1H-imidazole-1-carbonothioyl)oxy)(2-cyclopropylphenyl)methyl)pyrrolidine-1-carboxylate (2.5 g, 5.852 mmol) in toluene (10 mL) was added tributyltin hydride (2.55 g, 8.778 mmol) and a catalytic amount of AIBN (192.06 g, 1.1704 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was washed with saturated aqueous KF (50 mL) and extracted with EA (50 mL × 3). The organic phase was dried over Na 2 SO 4 filtered, and concentrated. The residue was purified by preparative HPLC (NaHCO 3 ) to give tert-butyl 2-(2-cyclopropylbenzyl)pyrrolidine-1-carboxylate (650 mg) as a yellow oil.

[0219] Step 4: 2-(2-Cyclopropylbenzyl)pyrrolidine tert-Butyl 2-(2-cyclopropylbenzyl)pyrrolidine-1-carboxylate (600.00 mg, 1.992 mmol) was added to a solution of MTBE / HCl (10 mL, 4 M). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, the pH was adjusted to 10 using saturated Na 2 CO 3 solution, stirred for an additional 15 min, and extracted with EA (30 mL × 3). The organic phase was dried over Na 2 SO 4 filtered, and concentrated to give 2-(2-cyclopropylbenzyl)pyrrolidine (302.00 mg) as a yellow oil. 1 1H NMR (400 MHz, CDCl 3)δ ppm: 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)pyrrolidine [Chemical Structure] Step 1: 2-(Azetidin-1-yl)benzaldehyde To a solution of 2-fluorobenzaldehyde (10 g, 80.6 mmol) and azetidine (9.04 g, 96.7 mmol) in DMSO (50 mL), K 2 CO 3 (33.4 g, 241.17 mmol) was added and the mixture was stirred at 80 °C for 24 h. The mixture was poured into water (300 mL) and extracted with EA (100 mL × 3). The combined organic phases were washed with brine (400 mL), dried over anhydrous Na 2 SO 4 and filtered, then concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 100 / 1 - 20 / 1) to give 2-(azetidin-1-yl)benzaldehyde (9 g, crude) as a yellow oil.

[0221] Step 2: 1-(2-(Azetidin-1-yl)phenyl)-N-(4-bromophenyl)methanimine To a mixture of 2-(azetidin-1-yl)benzaldehyde (4 g, 24.81 mmol) and 4-bromoaniline (4.27 g, 24.81 mmol) in toluene (40 mL) were added 4-methylbenzenesulfonic acid (854 mg, 4.96 mmol) and 4 Å molecular sieves (4 g). The mixture was stirred at 140 °C for 6 h and then concentrated under reduced pressure. Crude 1-(2-(azetidin-1-yl)phenyl)-N-(4-bromophenyl)methanimine (9 g) was obtained as a yellow solid and used in the next step without further purification.

[0222] Step 3: N-(1-(2-(azetidin-1-yl)phenyl)but-3-en-1-yl)-4-bromoaniline To a mixture of 1-(2-(azetidin-1-yl)phenyl)-N-(4-bromophenyl)methanimine (9 g, 28.55 mmol) in DCM (50 mL) was added 2 allylmagnesium bromide (128.5 mL, 1 M) at -20 °C under N. The mixture was stirred at room temperature for 2 h. Then the mixture was poured into saturated NH 4 Cl (200 mL) and extracted with EA (200 mL × 3). The combined organic phases were washed with brine (400 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 20 / 1 to 1 / 1) to give N-(1-(2-(azetidin-1-yl)phenyl)but-3-en-1-yl)-4-bromoaniline (3 g) as a yellow oil.

[0223] Step 4: 4-(2-(azetidin-1-yl)phenyl)-4-((4-bromophenyl)amino)butan-1-ol To a solution of N-(1-(2-(azetidin-1-yl)phenyl)but-3-en-1-yl)-4-bromoaniline (3 g, 8.4 mmol) in THF (20 mL) was added 2 BH under N atmosphere at 0 °C. 3THF (25 g, 25.19 mmol) was added. The mixture was stirred at 25 °C for 2 hours. NaOH (1.01 g, 25.19 mmol) and H 2 O 2 (9.5 g, 83.97 mmol) were added at 0 °C, and then the mixture was stirred for 3 hours. The mixture was poured into H 2 O (50 mL) and extracted with EA (100 mL × 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 4-(2-(azetidin-1-yl)phenyl)-4-((4-bromophenyl)amino)butan-1-ol (0.9 g) was obtained as a yellow oil by purification by column chromatography on silica gel (eluent: PE:EA = 1 / 1~0 / 1).

[0224] Step 5: 2-(2-(azetidin-1-yl)phenyl)-1-(4-bromophenyl)pyrrolidine To a solution of 4-(2-(azetidin-1-yl)phenyl)-4-((4-bromophenyl)amino)butan-1-ol (0.9 g, 2.4 mmol) in THF (5 mL) were added TEA (960 mg, 9.59 mmol) and MsCl (329 mg, 2.88 umol) at 0 °C. After stirring at 25 °C for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, eluent: PE / EA = 1 / 1) to give 2-(2-(azetidin-1-yl)phenyl)-1-(4-bromophenyl)pyrrolidine (388.6 mg) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.24 - 7.18 (m, 2H), 7.17 - 7.11 (m, 1H), 6.94 (dd, J = 1.4, 7.6 Hz, 1H), 6.74 - 6.66 (m, 1H), 6.55 (dd, J = 0.8, 8.0 Hz, 1H), 6.39 - 6.31 (m, 2H), 4.80 (d, J = 7.5 Hz, 1H), 4.11 - 3.91 (m, 4H), 3.69 - 3.57 (m, 1H), 3.36 (q, J = 8.8 Hz, 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

Chemical Structure

[0226] Step 2: tert-Butyl 2-(2-(1,1-difluoroethyl)phenyl)-1H-pyrrole-1-carboxylate To a stirred solution of 1-bromo-2-(1,1-difluoroethyl)benzene (1.5 g, 6.786 mmol) in THF (18 mL) and H 2 O (1.8 mL) were added [1-[(tert-butoxy)carbonyl]-1H-pyrrol-2-yl]boronic acid (1.44 g, 6.824 mmol), X-Phos (0.65 g, 1.363 mmol), K 3 PO 4 (4.34 g, 20.446 mmol) and Pd(OAc) 2(152.8 mg, 0.680 mmol) was added. Under a nitrogen atmosphere, after stirring at 70 °C for 4.5 h, the reaction mixture was diluted with water (50 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 50 / 1) to obtain 2.2729 g of tert-butyl 2-[2-(1,1-difluoroethyl)phenyl]-1H-pyrrole-1-carboxylate (crude) as a dark yellow oil.

[0227] Step 3: tert-Butyl 2-(2-(1,1-difluoroethyl)phenyl)pyrrolidine-1-carboxylate To a stirred solution of tert-butyl 2-[2-(1,1-difluoroethyl)phenyl]-1H-pyrrole-1-carboxylate (2.2729 g, 7.395 mmol) in EtOH (45 mL) was added PtO 2 (1.1365 g, 5.005 mmol) and concentrated HCl acid (4 mL) portionwise. The resulting mixture was stirred at room temperature for 5 h under an H 2 atmosphere (1 atm). After filtering off the PtO 2 , the filtrate was concentrated. The residue was diluted at 0 °C with saturated aqueous NaHCO 3 (200 mL) and then extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na 2 SO 4 and concentrated to obtain 1.7408 g of tert-butyl 2-[2-(1,1-difluoroethyl)phenyl]pyrrolidine-1-carboxylate (crude) as a dark yellow oil.

[0228] Step 4: 2-(2-(1,1-Difluoroethyl)phenyl)pyrrolidine A solution of tert-butyl 2-[2-(1,1-difluoroethyl)phenyl]pyrrolidine-1-carboxylate (1.7408 g, 5.591 mmol) in DCM (35 mL) was added dropwise with HCl solution (4 mL, 4 N in 1,4-dioxane). The resulting mixture was stirred at room temperature for 4 h under N 2 atmosphere. After adjusting the pH value to 8 with saturated NaHCO 3 aqueous solution, the resulting mixture was extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (150 mL) and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, CH 3 CN in water (0.05% NH 4 HCO 3 ), gradient from 10% to 61% in 25 min; detector, UV 220 nm. The resulting eluate was extracted with DCM (3 × 100 mL). Next, the combined organic layers were concentrated to obtain (2-[2-(1,1-difluoroethyl)phenyl]pyrrolidine) (703.1 mg) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ ppm: 7.74 (d, J = 7.9 Hz, 1H), 7.50 - 7.39 (m, 2H), 7.27 (t, J = 7.7 Hz, 2H), 4.56 (t, J = 7.8 Hz, 1H), 3.27 (ddd, J = 9.8, 7.4, 5.1 Hz, 1H), 3.06 (dt, J = 9.8, 7.4 Hz, 1H), 2.23 (dtd, J = 12.8, 7.8, 4.9 Hz, 1H), 2.05 (s, 1H), 2.03 - 1.94 (m, 5H), 1.94 - 1.81 (m, 1H), 1.78 - 1.58 (m, 1H). MS (ESI, m / e) [M + 1] + 212.1.

[0229] Intermediate 2s: 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)piperidine

Chemical Structure

[0230] Step 2: 2-(2-Cyclopropylphenyl)pyridine To a stirred solution of 1-bromo-2-cyclopropylbenzene (12 g, 60.891 mmol) in dioxane (120 mL) was added 2-(tributylstannyl)pyridine (26.90 g, 73.069 mmol) and Pd(PPh 3 ) 4 (7.04 g, 6.089 mmol). The mixture was stirred at 100 °C overnight under a N 2 atmosphere. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with 50 mL of brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 70 / 1) to afford 2-(2-cyclopropylphenyl)pyridine (5.80 g) as a pale yellow oil.

[0231] Step 3: 2-(2-Cyclopropylphenyl)piperidine To a stirred solution of 2-(2-cyclopropylphenyl)pyridine (2.5 g, 12.820 mmol) in EtOH (100 mL) was added HCl acid (concentrated, 3.5 mL) and PtO 2 (0.875 g, 3.846 mmol). The resulting mixture was stirred at room temperature for 4 h under an H 2 (1 atm) atmosphere. After filtering off and removing the PtO 2 , the filtrate was concentrated. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, water and 0.05% TFA in CH 3 CN, gradient of 0% to 10% in 30 min; detector, UV 220 nm to give 900 mg of the crude product, which was further purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 Column 30×150 mm 5um; mobile phase A: water (10 mMOL / L NH4HCO3), mobile phase B: CH 3 CN; flow rate: 60 mL / min; gradient: 25% to 37% of B in 9 min; 254 and 220 nm; Rt: 7.92 min) to give 2-(2-cyclopropylphenyl)piperidine (280 mg) as a yellow oil.

[0232] Step 4: 1-(4-Bromophenyl)-2-(2-cyclopropylphenyl)piperidine To a stirred mixture of 2-(2-cyclopropylphenyl)piperidine (2.50 g, 12.437 mmol), (4-bromophenyl)boronic acid (4.975 g, 24.874 mmol), Cu(OAc) 2 (5.627 g, 31.093 mmol) and activated 4 Å molecular sieves (2.0 g) in DCM (250 mL) was added dropwise DIPEA (4.011 g, 31.093 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h under an O 2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified under the following conditions (column: XBridge Prep OBD C18 Column 30×150 mm 5um; mobile phase A: water (0.05% TFA), mobile phase B: CH 3CN; Flow rate: 60 mL / min; Gradient: 43% B to 46% B in 9 minutes; 254 and 220 nm; Purified by preparative HPLC at Rt: 7.40 minutes) to obtain 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)piperidine (310 mg) as a brown solid. 1 H NMR (300 MHz, methanol-d 4 ) δ ppm: 7.46 (s, 2H), 7.31 (d, J = 8.5 Hz, 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 = 8.4 Hz, 2H), 0.60 (d, J = 6.0 Hz, 1H), 0.50 (d, J = 5.6 Hz, 1H). MS (ESI, m / e) [M+1] + 357.9.

[0233] Intermediate 2-t: 2-(2-cyclopropylphenyl)-4-methylpyrrolidine

Chemical formula

[0234] Step 2: 4 - Methylpyrrolidin - 2 - one To a solution of methyl 3 - methyl - 4 - nitrobutanoate (20 g, 124.10 mmol) in MeOH (200 mL) was added Raney Ni (728.41 mg, 12.41 mmol). The mixture was stirred at 50 °C for 4 h under H 2 atmosphere. TLC indicated that the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to obtain 4 - methylpyrrolidin - 2 - one (10 g) as a yellow solid, which was used in the next step without further purification.

[0235] Step 3: tert - Butyl 4 - methyl - 2 - oxopyrrolidine - 1 - carboxylate To a mixture of 4 - methylpyrrolidin - 2 - one (10 g, 100.88 mmol), DMAP (6.16 g, 50.44 mmol), and TEA (10.21 g, 100.88 mmol) in THF (100 mL) was added (Boc) 2 O (44.03 g, 201.75 mmol). The mixture was stirred at 25 °C for 3 h. TLC indicated that the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 / 1 - 50 / 1). tert - Butyl 4 - methyl - 2 - oxopyrrolidine - 1 - carboxylate (13 g, 64.68% yield) was obtained as a white solid. 1 1H NMR (400 MHz, CDCl 3 ) δ ppm: 3.87 (dd, J = 10.7, 7.6 Hz, 1H), 3.29 (dd, J = 10.7, 6.9 Hz, 1H), 2.64 (dd, J = 17.0, 8.1 Hz, 1H), 2.39 (dd, J = 14.6, 7.5 Hz, 1H), 2.16 (dd, J = 17.0, 8.1 Hz, 1H), 1.53 (s, 9H), 1.14 (d, J = 6.6 Hz, 3H).

[0236] Step 4: tert-Butyl (4-(2-cyclopropylphenyl)-2-methyl-4-oxobutyl) carbamate A mixture of 1-bromo-2-cyclopropylbenzene (3.5 g, 17.76 mmol) in THF (50 mL) was degassed and purged three times with N 2 , then n-BuLi (1.04 g, 16.28 mmol) was added dropwise to the mixture at -68 °C. After stirring for 10 minutes, tert-Butyl 4-methyl-2-oxopyrrolidine-1-carboxylate (2.95 g, 14.80 mmol) in THF (10 mL) was then added to the mixture. Next, the mixture was stirred at -68 °C for 2 hours under a N 2 atmosphere. TLC indicated that the reaction was complete. The reaction mixture was quenched with an aqueous NH 4 Cl solution (20 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1). tert-Butyl (4-(2-cyclopropylphenyl)-2-methyl-4-oxobutyl) carbamate (3.6 g, 76.63% yield) was obtained as a yellow oil. 1 1H NMR (400 MHz, CDCl 3 ) δ ppm: 7.44 (dd, J = 7.7, 1.10 Hz, 1H), 7.32 - 7.38 (m, 1H), 7.17 - 7.24 (m, 1H), 7.03 (d, J = 7.9 Hz, 1H), 4.68 (s, 1H), 3.12 (t, J = 6.3 Hz, 2H), 3.00 (dd, J = 16.8, 5.51 Hz, 2H), 2.77 (dd, J = 16.8, 7.72 Hz, 1H), 2.24 - 2.50 (m, 3H), 1.44 (s, 10H), 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-one A solution of tert-butyl (4-(2-cyclopropylphenyl)-2-methyl-4-oxobutyl)carbamate (3.5 g, 11.03 mmol) in DCM (50 mL) was degassed and purged three times with N 2 and then TFA (12.57 g, 110.26 mmol) was added. The mixture was stirred at 20 °C for 1 h under N 2 atmosphere. TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to afford a residue. The crude product (2.0 g) was used in the next step without purification. 1 H NMR (400 MHz, CDCl3) δ ppm: 7.52 (d, J = 7.7 Hz, 1H), 7.27 - 7.44 (m, 8H), 7.24 (d, J = 1.1 Hz, 1H), 7.08 - 7.19 (m, 4H), 6.97 (d, J = 7.7 Hz, 3H), 4.46 (t, J = 7.2 Hz, 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 = 5.5 Hz, 3H), 1.08 - 1.20 (m, 12H), 0.89 - 0.98 (m, 9H), 0.65 - 0.71 (m, 4H).

[0238] Step 6: 2-(2-Cyclopropylphenyl)-4-methylpyrrolidine A solution of 4-amino-1-(2-cyclopropylphenyl)-3-methylbutan-1-one (2.0 g, 9.20 mmol) in EtOH (20 mL) and HOAc (2 mL) was degassed and purged three times with N 2 and then NaBH 3 CN (983.23 mg, 15.56 mmol) was added to the solution portionwise. The mixture was stirred at 25 °C for 2 h under N 2 atmosphere. LC / MS indicated that the reaction was complete. The reaction mixture was adjusted to pH = 10 with aqueous Na 2 CO 3 solution (1 N) and extracted with EA (20 mL × 5). The combined organic layers were washed with brine (50 mL) and Na 2 SO 4It was dried above and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (TFA conditions). 2-(2-Cyclopropylphenyl)-4-methylpyrrolidine (421 mg) was obtained as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.48 - 7.59 (m, 1H), 7.11 - 7.25 (m, 2H), 7.01 (d, J = 7.3 Hz, 1H), 4.82 - 4.91 (m, 1H), 3.39 (dd, J = 9.9, 6.8 Hz, 1H), 3.24 (dd, J = 10.1, 7.5 Hz, 1H), 2.77 (dd, J = 10.2, 7.8 Hz, 1H), 2.29 - 2.51 (m, 2H), 2.00 (dd, J = 8.3, 5.5 Hz, 1H), 1.35 (d, J = 9.8 Hz, 1H), 1.08 - 1.15 (m, 3H), 0.88 - 0.98 (m, 2H), 0.61 - 0.71 (m, 2H). MS (ESI, m / e) [M+1] + 202.1.

[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

Chemical Structure

[0240] Step 2: (S)-2-(2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)spiro[3.5]nonan-7-one A solution of (S)-2-(2-cyclopropylphenyl)-1-(8,11-dioxadispiro[3.2.47.24]tridecane-2-yl)pyrrolidine (2 g, 5.45 mmol) in acetone (27 mL) was added 1N HCl acid (27 mL, 27.25 mmol). The mixture was stirred at 15 °C for 6 hours. TLC indicated that the reaction was complete. After removal of the solvent, the residue was dissolved in EA (20 mL) and adjusted to pH = 9 using a saturated NaHCO 3 aqueous solution. The organic layer was washed with water and brine and dried over Na 2 SO 4 then filtered and concentrated to obtain (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)spiro[3.5]nonan-7-one (1.7 g, crude) as a yellow oil.

[0241] Step 3: (S)-2-(2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)spiro[3.5]nona-6-en-7-yl trifluoromethanesulfonate A mixture solution of (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)spiro[3.5]nonan-7-one (1.6 g, 4.95 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.12 g, 5.94 mmol) in THF (20 mL) was cooled to -78 °C. 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 indicated that the reaction was complete. The mixture was saturated with NH4 It was poured into an aqueous solution of Cl and extracted with EA. The organic layer was washed with water and brine, and Na 2 SO 4 It was dried over the above, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 50 / 1 to 5 / 1) to obtain (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)spiro[3.5]non-6-en-7-yl trifluoromethanesulfonate (2.4 g, crude) as a yellow oil.

[0242] Step 4: (S)-2-(2-Cyclopropylphenyl)-1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[3.5]non-6-en-2-yl)pyrrolidine A mixed solution of (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)spiro[3.5]non-6-en-7-yl trifluoromethanesulfonate (2.2 g, 4.83 mmol), B 2 PIN 2 (1.84 g, 7.25 mmol), KOAc (1.42 g, 14.49 mmol) and Pd(dppf)Cl 2 (351 mg, 0.48 mmol) was stirred at 85 °C for 3 hours. TLC indicated that the reaction was complete. The mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 10 / 1 to 5 / 1) to obtain (S)-2-(2-cyclopropylphenyl)-1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[3.5]non-6-en-2-yl)pyrrolidine (700 mg, 33% yield) as a yellow solid. 1 1H NMR (400 MHz, CDCl 3)δ ppm: 7.66 (t, J = 6.1 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.25 - 7.12 (m, 4H), 7.04 - 6.99 (m, 1H), 6.35 (s, 1H), 4.39 (s, 1H), 3.40 (s, 1H), 3.28 - 3.10 (m, 1H), 2.73 (s, 1H), 2.38 - 2.25 (m, 1H), 2.05 (s, 2H), 1.99 - 1.80 (m, 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)pyrrolidin-2-yl)phenyl)piperazine-1-carboxylate [Chemical Structure] Step 1: tert-Butyl 4-(2-formylphenyl)piperazine-1-carboxylate To a solution of 2-fluorobenzaldehyde (13.33 g, 107.38 mmol) and tert-butyl piperazine-1-carboxylate (30.0 g, 161.07 mmol) in DMSO (150 mL), K 2 CO 3 (44.52 g, 322.15 mmol) was added. The mixture was stirred at 100 °C for 12 h. TLC indicated that the reactants were completely consumed. The reaction mixture was cooled to room temperature, poured into H 2 O (150 mL), extracted with EA (150 mL × 3), dried over Na 2 SO 4 and filtered and concentrated. The residue was purified by column chromatography (silica gel, PE / EA = 100 / 1 - 30 / 1). tert-Butyl 4-(2-formylphenyl)piperazine-1-carboxylate (8.5 g) was obtained as a yellow solid. 1 1H NMR (400 MHz, CDCl 3)δ ppm: 1.50 (s, 9H), 3.02 - 3.08 (m, 4H), 3.61 - 3.66 (m, 4H), 7.11 (d, J = 8.2 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.52 - 7.58 (m, 1H), 7.83 (dd, J = 7.7, 1.8 Hz, 1H), 10.36 (s, 1H).

[0244] Step 2: (E)-tert-Butyl 4-(2-(((4-bromophenyl)imino)methyl)phenyl)piperazine-1-carboxylate To a solution of tert-butyl 4-(2-formylphenyl)piperazine-1-carboxylate (8 g, 27.55 mmol) and 4-bromoaniline (4.74 g, 27.55 mmol) in toluene (100 mL) were added 4 Å molecular sieves (5 g) and TsOH (474.45 mg, 2.76 mmol). The mixture was stirred at 120 °C for 12 h. TLC indicated that the reactants were completely consumed. 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) was obtained as a brown oil. 1 H NMR (400 MHz, CDCl 3 )δ ppm: 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, 1.6 Hz, 1H), 7.50 - 7.54 (m, 2H), 8.83 (s, 1H).

[0245] Step 3: tert-Butyl 4-(2-(1-((4-bromophenyl)amino)but-3-en-1-yl)phenyl)piperazine-1-carboxylate A solution of (E)-tert-butyl 4-(2-(((4-bromophenyl)imino)methyl)phenyl)piperazine-1-carboxylate (8 g, 18.0 mmol) in DCM (100 mL) was added with allylmagnesium bromide (1 M, 18.0 mL) at -20 °C. The mixture was stirred at -20 °C for 2 h. TLC indicated that the reactants were completely consumed. The reaction mixture was poured into NH 4 Cl aqueous solution (150 mL), extracted with EA (150 mL×3), dried over Na 2 SO 4 and filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether). tert-Butyl 4-(2-(1-((4-bromophenyl)amino)but-3-en-1-yl)phenyl)piperazine-1-carboxylate (6.0 g) was obtained as a yellow oil. 1 1H NMR (400 MHz, CDCl 3 ) δ ppm: 1.51 (s, 9H), 2.47 - 2.66 (m, 2H), 2.83 - 2.98 (m, 5H), 3.48 - 3.75 (m, 3H), 4.23 (s, 1H), 4.89 (dd, J = 8.1, 4.9 Hz, 1H), 5.10 - 5.21 (m, 2H), 5.79 (ddt, J = 17.0, 10.1, 6.9 Hz, 1H), 6.40 - 6.44 (m, 2H), 7.10 - 7.20 (m, 4H), 7.24 (dd, J = 7.2, 1.5 Hz, 1H), 7.34 (dd, J = 7.6, 1.5 Hz, 1H).

[0246] Step 4: tert-Butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenyl)piperazine-1-carboxylate To a solution of tert-butyl 4-(2-(1-((4-bromophenyl)amino)but-3-en-1-yl)phenyl)piperazine-1-carboxylate (6 g, 12.33 mmol) in THF (100 mL) was added BH 3 .THF (1 M, 185.02 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h. Then, NaOH (1.23 g, 30.84 mmol) and H 2 O 2(6.29 g, 185.02 mmol) was added to the mixture at 0 °C. The mixture was stirred at 25 °C for 8 h. TLC indicated that the reactant 4 was completely consumed. The reaction mixture was poured into NH 4 Cl aqueous solution (150 mL), extracted with EA (150 mL × 3), dried over Na 2 SO 4 and filtered and concentrated. The residue was purified by column chromatography (silica gel, PE / EA = 100 / 1 to 30 / 1). tert-Butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenyl)piperazine-1-carboxylate (3.5 g) was obtained as a yellow solid. 1 1H NMR (400 MHz, CDCl 3 ) δ ppm: 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, 5.5 Hz, 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)phenyl)piperazine-1-carboxylate To a solution of tert-butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenyl)piperazine-1-carboxylate (3.5 g, 6.94 mmol) in DCM (50 mL) and TEA (3.51 g, 34.69 mmol) was added MsCl (715.29 mg, 6.24 mmol) at 0 °C, and the mixture was stirred at 25 °C for 1.5 h. LCMS indicated that the reactant was completely consumed and one major peak with the desired MS was observed. The reaction mixture was poured into NH 4 Cl aqueous solution (150 mL), extracted with EA (150 mL × 3), dried over Na 2 SO 4It was dried, 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. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 1.47 - 1.54 (m, 9H), 1.90 - 1.98 (m, 1H), 1.98 - 2.17 (m, 2H), 2.40 - 2.52 (m, 1H), 2.86 - 3.02 (m, 4H), 3.35 - 3.43 (m, 1H), 3.55 - 3.67 (m, 3H), 3.67 - 3.75 (m, 1H), 5.07 - 5.12 (m, 1H), 6.27 - 6.34 (m, 2H), 7.01 - 7.07 (m, 1H), 7.08 - 7.12 (m, 1H), 7.15 - 7.26 (m, 4H). MS (ESI, m / e) [[M+1]] + 486.1.

[0248] Intermediate 2-w: 6-(2-cyclopropylphenyl)-5-azaspiro[2.4]heptane

Chemical Structure

[0249] Step 2: tert-Butyl 2-(2-cyclopropylphenyl)-4-oxopyrrolidine-1-carboxylate To a solution of tert-butyl 2-(2-cyclopropylphenyl)-4-hydroxypyrrolidine-1-carboxylate (2.3 g, 7.6 mmol) in DCM (30 mL) was added NaHCO 3 (640 mg, 7.6 mmol) and Dess-Martin periodinane (3.2 g, 7.6 mmol). The mixture was stirred at 20 °C for 12 h. TLC indicated that the reaction was complete. The reaction mixture was quenched with saturated Na 2 SO 3 aqueous solution (30 mL). The organic layer was washed with brine (30 mL), dried over Na 2 SO 4 and concentrated to afford tert-butyl 2-(2-cyclopropylphenyl)-4-oxopyrrolidine-1-carboxylate (2.1 g, crude) as a yellow oil.

[0250] Step 3: tert-Butyl 2-(2-cyclopropylphenyl)-4-methylenepyrrolidine-1-carboxylate To a mixture of Ph 3 P + MeBr - (5.5 g, 15.3 mmol) in THF (25 mL) was added t-BuOK (1.7 g, 15.3 mmol) in one portion. The mixture was stirred at 20 °C for 1 h. Then, tert-butyl 2-(2-cyclopropylphenyl)-4-oxopyrrolidine-1-carboxylate (2.3 g, 7.64 mmol) was added and the mixture was stirred at 20 °C for 12 h. TLC indicated that the reaction was complete. The reaction mixture was quenched with saturated NH 4 Cl aqueous solution (25 mL) and then extracted with EA (25 mL). The organic layer was washed with brine (25 mL), dried over Na 2 SO 4It was dried and concentrated above. The residue was purified by column chromatography on silica gel eluted with PE / EA = 10 / 1 to obtain tert-butyl 2-(2-cyclopropylphenyl)-4-methylenepyrrolidine-1-carboxylate (1.3 g, yield: 56%).

[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 Et 2 Zn (1 M in toluene, 15 mL, 15 mmol) was added to the mixture at 0 °C, and ClCH 2 I (5.3 g, 30 mmol) was added. Next, the mixture was stirred at 20 °C for 12 hours. TLC showed that a new spot was formed and no starting material remained. The reaction mixture was quenched with saturated NH 4 Cl aqueous solution (50 mL) and extracted with EA (50 mL). The organic layer was washed with brine (50 mL) and dried over Na 2 SO 4 It was dried and concentrated above to obtain tert-butyl 6-(2-cyclopropylphenyl)-5-azaspiro[2.4]heptane-5-carboxylate (1 g, crude) as a yellow oil, which was used directly in the next step.

[0252] Step 5: 6-(2-cyclopropylphenyl)-5-azaspiro[2.4]heptane A solution of tert-butyl 6-(2-cyclopropylphenyl)-5-azaspiro[2.4]heptane-5-carboxylate (1 g, 3.2 mmol) in HCl / EA (10 mL, 4 M) was stirred at 20 °C for 2 hours. LC / MS showed that the reaction was complete. The mixture was concentrated. The residue was purified by preparative HPLC (0.1% TFA conditions). The desired eluent was basified to pH = 10 using saturated Na 2 CO 3 aqueous solution and then extracted with EA (200 mL × 4). The organic layers were combined and Na2 SO 4 It was dried and concentrated above to obtain 6-(2-cyclopropylphenyl)-5-azaspiro[2.4]heptane (293 mg) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.60 (dd, J = 7.6, 1.3 Hz, 1H), 7.13 - 7.25 (m, 2H), 7.01 (d, J = 7.5 Hz, 1H), 4.97 (t, J = 7.8 Hz, 1H), 3.02 - 3.13 (m, 2H), 2.34 (s, 1H), 2.14 (dd, J = 12.3, 7.2 Hz, 1H), 2.04 (t, J = 8.4, 1H), 1.81 - 1.90 (m, 1H), 0.87 - 1.02 (m, 2H), 0.53 - 0.76 (m, 6H). MS (ESI, m / e) [M+1] + 214.1.

[0253] Intermediate 2-x: (R)-1-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)benzyl)-4-methylpiperazine

Chemical formula

[0254] Step 2: (R)-2,2,2-Trifluoro-1-(2-(2-vinylphenyl)pyrrolidin-1-yl)ethenone In dioxane (120 mL), H 2 O (12 mL), a mixture of (R)-1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethanone (5 g, 15.52 mmol), potassium trifluoro(vinyl)borate (2.91 g, 21.73 mmol) and Cs 2 CO 3 (10.11 g, 31.04 mmol) was added with Pd(dppf)Cl 2 (567 mg, 776 μmol) at 20 °C. The mixture was purged with N 2 three times and then heated to 100 °C for 5 h. TLC and LC / MS indicated that the reactants were completely consumed. The reaction mixture was concentrated under reduced pressure (to about 30 mL). The residue was poured into ice water (50 mL). The aqueous phase was extracted with EA (50 mL × 3). The combined organic phases were dried over anhydrous Na 2 SO 4 and filtered and concentrated. The crude product was purified by column chromatography (silica gel, PE / EA = 100 / 1 - 50 / 1). (R)-2,2,2-Trifluoro-1-(2-(2-vinylphenyl)pyrrolidin-1-yl)ethenone (3.4 g, 12.63 mmol, 81.34% yield) was obtained as a yellow oil. 1 1H NMR (400 MHz, CDCl 3 ) δ ppm: 7.44 - 7.51 (m, 1H), 7.21 - 7.27 (m, 2H), 6.88 - 7.07 (m, 2H), 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, 1H), 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 In THF (60 mL), H 2(R)-2,2,2-Trifluoro-1-(2-(2-vinylphenyl)pyrrolidin-1-yl)ethanone (3.4 g, 12.63 mmol) and K 2 O S O 4 .2H 2 O (186 mg, 505.1 μmol) in a mixture of NaIO 4 (10.8 g, 50.51 mmol) was added portionwise at 10 °C. The mixture was stirred at 10 °C for 2 h. TLC indicated that the reactants were completely consumed. The reaction mixture was concentrated to remove THF. The aqueous phase was extracted with EA (50 mL × 3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and filtered and concentrated. (R)-2-(1-(2,2,2-Trifluoroacetyl)pyrrolidin-2-yl)benzaldehyde (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-trifluoroacetyl)pyrrolidin-2-yl)benzyl)piperazine-1-carboxylate To a mixture of (R)-2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzaldehyde (3.4 g, 12.54 mmol) and tert-butyl piperazine-1-carboxylate (4.67 g, 25.07 mmol) in DCE (100 mL), NaBH(OAc) 3 (10.6 g, 50.16 mmol) was added portionwise at 10 °C. The mixture was stirred at 10 °C for 10 h. TLC indicated that the reactants were completely consumed. The reaction mixture was washed with NaHCO 3 (50 mL) and then the organic phase was separated. The organic phase was dried over anhydrous Na 2 SO 4It was dried, filtered, and concentrated. (R)-tert-Butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzyl)piperazine-1-carboxylate (3.5 g) was obtained as a yellow oil. MS (ESI, m / e) [M+1] + 442.3

[0257] Step 5: (R)-tert-Butyl 4-(2-(pyrrolidin-2-yl)benzyl)piperazine-1-carboxylate To a solution of (R)-tert-Butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzyl)piperazine-1-carboxylate (3.3 g, 7.47 mmol) in EtOH (50 mL), NaBH 4 (662.13 mg, 16.44 mmol) was added portionwise at 20 °C. The mixture was stirred at 20 °C for 4 h. TLC indicated that the reactant was completely consumed. The reaction mixture was concentrated to remove EtOH (ca. 10 mL) and poured into ice water (20 mL). The aqueous phase was extracted with EA (50 mL×3). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 and filtered and concentrated. (R)-tert-Butyl 4-(2-(pyrrolidin-2-yl)benzyl)piperazine-1-carboxylate (2.55 g, crude) was obtained as a yellow oil. MS (ESI, m / e) [M+1] + 346.3

[0258] Step 6: (R)-tert-Butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)benzyl)piperazine-1-carboxylate To a mixture of (R)-tert-Butyl 4-(2-(pyrrolidin-2-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 Cs 2 CO 3 (4.81 g, 14.76 mmol) in toluene (100 mL), Pd(OAc) 2(166 mg, 738 μmol) was added at 20 °C. The mixture was purged three times with N 2 and then heated to 105 °C over 10 h. TLC indicated that the reactant had been completely consumed. The reaction mixture was poured into ice water (50 mL), and the organic phase was separated. The organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated. (R)-tert-Butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)benzyl)piperazine-1-carboxylate (1.25 g) was obtained as an orange solid. 1 1H NMR (400 MHz, CDCl3) δ ppm: 7.05 - 7.24 (m, 6H) 6.40 (d, J = 8.9 Hz, 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)benzyl)piperazine A solution of (R)-tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)benzyl)piperazine-1-carboxylate (1.25 g, 2.50 mmol) in TFA (20 mL) and DCM (60 mL) was stirred at 20 °C for 12 h. LC / MS indicated that the reactant had been completely consumed and the desired compound had been formed. The reaction solution was concentrated. The residue was diluted with EA (50 mL). The organic phase was washed with saturated aqueous NaHCO 3 , and the organic phase was separated. The organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated. (R)-1-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)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)benzyl)-4-methylpiperazine To a mixture of (R)-1-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)benzyl)piperazine (1 g, 2.50 mmol) and HCHO (374.99 mg, 12.49 mmol) in DCE (50 mL), NaBH(OAc) 3 (2.1 g, 10 mmol) was added portionwise at 20 °C. The mixture was stirred at 20 °C for 1 h. LC / MS indicated that the reactants were completely consumed and the desired compound was formed. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative HPLC (Phenomenex luna C18 250 mm * 100 mm * 10 um; mobile phase: [water (0.1% TAF)-ACN]). The purified solution was concentrated. The aqueous phase was basified with saturated NaHCO 3 and then extracted with EA (50 mL×3). The combined organic phases were dried over anhydrous Na 2 SO 4 and filtered and concentrated. (R)-1-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)benzyl)-4-methylpiperazine (440 mg) was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.01 - 7.24 (m, 6H), 6.36 (d, J = 8.8 Hz, 2H), 5.22 (d, J = 8.2 Hz, 1H), 3.88 (d, J = 12.8 Hz, 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 = 5.7 Hz, 1H). MS (ESI, m / e) [M+1] + 414.2.

[0261] Intermediate 2-y: tert-Butyl (R)-4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)benzyl)piperidine-1-carboxylate

Chemical Structure

[0262] Step 2: (R)-tert-Butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzylidene)piperidine-1-carboxylate To a mixture of (R)-1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethanone (3 g, 9.31 mmol), (E)-tert-butyl 4-((2-tosylhydrazono)methyl)piperidine-1-carboxylate (5.33 g, 13.97 mmol) and t-BuOLi (2.98 g, 37.24 mmol) in dioxane (100 mL) was added Pd(PPh 3 ) 2 Cl 2 (670.5 mg, 931 μmol) at 20 °C. The mixture was purged with N 2 three times and then heated to 100 °C for 3 h. TLC indicated that the reactants were completely consumed. The reaction mixture was concentrated under reduced pressure (to ca. 20 mL). The residue was poured into ice water (30 mL) and extracted with EA (50 mL × 3). The combined organic phases were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4It was dried, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, PE / EA = 30 / 1 to 10 / 1). (R)-tert-Butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzylidene)piperidine-1-carboxylate (2.17 g, 4.95 mmol, 53.08% yield) was obtained as a red oil. 1 H NMR (400 MHz, CDCl 3 ) 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-trifluoroacetyl)pyrrolidin-2-yl)benzyl)piperidine-1-carboxylate To a solution of (R)-tert-Butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzylidene)piperidine-1-carboxylate (2.3 g, 5.25 mmol) in MeOH (30 mL) was added Pd / C (300 mg, 10% wet). The mixture was purged with H 2 three times, and then stirred at 20 °C for 10 h under H 2 at 15 Psi. LC / MS indicated that the reactant was completely consumed and the desired compound was formed. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated. (R)-tert-Butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzyl)piperidine-1-carboxylate (2.3 g, crude) was obtained as a brown solid. 1 H NMR (400 MHz, CDCL 3)δ ppm: 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)piperidine-1-carboxylate MeOH (10 mL), H 2 To a solution of (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzyl)piperidine-1-carboxylate (2.3 g, 5.22 mmol) in MeOH (10 mL), H 2 O (10 mL), and THF (10 mL) was added LiOH.H 2 SO 4 O (438.5 mg, 10.44 mmol) at 20 °C. The mixture was heated to 50 °C over 1 hour. TLC indicated that the reactant was completely consumed. The reaction mixture was concentrated under reduced pressure to remove MeOH and THF. The aqueous phase was extracted with EA (30 mL × 3). The combined organic phases were dried over anhydrous Na + SO

[0265] Step 5: (R)-tert-Butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)benzyl)piperidine-1-carboxylate (R)-tert-Butyl 4-(2-(pyrrolidin-2-yl)benzyl)piperidine-1-carboxylate (1.4 g, 4.06 mmol), 1-bromo-4-iodobenzene (1.72 g, 6.10 mmol), X-phos (387 mg, 812 umol), and Cs 2 CO 3(2.64 g, 8.12 mmol) of the mixture, Pd(OAc) 2 (90 mg, 406 μmol) was added at 20 °C. The mixture was purged three times with N 2 and then heated to 100 °C for 5 h. TLC indicated that the reactants were completely consumed. The reaction mixture was cooled to room temperature, poured into ice water (30 mL), and then separated. The organic phase was washed with brine, dried over anhydrous Na 2 SO 4 filtered, and concentrated. The crude product was purified by column chromatography (silica gel, eluent: PE / EA = 100 / 1 - 50 / 1). (R)-tert-Butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)benzyl)piperidine-1-carboxylate (720 mg) was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.00 - 7.24 (m, 6H) 6.27 (d, J = 9.0 Hz, 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 = 12.1 Hz, 2H) 1.48 (s, 9H) 1.23 - 1.31 (m, 2H). MS (ESI, m / e) [M + 1] + 498.9.

[0266] Intermediate 2 - z: (S)-N,N-Dimethyl-2-(pyrrolidin-2-yl)aniline

Chemical Structure

[0267] Step 2: (S)-tert - butyl 2-(2 - aminophenyl)pyrrolidine - 1 - carboxylate To a solution of (S)-tert - butyl 2-(2 - ((diphenylmethylene)amino)phenyl)pyrrolidine - 1 - carboxylate (262 mg, 613 μmol, 1 equiv) in THF (5 mL) was added 10 mL of 0.5 N HCl acid. The mixture was stirred at 20 °C overnight. By TLC, it was shown that (S)-tert - butyl 2-(2 - ((diphenylmethylene)amino)phenyl)pyrrolidine - 1 - carboxylate was completely consumed. The mixture was adjusted to pH ~8 using saturated NaHCO 3 aqueous solution and then extracted with EA (20 mL). The organic phase was washed with brine and dried over Na 2 SO 4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 10 / 1 - 1 / 1) to give (S)-tert - butyl 2-(2 - aminophenyl)pyrrolidine - 1 - carboxylate (50 mg). 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 6.91 - 7.16 (m, 2H), 6.70 - 6.87 (m, 1H), 6.62 - 6.70 (m, 1H), 4.60 - 5.06 (m, 1H), 3.36 - 3.97 (m, 4H), 2.13 - 2.35 (m, 1H), 1.83 - 2.01 (m, 3H), 1.16 - 1.54 (m, 9H).

[0268] Step 3: (S)-tert-Butyl 2-(2-(dimethylamino)phenyl)pyrrolidine-1-carboxylate To a solution of (S)-tert-butyl 2-(2-aminophenyl)pyrrolidine-1-carboxylate (6.5 g, 22.87 mmol) in MeOH (200 mL) were added aqueous HCHO solution (37%, 11.14 g, 137.22 mmol) and NaH 3 CN (5.95 g, 114.35 mmol). The mixture was stirred at 20 °C for 14 h. TLC indicated that (S)-tert-butyl 2-(2-aminophenyl)pyrrolidine-1-carboxylate had been completely consumed. The mixture was evaporated under reduced pressure. The residue was dissolved in DCM (100 mL), washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 100 / 1 to 30 / 1) to give (S)-tert-butyl 2-(2-(dimethylamino)phenyl)pyrrolidine-1-carboxylate (5.9 g). 1 1H NMR (400 MHz, CDCl 3 ) δ ppm: 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 To a solution of (S)-tert-butyl 2-(2-(dimethylamino)phenyl)pyrrolidine-1-carboxylate (5.90 g, 20.32 mmol) in DCM (30 mL) was added TFA (30 mL). The mixture was stirred at 20 °C for 2 h. TLC indicated that (S)-tert-butyl 2-(2-(dimethylamino)phenyl)pyrrolidine-1-carboxylate was completely consumed. The mixture was poured into water and then adjusted to pH ~10 using aqueous NaOH (2N). The mixture was extracted with DCM (50 mL × 3), washed with brine and water, and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford (S)-N,N-dimethyl-2-(pyrrolidin-2-yl)aniline (3.248 g). 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.38 - 7.52 (m, 1H) 7.18 - 7.24 (m, 1H) 7.03 - 7.16 (m, 2H) 4.59 (t, J = 7.9 Hz, 1H), 3.24 (ddd, J = 10.0, 7.6, 5.1 Hz, 1H), 3.00 (dt, J = 9.8, 7.7 Hz, 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

Chemical Structure

[0271] Step 2: (S)-N,N-bis(methyl-d3)-2-(pyrrolidin-2-yl)aniline To a solution of (S)-2-(2-(bis(methyl-d3)amino)phenyl)pyrrolidine-1-carboxylate (275 mg, 927.68 μmol) in DCM (10 mL) was added TFA (5 mL). The mixture was stirred at 20 °C for 2 h. TLC indicated that the reactant was completely consumed. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in DCM (20 mL), washed with saturated Na 2 CO 3 aqueous solution (20 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give (S)-N,N-bis(methyl-d3)-2-(pyrrolidin-2-yl)aniline (100 mg). 1 H NMR (400 MHz, CDCl 3)δ ppm: 7.42 (dd, J = 7.7, 1.3 Hz, 1H), 7.19 - 7.26 (m, 1H), 7.07 - 7.18 (m, 2H), 4.63 (t, J = 7.9 Hz, 1H), 3.24 (ddd, J = 10.3, 7.4, 5.4 Hz, 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

Chemical Structure

[0273] Step 2: 1-(2-cyclopropylphenyl)pyrrolidine-2-carbaldehyde (COCl) in DCM (20 mL) 2 To a solution of (700.9 mg, 5.52 mmol) was added dropwise DMSO (862.93 mg, 11.04 mmol) 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) in DCM (2 mL) was added dropwise at -65°C. The mixture was further stirred at -65°C for 1 h. TLC showed that the reactants were completely consumed. To the reaction mixture was added TEA (2.89 g, 29.45 mmol) and warmed to 20°C for 0.5 h. The reaction mixture was poured into water, extracted with DCM and washed with anhydrous Na 2 SO 4 It was dried over and concentrated under reduced pressure to give 1-(2-cyclopropylphenyl)pyrrolidine-2-carbaldehyde (1.2 g, crude). 1 H NMR (400 MHz, CDCl 3 )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)pyrrolidin-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate To a solution of 1-(2-cyclopropylphenyl)pyrrolidine-2-carbaldehyde (600 mg, 2.79 mmol) in DCM (10 mL), NaBH(OAc) 3(1.18 g, 5.57 mmol) was slowly added at 0 °C. Next, tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (803.46 mg, 2.79 mmol) was added into the mixture at 0 °C. The mixture was stirred at 20 °C for 1 h. TLC indicated that the reactants were completely consumed. The reaction mixture was poured into water, extracted with DCM (10 mL), and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , PE / EA = 100 / 1 - 0 / 1). tert-Butyl 6-((1-(2-cyclopropylphenyl)pyrrolidin-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (600 mg) was obtained. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.07 - 7.14 (m, 1H), 7.01 (d, J = 7.9 Hz, 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, 5.1 Hz, 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 A solution of tert-butyl 6-((1-(2-cyclopropylphenyl)pyrrolidin-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (600 mg, 1.51 mmol) in DCM (8 mL) was treated with TFA (2 mL) at 20 °C. The mixture was stirred at 20 °C for 1 h. TLC indicated that the reactant was completely consumed. The reaction mixture was concentrated to afford 2-((1-(2-cyclopropylphenyl)pyrrolidin-2-yl)methyl)-2,6-diazaspiro[3.3]heptane (326 mg) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.10 (t, J = 7.3 Hz, 1H), 6.99 - 7.04 (m, 1H), 6.91 (s, 1H), 6.80 - 6.88 (m, 1H), 3.78 (br, 4H), 3.57 - 3.74 (m, 2H), 3.22 - 3.40 (m, 4H), 2.80 - 3.03 (m, 3H), 2.55 (d, J = 12.6 Hz, 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)pyrrolidin-1-yl)cyclobutyl)piperidine

Chemical Structure

[0277] Step 2: tert-Butyl 4-(3-oxocyclobutyl)piperidine-1-carboxylate N 2 Under an atmosphere, to a mixture of Zn (1.22 g, 18.62 mmol) in HOAc (3.73 g, 62.07 mmol) was added tert-butyl 4-(2,2-dichloro-3-oxocyclobutyl)piperidine-1-carboxylate (2.0 g, 6.21 mmol) in Diox (15 mL) at 15 °C, and the mixture was stirred at 15 °C for 12 h. Using 33% aqueous NaOH, the mixture was adjusted to pH ca. 9 and extracted with EA (50 mL × 3). After drying and concentration, the residue was purified by column chromatography (SiO 2 , PE / EA = 50 / 1 to 10 / 1). tert-Butyl 4-(3-oxocyclobutyl)piperidine-1-carboxylate (1.0 g, 3.95 mmol) was obtained. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 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 = 12.8 Hz, 2H) 1.35 - 1.36 (m, 1H) 1.47 (s, 8H) 1.15 (d, J = 12.3, 4.3 Hz, 2H).

[0278] Step 3: (S)-tert-Butyl 4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclobutyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(3-oxocyclobutyl)piperidine-1-carboxylate (0.7 g, 2.76 mmol, 1 equiv) and (S)-2-(2-cyclopropylphenyl)pyrrolidine (569.23 mg, 3.04 mmol) in DCE (20 mL), AcOH (331.86 mg, 5.53 mmol) and NaBH(OAc) 3 (1.17 mg, 5.53 mmol) were added. The mixture was stirred at 25 °C for 1 h. TLC indicated that the reactants were completely consumed. The reaction mixture was quenched with an aqueous solution of Na 2 CO 3 (20 mL), extracted with EA (20 mL × 3), dried over Na 2 SO 4 and filtered, and concentrated. The residue was purified by preparative MPLC. (S)-tert-Butyl 4-(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)cyclobutyl)piperidine A mixture of (S)-tert-butyl 4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclobutyl)piperidine-1-carboxylate (0.9 g, 2.12 mmol) in DCM (5 mL) and TFA (5 mL) was stirred at 25 °C for 1 h. LC / MS indicated that the reactants were completely consumed and one major peak with the desired mass signal was shown. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H 2 O (10 mL), saturated with Na 2 CO 3An aqueous solution was used to adjust the pH to approximately 9. The mixture was extracted with EA (10 mL × 3), and dried over Na 2 SO 4 filtered, and concentrated. (S)-4-(3-(2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)cyclobutyl)piperidine (643 mg) was obtained. 1 1H NMR (400 MHz, CDCl 3 ) δ ppm: 7.66 - 7.56 (m, 1H), 7.21 - 7.08 (m, 2H), 6.97 (d, J = 7.5 Hz, 1H), 6.34 (s, 1H), 3.96 (q, J = 7.7 Hz, 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)phenoxy)-1-methylpiperidine

Chemical Structure

[0281] Step 2: (E)-tert-butyl 4-(2-(((4-bromophenyl)imino)methyl)phenoxy)piperidine-1-carboxylate A mixture of tert-butyl 4-(2-formylphenoxy)piperidine-1-carboxylate (4.30 g, 14.08 mmol), 4-bromoaniline (2.42 g, 14.08 mmol), TsOH (133.93 mg, 0.7 mmol) and 4 Å molecular sieve (2.15 g) in toluene (43 mL) was stirred at 140 °C for 12 h. TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain crude (E)-tert-butyl 4-(2-(((4-bromophenyl)imino)methyl)phenoxy)piperidine-1-carboxylate (7.5 g, crude), which was used directly in the next step.

[0282] Step 3: tert-butyl 4-(2-(1-((4-bromophenyl)amino)but-3-en-1-yl)phenoxy)piperidine-1-carboxylate To a solution of (E)-tert-butyl 4-(2-(((4-bromophenyl)imino)methyl)phenoxy)piperidine-1-carboxylate (5.7 g) in DCM (50 mL) was added dropwise allylmagnesium bromide (49.63 mL, 1 M in THF) at 0 °C. The mixture was stirred at 0 - 15 °C for 3 h. TLC indicated that the reaction was complete. The reaction mixture was poured into 4 aqueous HCl solution (50 mL) and extracted with EA (50 mL × 2). The combined organic layers were washed with brine (50 mL) and 2 SO 4It was dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 50 / 1 to 20 / 1) to obtain tert-butyl 4-(2-(1-((4-bromophenyl)amino)but-3-en-1-yl)phenoxy)piperidine-1-carboxylate (4.2 g). MS (ESI, m / e) [M+1] + 502.2。

[0283] Step 4: tert-butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenoxy)piperidine-1-carboxylate To a solution of tert-butyl 4-(2-(1-((4-bromophenyl)amino)but-3-en-1-yl)phenoxy)piperidine-1-carboxylate (3.3 g, 6.58 mmol) in THF (50 mL) was added BH 3 .THF (65.8 mL, 1 M in THF) at 0 °C. The mixture was stirred at 0 °C for 3 hours. Then, H 2 O 2 (6.58 mL, 65.81 mmol) was added dropwise and stirred at 0 °C for 1 hour. An aqueous NaOH solution (2.63 g, 65.81 mmol, 4 M) was added dropwise and stirred at 0 - 15 °C for 2 hours. TLC indicated that the reaction was complete. The mixture was poured into saturated Na 2 S 2 O 3 aqueous solution (50 mL), stirred for 0.5 hour, and extracted with EA (100 mL × 2). The combined organic layers were washed with saturated Na 2 S 2 O 3 aqueous solution (50 mL), NaHCO 3 aqueous solution (50 mL), and brine (50 mL), dried over Na 2 SO 4 filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , PE / EA = 5 / 1 to 2 / 1) to obtain tert-butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenoxy)piperidine-1-carboxylate (2.4 g). MS (ESI, m / e) [M+1]+ 520.3。

[0284] Step 5: tert-Butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenoxy)piperidine-1-carboxylate To a mixture of tert-butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenoxy)piperidine-1-carboxylate (2.3 g, 4.43 mmol) and TEA (1.34 g, 13.28 mmol) in DCM (23 mL) was added MsCl (1.01 mg, 8.86 mmol) at 0 °C, and the mixture was stirred at 25 °C for 5 h. TLC indicated that the reaction was complete. The reaction mixture was poured into H 2 2O (20 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na 2 2SO 4 4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 10 / 1 to 2 / 1) to obtain tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenoxy)piperidine-1-carboxylate. MS (ESI, m / e) [M+1] + 502.2。

[0285] Step 6: 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenoxy)piperidine To a mixture of tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenoxy)piperidine-1-carboxylate (1.8 g, 3.59 mmol) in DCM (20 mL) was added TFA (7 mL), and the mixture was stirred at 15 °C for 3 h. TLC indicated that the reaction was complete. The mixture was concentrated under reduced pressure to obtain 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenoxy)piperidine (1.8 g, TFA salt, crude). MS (ESI, m / e) [M+1] + 402.2。

[0286] Step 7: 4-(2-(1-(4-Bromophenyl)pyrrolidin-2-yl)phenoxy)-1-methylpiperidine To a solution of 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenoxy)piperidine (1.0 g, 2.49 mmol) in MeOH (10 mL) were added aqueous HCHO solution (37%, 1.01 g, 12.46 mmol) and NaBH 3 CN (496.74 mg, 4.47 mmol), and the mixture was stirred at 15 °C for 3 h. TLC indicated the completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was poured into saturated NaHCO 3 aqueous solution (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were dried over Na 2 SO 4 and filtered, and then concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 1 / 1 - 1 / 10) to obtain 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenoxy)-1-methylpiperidine. 1 1H NMR (400 MHz, CDCl 3 ) δ ppm: 7.15 - 7.24 (m, 3H) 6.99 (dd, J = 7.5, 1.3 Hz, 1H) 6.88 (d, J = 8.1 Hz, 1H) 6.79 - 6.85 (1H, m) 6.30 (2H, d, J = 9.0 Hz) 4.96 (1H, d, J = 7.9 Hz) 4.60 (1H, s) 3.63 - 3.70 (m, 1H) 3.32 - 3.41 (m, 1H) 2.64 - 2.87 (m, 4H) 2.46 (s, 3H) 2.29 - 2.40 (m, 1H) 2.14 - 2.24 (m, 2H) 1.92 - 2.10 (m, 5H). MS (ESI, m / e) [M + 1] + 415.1.

[0287] Intermediate 2 - z5: (S)-2-((2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)methyl)-7-azaspiro[3.5]nonane [Chemical Structure Diagram] Step 1: tert-Butyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate To a solution of (methoxymethyl)triphenylphosphonium chloride (3.72 g, 10.86 mmol) in toluene (30 mL) was added t-BuOK (1 M in THF, 10.86 mL, 10.86 mmol). The mixture was stirred at 25 °C for 20 min under N 2 protection. Next, tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (2 g, 8.36 mmol) in toluene (20 mL) was added. The mixture was stirred at 70 °C for 4 h. TLC indicated that the reactant was completely consumed. The reaction mixture was quenched with HN 4 Cl aqueous solution (30 mL), extracted with EA (50 mL × 3), dried over Na 2 SO 4 and filtered, and concentrated. The residue was purified by preparative MPLC to give tert-butyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g). MS (ESI, m / e) [M+1] + 268.3.

[0288] Step 2: tert-butyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylate A mixture of tert-butyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate (1 g, 3.74 mmol) in ACN (36 mL), H 2 O (9 mL) and TFA (0.3 mL) was stirred at 25 °C for 4 h. TLC indicated that the reactant was completely consumed. The reaction mixture was quenched with NaHCO 3 aqueous solution (20 mL), extracted with EA (20 mL × 3), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by preparative MPLC. tert-Butyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylate (390 mg) was obtained. 1 H NMR (400 MHz, CDCl 3)δ ppm: 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)pyrrolidin-1-yl)methyl)-7-azaspiro[3.5]nonane-7-carboxylate To a solution of tert-butyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylate (0.3 g, 1.18 mmol) and (S)-2-(2-cyclopropylphenyl)pyrrolidine (184.81 mg, 986.83 μmol) in DCE (5 mL), AcOH (118.52 mg, 1.97 mmol) and NaBH(OAc) 3 (418.30 mg, 1.97 mmol) were added. The mixture was stirred at 25 °C for 2 h. TLC indicated that the reactants were completely consumed. The reaction mixture was poured into an aqueous solution of Na 2 CO 3 (5 mL), extracted with EA (5 mL × 3), dried over Na 2 SO 4 , 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) was obtained. 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 A mixture of (S)-tert-butyl 2-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-7-azaspiro[3.5]nonane-7-carboxylate (0.3 g, 0.7 mmol) in DCM (1.5 mL) and TFA (1.5 mL) was stirred at 25 °C for 1 hour. LC / MS indicated that the reactant was completely consumed and showed one major peak with the desired mass signal. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H 2 O (10 mL) and adjusted to pH ca. 9 using Na 2 CO 3 . The mixture was extracted with EA (10 mL × 3), dried over Na 2 SO 4 , filtered, and concentrated. (S)-2-((2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)methyl)-7-azaspiro[3.5]nonane (180 mg) was obtained. 1 H NMR (400 MHz, CDCl 3 3) δ ppm: 7.58 (d, J = 7.7 Hz, 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 = 8.3 Hz, 1H), 3.27 (t, J = 7.7 Hz, 1H), 2.95 - 2.84 (m, 2H), 2.83 - 2.72 (m, 2H), 2.58 (dd, J = 8.0, 11.8 Hz, 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 = 14.3 Hz, 1H), 1.74 - 1.64 (m, 2H), 1.63 - 1.53 (m, 1H), 1.53 - 1.45 (m, 2H), 1.44 - 1.31 (m, 2H), 0.98 - 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

Chemical Structure

[0292] Step 2: tert-Butyl 4-((2-cyclopropylphenyl)amino)-4-(4-hydroxybutyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(but-3-en-1-yl)-4-((2-cyclopropylphenyl)amino)piperidine-1-carboxylate (2.5 g, 6.75 mmol) in THF (25 mL) was added BH 3 .THF (1 M, 33.74 mL, 33.74 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. Next, NaOH (2.5 M, 6.75 mL, 6.75 mmol) and H 2 O 2 (11.48 g, 101.21 mmol) were added to the mixture at 0 °C. The mixture was stirred at 25 °C for 2 h. TLC indicated that the reactant was completely consumed. The reaction mixture was poured into an aqueous solution of Na 2 SO 3 (100 mL), extracted with EA (100 mL × 3), and dried over Na​2 SO 4 It was dried, filtered, and concentrated above. After purifying the residue by preparative MPLC, tert-butyl 4-((2-cyclopropylphenyl)amino)-4-(4-hydroxybutyl)piperidine-1-carboxylate (1.2 g) was obtained. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.09 (d, J = 7.5 Hz, 1H), 7.07 - 7.01 (m, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.61 (t, J = 7.4 Hz, 1H), 3.95 (s, 1H), 3.77 - 3.67 (m, 1H), 3.63 - 3.50 (m, 1H), 3.11 - 2.93 (m, 2H), 2.55 - 2.41 (m, 1H), 2.00 (d, J = 11.7 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 To a solution of tert-butyl 4-((2-cyclopropylphenyl)amino)-4-(4-hydroxybutyl)piperidine-1-carboxylate (1 g, 2.57 mmol) in DCM (10 mL) and TEA (520.87 mg, 5.51 mmol) at 0 °C, MsCl (294.82 mg, 2.57 mmol) was added, and the mixture was stirred at 25 °C for 2 h. TLC indicated that the reactant was completely consumed. The reaction mixture was quenched with an aqueous solution of HN 4 Cl (10 mL), extracted with DCM (10 mL × 3), and dried over Na 2 SO 4 above, filtered, and concentrated. After purifying the residue by preparative MPLC, tert-butyl 1-(2-cyclopropylphenyl)-1,9-diazaspiro[5.5]undecane-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 A mixture of tert-butyl 1-(2-cyclopropylphenyl)-1,9-diazaspiro[5.5]undecane-9-carboxylate (0.7 g, 1.89 mmol) in DCM (4 mL) and TFA (4 mL) was stirred at 20 °C for 1 h. LC / MS indicated that the reactant was completely consumed and showed one major peak with the desired mass signal. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H 2 O (10 mL), and adjusted to pH ca. 9 using Na 2 CO 3 . The mixture was then extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried over Na 2 CO 3 , filtered, and concentrated to give 1-(2-cyclopropylphenyl)-1,9-diazaspiro[5.5]undecane (452 mg). 1 1H NMR (400 MHz, CDCl 3 ) 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, 12.8 Hz, 1H), 1.11 (d, J = 6.8 Hz, 3H), 0.94 (dd, J = 1.8, 8.6 Hz, 2H), 0.75 - 0.66 (m, 1H), 0.61 - 0.54 (m, 1H). MS (ESI, m / e) [M+1] + 271.4.

[0295] Intermediate 2-z7: 5-(2-Cyclopropylphenyl)-N,N-dimethylpyrrolidin-3-amine

Chemical Structure

[0296] Project 2: 1-(tert-Butylsulfonyl)-5-(2-cyclopropylphenyl)-N,N-dimethylpyrrolidin-3-amine To a mixture of 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3-one (3.5 g, 10.89 mmol) and dimethylamine hydrochloride (3.55 g, 43.55 mmol) in DCE (40 mL) was added NaBH(OAc)3 (6.92 g, 32.67 mmol). The mixture was stirred at 20 °C for 2 h under N 2 atmosphere. TLC indicated the completion of the reaction. The mixture was concentrated and purified by preparative HPLC (TFA conditions). 1-(tert-Butylsulfonyl)-5-(2-cyclopropylphenyl)-N,N-dimethylpyrrolidin-3-amine (2.2 g, 6.28 mmol, 57.64% yield) was obtained. MS (ESI, m / e) [M+1] + 351.3。

[0297] Step 3: 5-(2-Cyclopropylphenyl)-N,N-dimethylpyrrolidin-3-amine A mixture of 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)-N,N-dimethylpyrrolidin-3-amine (1.0 g, 2.85 mmol) in TFA (10 mL) was stirred at 70 °C for 12 h. TLC indicated the completion of the reaction. The mixture was concentrated and adjusted to pH ca. 10 using saturated Na 2 CO 3 aqueous solution (10 mL). The mixture was extracted with EA (10 mL × 5) and the combined organic layers were dried over anhydrous Na 2 SO 4 and then concentrated. 5-(2-Cyclopropylphenyl)-N,N-dimethylpyrrolidin-3-amine (170 mg) was obtained. 1 H NMR (400 MHz, CDCl 3)δ ppm: 7.52 - 7.63 (m, 1H), 7.11 - 7.24 (m, 2H), 7.00 (d, J = 7.5 Hz, 1H), 4.70 - 4.92 (m, 1H), 3.07 - 3.42 (m, 2H), 2.81 - 2.99 (m, 1H), 2.38 - 2.50 (m, 1H), 2.25 - 2.35 (m, 4H), 1.63 (dt, J = 11.9, 9.8 Hz, 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)pyrrolidin - 2 - yl)phenyl)piperidine - 1 - carboxylate [Chemical Structure] Step 1: (R) - tert - butyl 4 - (2 - (1 - (2,2,2 - trifluoroacetyl)pyrrolidin - 2 - yl)phenyl) - 5,6 - dihydropyridine - 1(2H) - carboxylate In toluene (100 mL) and H 2 O (5 mL), (R) - 1 - (2 - (2 - bromophenyl)pyrrolidin - 1 - yl) - 2,2,2 - trifluoroethanone (8 g, 24.8 mmol), tert - butyl 4 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl) - 5,6 - dihydropyridine - 1(2H) - carboxylate (11.5 g, 37.2 mmol), Pd(OAc) 2 (560 mg, 2.48 mmol), tricyclohexylphosphine (1.4 g, 4.96 mmol) and K 3 PO 4 (15.8 g, 74.4 mmol, 3.0 equiv) were heated to 100 °C under N 2 protection and stirred for 5 h. TLC indicated the completion of the reaction. The mixture was cooled to room temperature, diluted with EA (50 mL), washed with water (100 mL), brine (100 mL), and Na 2 SO 4The residue was purified by column chromatography on silica gel (eluent: PE / EA=5 / 1 to 2 / 1) to give (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (9 g, crude) as a brown solid. MS (ESI, m / e) [M+1] + 425.2.

[0299] Step 2: (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate CH 3 A mixture of (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (9 g, 21.2 mmol) and Pd / C (10%, 2 g) in OH (200 mL) was heated under H 2 Stirred at 20° C. under atmosphere (15 psi). LC / MS showed the reaction was complete. The mixture was filtered and the filtrate was concentrated to give (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate (7.5 g, crude) 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)piperidine-1-carboxylate CH 3 To a solution of (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate (7.5 g, 17.6 mmol) in OH (50 mL) was added H 2A solution of NaOH (2.8 g, 70.4 mmol) in O (30 mL) was added. Next, the mixture was heated to 40 °C and stirred for 2 h. TLC indicated that the reaction was complete. The mixture was concentrated under reduced pressure to remove the organic solvent, and the remaining aqueous solution was extracted with EA (100 mL). The organic layer was washed with brine (100 mL) and dried over Na 2 SO 4 and concentrated to obtain (R)-tert-butyl 4-(2-(pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate (6 g, crude). MS (ESI, m / e) [M+1] + 331.3.

[0301] Step 4: (R)-tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate A mixture of (R)-tert-butyl 4-(2-(pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate (2 g, 6.1 mmol), 1-bromo-4-iodobenzene (3.5 g, 12.2 mmol), Pd 2 (dba) 3 (559 mg, 0.61 mmol), BINAP (760 mg, 1.22 mmol) and t-BuOK (1.4 g, 12.2 mmol) in toluene (20 mL) was heated to 100 °C under N 2 protection and stirred for 12 h. TLC indicated that the reaction was complete. The mixture was cooled to room temperature, diluted with EA (20 mL), washed with water (20 mL) and brine (20 mL), and dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 20 / 1 - 15 / 1) to obtain (R)-tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate (2 g). 1 H NMR (400 MHz, CDCl 3)δ ppm: 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 = 6.8 Hz), 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 (9H, s). MS (ESI, m / e) [M + 1] + 487.8.

[0302] Intermediate 2 - z9: 1 - (Azetidin - 3 - yl) - 2 - (2 - cyclopropylphenyl)pyrrolidine [Chemical Structure] Step 1: tert - Butyl 3 - (2 - (2 - cyclopropylphenyl)pyrrolidin - 1 - yl)azetidine - 1 - carboxylate To a solution of 2 - (2 - cyclopropylphenyl)pyrrolidine (700 mg, 3.7 mmol) and tert - butyl 3 - oxoazetidine - 1 - carboxylate (632 mg, 3.7 mmol) in DCM (10 mL), NaBH(OAc) 3 (600 mg, 3 mmol) was added. The mixture was stirred at room temperature for 14 hours. Then, saturated NH 4 Cl aqueous solution (30 mL) was added to the reaction mixture with stirring. The organic phase was separated, washed with brine (10 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain 1 g of a crude product. MS (ESI, m / e) [M + 1] + 343.0.

[0303] Step 2: 1 - (Azetidin - 3 - yl) - 2 - (2 - cyclopropylphenyl)pyrrolidine A solution of tert-butyl 3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)azetidine-1-carboxylate (680 mg, 2.0 mmol) in DCM (10 mL) was added with TFA (2 mL). The mixture was stirred at room temperature for 4 h. The solvent was removed to obtain 700 mg of 1-(azetidin-3-yl)-2-(2-cyclopropylphenyl)pyrrolidine. 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]heptane-2-carboxylate To a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (3 g, 0.014 mol) in toluene (50 mL) was added t-BuOK (2.0 g, 0.018 mol). The mixture was stirred at 25 °C for 20 min under N 2 atmosphere. Next, (methoxymethyl)triphenylphosphonium chloride (6.2 g, 0.018 mol) in toluene (20 mL) was added. The mixture was stirred at 70 °C for 4 h. TLC indicated the completion of the reaction. After removing the solvent, the residue was purified by column chromatography on silica gel (eluent: PE / EA = 20 / 1) to obtain tert-butyl 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate (1 g). 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 5.81 (s, 1H), 3.86 - 4.00 (s, 4H), 3.55 (s, 3H), 2.86 (s, 2H), 2.79 (s, 2H), 1.43 (s, 9H).

[0305] Step 2: tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate CH 3 CN (36 mL) and H 2To a solution of tert-butyl 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 4.18 mmol) in O(9 mL), TFA (1 mL) was added, and then the mixture was stirred at room temperature for 2 h. TLC indicated that the reaction was complete. Na 2 CO 3 aqueous solution was used to adjust the reaction mixture to pH 8 - 9, and it was extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried, filtered, and concentrated to obtain tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (0.9 g), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 9.71 (d, J = 1.7 Hz, 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)pyrrolidin-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (0.9 g, 4.0 mmol) in DCE (30 mL), 2-(2-cyclopropylphenyl)pyrrolidine (0.68 g, 3.63 mmol) and HOAc (436 mg, 7.26 mmol) were added. After the mixture was stirred at room temperature for 30 min, NaBH(OAc) 3 (1.54 g, 7.26 mmol) was added, and then it was stirred for an additional 2 h. LC / MS indicated that the reaction was complete. The reaction mixture was treated with Na 2 CO 3It was quenched with an aqueous solution (10 mL), and then extracted with EA (3 × 50 mL). The organic layer was dried, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 2 / 1) to obtain tert-butyl 6-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylate (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 To a solution of tert-butyl 6-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylate (0.8 g, 2.0 mmol) in DCM (20 mL), TFA (10 mL) was added dropwise at 0 °C. Next, the mixture was stirred at room temperature for 2 hours. TLC indicated that the reaction was complete. Na 2 CO 3 The reaction mixture was adjusted to pH 8 - 9 using an aqueous solution of NaHCO₃, and then extracted with DCM. The organic layer was dried, filtered, and concentrated to obtain 6-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-2-azaspiro[3.3]heptane (250 mg). 1 ¹H NMR (400 MHz, CDCl 3 ) δ ppm: 7.57 (d, J = 7.4 Hz, 1H), 7.15 - 7.23 (m, 1H), 7.13 (dt, J = 1.3, 7.4 Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H), 3.70 - 3.84 (m, 1H), 3.62 (d, J = 1.7 Hz, 2H), 3.41 (s, 2H), 3.26 (t, J = 8.3 Hz, 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

Chemical Structure

[0309] Step 2: tert-Butyl 2-(2-cyclopropylphenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate To a solution of tert-butyl 2-(2-cyclopropylphenyl)-4-(tosyloxy)pyrrolidine-1-carboxylate (2.9 g, 6.3 mmol) in THF (50 mL) was added t-BuOK (1.4 g, 12.6 mmol) portionwise. After the addition, the mixture was stirred at 20 °C for 12 hours. TLC indicated that the reaction was complete. The mixture was quenched with saturated NH 4 Cl aqueous solution (50 mL) and extracted with EA (50 mL). The organic layer was washed with brine (50 mL) and dried over Na 2 SO 4It was dried and concentrated above. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 100 / 1) to obtain tert-butyl 2-(2-cyclopropylphenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (900 mg). MS (ESI, m / e) [M+1] + 286.4

[0310] Step 3: tert-butyl 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate To a solution of tert-butyl 2-(2-cyclopropylphenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (900 mg, 3.2 mmol) in toluene (20 mL) at 0 °C was added Et 2 Zn (1 M in toluene, 15.8 mL, 15.8 mmol) and ClCH 2 I (5.56 g, 32 mmol). Next, the mixture was stirred at 20 °C for 4 h. TLC indicated that the reaction was complete. The reaction mixture was quenched with saturated NH 4 Cl aqueous solution (20 mL) and extracted with EA (30 mL × 2). The organic layer was washed with brine (20 mL) and dried over Na 2 SO 4 and concentrated above. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 30 / 1) to obtain tert-butyl 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (500 mg). MS (ESI, m / e) [M+1] + 300.2

[0311] Step 4: 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexane A solution of tert-butyl 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (500 mg, 1.7 mmol) in HCl (4 M, 10 mL) in EA was stirred at 20 °C for 2 h. TLC indicated that the reaction was complete. The mixture was treated with saturated Na 2 CO3 It was quenched with an aqueous solution (20 mL) and extracted with EA (20 mL × 2). The organic layer was washed with brine (20 mL), and Na 2 SO 4 was dried over it, concentrated, and 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexane (293 mg) was obtained. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.63 (dd, J = 7.7, 1.3 Hz, 1H), 7.18 - 7.23 (m, 1H), 7.11 - 7.16 (m, 1H), 6.98 (d, J = 7.2 Hz, 1H), 4.54 (dd, J = 10.0, 7.0 Hz, 1H), 3.00 (td, J = 6.0, 2.6 Hz, 1H), 2.37 (dd, J = 12.3, 7.0 Hz, 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, 5.9 Hz, 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

Chemical Structure

[0313] Step 2: 1-(2-Cyclopropylphenyl)octahydrocyclopenta[c]pyrrole A solution of 3-(2-cyclopropylphenyl)hexahydrocyclopenta[c]pyrrol-1(2H)-one (1.0 g, 4.15 mmol, 1 equiv) in THF (20 mL) was added dropwise with BH 3 .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 h. TLC indicated that the reactant was completely consumed. At 0 °C, MeOH (2 mL) and 1 N HCl (20 mL) were carefully added to the reaction mixture. Next, the mixture was stirred at room temperature for 1 h. The reaction was quenched with an aqueous solution of Na 2 CO 3 (50 mL) and adjusted to pH ~9. The mixture was extracted with EA (50 mL × 3). The organic layer was washed with brine (50 mL × 2), dried, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 5 / 1) to obtain the target product (300 mg). 1 1H NMR (400 MHz, CDCl 3 3) δ ppm: 7.54 - 7.59 (m, 1H), 7.12 - 7.19 (m, 2H), 6.95 - 7.01 (m, 1H), 4.53 (d, J = 6.97 Hz, 1H), 3.02 - 3.09 (m, 1H), 2.89 - 3.02 (m, 2H), 2.65 (quin, J = 7.86 Hz, 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-dimethylethane-1-amine

Chemical Structure

[0315] Project 2: 2-((5-(2-Cyclopropylphenyl)pyrrolidin-3-yl)oxy)-N,N-dimethylacetamide A solution of 2-((1-(tert-Butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3-yl)oxy)-N,N-dimethylacetamide (8.4 g, 20.56 mmol) in TFA (100 mL) was stirred at 75 °C for 12 hours. LC / MS indicated that the reactant was completely consumed and the desired mass signal was shown. The reaction mixture was concentrated under reduced pressure until it became about 20 mL, and saturated NaHCO 3It was poured into an aqueous solution (50 mL) and adjusted to a pH of about 8. The aqueous phase was extracted with EA (100 mL × 3). The combined organic phases were washed with brine (50 mL × 2) and dried over anhydrous Na 2 SO 4 and 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 To a solution of 2-((5-(2-Cyclopropylphenyl)pyrrolidin-3-yl)oxy)-N,N-dimethylacetamide (1.2 g, 4.16 mmol) in THF (50 mL), BH 3 .DMS (8.32 mL, 83.2 mmol, 10 N in DMS) was added dropwise at 20 °C. The mixture was heated to 70 °C and stirred for 10 h. LC / MS indicated that the reactant was completely consumed. The reaction mixture was quenched with MeOH (10 mL) and decomplexed with HCl / MeOH (4 N, 20 mL) by refluxing for 2 h. LC / MS indicated that the desired compound was formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Xtimate C18 10u 250mm * 50 mm; mobile phase: [water (0.1% TFA)-ACN]). 2-((5-(2-Cyclopropylphenyl)pyrrolidin-3-yl)oxy)-N,N-dimethylethanamine (1.4 g, TFA salt) was obtained. This salt was dissolved in CH 3 CN (100 mL), and K 2 CO 3 (560.9 mg, 4.07 mmol, 1.5 equiv) was added to the solution all at once, and then the mixture was stirred at 20 °C for 2 h. The mixture was filtered and the filtrate was concentrated to give 2-((5-(2-Cyclopropylphenyl)pyrrolidin-3-yl)oxy)-N,N-dimethylethanamine (385 mg). 1 1H NMR (400 MHz, CDCl3 ) δ ppm: 7.46 - 7.57 (m, 1H), 7.10 - 7.20 (m, 2H), 6.93 - 7.02 (m, 1H), 4.91 (t, J = 8.0 Hz, 1H), 4.10 - 4.20 (m, 1H), 3.50 - 3.58 (m, 2H), 3.34 (dd, J = 11.3, 5.1 Hz, 1H), 3.05 - 3.18 (m, 1H), 2.54 (t, J = 5.8 Hz, 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

Chemical Structure

[0318] Step 2: (S)-tert-Butyl 2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate A mixture of (S)-2-(2-ethoxyphenyl)pyrrolidine (0.5 g, 2.61 mmol), tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (568.71 mg, 2.38 mmol), and HOAc (428.13 mg, 7.13 mmol) in DCE (5 mL) was stirred at 20 °C for 2 h. NaBH(OAc) 3 (1.01 g, 4.75 mmol) was added to the mixture, and the mixture was further stirred at 20 °C for 12 h. TLC indicated that the reaction was complete. Na 2 CO 3 The mixture was adjusted to pH ~11 using an aqueous Na 2 SO 4 solution and then extracted with EA (20 mL × 3). The combined organic layers were dried over Na + SO

[0319] Step 3: (S)-2-(2-(2-Ethoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane TFA (1.65 g, 14.47 mmol) was added to a solution of (S)-tert-butyl 2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.6 g, 1.45 mmol) in DCM (10 mL). The mixture was stirred at 20 °C for 1 h. TLC indicated the formation of one new spot. Na 2 CO 3 The reaction mixture was adjusted to pH 8 - 9 using an aqueous Na 2 solution and then extracted with DCM (10 mL × 5). The combined organic layers were washed with brine and dried over Na4 It was dried and concentrated above. (S)-2-(2-(2-Ethoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (360 mg) was obtained. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.49 - 7.58 (m, 1H), 7.13 - 7.21 (m, 1H), 6.93 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 4.04 (d, J = 7.1 Hz, 2H), 3.91 (t, J = 7.1 Hz, 1H), 3.07 - 3.21 (m, 2H), 2.72 - 2.90 (m, 4H), 2.40 (q, J = 8.4 Hz, 1H), 2.14 - 2.26 (m, 1H), 1.73 - 1.94 (m, 5H), 1.47 - 1.73 (m, 8H), 1.41 (t, J = 6.95 Hz, 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

Chemical Structure

[0321] Step 2: tert-Butyl 2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate A mixture of tert-butyl 2-(2-tosylhydrazono)-7-azaspiro[3.5]nonane-7-carboxylate (8.0 g, 19.63 mmol) and (2-methoxyphenyl)boronic acid (8.95 g, 58.89 mmol), Cs 2 CO 3 (19.19 g, 58.89 mmol) in dioxane (100 mL) was stirred at 110 °C for 4 h. TLC indicated that the reaction was complete. The mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE). tert-Butyl 2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (3.0 g) was obtained. MS (ESI, m / e) [M+1] + 332.3.

[0322] Step 3: tert-Butyl 2-(2-hydroxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate N 2 Under an atmosphere, BBr 3 (9.07 g, 36.20 mmol) was added to a solution of tert-butyl 2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (3.0 g, 9.05 mmol) in DCM (30 mL) at -78 °C. After the addition, the mixture was stirred at 20 °C for 6 h. LC / MS indicated that the reaction was complete. The mixture was quenched with an aqueous solution of Na 2 CO 3 and extracted with DCM (20 mL × 3). The combined organic phases were washed with brine and dried over Na 2 SO 4It was dried and concentrated above. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 20 / 1). tert-Butyl 2-(2-hydroxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (1.3 g) 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 To a solution of tert-butyl 2-(2-hydroxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (1.3 g, 4.10 mmol) and TEA (1.24 g, 6.14 mmol) in DCM (10 mL) at 0 °C, N 2 under an atmosphere of Tf 2 O (1.73 g, 12.29 mmol) was added. Next, the mixture was stirred at 25 °C for 1 hour. TLC indicated that the reaction was complete. The mixture was quenched with H 2 O (10 mL) and NH 4 Cl (10 mL) and extracted with DCM (10 mL × 3). The organic phase was washed with brine and dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 40 / 1) to obtain ert-butyl 2-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (1.84 g). MS (ESI, m / e) [M+1] + 450.2

[0324] Step 5: tert-Butyl 2-(2’-cyclopropyl-[1,1’-biphenyl]-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-Butyl 2-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (1.4 g, 3.11 mmol), 2-(2-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.52 g, 6.23 mmol) and Cs 2 CO 3 (3.04 g, 9.34 mmol) in dioxane (10 mL), Pd(dppf)Cl 2 was added under N 2 atmosphere. The mixture was stirred at 90 °C for 12 h. TLC showed that the reactants were completely consumed and one new spot was formed. The mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 50 / 1) to give tert-butyl 2-(2’-cyclopropyl-[1,1’-biphenyl]-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.6 mg). MS (ESI, m / e) [M+1] + 418.5.

[0325] Step 6: 2-(2’-Cyclopropyl-[1,1’-biphenyl]-2-yl)-7-azaspiro[3.5]nonane TFA (1.39 g, 14.37 mmol) was added to a mixture of tert-butyl 2-(2’-cyclopropyl-[1,1’-biphenyl]-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.6 g, 1.44 mmol) in DCM (5 mL). The mixture was stirred at 25 °C for 2 h. LC / MS showed that the reaction was complete. The reaction mixture was adjusted to pH ~10 using an aqueous Na 2 CO 3 solution and then extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to give 2-(2’-cyclopropyl-[1,1’-biphenyl]-2-yl)-7-azaspiro[3.5]nonane (340 mg). 11H NMR (400 MHz, CDCl 3 ) δ ppm: 7.34 - 7.46 (m, 2H), 7.22 - 7.32 (m, 3H), 7.13 - 7.22 (m, 2H), 7.06 (d, J = 7.5 Hz, 1H), 6.83 (d, J = 7.7 Hz, 1H), 3.46 (m, J = 9.15 Hz, 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

Chemical Structure

[0327] Step 2: (4 - ((2 - (2 - Cyclopropylphenyl)pyrrolidin - 1 - yl)methyl)phenyl)methanol To a solution of methyl 4 - ((2 - (2 - cyclopropylphenyl)pyrrolidin - 1 - yl)methyl)benzoate (2 g, 6 mmol) in THF (30 mL) was slowly added LiAlH 4 (46 g, 17.28 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. TLC indicated that the reactant was completely consumed. The residue was quenched with saturated aqueous NH4Cl solution (50 mL) and extracted with EA (50 mL). The organic phase was washed with brine and dried over Na 2 SO 4 and concentrated to afford (4 - ((2 - (2 - cyclopropylphenyl)pyrrolidin - 1 - yl)methyl)phenyl)methanol (1.5 g). MS (ESI, m / e) [M + 1] + 308.3.

[0328] Step 3: 4 - ((2 - (2 - Cyclopropylphenyl)pyrrolidin - 1 - yl)methyl)benzaldehyde To a solution of (4 - ((2 - (2 - cyclopropylphenyl)pyrrolidin - 1 - yl)methyl)phenyl)methanol (1.5 g, 4.89 mmol) in THF (20 mL) was added DMP (4.14 g, 9.78 mmol). The mixture was stirred at 25 °C for 4 hours. LC / MS indicated that the reactant was completely consumed and showed one major peak with the desired mass signal. The reaction mixture was quenched by the addition of Na 2 S 2 O 3 (25 ml) and NaHCO 3 (15 ml) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2) and dried over Na 2 SO 4 and concentrated to afford 4 - ((2 - (2 - cyclopropylphenyl)pyrrolidin - 1 - yl)methyl)benzaldehyde (1.5 g). 1 1H NMR (400 MHz, CDCl 3)δ ppm: 9.91 (s, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.14 - 7.18 (m, 1H), 7.09 (td, J = 7.4, 1.2 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 3.96 (t, J = 8.2 Hz, 1H), 3.86 (d, J = 13.8 Hz, 1H), 2.98 - 3.14 (m, 2H), 2.18 - 2.32 (m, 1H), 2.14 (q, J = 8.8 Hz, 1H), 1.98 (d, J = 7.7 Hz, 1H), 1.68 - 1.91 (m, 2H), 1.63 (dd, J = 9.7, 2.4 Hz, 1H), 0.80 - 0.95 (m, 2H), 0.63 - 0.74 (m, 1H), 0.48 - 0.61 (m, 1H).

[0329] Intermediates 2 - z17a and 2 - z17b: (S or R)-2-(3-chloro-2-cyclopropylphenyl)pyrrolidine; (R or S)-2-(3-chloro-2-cyclopropylphenyl)pyrrolidine

Chemical Structure

[0330] Step 2: tert-Butyl (4-(3-chloro-2-cyclopropylphenyl)-4-oxobutyl) carbamate To a solution of 1-bromo-3-chloro-2-cyclopropylbenzene (3 g, 13 mmol) in THF (30 mL) was added dropwise n-BuLi (2.5 M, 5.7 mL, 14.3 mmol) at -70 °C. After stirring at -70 °C for 30 minutes, a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (2.64 g, 14.3 mmol, 1.1 equiv) in THF (5 mL) was added dropwise to the mixture at -70 °C. The mixture was stirred at -70 °C for an additional 2 hours. TLC indicated 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) and dried over Na 2 SO 4 It was dried and concentrated above. The residue was purified by column chromatography on silica gel (eluent: PE / EA = 5 / 1) to obtain tert-butyl (4-(3-chloro-2-cyclopropylphenyl)-4-oxobutyl) carbamate (1.3 g). 1 1H NMR (400 MHz, CDCl 3 ) δ ppm: 7.35 (dd, J = 7.6, 1.7 Hz, 1H), 7.06 - 7.15 (m, 2H), 4.56 (s, 1H), 3.14 (q, J = 6.3 Hz, 2H), 2.89 (t, J = 7.2 Hz, 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-one To a solution of tert-butyl (4-(3-chloro-2-cyclopropylphenyl)-4-oxobutyl)carbamate (1.3 g, 3.8 mmol) in DCM (20 mL) was added TFA (4.4 g, 38 mmol). Next, the mixture was stirred at 20 °C for 2 h. TLC indicated that the reaction was complete. The mixture was concentrated under reduced pressure to afford 4-amino-1-(3-chloro-2-cyclopropylphenyl)butan-1-one (900 mg, crude). MS (ESI, m / e) [M+1] + 237.9。

[0332] Step 4: 2-(3-Chloro-2-cyclopropylphenyl)pyrrolidine A solution of 4-amino-1-(3-chloro-2-cyclopropylphenyl)butan-1-one (900 mg, 3.8 mmol) and AcOH (0.5 mL) in EtOH (10 mL) was heated to 65 °C and stirred for 3 h. Next, the mixture was cooled to room temperature and NaBH 3 CN (360 mg, 5.7 mmol, 1.5 equiv) was added thereto. The mixture was further stirred at room temperature for 1 h. TLC indicated that the reaction was complete. The reaction mixture was quenched and adjusted to pH ~10 with saturated Na 2 CO 3 aqueous solution and then extracted with EtOAc (20 mL × 3). The organic layers were combined, dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography on silica gel (eluent: EA / MeOH = 10 / 0~10 / 1) to afford racemic 2-(3-chloro-2-cyclopropylphenyl)pyrrolidine.

[0333] The racemic product was separated by SFC (equipment: Thar SFC350 preparative SFC; column: Chiralpak AD, 250 * 50 mm inner diameter 10u; mobile phase: CO 2 for A and MeOH (0.1% NH 3 .H 2O); Gradient: B% = 20%; Flow rate: 200 g / min; Wavelength: 220 nm; Column temperature: 40 °C; System backpressure: 100 bar) for purification to obtain two isomers: The 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) is (R or S)-2-(3-chloro-2-cyclopropylphenyl)pyrrolidine.

[0334] Intermediate 3-a: 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide

Chemical formula

[0335] Intermediate 3-b: 4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide

Chemical formula

[0336] Intermediate 3-c: 3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl)amino)benzenesulfonamide

Chemical formula

Chemical formula

[0337] Step 2: 1-(Tetrahydro-2H-pyran-4-yl)azetidin-3-amine dihydrochloride

Chemical formula

[0338] Step 3: 3-Nitro-4-((1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl)amino)benzenesulfonamide

Chemical formula

[0339] Intermediate 3-d: 4-(((1-Methylpiperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide

Chemical Structure

[0340] Intermediate 3-e: 3-Nitro-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzenesulfonamide

Chemical Structure

[0341] Intermediate 3-f: 3-Nitro-4-((1-(oxetan-3-yl)piperidin-4-yl)amino)benzenesulfonamide

Chem.

Chem.

[0342] Step 2: 1-(Oxetan-3-yl)piperidin-4-amine bis(2,2,2-trifluoroacetate)

Chem.

[0343] Step: 3: 3-Nitro-4-((1-(oxetan-3-yl)piperidin-4-yl)amino)benzenesulfonamide

Chem.

[0344] Intermediate 3-g: 4-(((3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)methyl)amino)-3-nitrobenzenesulfonamide

Chem.

Chem.

[0345] Step 2: 4-(((3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)methyl)amino)-3-nitrobenzenesulfonamide

Chemical formula

[0346] Intermediate 3-h: 4-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methoxy)-3-nitrobenzenesulfonamide

Chemical formula

[0347] Step 2: (4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methanol [Chemical formula] To a solution of ethyl 4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate (2.32 g, 8.1 mmol) in MTBE (50 mL) was added LAH (369 mg, 9.72 mmol). The mixture was stirred under reflux for 2 hours. The mixture was quenched with MeOH (10 ml) at 0 °C. The mixture was concentrated. The residue was purified by chromatography column on silica (eluent: EA / PE = 1 / 2) to give the product (1.5 g, 75.8%) as a yellow oil. MS (ESI, m / e) [M+1] + 245.1

[0348] Step 3: 4-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methoxy)-3-nitrobenzenesulfonamide [Chemical formula] A solution of (4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methanol (587 mg, 2.4 mmol) in THF (50 mL) was added to NaH (576 mg, 14.4 mmol). The mixture was stirred at room temperature for 0.5 h. Next, 4-fluoro-3-nitrobenzenesulfonamide (370 mg, 1.68 mmol) was added to the mixture. The mixture was stirred at room temperature overnight. The mixture was poured into saturated NaHCO 3 aqueous solution (200 mL), then adjusted to pH = 5 - 6 using HCl acid (1 M), and then extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with brine and dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography column on silica (eluent: EA / PE = 1 / 2) to obtain the product as a yellow solid. MS (ESI, m / e) [M+1] + 445.1.

[0349] Intermediate 3-i: 4-((4-fluoro-1-(tetrahydrofuran-3-yl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

Chemical Structure

Chemical Structure

[0350] Step 2: 4-((4-Fluoropiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

Chemical formula

[0351] Step 3: 4 - ((4 - Fluoro - 1 - (tetrahydrofuran - 3 - yl) piperidin - 4 - yl) methoxy) - 3 - nitrobenzenesulfonamide

Chemical Structure

[0352] Intermediate 3 - j: 3 - nitro - 4 - (((4 - (oxetan - 3 - yl)morpholin - 2 - yl)methyl)amino)benzenesulfonamide

Chemical Structure

Chemical Structure

[0353] Step 2: 4-((Morpholin-2-ylmethyl)amino)-3-nitrobenzenesulfonamide

Chemical Structure

[0354] Step 3: 3 - Nitro - 4 - (((4 - (oxetan - 3 - yl)morpholin - 2 - yl)methyl)amino)benzenesulfonamide

Chemical Structure

[0355] Intermediate 3-k: 4-(((4-Cyclopropylmorpholin-2-yl)methyl)amino)-3-nitrobenzenesulfonamide

Chemical Structure

[0356] Intermediate 3-l: 3-nitro-4-(((1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)benzenesulfonamide 2,2,2-trifluoroacetate

Chemical Structure

Chemical Structure

[0357] Step: 2: (1-(Oxetan-3-yl)piperidin-4-yl)methanamine bis(2,2,2-trifluoroacetate)

Chemical formula

[0358] Step: 3: 3-Nitro-4-(((1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)benzenesulfonamide 2,2,2-trifluoroacetate

Chemical formula

[0359] Intermediate 3-m: (R)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide

Chem.

[0360] Intermediate 3-n: 4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide

Chem.

[0361] Intermediate 3-o: 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide

Chem.

[0362] Project 2: 2-(4-Fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile To a solution of 1,6-dioxaspiro[2.5]octane-2-carbonitrile (169 g, 1.22 mol) in 1 L of dichloromethane was added 70% HF / Py (148 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. After diluting with 1000 mL of ethyl acetate, the reaction mixture was poured into NaHCO 3 (saturated) and adjusted to pH about 7 using solid NaHCO 3 The aqueous phase was extracted with 3 × 1000 mL of ethyl acetate, the organic layers were combined and then washed with 850 mL of 1% hydrogen chloride and 1 × 1000 mL of brine. Next, it was dried over anhydrous sodium sulfate, concentrated, and 139 g (crude) of 2-(4-fluorooxan-4-yl)-2-hydroxyacetonitrile was obtained as a pale yellow oil.

[0363] Project 3: (4-Fluorotetrahydro-2H-pyran-4-yl)methanol i-Propanol / H 2To a solution of 2-(4-fluorotetrahydro-4H-pyran-4-yl)-2-hydroxyacetonitrile (109 g, 685.5 mmol) in O(800 mL / 200 mL), NaBH 4 (39.1 g, 1028.3 mmol) was added portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 h, then quenched by the addition of 220 mL of acetone and stirred for an additional 1 h. The solid was filtered off and washed with 200 mL of ethyl acetate. The filtrate was concentrated and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 3 / 1) to afford 47.8 g of (4-fluorotetrahydro-4H-pyran-4-yl)methanol as a pale yellow oil.

[0364] Step 4: (4-Fluorotetrahydro-2H-pyran-4-yl)methyl methanesulfonate To a solution of (4-fluorotetrahydro-4H-pyran-4-yl)methanol (57.8 g, 431.3 mmol) and TEA (65.5 g, 647.0 mmol) in 500 mL of dichloromethane, MsCl (73.2 g, 647.0 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After quenching with 500 mL of water, the resulting mixture was extracted with 2 × 500 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford 105.8 g (crude) of (4-fluorotetrahydro-4H-pyran-4-yl)methyl methanesulfonate as a yellow oil.

[0365] Step 5: 2-((4-Fluorotetrahydro-2H-pyran-4-yl)methyl)isoindoline-1,3-dione A solution of (4-fluorotetrahydro-2H-pyran-4-yl)methyl methanesulfonate (105.8 g, 499.1 mmol) in 1 L of DMF was added to potassium 1,3-dioxo-2,3-dihydro-1H-isoindole-2-ide (138.5 g, 748.6 mmol). The resulting mixture was stirred at 140 °C overnight. After cooling to room temperature, the reaction mixture was poured into 3 L of water and then filtered. The filter cake was dried under reduced pressure to obtain 98 g (crude) of 2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)isoindoline-1,3-dione as an off-white solid.

[0366] Step 6: (4-Fluorotetrahydro-2H-pyran-4-yl)methanamine To a solution of 2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)isoindoline-1,3-dione (98 g, 372.6 mmol) in 1 L of EtOH was added NH 2 NH 2 .H 2 O (111.8 g, 2.24 mol). The resulting mixture was stirred at 70 °C overnight. After cooling to room temperature, the reaction mixture was concentrated and then diluted with 1 L of DCM. After removing the solid by filtration, the filtrate was concentrated and purified by silica gel column chromatography (eluent: CH 2 Cl 2 / MeOH = 100 / 1) to obtain 30.2 g of (4-fluorotetrahydro-2H-pyran-4-yl)methanamine as a pale yellow oil.

[0367] Step 7: 4-(((4-Fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide To a solution of (4-fluorotetrahydro-2H-pyran-4-yl)methanamine (30 g, 225.6 mmol) and 4-fluoro-3-nitrobenzene-1-sulfonamide (41.4 g, 188.0 mmol) in 500 mL of i-PrOH was added Na 2 CO 3(12.0 g, 112.8 mmol) was added. The resulting mixture was stirred at 60 °C for 2 hours, and a precipitate formed. After filtration, the filter cake was washed with 3 × 100 mL of water and then dried under infrared light to obtain 60.9 g of 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide as a yellow solid.

[0368] Intermediate 3-p: 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide [Chemical formula] Step 1: 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol CH in dry toluene (2 L) 3 MgBr (344.0 ml, 1.032 mol, 3 M in Et 2 O) in a stirred solution, a solution of 1,4-dioxaspiro[4.5]decan-8-one (70.0 g, 0.449 mol) in 350 ml of dry toluene was added dropwise. The resulting mixture was stirred at 5 - 10 °C for 2 hours. The mixture was poured into a saturated NH 4 Cl aqueous solution (3 L) and extracted with EtOAc (3 × 1 L). The combined organic phases were washed with brine (1.5 L), dried over Na 2 SO 4 and concentrated to obtain 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol (70.0 g, crude) as a white solid.

[0369] Step 2: 4-hydroxy-4-methylcyclohexan-1-one To a stirred solution of 0.05 N HCl (1800 mL), 8-methyl-1,4-dioxaspiro[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, solid NaCl was added until saturated, and then extracted with EtOAc (5 × 700 mL). The combined organic phases were dried over Na 2 SO 4It was dried and concentrated above to obtain 4-hydroxy-4-methylcyclohexan-1-one (105.0 g, crude) as a yellow oil.

[0370] Step 3: (S)-1-Methyl-4-(nitromethyl)cyclohex-3-en-1-ol CH 3 NO 2 (600.0 mL) of a stirred solution of 4-hydroxy-4-methylcyclohexan-1-one (105.0 g, 0.820 mol) was added to N 1 ,N 1 -Dimethylethane-1,2-diamine (7.216 g, 0.082 mol) was added. The mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel column chromatography eluting with EA / PE = 1 / 4 to obtain (S)-1-methyl-4-(nitromethyl)cyclohex-3-en-1-ol (96.0 g) as a yellow oil.

[0371] Step 4: (1r,4r)-1-Methyl-4-(nitromethyl)cyclohexan-1-ol To a stirred solution of (S)-1-methyl-4-(nitromethyl)cyclohex-3-en-1-ol (96.0 g, 0.561 mol) in DCM (1.5 L) was added Crabtree's catalyst (6.8 g, 0.008 mmol). The mixture was stirred at 50 °C overnight under an H 2 (30 atm) atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated to obtain (1r,4r)-1-methyl-4-(nitromethyl)cyclohexan-1-ol (100.0 g, crude) as a yellow oil.

[0372] Step 5: (1r,4r)-4-(Aminomethyl)-1-methylcyclohexan-1-ol To a stirred solution of (1r,4r)-1-methyl-4-(nitromethyl)cyclohexan-1-ol (120.0 g, 0.694 mol) in MeOH (1.5 L) was added 10% wet Pd / C (30.0 g). The mixture was under H 2It was stirred at 85 °C overnight under a (30 atm) atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated to obtain (1r,4r)-4-(aminomethyl)-1-methylcyclohexan-1-ol (95.0 g, crude) as a brown solid. 1 H NMR (300 MHz, methanol-d 4 ) δ ppm: 2.51 (d, J = 6.7 Hz, 2H), 1.86 - 1.58 (m, 4H), 1.40 - 1.50 (s, 2H), 1.35 - 1.26 (m, 1H), 1.21 (s, 3H), 1.16 - 0.95 (m, 2H).

[0373] Step 6: 4-((((1r,4r)-4-Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide To a stirred solution of (1r,4r)-4-(aminomethyl)-1-methylcyclohexan-1-ol (100.0 g, 0.699 mol) in THF (1 L) were added 4-fluoro-3-nitrobenzenesulfonamide (107.6 g, 0.489 mol) and TEA (141.2 g, 1.389 mol). The mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (3 × 800 mL). The combined organic phases were washed with brine (1 L), dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified three times by a slurry in EtOAc (800.0 mL) to obtain 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (144.6 g) as a yellow solid. 1H NMR (300 MHz, DMSO-d 6 ) δ ppm: 8.52 (t, J = 5.9 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 7.80 (dd, J = 9.2, 2.3 Hz, 1H), 7.42 - 7.11 (m, 3H), 4.24 (s, 1H), 3.31 (t, J = 6.3 Hz, 2H), 1.66 (d, J = 11.5 Hz, 3H), 1.53 (d, J = 12.7 Hz, 2H), 1.31 (td, J = 12.4, 3.4 Hz, 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)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide; [Chemical formula] Intermediate 3-q2: 4-((((1R,4R)-4-Hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide [Chemical formula] Step 1: Ethyl 4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexanecarboxylate To a solution of ethyl 4-oxocyclohexanecarboxylate (10 g, 58.75 mmol) in THF (100 mL), TMSCF 3 (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 indicated that the reactants were completely consumed. The reaction mixture was washed with saturated NaHCO 3 aqueous solution (50 mL × 2) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (50 mL × 2), dried over anhydrous Na 2 SO 4 and filtered, then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE / EA = 100 / 1 to 2 / 1). Ethyl 4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexanecarboxylate (8.12 g) was obtained as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm: 4.15 (q, J = 7.1 Hz, 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, 4.2 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H), 0.17 (d, J = 4.5 Hz, 9H).

[0375] Step 2: (4-(Trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl)methanol To a solution of ethyl 4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexanecarboxylate (8.10 g, 25.93 mmol) in THF (50 mL) was added LAH (1.97 g, 51.86 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 h. TLC indicated that the reactant was completely consumed. The reaction mixture was quenched by the addition of water (15 mL), and then extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The crude product (6.2 g, crude) was used in the next step without further purification.

[0376] Step 3: (4-(Trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl)methyl methanesulfonate To a solution of (4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl)methanol (6.2 g, 22.93 mmol) and TEA (4.64 g, 45.86 mmol) in DCM (60 mL) was added MsCl (5.91 g, 51.60 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 h. TLC indicated that the reactant was completely consumed. The reaction mixture was washed with saturated NaHCO 3 aqueous solution (50 mL × 2) and extracted with DCM (50 mL × 2). The combined organic phases were washed with brine (50 mL × 2), dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The crude product (8.52 g, crude) was used in the next step without further purification.

[0377] Step 4: ((4-(Azidomethyl)-1-(trifluoromethyl)cyclohexyl)oxy)trimethylsilane A solution of (4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl)methyl methanesulfonate (8.51 g, 24.42 mmol) in DMF (150 mL) was added with NaN 3 (7.94 g, 122.11 mmol) at 20 °C, and the mixture was stirred at 50 °C for 12 h. TLC indicated that the reactant was completely consumed. The mixture was diluted with water and extracted with MTBE (100 mL × 3), and dried over anhydrous Na 2 SO 4 and filtered. The combined organic layers were concentrated to obtain the crude product, which was used directly in the next step.

[0378] Step 5: (4-(Trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl)methanamine CH 3 To a mixture of ((4-(azidomethyl)-1-(trifluoromethyl)cyclohexyl)oxy)trimethylsilane (7.21 g, theoretical yield) in CH 2 OH (50 mL) was added Pd / C (2.5 g), and the mixture was stirred at 30 °C for 16 h under H

[0379] Step 6: 4-(((4-Hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide To a solution of 4-fluoro-3-nitrobenzenesulfonamide (2.50 g, 11.35 mmol) and (4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl)methanamine (4.59 g, 17.04 mmol) in DMF (75 mL) was added DIPEA (2.94 g, 22.74 mmol), and the mixture was stirred at 55 °C for 2 h. TLC indicated that the reactants were completely consumed. The reaction mixture was washed with water (200 mL) and extracted with EA (100 mL × 3). The combined organic phases were washed with brine (50 mL × 2) and dried over anhydrous Na 2 SO 4 , 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 (neutral). 4-((((1s,4s)-4-Hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (Intermediate 3-q1, retention time: 2.5 min) (1.04 g) was obtained as a yellow solid. 1 H NMR (400 MHz, methanol-d 4 ) δ ppm: 8.65 (d, J = 1.9 Hz, 1H), 8.49 (t, J = 4.7 Hz, 1H), 7.91 (dd, J = 9.1, 1.63 Hz, 1H), 7.17 (d, J = 9.3 Hz, 1H), 3.46 (t, J = 6.3 Hz, 2H), 2.06 (d, J = 4.1 Hz, 1H), 1.84 - 2.00 (m, 4H), 1.52 - 1.70 (m, 4H). MS (ESI, m / e) [M - 1] - 396.0; 4-((((1r,4r)-4-Hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (Intermediate 3-q2, retention time: 2.6 min) (842 mg) was obtained as a yellow solid. 1 H NMR (400 MHz, methanol-d 4)δ ppm: 8.65 (d, J = 1.9 Hz, 1H), 8.54 (t, J = 5.2 Hz, 1H), 7.90 (dd, J = 9.1, 1.6 Hz, 1H), 7.17 (d, J = 9.3 Hz, 1H), 3.33 - 3.41 (m, 2H), 1.24 (s, 1H), 1.87 (d, J = 12.5 Hz, 2H), 1.71 - 1.82 (m, 3H), 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)amino)-3 - nitrobenzenesulfonamide [Chemical Structure] Step 1: Ethyl 3 - oxabicyclo[3.1.0]hexane - 6 - carboxylate To a solution of 2,5 - dihydrofuran (10 g, 142.67 mmol) and ethyl 2 - diazoacetate (32.56 g, 285.35 mmol) in DCM (250 mL) was added Rh(AcO) 2 (63.06 mg, 2.85 mmol). The mixture was stirred at 20 °C for 12 h. TLC indicated that the reactants were completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative MPLC to give ethyl 3 - oxabicyclo[3.1.0]hexane - 6 - carboxylate (10.0 g). 1 1H NMR (400 MHz, CDCl 3 ) δ ppm: 4.08 - 4.16 (m, 2H), 3.92 (d, J = 8.6 Hz, 2H), 3.74 (d, J = 8.4 Hz, 2H), 2.13 - 2.17 (m, 2H), 1.59 (t, J = 3.1 Hz, 1H), 1.23 - 1.28 (m, 3H).

[0381] Step 2: 3 - Oxabicyclo[3.1.0]hexan - 6 - yl methanol To a solution of ethyl 3 - oxabicyclo[3.1.0]hexane - 6 - carboxylate (10 g, 64.03 mmol) in THF (50 mL) at 0 °C was added LiAlH 4(2.43 g, 64.03 mmol) was added. The mixture was stirred at 0 °C for 4 hours. TLC indicated that the reactant was completely consumed. The reaction mixture was poured into H 2 O (30 mL), extracted with EA (30 mL × 3), dried over Na 2 SO 4 and filtered and concentrated. 3-Oxabicyclo[3.1.0]hexan-6-ylmethanol (7.0 g, crude) was obtained and used in the next step without further purification.

[0382] Step 3: 3-Oxabicyclo[3.1.0]hexan-6-ylmethyl methanesulfonate To a solution of 3-oxabicyclo[3.1.0]hexan-6-ylmethanol (7.0 g, 61.33 mmol) in DCM (100 mL) were added MsCl (21.08 g, 183.98 mmol) and TEA (24.82 g, 245.31 mmol). The mixture was stirred at 25 °C for 5 hours. TLC indicated that the reactant was completely consumed. The reaction mixture was quenched with aqueous NH 4 Cl (30 mL), extracted with EA (30 mL × 3), dried over Na 2 SO 4 and filtered and concentrated. The residue was purified by column chromatography (SiO 2 , PE / EA = 100 / 1 - 30 / 1). 3-Oxabicyclo[3.1.0]hexan-6-ylmethyl methanesulfonate (3.5 g) was obtained. 1 1H NMR (400 MHz, CDCl 3 ) δ ppm: 4.15 (d, J = 7.5 Hz, 2H), 3.90 (d, J = 8.4 Hz, 2H), 3.71 (d, J = 8.4 Hz, 2H), 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 To a solution of 3-oxabicyclo[3.1.0]hexan-6-ylmethyl methanesulfonate (2 g, 10.4 mmol) in DMF (20 mL) was added NaN 3(676.37 mg, 10.4 mmol) was added. The mixture was stirred at 50 °C for 12 h. TLC indicated that the reactant was completely consumed. The reaction mixture was poured into H 2 O (30 mL), extracted with EA (30 mL × 3), dried over Na 2 SO 4 and filtered and concentrated. The crude product was used directly in the next step.

[0384] Step 5: 3-Oxabicyclo[3.1.0]hexan-6-ylmethanamine To a solution of 6-(azidomethyl)-3-oxabicyclo[3.1.0]hexane (1.4 g, 10.06 mmol) in DMF (15 mL) was added Pd / C (0.7 g, 1.006 mmol). The mixture was stirred at 25 °C for 2 h under H 2 atmosphere (15 Psi). LC / MS indicated that the reactant was completely consumed and one major peak with the desired mass signal was shown. The reaction mixture was filtered and used directly in the next step. MS (ESI, m / e) + 114.0.

[0385] Step 6: 4-(((3-Oxabicyclo[3.1.0]hexan-6-yl)methyl)amino)-3-nitrobenzenesulfonamide To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.5 g, 6.8 mmol) and 3-oxabicyclo[3.1.0]hexan-6-ylmethanamine (1 g, 8.84 mmol) in DMF (15 mL) was added DIEA (1.76 g, 13.6 mmol). The mixture was stirred at 60 °C for 2 h. LC / MS indicated that 4-fluoro-3-nitrobenzenesulfonamide was completely consumed and one major peak with the desired mass signal was shown. The reaction mixture was cooled to room temperature and poured into H 2 O (50 mL) with stirring. The precipitate was filtered, 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. 11H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.59 (br, 1H), 8.47 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.37 (s, 2H), 7.28 (d, J = 9.2 Hz, 1H), 3.72 (d, J = 8.2 Hz, 2H), 3.55 (d, J = 7.9 Hz, 2H), 3.36 (s, 2H), 1.71 (s, 2H), 1.05 (s, 1H). MS (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

Chemical Structure

Chemical Structure

[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

Chem.

[0388] Step 3: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-phenylpyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid

Chem.

[0389] Step 4: 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

Chemical formula

[0390] Example A2: 3 - ((1H - pyrrolo[2,3 - b]pyridin - 5 - yl)oxy) - 4' - (2 - (4 - chlorophenyl)pyrrolidin - 1 - yl) - N - ((3 - nitro - 4 - (((tetrahydro - 2H - pyran - 4 - yl)methyl)amino)phenyl)sulfonyl) - [1,1' - biphenyl] - 4 - carboxamide

Chemical Structure

[0391] Example A3: 3 - ((1H - pyrrolo[2,3 - b]pyridin - 5 - yl)oxy) - 4' - (2 - (3 - chlorophenyl)pyrrolidin - 1 - yl) - N - ((3 - nitro - 4 - (((tetrahydro - 2H - pyran - 4 - yl)methyl)amino)phenyl)sulfonyl) - [1,1' - biphenyl] - 4 - carboxamide

Chemical Structure

[0392] Example A4: 3 - ((1H - pyrrolo[2,3 - b]pyridin - 5 - yl)oxy) - 4' - (2 - (2 - chlorophenyl)pyrrolidin - 1 - yl) - N - ((3 - nitro - 4 - (((tetrahydro - 2H - pyran - 4 - yl)methyl)amino)phenyl)sulfonyl) - [1,1' - biphenyl] - 4 - carboxamide [Chemical formula] Following the same procedure as in Example A1, starting from 2 - (2 - chlorophenyl)pyrrolidine and 1 - bromo - 4 - iodobenzene, the desired compound was synthesized. 1 H NMR (400 MHz, DMSO - d 6)δ ppm: 12.17 (s, 1H), 11.70 (s, 1H), 8.61 (s, 1H), 8.57 (s, 1H), 8.05 (s, 1H), 7.83 (d, J = 9.4 Hz, 1H), 7.60 - 7.41 (m, 4H), 7.35 - 7.30 (m, 3H), 7.25 - 7.12 (m, 3H), 7.00 (d, J = 7.7 Hz, 1H), 6.90 (s, 1H), 6.48 - 6.27 (m, 3H), 4.97 (d, J = 7.4 Hz, 1H), 3.85 (d, J = 11.3 Hz, 2H), 3.74 (s, 1H), 3.31 - 3.19 (m, 4H), 2.43 - 2.35 (m, 1H), 1.99 - 1.83 (m, 4H), 1.60 (d, J = 12.5 Hz, 2H), 1.23 (s, 3H). MS (ESI, m / e) [M + 1] + 807.1.

[0393] Example A4a: (S)-3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; Example A4b: (R)-3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide [Chemical Structure] The two enantiomers A4a (the faster isomer) and A4b (the slower isomer) were separated by chiral preparative HPLC. The chiral separation conditions are shown below. The faster enantiomer eluted with a retention time of 1.1 minutes, yielding 252 mg of the product. The slower enantiomer eluted with a retention time of 1.8 minutes, yielding 238 mg of the product. The absolute configuration of the faster enantiomer was confirmed to be S by co-crystallization of Bcl2 with A4a. See the section "Protein Purification and Co-crystallization of Bcl2 with A4a".

[0394]

Table 2

[0395] Example A5: 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-3’-chloro-4’-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1’-biphenyl]-4-carboxamide

Chemical formula

Claims

1. Use of a compound represented by the following formula, which is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, or a pharma- ceutical acceptable salt thereof, in the preparation of a medicament for treating cancer.

2. 2. The use according to claim 1, wherein the cancer is chronic lymphocytic leukemia.

3. 2. The use according to claim 1, wherein the cancer is small lymphocytic leukemia.

4. 2. The use according to claim 1, wherein the cancer is melanoma.

5. 2. The use according to claim 1, wherein the cancer is a lymphoid malignancy of T-cell or B-cell origin.

6. 2. The use according to claim 1, wherein the cancer is myeloma.

7. 2. The use according to claim 1, wherein the cancer is follicular lymphoma.

8. The use according to claim 1, wherein the cancer is breast cancer.

9. 2. The use according to claim 1, wherein the cancer is myeloid leukemia.

10. The use according to claim 1, wherein the cancer is pancreatic cancer.

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